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Synthesis method of dienogest

A technique for the synthesis of dienogest, which is applied in the field of medicine, can solve the problems of long preparation time and unsatisfactory yield, and achieve the effects of reducing process cost, increasing yield, and solving wastewater problems

Inactive Publication Date: 2010-10-20
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This route uses propylene glycol as a protecting group to selectively protect the 3-position keto group in the presence of a dehydrating agent, but requires triethyl orthoformate and propylene glycol to be taken away in the reaction under reflux under the catalysis of p-toluenesulfonic acid The ethanol that generates prepares new dehydrating agent, and its preparation time is longer, and dehydrating agent is done and used now, we have tried this step reaction, and yield is not ideal (EP 0776904)

Method used

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Examples

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Embodiment 1

[0029] 1) Estro-5(10), 9(11)-diene-3,17-dione-3,3-(2,2-dimethylpropylene) ketal

[0030] Put 20.8g of 2,2-dimethyl-1,3-propanediol into a 500mL three-neck flask, add 100mL of isopropanol, stir until dissolved, then add 10mL of acetyl chloride, raise the temperature to 35℃~40℃ and stir for 10min, then cool down To -40°C, dissolve 8 g of estra-4,9-diene-3,17-dione in 50 mL of THF, add it dropwise into the three-necked flask within about 1 hour, keep stirring at the temperature for 2 hours, and add triethylamine dropwise When the pH of the reaction solution is alkaline, filter with suction, wash the filter cake with a small amount of THF, combine the filtrates, concentrate under reduced pressure to obtain a brownish-red oil, add 100 mL of ethyl acetate, wash the organic layer with 100 mL of water, and wash with 100 mL of saturated brine, anhydrous Dry over sodium sulfate overnight and filter. Purified by column chromatography with ethyl acetate:petroleum ether=1:50 and 1:20 to o...

Embodiment 2

[0043] 1) Estro-5(10), 9(11)-diene-3,17-dione-3,3-(2,2-dimethylpropylene) ketal

[0044] Put 83.2g of 2,2-dimethyl-1,3-propanediol into a 1000mL three-neck flask, add 400mL of isopropanol, stir until dissolved, then add 40mL of acetyl chloride, heat up to 35°C-40°C and stir for 10min, then cool down To -40°C, dissolve 32g of estra-4,9-diene-3,17-dione in 200mL THF, drop it into the three-necked flask within about 1 hour, keep stirring at the temperature for 2 hours, and add triethylamine dropwise When the pH of the reaction solution is alkaline, filter with suction, wash the filter cake with a small amount of THF, combine the filtrates, concentrate under reduced pressure to obtain a brownish-red oil, add 300 mL of ethyl acetate, wash the organic layer with 300 mL of water and 300 mL of saturated saline, and dry Dry over sodium sulfate overnight and filter. Purified by column chromatography with ethyl acetate:petroleum ether=1:50 and 1:20 to obtain 27.6g of white solid, yield ...

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Abstract

The invention belongs to the technical field of the medicine, and relates to a novel synthesis method of dienogest. The dienogest is obtained through 17-position epoxidation, cyaniding for ring opening and 3-positoin deprotection with estra-4, 9-diene-3, 17-dione as a starting material and 2, 2-dimethyl-1, 3-propylene glycol for protection of a 3-position ketone group. The invention has the advantages that the raw materials can be obtained easily and the operation is simple. Since the 2, 2-dimethyl-1, 3-propylene glycol with alkali resistance is used as a protective group for the 3-position ketone group, the invention effectively improves the yield of the 17-position epoxidation, and reduces the process cost. The post-treatment is improved, and the pH of the reaction solution is adjusted to be alkaline with alkali after reaction prior to regular operation, thereby solving the problem of wastewater. Therefore, the invention is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, relates to a synthesis method of dienogest, and also relates to its intermediate 17β-helix-1′, 2′-oxirane-5(10), 9(11)-estro Dien-3-one-3,3-(2,2-dimethylpropylene)-ketal and 17α-cyanomethyl-17β-hydroxy-5(10),9(11)-estradiene -The synthetic method of 3-keto-3,3-(2,2-dimethylpropylene)-ketal. Background technique [0002] Dienogest, chemical name 17α-cyanomethyl-17β-hydroxy-13β-methylsterane 4,9-dien-3-one, is a mixed progestin, which has 19-nortestosterone derivative Due to the dual properties of progesterone and progesterone derivatives, its endocrine pharmacology is very ideal, it only binds to progesterone receptors, and has no estrogenic, antiestrogenic and androgenic activities. Its compound tablet with ethinyl estradiol, trade name Valette, was first launched in Germany in 1995 and has become the best-selling oral contraceptive in Germany. The compound tablet with estradiol valerate, who...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00
CPCY02P20/55
Inventor 王绍杰陈博薛明星赵勇
Owner SHENYANG PHARMA UNIVERSITY
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