Process for the preparation of Vildagliptin
Publication Date: 2015-Jan-22
The IP.com Prior Art Database
Improved process for the preparation of Vildagliptin.
Stage-I: Preparation of 1-Chloroacetyl -2-(S)-2-cyanopyrrolidine (VIL-I)
Charge Dichloromethane, 300ml in to a clean and dry RBF under nitrogen atm. Cool reaction mass -5 to 5°C. To the reaction mass charge Chloroacetyl chloride 84.80ml at -5 to 5°C. Add solution of L-Prolinamide, 100g Dichloromethane 1000ml, Triethyl amine, 129ml to the reaction mass maintaining temperature -5 to 5°C. Stir the reaction mass at -5 to 5°C for 30min. raise the temperature of reaction mass to 24 to 30°C. Stir the reaction mass at 24-30°C for 2 to 3Hrs. Monitor the reaction by G.C., L-Prolinamide should be NMT 1.0%. After completion of reaction cool the reaction mass to 2 to 8°C. Add N, N dimethyl formamide, 88.5ml to the reaction mass to 2 to 8°C. After completion of N, N dimethyl formamide addition further add Phosphorus oxychloride, 105ml to reaction mass. After addition of Phosphorus oxychloride raise the temperature of reaction mass 21 to 25°C. Stir the reaction mass at 21-25°C for 2 to 3Hrs. Monitor the reaction by HPLC, VIL-IA intermediate should be NMT 5.0%.
After completion of reaction, cool the reaction mass to -5 to 5°C, Quench the reaction by adding water, 1000ml maintaining temperature 5 to 10°C. After water addition raise the temperature of reaction mass to 22 to 28°C stir and separated the layers. Aqueous layer further extracted using Dichloromethane, 2*300ml. Combine Dichloromethane layer washed with water, 500ml followed by 5% Sodium bi-carbonate solution, 500ml and water 500ml. After washing Dichloromethane layer dried over sodium sulphate, 10g. Dried dichloromethane layer concentrate under reduced pressure below 45°C till obtained oily mass/solids. Residual oily mass/solids swapped with Tertiary butyl methyl ether 2*50ml. To the concentrated oily mass/solids Add Isopropyl alcohol, 50ml followed by Tertiary butyl methyl ether, 400ml. Heat the reaction mass and stir at 45to 55°C. Further cool the reaction mass to -5 to 5°C and stir for atleast 1Hr. filter the product followed by washing with Tertiary butyl methyl ether, 100ml.
Dry the product at 30 to 40°C under reduced pressure 600-750mm/Hg for 3Hrs.
Dry weight of VIL-I: 106 – 125 gm.
Water content: NMT 0.5%
LOD: NMT 0.5%
W/w yield: 1.06 – 1.25
HPLC purity More than 98.0%
Stage-II: Preparation of (2S)-1[(3-hydroxytricyclo [18.104.22.168(3,7)]dec-1-yl)amino]acetyl]-2-
pyrrolidine carbonitrile (VIL-II) (Crude Vildagliptin)
Charge 3-Amino-1-adamantanol,97g in to clean and dry RBF under nitrogen atm. Charge Ethyl acetate, 1000ml to the reaction mass. Charge potassium carbonate, 96g to the reaction mass and stir the slurry at 25 to 31°C. Add solution of VIL-I, 100gm in ethyl acetate, 1000ml to reaction mass over 1Hr at 25-31°C. Stir the reaction mass at 25-31°C for 18 to 20Hrs further raised temperature of reaction mass to 37 to 43°C. Stir reaction mass at 37-43°C for 1Hr. monitor reaction by H...