Field of the Invention

The present invention relates to novel purification process for the Vildagliptin.

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 (2S)-1-[[(3-hydroxytricyclo[3.3.1.1<3 7> ]dec-1-yl)amino]acetyl]-2-pyrrolidine carbonitrile and has the structure of formula (I).

Vildagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor and is first disclosed in U.S. Pat. No. 6 166 063  where a process for producing the compound is also disclosed. The ""063 patent discloses a synthesis of Vildagliptin using the synthetic process represented in Scheme 1.

Vildagliptin 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. A process that yields Vildagliptin with a high enantiomeric purity is disclosed in International Patent Publication WO 2004/092127. This reference discloses compositions containing from 95% to 99.99% of (2S)-Vildagliptin. This patent discloses purification of Vildagliptin using 1 8-diazabicyclo[5.4.0]undec-7-ene  isopropanol and methyl tert butyl ether and further crystallisation with 2-butanone/ methyl tert butyl ether. The above process for preparation of Vildagliptin require many numbers of steps and involve less economic reagents like 1 8-diazabicyclo[5.4.0]undec-7-ene. The process is relatively less safe and time-consuming. Further  product obtained by using solvent recrystallisation is very low in yield. Hence such technology is not readily suitable for commercial production.
International Patent Publication WO 2008/084383 discloses crystallisation of Vildagliptin from a mixture of IPA and MTBE. But  product obtained by using solvent recrystallisation is very low in yield.
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 simplicity  purity and yield of the product.

Summary of the invention:

The invention provides Vildagliptin with high chemical and enantiomeric purity.

One aspect of the present invention is to provide purification process for Vildagliptin comprising acid base treatment to obtain pure Vildagliptin.

In another aspect of the present invention is to provide novel process for preparation of Vildagliptin  which comprises following steps;
a. Mixing (2S)-1-(chloroacetyl) pyrrolidine-2-carbonitrile  3-Amino -1-hydroxy adamantine  suitable solvent and suitable base 
b. stirring below 40oC till completion of the reaction 
c. Removing the unwanted solid material and distilling out the filtrate 
d. crystallizing the residue in suitable solvent 
e. Isolating the solid and dissolving the solid in suitable solvent 
f. stirring the solution with weak acid solution at pH 5.0to 6.0 
g. Discarding organic layer and adjusting the pH 7.5 to 8.0 using base 
h. Extracting the product in organic solvent 
i. Distilling out organic solvent to obtain oily residue 
j. Crystallizing the residue in suitable solvent system and then filtering and drying to get Vildagliptin 
k. Optionally purifying above Vildagliptin in using suitable solvent system.

Yet another aspect of the present invention is to provide novel process for preparation of Vildagliptin  which comprises following steps;
a. Mixing (2S)-1-(chloroacetyl) pyrrolidine-2-carbonitrile  3-Amino -1-hydroxy adamantine  Dimethyl formamide and potassium carbonate 
b. stirring below 40oC till completion of the reaction 
c. Removing the unwanted solid material and distilling out the filtrate 
d. crystallizing the residue in isopropyl acetate 
e. Isolating the solid and dissolving the solid in Dichloromethane 
f. Stirring the solution with potassium hydrogen sulphate solution at pH 5.0 - 6.0
g. Discarding organic layer and adjusting the pH 7.5 to 8.0 using potassium carbonate 
h. Extracting the product in dichloromethane 
i. Distilling out dichloromethane to obtain oily residue
j. Crystallizing the residue in isopropyl acetate and then filtering and drying to get Vildagliptin.
k. Optionally purifying above Vildagliptin in using suitable solvent system.

Detailed Description of the Invention:
The invention provides especially processes concerning carrying out of chemical synthesis and methods of purification of Vildagliptin.
The process for preparation of Vildagliptin is shown in the scheme I.

A substantial characteristic of the present invention is to provide novel purification process of Vildagliptin. The synthetic stage of preparation of Vildagliptin consists in a reaction of (2S)-1-(chloroacetyl) pyrrolidine-2-carbonitrile and 3-Amino -1-hydroxy adamantine in presence of solvents comprises ketone  ester and polar aprotic solvent wherein organic ketones that can be used for this purpose comprise e.g. acetone  2-butanone or cyclohexanone  applicable esters are e.g. ethyl acetate  isopropyl acetate or dimethyl carbonate while the polar aprotic solvent may be selected e.g. from dimethylformamide  dimethylacetamide  dimethylsulfoxide  N-methylpyrolidone  hexamethylphosphoramide  polyethylene glycols or crown ethers. An alkaline metal carbonate can be used as base.

The crude oily product can be crystallize in suitable solvent like acetone  2-butanone  cyclohexanone  ethyl acetate  isopropyl acetate or dimethyl carbonate.

This solid is further dissolved in water immiscible solvents like ester such as ethyl acetate  hydrocarbon such as toluene or chlorinated solvents like dichloromethane.

Vildagliptin is extracted in the aqueous solution at slight acidic pH as between 5.0 to 6.0 from the organic solvent in form of a salt like hydrochloride  methane sulphonate  sulphate  citrate  acetate  hydrogen sulphate or Fumarate using acids like hydrochloric acid  sulphuric acid  carboxylic acid such as acetic acid or benzoic acid  poly carboxylic acid such as fumaric acid or maleic acid  sulphonic acid such as methane sulphonic acid or p-toluene sulphonic acid or hydrogen sulphate such as potassium hydrogen sulphate or sodium hydrogen sulphate.

Aqueous layer is then basified at pH 7.5 to 8.0 using base like metal carbonates or hydroxides and then product is extracting in water immiscible solvents.

After removal of solvents product is crystallizing in solvent like acetone  2-butanone or cyclohexanone  applicable esters is e.g. ethyl acetate  isopropyl acetate or dimethyl carbonate.

The major advantage of this process is the removal of dimmer impurity and removal of unreacted starting material which results in to comparative quality and good yield.

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)-1-(chloroacetyl) pyrrolidine-2-carbonitrile
L-Prolinamide (100 g) was dissolved in Dimethyl formamide (400 ml) under nitrogen atmosphere. The reaction mass was cooled to 10-15°C and chloroacetyl chloride (128.6 g) was added in to it. The reaction mass was stirred for 2-3 hours at 25-30°C. Cyanuric chloride was added lot wise (96.9 g) (4 lots of equal qty) within 45-60 minutes at 25-30°C. The reaction mass was stirred for 2-3 hours at 25-30°C. The reaction mass was cooled to 10°C. Process Water (1000 ml) and ethyl acetate (500 ml) were added and stirred the reaction mass for 20-30 minutes. The reaction mass was filtered through hyflo bed. The layers were settled and separated. In organic layer the aqueous sodium carbonate solution (~175 ml  20%) was added up to pH 7.0 to 8.0. the reaction mass was stirred for 20-30 minutes. The layers were settled and separated. The organic layer was treated with activated carbon (2gm). The solvent was removed under vacuum. The Isopropyl alcohol (200 ml) was charged into the oily residue and Stirred for 1 hour at 25-30°C. The solid was filtered and washed with Isopropyl alcohol (50 ml). The product was dried under vacuum at 35-40°C. Yield: 47.68%

Example-2
Preparation of Vildagliptin
Dimethyl formamide (600 ml)  (2S)-1-(chloroacetyl) pyrrolidine-2-carbonitrile (100 g)  3-Amino -1-hydroxy adamantane (106.5) and potassium carbonate (239.8g) were mixed under nitrogen atmosphere. The reaction mixture was heated at 40oC 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). The wet solid was dissolved in methylene dichloride (300 ml) and stirred with Water (200 ml). Aqueous Potassium hydrogen sulphate solution [Approx. 300 ml  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 [Approx 150 ml  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) as charged 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°. Yield: 70%.

Dated this 05th day of Jan 2012


Dr. Alpesh Pathak
Applicant’s Agent