WO2014020462A1 - Improved process for preparation of vildagliptin intermediate - Google Patents
Improved process for preparation of vildagliptin intermediate Download PDFInfo
- Publication number
- WO2014020462A1 WO2014020462A1 PCT/IB2013/055570 IB2013055570W WO2014020462A1 WO 2014020462 A1 WO2014020462 A1 WO 2014020462A1 IB 2013055570 W IB2013055570 W IB 2013055570W WO 2014020462 A1 WO2014020462 A1 WO 2014020462A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cyano
- preparation
- pyrrolidine
- vildagliptin
- improved process
- Prior art date
Links
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
- the present invention relates to an improved process for preparation of Vildagliptin intermediate, 1-chloro acetyl (S)-2-cyano pyrrolidine.
- Vildagliptin is an active pharmaceutical substance with an empirical formula of C17H25N3O2 and a molecular weight of 303.40 g/mol.
- Vildagliptin is the international common accepted name for (S)-l-[N-(3-hydroxy-l-adamantyl)glycyl]pyrrolidine-2- carbonitrile and has the structure of formula (I).
- Vildagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor and is first disclosed in US6166063, where a process for producing the compound is also disclosed.
- the ⁇ 63 patent discloses a synthesis of Vildagliptin using the synthetic process represented in Scheme 1.
- the invention provides an improved process for preparation of Vildagliptin intermediate, 1-chloro acet l (S)-2-cyano pyrrolidine.
- One aspect of the present invention is to provide an improved process for preparation of Vildagliptin intermediate.
- in another aspect of the present invention is to provide an improved process for preparation of Vildagliptin, which comprises preparation of 1-chloro acetyl (S)-2-cyano pyrrolidine, which further comprises;
- the invention provides especially processes concerning preparation of Vildagliptin intermediate 1-chloro acetyl (S)-2-cyano pyrrolidine.
- the present invention provides an improved process for preparation of Vildagliptin, which comprises preparation of 1-chloro acetyl (S)-2-cyano pyrrolidine, which further comprises;
- PG is protecting group.
- suitable protecting group refers to the protecting group selected from t-butoxycarbonyl, benzyloxycarbonyl, isopropyloxycarbonyl, ethyloxycarbonyl, methyloxycarbonyl, formyl, trityl, acetyl, trichloroacetyl, dichloroacetyl, chloroacetyl, trifluoroacetyl, difluoroacetyl, fluoroacetyl, benzyl chloroformate, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4- ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3- chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbon
- the present invention provides an improved process for preparation of Vildagliptin, which comprises preparation of 1-chloro acetyl (S)-2-cyano pyrrolidine, which further comprises;
- the present invention provides an improved process for preparation of Vildagliptin, which comprises preparation of 1-chloro acetyl (S)-2-cyano pyrrolidine, which further comprises;
- 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; “nitrile 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, chlor
- suitable base refers to the base 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, 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.
- inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride; al
- suitable acid refers to the acid selected from the group of methane sulphonic acid, p-toluene sulphonic acid, hydrochloric acid, trifluroacetic acid, acetic acid, sulphuric acid, nitric acid their mixtures there of, more preferably methane sulphonic acid.
- the subsequent dehydration can be carried out in a solvent such as e.g. DMA, DMF, THF, dioxane, ethyl acetate or methylenechloride, preferably in methylenechloride or DMF or a mixture of methylenechloride and DMF, with a dehydrating agent such as e.g. trifluoro acetic anhydride, cyanuric chloride, chlormethyliminiumchloride, Vilsmeir reagent, SOCl 2 or POCI 3 , more preferably cyanuric chloride.
- a dehydrating agent such as e.g. trifluoro acetic anhydride, cyanuric chloride, chlormethyliminiumchloride, Vilsmeir reagent, SOCl 2 or POCI 3 , more preferably cyanuric chloride.
- the reaction of (S)-2-Cyano-pyrrolidine with C1CH2COC1 can be carried out in suitable solvent and in
- the present invention provides an improved process for preparation of Vildagliptin, which comprises preparation of N-boc L-prolinamide by condensing L-prolinamide with boc anhydride in presence of inorganic base and suitable solvent.
- the present invention provides an improved process for preparation of Vildagliptin, which comprises preparation of N-boc L-prolinamide by condensing L-prolinamide with boc anhydride in presence of potassium carbonate and acetonitrile.
- the present invention provides an improved process for preparation of Vildagliptin, which comprises conversion of N-boc L-prolinamide to N- -2-Cyano-pyrrolidine using dehydrating agent.
- the present invention provides an improved process for preparation of Vildagliptin, which comprises conversion of N-boc L-prolinamide to N- boc (S)-2-Cyano-pyrrolidine using cyanuric chloride and DMF.
- the present invention provides an improved process for preparation of Vildagliptin, which comprises removal of boc protection using suitable acid to obtain (S)-2-Cyano-pyrrolidine.
- the present invention provides an improved process for preparation of Vildagliptin, which comprises removal of boc protection using methane sulphonic acid to obtain (S)-2-Cyano-pyrrolidine.
- the present invention provides an improved process for preparation of Vildagliptin, which comprises reaction of (S)-2-Cyano-pyrrolidine with chloro acetyl chloride to obtain 1-chloro acetyl (S)-2-cyano pyrrolidine
- the present invention provides an improved process for preparation of Vildagliptin, which comprises reaction of (S)-2-Cyano-pyrrolidine with 2- chloro acetyl chloride to obtain 1-chloro acetyl (S)-2-cyano pyrrolidine in presence of tri ethyl amine and acetonitrile.
- the main embodiment of the present invention is to provide a process for preparing a Vildagliptin intermediate i.e., (2S)-l-(Chloroacetyl)-2-pyrrolidinecarbonitrile represented by Scheme III.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
Provided is an improved process for preparation of Vildagliptin intermediate, 1-chloro acetyl (S)-2-cyano pyrrolidine.
Description
IMPROVED PROCESS FOR PREPARATION OF
VILDAGLIPTIN INTERMEDIATE
Field of the Invention
The present invention relates to an improved process for preparation of Vildagliptin intermediate, 1-chloro acetyl (S)-2-cyano pyrrolidine.
Background of the Invention
Vildagliptin is an active pharmaceutical substance with an empirical formula of C17H25N3O2 and a molecular weight of 303.40 g/mol. Vildagliptin is the international common accepted name for (S)-l-[N-(3-hydroxy-l-adamantyl)glycyl]pyrrolidine-2- carbonitrile and has the structure of formula (I).
Vildagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor and is first disclosed in US6166063, where a process for producing the compound is also disclosed. The Ό63 patent discloses a synthesis of Vildagliptin using the synthetic process represented in Scheme 1.
However, the preparation process of Vildagliptin intermediate, 1-chloro acetyl (S)-2- c ano pyrrolidine has some problems. The acylation of (S)-prolinamide of the formula
with chloroacetyl chloride of the formula
is carried out in THF and thus formed l-(2-chloroacetyl)-pyrrolidine-2-carboxamide of the formula
is reacted with trifluoro acetic anhydride to obtain l-(2-chloroacetyl)-pyrrolidine-(2S)- carbonitrile.
Therefore, there is a need to develop an improved and commercially viable process of preparing pure Vildagliptin which is suitable for large-scale preparation, in lesser reaction time, in terms of consistency, simplicity, purity and yield of the product.
Compared to other reactions known in the art (e.g. from Journal of Medicinal Chemistry, 46(13), 2774-2789, 2003; Journal of Medicinal Chemistry, 45(12), 2362-2365, 2002; US 601 1155; US 2004/106802), the reaction of the present invention as described above unexpectedly exhibits a largely improved yield and selectivity.
Summary of the invention:
The invention provides an improved process for preparation of Vildagliptin intermediate, 1-chloro acet l (S)-2-cyano pyrrolidine.
One aspect of the present invention is to provide an improved process for preparation of Vildagliptin intermediate.
In another aspect of the present invention is to provide an improved process for preparation of Vildagliptin, which comprises preparation of 1-chloro acetyl (S)-2-cyano pyrrolidine, which further comprises;
a. Protecting the ring nitrogen of L-prolinamide using N-protecting group, b. dehydrating the amide group to obtain cyano group,
c. Removing the protecting group,
d. Reacting (S)-2-Cyano-pyrrolidine or its salt with chloro acetyl chloride.
Detailed Description of the Invention:
The invention provides especially processes concerning preparation of Vildagliptin intermediate 1-chloro acetyl (S)-2-cyano pyrrolidine.
In one embodiment the present invention provides an improved process for preparation of Vildagliptin, which comprises preparation of 1-chloro acetyl (S)-2-cyano pyrrolidine, which further comprises;
a. Protecting the ring nitrogen of L-prolinamide using suitable protecting group, b. dehydrating the amide group to obtain cyano group,
c. Removing the protective group,
d. Reacting (S)-2-Cyano-pyrrolidine with chloro acetyl chloride.
The process for preparation of Vildagliptin intermediate is shown in the scheme II.
Scheme-II
Wherein, PG is protecting group. As used herein the term " suitable protecting group" refers to the protecting group selected from t-butoxycarbonyl, benzyloxycarbonyl, isopropyloxycarbonyl, ethyloxycarbonyl, methyloxycarbonyl, formyl, trityl, acetyl, trichloroacetyl, dichloroacetyl, chloroacetyl, trifluoroacetyl, difluoroacetyl, fluoroacetyl, benzyl chloroformate, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4- ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3- chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4- cyanobenzyl oxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl, 1 , 1 -diphenyleth- 1 -yloxy carbonyl, 1 ,1-diphenylprop-l-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-
toluoyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1 -methyl cyclopentanyl oxycarbonyl, cyclohexanyloxy carbonyl, 1-methylcyclohexanyloxycarbonyl, 2- methylcyclo hexanyloxycarbonyl, 2-(4-toluoylsulfonyl) ethoxycarbonyl, 2- (methylsulfonyl) ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenyl methoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1 -(trimethylsilyl methyl) prop- 1 -enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyl oxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropyl methoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobornyl oxycarbonyl, 1- piperidyloxycarbonyl and 9-fluorenylmethylcarbonyl, more preferably t-butoxycarbonyl.
In another embodiment the present invention provides an improved process for preparation of Vildagliptin, which comprises preparation of 1-chloro acetyl (S)-2-cyano pyrrolidine, which further comprises;
a. Protecting the ring nitrogen of L-prolinamide using Di-tert-butyl dicarbonate, b. dehydrating the amide group to obtain cyano group,
c. Removing the boc protective group,
d. Reacting (S)-2-Cyano-pyrrolidine with 2-chloro acetyl chloride.
Yet, in another embodiment the present invention provides an improved process for preparation of Vildagliptin, which comprises preparation of 1-chloro acetyl (S)-2-cyano pyrrolidine, which further comprises;
a. Protecting the ring nitrogen of L-prolinamide using Di-tert-butyl dicarbonate in presence of inorganic base and suitable solvent,
b. Dehydrating amide group to obtain cyano group using dehydrating agent, c. Removing the protective group using suitable acid,
d. reacting (S)-2-Cyano-pyrrolidine with 2-chloro acetyl chloride in presence of suitable base and suitable solvent,
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; "nitrile 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 base" refers to the base 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, 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.
As used herein the present invention the term "suitable acid" refers to the acid selected from the group of methane sulphonic acid, p-toluene sulphonic acid, hydrochloric acid, trifluroacetic acid, acetic acid, sulphuric acid, nitric acid their mixtures there of, more preferably methane sulphonic acid.
The subsequent dehydration can be carried out in a solvent such as e.g. DMA, DMF, THF, dioxane, ethyl acetate or methylenechloride, preferably in methylenechloride or DMF or a mixture of methylenechloride and DMF, with a dehydrating agent such as e.g. trifluoro acetic anhydride, cyanuric chloride, chlormethyliminiumchloride, Vilsmeir reagent, SOCl2 or POCI3, more preferably cyanuric chloride.
The reaction of (S)-2-Cyano-pyrrolidine with C1CH2COC1 can be carried out in suitable solvent and in the presence of suitable base, more preferably in presence of acetonitrile and triethylamine.
In another embodiment the present invention provides an improved process for preparation of Vildagliptin, which comprises preparation of N-boc L-prolinamide by condensing L-prolinamide with boc anhydride in presence of inorganic base and suitable solvent.
Yet, in another embodiment the present invention provides an improved process for preparation of Vildagliptin, which comprises preparation of N-boc L-prolinamide by condensing L-prolinamide with boc anhydride in presence of potassium carbonate and acetonitrile.
In another embodiment the present invention provides an improved process for preparation of Vildagliptin, which comprises conversion of N-boc L-prolinamide to N- -2-Cyano-pyrrolidine using dehydrating agent.
Yet, in another embodiment the present invention provides an improved process for preparation of Vildagliptin, which comprises conversion of N-boc L-prolinamide to N- boc (S)-2-Cyano-pyrrolidine using cyanuric chloride and DMF.
In another embodiment the present invention provides an improved process for preparation of Vildagliptin, which comprises removal of boc protection using suitable acid to obtain (S)-2-Cyano-pyrrolidine.
Yet, in another embodiment the present invention provides an improved process for preparation of Vildagliptin, which comprises removal of boc protection using methane sulphonic acid to obtain (S)-2-Cyano-pyrrolidine.
In another embodiment the present invention provides an improved process for preparation of Vildagliptin, which comprises reaction of (S)-2-Cyano-pyrrolidine with chloro acetyl chloride to obtain 1-chloro acetyl (S)-2-cyano pyrrolidine
Yet, in another embodiment the present invention provides an improved process for preparation of Vildagliptin, which comprises reaction of (S)-2-Cyano-pyrrolidine with 2- chloro acetyl chloride to obtain 1-chloro acetyl (S)-2-cyano pyrrolidine in presence of tri ethyl amine and acetonitrile.
The main embodiment of the present invention is to provide a process for preparing a Vildagliptin intermediate i.e., (2S)-l-(Chloroacetyl)-2-pyrrolidinecarbonitrile represented by Scheme III.
Scheme-Ill
The present invention further illustrated in detail by the below examples which are however not limit to the scope of the invention.
Example-1
Preparation of (2S)-l-(Chloroacetyl)-2-cyanopyrrolidine
Dichloromethane (500 ml), L-Prolinamide (100 g), potassium carbonate (60.50 g) were mixed and stirred under nitrogen atmosphere in round bottom flask The reaction mass was cooled to 10-15°C and then Di-tert-butyl dicarbonate (210.30 g) was added. Reaction mixture was stirred till completion of the reaction. After completion water (500ml) was added and product was extracted in dichloromethane. Dichloro methane was removed and then dimethyl formamide (140 ml) and dichloromethane (700 ml) were added under nitrogen atmosphere. Cyanuric chloride (72.70 g) was charged in -2-3 equal lots to the reaction mass at 20-25°C under nitrogen atmosphere. The reaction mass was maintained at 35-40°C for 4-5 hrs. After completion of the reaction solid was filtered and washed with MDC. Methane sulfonic acid (252.60 g) was added to the filtrate and heated the reaction mass to 40-45°C for 3-4 hrs. After completion of the reaction the reaction mass was cooled at 0-5°C and Triethyl amine (88.65 g) and Chloroacetyl chloride (118.70 g) were added. The reaction mass was maintained at 20-30°C for 1-2 hrs under nitrogen atmosphere. After completion of the reaction water was charged and product was extracted in dichloromethane. Organic layer was washed first with dilute HC1 solution and then with ammonia solution. Organic solvent was removed and product was crystallized using isopropyl alcohol. Yield: 75.0gm
Example-2
Preparation of crude Vildagliptin
Dimethyl formamide (600 ml), (2S)-l-(chloroacetyl) pyrrolidine-2-carbonitrile (100 g), 3-Amino -1-hydroxy adamantane (106.5) and potassium carbonate (99.9g) were mixed under nitrogen atmosphere. The reaction mixture was heated at 40°C for 10 hrs. The solid was filtered and washed with DMF (200 ml). The solvent was distilled completely under vacuum and charged Isopropyl Acetate (600 ml) into the semi solid mass. The reaction mass was stirred at 5 - 10°C for 30 to 60 minutes. The solid was filtered and washed with Isopropyl Acetate (50 ml). Dried the material under vacuum at 50-55°C to obtain crude Vildagliptin (150.0 gm), HPLC purity: ~ 98.0
Example-3
Purification of crude Vildagliptin
Crude Vildagliptin (100. Og) was dissolved in methylene dichloride (300 ml) and stirred with Water (400 ml). Aqueous Potassium hydrogen sulphate solution (20%) was added drop wise in the reaction mixture to adjust pH 5.0 to 5.5 and then separated the aqueous layer. Potassium carbonate solution (20%) was added drop wise in the aqueous layer to adjust pH 7.5 to 8.0. The product was extracted in methylene dichloride (1000ml). The organic layer was distilled under vacuum up to 45°C to obtain the oily residue. Isopropyl Acetate (250ml) was added into the oily residue and stirred the reaction mass for 30-45 minutes at 40-45°C. Cooled the reaction mass at 10-15°C and filtered the solid. Washed the solid with Isopropyl Acetate (50 ml) and dried the product under vacuum at 35-40° C to obtain 85.0g pure Vildagliptin. HPLC purity: > 99.8
Claims
1. An improved process for preparation of Vildagliptin, which comprises preparation of 1-chloro acetyl (S)-2-cyano pyrrolidine compound of formula II,
(II)
which further comprises;
a. Protecting the ring nitrogen of L-prolinamide using N-protecting group, b. dehydrating the amide group to obtain cyano group,
c. Removing the protecting group,
d. Reacting (S)-2-Cyano-pyrrolidine or its salt with chloro acetyl chloride.
2. An improved process for preparation of Vildagliptin, which comprises preparation of 1-chloro acetyl (S)-2-cyano pyrrolidine, which further comprises;
a. Protecting the ring nitrogen of L-prolinamide using Di-tert-butyl dicarbonate, b. dehydrating the amide group to obtain cyano group,
c. Removing the boc protecting group,
d. Reacting (S)-2-Cyano-pyrrolidine or its salt with 2-chloro acetyl chloride.
3. An improved process for preparation of Vildagliptin, which comprises preparation of 1-chloro acetyl (S)-2-cyano pyrrolidine, which further comprises;
a. Protecting the ring nitrogen of L-prolinamide using Di-tert-butyl dicarbonate in presence of inorganic base and suitable solvent,
b. dehydrating the amide group to obtain cyano group using dehydrating agent, c. Removing the protective group using acid,
d. Reacting (S)-2-Cyano-pyrrolidine or its salt with 2-chloro acetyl chloride in presence of base and suitable solvent.
4. An improved process for preparation of Vildagliptin, which comprises preparation of 1-chloro acetyl (S)-2-cyano pyrrolidine, which further comprises;
a. Protecting the ring nitrogen of L-prolinamide using Di-tert-butyl dicarbonate in presence of potassium carbonate and dichloromethane,
b. dehydrating the amide group to obtain cyano group using cyanuric chloride, c. Removing the protective group using methane sulphonic acid,
d. Reacting (S)-2-Cyano-pyrrolidine or its salt with 2-chloro acetyl chloride in presence of triethylamine and isopropyl alcohol.
An improved process for preparation of Vildagliptin, which comprises preparation of N-boc L-prolinamide by condensing L-prolinamide with boc anhydride in presence of potassium carbonate and dichloromethane.
An improved process for preparation of Vildagliptin, which comprises conversion of N-boc L-prolinamide to N-boc (S)-2-Cyano-pyrrolidine using cyanuric chloride.
An improved process for preparation of Vildagliptin, which comprises removal of boc protection using methane sulphonic acid to obtain (S)-2-Cyano-pyrrolidine.
An improved process for preparation of Vildagliptin, which comprises reaction of (S)-2-Cyano-pyrrolidine with 2-chloro acetyl chloride to obtain 1-chloro acetyl (S)-2- cyano pyrrolidine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2214/MUM/2012 | 2012-08-01 | ||
| IN2214MU2012 | 2012-08-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2014020462A1 true WO2014020462A1 (en) | 2014-02-06 |
Family
ID=50027338
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2013/055570 WO2014020462A1 (en) | 2012-08-01 | 2013-07-08 | Improved process for preparation of vildagliptin intermediate |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2014020462A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804267A (en) * | 2014-02-21 | 2014-05-21 | 张家港威胜生物医药有限公司 | Simple environment-friendly synthesis process of vildagliptin |
| CN104030958A (en) * | 2014-06-06 | 2014-09-10 | 河北科技大学 | Synthesis method of (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile |
| CN106117104A (en) * | 2016-06-17 | 2016-11-16 | 东北制药集团股份有限公司 | A kind of preparation method of vildagliptin |
| CN108329322A (en) * | 2018-05-10 | 2018-07-27 | 上海医药集团青岛国风药业股份有限公司 | A kind of preparation method of vildagliptin ring amidine impurity |
| CN112028806A (en) * | 2020-08-25 | 2020-12-04 | 河北合佳医药科技集团股份有限公司 | Synthetic method of vildagliptin intermediate |
| CN112679406A (en) * | 2020-12-14 | 2021-04-20 | 河北合佳医药科技集团股份有限公司 | Continuous preparation method of vildagliptin |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6011155A (en) * | 1996-11-07 | 2000-01-04 | Novartis Ag | N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
| US6166063A (en) * | 1998-12-10 | 2000-12-26 | Novartis Ag | N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
| US20040106802A1 (en) * | 2002-04-08 | 2004-06-03 | Torrent Pharmaceuticals Ltd. | Novel compounds and therapeutic uses thereof |
| WO2004099185A1 (en) * | 2003-05-09 | 2004-11-18 | Fujisawa Pharmaceutical Co. Ltd. | 2-cyanopyrrolidine derivatives and their use as dpp-iv inhibitors |
| US20080167479A1 (en) * | 2007-01-10 | 2008-07-10 | Medichem, S.A. | Process for preparing vildagliptin |
-
2013
- 2013-07-08 WO PCT/IB2013/055570 patent/WO2014020462A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6011155A (en) * | 1996-11-07 | 2000-01-04 | Novartis Ag | N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
| US6166063A (en) * | 1998-12-10 | 2000-12-26 | Novartis Ag | N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
| US20040106802A1 (en) * | 2002-04-08 | 2004-06-03 | Torrent Pharmaceuticals Ltd. | Novel compounds and therapeutic uses thereof |
| WO2004099185A1 (en) * | 2003-05-09 | 2004-11-18 | Fujisawa Pharmaceutical Co. Ltd. | 2-cyanopyrrolidine derivatives and their use as dpp-iv inhibitors |
| US20080167479A1 (en) * | 2007-01-10 | 2008-07-10 | Medichem, S.A. | Process for preparing vildagliptin |
Non-Patent Citations (2)
| Title |
|---|
| VILLHAUER, EDWIN B. ET AL.: "1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: A Potent, Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties.", J. MED. CHEM., vol. 46, no. 13, 2003, pages 2774 - 2789 * |
| VILLHAUER, EDWIN B. ET AL.: "1-[2-[(5-Cyanopyridin-2-yl)amino]-ethylamino]acetyl-2-(S)-pyrrolidinecarbonitrile: A Potent, Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties.", J. MED. CHEM., vol. 45, no. 12, 2002, pages 2362 - 2365 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804267A (en) * | 2014-02-21 | 2014-05-21 | 张家港威胜生物医药有限公司 | Simple environment-friendly synthesis process of vildagliptin |
| CN103804267B (en) * | 2014-02-21 | 2016-06-08 | 张家港威胜生物医药有限公司 | A kind of synthesis technique of vildagliptin |
| CN104030958A (en) * | 2014-06-06 | 2014-09-10 | 河北科技大学 | Synthesis method of (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile |
| CN104030958B (en) * | 2014-06-06 | 2016-06-29 | 河北科技大学 | A kind of (S)-1-(2-chloracetyl) synthetic method of pyrrolidine-2-formonitrile HCN |
| CN106117104A (en) * | 2016-06-17 | 2016-11-16 | 东北制药集团股份有限公司 | A kind of preparation method of vildagliptin |
| CN108329322A (en) * | 2018-05-10 | 2018-07-27 | 上海医药集团青岛国风药业股份有限公司 | A kind of preparation method of vildagliptin ring amidine impurity |
| CN112028806A (en) * | 2020-08-25 | 2020-12-04 | 河北合佳医药科技集团股份有限公司 | Synthetic method of vildagliptin intermediate |
| CN112028806B (en) * | 2020-08-25 | 2022-09-30 | 河北合佳医药科技集团股份有限公司 | Synthetic method of vildagliptin intermediate |
| CN112679406A (en) * | 2020-12-14 | 2021-04-20 | 河北合佳医药科技集团股份有限公司 | Continuous preparation method of vildagliptin |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2477992B1 (en) | Processes for the preparation of darunavir and the amorphous form thereof | |
| WO2014020462A1 (en) | Improved process for preparation of vildagliptin intermediate | |
| KR101467598B1 (en) | Process for hcv protease inhibitor intermediate | |
| US7893103B2 (en) | Processes for the preparation of DPP IV inhibitors | |
| CA2763572C (en) | Substituted aminopropionic derivatives as neprilysin inhibitors | |
| EP2025672B1 (en) | Process for producing 1-carbamoyl-3,7-dioxo-1,4-diazepane compounds | |
| EP3297678B1 (en) | An improved processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof | |
| RU2730006C1 (en) | Method of producing 5r-[(benzyloxy)amino]piperidine-2s-carboxylic acid or derivative thereof | |
| TW200844092A (en) | New process | |
| EP3110795A1 (en) | Novel economic process for vildagliptin | |
| WO2017134588A1 (en) | Process for the preparation of ibrutinib | |
| CA2810393A1 (en) | Method of preparing 3-amino-4-(2-oxo-piperidin-1-yl)-butyric acid derivative for synthesizing medicament | |
| WO2020222158A1 (en) | Process for the preparation of 2-amino-n-(2,2,2-trifluoroethyl)-acetamide and salts thereof | |
| CN112028806B (en) | Synthetic method of vildagliptin intermediate | |
| WO2014002114A2 (en) | Process for the preparation of saxagliptin and hydrates thereof | |
| US8288561B2 (en) | Process for preparing valsartan | |
| US10472329B2 (en) | Process for the preparation of intermediates useful in the synthesis of Eluxadoline | |
| JP5704763B2 (en) | Production of trans-4-aminocyclopent-2-ene-1-carboxylic acid derivative | |
| JP2020507615A (en) | Improved process for the preparation of boronic esters | |
| CN114163372A (en) | Continuous preparation method of vildagliptin key intermediate | |
| WO2004099136A1 (en) | Process for producing pyrrolidine derivative | |
| WO2014155264A1 (en) | Process for the preparation of lacosamide using novel intermediates | |
| JP5944929B2 (en) | Process for the reduction of α-acyloxysulfide derivatives | |
| EP3941917A1 (en) | An improved process for the preparation of eliglustat and its intermediate | |
| EP1698621A1 (en) | Method for producing pyrrolidine derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13826529 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 13826529 Country of ref document: EP Kind code of ref document: A1 |