Preparation method of tauro ursodesoxy cholic acid

[0047] Example 1 Preparation of Tauroursodeoxycholic Acid

[0048] 39.2 g (0.1 mol) of ursodeoxycholic acid was added to 100 ml of N,N-dimethylformamide, and the mixture was stirred to dissolve (the rotation speed was 150 rpm, stirring for 10 minutes). Cool down to 10°C, add 12.66g (0.11mol) of N-hydroxysuccinimide, stir to dissolve (rotate at 135rpm for 20 minutes), add 24.76g (0.12mol) of dicyclohexylcarbodiimide and 4-di 0.12 g (0.001 mol) of methylaminopyridine, after all the materials were added, the reaction was stirred at 12° C. for 2.5 hours at a speed of 135 rpm, and the content of ursodeoxycholic acid detected by HPLC was less than 0.1%, and the reaction was stopped. In addition, 12 g (0.12 mol) of taurine was dissolved in 500 ml of sodium hydroxide aqueous solution (containing 4.8 g of sodium hydroxide, 0.12 mol) to obtain an aqueous solution of taurine sodium salt. The above dimethylformamide solution was added to the taurine sodium salt aqueous solution, and 34ml (0.24mol) of triethylamine was added dropwise. After the dropwise addition, the reaction was carried out at 20°C for 2 hours, and the rotation speed was 135rpm. 200ml of dichloromethane was added for extraction and liquid separation, and the aqueous layer was washed twice with 200ml of dichloromethane. After washing, add dilute hydrochloric acid to adjust the pH to 1.0 for the water layer, stir for 0.5 hours at 20°C and 135 rpm, concentrate, precipitate the product, filter with suction, wash with water, and dry at 75°C with air blowing. After drying, it weighed 40.0 g, the content was 99%, and the yield was 81%. The sample was inspected by infrared and hydrogen nuclear magnetic resonance spectroscopy, and the results (see attached figure 2 , 7 ), the infrared image of the reference substance with tauroursodeoxycholic acid (see attached figure 1 ), proton nuclear magnetic resonance spectrum (see attached Image 6 ) Consistent.

[0049] Example 2 Preparation of Tauroursodeoxycholic Acid

[0050] 39.2 g (0.1 mol) of ursodeoxycholic acid was added to 100 ml of tetrahydrofuran, and stirred to dissolve (rotating speed 150 rpm, stirring for 10 minutes). Cool down to 0°C, add 12.66g (0.11mol) of N-hydroxyphthalimide, stir to dissolve (rotate at 150rpm and stir for 20 minutes), add 15.14g (0.12mol) of diisopropylcarbodiimide and 0.12 g (0.001 mol) of 4-dimethylaminopyridine. After all the materials were added, the reaction was carried out at 8°C for 20 minutes. The content of ursodeoxycholic acid detected by HPLC was less than 0.1%, and the reaction was stopped. In addition, 12 g (0.12 mol) of taurine was dissolved in 500 ml of sodium hydroxide aqueous solution (containing 4.8 g of sodium hydroxide, 0.12 mol) to obtain an aqueous solution of taurine sodium salt. The above tetrahydrofuran solution was added to the taurine sodium salt aqueous solution, and 34 ml (0.24 mol) of triethylamine was added dropwise. After the dropwise addition, the reaction was carried out at 25° C. for 2.5 hours at a speed of 150 rpm. 200ml of dichloromethane was added for extraction and liquid separation, and the aqueous layer was washed twice with 200ml of dichloromethane. After washing, the water layer was added with dilute hydrochloric acid to adjust PH=1.0, stirred for 1.5 hours at 25°C and 150 rpm, concentrated, and precipitated the product. Filter by suction and wash with water. 75℃ blast drying. After drying, it weighs 36.0 g, the content is 97%, and the yield is 80%. The sample was inspected by infrared and hydrogen nuclear magnetic resonance spectroscopy, and the results (see attached image 3 , 8 ), the infrared image of the reference substance with tauroursodeoxycholic acid (see attached figure 1 ), proton nuclear magnetic resonance spectrum (see attached Image 6 ) Consistent.

[0051] Example 3 Preparation of Tauroursodeoxycholic Acid

[0052] 39.2 g (0.1 mol) of ursodeoxycholic acid was added to 100 ml of dimethyl sulfoxide, and the mixture was stirred to dissolve (the rotating speed was 150 rpm and the stirring was for 10 minutes). Cool down to 10°C, add 12.66g (0.11mol) of N-hydroxysuccinimide, stir to dissolve (rotation speed is 150rpm, stir 10), add 1-ethyl-3-(3-dimethylaminopropyl) carbon two 18.62g (0.12mol) of imine and 012g (0.001mol) of 4-dimethylaminopyridine. After all the materials were added, the reaction was stirred at 8°C for 20min at a speed of 150rpm. The content of ursodeoxycholic acid detected by HPLC was less than 0.1% , Stop the reaction. In addition, 12 g (0.12 mol) of taurine was dissolved in 500 ml of sodium hydroxide aqueous solution (containing 4.8 g of sodium hydroxide, 0.12 mol) to obtain an aqueous solution of taurine sodium salt. The above methylene chloride solution was added to the taurine sodium salt aqueous solution, and 34 ml (0.24 mol) of triethylamine was added dropwise. After the dropwise addition, the reaction was carried out at 22° C. for 2.4 hours. 300 ml of dichloromethane was added for extraction and liquid separation, and the aqueous layer was washed twice with 200 ml of dichloromethane. After washing, the water layer was added with dilute hydrochloric acid to adjust PH=2.0, stirred for 1 hour at 22° C. and 140 rpm, concentrated, and precipitated the product. Filter by suction and wash with water. 75℃ blast drying. After drying, it weighed 37.5 g, the content was 94%, and the yield was 75%. The sample was inspected by infrared and hydrogen nuclear magnetic resonance spectroscopy, and the results (see attached Figure 4 , 9 ), the infrared image of the reference substance with tauroursodeoxycholic acid (see attached figure 1 ), proton nuclear magnetic resonance spectrum (see attached Image 6 ) Consistent.