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Preparation method of desogestrel

A desogestrel, monohydrate technology, applied in the production of steroids, organic chemistry, bulk chemicals, etc. The effect of high yield, high stability and improved yield

Pending Publication Date: 2022-07-08
ZHEJIANG XIANJU JUNYE PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 2. CN101445542: The protection of 17-ethylene glycol is unstable, and many by-products are derived; the Jones reagent for oxidation still involves heavy metal Cr
[0009] 3. WO2013135744: 17-Ethylene glycol protection is unstable, and many by-products are derived;
[0011] Based on the problems existing in the preparation method of desogestrel in the prior art, a new preparation method of desogestrel is provided, which improves the unstable protection of 17-ethylene glycol in the prior art, derives more by-products and needs to use The problem of pollution caused by chromium-containing oxidants, while also improving the reaction yield, has become an urgent problem to be solved in the prior art

Method used

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  • Preparation method of desogestrel
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  • Preparation method of desogestrel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032]

[0033] Synthesis of compound 2: In the reactor, 1.5kg of 11α-hydroxy-18-methyl-estr-4-ene-3,17-dione (compound 1), 7.5kg of glacial acetic acid and p-toluenesulfonic acid monohydrate were successively 150g of PTSA (PTSA), under full stirring, 560g of ethanedithiol was added dropwise at 20~30°C for about 30 minutes; after the dropwise addition, the temperature was kept for 3 hours; the reaction solution was slowly poured into -5°C sodium hydroxide aqueous solution ( 7.5kg of sodium hydroxide and 30kg of water), separated and stirred for 2 hours, centrifuged, and the filter cake was rinsed with water; recrystallized from methanol to obtain 1.7kg of white solid (compound 2), mass yield 113%, HPLC purity: 98 %.

[0034] Synthesis of compound 3a: In the reaction kettle, add toluene (6.0kg), compound 2 (1.0kg), piperidine (600g) and PTSA (100g) successively, and reflux for 4 hours; cool to room temperature, suction filtration; in the filtrate Silica gel (500 g) was adde...

Embodiment 2

[0040]

[0041] Synthesis of Compound 2: In Reference Example 1, 50 g of (Compound 1) was added to obtain 58 g of (Compound 2); the mass yield was 116%, and the HPLC purity: 98%.

[0042] Synthesis of compound 3b: In the reaction kettle, add toluene (300g), compound 2 (50g), pyrrolidine (30g) and PTSA (5g) in turn, and reflux for 4 hours; cool to room temperature, suction filtration; add silica gel to the filtrate (25g), stirred for 1 hour, and suction filtered; the filtrate was concentrated under reduced pressure to an oily substance, which was recrystallized from ethyl acetate-petroleum ether to obtain compound 3b (45g), mass yield 90%, HPLC purity: 97%.

[0043] Synthesis of compound 4b: add liquid ammonia (400mL) in the low temperature reaction kettle, cool to -45°C~-50°C, add metallic lithium (6g) in 3 batches, add and stir for 1 hour, dropwise add the tetrahydrofuran solution of compound 3b (40 g of compound 3b was dissolved in 320 mL of tetrahydrofuran), about 1 hour...

Embodiment 3

[0048]

[0049] Synthesis of Compound 2: In Reference Example 1, 50 g of (Compound 1) was added to obtain 58 g of (Compound 2); the mass yield was 116%, and the HPLC purity: 98%.

[0050] Synthesis of compound 3c: In the autoclave, add compound 2 (50g), diethylamine (300g) and PTSA (5g) in turn, react at 120°C for 8 hours; cool to room temperature, release the pressure, open the autoclave, suction filtration, and concentrate , add toluene to dissolve, add silica gel (25g), stir for 1 hour, suction filtration; the filtrate is concentrated under reduced pressure to an oily substance, recrystallized from ethyl acetate-petroleum ether to obtain compound 3c (15g), mass yield 30%, HPLC purity: 92 %.

[0051] Synthesis of compound 4c: add liquid ammonia (100 mL) in the low temperature reaction kettle, cool to -45°C~-50°C, add metallic lithium (1.5g) in 3 batches, add and stir for 1 hour, dropwise add the tetrahydrofuran of compound 3b The solution (10 g of compound 3b was dissolv...

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PUM

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Abstract

The invention relates to a preparation method of desogestrel, which comprises the following specific steps: by taking 11 alpha-hydroxy-18-methyl-estra-4-ene-3, 17-diketone) as a starting material, carrying out 3-keto protection by using ethanedithiol, carrying out 17-keto protection by using imine, removing ethanedithiol from lithium liquid ammonia, carrying out IBX oxidation, carrying out wittig alkylenation reaction, carrying out acidolysis deprotection, and carrying out ethynylation by using acetylene potassium, so as to obtain the desogestrel.

Description

technical field [0001] The invention relates to a preparation method of a steroid compound, in particular to a synthesis method of desogestrel. Background technique [0002] Desogestrel is a third-generation oral potent progestogen without androgenic and estrogenic activity. Experiments have shown that its progesterone activity is 18 times stronger than norethisterone and 1 times more than norethisterone. The biggest feature is that it has no androgen effect. It can also increase high-density lipoprotein (HDL): the anti-estrogenic activity is also stronger than norethisterone and levonorgestrel. It has a significant ovulation inhibitory effect, and can still change the consistency of cervical mucus and inhibit the development of the endometrium. Its structural formula is as follows: [0003] [0004] There are many desogestrel processes, among which 11α-hydroxy-18-methyl-estr-4-ene-3,17-dione (compound 1) is used as the starting material: [0005] 1. US3927046: The s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J1/00
CPCC07J1/0096C07J11/00Y02P20/55
Inventor 张峥斌李纯尹金玉何成胜
Owner ZHEJIANG XIANJU JUNYE PHARM CO LTD
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