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A kind of preparation method of mitiglinide calcium intermediate

A technology of mitiglinide calcium and intermediates, which is applied in the chemical field, can solve the problems of high cost, difficult solvent recovery, low yield of cis-perhydroisoindole and the like, and achieves the effects of easy recovery and accelerated reaction rate.

Active Publication Date: 2021-07-27
JIANGXI JIMINKEXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In order to overcome the defects in the above-mentioned prior art and provide a preparation method that is more conducive to industrial production, the present invention provides a method for preparing cis-perhydroisoindole under the catalysis of sulfuric acid by using zinc chloride and potassium borohydride. It can effectively solve the problems of low yield of cis-perhydroisoindole, difficulty in solvent recovery and high cost

Method used

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  • A kind of preparation method of mitiglinide calcium intermediate
  • A kind of preparation method of mitiglinide calcium intermediate
  • A kind of preparation method of mitiglinide calcium intermediate

Examples

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Embodiment 1

[0037] Under the protection of nitrogen, control the temperature at 20-30°C, add 300mL tetrahydrofuran and 24.8g zinc chloride to a 1000mL three-necked flask and stir, add 8.4g potassium borohydride after 1 hour, and continue stirring for 1 hour. Then 7.2 g of cis-hexahydrophthalimide was added, and the reaction was stirred for two hours. Slowly raise the temperature and heat to reflux for two hours. Add 400 mL of toluene, distill to an internal temperature of about 94°C, and reflux for 3 hours. Continue to raise the temperature for distillation, distill off part of tetrahydrofuran until the internal temperature is about 105°C, and stop the distillation. After cooling to below 30°C, slowly add 100mL of hydrochloric acid with a mass concentration of 15% dropwise. After the dripping is completed, heat up and distill, distill off part of the solvent until the internal temperature reaches about 107°C and stop. Cool to below 30°C, add dropwise 150mL of 30% sodium hydroxide to adj...

Embodiment 2

[0040]Under the protection of nitrogen, control the temperature at 20-30°C, add 350mL tetrahydrofuran and 23.8g zinc chloride to a 1000mL three-necked flask and stir, add 8.0g potassium borohydride after 1 hour, and continue stirring for 1 hour. Then 7.6 g of cis-hexahydrophthalimide was added, and the reaction was stirred for two hours. Add 2.0 mL of concentrated sulfuric acid, slowly raise the temperature, and heat to reflux for two hours. Add 350 mL of toluene, distill to an internal temperature of about 94°C, and reflux for 3 hours. Continue to raise the temperature for distillation, distill part of THF until the internal temperature is about 100°C, and stop the distillation. Cool to below 30°C, slowly add 100mL of hydrochloric acid with a mass concentration of 15% dropwise, after the drop is completed, heat up and distill, distill off part of the solvent until the internal temperature reaches about 105°C and stop. Cool to below 30°C, add dropwise 150mL of 30% sodium hyd...

Embodiment 3

[0043] Under the protection of nitrogen, control the temperature at 20-30°C, add 300mL tetrahydrofuran and 24.0g zinc chloride to a 1000mL three-necked flask and stir, add 8.2g potassium borohydride after 1 hour, and continue stirring for 1 hour. Then 7.8 g of cis-hexahydrophthalimide was added, and the reaction was stirred for two hours. Add 2.0 mL of concentrated sulfuric acid, slowly raise the temperature, and heat to reflux for two hours. Add 400 mL of toluene, distill to an internal temperature of about 94°C, and reflux for 3 hours. Continue to raise the temperature for distillation, distill off part of tetrahydrofuran until the internal temperature is about 105°C, and stop the distillation. After cooling to below 30°C, slowly add 100mL of hydrochloric acid with a mass concentration of 15% dropwise. After the dripping is completed, heat up and distill, distill off part of the solvent until the internal temperature reaches about 107°C and stop. Cool to below 30°C, add dr...

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Abstract

The present invention relates to a preparation method of mitiglinide calcium intermediate. The method comprises the following steps: under the protection of nitrogen, sequentially add tetrahydrofuran and zinc chloride into a reactor for stirring, add potassium borohydride after 1 hour, and stir Two hours, then add cis-hexahydrophthalimide, stir for two hours, add a small amount of concentrated sulfuric acid, slowly raise the temperature, heat to reflux for two hours, add toluene, slowly distill to an internal temperature of about 94°C, Reflux reaction for 3 hours, continue to heat up and distill to an internal temperature of about 105°C, stop distillation, cool to below 30°C, slowly add 15% hydrochloric acid dropwise, after dropping, heat up and distill to an internal temperature of about 107°C, stop, and cool to below 30°C , dropwise adding 30% sodium hydroxide to adjust the pH value to 13-14, steam distillation, toluene extraction and drying to obtain cis-hexahydroisoindole.

Description

technical field [0001] The invention relates to the field of chemistry, and the invention relates to a preparation method of a drug synthesis intermediate cis-perhydroisoindole. Background technique [0002] Miglinide Calcium is a drug for the treatment of diabetes developed by Japan Tachibana Pharmaceutical Co., Ltd. It can be used alone for patients with type Ⅱ diabetes who cannot effectively control hyperglycemia through diet and exercise therapy. , The third meglitaide after nateglinide. [0003] Cis-perhydroisoindole is a key intermediate for the synthesis of mitiglinide, and its structural formula is as follows: [0004] [0005] Its synthesis method mainly contains: [0006] The first kind: take cis-tetrahydrophthalimide as raw material, get cis-isoindoline through reduction of lithium aluminum tetrahydrogen, and then get cis-perhydroisoindoline through catalysis [J.Org. Chem., 1955, 20(12):1687-1694]. [0007] The second type: using phthalonitrile as the start...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/44
CPCC07B2200/09C07D209/44
Inventor 郭林峰文万江彭常春张克勤何平清李义保
Owner JIANGXI JIMINKEXIN PHARMA