Preparation methods of arachidic cholic acid and arachidic cholic acid intermediate

A technique for intermediates and cholic acid, applied in the field of preparation of arachidonic cholic acid and intermediates thereof, can solve the problems of high production cost, harsh reaction conditions, unsuitable for industrialized production and the like

Active Publication Date: 2017-03-15
上海云晟研新生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by the present invention is to provide a peanut cholic acid preparation method in the prior art in order to overcome the defects of harsh reaction

Method used

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  • Preparation methods of arachidic cholic acid and arachidic cholic acid intermediate
  • Preparation methods of arachidic cholic acid and arachidic cholic acid intermediate
  • Preparation methods of arachidic cholic acid and arachidic cholic acid intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075]

[0076] Dissolve 1200g of methyl cholate intermediate III in 6800mL of tetrahydrofuran, cool to 0-5°C, add 590g of diethyl azodicarboxylate, and then add 430g of phthalimide. Add 800 g of triphenylphosphine in batches under stirring, stir at 10-20° C. for 16 hours after the addition, add 10 L of water, concentrate under reduced pressure to remove tetrahydrofuran, extract three times with 5 L of dichloromethane, and use 5% sodium sulfite (described The mass concentration is meant that the quality of sodium sulfite accounts for the percentage of the total mass of sodium sulfite aqueous solution), mass concentration 7% sodium bicarbonate (the mass concentration refers to the percentage that the quality of sodium bicarbonate accounts for the total mass of sodium bicarbonate aqueous solution), mass concentration 10% salt water (the mass concentration refers to the percentage of the mass of sodium chloride in the total mass of salt water) was washed twice, dried with anhyd...

Embodiment 2

[0078]

[0079] Dissolve 60 g of methyl cholate intermediate III in 470 mL of isopropyl ether, cool to 0-5°C, add 34 g of diisopropyl azodicarboxylate, and then add 17 g of succinimide. Add 22g of tricyclohexylphosphine in batches under stirring, stir at 10°C to 20°C for 16 hours after the addition, add 500mL of water, concentrate under reduced pressure to remove isopropyl ether, extract three times with 250mL of dichloromethane, and use a mass concentration of 5% Sodium sulfite (the mass concentration refers to the percentage that the quality of sodium sulfite accounts for the total mass of sodium bicarbonate aqueous solution), mass concentration 7% sodium bicarbonate (the mass concentration refers to the percentage that the quality of sodium bicarbonate accounts for the total mass of sodium bicarbonate aqueous solution ), mass concentration 10% salt water (the mass concentration refers to the percentage of the quality of sodium chloride in the total mass of salt water), wa...

Embodiment 3

[0081]

[0082] With peanut cholic acid intermediate II 1250g (purity 97.71%, differential refractive index detector detection), be dissolved in tetrahydrofuran 2500mL and methanol 2500mL, then add mass concentration and be 40% hydrazine hydrate 620mL (the described mass concentration refers to the quality of hydrazine % of the total mass of hydrazine hydrate), after the addition, stir at 15°C to 25°C for 8 hours, add 5L of water, concentrate under reduced pressure to remove tetrahydrofuran and methanol, extract twice with 4L of dichloromethane, and the mass concentration is 10% saline (The mass concentration refers to the percentage of the mass of sodium chloride in the total mass of the saline) washed twice, dried with anhydrous sodium sulfate and then concentrated to obtain a light yellow solid. Then recrystallized with 3.9 L of ethyl acetate to obtain 875 g of arachidic cholic acid intermediate I as off-white solid, with a yield of 91.6% and a purity of 98.78% (detected ...

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Abstract

The invention discloses preparation methods of arachidic cholic acid and arachidic cholic acid intermediate. The preparation method of the arachidic cholic acid intermediate I provided herein includes the steps: in an organic solvent, performing reductive reaction on arachidic cholic acid intermediate II or II' and a reducing agent to obtain the arachidic cholic acid intermediate I; hydrazine hydrate or methylamine is used as the reducing agent. According to the preparation method, commercially available chemical products such as methyl cholate serve as starting materials, the arachidic cholic acid intermediate I can be prepared only by two steps, the reaction route is short, total yield can reach up to 76%, the purity of the prepared products can reach up to 98.00%, highly toxic products such as sodium azide are omitted, catalytic hydrogenation conditions are avoided, and the preparation method is safe to perform, low in production cost, environmentally friendly and suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of arachidic cholic acid and its intermediate. Background technique [0002] Fatty acid-cholic acid conjugates (FABACs) are a class of compounds formed by the coupling of fatty acids and bile acids through amide bonds. FABACs can increase the solubility of cholesterol in bile in vitro, inhibit the crystallization of cholesterol in artificial bile and natural bile, and prevent Gallstones caused by high-fat diet, and can dissolve the formed cholesterol stones; it can also prevent atherosclerosis caused by high-fat diet. Israel Galmed Pharmaceuticals, a biopharmaceutical company dedicated to the development of oral drugs for liver diseases and gallstones, has announced in 2014 that the FDA has approved the new drug application for its fatty acid-cholic acid conjugate arachidic cholic acid (Aramchol, IV). At present, the clinical trial of arachidic cholic acid is coming to an end. Different doses of arachidic ...

Claims

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Application Information

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IPC IPC(8): C07J41/00C07J43/00
CPCC07J41/0005C07J41/0011C07J43/003
Inventor 应述欢皮红军陈健刘胜辉
Owner 上海云晟研新生物科技有限公司
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