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Belinostat (PXD101)
FAST TRACK FDA , ORPHAN STATUS
July 3, 2014 — The U.S. Food and Drug Administration today approved Beleodaq (belinostat) for the treatment of patients with peripheral T-cell lymphoma (PTCL), a rare and fast-growing type of non-Hodgkin lymphoma (NHL). The action was taken under the agency’s accelerated approval program.
Belinostat (PXD101) is a novel HDAC inhibitor with IC50 of 27 nM, with activity demonstrated in cisplatin-resistant tumors.
CLINICAL TRIALS…http://clinicaltrials.gov/search/intervention=Belinostat+OR+PXD101
MP 172–174 °C, (lit.(@) 172 °C). 1H NMR (400 MHz, DMSO-d6) δ = 10.75–10.42 (m, 2H), 9.15 (s, 1H), 7.92 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H),7.47 (d, J = 15.8 Hz, 1H), 7.24 (m, 2H), 7.10–7.01 (m, 3H), 6.51 (d, J = 15.8 Hz, 1H). MS (ESI): m/z = 318.6 [M+H] +.
@ Finn, P. W.; Bandara, M.; Butcher, C.; Finn, A.; Hollinshead, R.; Khan, N.; Law, N.; Murthy, S.; Romero,R.; Watkins, C.; Andrianov, V.; Bokaldere, R. M.; Dikovska, K.; Gailite, V.; Loza, E.; Piskunova, I.;Starchenkov, I.; Vorona, M.; Kalvinsh, I. Helv. Chim. Acta 2005, 88, 1630, DOI: 10.1002/hlca.200590129
Beleodaq and Folotyn are marketed by Spectrum Pharmaceuticals, Inc., based in Henderson, Nevada. Istodax is marketed by Celgene Corporation based in Summit, New Jersey.
Belinostat was granted orphan drug status for the treatment of Peripheral T-cell lymphoma (PTCL) in the US in September 2009 and the EU in October 2012. In July 2015, an orphan drug designation has also been granted for malignant thymoma in the EU.
Belinostat received its first global approval in the US-FDA on 3 July 2014 for the intravenous (IV) treatment of relapsed or refractory PTCL in adults.
Belinostat was approved by the U.S. Food and Drug Administration (FDA) on July 3, 2014. It was originally developed by CuraGen Pharma，then developed by Spectrum Pharmaceuticals cooperating with Onxeo, then marketed as Beleodaq® by Spectrum.
Beleodaq is a pan-histone deacetylase (HDAC) inhibitor selectively causing the accumulation of acetylated histones and other proteinsin tumor cells. It is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).
Beleodaq® is available as lyophilized powder for intravenous infusion, containing 500 mg of free Belinostat. The recommended dose is 1,000 mg/m2 once daily on days 1-5 of a 21-day cycle.
| MW 318.07 | |
| MF | C15H14N2O4S |
414864-00-9 cas no
866323-14-0
(2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]acrylamide
A novel HDAC inhibitor
PTCL comprises a diverse group of rare diseases in which lymph nodes become cancerous. In 2014, the National Cancer Institute estimates that 70,800 Americans will be diagnosed with NHL and 18,990 will die. PTCL represents about 10 to 15 percent of NHLs in North America.Belinostat inhibits the growth of tumor cells (A2780, HCT116, HT29, WIL, CALU-3, MCF7, PC3 and HS852) with IC50 from 0.2-0.66 μM. PD101 shows low activity in A2780/cp70 and 2780AD cells. Belinostat inhibits bladder cancer cell growth, especially in 5637 cells, which shows accumulation of G0-G1 phase, decrease in S phase, and increase in G2-M phase. Belinostat also shows enhanced tubulin acetylation in ovarian cancer cell lines. A recent study shows that Belinostat activates protein kinase A in a TGF-β signaling-dependent mechanism and decreases survivin mRNA.
Beleodaq works by stopping enzymes that contribute to T-cells, a type of immune cell, becoming cancerous. It is intended for patients whose disease returned after treatment (relapsed) or did not respond to previous treatment (refractory).
“This is the third drug that has been approved since 2009 for the treatment of peripheral T-cell lymphoma,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval expands the number of treatment options available to patients with serious and life-threatening diseases.”
The FDA granted accelerated approval to Folotyn (pralatrexate) in 2009 for use in patients with relapsed or refractory PTCL and Istodax (romidepsin) in 2011 for the treatment of PTCL in patients who received at least one prior therapy.
The safety and effectiveness of Beleodaq was evaluated in a clinical study involving 129 participants with relapsed or refractory PTCL. All participants were treated with Beleodaq until their disease progressed or side effects became unacceptable. Results showed 25.8 percent of participants had their cancer disappear (complete response) or shrink (partial response) after treatment.
The most common side effects seen in Beleodaq-treated participants were nausea, fatigue, fever (pyrexia), low red blood cells (anemia), and vomiting.
The FDA’s accelerated approval program allows for approval of a drug based on surrogate or intermediate endpoints reasonably likely to predict clinical benefit for patients with serious conditions with unmet medical needs. Drugs receiving accelerated approval are subject to confirmatory trials verifying clinical benefit. Beleodaq also received orphan product designation by the FDA because it is intended to treat a rare disease or condition.
Belinostat (trade name Beleodaq, previously known as PXD101) is a histone deacetylase inhibitor drug developed by TopoTargetfor the treatment of hematological malignancies and solid tumors.[2]
It was approved in July 2014 by the US FDA to treat peripheral T-cell lymphoma.[3]
In 2007 preliminary results were released from the Phase II clinical trial of intravenous belinostat in combination with carboplatin andpaclitaxel for relapsed ovarian cancer.[4] Final results in late 2009 of a phase II trial for T-cell lymphoma were encouraging.[5]Belinostat has been granted orphan drug and fast track designation by the FDA,[6] and was approved in the US for the use againstperipheral T-cell lymphoma on 3 July 2014.[3] It is not approved in Europe as of August 2014.[7]
The approved pharmaceutical formulation is given intravenously.[8]:180 Belinostat is primarily metabolized by UGT1A1; the initial dose should be reduced if the recipient is known to be homozygous for the UGT1A1*28 allele.[8]:179 and 181
NCI: A novel hydroxamic acid-type histone deacetylase (HDAC) inhibitor with antineoplastic activity. Belinostat targets HDAC enzymes, thereby inhibiting tumor cell proliferation, inducing apoptosis, promoting cellular differentiation, and inhibiting angiogenesis. This agent may sensitize drug-resistant tumor cells to other antineoplastic agents, possibly through a mechanism involving the down-regulation of thymidylate synthase
The study of inhibitors of histone deacetylases indicates that these enzymes play an important role in cell proliferation and differentiation. The inhibitor Trichostatin A (TSA) (Yoshida et al., 1990a) causes cell cycle arrest at both G1 and G2 phases (Yoshida and Beppu, 1988), reverts the transformed phenotype of different cell lines, and induces differentiation of Friend leukaemia cells and others (Yoshida et al., 1990b). TSA (and SAHA) have been reported to inhibit cell growth, induce terminal differentiation, and prevent the formation of tumours in mice (Finnin et al., 1999).
Trichostatin A (TSA)
Suberoylanilide Hydroxamic Acid (SAHA)
Cell cycle arrest by TSA correlates with an increased expression of gelsolin (Hoshikawa et al., 1994), an actin regulatory protein that is down regulated in malignant breast cancer (Mielnicki et al., 1999). Similar effects on cell cycle and differentiation have been observed with a number of deacetylase inhibitors (Kim et al., 1999). Trichostatin A has also been reported to be useful in the treatment of fibrosis, e.g., liver fibrosis and liver cirrhosis. See, e.g., Geerts et al., 1998.
Recently, certain compounds that induce differentiation have been reported to inhibit histone deacetylases. Several experimental antitumour compounds, such as trichostatin A (TSA), trapoxin, suberoylanilide hydroxamic acid (SAHA), and phenylbutyrate have been reported to act, at least in part, by inhibiting histone deacetylase (see, e.g., Yoshida et al., 1990; Richon et al., 1998; Kijima et al., 1993). Additionally, diallyl sulfide and related molecules (see, e.g., Lea et al., 1999), oxamflatin (see, e.g., Kim et al., 1999), MS-27-275, a synthetic benzamide derivative (see, e.g., Saito et al., 1999; Suzuki et al., 1999; note that MS-27-275 was later re-named as MS-275), butyrate derivatives (see, e.g., Lea and Tulsyan, 1995), FR901228 (see, e.g., Nokajima et al., 1998), depudecin (see, e.g., Kwon et al., 1998), and m-carboxycinnamic acid bishydroxamide (see, e.g., Richon et al., 1998) have been reported to inhibit histone deacetylases. In vitro, some of these compounds are reported to inhibit the growth of fibroblast cells by causing cell cycle arrest in the G1 and G2 phases, and can lead to the terminal differentiation and loss of transforming potential of a variety of transformed cell lines (see, e.g., Richon et al, 1996; Kim et al., 1999; Yoshida et al., 1995; Yoshida & Beppu, 1988). In vivo, phenybutyrate is reported to be effective in the treatment of acute promyelocytic leukemia in conjunction with retinoic acid (see, e.g., Warrell et al., 1998). SAHA is reported to be effective in preventing the formation of mammary tumours in rats, and lung tumours in mice (see, e.g., Desai et al., 1999).
The clear involvement of HDACs in the control of cell proliferation and differentiation suggest that aberrant HDAC activity may play a role in cancer. The most direct demonstration that deacetylases contribute to cancer development comes from the analysis of different acute promyelocytic leukaemias (APL). In most APL patients, a translocation of chromosomes 15 and 17 (t(15;17)) results in the expression of a fusion protein containing the N-terminal portion of PML gene product linked to most of RARσ (retinoic acid receptor). In some cases, a different translocation (t(11 ;17)) causes the fusion between the zinc finger protein PLZF and RARα. In the absence of ligand, the wild type RARα represses target genes by tethering HDAC repressor complexes to the promoter DNA. During normal hematopoiesis, retinoic acid (RA) binds RARα and displaces the repressor complex, allowing expression of genes implicated in myeloid differentiation. The RARα fusion proteins occurring in APL patients are no longer responsive to physiological levels of RA and they interfere with the expression of the RA- inducible genes that promote myeloid differentiation. This results in a clonal expansion of promyelocytic cells and development of leukaemia. In vitro experiments have shown that TSA is capable of restoring RA-responsiveness to the fusion RARα proteins and of allowing myeloid differentiation. These results establish a link between HDACs and oncogenesis and suggest that HDACs are potential targets for pharmaceutical intervention in APL patients. (See, for example, Kitamura et al., 2000; David et al., 1998; Lin et al., 1998).
BELINOSTAT
Furthermore, different lines of evidence suggest that HDACs may be important therapeutic targets in other types of cancer. Cell lines derived from many different cancers (prostate, coloreetal, breast, neuronal, hepatic) are induced to differentiate by HDAC inhibitors (Yoshida and Horinouchi, 1999). A number of HDAC inhibitors have been studied in animal models of cancer. They reduce tumour growth and prolong the lifespan of mice bearing different types of transplanted tumours, including melanoma, leukaemia, colon, lung and gastric carcinomas, etc. (Ueda et al., 1994; Kim et al., 1999).
Psoriasis is a common chronic disfiguring skin disease which is characterised by well-demarcated, red, hardened scaly plaques: these may be limited or widespread. The prevalence rate of psoriasis is approximately 2%, i.e., 12.5 million sufferers in the triad countries (US/Europe/Japan). While the disease is rarely fatal, it clearly has serious detrimental effects upon the quality of life of the patient: this is further compounded by the lack of effective therapies. Present treatments are either ineffective, cosmetically unacceptable, or possess undesired side effects. There is therefore a large unmet clinical need for effective and safe drugs for this condition. Psoriasis is a disease of complex etiology. Whilst there is clearly a genetic component, with a number of gene loci being involved, there are also undefined environmental triggers. Whatever the ultimate cause of psoriasis, at the cellular level, it is characterised by local T-cell mediated inflammation, by keratinocyte hyperproliferation, and by localised angiogenesis. These are all processes in which histone deacetylases have been implicated (see, e.g., Saunders et al., 1999; Bernhard et al, 1999; Takahashi et al, 1996; Kim et al , 2001 ). Therefore HDAC inhibitors may be of use in therapy for psoriasis. Candidate drugs may be screened, for example, using proliferation assays with T-cells and/or keratinocytes.
PXD101/Belinostat®
(E)-N-hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide, also known as PXD101 and Belinostat®, shown below, is a well known histone deacetylate (HDAC) inhibitor. It is being developed for treatment of a range of disorders mediated by HDAC, including proliferative conditions (such as cancer and psoriasis), malaria, etc.
PXD101 was first described in WO 02/30879 A2. That document describes a multi-step method of synthesis which may conveniently be illustrated by the following scheme.
GENERAL SYNTHESIS
IGNORE 10
ENTRY 45 IS BELINOSTAT
Scheme 1
By using amines instead of aniline, the corresponding products may be obtained. The use of aniline, 4-methoxyaniline, 4-methylaniline, 4-bromoaniline, 4-chloroaniline, 4-benzylamine, and 4-phenethyamine, among others, is described in the Examples below.
In another method, a suitable amino acid (e.g., ω-amino acid) having a protected carboxylic acid (e.g., as an ester) and an unprotected amino group is reacted with a sulfonyl chloride compound (e.g., RSO2CI) to give the corresponding sulfonamide having a protected carboxylic acid. The protected carboxylic acid is then deprotected using base to give the free carboxylic acid, which is then reacted with, for example, hydroxylamine 2-chlorotrityl resin followed by acid (e.g., trifluoroacetic acid), to give the desired carbamic acid.
One example of this approach is illustrated below, in Scheme 2, wherein the reaction conditions are as follows: (i) RSO2CI, pyridine, DCM, room temperature, 12 hours; (ii) 1 M LiOH or 1 M NaOH, dioxane, room temperature, 3-48 hours; (iii) hydroxylamine 2-chlorotrityl resin, HOAt, HATU, DIPEA, DCM, room temperature, 16 hours; and (iv) TFA/DCM (5:95, v/v), room temperature, 1.5 hours.
Scheme 2
Additional methods for the synthesis of compounds of the present invention are illustrated below and are exemplified in the examples below.
Scheme 3A
Scheme 3B
Scheme 4
Scheme 8
Scheme 9
SYNTHESIS
Example 1
3-Formylbenzenesulfonic acid, sodium salt (1)
Oleum (5 ml) was placed in a reaction vessel and benzaldehyde (2.00 g, 18.84 mmol) was slowly added not exceeding the temperature of the reaction mixture more than 30°C. The obtained solution was stirred at 40°C for ten hours and at ambient temperature overnight. The reaction mixture was poured into ice and extracted with ethyl acetate. The aqueous phase was treated with CaC03 until the evolution of C02 ceased (pH~6-7), then the precipitated CaSO4was filtered off and washed with water. The filtrate was treated with Na2CO3 until the pH of the reaction medium increased to pH 8, obtained CaCO3 was filtered off and water solution was evaporated in vacuum. The residue was washed with methanol, the washings were evaporated and the residue was dried in desiccator over P2Oβ affording the title compound (2.00 g, 51%). 1H NMR (D20), δ: 7.56-8.40 (4H, m); 10.04 ppm (1 H, s).
Example 2 3-(3-Sulfophenyl)acrylic acid methyl ester, sodium salt (2)
Sodium salt of 3-formylbenzenesulfonic acid (1) (1.00 g, 4.80 mmol), potassium carbonate (1.32 g, 9.56 mmol), trimethyl phosphonoacetate (1.05 g, 5.77 mmol) and water (2 ml) were stirred at ambient temperature for 30 min., precipitated solid was filtered and washed with methanol. The filtrate was evaporated and the title compound (2) was obtained as a white solid (0.70 g, 55%). 1H NMR (DMSO- dβl HMDSO), δ: 3.68 (3H, s); 6.51 (1 H, d, J=16.0 Hz); 7.30-7.88 (5H, m).
Example 3 3-(3-Chlorosulfonylphenyl)acrylic acid methyl ester (3)
To the sodium salt of 3-(3-sulfophenyl)acrylic acid methyl ester (2) (0.670 g, 2.53 mmol) benzene (2 ml), thionyl chloride (1.508 g, 0.9 ml, 12.67 mmol) and 3 drops of dimethylformamide were added and the resultant suspension was stirred at reflux for one hour. The reaction mixture was evaporated, the residue was dissolved in benzene (3 ml), filtered and the filtrate was evaporated to give the title compound (0.6’40 g, 97%).
Example 4 3-(3-Phenylsulfamoylphenyl)acrylic acid methyl ester (4a)
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.640 g, 2.45 mmol) in dichloromethane (2 ml) was added to a mixture of aniline (0.465 g, 4.99 mmol) and pyridine (1 ml), and the resultant solution was stirred at 50°C for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCI. The organic layer was washed successively with water, saturated NaCl, and dried (Na2S0 ). The solvent was removed and the residue was chromatographed on silica gel with chloroform-ethyl acetate (7:1 , v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.226 g, 29%). 1H NMR (CDCI3, HMDSO), δ: 3.72 (3H, s); 6.34 (1H, d, J=16.0 Hz); 6.68 (1 H, br s); 6.92-7.89 (10H, m).
Example 5 3-(3-Phenylsulfamoylphenyl)acrylic acid (5a)
3-(3-Phenylsulfamoylphenyl)acrylic acid methyl ester (4a) (0.220 g, 0.69 mmol) was dissolved in methanol (3 ml), 1N NaOH (2.08 ml, 2.08 mmol) was added and the resultant solution was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 10% HCI and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2Os to give the title compound as a white solid (0.173 g, 82%). Example 6 3-(3-Phenylsulfamoylphenyl)acryloyl chloride (6a)
To a suspension of 3-(3-phenylsulfamoylphenyl)acrylic acid (5a) (0.173 g, 0.57 mmol) in dichloromethane (2.3 ml) oxalyl chloride (0.17 ml, 1.95 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40°C for one hour and concentrated under reduced pressure to give crude title compound (0.185 g).
Example 7
N-Hydroxy-3-(3-phenylsulfamoylphenyl)acrylamide (7a) (PX105684) BELINOSTAT
To a suspension of hydroxylamine hydrochloride (0.200 g, 2.87 mmol) in tetrahydrofuran (3.5 ml) a saturated NaHCOβ solution (2.5 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a 3-(3-phenylsulfamoylphenyl)acryloyl chloride (6a) (0.185 g) solution in tetrahydrofuran (2.3 ml) was added and stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCI. The organic layer was washed successively with water and saturated NaCl, the solvent was removed and the residue was washed with acetonitrile and diethyl ether.
The title compound was obtained as a white solid (0.066 g, 36%), m.p. 172°C. BELINOSTAT
1H NMR (DMSO-d6, HMDSO), δ: 6.49 (1 H, d, J=16.0 Hz); 7.18-8.05 (10H, m); 9.16 (1 H, br s); 10.34 (1 H, s); 10.85 ppm (1 H, br s).
HPLC analysis on Symmetry C18column: impurities 4% (column size 3.9×150 mm; mobile phase acetonitrile – 0.1 M phosphate buffer (pH 2.5), 40:60; sample concentration 1 mg/ml; flow rate 0.8 ml/ min; detector UV 220 nm).
Anal. Calcd for C15Hι4N204S, %: C 56.59, H 4.43, N 8.80. Found, %: C 56.28, H 4.44, N 8.56.
https://www.google.com/patents/CN102786448A?cl=en
Example: belinostat (compound of formula I) Preparation of
Methods of operation:
The compound of formula II (4. Og) added to the reactor, was added methanol 30ml, and stirred to dissolve, was added IM aqueous sodium hydroxide solution (38mL), stirred at room temperature overnight, the reaction was completed, ethyl acetate was added (IOmL) ^ K (20mL), stirred for 5 minutes, phase separation, the ethyl acetate phase was discarded, the aqueous phase was acidified with 10% hydrochloric acid to pH2, stirred at room temperature for 30 minutes, filtered, washed with water, and dried to give hydrolyzate 3. lg, yield rate of 81.6%.
The hydrolyzate (3. Og) added to the reactor, was added methylene chloride (53. 2g), dissolved with stirring, was added oxalyl chloride (2.8mL, 0.0032mol) at room temperature was added I drop DMF, reflux I hours, concentrated and the residue was dissolved in THF (30mL) alternate, the other to take a reaction flask was added hydroxylamine hydrochloride (3. 5g, 0.05mol), THF (50mL), saturated aqueous sodium bicarbonate (40mL), the mixture at room temperature under stirring for 10 minutes, then was added to spare, stirred at room temperature for I hour, the reaction was complete, at – at room temperature was added ethyl acetate (50mL), 2M hydrochloric acid (50mL), stirred for 5 minutes the phases were separated, the aqueous phase was discarded, the organic layer was washed with water, saturated brine, dried, filtered and concentrated to give crude product belinostat, recrystallized from ethyl acetate, 50 ° C and dried for 8 hours to give white crystals 2. 6g, yield 83.8%. . 1H-NMR (DMS0-d6, 400MHz) δ: 6 50 (1H, d, J = 16. OHz); 7 07 (d, J = 7. 8Hz, 2H); 7 16 (t.. , J = 7. 3Hz, 1H);. 7 25 (m, 2H);. 7 45 (t, J = 7. 8Hz, 1H);. 7 60 (d, J = 15. 9Hz, 1H); 7 . 62 (d, J = 7. 7Hz, 1H);. 7 75 (d, J = 7. 8Hz, 1H);. 7 88 (br s. ‘1H);. 9 17 (br s’ 1H); 10. 35 (s, 1H);. 10 82ppm (br s, 1H). ·
Step a): Preparation of Compound III
The carboxy benzene sulfonate (224g, Imol), anhydrous methanol (2300g), concentrated hydrochloric acid (188. 6g) refluxing
3-5 hours, filtered and the filtrate was added anhydrous sodium bicarbonate powder (200g), stirred for I hour, filtered, the filter residue was discarded, the filtrate was concentrated. The concentrate was added methanol (2000g), stirred at room temperature for 30 minutes, filtered and the filtrate was concentrated to dryness, 80 ° C and dried for 4 hours to give a white solid compound III147g, yield 61.8%.
Step b): Preparation of Compound IV
Compound III (50g, 0. 21mol), phosphorus oxychloride (250mL) was refluxed for 2_6 hours, completion of the reaction, cooled to
0-5 ° C, was slowly added to ice water, stirred for 2 hours and filtered to give a brown solid compound IV40 g, due to the instability of Compound IV, directly into the next reaction without drying.
Preparation of Compound V: [0040] Step c)
The aniline (5. 58g, 0. 06mol) and 30mL of toluene added to the reactor, stirred to dissolve, in step b) the resulting compound IV (7. 05g, O. 03mol) was dissolved in 60 ml of toluene, at room temperature dropwise added to the reactor, the addition was completed, stirring at room temperature for 1-2 hours, the reaction was completed, the filtered solid washed with water, and then recrystallized from toluene, 50 ° C and dried for 4 hours to obtain a white crystalline compound V6. Og, yield 73%. mp:.. 144 4-145 2. . .
1H- bandit R (CDCl3, 400MHz) δ:…. 3 92 (s, 3H); 6 80 (. Br s, 1H); 7 06-7 09 (m, 2H); 7 11. . -7 15 (m, 1H);.. 7 22-7 26 (m, 2H);. 7 51 (t, J = 7. 8Hz, 1H);.. 7 90-7 93 (dt, J = . 1.2,7 8Hz, 1H); 8 18-8 21 (dt, J = I. 4, 7. 8Hz, 1H);… 8 48 (t, J = L 6Hz, 1H).
IR v ™ r: 3243,3198,3081,2953,1705,1438,1345,766,702,681cm-1.
Step d): Preparation of Compound VI
The anhydrous lithium chloride 2. 32g, potassium borohydride 2. 96g, THF50mL added to the reactor, stirring evenly, Compound V (8g, 0. 027mol) was dissolved in 7mL of tetrahydrofuran, was slowly dropped into the reactor was heated under reflux for 5 hours, the reaction was completed, the force mouth 40mL water and ethyl acetate 40mL, stirred for half an hour, allowed to stand for separation, the organic layer was washed with 40mL water, concentrated under reduced pressure to give the crude product, the crude product was recrystallized from toluene, solid 50 V dried for 4 hours to give a white crystalline compound VI6. 82g, yield 90. O%. mp:.. 98 2-98 6. . .
1H-NMR (DMS0-d6, 400ΜΗζ) δ:….. 4 53 (s, 2H); 5 39 (s, 1H); 6 99-7 03 (m, 1H); 7 08- 7. ll (m, 2H);.. 7 19-7 24 (m, 2H);.. 7 45-7 52 (m, 2H);.. 7 61-7 63 (dt, J = I. 8 , 7 4Hz, 1H);.. 7 79 (br s, 1H);. 10. 26 (s, 1H).
IRv =: 3453,3130,2964,1488,1151,1031, 757,688cm_10
Step e): Preparation of Compound VII
After Compound VI (7.5g, 0.028mol) dissolved in acetone was added 7ml, dichloromethane was added 60mL, supported on silica gel was added PCC at room temperature 20g, stirred at room temperature for 12-24 hours, the reaction was complete, filtered and the filtrate was purified The layers were separated and the aqueous layer was discarded after the organic phase is washed 30mL5% aqueous sodium bicarbonate, evaporated to dryness under reduced pressure to give the crude product, the crude product was recrystallized from toluene, 50 ° C and dried for 8 hours to give white crystalline compound VII4. 7g, yield 62.7%. mp:.. 128 1-128 5 ° C.
1H- bandit R (CDCl3,400MHz) δ:…. 7 08-7 15 (m, 4Η); 7 · 23-7 27 (m, 2H); 7 · 60-7 64 (t, J = 7 7Hz, 1Η);.. 8 00 (d, J = 7. 6Hz, 1Η);. 8 04 (d, J = 7. 6Hz, 1Η);. 8 30 (br s’ 1Η).; 10. 00 (S, 1Η).
IR ν ™ Γ: 3213,3059,2964,2829,1687,1480,1348,1159,1082,758,679cm_10
Preparation of compounds of formula II: [0055] Step f)
phosphoryl trimethylorthoacetate (2. 93g, 0. 0161mol) added to the reaction vessel, THF30mL, stirring to dissolve, cooled to -5-0 ° C, was added sodium hydride (O. 8g, content 80%) , the addition was completed, stirring for 10-20 minutes, was added dropwise the compound VII (4g, O. 0156mol) and THF (20mL) solution, stirred for 1_4 hours at room temperature, the reaction was complete, 10% aqueous ammonium chloride solution was added dropwise 50mL, and then After addition of 50mL of ethyl acetate, stirred 30min rested stratification, the aqueous layer was discarded, the organic phase was concentrated under reduced pressure to give the crude product, the crude product was recrystallized from methanol 60mL, 50 ° C and dried for 8 hours to give white crystalline compound 113. 6g, yield 75%. mp:.. 152 0-152 5 ° C.
1H-Nmr (Cdci3JOOmHz) δ:…. 3 81 (s, 3H); 6 40 (d, J = 16. 0Hz, 1H); 6 79 (. Br s, 1H); 7 08 ( d, J = 7. 8Hz, 2H);. 7 14 (t, J = 7. 3Hz, 1H);. 7 24 (m, 2H);. 7 46 (t, J = 7. 8Hz, 1H); 7. 61 (d, J = 16. ΟΗζ, ΙΗ);. 7 64 (d, J = 7. 6Hz, 1H);. 7 75 (d, J = 7. 8Hz, 1H);. 7 89 (br . s, 1H).
IR v ^ :: 3172,3081,2954,2849,1698,1475,1345,1157,773,714,677cm-1.
SYNTHESIS
US20100286279
SYNTHESIS AND SPECTRAL DATA
Journal of Medicinal Chemistry, 2011 , vol. 54, 13 pg. 4694 – 4720
(E)-N-Hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide (28, belinostat, PXD101).
http://pubs.acs.org/doi/full/10.1021/jm2003552
http://pubs.acs.org/doi/suppl/10.1021/jm2003552/suppl_file/jm2003552_si_001.pdf
The methyl ester (27) (8.0 g) was prepared according to reported synthetic route,
(Watkins, C. J.; Romero-Martin, M.-R.; Moore, K. G.; Ritchie, J.; Finn, P. W.; Kalvinsh, I.;
Loza, E.; Dikvoska, K.; Gailite, V.; Vorona, M.; Piskunova, I.; Starchenkov, I.; Harris, C. J.;
Duffy, J. E. S. Carbamic acid compounds comprising a sulfonamide linkage as HDAC
inhibitors. PCT Int. Appl. WO200230879A2, April 18, 2002.)
but using procedure D (Experimental Section) or method described for 26 to convert the methyl ester to crude
hydroxamic acid which was further purified by chromatography (silica, MeOH/DCM = 1:10) to
afford 28 (PXD101) as off-white or pale yellow powder (2.5 g, 31%).
LC–MS m/z 319.0 ([M +H]+).
1H NMR (DMSO-d6) 12–9 (very broad, 2H), 7.90 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.70 (d, J
= 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 15.8 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 7.08 (d,J = 7.8 Hz, 2H), 7.01 (t, J = 7.3 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H);
13C NMR (DMSO-d6) 162.1, 140.6, 138.0, 136.5, 135.9, 131.8, 130.0, 129.2, 127.1, 124.8, 124.1, 121.3, 120.4.
Anal.
(C15H14N2O4S) C, H, N
SYNTHESIS
PXDIOI / Belinostat®
(E)-N-hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide, also known as PXD101 and Belinostat®, shown below, is a well known histone deacetylate (HDAC) inhibitor. It is being developed for treatment of a range of disorders mediated by HDAC, including proliferative conditions (such as cancer and psoriasis), malaria, etc.
PXD101 was first described in WO 02/30879 A2. That document describes a multi-step method of synthesis which may conveniently be illustrated by the following scheme.
Scheme 1
Not isolated
ed on (A)
on (D)
d on (H)
There is a need for alternative methods for the synthesis of PXD101 and related compounds for example, methods which are simpler and/or employ fewer steps and/or permit higher yields and/or higher purity product.
Scheme 5
DMAP, toluene
Synthesis 1 3-Bromo-N-phenyl-benzenesulfonamide (3)
To a 30 gallon (-136 L) reactor was charged aniline (2) (4.01 kg; 93.13 g/mol; 43 mol), toluene (25 L), and 4-(dimethylamino)pyridine (DMAP) (12 g), and the mixture was heated to 50-600C. 3-Bromobenzenesulfonyl chloride (1) (5 kg; 255.52 g/mol; 19.6 mol) was charged into the reactor over 30 minutes at 50-600C and progress of the reaction was monitored by HPLC. After 19 hours, toluene (5 L) was added due to losses overnight through the vent line and the reaction was deemed to be complete with no compound (1) being detected by HPLC. The reaction mixture was diluted with toluene (10 L) and then quenched with 2 M aqueous hydrochloric acid (20 L). The organic and aqueous layers were separated, the aqueous layer was discarded, and the organic layer was washed with water (20 L), and then 5% (w/w) sodium bicarbonate solution (20 L), while maintaining the batch temperature at 45-55°C. The batch was then used in the next synthesis.
Synthesis 2 (E)-3-(3-Phenylsulfamoyl-phenyl)-acrylic acid ethyl ester (5)
To the batch containing 3-bromo-N-phenyl-benzenesulfonamide (3) (the treated organic layer obtained in the previous synthesis) was added triethylamine (2.97 kg; 101.19 g/mol; 29.4 mol), tri(o-tolyl)phosphine (119 g; 304.37 g/mol; 0.4 mol), and palladium (II) acetate (44 g; 224.51 g/mol; 0.2 mol), and the resulting mixture was degassed four times with a vacuum/nitrogen purge at 45-55°C. Catalytic palladium (0) was formed in situ. The batch was then heated to 80-900C and ethyl acrylate (4) (2.16 kg; 100.12 g/mol; 21.6 mol) was slowly added over 2.75 hours. The batch was sampled after a further 2 hours and was deemed to be complete with no compound (3) being detected by HPLC. The batch was cooled to 45-55°C and for convenience was left at this temperature overnight.
The batch was then reduced in volume under vacuum to 20-25 L, at a batch temperature of 45-55°C, and ethyl acetate (20 L) was added. The batch was filtered and the residue washed with ethyl acetate (3.5 L). The residue was discarded and the filtrates were sent to a 100 gallon (-454 L) reactor, which had been pre-heated to 600C. The 30 gallon (-136 L) reactor was then cleaned to remove any residual Pd, while the batch in the 100 gallon (-454 L) reactor was washed with 2 M aqueous hydrochloric acid and water at 45-55°C. Once the washes were complete and the 30 gallon (-136 L) reactor was clean, the batch was transferred from the 100 gallon (-454 L) reactor back to the 30 gallon (-136 L) reactor and the solvent was swapped under vacuum from ethyl acetate/toluene to toluene while maintaining a batch temperature of 45-55°C (the volume was reduced to 20-25 L). At this point, the batch had precipitated and heptanes (10 L) were added to re-dissolve it. The batch was then cooled to 0-100C and held at this temperature over the weekend in order to precipitate the product. The batch was filtered and the residue was washed with heptanes (5 L). A sample of the wet-cake was taken for Pd analysis. The Pd content of the crude product (5) was determined to be 12.9 ppm.
The wet-cake was then charged back into the 30 gallon (-136 L) reactor along with ethyl acetate (50 L) and heated to 40-500C in order to obtain a solution. A sparkler filter loaded with 12 impregnated Darco G60® carbon pads was then connected to the reactor and the solution was pumped around in a loop through the sparkler filter. After 1 hour, a sample was taken and evaporated to dryness and analysed for Pd content. The amount of Pd was found to be 1.4 ppm. A second sample was taken after 2 hours and evaporated to dryness and analysed for Pd content. The amount of Pd had been reduced to 0.6 ppm. The batch was blown back into the reactor and held at 40-500C overnight before the solvent was swapped under vacuum from ethyl acetate to toluene while maintaining a batch temperature of 45-55°C (the volume was reduced to 20-25 L). At this point, the batch had precipitated and heptanes (10 L) were added to re-dissolve it and the batch was cooled to 0-100C and held at this temperature overnight in order to precipitate the product. The batch was filtered and the residue was washed with heptanes (5 L). The filtrate was discarded and the residue was dried at 45-55°C under vacuum for 25 hours. A first lot of the title compound (5) was obtained as an off-white solid (4.48 kg, 69% overall yield from 3-bromobenzenesulfonyl chloride (1)) with a Pd content of 0.4 ppm and a purity of 99.22% (AUC) by HPLC.
Synthesis 3 (E)-3-(3-Phenylsulfamoyl-phenyl)-acrvlic acid (6)
To the 30 gallon (-136 L) reactor was charged the (E)-3-(3-phenylsulfamoyl-phenyl)- acrylic acid ethyl ester (5) (4.48 kg; 331.39 g/mol; 13.5 mol) along with 2 M aqueous sodium hydroxide (17.76 L; -35 mol). The mixture was heated to 40-50°C and held at this temperature for 2 hours before sampling, at which point the reaction was deemed to be complete with no compound (5) being detected by HPLC. The batch was adjusted to pH 2.2 using 1 M aqueous hydrochloric acid while maintaining the batch temperature between 40-500C. The product had precipitated and the batch was cooled to 20-300C and held at this temperature for 1 hour before filtering and washing the cake with water (8.9 L). The filtrate was discarded. The batch was allowed to condition on the filter overnight before being charged back into the reactor and slurried in water (44.4 L) at 40-500C for 2 hours. The batch was cooled to 15-20°C, held for 1 hour, and then filtered and the residue washed with water (8.9 L). The filtrate was discarded. The crude title compound (6) was transferred to an oven for drying at 45-55°C under vacuum with a slight nitrogen bleed for 5 days (this was done for convenience) to give a white solid (3.93 kg, 97% yield). The moisture content of the crude material was measured using Karl Fischer (KF) titration and found to be <0.1% (w/w). To the 30 gallon (-136 L) reactor was charged the crude compound (6) along with acetonitrile (47.2 L). The batch was heated to reflux (about 80°C) and held at reflux for 2 hours before cooling to 0-10°C and holding at this temperature overnight in order to precipitate the product. The batch was filtered and the residue was washed with cold acetonitrile (7.9 L). The filtrate was discarded and the residue was dried under vacuum at 45-55°C for 21.5 hours. The title compound (6) was obtained as a fluffy white solid (3.37 kg, 84% yield with respect to compound (5)) with a purity of 99.89% (AUC) by HPLC.
Synthesis 4 (E)-N-Hvdroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide (PXD101) BELINOSTAT
To the 30 gallon (-136 L) reactor was charged (E)-3-(3-phenylsulfamoyl-phenyl)-acrylic acid (6) (3.37 kg; 303.34 g/mol; 11.1 mol) and a pre-mixed solution of 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in isopropyl acetate (IPAc) (27 g in 30 L; 152.24 g/mol; 0.18 mol). The slurry was stirred and thionyl chloride (SOCI2) (960 mL; density ~1.631 g/mL; 118.97 g/mol; -13 mol) was added to the reaction mixture and the batch was stirred at 20-300C overnight. After 18.5 hours, the batch was sampled and deemed to be complete with no compound (6) being detected by HPLC. The resulting solution was transferred to a 100 L Schott reactor for temporary storage while the
30 gallon (-136 L) reactor was rinsed with isopropyl acetate (IPAc) and water. Deionized water (28.9 L) was then added to the 30 gallon (-136 L) reactor followed by 50% (w/w) hydroxylamine (6.57 L; -1.078 g/mL; 33.03 g/mol; -214 mol) and another charge of deionized water (1.66 L) to rinse the lines free of hydroxylamine to make a 10% (w/w) hydroxylamine solution. Tetrahydrofuran (THF) (6.64 L) was then charged to the
30 gallon (-136 L) reactor and the mixture was stirred and cooled to 0-100C. The acid chloride solution (from the 100 L Schott reactor) was then slowly charged into the hydroxylamine solution over 1 hour maintaining a batch temperature of 0-10°C during the addition. The batch was then allowed to warm to 20-300C. The aqueous layer was separated and discarded. The organic layer was then reduced in volume under vacuum while maintaining a batch temperature of less than 300C. The intention was to distill out 10-13 L of solvent, but this level was overshot. A larger volume of isopropyl acetate (IPAc) (16.6 L) was added and about 6 L of solvent was distilled out. The batch had precipitated and heptanes (24.9 L) were added and the batch was held at 20-30°C overnight. The batch was filtered and the residue was washed with heptanes (6.64 L). The filtrate was discarded and the residue was dried at 45-55°C under vacuum with a slight nitrogen bleed over the weekend. The title compound (PXD101) was obtained as a light orange solid (3.11 kg, 89% yield with respect to compound (6)) with a purity of 99.25% (AUC) by HPLC.
The title compound (PXD101) (1.2 kg, 3.77 mol) was dissolved in 8 volumes of 1:1 (EtOH/water) at 600C. Sodium bicarbonate (15.8 g, 5 mol%) was added to the solution. Water (HPLC grade) was then added at a rate of 65 mL/min while keeping the internal temperature >57°C. After water (6.6 L) had been added, crystals started to form and the water addition was stopped. The reaction mixture was then cooled at a rate of 10°C/90 min to a temperature of 0-10cC and then stirred at ambient temperature overnight. The crystals were then filtered and collected. The filter cake was washed by slurrying in water (2 x 1.2 L) and then dried in an oven at 45°C for 60 hours with a slight nitrogen bleed. 1.048 kg (87% recovery) of a light orange solid was recovered. Microscopy and XRPD data showed a conglomerate of irregularly shaped birefringant crystalline particles. The compound was found to contain 0.02% water.
As discussed above: the yield of compound (5) with respect to compound (1) was 69%. the yield of compound (6) with respect to compound (5) was 84%. the yield of PXD101 with respect to compound (6) was 89%.
Synthetic Commun. 2010, 40, 2520-2524.
FORMULATION
Formulation Studies
These studies demonstrate a substantial enhancement of HDACi solubility (on the order of a 500-fold increase for PXD-101) using one or more of: cyclodextrin, arginine, and meglumine. The resulting compositions are stable and can be diluted to the desired target concentration without the risk of precipitation. Furthermore, the compositions have a pH that, while higher than ideal, is acceptable for use.
UV Absorbance
The ultraviolet (UV absorbance E\ value for PXD-101 was determined by plotting a calibration curve of PXD-101 concentration in 50:50 methanol/water at the λmax for the material, 269 nm. Using this method, the E1i value was determined as 715.7.
Methanol/water was selected as the subsequent diluting medium for solubility studies rather than neat methanol (or other organic solvent) to reduce the risk of precipitation of the cyclodextrin.
Solubility in Demineralised Water
The solubility of PXD-101 was determined to be 0.14 mg/mL for demineralised water. Solubility Enhancement with Cvclodextrins
Saturated samples of PXD-101 were prepared in aqueous solutions of two natural cyclodextrins (α-CD and γ-CD) and hydroxypropyl derivatives of the α, β and Y cyclodextrins (HP-α-CD, HP-β-CD and HP-γ-CD). All experiments were completed with cyclodextrin concentrations of 250 mg/mL, except for α-CD, where the solubility of the cyclodextrin was not sufficient to achieve this concentration. The data are summarised in the following table. HP-β-CD offers the best solubility enhancement for PXD-101.
Phase Solubility Determination of HP-β-CD
The phase solubility diagram for HP-β-CD was prepared for concentrations of cyclodextrin between 50 and 500 mg/mL (5-50% w/v). The calculated saturated solubilities of the complexed HDACi were plotted against the concentration of cyclodextrin. See Figure 1.
CLIP
SPECTRUM
Tiny Biotech With Three Cancer Drugs Is More Alluring Takeover Bet Now
Forbes
The drug is one of Spectrum’s two drugs undergoing phase 3 clinical trials. Allergan paid Spectrum $41.5 million and will make additional payments of up to $304 million based on achieving certain milestones. So far, Raj Shrotriya, Spectrum’s chairman, …
A practical synthetic route of belinostat is reported. Belinostat was obtained via a five-step process starting from benzaldehyde and including addition reaction with sodium bisulfite, sulfochlorination with chlorosulfonic acid, sulfonamidation with aniline, Knoevenagel condensation, and the final amidation with hydroxylamine. Key to the strategy is the preparation of 3-formylbenzenesulfonyl chloride using an economical and practical protocol. The main advantages of the route include inexpensive starting materials and acceptable overall yield. The scale-up experiment was carried out to provide 169 g of belinostat with 99.6% purity in 33% total yield.
(E)-N-Hydroxy-3-((phenylamino)sulfonyl)phenyl)acrylamide (Belinostat, 1)
1
mp 172–174 °C, (lit.(@) 172 °C). 1H NMR (400 MHz, DMSO-d6) δ = 10.75–10.42 (m, 2H), 9.15 (s, 1H), 7.92 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H),7.47 (d, J = 15.8 Hz, 1H), 7.24 (m, 2H), 7.10–7.01 (m, 3H), 6.51 (d, J = 15.8 Hz, 1H). MS (ESI): m/z = 318.6 [M+H] +.
@ Finn, P. W.; Bandara, M.; Butcher, C.; Finn, A.; Hollinshead, R.; Khan, N.; Law, N.; Murthy, S.; Romero,R.; Watkins, C.; Andrianov, V.; Bokaldere, R. M.; Dikovska, K.; Gailite, V.; Loza, E.; Piskunova, I.;Starchenkov, I.; Vorona, M.; Kalvinsh, I. Helv. Chim. Acta 2005, 88, 1630, DOI: 10.1002/hlca.200590129
Belinostat (Beleodaq),
Belinostat is a drug which was developed by Spectrum Pharmaceuticals and is currently marketed by Onxeo as Beleodaq. The
drug, which received fast track designation by the United States Food and Drug Administration (US FDA) and was approved for
the treatment of hematological malignancies and solid tumors associated with peripheral T-cell lymphoma (PTCL) in 2014,58 is a histone deacetylase (HDAC) inhibitor and is the third such treatment to receive accelerated approval for PTCL, the others being
vorinostat (Zolinza) and pralatrexate (Folotyn).58 Although belinostat was not yet approved in Europe as of August 2014,58 the
compound exhibits a safety profile considered to be acceptable for HDAC inhibitors–less than 25% of patients reported adverse
effects and these most frequently were nausea, fatigue, pyrexia,anemia, and emesis.58 While several different synthetic approaches
have been reported for the preparation of belinostat and related HDAC inhibitors,59–62 the most likely process-scale approach has
been described in a patent application filed by Reisch and co-workers at Topotarget UK, which exemplifies the synthesis described in
Scheme 8 on kilogram scale.63
Commercially available 3-bromobenzenesulfonyl chloride (41) was reacted with aniline in the presence of aqueous sodium carbonate
to deliver sulfonamide 42 in 94% yield. Next, this aryl bromide was subjected to a Heck reaction involving ethyl acrylate to
give rise to cinnamate ester 43, which was immediately saponified under basic conditions and acidic workup to furnish the corresponding acid 44. This acid was activated as the corresponding acid chloride prior to subjection to hydroxylamine under basic conditions to form the hydroxamic acid, which was then recrystallized from an 8:1 ethanol/water mixture in the presence of a catalytic
amount of sodium bicarbonate to furnish crystalline belinostat (VI) in 87% overall yield from acid 44.61
Lee, H. Z.; Kwitkowski, V. E.; Del Valle, P. L.; Ricci, M. S.; Saber, H.;Habtemariam, B. A.; Bullock, J.; Bloomquist, E.; Li Shen, Y.; Chen, X. H.;Brown, J.; Mehrotra, N.; Dorff, S.; Charlab, R.; Kane, R. C.; Kaminskas, E.;Justice, R.; Farrell, A. T.; Pazdur, R. Clin. Cancer Res. 2015, 21, 2666.
59. Qian, J.; Zhang, G.; Qin, H.; Zhu, Y.; Xiao, Y. CN Patent 102786448A, 2012.
60. Wang, H.; Yu, N.; Chen, D.; Lee, K. C.; Lye, P. L.; Chang, J. W.; Deng, W.; Ng, M.C.; Lu, T.; Khoo, M. L.; Poulsen, A.; ngthongpitag, K.; Wu, X.; Hu, C.; Goh, K.C.; Wang, X.; Fang, L.; Goh, K. L.; Khng, H. H.; Goh, S. K.; Yeo, P.; Liu, X.; Bonday, Z.; Wood, J. M.; Dymock, B. W.; Kantharaj, E.; Sun, E. T. J. Med. Chem.2011, 54, 4694.
61. Yang, L.; Xue, X.; Zhang, Y. Synth. Comm. 2010, 40, 2520.
Let’s Research !!!!!
Identifications:| 1H NMR (Estimated) for Belinostat |
Experimental: 1H NMR (300 MHz, DMSO-d6): δ 6.52 (d, J=15.9 Hz, 1H), 6.81–7.12 (m, 6H), 7.33 (d, J=15.9 Hz, 1H), 7.47–7.67 (m, 3 H), 7.87 (s, 1H), 9.00–11.20 (br, 3H).
ANALYTICAL HPLC TEST METHOD
HPLC spectrum of Belinostat.
http://www.google.si/patents/CN102531972A?cl=en
Belinostat synthesis process related to the first report of the literature of W002 / 30879 A2, including preparation for Belinostat described as follows:
Example 3:
3- (3-sulfonate-yl) phenyl – acrylate preparation:
First, 3-bromophenyl sulfonate 37. Ig (257. 90g / mol, 0. 1439mol) was dissolved with stirring in 260mL toluene IL reactor was then added triethylamine 36. 5g (101. 19g / mol, 0. 3604mol), tri (o-methylphenyl) phosphine 0. 875g (304. 37g / mol, 0. 002874mol), palladium acetate 0. 324g (224. 51g, 0. 001441mol), the reaction mixture was heated to 45- 55 ° C with nitrogen pumping ventilation four, this time in the reaction system to generate the catalytically active 1 ^ (0). The temperature of the reaction system was raised to 80-90 ° C, within 2. 75h dropwise methacrylate 13. 6g (86. 04g / mol, 0. 1586mol), the reaction was continued after the cell by HPLC 3- bromophenyl sulfonyl chloride was completion of the reaction. The temperature of the reaction system was reduced to 45-55 ° C.
[0021] In at 45-55 ° C, the reaction mixture was concentrated under reduced pressure, ethyl acetate and n-heptane and recrystallized to give the product 29. 4g, 83% yield.
[0022] The spectral data:
1HNMR (DMS0-d6, HMDS0), δ (ppm): 3. 65 (3H, S, H-1); 6. 47 (1H, d, J = 16 0 Hz, H-2.); 7. 30 -8 00 (5H, m, H-3, H_4, H_5, H_6, H_7) m / e:. 264. 23
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Int. J. Cancer 2008, 122, 1400-1410.
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CLIP
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
(2E)-N-Hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide
|
|
| Clinical data | |
| Trade names | Beleodaq |
| AHFS/Drugs.com | beleodaq |
| Pregnancy category |
|
| Routes of administration |
Intravenous (IV) |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Bioavailability | 100% (IV) |
| Protein binding | 92.9–95.8%[1] |
| Metabolism | UGT1A1 |
| Excretion | Urine |
| Identifiers | |
| CAS Number | 866323-14-0  |
| ATC code | L01XX49 (WHO) |
| PubChem | CID 6918638 |
| ChemSpider | 5293831  |
| UNII | F4H96P17NZ |
| ChEBI | CHEBI:61076 |
| ChEMBL | CHEMBL408513 |
| Synonyms | PXD101 |
| Chemical data | |
| Formula | C15H14N2O4S |
| Molar mass | 318.348 g/mol |
| AZD1981; AZD-1981; 802904-66-1; UNII-2AD53WQ2CX; ; AZD 1981; | |
| Molecular Formula: | C19H17ClN2O3S |
|---|---|
| Molecular Weight: | 388.86788 g/mol |
https://ncats.nih.gov/files/AZD1981.pdf
SEE
AZD1981 is a potent, selective CRTh2 (DP2) receptor antagonist with IC50 of 4 nM, showing >1000-fold selectivity over more than 340 other enzymes and receptors, including DP1. Phase 2.
118 patients were randomised to treatment (AZD1981 n = 61; placebo n = 57); 83% of patients were male and the mean age was 63 years (range 43-83). There were no significant differences in the mean difference in change from baseline to end of treatment between AZD1981 and placebo for the co-primary endpoints of pre-bronchodilator FEV1 (AZD1981-placebo: -0.015, 95% CI: -0.10 to 0.070; p = 0.72) and CCQ total score (difference: 0.042, 95% CI: -0.21 to 0.30; p = 0.75). Similarly, no differences were observed between treatments for the other outcomes of lung function, COPD symptom score, 6-MWT, BODE index, and use of reliever medication. AZD1981 was well tolerated.
There was no beneficial clinical effect of AZD1981, at a dose of 1000 mg twice daily for 4 weeks, in patients with moderate to severe COPD. AZD1981 was well tolerated and no safety concerns were identified.
| Description | AZD1981 is a potent, selective CRTh2 (DP2) receptor antagonist with IC50 of 4 nM, showing >1000-fold selectivity over more than 340 other enzymes and receptors, including DP1. Phase 2. | |||||
|---|---|---|---|---|---|---|
| Targets | CRTh2 (DP2) receptor [1] | |||||
| IC50 | 4 nM | |||||
| In vitro | AZD1981, as a potent antagonist in a disease relevant cell system, inhibits DK-PGD2-induced CD11b expression in human eosinophils with IC50 of 10 nM. [1] AZD1981 blocks DP2-mediated shape change in human eosinophils and basophils in blood, as well as DP2-mediated chemotaxis of human Th2 cells and eosinophils. Moreover, AZD1981 also blocks the binding of [3H]PGD2 to mouse, rat, guinea pig, rabbit and dog recombinant DP2. [2] | |||||
| In vivo | AZD1981 has high oral bioavailability in male sprague dawley rats. [1] In guinea pig hind limb model, AZD1981 (100 nM) completely inhibits DK-PGD2-induced eosinophil mobilization. [2] | |||||
| Features | An orally available selective DP2(CRTh2) receptor antagonist in clinical development for asthma. | |||||
| DP2 binding studies | A scintillation proximity assay (SPA) following [3H]PGD2 binding to membranes of HEK cells expressing recombinant DP2 is used. The potency of AZD1981 as an antagonist is determined by quantifying its ability to displace specific radio-ligand binding. Briefly, membranes from HEK293 expressing recombinant human DP2 are pre-bound to Wheat Germ Agglutinin-coated PVT-SPA beads for 18 h at 4°C. Assays were started by the addition of 25 μL of membrane-coated beads (10 mg/mL of beads) to an assay buffer (50 mm HEPES pH 7.4 containing 5 mm MgCl2) containing 2.5 nM [3H]PGD2 in the absence or the presence of increasing concentrations of the tested compounds (50 μL final volume). Non-specific binding is determined in the same conditions but in the presence of 10 μM DK-PGD2. Plates are incubated for 2 h at room temperature, and bead-associated radioactivity is measured using a Wallac Microbeta counter. The concentration of the compounds causing 50% inhibition of binding of [3H]PGD2 to the receptor is calculated (IC50). Ki values have not been derived from IC50, as there is no evidence of a simple competitive interaction with PGD2. The same methodology is used for recombinant human, murine, rat, guinea pig, dog and rabbit DP2. Reversibility of binding to the human receptor was assessed by recovery of [3H]PGD2 binding after removal of AZD1981 by washing of the membrane-coated SPA beads. HEK-membrane-coated beads are incubated in the presence of AZD1981 for 2 h at room temperature to bind the compound to DP2. To remove the bound AZD1981, beads are centrifuged (1 min at 1300× g), and the pellet resuspended in 1 mL of assay buffer. This is repeated four times. Aliquots (30 μL) are transferred to 96-well plates, and [3H]PGD2 binding is evaluated as above. Parallel samples containing (i) 10 μM DK-PGD2 during the 2 h incubation and in the wash buffer; (ii) AZD1981 at 2 μM in the wash buffer; and (iii) vehicle are processed alongside to determine non-specific binding and the ‘no wash’ condition whilst controlling for loss of beads during the washing process. The time from first wash to end of first reading is approximately 13 min. |
|---|
| Animal Models | Male sprague dawley rats. |
|---|---|
| Formulation | |
| Dosages | 1 mg/kg(i.v.), 4 mg/kg(oral) |
| Administration | i.v. or oral administration |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
| Rat dose (mg/kg) = mouse dose (22.4 mg/kg) × | mouse Km(3) | = 11.2 mg/kg |
| rat Km(6) |
[1] Luker T, et al. Bioorg Med Chem Lett. 2011, 21(21), 6288-6292.
[2] Schmidt JA, et al. Br J Pharmacol. 2013, 168(7), 1626-1638.
| NCT Number | Recruitment | Conditions | Sponsor /Collaborators |
Start Date | Phases |
|---|---|---|---|---|---|
| NCT02031679 | Recruiting | Chronic Idiopathic Urticaria | Johns Hopkins University|AstraZeneca | January 2014 | Phase 2 |
| NCT01311635 | Completed | Healthy | AstraZeneca | April 2011 | Phase 1 |
| NCT01254461 | Completed | Drug Interaction | AstraZeneca | February 2011 | Phase 1 |
| NCT01265641 | Completed | Asthma | AstraZeneca | January 2011 | Phase 1 |
| NCT01199341 | Completed | Pharmakokinetic | AstraZeneca | October 2010 | Phase 1 |
| Patent ID | Date | Patent Title |
|---|---|---|
| US2015210655 | 2015-07-30 | CERTAIN (2S)-N-[(1S)-1-CYANO-2-PHENYLETHYL]-1,4-OXAZEPANE-2-CARBOXAMIDES AS DIPEPTIDYL PEPTIDASE 1 INHIBITORS |
| US2015072963 | 2015-03-12 | COMPOSITIONS AND METHODS FOR REGULATING HAIR GROWTH |
| US2014328861 | 2014-11-06 | Combination of CRTH2 Antagonist and a Proton Pump Inhibitor for the Treatment of Eosinophilic Esophagitis |
| US8772305 | 2014-07-08 | Substituted pyridinyl-pyrimidines and their use as medicaments |
| US8227622 | 2012-07-24 | Pharmaceutical Process and Intermediates 714 |
| US2012178764 | 2012-07-12 | Novel Compounds |
| US2011263614 | 2011-10-27 | Novel compounds |
| US7781598 | 2010-08-24 | Process for the preparation of substituted indoles |
| US7687535 | 2010-03-30 | Substituted 3-sulfur indoles |
| US2009163518 | 2009-06-25 | Novel Compounds |
///////////
CC1=C(C2=C(N1CC(=O)O)C=CC=C2NC(=O)C)SC3=CC=C(C=C3)Cl
AZD3514; AZD 3514; AZD-3514.
CAS 1240299-33-5
Chemical Formula: C25H32F3N7O2
Exact Mass: 519.25696
1-(4-(2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethyl)piperazin-1-yl)ethanone
Ethanone, 1-[4-[2-[4-[1-[7,8-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-b]pyridazin-6-yl]-4-piperidinyl]phenoxy]ethyl]-1-piperazinyl]
6-f4-{4-[2-f4-acetylpiperazin-l-yl)ethoxylphenyl}piperidin-l-yl)-3-( trifluoromethyr)-7,8-dihvdro [ 1 ,2,41 triazolo [4,3-bl pyridazine
6-(4-{4-[2-(4-acetylpiperazin-l- vDethoxyl phenyllpiperidin- l-vD-3-f trifluoromethyl)-7.,8-(iihv(iro [ 1 ,2,41 triazolo [4,3- blpyridazine
AZD-3514 is a potent androgen receptor downregulator with potential anticancer cancer activity. AZD3514 is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
AZD3514 is currently in Phase I trail. This trial is looking at a new drug called AZD3514 for men who have prostate cancer that has spread to other parts of the body and is no longer responding to hormone therapy. Doctors often use hormone therapy to treat prostate cancer. This may keep it under control for long periods of time. But researchers are looking for treatments that will help men who have prostate cancer that stops responding to hormone therapy. Prostate cancer needs the hormone testosterone to grow. The testosterone locks into receptors on the cancer cells. AZD3514 works by breaking down these receptors so that testosterone canÂ’t tell the prostate cancer cells to grow.
6-(4-{4-[2-(4-Acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-ihydro[1,2,4]triazolo[4,3-b]pyridazine
as a white, free flowing solid.
1H NMR (400 MHz, CDCl3): δ 1.62 (2H, m), 1.88 (2H, m), 2.02 (3H, s), 2.49 (4H, m), 2.65 – 2.78 (5H, m), 2.94 (2H, m), 3.15 (2H, t), 3.42 (2H, m), 3.57 (2H, m), 4.03 (2H, t), 4.24 (2H, m), 6.80 (2H, d), 7.06 (2H, d);
m/z = 520 [M+H]+. RT = 0.87: 99% purity.
HRMS found 520.26373,
Prostate cancer is the second leading cause of death from cancer among men in developed countries, and was projected to account for 25% of newly-diagnosed cases and 9% of deaths due to cancer in the USA in 2010. The androgen receptor (AR), a ligand binding transcription factor in the nuclear hormone receptor super family, is a key molecular target in the etiology and progression of prostate cancer.Binding of the endogenous AR ligand dihydrotestosterone stabilizes and protects the AR from rapid proteolytic degradation. The early stages of prostate cancer tumor growth are androgen dependent and respond well to androgen ablation, either via surgical castration or by chemical castration with a luteinizing hormone releasing hormone agonist in combination with an AR antagonist, such as bicalutamide.
Although introduction of androgen deprivation therapy represented a major advance in prostate cancer treatment, recurrence within 1–2 years typically marks transition to the so-called castrate-resistant state, in which the tumor continues to grow in the presence of low circulating endogenous ligand and is no longer responsive to classical AR antagonists. Castrate-resistant prostate cancer (CRPC) is a largely unmet medical need with a 5-year survival rate of less than 15%. Antimitotic agents docetaxel and cabazitaxel, testosterone biosynthesis inhibitor abiraterone acetate and second generation AR antagonist enzalutamide (MDV3100) are the currently approved small-molecule drugs that have been shown to provide survival benefit.
Recent evidence from both pre-clinical and clinical studies is consistent with the importance of re-activation of AR signaling in a majority of castrate-resistant prostate tumors. It is also well established that the functional AR in castrate-resistant tumors is frequently mutated or amplified, and that over-expression can convert hormone-responsive cell lines to hormone refractory. Recent second-generation AR antagonists have been designed that retain antagonism in over-expressing cell lines, and among these agents enzalutamide has recently successfully met efficacy criteria in a large Phase III clinical trial.
By analogy with fulvestrant, an estrogen receptor (ER) downregulator approved by the FDA in 2002 for treatment of advanced breast cancer and initially characterized as a pure ER antagonist, a ligand which downregulates the AR represents one of a number of potential approaches to treatment of CRPC via a sustained reduction in tumor AR content. We recently described derivation from a novel 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine ligand of AR inhibitor 1 The compound also causes AR downregulation15 and high plasma levels following oral administration in pre-clinical models compensate for moderate cellular potency
Figure 1.
Structures of lead AR downregulator 1 and chemotype 2.
Scheme 3.
Synthesis of compounds 10, 11a–b, 12. Reagents and conditions: (a) 2-(1-Methyl-1H-pyrazol-5-yl)ethanol,27 Ph3P, diisopropyl azodicarboxylate, THF, 20 °C; (b) 2-(4-acetylpiperazine-1-yl)ethanol,28 Ph3P, diisopropyl azodicarboxylate, THF, 20 °C; (c) H2, 10% Pd-C, MeOH, 50 °C.
PATENT
| Robert Hugh Bradbury, Gregory Richard Carr,Alfred Arthur Rabow, Korupoju Srinivasa Rao,Harikrishna Tumma, | |
| Applicant | Astrazeneca Ab, Astrazeneca Uk Limited |
Preparation of 6-f4-{4-[2-f4-acetylpiperazin-l-yl)ethoxylphenyl}piperidin-l-yl)-3-
( trifluoromethyr)-7,8-dihvdro [ 1 ,2,41 triazolo [4,3-bl pyridazine
A solution of acetyl chloride (0.027 mL, 0.38 mmol) in DCM (0.5 mL) was added dropwise to 6-[4- [4- [2-(piperazin- 1 -yl)ethoxy]phenyl]piperidin- 1 -yl] -3 -(trifluoromethyl)- 7,8-dihydro-[l,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.31 mmol) and triethylamine (0.088 mL, 0.63 mmol) in DCM (1 mL) cooled to 00C under nitrogen. The resulting solution was stirred at 00C for 5 minutes then allowed to warm to room temperature and stirred for 15 minutes. The reaction mixture was diluted with water (2 mL), passed through a phase separating cartridge and then the organic layer was evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep Cl 8 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-(4-{4-[2-(4-acetylpiperazin-l- yl)ethoxy]phenyl}piperidin-l-yl)-3-(trifluoromethyl)-7,8-dihydro[l,2,4]triazolo[4,3- b]pyridazine (80 mg, 49%) as a gum.
IH NMR (399.9 MHz, CDC13) δ 1.69 (2H, m), 1.95 (2H, m), 2.08 (3H, s), 2.56 (4H, m), 2.71 – 2.84 (5H, m), 3.00 (2H, m), 3.22 (2H, t), 3.48 (2H, m), 3.63 (2H, m), 4.10 (2H, t), 4.31 (2H, m), 6.86 (2H, d), 7.12 (2H, d); m/z = 520 [M+H]+.
The 6-[4-[4-[2-(piperazin- 1 -yl)ethoxy]phenyl]piperidin- 1 -yl]-3-(trifluoromethyl)-7,8- dihydro-[l,2,4]triazolo[4,3-b]pyridazine used as starting material was prepared as follows :-
Preparation of tert-butyl 4-[2-[4-(l-(benzyloxycarbonyl)-l,2,3,6-tetrahydropyridin-4- yl)phenoxy]ethyl]piperazine-l-carboxylate DIAD (12.60 mL, 64.00 mmol) was added dropwise to benzyl 4-(4-hydroxyphenyl)-5,6- dihydropyridine-l(2H)-carboxylate (obtained as described in Example 4.1, preparation of starting materials) (16.5 g, 53.34 mmol), tert-butyl 4-(2-hydroxyethyl)piperazine-l- carboxylate (CAS 77279-24-4) (14.74 g, 64.00 mmol) and triphenylphosphine (16.79 g, 64.00 mmol) in THF (150 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated to dryness then the residue was stirred in ether (200 mL) for 10 minutes at room temperature. The resulting precipitate was removed by filtration and discarded. The ether filtrate was washed with water (100 mL) followed by saturated brine (100 mL), then dried over MgSO4, filtered and evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 60% EtOAc in isohexane. Fractions containing the desired product were evaporated to dryness to afford tert-butyl 4-[2-[4-(l- (benzyloxycarbonyl)- 1,2,3, 6-tetrahydropyridin-4-yl)phenoxy]ethyl]piperazine-l- carboxylate (34.6 g, 82%) as a gum which was contaminated with 34% by weight triphenylphosphine oxide.
IH NMR (399.9 MHz, DMSO-d6) δ 1.40 (9H, s), 2.42 – 2.47 (6H, m), 2.71 (2H, m), 3.32 (4H, m), 3.62 (2H, m), 4.03 – 4.10 (4H, m), 5.12 (2H, s), 6.06 (IH, m), 6.92 (2H, d), 7.31 – 7.40 (7H, m); m/z = 522 [M+H]+.
Preparation of tert-butyl 4-[2-[4-(piperidin-4-yl)phenoxy]ethyl]piperazine-l- carboxylate tert-Butyl 4-[2-[4-(l-(benzyloxycarbonyl)-l,2,3,6-tetrahydropyridin-4- yl)phenoxy]ethyl]piperazine-l-carboxylate (66% pure by weight) (34.62 g, 43.80 mmol) and 5% palladium on carbon (50% wet) (4.47 g, 1.05 mmol) in MeOH (250 mL) were stirred under an atmosphere of hydrogen at 5 bar and 600C for 4 hours. The catalyst was removed by filtration and the solvents evaporated to give crude product. The crude product was purified by flash silica chromatography, eluting with 60% EtOAc in isohexane then 15% 2M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-[2-[4-(piperidin-4-yl)phenoxy]ethyl]piperazine-l-carboxylate (15.42 g, 90%) as a solid. IH NMR (399.9 MHz, CDC13) δ 1.46 (9H, s), 1.62 (2H, m), 1.81 (2H, m), 2.50 – 2.59 (5H, m), 2.73 (2H, m), 2.80 (2H, t), 3.18 (2H, m), 3.44 (4H, m), 4.09 (2H, t), 6.85 (2H, d), 7.13 (2H, d); m/z = 390 [M+H]+.
Preparation of tert-butyl 4-[2-[4-[l-(3-(trifluoromethyl)-[l,2,4]triazolo[4,3- b]pyridazin-6-yl]piperidin-4-yl]phenoxy]ethyl]piperazine-l-carboxylate
DIPEA (2.348 mL, 13.48 mmol) was added to 6-chloro-3-(trifluoromethyl)- [l,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (2 g, 8.99 mmol) and tert-butyl 4-[2-[4-(piperidin-4-yl)phenoxy]ethyl]piperazine-l- carboxylate (3.68 g, 9.44 mmol) in DMF (30 mL). The resulting solution was stirred at 800C for 2 hours. The reaction mixture was cooled to room temperature and the solvents evaporated to dryness. The resulting solid was triturated with water then collected by filtration, washed with ether and dried to afford tert-butyl 4-[2-[4-[l-(3-(trifluoromethyl)- [l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]ethyl]piperazine-l -carboxylate (5.02 g, 97%) as a solid.
IH NMR (399.9 MHz, CDC13) δ 1.46 (9H, s), 1.76 (2H, m), 2.00 (2H, m), 2.54 (4H, m), 2.75 – 2.86 (3H, m), 3.11 (2H, m), 3.46 (4H, m), 4.11 (2H, m), 4.37 (2H, m), 6.87 (2H, d), 7.13 (3H, m), 7.92 (IH, d); m/z = 576 [M+H]+.
Preparation of tert-butyl 4-[2-[4-[l-[3-(trifluoromethyl)-7,8-dihydro-
[1 ,2,4] triazolo [4,3-b] pyridazin-6-yl)piperidin-4-yl] phenoxy] ethyl] piperazine- 1- carboxylate
10% Palladium on carbon (0.924 g, 0.87 mmol) was added to tert-butyl 4-[2-[4-[l-(3- (trifluoromethyl)-[l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4- yl]phenoxy]ethyl]piperazine-l -carboxylate (2.5 g, 4.34 mmol) and ammonium formate (2.74 g, 43.43 mmol) in ethanol (100 mL). The resulting mixture was stirred at 78°C, with further portions of ammonium formate being added every 5 hours until the reaction was complete. The reaction mixture was cooled to room temperature and the catalyst was removed by filtration. The filtrate was evaporated to dryness, redissolved in DCM (100 mL) and the solution was washed with water (100 mL) followed by brine (50 mL), then the solvents were evaporated to afford tert-butyl 4-[2-[4-[l-[3-(trifluoromethyl)-7,8-dihydro- [l,2,4]triazolo[4,3-b]pyπdazin-6-yl)pipeπdin-4-yl]phenoxy]ethyl]piperazine-l-carboxylate (2.02O g, 81%) as a solid.
IH NMR (399.9 MHz, CDC13) δ 1.46 (9H, s), 1.69 (2H, m), 1.95 (2H, m), 2.52 (4H, m), 2.71 – 2.82 (5H, m), 3.00 (2H, m), 3.22 (2H, t), 3.45 (4H, m), 4.09 (2H, m), 4.31 (2H, m), 6.86 (2H, d), 7.12 (2H, d); m/z = 578 [M+H]+.
Preparation of 6- [4-[4- [2-(piperazin-l-yl)ethoxy] phenyl] piperidin-1-yl] -3- (trifluor omethyl)-7,8-dihydr o- [ 1 ,2,4] triazolo [4,3-b] pyridazine
TFA (10 mL) was added to tert-butyl 4-[2-[4-[l-[3-(trifluoromethyl)-7,8-dihydro- [l,2,4]triazolo[4,3-b]pyπdazin-6-yl)pipeπdin-4-yl]phenoxy]ethyl]piperazine-l-carboxylate (2.02 g, 3.50 mmol) in DCM (10 mL). The resulting solution was stirred at ambient temperature for 1 hour then added to an SCX column. The desired product was eluted from the column using 2M ammonia/MeOH and the solvents were evaporated to afford 6-[4-[4- [2-(piperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3-(trifluoromethyl)-7,8-dihydro- [l,2,4]triazolo[4,3-b]pyridazine (1.660 g, 99%) as a solid.
IH NMR (399.9 MHz, CDC13) δ 1.68 (2H, m), 1.95 (2H, m), 2.55 (4H, m), 2.70 – 2.80 (5H, m), 2.91 (4H, m), 3.00 (2H, m), 3.22 (2H, t), 4.09 (2H, t), 4.30 (2H, m), 6.87 (2H, d), 7.11 (2H, d); m/z = 478 [M+H]+.
Example 5.2
Larger scale preparation of 6-(4-{4-[2-(4-acetylpiperazin-l- vDethoxyl phenyllpiperidin- l-vD-3-f trifluoromethyl)-7.,8-dihvdro [ 1 ,2,41 triazolo [4,3- blpyridazine
Ammonium formate (99 g, 1568.94 mmol) was added to 6-[4-[4-[2-(4-acetylpiperazin-l- yl)ethoxy]phenyl]piperidin- 1 -yl]-3-(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazine (81.2 g, 156.89 mmol) and 10% palladium on carbon (8.35 g, 7.84 mmol) in EtOH (810 mL) under nitrogen. The resulting mixture was stirred at 700C for 6 hours, then ammonium formate (50 g) was added. The mixture was stirred at 700C for 2 hours then further portions of 10% palladium on carbon (8.35 g, 7.84 mmol) and ammonium formate (50 g) were added and stirring continued at 700C for a further 10 hours. Ammonium formate (50 g) was added and the reaction mixture was stirred at 700C for 24 hours then cooled to room temperature. The catalyst was removed by filtration and the reaction charged with further 10% palladium on carbon (8.35 g, 7.84 mmol) and stirred at 700C for 16 hours. Further ammonium formate (50 g) was added and the stirring continued for 5 hours. The reaction mixture was cooled to room temperature and a further portion of 10% palladium on carbon (8.35 g, 7.84 mmol) was added. The mixture was heated to 700C for a 30 hours, cooled to room temperature and the catalyst removed by filtration and washed with EtOH. The solvent was evaporated and the residue dissolved in DCM (500 mL) and the solution washed with water (500 mL). The aqueous layer was re-extracted with DCM (500 mL), then EtOAc (500 mL x 2). The combined extracts were dried over MgSO4, filtered and evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford a gum, which was slurried with ether (300 mL) and re-evaporated. Methyl tert-butyl ether (250 mL) was added and the mixture was stirred vigorously for 3 days. The solid was collected by filtration and dried to afford 6-(4-{4-[2-(4- acetylpiperazin- 1 -yl)ethoxy]phenyl}piperidin- 1 -yl)-3-(trifluoromethyl)-7,8- dihydro[l,2,4]triazolo[4,3-b]pyridazine (60.8 g, 75%) as a solid.
IH NMR (399.9 MHz, CDC13) δ 1.62 (2H, m), 1.88 (2H, m), 2.02 (3H, s), 2.49 (4H, m), 2.65 – 2.78 (5H, m), 2.94 (2H, m), 3.15 (2H, t), 3.42 (2H, m), 3.57 (2H, m), 4.03 (2H, t), 4.24 (2H, m), 6.80 (2H, d), 7.06 (2H, d); m/z = 520 [M+H]+.
The 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3-
(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazine used as starting material was prepared as follows :-
Preparation of 4-(piperidin-4-yl)phenol Benzyl 4-(4-hydroxyphenyl)-5,6-dihydropyridine-l(2H)-carboxylate (obtained as described in Example 4.1, preparation of starting materials) (37.7 g, 121.86 mmol) and 5% palladium on carbon (7.6 g, 3.57 mmol) in methanol (380 mL) were stirred under an atmosphere of hydrogen at 5 bar and 25°C for 2 hours. The catalyst was removed by filtration, washed with MeOH and the solvents evaporated. The crude material was triturated with diethyl ether, then the desired product collected by filtration and dried under vacuum to afford 4-(piperidin-4-yl)phenol (20.36 g, 94%) as a solid. IH NMR (399.9 MHz, DMSO-d6) δ 1.46 (2H, m), 1.65 (2H, m), 2.45 (IH, m), 2.58 (2H, m), 3.02 (2H, m), 6.68 (2H, d), 7.00 (2H, d), 9.15 (IH, s); m/z = 178 [M+H]+.
Preparation of 4- { 1- [3-(trifluor omethyl) [1 ,2,4] triazolo [4,3-b] pyridazin-6-yl] piperidin- 4-yl}phenol
DIPEA (48.2 mL, 276.86 mmol) was added to 6-chloro-3-(trifluoromethyl)- [l,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (24.65 g, 110.74 mmol) and 4-(piperidin-4-yl)phenol (20.61 g, 116.28 mmol) in DMF (200 mL). The resulting solution was stirred at 800C for 1 hour. The reaction mixture was cooled to room temperature, then evaporated to dryness and re-dissolved in DCM (1 L) and washed with water (2 x 1 L). The organic layer was washed with saturated brine (500 mL), then dried over MgSO4, filtered and evaporated to afford crude product. The crude product was triturated with ether to afford 4-{l-[3- (trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (36.6 g, 91%) as a solid.
IH NMR (399.9 MHz, DMSO-d6) δ 1.64 (2H, m), 1.87 (2H, m), 2.75 (IH, m), 3.09 (2H, m), 4.40 (2H, m), 6.69 (2H, d), 7.05 (2H, d), 7.65 (IH, d), 8.24 (IH, d), 9.15 (IH, s); m/z = 364 [M+H]+.
Preparation of 2-(4-{l-[3-(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin-6- yl]piperidin-4-yl}phenoxy)ethanol
A solution of ethylene carbonate (121 g, 1376.13 mmol) in DMF (200 mL) was added dropwise to a stirred suspension of 4-{l-[3-(trifluoromethyl)[l,2,4]triazolo[4,3- b]pyridazin-6-yl]piperidin-4-yl}phenol (100 g, 275.23 mmol) and potassium carbonate (76 g, 550.45 mmol) in DMF (200 mL) at 800C over a period of 15 minutes under nitrogen.
The resulting mixture was stirred at 800C for 20 hours. The reaction mixture was cooled to room temperature, then concentrated and diluted with DCM (2 L), and washed sequentially with water (1 L) and saturated brine (500 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Fractions containing the desired product were evaporated to dryness then triturated with EtOAc (150 mL). The resulting solid was washed with further EtOAc (50 mL) and ether then dried to give 2-(4- { 1 -[3-(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4- yl}phenoxy)ethanol. The filtrate was evaporated and further purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Fractions containing the desired product were evaporated to dryness then triturated with ether, dried and combined with the material previously collected to afford 2-(4- { 1 -[3-
(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (89 g, 79%) as a solid.
IH NMR (399.9 MHz, DMSO-d6) δ 1.66 (2H, m), 1.88 (2H, m), 2.80 (IH, m), 3.10 (2H, m), 3.70 (2H, m), 3.95 (2H, t), 4.41 (2H, m), 4.85 (IH, t), 6.87 (2H, d), 7.18 (2H, d), 7.67 (IH, d), 8.25 (IH, d); m/z = 408 [M+H]+.
Preparation of 2-(4-{ 1- [3-(trifluoromethyl) [ 1 ,2,4] triazolo [4,3-b] pyridazin-6- yl] piperidin-4-yl}phenoxy)ethyl methanesulfonate
A solution of methanesulfonyl chloride (20.37 mL, 262.16 mmol) in DCM (300 mL) was added to 2-(4- { 1 -[3-(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4- yl}phenoxy)ethanol (89 g, 218.46 mmol) and triethylamine (60.9 mL, 436.93 mmol) in DCM (900 mL) at 00C over a period of 30 minutes under nitrogen. The resulting solution was stirred at 00C for 1 hour. The reaction mixture was diluted with DCM (1 L), and washed with water (2 L). The organic layer was dried over MgSO4, filtered and evaporated to afford 2-(4- { 1 -[3-(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4- yl}phenoxy)ethyl methanesulfonate (104 g, 98%) as a solid.
IH NMR (399.9 MHz, DMSO-d6) δ 1.67 (2H, m), 1.89 (2H, m), 2.83 (IH, m), 3.11 (2H, m), 3.23 (3H, s), 4.23 (2H, t), 4.41 (2H, m), 4.52 (2H, t), 6.91 (2H, d), 7.21 (2H, d), 7.66 (IH, d), 8.24 (IH, d); m/z = 486 [M+H]+. Preparation of 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3- (trifluor omethyl) [ 1 ,2,4] triazolo [4,3-b] pyridazine DIPEA (107 mL, 613.00 mmol) was added to 2-(4-{l-[3-
(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (99 g, 204.33 mmol) and N-acetylpiperazine (28.8 g, 224.77 mmol) in DMA (500 mL). The resulting solution was stirred at 1100C for 1 hour. The reaction mixture was cooled to room temperature and the solvents were evaporated. The residue was dissolved in ethyl acetate (1 L) and the solution was washed with water (1 L). The aqueous was re-extracted with ethyl acetate (1 L) and the combined organics were washed with brine (1 L), dried over MgSO4, filtered and evaporated to give crude product. The aqueous layer was basifϊed to pH 12 with 2M NaOH, then extracted with ethyl acetate (1 L), washed with brine (IL), dried over MgSO4, filtered and evaporated to give further crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM then 5% MeOH in DCM. Pure fractions were evaporated to give 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3- (trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazine (81 g, 77%) as a solid. IH NMR (399.9 MHz, DMS0-d6) δ 1.59-1.73 (2H, m), 1.87 (2H, d), 1.99 (3H, s), 2.42 (2H, t), 2.71 (2H, t), 2.76-2.86 (IH, t), 3.08 (2H, t), 3.38-3.47 (4H, m), 4.08 (2H, t), 4.41 (2H, d), 6.88 (2H, d), 7.18 (2H, d), 7.62 (IH, d), 8.26 (IH, d); m/z = 518 [M+H]+.
Example 5.5
Alternative route for the preparation of 6-(4-{4-[2-(4-acetylpiperazin-l- vDethoxyl phenyllpiperidin- l-vD-3-f trifluoromethyl)-7.,8-(iihv(iro [ 1 ,2,41 triazolo [4,3- blpyridazine Form A
Methanol (375.0 mL) was added to 6-[4-[4-[2-(4-acetylpiperazin-l- yl)ethoxy]phenyl]piperidin-l-yl]-3-(trifluoromethyl)[ 1,2,4] triazolo[4,3-b]pyridazine (25.0 g, 48 m mol) in a 2.0 L autoclave reactor and to this was added 10% Pd/C (12.5 g, 50% w/w) paste at 22-25°C under nitrogen gas atmosphere. The reaction was performed under hydrogen pressure (5.0 bar) at 500C temperature for 10.0 h. The reaction mass was cooled to room temperature and the catalyst removed by filtration. Filtered cake was washed with methanol. The solvent was evaporated and the residue was azeotropically distilled by ethylacetate (2 x 125.0 mL) at 400C under reduced pressure to 3.0 rel vol (75.0 mL). Drop wise addition of tert-butylmethylether (MTBE, 375.0 mL) to the reaction mass resulted in solid material, which was collected by filtration and washed with MTBE (50.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 500C to afford the desired product 6-(4-{4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl}piperidin-l-yl)-3- (trifluoromethyl)-7,8-dihydro[l,2,4]triazolo [4,3-b]pyridazine (22.3 g, 88%) as a white color free flowing solid. The isolated material was confirmed by XRPD as Form A. IH NMR (400.13 MHz, CDC13): δ 1.62 (2H, m), 1.88 (2H, m), 2.02 (3H, s), 2.49 (4H, m), 2.65 – 2.78 (5H, m), 2.94 (2H, m), 3.15 (2H, t), 3.42 (2H, m), 3.57 (2H, m), 4.03 (2H, t), 4.24 (2H, m), 6.80 (2H, d), 7.06 (2H, d); m/z = 520 [M+H]+.
The 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3- (trifluoromethyl)[ 1,2,4] triazolo[4,3-b]pyridazine used as starting material was prepared as follows :-
Preparation of 4- { 1- [3-(trifluor omethyl) [1 ,2,4] triazolo [4,3-b] pyridazin-6-yl] piperidin- 4-yl}phenol: Dimethylacetamide (250.0 mL) was added to 6-chloro-3-(trifluoromethyl)- [l,2,4]triazolo[4,3-b]pyridazine [CAS: 40971-95-7] (50.0 g, 225 m mol) at 22-25°C in a suitable round bottom flask followed by 4-(piperidin-4-yl)phenol [CAS: 62614-84-0] (60.9 g, 236 m mol) at 22-25°C. The reaction mass was stirred to obtain a clear solution. Triethylamine (79.1 mL, 561 m mol) was slowly added to the reaction mass by drop wise addition over a period of 60 min at 25-300C. Temperature was raised to 400C and the reaction mass stirred for 1.0 h. After completion of reaction, water (500.0 mL) was added to the reaction mass by drop wise addition over a period of 30 min at 40-430C. The slurry mass was stirred for 30 min at 400C and then filtered under reduced pressure. The wet material was slurry washed using water (500.0 mL) for 30 min at 400C. The solid was collected by filtration and the material washed with water (125.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 500C to afford the desired product 4-{l-[3-(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (75.1 g, 89.9%) as a free flowing solid. IH NMR (400.13 MHz, DMSO-d6): δ 1.64 (2H, m), 1.87 (2H, m), 2.75 (IH, m), 3.09 (2H, m), 4.40 (2H, m), 6.69 (2H, d), 7.05 (2H, d), 7.65 (IH, d), 8.24 (IH, d), 9.15 (IH, s); m/z = 364 [M+H]+.
Preparation of 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3- (trifluor omethyl) [ 1 ,2,4] triazolo [4,3-b] pyridazine:
Dichloromethane (225.0 mL) and 4-{l-[3-(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin- 6-yl]piperidin-4-yl} phenol (50.0 g, 138 m mol) were charged to a suitable round bottom flask at 22-25°C. Triphenylphosphine (72.2 g, 275 m mol) and l-[4-(2-hydroxy- ethyl)piperazin-l-yl]ethanone [CAS: 83502-55-0] (47.4 g, 275 m mol) were added successively to the reaction mass and stirred for 10 min at 22-25°C. Di-isopropyl azodicarboxylate (55.65 g, 275 m mol) in dichloromethane (75.0 mL) was added to the reaction mass slowly drop wise at 25-300C over a period of 60-90 min. The resulting reaction mass was stirred for 1.0 h at 25-300C to complete the reaction. n-Heptane (600.0 mL) was introduced to the reaction mass by drop wise addition over a period of 15-30 min at 22-25°C and stirred for 30 min at the same temperature. Thus precipitated solid was filtered and washed with n-heptane (150.0 mL). The material was then suck dried for 30 min under reduced pressure. The crude material was purified by slurry washing in methanol (325.0 mL) at 22-25°C. The solid was then collected by filtration and washed with methanol (50.0 mL). The material was dired under reduced pressure with nitrogen gas bleed at 500C to afford the desired product 6-[4-[4-[2-(4-acetylpiperazin-l- yl)ethoxy]phenyl]piperidin- 1 -yl]-3-(trifluoromethyl)[ 1 ,2,4] triazolo[4,3-b]pyridazine (61.2 g, 84%) as a free flowing solid.
IH NMR (400.13 MHz, DMSO-d6): δ 1.59-1.73 (2H, m), 1.87 (2H, d), 1.99 (3H, s), 2.42 (2H, t), 2.71 (2H, t), 2.76-2.86 (IH, t), 3.08 (2H, t), 3.38-3.47 (4H, m), 4.08 (2H, t), 4.41 (2H, d), 6.88 (2H, d), 7.18 (2H, d), 7.62 (IH, d), 8.26 (IH, d); m/z = 518 [M+H]+.
Example 5.8
Preparation of 6-(4-{4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl}piperidin-l-yl)-3-(trifluor omethyl)-7,8-dihydr 0 [1 ,2,4] triazolo [4,3-b] pyridazine maleate
A clear solution of maleic acid (0.445 g, 3.84 m mol) in methanol (1.0 mL) was added to a clear solution of 6-(4-{4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl}piperidin-l-yl)-3- (trifluoromethyl)-7,8-dihydro[l,2,4]triazolo[4,3-b]pyridazine, obtained as described in Example 5.5, (2.0 g, 3.84 m mol) in methanol (2.0 mL) at 22-25°C and the resulting clear solution heated to 500C for 30 min. The reaction mass was cooled to 22-25°C and ethylacetate (16.0 mL) added drop wise to the reaction mass at 22-25°C. The reaction mass was then stirred for 60 min at 22-25°C. The resulting white color material was collected by filtration and washed with ethylacetate (5.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 500C to afford the desired product 6-(4- {4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl}piperidin-l-yl)-3-(trifluoromethyl)-7,8- dihydro[l,2,4]triazolo[4,3-b]pyridazine maleate (2.21 g, 90.0%) as free flowing white color material.
IH NMR (400.13 MHz, DMSO-d6): δ 1.62 (2H, m), 1.77 (2H, m), 2.02 (3H, s), 2.75 (IH, m), 2.77 (2H, m), 2.80 (2H, m), 2.95 (4H, m), 3.16 (2H, t), 3.36 (6H, m), 4.22 (4H, m), 6.08 (2H, s), 6.91 (2H, d), 7.17 (2H, d).
PAPER
Bioorg Med Chem Lett. 2013 Apr 1;23(7):1945-8
Volume 23, Issue 7, 1 April 2013, Pages 1945–1948
Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
http://www.sciencedirect.com/science/article/pii/S0960894X13002321
SYNTHESIS
AZD 3514
6-(4-{4-[2-(4-Acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine AZD 3514
1: Bradbury RH, Acton DG, Broadbent NL, Brooks AN, Carr GR, Hatter G, Hayter BR, Hill KJ, Howe NJ, Jones RD, Jude D, Lamont SG, Loddick SA, McFarland HL, Parveen Z, Rabow AA, Sharma-Singh G, Stratton NC, Thomason AG, Trueman D, Walker GE, Wells SL, Wilson J, Wood JM. Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer. Bioorg Med Chem Lett. 2013 Apr 1;23(7):1945-8. doi: 10.1016/j.bmcl.2013.02.056. Epub 2013 Feb 21. PubMed PMID: 23466225.
Some pics, Team at Astrazeneca , Bangalore, INDIA
Associate Research Scientist II at AstraZeneca India Pvt Ltd
Associate Research Scientist at AstraZeneca
Route Scouting, Process Design, Technology Transfer, Trouble shooting, QbD, Green Chemistry
///////////////AZD 3514 MALEATE, AZD 3514 , AZD-3514, Prostate cancer, Androgen receptor downregulator, AZD3514, 1240299-33-5
Lobeglitazone Sulfate, CKD-501, IDR-105
(Duvie®)Approved KOREA
Chong Kun Dang (Originator)
Adjunct to diet and exercise to improve glycemic control in adults with type 2 Diabetes mellitus
A dual PPARα and PPARγ agonist used to treat type 2 diabetes.
Trade Name：Duvie®MOA：Dual PPARα and PPARγ agonistIndication：Type 2 diabetes
CAS No. 607723-33-1(FREE)
CAS 763108-62-9(Lobeglitazone Sulfate)
2,4-Thiazolidinedione, 5-((4-(2-((6-(4-methoxyphenoxy)-4- pyrimidinyl)methylamino)ethoxy)phenyl)methyl)-, sulfate (1:1);
Lobeglitazone (trade name Duvie, Chong Kun Dang) is an antidiabetic drug in the thiazolidinedione class of drugs. As an agonistfor both PPARα and PPARγ, it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin.[3]
Chong Kun Dang
Lobeglitazone sulfate was approved by the Ministry of Food and Drug Safety (Korea) on July 4, 2013. It was developed and marketed as Duvie® by Chong Kun Dang Corporation.
Lobeglitazone is an agonist for both PPARα and PPARγ, and it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.
Duvie® is available as tablet for oral use, containing 0.5 mg of free Lobeglitazone. The recommended dose is 0.5 mg once daily.
Lobeglitazone which was reported in our previous works belongs to the class of potent PPARα/γ dual agonists (PPARα EC50: 0.02 μM, PPARγ EC50: 0.018 μM, rosiglitazone; PPARα EC50: >10 μM, PPARγ EC50: 0.02 μM, pioglitazone PPARα EC50: >10 μM, PPARγ EC50: 0.30 μM). Lobeglitazone has excellent pharmacokinetic properties and was shown to have more efficacious in vivo effects in KKAy mice than rosiglitazone and pioglitazone.17 Due to its outstanding pharmacokinetic profile, lobeglitazone was chosen as a promising antidiabetes drug candidate.
Lobeglitazone is used to assist regulation of blood glucose level of diabetes mellitus type 2 patients. It can be used alone or in combination with metformin.[4]
Lobeglitazone was approved by the Ministry of Food and Drug Safety (Korea) in 2013, and the postmarketing surveillance is on progress until 2019.[4][5]
SYNTHESIS
Chong Kun Dang’s Modcol Flu Dry Syrup is released in four different versions: All-Day, Night, Nose and Cough. [CHONG KUN DANG]
PAPER
Org. Process Res. Dev. 2007, 11, 190-199.
http://pubs.acs.org/doi/abs/10.1021/op060087u
A scaleable synthetic route to the potent PPARα/γ dual agonistic agent, lobeglitazone (1), used for the treatment of type-2 diabetes was developed. The synthetic pathway comprises an effective five-step synthesis. This process involves a consecutive synthesis of the intermediate, pyrimidinyl aminoalcohol (6), from the commercially available 4,6-dichloropyrimidine (3) without the isolation of pyrimidinyl phenoxy ether (4). Significant improvements were also made in the regioselective 1,4-reduction of the intermediate, benzylidene-2,4-thiazolidinedione (10), using Hantzsch dihydropyridine ester (HEH) with silica gel as an acid catalyst. The sulfate salt form of lobeglitazone was selected as a candidate compound for further preclinical and clinical study. More than 2 kg of lobeglitazone sulfate (CKD-501, 2) was prepared in 98.5% purity after the GMP batch. Overall yield of 2 was improved to 52% from 17% of the original medicinal chemistry route.
Silica gel TLC Rf = 0.35 (detection: iodine char chamber, ninhydrin solution, developing solvents: CH2Cl2/MeOH, 20:1); mp 111.4 °C; IR (KBr) ν 3437, 3037, 2937, 2775, 1751, 1698, 1648, 1610, 1503, 1439, 1301, 1246, 1215, 1183 cm-1;
1H NMR (400 MHz, CDCl3) δ 3.09 (m, 4H), 3.29 (m, 1H), 3.76 (s, 3H), 3.97 (m, 2H), 4.14 (m, 2H), 4.86 (m, 1H), 6.06 (bs, 1H), 6.86 (m, 2H), 7.00 (m, 2H), 7.13 (m, 4H), 8.30 (s, 1H), 11.99 (s, NH);
13C NMR (100 MHz, CDCl3) δ 37.1, 38.2, 53.7, 53.8, 56.3, 62.2, 65.8, 86.0, 115.1, 116.0, 123.0, 129.8, 131.2, 145.7, 153.4, 157.9, 158.1, 161.1, 166.5, 172.4, 172.5, 176.3, 176.5;
MS (ESI)m/z (M + 1) 481.5; Anal. Calcd for C24H26N4O9S2: C, 49.82; H, 4.53; N, 9.68; S, 11.08. Found: C, 49.85; H, 4.57; N, 9.75; S, 11.15.
PATENT
Clip
Lobeglitazone sulfate (Duvie) Lobeglitazone sulfate, an oral peroxisome proliferator-activated receptor (PPARa/c) dual agonist with IC50 = 20 and 18 nM respectively, was developed by Chong Kun Dang Pharmaceutical in Korea for the treatment of diabetes.135 This drug is differentiated from two other PPAR agonists available—pioglitazone and rosiglitazone —which lack PPARa activity.135 The most likely processscale preparation of lobeglitazone sulfate follows the route described in a process communication from Chong Kun Dang Pharmaceutical.136
Commercially available 4,6-dichloropyrimidine (152) was treated with a stoichiometric equivalent of p-methoxyphenol (153) in the presence of KF in warm DMF (Scheme 24). Upon completion of this reaction, 2-methylaminoethanol was added to the mixture to provide pyrimidine 154 in high yield.137
Next, alcohol 154 underwent a substitution reaction with p-fluorobenzaldehyde (155) under basic conditions to provide alkoxy benzaldehyde 156 which was converted to the benzylidene thiazolidindione 158 upon subjection to Knoevenagel conditions with 2,4-thiazolidinedione (157) in 90% yield.
Finally, reduction of olefin 158 was facilitated by treatment with the Hantzsch ester (159) in the presence of silica gel followed by treatment with methanolic sulfuric acid (96%) at low temperature to ultimately furnish lobeglitazone sulfate in 90% yield.
135. Jin, S. M.; Park, C. Y.; Cho, Y. M.; Ku, B. J.; Ahn, C. W.; Cha, B.-S.; Min, K. W.;Sung, Y. A.; Baik, S. H.; Lee, K. W.; Yoon, K.-H.; Lee, M.-K.; Park, S. W. Diab.Obes. Metab. 2015, 17, 599.
136. Lee, H. W.; Ahn, J. B.; Kang, S. K.; Ahn, S. K.; Ha, D.-C. Org. Process Res. Dev.2007, 11, 190.
137. Lee, H. W.; Kim, B. Y.; Ahn, J. B.; Kang, S. K.; Lee, J. H.; Shin, J. S.; Ahn, S. K.; Lee,S. J.; Yoon, S. S. Eur. J. Med. Chem. 2005, 40, 862.
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
5-[(4-[2-([6-(4-Methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl)methyl]-1,3-thiazolidine-2,4-dione
|
|
| Clinical data | |
| Trade names | Duvie |
| Routes of administration |
Oral |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Protein binding | >99%[1] |
| Metabolism | liver (CYP2C9, 2C19, and 1A2)[1] |
| Biological half-life | 7.8–9.8 hours[2] |
| Identifiers | |
| CAS Number | 607723-33-1 |
| PubChem | CID 9826451 |
| DrugBank | DB09198 |
| ChemSpider | 8002194 |
| Synonyms | CKD-501 |
| Chemical data | |
| Formula | C24H24N4O5S |
| Molar mass | 480.53616 g/mol |
Identifications:
| 1H NMR (Estimated) for Lobeglitazone |
Experimental: 1H NMR (400 MHz, CDCl3) δ 3.12 (m, 4H), 3.45 (m, 1H), 3.83 (s, 3H), 4.00 (m, 2H), 4.16 (m, 2H), 4.50 (m, 1H), 5.84 (bs, 1H), 6.83 (m, 2H), 7.06 (m, 2H), 7.15 (m, 2H), 8.31 (s, 1H), 8.89 (bs, NH).
///Lobeglitazone Sulfate, CKD-501, Duvie®, Approved KOREA, Chong Kun Dang, A dual PPARα and PPARγ agonist , type 2 diabetes, CKD 501, 763108-62-9, 607723-33-1, IDR-105
CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC.OS(=O)(=O)O
TOFOGLIFLOZIN
托格列净
CSG-452, R-7201, RG-7201
903565-83-3 (anhydrous)
(1S,3′R,4′S,5′S,6′R)-6-(4-Ethylbenzyl)-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′-pyran]-3′,4′,5′-triol hydrate (1:1)
THERAPEUTIC CLAIM Treatment of diabetes mellitus
CHEMICAL NAMES
1. Spiro[isobenzofuran-1(3H),2′-[2H]pyran]-3′,4′,5′-triol, 6-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-6′-(hydroxymethyl)-, hydrate (1:1), (1S,3’R,4’S,5’S,6’R)-
2. (1S,3’R,4’S,5’S,6’R)-6-[(4-ethylphenyl)methyl]-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′-pyran]-3′,4′,5′-triol monohydrate
3. (1S,3’R,4’S,5’S,6’R)-6-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-6′-(hydroxymethyl)-
spiro[isobenzofuran-1(3H),2′-[2H]pyran]-3′,4′,5′-triol monohydrate
(3S,3’R,4’S,5’S,6’R)-5-[(4-ethylphenyl)methyl]-6′-(hydroxymethyl)spiro[1H-2-benzofuran-3,2′-oxane]-3′,4′,5′-triol;hydrate
MW404.5, MF C22H26O6
INNOVATOR Chugai Pharmaceuticals
Sanofi, kowa
Deberza®………..KOWA/Apleway®……………SANOFI
CODE DESIGNATION CSG 452
Tofogliflozin (USAN, codenamed CSG452) is an experimental drug for the treatment of diabetes mellitus and is being developed byChugai Pharma in collaboration with Kowa and Sanofi.[1] It is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. As of September 2012, the drug is in Phase III clinical trials.[2][3]
Tofogliflozin is an SGLT-2 inhibitor first launched in 2014 in Japan by Sanofi and Kowa for the oral treatment of type II diabetes.
The product was discovered by Chugai and was licensed to Roche in 2007. In 2011, this license agreement was terminated. In 2012, the product was licensed to Kowa and Sanofi by Chugai Pharmaceutical in Japan for the treatment of diabetes type 2. In 2015, the license between Kowa and Chugai was expanded for developments and marketing of the agent in the U.S. and the E.U.
The active moiety or anhydrous form (ChemSpider ID: 28530778, CHEMBL2110731) has the chemical formula C22H26O6 and amolecular mass of 386.44 g/mol.
The United States Adopted Name tofogliflozin applies to the monohydrate, which is the form used as a drug.[4] The International Nonproprietary Name tofogliflozin applies to the anhydrous compound[5] and the drug form is referred to as tofogliflozin hydrate.
Several drugs are available for the treatment of type 2 diabetes mellitus (T2DM), but few patients achieve and maintain glycaemic control without weight gain and hypoglycaemias. Sodium glucose co-transporter 2 (SGLT-2) inhibitors are an emerging class of drugs with an original mechanism of action involving inhibition of renal glucose reabsorption. Two agents of this class, dapagliflozin and canagliflozin, have already been approved, although we need more data on cardiovascular outcomes along with bladder and breast cancer. Tofogliflozin is a further SGLT-2 inhibitor, which exhibits the highest selectivity for SGLT-2, the most potent antidiabetic action and a reduced risk of hypoglycaemia. Recently, a 52-week, multicentre, open-label, randomised controlled trial in Japanese T2DM patients has shown that tofogliflozin exhibits adequate safety and efficacy as monotherapy or as add-on treatment in patients suboptimally controlled with oral agents. Despite the very promising characteristics of this new drug, important questions remain to be answered, mainly additional data on safety outcomes and potential beneficial effects of tofogliflozin, for instance in prediabetes and diabetic nephropathy. Moreover, it would be welcome to examine the utility of its therapeutic use in combination with insulin and metformin.
Tofogliflozin has recently demonstrated safety and efficacy as monotherapy or add-on treatment . This is very important, granted our expectations of SGLT-2 inhibitors as useful alternative oral hypoglycaemic agents. Although important questions remain to be answered, the results of the new trial add to the importance of SGLT-2 inhibitors as a useful new class of oral hypoglycaemic agents.
CLIP
There are two scalable synthetic routes reported to prepare tofogliflozin.2 An efficient production synthesis of tofogliflozin hydrate from alcohol 2 was first described by Murakata et al. (Scheme 1, route 1).2a In 2016, Ohtake et al. reported an improved synthetic route, which achieved in just 7 linear steps (Scheme 1, route 2).2b They selected the optimal protecting groups for the purpose of chemoselective activation and crystalline purification, and obtained the pure tofogliflozin in a good overall yield. However, these methods suffer from several drawbacks. Firstly, some reagents, such as BH3 (Scheme 1, route 2) and 2-Methoxyproene (3, Scheme 1), are toxic or highly volatile. Meanwhile, the use of Palladium reagents may lead to an excess of residual heavy metal in the final product. Secondly, manufacturing costs in these methods are high due to the application of expensive raw materials and reagents. Last but not least, the key tactical stages that involve Br/Li exchange of aryl bromide followed by addition to gluconolactone 5 need the cryogenic conditions (< -60 oC), and this method is not suitable for industrial production. Herein, we report a newly developed synthetic method for tofogliflozin hydrate starting from readily available raw materials and affording good overall yield.
SCHEME 2 FOR
2. (a) Murakata, M.; Ikeda, T.; Kimura, N.; Kawase, A.; Nagase, M.; Yamamoto, K.; Takata, N.; Yoshizaki, S.; Takano, K. Crystal of spiroketal derivative, and process for production thereof. European Appl. EP 2308886 A1, April 13, 2011. (b) Ohtake, Y.; Emura, T.; Nishimoto, M.; Takano, K.; Yamamoto, K.; Tsuchiya, S.; Yeu, S.; Kito, Y.; Kimura, N.; Takeda, S.; Tsukazaki, M.; Murakata, M.; Sato, T. J. Org. Chem. 2016, 81, 2148.
CLIP
Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.-H.; Ahn, K.-H.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55, 7828−7840
DOI: 10.1021/acs.joc.5b02734 J. Org. Chem. 2016, 81, 2148−2153
(1S,3′R,4′S,5′S,6′R)-6-[(4-Ethylphenyl)methyl]-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′- pyran]-3′,4′,5′-triol (1, tofogliflozin).
To a solution of 17b (89.9 g, 145 mmol) in DME (653 mL) and MeOH (73.0 mL), 2 N NaOH aq. solution (726 mL, 1.45 mol) was added dropwise for 1 h at waterbath temperature. After stirring at rt for 1 h, 2 N H2SO4 aq. solution (436 mL) was added slowly to the mixture. Water (700 mL) was added to the mixture, and the resultant mixture was extracted with AcOEt (500 mL × 2). The resultant organic layer was washed with brine (1.00 L) and then dried over anhydrous Na2SO4 (250 g). The mixture was concentrated in vacuo to obtain 1 (57.3 g, quant) as a colorless amorphous solid;
[α]D 26 +24.2° (c 1.02, MeOH);
1 H NMR (400 MHz, CD3OD) δ: 1.19 (3H, t, J = 7.6 Hz), 2.58 (2H, q, J = 7.6 Hz), 3.42−3.47 (1H, m), 3.63−3.67 (1H, m), 3.75−3.88 (4H, m), 3.95 (2H, s), 5.06 (1H, d, J = 12.5 Hz), 5.12 (1H, d, J = 12.5 Hz), 7.07−7.14 (4H, m), 7.17−7.23 (3H, m);
13C NMR (100 MHz, CD3OD) δ: 16.3, 29.4, 42.3, 62.8, 71.9, 73.4, 74.9, 76.2, 76.4, 111.6, 121.8, 123.6, 128.9, 129.9, 131.1, 139.7, 139.9, 140.2, 142.6, 143.2;
MS (ESI) m/z: 387 [M + H]+ ; HRMS (ESI) calcd for C22H27O6 [M + H]+ 387.1802, found 387.1801
DOI: 10.1021/acs.joc.5b02734 J. Org. Chem. 2016, 81, 2148−2153
Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.-H.; Ahn, K.-H.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55, 7828−7840
SGLT2 inhibitors inhibitors represent a novel class of agents that are being developed for the treatment or improvement in glycemic control in patients with type 2 diabetes. Glucopyranosyl-substituted benzene derivative are described in the prior art as SGLT2 inhibitors, for example in
WO 01/27128, WO 03/099836, WO 2005/092877, WO 2006/034489,
WO 2006/064033, WO 2006/117359, WO 2006/117360,
WO 2007/025943, WO 2007/028814, WO 2007/031548,
WO 2007/093610, WO 2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940.
PATENTS
Papers
Chinese Chemical Letters, 2013 , vol. 24, 2 pg. 131 – 133
Journal of Medicinal Chemistry, 2012 , vol. 55, 17 pg. 7828 – 7840
NMR
1 H-NMR (CD 3 OD) δ: 1.19 (3H, t, J = 7.5Hz), 2.59 (2H, q, J = 7.5Hz) ,3.42-3 .46 (1H , m), 3.65 (1H, dd, J = 5.5,12.0 Hz) ,3.74-3 .82 (4H, m), 3.96 (2H, s), 5.07 (1H , d, J = 12.8Hz), 5.13 (1H, d, J = 12.8Hz) ,7.08-7 .12 (4H, m) ,7.18-7 .23 (3H, m) .
MS (ESI +): 387 [M +1] +.
Second set
http://pubs.acs.org/doi/full/10.1021/jm300884k
J. Med. Chem., 2012, 55 (17), pp 7828–7840
1H NMR (400 MHz, CD3OD) δ: 1.20 (3H, t, J = 7.6 Hz), 2.58 (2H, q, J = 7.6 Hz), 3.42–3.47 (1H, m), 3.63–3.67 (1H, m), 3.75–3.88 (4H, m), 3.95 (2H, s), 5.06 (1H, d, J = 12.3 Hz), 5.12 (1H, d, J = 12.5 Hz), 7.07–7.14 (4H, m), 7.17–7.23 (3H, m).
13C NMR (100 MHz, CD3OD) δ: 16.3, 29.4, 42.3, 62.8, 71.9, 73.4, 74.9, 76.2, 76.4, 111.6, 121.8, 123.6, 128.9, 129.9, 131.1, 139.7, 139.9, 140.2, 142.6, 143.2.
MS (ESI): 387 [M + H]+. HRMS (ESI), m/z calcd for C22H27O6 [M + H]+ 387.1802, found 387.1801.
THIRD SET
(1S,3′R,4′S,5′S,6′R)-6-[(4-Ethylphenyl)methyl]-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′- pyran]-3′,4′,5′-triol (1, tofogliflozin).
To a solution of 17b (89.9 g, 145 mmol) in DME (653 mL) and MeOH (73.0 mL), 2 N NaOH aq. solution (726 mL, 1.45 mol) was added dropwise for 1 h at waterbath temperature. After stirring at rt for 1 h, 2 N H2SO4 aq. solution (436 mL) was added slowly to the mixture. Water (700 mL) was added to the mixture, and the resultant mixture was extracted with AcOEt (500 mL × 2). The resultant organic layer was washed with brine (1.00 L) and then dried over anhydrous Na2SO4 (250 g). The mixture was concentrated in vacuo to obtain 1 (57.3 g, quant) as a colorless amorphous solid;
[α]D 26 +24.2° (c 1.02, MeOH);
1 H NMR (400 MHz, CD3OD) δ: 1.19 (3H, t, J = 7.6 Hz), 2.58 (2H, q, J = 7.6 Hz), 3.42−3.47 (1H, m), 3.63−3.67 (1H, m), 3.75−3.88 (4H, m), 3.95 (2H, s), 5.06 (1H, d, J = 12.5 Hz), 5.12 (1H, d, J = 12.5 Hz), 7.07−7.14 (4H, m), 7.17−7.23 (3H, m);
13C NMR (100 MHz, CD3OD) δ: 16.3, 29.4, 42.3, 62.8, 71.9, 73.4, 74.9, 76.2, 76.4, 111.6, 121.8, 123.6, 128.9, 129.9, 131.1, 139.7, 139.9, 140.2, 142.6, 143.2;
MS (ESI) m/z: 387 [M + H]+ ; HRMS (ESI) calcd for C22H27O6 [M + H]+ 387.1802, found 387.1801
DOI: 10.1021/acs.joc.5b02734 J. Org. Chem. 2016, 81, 2148−2153
Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.-H.; Ahn, K.-H.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55, 7828−7840
PATENT
Prepn
[Example 1] (1S, 3’R, 4’S, 5’S, 6’R) -6 – [(4 – ethyl-phenyl) methyl] -3 ‘, 4’, 5 ‘, 6′-tetrahydro- -6′-(hydroxymethyl) – spiro [isobenzofuran -1 (3H), 2’-[2H] pyran] -3 ‘, 4′, one of the preparation step [compound of formula (IX)] 5’-triol Preparation of methanol (2 – hydroxymethyl-phenyl – bromo-4)
To the mixing solution (1mol / L, 78.9kg, 88.4mol) of borane-tetrahydrofuran complex in tetrahydrofuran (6.34kg, 61.0mol) and, trimethoxyborane, two tetrahydrofuran (33.1kg) in – bromoterephthalic was added at below 30 ℃ solution (7.5kg, 30.6mol) of the acid, and the mixture was stirred for 1 hour at 25 ℃. Then cooled to 19 ℃ The reaction mixture was stirred for 30 minutes and added a mixed solution of tetrahydrofuran and methanol (3.0kg) of (5.6kg). In addition to methanol (15.0kg) in the mixture was kept for a while.
Again, to the mixing solution (1mol / L, 78.9kg, 88.4mol) of borane-tetrahydrofuran complex in tetrahydrofuran (6.34kg, 61.0mol) and, trimethoxyborane, two tetrahydrofuran (33.0kg) in – was added at below 30 ℃ solution (7.5kg, 30.6mol) of bromo terephthalic acid, and the reaction was carried out for 1 hour at 25 ℃. Then cooled to 18 ℃ The reaction mixture was stirred for 30 minutes and added a mixed solution of tetrahydrofuran and methanol (3.0kg) of (5.6kg). After addition of methanol (15.0kg) in the mixture is combined with the reaction mixture obtained in the previous reaction, and then the solvent was distilled off under reduced pressure. After addition of methanol (36kg) residue was obtained, and the solvent was evaporated under reduced pressure. Furthermore, (54 ℃ dissolved upon confirmation) which was dissolved by warming was added to methanol (36kg) to the residue. After cooling to room temperature the solution was stirred for 30 minutes added water (60kg). After addition of water (165kg) In addition to this mixture was cooled to 0 ℃, and the mixture was stirred for one hour. Centrifuge the obtained crystals were washed twice with water (45kg), and dried for 2 hours under reduced pressure to give (11.8kg, 54.4mol, 89% yield) of the title compound.
1 H-NMR (DMSO-d 6) δ: 4.49 (4H, t, J = 5.8Hz), 5.27 (1H, t, J = 5.8Hz), 5.38 (1H, t, J = 5.8Hz), 7.31 (1H, d, J = 7.5Hz), 7.47 (1H, d, J = 7.5Hz), 7.50 (1H, s).
Preparation of benzene (ethoxy methyl – methyl – – methoxy-1 1) – bromo-1 ,4 – 2:2 process bis
(- Bromo-4 – 2-hydroxyethyl methyl phenyl) in tetrahydrofuran (57kg) in the solution (8.0kg, 36.9mol) of methanol, I added (185.12g, 0.74mol) of pyridinium p-toluenesulfonate. After cooling to -15 ℃ below the mixture, 2 – was added at -15 ℃ or less (7.70kg, 106.8mol) methoxy propene, and the mixture was stirred 1 h at -15 ~ 0 ℃. Was added aqueous potassium carbonate (25 wt%, 40kg) and the reaction mixture was warmed to room temperature and separate the organic layer was added toluene (35kg). After washing with water (40kg) The organic layer was evaporated under reduced pressure. Was dissolved in toluene (28kg) and the residue obtained was obtained as a toluene solution of the title compound.
1 H-NMR (CDCl 3) δ: 1.42 (6H, s), 1.45 (6H, s), 3.24 (3H, s), 3.25 (3H, s), 4.45 ( 2H, s), 4.53 (2H, s), 7.28 (1H, dd, J = 1.5,8.0 Hz), 7.50 (1H, d, J = 8.0Hz), 7. 54 (1H, d, J = 1.5Hz).
MS (ESI +): 362 [M +2] +.
Preparation of on – (3R, 4S, 5R, 6R) -3,4,5 – tris (trimethylsilyloxy)-6 – trimethylsilyloxy methyl – tetrahydropyran-2: Step 3
Glucono -1,5 – – D-(+) in tetrahydrofuran (70kg) in the solution (35.8kg, 353.9mol) of N-methylmorpholine (7.88kg, 44.23mol) and lactone, chlorotrimethylsilane ( was added at 40 ℃ less 29.1kg, and 267.9mol), and the mixture was stirred for 2 hours at 30 ~ 40 ℃ resulting mixture. Was cooled to 0 ℃ the reaction mixture was added toluene (34kg) water (39kg), and the organic layer was separated. Twice sodium dihydrogen phosphate aqueous solution (5 wt%, 39.56kg) in, washed once with water (39kg) the organic layer the solvent was evaporated under reduced pressure. Was dissolved in toluene (34.6kg) and the residue obtained was obtained as a toluene solution of the title compound.
1 H-NMR (CDCl 3) δ: 0.13 (9H, s), 0.17 (9H, s), 0.18 (9H, s), 0.20 (9H, s), 3.74- 3.83 (3H, m), 3.90 (1H, t, J = 8.0Hz), 3.99 (1H, d, J = 8.0Hz), 4.17 (1H, dt, J = 2 .5,8.0 Hz).
Step 4: (1S, 3’R, 4’S, 5’S, 6’R) -3 ‘, 4’, 5 ‘, 6′-tetrahydro -6,6′ – bis (hydroxymethyl) – spiro [ (3H), 2’-[2H] pyran] -3 ‘, 4′, 5’-Preparation of triol isobenzofuran-1
(Methyl – – – methoxy 1-ethoxy-methyl) – bromo-1 ,4 – 2 prepared in step 2 bis cooled to below -10 ℃ toluene solution of benzene, hexane solution to (15 wt% n-butyl lithium , was added at below 0 ℃ 18.2kg, and 42.61mol), and the mixture was stirred 1.5 h at 5 ℃ resulting mixture. (10.5kg, 40.7mol), was added tetrahydrofuran (33.4kg) then magnesium bromide diethyl ether complex in the mixture, and the mixture was stirred for 1 hour at 25 ℃. Was added at below -10 ℃ toluene solution of the on – tris (trimethylsilyloxy) -6 – – 3,4,5 cooled to -15 ℃ below the mixture prepared in step 3 trimethylsilyloxy methyl – tetrahydropyran-2 was. After stirring 0.5 h at -15 ℃ or less, poured into 20% aqueous ammonium chloride solution to (80kg) of this solution, and the organic layer was separated. After washing with water (80kg) and the organic layer obtained, and the solvent was evaporated under reduced pressure. I was dissolved in methanol (43kg) residue was obtained. Was stirred for 1 hour at 20 ℃ was added (1.4kg, 7.4mol) and p-toluenesulfonic acid monohydrate in the mixture. Thereafter, it was stirred for another hour and cooled to 0 ℃, centrifuged crystals obtained was washed with methanol (25kg), and dried for 8 hours at reduced pressure under 40 ℃, (5.47kg, yield the title compound I got 50%) rate.
1 H-NMR (DMSO-d 6) δ :3.20-3 .25 (1H, m) ,3.41-3 .45 (1H, m) ,3.51-3 .62 (4H, m) , 4.39 (1H, t, J = 6.0Hz) ,4.52-4 .54 (3H, m), 4.86 (1H, d, J = 4.5Hz), 4.93 (1H, d, J = 5.5Hz), 4.99 (1H, d, J = 12.5Hz), 5.03 (1H, d, J = 12.5Hz), 5.23 (1H, t, J = 5 .8 Hz) ,7.24-7 .25 (2H, m), 7.29 (1H, dd, J = 1.5,8.0 Hz).
Step 5: (1S, 3’R, 4’S, 5’S, 6’R) -6 – [(methoxycarbonyl) methyl] -3 ‘, 4’, 5 ‘, 6′-tetrahydro-3’ , 4 ‘, 5′-tris (methoxycarbonyl) oxy-6′-[(methoxycarbonyl) methyl] – Preparation of [(3H), 2’-[2H] pyran isobenzofuran] spiro
(1S, 3’R, 4’S, 5’S, 6’R) – tetrahydro -6,6 ‘- bis (hydroxymethyl) – spiro [isobenzofuran -1 (3H), 2’-[2H] pyran ] -3 ‘, 4′, 5’-triol 4 (5.3kg, 17.8mol) and – dissolved in acetonitrile (35kg) (13.7kg, 112.1mol) a chloroformate, in the solution of dimethylaminopyridine I was added at 12 ℃ or less (10.01kg, 105.9mol) methyl. Heated to 20 ℃, After stirring for 1 h, was added ethyl acetate (40kg) and water (45kg), and the organic layer was separated and the mixture. Once (45.4kg) aqueous solution consisting of (9.01kg) sodium chloride and potassium hydrogen sulfate (1.35kg), sodium chloride aqueous solution (weight 10%, 44.5kg), sodium chloride aqueous solution (the organic layer was washed successively 20% by weight, in 45.0kg), and the solvent was evaporated under reduced pressure. Was dissolved in ethylene glycol dimethyl ether (18kg) and the residue obtained was then evaporated under reduced pressure. Was dissolved in ethylene glycol dimethyl ether (13.2kg) again and the residue obtained was obtained as ethylene glycol dimethyl ether solution of the title compound. I was used as it was in the six step.
1 H-NMR (CDCl 3) δ: 3.54 (3H, s), 3.77 (6H, s), 3.811 (3H, s), 3.812 (3H, s), 4.23 ( 1H, dd, J = 2.8,11.9 Hz), 4.32 (1H, dd, J = 4.0,11.9 Hz) ,4.36-4 .40 (1H, m), 5.11 -5.24 (5H, m), 5.41 (1H, d, J = 9.8Hz), 5.51 (1H, t, J = 9.8Hz), 7.25 (1H, d, J = 7.5Hz), 7.42 (1H, d, J = 7.5Hz), 7.44 (1H, s).
MS (ESI +): 589 [M +1] +, 606 [M +18] +.
Step 6: (1S, 3’R, 4’S, 5’S, 6’R) -6 – [(4 – ethyl-phenyl) methyl] -3 ‘, 4’, 5 ‘, 6’-tetrahydro-3 ‘4’, 5′-tris (methoxycarbonyl) oxy-6′-[(methoxycarbonyl) methyl] – Preparation of [(3H), 2′-[2H] pyran isobenzofuran] spiro
[(Methoxycarbonyl) methyl] -3 ‘, 4’, 5 ‘, 6’-tetrahydro – (1S, 3’R, 4’S, 5’S, 6’R) -6 which had been prepared in Step 5 – 3 ‘, 4′, 5′-tris (methoxycarbonyl) oxy-6′-[(methoxycarbonyl) methyl] – spiro [isobenzofuran -1 (3H), 2’-[2H] pyran] Ethylene glycol dimethyl ether in solution, 2 – (2.46kg, 17.8mol), 4 butanol (25kg), anhydrous potassium carbonate – – methyl-2 were sequentially added (3.73kg, 24.9mol) ethyl phenyl boronic acid, in the reaction vessel was replaced with argon atmosphere, was bubbled with argon mixture. To the mixture – after the addition (0.72kg, 0.88mol) and palladium (II) chloride dichloromethane adduct [1,1 ‘-bis (diphenylphosphino) ferrocene], it was replaced with argon again inside of the vessel, one at 80 ℃ I was stirring time. After cooling, I added sequentially (0.859kg, 5.3mol) of ethylene glycol dimethyl ether (9.85kg), ethyl acetate (19kg), N-acetyl-L-cysteine in the mixture. After stirring for 2.5 h the mixture was filtered and added Celite (5.22kg), and washed with ethyl acetate (78kg) and the filter residue. The combined washings and filtrate, and the solvent is evaporated off under reduced pressure, and in addition (0.58kg, 3.6mol) and ethanol (74kg), N-acetyl-L-cysteine residue was obtained, which is heated to 70 ℃ or I was dissolved residue is then. After addition of water (9.4kg) in the solution, cooled to 60 ℃, and the mixture was stirred for 1 h. After confirming solid precipitated, cooled to 0 ℃ from 60 ℃ over 2.5 hours or more The mixture was stirred for 1 hour or more at 5 ℃ less. Centrifuge the resulting solid was washed twice with a mixture of water (35kg) and ethanol (55kg). Was dissolved at 70 ℃ ethanol (77kg) again, wet powder was obtained (10.21kg), cooled to 60 ℃ added water (9.7kg), and the mixture was stirred for 1 h. After confirming solid precipitated, cooled to 0 ℃ from 60 ℃ over 2.5 hours or more, and the mixture was stirred for 1 hour or more at 5 ℃ less. (9.45kg, dry powder rate 8.47kg, 13.7mol which was centrifuged obtained crystals were washed with a mixture of water (32kg) and ethanol (51kg), was obtained as a moist powder the title compound, 77% overall yield from the previous step).
1 H-NMR (CDCl 3) δ: 1.20 (3H, t, J = 7.5Hz), 2.60 (2H, q, J = 7.5Hz), 3.50 (3H, s), 3 .76 (3H, s), 3.77 (3H, s), 3.81 (3H, s), 3.96 (2H, s), 4.23 (1H, dd, J = 2.8,11 .9 Hz), 4.33 (1H, dd, J = 4.5,11.9 Hz) ,4.36-4 .40 (1H, m) ,5.11-5 .20 (3H, m), 5 .41 (1H, d, J = 10.0Hz), 5.51 (1H, t, J = 10.0Hz) ,7.07-7 .11 (4H, m), 7.14 (1H, d, J = 7.8Hz), 7.19 (1H, dd, J = 1.5,7.8 Hz), 7.31 (1H, d, J = 1.5Hz).
MS (ESI +): 619 [M +1] +, 636 [M +18] +.
Step 7: (1S, 3’R, 4’S, 5’S, 6’R) -6 – [(4 – ethyl-phenyl) methyl] -3 ‘, 4’, 5 ‘, 6’-tetrahydro-6 , 4 ‘, 5′-Preparation of triol’ – -3 [(3H), 2′-[2H] pyran isobenzofuran] spiro – (hydroxymethyl) ‘
(1S, 3’R, 4’S, 5’S, 6’R) -6 – [(4 – ethyl-phenyl) methyl] -3 ‘, 4’, 5 ‘, 6′-tetrahydro-3’, 4 ‘, 5′-tris (methoxycarbonyl) oxy-6′-[(methoxycarbonyl) methyl] – wet powder spiro [(3H), 2’-[2H] pyran isobenzofuran -1] (8.92kg, In addition at 20 ℃ (4mol / L, 30.02kg, the 104.2mol) aqueous solution of sodium hydroxide, 1 hour the reaction mixture to a solution of (28kg) ethylene glycol dimethyl ether dry end conversion 8.00kg, of 12.9mol) the mixture was stirred. And the organic layer was separated by addition of water (8.0kg) in the mixture. The ethyl acetate aqueous sodium chloride solution (25 wt%, 40kg) and a (36kg) in the organic layer and the aqueous layer was removed after washing. The washed again aqueous sodium chloride solution (25 wt%, 40kg) in the organic layer was evaporated under reduced pressure. Were added and acetone (32.0kg) water (0.8kg) residue was obtained. After the solvent was evaporated under reduced pressure, dissolved in acetone (11.7kg) in water (15.8kg) and the residue obtained was cooled to below 5 ℃. Was added below 10 ℃ water (64kg) to the mixture, and the mixture was stirred for 1 hour at below 10 ℃. Centrifuge the resulting crystals were washed with a mixture of water (8.0kg) and (1.3kg) acetone. For 8 hours through-flow drying 13 ~ 16 ℃ temperature ventilation, under the conditions of 24-33% relative humidity the wet powder, the monohydrate crystal (3.94kg, 9.7mol, 75% yield) of the title compound I was obtained as: (4.502 wt% water content).
Method of measuring the amount of water:
Analysis: coulometric KF titration analyzer: trace moisture measurement device manufactured by Mitsubishi Chemical Corporation Model KF-100
Anolyte: Aqua micron AX (manufactured by Mitsubishi Chemical Corporation)
Catholyte: Aqua micron CXU (manufactured by Mitsubishi Chemical Corporation)
1 H-NMR (CD 3 OD) δ: 1.19 (3H, t, J = 7.5Hz), 2.59 (2H, q, J = 7.5Hz) ,3.42-3 .46 (1H , m), 3.65 (1H, dd, J = 5.5,12.0 Hz) ,3.74-3 .82 (4H, m), 3.96 (2H, s), 5.07 (1H , d, J = 12.8Hz), 5.13 (1H, d, J = 12.8Hz) ,7.08-7 .12 (4H, m) ,7.18-7 .23 (3H, m) .
MS (ESI +): 387 [M +1] +.
PATENT
Example 1 Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose Step 1: Synthesis of 3,4,5-tris(trimethylsilyloxy)-6-trimethylsilyloxymethyl-tetrahydropyran-2-one
To a solution of D-(+)-glucono-1,5-lactone (7.88 kg) and N-methylmorpholine (35.8 kg) in tetrahydrofuran (70 kg) was added trimethylsilyl chloride (29.1 kg) at 40° C. or below, and then the mixture was stirred at a temperature from 30° C. to 40° C. for 2 hours. After the mixture was cooled to 0° C., toluene (34 kg) and water (39 kg) were added thereto. The organic layer was separated and washed with an aqueous solution of 5% sodium dihydrogen phosphate (39.56 kg×2) and water (39 kg×1). The solvent was evaporated under reduced pressure to give the titled compound as an oil. The product was used in the next step without further purification.
1H-NMR (CDCl3) δ: 0.13 (9H, s), 0.17 (9H, s), 0.18 (9H, s), 0.20 (9H, s), 3.74-3.83 (3H, m), 3.90 (1H, t, J=8.0 Hz), 3.99 (1H, d, J=8.0 Hz), 4.17 (1H, dt, J=2.5, 8.0 Hz).
Step 2: Synthesis of 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene
Under a nitrogen atmosphere, to a solution of 2,4-dibromobenzyl alcohol (40 g, 0.15 mol) in tetrahydrofuran (300 ml) was added 2-methoxypropene (144 ml, 1.5 mol) at room temperature, and then the mixture was cooled to 0° C. At the same temperature, pyridinium p-toluenesulfonic acid (75 mg, 0.30 mmol) was added and the mixture was stirred for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate cooled to 0° C., and extracted with toluene. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the titled compound as an oil in quantitative yield. The product was used in the next step without further purification.
1H-NMR (CDCl3) δ: 1.44 (6H, s), 3.22 (3H, 4.48 (2H, s), 7.42 (1H, d, J=8.0 Hz), 7.44 (1H, dd, J=1.5, 8.0 Hz), 7.68 (1H, d, J=1.5 Hz).
Step 3: Synthesis of 2,3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-(4-ethylphenyl)hydroxymethyl-2-(1-methoxy-1-methylethoxymethyl)phenyl)tetrahydropyran
Under a nitrogen atmosphere, 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene (70 g, 207 mmol), which was obtained in the previous step, was dissolved in toluene (700 mL) and t-butylmethyl ether (70 ml), and n-butyllithium in hexane (1.65 M, 138 ml, 227 mmol) was added dropwise at 0° C. over 30 minutes. After the mixture was stirred for 1.5 hours at 0° C., the mixture was added dropwise to a solution of 3,4,5-tris(trimethylsilyloxy)-6-trimethylsilyloxymethyl-tetrahydropyran-2-one (Example 1, 108 g, 217 mol) in tetrahydrofuran (507 ml) at −78° C., and the reaction mixture was stirred for 2 hours at the same temperature. Triethylamine (5.8 ml, 41 mmol) and trimethylsilyl chloride (29.6 ml, 232 mmol) were added thereto, and the mixture was warmed to 0° C. and stirred for 1 hour to give a solution containing 2,3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-bromo-2-(1-methoxy-1-methylethoxymethyl)phenyl)tetrahydropyran.
The resulting solution was cooled to −78° C., and n-butyllithium in hexane (1.65 M, 263 ml, 434 mmol) was added dropwise thereto at the same temperature. After the mixture was stirred at −78° C. for 30 minutes, 4-ethylbenzaldehyde (62 ml, 455 mmol) was added dropwise at −78° C., and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the organic layer was separated, and washed with water. The solvent was evaporated under reduced pressure to give a product containing the titled compound as an oil (238 g). The product was used in the next step without further purification.
A portion of the oil was purified by HPLC (column: Inertsil ODS-3, 20 mm I.D.×250 mm; acetonitrile, 30 mL/min) to give four diastereomers of the titled compound (two mixtures each containing two diastereomers).
Mixture of Diastereomers 1 and 2:
1H-NMR (500 MHz, CDCl3) δ: −0.47 (4.8H, s), −0.40 (4.2H, s), −0.003-0.004 (5H, m), 0.07-0.08 (1314, m), 0.15-0.17 (18H, m), 1.200 and 1.202 (3H, each t, J=8.0 Hz), 1.393 and 1.399 (3H, each s), 1.44 (3H, s), 2.61 (2H, q, J=8.0 Hz), 3.221 and 3.223 (3H, each s), 3.43 (1H, t, J=8.5 Hz), 3.54 (1H, dd, J=8.5, 3.0 Hz), 3.61-3.66 (1H, m), 3.80-3.85 (3H, m), 4.56 and 4.58 (1H, each d, J=12.4 Hz), 4.92 and 4.93 (1H, each d, J=12.4 Hz), 5.80 and 5.82 (1H, each d, J=3.0 Hz), 7.14 (2H, d, J=8.0 Hz), 7.28-7.35 (3H, m), 7.50-7.57 (2H, m).
MS (ESI+): 875 [M+Na]+.
Mixture of Diastereomers 3 and 4:
1H-NMR (500 MHz, toluene-d8, 80° C.) δ: −0.25 (4H, s), −0.22 (5H, s), 0.13 (5H, s), 0.16 (4H, s), 0.211 and 0.214 (9H, each s), 0.25 (9H, s), 0.29 (9H, s), 1.21 (3H, t, J=7.5 Hz), 1.43 (3H, s), 1.45 (3H, s), 2.49 (2H, q, J=7.5 Hz), 3.192 and 3.194 (3H, each s), 3.91-4.04 (4H, m), 4.33-4.39 (2H, m), 4.93 (1H, d, J=14.5 Hz), 5.10-5.17 (1H, m), 5.64 and 5.66 (1H, each s), 7.03 (2H, d, J=8.0 Hz), 7.28-7.35 (3H, m), 7.59-7.64 (1H, m), 7.87-7.89 (1H, m).
MS (ESI+): 875 [M+Na]+.
Step 4: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)hydroxymethyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose
Under a nitrogen atmosphere, the oil containing 2,3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-(4-ethylphenyl)hydroxymethyl-2-(1-methoxy-1-methylethoxymethyl)phenyl)tetrahydropyran (238 g), which was obtained in the previous step, was dissolved in acetonitrile (693 ml). Water (37 ml) and 1N HCl aq (2.0 ml) were added and the mixture was stirred at room temperature for 5.5 hours. Water (693 ml) and n-heptane (693 ml) were added to the reaction mixture and the aqueous layer was separated. The aqueous layer was washed with n-heptane (693 ml×2), and water was evaporated under reduced pressure to give a product containing water and the titled compound (a diastereomer mixture) as an oil (187 g). The product was used in the next step without further purification.
1H-NMR (500 MHz, CD3OD) δ: 1.200 (3H, t, J=7.7 Hz), 1.201 (3H, t, J=7.7 Hz), 2.61 (2H, q, J=7.7 Hz), 3.44-3.48 (1H, m), 3.63-3.68 (111, m), 3.76-3.84 (4H, m), 5.09 (1H, d, J=12.8 Hz), 5.15 (1H, d, J=12.8 Hz), 5.79 (1H, s), 7.15 (2H, d, J=7.7 Hz), 7.24 and 7.25 (1H, each d, J=8.4 Hz), 7.28 (2H, d, J=7.7 Hz), 7.36 (1H, dd, J=8.4, 1.5 Hz), 7.40-7.42 (114, m).
MS (ESI+): 425 [M+Na]+.
Step 5: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose (crude product)
To a solution of the oil containing 1,1-anhydro-1-C-[5-(4-ethylphenyl)hydroxymethyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose (187 g), which was obtained in the previous step, in 1,2-dimethoxyethane (693 ml) was added 5% Pd/C (26 g, 6.2 mmol, water content ratio: 53%), and the mixture was stirred in the atmosphere of hydrogen gas at room temperature for 4 hours. After filtration, the filtrate was evaporated under reduced pressure to give an oil containing the titled compound (59 g). The purity of the resulting product was 85.7%, which was calculated based on the area ratio measured by HPLC. The product was used in the next step without further purification.
1H-NMR (CD3OD) δ: 1.19 (3H, t, J=7.5 Hz), 2.59 (2H, q, J=7.5 Hz), 3.42-3.46 (1H, m), 3.65 (1H, dd, J=5.5, 12.0 Hz), 3.74-3.82 (4H, m), 3.96 (2H, s), 5.07 (1H, d, J=12.8 Hz), 5.13 (1H, d, J=12.8 Hz), 7.08-7.12 (4H, m), 7.18-7.23 (3H, m).
MS (ESI+): 387 [M+1]+.
Measurement Condition of HPLC:
Column: Cadenza CD-C18 50 mm P/NCD032
Mobile phase: Eluent A: H2O, Eluent B: MeCN
Gradient operation: Eluent B: 5% to 100% (6 min), 100% (2 min)
Flow rate: 1.0 mL/min
Temperature: 35.0° C.
Detection wavelength: 210 nm
Step 6: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-2,3,4,6-tetra-O-methoxycarbonyl-β-D-glucopyranose
Under a nitrogen atmosphere, to a solution of the oil containing 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose (59 g) and 4-(dimethylamino)pyridine (175 g, 1436 mmol) in acetonitrile (1040 ml) was added dropwose methyl chloroformate (95 ml, 1231 mmol) at 0° C. The mixture was allowed to warm to room temperature while stirred for 3 hours. After addition of water, the mixture was extracted with isopropyl acetate. The organic layer was washed with an aqueous solution of 3% potassium hydrogensulfate and 20% sodium chloride (three times) and an aqueous solution of 20% sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the resulting residue was added ethanol (943 mL) and the mixture was heated to 75° C. to dissolve the residue. The mixture was cooled to 60° C. and a seed crystal of the titled compound was added thereto. The mixture was cooled to room temperature and stirred for 1 hour. After precipitation of solid was observed, water (472 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. The resulting crystal was collected by filtration, washed with a mixture of water and ethanol (1:1), and dried under reduced pressure to give the titled compound (94 g). To the product (91 g) was added ethanol (1092 ml), and the product was dissolved by heating to 75° C. The solution was cooled to 60° C. and a seed crystal of the titled compound was added thereto. The mixture was cooled to room temperature and stirred for 1 hour. After precipitation of solid was observed, water (360 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. The resulting crystal was collected by filtration, washed with a mixture of water and ethanol (1:1), and dried under reduced pressure to give the titled compound [83 g, total yield from 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene used in Step 3: 68%].
1H-NMR (CDCl3) δ: 1.20 (3H, t, J=7.5 Hz), 2.60 (2H, q, J=7.5 Hz), 3.50 (3H, s), 3.76 (3H, s), 3.77 (3H, s), 3.81 (3H, s), 3.96 (2H, s), 4.23 (1H, dd, J=2.5, 11.8 Hz), 4.33 (1H, dd, J=4.5, 12.0 Hz), 4.36-4.40 (1H, m), 5.11-5.20 (3H, m), 5.41 (1H, d, J=10.0 Hz), 5.51 (1H, t, J=10.0 Hz), 7.07-7.11 (4H, m), 7.14 (1H, d, J=7.5 Hz), 7.19 (1H, dd, J=1.5, 7.8 Hz), 7.31 (1H, d, J=1.5 Hz).
MS (ESI+): 619 [M+1]+, 636 [M+18]+.
Another preparation was carried out in the same manner as Step 6, except that a seed crystal was not used, to give the titled compound as a crystal.
Step 7: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose
To a solution of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-2,3,4,6-tetra-O-methoxycarbonyl-β-D-glucopyranose (8.92 kg as wet powder, corresponding to 8.00 kg of dry powder) in 1,2-dimethoxyethane (28 kg) was added a solution of sodium hydroxide (4 mol/L, 30.02 kg) at 20° C., and the mixture was stirred for 1 hour. Water (8.0 kg) was added to the mixture and the layers were separated. To the organic layer were added an aqueous solution of 25% sodium chloride (40 kg) and ethyl acetate (36 kg). The organic layer was separated, washed with an aqueous solution of 25% sodium chloride (40 kg), and the solvent was evaporated under reduced pressure. The purity of the resulting residue was 98.7%, which was calculated based on the area ratio measured by HPLC. To the resulting residue were added acetone (32.0 kg) and water (0.8 kg), and the solvent was evaporated under reduced pressure. To the resulting residue were added acetone (11.7 kg) and water (15.8 kg), and the solution was cooled to 5° C. or below. Water (64 kg) was added to the solution at 10° C. or below, and the mixture was stirred at the same temperature for 1 hour. The resulting crystal was collected by centrifugation, and washed with a mixture of acetone (1.3 kg) and water (8.0 kg). The resulting wet powder was dried by ventilation drying under a condition at air temperature of 13 to 16° C. and relative humidity of 24% to 33% for 8 hours, to give a monohydrate crystal (water content: 4.502%) of the titled compound (3.94 kg). The purity of the resulting compound was 99.1%, which was calculated based on the area ratio measured by HPLC.
1H-NMR (CD3OD) δ: 1.19 (3H, t, J=7.5 Hz), 2.59 (2H, q, J=7.5 Hz), 3.42-3.46 (1H, m), 3.65 (1H, dd, J=5.5, 12.0 Hz), 3.74-3.82 (4H, m), 3.96 (2H, s), 5.07 (1H, d, J=12.8 Hz), 5.13 (1H, d, J=12.8 Hz), 7.08-7.12 (4H, m), 7.18-7.23 (311, m).
MS (ESI+): 387 [M+1]+.
Measurement Condition of HPLC:
Column: Capcell pack ODS UG-120 (4.6 mm I.D.×150 mm, 3 μm, manufactured by Shiseido Co., Ltd.)
Mobile phase: Eluent A: H2O, Eluent B: MeCN
Mobile phase sending: Concentration gradient was controlled by mixing Eluent A and Eluent B as indicated in the following table.
| TABLE 1 | ||||
| Time from | ||||
| injection (min) | Eluent A (%) | Eluent B (%) | ||
| 0 to 15 | 90→10 | 10→90 | ||
| 15 to 17.5 | 10 | 90 | ||
| 17.5 to 25 | 90 | 10 | ||
Flow rate: 1.0 mL/min
Temperature: 25.0° C.
Detection wavelength: 220 nm
Method for Measurement of Water Content:
Analysis method: coulometric titration method
KF analysis apparatus: Type KF-100 (trace moisture measuring apparatus manufactured by Mitsubishi Chemical Corporation)
Anode solution: Aquamicron AX (manufactured by Mitsubishi Chemical Corporation)
Cathode solution: Aquamicron CXU (manufactured by Mitsubishi Chemical Corporation)
PATENT
The compound of the present invention can be synthesized as shown in Scheme 1:
wherein R11 and R12 have the same meaning as defined above for substituents on Ar1, A is as defined above, and P represents a protecting group for a hydroxyl group.
CLIP
Tofogliflozin hydrate (Deberza)
Tofogliflozin hydrate, which is a sodium-glucose co-transporter 2 inhibitor, was approved in Japan for the treatment of type 2 diabetes
at the same time as luseogliflozin hydrate (XIX). The drug was discovered by Chugai Pharmaceutical and jointly developed
with Sanofi-Aventis and Kowa.263
Tofogliflozin hydrate reduces glucose levels by inhibiting the reuptake of glucose by selectively
inhibiting SGLT2, and plays a key role in the reuptake of glucose in the proximal tubule of the kidneys.264–266 The synthetic
approach described in Scheme 48 represents the largest scale reported to date in a patent application.263,266–268
Reduction of commercially available 2-bromoterephtalic acid (268, Scheme 48) through the use of trimethoxyborane and borane-THF proceeded in 89% yield to afford diol 269.
Subjection of this compound to 2-methoxypropene (270) under acidic conditions generated bis-acetonide 271. This bromide then underwent lithium–halogen exchange followed by exposure to magnesium bromide and treatment with lactone 272 (which was prepared by persilylation of commercially available (3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl)tetrahydro-2Hpyran-2-one (277, Scheme 49).
This mixture was worked up with aqueous ammonium chloride and upon treatment with p-TsOH in methanol resulted in spiroacetal 273. Next, global protection of all alcohol functionalities within 273 was affected by reaction with methylchloroformate and DMAP in acetonitrile.
The benzyl carbonate within 274 was selectively exchanged via Suzuki coupling with 4-ethylphenylboronic acid (275) to afford methylene dibenzyl system 276. Subsequent treatment with aqueous sodium hydroxide in methanol followed by crystallization from 1:6 acetone and water furnished the desired product tofogliflozin hydrate (XXXIV) in 75% yield.
263 Takamitsu, K.; Tsutomu, S.; Masahiro, N. WO Patent 2006080421A1, 2006.
264. http://www.info.pmda.go.jp/shinyaku/P201400036/index.html.
265. Pafili, K.; Papanas, N. Expert Opin. Pharmacother. 2014, 15, 1197.
266. Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.;Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S. Y.; Ahn, K. H.;Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.;Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55, 7828.
267. Murakata, M.; Ikeda, T.; Kawase, A.; Nagase, M.; Kimura, N.; Takeda, S.;Yamamoto, K.; Takano, K.; Nishimoto, M.; Ohtake, Y.; Emura, T.; Kito, Y. WOPatent 2011074675A1, 2011.
268. Murakata, M.; Takuma, I.; Nobuaki, K.; Masahiro, N.; Kawase, A.; Nagase, M.;Yamamoto, K.; Takata, N.; Yoshizaki, S. WO Patent 2009154276A1, 2009.
Paper
A newly process for the synthesis of tofogliflozin hydrate, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, was described. Three improvements were achieved, including the development of a regioselective Friedel–Crafts reaction, a high-yield reduction, and a mild metal–halogen exchange. These improvements ultimately resulted in the isolation of tofogliflozin hydrate as a white solid in >99% purity (HPLC area) and 23% overall yield after 12 steps without column chromatography.
Tofogliflozin hydrate white solid with 99.56% purity by HPLC. Water content: 4.47%.
Mp: 71−80 oC. [α]20 D = +23.9 (c = 1.0, CH3OH).
1H NMR (400 MHz, CD3OD) δ 7.23-7.18 (m, 3H), 7.12-7.08(m, 4H), 5.13 (d, J = 12.4 Hz, 1H), 5.07 (d, J = 12.4 Hz, 1H), 3.96 (s, 2H), 3.83-3.73 (m, 4H), 3.65 (dd, J = 11.9, 5.5 Hz, 1H), 3.41-3.47 (m, 1H), 2.59 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H).
13C NMR (100 MHz, CD3OD) δ 143.2, 142.6, 140.2, 139.9, 139.7, 131.2, 129.9, 128.9, 123.6, 121.8, 111.6, 76.4, 76.2, 74.9, 73.4, 71.9, 62.8, 42.3, 29.5, 16.3.
HRMS (ESI) m/z: [M+H]+ Calcd for C22H27O6 387.1802; Found 387.1805.
IR (KBr, cm-1) ν: 3362, 2962, 2927, 1637, 1513, 1429, 1095, 1034, 808, 770. Spectroscopic data were identical with those reported.1b, 2
1. (a) Suzuki, M.; Honda, K.; Fukazawa, M.; Ozawa, K.; Hagita, H.; Kawai, T.; Takeda, M.; Yata, T.; Kawai, M.; Fukuzawa, T.; Kobayashi, T.; Sato, T.; Kawabe, Y.; Ikeda, S. J. Pharmacol. Exp. Ther. 2012, 341, 692.
(b) Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.-H.; Ahn. K.-H.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55, 7828.
(c) Ikeda, S.; Takano, Y.; Cynshi, O.; Tanaka, R.; Christ, A. D.; Boerlin, V.; Beyer, U.; Beck, A.; Ciorciaro, C.; Meyer, M.; Kadowaki, T. Diabetes, Obesity and Metabolism 2015, 17, 984.
2. (a) Murakata, M.; Ikeda, T.; Kimura, N.; Kawase, A.; Nagase, M.; Yamamoto, K.; Takata, N.; Yoshizaki, S.; Takano, K. Crystal of spiroketal derivative, and process for production thereof. European Appl. EP 2308886 A1, April 13, 2011.
(b) Ohtake, Y.; Emura, T.; Nishimoto, M.; Takano, K.; Yamamoto, K.; Tsuchiya, S.; Yeu, S.; Kito, Y.; Kimura, N.; Takeda, S.; Tsukazaki, M.; Murakata, M.; Sato, T. J. Org. Chem. 2016, 81, 2148.
 |
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| Systematic (IUPAC) name | |
|---|---|
|
(1S,3′R,4′S,5′S,6′R)-6-(4-Ethylbenzyl)-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′-pyran]-3′,4′,5′-triol hydrate (1:1)
|
|
| Legal status | |
| Legal status |
|
| Identifiers | |
| CAS Number | 1201913-82-7 903565-83-3 (anhydrous) |
| ATC code | None |
| PubChem | CID 46908928 |
| ChemSpider | 28527871 |
| KEGG | D09978 |
| ChEMBL | CHEMBL2105711 |
| Synonyms | CSG452 |
| Chemical data | |
| Formula | C22H28O7 |
| Molar mass | 404.45 g/mol |
//////////TOFOGLIFLOZIN, 托格列净 , CSG-452, R-7201, RG-7201, 1201913-82-7 , 903565-83-3, oral hypoglycaemic agents, SGLT-2 inhibitors, type 2 diabetes mellitus, Deberza
CCc1ccc(cc1)Cc2ccc3c(c2)[C@]4([C@@H]([C@H]([C@@H]([C@H](O4)CO)O)O)O)OC3.O
The glucopyranosyl-substituted benzene derivatives are proposed as inducers of urinary sugar excretion and as medicaments in the treatment of diabetes.
The term “canagliflozin” as employed herein refers to canagliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:
The compound and methods of its synthesis are described in WO 2005/012326 and WO 2009/035969 for example. Preferred hydrates, solvates and crystalline forms are described in the patent applications WO 2008/069327 for example.
atigliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:
The compound and methods of its synthesis are described in WO 2004/007517 for example.
ipragliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:
The compound and methods of its synthesis are described in WO 2004/080990, WO 2005/012326 and WO 2007/114475 for example.
tofogliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:
The compound and methods of its synthesis are described in WO 2007/140191 and WO 2008/013280 for example.
remogliflozin and prodrugs of remogliflozin, in particular remogliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods of its synthesis are described in the patent applications EP 1213296 and EP 1354888 for example.
sergliflozin and prodrugs of sergliflozin, in particular sergliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods for its manufacture are described in the patent applications EP 1344780 and EP 1489089 for example.
luseoghflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:
ertugliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:
and is described for example in WO 2010/023594.
The compound of the formula
is described for example in WO 2008/042688 or WO 2009/014970.
The compound is described for example in WO 03/099836. Crystalline forms are described for example in WO 2008/002824.
The compound is described for example in EP 1354888 A1.
The compounds are described in EP 1 329 456 A1 and a crystalline form ofSergliflozin etabonate is described in EP 1 489 089 A1.
The compound is described in WO 2006/034489.
The compound (4-(Azulen-2-ylmethyl)-2-(β-D-glucopyranos-1-yl)-1-hydroxy-benzene) is described in WO 2004/013118 and WO 2006/006496. The crystalline choline salt thereof is described in WO 2007/007628.
The compound is described in WO 2004/080990 and WO 2005/012326. A cocrystal with L-proline is described in WO 2007/114475.
wherein R denotes methoxy or trifluoromethoxy. Such compounds and their method of production are described in WO 2004/007517, DE 102004063099 and WO 2006/072334.
The compound is described in WO 2005/012326. A crystalline hemihydrate is described in WO 2008/069327.
wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert. butyl. Such compounds are described in WO 2007/140191 and WO 2008/013280.
Eliglustat tartrate (Cerdelga) エリグルスタット酒石酸塩
依利格鲁司特
エリグルスタット,サーデルガ
FOR TREATMENT OF GAUCHERS DISEASE
ELIGLUSTAT; Cerdelga; Genz 99067; Genz-99067; UNII-DR40J4WA67; GENZ-112638;
CAS 491833-29-5 FREE FORM
| Molecular Formula: | C23H36N2O4 |
|---|---|
| Molecular Weight: | 404.54294 g/mol |
N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide
N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide;(2R,3R)-2,3-dihydroxybutanedioic acid
Mechanism of Action: glucosylceramide synthase inhibitor
Indication: Type I Gaucher Disease
Date of Approval: August 19, 2014 (US)
US patent number:US6916802 , US7196205 , US7615573
Patent Expiration Date: Apr 29, 2022 (US6916802, US7196205, US7615573)
Exclusivity Expiration Date:Aug 19, 2019(NCE), Aug 19, 2021 (ODE)
Originator:University of Michigan
Developer: Genzyme, a unit of Sanofi
Eliglustat, marketed by Genzyme as CERDELGA, is a glucosylceramide synthase inhibitor indicated for the long-term treatment of type 1 Gaucher disease. Patients selected for treatment with Eliglustat undergo an FDA approved genotype test to establish if they are CYP2D6 EM (extensive metabolizers), IM (intermediate metabolizers), or PM (poor metabolizers), as the results of this test dictate the dosage of Eliglustat recommended. Eliglustat was approved for use by the FDA in August 2014.
Eliglustat (INN, USAN;[1] trade name Cerdelga) is a treatment for Gaucher’s disease developed by Genzyme Corp that was approved by the FDA August 2014.[2] Commonly used as the tartrate salt, the compound is believed to work by inhibition ofglucosylceramide synthase.[3][4] According to an article in Journal of the American Medical Association the oral substrate reduction therapy resulted in “significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count” in untreated adults with Gaucher disease Type 1.[5]
Cerdelga, capsule, 84 mg/1, oralGenzyme Corporation, 2014-09-03, 
CAS 928659-70-5
CERDELGA (eliglustat) capsules contain eliglustat tartrate, which is a small molecule inhibitor of glucosylceramide synthase that resembles the ceramide substrate for the enzyme, with the chemical name N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (2R,3R)-2,3-dihydroxysuccinate. Its molecular weight is 479.59, and the empirical formula is C23H36N2O4+½(C4H6O6) with the following chemical structure:
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Each capsule of CERDELGA for oral use contains 84 mg of eliglustat, equivalent to 100 mg of eliglustat tartrate (hemitartrate salt). The inactive ingredients are microcrystalline cellulose, lactose monohydrate, hypromellose and glyceryl behenate, gelatin, candurin silver fine, yellow iron oxide, and FD&C blue 2.
In 2014, the annual cost of Cerdelga hard gelatin capsules taken orally twice a day was $310,250. Genzyme’s flagship Imiglucerase(brand name Cerezyme) cost about $300,000 for the infusions if taken twice a month.[6] Manufacturing costs for Cerdelga are slightly lower than for Cerezyme. Genzyme’s maintains higher prices for orphan drugs—most often paid for by insurers— in order to remain financially sustainable.[6]
Chemically Eliglustat is named N-[(1 R,2R)-2-(2,3-dihydro-1 ,4-benzodioxin-6-yl)-2-hydroxy-1 -(1 -pyrrolidinylmethyl)ethyl]-Octanamide(2R!3R)-2,3-dihydroxybutanedioate and the hemitartarate salt of eliglustat has the structural formula as shown in Formula I.
Formula I
Eliglustat hemitartrate (Genz-1 12638), currently under development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy. Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase, and is currently under development by Genzyme.
U.S. patent No. 7,196,205 discloses a process for the preparation of Eliglustat or a pharmaceutically acceptable salt thereof.
U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 discloses process for preparation of Eliglustat and intermediates thereof.
U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of Eliglustat, (ii) a hemitartrate salt of Eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.
It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailablity patterns compared to crystalline forms [Konne T., Chem pharm Bull., 38, 2003(1990)]. For some therapeutic indications one bioavailabihty pattern may be favoured over another. An amorphous form of Cefuroxime axetil is a good example for exhibiting higher bioavailability than the crystalline form.
CLIP
Eliglustat tartrate, developed and marketed by Genzyme Corporation (a subsidiary of Sanofi), was approved by the US FDA in August 2014 for the treatment of nonneuropathic (type 1) Gaucher disease (GD1) in both treatment-naïve and treatment-experienced adult patients.98
It is the first oral treatment to be approved for first-line use in patients with Gaucher disease type 1, which is a rare lysosomal storage disease characterized by accumulation of lipid glucosylceramide (GL-1) due to insufficient production of the enzyme glucosylceramidase.99,100
Clinical complications include hepatosplenomegaly, anemia, thrombocytopenia, and bone involvement.101 Eliglustat is a specific inhibitor of glucosylceramide synthase with an IC50 of 10 ng/mL and acts as substrate reduction therapy for GD1;102 it has demonstrated non-inferiority to enzyme replacement therapy, which is the current standard of care, in Phase III trials.99
While the process-scale route has not yet been disclosed,103 the largest scale route to eliglustat tartrate reported to date is described in Scheme 15.104
Condensation of commercially available S-(+)-2-phenyl glycinol (87) with phenyl bromoacetate (88) in acetonitrile in the presence of N,N-diisopropylethylamine (DIPEA) provided morpholin-2-one 89 upon treatment with HCl.Neutralization with NaHCO3 followed by coupling with aldehyde 90 in refluxing EtOAc/toluene yielded oxazine adduct 91, which was isolated as a precipitate from methyl-tert-butyl ether (MTBE).
The stereochemistry of the three new stereocenters in 91 can be rationalized through the cycloaddition of an ylide intermediate in the sterically-preferred S-configuration (generated by the reaction of the morpholinone 89 with aldehyde 90) with a second equivalent of the aldehyde. With the morpholinone in a chair conformation in which the phenyl group is equatorial, endo axial approach of the dipolarophile to the less-hindered face of the ylide and subsequent ring flip of the morpholinone ring to a boat conformation positions all exocyclic aryl substituents in a pseudoequatorial configuration. 105
Opening of oxazine 91 with pyrrolidine in refluxing THF followed by addition of HCl in refluxing MeOH gave amide 92, which was reduced to amine 93 using LiAlH4 in refluxing THF.
Subsequent hydrogenation with Pd(OH)2 in EtOH cleaved the phenylethanol group to give the free amine, which was converted to dioxalate salt 94 by treatment with oxalic acid in methyl isobutylketone (MIBK). Subjection of aminoethanol 94 to aqueous sodium hydroxide followed by coupling with palmitic acid Nhydroxysuccinimide (NHS)-ester (95) gave eliglustat as the corresponding freebase (96) in 9.5% overall yield from 87.
Salt formation with L-tartaric acid (0.5 equiv) then provided eliglustat tartrate (XII).106
98. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm410585.htm.
99. Poole, R. M. Drugs 2014, 74, 1829.
100. Kaplan, P. Res. Rep. Endocr. Disord. 2014, 4, 1.
101. Pastores, G. M.; Hughes, D. Clin. Invest. 2014, 4, 45.
102. Shayman, J. A. Drugs Future 2010, 35, 613.
103. Javed, I.; Dahanukar, V. H.; Oruganti, S.; Kandagatla, B. WO Patent2,015,059,679, 2015.
104. Hirth, B.; Siegel, C. WO Patent 2,003,008,399, 2003.
105. Anslow, A. S.; Harwood, L. M.; Phillips, H.; Watkin, D.; Wong, L. F. Tetrahedron:Asymmetry 1991, 2, 1343.
106. Liu, H.; Willis, C.; Bhardwaj, R.; Copeland, D.; Harianawala, A.; Skell, J.;Marshall, J.; Kochling, J.; Palace, G.; Peterschmitt, J.; Siegel, C.; Cheng, S. WO Patent 2,011,066,352, 2011.
CLIP
TAKEN FROM
http://www.xinbiaopin.com/a/zuixindongtai/huaxuepinshuju/2015/0310/2383.html
Nmr predict
![N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide NMR spectra analysis, Chemical CAS NO. 491833-29-5 NMR spectral analysis, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide H-NMR spectrum](https://i0.wp.com/pic11.molbase.net/nmr/nmr_image/2014-09-06/001/571/702/491833-29-5-1h.png)
13 C NMR
![N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide NMR spectra analysis, Chemical CAS NO. 491833-29-5 NMR spectral analysis, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide C-NMR spectrum](https://i1.wp.com/pic11.molbase.net/nmr/nmr_image/2014-09-06/001/571/702/491833-29-5-13c.png)
CAS NO. 491833-29-5, N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide
C-NMR spectral analysis
PATENT
http://www.google.com/patents/WO2013059119A1?cl=en
http://www.google.com/patents/US7196205
Compound 7
(1R,2R)-Nonanoic acid[2-(2′,3′-dihydro-benzo[1,4]dioxin-6′-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide
This compound was prepared by the method described for Compound 6 using Nonanoic acid N-hydroxysuccinimide ester. Analytical HPLC showed this material to be 98.4% pure. mp 74–75° C.
1H NMR (CDCl3) δ 6.86–6.76 (m, 3H), 5.83 (d, J=7.3 Hz, 1H), 4.90 (d, J=3.3 Hz, 1H), 4.24 (s, 4H), 4.24–4.18 (m, 1H), 2.85–2.75 (m, 2H), 2.69–2.62 (m, 4H), 2.10 (t, J=7.3 Hz, 2H), 1.55–1.45 (m, 2H), 1.70–1.85 (m, 4H), 1.30–1.15 (m, 10H), 0.87 (t, J=6.9 Hz, 3H) ppm.
Intermediate 4(1R,2R)-2-Amino-1-(2′,3′-dihydro-benzo[1,4]dioxin-6′-yl)-3-pyrrolidin-1-yl-propan-1-ol
Intermediate 3 (5.3 g, 13.3 mmol) was dissolved in methanol (60 mL). Water (6 mL) and trifluoroacetic acid (2.05 m/L, 26.6 mmol, 2 equivalents) were added. After being placed under nitrogen, 20% Palladium hydroxide on carbon (Pearlman’s catalysis, Lancaster or Aldrich, 5.3 g) was added. The mixture was placed in a Parr Pressure Reactor Apparatus with glass insert. The apparatus was placed under nitrogen and then under hydrogen pressure 110–120 psi. The mixture was stirred for 2–3 days at room temperature under hydrogen pressure 100–120 psi. The reaction was placed under nitrogen and filtered through a pad of celite. The celite pad was washed with methanol (100 mL) and water (100 mL). The methanol was removed by rotoevaporation. The aqueous layer was washed with ethyl acetate three times (100, 50, 50 mL). A 10 M NaOH solution (10 mL) was added to the aqueous layer (pH=12–14). The product was extracted from the aqueous layer three times with methylene chloride (100, 100, 50 mL). The combined organic layers were dried with Na2SO4, filtered and rotoevaporated to a colorless oil. The foamy oil was vacuum dried for 2 h. Intermediate 4 was obtained in 90% yield (3.34 g).
Intermediate 3(1R,2R,1″S)-1-(2′,3′-Dihydro-benzo[1,4]dioxin-6′-yl)-2-(2″-hydroxy -1′-phenyl-ethylamino)-3-pyrrolidin-1-yl-propan-1-ol
To a 3-neck flask equipped with a dropping funnel and condenser was added LiAlH4 (Aldrich, 1.2 g, 31.7 mmol, 2.5 equivalents) and anhydrous THF (20 mL) under nitrogen. A solution of Intermediate 2 (5.23 g, 12.68 mmol) in anhydrous THF (75 mL) was added dropwise to the reaction over 15–30 minutes. The reaction was refluxed under nitrogen for 9 hours. The reaction was cooled in an ice bath and a 1M NaOH solution was carefully added dropwise. After stirring at room temperature for 15 minutes, water (50 mL) and ethyl acetate (75 mL) was added. The layers were separated and the aqueous layer was extracted twice with ethyl acetate (75 mL). The combined organic layers were washed with saturated sodium chloride solution (25 mL). After drying with Na2SO4 the solution was filtered and rotoevaporated to yield a colorless to yellow foamy oil. Intermediate 3 was obtained in 99% yield (5.3 g).
PATENT
EXAMPLES
Example 1 : Preparation of amorphous form of eliglustat hemitartarate.
500mg of eliglustat hemitartarate was dissolved in 14 mL of dichloromethane at 26°C and stirred for 15 min. The solution is filtered to remove the undissolved particles and the filtrate is distilled under reduced pressure at 45°C. After distillation the solid was dried under vacuum at 45°C.
PATENT
PAPER
Journal of Medicinal Chemistry (2012), 55(9), 4322-4335
OLD CLIPS
What is Eliglustat?
Eliglustat tartrate (Genz-1 12638) is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of gaucher disease and other lysosomal storage disorders, which is currently under development.
Eliglustat is chemically known as 1 R, 2R-Octanoic acid [2-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1 -ylmethyl]-ethyl]-amide, having a structural formula I depicted here under.
Formula I
Eliglustat hemitartrate (Genz-1 12638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy.
Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase.
U.S. patent No. 7,196,205 (herein described as US’205) discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof. In this patent, eliglustat was synthesized via a seven-step process involving steps in that sequence:
(i) coupling S-(+)-2-phenyl glycinol with phenyl bromoacetate followed by column chromatography for purification of the resulting intermediate,
(ii) reacting the resulting (5S)-5-phenylmorpholin-2-one with 1 , 4-benzodioxan-6-carboxaldehyde to obtain a lactone,
(iii) opening the lactone of the oxazolo-oxazinone cyclo adduct via reaction with pyrrolidine,
(iv) hydrolyzing the oxazolidine ring, (v) reducing the amide to amine to obtain sphingosine like compound, (vi) reacting the resulting amine with octanoic acid and N-hydroxysuccinimide to obtain crude eliglustat, (vii) purifying the crude eliglustat by repeated isolation for four times from a mixture of ethyl acetate and n-heptane.
U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 disclose processes for preparation of eliglustat and intermediates thereof.
U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of eliglustat, (ii) a hemitartrate salt of eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.
WO 2015059679
| Process for the preparation of eliglustat free base – comprising the reaction of S-(+)-phenyl glycinol with phenyl-alpha-bromoacetate to obtain 5-phenylmorpholin-2-one, which is further converted to eliglustat. | |
| Dr Reddy’s Laboratories Ltd | |
| New crystalline eliglustat free base Form R1 and a process for its preparation are claimed. Also claimed is a process for the preparation of eliglustat free base which comprises the reaction of S-(+)-phenyl glycinol with phenyl-alpha-bromoacetate to obtain 5-phenylmorpholin-2-one, which is further converted to eliglustat.Further eliglustat oxalate, its crystalline form, and a process for the preparation of crystalline eliglustat oxalate, are claimed. | |
Eliglustat tartrate (Genz-1 12638) is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of gaucher disease and other lysosomal storage disorders, which is currently under development.
Eliglustat is chemically known as 1 R, 2R-Octanoic acid [2-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1 -ylmethyl]-ethyl]-amide, having a structural formula I depicted here under.
Formula I
Eliglustat hemitartrate (Genz-1 12638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy.
Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase.
U.S. patent No. 7,196,205 (herein described as US’205) discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof. In this patent, eliglustat was synthesized via a seven-step process involving steps in that sequence:
(i) coupling S-(+)-2-phenyl glycinol with phenyl bromoacetate followed by column chromatography for purification of the resulting intermediate,
(ii) reacting the resulting (5S)-5-phenylmorpholin-2-one with 1 , 4-benzodioxan-6-carboxaldehyde to obtain a lactone,
(iii) opening the lactone of the oxazolo-oxazinone cyclo adduct via reaction with pyrrolidine,
(iv) hydrolyzing the oxazolidine ring, (v) reducing the amide to amine to obtain sphingosine like compound, (vi) reacting the resulting amine with octanoic acid and N-hydroxysuccinimide to obtain crude eliglustat, (vii) purifying the crude eliglustat by repeated isolation for four times from a mixture of ethyl acetate and n-heptane.
U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 disclose processes for preparation of eliglustat and intermediates thereof.
U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of eliglustat, (ii) a hemitartrate salt of eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.
Example 1 : Preparation of 5-phenyl morpholine-2-one hydrochloride
To a (S) + phenyl glycinol (100g) add N, N-diisopropylethylamine (314ml) and acetonitrile (2000ml) under nitrogen atmosphere at room temperature. It was cooled to 10- 15° C. Phenyl bromoacetate (172.4g) dissolved in acetonitrile (500ml) was added to the above solution at 15° C over a period of 30 min. The reaction mixture is allowed to room temperature and stirred for 16-20h. Progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at a water bath
temperature less than 25° C to get a residue. The residue was dissolved in ethyl acetate (1000ml) and stirred for 1 h at 15-20°C to obtain a white solid. The solid material obtained was filtered and washed with ethyl acetate (200ml). The filtrate was dried over anhydrous sodium sulphate (20g) and concentrated under reduced pressure at a water bath temperature less than 25° C to give crude compound (1000g) as brown syrup. The Crude brown syrup is converted to HCI salt by using HCI in ethyl acetate to afford 5-phenyl morpholine-2-one hydrochloride (44g) as a white solid. Yield: 50%, Mass: m/z = 177.6; HPLC (% Area Method): 90.5%
Example 2: Preparation of (1 R,3S,5S,8aS)-1 ,3-Bis-(2′,3′-dihydro-benzo[1 ,4] dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one.
5-phenyl morpholine-2-one hydrochloride (100g) obtained from above stage 1 is dissolved in toluene (2500ml) under nitrogen atmosphere at 25-30°C. 1 ,4-benzodioxane-6-carboxaldehyde (185.3g) and sodium sulphate (400g) was added to the above solution and the reaction mixture was heated at 100-105°C for 72h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature less than 25° C to get a residue. The residue was cooled to 10°C, ethyl acetate (2700ml) and 50% sodium bisulphate solution (1351 ml) was added to the residue and stirred for 1 h at 10°C to obtain a white solid. The obtained white solid was filtered and washed with ethyl acetate. The separated ethyl acetate layer was washed with water (1000ml), brine (1000ml) and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure at a water bath temperature of 45-50°C to get a crude material. The obtained crude material is triturated with diethyl ether (1500ml) to get a solid material which is filtered and dried under vacuum at room temperature for 2-3h to afford (1 R,3S,5S,8aS)-1 ,3-Bis-(2′,3′-dihydro-benzo[1 ,4]dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one (148g) as a yellow solid. Yield: 54%, Mass: m/z = 487.7; HPLC (% Area Method): 95.4 %
Example 3: Preparation of (2S,3R,1 “S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)-3-hydroxy-2-(2″-hydroxy-1 ”^henyl-ethy^
(1 R,3S,5S,8aS)-1 !3-Bis-(2′!3′-dihydro-benzo[1 ,4]dioxin-6′-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one (70g) obtained from above stage 2 was dissolved in chloroform (1400ml) at room temperature. It was cooled to 0-5°C and pyrrolidone (59.5ml) was added at 0-5°C over a period of 30 minutes. The reaction mixture was allowed to room temperature and stirred for 16-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature of 40-45°C to obtain a crude. The obtained crude was dissolved in methanol (1190ml) and 1 N HCI (1 190ml) at 10-15° C, stirred for 10 minutes and heated at 80-85°C for 7h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, methanol was concentrated under reduced pressure at a water bath temperature of 50-55°C.The aqueous layer was extracted with ethyl acetate and the organic layer was washed with 1 N HCI (50ml). The aqueous layer was basified with saturated sodium bicarbonate solution up to pH 8-9 and extracted with ethyl acetate (3x70ml). The combined organic layers was washed with brine (100ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure at a water bath temperature of 50-55°C to afford (2S,3R,1″S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)-3-hydroxy-2-(2″-hydroxy-1 “-phenyl-ethylamino)-1 -pyrrolidin-1 -yl-propan-1 -one (53g) as a yellow foamy solid. Yield: 90%, Mass: m/z = 412.7, HPLC (% Area Method): 85.1 %
Example 4: Preparation of (1 R,2R,1 “S)-1-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)2-hydroxy-2-(2”-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1-yl-propan-1-ol.
(2S,3R,1 “S)-3-(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6’-yl)-3-hydroxy-2-(2”-hydroxy-1 “-phenyl-ethylamino)-1 -pyrrolidin-1 -yl-propan-1 -one (2.5g) obtained from above stage 3 dissolved in Tetrahydrofuran (106ml) was added to a solution of Lithium aluminium hydride (12.2g) in tetrahydrofuran (795ml) at 0°C and the reaction mixture was heated at 60-65°C for 10h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 5- 10°C and quenched in saturated sodium sulphate solution (100ml) at 5-10°C. Ethyl acetate was added to the reaction mass and stirred for 30-45 min. The obtained solid is filtered through celite bed and washed with ethyl acetate. Filtrate was dried over anhydrous sodium sulphate and concentrated under reduced pressure at a water bath temperature of 50°C to afford (1 R,2R, 1″S)-1 -(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6′-yl)2-hydroxy-2-(2″-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1 -yl-propan-1 -ol (43.51 g) as a yellow gummy liquid. The crude is used for the next step without further purification. Yield: 85%, Mass: m/z = 398.7, HPLC (% Area Method): 77 %
Example 5: Preparation of (1 R, 2R)-2-Amino-1-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol.
(1 R,2R,1 “S)-1 -(2′,3′-(Dihydro-benzo[1 ,4]dioxin-6’-yl)2-hydroxy-2-(2”-hydroxy-1 ‘-phenyl-ethylamino)-3-pyrrolidin-1 -yl-propan-1 -ol (40g) obtained from above stage 4 was dissolved in methanol (400ml) at room temperature in a 2L hydrogenation flask. Trifluoroacetic acid (15.5ml) and 20% Pd (OH) 2(40g) was added to the above solution under nitrogen atmosphere. The reaction mixture was hydrogenated under H2, 10Opsi for 16-18h at room temperature. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was filtered through celite bed and washed with methanol (44ml) and water (44ml). Methanol was concentrated under reduced pressure at a water bath temperature of 50-55°C and the aqueous layer was washed with ethyl acetate. The aqueous layer was basified with 10M NaOH till the PH reaches 12-14 and then extracted with dichloromethane (2x125ml). The organic layer was dried over anhydrous sodium sulphate (3gm) and concentrated under reduced pressure at a water bath temperature of 45°C to obtain a gummy liquid. The gummy liquid was triturated with methyl tertiary butyl ether for 1 h to get a white solid, which is filtered and dried under vacuum at room temperature to afford (1 R, 2R)-2-Amino-1 -(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol (23g) as a white solid. Yield: 82.3%, Mass (m/zj: 278.8, HPLC (% Area Method): 99.5%, Chiral HPLC (% Area Method): 97.9%
Example 6: Preparation of Eliglustat {(1 R, 2R)-Octanoic acid[2-(2′,3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1-ylmethyl-ethyl]-amide}.
(1 R, 2R)-2-Amino-1 -(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol (15g) obtained from above stage 5 was dissolved in dry dichloromethane (150ml) at room temperature under nitrogen atmosphere and cooled to 10-15° C. Octanoic acid N-hydroxy succinimide ester (13.0 g)was added to the above reaction mass at 10-15° C and stirred for 15 min. The reaction mixture was stirred at room temperature for 16h-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 15°C and diluted with 2M NaOH solution (100 ml_) and stirred for 20 min at 20 °C. The organic layer was separated and washed with 2M sodium hydroxide (3x90ml).The organic layer was dried over anhydrous sodium sulphate (30g) and concentrated under reduced pressure at a water bath temperature of 45°C to give the crude compound (20g).The crude is again dissolved in methyl tertiary butyl ether (25 ml_) and precipitated with Hexane (60ml). It is stirred for 10 min, filtered and dried under vacuum to afford Eliglustat as a white solid (16g). Yield: 74%, Mass (m/zj: 404.7 HPLC (% Area Method): 97.5 %, ELSD (% Area Method): 99.78%, Chiral HPLC (% Area Method): 99.78 %.
Example 7: Preparation of Eliglustat oxalate.
Eliglustat (5g) obtained from above stage 6 is dissolved in Ethyl acetate (5ml) at room temperature under nitrogen atmosphere. Oxalic acid (2.22g) dissolved in ethyl acetate (5ml) was added to the above solution at room temperature and stirred for 14h. White solid observed in the reaction mixture was filtered and dried under vacuum at room temperature for 1 h to afford Eliglustat oxalate as a white solid (4g). Yield: 65.46%, Mass (m/zj: 404.8 [M+H] +> HPLC (% Area Method): 95.52 %, Chiral HPLC (% Area Method): 99.86 %
| FDA Orange Book Patents: 1 of 3 | |
|---|---|
| Patent | 6916802 |
| Expiration | Apr 29, 2022 |
| Applicant | GENZYME CORP |
| Drug Application | N205494 (Prescription Drug: CERDELGA. Ingredients: ELIGLUSTAT TARTRATE) |
| FDA Orange Book Patents: 2 of 3 | |
|---|---|
| Patent | 7196205 |
| Expiration | Apr 29, 2022 |
| Applicant | GENZYME CORP |
| Drug Application | N205494 (Prescription Drug: CERDELGA. Ingredients: ELIGLUSTAT TARTRATE) |
| Patent ID | Date | Patent Title |
|---|---|---|
| US8003617 | 2011-08-23 | Methods of Treating Diabetes Mellitus |
| US2010298317 | 2010-11-25 | METHOD OF TREATING POLYCYSTIC KIDNEY DISEASES WITH CERAMIDE DERIVATIVES |
| US7763738 | 2010-07-27 | SYNTHESIS OF UDP-GLUCOSE: N-ACYLSPHINGOSINE GLUCOSYLTRANSFERASE INHIBITORS |
| US7615573 | 2009-11-10 | Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors |
| US2009105125 | 2009-04-23 | Methods of Treating Fatty Liver Disease |
| US7265228 | 2007-09-04 | Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors |
| US7196205 | 2007-03-27 | Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors |
| US6855830 | 2005-02-15 | Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors |
| Patent ID | Date | Patent Title |
|---|---|---|
| US2016068519 | 2016-03-10 | INHIBITORS OF THE ENZYME UDP-GLUCOSE: N-ACYL-SPHINGOSINE GLUCOSYLTRANSFERASE |
| US2015148534 | 2015-05-28 | SYNTHESIS OF UDP-GLUCOSE: N-ACYLSPHINGOSINE GLUCOSYL TRANSFERASE INHIBITORS |
| US2015051261 | 2015-02-19 | Methods of Treating Fatty Liver Disease |
| US8779163 | 2014-07-15 | Synthesis of UDP-Glucose: N-acylsphingosine glucosyl transferase inhibitors |
| US2013137743 | 2013-05-30 | AMORPHOUS AND A CRYSTALLINE FORM OF GENZ 112638 HEMITARTRATE AS INHIBITOR OF GLUCOSYLCERAMIDE SYNTHASE |
| US2013095089 | 2013-04-18 | GLUCOSYLCERAMIDE SYNTHASE INHIBITORS AND THERAPEUTIC METHODS USING THE SAME |
| US2012322786 | 2012-12-20 | 2-ACYLAMINOPROPOANOL-TYPE GLUCOSYLCERAMIDE SYNTHASE INHIBITORS |
| US8138353 | 2012-03-20 | SYNTHESIS OF UDP-GLUCOSE: N-ACYLSPHINGOSINE GLUCOSYLTRANSFERASE INHIBITORS |
| US2012022126 | 2012-01-26 | Method Of Treating Diabetes Mellitus |
| US8003617 | 2011-08-23 | Methods of Treating Diabetes Mellitus |
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
N-[(1R,2R)-1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-(1-pyrrolidinyl)-2-propanyl]octanamide
|
|
| Clinical data | |
| Trade names | Cerdelga |
| Legal status | |
| Legal status |
|
| Identifiers | |
| CAS Number | 491833-29-5 |
| ATC code | A16AX10 (WHO) |
| PubChem | CID 23652731 |
| ChemSpider | 28475348 |
| ChEBI | CHEBI:82752 |
| Chemical data | |
| Formula | C23H36N2O4 |
| Molar mass | 404.543 g/mol |
| Patent Number | Pediatric Extension | Approved | Expires (estimated) | |
|---|---|---|---|---|
| US6916802 | No | 2002-04-29 | 2022-04-29 | |
| US7196205 | No | 2002-04-29 | 2022-04-29 | |
| US7615573 | No | 2002-04-29 | 2022-04-29 | |
///////////491833-29-5, 928659-70-5, eliglustat hemitartrate, eliglustat L-tartrate, ELIGLUSTAT, Cerdelga, Genz 99067, Genz-99067, UNII-DR40J4WA67, GENZ-112638, エリグルスタット酒石酸塩 , FDA 2014, GAUCHERS DISEASE, 依利格鲁司特, エリグルスタット,サーデルガ
CCCCCCCC(=O)N[C@H](CN1CCCC1)[C@@H](C2=CC3=C(C=C2)OCCO3)O
New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd
FOR Cancer; Parasitic infection; Plasmodium falciparum infection; Viral infection
KUMAR, Ashok; (IN).
SINGH, Dharmendra; (IN).
MAURYA, Ghanshyam; (IN).
WAKCHAURE, Yogesh; (IN)
IPCA LABORATORIES LIMITED [IN/IN]; 48, Kandivli Industrial Estate, Charkop, Kandivali (West), Mumbai 400067 (IN)
Novel process for preparing artemisinin or its derivatives such as dihydroartemisinin, artemether, arteether and artesunate. Also claims novel intermediates of artemesinin such as artemisinic acid or dihydroartemisinic acid. Discloses the use of artemisinin or its derivatives, for treating malaria, cancer, viral and parasitic infections.
In July 2016, Newport Premium™ reported that IPCA was capable of producing commercial quantities of artemether, arteether and artesunate; and holds an inactive US DMF for artemether since February 2009. In July 2016, IPCA’s website lists artemether, arteether and artesunate under its products and also lists artemether and artesunate as having EDMF and WHO certificates. The assignee also has Canada HPFB certificate for artemether.
The Central Drug Research Institute (CDRI) in collaboration with IPCA is developing CDRI-97/78 (1,2,4 trioxane derivative), a synthetic artemisinin substitute for treating drug resistant Plasmodium falciparum infection. In July 2016, CDRI-97/78 was reported to be in phase 1 clinical development. IPCA in collaboration with CDRI was also investigating CDRI-99/411, a synthetic artemisinin substitute for treating malaria; but its development had been presumed to have been discontinued; however, this application’s publication would suggest otherwise.
Writeup
Artemisinin is an active phytoconstituent of Chinese medicinal herb Artemisia annua, useful for the treatment of malaria. Generally, artemisinin/artemisinic acid is obtained by extraction of the plant, Artemisia annua. The plant Artemisia annua was first mentioned in an ancient Chinese medicine book written on silk in the West Han Dynasty at around 200 B.C. The plant’s anti-malarial application was first described in a Chinese pharmacopeia, titled “Chinese Handbook of Prescriptions for Emergency Treatments,” written at around 340 A.D.
Artemisinin being poorly bioavailable limits its effectiveness. Therefore semisynthetic derivatives of artemisinin such as artesunate, dihydroartemisinin, artelinate, artemether, arteether have been developed to improve the bioavailability of Artemisinin.
Artemisinin and its derivatives – dihydroartemisinin, artemether, arteether, and artesunate being a class of antimalarials compounds used for the treatment of uncomplicated, severe complicated/cerebral and multi drug resistant malaria. Additionally, there are research findings that artemisinin and its derivatives show anti-parasite, anti-cancer, and anti-viral activities.
Dihydroartemisinin Artesunate
The content of Artemisinin in the plant Artemisia annua varies significantly according to the climate and region/geographical area where it is cultivated. Further, the extraction methods provide artemisinin or artemisinic acid from the plant in very poor yields and therefore not sufficient to accommodate the ever-growing need for this important drug. Consequently, widespread use of these valuable drugs has been hampered due to the low availability of this natural product. Therefore, research has focused on the syntheses of this valuable drug in a larger scale to meet the increasing global demand and accordingly ample literature is available on the synthesis of artemisinin or its derivatives, but no commercial success being reported / known till date.
Artemisinin can be prepared synthetically from its precursors such as artemisinic acid or dihydroartemisinic acid according to literature methods known to skilled artisans. For example, dihydroartemisinic acid can be converted to artemisinin by a combination of photooxidation and air-oxidation processes as described in U.S. Patent No. 4,992,561.
Amorphadiene is an early starting material for synthesis of Artemisinic acid or dihydroartemisinic acid, which is an important intermediate for producing Artemisinin commercially, and WO2006128126 reported a preparation method as mentioned in scheme- 1.
acid
In accordance with the scheme 1, the amorphadiene is treated with di(cyclohexyl)borane ( δΗι ΒΗ followed by reaction with H2O2 in presence of NaOH to obtain the amorph-4-ene 12-ol which is further oxidized to dihydroartemisinic acid using CrCb/ifcSC^. The formation of amorph-4-ene 12-ol is taking place via epoxidation of the exocyclic double bond. However, the reported yields of this synthesis are very low, making it unviable to produce artemisinic acid at a cheaper cost than natural extraction, for commercial use.
Amorpha -4, 11-diene
A similar method is published in, WO2009088404, for synthesis of dihydroartemisinic acid through preparation of amorph-4-ene-12-ol via epoxide formation, albeit, predominantly at exo position by reacting the amorpha-4,11-diene with H2O2 in presence of porphyrin catalyst (TDCPPMnCl). During reaction, epoxidation also occurred at endo position leading to formation of Amorphadiene- 4,5- epoxide that remain as impurity. The formed exo epoxide (amorphadiene – 11, 12 – epoxide) is further reduced to get amorph- 4-ene 12-ol and then converted to dihydroartemisinic acid and finally converted into artemisinin.
Amorphadiene-11,12-epoxide
This process involves expensive & industry unfriendly reagents. Moreover, desired stereo isomers were obtained only in poor yields, because several purification steps were needed to get desired stereo isomers leading to escalated production/operational costs.
Therefore there remains a need in the art to improve the yield of Dihydroartemisinic acid, which could potentially reduce the cost of production of Artemisinin and/or its derivatives. Consequently it is the need of the hour to provide a synthetic and economically viable process to meet the growing worldwide demand by improving the process for Artemisinin and/or its derivatives to obtain them in substantially higher yields with good purity by plant friendly operations like crystallization/extractions rather than column chromatography/other cost constraint procedures.
Therefore, the object of the invention is to prepare Artemisinic acid of formula-II, Dihydroartemisinic acid of formula-IIa, Artemisinin and its derivatives through Amorphadiene- 4,5- epoxide.
DHAA methyl ester
Scheme 2
Method 4 (From compound of formula IV (R = CI)):
In the 4-neck round bottom flask was charged Diphenyl sulfoxide (23.8 g), NaHC03 (32.96 g) and DMSO (80 ml) at 30°C. Further a solution of compound of formula IV (R = CI) (10 g) in DMSO (20 ml) was charged to the reaction mass at 30°C followed by heating and maintaining the temperature for 40 hours at 80°C till completion. DMSO was distilled out under vacuum. The reaction mass was cooled followed by charging water
(100 ml) and toluene (100 ml) to the reaction mass with stirring for 30 minutes at 28°C. The layers were separated out and aqueous layer was back extracted with toluene (2 X 100 ml). The organic layer was washed with water (100 ml) and saturated brine solution (100 ml). Solvent was distilled out under vacuum at 50°C, and the crude mass degassed under vacuum at 50-55°C. IPA (40 ml) was charged to the mass. Simultaneous addition of hydrazine hydrate (65% in aqueous solution) (3.8 g) and hydrogen peroxide (50% in aqueous solution) (2.5 ml) was done at 30-32°C over a period of 3.25 hours. After completion, reaction mass was cooled up to 5-10°C and water (100ml) was added to the reaction mass. The pH of the reaction mass was adjusted to 3.8 with dilute 8% aqueous HC1 (24 ml) at 10°C. Ethyl acetate (60 ml) was added to the reaction mass at 10°C and stirred for 15 minutes at 15-20°C. The layers were separated. Aqueous layer was back extracted with ethyl acetate (2 X 20 ml). The combined organic layer was washed with 10%) sodium metabisulfite solution (50 ml), water (50 ml) and saturated brine solution (50 ml). The organic layer was distilled out under vacuum at 45°C and the obtained crude mass was degassed at 50-55°C. To this was added DME (40 ml), Biphenyl (0.9 g) and Li-metal (1.63 g) and the reaction mass was maintained for 10 hours at 80-85°C till reaction completion. The reaction mass was cooled up to 0-5°C followed by drop wise addition of water within one hour, and the reaction stirred for two hours at 20-25°C. Toluene (35 ml) was charged with stirring and layers were separated. The aqueous layer was washed with toluene (35 ml) and the combined toluene layer was washed with water (20 ml). The combined aqueous layer was again washed with toluene (20 ml). The aqueous layer was cooled to 10-15°C and pH adjusted to 3.5-4 with dilute 16% aqueous HC1. MDC (50 ml) was charged and stirred 30 minutes at 20-25°C followed by separation of layers. The aqueous layer extracted with MDC (25 ml) and the combined MDC layer was washed with water (50 ml), then with saturated NaCl solution (25 ml). The solvent was distilled out under vacuum at 40-45°C and the crude mass (Purity: 70-80%>) was degassed at 65-70°C. The crude product (10 g) was dissolved in ethyl acetate (200 ml). 10%> aqueous NaOH (100 ml) was charged to the reaction mass and stirred one hour at 20°C followed by layer separation. Again 10%> aqueous NaOH (100ml) was added to the organic layer, stirred for 30 minutes and layers were separated out. The pH of the combined NaOH solution wash was adjusted to 4.0 with dilute 16%> aqueous HC1 at 5-10°C under stirring. Ethyl acetate (850 ml) was charged to aqueous acidic mass, stirred 30 minutes and layers were separated out. The aqueous layer was back extracted with ethyl acetate (2 X 30 ml) and the combined organic layer was washed with water (100 ml) and saturated brine (50 ml). The organic layer was dried over sodium chloride, solvent was distilled out under vacuum and the purified mass was degassed under vacuum at 50-55°C to obtain Dihydroartemisinic acid (Purity: 90-95%).
b) Methyl ester of Dihydroartemisinic acid:
To a clear solution of Dihydroartemisinic acid (40 g) dissolved in MDC (120 ml) was added thionyl chloride (SOCh) (14.85 ml) at 10±2°C and reaction mass was heated to reflux temperature 40±2°C. After the completion of reaction, solvent was distilled out and excess SOCh was removed under reduced pressure. The resulting concentrated mass of acid chloride was dissolved in MDC (200 ml). In another RBF was taken triethylamine (30.6 ml) and methanol (120 ml). To this solution was added above acid chloride solution at 30±2°C and maintained till completion of reaction. To the reaction mass was added water (400 ml) and organic layer was separated. The aqueous layer was washed with MDC and mixed with main organic layer and the combined organic layer was back washed with water till neutral pH. Then organic layer was concentrated to give methyl ester of Dihydroartemisinic acid as a brown color oily mass.
Weight: 41.88 gm
Yield = 98%
c) Artemisinin:
Methyl ester of dihydroartemisinic acid (67.7 g) was dissolved in methanol (338 ml). To this solution was added Sodium molybdate (29.5 g), 50% hydrogen peroxide (147.3 g) was added at 30±2°C and reaction was maintained for 3-4 hours. After completion of reaction was added water (300 ml) and MDC (300 ml) to the reaction mass. The organic layer was separated and aqueous layer washed with MDC (100 ml). The combined organic layer was concentrated to 475 ml containing hydroperoxide intermediate and directly used for next stage reaction. In another RBF containing MDC (475 ml) was added benzene sulfonic acid (1.27 g) and Indion resin (6.7 g). This heterogeneous solution was saturated with oxygen by passing O2 gas for 10 min at 0±2°C. To this was added previous stage hydroperoxide solution at same temperature with continuous 02 gas purging within 30-40 minutes. The oxygen gas was passed at same temp for 4 hours and temperature raised to 15±2°C with continued passing of oxygen for 5 hours. The
mixture was stirred at 25-30°C for 8-10 hours followed by filtration of resin. The filtrate was washed with water (200 ml X 3) and the combined aqueous layer back washed with MDC (50 ml). The combined organic layer was concentrated to give crude Artemisinin. Weight: 54 gm
Yield= 70.7%
Purification of Artemisinin:
Crude Artemisinin (10 g) was dissolved in ethyl acetate (25 ml) at 45-50°C. The solution was cooled to 30-35°C followed by addition of n-Hexane (100 ml). The material was isolated, stirred for 2 hours, filtered and vacuum dried at 45°C.
Weight: 4 gm
Yield: 40%
////////New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd, malaria, Cancer, Parasitic infection, Plasmodium falciparum infection, Viral infection, artemether artemisinin, artemotil, artenimol, artesunate,
Lurasidone – it having been developed and launched by Sumitomo Dainippon Pharma. Lurasidone was launched for schizophrenia in the US by Sumitomo’s US subsidiary Sunovion Pharmaceuticals.
WO 2016110798, Piramal Enterprises Ltd, New Patent, Lurasidone
An improved process for the preparation of lurasidone and its intermediate
PIRAMAL ENTERPRISES LIMITED [IN/IN]; Piramal Tower Ganpatrao Kadam Marg, Lower Parel Mumbai 400013 (IN)
GHARPURE, Milind; (IN).
TIWARI, Shashi Kant; (IN).
WAGH, Ganesh; (IN).
REVANAPPA, Galge; (IN).
WARPE, Manikrao; (IN).
ZALTE, Yogesh; (IN).
From left: Anand Piramal, executive director, Piramal Group; Swati Piramal, vice-chairperson, Piramal Group; Ajay Piramal, chairman, Piramal Group; Nandini Piramal, executive director, Piramal Enterprises; and Peter DeYoung, president, Piramal Enterprises
Improved process for preparing pure (3aR,7aR)-4′-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1′-piperazin]-1′-ium methanesulfonate, useful as a key intermediate in the synthesis of lurasidone. Also claims a process for purifying lurasidone hydrochloride, useful for treating schizophrenia and bipolar disorders. In July 2016, Newport Premium™ reported that Piramal Enterprises was capable of producing commercial quantities of lurasidone hydrochloride and holds an active US DMF for the drug since March 2015.
Lurasidone (the Compound-I), is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorders.The drug is marketed as hydrochloride salt (the compound-I.HCl) by Sunovion Pharms Inc.under the tradename”LATUDA”, in the form of oral tablets. Latuda is indicated for the treatment of patients with schizophrenia. Lurasidone hydrochloride has the chemical name ((3aR,4S,7R,7aS)-2-[((lR,2R)-2-{ [4-(l,2-benzisothiazol-3-yl)-piperazin-l-yl]methyl}cyclohexyl)-methyl]hexahydro-lH-4,7-methanisoindol-l,3-dione hydrochloride, and is structurally represented as follows;
Compound-I.HCl
Lurasidone being an important antipsychotic agent; a number of processes for its preparation as well as for its intermediates are known in the art.
US Patent No. 5,532,372 describe a process for the synthesis of Lurasidone, which is illustrated below in Scheme-I. In the process, the compound, cyclohexane- l,2-diylbis(methylene) dimethanesulfonate(referred to as the compound-Ill) is reacted with 3-(l-piperazinyl-l,2-benzisothiazole(referred to as the compound-IV) in acetonitrile, and in the presence of sodium carbonate to provide corresponding quaternary ammonium salt as 4′-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2, r-piperazin]-l’-ium methanesulfonate (the compound-II). The compound-II is further treated with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide in xylene, in the presence of potassium carbonate and dibenzo-18-crown-6-ether to provide lurasidone.
Scheme-I
US Published Patent Application 2011/0263848 describes a process for the preparation of the quaternary ammonium salt (the compound-II) which comprises reacting 4-(l,2-benzisothiazol-3-yl)piperazine with (lR,2R)-l,2-bis(methanesulfonyloxymethyl)- cyclohexane in a solvent such as toluene in the presence of a phosphate salt.
Indian Published Patent Application 2306/MUM/2014 (” the IN’2306 Application”) describes a process for the synthesis of lurasidone and the intermediates thereof, comprising reacting (R,R) trans l,2-bis(methane sulphonyl methyl)cyclohexane with 3-(Piperazine-l-yl)benzo[d]isothiazole in presence of a mixture of two or more polar aprotic solvents selected from acetonitrile, N,N-dimethyl formamide (DMF) and/or Ν,Ν-dimethyl acetamide (DMAc), and a base at reflux temperature to obtain the quaternary ammonium salt (the compound II), which is then converted to lurasidone. The IN’2306 application demonstrated preparation of the compound II using the solvent combination such as acetonitrile-DMF and acetonitrile-DMAc.
US Published Patent Application 2011/0263847 describes a process for the preparation of the quaternary ammonium salt (the compound-II) comprising reacting 4-(l,2-benzisothiazol-3-yl)piperazine with (lR,2R)-l,2-bis(methanesulfonyloxymethyl)cyclohexane in a solvent such as toluene, wherein the piperazine compound is used in an excess amount i.e. 1.8 to 15 moles with respect to ( 1R,2R)- 1 ,2-bis(methanesulfonyloxymethyl)cyclohexane.
Chinese Published Patent Application 102731512 describes a process for the preparation of the quaternary ammonium salt (the compound-II) comprises reaction of 4-(l,2-benzisothiazol-3-yl)piperazine with (lR,2R)-l,2-bis(methanesulfonyloxymethyl)cyclohexane in a solvent such as toluene in the presence of a phase transfer catalyst.
In addition to the afore discussed patent documents, there are a number of patent documents that describe a process for the preparation of the quaternary ammonium salt (the compound-II), the key intermediate for the synthesis of lurasidone. For instance, Published PCT application WO2012/131606 A 1, Indian Published patent application 217/MUM/2013, Chinese published patent applications 102863437, 103864774 and 102827157 describe a process for the preparation of the quaternary ammonium salt (compound-II) comprises reaction of 4-(l,2-benzisothiazol-3-yl)piperazine with (lR,2R)-l,2-bis(methanesulfonyloxymethyl)cyclohexane in a solvent or a solvent mixture such as acetonitrile, acetonitrile : water solvent mixture, toluene or DMF, in the presence of a base.
It is evident from the discussion of the processes for the preparation of the quaternary ammonium salt (the compound-II), described in the afore cited patent documents that the reported processes primarily involve use of acetonitrile either as the single solvent or in a mixture of solvents. Acetonitrile is a relatively toxic, and not an environment friendly solvent. Due to its toxic nature, it can cause adverse health effects also. Acetonitrile is covered under Class 2 solvents i.e. solvents to be limited, and residual solvent limit of acetonitrile is 410 ppm in a drug substance as per the ICH (International Conference on Harmonisation) guidelines for residual solvents. Moreover, acetonitrile is a costlier solvent, which renders the process costlier and hence, is not an industrially feasible solvent.
It is also evident from the discussion of the processes described in afore cited patent documents that some of the reported processes involve use of high boiling solvents such as toluene and dimethylformamide as reaction solvent, which subsequently require high reaction temperatures, and this in turn leads to tedious workup procedures. In view of these drawbacks, there is a need to develop an industrially viable commercial process for the preparation of lurasidone and its intermediates; which is simple, efficient and cost-effective process and provides the desired compounds in improved yield and purity.
Inventors of the present invention have developed an improved process that addresses the problems associated with the processes reported in the prior art. The process of the present invention does not involve use of any toxic and/or costly solvents. Moreover, the process does not require additional purification steps and critical workup procedure. Accordingly, the present invention provides a process for the preparation of lurasidone and its intermediates, which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations.
Scheme-II
Scheme-Ill
EXAMPLES
Example-1: Preparation of (3aR,7aR)-4′-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,l’-piperazin]-l’-ium methanesulfonate(the compound II)
Charged 150.0 mL (3v) of isopropyl alcohol (IPA) in a flask followed by the addition of the compound-Ill (50.0 g) , 3-(l-Piperazinyl)-l, 2-Benzisothiazole (32.84 g), sodium carbonate granular (10.79 g) and water 50 mL (lv). The reaction mixture was heated at a temperature of 82-85 °C for 24 to 25 h. Cooled the reaction mixture to room temperature, filtered on Buchner funnel and the filtrate was collected.
The filtrate was evaporated under vacuum at 55-65°C till visible solid appears in the reaction mass. The solid was stirred in 75 mL of toluene at room temperature and the solid was filtered. The wet cake was transferred to a flask and added 125 mL of acetone to it; followed by stirring at room temperature. The resulting solid was filtered to yield the pure title compound (II).
Yield: 63.4 g (90 %)
Purity (by HPLC): 99.79 %
Unreacted compound-IV as impurity in 0.05 % .
Example-2: Preparation of Lurasidone free base.
Charged 150.0 mL of Ν,Ν-dimethylformamide (DMF) in a flask followed by the addition of 50.0 g of the compound-II (as obtained in the above example-1), 19.5 g (3aR,4S,7R,7aS)-4,7-methano-lH-isoindole-l,3(2H)-dione and 19.5 g of potassium carbonate. The reaction mixture was heated at a temperature of about 125 °C for 24 h. The reaction mixture was cooled to room temperature and 400 mL of water was added to it. The reaction mixture was stirred, and the precipitated product was filtered. The wet cake was washed with IPA and Lurasidone free base is obtained as the pure product. [Yield: 46.52 g (80 %)]
Example-3: Purification of Lurasidone hydrochloride.
Charged water (200 ml) and IPA (200 ml) in flask followed by the addition of Lurasidone hydrochloride (50 gm, residual acetone: 5769 ppm). The reaction mixture was heated at a temperature of 75-80 °C for about 30 min. The reaction mixture was cooled to 20-30 °C and stirred for about 2 hours. The precipitated solid was filtered and isolated as pure Lurasidone hydrochloride (residual acetone: 2 ppm)
///////////////WO 2016110798, Piramal Enterprises Ltd, New Patent, Lurasidone
Doravirine, MK-1439……….. AN ANTIVIRAL
3-Chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydro-3-pyridinyl}oxy)benzonitrile
Benzonitrile, 3-chloro-5-[[1-[(4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-2-oxo-4-(trifluoromethyl)-3-pyridinyl]oxy]-
3-chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile
(3-Chloro-5-((1-((4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile)
1338225-97-0 CAS
MF C17H11ClF3N5O3
MW 425.7 Merck Sharp & Dohme Corp
Merck Frosst Canada Ltd. INNOVATOR
Jason Burch, Bernard Cote, Natalie Nguyen,Chun Sing Li, Miguel St-Onge, Danny Gauvreau,
Reverse transcriptase inhibitor
UNII:913P6LK81M
WO 2015084763
CONTD………………………
13C NMR DMSOD6
1H NMR DMSOD6
3-chloro-5-((2-oxo-1-((5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile.
1H NMR (400 MHz, DMSO-d6) δ 11.47 (br. s., 1H), 11.40 (s, 1H), 7.93 (d, J = 7.3 Hz, 1H), 7.75 (t, J =1.5 Hz, 1H), 7.58 (dd, J = 1.2, 2.3 Hz, 1H), 7.51 (t, J = 2.1 Hz, 1H), 6.66 (d, J = 7.3 Hz, 1H), 5.02 (s, 2H)
13C NMR (101 MHz, DMSO-d6) δ 157.25, 156.20, 155.97, 142.52, 140.09 (q, JC-F = 2.0 Hz), 137.74,134.97, 130.17 (q, JC-F = 31.2 Hz), 126.53, 121.70 (q, JC-F = 274.7 Hz), 121.16, 118.37, 116.96, 113.70,99.96 (q, JC-F = 4.0 Hz), 44.90
19F NMR (376 MHz, DMSO-d6) δ -62.24 (s, 1F)
HRMS [M + H]+ for C16H10ClF3N5O3 calcd, 412.0419; found, 412.0415.
mp 148.46-156.11 °C
REF Org. Process Res. Dev., Article ASAP, DOI: 10.1021/acs.oprd.6b00163
http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00163
Doravirine (MK-1439) is a non-nucleoside reverse transcriptase inhibitor under development by Merck & Co. for use in the treatment of HIV/AIDS. Doravirine demonstrated robust antiviral activity and good tolerability in a small clinical study of 7-day monotherapy reported at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013. Doravirine appeared safe and generally well-tolerated with most adverse events being mild-to-moderate.[2][3]
Highly active antiretroviral therapy (HAART) is the standard of care for the treatment of HIV infection. Typically, this protocol recommends the combination of two nucleoside reverse-transcriptase inhibitors (NRTIs) with either a non-nucleoside reverse-transcriptase inhibitor (NNRTI), a ritonavir-boosted protease inhibitor or an integrase inhibitor.
NNRTI-based combinations have become first-line therapy mainly because of their demonstrated efficacies, convenient dosing regimen and relatively low toxicities. These inhibitors block the polymerase activity of the HIV reverse transcriptase by binding to an allosteric hydrophobic pocket adjacent to the active site. Efavirenz (1, ) is a first generation NNRTI that has been conveniently co-formulated with NRTIs tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) as a once-a-day fixed-dose combination (Atripla®). Although recommended for the therapy of treatment-naïve patients, efavirenz suffers from neurocognitive side effects, teratogenicity and exacerbation of hyperlipidemia. Moreover, the low barrier to genetic resistance of first generation NNRTIs led to the emergence of resistant viruses bearing mutations K103N and Y181C in patients failing therapy.
Figure .
Structures of marketed and lead NNRTIs.
Second generation NNRTIs etravirine (2) and rilpivirine (3) efficiently suppress the replication of the K103N resistant mutants as shown by an improved activity in cell culture assays . Etravirine (200 mg, bid) is approved for use in treatment-experienced adult patients with multi-drug resistance. With an improved pharmacokinetic profile, the close analog rilpivirine (25 mg, qd) was recently approved for use in treatment-naïve patients. Phase III data reveal that at the 96-week point, a rilpivirine/truvada® combination was better tolerated than efavirenz/truvada®. However, the virologic failure rate was twice as high for rilpivirine (14%) than it was for efavirenz (8%). For patients with viral load greater than 500,000 copies/mL, the response rate is 62% (rilpivirine) versus 81% (efavirenz). As a result, rilpivirine is not recommended for treating HIV patients with viral load >500,000 copies/mL. This difference in treatment durability could be explained by the much higher ratio of trough concentration over the antiviral activity for efavirenz versus rilpivirine.
Investigational next-generation, non-nucleoside reverse transcriptase inhibitor (NNRTI), at the 21st Conference on Retroviruses and Opportunistic Infections (CROI). Interim data demonstrating potent antiretroviral (ARV) activity for four doses (25, 50, 100 and 200 mg) of once-daily, oral doravirine in combination with tenofovir/emtricitabine in treatment-naïve, HIV-1 infected adults after 24 weeks of treatment were presented during a late-breaker oral session. Based on these findings as well as other data from the doravirine clinical program, Merck plans to initiate a Phase 3 clinical trial program for doravirine in combination with ARV therapy in the second half of 2014.
“Building on our long-standing commitment to the HIV community, Merck continues to evaluate new candidates we believe have the potential to make a meaningful difference in the lives of HIV patients,” said Daria Hazuda, Ph.D., vice president, Infectious Diseases, Merck Research Laboratories. “We look forward to advancing doravirine into Phase 3 clinical trials in the second half of 2014.”
Doravirine Clinical Data
This randomized, double-blind clinical trial examined the safety, tolerability and efficacy of once-daily doravirine (25, 50, 100 and 200 mg) in combination with once-daily tenofovir/emtricitabine versus efavirenz (600 mg), in treatment-naïve, HIV-1 infected patients. The primary efficacy analysis was percentage of patients achieving virologic response (< 40 copies/mL).
At 24 weeks, doravirine doses of 25, 50, 100, and 200 mg showed virologic response rates consistent with those observed for efavirenz at a dose of 600 mg. All treatment groups showed increased CD4 cell counts.
|
Proportion of Patients with Virologic |
Mean CD4 Change |
|||||||
| Treatment* | Dose (mg) | n/N |
% <40 |
cells/μL
|
||||
| Doravirine | 25 | 32/40 | 80.0 (64.6, 90.9) | 158 (119, 197) | ||||
| 50 | 32/42 | 76.2 (60.5, 87.9) | 116 (77, 155) | |||||
| 100 | 30/42 | 71.4 (55.4, 84.3) | 134 (100, 167) | |||||
| 200 | 32/41 | 78.0 (62.4, 89.4) | 141 (96, 186) | |||||
| Efavirenz | 600 | 27/42 | 64.3 (48.0, 78.4) | 121 (73, 169) | ||||
| Missing data approach: | Non-completer = Failure | Observed Failure | ||||||
|
*In combination with tenofovir/emtricitabine |
||||||||
The incidence of drug-related adverse events was comparable among the doravirine-treated groups. The overall incidence of drug-related adverse events was lower in the doravirine-treated groups (n=166) than the efavirenz-treated group (n=42), 35 percent and 57 percent, respectively. The most common central nervous system (CNS) adverse events at week 8, the primary time point for evaluation of CNS adverse experiences, were dizziness [3.0% doravirine (overall) and 23.8% efavirenz], nightmare [1.2% doravirine (overall) and 9.5% efavirenz], abnormal dreams [9.0% doravirine (overall) and 7.1% efavirenz], and insomnia [5.4% doravirine (overall) and 7.1% efavirenz].
Based on the 24-week data from this dose-finding study, a single dose of 100 mg doravirine was chosen to be studied for the remainder of this study, up to 96 weeks.
About Doravirine
DORAVIRINE
Doravirine, also known as MK-1439, is an investigational next-generation, NNRTI being evaluated by Merck for the treatment of HIV-1 infection. In preclinical studies, doravirine demonstrated potent antiviral activity against HIV-1 with a characteristic profile of resistance mutations selected in vitro compared with currently available NNRTIs. In early clinical studies, doravirine demonstrated a pharmacokinetic profile supportive of once-daily dosing and did not show a significant food effect.
Merck’s Commitment to HIV
For more than 25 years, Merck has been at the forefront of the response to the HIV epidemic, and has helped to make a difference through our proud legacy of commitment to innovation, collaborating with the community, and expanding global access to medicines. Merck is dedicated to applying our scientific expertise, resources and global reach to deliver healthcare solutions that support people living with HIV worldwide.
About Merck
Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.
PATENT
The compound 3 -chloro-5-( { 1 – [(4-methyl-5 -oxo-4,5 -dihydro- 1 H- 1 ,2,4-triazol-3 – yl)methyl]-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl}oxy)benzonitrile has the following chemical structure.
Anhydrous 3 -chloro-5-( { 1 – [(4-methyl-5 -oxo-4,5 -dihydro- 1 H- 1 ,2,4-triazol-3 -yl)methyl] -2-oxo-4- (trifluoromethyl)-l,2-dihydropyridin-3-yl}oxy)benzonitrile is known to exist in three crystalline forms – Form I, Form II and Form III. The differential scanning calorimetry (DSC) curve for crystalline anhydrous Form II shows an endotherm with an onset at 230.8° C, a peak maximum at 245.2°C, and an enthalpy change of 3.7 J/g, which is due to polymorphic conversion of anhydrous Form II to anhydrous Form I, and a second melting endotherm with an onset at 283.1°C, a peak maximum at 284.8°C, and an enthalpy change of 135.9 J/g, due to melting of Anhydrous Form I. Alternative production and the ability of this compound to inhibit HIV reverse transcriptase is illustrated in WO 201 1/120133 Al, published on October 6, 201 1, and US 201 1/0245296 Al, published on October 6, 201 1, both of which are hereby incorporated by reference in their entirety.
The process of the present invention offers greater efficiency, reduced waste, and lower cost of goods relative to the methods for making the subject compounds existing at the time of the invention. Particularly, the late stage cyanation and methylation steps are not required.
The following examples illustrate the invention. Unless specifically indicated otherwise, all reactants were either commercially available or can be made following procedures known in the art. The following abbreviations are used:
EXAMPLE 1
Step 1
1 2
3-(Chloromethyl)-l-(2-methoxypropan-2-yl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (2): A
100 ml round bottom flask equipped with stir bar and a nitrogen inlet was charged with 1 (5 g, 33.9 mmol) and (lS)-(+)-10-camphorsulfonic acid (0.39 g, 1.694 mmol) at ambient temperature. After 2,2-dimethoxy propane (36.0 g, 339 mmol) was charged at ambient temperature, the resulting mixture was heated to 45°C. The resulting mixture was stirred under nitrogen at 45°C for 18 hours and monitored by HPLC for conversion of the starting material (< 5% by HPLC). After the reaction was completed, the batch was taken on to the next step without further workup or isolation. ‘H NMR (CDCI3, 500 MHz): 4.45 (s, 2H), 3.35 (s, 3H), 3.21 (s, 3H), 1.83 (s, 6H).
Step 2
3-Fluoro-l-((l-(2-methoxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)methyl)-4-(trifluoromethyl)pyridin-2(lH)-one (3): A mixture of 2 (100 mg, 93.1% purity, 0.49 mmol), pyridone (1 17 mg, 97.6% purity, 0.49 mmol) and K2CO3 (82 mg, 0.59 mmol) in DMF (0.5 ml) was aged with stirring at ambient temperature for 3h. After the reaction was completed, the batch was taken on to the next step without further work up or isolation.
Step 3
3-Chloro-5-((l-((l-(2-methoxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)methyl)-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (4): To a mixture of compound 3 in DMF (reaction mixture from the previous step) was added 3-chloro-5- hydroxybenzonitrile (1.77 g, 1 1.5 mmol) at ambient temperature. The resulting mixture was then heated to 95-100°C and held for 20 hours.
Upon completion (typically 18-20 hours), the reaction was cooled to room temperature, diluted with ethyl acetate and washed with water. The aqueous cut was back extracted with ethyl acetate. The organic layers were combined and then concentrated to an oil. MeOH (80 ml) was added and the resulting slurry was taken on to the next step. XH NMR (CDC13, 500 MHz): 7.60 (d, IH), 7.42 (s, IH), 7.23 (s, IH), 7.12 (s, IH), 6.56 (d, IH), 5.14 (s, 2H), 3.30 (s, 3H), 3.22 (s, 3H), 1.82 (s, 6H).
Step 4
4 5
3-Chloro-5-((l-((4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)methyl)-2-oxo-4- (trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (5): To a solution of 4 (5.74 g., 1 1.53 mmol) in MeOH (from previous step) was added concentrated hydrochloric acid (lml, 12.18 mmol) at ambient temperature. The resulting mixture was agitated for 1 hour at room temperature.
The resulting solids were collected by filtration and dried under a nitrogen sweep, providing 5 as a white solid (2.63 g, 46% yield): XH NMR (DMSO, 400 MHz): 1 1.74 (S, IH), 7.92 (d, IH), 7.76 (s, IH), 7.61 (s, IH), 7.54 (s, IH), 6.69 (d, IH), 5.15 (s, 2H), 3.10 (s, 3H)
EXAMPLE 2
Step 1
Phenyl methylcarbamate: 40% Aqueous methylamine (500 g, 6.44 mol) was charged to a 2 L vessel equipped with heat/cool jacket, overhead stirrer, temperature probe and nitrogen inlet. The solution was cooled to -5 °C. Phenyl chloroformate (500.0 g, 3.16 mol) was added over 2.5 h maintaining the reaction temperature between -5 and 0 °C. On complete addition the white slurry was stirred for lh at ~0 °C.
The slurry was filtered, washed with water (500 mL) and dried under 2 sweep overnight to afford 465g (96%> yield) of the desired product as a white crystalline solid; 1H NMR (CDCI3, 500 MHz): δ 7.35 (t, J = 8.0 Hz, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 4.95 (br s, 1H), 2.90 (d, J = 5 Hz, 3H).
Step 2
2-(2-Hydroxyacetyl)-N-methylhydrazinecarboxamide: Part A: Phenyl methylcarbamate (300 g, 1.95 mol) was charged to a 2 L vessel with cooling jacket, overhead stirrer, temperature probe, reflux condenser and nitrogen inlet. IPA (390 mL) was added at 23 °C. Hydrazine hydrate (119 g, 2.33 mol) was added and the slurry heated to 75 °C for 6 h.
Part B: On complete reaction (>99% conversion by HPLC), IPA (810 mL) and glycolic acid (222 g, 2.92 mol) were added and the mixture stirred at 83-85 °C for 10-12 h. The reaction mixture is initially a clear colorless solution. The mixture is seeded with product (0.5 g) after 4h at 83-85 °C. The slurry was slowly cooled to 20 °C over 2h and aged for lh.
The slurry was filtered and washed with IPA (600 mL). The cake was dried under 2 sweep to afford 241.8g (81% yield) of the desired product as a white crystalline solid: XH NMR (D20, 500 MHz): δ 4.11 (s, 2H), 2.60 (s, 3H).
Step 3
3-(Hydroxymethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one: 2-(2-Hydroxyacetyl)-N- methylhydrazinecarboxamide (130 g @ ~95wt%, 0.84 mol), w-propanol (130 mL) and water (130 mL) were charged to a 1 L vessel with jacket, overhead stirrer, temperature probe, reflux condenser and nitrogen inlet. Sodium hydroxide (pellets, 16.8 g, 0.42 mol) was added and the slurry warmed to reflux for 3h. The reaction mixture was cooled to 20 °C and the pH adjusted to 6.5 (+/- 0.5) using cone hydrochloric acid (28.3 mL, 0.34 mol). Water was azeotropically removed under vacuum at 40-50 °C by reducing the volume to -400 mL and maintaining that volume by the slow addition of n-propanol (780 mL). The final water content should be <3000 ug/mL. The resultant slurry (~ 400 mL) was cooled to 23 °C and heptane (390 ml) was added. The slurry was aged lh at 23 °C, cooled to 0 °C and aged 2h. The slurry was filtered, the cake washed with 1 :2 n-PrOH/heptane (100 mL) and dried to provide 125g (85% yield) of an off- white crystalline solid. The solid is ~73 wt% due to residual inorganics (NaCl): ‘H NMR (CD3OD, 500 MHz): δ 3.30 (s, 3H), 4.46 (s, 2H).
Step 4
3-(Chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (1): A mixture of 3- (Hydroxymethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (54 g, at 73wt%, 307 mmol) in ethyl acetate (540 mL) was stirred at 45 °C. SOCI2 (26.9 mL, 369 mmol) was added over 30-45 min and aged at 50 °C for 2h. Monitor reaction progress by HPLC. On complete reaction (>99.5% by area at 210nm.), the warm suspension was filtered and the filter cake (mainly NaCl) was washed with ethyl acetate (108 mL). The combined filtrate and wash were concentrated at 50-60 °C under reduced pressure to approximately 150 mL. The resulting slurry was cooled to -10 °C and aged lh. The slurry was filtered and the filter cake washed with ethyl acetate (50 mL). The cake was dried under 2 sweep to afford 40. lg (86% yield) of the desired product as a bright yellow solid: ‘H NMR (CD3OD, 500 MHz): δ 3.30 (s, 3H), 4.58 (s, 2H).
EXAMPLE 3
3-fluoro-4-(trifluoromethyl)pyridin-2(lH)-one (2): To a 250 ml round bottom flask equipped with overhead stirring and a nitrogen inlet was added a mixture of sulfuric acid (24.31 ml, 437 mmol) and water (20.00 ml). To this was added 2,3-difluoro-4-(trifluoromethyl)pyridine (6.83 ml, 54.6 mmol) and the mixture was heated to 65 °C and stirred for 4 h. By this time the reaction was complete, and the mixture was cooled to room temperature. To the flask was slowly added 5M sodium hydroxide (43.7 ml, 218 mmol), maintaining room temperature with an ice bath. The title compound precipitates as a white solid during addition. Stirring was maintained for an additional lh after addition. At this time, the mixture was filtered, the filter cake washed with 20 mL water, and the resulting white solids dried under nitrogen. 3-fluoro-4- (trifluoromethyl)pyridin-2(lH)-one (2) was obtained as a white crystalline solid (9.4g, 51.9 mmol, 95 % yield): ¾ NMR (CDC13, 400 MHz): 12.97 (br s, 1H), 7.36 (d, 1H), 6.44 (m, 1H).
EXAMPLE 4
Step 1 – Ethyl Ester Synthesis Experimental Procedure;
Ethyl 2-(3-chloro-5-cyanophenoxy)acetate (A): A 1L round bottom flask equipped with overhead stirring was charged with 3-chloro-5-hydroxybenzonitrile (50.0 g, 98 wt% purity, 319 mmol) and 15% aqueous DMF (200 mL DMF + 35.5 mL FLO). To the resulting solution was added diisopropylethylamine (61.3 mL, 99.0% purity, 1.1 equiv) and ethyl 2-bromoacetate (35.7 g, 98% purity, 1.15 equiv) at ambient temperature. The resulting solution was warmed to 50°C under nitrogen and aged for 12 h. Upon completion of the reaction the batch was cooled to 0- 5°C. To the clear to slightly cloudy solution was added 5% seed (3.8g, 16.0 mmol). H20 (64.5mL) was added to the thin suspension via syringe pump over 3h while maintaining the temp at 0-5 °C. Additional FLO (200mL) was added over lh while maintaining the temp at 0-5 °C. The final DMF/FLO ratio is 1 : 1.5 (10 vol). The resulting slurry was typically aged lh at 0-5 °C. The batch was filtered and the cake slurry washed with 2: 1 DMF/water (150 mL, 3 vol), followed by water (200 mL, 4 vol). The wet cake was dried on the frit with suction under a nitrogen stream at 20-25 °C; note: heat must not be applied during drying as product mp is 42 °C. The cake is considered dry when H20 is <0.2%. Obtained 73.4 g ethyl ester as a light tan solid, 96% yield (corrected), 99.5 LCAP: XH NMR (CDC13, 400 MHz) δ = 7.29 (s, 1H), 7.15 (s, 1H), 7.06 (s, 1H), 4.67 (s, 2H), 4.32 (q, 2H), 1.35 (t, 3H) ppm. Step 2 – Pyridone Synthesis
Synthetic Scheme; batch
TEA, TFAA, 10 °C;
then MeOH, rt
[isolated solid, A] [PhMe exit stream, B]
[PhMe/MeOH solution, C] [PhMe/MeOH/NH3 solution, D] [isolated solid, E]
Experimental Procedures;
Aldol Condensation, Ester A to Diene C
(2E/Z,4E)-Ethyl 2-(3-chloro-5-cyanophenoxy)-5-ethoxy-3-(trifluoromethyl)penta-2,4- dienoate (C): Ester A (25.01 g, 104.4 mmol, 1.00 equiv) was charged to toluene (113.43 g, 131 mL, 5.24 vol) and 4-ethoxy-l, l, l-trifluoro-3-buten-2-one (26.43 g, 157.2 mmol, 1.51 equiv) was added.
The flow reactor consisted of two feed solution inlets and an outlet to a receiving vessel. The flow reactor schematic is shown in Figure 1.
The ester solution was pumped to one flow reactor inlet. Potassium tert-pentoxide solution was pumped to the second reactor inlet. Trifluoroacetic anhydride was added continuously to the receiver vessel. Triethylamine was added continuously to the receiver vessel. The flow rates were: 13 mL/min ester solution, 7.8 mL/min potassium tert-pentoxide solution, 3.3 mL/min trifluoroacetic anhydride and 4.35 mL/min triethylamine.
Charged toluene (50 mL, 2 vol) and potassium trifluoroacetate (0.64 g, 4.21 mmol, 0.04 equiv) to the receiver vessel. The flow reactor was submerged in a -10 °C bath and the pumps were turned on. The batch temperature in the receiver vessel was maintained at 5 to 10 °C throughout the run using a dry ice/acetone bath. After 13.5 min the ester solution was consumed, the reactor was flushed with toluene (10 mL) and the pumps were turned off.
The resulting yellow slurry was warmed to room temperature and aged for 4.5 h. Charged methanol (160 mL) to afford a homogeneous solution which contained 81.20 area percent diene C by HPLC analysis.
The solution of diene C (573 mL) was used without purification in the subsequent reaction. Cyclization, Diene C to E
3-Chloro-5-((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (E): To a solution of diene C in PhMe/MeOH (573 mL; 40.69 g, 104.4 mmol theoretical C) was charged methanol (25 mL, 0.61 vol). Ammonia (32 g, 1.88 mol, 18 equiv based on theoretical C) was added and the solution was warmed to 60 °C. The reaction was aged at 60 °C for 18 h. The temperature was adjusted to 35-45 °C and the pressure was decreased maintain a productive distillation rate. The batch volume was reduced to -300 mL and methanol (325 mL, 8 vol) was charged in portions to maintain a batch volume between 250 and 350 mL. The heating was stopped and the system vented. The resulting slurry was cooled to room temperature and aged overnight.
The batch was filtered and the cake washed with methanol (3x, 45 mL). The wet cake was dried on the frit with suction under a nitrogen stream to afford 18.54 g of a white solid: XH NMR (DMSO-i/6, 500 MHz): δ 12.7 (br s, 1H), 7.73 (t, 1H, J= 1.5 Hz), 7.61-7.59 (m, 2H), 7.53 (t, 1H, J= 2.0 Hz), 6.48 (d, 1H, J= 7.0 Hz) ppm.
Step 3 – Chlorination, Alkylation and Isolation of 3-Chloro-5-({l-[(4-methyl-5-oxo-4,5-dihydro- lH-l,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl}oxy)benzonitrile
3-(Chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one: 3-(Hydroxymethyl)-4-methyl-lH- l,2,4-triazol-5(4H)-one (1.638 kg of 68wt%, 8.625 mol) and N-methylpyrrolidinone (8.9 L) was charged into a 30 L vessel. The suspension was aged for lOh at ambient temperature. The slurry was filtered through a 4L sintered glass funnel under 2 and the filter cake (mainly NaCl) was washed with NMP (2.23 L). The combined filtrate and wash had a water content of 5750 μg/mL. The solution was charged to a 75L flask equipped with a 2N NaOH scrubber to capture off-gasing vapors. Thionyl chloride (0.795 L, 10.89 mol) was added over lh and the temperature rose to 35 °C. HPLC analysis indicated that the reaction required an additional thionyl chloride charge (0.064 L, 0.878 mol) to bring to full conversion. The solution was warmed to 50 °C, placed under vacuum at 60 Torr (vented to a 2N NaOH scrubber), and gently sparged with subsurface N2 (4 L/min). The degassing continued for lOh until the sulfur dioxide content in the solution was <5 mg/mL as determined by quantitative GC/MS. The tan solution of 3-(chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one in NMP weighed 13.0 kg and was assayed at 9.63 wt% providing 1.256 kg (97% yield).
3-chloro-5-((l-((4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)methyl)-2-oxo-4- (trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile: To a 75L flask was charged a 9.63wt% solution of 3-(chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one in NMP (1 1.6 kg, 7.55 mol), 3 -chloro-5 -((2-oxo-4-(trifluoromethyl)- 1 ,2-dihydropyridin-3 -yl)oxy)benzonitrile (2.00 kg, 6.29 mol), NMP (3.8 L) and 2-methyl-2-butanol (6.0 L). To the resulting suspension was slowly added N,N-diisopropylethylamine (4.38 L, 25.2 mol) over 4h. The reaction was aged 18h at ambient temperature. The reaction is considered complete when HPLC indicates <1% 3 -chloro-5 -((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile remaining. The tan solution was quenched with acetic acid (1.26 L, 22.0 mol) and aged at ambient temperature overnight. The tan solution was warmed to 70 °C. Water (2.52 L) was added and the batch was seed with anhydrate Form II (134 g). The thin suspension was aged lh at 70 °C. Additional water (14.3 L) was added evenly over 7 h. The slurry was aged 2h at 70 °C and then slowly cooled to 20 °C over 5 h. The slurry was filtered and washed with 2 : 1 NMP/water (6 L), followed by water washes (6 L x 2). The filter cake was dried over a 2 sweep to give 2.53 kg (85% yield – corrected) of a white solid that was confirmed to be crystalline Form II by X-ray powder detraction analysis.
PATENT
The following scheme is an example of Step 3A.
EXAMPLE 1
1
Step 1
c| 0. h CH3NH3 Me.NA0.Ph
H
Phenyl methylcarbamate: 40% Aqueous methylamine (500 g, 6.44 mol) was charged to a 2 L vessel equipped with heat/cool jacket, overhead stirrer, temperature probe and nitrogen inlet. The solution was cooled to -5 °C. Phenyl chloroformate (500.0 g, 3.16 mol) was added over 2.5 h maintaining the reaction temperature between -5 and 0 °C. On complete addition the white slurry was stirred for lh at ~0 °C.
The slurry was filtered, washed with water (500 mL) and dried under a nitrogen sweep overnight to afford 465g (96% yield) of the desired product as a white crystalline solid; XH NMR (CDCI3, 500 MHz): δ 7.35 (t, J = 8.0 Hz, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 4.95 (br s, 1H), 2.90 (d, J = 5 Hz, 3H).
Step 2
2-(2-Hydroxyacetyl)-N-methylhydrazinecarboxamide: Part A: Phenyl methylcarbamate (300 g, 1.95 mol) was charged to a 2 L vessel with cooling jacket, overhead stirrer, temperature probe, reflux condenser and nitrogen inlet. IPA (390 mL) was added at 23 °C. Hydrazine hydrate (119 g, 2.33 mol) was added and the slurry heated to 75 °C for 6 h.
Part B: On complete reaction (>99% conversion by HPLC), IPA (810 mL) and glycolic acid (222 g, 2.92 mol) were added and the mixture stirred at 83-85 °C for 10-12 h. The reaction mixture was initially a clear colorless solution. The mixture was seeded with product (0.5 g) after 4h at 83-85 °C. The slurry was slowly cooled to 20 °C over 2h and aged for lh. Seed was used to advance the crystallization, but the crystalline product can be precipitated and isolated without seed by allowing the solution to age at 83-85 °C for 4 hours.
The slurry was filtered and washed with IPA (600 mL). The cake was dried under a nitrogen sweep to afford 241.8g (81% yield) of the desired product as a white crystalline solid: XH NMR (D20, 500 MHz): δ 4.11 (s, 2H), 2.60 (s, 3H).
Step 3
3-(Hydroxymethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one: 2-(2-Hydroxyacetyl)-N-methylhydrazinecarboxamide (130 g @ ~95wt%, 0.84 mol), w-propanol (130 mL) and water (130 mL) were charged to a 1 L vessel with jacket, overhead stirrer, temperature probe, reflux condenser and nitrogen inlet. Sodium hydroxide (pellets, 16.8 g, 0.42 mol) was added and the slurry warmed to reflux for 3h. The reaction mixture was cooled to 20 °C and the pH adjusted to 6.5 (+/- 0.5) using concentrated hydrochloric acid (28.3 mL, 0.34 mol). Water was
azeotropically removed under vacuum at 40-50 °C by reducing the volume to -400 mL and maintaining that volume by the slow addition of n-propanol (780 mL). The final water content was <3000 ug/mL. The resultant slurry (~ 400 mL) was cooled to 23 °C and heptane (390 ml) was added. The slurry was aged lh at 23 °C, cooled to 0 °C and aged 2h. The slurry was filtered, the cake washed with 1 :2 n-PrOH/heptane (100 mL) and the filter cake was dried under a nitrogen sweep to provide 125g (85% yield) of an off-white crystalline solid. The solid was -73 wt% due to residual inorganics (NaCl): ¾ NMR (CD3OD, 500 MHz): δ 3.30 (s, 3H), 4.46 (s, 2H).
Step 4
3-(Chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (1): A mixture of 3-(Hydroxymethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (54 g, at 73wt%, 307 mmol) in ethyl acetate (540 mL) was stirred at 45 °C. SOCl2 (26.9 mL, 369 mmol) was added over 30-45 min and aged at 50 °C for 2h. The reaction progress was monitored by HPLC. On complete reaction (>99.5% by area at 210nm), the warm suspension was filtered and the filter cake (mainly NaCl) was washed with ethyl acetate (108 mL). The combined filtrate and wash were concentrated at 50-60 °C under reduced pressure to approximately 150 mL. The resulting slurry was cooled to – 10 °C and aged lh. The slurry was filtered and the filter cake washed with ethyl acetate (50 mL). The cake was dried under a nitrogen sweep to afford 40. lg (86% yield) of the desired product as a bright yellow solid: XH NMR (CD3OD, 500 MHz): δ 3.30 (s, 3H), 4.58 (s, 2H).
EXAMPLE 2
Step 1 – Ethyl Ester Synthesis
Experimental Procedure;
A
Ethyl 2-(3-chloro-5-cyanophenoxy)acetate (A): A 1L round bottom flask equipped with overhead stirring was charged with 3-chloro-5-hydroxybenzonitrile (50.0 g, 98 wt% purity, 319 mmol) and 15% aqueous DMF (200 mL DMF + 35.5 mL Η20). To the resulting solution was added diisopropylethylamine (61.3 mL, 99.0% purity, 1.1 equiv) and ethyl 2-bromoacetate (35.7 g, 98% purity, 1.15 equiv) at ambient temperature. The resulting solution was warmed to 50°C under nitrogen and aged for 12 h. Upon completion of the reaction the batch was cooled to 0-5°C. To the clear to slightly cloudy solution was added 5% seed (3.8g, 16.0 mmol). H20 (64.5mL) was added to the thin suspension via syringe pump over 3h while maintaining the temperature at 0-5 °C. Additional H20 (200mL) was added over lh while maintaining the temp at 0-5 °C. The final DMF/H20 ratio is 1 : 1.5. The resulting slurry was aged lh at 0-5 °C. The batch was filtered and the cake slurry washed with 2: 1 DMF/water (150 mL), followed by water (200 mL). The wet cake was dried on the frit with suction under a nitrogen stream at 20-25 °C. The cake is considered dry when H20 is <0.2%. Obtained 73.4 g ethyl ester as a light tan solid, 96% yield: XH NMR (CDC13, 400 MHz) δ = 7.29 (s, 1H), 7.15 (s, 1H), 7.06 (s, 1H), 4.67 (s, 2H), 4.32 (q, 2H), 1.35 (t, 3H) ppm. Seed was used to advance the crystallization, but the crystalline product can be precipitated and isolated without seed by allowing the solution to age at 0-5 °C for at least about 2 hours.
Step 2 – Pyridone Synthesis
Synthetic Scheme;
Experimental Procedures;
Aldol Condensation
(2E/Z,4E)-Ethyl 2-(3-chloro-5-cyanophenoxy)-5-ethoxy-3-(trifluoromethyl)penta-2,4-dienoate (C): Ethyl 2-(3-chloro-5-cyanophenoxy)acetate (25.01 g, 104.4 mmol, 1.00 equiv) was charged to toluene (113.43 g, 131 mL) and 4-ethoxy-l, l,l-trifluoro-3-buten-2-one (26.43 g, 157.2 mmol, 1.51 equiv) was added.
The flow reactor consisted of two feed solution inlets and an outlet to a receiving vessel. The flow reactor schematic is shown in Figure 1.
The ester solution was pumped to one flow reactor inlet. Potassium tert-amylate solution was pumped to the second reactor inlet. Trifluoroacetic anhydride was added continuously to the receiver vessel. Triethylamine was added continuously to the receiver vessel.
The flow rates were: 13 mL/min ester solution, 7.8 mL/min potassium tert-amylate solution, 3.3 mL/min trifluoroacetic anhydride and 4.35 mL/min triethylamine.
Charged toluene (50 mL) and potassium trifluoroacetate (0.64 g, 4.21 mmol, 0.04 equiv) to the receiver vessel. The flow reactor was submerged in a -10 °C bath and the pumps were turned on. The batch temperature in the receiver vessel was maintained at 5 to 10 °C throughout the run using a dry ice/acetone bath. After 13.5 min the ester solution was consumed, the reactor was flushed with toluene (10 mL) and the pumps were turned off.
The resulting yellow slurry was warmed to room temperature and aged for 4.5 h. Charged methanol (160 mL) to afford a homogeneous solution which contained 81.20 LCAP diene .
The solution of diene (573 mL) was used without purification in the subsequent reaction.
Cyclization
3-Chloro-5-((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (E): To a solution of diene in PhMe/MeOH (573 mL; 40.69 g, 104.4 mmol theoretical) was charged methanol (25 mL). Ammonia (32 g, 1.88 mol, 18 equiv based on theoretical) was added and the solution was warmed to 60 °C. The reaction was aged at 60 °C for 18 h. The temperature was adjusted to 35-45 °C and the pressure was decreased to maintain a productive distillation rate. The batch volume was reduced to -300 mL and methanol (325 mL) was charged in portions to maintain a batch volume between 250 and 350 mL. The heating was stopped and the system vented. The resulting slurry was cooled to room temperature and aged overnight.
The batch was filtered and the cake washed with methanol (3x, 45 mL). The wet cake was dried on the frit with suction under a nitrogen stream to afford 18.54 g of a white solid: XH NMR (DMSO-ifc, 500 MHz): δ 12.7 (br s, 1H), 7.73 (t, 1H, J= 1.5 Hz), 7.61-7.59 (m, 2H), 7.53 (t, 1H, J= 2.0 Hz), 6.48 (d, 1H, J= 7.0 Hz) ppm.
Step 3 – Chlorination, Alkylation and Isolation of 3-Chloro-5-({l-[(4-methyl-5-oxo-‘ dihydro-lH-l,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl}oxy)benzonitrile
3-(Chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one: 3-(Hydroxymethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (1.638 kg of 68wt%, 8.625 mol) and N-methylpyrrolidinone (8.9 L) was charged into a 30 L vessel. The suspension was aged for lOh at ambient temperature. The slurry was filtered through a 4L sintered glass funnel under 2 and the filter cake (mainly NaCl) was washed with NMP (2.23 L). The combined filtrate and wash had a water content of 5750 μg/mL. The solution was charged to a 75L flask equipped with a 2N NaOH scrubber to capture off-gasing vapors. Thionyl chloride (0.795 L, 10.89 mol) was added over lh and the temperature rose to 35 °C. HPLC analysis indicated that the reaction required an additional thionyl chloride charge (0.064 L, 0.878 mol) to bring to full conversion. The solution was warmed to 50 °C, placed under vacuum at 60 Torr (vented to a 2N NaOH scrubber), and gently sparged with subsurface nitrogen (4 L/min). The degassing continued for lOh until the sulfur dioxide content in the solution was <5 mg/mL as determined by quantitative GC/MS. The tan solution of 3-(chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one in NMP weighed 13.0 kg and was assayed at 9.63 wt% providing 1.256 kg (97% yield).
3-chloro-5-((l-((4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)methyl)-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile: To a 75L flask was charged a 9.63wt% solution of 3-(chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one in NMP (1 1.6 kg, 7.55 mol), 3-chloro-5-((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (2.00 kg, 6.29 mol), NMP (3.8 L) and 2-methyl-2-butanol (6.0 L). To the resulting suspension was slowly added N,N-diisopropylethylamine (4.38 L, 25.2 mol) over 4h. The reaction was aged 18h at ambient temperature. The reaction is considered complete when HPLC indicated <1% 3-chloro-5-((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile remaining. The tan solution was quenched with acetic acid (1.26 L, 22.0 mol) and aged at ambient temperature overnight. The tan solution was warmed to 70 °C. Water (2.52 L) was added and the batch was seeded with anhydrate Form II (134 g)(procedures for making anhydrate Form II are described in WO2014/052171). The thin suspension was aged lh at 70 °C. Additional water (14.3 L) was added evenly over 7 h. The slurry was aged 2h at 70 °C and then slowly cooled to 20 °C over 5 h. The slurry was filtered and washed with 2 : 1 NMP/water (6 L), followed by water washes (6 L x 2). The filter cake was dried under N2 to give 2.53 kg (85% yield) of a white solid that was confirmed to be crystalline Form II of the title compound by X-ray powder detraction analysis.
EXAMPLE 3
Ethyl 2-(3-chloro-5-cyanophenoxy)acetate (A):
70%
Step 3
Three step one pot sequence
Steps 1 and 2:
To an oven dried 250mL round bottom flask was added sodium 2-methylpropan-2-olate (12.85 g, 134 mmol) and BHT (0.641 g, 2.91 mmol) then added DMF (30mL). After lOmin, a light yellow solution resulted. 2-Phenylethanol (7.66 ml, 63.9 mmol) was added and the solution exothermed to 35 °C. The light yellow solution was warmed to 55 °C and then a solution of 3,5-dichlorobenzonitrile (10 g, 58.1 mmol) in DMF (15mL) was added over 2h via syringe pump. The resulting red-orange suspension was aged at 55-60 °C. After 2h, HPLC showed >98% conversion to the sodium phenolate.
Step 3:
The suspension was cooled to 10 °C, then ethyl 2-bromoacetate (8.70 ml, 78 mmol) was added over lh while maintaining the temperature <20 °C. The resulting mixture was aged at ambient temperature. After lh, HPLC showed >99% conversion to the title compound.
Work-up and isolation:
To the suspension was added MTBE (50mL) and H20 (50mL) and the layers were separated. The organic layer was washed with 20% aq brine (25mL). The organic layer was assayed at 12.5g (90% yield). The organic layer was concentrated to -38 mL, diluted with hexanes (12.5mL) and then cooled to 5 °C. The solution was seeded with 0.28g (2 wt%) of crystalline ethyl 2-(3-chloro-5-cyanophenoxy)acetate and aged 0.5h at 5 °C to give a free flowing slurry. Hexane (175mL) was added to the slurry over lh at 0-5 °C. The slurry was filtered at 0-5 °C, washed with hexane (50 mL) and dried under a nitrogen sweep to give 9.8g (70% yield) of the title compound as a white crystalline solid. Seed was used to advance the crystallization, but the crystalline product can be precipitated and isolated without seed by allowing the solution to age at 0-5 °C for at least about 2 hours.
Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses
Bioorg Med Chem Lett 2014, 24(3): 917
http://www.sciencedirect.com/science/article/pii/S0960894X13014546
The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.
Scheme 1.
Reagents and conditions: (a) K2CO3, NMP, 120 °C; (b) KOH, tert-BuOH, 75 °C; (c) Zn(CN)2, Pd(PPh3)4, DMF, 100 °C.
Reagents and conditions: (a) K2CO3, DMF, −10 °C; (b) MeI or EtI, K2CO3, DMF.
36 IS DORAVIRINE
PATENT
WO 2011120133
http://www.google.com/patents/WO2011120133A1?cl=en
Scheme I depicts a method for preparing compounds of Formula I in which hydroxypyridine 1-1 is alkylated with chlorotriazolinone 1-2 to provide 1-3 which can be selectively alkylated with an alkyl halide (e.g., methyl iodide, ethyl iodide, etc.) to afford the desired 1-4. Scheme I
Scheme II depicts an alternative route to compounds of the present invention, wherein fluorohydroxypyridine II-l can be alkylated with chlorotriazolinone II-2 to provide the alkylated product II-3 which can be converted to the desired II-5 via nucleophilic aromatic substitution (S] fAr) using a suitable hydroxyarene II-4.
Scheme II
Hydroxypyridines of formula I-l (Scheme 1) can be prepared in accordance with Scheme III, wherein a SNAr reaction between pyridine III-l (such as commercially available 2- chloro-3-fluoro-4-(trifluoromethyl)pyridine) and hydroxyarene H-4 can provide chloropyridine III-2, which can be hydrolyzed under basic conditions to the hydroxypyridine I-l. Scheme III
Another method for preparing hydroxypyridines of formula I-l is exemplified in Scheme IV, wherein S Ar coupling of commercially available 2-chloro-3-fluoro-4- nitropyridone-N-oxide IV-1 with a suitable hydroxyarene II-4 provides N-oxide IV-2, which can first be converted to dihalides IV-3 and then hydro lyzed to hydroxypyridine IV-4. Further derivatization of hydroxypyridine IV-4 is possible through transition metal-catalyzed coupling processes, such as Stille or boronic acid couplings using a PdLn catalyst (wherein L is a ligand such as triphenylphosphine, tri-tert-butylphosphine or xantphos) to form hydroxypyridines IV-5, or amination chemistry to form hydroxypyridines IV-6 in which R2 is N(RA)RB.
Scheme IV
IV-1
– – Scheme V depicts the introduction of substitution at the five-position of the hydroxypyridines via bromination, and subsequent transition metal-catalyzed chemistries, such as Stille or boronic acid couplings using PdLn in which L is as defined in Scheme IV to form hydroxypyridines V-3, or amination chemistry to form hydroxypyridines V-4 in which R3 is N(RA)RB.
Scheme V
As shown in Scheme IV, fiuorohydroxypyridines II-l (Scheme II) are available from the commercially available 3-fluoroypridines VI- 1 through N-oxide formation and rearrangement as described in Konno et al., Heterocycles 1986, vol. 24, p. 2169.
Scheme VI
The following examples serve only to illustrate the invention and its practice. The examples are not to be construed as limitations on the scope or spirit of the invention.
The term “room temperature” in the examples refers to the ambient temperature which was typically in the range of about 20°C to about 26°C.
EXAMPLE 1
3-Chloro-5-({ l-[(4-methyl-5-oxo-4,5-dihydro-lH-l ,2,4-triazol-3-yl)methyl]-2-oxo-4- (trifluoromethyl)-l ,2-dihydropyridin-3-yl}oxy)benzonitrile (1-1)
Step 1(a):
A mixture of the 3-bromo-5-chlorophenol (3.74 g; 18.0 mmol), 2-chloro-3-fluoro- 4-(trifluoromethyl)pyridine (3.00 g; 15.0 mmol) and 2CO3 (2.49 g; 18.0 mmol) in NMP (15 mL) was heated to 120°C for one hour, then cooled to room temperature. The mixture was then diluted with 250 mL EtOAc and washed with 3 x 250 mL 1 :1 H20:brine. The organic extracts were dried (Na2S04) and concentrated in vacuo. Purification by ISCO CombiFlash (120 g column; load with toluene; 100:0 to 0:100 hexanes:CH2Cl2 over 40 minutes) provided title compound (1-2) as a white solid. Repurification of the mixed fractions provided additional title compound. lH NMR (400 MHz, CDCI3): δ 8.55 (d, J = 5.0 Hz, 1 H); 7.64 (d, J = 5.0 Hz, 1 H);
7.30 (s, 1 H); 6.88 (s, 1 H); 6.77 (s, 1 H).
3-(3-bromo-5-chlorophenoxy)-4-(trifluoromethyl)pyridin-2-ol (1-3)
To a suspension of 3-(3-bromo-5-chlorophenoxy)-2-chloro-4- (trifluoromethyl)pyridine (1-2; 3.48 g; 8.99 mmol) in lBuOH (36 mL) was added KOH (1.51 g; 27.0 mmol) and the mixture was heated to 75°C overnight, at which point a yellow oily solid had precipitated from solution, and LCMS analysis indicated complete conversion. The mixture was cooled to room temperature, and neutralized by the addition of -50 mL saturated aqueous NH4CI. The mixture was diluted with 50 mL H2O, then extracted with 2 x 100 mL EtOAc. The combined organic extracts were dried (Na2S04) and concentrated in vacuo. Purification by ISCO CombiFlash (120 g column; dry load; 100:0 to 90: 10 CH2Cl2:MeOH over 40 minutes) provided the title compound (1-3) as a fluffy white solid. lH NMR (400 MHz, DMSO): δ 12.69 (s, 1 H); 7.59 (d, J = 6.9 Hz, 1 H); 7.43 (t, J = 1.7 Hz, 1 H); 7.20 (t, J = 1.9 Hz, 1 H); 7.13 (t, J = 2.0 Hz, 1 H); 6.48 (d, J = 6.9 Hz, 1 H).
3-chloro-5-{[2-hydroxy-4-(trifluoromethyl)pyridin-3-yl]oxy}benzonitrile (1-4)
To a suspension of 3-(3-bromo-5-chlorophenoxy)-4-(trifluoromethyl)pyridin-2-ol (1-3; 3.25 g; 8.82 mmol) in NMP (29 mL) was added CuCN (7.90 g; 88 mmol) and the mixture was heated to 175°C for 5 hours, then cooled to room temperature slowly. With increased fumehood ventilation, 100 mL glacial AcOH was added, then 100 mL EtOAc and the mixture was filtered through Celite (EtOAc rinse). The filtrate was washed with 3 x 200 mL 1 : 1 H20:brine, then the organic extracts were dried (Na2S04) and concentrated in vacuo.
Purification by ISCO CombiFlash (120 g column; dry load; 100:0 to 90:10 CH2Cl2:MeOH over 40 minutes), then trituration of the derived solid with Et20 (to remove residual NMP which had co-eluted with the product) provided the title compound (1-4). lH NMR (400 MHz, DMSO): δ 12.71 (s, 1 H); 7.75 (s, 1 H); 7.63-7.57 (m, 2 H); 7.54 (s, 1 H); 6.49 (d, J = 6.9 Hz, 1 H).
Step 1(d): 5-(chloromethyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (1-5)
The title compound was prepared as described in the literature: Cowden, C. J.; Wilson, R. D.; Bishop, B. C; Cottrell, I. F.; Davies, A. J.; Dolling, U.-H. Tetrahedron Lett. 2000, 47, 8661.
3 -chloro-5 -( { 2-oxo- 1 – [(5 -oxo-4,5 -dihydro- 1 H- 1 ,2,4-triazol-3 -yl)methyl] – 4- (trifiuoromethyl)- 1 ,2-dihydropyridin-3 -yl } oxy)benzonitrile (1-6)
A suspension of the 3-chloro-5-{[2-hydroxy-4-(trifluoromethyl)pyridin-3- yl]oxy}benzonitrile (1-4; 2.00 g; 6.36 mmol), 5-(chloromethyl)-2,4-dihydro-3H-l,2,4-triazol-3- one (1-5; 0.849 g; 6.36 mmol) and K2CO3 (0.878 g; 6.36 mmol) in DMF (32 mL) was stirred for 2 hours at room temperature, at which point LCMS analysis indicated complete conversion. The mixture was diluted with 200 mL Me-THF and washed with 150 mL 1 : 1 : 1 H20:brine:saturated aqueous NH4CI, then further washed with 2 x 150 mL 1 : 1 H20:brine. The aqueous fractions were further extracted with 150 mL Me-THF, then the combined organic extracts were dried (Na2S04) and concentrated in vacuo. Purification by ISCO CombiFlash (80 g column; dry load; 100:0 to 90:10 EtOAc:EtOH over 25 minutes) provided the title compound (1-6) as a white solid. lH NMR (400 MHz, DMSO): δ 1 1.46 (s, 1 H); 1 1.39 (s, 1 H); 7.93 (d, J = 7.3 Hz, 1 H); 7.76 (s, 1 H); 7.58 (s, 1 H); 7.51 (s, 1 H); 6.67 (d, J = 7.3 Hz, 1 H); 5.02 (s, 2 H).
Step 1(f): 3 -chloro-5 -( { 1 – [(4-methyl-5-oxo-4,5 -dihydro- 1 H- 1 ,2,4-triazol-3 -yl)methyl] -2- oxo-4-(trifluoromethyl)- 1 ,2-dihydropyridin-3 -yl } oxy)benzonitrile (1 -1 )
A solution of 3-chloro-5-({2-oxo-l -[(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)methyl]- 4-(trifluoromethyl)-l ,2-dihydropyridin-3-yl}oxy)benzonitrile (1-6; 2.37 g; 5.76 mmol) and K2CO3 (0.796 g; 5.76 mmol) in DMF (58 mL) was cooled to 0°C, then methyl iodide (0.360 mL; 5.76 mmol) was added. The mixture was allowed to warm to room
temperature, and stirred for 90 minutes, at which point LCMS analysis indicated >95%
conversion, and the desired product of -75% LCAP purity, with the remainder being unreacted starting material and 6/s-methylation products. The mixture was diluted with 200 mL Me-THF, and washed with 3 x 200 mL 1 : 1 H20:brine. The aqueous fractions were further extracted with 200 mL Me-THF, then the combined organic extracts were dried (Na2S04) and concentrated in vacuo. The resulting white solid was first triturated with 100 mL EtOAc, then with 50 mL THF, which provided (after drying) the title compound (1-1) of >95% LCAP. Purification to >99% LCAP is possible using Prep LCMS (Max-RP, 100 x 30 mm column; 30-60% CH3CN in 0.6% aqueous HCOOH over 8.3 min; 25 mL/min). lH NMR (400 MHz, DMSO): δ 1 1.69 (s, 1 H); 7.88 (d, J = 7.3 Hz, 1 H); 7.75 (s, 1 H); 7.62 (s, 1 H); 7.54 (s, 1 H); 6.67 (d, J = 7.3 Hz, 1 H); 5.17 (s, 2 H); 3.1 1 (s, 3 H). EXAMPLE 1A
3-Chloro-5-({ l-[(4-methyl-5-oxo-4,5-dihydro-lH-l ,2,4-triazol-3-yl)methyl]-2- (trifluoromethyl)-l ,2-dihydropyridin-3-yl}oxy)benzonitrile (1-1)
Step lA(a): 2-chloro-3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine (1A-2)
A mixture of the 3-chloro-l-iodophenol (208 g; 816.0 mmol), 2-chloro-3-fluoro-
4-(trifluoromethyl)pyridine (155 g; 777.0 mmol) and K2CO3 (161 g; 1 165.0 mmol) in NMP (1.5 L) was held at 60°C for 2.5 hours, and then left at room temperature for 2 days. The mixture was then re-heated to 60°C for 3 hours, then cooled to room temperature. The mixture was then diluted with 4 L EtOAc and washed with 2 L water + 1 L brine. The combined organics were then washed 2x with 500 mL half brine then 500 mL brine, dried over MgS04 and concentrated to afford crude 1A-2. lH NMR (500 MHz, DMSO) δ 8.67 (d, J = 5.0 Hz, 1 H), 7.98 (d, J = 5.0 Hz, 1 H), 7.63-7.62 (m, 1 H), 7.42-7.40 (m, 1 H), 7.22 (t, J = 2.1 Hz, 1 H).
Step lA(b): 2-chloro-3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine (1A-3)
To a suspension of 3-(3-chloro-5-iodophenoxy)-2-chloro-4- (trifluoromethyl)pyridine (1A-2; 421 g, 970 mmol) in t-BuOH (1 L) was added KOH (272 g, 4850 mmol) and the mixture was heated to 75°C for 1 hour, at which point HPLC analysis indicated >95% conversion. The t-BuOH was evaporated and the mixture diluted with water (7mL/g, 2.4L) and then cooled to 0°C, after which 12N HC1 (~240mL) was added until pH 5. This mixture was then extracted with EtOAc (20mL/g, 6.5L), back extracted with EtOAc 1 x 5mL/g (1.5L), washed 1 x water:brine 1 : 1 (l OmL/g, 3.2L), 1 x brine (lOmL/g, 3.2L), dried over MgS04, filtered and concentrated to afford a crude proudct. The crude product was suspended in MTBE (2.25 L, 7mL/g), after which hexanes (1 L, 3 mL/g) was added to the suspension over ten minutes, and the mixturen was aged 30minutes at room temperature. The product was filtered on a Buchner, rinsed with MTBE hexanes 1 :2 (2 mL/g = 640 mL), then hexanes
(640mL), and dried on frit to afford 1A-3. lH NMR (400 MHz, acetone-d6): δ 11.52 (s, 1 H); 7.63 (d, J = 7.01 Hz, 1 H); 7.50-7.48 (m, 1 H); 7.34-7.32 (m, 1 H); 7.09-7.07 (m, 1 H); 6.48 (d, J = 7.01 Hz, 1 H).
Step lA(c): 3-chloro-5-{[2-hydroxy-4-(trifluoromethyl)pyridin-3-yl]oxy}benzonitrile (1-4)
A solution of 3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridin-2-ol (1A-3; 190 g; 457 mmol) in DMF (914 mL) was degassed for 20 minutes by bubbling N2, after which CuCN (73.7 g; 823 mmol) was added, and then the mixture was degassed an additional 5 minutes. The mixture was then heated to 120°C for 17 hours, then cooled to room temperature and partitioned between 6 L MeTHF and 2 L ammonium buffer (4:3: 1 = NH4CI
sat/water/NH-iOH 30%). The organic layer washed with 2 L buffer, 1 L buffer and 1 L brine then, dried over MgS04 and concentrated. The crude solid was then stirred in 2.2 L of refluxing
MeCN for 45 minutes, then cooled in a bath to room temperature over 1 hour, aged 30 minutes, then filtered and rinsed with cold MeCN (2 x 400mL). The solid was dried on frit under N2 atm for 60 hours to afford title compound 1-4. lH NMR (400 MHz, DMSO): δ 12.71 (s, 1 H); 7.75 (s, 1 H); 7.63-7.57 (m, 2 H); 7.54 (s, 1 H); 6.49 (d, J = 6.9 Hz, 1 H).
Steps lA(d) and lA(e)
The title compound 1-1 was then prepared from compound 1-4 using procedures similar to those described in Steps 1(d) and 1(e) set forth above in Example 1.
Patent
Crystalline anhydrous Form II of doravirine, useful for the treatment of HIV-1 and HIV-2 infections. The compound was originally claimed in WO2008076223. Also see WO2011120133. Merck & Co is developing doravirine (MK-1439), for the oral tablet treatment of HIV-1 infection. As of April 2014, the drug is in Phase 2 trials.
The next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) doravirine (formerly MK-1439) showed potent antiretroviral activity and good tolerability in combination with tenofovir/FTC (the drugs in Truvada) in a dose-finding study presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI) last week in Boston.
NNRTIs are generally well tolerated and well suited for first-line HIV treatment, but as a class they are susceptible to resistance. Pre-clinical studies showed that Merck’s doravirine has a distinct resistance profile and remains active against HIV with common NNRTI resistance mutations including K103N and Y181C.
As reported at last year’s CROI, doravirine reduced HIV viral load by about 1.3 log in a seven-day monotherapy study. Doravirine is processed by the CYP3A4 enzyme, but it is neither a CYP3A4 inducer nor inhibitor, so it is not expected to have major drug interaction concerns.
Javier Morales-Ramirez from Clinical Research Puerto Rico reported late-breaking findings from a phase 2b study evaluating the safety and efficacy of various doses of doravirine versus efavirenz (Sustiva) for initial antiretroviral therapy.
This study included 208 treatment-naive people living with HIV from North America, Europe and Asia. More than 90% were men, 74% were white, 20% were black and the median age was 35 years. At baseline, the median CD4 cell count was approximately 375 cells/mm3 and 13% had received an AIDS diagnosis. Study participants were stratified by whether their viral load was above (about 30%) or below 100,000 copies/ml; median HIV RNA was approximately 4.5 log10.
Morales-Ramirez reported 24-week results from part 1 of the study, which will continue for a total of 96 weeks. In this part, participants were randomly allocated into five equal-sized arms receiving doravirine at doses of 25, 50, 100 or 200mg once daily, or else efavirenz once daily, all in combination with tenofovir/FTC.
At 24 weeks, 76.4% of participants taking doravirine had viral load below 40 copies/ml compared with 64.3% of people taking efavirenz. Response rates were similar across doravirine doses (25mg: 80.0%; 50mg: 76.2%; 100mg: 71.4%; 200mg: 78.0%). More than 80% of participants in all treatment arms reached the less stringent virological response threshold of <200 copies/ml.
Both doravirine and efavirenz worked better for people with lower pre-treatment viral load in an ad hoc analysis. For people with <100,000 copies/ml at baseline, response rates (<40 copies/ml) ranged from 83 to 89% with doravirine compared with 74% with efavirenz. For those with >100,000 copies/ml, response rates ranged from 50 to 91% with doravirine vs 54% with efavirenz.
Median CD4 cell gains were 137 cells/mm3 for all doravirine arms combined and 121 cells/mm3 for the efavirenz arm.
Doravirine was generally safe and well tolerated. People taking doravirine were less than half as likely as people taking efavirenz to experience serious adverse events (3.0% across all doravirine arms vs 7.1% with efavirenz) or to stop treatment for this reason (2.4 vs 4.8%). Four people taking doravirine and two people taking efavirenz discontinued due to adverse events considered to be drug-related.
The most common side-effects were dizziness (3.6% with doravirine vs 23.8% with efavirenz), abnormal dreams (9.0 vs 7.1%), diarrhoea (4.8 vs 9.5%), nausea (7.8 vs 2.4%) and fatigue (6.6 vs 4.8%). Other central nervous system (CNS) adverse events of interest included insomnia (5.4 vs 7.1%), nightmares (1.2 vs 9.5%) and hallucinations (0.6 vs 2.4%). Overall, 20.5% of people taking doravirine reported at least one CNS side-effect, compared with 33.3% of people taking efavirenz.
People taking doravirine had more favourable lipid profiles and less frequent liver enzyme (ALT and AST) elevations compared with people taking efavirenz.
The researchers concluded that doravirine demonstrated potent antiretroviral activity in treatment-naive patients, a favourable safety and tolerability profile, and fewer drug-related adverse events compared with efavirenz.
Based on these findings, the 100mg once-daily dose was selected for future development and will be used in part 2 of this study, a dose-confirmation analysis that will enrol an additional 120 participants.
In the discussion following the presentation, Daniel Kuritzkes from Harvard Medical School noted that sometimes it takes longer for viral load to go down in people who start with a high level, so with further follow-up past 24 weeks doravirine may no longer look less effective in such individuals.
Morales-Ramirez J et al. Safety and antiviral effect of MK-1439, a novel NNRTI (+FTC/TDF) in ART-naive HIV-infected patients. 21st Conference on Retroviruses and Opportunistic Infections, Boston, abstract 92LB, 2014.
Wednesday Mar 19 | Posted by: roboblogger | Full story: EDGE
Earlier this month, at the 21st Conference on Retroviruses and Opportunistic Infections , Merck indicated plans to initiate a Phase 3 clinical trial program for doravirine in combination with ARV therapy in the second half of 2014.
Doravirine is non-nucleoside reverse transcriptase inhibitor (NNRTI) currently in phase III clinical trials for the treatment of HIV infection. Herein we describe a robust kilo-scale synthesis for its manufacture. The structure and origin of major impurities were determined and their downstream fate-and-purge studied. This resulted in a redesign of the route to introduce the key nitrile functionality via a copper mediated cyanation which allowed all impurities to be controlled to an acceptable level. The improved synthesis was scaled to prepare ∼100 kg batches of doravirine to supply all preclinical and clinical studies up to phase III. The synthesis affords high-quality material in a longest linear sequence of six steps and 37% overall yield.
Gauthier, D. R., Jr.; Sherry, B. D.; Cao, Y.; Journet, M.; Humphrey, G.; Itoh, T.; Mangion, I.; Tschaen, D. M.Org. Lett. 2015, 17, 1353, DOI: 10.1021/ol503625z………..http://pubs.acs.org/doi/full/10.1021/ol503625z
The development of an efficient and robust process for the production of HIV NNRTI doravirine is described. The synthesis features a continuous aldol reaction as part of a de novo synthesis of the key pyridone fragment. Conditions for the continuous flow aldol reaction were derived using microbatch snapshots of the flow process.
Doravirine (1). A 75 L flask was charged a 9.63 wt% solution of 16 in NMP (11.6kg, 7.55 mol). Charged 10(2.00 kg, 6.29 mol), NMP
(3.8 L) and 2-methyl-2-butanol (6.0 L). To theresulting suspension was slowly added N,N-diisopropylethylamine (4.38 L, 25.2 mol) over 4 h. The reaction was aged for 18 h at ambient temperature. The tan solution was quenched with acetic acid (1.26 L, 22.0 mol) and aged at ambient temperature overnight. The tan solution was warmed to 70 °C. Water (2.52 L) was added and the batch was seeded with crystalline 1 (134 g) to induce crystallization. The thin suspension was aged 1 h at 70 °C. Additional water (14.3 L)
was added over 7 h. The slurry was aged for 2 h at 70 °C and slowly cooled to 20 °C over 5 h. The slurry was filtered and washed with 2:1 NMP/water (6 L), followed by water (6 L x 2). The filter cake was dried under nitrogen to give 2.53 kg (85% yield) of 1 as a white solid.
Characterization Data : 1H NMR (DMSO-d6, 500 MHz): δ 3.11 (s,3H), 5.17 (s, 2H), 6.66 (d, 1H, J = 7.4 Hz), 7.52 (m, 1H), 7.61 (dd, 1H, J = 2.4, 1.3 Hz), 7.74 (dd, 1H, J = 1.8, 1.4Hz), 7.89 (d, 1H, J = 7.4 Hz), 11.68 (s, 1H) ppm.
13C NMR (DMSO-d6, 125.7 MHz): δ 26.7, 43.3, 100.2, 113.6,116.8, 118.4, 121.1, 121.6, 126.5, 129.9, 134.9, 137.3, 140.1, 143.2, 155.0, 156.0, 157.2 ppm.
19F NMR (DMSO-d6,470.5 MHz): δ -62.3 ppm.
HMRS (ESI) calcd for C17H12N5O3F3Cl [M+H]+ 426.0581, found 426.0588.
13C NMR
1H NMR
| US20100034813 * | 8 Nov 2007 | 11 Feb 2010 | Yi Xia | Substituted pyrazole and triazole compounds as ksp inhibitors |
| US20100256181 * | 14 Nov 2008 | 7 Oct 2010 | Tucker Thomas J | Non-nucleoside reverse transcriptase inhibitors |
| US20110245296 * | 6 Oct 2011 | Jason Burch | Non-nucleoside reverse transcriptase inhibitors |
| Reference | ||
|---|---|---|
| 1 | * | COWDEN ET AL.: “A new synthesis of 1,2,4-triazolin-5-ones: application to the convergent synthesis of an NK1 antagonist.“, TETRAHEDRON LETTERS, vol. 41, no. 44, 2000, pages 8661 – 8664, XP004236142 |
| Patent ID | Date | Patent Title |
|---|---|---|
| US2015329521 | 2015-11-19 | PROCESS FOR MAKING REVERSE TRANSCRIPTASE INHIBITORS |
| US9150539 | 2015-10-06 | Crystalline form of a reverse transcriptase inhibitor |
| US2015232447 | 2015-08-20 | CRYSTALLINE FORM OF A REVERSE TRANSCRIPTASE INHIBITOR |
| US2013296382 | 2013-11-07 | NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS |
| US2011245296 | 2011-10-06 | NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS |
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
3-Chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydro-3-pyridinyl}oxy)benzonitrile
|
|
| Clinical data | |
| Routes of administration |
Oral[1] |
| Legal status | |
| Legal status |
|
| Identifiers | |
| CAS Number | 1338225-97-0 |
| ATC code | none |
| PubChem | CID 58460047 |
| ChemSpider | 28424197 |
| UNII | 913P6LK81M |
| KEGG | D10624 |
| ChEMBL | CHEMBL2364608 |
| Synonyms | MK-1439 |
| PDB ligand ID | 2KW (PDBe, RCSB PDB) |
| Chemical data | |
| Formula | C17H11ClF3N5O3 |
| Molar mass | 425.75 g/mol |
//////////Doravirine, MK-1439, 1338225-97-0 , Merck Sharp & Dohme Corp, Reverse transcriptase inhibitor, ANTIVIRAL, Non-nucleoside reverse transcriptase, HIV, Triazolinone, Pyridone, Inhibitor,
AND
Cn1c(n[nH]c1=O)Cn2ccc(c(c2=O)Oc3cc(cc(c3)Cl)C#N)C(F)(F)F
Sreeni Labs Private Limited, Hyderabad, India is ready to take up challenging synthesis projects from your preclinical and clinical development and supply from few grams to multi-kilo quantities. Sreeni Labs has proven route scouting ability to design and develop innovative, cost effective, scalable routes by using readily available and inexpensive starting materials. The selected route will be further developed into a robust process and demonstrate on kilo gram scale and produce 100’s of kilos of in a relatively short time.
Accelerate your early development at competitive price by taking your route selection, process development and material supply challenges (gram scale to kilogram scale) to Sreeni Labs…………
Sreeni Labs based in Hyderabad, India is working with various global customers and solving variety of challenging synthesis problems. Their customer base ranges from USA, Canada, India and Europe. Sreeni labs Managing Director, Dr. Sreenivasa Reddy Mundla has worked at Procter & Gamble Pharmaceuticals and Eli Lilly based in USA.
The main strength of Sreeni Labs is in the design, development of innovative and highly economical synthetic routes and development of a selected route into a robust process followed by production of quality product from 100 grams to 100s of kg scale. Sreeni Labs main motto is adding value in everything they do.
They have helped number of customers from virtual biotech, big pharma, specialty chemicals, catalog companies, and academic researchers and drug developers, solar energy researchers at universities and institutions by successfully developing highly economical and simple chemistry routes to number of products that were made either by very lengthy synthetic routes or by using highly dangerous reagents and Suzuki coupling steps. They are able to supply materials from gram scale to multi kilo scale in a relatively short time by developing very short and efficient synthetic routes to a number of advanced intermediates, specialty chemicals, APIs and reference compounds. They also helped customers by drastically reducing number of steps, telescoping few steps into a single pot. For some projects, Sreeni Labs was able to develop simple chemistry and avoided use of palladium & expensive ligands. They always begin the project with end in the mind and design simple chemistry and also use readily available or easy to prepare starting materials in their design of synthetic routes
Over the years, Sreeni labs has successfully made a variety of products ranging from few mg to several kilogram scale. Sreeni labs has plenty of experience in making small select libraries of compounds, carbocyclic compounds like complex terpenoids, retinal derivatives, alkaloids, and heterocyclic compounds like multi substituted beta carbolines, pyridines, quinolines, quinolones, imidazoles, aminoimidazoles, quinoxalines, indoles, benzimidazoles, thiazoles, oxazoles, isoxazoles, carbazoles, benzothiazoles, azapines, benzazpines, natural and unnatural aminoacids, tetrapeptides, substituted oligomers of thiophenes and fused thiophenes, RAFT reagents, isocyanates, variety of ligands, heteroaryl, biaryl, triaryl compounds, process impurities and metabolites.
Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They can also take up custom synthesis and scale up of medchem analogues and building blocks. They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving couple of PO based (fee for service) projects.
Some of the compounds prepared by Sreeni labs;
See presentation below
LINK ON SLIDESHARE
Managing Director at Sreeni Labs Private Limited\
QUOTE………….
One virtual biotech company customer from USA, through a common friend approached Sreeni Labs and told that they are buying a tetrapeptide from Bachem on mg scale at a very high price and requested us to see if we can make 5g. We accepted the challenge and developed solution phase chemistry and delivered 6g and also the process procedures in 10 weeks time. The customer told that they are using same procedures with very minor modifications and produced the tetrapeptide ip to 100kg scale as the molecule is in Phase III.
One East coast customer in our first meeting told that they are working with 4 CROs of which two are in India and two are in China and politely asked why they should work with Sreeni Labs. We told that give us a project where your CROs failed to deliver and we will give a quote and work on it. You pay us only if we deliver and you satisfy with the data. They immediately gave us a project to make 1.5g and we delivered 2g product in 9 weeks. After receiving product and the data, the customer was extremely happy as their previous CRO couldn’t deliver even a milligram in four months with 3 FTEs.
One Midwest biotech company was struggling to remove palladium from final API as they were doing a Suzuki coupling with a very expensive aryl pinacol borane and bromo pyridine derivative with an expensive ligand and relatively large amount of palldium acetate. The cost of final step catalyst, ligand and the palladium scavenging resin were making the project not viable even though the product is generating excellent data in the clinic. At this point we signed an FTE agreement with them and in four months time, we were able to design and develop a non suzuki route based on acid base chemistry and made 15g of API and compared the analytical data and purity with the Suzuki route API. This solved all three problems and the customer was very pleased with the outcome.
One big pharma customer from east coast, wrote a structure of chemical intermediate on a paper napkin in our first meeting and asked us to see if we can make it. We told that we can make it and in less than 3 weeks time we made a gram sample and shared the analytical data. The customer was very pleased and asked us to make 500g. We delivered in 4 weeks and in the next three months we supplied 25kg of the same product.
Through a common friend reference, a European customer from a an academic institute, sent us an email requesting us to quote for 20mg of a compound with compound number mentioned in J. med. chem. paper. It is a polycyclic compound with four contiguous stereogenic centers. We gave a quote and delivered 35 mg of product with full analytical data which was more pure than the published in literature. Later on we made 8g and 6g of the same product.
One West coast customer approached us through a common friend’s reference and told that they need to improve the chemistry of an advanced intermediate for their next campaign. At that time they are planning to make 15kg of that intermediate and purchased 50kg of starting raw material for $250,000. They also put five FTEs at a CRO for 5 months to optimize the remaining 5 steps wherein they are using LAH, Sodium azide, palladium catalyst and a column chromatography. We requested the customer not to purchase the 50kg raw material, and offered that we will make the 15kg for the price of raw material through a new route in less than three months time. You pay us only after we deliver 15 kg material. The customer didn’t want to take a chance with their timeline as they didn’t work with us before but requested us to develop the chemistry. In 7 weeks time, we developed a very simple four step route for their advanced intermediate and made 50g. We used very inexpensive and readily available starting material. Our route gave three solid intermediates and completely eliminated chromatographic purifications.
One of my former colleague introduced an academic group in midwest and brought us a medchem project requiring synthesis of 65 challenging polyene compounds on 100mg scale. We designed synthetic routes and successfully prepared 60 compounds in a 15 month time.
UNQUOTE…………
The man behind Seeni labs is Dr. Sreenivasa Reddy Mundla
Managing Director at Sreeni Labs Private Limited
Sreeni Labs Private Limited
Road No:12, Plot No:24,25,26
Links
LINKEDIN https://in.linkedin.com/in/sreenivasa-reddy-10b5876
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EMAIL mundlasr@hotmail.com, Info@sreenilabs.com, Sreeni@sreenilabs.com
Dr. Sreenivasa Reddy Mundla
Dr. M. Sreenivasa Reddy obtained Ph.D from University of Hyderabad under the direction Prof Professor Goverdhan Mehta in 1992. From 1992-1994, he was a post doctoral fellow at University of Wisconsin in Professor Jame Cook’s lab. From 1994 to 2000, worked at Chemical process R&D at Procter & Gamble Pharmaceuticals (P&G). From 2001 to 2007 worked at Global Chemical Process R&D at Eli Lilly and Company in Indianapolis.
In 2007 resigned to his job and founded Sreeni Labs based in Hyderabad, Telangana, India and started working with various global customers and solving various challenging synthesis problems.
The main strength of Sreeni Labs is in the design, development of a novel chemical route and its development into a robust process followed by production of quality product from 100 grams to 100’s of kg scale.
They have helped number of customers by successfully developing highly economical simple chemistry routes to number of products that were made by Suzuki coupling. they are able to shorten the route by drastically reducing number of steps, avoiding use of palladium & expensive ligands. they always use readily available or easy to prepare starting materials in their design of synthetic routes.
Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving PO based projects
August 2007 – Present (8 years 11 months)
Sreeni Labs Profile
March 2001 – August 2007 (6 years 6 months)
July 1994 – February 2001 (6 years 8 months)
With Sreenivasa Mundla, Narahara sastry, Ram Kishan Rao, Jagadeesh Bharatam, Jagadish Gunjur and Jagadish Bharatham.
PUBLICATIONS
Jianye Zhang · Zhiqian Dong · Sreenivasa Reddy Mundla · X Eric Hu · William Seibel ·Ruben Papoian · Krzysztof Palczewski · Marcin Golczak
Article: ChemInform Abstract: Regioselective Synthesis of 4Halo ortho-Dinitrobenzene Derivative
Aug 2010 · ChemInform
Hong-yu Li · William T. McMillen · Charles R. Heap · Denis J. McCann · Lei Yan · Robert M. Campbell · Sreenivasa R. Mundla · Chi-Hsin R. King · Elizabeth A. Dierks · Bryan D. Anderson · Karen S. Britt · Karen L. Huss
Apr 2008 · Journal of Medicinal Chemistry
Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer
Feb 2008 · ChemInform
Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer
Nov 2007 · Tetrahedron
Hong-yu Li · Yan Wang · Charles R Heap · Chi-Hsin R King · Sreenivasa R Mundla · Matthew Voss · David K Clawson · Lei Yan · Robert M Campbell · Bryan D Anderson · Jill R Wagner ·Karen Britt · Ku X Lu · William T McMillen · Jonathan M Yingling
Apr 2006 · Journal of Medicinal Chemistry
Hui Cao · Sreenivasa R. Mundla · James M. Cook
Aug 2003 · Tetrahedron Letters
Article: ChemInform Abstract: A New Method for the Synthesis of 2,6-Dinitro and 2Halo6-nitrostyrenes
Nov 2000 · ChemInform
Article: ChemInform Abstract: A Novel Method for the Efficient Synthesis of 2-Arylamino-2-imidazolines
TGF-β inhibitors
The present invention provides 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl) -5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate, i.e., Formula I.
EXAMPLE 1 Preparation of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl-5,6-dihydro-4H -pyrrolo[1,2-b]pyrazole monohydrate
Galunisertib
1H NMR (CDCl3): δ=9.0 ppm (d, 4.4 Hz, 1H); 8.23-8.19 ppm (m, 2H); 8.315 ppm (dd, 1.9 Hz, 8.9 Hz, 1H); 7.455 ppm (d, 4.4 Hz, 1H); 7.364 ppm (t, 7.7 Hz, 1H); 7.086 ppm (d, 8.0 Hz, 1H); 6.969 ppm (d, 7.7 Hz, 1H); 6.022 ppm (m, 1H); 5.497 ppm (m, 1H); 4.419 ppm (t, 7.3 Hz, 2H); 2.999 ppm (m, 2H); 2.770 ppm (p, 7.2 Hz, 7.4 Hz, 2H); 2.306 ppm (s, 3H); 1.817 ppm (m, 2H). MS ES+: 370.2; Exact: 369.16
ABOVE MOLECULE IS
https://newdrugapprovals.org/2016/05/04/galunisertib/
Galunisertib
Phase III
A TGF-beta receptor type-1 inhibitor potentially for the treatment of myelodysplastic syndrome (MDS) and solid tumours.
LY-2157299
CAS No.700874-72-2
READ MY PRESENTATION ON
KEYWORDS Sreenivasa Mundla Reddy, Managing Director, Sreeni Labs Private Limited, Hyderabad, Telangana, India, new, economical, scalable routes, early clinical drug development stages, Custom synthesis, custom manufacturing, drug discovery, PHASE 1, PHASE 2, PHASE 3, API, drugs, medicines
New Drug Approvals 