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WO2011101861A1 - Process for preparation of dpp-iv inhibitors - Google Patents

Process for preparation of dpp-iv inhibitors Download PDF

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Publication number
WO2011101861A1
WO2011101861A1 PCT/IN2011/000057 IN2011000057W WO2011101861A1 WO 2011101861 A1 WO2011101861 A1 WO 2011101861A1 IN 2011000057 W IN2011000057 W IN 2011000057W WO 2011101861 A1 WO2011101861 A1 WO 2011101861A1
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formula
compound
pyrrolidine
amino
solvent
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French (fr)
Inventor
Manne Satyanarayana Reddy
Sajja Eswaraiah
Ghojala Venkat Reddy
Bairy Kondal Reddy
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MSN Laboratories Pvt Ltd
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MSN Laboratories Pvt Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to novel process for the preparation of DPP-IV inhibitors, such as l-[[(3-hydroxy-l-adamantyl) amino] acetyl] -2-cyano-(S)-pyrrolidine compound of formula- 1 r
  • DPP-IV Dipeptidylpeptidase IV
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • 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, W
  • neutropenia neuronal disorders, tumor metastasis, benign prostatic hypertrophy, gingivitis and hypertension.
  • 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- 1 of desired enantiomer.
  • the compound of formula- 1 is one of the important drugs available in the market for the treatment of diabetes. Hence there is a necessity to develop an alternate process for preparing the same.
  • 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.
  • the first aspect of the present invention is to provide a novel 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 l-aminoadamantane-3-ol compound of formula-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,
  • 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;
  • 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 W 201 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,
  • 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
  • Figure-1 PXRD of prior art crystalline form of 1- [[(3 -hydroxy- 1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine compound of formula- 1.
  • alkyl refers to straight chain or branched hydrocarbon groups, generally having specified number of carbon atoms.
  • a "C 1.12 alkyl” refers to alkyl group having 1 to 12 carbon atoms.
  • alkyl groups include, without limitation, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pent-l-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.
  • aryl-Ci -6 alkyl refers to an aryl group attached to the substrate through an alkyl group containing one to six carbon atoms.
  • 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.
  • monocyclic aryl groups include, without limitation, phenyl, pyrrolyl, pyranyl, furanyl, 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.
  • 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.
  • suitable solvent refers to the solvent selected from “polar solvents” such as water; "polar aprotic solvents” such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; “ftitrile solvents” such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like; “ether solvents” such as di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert- butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane; “alcohol solvents” such as methanol, ethanol, n-propanol, isopropanol and n-butanol and the like; “chloro solvents” such as methylene chloride, ethylene dichloride, carbon tetra chloride, chloro
  • suitable bases refers to the bases selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, W sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like lithium carbonate, sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and their mixtures there of. ⁇
  • the compound of formula- 1 chemically known as l-[[(3- hydroxy-l-adamantyl) amino] acetyl] -2 -cyano-(S)-pyrrolidine is vildagliptin.
  • 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- 1, which comprises of the following steps;
  • Suitable base used in the step a) and step b) is selected from either inorganic base selected from hydroxides of 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 -methyl ethyl)-2-propanamine, 4-ethylmorpholine, 4- dimethylamino pyridine, 4-dimethyl
  • 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, tetrahydrofuran, 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
  • 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 ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
  • 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-Dimethylaminopyridine (DMAP), thionyl chloride, phosphorous pentachloride and the solvent used is as defined in step a).
  • 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, tetrahydrofuran 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 pro
  • 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.
  • 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.
  • the present invention provides the process for the preparation of compound of formula- 1, which comprises of
  • 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;
  • 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.
  • 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 also provides an improved process for the preparation of 1 -[[(3 -hydroxy- 1 -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 in presence of suitable base such as alkali metal carbonate or bicarbonates, preferably potassium bicarbonate in a suitable chloro solvent like methylene chloride 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 compound of formula-9,
  • the third aspect of the present invention provides novel process for the preparation of pyrrolidine-2-carbonitrile compound of formula-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,
  • 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 present invention also provides a process for the process for the preparation of pyrrolidine-2-carbonitrile compound of formula-6, comprises of treating the L-prolinamide compound of formula-7 with trifluoro acetic anhydride in a suitable ether solvent; preferably tetrahydrofuran, followed by treating with inorganic base provides pyrrolidine-2-carbonitrile compound of formula-6
  • the suitable inorganic base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates and alkali metal alkoxides; preferably sodium carbonate or potassium carbonate.
  • 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- -ol compound of formula-2
  • 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.
  • 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 thereof.
  • transition metals such as Ni, Pd, Pt, Rh, Re, Ru and Ir, including oxides and combination thereof.
  • 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, tetrahydofuran, ethyl acetate, acetic acid, dichloromethane and the like.
  • the compound of formula- 1 can be further micronized or milled to get the desired particle size. Novel process for the preparation of l-[[(3-hydroxy-l -adamantyl)amino]acetyl]-
  • R is alkyl group which may be a straight or branched chain ,
  • aryl-C 1-6 alkyl aryl group which is substituted or unsubstituted aromatic group
  • R is M wherein M is an alkali metal
  • the suitable solvent is selected from ether solvents, ester solvents, nitrile solvents and hydrocarbon solvents or mixtures thereof; preferably tetrahydrofuran; the suitable temperature is reflux temperature of the solvent used;
  • the suitable solvent is selected from ether solvents, chloro solvents; preferably methylene chloride.
  • (S)-pyrrolidine was analyzed by HPLC using the following conditions: Column: Unison C8 150 x 4.6 mm; 5 ⁇ or equivalent; Flow rate: 1.0 ml/min; wavelength: 210 nm; Temperature: 25°C; Injection volume: 10 ⁇ ; Run time: 50 min; Diluent: Water: Acetonitrile in the ratio of 90:10(v/v), and aqueous potassium di hydrogenphosphate having 7.3 pH and acetonitrile in the ration of 90: 10:10(v/v) as mobile phase-A and methanol as mobile phase-B.
  • Example-2 Preparation of t-butyl 2-(3-hydroxyadamantan-l-yl amino) acetate compound of formula 4a:
  • Trifluoroacetic anhydride (122.65 grams) was added to the L-prolinamide (50 grams) in tetrahydrofuran (500 ml) at 0-5°C. The reaction mixture was stirred for 3 hours at 25-30°C. Sodium carbonate (185.72 grams) was added to the reaction mixture at 0-5°C and stirred for one hour. The reaction mixture was filtered and washed with tetrahydrofuran. The filtrate was concentrated and toluene was added to the residue. The reaction mixture was stirred for one hour and filtered. The toluene layer was distilled off completely under reduced pressure to provide the title compound.
  • Trifluoroacetic anhydride (61.33 grams) was added to the L-prolinamide (25 grams) in tetrahydrofuran (500 ml) at 0-5°C. The reaction mixture was stirred for 3 hours at 25-30°C. Potassium carbonate (125 grams) was added to the reaction mixture at 0-5°C and stirred for one hour. The reaction mixture was filtered and washed with tetrahydrofuran. The filtrate was concentrated and toluene was added to the residue. The reaction mixture was stirred for one hour and filtered. The toluene layer was distilled off completely under reduced pressure to provide the title compound.

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Abstract

Process for the preparation of DPP-IV inhibitors, such as 1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine are disclosed.

Description

Process for preparation of DPP-IV inhibitors
Related Application:
This application claims the benefit of priority of our Indian patent application numbers 225/CHE/2010 filed on 29th January 2010 which is incorporated herein by reference.
Field of the Invention:
The present invention relates to novel process for the preparation of DPP-IV inhibitors, such as l-[[(3-hydroxy-l-adamantyl) amino] acetyl] -2-cyano-(S)-pyrrolidine compound of formula- 1 r
Figure imgf000002_0001
Formula- 1
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, W
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 silica gel 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- 1 of desired enantiomer. The compound of formula- 1 is one of the important drugs available in the market for the treatment of diabetes. Hence there is a necessity to develop 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 l-[[(3-hydroxy-l-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine compound of formula- 1, which comprises of the following steps; a) Reacting l-aminoadamantane-3-ol compound of formula-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 compounds 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 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-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- r
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 formula-2 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 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 W 201 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-tert-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- 1 1,
b) reducing the compound of formula- 11 with a suitable reducing agent provides the 2- (3 -hydroxyadamantan- 1 -yl amino) acetic acid compound of formula-5.
Brief description of drawings:
Figure-1: PXRD of prior art crystalline form of 1- [[(3 -hydroxy- 1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine compound 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 "C 1.12 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-l-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-6 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, furanyl, 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.
As used herein the term "suitable solvent" refers to the solvent selected from "polar solvents" such as water; "polar aprotic solvents" such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; "ftitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like; "ether solvents" such as di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert- butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol and n-butanol and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform and the like; "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane; "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like; "esters solvents" such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; and their mixtures thereof.
As used herein the present invention the term "suitable bases" refers to the bases selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, W sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like lithium carbonate, sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and their mixtures there of. ·
In the present invention the compound of formula- 1 chemically known as l-[[(3- hydroxy-l-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- 1, 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 solvents 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 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 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 hydroxides of 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 -methyl ethyl)-2-propanamine, 4-ethylmorpholine, 4- dimethylamino pyridine, 4-dimethylaminopyridine, 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, tetrahydrofuran, 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 ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium 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-Dimethylaminopyridine (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, tetrahydrofuran 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, Ν,Ν-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 recrystallization 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 suitable 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
Figure imgf000010_0001
VILDAGLIPTIN
Formula-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 in 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 compound of formula-9,
c) reacting the compound of formula-9 with l-aminoadamantane-3-ol compound of formula-2 in presence of a suitable alkali metal carbonates/bicarbonates preferably potassium bicarbonate in suitable ether solvent like tetrahydrofuran 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. Further the present invention also provides an improved process for the preparation of 1 -[[(3 -hydroxy- 1 -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 in presence of suitable base such as alkali metal carbonate or bicarbonates, preferably potassium bicarbonate in a suitable chloro solvent like methylene chloride 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 compound of formula-9,
c) reacting the compound of formula-9 with l-aminoadamantane-3-ol compound of formula-2 in presence of a suitable alkali metal carbonates/bicarbonates preferably potassium carbonate in a suitable ether solvent like tetrahydrofuran 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.
The present invention schematically represented as scheme-2 given below:
Scheme-2
Figure imgf000012_0001
Formula-1
The third aspect of the present invention provides novel process for the preparation of pyrrolidine-2-carbonitrile compound of formula-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-tert-butyl dicarbonate followed by trifluoroacetic anhydride to provide the pyrrolidine-2-carbonitrile compound 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. Scheme -3
O ,0 CN u H — V 1.BOC :
H,∞ HN^ < J - nS-bUutSanS.o.l HN ^ J— 2.—TFA -A H
Formula-10 Formula-7 Formula-6
Further the present invention also provides a process for the process for the preparation of pyrrolidine-2-carbonitrile compound of formula-6, comprises of treating the L-prolinamide compound of formula-7 with trifluoro acetic anhydride in a suitable ether solvent; preferably tetrahydrofuran, followed by treating with inorganic base provides pyrrolidine-2-carbonitrile compound of formula-6
The suitable inorganic base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates and alkali metal alkoxides; preferably sodium carbonate or potassium carbonate.
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- -ol compound of formula-2
Figure imgf000014_0001
Formula-2
with 2-oxoacetic acid in the presence of a suitable solvent to provide the 2-(3- hydroxyadamantan-l-yl formula- 1 1,
Figure imgf000014_0002
Formula- 11
b) reducing the compound of formula- 1 1 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 thereof. 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, tetrahydofuran, ethyl acetate, acetic acid, dichloromethane and the like.
The compound of formula- 1 can be further 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. Sche -4
Figure imgf000015_0001
Wherein R is alkyl group which may be a straight or branched chain ,
aryl-C1-6 alkyl, aryl group which is substituted or unsubstituted aromatic group,
or
R is M wherein M is an alkali metal
Further the present invention also provides a process for the preparation of (S)-l- (2-chloroacetyl)pyrrolidine-2-carboxamide compound of formula-8 comprises of following steps;
a) Reacting (S)-pyrrolidine-2-carboxylic acid compound of formula- 17
COOH
Formula- 17
reacts with chloroacetyl chloride in a suitable solvent at a suitable solvent provides (S)-l-(2-chloroacetyl)pyrrolidine carboxylic acid compound of formula- 18, H
Figure imgf000016_0001
Formula- 18
b) treating the compound of formula- 18 with dicyclohexylcarbodiimide in a suitable solvent followed by treating with ammonium bicarbonate provides compound of formula-8.
Wherein in step a) the suitable solvent is selected from ether solvents, ester solvents, nitrile solvents and hydrocarbon solvents or mixtures thereof; preferably tetrahydrofuran; the suitable temperature is reflux temperature of the solvent used;
Instep b) the suitable solvent is selected from ether solvents, chloro solvents; preferably methylene chloride.
The following are the possible process impurities, which are well controlled in the preparation of vildagliptin by the present invention.
Figure imgf000016_0002
PXRD analysis of crystalline 1- [[(3 -hydroxy- 1-adamantyl) amino] acetyl]-2- cyano-(S)-pyrrolidine was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045 min. The related substance of l-[[(3-hydroxy- 1-adamantyl) amino] acetyl] -2-cyano-
(S)-pyrrolidine was analyzed by HPLC using the following conditions: Column: Unison C8 150 x 4.6 mm; 5μπι or equivalent; Flow rate: 1.0 ml/min; wavelength: 210 nm; Temperature: 25°C; Injection volume: 10 μΐ; Run time: 50 min; Diluent: Water: Acetonitrile in the ratio of 90:10(v/v), and aqueous potassium di hydrogenphosphate having 7.3 pH and acetonitrile in the ration of 90: 10:10(v/v) as mobile phase-A and methanol as mobile phase-B.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of l-aminoadamantane-3-ol compound of formula-2:
A mixture of concentrated nitric acid (35.25 grams) and concentrated sulfuric acid (460 grams) was added to amantadine hydrochloride (25 grams) at 0°C and stirred for 2 hours at 8-12° C and then the reaction mixture was poured into ice-cold water. The reaction mixture was basified with sodium hydroxide, filtered and washed with water. Methylene chloride (1200 ml) was added to the wet solid and stirred for 30 minutes. The solid was removed by filtration and washed with methylene chloride. The filtrate was distilled under reduced pressure and the obtained compound was recrystallized from cyclohexane to get the title compound.
Yield: 16 grams
Example-2: Preparation of t-butyl 2-(3-hydroxyadamantan-l-yl amino) acetate compound of formula 4a:
To the solution of l-aminoadamantane-3-ol (50 grams) in 500 ml of THF added tertiary butyl bromoacetate (58 grams) and potassium carbonate (130 grams) and 1.0 grams of potassium iodide. Stirred the reaction mixture for 5 hours at reflux temperature. Cooled the reaction mixture to room temperature. Filtered the reaction mixture and the filtrate was washed with water. Distilled off the solvent completely to get the title compound
Yield: 78 grams.
Example-3: Preparation of 2-(3-hydroxyadamantan-l-yl-amino) acetic acid compound of formula 5:
To the solution of compound of formula-4a (50 grams) dissolved in methanol (150 ml) added aqueous potassium hydroxide (10 grams in 100ml of water). Stirred the reaction mixture for 12 hrs at room temperature. The reaction mixture was acidified with hydrochloric acid and the compound was extracted using n-butanol. The solvent was distilled off completely and the residue obtained was triturated with cyclohexane to get the title compound as a solid.
Yield: 36 grams.
Example- 4: Preparation of L-proIinamide:
To L-proline methyl ester hydrochloride (100 grams) in 1200 ml of n-butanol was added and stirred for 10 minutes. 650 ml of aqueous ammonia was added to the reaction mixture and stirred for 10 hours at room temperature. The aqueous and organic layers were separated. The organic layer was dried over sodium sulfate. The solvent was distilled off completely from organic layer. To the obtained compound, cyclohexane (300 ml) was added and stirred for 30 minutes. The reaction mixture was filtered and the solid obtained was dried to get the title compound.
Yield: 55 grams.
Example-5: Preparation of BOC protected L-prolinamide:
To a solution of L-prolinamide (50 grams) of in 300 ml of dichloromethane triethyl amine (121.5 ml) was added and cooled the mixture to 0-5°C. Di-tert-butyl dicarbonate (154.5 ml dissolved in 200 ml of dichloromethane) was added slowly to the reaction mixture. The reaction mixture was stirred for 6 hrs at room temperature. The solvent was distilled off completely from the reaction mixture. Dichloromethane was added to the residue, stirred for 30 min and distilled off to get the title compound.
Yield: 85 grams.
Example-6: Preparation of pyrroIidine-2-carbonitriIe:
To the BOC protected L-prolinamide (50 grams) in tetrahydrofuran (500 ml), trifluoroacetic anhydride (98.15 grams) was added at 0-5°C. The reaction mixture was stirred for 3 hours at room temperature. Ammonium bicarbonate solution was added to the reaction mixture at 0-5 °C and stirred for one hour. The reaction mixture was filtered and washed with tetrahydrofuran. The filtrate was concentrated and toluene was added to the residue stirred for one hour and filtered. The toluene layer was distilled off completely under reduced pressure to provide the title compound.
Yield: 24 grams. Example-7: Preparation of pyrrolidine-2-carbonitrile:
Trifluoroacetic anhydride (122.65 grams) was added to the L-prolinamide (50 grams) in tetrahydrofuran (500 ml) at 0-5°C. The reaction mixture was stirred for 3 hours at 25-30°C. Sodium carbonate (185.72 grams) was added to the reaction mixture at 0-5°C and stirred for one hour. The reaction mixture was filtered and washed with tetrahydrofuran. The filtrate was concentrated and toluene was added to the residue. The reaction mixture was stirred for one hour and filtered. The toluene layer was distilled off completely under reduced pressure to provide the title compound.
Yield: 30 grams
Example-8: Preparation of pyrrolidine-2-carbonitrile:
Trifluoroacetic anhydride (61.33 grams) was added to the L-prolinamide (25 grams) in tetrahydrofuran (500 ml) at 0-5°C. The reaction mixture was stirred for 3 hours at 25-30°C. Potassium carbonate (125 grams) was added to the reaction mixture at 0-5°C and stirred for one hour. The reaction mixture was filtered and washed with tetrahydrofuran. The filtrate was concentrated and toluene was added to the residue. The reaction mixture was stirred for one hour and filtered. The toluene layer was distilled off completely under reduced pressure to provide the title compound.
Yield: 16 grams
Example-9: Preparation of Vildagliptin compound of formula-1:
To the solution of 2-(3-hydroxyadamantan-l-yl amino) acetic acid (50 grams) dissolved in dichloromethane (500 ml) added pyrrolidine-2-carbonitrile (22 grams), Ν,Ν'-dicyclohexylcarbodiimide (DCC) (45.80 grams) and of DMAP (27.15 grams). The reaction mixture was stirred for 6 hours at room temperature. The reaction mixture was quenched with water and the compound was extracted with n-butanol. The n-butanol was distilled off completely under reduced pressure. To the residue obtained added 2- butanone and then added methyl tertiary butyl ether and stirred the reaction mixture at 25-30° C for 45 minutes. The solid obtain was filtered, washed with methyl tertiary butyl ether and then dried to get the title compound.
Yield: 54 grams. Example-10: Preparation of (S)-l-(2-chloroacetyI) pyrrolidine-2-carboxamide compound of formula-8:
A mixture of potassium carbonate (121 grams) and tetrahydrofuran was cooled to 0-5° C. Added chloroacetyl chloride (29.72 grams) to the reaction mixture at 0° C and then stirred the reaction mixture at 0° C for 10 minutes. L-prolinamide (25 grams) in tetrahydrofuran (500 ml) was added to the reaction mixture slowly at 0-5° C. Stirred the reaction mixture at room temperature for 5 hours. Filtered the reaction mass and washed with tetrahydrofuran (25 ml). The filtrate was distilled under reduced pressure. Methyl tertiary butyl ether (200ml) was added to the residue and stirred for 1 hour at room temperature. The solid obtained was filtered, washed with methyl tertiary butyl ether and then dried to get the title compound.
Yield: 25 grams.
Example-11: Preparation of (S)-l-(2-chloroacetyl) pyrrolidine-2-carboxamide compound of formula-8:
A mixture of sodium carbonate (278.9 grams) and methylene chloride (1500 ml) was cooled to 0-5° C. Added chloroacetyl chloride (173.3 grams) to the reaction mixture at 0° C and then stirred the reaction mixture at 0° C for 10 minutes. L-prolinamide (100 grams) in methylene chloride (1500 ml) was added to the reaction mixture slowly at 0-5° C. Stirred the reaction mixture at room temperature for 3 hours. Cooled the reaction mixture to 0-5°C and slowly added chloroacetyl chloride (173.3 grams) to it. Stirred the reaction mixture at room temperature for 4 hours. Filtered the reaction mass and washed with methylene chloride (250 ml). The filtrate was distilled under reduced pressure. Methyl tertiary butyl ether (800 ml) was added to the residue and stirred for 1 hour at room temperature. The solid obtained was filtered, washed with methyl tertiary butyl ether (20 ml) and then dried to get the title compound.
Yield: 148 grams.
Example-12: Preparation of (S)-l-(2-chloroacetyl) pyrrolidine carboxylic acid compound of formula-18:
To a mixture of (S)-pyrrolidine-2-carboxylic acid (50 grams) and tetrahydrofuran (500 ml) slowly added chloroacetyl chloride (58.9 grams). Stirred the reaction mixture for 2.5 hours at 65-70°C. Water was added to the reaction mixture and stirred for 10 minutes. Ethyl acetate (500 ml) was added to the reaction mixture and separated the both aqueous and organic layers. Distilled off the solvent completely from organic layer under reduced pressure. Cooled the residue to 25-30°C and added methyl tertiary butyl ether (500 ml) to it. Stirred the reaction mixture for 10 minutes and cooled to 0-5 °C. Stirred the reaction mixture for 45 minutes at the same temperature. Filtered the solid and washed with methyl tertiary butyl ether. Dried the material to get the title compound.
Yield: 58 grams. Example-13: Preparation of (S)-l-(2-chIoroacetyl) pyrrolidine-2-carboxamide compound of formula-8:
A solution of dicyclohexylcarbodiimide(DCC)(64.7 grams) dissolved in methylene chloride (200 ml) was slowly added to a 0-5°C pre-cooled solution of (S)-l-(2- chloroacetyl) pyrrolidine carboxylic acid (50 grams) dissolved in methylene chloride (1000 ml). Raised the temperature of the reaction mixture to 25-30°C and stirred for 1 hour at same temperature. Ammonium bicarbonate (248 grams) was added to the reaction mixture at 25-30°C. Stirred the reaction mixture for 3 hours at same temperature. Filtered the reaction mixture after completion of the reaction. Filtrate was distilled off under reduced pressure followed by co-distillation with methyl tertiary butyl ether. Methyl tertiary butyl ether was added to the obtained compound and stirred for 1 hour at 25- 30°C. Filtered the solid and washed with methyl tertiary butyl ether. Dried the material to get the title compound.
Yield: 34 grams Example-14: Preparation of (S)-l-(2-chloroacetyl) pyrrolidine-2-carbonitrile compound of formula-9:
A solution of (S)-l-(2-chloroacetyl)pyrrolidine-2-carboxamide (2.0 grams) and dimethylsulfoxide (1.31 grams) in dichloromethane (20 ml) was cooled to -78°C. To the reaction mixture was added a solution of oxalyl chloride (1.59 grams), and triethyl amine (3.2 grams) with constant stirring. The reaction mixture was stirred for 30 min, quenched with water and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate and distilled off to provide the title compound. Yield: 0.5 grams.
Example-15: Preparation of (S)-(l)-(2-chloroacetyl) pyrrolidine-2-carbonitriIe compound of formula-9:
(S)-l-(2-chloroacetyl)pyrrolidine-2-carboxamide (22 grams) taken in tetrahydrofuran (250 ml) and then cooled to 0° C. Trifluoroacetic anhydride (48.4 grams) was added to the reaction mixture slowly and stirred for 1 hour at room temperature. The reaction mixture was cooled to 0° C and ammonium bicarbonate solution was added to the reaction mixture. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. Toluene (250 ml) was added to the residue and then stirred at room temperature for 45 minutes, filtered and the filtrate was distilled off under reduced pressure. 2-butanone (4 ml) and cyclohexane (35 ml) was added to the residue at 25-30° C and stirred at 25-30° C for 15 minutes. The solid obtain was filtered, washed with cyclohexane and dried to get the title compound.
Yield: 22 grams.
Example-16: Preparation of (S)-(l)-(2-chloroacetyl) pyrroIidine-2-carbonitrile compound of formula-9:
(S)-l-(2-chloroacetyl)pyrrolidine-2-carboxamide (43 grams) taken in tetrahydrofuran (430 ml) and then cooled to 0° C. Trifluoroacetic anhydride (110.2 grams) was added to the reaction mixture slowly and stirred for 30 minutes at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 6 hours at same temperature. The reaction mixture was cooled to 0° C and ammonium bicarbonate solution was added slowly to the reaction mixture. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. Toluene (250 ml) was added to the residue and then stirred at room temperature for 1 hour, filtered and the filtrate was distilled off under reduced pressure. Methyl tertiary butyl ether (50 ml) was added to the residue at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 30 minutes at same temperature. The solid obtain was filtered, washed with methyl tertiary butyl ether and dried to get the title compound.
Yield: 29 grams. Example-17: Preparation of 2-(3-hydroxyadamantan-l-yl-imino) acetic acid compound of formula 11:
To the solution of l-aminoadamantane-3-ol (5 grams) in 50 ml of tetrahydrofuran 2-oxo acetic acid (2.25 grams) was added and stirred. The reaction mixture was heated to reflux for 3 hrs. The reaction mixture was cooled to room temperature and quenched with water. The reaction mixture was extracted with dichloromethane. The dichloromethane solvent was dried and distilled off to get the title compound.
Yield: 6 grams. Example-18: Preparation of 2-(3-hydroxyadamantan-l-yl-amino) acetic acid compound of formula 5:
To a solution of 2-(3-hydroxyadamantan-l-yl-imino) acetic acid (6 grams) in methanol (50 ml), sodium borohydride (lgram) was added slowly with stirring. The reaction mixture was stirred for 30 min and quenched with aqueous hydrochloric acid. The reaction mixture was extracted with ethyl acetate. The solvent was distilled off; dichloromethane (10ml) was added to the solid obtained stirred for 30min and filtered to obtain the title compound.
Yield: 5.8 grams ExampIe-19: Preparation of t-butyl 2-(adamantan-l-yI amino) acetate compound of formula 15a:
To the solution of 1-aminoadamantane (25 grams) in 500 ml of THF added tertiary butyl bromoacetate (32 grams) and potassium carbonate (69 grams) and 1.69 grams of potassium iodide. Stirred the reaction mixture for 5 hours at reflux temperature. Cooled the reaction mixture to room temperature. Filtered the reaction mixture and the filtrate was distilled off completely to get the title compound
Yield: 39 grams.
Example-20: Preparation of 2-(adamantan-l-yl-amino) acetic acid compound of formula 16:
To the solution of compound of formula- 15a (50 grams) dissolved in methanol (150 ml) added aqueous potassium hydroxide (10 grams in 100ml of water). Stirred the reaction mixture for 12 hrs at room temperature. The reaction mixture was acidified with hydrochloric acid and the compound was extracted using n-butanol. The solvent was distilled off completely and the residue obtained was crystallized from cyclohexane to get the title compound as a solid.
Yield: 35 grams.
Example-21: Preparation of tert-butyl 2-(3-hydroxyadamantan-l-yl-amino) acetate compound of formula-4a:
To the 2% aqueous solution of potassium hydroxide(5.0 g) added potassium permanganate (20 g) and heated the reaction mixture to 60°C. Added compound of formula- 15a(25 g) to the reaction mixture. Heated the reaction mixture to 90°C and stirred for 1.5 hrs at same temperature. Cooled the reaction mixture and acidified with aqueous HC1. Sodium bisulfite was added to remove Mn02 and the suspension was filtered. The aqueous filtrate was saturated with sodium chloride and extracted with 95:5 ethyl acetate and methanol. The organic extracts were combined and dried using sodium sulfate. Distilled off the solvent completely to get the title compound.
Yield: 21 grams
ExampIe-22: Preparation of Vildagliptin compound of formula-1:
, To a mixture of l-aminoadamantane-3-ol (26 grams), (S)-(l)-(2-chloroacetyl) pyrrolidine-2-carbonitrile (22.8 grams) in tetrahydrofuran (300 ml) added potassium
i
carbonate (64.3 grams) and potassium iodide (0.774 grams). The mixture was heated to 60-65° and stirred for 5 hours. After completion, the reaction mixture was cooled to 25-30° C and filtered. The filtrate was distilled under reduced pressure. 2-butanone (20 ml), methyl tertiary butyl ether (80 ml) was added to the residue at 25-30° C, and stirred for 45 minutes. The solid obtain was filtered, washed with methyl tertiary butyl ether and then dried to get the title compound.
Yield: 34 grams. Example-23: Preparation of Vildagliptin compound of formula-1:
To a mixture of l-aminoadamantane-3-ol (26 grams), (S)-(l)-(2-chloroacetyl) pyrrolidine-2-carbonitrile (22.8 grams) in tetrahydrofuran (300 ml) added potassium carbonate (64.3 grams) and potassium iodide (0.774 grams). The mixture was heated to 60-65° and stirred for 5 hours. After completion, the reaction mixture was cooled to 25-30° C and filtered. The filtrate was distilled under reduced pressure. Added acetonitrile(40 ml) and distilled off completely under reduced pressure. Added Ethyl acetate (40 ml), cyclohexane (20 ml) to the residue at 25-30° C, and stirred for 45 minutes. The solid obtain was filtered, dried to get the title compound.
Yield: 32 grams.
ExampIe-24: Preparation of Vildagliptin compound of formula-1:
A mixture of l-aminoadamantane-3-ol (100 grams), tetrahydrofuran (1000 ml) potassium carbonate (123 grams) and potassium iodide (4.87 grams) was heated to 60- 65°C. Added (S)-(l)-(2-chloroacetyl) pyrrolidine-2-carbonitrile (77.4 grams) dissolved in tetrahydrofuran (500 ml) to it slowly. Stirred the reaction mixture for 2 hours at 60-65° and stirred for 5 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C. Filtered the reaction mixture and washed with tetrahydrofuran. The filtrate was distilled off completely under reduced pressure. Added ethyl acetate (500 ml) and distilled off completely under reduced pressure. Added Ethyl acetate (100 ml), to the residue at 25-30° C, and stirred for 20 minutes. Cooled the reaction mixture to 0-5°C and stirred for 30 minutes at same temperature. The solid obtain was filtered, washed with ethyl acetate and dried to get the title compound.
Yield: 125 grams
Example-25: Preparation of Vildagliptin compound of formula-1:
To a mixture of l -aminoadamantane-3-ol (26 grams), (S)-(l)-(2-chloroacetyl) pyrrolidine-2-carbonitrile (22.8 grams) in tetrahydrofuran (300 ml) added potassium carbonate (64.3 grams) and potassium iodide (0.774 grams). The mixture was heated to 60-65° and stirred for 5 hours. After completion, the reaction mixture was cooled to 25-30° C and filtered. The filtrate was distilled under reduced pressure. Added methanol (10 ml), methylene chloride (50 ml) to the residue at 25-30° C, and stirred for 45 minutes. The solid obtain was filtered, dried to get the title compound. Yield: 30 grams.
Example-26: Purification of Vildagliptin compound of formula-1:
A solution of Vildagliptin (25 grams) in ethyl acetate (60 ml) and 2-propanol (15 ml) heated to 70-75° C and then stirred for 1 hour. The reaction mixture was cooled to 20-25° C and then stirred for 2 hours. The solid obtained was filtered, and dried to get the title compound. PXRD of the obtained solid is shown in Figure-I.
Yield: 16 grams; MR: 148-150°C
Example-27: Purification of Vildagliptin compound of formula-1:
A suspension of Vildagliptin (25 grams) in ethyl acetate (75 ml) heated to 70-75° C and then stirred for 1 hour. The reaction mixture was cooled to 20-25° C and then stirred for 2 hours. The solid obtained was filtered, and dried to get the title compound. PXRD of the obtained solid is similar to the PXRD shown in Figure-I.
Yield: 15 grams.
MR: 148-150°C
ExampIe-28: Purification of Vildagliptin compound of formula-1:
A solution of Vildagliptin (25 grams) in ethyl acetate (60 ml) and methanol (15 ml) heated to 70-75° C and then stirred for 1 hour. The reaction mixture was cooled to 20-25° C and stirred for 2 hours. The solid was filtered, and dried to get the title compound. PXRD of the obtained solid is similar to the PXRD shown in Figure-I.
Yield: 17 grams
MR: 148-150°C
Purity by HPLC: 99.99%
Particle Size Distribution: D(0.1): 28.34 μιη; D(0.5): 70.36 μιη; D(0.9): 135.29 μιη; D[4,3]: 76.4 um
Example-29: Purification of Vildagliptin compound of formula-1:
A solution of Vildagliptin (35 grams) and 2-butanone (105 ml) heated to 80-85° C and then stirred for 1 hour. The reaction mixture was cooled to 0-5° C and then stirred for 1 hour. The solid obtained was filtered, washed with 1 :1 mixture of 2-butanone and methyl tertiary butyl ether and dried to get the title compound. PXRD of the obtained solid is similar to the PXRD shown in Figure-I.
Yield: 24 grams
MR: 148-150°C

Claims

We Claim:
1. A process for the preparation of l-[[(3-hydroxy-l-adamantyl)amino]acetyl]-2-cyano- (S)-pyrrolidine compound of formula- 1 ,
Figure imgf000028_0001
Formula- 1
which comprises of the following steps;
a) Reacting the l-aminoadamantan -3-ol compound of formula-2
Figure imgf000028_0002
Formula-2
wherein P is hydrogen or hydroxy protecting group;
with 2-halo acid derivative or its salt compounds of general foimula-3
X-CH2-COOR
Formula-3
wherein in X is halogen and R is a hydrogen or an C 1.12 alkyl group which may be a straight or branched chain, or an aryl-C1- alkyl, or an aryl group which is substituted or unsubstituted aromatic group, or R is M wherein M is an alkali metal;
in presence of suitable base selected from organic or inorganic bases in a suitable solvent selected from esters, alcohols, ketones, nitriles, ethers, polar solvents or their mixtures thereof, to provide the corresponding 2-(3-hydroxyadamantan-l-yl amino)acid derivative or its salt compounds of general formula-4,
Figure imgf000028_0003
Formula-4
wherein R is as defined above, b) hydrolyzing the 2-(3-hydroxyadamantan-l-yl amino)acid derivative of general formula-4 if R and P are other than hydrogen, with a suitable inorganic base in presence or absence of a solvent to provide the acid compound of formula-5,
Figure imgf000029_0001
Formula-5
c) reacting the compound of formula-5 with pyrrolidine-2-carbonitrile compound of formula-6
Figure imgf000029_0002
Formula-6
in the 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 suitable solvent to provide the compound of formula- 1 ,
d) optionally purifying the compound of formula- 1 using suitable solvent system provides the pure vildagliptin.
2. A process of claim 1, wherein
a) The suitable base used either an inorganic base selected from a group which includes but is not limited to hydroxides of 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 an 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-dimethylaminopyridine, l,8-diazabicyclo[5.4.0]undec- 7-ene, 1 ,4-diazabicyclo [2.2.2]octane, pyridine and the like;
8. The process according to claim-7, the suitable condensing agent is N,N'-Dicyclohexyl carbodiimide (DCC) in presence of 4-Dimethylaminopyridine (DMAP).
9. A process for the preparation of l-[[(3-hydroxy-l-adamantyl) amino] acetyl]-2- cyano-(S)-pyrrolidine compound of formula- 1 comprising of condensing 2-(3- hydroxyadamantan-l-yl amino) acetic acid compound of formula-5, with pyrrolidine- 2-carbonitrile compound of formula-6 in presence of DCC an DMAP in methylene chloride.
10. 2-(3-0-protected adamantan-l-yl amino)acid derivatives having the following structural formula,
Figure imgf000030_0001
wherein P is hydrogen or hydroxy protecting group; R is a hydrogen or an Ci-i2 alkyl group which may be a straight or branched chain, or an aryl-Ci-6 alkyl, or an aryl group which is substituted or unsubstituted aromatic group, or R is M wherein M is an alkali metal.
1 1. 2-(3-hydroxyadamantan-l-yl amino)acid compound of formula-5.
Figure imgf000030_0002
Formula-5
12. t-butyl 2-(3-hydroxyadamantan-l-yl amino) acetate compound of formula-4a,
Figure imgf000030_0003
Formula-4a
13. A process for the preparation of compound of formula- 1, which comprises of
a) Reacting the l-aminoadamantane-3-ol compound of formula-2 b) The suitable solvent is selected from a group which includes 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;
5 aromatic hydrocarbon solvents like toluene, xylene, or halogenated solvents such as dichloromethane, chloroform, ethylene dichloride and the like; ethers, such as diethyl ether, tetrahydrofuran 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 10 N,N-dimethylformamide, Ν,Ν-dimethyl acetamide, N-methyl-2-pyrrolidone or hexamethyl phosphoric triamide; and sulfoxides, such as dimethyl sulfoxide. c) the condensing agent is selected from Ν,Ν'-Dicyclohexyl carbodiimide (DCC) in presence of hydroxybenzotriazole (HOBT), Ν,Ν'-Dicyclohexyl carbodiimide (DCC) in presence of 4-Dimethylaminopyridine (DMAP), thionyl chloride,
15 phosphorous pentachloride.
3. A process for the preparation of 1 -[[(3 -hydroxy- 1-adamantyl) amino] acetyl]-2- cyano-(S)-pyrrolidine compound of formula- 1 comprising of condensing 2-(3- hydroxyadamantan-l-yl amino) acetic acid compound of formula-5 with pyrrolidine-
20 2-carbonitrile compound of formula-6
4. The process according to claim-3, the condensation reaction is carried out in a suitable solvent in presence of a suitable condensing agent.
25 5. The process according to claim-4, the suitable solvent is selected from chloro solvents, ether solvents or their mixtures thereof.
6. The process according to claim-5, the suitable solvent is methylene chloride.
,30 7. The process according to claim-4, the suitable condensing agent is selected from
Ν,Ν'-Dicyclohexyl carbodiimide (DCC) in presence of hydroxybenzotriazole (HOBT), Ν,Ν'-Dicyclohexyl carbodiimide (DCC) in presence of 4- Dimethylaminopyridine (DMAP).
Figure imgf000032_0001
Formula-2
with tertiary butyl bromoacetate compound of formula-3a in presence of potassium carbonate in tetrahydrofuran to provide the t-butyl 2-(3- hydroxyadamantan-l-yl amino) acetate compound of formula-4a,
Figure imgf000032_0002
Formula-4a
b) hydrolyzing the t-butyl 2-(3-hydroxyadamantan-l -yl amino) acetate compound of formula-4a with aqueous sodium hydroxide to provide the acid compound of formula-5,
Figure imgf000032_0003
Formula-5
c) reacting the compound of formula-5 with pyrrolidine-2-carbonitrile compound of formula-6,
Figure imgf000032_0004
Formula-6
in presence of DCC an DMAP in methylene chloride to provide the compound of formula- 1.
14. An improved process for the preparation of l-[[(3-hydroxy-l-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine compound of formula- 1 ,
Figure imgf000032_0005
Formula- 1 which comprises of the following steps;
a) Reacting the L-prolinamide compound of formula- 7
Figure imgf000033_0001
Formula-7
with 2-chloro acetyl chloride in presence of suitable base such as alkali metal carbonate or bicarbonates, preferable potassium bicarbonate in a suitable ether solvent like tetrahydrofuran to provide the (S)-l-(2-chloroacetyl)pyrrolidine-2- carboxamide compound of formula-8,
Figure imgf000033_0002
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 compound of formula-9,
CN
Figure imgf000033_0003
Formula-9
c) reacting the compound of formula-9 with l-aminoadamantane-3-ol compound of formula-2,
Figure imgf000033_0004
Formula-2
in presence of a suitable alkali metal carbonates/bicarbonates preferably potassium bicarbonate in suitable ether solvent like tetrahydrofuran to provide the compound of formula- 1 , d) purifying the compound of formula- 1 using a suitable solvent to provide the pure compound of formula- 1.
15. An improved process for the preparation of l-[[(3-hydfoxy-l-adamantyl) amino] acetyl] -2-cyano-(S)-pyrrolidine compound of formula- 1,
Figure imgf000034_0001
which comprises of the following steps;
a) Reacting the L-prolinamide compound of formula-7
O
H2N— ¾
For ™moula-7
with 2-chloro acetyl chloride in presence of sodium carbonate in a methylene chloride to provide the (S)-l-(2-chloroacetyl)pyrrolidine-2-carboxamide compound of formula-8,
Figure imgf000034_0002
Formula-8
b) treating the compound of formula-8 with trifluoroacetic anhydride in tetrahydrofuran to provide the (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile compound of formula-9,
Figure imgf000034_0003
c) reacting the compound of formula-9 with l-aminoadamantane-3-ol compound of formula-2,
Figure imgf000035_0001
Formula-2
in presence of potassium carbonate in tetrahydrofuran to provide the compound of formula- 1,
d) purifying the compound of formula- 1 using a suitable solvent to provide the pure compound of formula- 1.
16. A process for the preparation of pyrrolidine-2-carbonitrile compound of formula-6,
CN
Figure imgf000035_0002
Formula-6
which comprises of the following steps;
a) reacting the methyl pyrrolidine-2-carboxylic acid compound of formula- 10
Figure imgf000035_0003
Formula- 10
with aqueous ammonia in the presence of a suitable alcoholic solvent to provide L-prolinamide compound of formula-7,
o
H2 — g
Formula-7
b) treating the compound of formula-7 with di-ter/-butyl dicarbonate, followed by trifluoroacetic acid to provide the pyrrolidine-2-carbonitrile compound of formula-6.
17. A process for the preparation of 2-(3-hydroxyadamantan-l-yl amino) acetic acid compound of formula-5,
Figure imgf000036_0001
Formula-5
which comprises of the following steps
a) reacting l-aminoadamantane- -ol compound of formula-2
Figure imgf000036_0002
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- 1 1 ,
Figure imgf000036_0003
Formula- 1 1
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.
18. A process for the purification of 1- [[(3 -hydroxy- 1-adamantyl) amino] acetyl]-2- cyano-(S)-pyrrolidine compound of formula- 1, which comprises of recrystallization of compound of formula- 1 from a mixture of ethyl acetate and methanol at temperature ranges from -10°C to reflux temperature of the solvent.
19. A process for the preparation of pyrrolidine-2-carbonitrile compound of formula-6
CN
Figure imgf000036_0004
Formula-6
comprises of treating the L-prolinamide compound of formula-7,
Figure imgf000037_0001
Formula-7
with trifluoro acetic anhydride in a suitable solvent, followed by treating with inorganic base provides pyrrolidine-2-carbonitrile compound of formula-6.
20. The process according to claim- 19, the inorganic base selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates and alkali metal alkoxides. 21. The process according to claim-20, the inorganic base is selected from alkali metal carbonates.
22. The process according to claim-20, the inorganic base is sodium carbonate or potassium carbonate.
23. The process according to claim- 19, the suitable solvent is selected from ether solvents, hydrocarbon solvents and chloro solvents.
24. The process according to claim-23, the suitable solvent is ether solvent.
25. The process according to claim-24, the suitable solvent is tetrahydrofuran.
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