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Synthesis method of levonorgestrel

A technology of levonorgestrel and a synthesis method is applied in the field of drug preparation, can solve the problems of unsuitability for industrialized safe production, dangerous large lithium ammonia reagent, long reaction route and the like, achieves good market prospect, low operating cost, Easy route effect

Active Publication Date: 2020-09-01
ZHEJIANG SHENZHOU PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] This synthetic route involves the reaction with the ammonium complex of alkynyllithium to form an alkynyl adduct, which requires the use of a more dangerous lithium ammonia reagent, which is prone to pollution and has a long reaction route, which is not suitable for industrialized safe production.

Method used

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  • Synthesis method of levonorgestrel
  • Synthesis method of levonorgestrel

Examples

Experimental program
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Embodiment 1

[0024] A kind of synthetic method of embodiment 1 levonorgestrel, comprises the steps:

[0025] 1) Protection reaction: Add 50gDL-ethyl diketone (1) to 1000ml methanol, add 50ml trimethyl orthoformate, 0.5g pyridinium hydrobromide, control the temperature at 60°C and stir the reaction. After the reaction, add 0.5ml Triethylamine, cooled to -10°C, filtered and dried to obtain 50g of intermediate 2;

[0026] 2) Alkynylation reaction: Add 50 g of intermediate (2) obtained in step 1) to 500 ml of acetone, add 100 g of potassium tert-butoxide, pass through acetylene, and control the reaction at -20 ° C. After the reaction, add 10% Aqueous hydrochloric acid was neutralized to neutral, concentrated, added water for water analysis, and filtered to obtain 53g of intermediate (3);

[0027] 3) Hydrolysis reaction: 53g of intermediate (3) obtained in step 2) was added to 530ml of tetrahydrofuran, 100ml of 20% hydrochloric acid aqueous solution was added, and the reaction was stirred at 5...

Embodiment 2

[0028] A kind of synthetic method of embodiment 2 levonorgestrel, comprises the steps:

[0029] 1) Protection reaction: Add 50gDL-ethyl diketone (1) to 50ml ethanol, add 250ml triethyl orthoformate, 2g pyridine hydrochloride, control the temperature at 40°C and stir the reaction. After the reaction, add 2ml triethylamine , cooled to 5°C, filtered and dried to obtain 51g of intermediate 2;

[0030] 2) Alkynylation reaction: 51g of intermediate (2) obtained in step 1) was added to 250ml of tetrahydrofuran, 26g of potassium isobutoxide was added, acetylene was passed through, and the reaction was stirred at 10°C. After the reaction, 20% sulfuric acid was added The aqueous solution was neutralized to neutral, concentrated, added water for water analysis, filtered to obtain the crude product, and the crude product was obtained with ethanol to obtain 53g of intermediate (3);

[0031] 3) Hydrolysis reaction: 53g of intermediate (3) obtained in step 2) was added to 1500ml of acetone,...

Embodiment 3

[0032] A kind of synthetic method of levonorgestrel of embodiment 3 comprises the steps:

[0033] 1) Protection reaction: Add 50gDL-ethyl diketone (1) to 200ml pyrrolidine, add 100ml triethyl orthoformate, 10g p-toluenesulfonic acid, control the temperature at 20°C and stir the reaction. After the reaction is over, add 10ml pyridine, Cool down to -5°C, filter, and dry to obtain 55g of intermediate 2;

[0034] 2) Alkynylation reaction: 55g of the intermediate (2) obtained in step 1) was added to 1500ml of toluene, 250g of sodium ethylate was added, acetylene was passed through, and the reaction was stirred at 40°C. After the reaction was completed, it was added to 30% acetic acid aqueous solution and to neutrality, concentrated, added water for water analysis, filtered to obtain 57g intermediate (3);

[0035] 3) Hydrolysis reaction: 57g of intermediate (3) obtained in step 2) was added to 300ml of methyl tetrahydrofuran, 29ml of 30% aqueous sulfuric acid was added, and the rea...

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Abstract

The invention discloses a synthesis method of levonorgestrel, and belongs to the technical field of preparation and processing of medicines. According to the method, DL-ethyl diketone is used as an initial raw material, and the levonorgestrel disclosed by the invention is prepared through three steps of protection, ethynylation and hydrolysis. According to the preparation method of the levonorgestrel, the defects of a traditional process are overcome, a lithium ammonia reagent with large potential safety hazards is prevented from being used, reaction conditions are mild, operation is safe, andthe method is high in overall conversion rate, easy and convenient to operate, suitable for industrial production and wide in market prospect.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a synthesis 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 mainly used as family visiting contraceptive and emergency contraceptive. Used in combination with hormones, it is a short-acting and long-acting oral contraceptive that can inhibit ovulation and is currently the most widely used contraceptive at home and abroad. It can also be used to treat symptoms such as irregular menstruation, functional uterine bleeding and endometriosis. [0003] CN101982472A discloses a method for synthesizing levonorgestrel from Worms, which starts with 18-methylestro-2,5(10)-diene-3-methoxy-17-one The raw material is ethynylated with lithium acetylene, then hydrolyzed to obtain levonorgestrel, and its synthetic route is as follows: [0004] [0005] This synthetic ro...

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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