A kind of synthetic method of tibolone

A synthetic method, the technology of tibolone, applied in the field of synthesis of steroidal compounds, can solve the problems of unfavorable large-scale production operation and low yield, and achieve the effects of saving labor and energy costs, simple operation, and reducing raw material costs

Active Publication Date: 2021-04-20
ZHEJIANG XIANJU JUNYE PHARM CO LTD +1
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  • Claims
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AI Technical Summary

Problems solved by technology

[0003] Among the above concentrated tibolone synthesis methods, the first and second methods have low yields, and both have ultra-low temperature reactions, which are not conducive to large-scale production operations

Method used

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  • A kind of synthetic method of tibolone
  • A kind of synthetic method of tibolone
  • A kind of synthetic method of tibolone

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Effect test

Embodiment 1

[0028] A kind of synthetic method of embodiment 1 tibolone, described synthetic route is as follows

[0029]

[0030] 1) Alkynylation reaction:

[0031] 800kg of toluene, 20kg of potassium hydroxide, and 40kg of tert-butanol were dehydrated under normal pressure under reflux for 2 hours, cooled to 30°C, and a solution formed by dissolving 100kg of acid decarboxylate (I) in 200kg of toluene was added, and stirred for 10 minutes. Feed acetylene gas, start to detect TLC after 6 hours of ventilating, TLC analysis raw material reaction is complete, stop ventilating, add 200kg water to quench washing, separate layers. Concentrate under reduced pressure, add 100kg of ethanol, discharge, and dry to obtain 100kg of norethindrone (II), with a mass yield of 100%, detection by HPLC ≥ 99%, and single impurity ≤ 0.5%.

[0032] 2) Acylation reaction

[0033] Step 1) Add 200kg of acetic anhydride to 100kg of norethindrone (II) obtained, 100kg of pyridine, add 120kg of acetyl chloride dro...

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Abstract

A synthetic method for tibolone, specifically comprising the following steps: 1) acetylenylation reaction: acidic decarboxylation (I) toluene solution, feed acetylene gas to the raw material to react to obtain norethindrone (II); 2) acylation reaction, Step 1) Add acetic anhydride and acid-binding agent to the obtained norethindrone (II), add acetyl chloride dropwise under control at room temperature, and stir the reaction for 6 hours until the raw materials are completely reacted to obtain the acylate (III); 3) debromination reaction, the acyl compound reaction to obtain norethindrone 4,6-diene acetate (V); 4) methylation reaction, norethindrone 4,6-diene acetate (V), add ether solvent, and cool to -10~30°C , drop methylation reagent, control the temperature at 0-5°C and stir the reaction until the raw materials react completely to obtain 7α-norethindrone methyl acetate (VI); 5) transposition reaction, 7α-norethindrone methyl acetate (VI) React to get transposition (VII) wet product; 6) hydrolysis reaction, translocation (VII) reaction to get tibolone.

Description

technical field [0001] The present invention relates to a kind of synthetic method of steroid compound. Background technique [0002] Tibolone is a tissue-selective modulator of estrogen activity (STEARs), a synthetic steroid hormone. Clinically, it is mainly used in perimenopausal and postmenopausal women to relieve vasomotor symptoms, improve urogenital atrophy symptoms, prevent bone loss and reduce the incidence of fractures, and improve life-related quality. In 1967, the literature introduced that tibolone was obtained from dehydroepiandrosterone as a raw material through 11 steps of reaction, with a total yield of 8.9%. Step-by-step synthesis of tibolone, with a total yield of 5.47%; in 2004, the world patent WO2004031204 reported the third method, using nandrolone to synthesize tibolone through 8 steps, with a yield of 18.04%; WO2004078774 reported the fourth method, the same Nandrolone was used to synthesize tibolone through 8 steps, and the yield was 21.5%. [000...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J1/00
CPCC07J1/0096
Inventor 徐思虎张峥斌陈应惠李纯吴孝凯泮宝峰
Owner ZHEJIANG XIANJU JUNYE PHARM CO LTD
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