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Synthesis method of desogestrel drug intermediate

A desogestrel and synthesis method technology, applied in the directions of steroids, organic chemistry, etc., can solve the problems of large environmental pollution, low purity, low yield, etc., and achieves low equipment investment, high purity, and high yield. Effect

Inactive Publication Date: 2016-05-04
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In order to solve the existing problems such as low yield, low purity, and large environmental pollution in the introduction of 11-position hydroxyl group and the oxidation process of 11-position hydroxyl group in the preparation process of desogestrel, the purpose of the present invention is to disclose a Using D-13β-ethyl-3-methoxy-estradiol-1,3,5(10),8(9)-tetraen-17β-alcohol I as the raw material, compound II was obtained by protecting the 17-position hydroxyl group; The reaction in an acidic mixed solvent converts the 8,9-position double bond into a 9,11-position double bond compound III, and the compound III is converted into the 11-position hydroxyl compound IV after hydroxylation, and the compound IV is oxidized by an oxidizing reagent to obtain Oxogestrel Pharmaceutical Intermediate V

Method used

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  • Synthesis method of desogestrel drug intermediate
  • Synthesis method of desogestrel drug intermediate
  • Synthesis method of desogestrel drug intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1: 17β-benzyloxy-D-13β-ethyl-3-methoxyestr-1,3,5(10),8(9)-tetraene (compound II)

[0020]

[0021] Under ice bath, 0.45g of sodium hydride (1.5mmol) was added to 5mL of dimethylformamide solution, and the dried compound I (0.42g, 1.2mmol) was dissolved in 5mL of dry tetrahydrofuran. Add the solution of compound I dropwise to the above solution within 40 minutes, then add benzyl bromide (2.0mmol) dropwise, and the dropwise addition is completed in 30 minutes, and the mixture is stirred at 20-30 degrees Celsius for 20 hours under the protection of nitrogen. , add 30mL of water to dilute, stir to precipitate solid, filter and wash the filter cake with water, grind the solid with cyclohexane, filter and dry to obtain 0.55g of compound II as a white solid with a yield of 95%. Example 2: 17β-benzyloxy-D-13β-ethyl-3-methoxyestr-1,3,5(10),9(11)-tetraene (compound III)

Embodiment 2

[0021] Under ice bath, 0.45g of sodium hydride (1.5mmol) was added to 5mL of dimethylformamide solution, and the dried compound I (0.42g, 1.2mmol) was dissolved in 5mL of dry tetrahydrofuran. Add the solution of compound I dropwise to the above solution within 40 minutes, then add benzyl bromide (2.0mmol) dropwise, and the dropwise addition is completed in 30 minutes, and the mixture is stirred at 20-30 degrees Celsius for 20 hours under the protection of nitrogen. , add 30mL of water to dilute, stir to precipitate solid, filter and wash the filter cake with water, grind the solid with cyclohexane, filter and dry to obtain 0.55g of compound II as a white solid with a yield of 95%. Example 2: 17β-benzyloxy-D-13β-ethyl-3-methoxyestr-1,3,5(10),9(11)-tetraene (compound III)

[0022]

[0023] Compound II (0.51g, 1.3mmol) and p-toluenesulfonic acid (0.09g, 0.307mmol) were dissolved in a mixed solvent of 6mL of glacial acetic acid and 6mL of toluene, and refluxed at 115 degrees Ce...

Embodiment 3

[0024] Example 3: 17β-Benzyloxy-D-13β-Ethyl-11α-Hydroxy-3-methoxyestro-1,3,5(10)-triene (Compound IV)

[0025]

[0026] Compound III (0.42 g, 1.1 mmol) was dissolved in 10 mL of dry THF solvent, followed by the addition of 1M BH 3 .THF solution 5mL, under the protection of nitrogen, react at 25 degrees Celsius for 4 hours, slowly add 0.5mL of water dropwise, then add 30% aqueous sodium hydroxide solution 3mL and 30% hydrogen peroxide 3mL, the reaction solution continues to react at 25 degrees Celsius for 1 hour After the reaction, 25 mL of water was added, the reaction solution was extracted three times with ether (45 mL), the organic phase was washed with saturated sodium bisulfite solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 0.41 g of compound IV with a yield of 90%.

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Abstract

The invention discloses a synthesis method of a desogestrel drug intermediate. The synthesis method comprises the following steps: taking a compound I as a raw material, and protecting by 17-site hydroxyl to obtain a compound II; reflowing the compound II in an acidic mixed solvent to obtain a compound III; taking the compound III to be subjected to a hydroxylation reaction, so as to obtain a compound IV; oxidizing the compound IV by an oxide to obtain the desogestrel drug intermediate V. The preparation method disclosed by the invention is simple and has moderate reaction conditions, and the yield is relatively high.

Description

(1) Technical field [0001] The invention relates to a method for synthesizing a desogestrel pharmaceutical intermediate. (2) Background technology [0002] Desogestrel is the first widely clinically used drug among the third-generation progestogens. It is a progestogen with high efficiency and contraceptive effect. It is highly selective, has little impact on human physiological metabolism, and has few side effects. It is compatible with estrogen The drug is a widely used contraceptive drug. [0003] The synthetic method of desogestrel is a lot, wherein U.S. Patent US20050234251 adopts 18-methylestr-4-ene-3,17-dione (compound A) as starting material, introduces 11-position hydroxyl (compound A) by microbial conversion method B), then obtain desogestrel by correspondingly modifying the 3-position, 11-position and 17-position. The process route is short, but the overall yield is low due to the low yield of the 11-position hydroxyl compound introduced by the microbial method....

Claims

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Application Information

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IPC IPC(8): C07J1/00
CPCC07J1/0077
Inventor 李佰林应明华朱秀燕娄玲珠
Owner ZHEJIANG XIANJU PHARMA
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