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Synthetic method of androst-4-en-3-one-17β-carboxylate methyl ester

A technology of methyl carboxylate and a synthesis method, which is applied in the synthesis field of androst-4-ene-3-one-17β-carboxylate methyl ester, can solve the problems of high pollution, high cost, complicated process, etc. The effect of stable source, simple and simple process, and low price

Active Publication Date: 2021-05-11
湖南玉新药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, in the traditional synthesis of androst-4-en-3-one-17β-carboxylate methyl ester, its weight yield is low, high pollution, high cost, complex process, difficult to meet the needs of industrial production

Method used

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  • Synthetic method of androst-4-en-3-one-17β-carboxylate methyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Synthesis of 3-methoxy-androst-3,5-dien-17-one (2)

[0032] Under nitrogen protection, add 57.28 grams (0.2 moles) of 4AD, 250 milliliters of anhydrous tetrahydrofuran, 50 grams (0.471 moles) of trimethyl orthoformate, and 0.6 grams (3.15 millimoles) of p-toluenesulfonic acid to the reaction flask at 5 ° C Keep warm for 5 hours, and TLC detects the end point of the reaction. After the reaction, add 1 gram (10 mmol) of triethylamine, stir for 30 minutes, and terminate the reaction. Add 500 ml of water dropwise, stir and crystallize at 5°C for 2 hours, filter to obtain off-white crystals. After drying at 70°C, 58.77 g (0.195 mol) was obtained. Yield: 97.3%.

Embodiment 2

[0034] Synthesis of androst-4-en-3-one-17β-carbaldehyde (3)

[0035] Under the protection of nitrogen, 54.8 grams (0.16 moles) of (methoxymethyl) triphenylphosphorous chloride were added to the reaction flask, 500 milliliters of anhydrous tetrahydrofuran, 18.5 grams (0.165 moles) of potassium tert-butoxide were added, and stirred at room temperature for 1 Hour. Add 30.14 g (0.1 mol) of 3-methoxy-androst-3,5-dien-17-one, and react at room temperature for 12 hours. The end point of the reaction was detected by TLC. After the reaction was complete, 150 ml of 6N hydrochloric acid solution was added dropwise, and stirred at room temperature for 3 hours. The end point of the reaction was detected by TLC. After the reaction was complete, sodium bicarbonate solution was added dropwise to adjust the pH to 7, tetrahydrofuran was recovered under reduced pressure, the temperature was lowered to 5°C, and kept for 2 hours, filtered, and vacuum-dried at 60°C to obtain androst-4-en-3-one -1...

Embodiment 3

[0037] Synthesis of androst-4-en-3-one-17β-methyl carboxylate (1)

[0038] Add 30 g (0.1 mol) of androst-4-en-3-one-17β-formaldehyde into the reaction flask, 300 ml of anhydrous methanol, and 1.66 g (10 mmol) of potassium iodide, control the temperature at 20°C, and add dropwise 27 grams (0.3 moles) of oxidized tert-butanol was added in about 30 minutes, and the temperature was raised to reflux for 6 hours. TLC detected that the reaction was complete, and 27.7 grams (0.22 moles) of sodium sulfite (dissolved in 100 milliliters of water) was added to terminate the reaction, and concentrated under reduced pressure. Add 200 ml of water, stir at room temperature for 2 hours, filter, and dry at 60°C to obtain 30.75 g (0.093 mol) of off-white solid, yield: 93%.

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Abstract

The invention discloses a method for synthesizing methyl androst-4-ene-3-one-17β-carboxylate, which comprises the following steps: (a) using sterol fermentation product androst-4-ene-3,17-di The ketone is used as the starting material, and the 3-position ketone group is etherified and protected to obtain the compound of formula 2; (b) the 17-position ketone of the formula 2 compound is subjected to Witt reaction and hydrolysis rearrangement to obtain the compound of formula 3; (c) the compound of formula 3 The compound is esterified, and then the androst-4-ene-3-one-17β-carboxylate methyl ester described in Formula 1 is collected from the reaction product. The invention has stable source of raw materials, less pollution, environmental protection and low price, and is a synthesis method with low cost, simple and convenient process and more green and environmental protection. The reaction formula is as follows:

Description

technical field [0001] The invention relates to a method for synthesizing a steroid hormone drug intermediate from a sterol fermentation product, in particular to an intermediate of androst-4-en-3-one-17β-carboxylate of finasteride and dutasteride A method for the synthesis of methyl esters. Background technique [0002] Steroids are the second largest class of drugs in the world after antibiotics. The traditional synthesis of steroid hormones is derived from dienes obtained from the degradation of turmeric extract (dioscin) as raw materials. [0003] Finasteride is currently the first-line clinical drug for the treatment of benign prostatic hypertrophy and benign prostatic hyperplasia in elderly men, and it is also used to treat early-stage prostate cancer. Androst-4-en-3-one-17β-carboxylate methyl ester is an important intermediate in the production of finasteride, dutasteride, etc. [0004] The traditional production method of androst-4-en-3-one-17β-carboxylate methyl ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J1/00
CPCC07J1/0025
Inventor 刘红周楷兰申玉良曹春宇王力彭正中
Owner 湖南玉新药业有限公司
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