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Preparation method of levonorgestrel

Inactive Publication Date: 2020-09-11
ZHEJIANG SHENZHOU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The above two synthetic routes will generate water during the reaction process, which is not conducive to the progress of the alkynylation reaction, and the overall conversion rate is not high, so it is not suitable for industrial production.

Method used

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  • Preparation method of levonorgestrel
  • Preparation method of levonorgestrel
  • Preparation method of levonorgestrel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1 A kind of preparation method of levonorgestrel comprises the steps:

[0026] 1) Alkynylation: Dissolve 50g of 18-methylestro-2,5(10)-diene-3-methoxy-17-one (1) in 750ml of THF, add 50g of potassium tert-butoxide, and control the temperature Pass through acetylene at 5°C, stir the reaction, after the reaction, add 5% hydrochloric acid aqueous solution to neutralize to neutral, concentrate, add water for water analysis, filter to obtain 52g of intermediate 2;

[0027] 2) Hydrolysis reaction: 52g of intermediate (2) obtained in step 1) was dissolved in 1500ml of acetone, 250ml of 5% hydrochloric acid aqueous solution was added, and reacted at 0°C. After the reaction, 10% sodium carbonate aqueous solution was added to neutralize to neutrality, Concentrate, add water for water analysis, and filter to obtain a crude product. The crude product is refined with methanol and dried to obtain 43 g of levonorgestrel. The total mass yield of the product is 86%, and the H...

Embodiment 2

[0028] Embodiment 2 A kind of preparation method of levonorgestrel, comprises the steps:

[0029] 1) Alkynylation reaction: 50g of 18-methylestro-2,5(10)-diene-3-methoxy-17-one (1) was dissolved in 250ml of dimethyl sulfoxide, and 100g of isopropanol was added Potassium, control the temperature at 30°C and pass through acetylene, stir the reaction, after the reaction, add 10% sulfuric acid aqueous solution A to neutralize to neutral, concentrate, add water for water analysis, filter to obtain 53g of intermediate 2;

[0030] 2) Hydrolysis reaction: Dissolve 53g of intermediate (2) obtained in step 1) in 250ml of tetrahydrofuran, add 27ml of 30% aqueous hydrochloric acid, and react at -10°C. After the reaction, add 5% aqueous sodium hydroxide to neutralize Neutral, concentrated, added water for water analysis, filtered to obtain a crude product, which was refined with ethanol and dried to obtain 43.5 g of levonorgestrel with a total mass yield of 87% and an HPLC content of 99.2%...

Embodiment 3

[0031] Embodiment 3 A kind of preparation method of levonorgestrel, comprises the steps:

[0032] 1) Alkynylation reaction: 50g of 18-methylestr-2,5(10)-diene-3-methoxy-17-one (1) was dissolved in 1500ml of toluene, 250g of sodium ethylate was added, and the temperature was controlled at -20 Pass through acetylene at ℃, stir the reaction, after the reaction, add 30% acetic acid aqueous solution to neutralize to neutral, concentrate, add water for water analysis, filter to obtain 51g of intermediate 2;

[0033] 2) Hydrolysis reaction: Dissolve 51 g of intermediate (2) obtained in step 1) in 750 ml of butanone, add 70 ml of 10% sulfuric acid aqueous solution, and react at 50 ° C. After the reaction, add 30% sodium sulfite aqueous solution to neutralize , concentrated, added water for water analysis, filtered to obtain a crude product, which was refined with acetone and dried to obtain 43g of levonorgestrel, with a total mass yield of 86% and an HPLC content of 99.4%.

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Abstract

The invention discloses a preparation method of levonorgestrel, and belongs to the technical field of medicine preparation and processing. According to the method, 18-methylestra-2,5(10)-diene-3-methoxy-17-ketone is used as an initial raw material, and the levonorgestrel disclosed by the invention is prepared by virtue of two steps of ethynylation and hydrolysis. According to the preparation method of the levonorgestrel, the defects of a traditional process are overcome and reaction conditions are mild; the method is high in overall conversion rate, easy and convenient to operate, suitable forindustrial production and wide in market prospect.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a preparation method of levonorgestrel. Background technique [0002] The chemical name of levonorgestrel is D(-)-17α-ethynyl-17β-hydroxy-18-methylestr-4-en-3-one, which is a widely used oral contraceptive. Levonorgestrel can inhibit ovulation and prevent implantation of fertile eggs, and at the same time increase the concentration of cervical mucus and prevent sperm from advancing. It is one of the most widely used emergency contraceptives at home and abroad. Levonorgestrel can also be used to treat irregular menstruation, functional uterine bleeding and endometriosis. [0003] Existing levonorgestrel synthetic method mainly contains two kinds: [0004] Method ①Using DL-18-methyl-4-estrene-3,17-dione as the starting material, acetylene reaction in the presence of potassium hydroxide to prepare 18-methyl norethindrone. The synthetic route is as follows: [0005] ...

Claims

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Application Information

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IPC IPC(8): C07J1/00
CPCC07J1/0096
Inventor 邵振平王荣王炳乾王洪福黄橙橙雷灵芝王友富
Owner ZHEJIANG SHENZHOU PHARMA
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