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A kind of preparation method of 17α-hydroxyprogesterone

A technology of hydroxyprogesterone and hydroxyl, which is applied in the field of preparation of 17α-hydroxyprogesterone, can solve the problems of low yield and achieve the effects of short route, mild reaction conditions and easy availability of raw materials

Active Publication Date: 2016-02-10
BAODING BR BIO STEROIDS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] IsseiN (IsseiN, ShinichiroF, HiroakiU. The Synthesis of the Corticoid Side Chain. I. An Improved Method for the Preparation of 17α-HydroxyprogesteroneromAndrost-4-ene-3, 17-dione. Bull. Chem.oc. Jpn., 1985, 58: 978-980) etc. 4-ene-3,17-dione as raw material, in the first step for specific regioselective or stereoselective addition of 17-keto group, in the second step under TSOH, use trimethyl orthoformate in ethylene di The carbonyl and hydroxyl groups are protected by treatment in alcohol, followed by iodomethane reaction and other treatments, and 17α-hydroxyprogesterone (6) is synthesized from 17β-cyano-17-α-hydroxyl compound (2a) under acidic conditions by hydration and rearrangement. Method yield is low, only 69%

Method used

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  • A kind of preparation method of 17α-hydroxyprogesterone
  • A kind of preparation method of 17α-hydroxyprogesterone
  • A kind of preparation method of 17α-hydroxyprogesterone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Put anhydrous methanol (25.0mL) and 4-AD (11.50g) into the dry reactor (the reactor was blown dry with nitrogen) and stirred, then added trimethyl orthoformate (6.80g) and PTS (0.187g), at 40°C Stir and keep warm for 4 hours, take a sample point plate [developer = ethyl acetate / petroleum ether (EA / PE) = 2.5 / 1] and cool down to room temperature after no raw materials, add triethylamine to neutralize pH = 7, cool down to -5 °C, Stir for 1 h, filter, rinse with an appropriate amount of cold methanol and dry to obtain 3-methoxyandrost-3,5-dien-17-one.

[0028] Potassium hydroxide and calcium carbide were ground into powders with a mixer respectively, and passed through a 50-mesh sieve for subsequent use. Potassium hydroxide (7.75g), calcium carbide (21.00g), tert-butanol (24.5mL) and ethylenediamine (65.0 mL) was added to a 500g reaction flask, kept at 40°C for 16h, cooled to 25°C, added 3-methoxyandrost-3,5-dien-17-one (11.80g) and stirred for 5h, and slowly added dropwise...

Embodiment 2

[0034] Put absolute ethanol (25.0mL) and 4-AD (11.00g) into the dry reaction kettle (the reaction kettle was blown dry with nitrogen) and stirred, then added triethyl orthoformate (7.80g) and PTS (0.187g), 40°C Stir and keep warm for 4 hours, take a sample point plate (developer = EA / PE = 2.5 / 1) and cool down to room temperature after there is no raw material, add triethylamine to neutralize pH = 7, cool down to -5°C, stir for 1 hour, filter, and appropriate amount of cold methanol Rinse and dry to obtain 3-ethoxyandrost-3,5-dien-17-one.

[0035] Potassium hydroxide and calcium carbide were ground into powder with a mixer respectively, and passed through an 80-mesh sieve for later use. Potassium hydroxide (7.75g), calcium carbide (21.00g), tert-butanol (24.5mL) and ethylenediamine (65.0 mL) was added to a 500g reaction flask, kept at 40°C for 16h, cooled to 25°C, added 3-ethoxyandrost-3,5-dien-17-one (11.80g) and stirred for 5h, and slowly added dropwise under nitrogen protect...

Embodiment 3

[0037] Put anhydrous methanol (25.0mL) and 4-AD (10.00g) into the dry reactor (the reactor was blown dry with nitrogen) and stirred, then added trimethyl orthoformate (6.80g) and PTS (0.187g), 40°C Stir and keep warm for 4 hours, take a sample point plate (developer = EA / PE = 2.5 / 1) and cool down to room temperature after there is no raw material, add triethylamine to neutralize pH = 7, cool down to -5°C, stir for 1 hour, filter, and appropriate amount of cold methanol Rinse and dry to obtain 3-methoxyandrosta-3,5-dien-17-one.

[0038] Grind sodium hydroxide and calcium carbide into powder with a mixer, and pass through a 50-mesh sieve for later use. Mix sodium hydroxide (5.85g), calcium carbide (21.00g), propanol (19.6mL) and diethylamine (70.0mL ) into a 500g reaction flask, kept at 40°C for 16h, cooled to 25°C, added 3-methoxyandrost-3,5-dien-17one and stirred for 5h, under nitrogen protection, slowly added acetic acid, water, concentrated Sulfuric acid, control the temper...

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Abstract

The invention relates to a method for preparing 17alpha-hydroxyl progesterone. The method comprises the following steps: a, protecting 3-carbonyl group of 4-androstenedione through ortho formate to obtain etherate; b, enabling reaction between calcium carbide, lower alcohol and strong alkali under the organic alkali condition, adding the etherate obtained in the step a, and enabling reaction to obtain 17beta-alkynyl-17alpha-hydroxyl substitute; c, conducting hydration rearrangement on the 17beta-alkynyl-17alpha-hydroxyl substitute under the acidic condition to obtain the 17alpha-hydroxyl progesterone; d, purifying the product obtained in the step c. According to the method, 4-androstenedione is used as substrate to prepare the 17alpha-hydroxyl progesterone through three steps of reaction of etherification, ethynylation and hydrolysis, and the total yield can reach 88% or above.

Description

technical field [0001] The invention relates to a preparation method of 17α-hydroxyprogesterone, in particular to a method for producing 17α-hydroxyprogesterone from 4-androstenedione as a starting material. Background technique [0002] Before the 1960s, my country had always been a major importer of steroid drug intermediates. Since Huang Minglong used domestic diosgenin and turmeric as starting materials, steroids (4-androstenedione, 17α-hydroxy lutein Ketone, cortisone acetate), gradually transformed from a big importer to a big exporter. In the 21st century, due to the development of the paper industry and the oil industry, the by-product phytosterols have accumulated in large quantities around the world, and the cost of producing 4-androstenedione (4-AD) from phytosterols is much lower than that produced by traditional diene methods. The present invention describes a method for producing 17α-hydroxyprogesterone from 4-androstenedione. [0003] The current domestic pro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J7/00
CPCC07J7/004
Inventor 李超余伟
Owner BAODING BR BIO STEROIDS CO LTD
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