Synthesis method of vildagliptin

[0029] (1) Preparation of (S)-1-(2-oxoacetyl)pyrrolidine-2-carbonitrile

[0030] Add 16.2g (0.22mol) glyoxylic acid, 47.9g (0.25mol) EDCI, 33.7g (0.25mol) HOBT, 52.5g (0.52mol) triethylamine and 240 mL dichloromethane to the reaction flask, cool to 0 ℃~5℃, after stirring for 1.5h, add 20.0g (0.21mol) (S)-pyrrolidine-2-carbonitrile in batches at 0℃~5℃, then remove the ice bath, carry out at 20~25℃ The reaction was stirred for 16 hours, monitored by HPLC, and the conversion of the starting material (S)-pyrrolidine-2-carbonitrile was complete. The post-processing method is as follows: add 100 mL of water to the reaction solution, extract with dichloromethane (100 mL×2), separate the layers, wash the organic phase with 100 mL of saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to remove the solvent to obtain 28.5 g of a light yellow oily liquid. , the yield is 89%.

[0031] (2) Preparation of sodium 2-((S)-2-cyanopyrrolidin-1-yl)-1-hydroxy-

[0038] (1) Preparation of (S)-1-(2-oxoacetyl)pyrrolidine-2-carbonitrile

[0039] Add 15.5g (0.21mol) glyoxylic acid, 44.1g (0.23mol) EDCI, 28.4g (0.21mol) HOBT, 42.5g (0.42mol) triethylamine and 240 mL dichloromethane to the reaction flask, cool to 0 ℃~5℃, after stirring for 1h, add 20.0g (0.21mol) (S)-pyrrolidine-2-carbonitrile in batches at 0℃~5℃, then remove the ice bath, and carry out the reaction at 20~25℃ , stirred for 16 hours, monitored by HPLC, the conversion of the raw material (S)-pyrrolidine-2-carbonitrile was complete. The post-processing method is as follows: add 100 mL of water to the reaction solution, extract with dichloromethane (100 mL×2), separate the layers, wash the organic phase with 100 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove the solvent to obtain 27.9 g of a light yellow oily liquid. , the yield is 87%.

[0040] (2) Preparation of sodium 2-((S)-2-cyanopyrrolidin-1-yl)-1-hydroxy-2-oxoetha

[0045] (1) Preparation of (S)-1-(2-oxoacetyl)pyrrolidine-2-carbonitrile

[0046] Add 17.0g (0.23mol) glyoxylic acid, 47.9g (0.25mol) EDCI, 31.1g (0.23mol) HOBT, 52.5g (0.52mol) triethylamine and 240 mL dichloromethane to the reaction flask, cool to 0 ℃~5℃, after stirring for 2.5h, add 20.0g (0.21mol) (S)-pyrrolidine-2-carbonitrile in batches at 0℃~5℃, then remove the ice bath, carry out at 20~25℃ The reaction was stirred for 14 hours, monitored by HPLC, and the conversion of the starting material (S)-pyrrolidine-2-carbonitrile was complete. The post-processing method is as follows: adding 100 mL of water to the reaction solution, extracting with dichloromethane (100 mL×2) for separation, washing the organic phase with 100 mL saturated brine, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to remove the solvent to obtain 27.1 g of a light yellow oily liquid. Yield 85%.

[0047] (2) Preparation of sodium 2-((S)-2-cyanopyrrolidin-1-yl)-1-hydroxy-2-ox