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Synthesis method of levonorgestrel

A technology of levonorgestrel and its synthetic method, which is applied in the field of drug synthesis, can solve the problems of difficult complete reaction of raw materials, large amount of tetrahydrofuran, and influence on the reaction process, etc., and achieves simplified production process, reduced separation and purification operations, and good safety Effect

Active Publication Date: 2022-03-15
湖南科益新生物医药有限公司
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

However, the solubility of acetylene gas in tetrahydrofuran is limited, resulting in a large amount of tetrahydrofuran; and acetylene gas reacts with potassium hydroxide to generate water, which will affect the reaction process, and the potassium hydroxide and acetylene used need to be greatly excessive; and after introducing acetylene gas, A paste is formed in the tetrahydrofuran solvent of potassium hydroxide, and it is difficult to stir, so that it is difficult to completely react the raw materials
In addition, acetylene gas is an explosive and combustible gas, and there is a problem of safety in use

Method used

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  • Synthesis method of levonorgestrel
  • Synthesis method of levonorgestrel
  • Synthesis method of levonorgestrel

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preparation example Construction

[0033] One embodiment of the present invention provides a synthesis method of levonorgestrel, comprising the following steps S10-S30.

[0034] Step S10: alkynylation of the compound of formula (I) and trialkylsilylacetylene in the first organic solvent under the action of an organometallic reagent to obtain a reaction solution containing the compound of formula (II);

[0035]

[0036] Wherein, the chemical name of the compound of formula (I) is 18-methylestro-2,5(10)-diene-3-methoxyl-17-ketone, also known as ethyl Woshi; formula (II ) compound has the chemical name 13β-ethyl-18,19-bisanor-17β-hydroxypregna-2,5(10)-diene-3-methoxy-20-trialkylalkynyl.

[0037] In some examples, in step S10, the organometallic reagent is n-butyllithium or lithium diisopropylamide. Alternatively, the organometallic reagent is n-butyllithium.

[0038] In some examples, in step S10, the alkyl group of the trialkylsilylacetylene has 1-5 carbon atoms. Optionally, the alkyl group of the trialkyls...

Embodiment 1

[0078] Add 500 mL of THF to 450 mL of n-butyllithium (2.5 M) solution, cool to -10°C, add 105 g of trimethylsilylacetylene dropwise, and keep warm at -10 to 0°C for 0.5 hours. Add 100 g of ethyl Worcester, and keep the reaction at -10~0°C for 2 hours. After adding 400 mL of methanol, 100 mL of water was added, and the temperature was raised to 20° C. to 30° C. to react for 2 hours. 200 g of concentrated hydrochloric acid was added, and the temperature was raised to 50° C. to 60° C. to react for 2 hours. Add potassium carbonate solution for neutralization, concentrate to a certain amount, add 500 mL of water for water analysis, and filter to obtain crude levonorgestrel. The crude product of levonorgestrel was dissolved by adding acetone to raise the temperature, cooled and crystallized, filtered, and then refined once with acetone to obtain 93.6 g of white solid with an HPLC purity of 99.2%. After testing, the infrared spectrum of the white solid is as follows figure 1 Shown...

Embodiment 2

[0080] Add 600 mL of n-butyllithium (2.5M) solution to dilute with 600 mL of ethylene glycol dimethyl ether, cool to -20°C, add 155 g of trimethylsilylacetylene dropwise, and keep warm at -15 to 0°C for 0.5 hours. Add 100 g of ethyl Worcester, keep warm at -15 to 0°C and react for 3 hours. After adding 400 mL of methanol, 100 mL of water was added, and the temperature was raised to 20° C. to 30° C. to react for 2 hours. Add 250 g of hydrobromic acid, raise the temperature to 60-70°C and react for 1 hour. Add potassium hydroxide solution for neutralization, concentrate to a certain amount, add 500 mL of water for water analysis, and filter to obtain a crude product. The crude product was dissolved in tetrahydrofuran and then evaporated to a small amount to obtain a white solid. It was refined once more with acetone to obtain 86.3 g of levonorgestrel with an HPLC purity of 99.4%.

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Abstract

The invention relates to a method for synthesizing levonorgestrel, which is characterized in that a compound shown as a formula (I) is used as a raw material, the levonorgestrel is synthesized by adopting a one-pot method, the separation and purification operation of an intermediate is reduced, the production process is greatly simplified, the reaction speed is high, and the production period is short; the synthesis method does not need acetylene gas, and is good in safety, high in yield, low in production cost and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a synthesis method of levonorgestrel. Background technique [0002] The chemical name of levonorgestrel is 13-ethyl-17-hydroxy-18,19-bis-demethyl-17a-pregna-4-en-20-yn-3-one, and its English name is levonorgestrel. Levonorgestrel is a fast-acting, short-term oral contraceptive, which mainly acts on the hypothalamus and pituitary gland, which can reduce or disappear the peak levels of follicle-stimulating hormone and luteinizing hormone in the middle period of menstruation, and inhibit ovulation; at the same time, it can also change the cervical The physical and chemical properties of mucus affect the normal development of the endometrium, making it asynchronous with the development of fertilized eggs, interfering with implantation, making fertilized eggs denature and stop developing, and achieving the purpose of avoiding pregnancy. [0003] The traditional production proc...

Claims

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Application Information

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IPC IPC(8): C07J1/00
CPCC07J1/0096Y02P20/55
Inventor 谢祚宜曾春玲靳志忠刘喜荣
Owner 湖南科益新生物医药有限公司
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