Sign In to Follow Application
View All Documents & Correspondence

Process For The Preparation Of Dpp Iv Inhibitors

Abstract: The present invention relates to a novel process for the preparation of DPP-IV inhibitors

Get Free WhatsApp Updates!
Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
29 January 2010
Publication Number
31/2011
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2018-03-27
Renewal Date

Applicants

MSN LABORATORIES LIMITED
FACTORY: Sy.No.317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST)-502 329.

Inventors

1. MANNE SATYANARAYANA REDDY
MSN LABORATORIES LIMITED, FACTORY: Sy.No.317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST)-502 329.
2. SAJJA ESWARAIAH
MSN LABORATORIES LIMITED, FACTORY: Sy.No.317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST)-502 329.
3. GHOJALA VENKAT REDDY
MSN LABORATORIES LIMITED, FACTORY: Sy.No.317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST)-502 329.
4. BAIRY KONDAL REDDY
MSN LABORATORIES LIMITED, FACTORY: Sy.No.317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST)-502 329.

Specification

Field of the Invention: The present invention relates to novel process for the preparation of DPP-IV inhibitors, such as l-[[(3-hydroxy-l-adaniantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine compound of formula-1 represented by the following structure Dipeptidylpeptidase IV (DPP-IV) inhibitors are useful in the treatment of diabetes mellitus. Diabetes mellitus is a relatively common disorder which is characterized by hyperglycemia. There are three basic types of diabetes mellitus, type I or insulin-dependent diabetes mellitus (IDDM), type 2 or non-insulin- dependent diabetes mellitus (NIDDM), and type-A insulin resistance Compound of formula-1, is a dipeptidylpeptidase IV (DPP-IV) inhibitor, useful in the treatment of diabetes mellitus preferably non-insulin-dependent diabetes mellitus or Impaired Glucose Metabolism (IGM) or impaired glucose tolerance, arthritis, obesity, osteoporosis, allograft transplantation, calcitonin-osteoporosis, heart failure, neurodegenerative diseases, cardiovascular or renal diseases, and neurodegenerative or cognitive disorders, hyperglycemia, insulin resistance, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis, vascular restenosis, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, retinopathy, nephropathy, neuropathy, syndrome X, ovarian hyper androgenism (polycystic ovarian syndrome), type 2 diabetes, growth hormone deficiency, neutropenia, neuronal disorders, tumor metastasis, benign prostatic hypertrophy, gingivitis and hypertension. Background of the Invention: The compound of formula-1 and process for its preparation is first disclosed in United States patent literature US 6166063. The disclosed process comprises of reaction of l-aminoadamantane-3-ol with 1-chloroacetyl chloride in presence of potassium carbonate in methylene chloride and maintained for about 6 days to provide the compound of formula-1. Thus obtained crude pasty material further purified on silicagel employing SIMS/Biotage Flash chromatography using methanol and methylene chloride as a solvent. It seems to be that the process is not suitable in commercial scale as it involve chromatographic technique for purification. Further involves longer reaction time, which may lead to the increase in cost of production. The compound of formula-1 can exist as the (2S) and (2R) enantiomers. The stereoisomer with the desired biological activity is the (2S) enantiomer. Accordingly, it is desirable to synthesize (2S)-vildagliptin with high stereo chemical purity. Hence it is necessary to obtain the high pure compound of formula-! of desired enatiomer. The compound of formula-1 is one of the important drugs available in the market for the treatment of diabetes. Hence it is advantageous to have an alternate process for preparing the same. Hence the main aspect of the present invention is to provide a novel process for the preparation of compound of formula-1 and also improved process for formula-1 which is economical, commercially viable and also avoids the all the above mentioned problems. Brief description of the Invention: The first aspect of the present invention is to provide a novel process for the preparation of 1-[[(3-hydroxy-1-adamantyl) amino] £K;etyl]-2-cyano-(S)-pyrrolidine compound of formula-1, which comprises of the following steps; a) Reacting l-aminoadamantane-3-ol compound of fonnula-2 with 2-halo acid derivative or its salt compounds of general formula-3 in presence of base in a suitable solvent to provide the corresponding 2-(3-hydroxyadamantan-l-yl amino)acid derivative or its salt compounds of general formula-4, b) hydrolyzing 2-(3-hydroxyadamantan-l-yl amino)acid derivative or its salt compoimds of general formula-4 with a suitable base in presence or absence of a solvent to provide the acid compound of formula-5. c) reacting the compound of fonnula-5 with pyrrolidine-2-carbonitrile compound of formula-6 in presence of a suitable condensing agent to provide the compound of fonnula-l,or condensing the compound of formula-4 with pyrrolidine-2-carbonitrile compound of formula-8 in presence of a suitable base in suitable solvent to provide the compound of formula-1, d) optionally purifying the compound of formula-1 using suitable solvent system provides the pure compound of formula-1. The second aspect of the present invention relates to an improved process for the preparation of compound of formula-1, which comprises of the following steps; a) Reacting the L-prolinamide compound of formula-7 with 2-chloro acetyl chloride in presence of suitable base in a suitable solvent to provide the (S)-l-(2-chloroacetyl)pyrrolidine-2-carboxamide compound of formula-8, b) treating the compound of formula-8 with trifluoroacetic anhydride in a suitable solvent to provide the (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile compound of formula-9, c) reacting the compound of formula-9 with l-aminoadamantane-3-ol compound of fonnula-2 in presence of a suitable base in suitable solvent to provide the compound offormula-1, d) optionally purifying the compound offormula-1 using a suitable solvent provides the pure compound of formula-1. The third aspect of the present invention is to provide novel process for the preparation of pyrrolidine-2-carbonitrile compound of formula-6, which comprises of a) reacting the methyl pyrrolidine-2-carboxylic acid compound of formula-10 with aqueous ammonia in the presence of a suitable solvent to obtain L-prolinamide compound of formula-7, b) treating the compound of formula-7 with Di-rerf-butyl dicarbonate followed by trifluoroacetic anhydride to provide the pyrrolidine-2-carbonitrile, compound of formula-6. The fourth aspect of the present invention is to provide an alternate process for the preparation of 2-(3-hydroxyadamantan-l-yl amino) acetate compound of formula-5, which comprises of the following steps a) reacting l-aminoadamantane-3-ol compound of formula-2 with 2-oxoacetic acid in the presence of a suitable solvent to provide the 2-(3-hydroxyadamantan-l-yl imino)acetic acid compound of formula-11, b) reducing the compound of formula-11 with a suitable reducing agent provides the 2-(3-hydroxyadamantan-l-yl ammo) acetic acid compound of formula-5. Brief description of drawings: Figure-1: Prior art crystalline form of l-[[(3-hydroxy-l-adamantyl) amino] acetyl]-2- cyano-(S)-pyrrolidine compoimd of formula-1. Detailed description of the invention: Unless otherwise indicated, this disclosure uses definitions provided below. As used herein, the term "alkyl" refers to straight chain or branched hydrocarbon groups, generally having specified number of carbon atoms. A "Ci-u alkyl" refers to alkyl group having 1 to 12 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-l-yl, 3-methylbut-2-yl,2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl and the like. As used herein, the term "aryl-Ci-e alkyl" refers to an aryl group attached to the substrate through an alkyl group containing one to six carbon atoms. The term "aryl" refers to monovalent or divalent aromatic groups respectively including 5 and 6 membered monocyclic aromatic groups that contain zero to four heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of monocyclic aryl groups include, without limitation, phenyl, pyrrolyl, pyranyl, fiiranyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyradazinyl, pyrimidinyl, and the like. The aryl groups also include bicyclic groups, tricyclic groups etc including fused 5 and 6 membered rings described above. Examples of multicyclic aryl groups include, without limitation, naphthyl. biphenyl, anthracenyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl. indolyl, benzofuranyl, purinyl, indolizinyl and the like. The aryl groups may be attached to the substrate at any ring atom, unless such attachment would violate valence requirements. Aryl groups may include one or more non hydrogen substituents unless such substitution would violate valence requirements. Useful substituents include, without limitation alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, halo, hydroxy, mercapto, nitro, amino, alkyl amino and the like. In the present invention the compound of formula-1 chemically known as l-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine is vildagliptin. Accordingly the first aspect of the present invention provides a novel process for the preparation of l-[[(3-hydroxy-l-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine compound of formula:!, which comprises of the following steps; a) Reacting the l-aminoadamantane-3-ol compound of formula-2 with 2-halo acid derivative or its salt compounds of general formula-3, in presence of suitable base selected from organic or inorganic bases in a suitable solvent selected from esters, alcohols, ketones, nitriles, ethers, polar and mixtures thereof, to provide the corresponding 2-(3-hydroxyadamantan-l-yl amino)acid derivative or its salt compounds of general formula-4, b) hydrolyzing the 2-(3-hydroxyadamantan-l-yl amino)acid derivative of general formula-4 if R is other than hydrogen, with a suitable inorganic base in presence or absence of a solvent to provide the acid compoimd of formula-5, c) reacting the compound of formula-5 with pyrrolidine-2-carbonitrile compound of formula-6, in presence of a suitable condensing agent to provide the compound of formula-1, or condensing the compound of formula-4 with pyrrolidine-2-carbonitrile compound of formula-6 in presence of a suitable base in a suitable solvent to provide the compound of formula-1, d) optionally purifying the compound of formula-1 using suitable solvent system provides the pure compound of formula-1. If the hydroxyl is protected by a protecting group, it is removed by treatment with a base or by the process known in the art to provide the compound of formula-1. Suitable base used in the step a) and step b) is selected from either inorganic base selected from alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like; or organic base which is selected from a group which includes but is not limited to triethyl amine, tributyl amine, diisopropyl ethylamine, N-(l-methylethyl)-2-propanamine, 4-ethylmorpholine, 4-dimethylamino pyridine, 4-dimethylaniinopyridine, l,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo [2.2.2]octane, pyridine and the like. The suitable solvent used is selected from water, aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydroftiran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate, propyl acetate, butyl acetate; alcohol like methanol, ethanol,l-propanol, isopropyl alcohol, n-butanol; or nitriles like acetonitrile and propionitrile and the like The reactions are carried out in the presence/or absence of a phase transfer catalyst which is selected from the group consisting of but not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammoniimi acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl anmionium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide. In the step c) the condensing agent used is selected from N,N'-Dicyclohexyl carbodiimide (DCC) in presence of hydroxybenzotriazole (HOBT), N,N'-Dicyclohexyl carbodiimide (DCC) in presence of 4-Dimethylaniinopyridine (DMAP), thionyl chloride, phosphorous pentachloride and the solvent used is as defined in step a). In the step d) the solvent system used for purification may comprise of a single solvent or mixture of solvents selected from a group consisting of but not limited to "polar protic solvent" like water; polar solvent like tetrahydrofuran, dimethyl acetamide, dimethyl sulfoxide; alcoholic solvents such as methanol, ethanol, isopropanol; aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; aromatic hydrocarbon solvents like toluene, xylene, or halogenated solvents such as dichloromethane, chloroform, ethylene dichloride and the like; ethers, such as diethyl ether, tetrahydrofiiran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate methyl acetate and propyl acetate; or nitrile solvents like acetonitrile and propionitrile and the like; amide solvents such as N,N-dimethylformamide, N,N-dimethyl acetamide, N-methyl-2-pyrrolidone or hexamethyl phosphoric triamide; and sulfoxides, such as dimethyl sulfoxide or mixtures thereof The purification of compound of formula-1 by recrystalli2ation from various solvents like 2-butanone, ethyl acetate or mixture of solvents such as ester and alcohol solvents like ethyl acetate/methanol, ethyl acetate/2-propanol and also from mixture of chloroform/methanol, 2-butanone/MTBE provided the same crystalline compound having MR 148°-150°C and the PXRD of which exactly matches with the PXRD diffractogram of the prior art crystalline form disclosed in Journal of Medicinal Chemistry, 2003, Vol. 46, No. 13, pages 2774-2789. The said journal cites an example of recrystallisation of vildagliptin from a mixture of ethyl acetate/2-propanol which provided a compound having MR 148°-150°C. The X-ray diffractogram of the disclosed prior art crystalline form of l-[[(3-hydroxy-l-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine compound of formula-1 was shown in figure-1. The reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -10°C to 100°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 24 hours (more preferably from 1 to 10 hours) will usually suffice. In a preferred embodiment, the present invention provides the process for the preparation of compound of formula-1, which comprises of a) Reacting the l-aminoadamantane-3-ol compound of formula-2 with tertiary butyl bromoacetate compound of formula-3a in presence of a suitable alkali metal carbonate like potassium carbonate in a suitable ether solvent like tetrahydrofuran to provide the t-butyl 2-(3-hydroxyadamantan-l-yl amino) acetate compound of formula-4a, b) hydrolyzing the t-butyl 2-(3-hydroxyadamantan-l-yl amino) acetate compound of formula-4a with a suitable base like alkali metal hydroxide, sodium hydroxide or potassium hydroxide in water to provide the acid compound of formula-5, c) reacting the compound of formula-5 with pyrrolidine-2-carbonitrile compound of formula-6 in presence of a suitable condensing agent like DCC and DMAP in a smtable chloro solvent like methylene chloride to provide the compound of formula-1. The above aspects of the present invention are represented in scheme-1. Scheme-1 The second aspect of the present invention provides an improved process for the preparation of l-[[(3-hydroxy-l-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine compound of formula-1, which comprises of the following steps; a) Reacting the L-prolinamide compound of formula-7 with 2-chloro acetyl chloride m presence of suitable base such as alkali metal carbonate or bicarbonates, preferably potassium bicarbonate in a suitable ether solvent like tetrahydrofuran to provide the (S)-l-(2-chloroacetyl)pyrrolidine-2-carboxamide compound of formula-8, b) treating the compound of formula-8 with trifluoroacetic anhydride in a suitable ether solvent like tetrahydrofuran to provide the (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile compoimd of formula-9, c) reacting the compoimd of formula-9 with l-aminoadamantane-3-ol compound of formula-2 in presence of a suitable alkali metal carbonates/bicarbonates preferably potassium bicarbonates in suitable ether solvent like tetrahyrofuran to provide the compound of formula-1, d) purifying the compound of formula-1 using a suitable solvent selected from ester, alcohol or mixtures thereof, preferably ethylaceate and methanol provides the pure compound of formula-1. In the step b) amide group is converted into cyano group using trifluoroacetic anhydride. This reaction was alternatively carried out using phosphorus oxychloride in presence of imidazole. The other reagents which can be used are oxalyl chloride in dimethylsulfoxide or carbon tetrachloride in the presence of triphenyl phosphene. In the step d) the compound of formula-1 when purified by recrystallizing it from a mixture of ethyl acetate/methanol provides the crystalline compound having MR 148°-150°C, the PXRD chromatogram of which exactly matched with the PXRD chromatogram of the prior art crystalline form having MR 148°-150°C disclosed in Journal of Medicinal Chemistry, 2003, Vol. 46, No. 13, pages 2774-2789.. The present invention schematically represented as scheme-2 given below: The third aspect of the present invention provides novel process for the preparation of pyrrolidine-2-carbonitrile compound of fonnula-6, which comprises of the following steps; a) reacting methyl pyrrolidine-2-carboxylic acid compound of formula-10 with aqueous ammonia in the presence of a suitable alcoholic solvent, preferably n-butanol to provide L-prolinamide compound of formula-7, b) treating the compound of formula-7 with di-rer/-butyl dicarbonate followed by trifluoroacetic anhydride to provide the pyrrolidine-2-carbonitrile compoimd of formula-6. In the step b) of the above process amide group is converted into cyano group using trifluoroacetic anhydride. This reaction was alternatively carried out using phosphorus oxychloride in presence of imidazole. The other reagents which can be used are oxalyl chloride in dimethylsulfoxide or carbon tetrachloride in the presence of triphenyl phosphene. The present invention schematically represented as scheme-3 given below. The fourth aspect of the present invention provides an alternate process for the preparation of 2-(3-hydroxyadamantan-l-yl amino) acetic acid compound of formula-5, which comprises of the following steps a) reacting the 1 -aminoadamantane-3-ol compound of formula-2 with 2-oxoacetic acid in the presence of a suitable solvent to provide the 2-(3-hydroxyadamantan-1-yl imino)acetic acid compound of formula-11, b) reducing the compound of formula-11 with a suitable reducing agent provides the 2- (3-hydroxyadamantan-l-yl amino)acetic acid compound of formula-5. In the step b) the carbon-nitrogen double bond present in compound of formula-11 is reduced using a reducing agent selected from sodium borohydride, sodium cyanoborohydride, diborane, and hydrogen in presence of a catalyst. The reduction can be performed using a number of catalysts. These include, without limitation heterogeneous catalysts containing from about 0.1% to about 20% by weight of transition metals such as Ni, Pd, Pt, Rh, Re, Ru and Ir, including oxides and combination tiiereof. Preferably the reduction can be carried out using sodium borohydride. The suitable solvent used in the present aspect is selected from water, alcohols, ethers, ester, acids and hydrocarbon solvents such as, methanol, ethanol, isopropyl alcohol, tetrahydofiiran, ethyl acetate, acetic acid, dichloromethane and the like. The compoimd of formula-1 can be fiirther micronized or milled to get the desired particle size. Novel process for the preparation of l-[[(3-hydroxy-l-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine compound of formula-1 illustrated in the following scheme-4. Wherein G is a -NH protecting group Wherein X is a halogen Wherein R is 012 alky! group which may be a straight or branched chain, aryl-Ci aiicyl, aryl group which is substituted or unsubstituted aromatic group, or R is M wherein M is an ail

Documents

Application Documents

# Name Date
1 0225-che-2010 drawings 29-01-2010.pdf 2010-01-29
2 0225-che-2010 description(complete) 29-01-2010.pdf 2010-01-29
3 0225-che-2010 claims 29-01-2010.pdf 2010-01-29
4 0225-che-2010 abstract 29-01-2010.pdf 2010-01-29
5 0225-che-2010 form-2 29-01-2010.pdf 2010-01-29
6 0225-CHE-2010 FORM-1 29-01-2010.pdf 2010-01-29
7 0225-che-2010 correspondence oters 29-01-2010.pdf 2010-01-29
8 225-CHE-2010 CORRESPONDENCE OTHERS 03-10-2011.pdf 2011-10-03
9 225-CHE-2010 FORM-18 03-10-2011.pdf 2011-10-03
10 225-CHE-2010-Form 3-240816.pdf 2016-08-31
11 225-CHE-2010-FER.pdf 2016-12-21
12 Other Document [21-06-2017(online)].pdf 2017-06-21
13 Examination Report Reply Recieved [21-06-2017(online)].pdf 2017-06-21
14 Description(Complete) [21-06-2017(online)].pdf_93.pdf 2017-06-21
15 Description(Complete) [21-06-2017(online)].pdf 2017-06-21
16 Correspondence [21-06-2017(online)].pdf 2017-06-21
17 225-CHE-2010-HearingNoticeLetter.pdf 2017-10-23
18 225-CHE-2010-Correspondence to notify the Controller (Mandatory) [20-11-2017(online)].pdf 2017-11-20
19 225-CHE-2010-Annexure (Optional) [20-11-2017(online)].pdf 2017-11-20
20 Drawing_Granted 295072_27-03-2018.pdf 2018-03-27
21 Description_Granted 295072_27-03-2018.pdf 2018-03-27
22 Claims_Granted 295072_27-03-2018.pdf 2018-03-27
23 Abstract_Granted 295072_27-03-2018.pdf 2018-03-27
24 225-CHE-2010-PatentCertificate27-03-2018.pdf 2018-03-27
25 225-CHE-2010-IntimationOfGrant27-03-2018.pdf 2018-03-27

Search Strategy

1 225srchstr_09-12-2016.pdf

ERegister / Renewals