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Preparation method of 3-hydroxy-6-ketocholanic acid with low cost and high yield

A high-yield technology of ketocholanoic acid is applied in the field of preparation of 3α-hydroxy-6-keto-5β-cholestane-24-acid, and can solve the problems of hindering the research and application of porcine bile acid synthesis, and the like, Achieve the effect of improving the level of medicine, simple follow-up treatment, and simple operation

Inactive Publication Date: 2020-06-05
上海慈瑞医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The lack of impurity reference substances in the synthesis process hinders the synthesis research and application of porcine bile acid as raw material

Method used

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  • Preparation method of 3-hydroxy-6-ketocholanic acid with low cost and high yield
  • Preparation method of 3-hydroxy-6-ketocholanic acid with low cost and high yield
  • Preparation method of 3-hydroxy-6-ketocholanic acid with low cost and high yield

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Take 100g of hyodeoxycholic acid, dissolve it in 1.2L of acetonitrile-water (volume ratio 10:1) mixed solvent, add 2.5g of ammonium bromide, add 50mL of 10wt% sulfuric acid, stir evenly, cool down to below 10°C, slowly drop Add 150mL of 10wt% potassium bromate solution, stir at room temperature for 24h, monitor the reaction degree with HPLC; add 15mL of 10wt% potassium bisulfite solution to terminate the reaction, stir for 10min, add 3L of water, stir well; stir and crystallize at room temperature for 0.5h, Suction filtration, washing the crystals with distilled water several times until neutral, suction filtration to obtain a white solid, transfer to 60℃±5℃ and dry for 6h to obtain 3α-hydroxy-6-keto-5β-cholestane-24-acid white powder 86.7g, with a purity of 98.3% and a yield of 86.7% as determined by high performance liquid phase-evaporative light detector (HPLC-ELSD).

Embodiment 2

[0039] Take 100g of hyodeoxycholic acid, dissolve it in 20 times of tetrahydrofuran-methanol-water (volume ratio 1:1:1) mixed solvent 2L, add 12g of potassium bromide, add 80mL of 10wt% hydrochloric acid, stir well, slowly drop Add 100mL of 15wt% sodium bromate solution, stir the reaction at room temperature for 1h, and monitor the reaction degree with HPLC; then add 80mL of 10wt% potassium sulfite solution to terminate the reaction, after stirring for 10min, add 1.2L of water, stir well; stir and crystallize at room temperature 2h, filter with suction, wash the crystals with distilled water several times until neutral, and centrifuge to obtain 3α-hydroxy-6-keto-5β-cholestan-24-acid as a white solid, which is transferred to an oven at 80-100°C for 4 hours to obtain White powder 87.3g, high performance liquid phase - evaporative light detector (HPLC-ELSD) assay purity 99.1%, yield 87.3%.

Embodiment 3

[0041] Take 100g of hyodeoxycholic acid, dissolve it in 1000mL of 10 times acetone-ethanol-water (volume ratio 3:1:1) mixed solvent, add 13g of sodium bromide, then add 2mL of formic acid, stir well, then cool down to 10°C Next, slowly add 130mL of 15wt% sodium bromate solution dropwise, stir at room temperature for 6h, and monitor the reaction degree with HPLC; then add 130mL of 10wt% sodium bisulfite solution to terminate the reaction, after stirring for 10min, add 1000mL of water, and stir evenly; room temperature Stir and crystallize for 1 hour, filter with suction, wash the crystals with distilled water several times until neutral, filter with suction to obtain a white solid, transfer to a 40°C oven and dry for 24 hours to obtain 3α-hydroxy-6-keto-5β-cholestane-24-acid 89.5 g of white powder, with a purity of 98.6% and a yield of 89.5% as determined by high performance liquid phase-evaporative light detector (HPLC-ELSD).

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Abstract

The invention discloses a preparation method of 3 alpha-hydroxy-6-keto-5 beta-cholestane-24-acid with low cost and high yield, which is characterized by comprising the following steps: adding hyodeoxycholic acid into a mixed solution of an organic solvent and water, and stirring to dissolve; adding bromide and acid, stirring and dissolving; bromate is added for reaction; adding a terminating agent, and stirring to terminate the reaction; adding water to crystallize the product; and carrying out solid-liquid separation, washing a solid product with water for multiple times, and drying to obtainthe 3 alpha-hydroxy-6-keto-5 beta-cholestane-24-acid. According to the method, a common and safe reagent is adopted, the hyodeoxycholic acid is selectively oxidized into the 3 alpha-hydroxy-6-keto-5beta-cholestane-24-acid under a relatively mild condition, the product purity is greater than 98.0%, and the yield is greater than 85%. The method has the advantages of cheap reagents, simple operation, high process reproducibility, simple post-treatment, high product purity and high yield, and can easily implement industrial production.

Description

technical field [0001] The invention relates to a low-cost and high-yield preparation method of 3α-hydroxy-6-keto-5β-cholestane-24-acid, which belongs to the technical field of chemical synthesis. Background technique [0002] The chemical name of hyodeoxycholic acid is 3α, 6α-dihydroxy-5β-cholestane-24-acid, which is a cholic acid extracted from pig bile, hereinafter referred to as HDCA, which can inhibit the formation of cholic acid and dissolve fat , reduce blood cholesterol and triglycerides, suitable for Ia or Ib hyperlipidemia, atherosclerosis, and have certain antibacterial effects on pertussis bacillus, diphtheria bacillus, Staphylococcus aureus, etc., can also be used as Anti-inflammatory drugs, treatment of chronic bronchitis, viral upper respiratory tract inflammation in children, etc. [0003] 3α-hydroxy-6-keto-cholanic acid is one of the oxidation products of hyodeoxycholic acid, the chemical name is 3α-hydroxy-6-keto-5β-cholestane-24-acid, which has similar p...

Claims

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Application Information

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IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 许洁谢光华尹九灵
Owner 上海慈瑞医药科技股份有限公司
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