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WO2011101861A1 - Procédé de préparation d'inhibiteurs de la dpp-iv - Google Patents

Procédé de préparation d'inhibiteurs de la dpp-iv 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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Prior art keywords
formula
compound
pyrrolidine
amino
solvent
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PCT/IN2011/000057
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English (en)
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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation d'inhibiteurs de la DPP-IV, tels que le composé 1-[[(3-hydroxy-1-adamantyl)amino]acétyl]-2-cyano-(S)-pyrrolidine de formule 1.
PCT/IN2011/000057 2010-01-29 2011-01-28 Procédé de préparation d'inhibiteurs de la dpp-iv Ceased WO2011101861A1 (fr)

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IN225/CHE/2010 2010-01-29

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Cited By (21)

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CN102617434A (zh) * 2012-03-29 2012-08-01 中国科学院上海有机化学研究所 一锅法制备维达列汀
WO2013179300A2 (fr) 2012-05-04 2013-12-05 Megafine Pharma (P) Ltd. Procédé de préparation de vildagliptine et de son intermédiaire
CN103804204A (zh) * 2014-02-21 2014-05-21 张家港威胜生物医药有限公司 一种制备维达列汀关键中间体3-氨基-1-金刚烷醇的方法
CN104016896A (zh) * 2014-06-24 2014-09-03 万特制药(海南)有限公司 一种维达列汀碱水解杂质的制备方法
CN104030958A (zh) * 2014-06-06 2014-09-10 河北科技大学 一种（s）-1-（2-氯乙酰基）吡咯烷-2-甲腈的合成方法
WO2015123998A1 (fr) * 2014-02-21 2015-08-27 张家港威胜生物医药有限公司 Procédé de synthèse de la vildagliptine
CN105439873A (zh) * 2014-08-20 2016-03-30 天津药物研究院 3-羟基-1-金刚烷胺的制备方法
CN105712919A (zh) * 2014-12-04 2016-06-29 南京优科生物医药研究有限公司 酰胺缩合剂在维格列汀合成方法中的应用
CN106117104A (zh) * 2016-06-17 2016-11-16 东北制药集团股份有限公司 一种维格列汀的制备方法
JP2017507934A (ja) * 2014-02-28 2017-03-23 ヒカル リミテッド ビルダグリプチンのための新規な実用的プロセス
EP3082801A4 (fr) * 2013-12-18 2017-07-26 Harman Finochem Limited Procédé économique et avancé pour la préparation de vildagliptine pure
CN107033054A (zh) * 2017-06-19 2017-08-11 河北富格药业有限公司 一种维格列汀的合成方法
CN108329322A (zh) * 2018-05-10 2018-07-27 上海医药集团青岛国风药业股份有限公司 一种维格列汀环脒杂质的制备方法
CN108503571A (zh) * 2018-06-02 2018-09-07 大连正邦信息咨询有限公司 一种维达列汀的合成方法
CN108658826A (zh) * 2018-06-02 2018-10-16 大连正邦信息咨询有限公司 一种制备维达列汀的方法
CN109761876A (zh) * 2019-01-17 2019-05-17 深圳市第二人民医院 治疗糖尿病的药物沙格列汀的制备方法
CN110092738A (zh) * 2019-04-24 2019-08-06 深圳市第二人民医院 维格列汀的制备方法
CN110105232A (zh) * 2019-05-10 2019-08-09 中国农业大学 一种金刚烷胺半抗原及其制备方法和应用
CN111138334A (zh) * 2020-01-13 2020-05-12 天津民祥生物医药股份有限公司 一种维格列汀的制备方法
WO2022003405A1 (fr) 2020-07-03 2022-01-06 Savoi Guilherme Procédé monotope permettant d'obtenir un composé intermédiaire pyrrolidine-2-carbonitrile et procédé télescopique à l'échelle industrielle permettant de préparer du (2s)-1-[n-(3-hydroxyadamantan-1-yl)glycyl]-2-pyrrolidinecarbonitrile (vildagliptine) l'utilisant
CN114380729A (zh) * 2021-12-31 2022-04-22 东北制药集团股份有限公司 一种高纯度维格列汀的制备方法

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