A method for synthesizing difluprednate from sterol fermentation product

A technology of sterol fermentation product and difluprednate, which is applied in the directions of steroids, organic chemistry, etc., to avoid the heavy metal pollutant chromium, the source of raw materials is cheap, and the source of raw materials is easy to obtain.

Inactive Publication Date: 2016-01-20
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The purpose of the present invention is to provide a more green and environmentally friendly synthetic method in order to overcome the existing synthetic defects of difluprednate

Method used

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  • A method for synthesizing difluprednate from sterol fermentation product
  • A method for synthesizing difluprednate from sterol fermentation product
  • A method for synthesizing difluprednate from sterol fermentation product

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Embodiment 1: Synthesis of androst-1,4,9(11)-triene-3,17-dione (compound of formula 3)

[0055] Under argon protection, add 15.0g 9α-hydroxy-1,4-diene-3,20-dione (compound of formula 2), 100mL benzene, 35mL (5 times equivalent) of BF to the reaction flask 3 AcOH solution, reflux and stir for 30 minutes, cool at room temperature, add 50mL of water, stir for 30 minutes, let the solution separate, wash the organic phase with water, dry over anhydrous sodium sulfate, and drain to obtain 14.2g of light yellow solid (compound of formula 3) , 90% yield.

[0056] Formula 3 compound: molecular weight, 282.38; 1 HNMR (400MHz, CDCl 3 ): δ7.18(d, J=10.2Hz, 1H, C 1 H),6.28(dd,J=10.2,1.8Hz,1H,C 2 H),6.08(s,1H,C 4 H),5.58(s,1H,C 11 H),1.43(s,3H,C 19 H),0.91(s,3H,C 18 H).

Embodiment 2

[0057] Example 2: Synthesis of 17β-hydroxy-17α-acetylene-pregna-1,4,9(11)-trien-3-one (compound of formula 4)

[0058] Under argon protection, add 10g of potassium hydroxide, 40mL of tetrahydrofuran and 9mL of ethanol into the reaction flask, stir at 60°C for 2 hours, cool to 3°C, and pour pure acetylene gas into the solution for 2 hours (8 times equivalent) , then add 12mL tetrahydrofuran solution containing 5.9g androst-1,4,9(11)-triene-3,17-dione (Formula 3) into the above solution, stir and react for 2 hours, TLC detects that the reaction is complete , then added 60 mL of 10% hydrochloric acid solution to the solution, stirred for 1 hour, filtered, washed with water, dried over anhydrous sodium sulfate, and drained to obtain 6.1 g of light yellow powder (compound of formula 4), with a yield of 95%.

[0059] Formula 4 compound: molecular weight, 308.41; 1 HNMR (400MHz, CDCl 3 )δ7.20(d,J=10.2Hz,1H,C 1 H), 6.26(d, J=10.2Hz, 1H, C 2 H),6.05(s,1H,C 4 H), 5.58(d, J=5.4Hz, 1...

Embodiment 3

[0060] Example 3: Synthesis of 17-acetylene-pregna-1,4,9(11), 16(17)-tetraen-3-one (compound of formula 5)

[0061] Under argon protection, dissolve 308 mg of 17β-hydroxy-17α-acetylene-pregna-1,4,9(11)-trien-3-one (compound of formula 4) in 2 mL of treated benzene, add 1 mL of redistilled Add 0.29mL of phosphorus oxychloride slowly under stirring in an ice-water bath. After the dropwise addition, reflux at 80°C for 6 hours. After cooling, pour the solution into 10mL of 10% hydrochloric acid in an ice-water bath, stir for 30 minutes, and use two After extraction with methyl chloride, the extract was washed with water, saturated brine, and water respectively, dried over anhydrous sodium sulfate, and 197 mg of a white solid (compound of formula 5) was obtained by column chromatography, with a yield of 67.5%.

[0062] Formula 5 compound: molecular weight, 290.40; 1 HNMR (400MHz, CDCl 3 ):δ7.20(d,J=10.2Hz,1H,C 1 H), 6.29(d, J=10.2Hz, 1H, C 2 H),6.11(s,1H,C 4 H),6.07(s,1H,C 16...

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Abstract

The invention provides a method for synthesizing difluprednate from a sterol fermentation product. The sterol fermentation product, namely 9 Alpha-hydroxyl-androstane-1,4-diene-3,17-diketone (9 Alpha-OH-AD) obtained by fermenting phytosterol of which the content in byproducts of the grease industry is very high, serves as a starting raw material. The method comprises the following 15 reaction steps in total: dehydrating steride 9-hydroxyl to form a double-bond; adding 17-carbonyl with acetylene; dehydrating; producing 21-copper carbonyl under an acid condition; epoxidizing 16,17-double bond; oxidizing periodide and introducing 21-hydroxyl; performing ring opening on 16,17 Alpha-epoxy hydrobromate; hydrogenating for removing 16 Beta bromine; forming a ring on orthoester; performing ring opening; esterifying; epoxidizing 9,11-double bond-Beta; enolizing and esterifying; performing ring opening on 6-electrophilic fluoro; and performing ring opening on 9,11-epoxy fluoro. According to the method, steride 17 Alpha and 21-dyhydroxyl are efficiently built by means of periodide oxidization, epoxide ring-opening and debromination and an important intermediate type 11 compound is obtained; in the whole process, a large quantity of heavy metal pollutant chromium which is generated when producing corticoid medicines in the traditional industry is effectively avoided, so that the method is green, environment-friendly and suitable to industrialized production.

Description

technical field [0001] The invention relates to a method for synthesizing difluprednate from a sterol fermentation product. Background technique [0002] Steroid drugs are the second largest class of drugs in the world after antibiotics in sales, and their molecular structures can be derived from steroid hormone intermediates. The traditional synthesis of steroid hormone drugs is based on dienes obtained from the degradation of diosgenin. [0003] At present, dienes are obtained from the degradation of diosgenin in industry, and each ton of product produces more than 2 tons of chromium-containing waste residue. Chromium-containing wastewater is harmful to the environment and human body. For the inorganic waste water discharged by pharmaceutical companies, the chromium content is also an important test. Project, so the preparation of difluprednate just faces the problems of pollution, poor economic and environmental protection from the starting material. [0004] With the c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J5/00C07J13/00C07J71/00
Inventor 丁凯徐飞飞
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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