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WO2012022994A1 - Procédé de préparation de vildagliptine - Google Patents

Procédé de préparation de vildagliptine Download PDF

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Publication number
WO2012022994A1
WO2012022994A1 PCT/HU2011/000087 HU2011000087W WO2012022994A1 WO 2012022994 A1 WO2012022994 A1 WO 2012022994A1 HU 2011000087 W HU2011000087 W HU 2011000087W WO 2012022994 A1 WO2012022994 A1 WO 2012022994A1
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WIPO (PCT)
Prior art keywords
formula
vildagliptin
process according
acid
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/HU2011/000087
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English (en)
Inventor
András MRAVIK
Balázs VOLK
Imre KÖHEGYI
Gábor NÉMETH
Tamás Nagy
Kálmán NAGY
Judit Broda
Adrienn Keszthelyi
Erzsébet Szabó
József Barkóczy
György RUZSICS
Tibor BAKÓ
József DEBRECZENI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Egis Pharmaceuticals PLC
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Egis Pharmaceuticals PLC
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Publication of WO2012022994A1 publication Critical patent/WO2012022994A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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

Definitions

  • DPP-IV Dipeptidyl peptidase-IV
  • GLP-1 glucagon like peptide- 1
  • NIDDM non-insulin-dependent diabetes mellitus
  • 'M' stands for an alkali metal, alkaline earth metal or transitional metal cation
  • 'A' stands for an organic or inorganic anion
  • 'n' is 1 or 2
  • 'z' stands for a number between 0.5 to 4 have been described in WO 1 1042765.
  • the compounds of the Formula IV are adducts of vildagliptin base and an ionic compound, wherein the cation of said ionic compound is preferably an alkali metal or an ion [cation] of an element belonging to the d-field , the anion is an acyl residue of an organic or inorganic acid.
  • the application further discloses the hydrates of the vildagliptin complexes as well.
  • vildagliptin is synthesized by coupling 3-amino- adamantan-l-ol of the Formula
  • the coupling reaction is carried out in THF in the presence of threefold amount of potassium carbonate using 2 to 3 equivalent of the 3-amino-adamantan-l-ol of the Formula V calculated for the molar amount of the compound of the formula VI for 2 hours at 0 °C and the reaction mixture is kept on room temperature for 1 to 3 days.
  • the coupling reaction is described generally for synthesizing several related compounds. The yield is 30 to 50 % after purification by chromatography.
  • a dehydration agent preferably chloromethylene dimethyl ammonium-chloride.
  • the coupling reaction of the thus obtained l-(2-chloroacethyl)- pyrrolidine-(2S)-carbonitrile of the formula VI and 3-amino-adamantan-l-ol of the formula V is carried out in the known manner. According to the description, using the disclosed process, a product with high optical purity (over 99,99 %) can be obtained. There is no data about the impurity profile of the product (chemical purity) and no chiral or achiral data about the purity of the product prepared by the examples are disclosed.
  • acylation of (5)-prolinamide of the formula VII is carried out with chloroacetyl chloride in an ether type solvent in the presence of triethylamine.
  • the obtained amide of the Formula IX is reacted with trifluoroacetic acid anhydride in an ether type solvent to form l-(2-chloroacethyl)-pyrrolidine-(25)- carbonitrile of Formula VI.
  • the purity of the obtained product is not disclosed.
  • the melting point of the product is 57-62 °C, which is lower than the corresponding melting point disclosed in the prior art (65-67 °C).
  • the yield of the dehydration is 77 %.
  • the preparation of the vildagliptin is carried out in a mixture of isopropyl acetate, DMF and ethylmethyl ketone using the 3-amino-adamantan-l-ol of the Formula V.
  • Vildagliptin of the formula I is obtained in two fractions with the purities of 99 % and 90 %, without disclosing the yield. After recrystallizing the first fraction from methylethyl ketone, a product with 99,9 % chemical purity was obtained. Product with the same purity can be obtained from the second fraction only after two recrystallizations.
  • vildagliptin of the Formula I is obtained using (S)-prolinamide of the Formula VII as starting material in several steps.
  • the optical impurity of the final product should be considered besides the chemical impurity.
  • Such an optical impurity namely l-[2-(3-hydroxyadamant-l-yl- amino)acetyl]pyrrolidine-(2i?)-carbonitrile of the formula
  • vildagliptin enantiomer or vildagliptin antipode can be obtained in case of vildagliptin due to the (i?)-enantiomer content of the starting product of the Formula VII and due to the racemization occurring during the preparation process.
  • the nitrile function is formed by dehydrating the acid amide in all known processes.
  • Another disadvantage of the known methods resides in that the reagents and solvent used during this process are all toxic and environmentally harmful. Therefore there is a considerable need to provide a process, which avoids the above-mentioned disadvantages.
  • the object of the present invention is a process for preparing l-[2-(3- hydroxyadamant-l -yl-amino)acetyl]pyrrolidine-(2S)-carbonitrile of the Formula I (hereinafter vildagliptin) starting from ( ⁇ )-l-[2-(3-hydroxiadamant-l-yl- amino)acetyl rrolidine-2-carbonitrile of the Formula I (hereinafter vildagliptin) starting from ( ⁇ )-l-[2-(3-hydroxiadamant-l-yl- amino)acetyl rrolidine-2-carbonitrile of the Formula I (hereinafter vildagliptin) starting from ( ⁇ )-l-[2-(3-hydroxiadamant-l-yl- amino)acetyl rrolidine-2-carbonitrile of the Formula I (hereinafter vildagliptin) starting from ( ⁇ )-l-[2-(3-hydroxi
  • a further object of the present invention is a process for preparing vildagliptin complexes of the Formula IV, in particular vildagliptin calcium-chloride trihydrate complex of the Formula
  • Another object of the present invention is a process for preparing racemic base of the Formula III starting from l-[2-(3-hydroxyadamant-l-yl-amino)acetyl]pyrrolidine- (2R)-carbonitrile of the Formula XI, which is a byproduct of the process.
  • the present invention relates to vildagliptin O, O '-di-p-toluene-(2i?,5/?)- hydrogentartarate dihydrate diastereomer salt of the Formula
  • a further object of the present invention is vildagliptin O,O '-dibenzoyl-(25',5S)- hydrogentartarate of the Formula
  • the process according to the present invention results in a vildagliptin of the Formula I and vildagliptin complex of the Formula IV having higher chemical and optical purity compared to the products obtained in known processes starting form the (S)-prolinamide of the Formula VII.
  • the reagents and solvents, which are used during the present process have lower impact on the environment than the reagents and solvents of the known processes.
  • the compound of the Formula IX which is a byproduct of the processes, can be recycled.
  • Another advantage of the present process is the use of the racemic base of the Formula (III) as a starting compound, which can be easily synthesized, instead of the optically active (S)- prolinamide of the Formula VII.
  • the process of the present invention is environmentally friendly, results in a product with high purity, consists only few steps and the amount of the obtained byproduct can be reduced.
  • the process for the preparation of the vildagliptin of the Formula I starting form the easily synthesized racemic base of the Formula III has never been described in the prior art.
  • the aim of the present invention is to provide a process for preparing vildagliptin of the Formula I starting from the racemic base of the Formula III, which results in a product with high chemical and optical purity at the same time.
  • Vildagliptin obtained by the present process contains the impurity of the Formula V, X and XI in an amount less than 0,01 % individually, measured by HPLC and GC.
  • the total amount of the impurities is not more than 0,02 %.
  • concentration of any impurities as well as the sum of impurities in the product is significantly lower than the limit prescribed in the requirements of the pharmaceutical standards and guidelines.
  • the preferred diacyl tartarate derivatives are the compounds of the Formulae
  • ⁇ , ⁇ '-dibenzoyl- (2S, 3iS)-tartarate of the Formula XIV-a forms a poorly soluble diastereomeric salt with vildagliptin
  • 0,O'-di- ⁇ -toluoyl-(2S,55)-tartarate of the Fomula XlV-b having the same configuration and a similar structure forms a poorly soluble diastereomeric salt with vildagliptin antipode of the formula XI.
  • the racemic base of the Formula III is reacted with an optically active acid in an appropriate solvent or mixture of solvents and the formed vildagliptin salt or solvate or hydrate thereof is crystallized and isolated by filtration.
  • the racemic base of the Formula III is reacted with O,O'-di p-toluoyl-(2i-, 5i?)-tartarate of the Formula XIII-b in an appropriate solvent or mixture of solvents and the thus formed vildagliptin salt of the formula XV or solvate or hydrate thereof is obtained by filtration.
  • the racemic base of the Formula III is reacted with O,O'-dibenzoyl-(2S,5S)-tartarate of the Formula XIV-a in an appropriate solvent or mixture of solvents and the thus formed vildagliptin salt of the formula XVI or solvate or hydrate thereof is obtained by filtration. If so required, the obtained salts of the above processes are further purified by one or more recrystallization steps from the appropriate solvent or mixture of solvents.
  • Suitable solvents or mixture of solvents are preferably aliphatic Ci-C 6 alcohols or mixture thereof with other aliphatic CrC 6 alcohols or with water, more preferably methanol, ethanol, 1-propanol, isopropyl alcohol, or mixture thereof with any other or with water.
  • Further solvents can be esters of aliphatic Cj-Q alcohols with Q-C4 organic acids or anhydrous or aqueous mixtures thereof, preferably ethylacetate, isopropyl-acetate, more preferably ethyl-acetate.
  • Further suitable solvents can be selected from acetone, acetonitrile, ethylmethyl ketone, tetrahydrofurane, dioxane or mixture thereof with water or any of the above mentioned esters.
  • Vildagliptin of the Formula I can be prepared by known processes starting from the diastereomeric salt obtained according to any of the above process variants.
  • the diastereomeric salt is suspended in the mixure of water and a water-immiscible solvent, preferably in a mixture of water and an C]-C 6 esther, more preferably mixture of water and ethyl acetate.
  • a mineral acid with intensive stirring, the phases are separated.
  • the aqueous phase is washed with ethyl-acetate and it is alkalinized by a basic compound, preferably an alkali metal hydroxide or alkali metal carbonate, more preferably sodium carbonate.
  • Vildagliptin of the Formula I is extracted with an appropriate solvent, preferably with dichloro methane and the solvent is evaporated.
  • optical active acid preferably an acid of the Formula XIII or XIV, more preferably 0.5-0.8 mole of an acid of the Formula XIII or Formula XIV, most preferably 0.5-0.7 mole of acid of the Formula XIII or Formula XIV are added to each mole of base and optionallyother achiral acids are used in an amount of 0.0-2.0 mole equivalent, preferably 0.2-0.5 mole equivalent, more preferably 0.3-0.5 mole equivalent.
  • Olether achiral acid stands for mineral acids, preferably hydrochloric acid, sulfuric acid, phosphoric acid; or an organic acid, preferably acetic acid.
  • the most preferable acid is hydrochloric acid.
  • Mineral acids are used advantageously in an amount of 0.0-0.9 mole equivalent, more preferably 0.2-0.5 mole equivalent, most preferably 0.3-0.5 mole equivalent, organic acids are used preferably in an amount of 0-2 mole equivalent.
  • the racemic base of the Formula III is reacted with an optically active acid in an appropriate solvent or mixture of solvents and the thus formed vildagliptin antipode salt, formed with the optical active acid, or solvate or hydrate thereof is crystallized and obtained by filtration.
  • the racemic base of the Formula III is reacted with O,O'-dibenzoyl-(2i?, 3i?)-tartarate of the Formula XIII-a in an appropriate solvent or mixture of solvents and the thus formed diastereomeric vildagliptin salt or solvate or hydrate thereof is obtained by filtration.
  • the racemic base of the Formula III is reacted with O,O'-di-j9-toluoyl-(25, JiS -tartarate of the Fomula XIV -b in an appropriate solvent or mixture of solvents and the formed diastereomeric vildagliptin salt or solvate or hydrate thereof is obtained by filtration.
  • vildagliptin base of the Formula I is obtained from the filtrate and it is reacted with one the optically active acid of the Formula (XIII-b) or (XlV-a) and the thus formed salts of the Formula (XV) or (XVI) or solvates or hydrates thereof are optionally purified by any of the processes described above and can be converted to vildagliptin base of the Formula I.
  • 'M' stands for an alkali metal, alkaline earth metal or transitional metal cation
  • 'A' stands for an organic or inorganic anion
  • 'n' is 1 or 2
  • 'z' stands for a number between 0,5 to 4 , especially the vildagliptin calcium-chloride trihydrate complex of the Formula II can be obtained by the process of the present invention.
  • the disatereomeric salts of the Formula XV or XVI are converted to vildagliptin adduct of the Formula IV, and the product is obtained by filtration.
  • the conversion is carried out by reacting the diastereomeric salt with an appropriate metal salt and with metal hydroxide, metal oxide, which correspond to the used metal ion or other basic salts, alkali metal hydroxides, alkali metal hydrogen carbonates, carbonates formed with the acid of the metal ion, preferably with metal hydroxide, metal oxide, most preferably with the metal hydroxide.
  • metal hydroxide metal oxide
  • the thus formed adduct of the Formula II or IV is obtained by filtration.
  • the solution obtained by the above reaction is filtered, evaporated and crystallized by adding another solvent to obtain the adduct of the Formula II or IV.
  • the metal salt can be for example halogenide, sulfate or acetate of magnesium calcium or zinc, hydrates or solvates thereof, preferably aqueous or anhydrous calcium chloride.
  • the basic salt can be for example hydroxide or oxide of magnesium calcium or zinc, or hydroxide, hydrogen carbonate, carbonate of alkali metals, preferably magnesium, calcium or zinc hydroxide, more preferably calcium hydroxide.
  • the solvent for obtaining the adduct can be selected from aliphatic C]-C 6 alcohols, such as methanol, ethanol, propanol, isopropyl alcohol, or mixture thereof with any other and/or water.
  • the obtained adduct of the Formula II or IV can be purified by crystallizing using an appropriate solvent, which can be selected from aliphatic Cj-C 6 alcohols, such as methanol, ethanol, propanol, isopropyl alcohol, or mixture thereof with any other and/or water.
  • Further solvents can be esters of aliphatic Cj-C6 alcohols and C1-C4 organic acids, preferably ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or aqueous or anhydrous mixtures thereof with aliphatic Ci-C 6 alcohols, preferably ethanol or isopropyl alcohol.
  • Further suitable solvents are the mixtures of water and Cj-Q alcohols, acetone, acetonitrile or tetrahydrofurane.
  • a preferable representative of the adduct of the Formula IV is the vildagliptin calcium trihydrate complex of the Formula II, which is prepared starting from the racemic base of the formula III.
  • the preparation is preferably carried out by reacting the racemic base of the Formula III with hydrochloric acid and O,(7'-di-p-toluoyl- (2i?,5i?)-tartarate of the Formula XIII-b in the mixture on water and methanol.
  • the obtained crystalline compound of the formula XV is filtered and recrystallized form aqueous methanol twice.
  • calcium chloride is added, and after dissolution, calcium hydroxide is added of the solution.
  • the solution is filtered and evaporated. Hot isopropyl alcohol is added to the remaining solution and water is added to it.
  • the compound of the Formula II is crystallized and filtered.
  • the product is dissolved in ethanol and after evaporation in part, isopropyl alcohol and water are added to the solution.
  • the precipitated complex is crystallized, washed and dried in vacuum.
  • the vildagliptin antipode which is obtained by several processes, is reacted with strong base, preferably alkali metal hydride, alkali earth metal hydride, more preferably sodium hydride in aprotic solvents (for example tetrahydrofurane, 1,4-dioxane, 1,2-dimethoxy ethane, diethyl ether, toluene) at -50 °C to +150 °C and after adding weak acid the racemic base of the Formula III is obtained, which is recycled to the processes of the present invention.
  • strong base preferably alkali metal hydride, alkali earth metal hydride, more preferably sodium hydride in aprotic solvents (for example tetrahydrofurane, 1,4-dioxane, 1,2-dimethoxy ethane, diethyl ether, toluene) at -50 °C to +150 °C and after adding weak acid the racemic base of the Formula
  • the obtained diastereomeric salt is added to 560 ml of the mixture of water and methanol (1 :1 by volume) preheated to 50 °C and the salt is dissolved by warming to reflux and the precipitation is started spontaneously by cooling to about 55 °C. The temperature is reduced to 20 °C within 2 hours and the suspension is further stirred for 1 hour. The product is filtered, washed and dried, Yield: 52.7 g (84.2 %)
  • the recrystallization process is repeated according to the above process in 480 ml of the mixture of water and methanol (1 :1).
  • the crystals are filtered, washed twice in 1 ml ethyl-acetate and dried under infrared lamp. Yield: 0.50 g white crystals.
  • the obtained salt is recrystallized form the mixture of 3 ml of ethanol and 4 ml of ethyl methyl ketone, washed by ethyl methyl ketone and ethyl acetate on the filter and dried.
  • R KBT cm 1 3510, 31 12, 2931, 1726, 1678, 1600, 1453, 1392, 1335, 1262, 1115.
  • the aqueous phase is extracted with 10 ml and further 5 ml of dichloromethane.
  • the collected organic phases are dried on sodium sulfate. After filtering the drying agent,t the solution containing dichloromethane is evaporated.
  • the obtained oil is treated with 2 ml of boiling ethyl acetate and the solvent is evaporated under reduced pressure.
  • the phases are separated following the dissolution of the salt, the aqueous phase is extracted with 2x50 ml of dichloromethane.
  • the organic phase is evaporated after drying. 100 ml of boiling ethyl acetate is added to the remaining product and it is cooled to room temperature in 1 hour while stirring and after stirring for half an hour it is cooled to 5-10 °C and stirring is kept on for a further half an hour.
  • the crystalline product is filtered and washed with 10 ml and 5 ml of ethyl acetate. It is dried under an infrared lamp at ca. 50 °C.
  • the yielded 18.4 g of racemic base are recrystallized form 100 ml of acetonitrile and filtered at room temperature. Yield: 16.2 g (53.4 mmole; 81 %) of racemic base
  • 0.20 g (5.0 mmole, 60 w/w% suspension) of sodium hydride are added to 10 ml of toluene under argon while intensive stirring. After stirring for 10 minutes, 1.0 g (3.3 mmole) of 1 - [2-(3 -hydroxiadamant- 1 -yl-amino)acetyl]pyrrolidin-(2i?)-carbonitrile are added to the mixture. The temperature of the mixture is increased to 80 °C in 40 minutes while intensive stirring and it is stirred for 3 hours at this temperature. The inner temperature is increased to 105 °C in 30 minutes and stirring is kept on for 1 hour.
  • the suspension is cooled to room temperature and the solution of 0.51 g (8.4 mmole) of acetic acid and 2 ml of toluene is added dropwise. It is stirred for 1 hour at 30 °C and for 1 further hour at 45 °C. After cooling to room temperature, the mixture is filtered. The yield is 1.41 g of solid product after drying.
  • the obtained product is added to the solution of 0.16 g (4.0 mmole) of sodium hydroxide and 5 ml of water and 30 ml of dichloromethane and 0.60 g of sodium chloride are added to the two- phase mixture while stirring. The phases are separated and the aqueous phase is extracted with 5 ml of dichloromethane.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé pour préparer de 1-[2-(3- hydroxyadamant-1-yl-amino)acétyl]pyrrolidine-(2S)-carbonitrile représenté par la formule I ou des complexes de vildagliptine représentés par la formule IV, en particulier un complexe de vildagliptine-chlorure de calcium trihydrate représenté par la formule II à partir de (±)-1-[2-(3-hydroxiadamant-1-yl- amino)acétyl]pyrrolidine-2-carbonitrile représenté par la formule III (base racémique).
PCT/HU2011/000087 2010-08-19 2011-08-19 Procédé de préparation de vildagliptine Ceased WO2012022994A1 (fr)

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HUP1000444 2010-08-19
HU1000444A HU231050B1 (hu) 2010-08-19 2010-08-19 Eljárás gyógyszerhatóanyag előállítására

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112345668A (zh) * 2020-11-10 2021-02-09 南京奥赛斯生物科技有限公司 一种分离维格列汀中间体与r型异构体的高效液相色谱方法
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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUP1600051A2 (en) * 2016-02-01 2017-08-28 Egyt Gyogyszervegyeszeti Gyar Mirabegron cocrystals

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US3991077A (en) * 1972-10-19 1976-11-09 Ajinomoto Co., Inc. Method of racemizing optically active N-acylamino acids
WO2004092127A1 (fr) 2003-04-16 2004-10-28 Novartis Ag Procede de preparation de 2-cyanopyrrolidines n-substituees
EP1137635B1 (fr) 1998-12-10 2005-10-19 Novartis AG 2-cyanopyrrolidines n-substitues
WO2007019255A2 (fr) 2005-08-04 2007-02-15 Novartis Ag Nouveaux composes
WO2008084383A2 (fr) 2007-01-10 2008-07-17 Medichem, S.A. Procédé de préparation de la vildagliptine
WO2010022690A2 (fr) 2008-08-26 2010-03-04 Zentiva, K.S. Méthode de préparation de vildagliptine extrêmement pure
WO2011042765A1 (fr) 2009-10-07 2011-04-14 Egis Gyógyszergyár Nyilvánosan Müködö Részvény-Társaság Complexes de sel inorganique de vildaglipdine

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US3991077A (en) * 1972-10-19 1976-11-09 Ajinomoto Co., Inc. Method of racemizing optically active N-acylamino acids
EP1137635B1 (fr) 1998-12-10 2005-10-19 Novartis AG 2-cyanopyrrolidines n-substitues
WO2004092127A1 (fr) 2003-04-16 2004-10-28 Novartis Ag Procede de preparation de 2-cyanopyrrolidines n-substituees
WO2007019255A2 (fr) 2005-08-04 2007-02-15 Novartis Ag Nouveaux composes
WO2008084383A2 (fr) 2007-01-10 2008-07-17 Medichem, S.A. Procédé de préparation de la vildagliptine
WO2010022690A2 (fr) 2008-08-26 2010-03-04 Zentiva, K.S. Méthode de préparation de vildagliptine extrêmement pure
WO2011042765A1 (fr) 2009-10-07 2011-04-14 Egis Gyógyszergyár Nyilvánosan Müködö Részvény-Társaság Complexes de sel inorganique de vildaglipdine

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HANS-JÜRGEN FEDERSEL: "Asymmetry on large scale: the roadmap to stereoselective processes", NATURE REVIEWS DRUG DISCOVERY, vol. 4, no. 8, 1 August 2005 (2005-08-01), pages 685 - 697, XP055012854, ISSN: 1474-1776, DOI: 10.1038/nrd1798 *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN112345668A (zh) * 2020-11-10 2021-02-09 南京奥赛斯生物科技有限公司 一种分离维格列汀中间体与r型异构体的高效液相色谱方法

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HU231050B1 (hu) 2020-02-28
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