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Fidaxomicin, フィダキソマイシン

February 22, 2016 2:44 pm / Leave a comment

Fidaxomicin (C₅₂H₇₄Cl₂O₁₈, M_r = 1058.0 g/mol)

Launched – 2011 MERCK, Clostridium difficile-associated diarrhea

CUBIST ….INNOVATOR

OPT-80
PAR-101

Also tiacumicin B or lipiarmycin A3,

A bacterial RNA polymerase inhibitor as macrocyclic antibiotic used to treat clostridium difficile-associated diarrhea (CDAD).

SYNTHESIS

str1

REFERENCES

US 4918174

WO 2006085838

J ANTIBIOTICS 1987, 40, PG 567-574 AND 575-588

Idaxomicin(trade names Dificid, Dificlir, and previously OPT-80 and PAR-101) is the first in a new class of narrow spectrum macrocyclic antibiotic drugs.^[2] It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis.^[3]^[4] Fidaxomicin is non-systemic, meaning it is minimally absorbed into the bloodstream, it is bactericidal, and it has demonstrated selective eradication of pathogenic Clostridium difficile with minimal disruption to the multiple species of bacteria that make up the normal, healthy intestinal flora. The maintenance of normal physiological conditions in the colon can reduce the probability of Clostridium difficile infection recurrence.^[5] ^[6]

Fidaxomicin is an antibiotic approved and launched in 2011 in the U.S. for the treatment of Clostridium difficile-associated diarrhea (CDAD) in adults 18 years of age and older. In September 2011, the product received a positive opinion in the E.U. and final approval was assigned in December 2011.

First E.U. launch took place in the U.K. in June 2012. Optimer Pharmaceuticals, now part of Cubist (now, Merck & Co.), is conducting phase III clinical trials for the prevention of Clostridium difficile-associated diarrhea in patients undergoing hematopoietic stem cell transplant

In 2014 Astellas initiated in Europe a phase III clinical study for the treatment of Clostridium difficile infection in pediatric patients. Preclinical studies are ongoing for potential use in the prevention of methicillin-resistant Staphylococcus (MRS) infection.

The compound is a novel macrocyclic antibiotic that is produced by fermentation. Its narrow-spectrum activity is highly selective for C. difficile, thus preserving gut microbial ecology, an important consideration for the treatment of CDAD.

It is marketed by Cubist Pharmaceuticals after acquisition of its originating company Optimer Pharmaceuticals. The target use is for treatment of Clostridium difficile infection.

In May 2005, Par Pharmaceutical and Optimer entered into a joint development and collaboration agreement for fidaxomicin. However, rights to the compound were returned to Optimer in 2007. The compound was granted fast track status by the FDA in 2003. In 2010, orphan drug designation was assigned to fidaxomicin in the U.S. by Optimer Pharmaceuticals for the treatment of pediatric Clostridium difficile infection (CDI). In 2011, the compound was licensed by Optimer Pharmaceuticals to Astellas Pharma in Europe and certain countries in the Middle East, Africa, the Commonwealth of Independent States (CIS) and Japan for the treatment of CDAD. In 2011, fidaxomicin was licensed to Cubist by Optimer Pharmaceuticals for comarketing in the U.S. for the treatment of CDAD. In July 2012, the product was licensed by Optimer Pharmaceuticals to Specialised Therapeutics Australia in AU and NZ for the treatment of Clostridium difficile-associated infection. OBI Pharma holds exclusive commercial rights in Taiwan, where the compound was approved for the treatment of CDAD in September 2012, and in December 2012, the product was licensed to AstraZeneca in South America with commercialization rights also for the treatment of CDAD. In October 2013, Optimer Pharmaceuticals was acquired by Cubist.

Fidaxomicin is available in a 200 mg tablet that is administered every 12 hours for a recommended duration of 10 days. Total duration of therapy should be determined by the patient’s clinical status. It is currently one of the most expensive antibiotics approved for use. A standard course costs upwards of £1350.^[7]

Fidaxomicin (also known as OPT-80 and PAR-101 ) is a novel antibiotic agent and the first representative of a new class of antibacterials called macrocycles. Fidaxomicin is a member of the tiacumicin family, which are complexes of 18-membered macrocyclic antibiotics naturally produced by a strain of Dactylosporangium aurantiacum isolated from a soil sample collected in Connecticut, USA.

The major component of the tiacumicin complex is tiacumicin B. Optically pure R-tiacumicin B is the most active component of Fidaxomicin. The chiral center at C(19) of tiacumicinB affects biological activity, and R-tiacumicin B has an R-hydroxyl group attached at this position. The isomer displayed significantly higher activity than other tiacumicin B-related compounds and longer post-antibiotic activity.

Tiacumicins are a family of structurally related compounds that contain the 18-membered macrolide ring shown below.

At present, several distinct Tiacumicins have been identified and six of these

(Tiacumicin A-F) are defined by their particular pattern of substituents R¹, R², and R³ (US Patent No. 4,918,174; J. Antibiotics, 1987, 575-588).

The Lipiarmycins are a family of natural products closely related to the Tiacumicins. Two members of the Lipiarmycin family (A3 and B3) are identical to Tiacumicins B and C respectively (J. Antibiotics, 1988, 308-315; J. Chem. Soc. Perkin Trans 1, 1987, 1353-1359).

The Tiacumicins and the Lipiarmycins have been characterized by numerous physical methods. The reported chemical structures of these compounds are based on spectroscopy (UV-vis, IR and ^!H and ¹³C NMR), mass spectrometry and elemental analysis (See for example: J. Antibiotics, 1987, 575-588; J. Antibiotics, 1983, 1312-

1322).

Tiacumicins are produced by bacteria, including Dactylosporangium aurantiacum subspecies hamdenensis, which may be obtained from the ARS Patent Collection of the Northern Regional Research Center, United States Department ofAgriculture, 1815 North University Street, Peoria, IL 61604, accession number NRRL

18085. The characteristics of strain AB 718C-41 are given in J. Antibiotics, 1987,567-574 and US Patent No. 4,918,174.

Lipiarmycins are produced by bacteria including Actinoplanes deccanensis (US Patent No. 3,978,211). Taxonomical studies of type strain A/10655, which has been deposited in the ATCC under the number 21983, are discussed in J. Antibiotics,1975, 247-25.

Tiacumicins, specifically Tiacumicin B, show activity against a variety of bacterial pathogens and in particular against Clostridium difficile, a Gram-positive bacterium (Antimicrob. Agents Chemother. 1991, 1108-1111). Clostridium difficile is an anaerobic spore-forming bacterium that causes an infection of the bowel.

As per WIPO publication number 2006085838, Fidaxomicin is an isomeric mixture of the configurationally distinct stereoisomers of tiacumicin B, composed of 70 to 100% of R-tiacumicin B and small quantities of related compounds, such as S-tiacumicin B and lipiarmycin A4. Fidaxomicin was produced by fermentation of the D aurantiacum subspecies hamdenensis (strain 718C-41 ). It has a narrow spectrum antibacterial profile mainly directed against Clostridium difficile and exerts a moderate activity against some other gram-positive species.

Fidaxomicin is bactericidal and acts via inhibition of RNA synthesis by bacterial RNA polymerase at a distinct site from that of rifamycins. The drug product is poorly absorbed and exerts its activity in the gastrointestinal (Gl) tract, which is an advantage when used in the applied indication, treatment of C. difficile infection (CDI) (also known as C. difficile-associated disease or diarrhoea [CDAD]). Fidaxomicin is available as DIFICID oral tablet in US market.

Its CAS chemical name is Oxacyclooctadeca-3,5,9, 13, 15-pentaen-2-one, 3-[[[6-deoxy-4-0-(3,5dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-0-methyl-P-D-manno pyranosyl]oxy]methyl]-12[[6-deoxy-5-C-methyl-4-0-(2-methyl-1 -oxopropyl)- -D-lyxo-hexo pyranosyl]oxy]-1 1 -ethyl-8-hydroxy-18-[(1 R)-1 -hydroxyethyl] -9,13,15-trimethyl-, (3E.5E, 8S.9E.1 1 S.12R.13E, 15E.18S)-.

Structural formula (I) describes the absolute stereochemistry of fidaxomicin as determined by x-ray.

(I)

WIPO publication number 2004014295 discloses a process for preparation of Tiacumicins that comprises fermentation of Dactylosporangium aurantiacum NRRL18085 in suitable culture medium. It also provides process for isolation of tiacumicin from fermentation broth using techniques selected from the group consisting of: sieving and removing undesired material by eluting with at least one solvent or a solvent mixture; extraction with at least one solvent or a solvent mixture; Crystallization; chromatographic separation; High-Performance Liquid Chromatography (HPLC); MPLC; trituration; and extraction with saturated brine with at least one solvent or a solvent mixture. The product was isolated from /so-propyl alcohol (IPA) having a melting point of 166-169 °C.

U.S. Patent No. 7378508 B2 discloses polymorphic forms A and B of fidaxomicin, solid dosage forms of the two forms and composition thereof. As per the ‘508 patent form A is obtained from methanol water mixture and Form B is obtained from ethyl acetate.

J. Antibiotics, vol. 40(5), 575-588 (1987) discloses purification of Tiacumicins using suitable solvents wherein tiacumicin B exhibited a melting point of 143-145 °C.

PCT application WO2013170142A1 describes three crystalline forms of Fidaxomicn namely, Form-Z, Form-Z1 and Form-C. IN2650/CHE/2013 describes 6 crystalline polymorphic forms of Fidaxomicin namely, Forms I, Form la, Form II, Form Ha, Form III and Form Ilia).

Mechanism

Fidaxomicin binds to and prevents movement of the “switch regions” of bacterial RNAP polymerase. Switch motion is important for opening and closing of the DNA:RNA clamp, a process that occurs throughout RNA transcription but especially during opening of double standed DNA during transcription initiation.^[8] It has minimal systemic absorption and a narrow spectrum of activity; it is active against Gram positive bacteria especially clostridia. The minimal inhibitory concentration (MIC) range for C. difficile (ATCC 700057) is 0.03–0.25 μg/mL.^[3]

Clinical trials

Good results were reported by the company in 2009 from a North American phase III trial comparing it with oral vancomycin for the treatment of Clostridium difficile infection (CDI)^[9]^[10] The study met its primary endpoint of clinical cure, showing that fidaxomicin was non-inferior to oral vancomycin (92.1% vs. 89.8%). In addition, the study met its secondary endpoint of recurrence: 13.3% of the subjects had a recurrence with fidaxomicin vs. 24.0% with oral vancomycin. The study also met its exploratory endpoint of global cure (77.7% for fidaxomicin vs. 67.1% for vancomycin).^[11] Clinical cure was defined as patients requiring no further CDI therapy two days after completion of study medication. Global cure was defined as patients who were cured at the end of therapy and did not have a recurrence in the next four weeks.^[12]

Fidaxomicin was shown to be as good as the current standard-of-care, vancomycin, for treating CDI in a Phase III trial published in February 2011.^[13] The authors also reported significantly fewer recurrences of infection, a frequent problem with C. difficile, and similar drug side effects.

Approvals and indications

For the treatment of Clostridium difficile-associated diarrhea (CDAD), the drug won an FDA advisory panel’s unanimous approval on April 5, 2011^[14] and full FDA approval on May 27, 2011.^[15]

PAPER

Enantioselective synthesis of putative lipiarmycin aglycon related to fidaxomicin/tiacumicin B
Angew Chem Int Ed 2015, 54(6): 1929

Enantioselective Synthesis of Putative Lipiarmycin Aglycon Related to Fidaxomicin/Tiacumicin B (pages 1929–1932)

Dr. William Erb, Dr. Jean-Marie Grassot, Dr. David Linder, Dr. Luc Neuville and Prof. Dr. Jieping Zhu

Article first published online: 24 NOV 2014 | DOI: 10.1002/anie.201409475

Chain gang: In the synthesis of the title compound, the ene-diene ring-closing metathesis was used for the formation of the 18-membered macrolactone and the stereogenic centers of the molecule were installed by Brown’s alkoxyallylboration, allylation, and an Evans aldol reaction, while iterative Horner–Wadsworth–Emmons reactions were used for chain elongation.

http://onlinelibrary.wiley.com/doi/10.1002/anie.201409475/full

http://onlinelibrary.wiley.com/store/10.1002/anie.201409475/asset/supinfo/anie_201409475_sm_miscellaneous_information.pdf?v=1&s=75d40b6f8b214578d5a65518e7f384f03f377c35

PAPER

Total synthesis of the glycosylated macrolide antibiotic fidaxomicin
Org Lett 2015, 17(14): 3514

http://pubs.acs.org/doi/abs/10.1021/acs.orglett.5b01602

http://pubs.acs.org/doi/suppl/10.1021/acs.orglett.5b01602/suppl_file/ol5b01602_si_001.pdf

The first enantioselective total synthesis of fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is reported. This novel glycosylated macrolide antibiotic is used in the clinic for the treatment of Clostridium difficile infections. Key features of the synthesis involve a rapid and high-yielding access to the noviose, rhamnose, and orsellinic acid precursors; the first example of a β-selective noviosylation; an effective Suzuki coupling of highly functionalized substrates; and a ring-closing metathesis reaction of a noviosylated dienoate precursor. Careful selection of protecting groups allowed for a complete deprotection yielding totally synthetic fidaxomicin.

The identity of the synthetic compound to an authentic sample of fidaxomicin (1) was confirmed by coinjection on RP-HPLC and an equimolar mixed NMR-sample with an authentic sample. Rƒ = 0.44 (MeOH/CH2Cl2 1/10).

HRMS ESI calcd. for [C52H74Cl2NaO18] + [M+Na]+ : 1079.4144; found:1079.4151.

1H NMR (600 MHz, Methanol-d4 , containing HCOO- ) δ 7.23 (d, J = 11.5 Hz, 1H), 6.60 (dd, J = 14.9, 11.8 Hz 1H), 5.95 (ddd, J = 14.7, 9.5, 4.8 Hz, 1H), 5.83 (s, 1H), 5.57 (ap t, J = 8.2 Hz, 1H), 5.14 (ap d, J = 10.7, 1H), 5.13 (dd, J = 9.7 Hz, 1H), 5.02 (d, J = 10.2 Hz, 1H), 4.74-4.70 (m, 1H), 4.71 (s, 1H), 4.64 (s, 1H), 4.61 (d, J = 11.6 Hz, 1H), 4.44 (d, J = 11.6 Hz, 1H), 4.22 (ap s, 1H), 4.02 (p, J = 6.3 Hz, 1H), 3.92 (dd, J = 3.2, 1.2 Hz, 1H), 3.75 (ddd, J = 13.9, 10.2, 3.3 Hz, 1H) 3.71 (d, J = 9.7 Hz 1H), 3.58-3.52 (m, 2H) 3.54 (s, 3H), 3.15-3.06 (m, 1H), 3.04-2.95 (m, 1H), 2.76-2.66 (m, 3H), 2.60 (hept, J= 7.0 Hz, 1H), 2.49 (ddd, J = 14.9, 9.5, 4.4 Hz, 1H), 2.43 (ddd, J = 13.8, 8.8, 4.5 Hz, 1H), 2.05-1.98 (m, 1H), 1.82 (d, J = 1.3 Hz, 3H), 1.76 (ap s, 3H), 1.66 (ap s, 3H), 1.32-1.27 (m, 4H), 1.22-1.15 (m, 12H), 1.15 (s, 3H), 1.13 (s, 3H), 0.88 (t, J = 7.4 Hz, 3H).

RP-HPLC tR = 14.87 min (A: H2O+0.1% HCOOH; Solvent B: MeCN+0.1% HCOOH; 1 mL/min; T = 20°C; B[%] (tR [min])= 10 (0 to 3); 100 (15).

PATENT

WO 2004014295

http://www.google.co.in/patents/WO2004014295A2?cl=en

The term “Tiacumicin B” refers to molecule having the structure shown below:

Example 1

Dactylosporangium aurantiacum subsp. hamdenensis AB 718C-41 NRRL 18085 (-20 °C stock), was maintained on 1 mL of Medium No. 104 (Table 1). After standard sterilization conditions (30 min., 121 °C, 1.05 kg/cm²) the seed flask (250 mL) containing Medium No. 104 (50 mL) was inoculated with AB 718C-41 NRRL 18085 on a shaker (set @ 250 rpm) at 30 °C for 72 hr. Five percent vegetative inoculum from the first passage seed flask was then transferred aseptically to a fermentation flask containing the same ingredients as in Table 1.

Table 1: Ingredients of Medium No. 104

Fermentation flasks were incubated on a rotary shaker at 30 °C for 3 to 12 days. Samples of the whole culture fermentation broth were filtered. The filter cake was washed with MeOH and solvents were removed under reduced pressure. The residue was re-constituted in methanol to the same volume of the original fermentation broth. Analysis was performed using a Waters BREEZE HPLC system coupling with Waters 2487 2-channel UV/Vis detector. Tiacumincins were assayed on a 50 x 4.6 μm I.D., 5 μm YMC ODS-A column (YMC catalog # CCA AS05- 0546WT) with a mobile phase consisting of 45% acetonitrile in water containing 0.1% phosphoric acid at a flow rate of 1.5 mL/minute. Tiacumicins were detected at 266 nm. An HPLC chromatogram of a crude product (Tiacumicin B retention time @ 12.6 minutes) is shown in Fig. 1. In this example the crude yield of Tiacumicin B was about 250 mg/L after 7 days. After purification by HPLC, the yield of Tiacumicin B was about 100 mg/L.

Example 2

After standard sterilization conditions (30 min, 121 °C, 1.05 kg/cm²) the seed flask (250 mL) containing Medium No. 104 (50 mL) was inoculated with AB 718C- 41 NRRL 18085 and incubated on a shaker (set @ 250 rpm) at 30° C for 72 hr. Five percent vegetative inoculum from the first passage seed flask was transferred aseptically to a seed flask containing the same ingredients as in Table 1 and was incubated on a rotary shaker at 30 °C for 72 hr. Five percent inoculum from the second passage seed flasks was then used to inoculate with AB 718C-41 NRRL 18085 in a 5-liter fermenter containing Medium No. 104 (2.5 L). Excessive foam formation was controlled by the addition of an antifoaming agent (Sigma A-6426). This product is a mixture of non-silicone organic defoamers in a polyol dispersion.

Glucose consumption was monitored as a growth parameter and its level was controlled by the addition of the feeding medium. Feeding medium and conditions in Example 2 were as follows:

Feeding medium:

Fermenter Medium: No. 104

Fermenter Volume: 5 liters

Sterilization: 40 minutes, 121° C, 1.05 kg/cm²

Incubation Temperature: 30 °C.

Aeration rate: 0.5-1.5 volumes of air per culture volume and minute

Fermenter Agitation: 300-500 rpm

The fermentation was carried out for 8 days and the XAD-16 resin was separated from the culture broth by sieving. After washing with water the XAD-16 resin was eluted with methanol (5-10 x volume of XAD-16). Methanol was evaporated and the oily residue was extracted three times with ethyl acetate. The extracts were combined and concentrated under reduced pressure to an oily residue. The oily residue was dried and washed with hexane to give the crude product as a pale brown powder and its HPLC chromatogram (Tiacumincin B rete tion time @ 11.8 minutes) is shown in Figure 2. This was purified by silica gel column (mixture of ethyl acetate and hexane as eluent) and the resultant material was further purified by RP-HPLC (reverse phase HPLC) to give Tiacumicin B as a white solid. The purity was determined to be >95% by HPLC chromatography and the chromatogram (Tiacumincin B retention time @ 12.0 minutes) is shown in Figure 3. Analysis of the isolated Tiacumincin B gave identical ^!H and ¹³C NMR data to those reported in J. Antibiotics, 1987, 575-588, and these are summarized below. Tiacumicin B: mp 129-140 °C (white powder from RP-HPLC); mp 166-169 °C (white needles from isopropanol); [α]_D ²⁰-6.9 (c 2.0, MeOH); MS m/z (ESI) 1079.7(M + Na)⁺; H NMR (400 MHz, CD₃OD) δ 7.21 (d, IH), 6.59 (dd, IH), 5.95 (ddd, IH), 5.83 (br s, IH), 5.57 (t, IH), 5.13 (br d, IH), 5.09 (t, IH), 5.02 (d, IH), 4.71 (m, IH), 4.71 (br s, IH), 4.64 (br s, IH), 4.61 (d, IH), 4.42 (d, IH), 4.23 (m, IH), 4.02 (pentet, IH), 3.92 (dd, IH), 3.73 (m, 2H), 3.70 (d, IH), 3.56 (s, 3H), 3.52-3.56 (m, 2H), 2.92 (m, 2H), 2.64-2.76 (m, 3H), 2.59 (heptet, IH), 2.49 (ddd, IH), 2.42 (ddd, IH), 2.01 (dq, IH), 1.81 (s, 3H), 1.76 (s, 3H), 1.65 (s, 3H), 1.35 (d, 3H), 1.29 (m, IH), 1.20 (t, 3H), 1.19 (d, 3 H), 1.17 (d, 3H), 1.16 (d, 3H), 1.14 (s, 3H), 1.12 (s, 3H), 0.87 (t, 3H); ¹³C NMR (100 MHz, CD₃OD) δ 178.4, 169.7, 169.1, 154.6, 153.9, 146.2, 143.7, 141.9, 137.1, 137.0, 136.4, 134.6, 128.5, 126.9, 125.6, 124.6, 114.8, 112.8, 108.8, 102.3, 97.2, 94.3, 82.5, 78.6, 76.9, 75.9, 74.5, 73.5, 73.2, 72.8, 71.6, 70.5, 68.3, 63.9, 62.2, 42.5, 37.3, 35.4, 28.7, 28.3, 26.9, 26.4, 20.3, 19.6, 19.2, 18.7, 18.2, 17.6, 15.5, 14.6, 14.0, 11.4.

PATENT

http://www.google.com/patents/US7378508

macrolide of Formula I:

Structure of R-Tiacumicin B

The structure of the R-Tiacumicin B (the major most active component) is shown below in Formula I. The X-ray crystal structure of the R-Tiacumicin B was obtained as a colorless, parallelepiped-shaped crystal (0.08×0.14×0.22 mm) grown in aqueous methanol. This x-ray structure confirms the structure shown below. The official chemical name is 3-[[[6-Deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl]oxy]-methyl]-12(R)-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl]oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one.

7.2.1 Analytical Data of R-Tiacumicin B

The analytical data of R-Tiacumicin B (which is almost entirely (i.e., >90%) R-Tiacumicin).

mp 166-169° C. (white needle from isopropanol);

[α]_D ²⁰-6.9 (c 2.0, MeOH);

MS m/z (ESI) 1079.7(M+Na)⁺;

¹H NMR (400 MHz, CD₃OD) δ 7.21 (d, 1H), 6.59 (dd, 1H), 5.95 (ddd, 1H), 5.83 (br s, 1H), 5.57 (t, 1H), 5.13 (br d, 1H), 5.09 (t, 1H), 5.02 (d, 1H), 4.71 (m, 1H), 4.71 (br s, 1H), 4.64 (br s, 1H), 4.61 (d, 1H), 4.42 (d, 1H), 4.23 (m, 1H), 4.02 (pentet, 1H), 3.92 (dd, 1H), 3.73 (m, 2H), 3.70 (d, 1H), 3.56 (s, 3H), 3.52-3.56 (m, 2H), 2.92 (m, 2H), 2.64-2.76 (m, 3H), 2.59 (heptet, 1H), 2.49 (ddd, 1H), 2.42 (ddd, 1H), 2.01 (dq, 1H), 1.81 (s, 3H), 1.76 (s, 3H), 1.65 (s, 3H), 1.35 (d, 3H), 1.29 (m, 1H), 1.20 (t, 3H), 1.19 (d, 3H), 1.17 (d, 3H), 1.16 (d, 3 H), 1.14 (s, 3H), 1.12 (s, 3H), 0.87 (t, 3H);

¹³C NMR (100 MHz, CD₃OD) δ 178.4, 169.7, 169.1, 154.6, 153.9, 146.2, 143.7, 141.9, 137.1, 137.0, 136.4, 134.6, 128.5, 126.9, 125.6, 124.6, 114.8, 112.8, 108.8, 102.3, 97.2, 94.3, 82.5, 78.6, 76.9, 75.9, 74.5, 73.5, 73.2, 72.8, 71.6, 70.5, 68.3, 63.9, 62.2, 42.5, 37.3, 35.4, 28.7, 28.3, 26.9, 26.4, 20.3, 19.6, 19.2, 18.7, 18.2, 17.6, 15.5, 14.6, 14.0, 11.4.

PATENT

WO2013170142

http://www.google.com/patents/WO2013170142A1?cl=en

EXAMPLES

Example 1; General procedure for the preparation of crude Fidaxomycin

Fidaxomycin was prepared by:

i) culturing a microorganism in a nutrient medium to accumulate Fidaxomycin in the nutrient medium;

ii) isolating crude Fidaxomycin from the nutrient medium by methods known from the art;

iii) purifying Fidaxomycin by reversed phase chromatography using a mixture of acetonitrile, water and acetic acid as eluent; and iv) isolating the purified Fidaxomycin from the fractions.

Actionplanes deccanenesis was used during the cultivation. The nutrient medium comprises the following combination based on weight: from about 0% to about 5% Sucrose; from about 0% to about 3% Starch; from about 0.1% to about 1.0 % Soy peptone; from about 2% to about 5% Cotton seed meal; from about 0.01% to about 0.1% Potassium-dihydrogen Phosphate; from about 0.05% to about 0.5% Dipotassium-hydrogen Phosphate; from about 0.05% to about 0.5% Antifoam agent; from about 0% to about 2% Amberlite XAD-16N resin. The preferred temperature of the cultivation is from 28 to 32°C, and the pH is between 6.0 and 8.0. During the cultivation C-source is continuously fed.

The Fidaxomycin fermentation production can also be done by the following procedure:

The Fidaxomycin fermentation production can include a step of inoculation followed by fermentation as follows:

Inoculation: Actinoplanes deccanenesis strain is inoculated into the seed medium. The inoculation parameters are adjusted and maintained until the inoculum transferred to the main fermentation. The inoculum medium comprises: from about 0 to about 5% glucose, from about 0 to about 1% yeast extract, from about 0 to about 1% soy peptone, from about 0 to about 0.5% CaCo₃, from about 0 to about 0.2% MgS0 -7H₂0, from about 0 to about 0.2% K₂HP0₄, from about 0 to about 0.2% KC1, from about 0 to about 0.3% Polypropylene glycol. The pH is adjusted by adding Hydrochloric acid and/or Sodium/potassium hydroxide.

Inoculation parameters :

Inoculation time: 40-48 ± 24 hours.

At the end of the inoculation, the inoculum (or a part of it) is transferred into the sterile fermentation medium at a ratio of 8-15 ± 5 %.

Fermentation: the fermentation medium comprises: from about 0 to aboutl0% Sucrose/Hydrolyzed Starch, from about 0 to about 1% Soy peptone, from about 0 to about 5% Cotton seed meal, from about 0 to about 0.3% K₂HP0₄, from about 0 to about 0.2% KH₂P0₄, from about 0 to aboutl% KC1, from about 0 to about 0.5% Polypropylene glycol (PPG). The pH is adjusted by adding Hydrochloric acid and/or Sodium/potassium hydroxide.

The sterile fermentation medium is seeded with the inoculum.

Feeding:

C-source is fed during the fermentation, For C-source feeding sucrose or hydrolyzed-starch can be applied. Total amount of fed C-source is 0 – 15% related to the initial volume.

Fermentation parameters :

In case of foaming, sterile antifoaming agent should be added.

Fermentation time: 168-192 ± 24 hours.

The inoculation/fermentation medium may also include from about 0% to about 2% Amberlite XAD-16N resin.

Upon completion of fermentation, the Fidaxomycin is extracted from the fermented broth with an organic solvent such as, for example, ethyl acetate, isobutyl acetate or isobutanol. The organic phase is concentrated and the Fidaxomycin is precipitated by addition of an antisolvent such as, for example, n-hexane. Optionally the precipitate can be suspended in a second antisolvent. After filtration and drying, crude Fidaxomycin is obtained.

DIFICID (fidaxomicin) is a macrolide antibacterial drug for oral administration. Its CAS chemical name is Oxacyclooctadeca-3,5,9,13,15-pentaen-2-one, 3-[[[6-deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-Omethyl- β-D- mannopyranosyl]oxy]methyl]-12-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxohexopyranosyl] oxy]-11-ethyl-8 -hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-,(3E,5E,8S,9E,11S,12R,13E,15E,18S)-. The structural formula of fidaxomicin is shown in Figure 1.

Figure 1: Structural Formula of Fidaxomicin

Image result for Fidaxomicin

Patent

WO 2016024243, New patent, Dr Reddy’s Laboratories Ltd, Fidaxomicin

WO2016024243, FIDAXOMICIN POLYMORPHS AND PROCESSES FOR THEIR PREPARATION

DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No. 3, Banjara Hills, Telangana State, India Hyderabad 500034 (IN)

CHENNURU, Ramanaiah; (IN).
PEDDY, Vishweshwar; (IN).
RAMAKRISHNAN, Srividya; (IN)

Aspects of the present application relate to crystalline forms of Fidaxomicin IV, V & VI and processes for their preparation. Further aspects relate to pharmaceutical compositions comprising these polymorphic forms of fidaxomicin

The occurrence of different crystal forms, i.e., polymorphism, is a property of some compounds. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physico-chemical properties.

Polymorphs are different solid materials having the same molecular structure but different molecular arrangement in the crystal lattice, yet having distinct physico-chemical properties when compared to other polymorphs of the same molecular structure. The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, “Tricky Business,” Science News, August 21 , 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.

There remains a need for additional polymorphic forms of fidaxomicin and for processes to prepare polymorphic forms in an environmentally-friendly, cost-effective, and industrially applicable manner.

G.V. Prasad, chairman, Dr Reddy’s Laboratories

EXAMPLES

Example 1 : Preparation of fidaxomicin Form IV:

Fidaxomicin (0.5 g) and a mixture of 1 ,4-Dioxane (10 mL), THF (10 ml) and water (20mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:

Starting temperature: 25 °C;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 25 °C over a period of 2 hours;

Temperature maintained at 25 °C for 6 hours.

After completion of temperature cycling process, the slurry was filtered under suction, followed by drying in air tray dryer (ATD) at 40^°C to a constant weight to produce crystalline fidaxomicin form-IV.

Example 2: Preparation of fidaxomicin Form V:

Fidaxomicin (1 g) and a mixture of propylene glycol (10 mL) and water (20mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:

Starting temperature is 25 °C;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 25 °C over a period of 2 hours;

Temperature maintained at 25 °C for 6 hours.

After completion of temperature cycling process, the slurry was filtered under suction, followed by drying in air tray dryer (ATD) at 40°C to a constant weight to produce crystalline fidaxomicin form-V.

Example 3: Preparation of fidaxomicin Form VI:

Fidaxomicin (0.5 mg) and MIBK (10 mL) were charged in Easy max reactor (Mettler Toledo) and the mixture was heated to 80°C. n-heptane (20 mL) was added to the solution at the same temperature. The mixture was stirred for 1 hour. The reaction mass was then cooled to 25°C. Solid formed was filtered at 25°C and dried at 40°C in air tray dryer (ATD) to a constant weight to produce crystalline fidaxomicin form VI.

Example 4: Preparation of fidaxomicin Form V:

Fidaxomicin (500 mg) and a mixture of R-propylene glycol (5 mL) and water (15 mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:

Starting temperature is 25 °C;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 25 °C over a period of 2 hours;

Temperature maintained at 25 °C for 2 hours.

After completion of temperature cycling process, the slurry was filtered and dried at 25°C to produce crystalline fidaxomicin form-V.

Example 5: Preparation of fidaxomicin Form V:

Fidaxomicin (1 g) and a mixture of S-propylene glycol (3 ml_) and water (30 mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:

Starting temperature is 25 °C;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 25 °C over a period of 2 hours;

Temperature maintained at 25 °C for 2 hours.

After completion of temperature cycling process, the slurry was filtered and dried at 25°C to produce crystalline fidaxomicin form-V.

Example 6: Preparation of fidaxomicin Form V:

Fidaxomicin (40 g) and a mixture of propylene glycol (400 mL) and water (1600 mL) were charged in Chem glass reactor. The reactor was set to temperature cycle with following parameters:

Starting temperature is 25 °C;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 25 °C over a period of 2 hours;

Temperature maintained at 25 °C for 6 hours.

The 10-member board at pharmaceutical major Dr Reddy’s thrives on diversity. Liberally sprinkled with gray hairs, who are never quite impressed with powerpoint presentations, “they want information to be pre-loaded so that the following discussions (at the board level) are fruitful,” says Satish Reddy, Chairman, Dr Reddy’s. That said, the company has now equipped its board members with a customized application (that runs on their tablets) to manage board agenda and related processes.

see at

http://articles.economictimes.indiatimes.com/2014-10-31/news/55631761_1_board-members-board-agenda-dr-reddy-s

Dr. Reddy’s Laboratories Managing Director and Chief Operating Officer Satish Reddy addressing

References

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5Louie, T. J.; Emery, J.; Krulicki, W.; Byrne, B.; Mah, M. (2008). “OPT-80 Eliminates Clostridium difficile and is Sparing of Bacteroides Species during Treatment of C. Difficile Infection”. Antimicrobial Agents and Chemotherapy 53 (1): 261–3. doi:10.1128/AAC.01443-07. PMC 2612159. PMID 18955523.
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7http://www.medicinescomplete.com/mc/bnf/current/PHP18388-dificlir.htm#PHP18388-dificlir
8Srivastava, Aashish; Talaue, Meliza; Liu, Shuang; Degen, David; Ebright, Richard Y; Sineva, Elena; Chakraborty, Anirban; Druzhinin, Sergey Y; Chatterjee, Sujoy; Mukhopadhyay, Jayanta; Ebright, Yon W; Zozula, Alex; Shen, Juan; Sengupta, Sonali; Niedfeldt, Rui Rong; Xin, Cai; Kaneko, Takushi; Irschik, Herbert; Jansen, Rolf; Donadio, Stefano; Connell, Nancy; Ebright, Richard H (2011). “New target for inhibition of bacterial RNA polymerase: ‘switch region'”. Current Opinion in Microbiology 14 (5): 532–43. doi:10.1016/j.mib.2011.07.030. PMC 3196380. PMID 21862392.
9″Optimer’s North American phase 3 Fidaxomicin study results presented at the 49th ICAAC” (Press release). Optimer Pharmaceuticals. September 16, 2009. Retrieved May 7, 2013.
10″Optimer Pharmaceuticals Presents Results From Fidaxomicin Phase 3 Study for the Treatment” (Press release). Optimer Pharmaceuticals. May 17, 2009. Retrieved May 7, 2013.
11Golan Y, Mullane KM, Miller MA (September 12–15, 2009). Low recurrence rate among patients with C. difficile infection treated with fidaxomicin. 49th interscience conference on antimicrobial agents and chemotherapy. San Francisco.
12Gorbach S, Weiss K, Sears P; et al. (September 12–15, 2009). Safety of fidaxomicin versus vancomycin in treatment of Clostridium difficile infection. 49th interscience conference on antimicrobial agents and chemotherapy. San Francisco.
13Louie, Thomas J.; Miller, Mark A.; Mullane, Kathleen M.; Weiss, Karl; Lentnek, Arnold; Golan, Yoav; Gorbach, Sherwood; Sears, Pamela; Shue, Youe-Kong; Opt-80-003 Clinical Study, Group (2011). “Fidaxomicin versus vancomycin for Clostridium difficile infection”. New England Journal of Medicine 364 (5): 422–31. doi:10.1056/NEJMoa0910812. PMID 21288078.
14Peterson, Molly (Apr 5, 2011). “Optimer wins FDA panel’s backing for antibiotic fidaxomicin”. Bloomberg.
15Nordqvist, Christian (27 May 2011). “Dificid (fidaxomicin) approved for Clostridium difficile-associated diarrhea”. Medical News Today.

ARNONE A ET AL: “STRUCTURE ELUCIDATION OF THE MACROCYCLIC ANTIBIOTIC LIPIARMYCIN“, JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, CHEMICAL SOCIETY, LETCHWORTH; GB, 1 January 1987 (1987-01-01), pages 1353-1359, XP000578201, ISSN: 0300-922X, DOI: 10.1039/P19870001353

Fidaxomicin
Systematic (IUPAC) name

3-(((6-Deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl)oxy)-methyl)-12(R)-[(6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl)oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one
Clinical data
Trade names	Dificid, Dificlir
Licence data	US FDA:link
Pregnancy category	AU: B1 US: B (No risk in non-human studies)
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	Minimal systemic absorption^[1]
Biological half-life	11.7 ± 4.80 hours^[1]
Excretion	Urine (<1%), faeces (92%)^[1]
Identifiers
CAS Number	873857-62-6
ATC code	A07AA12
PubChem	CID 11528171
ChemSpider	8209640
UNII	Z5N076G8YQ
KEGG	D09394
ChEBI	CHEBI:68590
ChEMBL	CHEMBL1255800
Synonyms	Clostomicin B1, lipiarmicin, lipiarmycin, lipiarmycin A3, OPT 80, PAR 01, PAR 101, tiacumicin B
Chemical data
Formula	C₅₂H₇₄Cl₂O₁₈
Molar mass	1058.04 g/mol

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///////////Fidaxomicin, OPT-80, PAR-101, japan 2018

CC[C@H]1/C=C(/[C@H](C/C=C/C=C(/C(=O)O[C@@H](C/C=C(/C=C(/[C@@H]1O[C@H]2[C@H]([C@H]([C@@H](C(O2)(C)C)OC(=O)C(C)C)O)O)\C)\C)[C@@H](C)O)\CO[C@H]3[C@H]([C@H]([C@@H]([C@H](O3)C)OC(=O)C4=C(C(=C(C(=C4O)Cl)O)Cl)CC)O)OC)O)\C

Fidaxomicin

- Synonyms:OPT-80; PAR-101; Tiacumicin B
- ATC:A07AA12
Use:macrocyclic, antibotic, RNA polymerase inhibitor
Chemical name:3-(((6-Deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl)oxy)-methyl)-12(R)-[(6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl)oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one
Formula:C₅₂H₇₄Cl₂O₈

MW:1058.0 g/mol
CAS-RN:873857-62-6

Substance Classes

Macrolide antibiotics

Enzymes

Dactylosporangium aurantiacum hamdenesis

Synthesis Path

Trade Names

Country	Trade Name	Vendor	Annotation
USA	Dificid	Optimer Pharmceuticals, 2011

Formulations

tabl. 200 mg

References

- WO 2004 014295 (Optimer Pharmaceuticals; 19.2.2004; USA-prior. 29.7.2002).
- US 7 507 564 (Optimer Pharmaceuticals; 24.3.2009; USA-prior. 29.7.2002).
- US 7 378 508 (Optimer Pharmaceuticals; 27.5.2008; USA-prior. 22.7.2007).
- US 3 978 211 (Gruppo Lepetit; 31.10.1974; GB-prior. 22.11.1973).
- US 4 918 174 (Abbott Laboratories; 17.10.1990; USA-prior. 26.9.1986).
- EP 923 594 (Abbott Laboratories; 2.10.2002; USA-prior. 12.7.1996).

WO 2016024284, New Patent, MIRABEGRON, Wanbury Ltd

February 22, 2016 8:23 am / Leave a comment

WO 2016024284, New Patent, MIRABEGRON, Wanbury Ltd

WANBURY LTD. [IN/IN]; BSEL tech park, B wing, 10th floor, sector 30A opp. Vashi Railway Station, Vashi Navi Mumbai 400703 Maharashtra (IN)

DR. NITIN SHARADCHANDRA PRADHAN; (IN).
DR. NILESH SUDHIR PATIL; (IN).
DR. RAJESH RAMCHANDRA WALAVALKAR; (IN).
MR. NILESH SUBHASH KULKARNI; (IN).
MR. SANTOSH NAMDEV RAWOOL; (IN).
MR. PURUSHOTTAM EKANATH AWATE; (IN)

LEFT , DR K CHANDRAN, DIRECTOR WANBURY

MR ASOK SHINKAR

The present invention relates to a novel process for preparation of Mirabegron of Formula (I) using intermediates of Formula (II), (IIIa), (Illb) and (IV).

The present invention relates to a process for preparation of Mirabegron of Formula

(I).

Formula (I)

The present invention further relates to the preparation of Mirabegron of Formula (I) by using compounds of Formula (II), (Ilia), (Illb) and (IV)

Formula (II)

Formula (IlIa) Formula (Illb)

Formula (IV)

Furthermore, the present invention relates to process for preparation of compound of Formula (II), (Ilia), (Illb) and (IV).

Background of the invention:

Mirabegron is chemically known as 2-amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thiazoleactamide and is marketed under trade name Myrbetiq.

Mirabegron is a drug used for treatment of overactive bladder. It was first disclosed in US 6,346,532, wherein (R)-Styrene oxide is reacted with 4-nitrophenyl ethyl amine hydrochloride to obtain (R)-l- phenyl-2-[[2-(4-nitrophenyl)ethyl]amino]ethanol, the later is then protected with BOC anhydride and subjected to reduction in the presence of Pd/C to yield N-[2-(4-Aminophenyl)ethyl]-N-[(2R)-2-hydroxy-2-phenylethyljcarbamic acid tert-butyl ester. Thus formed compound was then coupled with (2-amino-l,3-thiazol-4yl) acetic acid to obtain BOC protected Mirabegron which is de-protected to give Mirabegron hydrochloride.

The synthetic route proposed in US 6,346,532 is presented in Scheme-I.

Scheme-I

The major draw-backs of the presented synthetic scheme are as follows:

1. Less atomic efficiency

2. Low yield and extensive impurities formations

3. Use of expensive and sensitive protecting agents

4. Column chromatographic techniques for purifications of intermediates.

One more synthetic route for the preparation of Mirabegron have been proposed US 6,346,532, however it is not exemplified.

US 7,342,117 disclose a process for preparation of Mirabegron. The process involves the step of condensation of 4-nitrophenyl ethylamine and (R)- mandelic acid in presence of tri ethylamine, hydroxybentriazole and l-(3-dimethylaminopropyl)-3-ethyl carbodiimide in N,N-dimethylformamide to obtain compound of Formula (A). The second step involves conversion of compound of Formula (A) to compound of Formula (B) in presence of l,3-dimethyl-2-imidazolidone and borontetrahydro fluoride in tetrahydrofuran. In third step, compound of Formula (B) is subjected to reduction using 10% palladium-carbon in methanol to afford (R)-2-[[2′-(4-aminophenyl)-ethyl amino] -1-phenylethanol (Formula IV), which was further condensed with 2-aminothiazol-4-yl acetic acid in presence of l-(3-dimethylaminopropyl)-3 -ethyl carbodiimide and hydrochloric acid in water to obtain Mirabegron of Formula (I). The schematic representation is as Scheme-II

Another patent application CN103193730, discloses a novel process for preparation of Mirabegron wherein the amino group of 2-aminothiazole-5-acetic acid is protected with a protecting group and is condensed with 4-amino phenyl ethanol to obtain an intermediate (A); which on further oxidation yields intermediate (B). The intermediate B is subjected to reductive amination with (R)-2-amino-l -phenyl ethanol and deprotection, simultaneously to yield Mirabegron. The schematic representation is as Scheme-Ill.

Formula (I)

Scheme-Ill

Other references wherein process for preparation of Mirabegron are disclosed CN103387500 and CN103232352.

Most of the prior art reported for preparation of Mirabegron uses expensive and sensitive protecting agents thereby making process less feasible on industrial scale. Furthermore, the yield and purity of Mirabegron obtained by the processes known in art is not satisfactory. It is well known fact that pharmaceutical products like Mirabegron should have high purity due to the therapeutic advantages and also due to the stringent requirements of regulatory agencies. The purity requirements can be fulfilled either by avoiding the formation of by-products during the process or by purifying the end product of the process. The inventors of present invention have skillfully developed the process to provide Mirabegron with unachieved level of purity. Furthermore, the process of present invention is simple, industrially viable, and economic and avoids unfavorable reaction conditions.

According to present invention, the process for preparation of compound of Formula (IV), is depicted in Scheme IV

The present invention further relates to a process for preparation of Mirabegron of Formula (I)

The schematic reaction scheme of Mirabegron according to present invention is depicted in Scheme-V.

Wherein R is -OH or -CI

The detail of the invention provided in the following examples is given by the way of illustration only and should not be construed to limit the scope of the present invention.

EXAMPLES

Example 1: Preparation of [2-(formylamino)-l,3-thiazol-4-yl]acetyl chloride; Formula (V); wherein R is -CI

20g of [2-(formylamino)-l,3-thiazol-4-yl]acetic acid was added to 250 ml of methylene dichloride and the mixture was cooled to -10°C followed by lot wise addition of 25g of phosphorous pentachloride. The mixture stirred while maintaining temperature of -10°C for 2-3 hours. After confirming completion of reaction, the product was filtered out, washed with methylene dichloride and dried to obtain 24g (Yield: 92%) of compound of Formula (V); wherein R is -CI

Example 2: Preparation of 4-nitrophenyl-[2-(formylamino)-l,3-thiazol-4-yl]acetate; Formula (IlIa)

2g of p-nitrophenol was added to 40ml of methylene chloride and 4.963g of potassium carbonate, the mixture was cooled to 10-15°C followed by lot wise addition of 3.95g of compound of Formula (V) of example 1. After confirming completion of reaction, 5.87g (Yield: 99%) of compound of Formula (Ilia) was isolated. The obtained compound has been identified by;

HNMR(D₂0 Exchange)

8.614 (S,lH),7.359(d,2H),8.119(d,2H),6.561(S,lH),3.765(S,2H).

Example 3: Preparation of (2-amino-l,3-thiazol-4-yl)acetyl chloride; Formula (VI); wherein R is -CI

5g of (2-amino-l,3-thiazol-4-yl)acetic acid was added to 50 ml of methylene dichloride with few drops of dimethylformamide and 6g of oxalyl chloride at temperature ranging from 0-5°C. the mixture was maintained at 0-5°C for 4-5 hours and after completion of reaction, solid mass was filtered out, washed with methylene dichloride and dried to afford 5g (Yield: 89%) of compound of Formula (VI); wherein R is -CI

Example 4: Preparation of 4-nitrophenyl-(2-amino-l,3-thiazol-4-yl)acetate; Formula (Illb)

2g of p-nitrophenol was added to 40ml of methylene chloride and 4.96g of potassium carbonate, and the mixture was cooled to 10-15 °C followed by lot wise addition of 3.95g of compound of Formula (VI) prepared in example 3. After confirming completion of reaction, 6.18g (Yield: 99%) of 4-nitrophenyl-(2-amino-l,3-thiazol-4-yl)acetate of Formula (Illb) was isolated.

The obtained compound has been identified by

HNMR ( D₂O Exchange)

7.359(d,2H),8.1 19(d,2H),6.425(S,lH).3.775(S,2H).

Example 5: In-situ preparation of (lR)-2-[[2-(4-aminophenyl)ethyl]amino]-l-phenylethanol or its hydrochloride salt, of Formula (IV)

Step I – Preparation of (2R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylethanamide of Formula (IX)

(R)-2-hydroxy-2-phenylacetic acid (75g), triethylamine (50g), hydroxybenzotriazole (HOBt) (33.3g) and l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC.HC1) (50g) were added to a mixture of 2-(4-nitrophenyl)ethylamine hydrochloride (100g) in Ν,Ν-dimethylformamide (375ml) at 25-30°C. The mixture was stirred for 30 minutes followed by addition of another lot of HOBt (33.3g) and EDC.HC1 (50g) in reaction mixture. The reaction mixture was maintained at 25-30°C for 15 hours under stirring. After completion of reaction, water (1850ml) was added to the reaction mixture and stirred. Subsequently, ethyl acetate (1500ml) was added to the reaction mixture at 25-30°C and stirred. The organic phase was separated from aqueous phase, and was washed sequentially with 1M HC1 solution, 20%aqueous potassium carbonate solution and water. The organic solvent was distilled out under reduced pressure to obtain residue comprising of (2R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl] -2 -phenyl ethanamide of Formula (IX)

Step II – Preparation of (2R)-2-hydroxy-N-[2-(4-aminophenyl)ethyl]-2-phenylethanamide of Formula (X)

The residue from step I, methanol (740ml) and Raney Nickel (14.8g) were charged into an autoclave vessel, 10 kg/cm2 hydrogen gas pressure was applied to the reaction mixture at 25-30°C and the mixture was maintained under stiring 6 hours. Reaction mixture filtered through hyflo bed. Distilled off the solvent completely from the filtrate under reduced pressure to obtain residue comprising (2R)-2-hydroxy-N-[2-(4-aminophenyl)ethyl]-2-phenylethanamide of Formula (X)

Step III – Preparation of (lR)-2-[[2-(4-aminophenyl)ethyl]amino]-l-phenylethanol dihydrochloride salt, of Formula (IV)

The residue of step II was added in tetrahydrofuran (665ml) and the mixture was cooled to -5 to 0°C. To this cooled mixture was then successively added sodium borohydride (56.26g) and BF3-diethyl ether (466g), and the mixture was stirred for 15 minutes. The temperature of reaction mixture was gradually increased to 50-55°C and was maintained under stirring for 5 hours. After completion of reaction, the reaction mixture was cooled to 0-5°C and 50% sodium hydroxide solution was added till pH is basic. The temperature of reaction mixture is then raised to 25-30°C followed by addition of ethyl acetate (500ml). The organic layer was separated and subjected to distillation to afford a residue. To the residue was added isopropyl alcohol (665ml) and mixture was refluxed for 30 minutes. The mixture was then allowed to cool to 40-45°C, isopropyl alcohol hydrochloride (200ml) was added till pH acidic and mixture was stirred for 2 hours to afford precipitate. The precipitate was filtered out and washed with isopropyl alcohol. The wet cake thus obtained was added to 20% aqueous sodium hydroxide solution (till pH basic) followed by addition of dichloromethane (500ml). The organic layer was separated from aqueous layer and was subjected to distillation under reduced pressure to obtain residue. The residue was taken in toluene (500ml), heated to 55-60°C for 30 minutes and cooled to 10-15°C. The precipitate obtained was filtered, washed with toluene and to the wet cake afforded was added isopropyl alcohol (665ml). The mixture was refluxed for 30 minutes and then cooled to 50-55°C. At 50-55°C slowly isopropyl alcohol hydrochloride (200ml) till pH acidic was added and mixture was stirred for 2 hours to obtain precipitate. The precipitate was filtered out, washed with isopropyl alcohol and dried to get (lR)-2-[[2-(4-aminophenyl)ethyl]amino]-l-phenylethanol dihydrochloride salt, of Formula (IV)

Yield-70%

HPLC Purity: 98%

Example 6: Alternate method for preparation of (2R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylethanamide of Formula (IX)

Step I – A mixture of (R)-2-hydroxy-2-phenylacetic acid (lOg), dichloromethane (50ml) and triethylamine (24ml) was cooled to 0-5°C and slowly para-toluene sulfonyl chloride (12.53g) was added to it. The temperature of reaction mixture was raised to 25-30°C and maintained for 12 hours. After completion of reaction, water (100ml) was added to the reaction mixture and the mixture was stirred for 15 minutes. The organic phase was separated and distills out completely under reduced pressure to obtain [(R)-2-hydroxy -2-phenyl acetic tosyl ester].

Yield-56%

Step II – 2-(4-nitrophenyl)ethylamine hydrochloride (6g) was added to dichloromethane (50ml) and stirred for 30 minutes at 25-30°C. The mixture was

then cooled to 0-5 °C and triethylamine (13ml) was added. To say cooled mixture was then slowly added a mixture of (R)-2-hydroxy -2-phenyl acetic tosyl ester (lOg) and dichloromethane (50ml). The temperature of reaction mixture was then raised to reflux temperature and maintained for 5 hours. After completion of reaction, water (50ml) was added to the reaction mixture and the mixture was stirred for 15 minutes. The organic phase was separated and distill out completely under reduced pressure to obtain (R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenylacetamide

Yield-70%, Purity-96%

Example 7: Preparation of compound of Formula (II) from compound of Formula (V); wherein R is -OH

1.58g of [2-(formylamino)-l,3-thiazol-4-yl]acetic acid of Formula (V) was added solution of (1R )-2-{[2-(4-aminophenyl)ethyl]amino}-l-phenylethanol of Formula (IV) in water (2g of Formula (IV) in 50ml water) followed by addition of 0.66g concentrated hydrochloric acid and 3.27g of l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was stirred at 25-30°C for 0.5 hours. After completion of reaction, pH was adjusted to 8-9 using aqueous saturated solution of sodium carbonate. The solid precipitated out was filtered, washed with water and dried to obtain 2.1g of compound of Formula (II). (Yield: 72%) The obtained compound has been identified by HNMR

2.502(m,4H),2.599(m,2H),3.685(S,2H),4.9(S, NH protons),7.01(m, 10H, aromatic), 8.54(S,1H), 10.0(S, -OH proton),

HNMR(D20 Exchange) 2.502(m,4H),2.60(m,2H),4.57(m,lH),7.0(m, 10H, aromatic), 8.43(S,1H)

Example 8: Preparation of compound of Formula (II) from compound of Formula (V); wherein R is -CI

lOg of ( 1R)-2-{[2-(4-aminophenyl)ethyl]amino}-l-phenylethanol of Formula (IV) (prepared by methods known in prior art/ as given in example 5), was added to 150ml of acetonitrile with 16.17g of potassium carbonate and the mixture was cooled to 10-15°C. 18.8g of Formula (V) of example 1 was added to above mixture at 10-15°C in lot wise. After completion of reaction, the reaction mixture was concentrated under vacuum and 90ml of water was added for isolation. The product was then filtered out, washed with water and dried to obtain 72g (Yield: 70%) of compound of Formula (II).

Example 9: Preparation of compound of Formula (II) from compound of Formula (IlIa)

5.87g of compound of Formula (IlIa) was added to 40 ml of methylene dichloride with 2.36 g of potassium carbonate and 3.67g of ( 1))-2-{[2-(4-aminophenyl)ethyl]amino}-l-phenylethanol (Formula-IV ; prepared by methods known in prior art/ as given in example 5) . The mixture was stirred at 25-30°C for 1 hour. After completion of reaction, the reaction mixture was concentrated followed by addition of 60 ml of water to isolate lg of compound of Formula (II).

Example 10: Insitu preparation of compound of Formula (II) without isolation of compound of Formula (IlIa)

2g of p-nitrophenol was added to 40 ml of methylene chloride with 4.963g of potassium carbonate, and the mixture was cooled to 10-15°C followed by lot wise addition of 3.95g of [2-(formylamino)-l,3-thiazol-4-yl]acetyl chloride of Formula (V) of example 1. After confirming complete formation of compound of Formula (Ilia), 2.36g of potassium carbonate and 3.67g of (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-1 -phenyl ethanol of Formula (IV) (prepared by methods known in prior art/ as given in example 5) was added insitu, and the mixture was stirred at 25-30°C for 1 hour. After completion of reaction, the reaction mixture was concentrated followed by addition of 60 ml of water to isolate lg of compound of Formula (II).

Example 11: Preparation of Mirabegron from compound of Formula (II)

To 2g of compound of Formula (II) was added 30ml of 10% sodium hydroxide and the mixture was stirred at 55-60°C for 3 hours. After completion of reaction, the mixture was cooled to 25-30°C and the solid obtained was filtered, washed with water and dried to yield 1.3g of Mirabegron. (Yield: 70%)

Example 12: Preparation of Mirabegron from compound of Formula (Illb)

6.18g of 4-nitrophenyl-(2-amino-l,3-thiazol-4-yl)acetate was added to 40ml of methylene dichloride with 2.36g of potassium carbonate and 3.65g of (1R)-2-{ [2-(4-aminophenyl)ethyl]amino}-l-phenylethanol of Formula (IV) (prepared by methods known in prior art/ as given in example 5), and the mixture was stirred at 25-30°C for 1 hour. After completion of reaction, solid was filtered out, washed with methylene dichlrode and dried to yield lg of Mirabegron of Formula (I).

Example 13: Insitu preparation of Mirabegron without isolation of compound of Formula (Illb)

To 40ml of methylene chloride was added 2g of p-nitrophenol and 4.96g of potassium carbonate, and the mixture was cooled to 10-15°C followed by lot wise addition of 3.95g of compound of Formula (VI) prepared in example 3. After confirming complete formation of compound of Formula (Illb), 2.36g of potassium carbonate and 3.65g of (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-l-phenylethanol of Formula (IV) (prepared by methods known in prior art/ as given in example 5) was added insitu, and the mixture was stirred at 25-30°C for 1 hour. After completion of reaction, After completion of reaction, solid was filtered out, washed with methylene dichlrode and dried to yield lg of Mirabegron of Formula (I).

Example 14: Preparation of Mirabegron from compound of Formula (VI); wherein R is -CI

To 20ml of acetone was added 2g of (l/?)-2-{[2-(4-aminophenyl)ethyl]amino}-l-phenylethanol of Formula (IV) and 2.15g of potassium carbonate, and the mixture was cooled to 10-15°C followed by addition of (2-amino-l,3-thiazol-4-yl)acetyl chloride of Formula (VI). After completion of reaction, acetone was concentrated under vacuum and 90ml of water was added for for isolation. The product was then filtered out, washed with water and dried to obtain 2g (Yield: 70%) of Mirabegron.

/////WO-2016024284, WO 2016024284, New Patent, MIRABEGRON, Wanbury Ltd

WO 2016024289, NILOTINIB, New Patent by SUN PHARMA

February 22, 2016 4:39 am / 1 Comment on WO 2016024289, NILOTINIB, New Patent by SUN PHARMA

NILOTINIB

WO 2016024289, NILOTINIB, New Patent by SUN

SUN PHARMACEUTICAL INDUSTRIES LTD [IN/IN]; 17/B, Mahal Industrial Estate, Off Mahakali Caves Road, Andheri (east), Mumbai 400093 (IN)

THENNATI, Rajamannar; (IN).
KILARU, Srinivasu; (IN).
VALANCE SURENDRAKUMAR, Macwan; (IN).
SHRIPRAKASH DHAR, Dwivedi; (IN)

The present invention provides novel salts of nilotinib and polymorphs thereof. The acid addition salts of nilotinib with benzenesulfonic acid, butanedisulfonic acid, 1-5- naphthalenedisulfonic acid, naphthalene-1-sulfonic acid and 1-hydroxynaphthoic acid; hydrates and anhydrates thereof.

Nilotinib, 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino] -benzamide, having the following formula

is marketed under the name Tasigna® in US and Europe. Tasigna contains nilotinib monohydrate monohydrochloride salt and is available as capsules for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Tasigna is also indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib.

Nilotinib is considered a low solubility/low permeability (class IV) compound in the Biopharmaceutics Classification System (BCS). Therefore, dissolution of nilotinib can potentially be rate limiting step for in-vivo absorption. It is soluble in acidic media; being practically insoluble in buffer solutions of pH 4.5 and higher.

WIPO publication 2014059518A1 discloses crystalline forms of nilotinib hydrochloride and methods of the preparation of various crystalline solvates of nilotinib hydrochloride including benzyl alcohol, acetic acid and propylene glycol.

WIPO publication 2011033307A1 discloses nilotinib dihydrochloride and its hydrates and method for their preparation.

WIPO publication 2011163222A1 discloses the preparation of nilotinib salts and crystalline forms thereof. The salts of nilotinib disclosed are hydrochloride, fumarate, 2-chloromandelate, succinate, adipate, L-tartrate, glutarate, p-toluenesulfonate, camphorsulfonate, glutamate, palmitate, quinate, citrate, maleate, acetate, L-malate, L-aspartate, formate, hydrobromide, oxalate and malonate.

WIPO publication number 2011086541A1 discloses a nilotinib monohydrochloride monohydrate salt and methods for preparing.

WIPO publication number 2010054056A2 describes several crystalline forms of nilotinib hydrochloride.

WIPO publication number 2007/015871A1 discloses the preparation of nilotinib salts and crystalline forms thereof. The salts are mixtures of nilotinib and one acid wherein the acids are selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, sulfonic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sul- fonic acid, citric acid, fumaric acid, gentisic acid, malonic acid, maleic acid, and tartaric acid.

WIPO publication number 2007015870A2 discloses several nilotinib salts including amorphous and crystalline forms of nilotinib free base, nilotinib HC1 and nilotinib sulfate along with their hydrate and solvates.

EXAMPLES:

Example 1: Preparation of nilotinib benzenesulfonate crystalline Form I

Nilotinib base (1 g) was suspended in water (20 ml). A solution of benzenesulfonic acid (0.4 g) in water (3ml) was added and the content was heated at 60 °C for 2-3 h. The mixture was cooled to 25-30 °C, filtered, washed with water (3 x 5 ml) and dried under vacuum for 2 h at 50-55 °C.

1H NMR (500 MHz, DMSO-d6) δ 2.40 (s,3H), 2.42 (s,3H), 7.35-7.37 (m,3H), 7.51-7.66 (m,5H),7.83 (d,lH), 7.96 (s,lH),8.08 (s,lH),8.30 (s,lH) 8.39 (s,lH),8.54 (d,lH), 8.61 (d,lH), 8.64 (s,lH), 8.75 (d,lH), 9.25 (s,lH), 9.34 (d,lH), 9.61 (s,lH), 10.84 (s,lH).

The salt provides an XRPD pattern substantially same as set forth in FIG. 1.

Example 2: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form II

Nilotinib base (100 g) was dissolved in 20 % water in THF solution (2000 ml) at 60-65 °C and insoluble matter was filtered. The filtrate was concentrated under vacuum below 60 °C. Filtered water (1000 ml) was added to the reaction mixture and it was heated at 50-55 °C, followed by addition of 1,4-butanedisulfonic acid -60% aqueous solution (28.6 ml) at same temperature. The content was stirred at 50-55 °C for 2-3h. Reaction mixture as cooled to 25-30 °C and product was filtered, washed with water (200 ml x 2) and dried in air oven at 50-55 °C (yield: 115 g).

Sun Pharma managing director Dilip Shanghvi.

Purity (by HPLC):99.76%

1H NMR (400 MHz,DMSO-d6) δ 1.63-1.66(m,2H), 2.40(d,3H),2.42(s,3H),2.43-2.47(m,2H), 7.51-7.62(m,3H),7.85(dd,lH),7.96(s,lH),8.08(s,lH),8.34(s,lH),8.38(d,lH),8.52-8.55(m,lH), 8.60-8.62 (m,2H), 8.75(d,lH), 9.25(S,1H),9.34(S,1H),9.59(S,1H),10.86(S,1H)

Water content: 7.95 %.

The salt has a XRPD pattern substantially same as set forth in FIG. 2.

Example 3: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form II

Nilotinib base (300 g) was suspended in methanol (3000 ml) and aqueous hydrochloric acid was added to get pH less than 2. Reaction contents were heated at reflux and was filtered and washed with methanol (100 ml). 5% (w/w) NaOH (1200 ml) solution was added at 40-45 °C within 15 min, reaction mixture was stirred for 2h. Product was filtered, washed with water

(300 ml x 3) and dried for lh. Wet material was suspended in water (3000 ml), heated at 50- 55 °C followed by addition of 1,4-butanedisulfonic acid -60% aqueous solution. The reaction mixture was stirred at 50-55°C for 2hrs. Product was filtered at room temperature, washed with water (500 ml x 2) and dried in air oven at 50-55 °C (yield: 293 g).

Purity (by HPLC): 99.88 %

¹H NMR (400 MHz,DMSO-d6+TFA-dl) δ 1.75-1.78(m,2H), 2.36(d,3H),2.38(s,3H),2.69- 2.72(m,2H),7.45(d,lH),7.68(d,lH),7.83(s,lH),7.88(dd,lH),7.97(s,lH),8.16-8.19(m,lH), 8.35

(s,2H), 8.63(d,lH),8.68(d,lH),9.04(d,lH),9.21(d,lH),9.53(br s,lH),9.69(d,lH)10.80 (s,lH)

Water content: 6.44 %

Example 4: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form III

Nilotinib butanedisulfonate (210g) was dissolved in acetic acid water mixture (50:50) (2520 ml) at 75-80 °C and was filtered to remove insoluble matter and washed with acetic acid water mixture (50:50) (210 ml). Water (3150ml) was added to the filtrate and stirred first at room temperature and then at 0-5 °C. Product was filtered and washed with water. Material was dried in air oven at 70-75 °C. Dried material was leached with methanol (3438 ml) at reflux temperature, filtered and dried in air oven 70-75°C (yield: 152.6 g)

Purity (by HPLC): 99.89 %

1H NMR (400 MHz,DMSO-d6+TFA-dl) δ 1.73-1.77(m,2H), 2.40(s,6H),2.67-2.70(m,2H), 7.50 (d,lH), 7.70(d,lH), 7.88-7.92(m,2H), 8.07(s,lH),8.23 (dd,lH), 8.34(s,2H), 8.67 (d,lH), 8.72 (d,lH), 9.09(d,lH), 9.23 (s,lH), 9.54(d,lH), 9.74(d,lH), 10.86(s,lH).

Water content: 0.61 %

The salt provides an XRPD pattern substantially same as set forth in FIG. 3.

Example 5: Preparation of crystalline form of nilotinib butanedisulfonate (2: 1)

Crystalline Nilotinib butanedisulfonate (1 g) of Example 2 was suspended in methanol (20 ml) and was stirred at reflux for 60 min. The mixture was cooled to room temperature. Solid was filtered, washed with methanol (2 ml x 3) and dried in air oven at 70-75°C (yield: 0.8 g)

Example 6: Preparation of nilotinib butanedisulfonate (1: 1) crystalline Form IV

Nilotinib base (20 g) was suspended in methanol (800 ml) and 1,4-butanedisulfonic acid -60

% aqueous solution (6 ml) was added at 50-55 °C, and was filtered to remove insoluble matter. Filtrate was stirred at room temperature for 2-3 h. Product formed was filtered, washed with methanol (20 ml x 2) and dried the product in air oven at 70-75 °C (yield: 18.4 g).

Purity (by HPLC):99.86 %

1H NMR (400 MHz,DMSO-d6) δ 1.64-1.68(m,4H), 2.47-2.5 l(m,4H), 2.41(s,3H), 2.42(d,3H), 7.52(d,lH), 7.83-7.89(m,2H), 7.99(s,lH), 8.15(s,lH), 8.36 (d,lH), 8.39(s,lH), 8.65-8.66(m,2H), 8.79(d,lH), 8.89(br s,lH), 9.36(s,lH), 9.41(br s,lH), 9.74(d,lH), 10.91(s,lH).

The salt has XRPD pattern substantially same as set forth in FIG. 4.

Example 7: Preparation of nilotinib 1,5-napthalenedisulfonic acid salt (2: 1) crystalline Form V

Nilotinib base (1 g) was suspended in water (20 ml). A solution of 1,5-napthalenedisulfonic acid (0.4 g; 0.6 eq.) in water (5ml) was added and the content was heated at 50-55 °C for lh. The mixture was cooled to 25-30 °C, filtered and washed with water (10 ml). The product was dried in air oven at 50-55°C (yield: 1.2 g).

1H NMR (400 MHz,DMSO-d6) δ 2.39 (s,3H), 2.42 (s,3H), 7.45-7.61 (m,4H),7.84 (d,lH), 7.97(s,2H),8.08 (m,lH),8.31 (s,lH) 8.38 (s,lH),8.55 (d,lH), 8.63 (s,2H), 8.75 (s,lH), 8.92 (d,lH), 9.26 (s, 1H), 9.34 (s,lH),9.62 (s,lH), 10.85 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 5.

Example 8: Preparation of nilotinib 1,5-napthalenedisulfonic acid salt (1: 1) crystalline Form VI

Nilotinib base (1 g) was suspended in water (20 ml). A solution of 1,5-napthalenedisulfonic acid (0.8 g; 1.2eq) in water (5 ml) was added and the content was heated at 50-55 °C for 1 h. The mixture was cooled to 25-30 °C, filtered, washed with water (10 ml) and dried in air oven at 50-55 °C (yield: 1.4g).

1H NMR(400 MHz,DMSO-d6) δ 2.40 (s,3H),2.41 (s,3H), 7.43-7.52 (m,3H),7.61 (d,lH), 7.85-7.99(m,5H),8.11 (s,lH),8.34 (s,2H), 8.64-8.67 (m,2H), 8.89-8.92 (m,4H),9.40(d,2H), 9.72 (s,lH), 10.87 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 6.

Example 9: Preparation of nilotinib napthalene-1- sulfonic acid salt crystalline Form VII Nilotinib base (1 g) was suspended in water (10 ml) and heated to 50-55 °C. A solution of napthelene-1 -sulfonic acid and methanol (10 ml) was added to it and heated at 70-75 °C for 30 min. The mixture was cooled to 25-30 °C and stirred for 10 min. The product was filtered, washed with water (2 x 2 ml) and dried under vacuum for 1-2 h at 50-55 °C.

1H NMR (400 MHz,DMSO-d6) δ 2.41 (s,3H),2.42 (s,3H), 7.46-7.58 (m,5H), 7.70-8.00 (m,7H)8.11(s,lH)8.31(s,lH),8.37(s,lH),8.63-8.66 (m,3H), 8.81-8.89 (m,2H), 9.31 (s,lH), 9.37 (d,lH), 9.71 (d,lH), 10.86 (s,lH)

The salt has a XRPD pattern substantially same as set forth in FIG. 7.

Example 10: Preparation of nilotinib l-hydroxy-2-napthoic acid salt crystalline Form VIII Nilotinib base (1 g) was suspended in water (20 ml) and heated to 50-55 °C. l-Hydroxy-2-napthoic acid was added to it and the content was heated at 50-55 °C for 1 h. Methanol (5 ml) was added to the mixture and stirred for 30 min. The content was filtered, washed with water (2 x 2 ml) and dried under vacuum for 1 h at 50-55 °C.

1H NMR (400 MHz, DMSO-d6) δ 2.25 (s,3H), 2.41 (s,3H), 7.40-7.92 (m,l lH), 8.23-8.73 (m,8H), 9.24 (s,lH), 9.34(s,lH), 10.70 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 8.

Nilotinib
Systematic (IUPAC) name


4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide
Clinical data
Trade names	Tasigna
AHFS/Drugs.com	monograph
MedlinePlus	a608002
Licence data	EMA:Link, US FDA:link
Pregnancy category	AU: D US: D (Evidence of risk)
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	30%^[1]
Protein binding	98%^[1]
Metabolism	Hepatic (mostly CYP3A4-mediated)^[1]
Biological half-life	15-17 hours^[1]
Excretion	Faeces (93%)^[1]
Identifiers
CAS Number	641571-10-0(base)
ATC code	L01XE08
PubChem	CID 644241
IUPHAR/BPS	5697
DrugBank	DB04868
ChemSpider	559260
UNII	F41401512X
KEGG	D08953
ChEBI	CHEBI:52172
ChEMBL	CHEMBL255863
PDB ligand ID	NIL (PDBe, RCSB PDB)
Chemical data
Formula	C₂₈H₂₂F₃N₇O
Molar mass	529.5245 g/mol

//////////////WO 2016024289, WO-2016024289, NILOTINIB, New Patent, SUN

Cc1ccc(cc1Nc2nccc(n2)c3cccnc3)C(=O)Nc4cc(cc(c4)n5cc(nc5)C)C(F)(F)F

Bromuconazole

February 20, 2016 9:01 am / Leave a comment

Bromuconazole

116255-48-2; HSDB 7419

Molecular Formula:	C₁₃H₁₂BrCl₂N₃O
Molecular Weight:	377.06388 g/mol

1-[[4-bromo-2-(2,4-dichlorophenyl)oxolan-2-yl]methyl]-1,2,4-triazole

1-[[4-Bromo-2-(2,4-dichlorophenyl)tetrahydro-2-furanyl]methyl]-1H-1,2,4-triazole

1-[(2RS,4RS;2RS,4SR)-4-bromo-2-(2,4-dichlorophenyl)tetrahydrofurfuryl]-1H-1,2,4-triazole

Manufacturers’ Codes: LS-860263

Trademarks: Granit (Rh>e-Poulenc)

Percent Composition: C 41.41%, H 3.21%, Br 21.19%, Cl 18.80%, N 11.14%, O 4.24%

Melting point: mp 84°

Toxicity data: LD50 orally in rats, mice: 365, 1151 mg/kg; LD50 dermally in rats: >2000 mg/kg; LD50 by inhalation in rabbits: >5 mg/l; LC50(96 hr) in rainbow trout, bluegill sunfish (mg/l): 1.7, 3.1 (Pepin)

Use: Agricultural fungicide.

Properties: White to off-white odorless powder, mp 84°. Moderate to high soly in organic solvents; soly in water 50 mg/l. Vapor pressure (25°): 0.3 ´ 10-7 mm Hg. LD50 orally in rats, mice: 365, 1151 mg/kg; LD50 dermally in rats: >2000 mg/kg; LD50 by inhalation in rabbits: >5 mg/l; LC50(96 hr) in rainbow trout, bluegill sunfish (mg/l): 1.7, 3.1 (Pepin).

Bromuconazole

Literature References: Ergosterol biosynthesis inhibiting triazole. Prepn: A. Greiner, R. Pepin, EP 258161 (1988 to Rhone Poulenc), C.A. 109, 110440v (1988). Properties and antifungal activity: R. Pepin et al., Brighton Crop Prot. Conf. – Pests Dis. 1990, 439. Effect on fungus ultrastructure: M. Mangin-Peyrard, R. Pepin, Z. Pflanzenkrankh. Pflanzenschutz 103, 142 (1996). Determn by TLC in water: S. Butz, H.-J. Stan, Anal. Chem. 67, 620 (1995); by GC with atomic emission detection in foodstuffs: H.-J. Stan, M. Linkerhägner, J. Chromatogr. A 750, 369 (1996). Field trials in combination with iprodione, q.v.: P. Duvert et al., Agro-Food-Ind. Hi-Tech 7, 34 (1996); in combination with prochloraz, q.v.: eidem, Phytoma 490, 32 (1997).

Patent	Submitted	Granted
Phthalamide derivatives [US7132455]	2006-02-16	2006-11-07
Crystal modification II of 2-[2-(1-chloro-cyclopropyl)-3-(2-chlorophenyl)-2-hydroxy-propyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione [US7176226]	2006-05-18	2007-02-13
Anthranilamide insecticides [US7211270]	2006-03-09	2007-05-01
2-Phenyl-2-substituted-1,3-diketones [US7227043]	2006-03-16	2007-06-05
Biphenyl derivatives and their use as fungicides [US7241721]	2006-05-11	2007-07-10
Cyano anthranilamide insecticides [US7247647]	2006-05-25	2007-07-24
3-Phenyl substituted 3-substituted-4ketolactams and ketolactones [US7329634]	2006-05-04	2008-02-12
Substituted isoxazoles as fungicides [US7338967]	2006-04-06	2008-03-04
Insecticidal anthranilamides [US7338978]	2006-04-13	2008-03-04
Pyrazolyl carboxanilides for controlling unwanted microorganisms [US7358214]	2006-04-27	2008-04-15

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C1=CC(=C(C=C1Cl)Cl)C2(CC(CO2)Br)C[N]3C=NC=N3

Bromuconazole

Identification
N^o CAS	116255-48-2
SMILES	[Masquer] C1=CC(=C(C=C1Cl)Cl)C2(CC(CO2)Br)C[N]3C=NC=N3 PubChem, vue 3D
InChI	[Afficher]
Apparence	cristaux incolores ou poudre sans odeur¹.
Propriétés chimiques
Formule brute	C₁₃H₁₂Br Cl₂N₃O [Isomères]
Masse molaire²	377,064 ± 0,017 g/mol C 41,41 %, H 3,21 %, Br 21,19 %, Cl 18,8 %, N 11,14 %, O 4,24 %,
Propriétés physiques
T° fusion	84 °C¹
Solubilité	dans l’eau : 0,5 g·l^-1¹
Pression de vapeur saturante	à 25 °C : négligeable¹

Saperconazole

February 20, 2016 8:45 am / Leave a comment

Saperconazole

CAS 110588-57-3

4-[4-[4-[4-[[2-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one

(±)-1-sec-butyl-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-D2-1,2,4-triazolin-5-one

2-butan-2-yl-4-[4-[4-[4-[[(2R,4S)-2-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one

R-66905

MF: C35H38F2N8O4

MW: 672.72

Percent Composition: C 62.49%, H 5.69%, F 5.65%, N 16.66%, O 9.51%

Properties: Crystals from acetonitrile, mp 189.5°. Poorly sol in water.

Melting point: mp 189.5°

Therap-Cat: Antifungal.

Janssen Pharmacuetica N.V.

PHASE 2

Systemic fungal diseases (systemic mycoses) are typically chronic conditions that develop very slowly. These diseases are often induced by opportunistic causative fungi that are not normally pathogenic and commonly live in the patient’s body or are commonly found in the environment. While systemic fungal diseases used to be relatively rare in temperate countries, there has been an increasing incidence of numerous life-threatening systemic fungal infections that now represent a major threat to susceptible patients. Susceptible patients include immunocompromised patients, particularly those already hospitalized, and patients compromised by HIV infection, ionizing irradiation, corticosteroids, immunosuppressives, invasive surgical techniques, prolonged exposure to antimicrobial agents, and the like, or by diseases or conditions such as cancer, leukemia, emphysema, bronchiectasis, diabetes mellitus, burns, and the like. The symptoms manifested by these fungal diseases are generally not intense, and may include chills, fever, weight loss, anorexia, malaise, and depression.
The most common systemic fungal infections in humans are blastomycosis, candidosis, aspergillosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, and cryptococcosis.
Fungal diseases are often confined to typical anatomic sites, and many involve a primary focus in the lung, with more characteristic manifestations of specific fungal infections appearing once the infection spreads from a primary site. For example, blastomycosis primarily involves the lungs, and occasionally spreads to the skin. Similarly, the primary form of coccidioidomycosis occurs as an acute, benign, self-limiting respiratory disease, which can then progress to a chronic, often-fatal infection of the skin, lymph glands, liver, and spleen. Other infectious diseases such as paracoccidioidomycosis and candidiasis present in different manners, and depending on the etiology, may exhibit several forms involving internal organs, the lymph nodes, skin, and mucous membranes. Diagnosis of specific fungal diseases can be made by isolation of the causative fungus from various specimens, such as sputum, urine, blood, or the bone marrow, or with certain fungus types, through evidence of tissue invasion.
Many patients suffering from severe systemic fungal infections are hardly, or not at all, able to receive medication via oral administration, as such patients are often in a coma or suffering from severe gastroparesis. As a result, the use of insoluble or sparingly soluble antifungals such as itraconazole free base, which are difficult to administer intravenously to treat such patients, is significantly impeded.
Local or superficial fungal infections are caused by dermatophytes or fungi that involve the outer layers of the skin, nails, or hair. Such infections may present as a mild inflammation, and can cause alternating remissions and eruptions of a gradually extending, scaling, raised lesion. Yeast infections, such as candidiasis and oral candidiasis (thrush), are usually localized to the skin and mucous membranes, with the symptoms varying depending on the site of infection. In many instances, such infections appear as erythematous, often itchy, exudative patches in the groin, axillas, umbilicus, between toes, and on finger-webs. Oral thrush involves an inflamed tongue or buccal mucosa, typically accompanied by white patches of exudate. Chronic mucocutaneous candidiasis is manifested in the form of red, pustular, crusted, thickened lesions on the forehead or nose.Itraconazole or (±)-£is-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(lH-l-2,4-triazol-l- ylmethyl)- 1 ,3-dioxolan-4-yl]methoxy]phenyl]- 1 -ρiperazinyl]phenyl]-2,4-dihydro-2-( 1 – methyl-propyl)-3H-l,2,4-triazol-3-one, is a broadspectrum antifungal compound developed for oral, parenteral and topical use and is disclosed in US-4,267,179.

Its difluoro analog, saperconazole or (±)-_πs-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2- ( 1H- 1 ,2,4-triazol- 1-yl-methyl)- 1 ,3-dioxolan-4-yl]methoxy]phenyl] – 1 -piperazinyl]- phenyl]-2,4-dihydro-2-(l-methylpropyl)-3H-l,2,4-triazol-3-one, has improved activity against Aspergillus spp. and is disclosed in US-4,916,134. Both compounds exist as a mixture of four stereoisomers.

The development of effϊcaceous pharmaceutical compositions of itraconazole and saperconazole is hampered considerably by the fact that said compounds are only very sparingly soluble in water. The solubility of both compounds can be increased by complexation with cyclodextrins or derivatives thereof as described in WO 85/02767 and US-4,764,604.

Unexpectedly, it has now been found that each of the individual stereoisomers of itraconazole and saperconazole have greater water solubility than the diastereomeric mixtures of said compounds, in particular when complexed with cyclodextrin or its derivatives. As a result, pharmaceutical compositions having good bioavailability, yet comprising less cyclodextrin as a complexing agent, can be prepared. The present invention is concemced with the stereoisomeric forms of itraconazole (X = CI) and saperconazole (X = F), which may be represented by the formula

cis-©,and the pharmaceutically acceptable acid addition salt forms thereof. The three asterisks indicate the three chiral centers, and ‘cis’ means that the (lH-l,2,4-triazol-l-ylmethyl) moiety and the substituted phenoxy moiety are located at the same side of the plane defined by the 1,3-dioxolane ring.

The four possible stereoisomeric cis forms can be described using various rules of nomenclature. The following tables show the correlation among the C. A. stereochemical descriptor, the absolute configuration at each of the chiral centers and the specific optical

20 rotation [α]_jj in 1% methanol (itraconazole; table I) (saperconazole; table H).

Table I

itraconazole

Table π

saperconazole

Synthesis

US 4916134

http://www.google.co.in/patents/US4916134

PATENT

WO 2005118577

Itraconazole is a broad-spectrum antifungal agent developed for oral, parenteral and topical use, and is disclosed in U.S. Patent No. 4,267,179. Itraconazole is a synthetic triazole derivative that disrupts the synthesis of ergosterol, the primary sterol of fungal cell membranes. This disruption appears to result in increased permeability and leakage of intracellular content, and at high concentration, cellular internal organelles involute, peroxisomes increase, and necrosis occurs.
As set forth in the USP Dictionary of Drug Names and USAN, itraconazole is defined as 4-[4-[4-[4- [[2-(2,4-dichlorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl] methoxy]phenyl]-l-piperazinyl]phenyl]- 2,4-dihydro-2-(l-methylpropyl)-3H-l,2,4-triazol-3-one, or alternatively, as (±)-l-5ec-butyl-4-[/7-[4-[/7-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl]methoxy]phenyl]-l-piperazinyl]phenyl]-Δ²-l,2,4-triazolin-5-one. There are three asymmetric carbons in itraconazole: one in the sec-butyl side chain on the triazolone and two in the dioxolane ring. As a result, eight possible stereoisomers of itraconazole exist: (R,R,R), (S,S,S), (R,R,S), (S,S,R), (R,S,S), (R,S,R), (S,R,S), and (S,R,R).
(±)Cz^‘s-Itraconazole comprises a mixture of only those isomers that describe a “cis” relationship in the dioxolane ring, i.e., the (1Η-1, 2, 4-triazol-l-ylmethyl) moiety and the substituted phenoxy moiety are located on the same side of a plane defined by the 1, 3-dioxolane ring. By convention, the first represented chiral center is at the C-2 position of the dioxolane ring, the second is at the C-4 position of the dioxolane ring, and the third is in the sec-butyl group. Hence, (±)c.s-itraconazole is a mixture of (R,S,S), (R,S,R), (S,R,S) and (S,R,R) isomers.
The four possible stereoisomeric cis forms of itraconazole, and
diastereomeric pairs thereof, are described in more detail in U.S. Patent Nos. 5,474,997 and 5,998,413. In general, the individual stereoisomeric forms of c s-itraconazole have antifungal properties, and contribute to the overall activity of (±)cw-itraconazole.
(±)Ciy-Itraconazole free base is only very sparingly soluble in water, and thus it is extremely difficult to prepare effective pharmaceutical compositions containing the same. A number of means have been used to increase the solubility of itraconazole free base, including complexing or co-formulation with cyclodextrins or derivatives thereof, as described in U.S. Patent No. 4,764,604, U.S. Patent No.5,998,413, and U.S. Patent No. 5,707,975, and coating beads with a film comprising a hydrophilic polymer and itraconazole, as described in U.S. Patent No. 5,633,015.
[0014] Another approach to increase solubility of itraconazole focuses on preparation of the stereoisomers of c s-itraconazole, and in particular (2R, 4S) itraconazole, which may comprise a mixture of two diastereomers ((R,S,S) and
(R,S,R)), as described in U.S. Patent Nos. 5,414,997 and 5,998,413.

Commercially available itraconazole (SPORANOX^® brand (±)cis-itraconazole, Janssen Pharmaceutica Products, L.P., Titusville, NJ, U.S.A.) is a free base and a racemic mixture of the cis isomer in the dioxolane ring and is represented by structural formula (I):

(i)

SPORANOX has been approved for use as an antifungal agent for treating immunocompromised and non-immunocompromised patients having: blastomycosis (pulmonary and extrapulmonary); histoplasmosis, including chronic cavitary pulmonary disease and disseminated non-meningeal histoplasmosis; and aspergillosis. In addition, in non-immunocompromised patients, it has been approved for treatment of onychomycosis. See generally, Physician ‘s Desk Reference, 56^th ed. (2002). The compound has also been investigated for use in coccidioidomycosis, cryptococcosis, dermatophyte, and candidiasis infections.
Adverse effects associated with the administration of (±)cts-itraconazole free base include nausea, vomiting, anorexia, headache, dizziness, hepatotoxicity, and inhibition of drug metabolism in the liver, leading to numerous, clinically significant, adverse drug interactions. See, Physician ‘s Desk Reference, 56^th ed. (2002); Honig et al., J. Clin. Pharmacol. 33:1201-1206 (1993) (terfenadine interaction); Gascon and Dayer, Eur. J. Clin. Pharmacol., 41_:573-578 (1991) (midazolam interaction); and Neuvonen et al, Clin. Pharmacol. Therap., 60:54-61 (1996) (lovastatin interaction). Reactions associated with hypersensitivity, such as urticaria and serum liver enzymes elevation, are also associated with the administration of the drug. A more serious, though less common, adverse effect is hepatotoxicity. See, e.g., Lavrijsen et al., Lancet, 340:251-252 (1992).
In addition, as discussed herein, c/s-itraconazole free base is only very sparingly soluble in water. Thus, due to its relative non-polarity and insolubility, itraconazole free base suffers from two other drawbacks: it cannot be readily formulated in parenteral solution, and it does not effectively penetrate the blood-brain barrier. The latter problem is exacerbated by drug interactions, such as one observed between itraconazole free base and valproate, as described in Villa et al. , Rev. Inst. Med. Trop., Sao Paulo, pp. 231-234 (Jul-Aug 2000), which is incorporated by reference herein in its entirety. In another case of CNS fungal infection, extremely high doses of itraconazole free base were used to treat residual aspergillus infection, as reported by Imai et al., Intern. Med, 38(10):829-832 (1999), which is incorporated by reference herein in its entirety. As a result, numerous therapeutic indications that require rapid achievement of effective blood levels or access to the CNS are difficult to treat or beyond treatment with itraconazole free base.
Furthermore, the emergence of antifungal resistance (e.g., in Aspergillus fumigatus isolates as described by Dannaoui et al., J. Antimicrob. Chemother., 47:333-340 (2001), which is incorporated by reference herein in its entirety) presents an added challenge to the efficacy of itraconazole free base. For those strains of fungi that show resistance, high and relatively constant levels of itraconazole free base must be produced in the target organs of infected patients.
Over the years, a number of formulation routes have been used in order to enhance the adsorption and bioavailability of itraconazole. For example, the currently marketed SPORANOX^® solid dosage capsule form of itraconazole free base utilizes sugar-based beads coated with a hydrophilic polymer and an amorphous film of itraconazole. See Physicians Desk Reference, 56^th ed., pp.1800- 1804 (2002); and U.S. Patent No. 5,633,015. This dosage form requires up to two capsules three times daily depending on the condition being treated.
Even with the various formulation routes, the dosage amounts and dose frequency for itraconazole can be burdensome to patients. In addition, administration of existing dosage forms of itraconazole have shown significant variability in bioavailability and adsorption, which likely results from food effects. See, Physician ‘s

Desk Reference, 56^th ed., pp. 1800-1804 (2002). Thus, it would be desirable to increase bioavailability and adsorption and decrease the per-dose pill count and decrease dosing frequency (e.g., twice a day to once a day) associated with administration of itraconazole in order to provide an improvement over current therapy, particularly with regard to patient compliance, convenience, ease of ingestion, especially with regard to immunocompromized polypharmacy patients (e.g., AIDS or cancer patients).

Posaconazole and Saperconazole Chemistry and Uses
Other related conazoles have also been discovered and used as antifungals. Two of these conazoles that are closely structurally related to itraconazole are posaconazole and saperconazole. Posaconazole (CAS Registry Number: 171228-49-2; CAS Name: 2,5-Anhydro-l ,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[l -[(1 S,2S)- 1 -ethyl-2-hydroxypropyl]- 1 ,5-dihydro-5-oxo-4H- 1 ,2,4-triazol-4-yl]phenyl]- 1 -piperazinyl]phenoxy]methyl]- 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)-D-t/Veo-pentitol; Additional Name: (3R-c s)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(l,2,4-triazol-l-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin- 1 -yl]phenyl]-2-[l (S)-ethyl-2(S)-hydroxypropyl]-3,4-dihydro-2H-l,2,4-triazol-3-one) is represented by structural formula (II):

(II)

Saperconazole (CAS Registry Number: 110588-57-3; CAS Name: 4-[4-[4-[4-[[2-(2,4-Difluorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl]methoxy]phenyl]- 1 -piperazinyl]phenyl]-2,4-dihydro-2-(l -methylpropyl)-3H- 1 ,2,4-triazol-3-one; Additional Name: (±)-l-sec-butyl-4-[ -[4-| -[[(2R* 4S*)-2-(2,4- difluorophenyl)-2-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)- 1 ,3 -dioxolan-4-yl]methoxy]phenyl]- 1 -piperazinyl]phenyl]-Δ2-l,2,4-triazolin-5-one) is represented by structural formula (III):

(III)

Consequently, there is a need for soluble forms of conazoles including cis itraconazole, posaconazole and saperconazole that can be readily formulated for use in various modes of administration, including parenteral and oral administration.

PATENT

EP 0283992

A. Preparation of intermediates: Example 1a) utilizing water separator, by 200 parts of glycerin, 90 parts of 1- (2,4-difluorophenyl) -2- (1H-1,2,4- three mixture of 1-yl) ethanone, 600 parts of methanesulfonic acid, 190 parts of benzene was stirred first at reflux for 3 hours, then stirred at room temperature overnight. The reaction mixture was added dropwise a solution of sodium bicarbonate. The product was extracted with chloroform, the extract was washed with water, dried, filtered and evaporated. With 4-methyl-2-pentanone and the residue triturated product was filtered off and dried, yielding 80 parts (67.2%) (cis + trans) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol (intermediate 1).

b) by 69 parts of 3,5-dinitrobenzoyl chloride, 80 parts of (cis + trans) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol, 400 parts of pyridine and 520 parts of dichloromethane was stirred at room temperature for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in water. The product was extracted with chloroform. The extract was dried, filtered and evaporated. The residue was subjected to silica gel column chromatography, eluting with chloroform / methanol (99:1v / v). Pure fractions were collected, the eluent was evaporated, to give 90 parts (70.4%) of cis -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1 ylmethyl) -1,3-dioxolane-4-methanol 3,5-dinitrobenzoate (residue) (intermediate 2).

c) by 90 parts of (cis) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxo- dioxolan-4-methanol 3,5-dinitrobenzoate, 16 parts of 50% sodium hydroxide solution, 800 parts of 1,4-dioxane, 400 parts of water and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the product was extracted with dichloromethane, extracts washed with water, dried, filtered and evaporated. With 4-methyl-2-pentanone and the residue triturated product was filtered off and dried, yielding 30 parts (56.0%) of cis -2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1,3-dioxolane-4-methanol (residue) (intermediate 3).

d) by 11.4 parts of methanesulfonyl chloride, 25 parts of cis -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1, mixture of 1,3-dioxolane-4-methanol, 300 parts of pyridine, 390 parts of dichloromethane was stirred at room temperature for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in chloroform. The organic phase was dried, filtered and evaporated. The residue was triturated with dipropyl ether. The product was filtered off and dried, yielding 29.4 parts (93.2%) of cis -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) – 1,3-dioxolane-4-methanol methanesulfonate (residue) of intermediate 4).

In a similar manner there were also prepared: cis-2- (2,4-difluorophenyl) -2- (1H- imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol mesylate ethanedioate (1/1) (interm. 5).

Example 2a) over 2 hours, dissolved in 100 parts of pyridine 121.2 parts of 2-naphthalenesulfonyl chloride was added dropwise to a stirred, was dissolved in 1300 parts of dichloromethane, and 122.0 parts of (cis + trans ) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol and 1.0 parts of N, N- dimethyl-4-pyridin-amine solution. Upon completion, stirring was continued at room temperature overnight. The reaction mixture was washed twice with water, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with chloroform. Pure fractions were collected, the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 102.3 parts (51.0%) of cis – [[2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-yl-methyl ) -1,3-dioxolan-4-yl] methyl] -2-naphthalene sulfonate; mp139.5 ℃ (intermediate 6).

Example 3a) at 70 ℃, under nitrogen atmosphere, by 9.0 parts of 4- [4- (4-nitrophenyl) -1-piperazinyl] phenol, 13.6 parts of cis-2- [2,4- difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol methanesulfonate ester, 6.0 parts of potassium hydroxide and 90 parts of a mixture of DMF was stirred overnight. After cooling, the reaction mixture was diluted with water. The precipitated product was filtered off and purified by silica gel column chromatography, the chloroform / ethyl acetate / hexane / methanol (500:300:200:0.5v / v / v / v) mixture as eluent. Pure fractions were collected, the eluent was evaporated. The residue was crystallized 4-methyl-2-pentanone. The product was filtered off and dried, yielding 6.69 parts (38.5%) of cis -1- [4 – [[2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol – 1- ylmethyl) -1,3-dioxolan-4-yl] methoxy) phenyl] -4- (4-nitrophenyl) piperazine; mp169.8 ℃ (Intermediate 7) .

b) at atmospheric pressure, 50 ℃, with 2 parts of 5% palladium – on-charcoal catalyst by 38.3 parts of cis -1- [4 – [[2- (2,4-difluorophenyl) -2- (1H -1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -4- (4-nitrophenyl) piperazine, 2 parts of a solution of thiophene (4% solution in methanol) and 600 parts of 2-methoxy-ethanol mixture. After absorption of the calculated amount of hydrogen finished, hot filtered to remove the catalyst, and the filtrate was saturated with water. After cooling, the precipitated product was filtered off, washed with water and 2-propanol and crystallized from 1,4-dioxane. The product was filtered off and dried, yielding 22.7 parts (62.6%) of cis-4- [4- [4 – [[2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] aniline; mp193.0 ℃ (interm. 8).

Example 4a) by 10 parts of 2,4-dihydro-4- [4- [4- [4-methoxyphenyl) -1-piperazinyl] phenyl] -3H-1,2,4- triazol-3-one (U.S. Patent No. 4,267,179 in the implementation of the method in Example ⅩⅦ obtained), 1.5 parts of sodium hydride (50% dispersion), 300 parts of the mixture consisting of dimethyl sulfoxide, at 60 ℃ under a nitrogen atmosphere begging, stirring, until no bubble up. Was then added 5.24 parts of 2-bromopropane, and at 60 ℃, stirring was continued for 1 hour. Further added 1.5 parts of sodium hydride (50% dispersion) and stirring was continued until no more bubble up. Then 5.24 parts of 2-bromopropane was added, and the whole was stirred for 1 hour at 60 ℃. The reaction mixture was cooled, poured into water and the product was extracted with chloroform. The extract was washed with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography, eluting with chloroform / methanol (99:1v / v). Pure fractions were collected, the eluent was evaporated, the residue was crystallized in 1-butanol, yielding 5.2 parts (47% (2,4-dihydro-4- [4- [4- (4-methoxyphenyl ) -1-piperazinyl] phenyl] -2- (1-methylethyl) -3H-1,2,4- triazol-3-one; mp209.5 ℃ (intermediate 9).

b) by 4.7 parts of 2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -2- (1-methylethyl) -3H-1,2,4- triazol-3-one, a mixture of 75 parts of 48% aqueous hydrobromic acid was stirred at reflux for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in a mixture of methanol and water. With sodium bicarbonate solution, and the whole was, and the product was extracted with chloroform. The extract was dried, filtered and evaporated. The residue was triturated with 2-propanol, yielding 3.9 parts (86%) of 2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -2 – (1-methylethyl) -3H-1,2,4- triazol-3-one, mp208.4 ℃ (intermediate 10).

PATENT

EP 0228125

Literature References:

Orally active, fluorinated triazole antifungal. Prepn: J. Heeres et al., EP 283992; eidem, US 4916134 (1988, 1990 both to Janssen).

In vitro antifungal activity: F. C. Odds, J. Antimicrob. Chemother. 24, 533 (1989);

D. W. Denning et al., Eur. J. Clin. Microbiol. Infect. Dis. 9, 693 (1990).

In vivo efficacy vs Aspergillus species: J. Van Cutsem et al., Antimicrob. Agents Chemother. 33, 2063 (1989).

ChemMedChem (2010), 5(5), 757-69

Jingxi Huagong Zhongjianti (2009), 39(5), 8-12, 22

EP0006711A1 *	13 Jun 1979	9 Jan 1980	Janssen Pharmaceutica N.V.	Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)-methyl-1H-imidazoles and 1H-1,2,4-triazoles, processes for preparing them and compositions containing them
EP0118138A1 *	24 Jan 1984	12 Sep 1984	Janssen Pharmaceutica N.V.	((4-(4-(4-Phenyl-1-piperazinyl)phenoxymethyl)-1,3-dioxolan-2-yl)methyl)-1H-imidazoles and 1H-1,2,4-triazoles
DE2804096A1 *	31 Jan 1978	3 Aug 1978	Janssen Pharmaceutica Nv	1-(1,3-dioxolan-2-ylmethyl)-1h-imidazole und -1h-1,2,4-triazole und deren salze, verfahren zu ihrer herstellung und ihre verwendung bei der bekaempfung pathogener pilze und bakterien

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///////Antifungal, Triazoles,

CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OCC5COC(O5)(CN6C=NC=N6)C7=C(C=C(C=C7)F)F

Saroglitazar, Lipaglyn by Zydus Cadila

February 18, 2016 8:03 am / Leave a comment

(2S)-2-Ethoxy-3-[4-(2-{2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrol-1-yl}ethoxy)phenyl]propanoic acid

(αS)-α-Ethoxy-4-[2-[2-methyl-5-[4-(methylthio)phenyl]-1H-pyrrol-1-yl]ethoxy]benzenepropanoic Acid

alpha-ethoxy-4-(2-(2-methyl-5-(4-methylthio)phenyl))-1H-pyrrol-1-yl)ethoxy))benzenepropanoic acid

alpha-ethoxy-4-(2-(2-methyl-5-(4-methylthio)phenyl))-1H-pyrrol-1-yl)ethoxy))benzenepropanoic acid magnesium salt

(2S)-2-ethoxy-3-[4-[2-[2-methyl-5-(4-methylsulfanylphenyl)pyrrol-1-yl]ethoxy]phenyl]propanoic acid

Benzenepropanoic acid, α-ethoxy-4-[2-[2-methyl-5-[4-(methylthio)phenyl]-1H-pyrrol-1-yl]ethoxy]-, (αS)-

ZYH1 compound

E0YMX3S4JD

Cas no 495399-09-2

Saroglitazar, Lipaglyn

Molecular Weight	439.56706 g/mol
Molecular Formula	C₂₅H₂₉NO₄S

Cadila Healthcare Ltd innovator

Zydus-Cadila has developed and launched saroglitazar (ZYH-1; Lipaglyn; structure shown), a lipid metabolism modulator, a potent PPAR-alpha agonist with relatively weak PPAR-gamma activity, an insulin sensitizer (glucose-lowering agent), for the once-daily oral treatment of metabolic disorders, including diabetic dyslipidemia and hypertriglyceridemia . The company is also developing saroglitazar for the potential treatment of lipodystrophy, nonalcoholic steatohepatitis (NASH) and type II diabetes.

In June 2013, the Drug Controller General of India (DCGI) approved the drug for launch in India ; in September 2013, the drug was launched. In May 2014, a phase III trial for lipodystrophy was initiated . In January 2015, a phase III study for NASH was initiated .

In February 2015, phase III development was ongoing in type II diabetes . In November 2015, a phase II trial was planned in the US . In June 2016, the US FDA approved the company’s plan to initiate a phase II trial of saroglitazar in patients with NASH .

In June 2012, the company was seeking to outlicense the drug for regional/global partnerships.

By June 2012, an NDA filing had been made for dyslipidemia . In June 2013, the DCGI approved the drug for launch in India . By September 2013, the drug was launched for dyslipidemia and hypertriglyceridemia .

Saroglitazar was approved by the Drug Controller General of India (DCGI) on June 5, 2013. It was developed and marketed as Lipaglyn^® by Zydus cadila.

Saroglitazar is novel first in class drug which acts as a dual PPAR agonist at the subtypes α (alpha) and γ (gamma) of the peroxisome proliferator-activated receptor (PPAR). Agonist action at PPARα lowers high blood triglycerides, and agonist action on PPARγ improves insulin resistance and consequently lowers blood sugar. It is indicated for for the treatment of diabetic dyslipidemia and hypertriglyceridemia with type 2 diabetes mellitus not controlled by statin therapy.

Lipaglyn^® is available as tablet for oral use, containing 4 mg of free Saroglitazar. The recommended dose is 4 mg orally once daily.

Zydus-Cadila has developed and launched saroglitazar for treating diabetic dyslipidemia and hypertriglyceridemia.

In September 2013, saroglitazar was launched in India for treating dyslipidemia and hypertriglyceridemia.

As of March 2015, Zydus-Cadila is developing saroglitazar for treating nonalcoholic steatohepatitis and type II diabetes (both in phase III clinical trials).

str1

Saroglitazar (INN, trade name Lipaglyn) is a drug for the treatment of type 2 diabetes mellitus and dyslipidemia. It is approved for use in India by the Drug Controller General of India.^[1] Saroglitazar is indicated for the treatment of diabetic dyslipidemia andhypertriglyceridemia with type 2 diabetes mellitus not controlled by statin therapy. In clinical studies, saroglitazar has demonstrated reduction of triglycerides (TG), LDL cholesterol, VLDL cholesterol, non-HDL cholesterol and an increase in HDL cholesterol a characteristic hallmark of atherogenic diabetic dyslipidemia (ADD). It has also shown favorable Anti-diabetic medication property by reducing the fasting plasma glucose and HBA_1c in diabetes patients. The recommended dose of saroglitazar is one tablet of 4 mg once a day.

In February 2013, Saroglitazar became the first glitazar that has been approved by any FDA for clinical use. Saroglitazar is marketed under the trade name Lipaglyn and developed by Zydus Cadila. Saroglitazar (2 and 4 mg q.d.) is currently approved in India by Drug Controller General of India (DCGI ) for the management of diabetic dyslipidemia and hypertriglyceridemia in T2DM not controlled by statin therapy. Lipaglyn provides the option of a once-daily oral therapy for the patients suffering from diabetic dyslipidemia.

Saroglitazar has another first attached to it. It is the first indigenously developed NCE by any Indian company; in this case Zydus Cadila.

Lipaglyn is indicated 4 mg (or 2 mg where such a need arise) oral dose once daily.

Saroglitazar Synthesis

http://ayurajan.blogspot.in/2016/01/saroglitazar.html
WO2003009841A1:

Identification:

1H NMR (Estimated) for Saroglitazar

http://ayurajan.blogspot.in/2016/01/saroglitazar.html

Experimental: ¹H NMR: 1.14 (3H, t, J = 6.9Hz); 2.37 (3H, s); 2.48 (3H, s); 2.92-3.06 (2H, m); 3.32-3.42 (1H, m); 3.57-3.64 (1H, m); 3.9 (2H, t, J=6.36 Hz); 4.0 (1H, dd); 4.28(2H, t, J = 6.2 Hz); 5.9 (1H, d, J = 3.3 Hz); 6.08 (1H, d, J = 3.38 Hz); 6.6 (2H, d, J = 8.5Hz); 7.1(2H, d, J = 8.5Hz); 7.26 (2H, d, J = 8.4Hz); 7.3 (2H, d, J = 8.34Hz)

Synthesis

Details see below

Mechanism of action

Efficacy

Being a dual PPAR agonist, Saroglitazar (Lipaglyn) helps in controlling blood glucose and Lipid parameters especially high triglycerides and high non HDL-Cholesterol.^[3] Lipaglyn effectively reduces triglycerides and non HDL-C and controlles high blood sugar, a typical situation in Insulin Resistance condition.^[4]^[5]

Safety

Saroglitazar has not demonstrated any of the adverse effects like weight gain and edema that are usually identified with similar molecules like the glitazone class of drugs.^[6] Because it is an insulin sensitizer, Saroglitazar (Lipaglyn) has less potential for hypoglycemia. No major serious adverse events have been reported; however, long-term cardiovascular safety has not been established.^[7]

Saroglitazar, is a drug for the treatment of diabetic dyslipidemia and hypertriglyceridemia with Type 2 diabetes mellitus not controlled by statin therapy. Its trade name is Lipaglyn. It is also a 1,2-Diarylpyrroles derivative, which can be used in the preparation of Nonsteroidal anti-inflammatory drugs (NSAIDs).

References: Khanna, I. K., et al.: J. Med. Chem., 40, 1619 (1997)

PAPER

A new enantioselective synthesis of (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid esters (EEHP and IEHP), useful pharmaceutical intermediates of PPAR agonists
Tetrahedron Lett 2014, 55(21): 3223

http://www.sciencedirect.com/science/article/pii/S0040403914006200

PATENT

WO 2003009841

http://www.google.co.in/patents/WO2003009841A1?cl=en

PATENT

US 20030236254

http://www.google.com/patents/US20030236254

PATENT

US 20140099333

http://www.google.com/patents/US20140099333

PATENT

WO2014174524

http://patentscope.wipo.int/search/en/WO2014174524

(I)

The compound as claimed in claim 1 wherein R is -SMe and M⁺ is Mg⁺².

The compound of claim 1 is Saroglitazar.

PATENT

WO2014181362

http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014181362&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

3-Aryl-2-hydroxy propanoic acid derivatives serve as a key intermediate for the synthesis of many pharmaceutically important compounds especially, peroxime proliferator activated receptor (PPAR) agonist.

Optically active 3-aryl-2-alkoxy propanoic acid and its esters, particularly, ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (EEHP) and isopropyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (IEHP) are versatile chiral pharmacophores present in many pharmaceutically important compounds, especially in peroxisome proliferator activated receptor (PPAR) agonists that have beneficial effects in treating Type 2 diabetes.

Several PPAR agonists, in particular PPAR α/γ dual agonists, commonly termed as glitazars (Ragaglitazar, Tesaglitazar, Navaglitazar etc.), as shown in the figure below were developed by many pharmaceutical companies that have a potential application in the treatment of Type 2 diabetes and dyslipidemia.

However, many of these drugs were discontinued due to their undesirable side effects, but some of them still have great potential [For example, Saraglitazar (LipaglynTM) developed by Zydus Cadila got approval in India for the treatment of diabetic dyslipidemia or hypertriglyceridemia]. Several PPAR α/γ agonists possessing chiral (S)-l moieties are shown below.

Tesaglitazar Naveglitazar

In addition, these derivatives find an application in photosensitive materials, sweetening agents, treatment of certain eating disorders etc. Therefore, these compounds have attracted a great deal of attention of synthetic chemists and different methods of preparation of the compound of formula (S)-l have been extensively studied.

Generally, the reported protocols for the synthesis involve chiral pool approaches starting from L-tyrosine and its derivatives (Refer WO 02/24625, US 6559335B2, WO 2003/027084), asymmetric synthesis (Org. Lett. 2005, 7, 1947, US 2007/0149804) and resolution processes using chiral amines or enzymes (WO 2000/026200, WO 2001/11073, Org. Process Res. Dev. 2003, 7, 82, Org. Process Res. Dev. 2004, 8, 838, Tetrahedron Asymmetry 2009, 20, 2594).

Some of these methods have disadvantages such as expensive chiral starting materials and catalysts, low enantioselectivity and overall yields, problems associated with the O-alkylation step which often leads to the loss of optical purity, and many others.

The processes described in WO20026200 (Rao et. al.) uses benzyl bromide for benzylation, which is highly lachrymatory. Again, in the processes described, the debenzylation of the final intermediate was done by using Pd/C under pressure, which escalates the process economics.

WO2003024915 describes a process for the preparation 3-aryl-2-hydroxy propanoic acid derivatives from 3-(4-hydroxyphenyl)-2-oxopropanoic acid.

WO 2003008362 describes 3-Aryl-2-hydroxy propanoic acid derivatives of formula I and the preparation thereof.

wherein Rland R2 may be same or different and represent hydrogen or (CI- C6) alkyl.

The process is depicted in Scheme 1 below.

Scheme 1

In another process variant as in Scheme 2, WO’362 discloses a process for the preparation of novel 3-aryl-2 -hydroxy propanol and their derivatives of the formula (I)

wherein OR and OR together form a substituted or unsubstituted 5 membered cyclic structure containing carbon and oxygen atoms, which comprises: i) reducing the compound of formula (III) where R represents hydrogen or alkyl group, R3 represents benzyl to a compound of formula (IV) where R3 represents benzyl, ii) cyclizing the compound of formula (IV) to a compound of formula (V) where ORl and OR2 together form a substituted or unsubstituted 5 membered cyclic structure containing carbon and oxygen atoms and R3 represents benzyl and iii) debenzylating the compound of formula (V) in the presence of metal catalysts to yield pure compound of formula (I).

Scheme 2

Both the processes described in WO’362 result in poor overall yield and further fail to describe the preparation of compound of formula V using different alkylating agents. This document exemplifies the compound of formula V with similar ether groups as it fails to teach selective alkylation of formula IV.

WO2005019152 discloses an improved process for the preparation of compound of the general formula (la) and (lb).

Wherein, Rl represent H or (C1-C6) alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like. R2 represents (Ci-Ce) alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl and the like. R3 represents H, protecting groups such as benzyl, substituted benzyl, (C1-C3) alkyl and like.

The compound of general formula (la) is prepared according to the following schemes 3 and 4.

Scheme 3

Both the processes start with selective O-alkylation or O-aralkylation of L-Tyrosine of formula (2a) using a base, a chelating agent, an alkyl or aralkyl halide in the presence of solvents to obtain the compound of formula (3a), which is diazotized to obtain formula (4a) which upon dialkylation using an excess of alkylating agent and excess base, in presence of suitable solvent to obtain optically pure compound of formula (la). Alternatively, compound of formula (4a) may be selectively esterified to obtain compound of formula (5a), which is subsequently O-alkylated to obtain compound of formula (la) (Scheme 2).

However, the above processes have many disadvantages such as multistep synthesis including protection & deprotection and low overall yield. Further, low temperature diazotization on industrial scale is not viable. Moreover, the starting material is very expensive and hence escalates the process.

In the light of the foregoing, development of a new, alternate enantio-selective synthetic route to these important chiral intermediates, which are simple and can preserve the optical purity at the C-2 carbon of 3-Aryl-2-hydroxy propanoic acid derivatives, is highly desirable. There is a need for an efficient process for synthesis of 3-Aryl-2-hydroxy propanoic acid derivatives of formula (S)-l in high enantiopurity and good overall yield from commercially available starting material.

str1

OR

Synthesis of saroglitazar

1. 2-Bromo-1-[4-(methylthio)phenyl]ethanone is condensed with methyl acetoacetate in the presence of NaOMe and Na2SO4 in toluene, to give alpha-keto methyl ester ,

2. This alpha-keto methyl ester ,is hydrolyzed and decarboxylated by means of NaOH in MeOH/toluene at 50 °C giving diketone .

3. Diketone is subjected to Paal-Knorr reaction with ethanolamine in the presence of pivallic acid in toluene at 110 °C to yield pyrrole primary alcohol derivative .

4. Sulfonylation of this pyrrole primary alcohol with MsCl in the presence of Et3N,

5. O-alkylation of mesylate with ethyl 2(S)-ethoxy-3-(4-hydroxyphenyl)propionate in the presence of K2CO3, optionally in the presence of 18-crown-6 in toluene/THF at 80 °C provides ether.

6. Finally, hydrolysis of ethyl ester using NaOH in H2O affords the target saroglitazar.

PATENT

WO2015033357

saroglitazar magnesium alongwith its intermediates may be prepared by the reaction scheme- 1, scheme-2 and scheme-3 as shown below, which is also the scope of the present invention.

Scheme-1

EXAMPLES

Example-l:

Preparation of methanesulfonic acid 2-r2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol-l-yl]-ethyl ester (Al)

In a 5 Liter three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, sodium methoxide (165 g) and toluene (1000.0 ml) were added under nitrogen environment and cooled to 8°C to 12°C. Methyl acetoacetate (331.55 g) was added dropwise and stirred for 1 hour. 2-bromo-l-(4-methyl sulfonyl phenyl) ethanone (500.0 g) compound (El) in toluene (1500.0 ml) and sodium sulfate

(75.0 g) mixture was stirred for 10 min and filtered at 25° to 35°C. The filtrate as obtained was added dropwise into the previous reaction mixture and stirred at 30°C to 35°C for 30 min. The organic layer was collected and washed with 10% sodium bicarbonate solution. The separated organic layer was collected and washed with water. 2-[2-(4-Methyl sulfanyl-phenyl)-2-oxo-ethyl]-3-oxo-butynic acid methyl ester as obtained in toluene layer is diluted with methanol (2500 ml) and sodium hydroxide solution (89.75 g) in water (2500 ml) was added and heated to 50° to 55°C for 1 hour. The layers were separated and the toluene layer was collected and heated to 45° to 55°C and charcoalized. The reaction mixture was filtered and pivalic acid (57.3 g) and ethanol amine (143.9 g) were added and heated to 105° to 1 15°C for removing water azeotropically. The toluene layer was separated and triethyl amine (271.85 g) was added at 25° to 35°C and the reaction mixture was cooled to 10° to 20°C. Methane sulphonyl chloride (282.5 g) was added dropwise, and stirred for 2 hours and heated to 35° to 45°C. The reaction mixture was filtered and washed with toluene. Toluene was distilled out completely under the vacuum to obtain the residue. The residue was dissolved in toluene (1500 mL) and used for further process.

ExampIe-2:

Preparation of methanesulfonic acid 2-f2-methyl-5-(4-methylsulfanyl-pheny0-pyrrol- 1-viyethyl ester (Al)

In a 250 mL three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 4-(methylthio)benzaldehyde (10 g), methyl vinyl ketone (3.63 g), triethylamine (9.95 g) and 3-methyl-5-(2-hydroxyethyl)-4-methyI thiazolium iodide (stetter

catalyst) (2.8 g) were heated to 70°C to 80°C and maintained overnight. The reaction mixture was cooled to room temperature and ethanol (100 mL) was added. The reaction mixture was stirred for 30 min and filtered. The product was washed with ethanol and dried to obtain 1 ,4-diketo compound (CI).

1 ,4-diketo compound (CI) obtained above and toluene (50 mL) were heated to 45° to 55°C and charcoalized. The reaction mixture was filtered and pivalic acid (5.7 g) and ethanol amine (14.4 g) were added and heated to 105° to 1 15°C and cooled to 25°C. Triethyl amine (27.2 g) was added at 25° to 35°C and the reaction mixture was cooled to 10° to 20°C. Methane sulphonyl chloride (28.3 g) was added dropwise, and stirred for 2 hours and heated to 35° to 45°C. The reaction mixture was filtered and washed with toluene. Toluene was distilled out completely under the vacuum, methanol (2500 ml) was added and heated to 55° to 65 °C and charcoalized for 30 min. The reaction mixture was filtered and washed with methanol. The reaction mixture was cooled to 25° to 35°C and stirred for 30 min. Reaction mass was further cooled to -5° to 5°C and filtered. The wet-cake was washed with methanol and dried to obtain compound (Al). The compound (Al) was characterized as crystalline solid by x-ray powder diffraction (FIG.2).

Example-3:

Purification of methanesulfonic acid 2-r2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol-l-yl]-ethyl ester (Al)

In a 250 mL three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 70 g methanesulfonic acid 2-[2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol-l -yl]-ethyl ester (Al) and 420 mL ethyl acetate were added at 25°C. The reaction mixture was stirred for 30 min to obtain clear solution. 3.5 g charcoal was added and stirred for 30 min. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated and 315 mL methanol was added. The reaction mixture was stirred for 2 hours at 25°C and cooled to 0°C. The product precipitated was filtered and washed with methanol to obtain crystalline

compound (Al). The compound (Al) was characterized as crystalline solid by x-ray powder diffraction (FIG.3).

Example-4:

Preparation of saroglitazar magnesium (T)

In a 5 Liter three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (A) (100.0 g) and toluene (1300.0 ml) were charged and reaction mixture was heated to 45° to 55°C. Potassium carbonate (58.0 g) was added and stirred for 30 min. Toluene solution of methanesulfonic acid 2-[2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol- 1 -yl]-ethyl ester (Al) (150.24 g) obtained in example- 1, 18-Crown-6 (5.0 g) and THF (200.0 ml) were added and heated to 75°C to 85°C for 36 hour, The reaction mixture was cooled to 25° to 35°C and water (1000.0 ml) was added and stirred for 15 min. The separated aqueous layer was treated with toluene (200.0 ml) and stirred for 15 min. The organic, layers were combined and washed with caustic solution (600.0 ml). The separated organic layer was washed with water (600.0 ml) and characoalized with HP-120 (5.0 g) charcoal and stirred for 30 min and filtered. The filtrate was added sodium hydroxide 20.14 g solution in water (200.0 ml) and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with water (1800.0 ml) and stirred for 15 min. The separated aqueous layer was washed with n-butyl acetate. The separated aqueous layer was added magnesium acetate tetrahydrate solution (90.0 g) in water (100.0 ml) and stirred for 1 hour. The aqueous layer was extracted with methylene dichloride (2000 ml). The separated organic layer was washed with sodium chloride solution and charcoalized. The charcoalized solution was filtered and filtrate was distilled to remove toluene completely. The residue was diluted with toluene (1000 ml) and stirred for 30 min. The organic solution was added into n-heptane (1500 mL) and stirred for 3 hours. The product was filtered and washed with n-heptane and dried in vacuum tray dryer at 25°C to 30°C for 3 hours. The product was sieved through 0.5 mm sieve and milled through jet-milled. The product was further dried in vacuum tray drier at 40°C to 50°C for 6 hours followed by drying at 55°C to 65°C for 40 hours to obtain amorphous saroglitazar magnesium (I). The compound is characterized by x-ray power diffraction (FIG.l).

The reaction of methanesulfonic acid 2-[2-methyl-5-(4-methylsulfanyl-phenyl)-pyrrol-l-yl]-ethyl ester (Al) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (A) may also be performed in similar manner as above in absence of phase transfer catalyst 18-Crown-6.

ExampIe-5:

Preparation of saroglitazar (S)-(-)-phenyl ethylamine salt:

In a 250 mL three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, residue-A obtained in example- 1 and ethanol (400 mL) were stirred for 15 min. Sodium hydroxide 20.14 g solution in water (200.0 ml) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with water (1800.0 ml) and stirred for 15 min. The separated aqueous layer was washed with isopropyl acetate (400 mL). The separated aqueous layer was diluted with isopropyl acetate (500 mL) and acidified with cone. HCI at adjust the pH 2-3. The separated aqueous layer was washed with isopropyl acetate. The combined organic layer was treated with (S)-(-)-phenyl ethylamine (55.94 g) and stirred for 2 hours at 25°C and 30 min at 45°C. The reaction mixture was cooled to 0°C and stirred for 2 hours, filtered and washed with isopropyl acetate. The wet-cake was dried to obtain saroglitazar phenyl ethylamine salt.

ExampIe-6:

Preparation of saroglitazar magnesium from saroglitazar (SH-)-phenyl ethylamine salt:

In a 250 mL three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, saroglitazar phenyl ethylamine wet-cake obtained in example-7 and isopropyl acetate (800 mL) were added at 25°C. The reaction mixture was diluted with water (400.0 ml) and acidified with cone. HCI at adjust the pH 2-3. The separated aqueous layer was washed with isopropyl acetate. The combined organic layer was treated with sodium hydroxide solution (20.14 g) in water (200 mL) and stirred for 30 min. The separated aqueous layer was treated with magnesium acetate tetrahydrate (2.29 g) in water (5 mL) solution and stirred for 60 min. The reaction mixture was extracted with methylene dichloride (800 mL). The methylene dichloride was complete removed by distillation under vacuum below 40°C to obtain the residue. The residue was diluted with methylene dichloride (50 ml) and stirred for 30 min. The organic solution was added into n-heptane (1500 mL) and stirred for 3 hours. The product was filtered and washed with n-heptane and dried in vacuum tray dryer at 25°C to 30°C for 3 hours. The product was sieved through 0.5 mm sieve and milled through jet-milled. The product was further dried in vacuum tray drier at 40°C to 50°C for 6 hours followed by drying at 55°C to 65°C for 40 hours to obtain substantially amorphous saroglitazar magnesium (I). The compound is characterized by x-ray power diffraction (FIG.l).

PATENT

WO 2015029066

Dwivedi, Shri Prakash Dhar; Singh, Ramesh Chandra; Patel, Vikas; Desai, Amar Rajendra

Cadila Healthcare Ltd

Polymorphic form of pyrrole derivative and intermediate thereof

Pyrrole derivative of present invention is chemically 2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy)pKenyl)propanoate, which may be optically active or racemic and its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof. The INN name for pyrrole derivative is Saroglitazar® which is magnesium salt of pyrrole compound of Formula (I), having below chemical structure.

The present invention relates to Saroglitazar free acid of Formula (IA) or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable esters, stereoisomers, tautomers, analogs and derivs. thereof. The present invention also provides an amorphous form of saroglitazar free acid and processes of prepn. thereof. The present invention also provides pharmaceutical compn. comprising an amorphous form saroglitazar magnesium.

Amorphous forms of saroglitazar free acid and its salt form are claimed. Also claims the process for the synthesis the same compound. Useful for treating obesity, hyperlipidemia and hypercholesteremia. Picks up from WO2015011730, claiming the stable composition comprising saroglitazar magnesium or its derivatives. Zydus-Cadila has developed and launched saroglitazar for treating diabetic dyslipidemia and hypertriglyceridemia.

In September 2013, saroglitazar was launched for treating dyslipidemia and hypertriglyceridemia.

As of March 2015, Zydus-Cadila is developing saroglitazar for treating nonalcoholic steatohepatitis and type II diabetes (both in phase III clainical trials).

Pyrrole derivative of present invention is chemically 2-ethoxy-3-(4-(2-(2-methyl- 5-(4-(methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy)ph’enyl)propanoate, which may be optically active or racemic and its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof. The INN name for pyrrole derivative is Saroglitazar® which is magnesium salt of pyrrole compound o f saroglitazar,

the process comprising: 5WO 2015/029066 PCT/IN2014/000551 (a) dissolving saroglitazar magnesium of Formula (I) in one or more organic solvents to obtain a solution, (b) adding the solution in one or more o f anti-solvent at temperature from about -80°C to about 150°C to obtain saroglitazar magnesium o f Formula (I); and (c) obtaining the amorphous saroglitazar magnesium by removal of anti-solvent.

Example-1: Preparation of saroglitazar magnesium (Ί) In a 5 Liter three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 2-ethoxy-3-(4-hydroxy-phenyl)- propionic acid ethyl ester (A) (100.0 g) and cyclohexane (1300.0 ml) were charged and reaction mixture was heated to 45° to 55°C. Potassium carbonate (58.0 g) was added and stirred for 30 min. methanesulfonic acid 2-[2-methyl-5-(4-methyIsulfanyl-phenyl)-pyrroll-yl]-ethyl ester (A l) (150.24 g) and THF (200.0 ml) were added and heated to 75°C to 85°C for 36 hour. The reaction mixture was cooled to 25° to 35°C and water (1000.0 ml) was added and stirred for 15 min. The separated aqueous layer was treated with cyclohexane (200.0 ml) and stirred for 15 min. The organic layers were combined and washed with caustic solution (600.0 ml). The separated organic layer was washed with water (600.0 ml) and characoalized with (5.0 g) charcoal and stirred for 30 min and filtered. The filtrate was distilled to remove cyclohexane and the residue was collected (residue-A). The residue-A as obtained was treated with ethanol (400.0 ml) and stirred for 15 min. Sodium hydroxide 20.14 g solution in water (200.0 ml) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with water (1800.0 ml) and stirred for 15 min. The separated aqueous layer was washed with n-butyl acetate. The separated aqueous layer was added magnesium acetate tetrahydrate solution (90.0 g) in water (100.0 ml) and stirred for I hour. The aqueous layer was extracted with methylene dichloride (200 ml). The separated organic layer was washed with sodium chloride solution and charcoalized. The charcoalized solution was filtered and filtrate was distilled to remove methylene dichloride completely. The residue was diluted with methylene dichloride (1000 ml) and stirred for 30 min. The organic solution was added into n-heptane (1500 mL) and stirred for 3 hours. The product was filtered and washed with n-heptane and dried in vacuum tray dryer at 25°C to 30°C for 3 hours. The product was sieved through 0.5 mm sieve and milled through jet-milled. The product was further dried in vacuum tray drier at 40°C to 50°C for 6 hours followed by drying at 55°C to 65°C for 40 hours to obtain substantially amorphous saroglitazar magnesium (I). The compound is characterized by x-ray power diffraction (FIG.I).

PATENT

WO/2015/011730

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015011730

The present invention relates to the stable pharmaceutical composition of a suitable hypolipidemic agent. Preferably, the present invention discloses novel formulations of the compound of formula (I), or pharmaceutically acceptable salts of compounds of formula (I). More particularly the present invention relates to the stable pharmaceutical composition of compounds of formula (I) comprising compounds of formula (I) or its pharmaceutically acceptable salts, wherein the pH of the formulation is maintained above 7. formula (I)

The compounds of formula (I) are new synthetic compounds having hypolipidemic activity. The compounds of formula (I) are used primarily for triglyceride lowering, with concomitant beneficial effect on glucose lowering and cholesterol lowering.

The structural formula of compounds of formula (I) is shown below.

wherein ‘R’ is selected from hydroxy, hydroxyalkyl, acyl, alkoxy, alkylthio, thioalkyl, aryloxy, arylthio and M⁺ represents suitable metal cations such as Na⁺, K⁺, Ca⁺², Mg⁺² and the like. Preferably, R is selected from alkylthio or thioalkyl groups; most preferably R represents -SCH₃.The Mg⁺² salt is preferred. The compounds of formula (I) are generally insoluble in water, but freely soluble in dimethyl sulfoxide, dichloromethane & slightly soluble in methanol and IPA.

1H NMR PREDICT

13c NMR PREDICT

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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O=C(O)[C@@H](OCC)Cc3ccc(OCCn1c(ccc1C)c2ccc(SC)cc2)cc3

REFERENCES

“Zydus Group launches new diabetic drug”. The Times of India. Jun 6, 2013.
“Lipaglyn (Saroglitazar) for Treating Hypertriglycerdemia in Type II Diabetes, India”. Drug Development and Technology.
“The nuances of atherogenic dyslipidemia in diabetes: focus on triglycerides and current management strategies.”. Indian Heart Journal.
“Observational Study of Effects of Saroglitazar on Glycaemic and Lipid Parameters on Indian Patients with Type 2 Diabetes”. SCIENTIFIC REPORTS.
“From ‘Make in India’ to ‘Made in India’: the saroglitazar story.”. Indian Heart Journal.
“Observational study to evaluate the safety and efficacy of saroglitazar in Indian diabetic dyslipidemia patients.”. Indian Heart Journal.
Munigoti, SrinivasaP; Harinarayan, CV (2014). “Role of Glitazars in atherogenic dyslipidemia and diabetes: Two birds with one stone?”. Indian Journal of Endocrinology and Metabolism 18 (3): 283. doi:10.4103/2230-8210.131134. PMC 4056123.PMID 24944919.

Indian Pat. Appl. (2015), IN 2013MU02905

WO 2015033357

WO 2015150565

WO 2015001573

IN 2013MU02828

WO 2015029066

IN 2013MU01910

Cited Patent	Filing date	Publication date	Applicant	Title
WO2003009841A1 *	Jul 25, 2002	Feb 6, 2003	Cadila Healthcare Ltd	Novel pyrroles having hypolipidemic hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them and their use in medicine
WO2012104869A1	Jan 30, 2012	Aug 9, 2012	Cadila Healthcare Limited	Treatment for lipodystrophy
INMU19102013A				Title not available
US6987123	Aug 10, 2001	Jan 17, 2006	Cadila Healthcare Limited	Heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine
US7041837	Jul 19, 2002	May 9, 2006	Cadilla Healthcare Limited	Heterocyclic compounds having hypolipidemic, hypocholesteremic activities process for their preparation and pharmaceutical compositions containing them and their use in medicine
US7323491	Mar 1, 2004	Jan 29, 2008	Cadila Healthcare Limited	Heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine
US8110598		Feb 7, 2012	Cadila Healthcare Limited	Heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine
US8212057	Jul 25, 2002	Jul 3, 2012	Cadila Healthcare Limited	Pyrroles having hypolipidemic hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them and their use in medicine
US20110275669		Nov 10, 2011	Cadilla Healthcare Limited	Novel pyrroles having hypolipidemic hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them and their use in medicine

Zydus Cadila chairman and MD Pankaj R. Patel (centre) and deputy managing director Sharvil P. Patel (left) in Mumbai on Wednesday. (PTI)JUNE 5, 2013

Cadila banks on diabetes drug
Calcutta Telegraph
It generally takes around 10-15 years for a drug to be developed from the time of its discovery In the case of Lipaglyn, the molecule was identified in 2001, and Phase III clinical trials was completed around four years ago. While Zydus has not yet …http://www.telegraphindia.com/1130606/jsp/business/story_16976915.jsp

Mumbai, June 5: Cadila Healthcare will launch a homegrown drug against diabetes by the third quarter of this year.

The Drug Controller General of India has approved its drug — Lipaglyn — to treat “diabetic dyslipidemia”.

Diabetic dyslipidemia is a condition where a person is diabetic and has elevated levels of total cholesterol. Over 80 per cent of diabetic patients are dyslipidemic.

http://www.telegraphindia.com/1130606/jsp/business/story_16976915.jsp

Zydus Cadila said it is looking for partnership to market its new chemical entity (NCE) Lipaglyn, to be used for treating a type of diabetes in developed and developing markets. “Lipaglyn is the first glitazar to be approved in the world and the first NCE discovered and developed indigenously by an Indian pharma company.

The new drug is expected to be launched in Q3 of this fiscal in the country,” Zydus Cadila Chairman and Manging Director Pankaj Patel told reporters.

The company has spent USD 250 million in developing Lipaglyn and aims to spend another USD 150-200 million to launch the drug in overseas markets in next 3-5 years period, Patel said, adding that the company is looking for marketing partnerships.

“We expect this to be a blockbuster drug, which means over USD 1 billion sales a year, when the drug is sold globally, he said. The market for this drug is estimated at Rs 100 crore in the local market over the next three years and having market potential size of over USD 30 billion in the world market, he said.

Zydus Cadila took about eight years to develop the molecule and conducted clinical trials on more than 1,000 patients in India, Patel said, adding that the company is yet to finalise the price, but believes that it will be reasonably priced in the local market.

The company said that the Indian drug regulator Drug Controller General of India (DCGI) has approved Lipaglyn to be used for treating ‘diabetic dyslipidemia’.

Saroglitazar
Systematic (IUPAC) name

(2S)-2-Ethoxy-3-[4-(2-{2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrol-1-yl}ethoxy)phenyl]propanoic acid
Clinical data
Trade names	Lipaglyn
Pregnancy category	C
Legal status	Approved in India
Routes of administration	Oral
Identifiers
CAS Number	495399-09-2
ATC code	None
PubChem	CID 60151560
ChemSpider	32079086
Chemical data
Formula	C₂₅H₂₉NO₄S
Molar mass	439.56 g/mol

by WORLD DRUG TRACKER
DR ANTHONY

do not miss out on updates

see my update at https://newdrugapprovals.org/2015/03/09/saroglitazar-magnesium-new-patent-wo-2015029066-cadila-healthcare-ltd/ 9 may 2015

SEE.https://newdrugapprovals.org/2016/02/18/zydus-cadilas-lipaglyn-saroglitazar-won-a-lot-of-support-at-the-75th-anniversary-conference-of-the-american-diabetes-association/

Lipaglyn (Saroglitazar) won a lot of support at the 75th Anniversary Conference of the American Diabetes Association. Lipaglyn is currently under Phase III clinical development for treatment of Non Alcoholic SteatoHepatitis (NASH), a serious liver disease and an unmet healthcare need, globally. There is currently no drug approved for treating NASH. Lipaglyn is already approved in India for the treatment of diabetic dyslipidemia

Zydus Group

Speaking on the development, Mr. Pankaj R. Patel, Chairman and Managing Director, Zydus Cadila said, “These new robust scientific data on the safety and efficacy of Lipaglyn
(Saroglitazar) being presented at the 75^th Annual Scientific Sessions of the American Diabetes Association (ADA) reflect our continued commitment to millions of patients living with Diabetes, Dyslipidemia, Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH).”

Zydus Cadila, a leading global healthcare provider, today announced that new scientific and clinical data on Saroglitazar will be presented at the 75th Annual Scientific Sessions of the American Diabetes Association (ADA) in Boston, Massachusetts, USA from 5^thto 9^th June, 2015. Several analyses of real-world patient data of Saroglitazar will also be presented. The abstracts are available on theADA website.

Lipaglyn – The world’s first drug for treating Diabetic Dyslipidemia combines lipid and glucose lowering effects in one single molecule.

Pankaj Patel, chairman and MD, Cadila Healthcare Ltd

Zydus is an innovation-led global healthcare provider that discovers, manufactures and markets a broad range of healthcare therapies. The group employs over 19,000 people worldwide including over 1200 scientists engaged in research and is dedicated to creating healthier communities globally.

With a strong research pipeline of NCEs, biologics and vaccines, the group became India’s first pharmaceutical company to launch its own indigenously researched therapy Lipaglyn which is also the world’s first approved therapy for diabetic dyslipidaemia. Exemptia, the world’s first biosimilar of Adalimumab is also a product of Zydus innovation. Zydus also collaborates with partners to support and make therapies affordable and accessible to communities across the world.

As a leading healthcare provider, it aims to become a global research-based pharmaceutical company by 2020.

Zydus Group

Zydus Group

Lipaglyn (Saroglitazar) sparkled bright at the first ever Indian Heart Journal Award Ceremony at the Cardiological Society of India’s Annual Conference, Chennai attended by a galaxy of leading cardiologists from across India.

Pankaj R. Patel (left), Chairman & Managing Director, Zybus Cadila,

Ganesh Nayak, Chief Operating Officer and Executive Director, Zydus Cadila

Zydus Cadila has announced a breakthrough in the anti-diabetic drug Lipaglyn. Lipaglyn – The world’s first drug for treating Diabetic Dyslipidemia combines lipid and glucose lowering effects in one single molecule.

The Zydus Group announced a breakthrough in its research efforts with Lipaglyn (Saroglilazar), a novel drug targeted at bridging an unmet healthcare need for treating Diabetic Dyslipidemia or Hypertriglyeeridemia in Type II diabetes, not controlled by statins alone. The drug has been approved for launch in India by the Drug Controller General of India (DCGI). With a novel action that offers lipid and glucose lowering effects in one molecule, Lipaglyn is the first Glitazar to be approved anywhere in the world.
“Lipaglyn provides patients suffering from diabetic dyslipidemia the option of a once-daily oral therapy that has a beneficial effect on both lipid parameters as well as glycemic control,” said Pankaj R. Fatel, Chairman and Managing Director, Zydus Cadila. “It has always been our dream to take a molecule right from the concept stage up to its launch. Today, we have realized this dream. It is an important breakthrough and I would like to dedicate this to all the Indian research scientists in the Held of drug discovery,” Patel added,
Diabetic Dyslipidemia is a condition where a person is diabetic and has elevated levels of the total cholesterol, the “bad” low-density lipoprotein (LDL) cholesterol and the triglycerides and a decrease in the “good” high-density lipoprotein (HDL) cholesterol concentration in the blood. Optimal LDL cholesterol levels ibr adults with diabetes are less than 100 mg/dh, optimal HDL cholesterol levels are equal to or greater than 40 mg/dL, and desirable triglycerides levels are less than 150 mg/dLT LipaglynrM, a non-thiazoKdinedione, is the first therapy to be approved for this condition,
World over, it is estimated that 30% of all deaths occur due lo cardiovascular diseases (CVD). In India, one out of every five persons is at serious risk of developing CVD, Research has shown that diabetes is one of the major risk factors of CVD. India has a population of nearly 65 million diabetics and 77 million prc-diabctics, 85 – 97% of the diabetes patients suffer from dyslipidemia or lipid abnormalities. Hence, addressing the problem of diabetes and dyslipidemia is crucial in tackling the health risk posed by CVD.
Discovered by the Zydus Research Centre, the dedicated NCE research arm of the Zydus group, LipaglynrM is a best-in-class innovation, designed to have a unique cellular mechanism of action following an extensive structure-activity relationship study initiated in the year 2000, Lipaglyn1M has a predominant affinity to PPAR alpha isoform and moderate affinity to PPAR gamma isoform of PPAR nuclear receptor subfamily. The molecule has shown beneficial effects on lipids and glyeemic control without side effects. This molecule underwent extensive pre-clinical characterisation and the I.ND was submitted in the year 2004,
As a part of the clinical development programme, extensive Phase-I, Phase-II and Phase-Ill clinical trials were conducted to evaluate the phamacokinetics, pharmacodynamics, efficacy and safety of Lipaglyn. The new drug application for Lipaglyn1 was based on a comprehensive clinical development programme spanning eight years.
Results from the first Phase III programme with Pioglitazone as a comparator drug in diabetes patients showed that the 4 mg dose of Lipaglyn led to a reduction of triglycerides and LDL (bad) cholesterol, and an increase in HDL (good) cholesterol and also showed a reduction in Fasting Plasma Glucose and glycosylated haemoglobin (HbAlc) thereby confirming its beneficial effects of both lipid and glyeemic control in diabetic patients,
In the second Phase III study, Lipaglyn was studied in diabetic dyslipidemic patients insufficiently controlled with statin therapy. The results from this study confirmed that Lipaglyn had a pronounced beneficial effect on both the lipid and glyeemic parameters in these subjects.
In both the studies, Lipaglyn was well tolerated and had a better safety profile than the comparators. Importantly Lipaglyn1 M has a non-renal route of elimination, and did not show adverse events like edema, weight gain, myopathies or derangement of liver and/or kidney functions, thus making it sale and efficacious. LipaglynIM is recommended for once daily administration as 4 mg tablets.
Zydus will offer a dedicated LipaglynIM support programme to patients and earegivers, The programme shall provide important support and information regarding access, adherence, education and thereby help patients to start and appropriately manage their disease and therapy over time.

About Lipaglyn

Lipaglyn^[^TM^] (Saroglitazar) was launched in September 2013 in India, for treating Hypertriglyceridemia and Diabetic Dyslipidemia in Patients with Type 2 Diabetes not controlled by statins. Since then, more than 80,000 patients are availing this drug with a prescriber base over 3500 diabetologists, cardiologists and physicians. Lipaglyn^[^TM^] helps in a reduction of triglycerides and LDL (bad) cholesterol, and an increase in HDL (good) cholesterol and has also shown a reduction in Fasting Plasma Glucose and glycosylated haemoglobin (HbA1c), thereby confirming its beneficial effects on both lipid and glycemic control in diabetic patients. Lipaglyn^[^TM^] is a prescription medicine, and can be taken only under the advice and guidance of a registered medical practitioner.

About Zydus

Zydus Cadila is an innovative, global pharmaceutical company that discovers, manufactures and markets a broad range of healthcare therapies, including small molecule drugs, biologic therapeutics and vaccines. The group employs over 16,500 people worldwide including over 1200 scientists engaged in R & D and is dedicated to creating healthier communities globally. As a leading healthcare provider, it aims to become a global research based pharmaceutical company by 2020.

References

Zydus to present new scientific data on Lipaglyn in the US

New Delhi, Jun 8 (UNI) Healthcare services provider, Zydus Cadila today said the new scientific and clinical data on Lipaglyn (Saroglitazar) will be presented at the 75th annual scientific sessions of the American Diabetes Association (ADA) in Boston, Massachusetts, US from 5th to 9th June,2015.
Read more at http://www.uniindia.com/news/business-economy/zydus-to-present-new-scientific-data-on-lipaglyn-in-the-us/84440.html

READ …..https://newdrugapprovals.org/2013/06/07/cadila-banks-on-diabetes-druglipaglynsaroglitazar/

SEE…..https://newdrugapprovals.org/2015/03/09/saroglitazar-magnesium-new-patent-wo-2015029066-cadila-healthcare-ltd/

http://lipaglyn.com/downloads/Lipaglyn_Product_Monograph.pdf

http://www.ijpcs.net/sites/default/files/IJPCS_3_1_02_0.pdf

http://zyduscadila.com/wp-content/uploads/2015/08/Saroglitazar-in-Diabetic-Dyslipidemia-1-Year-Data.pdf

http://onlinelibrary.wiley.com/doi/10.1002/prp2.136/pdf

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CCO[C@@H](Cc1ccc(cc1)OCCn2c(ccc2c3ccc(cc3)SC)C)C(=O)O

CCOC(CC1=CC=C(C=C1)OCCN2C(=CC=C2C3=CC=C(C=C3)SC)C)C(=O)O

Vismodegib

February 16, 2016 7:52 am / Leave a comment

Vismodegib

2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide

Vismodegib; 879085-55-9; GDC-0449; 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide; Erivedge; HhAntag691; CUR-691
GDC-449
Hh-Antag691
HhAntag
R-3616
RG-3616

421.29706 g/mol

C₁₉H₁₄Cl₂N₂O₃S

LAUNCHED 2012

Vismodegib is a Hedgehog Pathway Inhibitor. The mechanism of action of vismodegib is as a Smoothened Receptor Antagonist.

Hedgehog Antagonist GDC-0449 is an orally bioavailable small molecule with potential antineoplastic activity. Hedgehog antagonist GDC-0449 targets the Hedgehog signaling pathway, blocking the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog signaling. The Hedgehog signaling pathway plays an important role in tissue growth and repair; aberrant constitutive activation of Hedgehog pathway signaling and uncontrolled cellular proliferation may be associated with mutations in the Hedgehog-ligand cell surface receptors PTCH and SMO.

NMR from net

Vismodegib is an active pharmaceutical ingredient produced by Genentech (Roche) and sold under the trade name Erivedge® (which contains crystalline Vismodegib as the active ingre-dient). Erivedge® is an oral Hedgehog signaling pathway inhibitor approved for the treatment of basal-cell carcinoma (BCC).

Developed and launched by Roche and its subsidiary Genentech, under license from Curis. Family members of the product Patent of vismodegib (WO2006028958),

Vismodegib was first disclosed in WO Patent Publication No. 06/028959. Vismodegib, chem-ically 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide, is represented by the following structure:

Vismodegib (trade name Erivedge) is a drug for the treatment of basal-cell carcinoma (BCC). The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administration (FDA) approval.^[1] The drug is also undergoing clinical trials for metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma as of June 2011.^[2] The drug was developed by thebiotechnology/pharmaceutical company Genentech, which is headquartered at South San Francisco, California, USA.

Indication

Vismodegib is indicated for patients with basal cell carcinoma (BCC) which has metastasized to other parts of the body, relapsed after surgery, or cannot be treated with surgery or radiation.^[3] ^[4]

Mechanism of action

The substance acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the hedgehog signaling pathway.^[2] SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway.^[5] This pathway is pathogenetically relevant in more than 90% of basal-cell carcinomas.^[6]

PAPER

Bioorg Med Chem Lett 2009, 19(19): 5576

http://www.sciencedirect.com/science/article/pii/S0960894X10012709

Figure 1.

Schematic for the discovery of 2 (GDC-0449) from 1, and the inspiration for further analogs 3 and 4

CN 103910671

http://www.google.com/patents/CN103910671A?cl=en

In embryonic development, Hedgehog signaling in cell differentiation, tissue development and organogenesis play an important role. In the adult body, Hedgehog signaling pathway is mainly in slumber, but when abnormal tissue growth and self-healing, Hedgehog pathway may be activated. With the in-depth study of the tumor, the presence of numerous evidence of abnormal tumor occurrence and the close relationship between Hedgehog signaling pathway, such as sporadic basal cell carcinoma, medulloblastoma, small cell lung cancer and gastrointestinal cancer and other diseases, therefore Hedgehog signaling pathway targeted anti-cancer therapy inhibitors become hot.

Vismodegib chemical name 2_ chlorine -N_ (4_ chlorine _3_ (_2_ pyridyl) phenyl) _4_ (methylsulfonyl) benzamide, is by Roche’s Genentech (Genentech) Hedgehog pathway inhibitors developed, and can be inhibited by binding seven transmembrane protein Smoothened (Smo), thereby preventing signal transduction. Vismodegib capsule in January 2012 I was approved and listed by the US Food and Drug Administration, under the trade name Erivedge, for the treatment of adults with the most common type of skin cancer – basal cell carcinoma. This medicine is not intended for surgery or radiotherapy of cancer and basal cell skin cancer locally advanced patients have been transferred. This was the first drug approved for the treatment of basal cell carcinoma.

W02006028958 Vismodegib disclose the following synthesis route:

Route One Negishi coupling reactions

wherein, X1 is chloro, bromo or iodo; X2 is bromo, iodo or tosylate. The route to the 2-halo-pyridine as starting material an organic zinc compound, and then prepared by Negishi coupling reaction to give 2- (2-chloro-5-nitrophenyl) pyridine. 2- (2-chloro-5-nitrophenyl) pyridine in turn through a reduction reaction with acylation reaction, to give the final product Vismodegib. The key coupling step of the route using an organic zinc reagent required to react under strict anhydrous, anaerobic conditions.

The second route Suzuki coupling reaction [0010]

wherein, X2 is bromo, iodo or tosylate. The route from 3-halo-4-chloro-nitrobenzene as raw material, and 2-chloro-5-nitrophenyl boronic acid pinacol ester, and then reacted with a 2-halo-pyridine was prepared to give 2- (2-chloro 5-nitrophenyl) pyridine. 2- (2-chloro-5-nitrophenyl) pyridine then after reduction and acylation reaction, to give the final product Vismodegib. The key coupling step of the route using the Suzuki coupling reaction, organic boron reagent price to use expensive, high production costs.

The route three Suzuki coupling reaction

wherein, X2 is bromo, iodo or tosylate. Similar to the second route, the route is still critical coupling step using a Suzuki coupling reaction, the same need to use expensive organic boron reagents, higher production costs.

route four Stille coupling reaction

The route to 2-p-toluenesulfonyl pyridine as starting material, is reacted with an organotin reagent, prepared to give pyridin-2-yl trimethyltin, then by Stille coupling reaction, was prepared to give 2- (2-chloro – 5- nitrophenyl) pyridine, followed by reduction reaction, acylation prepared to give Vismodegib. The key step of the route using the Stille coupling reaction, this step need to use expensive and toxic organotin reagents, and the need to carry out the reaction under strict anhydrous, anaerobic conditions.

A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising: a compound of formula III was prepared as a compound of Formula II;

Then, the compound of formula II with a compound of formula I, to give 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide;

Wherein, R1 is halogen or hydroxy, preferably chlorine, or a hydroxyl group.

2. A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising:

Wherein, X is halogen, preferably bromo or iodo condition is halo or hydroxy, preferably chlorine, or a hydroxyl group.

3. A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising:

Wherein, X is halogen, preferably bromo or iodo condition is halo or hydroxy, preferably chlorine, or a hydroxyl group.

Method 2 or claim 3,

Example 1: N–oxo-2- (2-chloro-5-nitrophenyl) pyridine

[0108] To a 100mL three-necked flask were added 30mmoll- oxopyrido, 10mmol2- bromo-1-chloro-4-nitrobenzene, 12mmol potassium carbonate, 0.05mmol tri-butyl acetate button and 0.15mmol phosphorus tetrafluoroborate salt, 40ml of toluene, IS gas exchange three times, under argon at reflux for 2 days, then the reaction mixture was poured into 100mL of ethyl acetate, filtered, and the filtrate was washed with saturated brine, dried and the solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: methanol / dichloromethane = 1/50), fractions were collected and the solvent was distilled off under reduced pressure to give a pale yellow solid, yield 60%.

1HMffi (500Hz, DMS0_d6): 8.35 (m, 3H), 7.90 (d, 1Η), 7.62 (q, 1Η), 7.55 (m, 1Η), 7.48 (m, 1Η);

MS: 251.1,253.1 ([Μ + Η] +).

2 Example: Ν–oxo-2- (2-chloro-5-nitrophenyl) pyridine

To a 100mL three-necked flask 30mmoll- oxopyrido, 10mmol2- bromo-1-chloro-4-nitrobenzene, 12mmol of potassium carbonate, 0.05mmol iodide and 0.1Ommoll, 10- Fei Luo Jie morpholine, 40ml of xylene, an argon gas exchange three times, under argon at reflux for 2 days, cooled to room temperature and then the reaction system was poured into 100mL methylene chloride, filtered and the filtrate washed with saturated brine, dried, filtered, The filtrate solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: methanol / dichloromethane = 1/50) to give a pale yellow solid, yield 42%. .

3 Example: 2- (2-chloro-5-nitrophenyl) pyridine

After 3.0mmol N- oxo added to 100mL of Lord vial _2_ (2_ chloro _5_ nitrophenyl) pyrazole 唳, 15mmol phosphorus trichloride and 30ml of chloroform was heated at reflux for 12h, the reaction It was poured into 100mL of water and extracted with ethyl acetate (50ml X 2), and the combined organic phase was dried and the solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: petroleum ether / ethyl acetate = 20/1) , fractions were collected, the solvent was distilled off under reduced pressure to give a white solid, yield 95%.

1Hnmr (SooHzJDCI3): 8.78 (d, 1H), 8.51 (d, 1H), 8.20 (m, 1H), 7.85 (m, 1H), 7.72 (d, 1H), 7.65 (d, 1H), 7.40 (m, 1H);

MS: 235.1,237.1 ([M + H] +).

4 Example 2: Preparation 4_ chlorine _3_ (topiramate 唳 _2_ yl) aniline

To a vial was added 100mL of Lord 20mmol2- (2- chloro-5-nitrophenyl) pyridine 唳, 50ml of acetic acid, heated to 80 ° C and stirred, and then slowly added IOOmmol iron, reaction 0.5h The reaction solution was poured into 200ml water and extracted with dichloromethane (150ml X 3), the combined organic phases, the organic phase was washed with saturated sodium carbonate solution (50ml X 3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propyl alcohol weight crystallized to give a pale yellow solid, yield 75%.

1HMflUSOOHz, DMS0_d6): 8.63 (m, 1H), 7.84 (m, 1H), 7.56 (d, 1H), 7.37 (m, 1H),

7.13 (d, 1H), 6.76 (d, 1H), 6.61 (q, 1H), 5.32 (s, 2H);

MS: 205.1,207.1 ([M + H] +).

5 Example: 4-chloro-3- (pyridin 唳-2-yl) aniline

to 100mL of God-shaped flask 20mmol2_ (2_ chlorine _5_ nitrophenyl) pyridine Jie set, 50ml of methanol, Ig activated carbon, 2mmol FeOOH and 60mmol85% of hydrazine hydrate, heated to reflux and stirred for 6 ~ 8h, after the completion of the reaction, was filtered, spin-dry the solvent, dissolved in 150ml of dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution (20ml X3), the organic phase was dried, evaporated under reduced pressure to give the crude product was recrystallized from n-propanol to give a pale yellow solid, yield 96%.

6 Example 2: Preparation 4_-chloro-3- (2-yl) aniline

20mmol N- oxo added to 100mL eggplant-shaped flask _2_ (2_ chloro _5_ nitrophenyl) pyridine, 50ml of acetic acid, heated to 80 ° C and stirred, and then iron powder was slowly added IOOmmol After 0.5h the reaction the reaction solution was poured into 200ml water and extracted with dichloromethane (150ml X3), the combined organic phases were washed with saturated sodium carbonate solution (50ml X3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propanol recrystallized to give a white solid, yield 70%.

Preparation 7.Α ~ chlorine -3_ (topiramate 唳 2-yl) aniline [0130] Example

20mmol N- oxo added to 100mL eggplant type flask _2_ (2_ chloro _5_ nitrophenyl) pyridine, 50ml of methanol, Ig active carbon, 2mmol FeOOH 60mmol85% hydrazine hydrate and heated to reflux and stirred for 6 ~ 8h, after the completion of the reaction, was filtered, spin-dry the solvent, dissolved in 150ml of dichloromethane, washed with saturated aqueous sodium bicarbonate solution, the organic phase (20mlX3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propyl alcohol weight crystallized to give a white solid, yield 82%.

Vismodegib Preparation: 8 Example

In the Lord 50ml vial, the 1.50mmol2- chloro-4-methanesulfonyl-chloride in 15ml of dry tetrahydrofuran, cooled to ice bath O ~ 10 ° C, a solution of 4-chloro-3 – (pyridin-2-yl) aniline in anhydrous tetrahydrofuran (1.47mmol / 10ml), triethylamine was added dropwise and then finished 2.5mmol of dropwise addition, the reaction at room temperature 4h, the reaction was completed, the reaction system was poured into 50ml water and stirred, precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 88%.

1HNMR (500Hz, DMS0_d6): 10.90 (s, 1H), 8.70 (d, 1H), 8.12 (d, 1H), 8.01 (t, 2H), 7.92 (m, 2H), 7.74 (q, 1H ), 7.69 (d, 1H), 7.58 (d, 1H), 7.44 (m, 1H), 3.34 (s, 3H).

MS: 421.1,423.1 ([M + H] +).

Vismodegib Preparation: 9 Example

In 50ml vial of God, will 1.50mmol2_ chlorine _4_ methylsulfonyl benzoic acid, 1.47mmol4_ chlorine _3_ (batch 唳 2-yl) aniline and triethylamine were dissolved in 25ml 2.5mmol anhydrous tetrahydrofuran in an ice bath to cool to O ~ 10 ° C, was added in portions N, N ‘- dicyclohexyl carbodiimide (DCC) 1.50mmol, After the addition, the reaction at room temperature 6h, after the reaction, white solid was removed by filtration, the filtrate was poured into 50ml water and stirred, precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 84%.

Vismodegib Preparation: 10 [0141] Example

In 50ml eggplant-shaped flask, 1.50mmol2- chloro-4-methanesulfonyl-benzoic acid was dissolved in 15ml of dichloromethane, cooled to ice bath O ~ 5 ° C, thionyl chloride was added dropwise 3.0mmol After stirring at room temperature 30min, removed by rotary evaporation dichloromethane and excess thionyl chloride, 15ml of anhydrous tetrahydrofuran was added, the ice bath was cooled to O ~ 10 ° C, solution of 4-chloro-3- (pyridin-2- yl) aniline in anhydrous THF (1.47mmol / 10ml), triethylamine was added dropwise and then finished 2.5mmol of dropwise addition, the reaction at room temperature 4h, the reaction was completed, the reaction was poured into 50ml water system and stirring, the precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 88%.

PATENT

CN 103910672

http://www.google.com/patents/CN103910672A?cl=en

Vismodegib PreparatioN

PATENT

WO2006028958

https://www.google.co.in/patents/WO2006028958A2?cl=en

Example 1 General Procedure

Compounds of examples 2-51 were prepared according to the following general procedures.

A: Suzuki Coupling Procedure

2 M aq. Potassium carbonate (5.0 eq) and 4:1 toluene :ethanol mixture (2.5 mL) were added to a microwave vial charged with the appropriate boronate ester (2.6 eq), aryl halide (0.35 mmol, 1.0 eq), and Pd(PPh₃)₄ (0.04 eq). The vial was sealed and heated with stirring in the microwave to 160 ⁰C for ten minutes. The solution was poured onto 2 M aq. Sodium hydroxide (20 mL), extracted with ethyl acetate (2 x 20 mL), dried (MgSO₄), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product.

B: Negishi Coupling Procedure

X = I or Br R = H, 3-Me, 4-Me₅ 5-Me, 6-Me

Aryl zinc bromide (0.5 M in THF, 2.5 eq) was added to an oven-dried microwave vial charged with the appropriate aryl halide (1.0 eq) and Pd(PPh₃)₄ (0.04 eq). The vial was sealed and heated with stirring in the microwave to 140 ⁰C for 10 minutes. The crude reaction mixture was concentrated and purified by chromatography on silica gel (conditions given below) to afford the desired product.

C: Iron Reduction of Aryl Nitro Group

R = I or pyridin-2-yl

The appropriate nitro aryl (1 mmol, 1 eq) in AcOH/EtOH (1:1, 0.42 M) was added slowly to a solution of Iron powder (6.0 eq) in AcOH/EtOH (1:2, 2 M) at 60 °C. The solution was stirred at 70 ⁰C for 30-60 minutes. The reaction mixture was cooled to 23 ⁰C, filtered through celite, washed with ethyl acetate, and concentrated. The oily residue was dissolved in ethyl acetate (30 mL), washed with saturated aq. NaHCO₃ (2 x 15 rnL) and water (2 x 10 niL), dried (MgSO₄), and concentrated. The oily residue was used with out further purification.

D: Amide Bond Formation

R = I or pyridin-2-yI

Acid chloride (1.05-1.1 eq) was added to a solution of aniline (1.0 eq) and TEA (1.1-1.5 eq) in methylene chloride at the indicated temperature. The solution was stirred for 0.5-3 hours, poured onto saturated aq. NaHCO₃, extracted twice with methylene chloride, dried (MgSO₄), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product.

E: EDC Amide Bond Formation

R = I or pyridin-2-yl

Carboxylic acid (1.1 eq) was added to a solution of aniline (1.0 eq) and EDC (1.4 eq) in methylene chloride (0.7 M in aniline). The solution was stirred at 23 ⁰C for 2 hours, poured onto a 1 :1 mixture of saturated aq. NH₄Cl and water, extracted twice with methylene chloride, dried (MgSO₄), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product. F: addition of amines to 2-chloropyridine

NHRR’ = ethanolamine, analine, benzylamine, 2-methylpropylamine, N-methylpiperazine, morpholine, 2-morpholinoethylamine

Primary or secondary amine (5 eq) in either BuOH or a mixture of BuOH/ethylene gylcol was heated to 170 to 220 ⁰C for 20 min in a sealed tube. The BuOH was removed under reduced pressure. In cases where ethylene glycol was used, the reaction was diluted with water, and the product was extracted into ethyl acetate, dried (MgSO^, and concentrated. The crude residue was purified by reverse phase HPLC to afford the desired product.

G: Amide bond coupling with HATU

HATU, DIPEA, DMF NaOH or NaHCO₃

ethyl acetate extraction

Aniline (1.0 eq) was added to a mixture of carboxylic acid (1.1 eq), HATU (1.1 eq) and DIPEA (2 eq) in DMF (0.1 – 0.2 M). After stirring overnight, the reaction mixture was diluted with 0.1 N sodium hydroxide or saturated NaHCθ₃, extracted into ethyl acetate and the combined organic layers were washed with brine. The organic layer was dried (MgSO₄), concentrated and the crude mixture was purified by reverse phase HPLC. H: Preparation of sulfonamide benzoic acids

Chlororsulfonylbenzoic acid (1.0 eq) was added to a solution of amine (1.1 eq) in 10-20% DEPEA/methanol (1 M) at 4 ⁰C. After 1 h, the reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC.

I : Stannylation of 2-pyridyl triflates

A solution of tetrakis-triphenylphosphinepalladium (0.04 eq.) in toluene (1 mL) was added to degassed solution of aryltriflate (1 eq), bis-trialkyltin (1.05 eq), and lithium chloride (3 eq) in dioxane. Heated to reflux for 2 hours, cooled to 23 ⁰C, diluted with ethyl acetate, washed with 10% NH₄θH_(aq) and brine, dried (MgSO₄) and concentrated. The crude material was used without further purification.

J: Stannylation of substituted pyridines

^ιM^mβ^co3 n-Butyl lithium (6 eq, 2.5 M in hexanes) was added dropwise to a solution of dimethylaminoethanol (3 eq) in hexane at 0 ⁰C. The solution was stirred at 0 ⁰C for thirty minutes before dropwise addition of the substituted pyridine (1 eq). The solution was stirred at 0 ⁰C for an additional hour, then cooled to -78 ⁰C. A solution of trialkyltin in hexane was added dropwise. The solution was stirred at -78 ⁰C for thirty minutes, warmed to 0 ⁰C, quenched with water, extracted twice with ether, dried (MgSO₄), and concentrated. K: Stille Coupling

Palladium catalyst (0.02 eq) was added to a degassed solution of aryliodide (1 eq), arylstannane (2 eq), and triphenylphosphine (0.16 eq) in NMP. Heated in the microwave to 130 ⁰C for 15 minutes. The reaction mixture was diluted with ethylacetate, washed with 10% NH₄θH_(aq) and brine, dried (MgSC>₄), concentrated and purified by silica gel chromatography.

L: Synthesis of alky lethers

A solution of hydroxypyridine (1 eq), alkyliodide (excess), and cesium carbonate in NMP was heated in the microwave to 100⁰C for ten minutes. The reaction mixture was diluted with ethylacetate, washed with 10% NH₄θH_(aq) and brine, dried (MgSC^), concentrated and purified by silica gel chromatography.

M: Methyl Ester Saponification

The methyl ester (leq) was hydrolyzed with LiOH (2eq) in 50/50 THF/water mix. Upon completion of the reaction the THF was evaporated under reduced pressure and the solution is acidified with HCl to pH 2. The resultant solid was filtered and dried to give the pure acid.

N: Bromination in the presence of a free acid functionality

The paramethylbenzoic acid (leq) was combined with Benzoyl Peroxide (O.leq) and N- Bromosuccinimde (0.9eq) in a solution of 5%AcOH in Benzene and heated in the microwave at 120°C for 5-15minutes. The product was separated from the starting material and di-bromo product via ISCO flash chromatography with an ethyl acetate (with 1% AcOH) and hexanes solvent system.

O: Sodium Methanesulfinate displacement of Bromine

To the bromine starting material (leq) was added sodium methanesulfinate (2eq) in DMF and heated to 120°C in the microwave for 5 minutes. Alternatively, the reaction was heated to 60°C in an oil bath for several hours until completed. Reaction mixture was concentrated under reduced pressure and extracted in ethyl acetate and water. The organic layer was dried over Magnesium Sulfate, filtered and concentrated in vacuo to yield generic methylsulfone.

P: Amine displacement of Bromine

To the bromo starting material (leq) was added appropriate amine (3eq) in either DMSO or BuOH and stirred at room temperature until complete. For less nucleophilic amines or anilines, the reactions were forced to completion using microwave conditions ranging from 150°-170°C for 15 minutes. Crude reactions were concentrated to dryness and either extracted with ethyl acetate and saturated bicarbonate if the reaction resulted in an intermediate or purified via HPLC if the reaction resulted in a final product.

Q: Thiol displacement of halogen

The paramethylbromo benzoate (leq) was treated with Potassium (or Cesium) Carbonate (1.5eq) and appropriate thiol derivative (l,leq) in DMF (or CH₃CN) and stirred overnight at room temperature. The DMF was evaporated in vacuo and the reaction was extracted with ethyl acetate and water. The organic layer was dried over Magnesium Sulfate , filtered and concentrated to yield the thiol or derivatized thiol compound.

R: Oxone Oxidation

oxone 2:1 MeOHTH₂O

Derivatized thiol (leq) was dissolved in MeOH while Oxone (2eq) was seperately dissolved in half the amount of water. Once all the oxone was dissolved, the solution was added to the thiol in MeOH solution at once and stirred until complete. The MeOH was evaporated in vacuo and the remaining water was extracted twice with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate and concentrated to yield the sulfone.

S: Thio lysis of epoxides at alumina surfaces

A mixture of epoxides (1.0 eq), thiophenol (1.5 eq) and neutral aluminum oxide (~70 eq) in diethyl ether was stirred for 3 h at room temperature while being monitored by TLC. The reaction mixture was filtered through Celite, washed with ethyl acetate and concentrated. Purified by silica gel chromatography (0-40% ethyl acetate/hexane) to yield β -hydroxysulfide product.

T: Conversion of nitrile group to carboxylic acid

A solution of benzonitrile (1.0 eq) and sodium hydroxide (2.0 eq) in H₂O was heated to 120 ° C for 2h. The reaction mixture was cooled to room temperature and acidified with HCl to pH 2. The resulting solid was filtered to afford the pure acid product.

U. Alkylation of phenols

The phenol was dissolved in DMF (1.0 ml). Cesium carbonate (1.0 eq.) and an alkyl bromide or alkyl iodide (1.0 to 2.0 eq.) were added, and the reaction was stirred at room temperature for 18 hrs or 5O⁰C for 1 to 24 hours. The reaction was quenched in water, and extracted with ethyl acetate twice. The organic extracts were washed with water once, brine once, dried with MgSC>₄, and evaporated to a crude oil which was purified on reverse phase HPLC.

V. Amide bond formation with an acid chloride and an aniline

The aniline was dissolved in THF (1.5 ml) and dichloromethane (1.5 ml). MP-Carbonate (1.5 eq.) and an acid chloride (1.1 eq.) were added, and the solution was stirred at room temperature for 18 hours. The reaction was diluted with methanol and dichloromethane, and filtered to remove the MP-Carbonate. The mother liquors were evaporated to a solid and purified by reverse phase HPLC.

W. Amidine formation from an imidate

A solution of freshly formed imidate in methanol was treated with a primary or secondary amine (1.5 eq.) at room temperature for 18 hours. The methanol was removed on a rotary evaporator and the residue purified by reverse phase HPLC.

Example 37 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-chloro-4- methylsulfonylbenzoic acid to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide. MS (Ql) 421.0 (M)⁺. The product was then dissolved in 1 Ν HCI solution followed by freebasing with 0.5 Ν NaOH solution (pH to 11). The resulting precipitate was filtered and vacuum-dry.

Procedure D may also be used to couple 4-chloro-3-(pyridin-2-yl)aniline and 2-chloro-4- (methylsulfonyl)benzoyl chloride to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-

(methylsulfonyl)benzamide which is collected by suction filtration and the HCl salt is washed with

Et₂O (or alternatively with MTBE). This material is freebased using EtOAc/aq NaHCO₃ and the organics are dried and concentrated to the solid freebase. This material is then crystallized from acetone :EtOAc (80:20, approx lOmL/g) which is then finally recrystallized from hot slurry of iPrOAc. 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide HCl salt may also be dissolved in distilled water followed by freebasing with 0.5 N NaOH solution (pH to 11) and filtering and vacuum drying the precipitate.

Patent

WO 2016020324, BASF AG, vismodegib , new patent

WO2016020324, MULTI-COMPONENT CRYSTALS OF VISMODEGIB AND SELECTED CO-CRYSTAL FORMERS OR SOLVENTS

BASF SE [DE/DE]; 67056 Ludwigshafen (DE)

VIERTELHAUS, Martin; (DE).
CHIODO, Tiziana; (DE).
SALVADOR, Beate; (DE).
VOSSEN, Marcus; (DE).
HAFNER, Andreas; (CH).
HINTERMANN, Tobias; (CH).
WEISHAAR, Walter; (DE).
HELLMANN, Rolf; (DE)

The present invention primarily relates to multi-component crystals comprising a compound of formula 1 and a second compound selected from the group consisting of co-crystal formers and sol-vents. The invention is further related to pharmaceutical compositions comprising such multi-component crystals. Furthermore, the invention relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease.

Developed and launched by Roche and its subsidiary Genentech, under license from Curis. Family members of the product Patent of vismodegib (WO2006028958),

formula 1

The present invention primarily relates to multi-component crystals comprising a compound of formula 1 (cf. above) and a second compound selected from the group consisting of co-crystal formers and solvents.

The invention is further related to pharmaceutical compositions comprising said multi-component crystals. Furthermore, the invention also relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease. Further details as well as further aspects of the present invention will be described herein below.

Vismodegib is a BCS class II compound with a high permeability but a low solubility where enhanced solubility or dissolution rates can lead to a significant advantage in respect to bio-availability.

Vismodegib is known to exist as crystalline free base. Salts of Vismodegib are men-tioned in US 7,888,364 B2 but not specified. In particular, the HCI salt is mentioned as intermediate but not characterized. Co-crystals or solvates are not reported at all.

The solubility of Vismodegib is reported to be 0.1 μg/mL at pH 7 and 0.99 mg/mL at pH 1 for Erivedge®. The absolute bio-availability after single dose is reported to be 31.8 % and the ex-posure is not linear at single doses higher than 270 mg. Erivedge® capsules do not have a food label. The estimated elimination half-life (t1/2) after continuous once-daily dosing is 4 days and 12 days after a single dose treatment (Highlights of Prescribing Information: ERIVEDGE® (vismodegib) capsule for oral use; Revised: 01/2012).

The discovery and preparation of new co-crystals or solvates offer an opportunity to improve the performance profile of a pharmaceutical product. It widens the reservoir of techniques/materials that a formulation scientist can use for designing a new dosage form of an active pharmaceutical ingredient (API) with improved characteristics. One of the most important characteristics of an API such as Vismodegib is the bio-availability which is often determined by the aqueous solubility.

A compound like Vismodegib may give rise to a variety of crystalline forms having dis-tinct crystal structures and physical characteristics like melting point, X-ray diffraction pattern, infrared spectrum, Raman spectrum and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetry (TG), and differential scanning calorimetry (DSC) as well as content of sol-vent in the crystalline form, which have been used to distinguish polymorphic forms.

Multi-component crystals comprising Vismodegib and selected co-crystal formers or solvents may improve the dissolution kinetic profile and allow to control the hygrosco-picity of Vismodegib.

Therefore, there is a need for multi-component crystals comprising Vismodegib that avoid the above disadvantages. In particular, it is an object of the present invention to provide multi-component crystals of Vismodegib with optimized manufacture, formula-tion, stability and/or biological efficacy

Example 1 :

314 mg Vismodegib and 86 mg maleic acid are suspended in toluene saturated with maleic acid for 2 d, filtered and dried.

TG data shows a mass loss of about 2.3 wt % between 100 and 1 18 °C which is attributed to rest solvent. DSC data shows a single endothermal peak with an onset of about 1 15 °C (99 J/g).

H-NMR spectroscopy indicates a molar ratio of Vismodegib to maleic acid of about 1 :1 .3. However single crystal X-ray data confirms a ratio of 1 :2 (Table 1 ).

update……………

Vismodegib Synthesis

WO2009126863A2: also see Ref. 1. It all started from here.

Identification:

1H NMR (Estimated) for Vismodegib

Experimental: ¹H NMR (400MHz, CDCl₃) δ (ppm): 9.58 (bs, 1H), 8.43 (d, J = 4.7Hz, 1H), 8.03 (dd, J = 2.6, 8.7Hz, 1H), 7.90 (d, J = 1.6Hz, 1H), 7.67-7.78 (m, 4H), 7.60 (d, J = 8.0Hz, 1H), 7. 51 (d, J = 8.8Hz, 1H), 7.23-7.24 (m, 1H), 3.01 (s, 3H).

UPDATES…….

Manufacturing Development and Genotoxic Impurity Control Strategy of the Hedgehog Pathway Inhibitor Vismodegib

Remy Angelaud^*†, Mark Reynolds†, Cadapakam Venkatramani‡, Scott Savage†, Huldreich Trafelet^§, Thomas Landmesser^§, Peter Demel^§, Michael Levis^§, Olivier Ruha^§, Baerbel Rueckert^§, and Heinz Jaeggi^§

^†Small Molecule Process Chemistry, ^‡Small Molecule Analytical Chemistry, Genentech, A Member of the Roche Group, 1 DNA Way, South San Francisco, California 94080, United States

^§ Siegfried AG, Untere Brühlstrasse 4, CH-4800 Zofingen, Switzerland

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00208, http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00208

*E-mail: angelaud.remy@gene.com.

The development work toward the robust and efficient manufacturing process to vismodegib, the active pharmaceutical ingredient (API) in Erivedge, is described. The optimization of the four-stage manufacturing process was designed to produce the API with the required critical quality attributes: (1) the selective catalytic hydrogenation reduction of the nitro compound 3 to the corresponding aniline 4 while minimizing the formation of potential genotoxic (mutagenic) impurities; (2) the control of the polymorphic phase and multipoint specification for particle size distribution.

Vismodegib

13C

////////////////

Supporting Info

References

“Vismodegib, First Hedgehog Inhibitor, Approved for BCC Patients”.
“Molecule of the Month”. June 2011.
“FDA approves Erivedge (vismodegib) capsule, the first medicine for adults with advanced basal cell carcinoma”.
Lacroix, Marc (2014). Targeted Therapies in Cancer. Hauppauge , NY: Nova Sciences Publishers. ISBN 978-1-63321-687-7.
“Vismodegib (GDC-0449) Smoothened Inhibitor – BioOncology”.
H. Spreitzer (4 July 2011). “Neue Wirkstoffe – Vismodegib”. Österreichische Apothekerzeitung (in German) (14/2011): 10.
FDA Professional Drug Information

External links

PatentSubmittedGranted

Pyridyl inhibitors of hedgehog signalling [US7888364]2006-03-232011-02-15

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2009281089]2009-11-12

ANTI-HEDGEHOG ANTIBODIES [US8030454]2010-01-072011-10-04

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2011092461]2011-04-21

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2012094980]2011-10-142012-04-19

COMBINATION THERAPY WITH NANOPARTICLE COMPOSITIONS OF TAXANE AND HEDGEHOG INHIBITORS [US2013045240]2010-08-252013-02-21

COMBINATION THERAPY WITH NANOPARTICLE COMPOSITIONS OF TAXANE AND HEDGEHOG INHIBITORS [US2014072630]2013-02-282014-03-13

Acyl guanidine derivatives modulating the hedgehog protein signaling pathway [US8889678]2010-07-192014-11-18

COMBINATION THERAPY [US2012184529]2012-01-032012-07-19

METHOD OF INHIBITING DYRK1B [US2014371251]2014-06-182014-12-18

USE OF SUBSTITUTED HEXITOLS INCLUDING DIANHYDROGALACTITOL AND ANALOGS TO TREAT NEOPLASTIC DISEASE AND CANCER STEM AND CANCER STEM CELLS INCLUDING GLIOBLASTOMA MULTIFORME AND MEDULLOBLASTOMA [US2014377336]2013-01-222014-12-25

SHH Regulation and Methods Thereof [US2012082623]2011-09-302012-04-05

NOVEL 2-PIPERIDIN-1-YL-ACETAMIDE COMPOUNDS FOR USE AS TANKYRASE INHIBITORS [US2015025070]2012-07-132015-01-22

Compositions and Methods for Modulating Neuron Degeneration and Neuron Guidance [US2011065645]2010-09-102011-03-17

SMOOTHENED ANTAGONISM FOR THE TREATMENT OF HEDGEHOG PATHWAY-RELATED DISORDERS [US2014200217]2014-01-242014-07-17

CN101072755A *	Sep 2, 2005	Nov 14, 2007	遗传技术研究公司	Pyridyl inhibitors of hedgehog signalling
CN102731373A *	Jul 19, 2012	Oct 17, 2012	南京药石药物研发有限公司	Preparation method of intermediate of antitumor drug GDC-0449 (vismodegib)
US20080132698 *	Nov 30, 2006	Jun 5, 2008	University Of Ottawa	Use of N-oxide compounds in coupling reactions
US20090076266 *	Sep 10, 2008	Mar 19, 2009	The University Of Houston System	Copper-catalyzed c-h bond arylation

NON-PATENT CITATIONS

Reference
1	*	GEORGETTE M. CASTANEDO，等: “Second generation 2-pyridyl biphenyl amide inhibitors of the hedgehog pathway“, 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 20, 15 September 2010 (2010-09-15), pages 6748 – 6753
2	*	曹萌，等: “Vismodegib 的合成“, 《第十一届全国青年药学工作者最新科研成果交流会论文集》, 21 June 2012 (2012-06-21)
3	*	耿一丁: “Vismodegib“, 《中国药物化学杂志》, vol. 22, no. 3, 20 June 2012 (2012-06-20)
4	*	邢其毅，等: “《基础有机化学》”, 31 December 2005, article “201310019450.0“, pages: 896-897

Vismodegib
Systematic (IUPAC) name


2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide
Clinical data
Trade names	Erivedge
AHFS/Drugs.com	monograph
Licence data	EMA:Link, US FDA:link
Pregnancy category	AU: X (High risk) US: D (Evidence of risk)
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	31.8%
Protein binding	>99%
Metabolism	<2% metabolised byCYP2C9, CYP3A4, CYP3A5
Biological half-life	4 days (continuous use), 12 days (single dose)
Excretion	Faeces (82%), urine (4.4%)
Identifiers
CAS Number	879085-55-9
ATC code	L01XX43
PubChem	CID 24776445
IUPHAR/BPS	6975
DrugBank	DB08828
ChemSpider	23337846
UNII	25X868M3DS
ChEBI	CHEBI:66903
ChEMBL	CHEMBL473417
Synonyms	GDC-0449, RG-3616
Chemical data
Formula	C₁₉H₁₄Cl₂N₂O₃S
Molar mass	421.30 g/mol

SEE…http://apisynthesisint.blogspot.in/2016/02/vismodegib.html

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CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl

Cipla, New Patent, WO 2016020664, Everolimus

February 15, 2016 6:29 am / Leave a comment

Cipla, New Patent, WO 2016020664, Everolimus

CIPLA LIMITED [IN/IN]; Peninsula Business Park Ganpatrao Kadam Marg Lower Parel Mumbai 400 013 (IN).
KING, Lawrence [GB/GB]; (GB) (MW only)

RAO, Dharmaraj Ramachandra; (IN).
MALHOTRA, Geena; (IN).
PULLELA, Venkata Srinivas; (IN).
ACHARYA, Vinod Parameshwaran; (IN)

WO2016020664, PROCESS FOR THE SYNTHESIS OF EVEROLIMUS AND INTERMEDIATES THEREOF

Everolimus (RAD-001) is the 40-O- 2-hydroxyethyl)-rapamycin of formula (I),

It is a derivative of sirolimus of formula III),

and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR). Everolimus is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer and other tumours. It is marketed by Novartis under the tradenames Zortress™ (USA) and Certican™ (Europe and other countries) in transplantation medicine, and Afinitor™ in oncology.

Trisubstituted silyloxyethyltrifluoromethane sulfonates (triflates) of the general formula (IV),

wherein R₂, R₃ are independently a straight or branched alkyl group, for example C^-Cw alkyl, and/or an aryl group, for example a phenyl group, are important intermediates useful in the synthesis of everolimus.

Everolimus and its process for manufacture using the intermediate 2-(t-butyldimethyl silyl) oxyethyl triflate of formula (IVA),

was first described in US Patent Number 5,665,772. The overall reaction is depicted in Scheme I.

Scheme

Everolimus (I)

For the synthesis, firstly sirolimus of formula (III) and 2-(t-butyldimethylsilyl)oxyethyl triflate of formula (IVA) are reacted in the presence of 2,6-Lutidine in toluene at around 60°C to obtain the corresponding 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin of formula (I la), which is then deprotected in aqueous hydrochloric acid and converted into crude everolimus [40-O-(2-Hydroxy)ethyl rapamycin] of formula (I).

However, this process results in the formation of impure everolimus, which requires purification by column chromatography. The process results in very poor overall yield and purity and thereby the process is not suitable for the commercial scale production of everolimus.

Moenius et al. (I. Labelled Cpd. Radiopharm. 43, 1 13-120 (2000) have disclosed a process to prepare C-14 labelled everolimus using the diphenyltert-butylsilyloxy-protective group of formula (IV B),

as the alkylation agent. The overall yield reported was 25%.

International patent application, publication number WO 2012/103960 discloses the preparation of everolimus using the alkylating agent 2-((2,3-dimethylbut-2-yl)dimethylsilyloxy)ethyl triflate of formula (IVC),

wherein the overall yield reported is 52.54%. The process involves a derivatization method based on the reaction of the triflate (IV) with a derivatization agent, which preferably is a secondary aromatic amine, typically N-methylaniline.

International patent application, publication number WO 2012/103959 also discloses the preparation of everolimus using the alkylating agent of formula (IVC). The process is based on a reaction of rapamycin with the compound of formula (IVC) in the presence of a base (such as an aliphatic tertiary amine) to form 40-O-2-(t-hexyldimethylsiloxy)ethylrapamycin, which is subsequently deprotected under acidic conditions to obtain everolimus.

European Patent Number 1518517B discloses a process for the preparation of everolimus which employs the triflate compound of formula (IVA), 2-(t-butyldimethyl silyl) oxyethyl triflate. The disclosed process for preparing the compound of formula (IVA) involves a flash chromatography purification step.

The compounds of formula (IV) are key intermediates in the synthesis of everolimus. However, they are highly reactive and also very unstable, and their use often results in decomposition during reaction with sirolimus. This is reflected by the fact that the yields of the reaction with sirolimus are very low and the compounds of formula (IV) are charged in high molar extent. Thus it is desirable to develop a process to stabilize compounds of formula (IV) without loss of reactivity.

Example 1 :

Step 1 : Preparation of protected everolimus (TBS-everoismus) of formula (Ma) using metal salt, wherein “Pg” is t-butyldimethylsilyl

t-butyldimethylsilyloxy ethanol, of formula (VA) (2.8g, 0.016mol) was dissolved in dichloromethane (DCM) (3 vol) and to this 2,6-Lutidine (3.50 g, 0.0327 mol) was added and the mixture was cooled to -40°C. Thereafter, trifluoromethane sulfonic anhydride (3.59ml, 0.021 mol) was added drop-wise. The mixture was maintained at -40°C for 30 minutes. Sirolimus (0.5g, 0.00054mol) was taken in another flask and dissolved in DCM (1 ml). To this sirolimus solution, silver acetate (0.018g, 0.000109mol) was added and cooled to -40°C. The earlier cooled triflate solution was transferred in 3 lots to the sirolimus solution maintaining temperature at -40°C. The reaction mixture was stirred at -40°C further for 15min before which it was slowly warmed to 0°C and further to RT. The reaction mixture was then warmed to 40°C and maintained at this temperature for 3 hours. The reaction was monitored by TLC. On completion of reaction, the reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous sodium sulphate and solvent was removed by vacuum distillation to obtain the title compound, which was directly used in the next step. HPLC product purity: 60%-85%.

Step 2: Preparation of everolimus of formula (I)

Protected everolimus of formula (I la) obtained in step 1 was dissolved in methanol (10 volumes) and chilled to 0-5° C. To this solution was added drop wise, a solution of 1 N HCI. The pH of the reaction was maintained between 1-3. The temperature of the reaction mixture was raised to 25° C and stirred for 1 hour. After completion of reaction, the reaction mixture was diluted with water (15 volumes) and extracted in ethyl acetate (2X20 volumes). The organic layers were combined and washed with brine, dried over sodium sulphate. The organic layer was distilled off under reduced pressure at 30-35° C, to obtain a crude everolimus (0.8 g). The crude everolimus was further purified by preparative HPLC to yield everolimus of purity >99%.

Example 2:

Step 1 : Preparation of TBS-everoiimus of formula (Ma) without using metal salt, wherein “Pg” is t-butyldimethylsilyl

t-butyldimethylsilyloxy ethanol, of formula (VA) (2.8g, 0.016mol) was dissolved in DCM (3 vol) and to this 2,6-Lutidine (3.50 g, 0.0327 mol) was added and the mixture was cooled to -40°C. Thereafter, trifluoromethane sulfonic anhydride (3.59ml, 0.021 mol) was added drop-wise. The mixture was maintained at -40°C for 30 minutes. Sirolimus (0.5g, 0.00054mol) was taken in another flask and dissolved in DCM (1 ml). The solution was cooled to -40°C. The earlier cooled triflate solution was transferred in 3 lots to the sirolimus solution maintaining temperature at -40°C. The reaction mixture was stirred at -40°C further for 15min before which it was slowly warmed to 0°C and further to RT. The reaction mixture was then warmed to 40°C and maintained at this temperature for 3 hours. On completion of reaction, the reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous sodium sulphate and

solvent was removed by vacuum distillation to obtain the title compound, which was directly used in next step. HPLC purity: 10%-20%.

Step 2: Preparation of everolimus of formula (I)

Example 3:

Preparation of crude Everolimus

Step 1 : Preparation of TBS-ethylene glycol of formula (Va)

Ethylene glycol (1.5L, 26.58 mol) and TBDMS-CI (485g, 3.21 mol) were mixed together with stirring and cooled to 0°C. Triethyl amine (679 ml, 4.83 mol) was then added at 0°C in 30-45 minutes. After addition, the reaction was stirred for 12 hours at 25-30°C for the desired conversion. After completion of reaction, the layers were separated and the organic layer (containing TBS-ethylene glycol) was washed with water (1 L.x2) and brine solution (1 L). The organic layer was then subjected to high vacuum distillation to afford 350g of pure product.

Step 2: Preparation of TBS-glycol-Triflate of formula (IVa)

The reaction was carried out under a nitrogen atmosphere. TBS- ethylene glycol prepared as per step 1 (85.10g, 0.48 mol) and 2, 6-Lutidine (84.28ml, 0.72 mol) were stirred in n-heptane (425ml) to give a clear solution which was then cooled to -15 to – 25°C. Trif!uoromethanesulfonic anhydride (Tf₂0) (99.74 ml, 0.590 mol) was added drop-wise over a period of 45 minutes to the n-heptane

solution (white precipitate starts to form immediately) while maintaining the reaction at -15 to -25°C. The reaction mixture was kept at temperature between -15 to -25°C for 2 hours. The precipitate generated was filtered off. The filtrate was then evaporated up to ~2 volumes with respect to TBS-ethyiene glycol (~200 ml).

Step 3: Preparation of TBS-evero!imus of formula (Ha)

30g of sirolimus (0,0328 mo!) and toluene (150m!) were stirred together and the temperature was slowly raised to 60-65°C. At this temperature, a first portion of TBS-g!yco!-triflate prepared as per step 2 (100ml) and 2,6-Lutidine (1 1.45ml, 0.086 moles) were added and stirred for 40 min. Further, a second portion of TBS- glycol-triflate (50mi) and 2, 6-Lutidine (19.45ml, 0.138 mol) were added and the reaction was stirred for another 40 min. This was followed by a third portion of TBS- glycol-triflate (50m!) and 2, 6-Lutidine (19.45ml, 0.138 mol), after which the reaction was stirred for further 90 minutes. The reaction was monitored through HPLC to check the conversion of Sirolimus to TBS-everolimus after each addition of TBS-glycol-trifiate. After completion of the reaction, the reaction mixture was diluted with n-heptane (150mi), cooled to room temperature and stirred for another 60 minutes. The precipitated solids were filtered off and the filtrate was washed with deionized water (450 ml x4) followed by brine solution (450ml). The filtrate was subsequently distilled off to afford TBS-everolimus (60-65g) with 60-70% conversion from sirolimus.

Step 4: Preparation of everolimus of formula (I)

TBS-everolimus (65g) obtained in step 3 was dissolved in 300 mi methanol and cooled to 0°C. 1 N HCI was then added to the methanol solution (pH adjusted to 2-3) and stirred for 2 h. After completion of reaction, toluene (360m!) and deionized wafer (360mi) were added to the reaction mixture and the aqueous layer was separated. The organic layer was washed with brine solution (360ml). The organic layer was concentrated to obtain crude everolimus (39g) with an assay content of 30-35%, HPLC purity of 60-65%.

The crude everolimus purified by chromatography to achieve purity more than 99 %.

////Cipla, New Patent, WO 2016020664, Everolimus, INDIA

Zydus Cadila, New Patent,US 20160039759, PERAMPANEL

February 15, 2016 6:07 am / Leave a comment

PERAMPANEL

Zydus Cadila, New Patent,US 20160039759, PERAMPANEL

(US20160039759) PROCESS FOR THE PREPARATION OF PERAMPANEL

CADILA HEALTHCARE LIMITED

Sanjay Jagdish DESAI
Jayprakash Ajitsingh Parihar
Kuldeep Natwarlal Jain
Sachin Ashokrao Patil

Perampanel, a non-competitive AMPA receptor antagonist, is the active ingredient of FYCOMPA® tablets (U.S) which is approved as an adjunctive therapy for the treatment of partial on-set seizures with or without secondarily generalized seizures in patients with aged 12 years and older. Chemically, Perampanel is 5′-(2-cyanophenyl)-1′-phenyl-2,3′-bipyridinyl-6′(1′H)-one, with an empirical formula C23H15N30 and molecular weight 349.384 g/mol which is represented by Formula (I).

U.S. Pat. No. 6,949,571 B2 discloses perampanel and its various processes for preparation thereof.

U.S. Pat. No. 7,759,367 B2 discloses the pharmaceutical composition of perampanel and an immunoregulatory agent and their uses.

U.S. Pat. No. 8,304,548 B2 discloses the reaction of 5′-bromo-1′-phenyl-[2,3′-bipyridin]-6′(1′H)-one with 2-(1,3,2-dioxaborinan-yl)benzonitrile in the presence of palladium compound, a copper compound, a phosphorus compound and a base to form perampanel of Formula (I). Also discloses the crystalline hydrate, anhydrous crystal Form I, anhydrous crystal Form III, & anhydrous crystal Form V of perampanel of Formula (I).

U.S. Pat. No. 7,803,818 B2 discloses an amorphous form of perampanel. U.S. Pat. No. 7,718,807 B2 discloses salts of perampanel. International (PCT) publication No. WO 2013/102897 A1 discloses anhydrous crystalline Form III, V & VII of perampanel.

U.S. PG-Pub. No. 2013/109862 A1 discloses the method for preparing 2-alkoxy-5-(pyridin-2-yl)pyridine, which is an intermediate for preparing perampanel key starting material 5-(2′-pyridyl)-2-pyridone.

U.S. Pat. No. 7,524,967 B2 discloses the preparation of 5-(2′-pyridyl)-2-pyridone, an intermediate in the preparation perampanel.

International (PCT) publication No. WO 2014/023576 A1 discloses the preparation of cyanophenyl boronic acid, an intermediate in the preparation perampanel.

The prior-art processes suffer with problems of poor yield and requirement of chromatographic purification or series of crystallizations which further reduces the overall yield of the final product, which is overcome by the process of the present invention.

Pankaj Patel, chairman, Zydus Cadila

EXAMPLES

The present invention is further illustrated by the following examples which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example-A: Preparation of 5-(2-pyridyl)-1,2-dihydropyridin-2-one In a 500 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, a solution of 188.80 g 5-bromo-2-methoxypyridine in 190 mL tetrahydrofuran and 12.92 g pyridine-2-yl boronic acid were added and refluxed. The reaction mixture was cooled to 25-30° C. and aqueous solution of hydrochloric acid was added and stirred for 1 hour. The reaction mixture was neutralized with aqueous sodium hydroxide and extracted with tetrahydrofuran.

The organic layer was washed with saline water, dried over anhydrous magnesium sulfate, and then evaporated to obtain the titled compound.

Example-1

Preparation of 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one

In a 2 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 201.5 g 5-(2-pyridyl)-1,2-dihydropyridin-2-one, 208.3 g N-bromosuccinimide and 1300 mL N,N-dimethylforamide were stirred at 25-30° C. for 2-3 hours. After completion of the reaction, the reaction mixture was poured into water and stirred for 30 min. The precipitate was filtered, washed with N,N-dimethylforamide and dried at 50° C. to obtain 230 g title compound.

Example-2

Preparation of 3-bromo-5-2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one

In a 500 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, a solution of 18.75 g 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one in 300 mL methylene dichloride, 18.36 g 1-phenyl boronic acid, 3.47 g palladium triphenylphosphine and 10 mL triethyl amine were added and the reaction mixture was stirred for 1 hour at 25-35° C. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was crystallised from ethyl acetate to obtain the title compound.

Example-3

Preparation of Perampanel

In a 1 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, a suspension of 188 g 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one, 161.2 g 2-(1,3,2-dioxaborinan-2-yl)benzonitrile, 3.0 g tetrakis(triphenylphosphine)-palladium(0), 10 mL triethylamine (10 mL) in 300 mL methylene dichloride were stirred at 25-30° C. for 12 hours. To the reaction mixture was added 5 mL conc. aqueous ammonia, 10 mL water and 40 mL ethyl acetate. The separated organic layer was washed with water and saturated saline solution and dried over magnesium sulfate. The solvent was removed under vacuum. Ethyl acetate was added to the residue and heated obtain clear solution. n-hexane was added to this solution and cooled to 25-30° C. The obtained solid was filtered and washed with ethyl acetate and dried to obtain perampanel.

Example-4

Preparation of 3-Bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one

In a 2 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 100 g 5-(2-pyridyl)-1,2-dihydropyridin-2-one, 108.5 g N-bromosuccinimide and 500 mL N,N-dimethylforamide were stirred at 30-35° C. for 3 hours. 100 mL water was added to the reaction mixture at 5-15° C. and stirred at 30-35° C. for 1 hour. The solid obtained was filtered, washed with water and dried to obtain 129 g 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one.

Example-5

Preparation of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one

In a 2 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 100 g 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one, 72.8 g phenylboronic acid and 500 mL N,N-dimethylformamide were added at 30-35° C. and stirred. 11.9 g copper acetate and 15.7 g pyridine were added and air was purged into the reaction mixture and stirred for 16 hours at 30-35° C. After the completion of the reaction, the reaction mixture was poured into 1200 mL aqueous ammonia at 10-15° C. and stirred for 2 hours at 30-35° C. The obtained solid was filtered, washed with water and dried to obtain 120 g 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one.

Example-6

Purification of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one

In a 1 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 100 g 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one and 500 mL isopropyl alcohol were stirred at 60-65° C. for 30 min. The reaction mixture was cooled to 20-25° C. and stirred for 30 min. The reaction mixture was filtered, washed with isopropanol and dried to obtain 96 g pure 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one.

Example-7

Preparation of Perampanel

In a 1 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 100 g 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one and 125 g 2-(1,3,2-dioxaborinan-2-yl)benzonitrile and 1500 mL N,N-dimethylformamide were added under inert atmosphere. 44 g potassium carbonate and 4.2 g palladium tetrakis were added and stirred at 115-125° C. for 3 hours. The solvent was removed under vacuum. Ethyl acetate was added to the residue and the organic layer was distilled off to obtain perampanel (78 g).

////////Zydus Cadila, New Patent,US 20160039759, PERAMPANEL

Benfotiamine, бенфотиамин , بينفوتيامين , 苯磷硫胺 , ベンフォチアミン

February 14, 2016 9:43 am / Leave a comment

Image result for benfotiamine

Benfotiamine

S-[(Z)-2-[(4-amino-2-methylpyrimidin-5-yl)methyl-formylamino]-5-phosphonooxypent-2-en-3-yl] benzenecarbothioate

Benphothiamine; Betivina; Biotamin; Neurostop; Nitanevril; cas 22457-89-2

C₁₉H₂₃N₄O₆PS MF

466.447882 g/mol MW

Benzenecarbothioic acid, S-[2-[[(4-amino-2-methyl-5-pyrimidinyl)methyl]formylamino]-1-[2-(phosphonooxy)ethyl]-1-propenyl] ester (9CI)
Benzoic acid, thio-, S-ester with N-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-N-(4-hydroxy-2-mercapto-1-methyl-1-butenyl)formamide dihydrogen phosphate (ester) (8CI)
Formamide, N-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-N-(4-hydroxy-2-mercapto-1-methyl-1-butenyl)-, S-benzoate O-(dihydrogen phosphate) (8CI)
8088CB
BTMP

Benfothiamine
Benfotiamine
Benzoylthiamine O-monophosphate
Benzoylthiamine monophosphate
Berdi
Betivina
Bietamine
Biotamin
Milgamma
N-[(4-Amino-2-methyl-5-pyrimidinyl)methyl]-N-(4-hydroxy-2-mercapto-1-methyl-1-butenyl)formamide S-benzoate O-phosphate
Neurostop
Nitanevril
S-Benzoylthiamine O-monophosphate
S-Benzoylthiamine monophosphate
Tabiomyl
Vitanevril

бенфотиамин [Russian] [INN]

بينفوتيامين [Arabic] [INN]

苯磷硫胺 [Chinese] [INN]

ベンフォチアミン

Title: Benfotiamine

CAS Registry Number: 22457-89-2

CAS Name: Benzenecarbothioic acid S-[2-[[(4-amino-2-methyl-5-pyrimidinyl)methyl]formylamino]-1-[2-(phosphonooxy)ethyl]-1-propenyl] ester

Additional Names: thiobenzoic acid S-ester with N-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-N-(4-hydroxy-2-mercapto-1-methyl-1-butenyl)formamide O-phosphate; S-benzoylthiamine monophosphate; BTMP

Trademarks: Biotamin (Sankyo); Vitanevril (Sanofi Winthrop)

Molecular Formula: C19H23N4O6PS

Molecular Weight: 466.45

EINECS:245-013-4
LD₅₀:2200 mg/kg (M, i.v.); 15 g/kg (M, p.o.)
ATC:A11DA03

Percent Composition: C 48.92%, H 4.97%, N 12.01%, O 20.58%, P 6.64%, S 6.87%

Literature References: Vitamin B1 source. Prepn: A. Ito et al., DE 1130811 (1962), C.A. 57, 13764h (1962). Exists as 3 temperature dependent crystalline forms, a, g, d: A. Ito et al., Takamine Kenkyusho Nempo 14, 64 (1962); C.A. 59, 3920a (1963). Pharmacokinetics: H. Nogami et al., Chem. Pharm. Bull. 18, 1937 (1970). Clinical bioequivalence to thiamine: R. Bitsch et al., Ann. Nutr. Metab. 35, 292 (1991).

Properties: Crystals, dec 165° (d-form).

Therap-Cat: Vitamin (enzyme cofactor).

thiamine, CAS 59-43-8

Benfotiamine (rINN, or S-benzoylthiamine O-monophosphate) is a synthetic S-acyl derivative of thiamine (vitamin B1).

It has been licensed for use in Germany since 1993 under the trade name Milgamma. (Combinations with pyridoxine or cyanocobalamin are also sold under this name.) It is prescribed there for treating sciatica and other painful nerve conditions.^[1]

It is marketed as a medicine and/or dietary supplement, depending on the respective Regulatory Authority.^{[citation needed]}

Uses

Benfotiamine is primarily marketed as an antioxidant dietary supplement. In a clinical study with six patients, benfotiamine lowered AGE by 40%.^[2]

Benfotiamine may be useful for the treatment of diabetic retinopathy, neuropathy, and nephropathy however “Most of the effects attributed to benfotiamine are extrapolated from in vitro and animal studies. Unfortunately apparent evidences from human studies are scarce and especially endpoint studies are missing. Therefore additional clinical studies are mandatory to explore the therapeutic potential of benfotiamine in both diabetic and non-diabetic pathological conditions”.^[3] It is thought that treatment with benfotiamine leads to increased intracellular thiamine diphosphate levels,^[3] a cofactor of transketolase. This enzyme directs advanced glycation and lipoxidation end products (AGE’s, ALE’s) substrates to the pentose phosphate pathway, thus reducing tissue AGEs.^[4]^[5]^[6]^[7]^[8]

Image result for benfotiamine

Pharmacology

After absorption, benfotiamine can be dephosphorylated by cells bearing an ecto-alkaline phosphatase to the lipid-soluble S-benzoylthiamine.^[9] Benfotiamine should not be confused with allithiamine, a naturally occurring thiamine disulfide derivative with a distinct pharmacological profile.^[10]

PATENT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=48F4CE7167F2EB243FBAF807987983D5.wapp1nB?docId=WO2014059702&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

The Benfotiamine, disclosed in US pat. no. 19623064000 US english names: S-benzoylthiamine O-monophosphate common name: Benfotiamine, chemical name: S − 2-[ [ (2-methyl-4-amino-5-pyrimidinyl) methyl ]-propionylamino ]-5-phosphonato-2-pentene-3-thiol benzoate, formula C 19 H 23 N 406 PS molecular weight 466.45 the following structural formula:

Chemical composition of the same species, in various physico-chemical conditions, crystallization into two or more different structure of the crystalline phenomenon, also referred to as polymorphs or homogeneous an image drug polymorph is a common phenomenon of drug discovery, drug quality is an important factor. Various polymorphs have different physical properties such as appearance, melting point, hardness, dissolution rate, chemical stability, mechanical stability, etc. differences, these differences in the physical properties of the sometimes affect the stability of the drug, bioavailability, even the drug availability. Thus, in drug development, it should be fully considered drug poly-type problems, the type of study and control in drug development of significant research content.

The benfotiamine, vitamin B 1 lipid-soluble derivatives, improved water-soluble vitamins B1 low bioavailability of disadvantages, increased blood and tissues. Thiamine concentration, thereby enhancing efficacy. The primary application to the following aspects (1) for thiamine deficiency disease prevention and treatment; (2) vitamin B 1 demand increases, from the food uptake is not sufficient make-up, fatigue, hyperthyroidism, gestation, lactation, vigorous manual labor, etc.); (3) for the treatment of non-l 酒性 lopinavir, grams of brain disease; (4) for the treatment of foot disease; (5) for the disease, the speculative and thiamine deficiency and metabolic disorders associated with treatment, such as: neuropathic pain; muscle pain, joint pain ; Peripheral-inflammatory, peripheral nerve

The paralysis; myocardial metabolism disorders, constipation, gastrointestinal motility dysfunction. The benfotiamine as vitamin B 1 supplemental agents have been in the united states, japan, europe, etc worldwide market. Recent studies have shown that, benfotiamine in diabetic peripheral neuropathy and retinopathy of significant therapeutic effect. In addition, our studies, benfotiamine may also be applied to the prevention and treatment of alzheimer’s disease, and aging.

Alzheimer’s disease (Altheimer’s disease, AD) is a cognitive, behavioral disorders is the primary clinical manifestations progressive neurodegenerative diseases, an age-related disorders, with age, their prevalence is a significant rise. 我国 the number of people in excess of 600 million AD patients, it is contemplated that in 2050 worldwide by the year AD patient may exceed 3000 million people as the medical scientific development, severe affect human health, mortality is a leading significant diseases such as cancer, stroke, cardiovascular disease, exhibit a decrease in mortality year by year, and AD mortality the rendering large increase in . In addition, alzheimer’s disease course long, the disabling rate is high, thus, alzheimer’s disease will be the 21 st century threaten both human diseases the most serious. It is estimated that worldwide by the year AD 2010 for medical costs up to 6040 of millions of dollars, the same global of the gross national product of 1%

China and the USA, the world there have been the following two classes of drugs approved for AD treatment: cholinesterase inhibitors and N-methyl D-aspartate (NMDA) receptor antagonist are both improved AD patient symptoms, slow disease progression does not prevent or reverse the progression of a disease. The benfotiamine by inhibiting the sugar synthase kinase -3 (Glycogen synthase kinase -3, GSK -3) activity, decrease in brain beta-amyloid protein (beta-amyloid, alpha beta) the deposition and tau protein phosphorylation, reduce alzheimer’s disease, pathological damage.

Presently available, benfotiamine primarily in the form of tablets and powders is administered in the form of, all formulations are not related to the benfotiamine feedstock form has not yet been the benfotiamine crystalline be systematically studied, the present US pat. no. first for benfotiamine of systematic study of various forms, illustrating different form benfotiamine characteristics and their feasibility. As a pharmaceutical agent

Thiamine derivatives such as thiamine monophosphate dihydrate and S-benzoyl thiamine monophosphate compounds and salts thereof are useful as therapeutics and nutrients. Further, some of the thiamine derivatives are known to be biochemically important compounds.

There are processes known where thiamine derivatives have been prepared by reacting thiamine with polyphosphoric acid derived from phosphoric acid; heating of the two gives a mixture of thiamine phosphate comprising thiamine 0- monophosphate, thiamine O-diphosphate, thiamine O-triphosphate and thiamine O-polyphosphate. Each polyphosphate may be isolated from the reaction mixture. However, the above prior process is commercially unpractical, because yields of the desired phosphates isolated are extremely poor.

In another process, orthophosphoric acid is used as phosphorylating agent to convert thiamine hydrochloride into thiamine monophosphate. The process demands heating acids like orthophosphoric acid which is considered to be highly unsafe up to 270° C. Moreover, this prior art process does not produce the desired product immediately after work up. The process requires 7 days to get all higher phosphates derivatives eq. Thiamine diphosphate (cocarboxylase) and thiamine triphosphate to convert into thiamine monophosphate. The prepared thiamine monophosphate dihydrate is converted into S-benzoyl thiamine monophosphate by reaction with benzoyl chloride or dibenzyl sulfide or Sodium benzoyl thiosulfate. Due to such drastic conditions the intermediate purity and in turn the product purity is extremely poor requiring series of purification steps.

In yet another process, compounds like P₂0₅ which are unsafe from operation point of view since it requires changing into orthophosphoric acid at considerably high temperature. This process gives the mixture of mono, di, tri and tetra phosphate derivatives of thiamine. The process provides that even after hydrolysis, the reaction mass contains only 61 -62% desired thiamine monophosphate dihydrate along with 31 -32 % cocarboxylase and 2-3 % thiamine triphosphate. Further, it requires their separation by means of techniques like Ion Exchange which is again troublesome and not advantageous from process point of view.

Thus, the processes known hitherto for the production of such thiamine derivatives such as thiamine monophosphate dihydrate and S-benzoyl thiamine monophosphate compounds and salts thereof have cost and/or lower yield with poor quality disadvantages. The prior art processes also suffer in that the workup of reaction mass is tedious which eventually increases the manufacturing cost.

PATENT

WO 2016079576

Preparation of Thiamine monophosphate

To the solution of 2500 g of Polyphosphoric acid and 25 g sodium pyrophosphate was added 700 g thiamine hydrochloride chloride and the mixture was heated slowly at 120 Deg C. After the ceasing of HCI gas evolution, which generally takes 3-4 hours. It was maintained for 2 hours and was further cooled to 50 Deg C. HPLC analysis shown the following analysis 7% of cocarboxylase ( thiamine diphosphate)

88.0% of thiamine monophosphate

1 .0% of thiamine triphosphate

1 .5% of thiamine chloride After cooling hot deminerahzed water was added and the reaction mass heated to 90 Deg C. The reaction mass was maintained at this temperature for 5-6 hours.

HPLC analysis of reaction mass shown the following analysis. 1 % of cocarboxylase

95% of thiamine monophosphate

1 .0% of thiamine chloride The reaction mass is allowed to cool up to 25 Deg C. To this was added 4000 ml Tri-n-butyl amine and 5000 ml chloroform. The two layer formed was separated and product was recovered from aqueous layer by adding 5000 ml methanol by filtration. Dry weight of thiamine monophosphate dihydrate was 862 g (almost 100 % yield ) of purity 99 % by HPLC. Melting point 198-200 Deg C.

EXAMPLE 2

Preparation of S-benzoyl thiamine monophosphate 100 g thiamine monophosphate dihydrate was added to 300 ml water and cooled up to 0 to 5 Deg C. 10 % caustic solution is run in to this solution to make pH 8 – 10. 75 g of benzoyl chloride was added drop wise to the mixture with stirring within 4 hours and maintained the reaction mixture alkaline by occasional addition of 25% aqueous sodium hydroxide. After the completion of reaction, the mass is concentrated to dryness and the product was isolated by adding acetone. The precipitated solid was filtered and dried. Dry weight of product was 75 g.

EXAMPLE 3 Preparation of Lithium salt of S-benzoyl thiamine monophosphate

To a mixture of 12 g of S-benzoyl thiamine O-monophosphate dihydrate with 35 ml of water is added with stirring and ice cooling a 10% solution of lithium hydroxide to adjust pH to about 8.0. The resulting solution is filtered, added with acetone and allowed to stand at cold place to precipitate crystals of Lithium salt of S-benzoyl thiamine O-monophosphate. The crystals are filtered and dissolved in a small amount of water. Acetone is then added to the solution to give a recrystallization of purified product, which is dried in vacuum oven. Yield -9 g and MP – decomposes at about 190°C. EXAMPLE 4

Preparation of Barium salt of S-benzoyl thiamine monophosphate

To a mixture of 15 g of S-benzoyl thiamine O-monophosphate dihydrate with 35 ml of water is added with stirring and ice cooling a 10% solution of Barium hydroxide to adjust pH to about 8.0. The resulting solution is filtered, added with acetone and allowed to stand at cold place to precipitate crystals of Barium salt of S-benzoyl thiamine O-monophosphate. The crystals are filtered and dissolved in a small amount of water. Acetone is then added to the solution to give a recrystallization of purified product, which is dried in vacuum oven. Yield 9 g and melt with decomposition at 180 Deg C. EXAMPLE 5

Preparation of Magnesium salt of S-benzoyl thiamine monophosphate

To a mixture of 15 g of S-benzoyl thiamine O-monophosphate dihydrate with 35 ml of water is added with stirring and ice cooling a 10% solution of Magnesium hydroxide to adjust pH to about 8.0. The resulting solution is filtered, added with acetone and allowed to stand at cold place to precipitate crystals of Magnesium salt of S-benzoyl thiamine O-monophosphate. The crystals are filtered and dissolved in a small amount of water. Acetone is then added to the solution to give a recrystallization of purified product, which is dried in vacuum oven. Yield 9 g and melt with decomposition at 205 Deg C.

WO 2014059702

PATENT

IN 2014MU03690

STR1

PATENT

CN 104418889

CN 103772432

PATENT

http://www.google.com/patents/CN103772432A?cl=en

Example 1:

Was added to the reaction kettle 4000kg polyphosphoric acid, heated to 100 ~ 120 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after kept at this temperature range 8 hours, was added water quenching 3000kg off after the reaction, the temperature was raised to 80-90 ° C hydrolysis of 10 hours; cooled to room temperature, was added to the kettle 5000kg trioctylamine mixture of methyl tert-butyl ether = WPA / 1/1; aqueous phase 5000kg methanol to precipitate a solid, centrifuged to obtain a monoester 1200kg vitamin BI phosphoric acid crude; the 1200kg Vitamin `prime BI phosphate monoester crude in 6000kg water mixed beating, down to O ~ 5 ° C, dropping liquid in this temperature range adjusting the PH value of the base system to 12.0 ~ 14.0; PH after adjustment to ensure that the reactor temperature 10 ~ 25 ° C within 1200kg of benzoyl chloride was added dropwise, after the addition is complete heat the reaction to completion; filtered and the filtrate adjust PH from 3.5 to 4.0 precipitated solid was isolated and dried to give a white solid 1200kg, namely benfotiamine. Yield: 77.38%, Purity: 98.70% ο

Example 2:

Was added to the reaction kettle 5000kg polyphosphoric acid, heated to 80 ~ 100 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after kept at this temperature range 6 hours, was added water quenching 5000kg off after the reaction was heated to reflux for 5 hours hydrolysis; cooled to room temperature, the autoclave was added to the mixture was extracted twice 4000kg trioctylamine / methyl tert-butyl ether = 1/1; aqueous phase 6000kg ethanol precipitation The solid obtained by centrifugation vitamin BI phosphate monoester 1200kg crude; after 1200kg vitamin BI crude phosphate monoester product mixing beating in 6000kg water, down to O ~ 5 ° C, solution of caustic soda adjust PH value system in this temperature range to 10.0 ~ 12.0; PH adjusting finished, to ensure the reactor temperature 10 ~ 25 ° C within 1200kg of benzoyl chloride was added dropwise, after the addition is complete heat the reaction to completion; filtered, the solid was filtered, the filtrate was adjusted to 3.5 ~ PH value 4.0 precipitated solid was isolated and dried to give a white solid 1250kg, namely benfotiamine. Yield: 80.61%, Purity: 98.50% ο

Example 3:

After the reactor was added 3000kg polyphosphoric acid, heated to 90 ~ 110 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after the insulation in this temperature range for 5 hours, 5000kg of water quenching off after the reaction, the temperature was raised to 90-100 ° C hydrolysis 5 hours; cooled to room temperature, was added to the kettle 5000kg trioctylamine methyl tert-butyl ether mixture was extracted twice = / 1/1; aqueous phase Join 7000kg acetone precipitate a solid, mono- 1230kg centrifuged to obtain crude vitamin BI phosphoric acid; vitamin BI after 1200kg crude phosphate monoester product mixing beating in 6000kg water, down to O ~ 5 ° C, solution of caustic soda adjusted within this temperature range System PH value to 11.0 ~ 13.0; PH after adjustment to ensure that the temperature of the reactor was added dropwise within 10 ~ 25 ° C within 1200kg benzoyl chloride, and after the addition is complete heat to the completion of the reaction; filtered, the filtrate was adjusted to 3.5 PH value to 4.0 precipitated solid was isolated and dried to give a white solid 1240kg, namely benfotiamine. Yield: 79.96%, Purity: 98.50% ο

Example 4

Was added to the reaction kettle 4000kg polyphosphoric acid, heated to 100 ~ 120 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after kept at this temperature range for 4 hours, water quenching 8000kg off after the reaction, the temperature was raised to 90 – 110 ° C hydrolysis seven hours; cooled to room temperature, was added to the kettle 4000kg trioctylamine / methyl tert-butyl ether mixture was extracted phosphoric = 1/1; aqueous phase 6000kg methanol precipitated solid was centrifuged to give 1200kg vitamin BI phosphate monoester crude; the 1200kg vitamin BI phosphate monoester crude 6000kg water were mixed after beaten, cooled to O ~ 5 ° C, caustic soda was added dropwise at this temperature adjustment range of the system PH value to 9.0 ~ 11.0; PH adjustment finished, the reactor temperature to ensure solution of 10 ~ 25 ° C within 1200kg benzoyl chloride, and after the addition is complete heat to the completion of the reaction; filtered, the filtrate was adjusted to PH value

3.5 to 4.0 precipitated solid was isolated and dried to give a white solid 1260kg, namely benfotiamine. Yield: 81.24%, Purity: 98.70% ο

Example 5

Was added to the reaction kettle 5000kg polyphosphoric acid, heated to 110 ~ 130 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after kept at this temperature range for 3 hours, water quenching 10000kg off after the reaction, the temperature was raised to 110 – 120 ° C under reflux for 3 hours hydrolysis; cooled to room temperature, the mixture was extracted phosphoric acid was added to the kettle 3000kg trioctylamine / methyl tert-butyl ether = 1/1; aqueous phase `6000kg ethanol was added to precipitate a solid, obtained by centrifugation 1200kg vitamin BI phosphate monoester crude; after 1200kg vitamin BI phosphate monoester crude mixing beating in 6000kg water, down to O ~ 5 ° C, solution of caustic soda in this temperature range adjusting the PH value of the system to the 8.0 ~ 10.0; PH adjusting finished, 1200kg of benzoyl chloride was added dropwise to ensure the kettle temperature within 10 ~ 25 ° C, after the addition is complete heat the reaction to completion; filtered, the filtrate was adjusted to PH value 3.5 to 4.0 precipitated solid was isolated and dried to give a white solid 1230kg, namely benfotiamine. Yield: 79.31%, purity: 98.60% ο

PATENT

Figure CN102911208AD00041

http://www.google.com/patents/CN102911208A?cl=en

Example I: Phosphorus oxychloride 15. 33g (O. Imol) was added to the water 10. 8mL, placed in an ice bath with stirring O. 5 hours was added portionwise thiamine 26. 53g (O. lmol), warmed to 50 ° C followed by stirring for 2 hours, cooled to room temperature to obtain a solution of phosphorus thiamine, thiamine HPLC phosphorus content of 91.36%, adjusted with 15% NaOH solution to pH 8_9 the solution was added 28. Ilg (O. 2mol) benzoyl chloride, the 0_5 ° C under stirring, monitoring the reaction solution and pH changes, the pH value is stable, does not change when the reaction liquid PH, stirring was continued for I hour the reaction, the solution was adjusted to pH 3. 5-4. 0, suction filtration to give 33. 58g benfotiamine white solid. Yield 71.9%.

MP: 164-165 ° C; H1 NMR (400MHz, CDCl3): 2.18 (s, 3H), 2.56 (s, 3H), 2 58 (t, / = 6 7,2H.), 4.. 33 (t, / = 6.7,2H), 4. 83 (s, 2H), 7. 44 (m, 2H), 7. 57 (dd, / = 7. 3, J = I. 5, 1H), 7. 60 (m, 2H), 7. 70 (s, 1H), 8. 67 (s, 1H).

Example 2: Phosphorus oxychloride 15. 33g (O. lmol) was added to a 7. 2mL of water, placed in an ice bath with stirring O. 5 hours was added portionwise thiamine 21. 23g (O. OSmol), warmed to 60 ° C followed by stirring for 2 hours, cooled to room temperature to obtain a solution of phosphorus thiamine, thiamine HPLC phosphorus content of 92.37%, adjusted with 15% NaOH solution to pH 8_9 the solution was added 28. Ilg (O. 2mol) benzoyl chloride, stirred at 0-5 ° C, and monitoring the pH of the reaction solution changes, stable pH, the reaction solution PH does not change when the stirring was continued for I hour the reaction, the solution pH adjusted to 3. 5-4. 0, suction filtration to give 27. 69g benfotiamine white solid. Yield 74.2%.

MP: 164-165 ° C; H1 NMR (400MHz, CDCl3):.. 2.18 (s, 3H), 2 56 (s, 3H), 2 58 (t, / = 6 7,2H.), 4. 33 (t, / = 6.7,2H), 4. 83 (s, 2H), 7. 44 (m, 2H), 7. 57 (dd, / = 7. 3, / = 1. 5, 1H ), 7. 60 (m, 2H), 7. 70 (s, 1H), 8. 67 (s, 1H).

Example 3: Phosphorus oxychloride 15. 33g (O. lmol) was added to a 3. 6mL of water, placed in an ice bath with stirring O. 5 hours was added portionwise thiamine 15. 92g (O. 06mol), warmed to 70 ° C followed by stirring for 2 hours, cooled to room temperature to obtain a solution of phosphorus thiamine, thiamine HPLC phosphorus content of 93.23%, adjusted with 15% NaOH solution to pH 8_9 the solution was added 28. Ilg (O. 2mol) benzoyl chloride, stirred at 0-5 ° C, and monitoring the pH of the reaction solution changes, stable pH, the reaction solution PH does not change when the stirring was continued for I hour the reaction, the solution pH adjusted to 3. 5-4. 0, filtration, benfotiamine was a white solid 23. 71g. Yield 84.7%.

MP: 164-165 ° C; H1 NMR (400MHz, CDCl3): 2.18 (s, 3H), 2.56 (s, 3H), 2 58 (t, / = 6 7,2H.), 4.. 33 (t, / = 6.7,2H), 4. 83 (s, 2H), 7. 44 (m, 2H), 7. 57 (dd, / = 7. 3, / = 1. 5, 1H), 7. 60 (m, 2H), 7. 70 (s, 1H), 8. 67 (s, 1H).

Example 4: Phosphorus oxychloride 15. 33g (O. lmol) was added to a 7. 2mL of water, placed in an ice bath with stirring O. 5 hours was added portionwise thiamine 10. 62g (O. 04mol), warmed to 80 ° C followed by stirring for 2 hours, cooled to room temperature to obtain a solution of phosphorus thiamine, thiamine HPLC phosphorus content of 95.26%, adjusted with 15% NaOH solution to pH 8_9 the solution was added 28. Ilg (O. 2mol) benzoyl chloride, stirred at 0-5 ° C, and monitoring the pH of the reaction solution changes, stable pH, the reaction solution PH does not change when the stirring was continued for I hour the reaction, the solution pH adjusted to 3. 5-4. 0, filtration, benfotiamine was a white solid 15. 22g. Yield 85.2%.

PATENT

http://www.google.com/patents/CN103724374A?cl=en

Synthesis I) thiamine monophosphate hydrochloride

In the reaction flask was added phosphate, thiamine hydrochloride, phosphorous pentoxide was added and stirred to dissolve, controlling the reaction temperature to complete the reaction thiamine hydrochloride, was added and stirring was continued after dropwise addition of concentrated hydrochloric acid hydrolysis of purified water was added dropwise acetone crystallization dropwise at raising grain, filtration, washed with acetone crystal, vacuum drying intermediates thiamine monophosphate hydrochloride;

2) Synthesis of crude benfotiamine

In the reaction flask thiamine monophosphate hydrochloride, dissolved in purified water, sodium hydroxide was added dropwise to adjust the pH to alkaline and steady, benzoyl chloride, sodium hydroxide was added dropwise while controlling alkaline pH, to control the temperature of the reaction pH remained stable, the end of the reaction, concentrated hydrochloric acid was added and extracted twice with ethyl acetate, the aqueous phase of sodium hydroxide was added dropwise until the pH is acidic, crystal seeding planting, filtration, purified water and acetone crystal, vacuum drying crude benfotiamine;

References

1 “BBC news story: Back pain drug ‘may aid diabetics'”. BBC News. 18 February 2003.
2
J Lin, A Alt, J Liersch, RG Bretzel, M Brownlee (May 2000). “Benfotiamine Inhibits Intracellular Formation of Advanced Glycation End Products in vivo” (PDF). Diabetes. 49 (Suppl1) (A143): 583.
3
Balakumar P, Rohilla A, Krishan P, Solairaj P, Thangathirupathi A (2010). “The multifaceted therapeutic potential of benfotiamine”. Pharmacol Res 61 (6): 482–8. doi:10.1016/j.phrs.2010.02.008. PMID 20188835.
4
Since AGEs are the actual agents productive of diabetic complications, in theory, if diabetic patients could block the action of AGEs completely by benfotiamine, strict blood sugar control, with its disruption of lifestyle and risks to health and life by severe hypoglycemic episodes, could be avoided, with revolutionary implications for the treatment of diabetes. Hammes, HP; Du, X; Edelstein, D; Taguchi, T; Matsumura, T; Ju, Q; Lin, J; Bierhaus, A; Nawroth, P; Hannak, D; Neumaier, M; Bergfeld, R; Giardino, I; Brownlee, M (2003). “Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy”. Nat Med 9 (3): 294–299. doi:10.1038/nm834.
5
Stirban A, Negrean M, Stratmann B; et al. (2007). “Adiponectin decreases postprandially following a heat-processed meal in individuals with type 2 diabetes: an effect prevented by benfotiamine and cooking method”. Diabetes Care 30 (10): 2514–6. doi:10.2337/dc07-0302. PMID 17630265.
6
Stracke H, Hammes HP, Werkmann D; et al. (2001). “Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats”. Exp. Clin. Endocrinol. Diabetes 109 (6): 330–6. doi:10.1055/s-2001-17399. PMID 11571671.
7
Stirban A, Negrean M, Stratmann B; et al. (2006). “Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes”. Diabetes Care 29 (9): 2064–71. doi:10.2337/dc06-0531. PMID 16936154.
8
Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ (2003). “Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine”. Diabetes 52 (8): 2110–20. doi:10.2337/diabetes.52.8.2110. PMID 12882930.
9
Yamazaki, M (1968). “Studies on the absorption of S-benzoylthiamine O-monophosphate : (I) Metabolism in tissue homogenates”. Vitamins 38 (1): 12–20.
10

Volvert, M.L.; Seyen, S.; Piette, M.; Evrard, B.; Gangolf, M.; Plumier, J.C.; Bettendorff, L. (2008). “Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives”. BMC Pharmacology 8 (1): 10. doi:10.1186/1471-2210-8-10. PMC 2435522. PMID 18549472.

External links

BBC news story (2003): Back pain drug ‘may aid diabetics’

CN101654464A *	Jul 28, 2009	Feb 24, 2010	湖北华中药业有限公司;湖北制药有限公司	Method for synthesizing vitamin B1 phosphatic monoester
CN102766163A *	Jun 29, 2012	Nov 7, 2012	暨明医药科技（苏州）有限公司	Synthesis method of phosphate monoester of vitamin B1
CN102911208A *	Sep 25, 2012	Feb 6, 2013	同济大学	Method for synthesizing benfotiamine
CA682778A *		Mar 24, 1964	Sankyo Kabushiki Kaisha	S-benzoylthiamine o-monophosphate and a process for preparing the same
US3507854 *	Apr 7, 1965	Apr 21, 1970	Sankyo Co	Process for preparing thiamine derivatives

CN103772432A *	Jan 3, 2014	May 7, 2014	湖北瑞锶科技有限公司	Production method of benfotiamine
CN103772432B *	Jan 3, 2014	Jan 20, 2016	湖北瑞锶科技有限公司	一种苯磷硫胺的生产方法

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Benfotiamine
Systematic (IUPAC) name


S-[2-{[(4-Amino-2-methylpyrimidin-5-yl)methyl] (formyl)amino}-5-(phosphonooxy)pent-2-en-3-yl] benzenecarbothioate
Clinical data
Trade names	Milgamma
AHFS/Drugs.com	International Drug Names
Legal status	OTC
Routes of administration	Oral
Identifiers
CAS Number	22457-89-2
ATC code	A11DA03
PubChem	CID 3032771
ChemSpider	2297665
UNII	Y92OUS2H9B
ChEBI	CHEBI:41039
ChEMBL	CHEMBL1491875
Synonyms	S-Benzoylthiamine O-monophosphate
Chemical data
Formula	C₁₉H₂₃N₄O₆PS
Molar mass	466.448 g/mol

Hamanaka, Wataru; JP 37011040 B 1962
(3) Koltunova, V. I.; Zhurnal Obshchei Khimii 1969, V39(1), P102-9
(4) GB 896089 1962 CAPLUS
(5) “Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US)
(6) Sunagawa, Genshun; JP 37013483 B 1962

///////benfotiamine, бенфотиамин , بينفوتيامين , 苯磷硫胺 , ベンフォチアミン

O=P(O)(O)OCCC(/SC(=O)c1ccccc1)=C(/N(C=O)Cc2cnc(nc2N)C)C

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Mechanism

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Fidaxomicin

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Synthesis Path

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Bromuconazole

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Details see below

Mechanism of action

Efficacy

Safety

OR

Synthesis of saroglitazar

1. 2-Bromo-1-[4-(methylthio)phenyl]ethanone is condensed with methyl acetoacetate in the presence of NaOMe and Na2SO4 in toluene, to give alpha-keto methyl ester ,

2. This alpha-keto methyl ester ,is hydrolyzed and decarboxylated by means of NaOH in MeOH/toluene at 50 °C giving diketone .

3. Diketone is subjected to Paal-Knorr reaction with ethanolamine in the presence of pivallic acid in toluene at 110 °C to yield pyrrole primary alcohol derivative .

4. Sulfonylation of this pyrrole primary alcohol with MsCl in the presence of Et3N,

5. O-alkylation of mesylate with ethyl 2(S)-ethoxy-3-(4-hydroxyphenyl)propionate in the presence of K2CO3, optionally in the presence of 18-crown-6 in toluene/THF at 80 °C provides ether.

6. Finally, hydrolysis of ethyl ester using NaOH in H2O affords the target saroglitazar.

PATENT

REFERENCES

Lipaglyn – The world’s first drug for treating Diabetic Dyslipidemia combines lipid and glucose lowering effects in one single molecule.

Zydus to present new scientific data on Lipaglyn in the US

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Indication

Mechanism of action

WO2009126863A2: also see Ref. 1. It all started from here.

Experimental: 1H NMR (400MHz, CDCl3) δ (ppm): 9.58 (bs, 1H), 8.43 (d, J = 4.7Hz, 1H), 8.03 (dd, J = 2.6, 8.7Hz, 1H), 7.90 (d, J = 1.6Hz, 1H), 7.67-7.78 (m, 4H), 7.60 (d, J = 8.0Hz, 1H), 7. 51 (d, J = 8.8Hz, 1H), 7.23-7.24 (m, 1H), 3.01 (s, 3H).

UPDATES…….

Manufacturing Development and Genotoxic Impurity Control Strategy of the Hedgehog Pathway Inhibitor Vismodegib

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Pankaj Patel, chairman, Zydus Cadila

EXAMPLES

Example-1

Preparation of 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one

Example-2

Preparation of 3-bromo-5-2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one

Example-3

Preparation of Perampanel

Example-4

Preparation of 3-Bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one

Example-5

Preparation of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one

Example-6

Purification of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one

Example-7

Preparation of Perampanel

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Uses

Experimental: ¹H NMR (400MHz, CDCl₃) δ (ppm): 9.58 (bs, 1H), 8.43 (d, J = 4.7Hz, 1H), 8.03 (dd, J = 2.6, 8.7Hz, 1H), 7.90 (d, J = 1.6Hz, 1H), 7.67-7.78 (m, 4H), 7.60 (d, J = 8.0Hz, 1H), 7. 51 (d, J = 8.8Hz, 1H), 7.23-7.24 (m, 1H), 3.01 (s, 3H).