Novel mitiglinide calcium preparing method

[0031] (1) Preparation of (S)-2-benzylsuccinic anhydride

[0032] Add 30.40g (0.16mol) of (S)-2-benzylsuccinic acid, 20mL of acetic anhydride, and 60mL of toluene into a 100mL three-necked flask in sequence, and stir and reflux for 1 hour. After the reaction is complete, cool to crystallize, filter, and dry to obtain white flakes Crystals 25.39 g.

[0033] (2) Amidation of (S)-2-benzylsuccinic anhydride

[0034] Add 25.39 g (0.13 mol) of (S)-2-benzylsuccinic anhydride and 300 mL of dichloromethane into a 500 mL three-necked flask in sequence. Under the condition of -10~5°C, a dichloromethane solution (20 mL) of 17.54 g (0.14 mol) of cis-perhydroisoindole was slowly added dropwise, stirred for 4 hours, and the reaction was completed. The reaction solution was washed with 0.5 mol / L HCl solution (100 mL×2), and then washed with 100 mL saturated brine. The organic phase was dried overnight with 50 g of anhydrous sodium sulfate. After filtration, the filtrate was desolvated to o

[0042] (1) Preparation of (S)-2-benzylsuccinic anhydride

[0043] Add 30.40g (0.16mol) of (S)-2-benzylsuccinic acid, 20mL of acetic anhydride, and 50mL of toluene into a 100mL three-necked flask in sequence, and stir and reflux for 1 hour. After the reaction is completed, cool to crystallize, filter, and dry to obtain white flakes Crystal 26.12g.

[0044] (2) Amidation of (S)-2-benzylsuccinic anhydride

[0045] Add 26.12 g (0.14 mol) of (S)-2-benzylsuccinic anhydride and 300 mL of dichloromethane into a 500 mL three-necked flask in sequence. At -5-5°C, a dichloromethane solution of cis-perhydroisoindole (19.89 g, 0.16 mol) was slowly added dropwise, and the reaction was stirred for 5 h. After the reaction was completed, the reaction solution was washed with 0.5 mol / L HCl solution (100 mL×2), and then washed with 100 mL saturated brine. The organic phase was dried overnight with 50 g of anhydrous sodium sulfate. After filtration, the filtrate was desolvated to obtain 40.33 g

[0053] (1) Preparation of (S)-2-benzylsuccinic anhydride

[0054] Add 30.40g (0.16mol) of (S)-2-benzylsuccinic acid, 20mL of acetic anhydride, and 60mL of toluene to a 100mL three-necked flask, mix well, stir and reflux for 1 hour, cool to crystallize, filter, and dry to obtain white flakes Crystals 25.19 g.

[0055] (2) Amidation of (S)-2-benzylsuccinic anhydride

[0056] Add 25.19 g (0.13 mol) of (S)-2-benzylsuccinic anhydride and 300 mL of dichloromethane into a 500 mL three-necked flask in sequence. Under the condition of -10~0°C, a dichloromethane solution of cis-perhydroisoindole (18.54 g, 0.15 mol) was slowly added dropwise, and the reaction was stirred for 3 h. After the reaction was completed, the reaction solution was washed with 0.5 mol / L HCl solution (100 mL×2), and then washed with 100 mL saturated brine. The organic phase was dried overnight with 50 g of anhydrous sodium sulfate. After filtration, the filtrate was desolvated to obtain 41.89 g of a light yellow