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Liarozole synthesis from Lednicer book 6 (Drugs of the Future citation).
Liarozole fumarate is prepared as shown in Scheme 20970301a. Anisol is reacted with 3-chlorobenzoyl chloride (I) under Friedel-Craft conditions to give (3-chlorophenyl)(4-methoxyphenyl)methanone (II). Nitration of (II) is carried out in dichloromethane at 10 C to yield (III). The methoxy group in (III) is replaced by the amino group by means of NH3 in 2-propanol at 100 C under pressure, giving (IV). By reduction of the keto function of (IV) with sodium borohydride in 2-propanol, the corresponding alcohol (V) is obtained, which upon treatment with 1,1′-carbonyldiimidazole in refluxing dichloromethane yields the imidazolyl compound (VI). Hydrogenation of the nitro group in (VI), followed by cyclization of (VII) in a refluxing mixture of formic acid and 4N hydrochloric acid, gives the benzimidazole derivative (VIII). Finally, the treatment of (VIII) with fumaric acid in ethanol yields liarozole fumarate (IX).
http://www.google.com/patents/WO1995022540A1?cl=en
Liarozole is a racemic mixture, i.e. a mixture of its optical isomers, and is specifically mentioned as compound 28 in EP-0,371,559. Said patent application mentions the use of compounds like liarozole in the treatment of epithelial disorders. EP-0,260,744 describes the use of compounds like liarozole for inhibiting or lowering androgen formation. Whereas EP-0,371,559 and EP-0,260,744 recognize that compounds like liarozole have stereochemically isomeric forms, no example of an enantiomerically pure form is given of liarozole.
Chemically liarozole is (±)-5-[3-chlorophenyl]-lH-imidazol-l-ylmethyl]-lH-benz- imidazole, and is represented by formula (I). As can be seen from the chemical structure, liarozole has one stereogenic center (indicated with an asterisk in formula (I)).
The subject of this invention is the enantiomerically pure dextrorotatory isomer or (+)-isomer of liarozole. Said isomer will hereinafter be referred to as (+)-liarozole. Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (-) or d and 1 are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is iaevorotatory and with (+) or d meaning that the compound is dextrorotatory. For a given chemical structure the optically active isomers having an opposite sign of optical rotation are called enantiomers. Said enantiomers are identical except that they are mirror images of one another. A 1: 1 -mixture of such enantiomers is called a racemic mixture.
General preparation of structures including liarozole have been extensively described in EP-0,371,559 and EP-0,260,744.
Enantiomerically pure (+)-liarozole may be prepared by reacting an enantiomerically pure intermediate diamine of formula (B)-(II) with formic acid or a functional derivative thereof.
Said functional derivative of formic acid is meant to comprise the halide, anhydride, amide and ester, including the ortho and imino ester form thereof. Also methanimidamide or an acid addition salt thereof can be used as cyclizing agent.
The general reaction conditions, work-up procedures and conventional isolation techniques for carrying out the above and following reactions are described in the prior art. When more specific conditions are required they are mentioned hereinunder. The enantiomerically pure intermediate diamine of formula (B)-(II) may be prepared by reducing an intermediate of formula (B)-(iπ) by a standard nitro-to-amine reduction reaction.
The desired enantiomer of the intermediate of formula (B)-(]H) can be prepared by fractional crystallization of a racemic mixture of the intermediate of formula (HI) with an enantiomerically pure chiral acid. Preferred chiral acid for the above fractional crystallization is 7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-l-methanesulfonic acid (i.e. 10-camphorsulfonic acid).
Appropriate solvents for carrying out said fractional crystallization are water, ketones, e.g. 2-propane, 2-butanone; alcohols, e.g. methanol, ethanol, 2-propanol. Mixtures of ketones and water are very suitable for the above fractional crystallization. Preferably a mixture of 2-propanone and water is used.
The ratio of water/2-propanone by volume may vary from 1/10 to 1/2. Preferred range of said ratio is 1/5 to 1/3.
The fractional crystallizations are suitably carried out below room temperature, preferably below 5°C.
It was also found that the subsequent reaction step can be carried out without any appreciable racemization.
Alternatively the (+)-isomer of the compound of formula (I) may be prepared by cyclizing an intermediate of formula (B)-(IV) following procedures as described above for the cyclization of intermediates of formula (B)-(II) and desulfurating the thus obtained intermediate of formula (B)-(V). In formulas (B)-(TV) and (B)-(V) R represents Ci^alkyl, wherein Ci-^alkyl means a straight or branch chained saturated hydrocarbon radicals having 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl. Preferably R is methyl.
The intermediates of formula (B)-(IV) may be prepared by reacting an intermediate of formula (B)-(VI) with a reagent of formula (VII), alkylating the thus formed thiourea derivative of formula (B)-(VIII) subsequently cyclizing the intermediate of formula
(B)-(D ), and reducing the nitro group of the intermediate (B)-(X). In the formulas
(Vπ), (B)-(Vm), (B)-(IX) and (B)-(X) R represents Ci^alkyl as defined hereinabove.
S OR
(B)-(IV)
Experimental part
A. Preparation of the intermediates
Example 1 a) A heterogeneous mixture of (±)-4-[(3-chlorophenyl)-lH-imidazol-l-ylmethyl]-2- nitrobenzenamine (the preparation of which is described in EP-371,559) (500 g) in
2-propanone (2000 ml) and water (100 ml) was stirred at 22°C. (-)-(lR)-7,7-dimethyl- 2-oxo-bicyclo[2.2.1]heptane-l-methanesulfonic acid (353.2 g) was added and the mixture became homogeneous after 10 minutes. The mixture was first stirred for 18 hours at 20°C and then for 3 hours at 0-5°C. The precipitate was filtered off, washed with 2-propanone/water 95/5 (150 ml) and dried, yielding 308.9 g (36.2%) of product A sample (306.7 g) was partitioned between dichloromethane (500 ml) and water (750 ml). Ammonium hydroxide (100 ml) was added. This mixture was stirred for 15 minutes. The aqueous layer was separated and extracted twice with dichloromethane (250 ml each time). The separated organic layer was washed with water (250 ml), dried, filtered and the solvent was evaporated, yielding 179.7 g of (-)-(B)-4-[(3-chlorophenyl)-
20 lH-imidazol-l-ylmethyl]-2-nitrobenzenamine; mp. 89.8°C; [α]D = -19.80° (c = 0.5% in methanol) (interm. 1). b) A mixture of intermediate (1)(179.7 g) in methanol (656 ml) and a solution of ammonia in methanol (32.7 ml) was hydrogenated at 20-25 °C with platinum on activated carbon (13.1 g) as a catalyst in the presence of thiophene (0.27 g). After uptake of hydrogen (3 eq.) the catalyst was filtered off and washed with 2-propanol (30 ml). A solution of hydrochloric acid in 2-propanol (522 ml) was added to the filtrate at <30°C. The mixture was stirred for 3 hours at 20 °C, then for 3 hours at 0-5 °C. The resulting precipitate was slowly filtered off, washed with methanol (100 ml) and dried
(50 °C), yielding 185.60 g (83.2%) (+)-(B)-4-[(3-chlorophenyl)-lH-imidazol-l-yl-
20 methyl]- 1,2-benzenediamine trihydrochloride; mp. 172.5°C; [α^ = +23.73° (c = 1% in methanol) (interm. 2).
Example 2 a) A mixture of (4-amino-3-nitrophenyl) (3-chlorophenyl)methanone (50 g), formamide (375 ml) and formic acid (63 ml) was stiιτed and refluxed for 17 hours. After cooling, the mixture was poured on ice. The precipitate was filtered off and dried, yielding 55 g (99.4%) of (±)-N-[(4-amino-3-nitrophenyl) (3-chlorophenyl)methyl]formamide (interm. 3). b) A mixture of intermediate (3) (50.7 g), hydrochloric acid 6N (350 ml) and 2-propanol (70 ml) was stirred and refluxed for 17 hours. The yellow precipitate was filtered off and dried in vacuo, yielding 51 g (97.8%) of (±)-4-amino-α-(3-chloro- phenyl)-3-nitrobenzenemethanamine monohydrochloride; mp. 263°C (interm.4). c) To a solution of intermediate (4) (43 g) in tetrahydrofuran (400 ml) at room temperature was added succesively N,N-diethylethanamine (13.8 g) and (R)-(-)-α- hydroxybenzeneacetic acid (20.8 g). Then a solution of 1-hydroxybenzotriazole monohydrate (22.2 g) in tetrahydrofuran (200 ml) was added. After complete addition a solution of N,N’-dicyclohexylcarbodiimide (33.9 g) in dichloromethane (300 ml) was introduced to the mixture. After stirring for 2 hours at room temperature N,N’- dicyclohexylurea was filtered off. The filtrate was washed with a solution of potassium carbonate (10%) and the organic layer was dried to give a mixture of diastereomers (60g) (fraction 1). The same experiment with intermediate (4) (16 g) as starting material resulted in a yield of 26 g of a mixture of diastereomers (fraction 2). Fraction 1 and 2 were combined and purified by HPLC (eluent : CH2θ2/ethyl acetate 90:10), yielding 30g (32.3%) of (±)-(R,B)-N-[(4-amino-3-nitrophenyl)(3-chlorophenyl)methyl]-α- hydroxybenzeneacetamide (interm.5). d) A mixture of intermediate (5) (30 g), hydrochloric acid 12N (300 ml) and 1-propanol (100 ml) was stirred and refluxed for 17 hours and poured on ice. The mixture was extracted with ethyl acetate. The aqueous phase was basified with ammonium hydroxide and extracted with dichloromethane. The dichloromethane extracts were dried, filtered and evaporated, yielding 7.3 g (36.0%) of (+)-(B)-4-amino-α-(3-chlorophenyl)-3- nitrobenzenemethanamine (interm. 6). e) A mixture of intermediate (6) (7.3 g), 2-isothiocyanato-l,l-dimethoxyethane (4.8 g) and methanol (75 ml) was stirred and refluxed for 2 hours. The mixture was evaporated to an oily residue, yielding 11 g (100%) of (+)-(B)-N-[(4-amino-3-nitrophenyl)(3- chlorophenyl)methyl]-N’-(2,2-dimethoxyethyl)thiourea (interm.7). f) A mixture of intermediate (7) (11 g), iodomethane (2 ml) and potassium carbonate (4.97 g) was stirred at room temperature for 48 hours. The solvent was evaporated and the residue was taken off with dichloromethane and washed with water. The organic layer was dried, filtered and evaporated, yielding 11.4 g of (+)-(S)-methyl (B)-N- [(4-amino-3-nitrophenyl)(3-chlorophenyl)methyl]-N’-(2,2-dimethoxyethyl)carbam- imidothioate as an oily residue (interm. 8). g) To intermediate (8) (11.4 g) at 0°C was added sulfuric acid (100ml) (precooled to 5°C). The mixture was stirred at 5°C until complete dissolution and then was warmed to room temperature. After stirring for 2 hours, the solution was poured on ice and basified with ammonium hydroxide. The aqueous solution was extracted with ethyl acetate. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (eluent : CH2CI2/CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 3.7 g (38.0%) of (+)-(B)-4-[(3-chlorophenyl)[2-(methylthio)-lH- imidazol-l-yl]methyl]-2-nitrobenzenamine (interm.9). h) A mixture of intermediate (9) (6.2 g), Raney nickel (6 g) and methanol (100 ml) was hydrogenated for 2 hours at 2 bar and at room temperature. After the calculated amount of hydrogen was taken up, the catalyst was filtered off. The filtrate, (+)-(B)-4-[(3- chlorophenyl)[2-(methylthio)-lH-imidazol-l-yl]methyl]-l,2-benzenediamine (interm. 10), was used for the next step. i) A mixture of intermediate (10) (5.7 g), methanimidamide monoacetate (5.2 g) and methanol (100 ml) was stirred and refluxed for 3 hours. The reaction mixture was evaporated and the residue was taken off in dichloromethane and washed with sodium hydrogen carbonate (10%). The organic layer was dried, filtered and evaporated. The oily residue was purified by column chromatography (eluent : CH2CI2/CH3OH 95:5). The eluent of the desired fraction was evaporated, yielding 4.9 g (83.7%) of (+)-(B)-5-[(3-cWorophenyl)[2-(methylthio)-lH-imidazol-l-yl]methyl]-lH-benzimidazole (interm. 11).
B. Preparation of the final compounds Example 3
A mixture of intermediate (2) (185 g) in water (512 ml) was stirred at 20 °C. Hydrochloric acid (289 ml) was added. Formic acid (85%) (61.17 ml) was added and this mixture was heated to 55°C. The reaction mixture was stirred for 3 hours at 55 °C and then cooled to 20°C. Dichloromethane (1223 ml) was added. Ammonium hydroxide (730 ml) was added dropwise at < 25°C. The separated organic layer was washed with water (500 ml), dried, filtered and the solvent was evaporated, yielding 152.88 g (108.5%) of product. A sample was dried (18 hours at 55 °C), yielding 3.18 g of (+)-(B)-5-[(3-chlorophenyl)-lH-imidazol-l-ylmethyl]-lH-benzimidazole; mp.
20 113.7°C; [αjj = +43.46° (c = 1% in methanol) (comp. 1).
Example 4
A mixture of intermediate (11) (4.9 g), Raney nickel (2 g) and ethanol (100ml) was stirred and refluxed for 5 days, while every day an additional amount of Raney nickel (2 g) was added. The catalyst was filtered off and rinsed with dichloromethane. The filtrate was evaporated and the residue was purified twice by column chromatography (silica gel; CH2CI2/CH3OH 95:5 ; CH2CI2/CH3OH NH4OH 80:20:3). The eluent of the desired fraction was evaporated and the residue was converted into the hydrochloride salt in 2-propanol and ethanol. The salt was recrystallized from 2-butanone, yielding 1.8 g (37.2%) of (+)-(B)-5-[(3-chlorophenyl)(lH-imidazol-l-yl)methyl]-lH-benzimidazole
20 monohydrochloride; mp. 212.1°C; [α]D = +42.43° (c = 1% in ethanol) (comp. 2)
Example 5
Compound (1) (149.7 g) was dissolved in 2-butanone (2424 ml). A mixture of hydrochloric acid in 2-propanol (82.6 ml) in 2-butanone (727 ml) was added over a 2 hour period at 20 °C. The reaction mixture was stirred for 16 hours at 20 °C. The precipitate was filtered off, washed with 2-butanone (242 ml) and dried (vacuum; 80°C); yielding 147.5 g (99.3%) of (+)-(B)-5-[(3-chlorophenyl)-lH-imidazol-l-ylmethyl]-lH-
20 benzimidazole monohydrochloride; mp. 214.5°C; [α] j = +36.20° (c = 1% in methanol) (comp. 2). Example 6
A mixture of compound (1) (0.72 g) in ethanol (5.1 ml; denaturated) was stirred at 20 °C until it became homogeneous. (E)-2-butenedioic acid (0.54 g) was added The mixture was stirred for 18 hours at 20 °C and then cooled 0-5 °C and precipitation resulted. More denaturated ethanol (2 ml) was added and the mixture was stirred for 2 hours at 20 °C. The precipitate was filtered off, washed with ethanol (3 ml; denaturated) and dried (vacuum; 50 °C), yielding 0.26 g (23.4%) (B)-5-[(3-chlorophenyl)-lH-imidazol-l-yl- methyl]-lH-benzimidazole (E)-2-butenedioate (2:3).ethanolate (2:1); mp. 111.2°C (comp. 3).
PAPER
Paper
1 Vahlquist, A; Blockhuys, S; Steijlen, P; Van Rossem, K; Didona, B; Blanco, D; Traupe, H (2013). “Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: Results of a randomized, double-blind, multinational, placebo-controlled phase II/III trial”. The British journal of dermatology 170 (1): n/a. doi:10.1111/bjd.12626. PMID 24102348.
Literature References: Inhibits cytochrome P450-dependent enzymes involved in steroid biosynthesis and retinoic acid catabolism. Prepn: A. H. M. Raeymaekers et al., EP 260744; eidem, US 4859684 (1988, 1989 both to Janssen). In vivo antitumor activity: R. Van Ginckel et al., Prostate 16, 313 (1990). Pharmacology and effect on steroid synthesis: J. Bruynseels et al., ibid., 345; and effect on retinoic acid: R. De Coster et al., J. Steroid Biochem. Mol. Biol. 43, 197 (1992). Clinical evaluation in prostate cancer: C. Mahler et al., Cancer 71, 1068 (1993); in psoriasis: P. Dockx et al., Br. J. Dermatol. 133, 426 (1995); in combination therapy for malignant brain tumors: M. E. Westarp et al., Onkologie 16, 22 (1993).
 |
|
| Names | |
|---|---|
| IUPAC name
6-[(3-Chlorophenyl)-imidazol-1-ylmethyl]-1H-benzimidazole
|
|
| Identifiers | |
| 115575-11-6 | |
| ChemSpider | 54664 |
| 5210 | |
| Jmol interactive 3D | Image |
| PubChem | 60652 |
| Properties | |
| C17H13ClN4 | |
| Molar mass | 308.77 g·mol−1 |
///////
C1=CC(=CC(=C1)Cl)C(C2=CC3=C(C=C2)N=CN3)N4C=CN=C4
ARN-509; cas 956104-40-8; ARN 509; UNII-4T36H88UA7;
ARN-509; JNJ-56021927; JNJ-927\
Phase III Prostate cancer
4-(7-(6-CYANO-5-(TRIFLUOROMETHYL)PYRIDIN-3-YL)-8-OXO-6-THIOXO-5,7-DIAZASPIRO[3.4]OCTAN-5-YL)-2-FLUORO-N-METHYLBENZAMIDE;
4-(7-(6-cyano-5-(trifluoroMethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspirooctan-5-yl)-2-fluoro-N-MethylbenzaMide;
| Molecular Formula: | C21H15F4N5O2S |
|---|---|
| Molecular Weight: | 477.434713 g/mol |
| Product Name | Sponsor Only | Condition | Start Date | End Date | Phase | Last Change Date |
|---|---|---|---|---|---|---|
| ARN-509 | Aragon Pharmaceuticals Inc | Hormone refractory prostate cancer | 31-JUL-10 | 30-JUN-13 | Phase 2 | 17-SEP-13 |
| Aragon Pharmaceuticals Inc | 31-MAR-13 | 30-JUN-13 | Phase 1 | 17-SEP-13 | ||
| Aragon Pharmaceuticals Inc | Hormone refractory prostate cancer | 31-OCT-13 | 31-DEC-16 | Phase 3 | 05-NOV-13 | |
| Aragon Pharmaceuticals Inc; Johnson & Johnson | Hormone refractory prostate cancer | 28-FEB-13 | 01-FEB-14 | Phase 1 | 07-OCT-13 | |
| Aragon Pharmaceuticals Inc | Hormone dependent prostate cancer | 28-FEB-13 | 28-FEB-18 | Phase 2 | 18-OCT-13 |
Apalutamide, also known as ARN-509 and JNJ-56021927 , is an androgen receptor antagonist with potential antineoplastic activity. ARN-509 binds to AR in target tissues thereby preventing androgen-induced receptor activation and facilitating the formation of inactive complexes that cannot be translocated to the nucleus. This prevents binding to and transcription of AR-responsive genes. This ultimately inhibits the expression of genes that regulate prostate cancer cell proliferation and may lead to an inhibition of cell growth in AR-expressing tumor cells.
Apalutamide (INN) (developmental code name ARN-509, also JNJ-56021927) is a non-steroidal antiandrogen that is under development for the treatment of prostate cancer.[1] It is similar to enzalutamide both structurally and pharmacologically,[2] acting as a selective competitive antagonist of the androgen receptor (AR), but shows some advantages, including greater potency and reduced central nervous system permeation.[1][3][4] Apalutamide binds weakly to the GABAA receptor similarly to enzalutamide, but due to its relatively lower central concentrations, may have a lower risk of seizures in comparison.[1][3][5] The drug has been found to be effective and well-tolerated in clinical trials thus far,[2][4] with the most common side effects reported including fatigue, nausea, abdominal pain, and diarrhea.[6][3][5] Apalutamide is currently in phase III clinical trials for castration-resistant prostate cancer.[7]
Recently, the acquired F876L mutation of the AR identified in advanced prostate cancer cells was found to confer resistance to both enzalutamide and apalutamide.[8][9] A newer antiandrogen, ODM-201, is not affected by this mutation, nor has it been found to be affected by any other tested/well-known AR mutations.[10]
Apalutamide may be effective in a subset of prostate cancer patients with acquired resistance to abiraterone acetate.[2]
The chemical structure of ARN-509 is very similar structure to that of Enzalutamide (MDV3100) with two minor modifications: (a) two methyl groups in the 5-member ring of MDV3100 is linked by a CH2 group in ARN-509; (b) the carbon atom in the benzene ring of MDV3100 is replaced by a nitrogen atom in ARN-509. ARN-509 is considered as a Me-Too drug of Enzalutamide (MDV3100). ARN-509 was claimed to be more active than Enzalutamide (MDV3100).
ARN-509 is a novel 2nd Generation anti-androgen that is targeted to treat castration resistant prostate cancers where 1st generation anti-androgens fail. ARN-509 is unique in its action in that it inhibits both AR nuclear translocation and AR binding to androgen response elements in DNA. Importantly, and in contrast to the first-generation anti-androgen bicalutamide, it exhibits no agonist activity in prostate cancer cells that over-express AR. ARN-509 is easily synthesized, and its oral bioavailability and long half-life allow for once-daily oral dosing. In addition, its excellent preclinical safety profile makes it well suited as either a mono- or a combination therapy across the entire spectrum of prostate cancer disease states. (source: http://www.aragonpharm.com/programs/arn509.htm).
ARN-509 is a competitive AR inhibitor, which is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/day of ARN-509 , whereas the same response required 100 mg/kg/day of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer. (source: Cancer Res. 2012 Jan 20. [Epub ahead of print] )
(source: Cancer Res. 2012 Jan 20. [Epub ahead of print] )
SYNTHESISS
WO 2008119015
WO2011103202
WO2014190895
WO2011103202
http://www.google.com/patents/WO2011103202A2?cl=en
Prostate cancer is one of the most common forms of cancer found in Western men and the second leading cause of cancer death in Western men. When prostate cancer is confined locally, the disease can usually be treated by surgery and/or radiation. Advanced disease is frequently treated with anti-androgen therapy, also known as androgen deprivation therapy. Administration of anti-androgens blocks androgen receptor (AR) function by competing for androgen binding; and therefore, anti-androgen therapy reduces AR activity. Frequently, such therapy fails after a time, and the cancer becomes hormone refractory, that is, the prostate cancer no longer responds to hormone therapy and the cancer does not require androgens to progress.
Overexpression of AR has been identified as a cause of hormone refractory prostate cancer (Nat. Med., 10:33-39, 2004; incorporated herein by reference). Overexpression of AR is sufficient to cause progression from hormone sensitive to hormone refractory prostate cancer, suggesting that better AR antagonists than the current drugs may be able to slow the progression of prostate cancer. It has been demonstrated that overexpression of AR converts anti-androgens from antagonists to agonists in hormone refractory prostate cancer. This work explains why anti-androgen therapy fails to prevent the progression of prostate cancer.
The identification of compounds that have a high potency to anatgonize AR activity would overcome the hormone refractory prostate cancer and slowdown the progression of hormone sensitive prostate cancer. Such compounds have been identified by Sayers et al. (WO 2007/126765, published Nov. 8, 2007; which is incorporated herein by reference). One compound is known as A52, a biarylthiohydantoin, and has the chemical structure
Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ (2015). “Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies”. Sci Rep 5: 12007. doi:10.1038/srep12007. PMC 4490394. PMID 26137992
11Clegg NJ, Wongvipat J, Tran C, Ouk S, Dilhas A, Joseph J, Chen Y, Grillot K, Bischoff ED, Cai L, Aparicio A, Dorow S, Arora V, Shao G, Qian J, Zhao H, Yang G, Cao C, Sensintaffar J, Wasielewska T, Herbert MR, Bonnefous C, Darimont B, Scher HI, Smith-Jones PM, Klang M, Smith ND, de Stanchina E, Wu N, Ouerfelli O, Rix P, Heyman R, Jung ME, Sawyers CL, Hager JH. ARN-509: a novel anti-androgen for prostate cancer treatment. Cancer Res. 2012 Mar 15;72(6):1494-1503. Epub 2012 Jan 20.PubMed PMID: 22266222.
| Patent ID | Date | Patent Title |
|---|---|---|
| US2014309262 | 2014-10-16 | ANDROGEN RECEPTOR MODULATOR FOR THE TREATMENT OF PROSTATE CANCER AND ANDROGEN RECEPTOR-ASSOCIATED DISEASES |
| US2014296312 | 2014-10-02 | TREATMENT OF BREAST CANCER |
| US2014243416 | 2014-08-28 | Topical Antiandrogen Therapy for the Treatment of Becker’s Nevus |
| US8802689 | 2014-08-12 | Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases |
| US2014107085 | 2014-04-17 | Bifunctional AKR1C3 Inhibitors/Androgen Receptor Modulators and Methods of Use Thereof |
| US2014088129 | 2014-03-27 | ANTI-ANDROGENS FOR THE TREATMENT OF NON-METASTATIC CASTRATE-RESISTANT PROSTATE CANCER |
| US2013225821 | 2013-08-29 | SYNTHESIS OF THIOHYDANTOINS |
| US2013116258 | 2013-05-09 | ANDROGEN RECEPTOR MODULATORS AND USES THEREOF |
| US2011003839 | 2011-01-06 | ANDROGEN RECEPTOR MODULATOR FOR THE TREATMENT OF PROSTATE CANCER AND ANDROGEN RECEPTOR-ASSOCIATED DISEASES |
| US2010190991 | 2010-07-29 | SYNTHESIS OF THIOHYDANTOINS |
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
4-[7-[6-Cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide
|
|
| Clinical data | |
| Pregnancy category |
|
| Routes of administration |
Oral |
| Identifiers | |
| CAS Number | 956104-40-8 |
| ATC code | None |
| PubChem | CID 24872560 |
| ChemSpider | 28424131 |
| Chemical data | |
| Formula | C21H15F4N5O2S |
| Molar mass | 477.434713 g/mol |
////////
CNC(=O)C1=C(C=C(C=C1)N2C(=S)N(C(=O)C23CCC3)C4=CN=C(C(=C4)C(F)(F)F)C#N)F
CNC(=O)C1=C(C=C(C=C1)N2C(=S)N(C(=O)C23CCC3)C4=CN=C(C(=C4)C(F)(F)F)C#N)F
Galeterone
SYNTHESIS SEE BELOW
A SARM potentially for the treatment of prostate cancer.
Research Code, TOK-001; VN; 124; 124-1; 1241
TOK-001; Galeterone; 851983-85-2; VN/124; UNII-WA33E149SW; VN/124-1;
CAS No. 851983-85-2(Galeterone)
(3S,8R,9S,10R,13S,14S)-17-(benzimidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-ol
Fast track 2012 f
| Molecular Formula: | C26H32N2O |
|---|---|
| Molecular Weight: | 388.54508 g/mol |
Galeterone (TOK-001 or VN/124-1) is a novel steroidal antiandrogen under development by Tokai Pharmaceuticals for the treatment of prostate cancer. It possesses a unique dual mechanism of action, acting as both an androgen receptor antagonist and an inhibitor of CYP17A1, an enzyme required for the biosynthesis of the androgens.[1] It shows selectivity for 17,20-lyase over 17-hydroxylase.[2]
As of 2016, galeterone is being compared to enzalutamide in a phase III clinical trial (ARMOR3-SV) for AR-V7-expressing metastatic castration-resistant prostate cancer.[3][4]
Specific Androgen Receptor Modulator CYP17 Inhibitor TOK-001 is an orally bioavailable small-molecule androgen receptor modulator and CYP17 lyase inhibitor with potential antiandrogen activity. Galeterone exhibits three distinct mechanisms of action: 1) as an androgen receptor antagonist, 2) as a CYP17 lyase inhibitor and 3) by decreasing overall androgen receptor levels in prostate cancer tumors, all of which may result in a decrease in androgen-dependent growth signaling. Localized to the endoplasmic reticulum (ER), the cytochrome P450 enzyme CYP17 (P450C17 or CYP17A1) exhibits both 17alpha-hydroxylase and 17,20-lyase activities, and plays a key role in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens.
Tokai’s lead product candidate is galeterone, a highly-selective, oral small molecule with the potential to transform the treatment of prostate cancer. We are focusing our late-stage development of galeterone on the treatment of men with metastatic, castration-resistant prostate cancer, or CRPC, whose prostate tumor cells express the AR-V7 splice variant.
We are conducting ARMOR3-SV, a Phase 3 clinical trial of galeterone evaluating whether administration of galeterone results in a statistically significant increase in radiographic progression-free survival as compared to Xtandi® (enzalutamide), an oral therapy currently approved for the treatment of CRPC, in AR-V7 positive metastatic CRPC patients. ARMOR3-SV is the first pivotal trial in prostate cancer to employ a precision medicine approach for patient selection. For more information regarding ARMOR3-SV, click here.
Galeterone has been studied in over 250 subjects in Phase 1 and Phase 2 clinical trials, including in CRPC patients with and without the AR-V7 splice variant. In these trials, galeterone demonstrated good tolerability and showed clinically meaningful reductions in levels of prostate specific antigen, or PSA, a biochemincal marker used to evaluate prostate cancer patients for signs of response to therapy.
We are currently focusing our late-stage development of galeterone on AR-V7 positive metastatic CRPC patients because it represents an unmet need in prostate cancer and our precision medicine approach provides an efficient development path. Based on the data we and our collaborators have produced to date, we also believe there is rationale for the broader clinical exploration of galeterone in the future.
Galeterone acts by disrupting the androgen receptor signaling pathway. This pathway is activated by the binding of male hormones (also known as androgens), such as testosterone and dihydrotestosterone (DHT) to androgen receptors in prostate cancer cells.
Galeterone disrupts the activation of the androgen receptor pathway in three ways:
Tokai retains global rights to galeterone. We intend to commercialize galeterone in the United States on our own, and to seek a partner to further develop and commercialize galeterone outside of the United States.
Galeterone has been granted Fast Track designation by U.S. Food and Drug Administration for the treatment of CRPC. Fast Track designation is designed to facilitate the development and expedite review of drugs intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.
Androgen receptor degradation, which reduces the amount of androgen receptor protein in the tumor cells.
Androgen receptor antagonism, which blocks the binding of testosterone or DHT with the androgen receptor.
Inhibition of the enzyme CYP17, which blocks the synthesis of testosterone.
DETAILED DESCRIPTION
1J loss reaction.
(1) raw material specifications to match.
acetate pregnancy dehydropregnenolone: toluene + ethanol: Batch steep: hydrochloric acid amine light = 1: 3: 0 4: 0.213, which pregnenolone acetate pregnancy 160kg, toluene + ethanol 320kg + 160kg, approved Steep 64kg, hydrochloric acid amine light 34kg.
(2) process operation.
In the first input 1000L tank oximation with hydroxylamine hydrochloride in pyridine, and then pumped into a mixed solvent of toluene and ethanol, the reaction solution was stirred and heated to complete dissolution, pregnancy-dehydropregnenolone acetate was added and heated under reflux for 3 hours, cooling and crystallization, The Department conducted into the centrifuge centrifugal drying, apply a recovery from the mother liquor, rinse with warm water mixture to no foam, centrifugal drying, drying to a moisture at 0.2% or less, that acetic acid in pregnancy dehydropregnenolone oxime (oxime compounds) 163kg, content of 99%, a melting point of 202-204 ° C, a yield of about 102% (for pregnenolone acetate pregnancy weight ratio).
2, heavy drain hydrolysis reaction.
(1) raw material specifications to match.
acetate pregnancy dehydropregnenolone waning: Benzene: Batch steep: phosphorus oxychloride and toluene: HCl + water = 1: 6 5: 0 4: 1: 3.5, which acetate pregnancy alcohol one hand 163kg, benzene 1060kg, batch steep 64kg, phosphorus oxychloride and toluene 80kg + 80kg, hydrochloric acid + water 245kg + 325kg.
(2) process operation.
The first drying 2000L rearrangement reaction tank, then pumped to the reaction tank benzene, alcohol into acetate pregnancy oxime, pulls out into benzene, stirring heated to reflux until the reaction mixture is completely dissolved, cooling to 1 (TC When, pyridine, of the reaction liquid at temperatures down to 6 ° C, start dropping a mixed solution of previously prepared phosphorus oxychloride and toluene (1: 1 mass ratio), slowly dropping, dropping control, first After slow fast reaction when dropping liquid temperature control in 4-8 ° C, the addition was complete, the reaction solution at 9-12 ° C for 3 hours the first time under.
After incubation, a solution has been a mixed solution of hydrochloric acid and water, good preparation, while dropping the reaction liquid temperature is controlled at 15-25 ° C, the addition was complete, the reaction solution at 15-25 ° C under a second Insulation 1. 5-2 hours. After incubation, stand 40 minutes, then points to lower acidic water layer, the remaining upper layer was added 0.3 times the amount of 30-35 ° C in the brine and let stand 20 minutes, a second watershed, sub lower aqueous layer was then allowed to stand for 30 minutes, a third water diversion, to give the final weight of the upper layer reaction solution was drained.
3, the red Dingding steam distillate process.
The rearrangement reaction liquid was pumped to punch distillate tank, conduct atmospheric distillate punch, has been rushed to the reaction mixture was distilled benzene mixed solvent only, at the start of the steam valve not to open too much, so as not to rush material, distillation after cooling discharge, centrifugal drying, washing with tap water to neutral, and then into the oven dried to a moisture in the square. 5% acetic acid in dehydroepiandrosterone (rearrangement thereof) The crude product is about 142kg, content of about 97.5%, a melting point of 160 ° C _165 ° C or so, yield about 88% (for acetate pregnancy dehydropregnenolone weight ratio).
4, refining processes.
The drying in acetic acid Dehydroepiandrosterone crude into refined tin, adding 8 times the weight of the crude methanol and 0.10 times the weight of activated carbon, heat, stirring to dissolve, reflux billion. 5 hours, filtered , concentrated, cooled to about 5 ° C, the discharge
| Patent ID | Date | Patent Title |
|---|---|---|
| US2011034428 | 2011-02-10 | Treatment of Prostate Cancer |
| US7875599 | 2011-01-25 | C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens, in vitro biological activities, pharmacokinetics and antitumor activity |
| US2010137269 | 2010-06-03 | Novel C-17-Heteroaryl Steroidal Cyp17 Inhibitors/Antiandrogens: Synehesis, In Vitro Biological Activities, Pharmacokinetics and Antitumor Activity |
| US2010048914 | 2010-02-25 | Novel C-17-Heteroaryl Steroidal Cyp17 Inhibitors/Antiandrogens, In Vitro Biological Activities, Pharmacokinetics and Antitumor Activity |
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| US2010048912 | 2010-02-25 | Novel C-17-Heteroaryl Steroidal CYP17 Inhibitors/Antiandrogens, In Vitro Biological Activities, Pharmacokinetics and Antitumor Activity |
| US2010048524 | 2010-02-25 | Novel C-17-Heteroaryl Steroidal CYP17 Inhibitors/Antiandrogens Synthesis In Vitro Biological Activities, Pharmacokinetics and Antitumor Activity |
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| US2011312924 | 2011-12-22 | NOVEL STEROIDAL CYP17 INHIBITORS/ANTIANDROGENS |
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Silberstein, John L.; Taylor, Maritza N.; Antonarakis, Emmanuel S. (2016-04-01). “Novel Insights into Molecular Indicators of Response and Resistance to Modern Androgen-Axis Therapies in Prostate Cancer”. Current Urology Reports 17 (4): 29. doi:10.1007/s11934-016-0584-4. ISSN 1534-6285. PMID 26902623.
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| Systematic (IUPAC) name | |
|---|---|
|
17-(1H-benzimidazol-1-yl)androsta-5,16-dien-3β-ol
|
|
| Clinical data | |
| Routes of administration |
Oral |
| Identifiers | |
| CAS Number | 851983-85-2 |
| PubChem | CID 11188409 |
| ChemSpider | 9363493 |
| KEGG | D10125  |
| Chemical data | |
| Formula | C26H32N2O |
| Molar mass | 388.25 |
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C[C@]12CC[C@@H](CC1=CC[C@@H]3[C@@H]2CC[C@]4([C@H]3CC=C4N5C=NC6=CC=CC=C65)C)O
CC12CCC(CC1=CCC3C2CCC4(C3CC=C4N5C=NC6=CC=CC=C65)C)O
IC200214; ITI-214
(6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-3-(phenylamino)-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(2H)-one phosphate
(6aR,9aS)-5-methyl-3-(phenylamino)-2-(4-(6-fluoropyridin-2-yl)-benzyl)-5,6a,7,8,9,9a-hexahydrocyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one…BASE
CAS: 1642303-38-5 (phosphate);
1160521-50-5 (free base).
Chemical Formula: C29H29FN7O5P
Molecular Weight: 605.5672
Takeda Pharmaceutical Company Limited,Intra-Cellular Therapies, Inc.
ITI-214 is an orally active, potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases. ITI-214 exhibited picomolar inhibitory potency for PDE1, demonstrated excellent selectivity against all other PDE families, and showed good efficacy in vivo. Currently, this investigational new drug is in Phase I clinical development and being considered for the treatment of several indications including cognitive deficits associated with schizophrenia and Alzheimer’s disease, movement disorders, attention deficit and hyperactivity disorders, and other CNS and non-CNS disorders.
Phosphodiesterase-1 (PDE-1) inhibitor
which is a picomolar PDE1 inhibitor with excellent selectivity against other PDE family members and against a panel of enzymes, receptors, transporters, and ion channels.
It is disclosed in WO 2009/075784 (U.S. Pub. No. 2010/0273754). This compound has been found to be a potent and selective phosphodiesterase 1 (PDE 1) inhibitor useful for the treatment or prophylaxis of disorders characterized by low levels of cAMP and/or cGMP in cells expressing PDE1, and/or reduced dopamine Dl receptor signaling activity (e.g., Parkinson’s disease, Tourette’s Syndrome, Autism, fragile X syndrome, ADHD, restless leg syndrome, depression, cognitive impairment of schizophrenia, narcolepsy); and/or any disease or condition that may be ameliorated by the enhancement of progesterone signaling. This list of disorders is exemplary and not intended to be exhaustive.
PATENT
WO 2013192556
http://www.google.com/patents/WO2013192556A2?cl=en
The method of making the Compound (ea^^a^-S^a ^^^a-hexahydro-S- methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)- cyclopent[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one is generally described in WO 2009/075784, the contents of which are incorporated by reference in their entirety. This compound can also be prepared as summarized or similarly summarized in the following
CMU PCU PHU PPU (SM2)
In particular, (6aR,9aS)-3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl- 5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)- one may be prepared as described or similarly described below.
PATENT
http://www.google.com/patents/WO2009075784A1?cl=en
EXAMPLE 14
(6aJ?,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6- fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]iinidazo[l,2-fl]pyrazolo[4,3- e]pyrimidin-4(2//)-one
This compound may be made using similar method as in example 13 wherein 2-(4-(bromomethyl)phenyl)-6-fluoropyridine may be used instead of 2-(4- (dibromomethyl)phenyl)-5-fluoropyridine.
PATENT
WO 2014205354
https://www.google.co.in/patents/WO2014205354A2?cl=en
EXAMPLES
The method of making the Compound (ea^^a^-S^a ^^^a-hexahydro-S-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one is generally described in WO 2009/075784, the contents of which are incorporated by reference in their entirety. This compound can also be prepared as summarized or similarly summarized in the following
CMU PCU PHU PPU (SM2)
In particular, (6aR,9aS)-3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (Int-5) may be prepared as described or similarly described below. The free base crystals and the mono-phosphate salt crystals of the invention may be prepared by using the methods described or similarly described in Examples 1-14 below.
Preparation of (6aR,9aS)-3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one
(4-(6-fluoropyridin-2-yl)phenyl)methanol
The mixture of Na2C03 (121 g), water (500 mL), THF (650 mL), PdCl2(PPh3)2 (997 mg), 2-bromo-6-fluoropyridine (100 g) and 4-(hydroxymethyl)phenylboronic acid (90.7 g) is stirred at 65°C for 4 h under the nitrogen atmosphere. After cooling to room temperature, THF (200 mL) is added. The organic layer is separated and washed with 5% NaCl solution twice. The organic layer is concentrated to 400 mL. After the addition of toluene (100 mL), heptane (500 mL) is added at 55°C. The mixture is cooled to room temperature. The crystals are isolated by filtration, washed with the mixture of toluene (100 mL) and heptane (100 mL) and dried to give (4-(6-fluoropyridin-2-yl)phenyl)methanol (103 g). ]H NMR (500 MHz, CDC13) δ 1.71-1.78 (m, 1H), 4.74-4.79 (m, 2H), 6.84-6.88 (m, 1H), 7.44-7.50 (m, 2H), 7.61-7.65 (m, 1H), 7.80-7.88 (m, 1H), 7.98-8.04 (m, 2H).
2-(4-(chloromethyl)phenyl)-6-fluoropyridine
The solution of thionylchloride (43.1 mL) in AcOEt (200 mL) is added to the mixture of (4-(6-fluoropyridin-2-yl)phenyl)methanol (100 g), DMF (10 mL) and AcOEt (600 mL) at room temperature. The mixture is stirred at room temperature for 1 h. After cooling to 10°C, 15% Na2C03 solution is added. The organic layer is separated and washed with water (500 mL) and 5% NaCl solution (500 mL) twice. The organic layer is concentrated to 500 mL. After the addition of EtOH (500 mL), the mixture is concentrated to 500 mL. After addition of EtOH (500 mL), the mixture is concentrated to 500 mL. After the addition of EtOH (500 mL), the mixture is concentrated to 500 mL. After addition of EtOH (200 mL), water (700 mL) is added at 40°C. The mixture is stirred at room temperature. The crystals are isolated by filtration and dried to give 2-(4-(chloromethyl)phenyl)-6-fluoropyridine (89.5 g). ]H NMR (500 MHz, CDC13) δ 4.64 (s, 2H), 6.86-6.90 (m, 1H), 7.47-7.52 (m, 2H), 7.60-7.65 (m, 1H), 7.82-7.88 (m, 1H), 7.98-8.03 (m, 2H).
6-chloro-l-(4-methoxybenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione
The mixture of 6-chloro-3-methyluracil (100 g), p-methoxybenzylchloride (107 g), K2CO3 (86.1 g) and DMAc (600 mL) is stirred at 75°C for 4 h. Water (400 mL) is added at 45°C and the mixture is cooled to room temperature. Water (800 mL) is added and the mixture is stirred at room temperature. The crystals are isolated by filtration, washed with the mixture of DMAc and water (1:2, 200mL) and dried to give 6-chloro-l-(4-methoxybenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (167 g). ]H NMR (500 MHz, CDC13) δ 3.35 (s, 3H), 3.80 (s, 3H), 5.21 (s, 2H), 5.93 (s, 1H), 6.85-6.89 (m, 2H), 7.26-7.32 (m, 2H).
izinyl-l-(4-methoxybenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione
The mixture of 6-chloro-l-(4-methoxybenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (165 g), IPA (990 mL), water (124 mL) and hydrazine hydrate (62.9 mL) is stirred at room temperature for 1 h. The mixture is warmed to 60°C and stirred at the same temperature for 4 h. Isopropyl acetate (1485 mL) is added at 45°C and the mixture is stirred at the same temperature for 0.5 h. The mixture is cooled at 10°C and stirred for lh. The crystals are isolated by filtration, washed with the mixture of IPA and isopropyl acetate (1:2, 330 mL) and dried to give 6-hydrazinyl-l-(4-methoxybenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (153 g). ]H NMR (500 MHz, DMSO-i¾) δ 3.12 (s, 3H), 3.71 (s, 3H), 4.36 (s, 2H), 5.01 (s, 2H), 5.14 (s, 1H), 6.87-6.89 (m, 2H), 7.12-7.17 (m, 2H), 8.04 (s, 1H).
7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione
To the mixture of DMF (725 mL) and 6-hydrazinyl-l-(4-methoxybenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (145 g) is added POCI3 (58.5 mL) at 5°C. The mixture is stirred at room temperature for 1 h. Water (725 mL) is added at 50°C and the mixture is stirred at room temperature for 1 h. The crystals are isolated by filtration, washed with the mixture of DMF and water (1:1, 290 mL) and dried to give 7-(4-methoxybenzyl)-5-methyl-
2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (145 g). ]H NMR (500 MHz, DMSO-i¾) δ 3.23 (s, 3H), 3.71 (s, 3H), 5.05 (s, 2H), 6.82-6.90 (m, 2H), 7.28-7.36 (m, 2H), 8.48 (s, IH), 13.51 (br, IH).
2-(4-(6-fluoropyridin-2-yl)benzyl)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione
The mixture of 2-(4-(chloromethyl)phenyl)-6-fluoropyridine (100 g), 7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (129 g), K2CO3(62.3 g) and DMAc (1500 mL) is stirred at 45°C for 5 h. Water (1500 mL) is added at 40°C and the mixture is stirred at room temperature for 1 h. The crystals are isolated by filtration, washed with the mixture of DMAc and water (1:1, 500 mL) and dried to give 2-(4-(6-fluoropyridin-2-yl)benzyl)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (207 g). ]H NMR (500 MHz, DMSO- ) δ 3.21 (s, 3H), 3.66 (s, 3H), 4.98 (s, 2H), 5.45 (s, 2H), 6.77-6.82 (m, 2H), 7.13-7.16 (m, IH), 7.25-7.30 (m, 2H), 7.41-7.44 (m, 2H), 7.92-7.96 (m, IH), 8.04-8.11 (m, 3H), 8.68 (s, IH).
2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione
The mixture of 2-(4-(6-fluoropyridin-2-yl)benzyl)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (105 g), CF3COOH (300 mL) and
CF3SO3H (100 g) is stirred at room temperature for 10 h. Acetonitrile (1000 mL) is added. The mixture is added to the mixture of 25% N¾ (1000 mL) and acetonitrile (500 mL) at 10°C. The mixture is stirred at room temperature for 1 h. The crystals are isolated by filtration, washed with the mixture of acetonitirile and water (1:1, 500 mL) and dried to give the crude product. The mixture of the crude product and AcOEt (1200 mL) is stirred at room temperature for 1 h. The crystals are isolated by filtration, washed with AcOEt (250 mL) and dried to give 2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (75.3 g). ]H NMR (500 MHz, DMSO-rf6) δ 3.16 (s, 3H), 3.50-4.00 (br, 1H), 5.40 (s, 2H), 7.13-7.16 (m, 1H), 7.41-7.44 (m, 2H), 7.91-7.94 (m, 1H), 8.04-8.10 (m, 3H), 8.60 (s, 1H).
2-(4-(6-fluoropyridin-2-yl)benzyl)-6-(((lR,2R)-2-hydroxycyclopentyl)amino)-5-methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
The mixture of BOP reagent (126 g), 2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (80 g), DBU (136 mL) and THF (1120 mL) is stirred at room temperature for 1 h. (lR,2R)-2-Aminocyclopentanol hydrochloride (37.6 g) and THF (80 mL) are added and the mixture is stirred at room temperature for 5 h. After the addition of 5% NaCl (400 mL) and AcOEt (800 mL), the organic layer is separated. The organic layer is washed with 10% NaCl (400 mL), 1M HC1 15% NaCl (400 mL), 5% NaCl (400 mL), 5% NaHC03 (400 mL) and 5%NaCl (400 mL) successively. After treatment with active charcoal, the organic layer is concentrated to 400 mL. After the addition of acetonitrile (800 mL), the mixture is concentrated to 400 mL. After the addition of acetonitrile (800 mL), seed crystals are added at 40°C. The mixture is concentrated to 400 mL. Water (800 mL) is added at room temperature and the mixture is stirred for 2 h. The crystals are isolated by filtration, washed with the mixture of acetonitrile and water (1:2, 400 mL) and dried to give 2-(4-(6-fluoropyridin-2-yl)benzyl)-6-(((lR,2R)-2-
hydroxycyclopentyl)amino)-5-methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (81.7 g). ]H NMR (500 MHz, CDC13) δ 1.47-1.59 (m, 1H), 1.68-1.93 (m, 3H), 2.02-2.12 (m, 1H), 2.24-2.34 (m, 1H), 3.42 (s, 3H), 3.98-4.12 (m, 2H), 4.68-4.70 (m, 1H), 5.37 (s, 2H), 6.86-6.90 (m, 1H), 7.36-7.42 (m, 2H), 7.58-7.63 (m, 1H), 7.81-7.88 (m, 1H), 7.89 (s, 1H), 7.97-8.01 (m, 2H).
(6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one
The mixture of 2-(4-(6-fluoropyridin-2-yl)benzyl)-6-(((lR,2R)-2-hydroxycyclopentyl)amino)-5-methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (80 g), p-toluenesulfonylchloride (38.6 g), Et3N (28.2 mL), N,N-dimethylaminopyridine (24.7 g) and THF (800 mL) is stirred at 50°C for 10 h. To the mixture is added 8M NaOH (11.5 mL) at room temperature and the mixture is stirred for 2 h. After the addition of 5% NaCl (400 mL) and AcOEt (800 mL), the organic layer is separated. The organic layer is washed with 5 NaCl (400 mL) twice. The organic layer is concentrated to 240 mL. After the addition of MeOH (800 mL), the mixture is concentrated to 240 mL. After the addition of MeOH (800 mL), the mixture is concentrated to 240 mL. After the addition of MeOH (160 mL), the mixture is stirred at room temperature for 1 h and at 0°C for 1 h. The crystals are isolated by filtration, washed with cold MeOH (160 mL) and dried to give (6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (55.7 g). ]H NMR (500 MHz, CDC13) δ 1.39-1.54 (m, 1H), 1.58-1.81 (m, 3H), 1.81-1.92 (m, 1H), 2.12-2.22 (m, 1H), 3.28 (s, 3H), 4.61-4.70 (m, 2H), 5.20 (s, 2H), 6.79-6.85 (m, 1H), 7.25-7.32 (m, 2H), 7.53-7.58 (m, 1H), 7.68 (s, 1H), 7.75-7.83 (m, 1H), 7.92-7.98 (m, 2H).
(6aR,9aS)-3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-5,6a,7,8,9,9a-
hexahydrocyclopenta[4,5]imi ]pyrimidin-4(2H)-one
The mixture of (6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (50 g) and toluene (1000 mL) is concentrated to 750 mL under the nitrogen atmosphere. Toluene (250 mL) and NCS (24 g) is added. To the mixture is added LiHMDS (1M THF solution, 204 mL) at 0°C and the mixture is stirred for 0.5 h. To the mixture is added 20% NH4C1 (50 mL) at 5°C. The mixture is concentrated to 250 mL. After the addition of EtOH (250 mL), the mixture is concentrated to 150 mL. After the addition of EtOH (250 mL), the mixture is concentrated to 200 mL. After the addition of EtOH (200 mL), the mixture is warmed to 50°C. Water (300 mL) is added and the mixture is stirred at 50°C for 0.5 h. After stirring at room temperature for 1 h, the crystals are isolated by filtration, washed with the mixture of EtOH and water (1:1, 150 mL) and dried to give (6aR,9aS)-3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (51.1 g). ]H NMR (500 MHz, CDC13) δ 1.46-1.61 (m, 1H), 1.67-1.90 (m, 3H), 1.92-2.00 (m, 1H), 2.19-2.27 (m, 1H), 3.37 (s, 3H), 4.66-4.77 (m, 2H), 5.34 (s, 2H), 6.87-6.93 (m, 1H), 7.35-7.41 (m, 2H), 7.59-7.65 (m, 1H), 7.82-7.91 (m, 1H), 7.97-8.05 (m, 2H).
EXAMPLE 1
Crystals of (6a/f,9a5)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one free base mono-ethanol solvate
The mixture of (6a/?,9a5′)-3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one (2.5 g), K2C03 (1.53 g), Pd(OAc)2 (12.5 mg), Xantphos (32 mg), aniline (0.76 mL), and xylene (12.5 mL) is stirred at 125°C for 7 h under nitrogen atmosphere. After addition of water (12.5 mL), the organic layer is separated. The organic layer is washed with water (12.5 mL) twice. The organic layer is extracted with the mixture of DMAc (6.25 mL) and 0.5N HCl (12.5 mL). The organic layer is extracted with the mixture of DMAc (3.2 mL) and 0.5N HCl (6.25 mL). After addition of DMAc (6.25 mL), xylene (12.5 mL) and 25 wt % aqueous NH3 solution to the combined aqueous layer, the organic layer is separated. The aqueous layer is extracted with xylene (6.25 mL). The combined organic layer is washed with water (12.5 mL), 2.5 wt % aqueous 1 ,2-cyclohexanediamine solution (12.5 mL) twice and water (12.5 mL) successively. After treatment with active charcoal, the organic layer is concentrated. After addition of EtOH (12.5 mL), the mixture is concentrated. After addition of EtOH (12.5 mL), the mixture is concentrated. After addition of EtOH (12.5 mL), n-heptane (25 mL) is added at 70°C. The mixture is cooled to 5°C and stirred at same temperature. The crystals are isolated by filtration and dried to give (ea^^a^-S^a ^^^a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one free base mono-ethanol solvate (2.56 g) as crystals.
]H NMR (500 MHz, DMSO-d6) δ 0.98-1.13 (m, 3H), 1.34-1.52 (m, 1H), 1.54-1.83 (m, 4H), 2.03-2.17 (m, 1H), 3.11 (s, 3H), 3.39-3.54 (m, 2H), 4.29-4.43 (m, 1H), 4.51-4.60 (m, 1H), 4.60-4.70 (m, 1H), 5.15-5.35 (m, 2H), 6.71-6.88 (m, 3H), 7.05-7.29 (m, 5H), 7.81-7.93 (m, 1H), 7.94-8.11 (m, 3H), 8.67 (s, 1H).
EXAMPLE 4
Crystals of (6a/f,9a5)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one free
Crystals of (6a«,9a5′)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one free base mono-n-propanol solvate (2.0 g) is dissolved with ethanol (10 mL) at 70°C. Isopropyl ether (20 mL) is added and the mixture is cooled to 45°C. Isopropyl ether (10 mL) is added and the mixture is stirred at 40°C. The mixture is cooled to 5°C and stirred at same temperature. The crystals are isolated by filtration and dried to give (ea/^^a^)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one free base non-solvate (1.7 g) as crystals.
[0082] ]H NMR (500 MHz, DMSO-d6) δ 1.32-1.51 (m, 1H), 1.53-1.83 (m, 4H), 1.97-2.20 (m, 1H), 3.11 (s, 3H), 4.49-4.60 (m, 1H), 4.60-4.69 (m, 1H), 5.13-5.37 (m, 2H), 6.70-6.90 (m, 3H), 7.04-7.31 (m, 5H), 7.82-7.93 (m, 1H), 7.93-8.12 (m, 3H), 8.67 (s, 1H).
EXAMPLE 5
Crystals of (6a/f,9a5)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one free base non-solvate
The mixture of (6a/?,9a5′)-3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one (25 g), K2C03 (15.4 g), Pd(OAc)2 (125 mg), Xantphos (321 mg), aniline (7.6 mL), DMAc (6.25 mL) and xylene (125 mL) is stirred at 125°C for 6.5 h under nitrogen atmosphere. After addition of water (125 mL) and DMAc (50 mL), the organic layer is separated. The organic layer is washed with the mixture of DMAc (50 mL) and water (125 mL) twice. The organic layer is extracted with the mixture of DMAc (50 mL) and 0.5N HCl (125 mL). The organic layer is extracted with the mixture of DMAc (50 mL) and 0.5N HCl (62.5 mL). After addition of DMAc (50 mL), xylene (125 mL) and 25 wt % aqueous NH3 solution (25 mL) to the combined aqueous layer, the organic layer is separated. The aqueous layer is extracted with xylene (62.5 mL). The combined organic layer is washed with the mixture of DMAc (50 mL) and water (125 mL), the mixture of DMAc (50 mL) and 2.5 wt % aqueous 1,2-cyclohexanediamine solution (125 mL) twice and the mixture of DMAc (50 mL) and water (125 mL) successively. After treatment with active charcoal (1.25 g), the organic layer is concentrated to 75 mL. After addition of EtOH (125 mL), the mixture is concentrated to 75 mL. After addition of EtOH (125 mL), the mixture is concentrated to 75 mL. After addition of EtOH (125 mL), n-heptane (250 mL) is added at 70°C. After addition of seed crystals of (6a/?,9a5′)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one non-solvate, the mixture is cooled to room temperature and stirred at room temperature. The crystals are isolated by filtration and dried to give (ea^^a^-S^a ^^^a-hexahydro-S-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo-[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one free base non-solvate (23.8 g) as crystals.
EXAMPLE 8
(6a/f,9a5)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one mono-phosphate salt
[0094] Crystals of (6a«,9a5′)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one free base non-solvate (20 g) are dissolved in acetonitrile (60 mL) at 50°C. After addition of the active charcoal (1 g), the mixture is stirred at same temperature for 0.5 h. The active charcoal is removed by filtration and washed with acetonitrile (40 mL). The filtrate and the washing are combined and warmed to 50°C. A solution of 85 wt. % phosphoric acid (2.64 mL) in acetonitrile (100 mL) is added. After addition of water (20 mL), the mixture is stirred at 50°C for lh. The crystals are isolated by filtration, washed with acetonitrile (60 mL x 3) and dried to give (6a/?,9a5′)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one mono-phosphate salt (20.5 g).
EXAMPLE 9
(6a/f,9a5)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one mono-phosphate salt
[0095] Crystals of (6a«,9a5′)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one free base mono-ethanol solvate (4 g) are dissolved in acetonitrile (12 mL) at 50°C. After addition of active charcoal (0.2 g), the mixture is stirred at same temperature for 0.5 h. Active charcoal is removed by filtration and washed with acetonitrile (8 mL). The filtrate and the washing are combined and warmed to 50°C. A solution of 85 wt. % phosphoric acid (0.528 mL) in acetonitrile (20 mL) is added. After addition of water (4 mL), the mixture is stirred at 50°C for lh. The crystals are isolated by filtration, washed with acetonitrile (12 mL x 3) and dried to give (6a/?,9a5′)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one mono-phosphate salt (4.01 g).
EXAMPLE 10
(6a/f,9a5)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one mono-phosphate salt
Crystals of (6a«,9a5′)-5,6a,7,8,9,9a-Hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one free base non-solvate (20 g) are dissolved in acetone (60 mL) at 32°C. After addition of active charcoal (1 g), the mixture is stirred at same temperature for 0.5 h. Active charcoal is removed by filtration and washed with acetone (40 mL). The filtrate and the washing are combined and warmed to 39°C. A solution of 85 wt. % phosphoric acid (2.64 mL) in acetone (100 mL) is added. After addition of water (20 mL), the mixture is stirred at 40°C for lh. The crystals are isolated by filtration, washed with acetone (60 mL x 3) and dried to give (6a/?,9a5′)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one mono-phosphate salt (22.86 g).
EXAMPLE 11
(6a/f,9a5)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one mono-phosphate salt
Crystals of (6a«,9a5′)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one free base mono-ethanol solvate (20 g) are dissolved in acetone (60 mL) at 38°C. After addition of active charcoal (1 g), the mixture is stirred at same temperature for 0.5 h. Active charcoal is removed by filtration and washed with acetone (40 mL). The filtrate and the washing are combined and warmed to 38°C. A solution of 85 wt. % phosphoric acid (2.64 mL) in acetone (100 mL) is added. After addition of water (20 mL), the mixture is stirred at 40°C for lh. The crystals are isolated by filtration, washed with acetone (60 mL x 3) and dried to give (6a/?,9a5′)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one mono-phosphate salt (23.2 g).
PAPER
A diverse set of 3-aminopyrazolo[3,4-d]pyrimidinones was designed and synthesized. The structure–activity relationships of these polycyclic compounds as phosphodiesterase 1 (PDE1) inhibitors were studied along with their physicochemical and pharmacokinetic properties. Systematic optimizations of this novel scaffold culminated in the identification of a clinical candidate, (6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-3-(phenylamino)-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(2H)-one phosphate (ITI-214), which exhibited picomolar inhibitory potency for PDE1, demonstrated excellent selectivity against all other PDE families and showed good efficacy in vivo. Currently, this investigational new drug is in Phase I clinical development and being considered for the treatment of several indications including cognitive deficits associated with schizophrenia and Alzheimer’s disease, movement disorders, attention deficit and hyperactivity disorders, and other central nervous system (CNS) and non-CNS disorders
The synthetic methods disclosed in WO 2009/075784 and WO 2013/192556 are particularly applicable, as they include the methods to prepare the compound of Formula I-B. Those skilled in the art will readily see how those methods are applicable to the synthesis of the compounds of the present invention.
Formula I-B
For example, Compounds of the Invention wherein any one or more of R1 through R8 are D, can be prepared from the corresponding aminocyclopentanol, according to the method described in WO 2009/075784 or WO 2013/192556. For example, by reacting said aminocyclopentanol, optionally as its acid salt, with Intermediate A in the presence of a coupling agent, e.g., benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent), and a base, e.g., l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a solvent such as tetrahydrofuran (THF). The intermediate alcohol is then cyclized by treatment with toluenesulfonyl chloride (TsCl) in the presence of one or more bases, such as dimethylaminopyridine (DMAP) and triethylamine (TEA) in a solvent, such as THF. The reaction is summarized in the following scheme:
The required aminocyclopentanols can be prepared by methods known to those skilled in the art. For example, the aminocyclopentanol wherein R1 is D can be prepared via a reductive amination procedure that uses a reducing agent such as sodium triacetoxyborodeuteride or sodium borodeuteride as the reducing agent. For example, an optionally protected (R)-2-hydroxycyclopentanone can be reacted with 4-methoxybenzylamine in the presence of sodium triacetoxyborodeuteride to yield the desired deuterated secondary amine, wherein P is the protecting group. Reaction of the resulting amine with a strong acid such as trifluoromethanesulfonic acid (TMFSA) will result in removal of the 4-methoxybenzyl group and the protecting group to yield the desired aminocyclopentanol. Those skilled in the art will know how to choose a suitable protecting group for the secondary alcohol such that deprotection can take place during the acid treatment step (e.g., a tert-butyldimethylsilyl group or a tert-butoxycarbonyl group). Alternatively, those skilled in the art could choose a protecting group that would survive this step. If desired, the protected intermediate can be purified by chiral HPLC in order to enhance the optical purity of the final
As another example, Compounds of the Invention wherein any one or more of R9 to R15 or R21 to R22 are D can be prepared from the corresponding benzyl halide, according to the method described in WO 2009/075784 or WO 2013/192556. For example, by reacting said benzyl halide with the Intermediate B in the presence of suitable base, such as cesium carbonate or potassium carbonate, in a suitable solvent, such as dimethylformamide or dimethylacetamide. The corresponding benzyl halide can be prepared by methods well known to those skilled in the art. The reaction is summarized in the following scheme:
As another example, compounds of the invention wherein any one or more of R16 to R20 are D can be prepared from the corresponding phenyl
isothiocyanate, according to the method described in WO 2009/075784 or WO
2013/192556. For example, by reacting said phenyl isothiocyanate with Intermediate C in a suitable solvent, such as dimethylformamide. The corresponding phenyl isothiocyanate can be prepared by methods well known to those skilled in the art. The reaction is summarized in the following scheme:
Alternatively, compounds of the invention wherein any one or more of R16 to R20 are D can be prepared from the corresponding aniline, according to the method described in WO 2009/075784 or WO 2013/192556. For example, by reacting said aniline with Intermediate D and a strong base, such as lithium
hexamethyldisilylazide (LiHMDS), in a suitable solvent, such as THF at elevated temperature. Such a reaction can also be achieved by catalytic amination using a catalyst, such as tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and a ligand, such as Xantphos. The corresponding aniline can be prepared by methods well known to those skil
EXAMPLE 1. (6aR,9a5)-5-Methyl-3-(2,3,4,5,6-pentadeuterophenylamino)-2-(4-(6-fluoropyridin-2-yl)-benzyl)-5,6fl,7,8,9,9fl-hexahydrocyclopent[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one
To a solution of (6a/?,9a5′)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-2-(4-(6-fluoropyridin-2-yl)-benzyl)-cyclopent[4,5]irnidazo[l,2-fl]pyrazolo[4,3-e]pyrimidin-4(2H)-one (200 mg, 0.444 mmol) and 2,3,4,5,6-pentadeuteroaniline (162 μΐ,, 1.8 mmol) in anhydrous 2-methyltetrahydrofuran (3 mL) is added LiHMDS (1.0 M in THF, 0.89 mL) dropwise at room temperature under argon atmosphere. The reaction mixture is gradually heated to 75 °C over a period of 90 min, and then heated at 75 °C for an hour. The mixture is cooled with an ice bath and then quenched by adding 0.2 mL of water. After solvent evaporation, the residue is dissolved in DMF and then filter with a 0.45 m microfilter. The collected filtrated is purified with a semi-preparative HPLC system using a gradient of 0 – 70% acetonitrile in water containing 0.1% formic acid over 16 min to give (6a/?,9a5′)-5-methyl-3-(2,3,4,5,6-pentadeuterophenylamino)-2-(4-(6-fluoropyridin-2-yl)-benzyl)-5,6fl,7,8,9,9fl-hexahydrocyclopent[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one as a formate salt, which is dissolved in ethyl acetate, basified with 12.5 mL of 5% sodium carbonate, and then extracted with ethyl acetate three times. The combined organic phase is evaporated to dryness. The residue is dissolved in 4.5 mL of THF and then filter through a 0.45 m microfilter. The filtrate is evaporated to dryness and further dried under vacuum to give (6a/?,9a5′)-5-methyl-3-(2,3,4,5,6-pentadeuterophenylamino)-2-(4-(6-fluoropyridin-2-yl)-benzyl)-5,6fl,7,8,9,9fl-hexahydrocyclopent[4,5]imidazo[l,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one as a white solid (185.8 mg, 81.6% yield). ¾ NMR (400 MHz, CDCb) δ 7.88 (d, / = 8.4 Hz, 2H), 7.88 – 7.77 (m, 1H), 7.58 (dd, J = 7.5, 2.4 Hz, 1H), 7.05 (d, J = 8.3 Hz, 2H), 6.90 – 6.80 (m, 2H), 4.94 (s, 2H), 4.82 – 4.68 (m, 2H), 3.34 (s, 3H), 2.27 (dd, / = 12.4, 5.7 Hz, 1H), 2.09 – 1.91 (m, 1H), 1.91 – 1.67 (m, 3H), 1.67 – 1.49 (m, 1H).MS (ESI) m/z 513.3 [M+H]+.
NEW YORK and OSAKA, Japan, Nov. 3, 2014 (GLOBE NEWSWIRE) — Intra-Cellular Therapies, Inc. (Nasdaq:ITCI) and Takeda Pharmaceutical Company Limited announced today that they have entered into an agreement to mutually terminate the February 2011 license agreement covering Intra-Cellular Therapies’ proprietary compound ITI-214 and related PDE1 inhibitors and to return the rights for these compounds to Intra-Cellular Therapies.
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Under the terms of the agreement, Intra-Cellular Therapies has regained all worldwide development and commercialization rights for the compounds previously licensed to Takeda. Takeda will be responsible for transitioning the compounds back toIntra-Cellular Therapies and will not participate in future development or commercialization activities. After transition of the program, Intra-Cellular Therapies plans to continue the clinical development of PDE1 inhibitors for the treatment of central nervous system, cardiovascular and other disorders.
“We are grateful for Takeda’s substantial efforts in advancing this program into clinical development,” said Dr. Sharon Mates, Chairman and CEO of Intra-Cellular Therapies. “This provides us with the opportunity to unify our PDE1 platform and we look forward to continuing the development of ITI-214 and our other PDE1 inhibitors.”
Intra-Cellular Therapies will discuss the PDE1 program in its previously announced earnings call on Monday, November 3, 2014 at 8:30 a.m. Eastern Time. To participate in the conference call, please dial 844-835-6563 (U.S.) or 970-315-3916 (International) five to ten minutes prior to the start of the call. The participant passcode is 25568442.
About PDE1 Inhibitors
PDE1 inhibitors are unique, orally available, investigational drug candidates being developed for the treatment of cognitive impairments accompanying schizophrenia, Alzheimer’s disease and other neuropsychiatric disorders and neurological diseases and may also treat patients with Attention Deficit Hyperactivity Disorder and Parkinson’s disease. These compounds may also have the potential to improve motor dysfunction associated with these conditions and may also have the potential to treat patients with multiple sclerosis and other autoimmune diseases and pulmonary arterial hypertension. These compounds are very selective for the PDE1 subfamily relative to other PDE subfamilies. They have no known significant off target activities at other enzymes, receptors or ion channels.
About Intra-Cellular Therapies
Intra-Cellular Therapies, Inc. (the “Company”) is developing novel drugs for the treatment of neuropsychiatric and neurodegenerative disease and other disorders of the central nervous system (“CNS”). The Company is developing its lead drug candidate, ITI-007, for the treatment of schizophrenia, behavioral disturbances in dementia, bipolar disorder and other neuropsychiatric and neurological disorders. The Company is also utilizing its phosphodiesterase platform and other proprietary chemistry platforms to develop drugs for the treatment of CNS disorders.
About Takeda Pharmaceutical Company Limited
Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for people worldwide through leading innovation in medicine. Additional information about Takeda is available through its corporate website, www.Takeda.com.
Source: Intra-Cellular Therapies, Inc.; Takeda Pharmaceutical Company Limited
| US20080188492 * | Jun 6, 2006 | Aug 7, 2008 | Intra-Cellular Therapies, Inc | Organic Compounds |
| US20100273754 * | Dec 6, 2008 | Oct 28, 2010 | Peng Li | Organic compounds |
| US20110237561 * | Dec 7, 2009 | Sep 29, 2011 | Peng Li | Organic compounds |
| US20120071450 * | Dec 7, 2009 | Mar 22, 2012 | Peng Li | Organic compounds |
| US20120238589 * | Sep 20, 2012 | Peng Li | Organic compounds |
| WO2014205354A3 * | Jun 20, 2014 | May 28, 2015 | Takeda Pharmaceutical Company Limited | Free base crystals |
| WO2015196186A1 * | Jun 22, 2015 | Dec 23, 2015 | Intra-Cellular Therapies, Inc. | Organic compounds |
| US8829008 | Jun 1, 2012 | Sep 9, 2014 | Takeda Pharmaceutical Company Limited | Organic compounds |
| US9000001 | Jul 18, 2012 | Apr 7, 2015 | Intra-Cellular Therapies, Inc. | Organic compounds |
| US9006258 | Dec 5, 2007 | Apr 14, 2015 | Intra-Cellular Therapies, Inc. | Method of treating female sexual dysfunction with a PDE1 inhibitor |
| US9073936 | Mar 13, 2014 | Jul 7, 2015 | Intra-Cellular Therapies, Inc. | Organic compounds |
| WO2009075784A1 * | Dec 6, 2008 | Jun 18, 2009 | Intra Cellular Therapies Inc | Organic compounds |
| WO2010065151A1 * | Dec 7, 2009 | Jun 10, 2010 | Intra-Cellular Therapies, Inc. | Organic compounds |
| WO2013192556A2 * | Jun 21, 2013 | Dec 27, 2013 | Intra-Cellular Therapies, Inc. | Salt crystal |
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O=C(C1=C(NC2=CC=CC=C2)N(CC3=CC=C(C4=NC(F)=CC=C4)C=C3)N=C1N56)N(C)C5=N[C@@]7([H])[C@]6([H])CCC7.O=P(O)(O)O
OR
Fc1cccc(n1)c2ccc(cc2)Cn7nc5N3C(=N[C@@H]4CCC[C@H]34)N(C)C(=O)c5c7Nc6ccccc6
The FDA has presented the draft of a revised guideline on dissolution testing for immediate release. Under certain conditions, the tests can now be standardised. Read on to get more information about FDA’s Guideline on Dissolution Testing.
http://www.gmp-compliance.org/enews_05230_FDA-Guideline-on-Dissolution-Testing_15398,Z-QCM_n.html
In August 2015, the FDA published the draft of a guideline on dissolution testing for immediate release solid oral dosage forms. It is planned that after its finalisation, a part of this guideline will replace the current guideline from August 1997.
The Biopharmaceutics Classification System (BCS) distinguishes 4 different classes of APIs depending on their solubility and permeability.
On the basis of this classification, a decision can be taken for determining when bioavailability or bioequivalence studies are required, or when a successful in vitro-in vivo correlation (IVIVC) is likely.
The BCS proposes that, for certain medicinal products which contain a high soluble API, dissolution testing can be standardised. Due to their high solubility…
View original post 121 more words
Supplier Qualification is more than auditing. Supplier qualification can be seen as a risk assessment tool. But what are the exact requirements for qualifying suppliers?
Supplier Qualification is more than auditing. Supplier qualification can be seen as a risk assessment tool. It should provide an appropriate level of confidence that suppliers, vendors and contractors are able to supply consistent quality of materials, components and services in compliance with regulatory requirements. An integrated supplier qualification process should also identify and mitigate the associated risks of materials, components and services. But what are the exact requirements?
They are wide-ranging and complex. There are different directives and regulations for medicinal drug products for human or veterinary use and for investigational medicinal drug products. Certain requirements in different directives and the EU-GMP Guidelines define expectations. Here are some examples:
Article 8 of EU-Directive 2001/83/EC
“The application [of a marketing authorization] shall be accompanied […] by […] a written confirmation that the manufacturer of the medicinal product has verified compliance of the manufacturer of active substance with principles and guidelines of good manufacturing practice by conducting audits.”
Article 46 of EU-Directive 2001/83/EC
“The holder of a manufacturing and/or import authorisation shall at least be obliged […] to use only active substances, which have been manufactured in accordance with GMP for active substances and distributed in accordance with GDP for active substances and … to ensure that the excipients are suitable for use in medicinal products by ascertaining what the appropriate GMP is.”
Article 46b of EU-Directive 2001/83/EC
“Active substances shall only be imported if they have been manufactured in accordance with standards of good manufacturing practice at least equivalent to those laid down by the European Union”. This can be shown by a written confirmation, or the exporting country is included in the so called white list, or a waiver has been granted.
EU-GMP Guidelines Chapter 5:
5.25 “The purchase of starting materials is an important operation which should involve staff who have a particular and thorough knowledge of the supplier.”
5.26 “Starting materials should only be purchased from approved suppliers …”
5.40 “…printed packaging materials shall be accorded attention similar to that given to starting materials.”
The revised Chapter 7 of the EU-GMP Guidelines describe the responsibilities of the Contract Giver when it comes to contract manufacturing and testing. He needs to assure the control of the outsourced activities, incorporating quality risk management principles and including continuous reviews of the quality of the Contract Acceptor’s performance. Audits are a helpful tool to asses the “legality, suitability and the competence of the Contract Acceptor“. The new Chapter 7 was obviously designed to intensify the control of Contract Acceptors by the Contract Giver and extend those controls to subcontractors.
The holder of the manufacturing authorisation is responsible for the supplier qualification by law but in fact the supplier qualification is one of the duties of the Qualified Person (which can be delegated) as defined in Annex 16 of the EU-GMP Guidelines. The QP of the marketing authorisation holder is responsible for certifying the drug product for the market place and is now being held accountable to ensure that all aspects of the supply chain have been made under the appropriate GMPs. However, according to Chapter 2 of the EU-GMP Guidelines, the heads of Production, Quality Control and Quality Assurance share the responsibility of approving and monitoring suppliers of materials (2.9).
So how to proceed? At the beginning of a supplier qualification process, the regulatory requirements regarding the type of material, component or service and the type of product (human/veterinary drug product or IMP) should be identified and specified. Audits, if required, should be planned and executed. The compliance of the selected supplier(s) with the requirements and user requirement specification should be demonstrated. The scope of an audit should cover this. But a successful audit is not the end of the qualification process. After finalising the contract, the compliance of the selected supplier(s) with the applicable requirements should be evaluated periodically. Changes at the supplier´s site (for example manufacturing process etc.) that pose a particular risk to the compliance with the requirements should be assessed. There needs to be a mechanism in place so that any change made by the supplier which could have an impact on the GMP status or the production or testing parameters have to be agreed to before any such changes are implemented. A supplier must also notify the contract giver immediately upon discovery of any deviation/non-conformance/complaint that may have an impact on the services provided. Those need to be assessed and respective actions need to be defined.
The use of Brokers:
Some raw materials are only available at reasonable costs if purchased through an intermediary, i.e. a Broker. If the material is critical to the process, e.g. an API or a key excipient this can give an added complexity to the process and this must be fully investigated with the Quality and Regulatory units being involved, before any orders are placed.
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A step-wise integrated risk-based approach to determine a control strategy for according to ICH Q3D has to consider data from all kinds of potential sources for elemental impurities in particular from excipients. Read more about the newly created Elemental Impurities Database as a valuable support for performing risk assessments for drug products.
http://www.gmp-compliance.org/eca_mitt_05257_15499_n.html
The new ICH Q3D Guideline on Elemental Impurities strongly advocates the use of risk assessments in order to define a final control strategy. Specific challenges appear when risks associated with production equipment, packaging material and excipients have to be determined, and quantified. In particular the contribution of elemental impurities from excipients is not easy to assess due to their big variety and the lack of information from excipient vendors.
Quite recently a pharma consortium started an initiative which aims to collect and share data from pharmaceutical excipients by establishing a database. This Elemental Impurities (EI) Database provides information required for performing a comprehensive risk assessment of a drug product with respect to elemental impurities. Interested companies can contribute to this database by providing information about excipients and may also benefit from this database by taking out information needed for their risk assessments.
The “Impurities Workshop” from 14-16 June 2016 in Heidelberg, Germany provides a comprehensive and practical oriented review of impurities analysis and characterisation in drug substances and drug products. Part III of the workshop on 16 June 2016 is specifically dedicated to Elemental Impurites. In the subsequent post-Conference Workshop on 17 June 2016 the above mentioned EI Database will be explained. The following questions will be discussed:
This post-Conference Workshop is free of charge. It ideally complements the previous parts of the “Impurities Workshop” and can be booked in combination with either Part III or all Parts of the “Impurities Workshop”. As we expect a high interest in this post-Conference Workshop participants joining the “Impurities Workshop” (one day or all three days) will be registered first
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Two Non-Compliance reports to API manufacturers from the Far East published in the EudraGMDP database reveal once more that basic requirements laid down in the ICH Q7 Guideline are not implemented. Read more details about those Non-Compliance Reports.
The Non-Compliance reports in the Eudra-GMDP database of the European Medicines Agency (EMA) are – to a certain extent – the European counterpart of FDA’s Warning Letters. These reports are first drawn up then put in the database after a GMP inspection performed by a representative of the European national competent authorities at an API or medicinal product manufacturer showed serious GMP deficiencies. Similar to Warning Letters, the consequences of Non-Compliance reports are for the companies concerned critical, e.g. withdrawal of the GMP certificate or product recalls.
Two Non-Compliance reports issued at the end of last year concerned API production sites in China and India.
Regarding the Chinese manufacturer “Minsheng…
View original post 346 more words
Indacaterol
QAB-149
CAS 753498-25-8 MALEATE
CAS 312753-06-3 (free base)
QAB-149 maleate
QAB-149-AFA
5-[2-(5,6-Diethylindan-2-ylamino)-1(R)-hydroxyethyl]-8-hydroxyquinolin-2(1H)-one maleate
R)-5-[2-[(5, 6-Diethyl-2, 3-dihydro-lH- inden-2-yl) amino]- 1 -hydroxy ethyl]-8-hydroxyquinolin-2(lH)-one, is an ultra long acting beta-adrenoceptor agonist developed by Novartis
Indacaterol (C 24 H 28 N 2 O 3 , M r = 392.49 g / mol) is chiral and is in the drug as R enantiomer and indacaterol ago. It is a derivative of 8-hydroxyquinoline and 2-aminoindan and has a certain structural similarity with other beta2-agonists , for example salbutamol . Indacaterol is lipophilic, which is a prerequisite for its long duration of action.
Indacaterol (INN) is an ultra-long-acting beta-adrenoceptor agonist[1] developed by Novartis. It was approved by the European Medicines Agency (EMA) under the trade name Onbrez Breezhaler on November 30, 2009,[2] and by the United States Food and Drug Administration (FDA), under the trade name Arcapta Neohaler, on July 1, 2011.[3] It needs to be taken only once a day,[4]unlike the related drugs formoterol and salmeterol. It is licensed only for the treatment of chronic obstructive pulmonary disease(COPD) (long-term data in patients with asthma are thus far lacking). It is delivered as an aerosol formulation through a dry powder inhaler.
Indacaterol maleate (QAB-149) is a long-acting inhaled beta2-adrenoceptor agonist. In 2008, it was filed for approval in the U.S. and the E.U. by Novartis for the treatment of chronic obstructive pulmonary disease (COPD).
In 2009, approval was granted by the EMEA and a complete response letter was assigned by the FDA.
In 2010, Novartis resubmitted an NDA seeking approval for the long-term maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD, including bronchitis and/or emphysema.
In 2011, the FDA approved this indication and in 2012 the product was launched in the U.S.
The product was approved and launched in Japan in 2011 for the treatment of COPD.
In 2010, indacaterol was first launched by Novartis in Denmark and Ireland.
A Phase III trial published in March 2010 examined the efficacy and safety of indacaterol in COPD patients.[5] This study, conducted in the U.S., New Zealand, and Belgium, compared indacaterol dry-powder inhaler to placebo in 416 COPD patients, mostly moderate to severe (mean FEV1 of 1.5 L). Indacaterol produced statistically improved FEV1 (both trough and AUC) and decreased use of rescue medication compared to placebo, but with safety and tolerability similar to those of placebo.
A year-long, placebo-controlled trial published in July 2010 suggests indacaterol may be significantly more effective than twice-daily formoterol in improving FEV1. There were some reductions in the need for rescue medication, but these were not significantly different; nor was there any difference in the rate of exacerbation between the 2 active treatments.[6]
A study published in October, 2011 in the European Respiratory Journal compared indacaterol with tiotropium over the study period of 12 weeks. The study found no statistical difference between the effects of the two drugs on FEV1. Indacaterol yielded greater improvements in transition dyspnoea index (TDI) total score and St. George’s Respiratory Questionnaire (SGRQ) total score.[7]
A recent Cochrane Library meta-analysis indicates that the clinical benefit in lung function from indacaterol is at least as good as that seen with twice-daily long-acting beta2-agonists. [8]
SYNTHESIS
Its synthesis is divided into two parts, a primary amine and a chiral epoxide.
Primary amine starting at 1,2 – diethyl benzene (JMC2010, 3676), two FC reaction into the ring post and then converted into oxime reduction, get four . Compound 5 obtained by Fries rearrangement 6 , phenolic hydroxyl group protected, chlorinated 7 , CBS asymmetric reduction to give the chiral secondary alcohols 8 , ring closure under alkaline conditions to obtain an epoxy compound 9 , a primary amine 4 on epoxy, to the benzyl protecting, salt to be Indacaterol Maleate.
http://www.google.com/patents/WO2013132514A2?cl=en
Indacaterol chemically known as (R)-5-[2-[(5, 6-Diethyl-2, 3-dihydro-lH- inden-2-yl) amino]- 1 -hydroxy ethyl]-8-hydroxyquinolin-2(lH)-one, is an ultra long acting beta-adrenoceptor agonist developed by Novartis and has the following structural formula:
Indacaterol maleate is a long acting inhaled β2- agonist. Indacaterol maleate is marketed under the trade name Arcapta Neohaler in US and Onbrez in Europe.
Indacaterol maleate was disclosed in US6878721 by Novartis. The process for Indacaterol is depicted below.
Indacaterol Maleate
VII
In the above process for preparing Indacaterol maleate involves the step of reacting 8 substituted oxy-5-(R)-oxiranyl-(lH)-quinolin-2-one (III) with 2-amino- (5,6-diethyl)-indan (IV) to form a intermediate 5-[(R)-2-(5,6-diethyl-indan-2- ylamino)-l-hydroxy-ethyl]-8-substituted oxy-(lH)-quinolin-2-one (V). This epoxide ring opening is not region specific thereby along with 5-[(R)-2-(5,6- diethyl-indan-2-ylamino)- 1 -hydroxy-ethyl]-8-substituted oxy-( 1 H)-quinol intone, below mentioned products are being produced as impurities.
The above reaction mixture contains only about 60% of desired compound i.e. 5-[(R)-2-(5, 6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-substituted oxy- (lH)-quinolin-2-one. The purification of this intermediate is done using silica gel chromatography which is tedious and requires large amounts of solvents, not suitable for industrial synthesis.
To overcome the above draw backs of the process for preparing Indacaterol, the patent US7534890 discloses a process that avoids the column purification by the formation of acid addition salts of intermediate (formula – IV).
Therefore, there exists a need to develop a novel process for the preparation of indacaterol maleate.
Examples
Example -1 Preparation of compound of IIIA, wherein R is Benzyl
The compound of formula IA (25 gm) was dissolved in DMSO (75 ml) and stirred for 15 min, then compound of formula IIA (0.09 mol) was added to the reaction mixture at 25 – 30°C. The triethylamine (0. 1 mol) was added to above contents slowly, following by added sodium iodide (0.03 mol) at same temperature and stirred the reaction mixture for 3 hours at same temperature. The purified water (250 ml) was added to the reaction mixture and stirred for 1.0 hour. The contents were filtered and washed with water. The wet material was dissolved in methanol (250 ml) and stirred for 30 minutes, and then water was added. The contents were stirred for lhour at 25 – 30°C and filtered to obtain the title compound. Yield: 76%
Example -2 Preparation of compound of IIIA, wherein R is Benzyl
The compound of formula IA (25 gm) was dissolved in DMSO (75 ml) and stirred for 15 min, then compound of formula IIA (0.09 mol) was added to the reaction mixture at 25 – 30°C. Potassium carbonate (0. 1 mol) was added to above contents slowly, following by added sodium iodide (0.03 mol) at same temperature and stirred the reaction mixture for 3 hours at same temperature. The purified water (250 ml) was added to the reaction mixture and stirred for 1.0 hour. The contents were filtered and washed with water. The wet material was dissolved in methanol (250 ml) and stirred for 30 minutes, and then water was added. The contents were stirred for lhour at 25 – 30 °C and filtered to obtain the title compound. Yield: 82%
Exam le -3 Preparation of compound of IIIA, wherein R is Benzyl
The compound of formula IA (25 gm) was dissolved in DMSO (75 ml) and stirred for 15 min, then compound of formula IIA (0.09 mol) was added to the reaction mixture at 25 – 30°C, then Sodium iodide (0.03 mol) was added to the reaction mixture at same temperature and stirred the reaction mixture for 3 hours at same temperature. The purified water (250 ml) was added to the reaction mixture and stirred for 1.0 hour. The contents were filtered and washed with water. The wet material was dissolved in methanol (250 ml) and stirred for 30 minutes, and then water was added. The contents were stirred for lho‘ur at 25 – 30 °C and filtered to obtain the title compound. Yield: 84%
Exam le -4 Preparation of compound of IVA, wherein R is Benzyl
The Borane-dimethyl sulfide (0.11 mol) was added at 0-5°C, followed by addition of R – (2)-Methyl CBS (0.01 mol) and stirred the contents for 10 minutes at same temperature. The compound of example-1 (20 gm) was dissolved in methylene chloride (200 ml) at same temperature and stirred the reaction mixture for 1.0 hour. The methanol was added to the reaction mixture followed by addition of 5% hydrogen peroxide (0.01 mol) at 0-5 °C and stirred the contents for 15 minutes at same temperature, gradually increased the temperature to 20- 30°C. The 6. ON sulfuric acid (10 ml) solution was added to the reaction mixture and stirred for 15 minutes.The layers were separated. The separated organic layer was washed with 2. ON sulfuric acid solution followed by washings with water, then distilled and dissolved in ethyl acetate. The contents were stirred for 1.0 hour, filtered and dried at 60°C. Yield: 85%; E.e: > 95%.
Example -5 Preparation of compound of formula VA (Indacaterol)
The compound of example-4 (10 gm) was dissolved in methanol (100 ml), followed by addition of acetic acid (50 ml) to the reaction mixture. The 5% Pd/C was added to the reaction mixture and applied hydrogen pressure 3-4 Kg/cm3‘ and then the contents were stirred for 4.0 hours at 25-30°C, filtered and distilled. The residue was dissolved in ethyl acetate, stirred for 10 min and distilled to obtain the compound. Yield: 79%
Example -6 Preparation of Indacaterol Maleate
To a methanolic solution of Indacaterol, maleic acid (0.9 mol) in methanol was slowly added at 25 -30°C and stirred the isolated compound for 2.0 hours at same temperature. The reaction mass was cooled to 0 -10°C and maintained for 2.0 hrs at same temperature. The contents were filtered, washed with methanol and dried at 60 -65 °C. Yield: 93%; E.e: >99%.
Example -7 Preparation of compound of formula IXA, wherein R and Rl is benzyl
The (Bromo compound) of formula I (25 gm) was dissolved in DMF (150 ml) and stirred the contents for 15 min. The 5,6-Diethyl indane N-benzyl amine (0.9 mol) was added to the above mixture at 25 -30°C, followed by the slow addition of triethylamine, then the reaction mixture was stirred for 5.0 min. The sodium iodide (0.01 mol) was added to the reaction mixture at same temperature and stirred for 3 hours at same temperature. The purified water was added to the reaction mixture, and then the contents were filtered and washed with water. The wet compound was dissolved in methanol then water was added to the contents and stirred for lhour at 25 -30 °C. The contents were filtered and dried the compound at 60°C. Yield: 70%.
Example -8 Preparation of compound of formula XA, wherein R and Rl is benzyl
A mixture of Borane-dimethyl sulfide (0.11 mol), R-(2)-Methyl CBS (0.01 mol) and methylene chloride was stirred for 10 minutes at 0-5 C. The compound of example-7 (20 gm) was dissolved in methylene chloride (200 ml) and was added to the reaction mixture at same temperature. The reaction mixture was stirred for 1.0 hour. The methanol was added to the reaction mixture followed by addition of 5% hydrogen peroxide (0.01 mol) at 0-5 C. Stirred the contents for 15 minutes at same temperature, gradually increased the temperature to 20-30°C. The 6. ON sulfuric acid (10 ml) solution was added to the reaction mixture and stirred for 5minutes.The layers were separated. The organic layer was washed with 2. ON sulfuric acid solution followed by washing with water. The organic layer was distilled and dissolved in ethyl acetate. Stirred the contents for 1.0 hour and filtered the compound. The compound was dried at 60°C. Yield: 80%; Purity E.e: > 95%.
Example -9 Preparation of compound of formula VA (Indacaterol)
The compound of example-8 (10 gm) was dissolved in methanol (100 ml), followed by addition of acetic acid (50 ml) to the reaction mixture. Then 5% Pd/C was added to the reaction mixture and applied hydrogen pressure 3-4 Kg/cm3 The content was stirred for 4.0 hours at 25-30°C, filtered and the filtrate was distilled. The residue was dissolved in ethyl acetate (50 ml), stirred the contents for 10 min and distilled to obtain the compound. Yield: 80%
PATENT
http://www.google.com/patents/WO2014139485A1?cl=en
WO 0075114 Al is the first to describe preparation of indacaterol ((i?)-2) (Scheme 1).
Scheme 1 The synthesis is a follow-up of the previously published method for the preparation of 8- benzyloxy-5-(i?)-oxiranyl-(lH)-quinolin-2-one, published in WO 9525104 Al.This synthesis of indacaterol ((i?)-2) was further modified un WO 04076422 Al, WO 04087668 Al and WO 05123684 A2 to be better applicable for the industrial production. A weak point of the above mentioned synthesis is the use of the expensive benzyl trichloromethyl dichloroiodate as the chlorination agent in the first step. A considerable weak point of the above mentioned synthesis is the formation of undesired side products during the reaction of 8-benzyloxy-5-(R)- oxiranyl-(lH)-quinolin-2-one with 2-amino-5,6-diethylindane (Scheme 2).
Scheme 2
Crude 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy-(lH)-quinolin-2- one ((i?)-l) can be purified from these undesired side products by conversion to the benzoate, which is then re-crystallized, reduced with hydrogen, converted to indacaterol maleinate, which is finally re-crystallized. According to WO 04076422 Al, WO 04087668 Al and WO 05123684 A2, the yield of 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)- 1 -hydroxyethyl]-8- benzyloxy-(lH)-quinolin-2-one ((i?)-l) benzoate from 8-benzyloxy-5-(i?)-oxiranyl-(lH)- quinolin-2-one is only 67%.
Scheme 3.
The starting 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one and 2-amino-5,6- diethylindane were prepared according to US 2004167167 Al and F. Baur et al. J. Med.
Chem. 2010, 53, 3675-3684. Example 1. Preparation of 5-[2-(5,6-diethyI ndan-2-yIamino)-l-hydroxyethyl]-8- benzyloxy-(lH)-quinoIin-2-one (1)
A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (1,15 g), 2-amino-5,6- diethylindane (0.83 g) and dimethyl sulfoxide (5 ml) was stirred at 20°C for 1 h. The resulting suspension was cooled down to 0°C and methanol (5 ml) was added at this temperature. Finely triturated NaB¾ (0.39 g) was added at 0°C and the resulting clear solution was stirred at 20°C for 16 hours. Water (20 ml) was added to the mixture and the mixture was stirred at 20°C for 6 h. The product was filtered off, washed with water and air-dried. The yield was 1.68 g (98%) of beige powder.
Example 2. Preparation of 5- [2-(5,6-diethyl-indan-2-yIamino)-l -hydrox ethyl] -8- benzyloxy-(lH)-quinolin-2-one (1) A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (1.95 g), 2-amino-5,6- diethylindane (1.25 g), dimethyl sulfoxide (8 ml) and acetic acid (0.05 ml) was stirred at 20°C for 2 h. The resulting suspension was cooled down to 0°C and methanol (8 ml) was added at this temperature. Finely triturated NaBH (1.13 g) was added at 0°C and the produced clear solution was stirred at 20°C for 3 h. Water (32 ml) was added to the mixture and the mixture was stirred at 20°C for 16 h. The product was filtered off, washed with water and air-dried. The yield was 2.75 g (95%) of beige powder.
Example 3. Preparation of 5-[2-(5,6-diethyI-indan-2-ylamino)-l-hydroxyethyI]-8- benzyloxy-(lH)-quinolin-2-one (1)
A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (115 mg), 2-amino-5,6- diethylindane (83 mg) and dimethyl acetamide (0.5 ml) was stirred at 20°C for 1 h. The resulting suspension was cooled down to 0°C and methanol (0.5 ml) was added at this temperature. Finely triturated NaBHU (39 mg) was added at 0°C and the obtained clear solution was stirred at 20°C for 16 h. Water (2 ml) was added to the mixture and the mixture was stirred at 20°C for 6 h. The product was filtered off, washed with water and air-dried. The yield was 160 mg (94%) of beige powder. Example 4. Preparation of 5-[2-(5,6-diethyI-indan-2-ylamino)-l-hydroxyethyI]-8- benzyloxy-(lH)-quinoLm-2-one (1)
A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (115 mg), 2-amino-5,6- diethylindane (83 mg) and dichloromethane (2 ml) was stirred at 20°C for 2 h. Finely triturated NaBH(OAc)3 (250 mg) was added at 20°C. The resulting mixture was stirred at 20°C for 16 h and then evaporated until dry. Water (2 ml) was added to the evaporation product and the mixture was stirred at 20°C for 6 h. The product was filtered off, washed with water and air-dried. The yield was 164 mg (96%) of beige powder.
Example 5. Preparation of 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8- benzyloxy-(li?)-quinolin-2-one (1)
A mixture of 8-benzyloxy-5-(2,2-dihydroxyacetyl)-lH-quinolin-2-one (33 mg), 2-amino-5,6- diethylindane (21 mg) and tetrahydrofuran (1 ml) was stirred at 20°C for 1 h. The resulting suspension was cooled down to 0°C and 1 M BH3 in tetrahydrofuran (0.5 ml) was added at this temperature. The produced clear solution was stirred at 20°C for 16 h and then evaporated until dry. Water (1 ml) was added to the evaporation product and the mixture was stirred at 20°C for 6 h. The product was filtered off, washed with water and air-dried. The yield was 48 mg (99%) of beige powder.
Example 6. Preparation of 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8- hydroxy-(l/Z)-quinolin-2-one (2) A mixture of 5-[2-(5,6-diethyl-indan-2-ylamino)- 1 -hydroxyethyl]-8-benzyloxy-(lH)-quinolin- 2-one (1) (1.21 g), ethanol (100 ml) and 5 % Pd / C (80 mg) was stirred in a hydrogen atmosphere at 20°C at the pressure of 101 kPa for 2 h. A TLC analysis of the mixture showed the pure reactant, therefore the mixture was filtered and fresh 5% Pd / C (80 mg) was added to the filtrate. The mixture was stirred in a hydrogen atmosphere at 20°C at the pressure of 101 kPa for 2 h. A TLC analysis of the mixture showed the reactant accompanied by a small amount of the product, therefore the mixture was filtered and fresh 5 % Pd / C (80 mg) was again added to the filtrate. The mixture was stirred under a hydrogen atmosphere at 40°C at the pressure of 101 kPa for 4 h. A TLC analysis of the mixture showed the pure product, therefore the mixture was hot filtered and the residue on the filter was extensively washed with hot ethanol. The filtrate was evaporated in an evaporator at a reduced pressure. The yield was 0.97 g (99%) of yellow powder. Example 7. Preparation 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-hydroxy- (lfl)-quinoIin-2-one (2)
A mixture of 5-[2-(5,6-diemyl-indan-2-ylammo)-l-hydroxyethyl]-8-benzyloxy-(lH)-quinolin- 2-one (1) (1,21 g), ethanol (100 ml) and Raney nickel (1 g) was stirred at 20°C for 2 h. The mixture was filtered and 5% Pd / C (0.1 g) was added to the filtrate. The mixture was stirred under a hydrogen atmosphere at 40°C at the pressure of 101 kPa at 40°C. A TLC analysis of the mixture showed the pure product, therefore the mixture was hot filtered and the residue on the filter was extensively washed with hot ethanol. The filtrate was evaporated in an evaporator at a reduced pressure. The yield was 0.96 g (98%) of yellow powder.
Example 8. Preparation of indacaterol ((R)-2)
Indacaterol ((i?)-2) was resolved from Z 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]- 8-hydroxy-(lH)-quinolin-2-one (2) (0.90 g) by means of preparative HPLC. Conditions of the resolution: UV detection at 260 nm, column length 500 mm, column internal diameter 50 mm, stationary phase Chiralcel OJ (20 μηι), temperature 25°C, flow rate 120 ml/min, mobile phase A: 500 ml of hexane + 1 ml triethylamine, mobile phase B: ethanol, isocratic elution 82% A + 18% B. The fractions containing indacaterol ((R)-2) were evaporated in an evaporator at a reduced pressure. The yield was 0.44 g (49%) of white powder. HPLC enantiomeric purity 99.0% ee.
Example 9. Preparation of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8- benzyloxy-(lH)-quinolin-2-one ((R)-l) 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy-(lH)-quinolin-2-one ((R)-l) was resolved from 5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy- (lH)-quinolin-2-one (1) (1.00 g) by means of preparative HPLC. Conditions of the resolution: UV detection at 260 nm, column length 500 mm, column internal diameter 50 mm, stationary phase Chiralcel AS-V (20 μηι), temperature 25°C, flow rate 120 ml/min, mobile phase A: phosphate buffer (1.15 g of NH4H2P04, dissolved in 1000 ml of water, adjusted to pH 6.0 with 25% aqueous NH3), mobile phase B: acetonitrile, isocratic elution 20% A + 80% B. The fractions containing 5-[(i?)-2-(5,6-diethyl-indan-2-ylamino)-l -hydroxyethyl]-8-benzyloxy- (lH)-quinolin-2-one ((R)-l) were evaporated in an evaporator at a reduced pressure to the volume of about 50 ml. 25% aqueous NH3 was added dropwise to the resulting suspension up to pH 8-9 and the product was extracted with ethyl acetate. The combined extracts were dried with Na2S04 and evaporated in an evaporator at a reduced pressure. The yield was 0.48 g (48%) of white powder. HPLC enantiomeric purity 99.2% ee.
Example 10. Preparation of indacaterol ((R)-2)
A mixture of 5-[(i-)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8-benzyloxy-(lH)- quinolin-2-one ((R)-l) (0.42 g, HPLC enantiomeric purity of 99.2% ee), ethanol (50 ml) and Raney nickel (0.5 g) was stirred at 20°C for 2 h. The mixture was filtered and 5% Pd / C (0.05 g) was added to the filtrate. The mixture was stirred under a hydrogen atmosphere at 40°C at the pressure of 101 kPa for 4 h. A TLC analysis of the mixture showed the pure product, therefore the mixture was hot filtered and the residue on the filter was extensively washed with hot ethanol. The filtrate was evaporated in an evaporator at a reduced pressure. The yield was 0.33 g (97%) of white powder. HPLC enantiomeric purity 99.0% ee.
PATENT
The compound 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]-8- hydroxy-(lH)-quinolin-2-one, which is known as Indacaterol (INN), and its corresponding salts are beta-selective adrenoceptor agonists with a potent bronchodilating activity. Indacaterol is especially useful for the treatment of asthma and chronic obstructive pulmonary disease (COPD) and is sold commercially as the maleate salt. WO 00/75114 and WO 2004/076422 describe the preparation of Indacaterol for the first time through the process:
regioisomer impurity
Puri
Dep
Overall
The condensation between the indanolamine and the quinolone epoxide leads to the desired product but always with the presence of a significant amount of impurities, the most significant being the dimer impurity, which is the
consequence of a second addition of the product initially obtained with another quinolone epoxide, as well as the formation of another isomer which is the result of the addition of the indanolamine to the secondary carbon of the epoxide.
In addition, the reaction conditions to achieve the opening of the epoxide require high energies (ex. 21 of WO 00/75114) with temperatures of 110 °C or more for several hours, which favours the appearance of impurities.
WO 2004/076422 discloses the purification of the reaction mixture by the initial formation of a salt with an acid, such as tartaric acid or benzoic acid,
hydrogenation and final formation of the maleate salt. However, the yield achieved by the end of the process is only 49% overall.
It has been found that impurities of tartrate and benzoate salts can exist in the final product as a result of displacing the tartrate or benzoate with maleate without prior neutralization to Indacaterol base. In addition, WO 2004/076422 discloses that proceeding via the free base of Indacaterol is not viable due to its instability in organic solvents. WO 00/75114 does disclose a method proceeding via the Indacaterol free base, but it is not isolated in solid form.
WO 2004/076422 furthermore discloses the method for obtaining the quinolone epoxide from the corresponding a-haloacetyl compound by reduction in the presence of a chiral catalyst, such as an oxazaborolidine compound, by proceeding via the a-halohydroxy compound.
Documents WO 2007/124898 and WO 2004/013578 disclose 8-(benzyloxy)-5- [(lR)-2-bromo-l-{[tert-butyl(dimethyl)silyl]oxy}ethyl]quinolin-2(lH)-one and 8- (benzyloxy)-5-[(lR)-2-bromo-l-{tetrahydro-2H-pyran-2-yl-oxy}ethyl]quinolin- 2(lH)-one, respectively. Said documents are however not concerned with the preparation of Indacaterol. There exists, therefore, the need to develop an improved process for obtaining Indacaterol and salts thereof, which overcomes some or all of the problems associated with known methods from the state of the art. More particularly, there exists the need for a process for obtaining Indacaterol and pharmaceutically acceptable salts thereof, which results in a higher yield and/or having fewer impurities in the form of the dimer and regioisomers impurities and/or salts other than the desired pharmaceutically acceptable salt.
Examples
Example 1 – protecting the ot-halohydroxy compound of formula VI
A flask is charged with 5 ml of tetrahydrofuran (THF) and 5 ml of toluene, p- toluene sulfonic acid (0,15 mmol) and molecular sieves are added with stirring for 30 minutes. 6 mmol of butyl-vinylether and 3 mmol of 8-(phenylmethoxy)-5-((R)- 2-bromo-l-hydroxy-ethyl)-(lH)-quinolin-2-one are added. The mixture is agitated at 20/25° C until completion of the reaction, followed by filtration and distillation of the filtrate to remove the solvent. The product is obtained in quantitative yield as an oil consisting of 50% of each of the diastereomers.
^-NMR (DMSO-c/6, δ), mixture 50/50 of diastereomers: 0.61 and 0.82 (3H, t, J=7.2 Hz, CHs-Pr-O), 1.12 and 1.22 (3H, d, J=5.6 Hz, acetalic CH3), 0.90-1.40 (4H, m, CH2 + CH2), 3.20-3.80 (4H, m, CH2-OAr + CH2-Br), 4.51 and 4.82 (1H, q, J = 5.6 Hz, acetalic CH), 5.18 and 5.24 (1H, dd, J=4.0, 8.0 Hz, CH-O-acetal), 6.56 and 6.58 (1H, d, J = 10.0 Hz, H4), 7.00-7.57 (7H, m), 8.17 and 8.23 (1H, d, J = 10.0 Hz, H3), 10.71 (1H, s, NH)
13C-NMR (DMSO-c/6, δ), mixture 50/50 of diastereoisomers: 13.5 and 13.7 CH3), 18.5 and 18.8 (CH2), 19.9 and 20.0 (acetalic CH3), 30.9 and 31.4 (CH2), 36.8 and 37.3 (CH2), 63.7 and 64.2 (CH2-Br), 69.8 and 69.9 (CH2-OAr), 73.8 and 75.1 (CH- O), 97.5 and 100.4 (acetalic CH), 111.8 (CH), 116.9 and 117.2 (C), 121.2 and 122.4 (CH), 122.3 and 122.6 (CH), 127.7 and 127.8 (C), 127.8 and 127.9 (CH), 128.2 and 128.3 (CH), 128.8 and 129.1 (C), 129.4 and 129.6 (C), 136.1 and 136.5 (CH), 136.5 and 136.6 (C), 144.0 and 144.2 (C), 160.7 and 160.8 (C=0). Example 2 – protecting the ot-halohydroxy compound of formula VI
Pivaloyl chloride (0.72 g) is added to a stirred mixture of 8-(phenylmethoxy)-5- 5 ((R)-2-chloro-l-hydroxy-ethyl)-(lH)-quinolin-2-one (0.74 g), dichloromethane (15 ml) and 4-dimethylaminopyridine (0.89 g) at 20/25° C, and the reaction is stirred until all the starting material disappeared . Water (22 ml) is added and the phases are separated.
10 The organic phase is washed with 1 M HCI (22 ml) and then with water (22 ml).
The solvent is removed and the residue is crystallized from acetone to obtain 0.82 g of the product.
^-NMR (DMSO-c/6, δ) : 1.13 (9H, s, CH3), 3.92 (1H, dd, J= 4.0, 12.0 Hz, CH2-Br), 15 4.00 (1H, dd, J= 8.4, 12.0 Hz, CH2-CI), 5.28 (2H, s, Ph-CH2-0), 6.25 (1H, dd, J = 4.0, 8.4 Hz, CH-OPiv), 6.59 (1H, d, J= 10.0 Hz, H4), 7.15 (1H, d, J= 8.4 Hz, H6), 7.20 (1H, d, J= 8.4 Hz, H7), 7.27-7.30 (1H, m, Ph), 7.33-7.37 (2H, m, Ph), 7.54- 7.56 (2H, m, Ph), 8.18 (1H, d, J= 10.0 Hz, H3), 10.77 (1H, s, NH).
20 13C-NMR (DMSO-c/6, δ) : 26.7 (3 x CH3), 38.3 (C), 46.4 (CH2-CI), 69.8 (CH2-Ph), 71.3 (CH-OPiv), 111.9 (CH), 116.8 (C), 120.5 (CH), 122.9(CH), 126.0 (C), 127.8 (2 x CH), 127.9 (CH), 128.3 (2 x CH), 129.5 (C), 136.0 (C), 136.5 (CH), 144.5 (C), 160.7 (CON), 176.2 (COO). Example 3 – preparation of the compound of formula IV
A flask is charged with 2.5 ml of THF and 2.5 ml of toluene, p-toluene sulfonic 5 acid (5 mg) and molecular sieves (0.2 g) are added with stirring for 30 minutes.
1.5 ml of butyl-vinylether and 2 g of 8-(phenylmethoxy)-5-((R)-2-bromo-l- hydroxy-ethyl)-(lH)-quinolin-2-one are added . The mixture is agitated at 20/25° C until completion of the reaction. 0.015 ml of diisopropylethyl amine is added, the mixture is filtered, and the solvent is distilled off.
10
The residue is dissolved in 6 ml of dimethylformamide (DMF), 1.9 ml of
diisoproypylethyl amine, 1.2 g sodium iodide, and 1.5 g of 2-amino-5,6- diethylindane are added and the mixture is heated to 100° C. After completion of the reaction the mixture is cooled to 20/25° C, 0.4 ml of concentrated hydrochloric 15 acid and 0.4 ml of water are added, and the mixture is stirred for 30 minutes.
HPLC analysis shows the expected product with a purity of 75% and being free from the dimer and regioisomer impurities.
20 20 ml of water, 20 ml of methylene chloride, and 3 ml of 6N NaOH are added with stirring. The organic phase is separated and washed with 20 ml of water. The organic phase is distilled and the solvent is changed to ethyl acetate with a final volume of 100 ml. The mixture is heated to 70° C, 0.8 g of L-tartaric acid is added, and stirring continues for 30 minutes at 70° C. The mixture is cooled
25 slowly to 20/25° C, filtered, and washed with 8 ml of ethyl acetate to obtain 8- (phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-(lH)- quinolin-2-one tartrate in 68% yield. The purity of the product is >95% by HPLC analysis. Example 4 – preparation of the compound of formula IV
A flask is charged with 19 ml of THF and 19 ml of toluene, p-toluene sulfonic acid (75 mg) and molecular sieves (1.5 g) are added and the mixture is stirred for 30 minutes. 11.2 ml of butyl-vinylether and 15 g of 8-(phenylmethoxy)-5-((R)-2- bromo-l-hydroxy-ethyl)-(lH)-quinolin-2-one are added. The mixture is agitated at 20/25° C until completion of the reaction. 0.1 ml of diisopropylethyl amine are added, the mixture is filtered, and the solvent is distilled off.
The residue is dissolved in 40 ml of butanone, 14.5 ml of diisoproypylethyl amine, 9 g sodium iodide, and 11.3 g of 2-amino-5,6-diethylindane are added and the mixture is heated to 90-100° C. After completion of the reaction the mixture is cooled to 20/25° C, 3 ml of concentrated hydrochloric acid and 3 ml of water are added, and the mixture is stirred for 30 minutes.
HPLC analysis shows the expected product with a purity of 84% and being free from the dimer and regioisomer impurities. 150 ml of water, 150 ml of methylene chloride, and 22.5 ml of 6N NaOH are added with stirring. The organic phase is separated and washed with 10 ml of water. The organic phase is distilled and the solvent is changed to isopropyl alcohol with a final volume of 300 ml. The mixture is heated to 70° C, 4.9 g of benzoic acid is added, and stirring continues for 30 minutes at 70° C. The mixture is cooled slowly to 20/25° C, filtered, and washed with 30 ml of isopropanol to obtain 8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy- ethyl]-(lH)-quinolin-2-one benzoate in 59 % yield. The purity of the product is > 99 % by HPLC analysis. Example 5 – preparation of the compound of formula IV
A flask is charged with 7.5 ml of THF and 7.5 ml of toluene, p-toluene sulfonic acid (30 mg) and molecular sieves (0.6 g) are added and the mixture is stirred for 30 minutes. 4.5 ml of butyl-vinylether and 6 g of 8-(phenylmethoxy)-5-((R)-2- bromo-l-hydroxy-ethyl)-(lH)-quinolin-2-one are added. The mixture is agitated at 20/25° C until completion of the reaction. 0.040 ml of diisopropylethyl amine are added, the mixture is filtered, and the solvent is distilled off.
The residue is dissolved in 18 ml of acetonitrile (ACN), 5,8 ml of diisoproypylethyl amine, 3.6 g sodium iodide, and 4.5 g of 2-amino-5,6-diethylindane are added and the mixture is heated to 80-90° C. After completion of the reaction the mixture is cooled to 20/25° C, 1.2 ml of concentrated hydrochloric acid and 1.2 ml of water are added, and the mixture is stirred for 30 minutes. HPLC analysis shows the expected product with a purity of 89% and being free from the dimer and regioisomer impurities.
60 ml of water, 60 ml of methylene chloride, and 9 ml of 6N NaOH are added with stirring. The organic phase is separated and washed with 60 ml of water. The organic phase is distilled and the solvent is changed to isopropyl alcohol with a final volume of 120 ml. The mixture is heated to 70° C, 1.9 g of succinic acid is added, and stirring continues for 30 minutes at 70° C. The mixture is cooled slowly to 20/25° C, filtered, and washed with 12 ml of isopropanol to obtain 8- (phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-(lH)- quinolin-2-one succinate in 56 % yield . The purity of the product is > 99 % by HPLC analysis. Example 6 : purification with EtOH/water
To 2.0 g of 8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l- hydroxy-ethyl]-(lH)-quinolin-2-one, a mixture of 35 ml/g of EtOH and 5 ml/g of water are added and heated to reflux. Once this temperature is reached, benzoic acid is added (1.2 eq.) as a solution in 5 ml/g of the mixture of EtOH/water. The temperature is maintained for 30 minutes. The mixture is then cooled slowly overnight to 20-25°C. The resulting suspension is filtered and a white solid is obtained and dried in vacuum. The white solid is analyzed by HPLC to determine the chromatographic purity and by chiral HPLC to determine the enantiomeric purity, obtaining a white solid product with a proportion of enantiomeric impurity below 0.05%. No other impurities are detected.
Example 7 : purification with Acetone/water
To 2.0 g of 8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l- hydroxy-ethyl]-(lH)-quinolin-2-one, a mixture of 35 ml/g of Acetone and 1 ml/g of water are added and heated to reflux. Once this temperature is reached, Dibenzoyl-L-tartaric monohydrate acid is added (1.2 eq.) as a solution in 5 ml/g of the mixture of Acetone /water. The temperature is maintained for 30 minutes. The mixture is then cooled slowly overnight to 20-25°C. The resulting suspension is filtered and a white solid is obtained and dried in vacuum. The white solid is analyzed by HPLC to determine the chromatographic purity and by chiral HPLC to determine the enantiomeric purity, obtaining a white solid product with a proportion of enantiomeric impurity below 0.05%. No other impurities are detected.
Example 8 : purification with EtOH/water
To 2.0 g of of 8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l- hydroxy-ethyl]-(lH)-quinolin-2-one, a mixture of 35 ml/g of EtOH and 5 ml/g of water are added and heated to reflux. Once this temperature is reached, L Tartaric acid is added (1.2 eq.) as a solution in 5 ml/g of the mixture of
EtOH/water. The temperature is maintained for 30 minutes. The mixture is then cooled slowly overnight to 20-25°C. The resulting suspension is filtered and a white solid is obtained and dried in vacuum. The white solid is analyzed by HPLC to determine the chromatographic purity and by chiral HPLC to determine the enantiomeric purity, obtaining a white solid product with a proportion of enantiomeric impurity below 0.06%. No other impurities are detected.
Example 9 : synthesis of protected benzyl Indacaterol
A solution of sodium carbonate (0.57 kg/kg, 2 equivalents) in water (13 l/kg) is prepared in another reactor. This carbonate solution is added to the product solution from example 1, diethyl indanolamine HCI (0.72 kg/kg, 1.2 equivalents) is added and the mixture is heated and distilled at atmospheric pressure until a volume of 13 l/kg . Water (3 l/kg) is added and the mixture is distilled at atmospheric pressure until a volume of 13 l/kg . The system is placed in reflux position and reflux is maintained for 20 hours. When the reaction is complete, the mixture is cooled to 20-25°C and methylene chloride (15 l/kg) is added. The mixture is agitated, decanted, and the aqueous phase is extracted with methylene chloride (5 l/kg). The organic phases are washed with water (5 l/kg).
Example 10 – preparation of Indacaterol maleate
28 g of 8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy- ethyl]-(lH)-quinolin-2-one tartrate is dissolved in a mixture of 560 ml of dichloromethane, 560 ml of water, and 30 ml of an aqueous solution of 6N sodium hydroxide under stirring . The phases are separated and the organic phase is washed with 280 ml of water. The organic phase is distilled to a final volume of 140 ml and 420 ml of methanol and 4.2 g of Pd/C (5% – 50% water) are added . The system is purged with nitrogen and subsequently with hydrogen at an overpressure of 0.3 bar and stirring until completion of the reaction. The catalyst is filtered off and the solvent is changed to isopropanol adjusting the final volume to 950 ml. The solution is heated to 70/80° C and a solution of 5.4 g maleic acid in 140 ml of isopropanol is added, maintaining the temperature between 70 and 80° C. The mixture is stirred at 70/80° C for 30 minutes and then slowly cooled to 20/25° C. The resulting suspension is filtered, the solid residue is washed with 90 ml of isopropanol and dried to obtain 18g of Indacaterol maleate (Yield : 79%). The product shows 99.6% purity by HPLC analysis.
Example 11 – Isolation of Indacaterol free base in solid form
lg of 8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy- ethyl]-(lH)-quinolin-2-one tartrate is dissolved in a mixture of 20 ml of dichloromethane,20 ml of water, andl ml of an aqueous solution of 6N sodium hydroxide under stirring. The phases are separated and the organic phase is washed with 10 ml of water.
The organic phase is distilled to a final volume of 5 ml and 15 ml of methanol and 0.15 g of Pd/C (5% – 50% water) are added . The system is purged with nitrogen and subsequently with hydrogen at an overpressure of 0.3 bar and stirring until completion of the reaction.
The catalyst is filtered off and the solvent is changed to isopropanol adjusting the final volume to 8 ml. The resulting suspension is cooled to 0-5°C, filtered and the solid residue is washed with isopropanol and dried to obtain 0.47 g of Indacaterol free base (77%) showing 99.6% purity by HPLC analysis.
A sample of Indacaterol free base stored at 20-25°C is analysed one month later without showing any loss of purity. Example 12 – obtaining the maleate salt from Indacaterol free base
0.47 g of solid Indacaterol are suspended in 20 ml of isopropanol, heated to 70/80° C, and a solution of 0.15 g of maleic acid in 5 ml of isopropanol are added, maintaining the temperature between 70 and 80° C. The mixture is cooled to 0/5°C and filtration of the resulting solid affords 0.52 g of Indacaterol maleate with a purity of 99.7%.
Comparative example 13 – direct conversion to Indacaterol maleate
8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]- (lH)-quinolin-2-one benzoate (4 g) is dissolved in acetic acid (40 ml). Pd/C (5 %, 50% wet, 0.6 g) is added and the product is hydrogenated under a hydrogen atmosphere. When the reaction is complete the catalyst is filtered off and the filtrate is vacuum distilled until a volume of 8 ml is reached.
Ethanol (40 ml) is added and the mixture is heated to 50° C. A solution of 1.2 g of maleic acid in 2.4 ml of ethanol is added and the mixture is seeded with
indacaterol maleate and then slowly cooled to 0/5° C. The solid is filtered and washed with 5 ml of ethanol and 3 ml of isopropanol to obtain 6.0 g of indacaterol maleate.
1H-NMR analysis of the solid shows the presence of acetic acid in 2-4 % by integration of the peak at δ 1.88 (400 MHz, DMSO-c/6) corresponding to acetic acid.
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| Citing Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| WO2014154841A1 * | Mar 27, 2014 | Oct 2, 2014 | Laboratorios Lesvi, S.L. | Process for the manufacture of (r)-5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-(1h)-quinolin-2-one |
 |
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 |
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| Systematic (IUPAC) name | |
|---|---|
|
5-[2-[(5,6-Diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxyquinolin-2(1H)-one
|
|
| Clinical data | |
| Trade names | Onbrez, Arcapta |
| AHFS/Drugs.com | International Drug Names |
| Licence data |
|
| Pregnancy category |
|
| Routes of administration |
Inhalation |
| Legal status | |
| Identifiers | |
| CAS Number | 312753-06-3 |
| ATC code | R03AC18 |
| PubChem | CID 6433117 |
| IUPHAR/BPS | 7455 |
| ChemSpider | 5293751 |
| UNII | 8OR09251MQ |
| KEGG | D09318 |
| ChEBI | CHEBI:68575  |
| ChEMBL | CHEMBL1095777 |
| Chemical data | |
| Formula | C24H28N2O3 |
| Molar mass | 392.490 g/mol |
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O=C4/C=C\c1c(c(O)ccc1[C@@H](O)CNC3Cc2cc(c(cc2C3)CC)CC)N4
.2HCl
SUVN-G3031
N-[4-(1-cyclobutyl piperidin-4-yloxy)-phenyl]-2-(morpholin-4-yl) acet amide dihydrochloride
N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride
SUVN-G3031
Base
Cas 1394808-82-2
SUVN-G3031 (in phase I)
Suven Life Sciences Limited, IN 2011CH00520
https://clinicaltrials.gov/ct2/show/NCT02342041
Useful for treating cognitive disorders, dementia, attention deficit hyperactivity disorder, epilepsy, sleep disorders, obesity, schizophrenia, eating disorders and pain.
Histamine H3 receptor antagonists
Neuropsychotherapeutics; Nootropics
Suven Life Sciences is developing, Histamine H3 receptor antagonists, SUVN-G3031 (in phase I)
H 3 receptors play a critical role as neuromodulators through their widespread distribution in the central nervous system. Blockade of this receptor augments the pre-synaptic release of both histamine and other neurotransmitters including acetylcholine from cholinergic neurons. Currently, several H 3 receptor antagonists/inverse agonists are in different stages of clinical trials for the potential treatment of narcolepsy, cognitive impairments associated with Alzheimer’s disease, Parkinson’s disease, schizophrenia and attention deficit hyperactivity disorder.
Histamine H3 receptor is a G-protein coupled receptor (GPCR) and one out of the four receptors of Histamine family. Histamine H3 receptor is identified in 1983 and its cloning and characterization were done in 1999. Histamine H3 receptor is expressed to a larger extent in central nervous system and lesser extent in the peripheral nervous system.
Literature evidence suggests that Histamine H3 receptor ligands can be used in treatment of cognitive disorders (British Journal of Pharmacology, 2008, 154(6), 1 166-1181), dementia (Drug News Perspective, 2010, 23(2), 99-103), attention deficit hyperactivity disorder, obesity (Indian Journal of Pharmacology, 2001, 33, 17-28), schizophrenia (Biochemical Pharmacology, 2007, 73(8), 1215-1224) and pain (Journal of Pharmacology and Experimental Therapeutics, 2011, 336(1), 30-37).
Patent publications WO 2007/137955, US 2009/0170869, US 2010/0029608, US 2010/0048580, WO 2009/100120, WO 2009/121812 and WO 2009/135842 disclosed series of compounds as ligands at Histamine H3 receptors. While some Histamine H3 receptor ligands have been disclosed, no compound till date is launched in market in this area of research, and there still exists a need and scope to discover new drugs with novel chemical structures for treatment of disorders affected by Histamine H3 receptors.
Drugmaker Suven Life Science, which is mostly into researching for new molecules used for ailments of the central nervous system, has completed the single ascending dose (SAD) studies for SUVN- G3031, which is likely to be used for cognitive dysfunction associated with Alzheimer’s and schizophrenia.
The phase-1 study was said to be designed to evaluate safety, tolerability and pharmacokinetics of SUVN-G3031 in healthy volunteers. It was found that the tolerability of SUVN-G3031 up to the highest dose administered in SAD study was ‘excellent’ with ‘no serious adverse events’. The drug candidate was demonstrated for one-day dosing.
HYDERABAD, INDIA (Nov 03, 2014) – Suven Life Sciences today informed that their NCE SUVN-3031 has commenced Phase 1 clinical trial in USA. SUVN-G3031 – A potent, selective, brain penetrant and orally active Histamine H3 antagonist for the treatment of cognitive dysfunction associated with Alzheimer’s Disease / Schizophrenia has completed all the pre-clinical, safety and early toxicological studies, GLP toxicological studies and was submitted forInvestigational New Drug Application {IND) to conduct Phase 1 clinical trial with the indication for Cognition in Alzheimer’s Disease under 505(1) of the Federal Food, Drug and Cosmetic Act (FDCA) which was assigned an IND number 123179.
Based on the IND “A Single Center, Double-blind, Placebo-controlled, Randomized, Phase 1 Study to Evaluate the safety, Tolerability, and Pharmacokinetics of SUVN-G3031 after Single Ascending Doses and Multiple Ascending Doses in Healthy Male Subjects” for Cognition in Alzheimer’s Disease is underway in USA
“We are very pleased that the second compound from our pipeline of molecules in CNS has moved into clinical trial that is being developed for cognitive disorders in Alzheimer’s and Schizophrenia with high unmet medical need which has huge market potential globally” says Venkat Jasti, CEO of Suven.
Suven Life Science is a biopharmaceutical company focused on discovering, developing and commercializing novel pharmaceutical products, which are first in class or best in class CNS therapies through the use of GPCR targets. The Company has eleven (11) internally-discovered therapeutic drug candidates currently in pre-clinical stage of development targeting conditions such as ADHD, dementia, major depressive disorder (MDD), Huntington’s disease, Parkinson’s disease and obesity in addition to this Phase 1 developmental candidate SUVN-G301 and Phase 2 a (PoC) ready SUVN-502 for Alzheimer’s disease and Schizophrenia.
SYNTHESIS
PATENT
WO2012114348
OR SEE
https://www.google.com/patents/US20140135304?cl=en22
PATENT
Scheme I as shown below.
PATENT
process for large scale production of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride of formula (I).
N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(moφholin-4-yl) acetamide dihydrochloride, is a promising pharmaceutical agent, which is potent and selective Histamine ¾ receptor ligand intended for the symptomatic treatment of cognitive disorders, dementia, attention deficit hyperactivity disorder, epilepsy, sleep disorders, sleep apnea, obesity, schizophrenia, eating disorders and pain. N-[4-(l-Cyclobutyl piperidin-4-yloxy) phehyl]-2-(morpholin-4-yl) acetamide dihydrochloride and its synthesis is disclosed by Ramakrishna et al. in WO20121 14348.
Currently N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl] -2-(morpholin-4-yl) acetamide dihydrochloride has completed preclinical studies and is ready to enter human clinical trials. The demand for N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride as a drug substance has increased substantially with the advent of its clinical testing. The future need for much larger amounts is projected due to the intended commercialization of N-[4-( 1 -Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride.
For the person skilled in art, it is a well known fact that various parameters will change during the manufacture of a compound on a large scale when compared to the synthetic procedures followed in laboratory. Therefore, there is a need to establish and optimize large scale manufacturing process. The process for the preparation of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride disclosed in WO20121 14348 was proved to be unsatisfactory for adaptation to the large scale manufacturing. Hence it is highly desirable to establish optimized manufacturing process of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl] -2 -(morpholin-4-yl) acetamide dihydrochloride of formula (I), which is amenable to the large scale manufacturing of the compound.
Example 1: Preparation of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(raorpholin-4-yl) acetamide dihydrochloride
Step (i): Preparation of l-cycIobutylpiperidin-4-ol
Ethylene dichloride (235 L) was charged into the reactor at 20-25 °C followed by 4-hydroxy piperidine (9.5 Kg, 93.92 M). The mass was stirred for ~ 15 minutes to obtain a clear, solution. Then cyclobutanone (7.9 Kg, 1 12.71 M) was charged into the reactor at 20-25 °C and stirred the mass for 90 minutes at the same temperature. The mass was cooled to 15-20 °C and started lot wise addition of sodium triacetoxy borohydride (39.9 Kg, 188.26 M) maintaining the mass temperature below 25 °C in ~ 110 minutes. After completion of addition, the mass was stirred for 30 minutes at ~ 20 °C. The mass temperature was raised to 25-30 °C and maintained at the same temperature for ~ 13.1 hours, while monitoring the progress of the reaction by Thin Layer Chromatography (TLC). After completion of the reaction, water (1 12 L) was charged into the reactor at 25-30 °C. The mass was then cooled to 15-20 °C and pH of the reaction mass was adjusted to 13.0-13.5 with a solution of aqueous sodium hydroxide (24.6 Kg of sodium hydroxide dissolved in 106 L of demineralised water (DM water) maintaining the mass
temperature below 20 °C in about 1 hour 20 minutes. In the meanwhile, nutsche filter with hyflow bed (using 4.75 Kg hyflow and 47.5 L DM water) was made ready for filtration of dirt and sodium acetate salt, for the purpose of clean layer separations during extraction of the product. The reaction mass was filtered through nutsche and the nutsche was washed with 23.75 L of ethylene dichloride. The filtrate containing the product was collected into clean and dedicated containers. The combined filtrate and washings were transferred to a reactor, stirred 15 minutes and settled for 15 minutes at 25-30 °C. The bottom organic layer (containing the product) was collected in dedicated containers and the mass was dried over anhydrous sodium sulfate (9.5 Kg). The supernatant, clean, dry organic layer was taken in a reactor and solvent was removed by distillation under vacuum maintaining mass temperature below 50 °C. The residual crude mass was cooled to 25-30 °C.
2nd extraction of the aqueous layer: The aqueous layer separated as above was taken in a reactor and charged dichloromethane (DCM) (56 L) at 25-30 °C. The mass was stirred 15 minutes and settled for 15 minutes. The bottom organic layer (containing product) was separated into dedicated containers. The aqueous layer was collected and taken for 3 rd extraction.
3 rd extraction of the aqueous layer: The aqueous layer separated as above was takenin a reactor and charged DCM (56 L) at 25-30 °C. The mass was stirred 15 minutes and settled for 15 minutes. The bottom organic layer (containing product) was separated into dedicated containers. The aqueous layer was collected and taken for 4th extraction.
4th extraction of the aqueous layer: The aqueous layer separated as above was taken in a reactor and charged DCM (56 L) at 25-30 °C. The mass was stirred 15 minutes and settled for 15 minutes. The bottom organic layer (containing product) was separated into dedicated containers. The aqueous layer was collected and taken for 5th extraction.
5th extraction of the aqueous layer: The aqueous layer separated as above was taken in a reactor and charged dichloromethane (56 L) at 25-30 °C. The mass was stirred 15 minutes and settled for 15 minutes. The bottom organic layer
(containing product) was separated into dedicated containers. The aqueous layer was collected in dedicated containers and kept aside.
The organic layer obtained from second extraction to fifth extraction was combined and dried over anhydrous sodium sulfate (13.5 Kg). The supernatant, clean, dry organic layer was taken in the reactor, containing the crude product obtained from first extraction, and solvent was removed by distillation under reduced pressure (>500 mm Hg) maintaining mass temperature below 50 °C. The residual mass was cooled to 25-30 °C and collected the technical product (14.36 Kg).
Yield: 98.49 %;
Ή-NMR (δ ppm, CDC13): 1.55 – 1.69 (5H, m), 1.83 – 2.02 (8H, m), 2.65 – 2.69 (3H, m), 3.66 – 3.70 (1H, m);
Mass (m/z): 156.2 (M+H)+.
Step (ii): Preparation of 4-(l-cyclobutylpiperidin-4-yIoxy)-l-nitrobenzene
Tetrahydrofuran (THF) (43.2 L) was charged into a Stainless steel reactor (SS reactor) at 25-30 °C under nitrogen atmosphere followed by addition of sodium hydride (5.22 Kg) maintaining mass temperature at 25-30 °C under nitrogen atmosphere. The contents were stirred for 15 minutes at 25-30 °C. The temperature of the reaction mass was raised to 35-40 °C.
THF (56.7 L) was charged into another SS reactor at 25-30 °C under nitrogen atmosphere by the addition of above obtained step (i) material (13.5 Kg, 86.96 M). The mass was stirred for 15 minutes at 25-30 °C to obtain a clear solution. The resulting solution was added to the above reactor containing sodium hydride in THF, maintaining the mass temperature of the main reactor at 35-40 °C over a period of ~ 45 minutes under nitrogen atmosphere. The resulting mass was further stirred for 90 minutes at 35-40 °C.
In the meanwhile THF (35.8 L) was charged into another SS reactor at 25-30 °C under nitrogen atmosphere, followed by the addition of 4-fluoro-l-nitrobenzene (14.72 Kg, 104.32 M). The contents of the reactor were stirred for 15 minutes at 25-30 °C to obtain a clear solution. The clear solution, thus obtained, was slowly transferred to the main reactor in ~ 45 minutes maintaining the mass temperature of the main reactor at 35-40 °C. The temperature of the reaction mass was further maintained at 35-40 °C for 5 hours under stirring and under nitrogen atmosphere, while monitoring the progress of the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 15-20 °C.
. Charged water (675 L) into another SS reactor under nitrogen atmosphere. The contents of the reactor were cooled to 5-10 °C. Then the reaction mass from the main reactor was transferred carefully to this reactor containing water, maintaining the mass temperature below 20 °C in ~ 45 minutes. The resulting mass was further stirred for 30 minutes maintaining the temperature at 15-20 °C. The solid mass was centrifuged and the mother liquors were collected in dedicated containers. The cake on the centrifuge was washed with water (2 x 135 L) and spin dried to obtain technical product (19.80 Kg).
Purity: 99.5 %.
Purification: Dissolved the technical product obtained as above (19.80 Kg) in ~ 200 L of 10 % aqueous acetic acid solution (~ 20.59 Kg acetic acid diluted with 180 L with water) at 25-30 °C.
1st toluene extraction: Stirred 15 minutes and then charged toluene (33 L) at 25-30 °C. Stirred 15 minutes and settled for 15 minutes and layers separated, The top organic layer containing the impurities was kept aside in a dedicated container.
2nd toluene extraction: The lower aqueous product layer was taken into the reactor again and charged toluene (33 L) at 25-30 °C. Stirred 15 minutes and settled for 15 minutes and layers separated. The top organic layer containing the impurities was kept aside in the dedicated container.
3rd toluene extraction: The lower aqueous product layer was taken again into the reactor and charged toluene (25 L) at 25-30 °C. Stirred 15 minutes and settled for 15 minutes and layers separated. The top organic layer containing the impurities was kept aside in the dedicated container.
The aqueous product layer was charged into the reactor at 25-30 °C. The mass was cooled to 10 – 15 °C. pH of the reaction mass was adjusted to 1 1.5 -12.0; with 20 % w/v aqueous sodium hydroxide solution (prepared by dissolving 15.44 Kg sodium hydroxide flakes in 69.3 L of DM water) while maintaining mass temperature at 10-15 °C for 1.45 hours. The resulting mass was stirred for 15 minutes at 25-30 °C at pH 11.55. The solids that separated were centrifuged. The cake was washed with (40 L x 2) DM water and the product was spin dried (19.9 Kg), Yield: 53.56 %
Purity: 99.52 %.
Ή-NMR (δ ppm, CDC13): 1.58 – 1.73 (2H, m), 1.84 – 1.93 (4H, m), 2.02 – 2.06 (4H, m), 2.19 (2H, s), 2.62 (2H, s), 2.71 – 2.76 (1H, m), 4.45 (1H, s), 6.93 – 6.95 (2H, d, J = 9.07 Hz), 8.18 – 8.20 (2H, d, J = 9.02 Hz);
Mass (m/z): 277.2 (M+H)+.
The aqueous layer (obtained after eentrifuging and washing the product) was collected in dedicated containers for isolation of the second crop.
Step (iii): Preparation of 4-(l-cyclobutylpiperidin-4-yloxy) aniline
The reaction was done in a SS reactor under nitrogen blanket. DM Water
(33.59 L) was charged into a SS reactor at 25-30 °C followed by iron powder (10.43 Kg, 186.75 M, 1 :4 ratio) under stirring. Then ammonium chloride (11.5 Kg, 215 M) was charged at 25-30 °C and stirred the contents for 15 minutes at 25-30 °C. The mass temperature was raised slowly to 95- 100 °C and maintained at that temperature (95-100 °C).for.^.90 minutes. The mass was cooled to 75-80 °C.
In the meanwhile, ethyl alcohol (128.7 L) was charged into another reactor at 25-30 °C, followed by addition above obtained compound (19.9 Kg). The contents were stirred for 15 minutes and then raised the mass temperature to 50-55 °C, where by a clear solution was obtained. The mass was slowly transferred to the main reactor, containing the activated iron powder at 78-80 °C over a period of ~ 70 minutes. The mass was further stirred for 3 hours, while maintaining the mass temperature at 75-80 °C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 25-30 °C and filtered through nutsche, containing hyflow bed. The filtrate was collected into dedicated containers. The bed was washed with 3 x 32.18 L of ethyl alcohol and collected the washings into dedicated containers. The combined filtrate was charged into a clean SS reactor at 25-30 °C. All the volatiles are distilled off under reduced pressure (> 500 mm Hg) maintaining the mass temperature below 55 °C. The residual mass was cooled to 25-30 °C and charged DM water (32.18 L). The pH of the reaction mass was adjusted to 9.0 – 10.0 with 91 L of sodium carbonate solution (prepared by dissolving 21.5 Kg of sodium carbonate in 80 L of DM water), while maintaining the mass temperature at 25-30 °C. Final pH is 9.14. The solid mass, separated in the reactor, was cehtrifuged and collected the filtrate in dedicated containers. The product was spin dried (20.34 Kg).
Ethylacetate (EtOAc) (80 L) was charged into a clean SS reactor at 25-30 °C followed by the wet cake (20.34 Kg) obtained above. The mass was stirred for 15 minutes at 25-30 °C. Then added DM water (32 L) and further stirred the mass for 15 minutes and settled for 15 minutes. The aqueous layer was separated and collected in dedicated containers.
The organic layer containing the product was filtered through nutsche filter through hyflow bed (formed with 5.15 Kg hyflow and 26 L water) and filtrate was collected in dedicated containers. The bed was washed with EtOAc (13 L). The combined organic layer and EtOAc washings were charged into a clean SS reactor. Charged 20 L DM water, stirred for 15 minutes and settled for 15 minutes at 25-30 °C. The aqueous layer is separated and the organic layer was dried over anhydrous sodium sulfate (20 Kg).
The clean, dried organic layer was charged into a reactor at 25-30 °C. Solvent was distilled off under reduced pressure (> 500 mm Hg) below 50 °C (Solvent recovered: 70 L). The residual product was cooled to 25-30 °C and unloaded into dedicated containers (12.30 Kg) and sent for complete analysis. Weight of the product: 12.3 Kg (wet with solvent EtOAc: 9.1 %),
Yield (on dry basis): 9.7.5 %;
Purity: 97.79 %;
IR (cm-‘): 3424, 3345, 2943, 1627, 1509, 1229, 1 168, 1044, 821 ;
1H-NMR (5 ppm, DMSO): 1.49 – 1.61 (4H, m), 1.71 – 1.83 (4H, m), 1.92 – 1.97 (5H, m), 2.52 – 2.53 (2H, m), 3.99 – 4.04 (1 H, m), 4.59 (2H, bs), 6.46 – 6.48 (2H, d, J = 8.60 Hz), 6.61 – 6.63 (2H, d, J = 8.66 Hz);
Mass (m/z): 247.4 (M+H)+.
Step (iv): Preparation of 2-chloro-N-[4-(l-cycIobutyI piperidin-4-yloxy).
phenyl] acetamide
The reaction was done in a SS reactor under nitrogen blanket. THF (89.6
L) was charged into a Glass reactor (GLR) at 25-30 °C followed by addition of above obtained material (1 1.2 Kg on dry basis, 45.46 M). The contents were stirred 15 minutes. Then charged anhydrous potassium carbonate (K2C03) powder (12.54 Kg, 90.73 M) into the reactor and stirred the mass for 15 minutes at 25-30 °C. The reaction mass was cooled to -10 to -5 °C by circulating brine in the jacket. Then a solution of chloroacetylchloride (6.72 Kg, 59.5 M) dissolved in THF (44.8 L) was slowly introduced into the reactor through a holding tank, under nitrogen atmosphere, in ~ 2.5 hours maintaining the mass temperature at -10 to -5 °C. The reaction mass was further maintained under stirring at -10 to -5 °C for another 2 hours while monitoring the progress of the reaction by TLC.
After completion of the reaction, slow addition of chilled DM water (186 L) through the addition funnel started at -10 to -5 °C. Towards the end of addition of DM water (addition time 45 minutes), it was so adjusted that the mass temperature reached 10-15 °C. After completion of addition of DM water the mass temperature was raised to 25-30 °C.
1st extraction: Ethyl acetate (1 12 L) charged into the reactor at 25-30 °C. The mass was stirred 30 minutes and settled for 30 minutes. Layers separated and the organic product layer was collected in dedicated containers.
2nd extraction: The aqueous layer obtained as above was charged into the reactor followed by EtOAc (1 12 L) at 25-30 °C. The mass was stirred 30 minutes and settled for 30 minutes. Layers separated and the organic product layer and the aqueous layer were collected in dedicated containers.
The combined organic layer, obtained from the above extractions, was charged into a clean GLR followed by the addition of 116 L of brine solution (prepared by dissolving 33.6 Kg sodium chloride in 1 12 L DM water) at 25-30 °C. The mass was stirred for 30 minutes and settled for 30 minutes at 25-30 °C. The aqueous layer was separated and collected in dedicated containers. The organic product layer was dried over anhydrous sodium sulfate (22.4 Kg). The volume of the organic layer was 360 L. The organic layer obtained as above was charged into a clean GLR at 25-30 °C. Solvent was distilled off under reduced pressure (> 500 mm Hg) maintaining mass temperature below 55 °C (volume of recovered solvent; 178 L). The mass was cooled to 25-30 °C. Solid mass separated in the reactor.
Recrystallization
Isopropanol (72.8 L) was charged into the reactor containing the solids (~ 13.5 Kg) at 25-30 °C, followed by methanol (~ 58.2 L) at 25-30 °C. Stirred the reaction mass at 25-30 °C for 30 minutes. The mass temperature was raised slowly to reflux temperature and maintained at reflux till a clear solution is obtained (~ 30 minutes). Then the mass was cooled to 25-30 °C and stirred the mass for 60 minutes. The mass was further cooled to -12 -15 °C, stirred for 30 minutes and centrifuged the material. The cake on the centrifuge was washed with 2 x 7 L isopropanol (25-30 °C) and spin dried thoroughly.
The wet cake (1 1.2 Kg) was dried in a vacuum tray drier (VTD) for ~ 4 hours at 40-50 °C to obtain crystallized product (9.7 Kg).
Yield: 66.12 %;
Purity (by HPLC): 99.56 %; – IR (cm-1): 3307, 3278, 2951, 1670.43, 1612, 1554.69, 1508.4/1240.28, 1 171.81 , 1047.39, 953.84, 832.32;
1H-NMR (δ ppm, DMSO): 1.53 – 1.61 (4H, m), 1.72 – 1.74 (2H, m), 1.87 – 1.99 (6H, m), 2.49 – 2.53 (2H, m), 2.64 – 2.68 (1H, m), 4.19 (2H, s), 4.24 – 4.29 (1H, m), 6.88 – 6.90 (2H, d, J = 8.96 Hz), 7.44 – 7.46 (2H, d, J = 8.96 Hz), 10.12 (1H, s); …. . . .. ■÷. “
Mass (m/z): 323.3, 325.2 (M+H)+.
Mother liquor obtained, after recrystallization and centrifuging the product, was processed for isolating second crop.
Step (v): Preparation of N-[4-(l-cycIoburyl piperidin-4-yIoxy) phenyI]-2-(morphoIin-4-yl) acetamide
Acetonitrile (1.41 L) was charged into the GLR at 25-30 °C under nitrogen atmosphere, followed by addition of the above obtained material (9.4 Kg, 29.11 M). Then, charged anhydrous K2C03 granules (6.0 Kg, 43.41 M) into the reactor at 25-30 °C. Stirred the reaction mass in the reactor for 10 minutes and charged morpholine (3.3 Kg, 37.88 M). The contents of the reactor were stirred for 15 minutes at 25-30 °C. The temperature of the reaction mass was raised slowly to reflux (80-82 °C) and maintained at reflux for 4 hours while monitoring the progress of the reaction every two hours by HPLC.
Analysis of the sample by HPLC after 4 hours reflux: 89.61 % product and 8.83 % starting material (SM).
Charged morpholine (253 grams) and K2C03 (400 grams) and further refiuxed. Analysis by of the sample at 7.5 hours: 92.8 % product and 5.63 % SM. So charged morpholine (506 grams), K2C03 (810 grams) and acetonitrile (30 L) and heated the mass at reflux for another five hours. Analysis of the sample at 12.5 hours: 96.78 % product and 2.06 % SM. Again charged K2C03 (820 grams), morpholine (255 gm) and acetonitrile (40 L) and maintained the mass under reflux. Analysis of the sample at 19.5 hours: 97.52 % product and 0.9 % SM. The reaction mass was cooled to 30-35 °C and filtered solids through nutsche at 30-35 °C. The cake on the nutsche was washed with 15 L acetonitrile; Mother liquors (~ 210 L filtrate) were taken back into the main reactor (GLR) and kept under stirring at 30 – 35 °C, while workup of the solid cake (22.4 Kg), containing the product along with salts, was going on in another reactor.
Wet weight of cake: 22.4 Kg (contained ~ 23 % product).
Charged 30 L water into another reactor followed by the wet cake obtained after nutsche filtration (22.4 Kg). Stirred the mass for 30 minutes and charged EtOAc (47 L). The mass was stirred 15 minutes and settled for 15 minutes. The organic layer containing the product was collected in dedicated containers. pH of the aqueous mother liquors was found to be 10.05 on pH meter.
2nd extraction: Charged the above obtained aqueous layer into the reactor followed by EtOAc (47 L). The mass was stirred 15 minutes and settled for 15 minutes and layers separated. The organic layer containing the product was collected in dedicated containers.
3nd extraction: Charged the above obtained aqueous layer into the reactor followed by EtOAc (40 L). The mass was stirred 15 minutes and settled for 15 minutes and layers separated. The organic layer containing the product was collected in dedicated containers.
The combined organic layer was dried over sodium sulfate (9.4 Kg) and the clean organic layer was taken for distillation under reduced pressure (> 500 mm Hg) at 50-55 °C. The mass was cooled to 25-30 °C. Added 23.5 L of acetonitrile and stirred well.
Part of the reaction mass (65 L of acetonitrile solution) from GLR was unloaded and charged into the above reaction mass at 25-30 °C and stirred 30 minutes, whereby a clear solution was obtained. The mass was transferred to the main reactor. Washing was given to this reactor with 20 L fresh acetonitrile at 40-45 °C and again transferred to the main reactor and stirred 15 minutes before sampling.
The final, uniformly mixed reaction mass was sampled from the main GLR and analyzed. HPLC: 99.09 % product and 0.31 % SM. So charged morpholine (510 grams) and K2C03 (825 grams) and the mass was heated to reflux and further maintained the mass at reflux temperature for 2 hours. A sample was analyzed after 2 hours reflux. Starting material was absent (product purity: 99.24 %).
The reflux was further continued for another 2 hours and then cooled the mass temperature to 30-35 °C. Solvent was distilled off under reduced pressure (> 500 mm Hg), maintaining mass temperature below 55 °C.
1st Extraction: Charged DM water (23.5 L) to the residual mass at 25-30 °C. Stirred the mass for 15 minutes and charged ethyl acetate (80 L). A clear solution was obtained. Stirred the mass for 15 minutes and settled the mass for 15 minutes. Layers separated and the product organic layer collected in dedicated containers. 2ndExtraction: The aqueous layer obtained as above (pH was found to be 9.9 on meter) was charged into the reactor followed by ethyl acetate (40 L). Stirred the mass for 15 minutes and settled the mass for 15 minutes. Layers separated and the product organic layer collected in dedicated containers.
3nd Extraction: The aqueous layer obtained as above was once again charged into the reactor followed by ethyl acetate (40 L). Stirred the mass for 15 minutes and settled the mass for 15 minutes. Layers separated and the product organic layer collected in dedicated containers.
Brine washing: The combined organic layer was taken in the reactor and charged
~ 35 L brine solution (prepared by dissolving 9.4 Kg sodium chloride in 28.2 L DM water). The mass was stirred for 15 minutes and settled for 30 minutes.
Layers separated and collected aqueous layer in dedicated containers.
The organic product layer was dried over anhydrous sodium sulfate (18.8
Kg). Total volume of the organic layer was 185 L. The solvent was distilled off under reduced pressure (> 500 mm Hg) maintaining mass temperature below 55 °C. Solid mass (Step-5 material) separated in reactor.
Yield: Quantitative; 5
Purity: 99.51 %;
1H-NMR (CDC13, δ ppm): 1.65 – 2.04 (12H, m), 2.61 – 2.63 (6H, m), 2.69 – 2.77 (1H, m), 3.12 (2H, s), 3.76 – 3.78 (4H, m), 4.26 – 4.27 (1H, m), 6.87 – 6.89 (2H, d, J = 8.82 Hz), 7.43 – 7.45 (2H, d, J – 8.80 Hz), 8.91 (1H, s);
Mass (m/z): 374.4 (M+H)+.
Step (vi): Preparation of N-[4-(l-CyclobutyI piperidin-4 yloxy) phenyl]-2-(morphoIin-4-yl) acetamide dihydrochloride
Charged isopropyl alcohol (75 L) into the reactor containing step (v) product. The reaction mass temperature was raised to 50-55 °C and stirred for 30 minutes to obtain a clear solution. The mass was cooled to 25 °C before starting the addition of isopropanolic hydrochloride (Isopropanolic HC1).
Isopropanolic HC1 (16.2 L, 16.1 % w/v) was diluted with isopropanol (8 L) and charged into a holding tank. Isopropanolic HC1 in the holding tank was transferred slowly into the reactor in 90 minutes, maintaining mass temperature ~ 22 – 28 °C (now and then giving jerks with brine in the reactor jacket). The resulting mass was further stirred under maintenance at 25-30 °C for 6 hours. The mass was centrifuged; the cake on the centrifuge was washed with fresh isopropanol, 16 L (for slurry wash) + 5.5 L (for spray wash) and spin dried to obtain 20.26 Kg of wet product. Purity: 99.37 %. The material was unloaded into trays and dried in a VTD at 50 – 60 °C for 16 hours.
Final weight: 12.62 Kg;
Yield: 97 %;
Ή-NMR (δ ppm, DMSO): 1.65 – 2.0 (4H, m), 2.13 – 2.19 (4H, m), 2.33 – 2.48 (2H, m), 2.8 – 3.42 (6H, m), 3.67 – 3.92 (6H, m), 4.16 (2H, s), 4.49 – 4.70 (2H, m), 6.97 – 7.03 (2H, m), 7.51 – 7.54 (2H, m), 10.54 (1H, bs), 10.73 (1H, bs), 1 1.01 (lH, bs);
Mass (m/z): 374.4 (M+H)+.
Step (vii): Recrystallization of N-[4-(l-CycIobutyl piperidin-4-yloxy) phenyl]-2-(morphoIin-4-yl) acetamide dihydrochloride
The reaction was done in a GLR reactor under nitrogen blanket. Methanol (24.8 L) was charged into a GLR followed by addition of above obtained technical material (6.2 Kg, 13.89 M) at 25-30 °C. The mass was stirred for 30 minutes to obtain a clear solution. Filtered the mass through nutsche and washed the nutsche with methanol (6.2 L). The filtrate and washing were charged into a clean GLR at 25-30 °C.
The contents of the reactor were heated to 62-63 °C, where a gentle reflux of methanol started. Addition of isopropanol (31 L) through the addition tank started at this temperature of ~ 62 °C. Addition of isopropanol was completed in one hour, while maintaining mass temperature at 62-63 °C. The mass was allowed to cool on its own to room temperature by applying air in the jacket. Solids were separated in the reactor at 48 °C in 3 hours. The mass was allowed to cool to ~ 35 °C on its own. The mass was further cooled to ~ 15 – 20 °C in 2 hours (brine jerks given to the reactor jacket) and the temperature was maintained at ~ 15 – 20 °C for 15 minutes.
The mass was centrifuged. The wet cake on the filter was washed with isopropanol (slurry wash) using 9 L isopropanol at 25-30 °C. The mass was spin dried in the centrifuge for 1 hour, unloaded (wet weight: 5.0 Kg) taken to vacuum tray drier and dried at 50-60 °C for 12 hours.
Weight of the product: 4.20 Kg;
Yield: 67.7 %;
HPLC purity (gradient): 99.71 %;
Any other impurity: < 0.1 %;
Salt content (di HC1): 16.16 %;
Melting Range: 247.0 – 249.5 °C;
DSC (2 °C / min, onset): 246.41 °C
TGA (5 °C / min): 0.45 %
Chemical Assay (% w/w): 101.53 %;
IR (cm“1): 3280, 3085, 2935, 2498, 1689, 1604, 1552, 1505, 1235, 1 120 and 830. Ή-NMR (δ ppm, DMSO): 1.62 – 2.0 (4H, m), 2.12 – 2.16 (4H, m), 2.37 – 2.42
(2H, m), 2.78 – 2.91 (2H, m), 3.16 – 3.60 (6H, m), 3.66 – 3.91 (5H, m), 4.17 (2H, s), 4.47 – 4.70 (1 H, m), 6.96 – 7.03 (2H, m), 7.52 – 7.56 (2H, m), 10.69 (1H, bs),
10.86 – 10.89 (1H, bd), 1 1.36 – 1 1.37 (1 H, bd);
Mass (m/z): 374.4 (M+H)+.
13C-NMR (DMSO, δ ppm): 13.48, 13.61, 24.94, 25.10, 25.98, 27.89, 43.85, 47.06,
52.00, 57.08, 58.16, 63.38, 67.29, 71.20, 1 16.33, 1 17.07, 121.36, 132.02, 132.24,
153.03, 153.37, 162.43.
SCHEME 1
Step (i): coupling of 4-hydroxy piperidine of formula (1) with cyclobutanone of formula (2) in presence of sodium triacetoxy borohydride in a suitable solvent to obtain l-cyclobutylpiperidin-4-ol of formula (3). The solvent used in the reaction can be selected from halohydrocarbons, preferably ethylene dichloride. This reaction is carried out at a temperature of 20 °C to 30 °C, preferably 25 °C to 30 °C. The duration of the reaction may range from 12 hours to 14 hours, preferably from a period of 13 hours to 13.5 hours.
Step (ii): coupling of 1 -cyclobutylpiperidin-4-ol of formula (3) with 4-fluoro-l-nitrobenzene of formula (4) in a suitable solvent and base to obtain 4-(l-cyclobutylpiperidin-4-yloxy)-l -nitrobenzene of formula (5). The solvent used in the reaction can be selected from ethers, preferably tetrahydrofuran. The base used in the reaction can be selected from alkali metal hydrides, preferably sodium hydride. This reaction is carried out at temperature of 30 °C to 45 °C, preferably 35 °C to 40 °C. The duration of the reaction may range from 5 hours to 6 hours, preferably from a period of 5.5 hours to 6 hours.
Step (iii): reduction of 4-(l-cyclobutylpiperidin-4-yloxy)-l -nitrobenzene of formula (5) using ammonium chloride and iron powder, in a suitable solvent to obtain 4-(l-cyclobutylpiperidin-4-yloxy) aniline of formula (6). The solvent used in the reaction can be selected from aqueous alcohols, preferably aqueous ethyl alcohol. This reaction is carried out at temperature of 70 °C to 85 °C, preferably 75 °C to 80 °C. The duration of the reaction may range from 3 hours to 5 hours, preferably for a period of 4 hours.
Step (iv): reaction of 4-(l-cyclobutylpiperidin-4-yloxy) aniline of formula (6) with chloroacetylchloride of formula (7) in a suitable solvent and base to obtain 2-chloro-N-[4-(l-cyclobutyl piperidin-4-yloxy)phenyl]acetamide of formula (8). The solvent used in reaction can be selected from ethers, preferably tetrahydrofuran. The base used in reaction can be selected from alkali metal carbonates, preferably potassium carbonate. This reaction is carried out at a temperature of -10 °C to 0 °C, preferably -10 °C to -5 °C. The duration of the reaction may range from 4.5 to 5.5 hours, preferably for a period of 5 hours.
Step (v): reaction of 2-chloro-N-[4-(l -cyclobutyl piperidin-4-yloxy)phenyl]acetamide of formula (8) with morpholine of formula (9) in a suitable solvent and base to obtain N-[4-(l-cyclobutyl piperidin^-yloxy) phenyl]-2-(morpholin-4-yl) acetamide of formula (10). The solvent used in the reaction can be selected from nitrile solvents, preferably acetonitrile. The base used in the reaction can be selected from alkalimetal carbonates, preferably potassium carbonate. This reaction is carried out at temperature of 75 °C to 85 °C, preferably 80 °C to 82 °C. The duration of the reaction may range from 20 hours to 30 hours, preferably for a period of 24 hours to 26 hours.
Step (vi): converting N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide of formula (10) in presence of isopropanolic hydrochloride and isopropanol to N-[4-(l-cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride of formula (11). This reaction is carried out at a temperature of 20 °C to 30 °C, preferably 25 °C to 30 °C. The duration of the reaction may range from 7 hours to 8.5 hours, preferably from a period of 7.5 hours to 8 hours.
Step (vii): recrystallization of N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride of formula (11) in presence of isopropanol and methanol to obtain N-[4-(l-Cyclobutyl piperidin-4-yloxy) phenyl] -2-(morpholin-4-yl) acetamide dihydrochloride of formula (I). This reaction is carried out at a temperature of 58 °C to 63 °C, preferably 62 °C to 63 °C. The duration of the reaction may range from 4 hours to 5 hours, preferably for a period of 4.5 hours.
SUVEN Life Sciences Ltd
REFERENCES
http://www.alzheimersanddementia.com/article/S1552-5260(14)01286-2/abstract
http://suven.com/news_Apr2015_13.htm
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