Tuesday, 15 September 2015

Pregabalin


Figure imgf000006_0004
Figure imgf000006_0005
15 16 (S)-Pregabalin
Figure imgf000010_0001
Figure imgf000011_0001

Example 7: Preparation of (S) Pregabalin from compound 19
1Og of compound 19 is dissolved in 440 ml 6 N HCl, and the solution is warmed to 125°C for 15 hours. After cooling, the mixture is diluted with water, and extracted three times with dichloromethane, then the aqueous phase is evaporated. After drying under high vacuum, the (S)-Pregabalin hydrochloride is obtained as crystals. (S)-Pregabalin is further resolved by dissolving (S)-Pregabalin hydrochloride in isobutanol, and then adding triethyl amine. The mixture is stirred for 45 minutes, and the product is filtered, washed with isobutanol.

Publication numberWO2006110783 A2
Publication typeApplication
Application numberPCT/US2006/013565
Publication dateOct 19, 2006
Filing dateApr 11, 2006
Priority dateApr 11, 2005
Also published asCA2603215A14 More »
InventorsAsher MaymonVinod Kumar KansalLilach Hedvati
ApplicantTeva PharmaAsher MaymonVinod Kumar KansalLilach Hedvati
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External Links: PatentscopeEspacenet










Citing PatentFiling datePublication dateApplicantTitle
WO2008007145A2 *Jul 12, 2007Jan 17, 2008Generics Uk LtdProcess of preparing a gamma-amino acid
WO2008117305A2 *Mar 3, 2008Oct 2, 2008Venkata Siva Kumar BobbaA novel process for preparing pregabalin and its acid addition salts
WO2009010554A1 *Jul 17, 2008Jan 22, 2009Esteve Labor DrProcess for the enantioselective preparation of pregabalin
WO2009022839A2 *Aug 11, 2008Feb 19, 2009Korea Advanced Inst Sci & TechNovel method for preparing pregabalin
WO2009080365A1 *Dec 18, 2008Jul 2, 2009Synthon BvPregabalin salts
WO2009081208A1 *Dec 19, 2008Jul 2, 2009Generics Uk LtdProcesses to pregabalin
WO2009087650A2 *Oct 14, 2008Jul 16, 2009Sundeep AuroraA novel process for synthesis of pregabalin from substituted cyclopropane intermediate and a process for enzymatic resolution of racemic pregabalin
WO2009141362A2 *May 19, 2009Nov 26, 2009Sandoz AgProcess for the stereoselective enzymatic hydrolysis of 5-methyl-3-nitromethyl-hexanoic acid ester
WO2009147434A1 *Jun 3, 2009Dec 10, 2009Generics [Uk] LimitedA novel and efficient method for the synthesis of an amino acid
WO2009149928A1 *Jun 10, 2009Dec 17, 2009Synthon B.V.Processes for making pregabalin and intermediates therefor
WO2014005494A1 *Jun 28, 2013Jan 9, 2014Sunshine Lake Pharma Co., Ltd.Method of preparing lactam compound
EP2017273A1 *Jul 18, 2007Jan 21, 2009Laboratorios del Dr. Esteve S.A.Process for the enantioselective preparation of pregabalin
US7586005Oct 28, 2008Sep 8, 2009Teva Pharmaceutical Industries Ltd.Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid
US7619112Aug 14, 2007Nov 17, 2009Teva Pharmaceutical Industries Ltd.Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid
US7678938Aug 14, 2007Mar 16, 2010Teva Pharmaceutical Industries Ltd.Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid
US7763749May 10, 2006Jul 27, 2010Teva Pharmaceutical Industries Ltd.Method for the preparation of Pregabalin and salts thereof
US7851651Oct 28, 2008Dec 14, 2010Teva Pharmaceutical Industries Ltd.Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid
US7923575Oct 19, 2009Apr 12, 2011Teva Pharmaceutical Industries LimitedAsymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid
US7960583Oct 28, 2008Jun 14, 2011Teva Pharmaceutical Industries Ltd.Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid
US7973196Aug 30, 2010Jul 5, 2011Teva Pharmaceutical Industries Ltd.Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid
US8097754Mar 24, 2008Jan 17, 2012Teva Pharmaceutical Industries Ltd.Synthesis of (S)-(+)-3-(aminomethyl)-5-methyl hexanoic acid
US8212071Nov 4, 2008Jul 3, 2012Teva Pharmaceutical Industries Ltd.Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid
US8546112May 19, 2009Oct 1, 2013Sandoz AgProcess for the stereoselective enzymatic hydrolysis of 5-methyl-3-nitromethyl-hexanoic acid ester

Tuesday, 8 September 2015

India rejects patent on Pfizer's arthritis drug

India rejects patent on Pfizer's arthritis drug


Mumbai: India has again denied Pfizer Inc a patent on its rheumatoid arthritis drug tofacitinib, the latest setback for a multinational drugmaker seeking to enforce its intellectual property rights in the country.
Representational image. AFP
Representational image. AFP
Pfizer sought a patent that covers an important chemical formulation of the active compound in the medicine, but the Indian Patent Office said the company would have to establish that the compound for which it is seeking a patent is therapeutically more effective than the active compound.

Monday, 7 September 2015

WO 2015129603, NEW PATENT, Daiichi Sankyo Co Ltd, Edoxaban

HIGH-PURITY CRYSTALS OF ACTIVE BLOOD COAGULATION FACTOR X (FXA) INHIBITOR

DAIICHI SANKYO COMPANY,LIMITED [JP/JP]; 3-5-1,Nihonbashi Honcho,Chuo-ku, Tokyo 1038426 (JP)
Claims highly pure crystalline form of edoxaban p-toluenesulfonate monohydrate. Useful for treating thrombotic diseases. Daiichi Sankyo had developed and launched edoxaban for treating non-valvular atrial fibrillation, deep vein thrombosis and pulmonary embolism, the drug was recently launched in US (in February 2015) and approved in Europe (in June 2015).
The present invention addresses the problem of providing high-purity crystals of a compound which is represented by formula (1a) and is an active blood coagulation factor X (FXa) inhibitor. High-purity crystals of a compound represented by formula (1a) which: are characterised by being obtained by a step for dissolving crystals in a solvent and thereafter performing recrystallisation; have a 0.03% or less maximum content of one impurity as the impurity content by percentage; and have a 0.13% or less total impurity content.
front page image

It shows the inhibitory effect of activated blood coagulation factor X (FXa), a compound useful as a prophylactic and / or therapeutic agent for thrombotic diseases, the following formula (1a)[Formula 1]

In N represented 1 - (5-Chloro-2-yl) -N 2 - ((1S, 2R, 4S) -4 - [(dimethylamino) carbonyl] -2 - {[(5-methyl-4 , 5,6,7-tetrahydro thiazolone [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) Etanjiamido p- toluenesulfonic acid monohydrate [hereinafter, may be referred to as compound (1a) is there
 (Reference Example 1) N 1 - (5-Chloro-2-yl) -N 2 - ((1S, 2R, 4S) -4 - [(dimethylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7 Synthesis of tetrahydro thiazolone [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) Etanjiamido p- toluenesulfonic acid monohydrate (1a) (WO 07 / the method described in 032 498 pamphlet) Was prepared by the method described in WO 07/032498 pamphlet, N 1 - (5-Chloro-2-yl) -N 2 - ((1S, 2R, 4S) -4 - [(dimethylamino) carbonyl] -2 - the {[(5-methyl-4,5,6,7-tetra-hydro thiazolopyridine [5,4-c] pyridine-2-yl) carbonyl] amino} cyclohexyl) Etanjiamido (86.8g), at 60 ℃, it was dissolved in 30% aqueous ethanol (418ml), p- 30% aqueous ethanol solution of toluene sulfonic acid monohydrate (29.0g) a (167ml) was added. The reaction mixture, after stirring for 1 hour at 70 ℃, was gradually cooled to room temperature, ethanol was added, and the mixture was stirred for 16 hours. The reaction solution under ice-cooling, after stirring for 1 hour, The crystals were collected by filtration to give the title compound 102.9g.
 The resulting compound, the absorption peak of the same intensity at the same wave number standard and the (known compound) was observed in the IR.
The obtained compound, in analysis using HPLC, as impurities, a peak of more impurities (both 0.03 wt%) is confirmed, the total of the impurities was 0.16 wt.% Since, its purity was 99.84% (Note that the content of% refers to% of the HPLC area value of the free form of formula (1a) compound).
1 H-NMR (DMSO-d6) delta: 1.45-1.54 (1H, M), 1.66-1.78 (3H, M), 2.03-2.10 (2H, M), 2.28 (3H, s), 2.79 (3H, s), 2.91-3.02 (1H, m), 2.93 (3H, s), 2.99 (3H, s), 3 .13-3.24 (2H, m), 3.46-3.82 (2H, m), 3.98-4.04 (1H, m), 4.43-4.80 (3H, m) , 7.11 (2H, d, J = 7.8Hz), 7.46 (2H, d, J = 8.2Hz), 8.01 (2H, d, J = 1.8Hz), 8.46 ( 1H, t, J = 1.8Hz), 8.75 (1H, d, J = 6.9Hz), 9.10-9.28 (1H, br.s), 10.18 (1H, br.s ), 10.29 (1H, s).
Elemental analysis: Anal. Calcd. For: C; 50.43%, H; 5.46%, N; 13.28%.
Found: C; 50.25%, H; 5.36%, N; 13.32%








/////////////WO 2015129603, NEW PATENT, Daiichi Sankyo Co Ltd, Edoxaban

EUTICALS SPA WO2015128440 New patent CRYSTALLINE FORM OF TIOTROPIUM BROMIDE WITH LACTOSE


WO2015128440
CRYSTALLINE FORM OF TIOTROPIUM BROMIDE WITH LACTOSE
EUTICALS SPA [IT/IT]; Viale Bianca Maria, 25 I-20121 Milano (IT)
A tiotropium bromide and cocrystal of lactose monohydrate is Disclosed HEREIN. In the tiotropium bromide cocrystal the components and lactose are preferably present in stoichiometric ratio An almost. Said cocrystal: has a single endothermic event at about 191-3 ° C Determined by DSC. A process for the preparation of the cocrystal est Disclosed. Preferably, the particle size cocrystal: has a distribution of D90 <10μ. The cocrystal est Disclosed for use as medicine, in Particular for the treatment of a respiratory complaint, Such As chronic obstructive pulmonary disease (COPD), bronchitis, emphysema and asthma.A pharmaceutical composition comprenant the active ingredient as cocrystal est Disclosed, in Particular for administration by inhalation. In the lathing box, Said: has a mean particle cocrystal size of 0.5 to 10 .mu.m, preferably 1 to 6 .mu.m, more preferably 1.5 to 5 microns.
Front page image

Tiotropium bromide (compound identified by CAS registry number 136310-93-5) was described for the first time in 1991 by Boheringer Inghelheim (EP 0418716) and presents the following structural formula:

Tiotropium bromide is an anticholinergic bronchodilator with a long-lasting effect, 24 hours, which may be used to treat respiratory complaints, particularly COPD (chronic obstructive pulmonary disease), bronchitis, emphisema and asthma.
Tiotropium bromide is preferably administered by inhalation: suitable inhalable powders packed into appropriate capsules may be used (Spiriva®; US7694676 and US8022082) or alternatively, it may be administered by the use of inhalable aerosols (EP2201934).
The correct manufacture of the above mentioned compositions, suitable for the administration of a pharmaceutically active substance by inhalation, is based on the definition of physical parameters, like a particular crystalline form (see for example US6608055 and US677423) and a defined particle size distribution (US7070800), which are connected with the nature of the active substance itself.
From literature data, Tiotropium Bromide is described to exist in different polymorphic forms as well as in an amorphous form. In more details, Tiotropium Bromide is described to exist in a crystalline monohydrate form (US6777423), in several anhydrous (US6608055, WO2006/1 17300, EP1682542) and solvate (US7879871 , W02010/101538, WO201 1/015882) polymorphic forms. Some of these polymorphic forms are unstable and may change. For example, the monohydrate form described in US6777423 may be easily transformed after a mild heating at 40°C for few hours into the corresponding anhydrous form described in US6608055.
Since the quality of a pharmaceutical formulation requires that an active substance should always have the same crystalline modification, the stability and properties of the crystalline active substance are subject to stringent regulatory requirements.
There is the need of a crystalline form of tiotropium bromide which is stable to humidity and to mechanical treatments, like the micronization or other milling techniques, and which meets the high demands mentioned above for any pharmaceutically active substance.
It has now surprisingly been found that a crystal modification of tiotropium bromide meeting the above requirements can be obtained in the form of a cocrystal with lactose. Unexpectedly, this cocrystal is stable towards the influence of moisture and humidity and to physical treatments like the micronization.
In the novel cocrystal the components tiotropium bromide and lactose are present in an almost stoichiometric ratio, as determined for example by NMR spectroscopy. Therefore, the present invention relates to a tiotropium bromide-lactose cocrystal in which the components tiotropium bromide and lactose are present, with the limit of resolution of the employed analytical technique (ie H-NMR), in a ratio of about 1 : 1.
This novel cocrystal is characterized by a single endothermic event at about 191-3°C determined by DSC and by an X-Ray spectrum with characteristic 2theta values at 13.08; 14.16; 14.68; 17.90; 18.58; 19.06; 19.44; 21.02; 22.58; 23.24; 25.26; 26.20; 27.24; 28.08; 28.42; 29.96; 30.18; 31.80; 34.50; 34.82; 35.58; 38.70; 39.26; 41.52 and 50.06.
The present invention also relates to the cocrystal herein disclosed for use as a medicament, in particular for the treatment of respiratory complaints, particularly for the treatment of COPD and/or asthma.

Example 1
Preparation of Tiotropium Bromide Cocrystal with lactose in dimethylsulfoxide and acetone
Tiotropium Bromide (4.25g; 8.99 mmoles) and lactose monohydrate (3.58g; 9.9 mmoles) were dispersed at room temperature in dimethylsulfoxide (7.2 ml). The mixture was heated under stirring at the temperature of 50-55°C to obtain a limpid solution. Then acetone (55 ml) was added dropwise in 30' maintaining the reaction mixture under stirring at 50-55°C. The obtained solution was cooled down at 20-25°C and kept at this temperature under stirring for 2 hours. After this period a suspension was obtained. The precipitate was recovered by suction and the wet product slurried in acetone (14.9 ml) under stirring for 90'. The product was recovered by filtration, washed on the filter with acetone (4 times with 8.5 ml each) and dried under vacuum at 40°C for 48 hours to afford 6.76g (8.1 1 mmoles; 90% molar yields) of dry product.
The obtained crystals were analysed by X-Ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and H-NMR (500 MHz) indicating that a new crystalline form, namely a cocrystal of Tiotropiumbromide with lactose is formed.
A representative DRX spectrum of Tiotropium Bromide cocrystal with lactose is shown in Figure 1 (third DRX spectrum from the bottom) overlapped with the DRX spectra of the employed starting materials (from the top respectively the DRX spectra of lactose monohydrate and of Tiotropium Bromide). The list of the characteristic diffraction peaks including normalised intensities of Tiotropium Bromide cocrystal is shown in table 1.
Table 1
2theta Intensity l/lo
11.360 420 21
12.340 453 23
13.080 366 18
13.520 843 42
14.160 1026 51
14.680 1098 54
15.280 659 33
theta Intensity l/lo 5.960 696 35 6.300 524 26 6.960 872 43 7.900 1472 73 8.580 1897 93 9.060 1847 91 9.440 1938 95 0.460 791 39 1.020 826 41 1.720 819 41 2.580 1712 84 3.240 2044 100 3.980 919 45 4.380 853 42 5.260 1499 74 6.200 1156 57 7.240 1240 61 8.080 1554 77 8.420 1935 95 9.960 1043 52 0.180 1024 51 0.500 819 41 0.900 924 46 1.800 1399 69 2.340 960 47 2.980 839 42 3.440 937 46 theta Intensity l/lo 4.500 1032 51 4.820 1424 70 5.580 1196 59 6.380 899 44 6.880 964 48 7.220 917 45 7.740 913 45 7.960 982 49 8.700 1163 57 9.260 1035 51 9.880 833 41 1.520 1396 69 1.940 976 48 3.400 1005 50 3.600 989 49 4.900 1074 53 5.360 893 44 6.920 1001 49 7.480 932 46 8.060 958 47 9.540 1107 55 0.060 1023 51 1.820 995 49 4.440 990 49 5.220 946 47 6.340 960 47 8.100 926 46 The DSC-thermograms of the lactose cocrystal with Tiotropium bromide shows an endothermic event at ca. 191-193°C indicating melting of this material. The obtained DSC-diagram is depicted in Figure 2.
In order to get an idea on the stoichiometry of the obtained cocrystal H-NMR spectra (500 MHz) were recorded. The samples were dissolved in d6-DMSO for analysis. The corresponding spectrum is shown in Figures 3 and 3A. In addition to the characteristic H-NMR signals of tiotropium there is a signal at 4,17 and 4, 18 ppm which is indicative of H1 ' of lactose (integration 1 H; ref Hyunnsook Ko et al. Bull. Korean Chem. Soc. 2005, Vol 26, No12, 2001-6). Integration of this signal compared to the signal at 4,12 ppm of CH 1 and 5 (integration 2H; ref. Zhenguang Lin et al. Spectrochimica Acta Part A 75 (2010), 1 159-1162) of Tiotropium shows that the cocrystal has a stoichiometry which is close to 1 : 1.

EUTICALS SPA





////////WO 2015128440, CRYSTALLINE FORM OF TIOTROPIUM BROMIDE WITH LACTOSE, EUTICALS SPA

IVACAFTOR NEW PATENT WO 2015128882 MSN LABORATORIES PRIVATE LIMITED PRIVATE LIMITED

MSN Labs
WO2015128882
CRYSTALLINE FORMS OF N-(2,4-DI-TERT-BUTYL-5-HYDROXYPHENYL)-1,4-DIHYDRO-4-OXOQUINOLINE-3-CARBOXAMIDE AND PROCESS FOR THE PREPARATION THEREOF
MSN LABORATORIES PRIVATE LIMITED


The present invention relates to crystalline forms ofN-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 and also process for the preparation of said compound of formula- 1 which is represented by the following structural formula:
front page image
Brief description of the invention:
The first aspect of the present invention is to provide a crystalline form of yV-(2,4-di-tert-butyl-5-hydroxy phenyl)- l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter designated as crystalline form-M).
The second aspect of the present invention is to provide a process for the preparation of crystalline form-M of N-(2,4-di-tert-butyl-5-hydroxy phenyl)- 1 ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
The third aspect of the present invention is to provide a crystalline form of N-(2,4-di-tert-butyl-5-hydroxy phenyl)- l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter designated as crystalline form-S).
The fourth aspect of the present invention is to provide a process for the preparation of crystalline form-S of N-(2,4-di-tert-butyl-5-hydroxy phenyl)- 1 ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
The fifth aspect of the present invention is to provide a crystalline form of JV-(2,4-di-tert-butyl-5-hydroxy phenyl)- l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter designated as crystalline form-N).
The sixth aspect of the present invention is to provide a process for the preparation of crystalline form-N of 7V-(2,4-di-tert-butyl-5-hydroxy phenyl)- 1 ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
The seventh aspect of the present invention is to provide an improved process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)- l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
The eighth aspect of the present invention is to provide a process for the preparation of crystalline form-B of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula-1.
Examples:
Example-1: Preparation of N-(2,4-di-tert-butyI-5-hydroxyphenyl)-l,4-dihydro-4-oxo quinoline-3-carboxamide (formula-1)
A mixture of 4-oxo-l,4-dihydroquinoline-3-carboxylic acid (5 gm), N,N-dimethylformamide (50 ml), 1-Hydroxybenzotriazole (HOBT) (3.40 gm), l-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HC1) (5.57 gm), 5-amino-2,4-di-tert-butylphenol (7.36 gm) and triethylamine (6 ml) was stirred for 52 hrs at 25-35° C. Distilled off the solvent completely under reduced pressure. Methanol (75 ml) was added to the obtained compound at 25-35° C and stirred for 45 min at the same temperature.
The reaction mixture was cooled to 0° C to 5° C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the ■ title compound.
Yield: 5 gm; Purity by HPLC: 99.5%.
The PXRD and DSC of the obtained compound are illustrated in figure- 1 and figure-5 respectively.

Claim:
1. A process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3 -carboxamide compound of formula-1 , comprising of reacting 4-oxo- l ,4-dihydroquinoline-3-carboxylic acid

with 5-Amino-2,4-di-tert-butylphenol

in presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), hydroxybenzotriazole (HOBt) and a suitable base in a suitable solvent provides N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l ,4-dihydroquinoline-3- carboxamide compound of formula-1 , optionally purifying the obtained compound from a suitable solvent provides pure compound of formula-1
Use of crystalline Form-M or Form-S or Form-N of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide according to the preceding claims for the preparation of pharmaceutical composition.
..........SEE MORE.......https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015128882&recNum=1&tab=PCTClaims&maxRec=&office=&prevFilter=&sortOption=&queryString=

Dr MSN Reddy, Chairman and Managing Director, MSN Laboratories



MSN Labs
MSN Labs
MSN Laboratories Pvt.Ltd.
MSN House
Plot No: C-24
Industrial Estate, Sanathnagar
Hyderabad - 18 Telangana, INDIA
Phone : +91 40 30438600
Fax : +91 40 30438638

 /////// IVACAFTOR,  NEW PATENT,  WO 2015128882,  MSN LABORATORIES PRIVATE LIMITED,

NEW PATENT, WO 2015128718, HIKAL LIMITED NOVEL ECONOMIC PROCESS FOR VILDAGLIPTIN


WO2015128718, NOVEL ECONOMIC PROCESS FOR VILDAGLIPTIN
HIKAL LIMITED [IN/IN]; 3A, International Biotech Park Hinjewadi 411057 Pune (IN)
The present invention relates to a commercially viable novel process for manufacturing Vildagliptin in high yield with high chemical and chiral purity.
front page image


Vildagliptin is chemically known as l-[{(3-hydroxy-l-adamantyl)amino}acetyl]-2-cyano(s)-pyrrolidine, which is a dipeptidylpeptidase IV (DPP-IV) inhibitor and found usefulness in the treatment of diabetes mellitus. Vilda liptin is represented below:

(Formula I)
Vildagliptin (I) and the process for its preparation was first disclosed in US Patent US 6,166,063. The said process is described in scheme (1) and involves purification by flash chromatography and therefore it can not be manufactured industrially.
Scheme 1:

Formula (1 )
A similar synthesis is subsequently reported in J Med. Chem. 2003, 46, 2774-2789. An improved process is described in PCT Patent Publication WO 2004/092127A1 , which is an improvement over the process in scheme (1) that involves the use of N-chloroacetyl
proline amide (III) in situ, use of Vilsmeier reagent for dehydration of amide to nitrile and replacement of column chromatography with crystallization making the process scalable. Another very similar synthesis of Vildagliptin is described in US Patent Publication US 2008/0167479A1 that involves the modification of dehydration of N-chloroacetyl proline amide (III) in scheme (1) to corresponding nitrile (IV) by using cheaper reagent cyanuric chloride. The related key intermediates 1 -(haloacetyl)-2-cyano pyrroloine are described in several patents although not targeting the synthesis of Vildagliptin. In International PCT Patent Publication WO 98/19998A2 proline amide is treated with bromoacetyl bromide followed by dehydration with TFAA. In another PCT Patent Publication WO 01/96295A2 the method described involve chloroacetylation in THF followed by dehydration with TFAA. In PCT Patent Publication WO 2006/10.0181, a process for the synthesis of l-(haloacetyl)-2-cyano pyrroloine is described wherein the proline amide was coupled with chloroacetyl chloride followed by dehydration of amide using Vilsmeier reagent and its variants e.g., POCl3-DMF, SOCl2-DMF, cyanuric chloride-DMF etc).
According to PCT Patent Publication WO 2004/092127A1 the process described involve coupling of (I) with chloroacetyl chloride in DMF-isopropylacetate followed by dehydration with Vilsmeier reagent to obtain (IV) that was converted to Vildagliptin by reaction with (V) in 2-butanone in presence of KI. Although the chiral purity of the final compound is very good (>99.99%) however there is no indication about yield and chemical purity.
Scheme 2

Formula (1)
The method disclosed in PCT Patent Publication WO 2008/084383A2 is described in scheme (3) that involves in situ preparation of compound (IV) in 66% yield by reaction of- (I) with (II) in DMF-isopropyl acetate followed by the addition of cyanuric chloride and final coupling was carried out in THF to minimize the formation of dialkyl product (VI).

Although the chiral purity is very good the chemical yield is moderate that too after repeated crystallizations thus making the process not feasible commercially. According to PCT Patent Publication WO2010/022690A2 the reaction of chloroacetyl chloride with prolinamide in ether type (THF) solvent resulting triethylamine hydrochloride contaminated amide (III) followed by dehydration with TFAA gave (IV) in 77% yield. The final step to Vildagliptin is carried out in a mixture of DMF, isopropyl acetate and ethyl methyl ketone and the product with 99.9% purity is obtained through a number of crystallization step of different fractions using methyl ethyl ketone. The yield is not reported for final step. It does not appear to be attractive for commercial purpose.
Scheme 4

Formula (1)
An altogether different method for the process of Vildagliptin is described in PCT Patent Publication WO201 1/101861 Al and summarized in scheme (4). The method involves preparation of acid (XI) by two different approaches consisting of coupling bromoacetyl ester (VII) with (V) followed by hydrolysis or formation of imine (X) by the reaction of (V) with 2-oxo acetic acid followed by reduction using NaBH4. All these steps are high yielding. Subsequently Vildagliptin is prepared by coupling of acid (XI) with (XII) using DCC-DMAP. The major drawback of the synthesis appears to be the significantly lower yield of final product after purification moreover the chiral integrity is not disclosed.
Another new approach (scheme 5) is described in PCT Patent Publication WO2012/00421 OA 1 that involves n-formyl protected acid (XIII) formed by the reaction of 3-hydroxy adamentyl amine with 50% aq. glyoxalic acid followed by the coupling of prolinamide with T3P or CDI followed by dehydration using TFAA. The hydrolysis of formyl group with acidic or basic condition produced Vildagliptin. Poor yield in the first step that involved costly 3-hydroxy adamantyl amine might be disadvantageous. Moreover the Yield of Vilgagliptin after final purification is very low and the chemical as well as chiral purity is not disclosed. Therefore this process does not look scalable.
Scheme 5

In yet another PCT Patent Publication WO 2013/083326A1 describes a process that involves the salt formation of prolinamide with chloro or bromo acetic acid followed by coupling with DCC to produce haloacetyl prolinamide which in situ reacted with 2.2 equivalent of 3-hydroxy adamentyl amine to compound (XXI) in 76.5% yield. The Vildagliptin is prepared by dehydration of compound (XXI) by POCI3 or isocyanuric acid in around 75% yields without any mention of chemical or chiral purity. The process does not offer any superiority over prior art except the use of inexpensive dehydrating agent. The use of high excess of 3-hydroxy adamantly amine however makes the process less attractive.

XXI
Accordingly therefore, based on the drawbacks mentioned in all the prior arts, there is an urgent need for economically viable synthesis of highly pure (both chemical and chiral) Vildagliptin to address mainly the drawbacks associated with the prior arts that can be defined as a process that involve use of less hazardous less costly and environment friendly reagents that will give highly pure material with fewer number of steps and finally cost effective.

Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of Vildagliptin of formula (I),

(Formula I)
which comprises the steps of:
(a) obtaining compound of formula (4) by reacting compound of formula (2) with compound of formula (3) under alkaline condition with or without a catalyst using a suitable solvent;
(b) obtaining a compound of formula (5) by hydrolyzing compound of formula (4) in acidic or basic condition with or without solvent;
(c) obtaining compound of formula (9) by reacting compound of formula (5) with (S)- pyrrolidine-2-carboxylic acid methyl ester and its salts of formula (6) in presence of a suitable acid-amine coupling agents in a suitable solvent or a combination of solvents;
(d) obtaining compound of formula (10) by reacting compound of formula (9) wherein R2 is H with compound of formula (7) in alkaline condition in a suitable solvent or a combination of solvents thereof;
(e) obtaining compound of formula (1 1) by reacting compound of formula (9) with ammonia optionally in a suitable organic solvent;
(f) optionally obtaining compound of formula (1 1) by reacting compound of formula (5) with L-prolinamide of formula (8) in presence of a suitable acid-amine coupling agents in a suitable solvent or a combination of solvents;
(g) obtaining compound of formula (12) by reacting compound of formula (10) with ammonia optionally in a suitable organic solvent;
(h) obtaining compound of formula (13) by dehydrating compound of formula (1 1) using a dehydrating agent in a suitable solvent;
(i) obtaining compound of formula (14) by dehydrating compound of formula (12) by a compatible dehydrating agent in a suitable solvent;
(j) obtaining Vildagliptin of formula (1) by dehydrating compound of formula (11),
The above process is illustrated in the followin general synthetic scheme 6):

(3)

Example 16.1: (S)-l-[2-(3-hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine-2-carbonitrile (Vildagliptin)
Dissolved (S)- 1 -[2 -(3 -hydroxy-adamantan- 1 -ylamino)-acetyl] -pyrrolidine-2-carboxylic acid amide (50 g, 1 eq.) by adding 2-Me-THF (250 mL, 10V) under stirring in a clean and dry 1 L 4 neck RBF equipped with magnetic stirrer, thermometer pocket, reflux condenser and an addition funnel. Meanwhile a mixture of trifluoroacetic acid (23.8 mL, 2 eq.) and trifluoroacetic anhydride (43.90 mL, 2.0 eq.) was prepared and added slowly under stirring to the reaction mass over 5-6 h. The stirring continued at 20-25°C for 1 h. The reaction mixture was cooled to 5-10 °C and a solution of K2C03 (214.1 g, 10 eq.) in water (300 mL, 6V) was added slowly over 30 min and stirred for 5-6 h. After complete conversion checked by HPLC, water (200 mL, 2 V) was added and stirred for 10 min. separated organic and aqueous layers. The aqueous layer was extracted using DCM (1 χ 200 mL) (DCM-1). The 2-Me-THF layer was concentrated to isolate crude product. Added aqueous citric acid solution (citric acid - 98 g, 3.0 eq; water - 6V) to crude product and washed the combined aqueous layer with DCM extract obtained above (DCM-1) and then followed by DCM (3 χ 100 mL). Adjusted pH of aqueous layer to 9-10 after DCM wash using aq. ammonia and extracted aqueous layer using DCM (4 x 100 mL). Washed combined DCM layer with water (50 mL, IV). Concentrate DCM layer followed by stripping of ethyl acetate to isolate crude product; yield range: 75-85%. HPLC purity: > 99%. The crude was further purified by crystallization by dissolving under reflux with ethyl acetate (255 mL, 6V w.r.t to crude wt.) and IPA (85 mL, 2V) and crude compound (42.4 g) under stirring It was allowed to cool to 20-25°C and then to 0-5°C and stirred for 1 h at 0-5°C. Filtered the solid formed and washed with chilled ethyl acetate (42.5 mL, 1 V). Suck dried the solid for 3-4 h to get pure Vildagliptin 34.50 g (60-75 %); Ή NMR (CDC13, 400 MHz) δ: 1.52-1.69 (m, 12H); 1.78 (brs, 2H); 2.04-2.38 (m, 6H); 3.37-3.69 (m, 4H); 4.76-4.78 (m, 0.8H); 4.85-4.87 (m, 0.2H).

claim:
(1) An improved process for the synthesis of a compound of formula (I),

(I)
which comprises the steps of:
a) reacting a compound of formula (2) with a compound of formula (3) under alkaline condition with or without a catalyst using a suitable solvent to get a compound of formula (4);

(2) (3) (4)
wherein R2 = H, C2-C6 alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C7-C10 alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc. or the hetero atom can be a part of the chain.
b) hydrolyzing a compound of formula (4) in acidic or basic condition with or without solvent to get a compound of formula (5);

(5)
Wherein R2 = H.
c) reacting a compound of formula (5) with L-proline alkyl ester and its salts of formula (6) in presence of a suitable acid-amine coupling agents in a suitable solvent or a combination of solvents to get a compound of formula (9);

(9) (6)
Wherein R\ = C1-C3 linear, cyclic or branched chain or C7-C10 alkyl aryl group and R2 = H, C2-C6 alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C7-C10 alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc. or the hetero atom can be a part of the chain.
d) reacting a compound of formula (9) with a compound of formula (7) in alkaline condition in a suitable solvent or a combination of solvents thereof to get a compound of formula (10);

(10) (7)
Wherein RP = R3O-CO- or R4SO2- and Ri = Q-C3 linear, cyclic or branched chain or C7-C[0 alkyl aryl group.
e) obtaining compound of formula (1 1) by reacting compound of formula (9) with ammonia optionally in a suitable or anic solvent;

(")
Wherein R2 = H, C2-C6 alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C7-C10 alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc. or the hetero atom can be a part of the chain.
f) optionally obtaining a compound of formula (1 1) by reacting a compound of formula (5) with L-prolinamide of formula (8) in presence of a suitable acid-amine coupling agents in a suitable solvent or a combination of solvents;

(8)
g) reacting a compound of formula (10) with ammonia optionally in a suitable organic solvent to get compound of formula (12);

(12)
Wherein RP = R3O-CO- or R4SO2- h) obtaining a compound of formula (13) by dehydrating a compound of formula ( 1 1) by using a dehydrating agent in a suitable solvent;

(13)
Wherein R2 = H, C2-C6 alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C7-Ci0 alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc. or the hetero atom can be a part of the chain
i) obtaining a compound of formula ( 14) by dehydrating compound of formula (12) by a dehydrating agent in a suitable solvent;

(14)
Wherein RP = R3O-CO- or R4S02-j) dehydrating compound of formula (1 1) using a suitable dehydrating agent in a suitable solvent to get Vildagliptin of formula (I); CLIPPED HERE        SEE MORE IN PATENT

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..................ceremony by Mr. Jai Hiremath, Vice-Chairman and Managing Director, Hikal and his wife

(From Left)
Dr. Peter Pollak, Kannan Unni, Prakash Mehta, Sugandha Hiremath, Baba Kalyani, Jai Hiremath, Shivkumar Kheny,Sameer Hiremath.

Jai Hiremath, Chairman and Managing Director
Jai Hiremath is the Chairman and Managing Director of Hikal Ltd. A Chartered Accountant from England and Wales, he has completed the Advanced Management Program for professionals and entrepreneurs from Harvard University, USA in 2004. He has more than 35 years of experience in the chemical and pharmaceutical industry. Mr. Hiremath established the company in 1988 and under his leadership; Hikal has grown to become one of leading life sciences companies globally.
Mr. Hiremath is the Past President of the Indian Chemical Council (ICC) and the former Chairman of the Chemical Committee of the Federation of Indian Chamber of Commerce and Industry (FICCI). Mr. Hiremath is also a board member of Novartis (India) Ltd and National Safety Council (NSC) of India. Most recently he has been elected to serve as a board member of DCAT (Drug, Chemical and Associated Technology Association) headquartered in New Jersey, U.S.A.
Sameer Hiremath, President and Joint Managing Director
Sameer Hiremath is the President & Joint Managing Director of Hikal Ltd. His responsibilities include overseeing the day to day operations of the company. Mr. Hiremath did his Chemical Engineering from MIT (Maharashtra Institute of Technology), Pune and an MBA cum M.S. degree in Information Technology from Boston University, USA. Over the years, he has held various positions at Hikal including that of Executive Director. He has over 16 years of experience in plant operations and manufacturing at Hikal.

Hikal is headquartered in Mumbai, India.
Hikal Ltd.
Great Eastern Chambers
Sector 11, CBD-Belapur
Navi Mumbai
India - 400 614
Tel: +91-22-3097 3100
Fax: +91-22-2757 4277
//////WO2015128718, HIKAL LIMITED,  NOVEL ECONOMIC PROCESS FOR VILDAGLIPTIN