Method for preparing tetraene methyl CAS

A technology of methyltetraene and hydroxyl, which is applied in the field of chemical preparation, can solve the problems of high cost of methyltetraene raw materials and difficulties in the 17-position hydroxyl of steroids, and achieve environmentally friendly costs, short process routes, and side effects. The effect of less product

Active Publication Date: 2016-02-24
ZHEJIANG XIANJU PHARMA
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  • Abstract
  • Description
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Problems solved by technology

[0008] The purpose of the present invention is to solve the technical problem that the cost of raw materials currently used

Method used

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  • Method for preparing tetraene methyl CAS

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Effect test

Embodiment 1

[0033] The first step is to add the dihydroxyprogesterone dehydrogenate to the dry 1000ml reaction flask 1 (10g, 0.029mol), 400mL of tetrahydrofuran, add phosphorus pentachloride (16g, 0.077mol) after cooling to -70℃, react at low temperature at -70℃ for 6 hours; after detecting no raw material by TLC , Add 10mL of water to quench the reaction, stir for 10 minutes; concentrate under reduced pressure, pour into ice water and stir for one hour, filter, wash with water, and dry at 60°C to obtain the elimination product 2 . The yield of this 11α hydroxyl elimination reaction is extremely high, the substrate conversion rate is above 95%, the molar yield is 95%, and the HPLC (HighPerformance Liquid Chromatography, high performance liquid chromatography) content is 95%.

[0034] The second step is to add the elimination product to the 2000ml reaction flask 2 (9g, 0.028mol), 400mL tetrahydrofuran, n-butyric acid (135g, 1.53mol), semicarbazide hydrochloride (1.08g, 9.68mmol) in 66 o C reac...

Embodiment 2

[0036] The first step is to add the dihydroxyprogesterone dehydrogenate to the dry 1000ml reaction flask 1 (10g, 0.029mol), 580mL of tetrahydrofuran, add phosphorus pentachloride (10g, 0.048mol) at -80℃, react at -80℃ for 10 hours; TLC (Thin Layer Chromatography) detects no raw material point, add 10mL of water The reaction was quenched and stirred for 10 minutes; concentrated under reduced pressure, poured into ice water and stirred for one hour, filtered, washed with water, and dried at 60°C to obtain the elimination product 2 , The molar yield is 92%, and the HPLC content is 90%.

[0037] The second step is to add the elimination product to the 2000ml reaction flask 2 (9g, 0.028mol), dichloromethane 400mL, n-butyric acid (135g, 1.53mol), semicarbazide hydrochloride (1.08g, 9.68mmol) in 50 o C react for 16 hours; after the reaction is over, cool to 0°C, add 20% sodium hydroxide solution to neutralize it, continue to stir for 1 hour, concentrate under reduced pressure, cool to 0°C...

Embodiment 3

[0039] The first step is to add the dihydroxyprogesterone dehydrogenate to the dry 1000ml reaction flask 1 (10g, 0.029mol), 290mL of tetrahydrofuran, add phosphorus pentachloride (30g, 0.144mol) at -50°C, react at low temperature at -50°C for 5 hours; TLC (Thin Layer Chromatography) detects no raw material point, add 30mL of water The reaction was quenched and stirred for 10 minutes; concentrated under reduced pressure, poured into ice water and stirred for one hour, filtered, washed with water, and dried at 60°C to obtain the elimination product 2 , The molar yield is 88%, and the HPLC content is 91%.

[0040] The second step is to add the elimination product to the 1000ml reaction flask 2 (9g, 0.028mol), 400mL tetrahydrofuran, acetic acid (135g, 2.25mol), semicarbazide hydrochloride (1.08g, 9.68mmol) in 66 o C react for 16 hours; concentrate under reduced pressure, add 180mL of water for precipitation, cool to 0℃, filter with suction, wash with water, and dry at 50℃ to obtain met...

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Abstract

The invention discloses a method for tetraene methyl CAS. A dihydroxy progesterone dehydrogenation complex serves as a raw material and is sequentially subjected to a 11 alpha hydroxyl elimination reaction and a 17 alpha hydroxyl elimination reaction to obtain tetraene methyl CAS. According to the method, the dihydroxy progesterone dehydrogenation complex serves as the raw material for the first time, the mole yield of each step is over 90%, the total mole yield is over 85%, the total weight yield ranges from 72% to 76%, and the method has the advantages that the raw material conversion rate is high, few by-products are generated, the product purity is high, the process route is short, and cost is low; an existing 17 alpha hydroxyl elimination process is improved, tetrahydrofuran is used as reaction solvent, semicarbazide hydrochloride is used as an eliminating reagent, monoacid of low fatty acid is used as a catalyst, selectivity of 17 alpha hydroxyl elimination is improved, and the yield of 17 alpha hydroxyl elimination is increased.

Description

technical field [0001] The invention relates to a method for preparing chemicals, in particular to a method for preparing an intermediate methyl tetraene of dexamethasone. Background technique [0002] Methyl tetraene (5ST) is a very important pharmaceutical intermediate with a great market prospect. It can be used as a starting material for the synthesis of various drugs such as dexamethasone. Dexamethasone belongs to adrenal cortex hormone drugs, has anti-inflammatory, anti-allergic, anti-shock effects, and is mainly used clinically for allergic and autoimmune diseases, such as rheumatoid arthritis, bronchial asthma, dermatitis and other allergic diseases . [0003] At present, methyl tetraenes are mainly prepared from mold dehydrogenation products through dehydration and reduction reactions. For example, the patent application number is 201010278556.9, the application date is September 10, 2010, and the publication number is CN101979399A. The production method of the st...

Claims

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Application Information

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IPC IPC(8): C07J7/00
CPCC07J7/002
Inventor 戴静陈德家袁云方伟明
Owner ZHEJIANG XIANJU PHARMA
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