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Method for preparing methyl tetraene

The technology of methyl tetraene and hydroxyl group is applied in the field of chemical preparation, which can solve the problems of difficulty in the 17-position hydroxyl group of steroids and high raw material cost of methyl tetraene, and achieves environmentally friendly cost, short process route, and improved selection. Effects of Sex and Yield

Active Publication Date: 2017-09-29
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 for the preparation of methyl tetraenes is high and it is very difficult to eliminate the 17-position hydroxyl of the steroid

Method used

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  • Method for preparing methyl tetraene

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Effect test

Embodiment 1

[0033] In the first step, add dihydroxyprogesterone dehydrogenate 1 (10g, 0.029mol) and 400mL tetrahydrofuran into a dry 1000ml reaction flask, add phosphorus pentachloride (16g, 0.077mol) after cooling down to -70°C, and React at low temperature at 70°C for 6 hours; after detecting no raw material point by thin layer chromatography (TLC), add 10 mL 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 store at 60°C Drying gave the eliminated 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 (High Performance Liquid Chromatography, high performance liquid chromatography) content is 95%.

[0034] In the second step, add elimination product 2 (9g, 0.028mol), tetrahydrofuran 400mL, n-butyric acid (135g, 1.53mol), semicarbazide hydrochloride (1.08g, 9.68 mmol) in ...

Embodiment 2

[0036] In the first step, add dihydroxyprogesterone dehydrogenate 1 (10g, 0.029mol) and 580mL tetrahydrofuran into a dry 1000ml reaction flask, add phosphorus pentachloride (10g, 0.048mol) at -80°C, and ℃ low temperature reaction for 10 hours; TLC (thin layer chromatography) to detect no raw material point, add 10 mL 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 Product 2 was eliminated, the molar yield was 92%, and the HPLC content was 90%.

[0037] In the second step, add elimination product 2 (9g, 0.028mol), dichloromethane 400mL, n-butyric acid (135g, 1.53mol), semicarbazide hydrochloride (1.08g, 9.68 mmol) in 50 o C was reacted for 16 hours; after the reaction was completed, the temperature was lowered to 0°C, and 20% sodium hydroxide solution was added to neutralize to neutrality, and stirring was continued for 1 hour, concentrated und...

Embodiment 3

[0039] In the first step, add dihydroxyprogesterone dehydrogenate 1 (10g, 0.029mol) and 290mL tetrahydrofuran into a dry 1000ml reaction flask, add phosphorus pentachloride (30g, 0.144mol) at -50°C, and ℃ low temperature reaction for 5 hours; TLC (thin layer chromatography) detection of no raw material point, add 30mL 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, dry at 60℃ to get Product 2 was eliminated, the molar yield was 88%, and the HPLC content was 91%.

[0040] In the second step, add elimination product 2 (9g, 0.028mol), tetrahydrofuran 400mL, acetic acid (135g, 2.25mol), semicarbazide hydrochloride (1.08g, 9.68 mmol) in 66 o C reaction for 16 hours; concentrated under reduced pressure, added 180 mL of water for water analysis, cooled to 0°C, filtered with suction, washed with water, and dried at 50°C to obtain methyltetraene 3 with a molar yield of 90% and ...

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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 fungal dehydrogenated 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 CN 101979399A. "The Production Method of the...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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