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Preparation method of 17β-androst-4-en-3-one-17-carboxylic acid

A technology of androstenedione and androstene, which is applied in the field of preparation of steroid hormone drug intermediates, can solve the problems of complicated process operation, difficult environmental protection treatment, expensive synthetic raw materials, etc., and achieves cheap and easy-to-obtain raw materials and good product quality , the effect of short synthetic route

Active Publication Date: 2020-06-26
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The purpose of the present invention is to solve the problems of expensive synthetic raw materials, long production cycle, complex process operation, difficult environmental protection treatment and high production cost in the traditional production process, and provide a new 17β-androst-4-en-3-one-17- The preparation method of carboxylic acid realizes that the raw material is cheap and easy to obtain, the process is simple and environment-friendly, the synthesis route is short, the synthesis yield is high, the product quality is good, and the production cost is reduced

Method used

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  • Preparation method of 17β-androst-4-en-3-one-17-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] A. Preparation of ether compounds

[0031] In a 1000ml three-neck flask, add 100g 4AD, 200ml ethanol, 80ml triethyl orthoformate, 2g p-toluenesulfonic acid, keep warm at 20-25°C and stir for 12-16 hours. TLC detects the end point of the reaction. After the reaction, add 3ml of pyridine, stirred for 20-25 minutes to neutralize the acid, then cooled the system to -5-0°C, stirred and crystallized for 2-3 hours, filtered with suction, washed with a small amount of ethanol, combined the lotion and filtrate, recovered the solvent and used the crude product; filtered The cake was dried below 70°C to obtain 101.6 g of etherified compound, the HPLC content was 99.2%, and the weight yield was 101.6%.

[0032] B. Preparation of epoxy

[0033]In a 2000ml three-neck flask, add 100g of the above ether compound, 600ml of dimethyl sulfoxide, and 60g of trimethylsulfur iodide, stir to dissolve completely, then slowly add 10g of 80% sodium hydride at 20-25°C, add After completion, cont...

Embodiment 2

[0039] A. Preparation of ether compounds

[0040] In a 1000ml three-neck flask, add 100g 4AD, 600ml dichloromethane, 80ml triethyl orthoformate, 2g p-toluenesulfonic acid, keep warm at 20-25°C and stir for 12-16 hours. TLC detects the end point of the reaction. , add 3ml of pyridine, stir for 20-25 minutes to neutralize the acid, concentrate under reduced pressure, recover dichloromethane, lower the temperature, add 100ml of ethanol, then cool the system to -5-0°C, stir and crystallize for 2-3 hours, and filter with suction. A small amount of ethanol was washed, the washing liquid and the filtrate were combined, the solvent was recovered and the crude product was reused; the filter cake was dried below 70°C to obtain 100.2 g of ether compound, the HPLC content was 99.4%, and the weight yield was 100.2%.

[0041] B. Preparation of epoxy

[0042] In a 2000ml three-necked flask, add 100g of the above self-made ether compound, 600ml of DME, and 60g of trimethylsulfur iodide, stir...

Embodiment 3

[0048] A. Preparation of ether compounds

[0049] In a 1000ml three-neck flask, add 100g 4AD, 200ml ethanol, and 80ml triethyl orthoformate, inject 2g of HCl gas, seal it, keep it warm at 2025°C and stir for 12-16 hours. TLC detects the end point of the reaction. After the reaction, add 3ml of pyridine, stirred for 20-25 minutes to neutralize the acid, then cooled the system to -5-0°C, stirred and crystallized for 2-3 hours, filtered with suction, washed with a small amount of ethanol, combined the lotion and filtrate, recovered the solvent and used the crude product; filtered The cake was dried below 70°C to obtain 103.2g of etherified compound,

[0050] HPLC content 99.1%, weight yield 103.2%.

[0051] B. Preparation of epoxy

[0052] In a 2000ml three-necked flask, add 100g of the above ether compound, 600ml of tetrahydrofuran, and 60g of trimethylsulfur iodide, stir to dissolve completely, then slowly add 10g of 80% methyl lithium at 20-25°C, after the addition is comple...

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Abstract

The invention discloses a preparation method of 17 beta-androst-4-ene-3-one-17-carboxylic acid. The preparation method comprises that 4-androstenedione (called as 4AD for short) as a raw material andtriethyl orthoformate undergo a reaction in an organic solvent under acid catalysis, the reaction product is after-treated to form an etherate, the etherate is dissolved in an organic solvent and undergoes a reaction with trimethylsulfonium iodide under strong base catalysis, the product is after-treated to form an epoxide, the epoxide is dissolved in an organic solvent and then is subjected to rearrangement under acid catalysis to form an aldehyde, and aldehyde is dissolved in an organic solvent and undergoes a catalytic oxidation reaction with hydrogen peroxide acid to produce 17 beta-androst-4-ene-3-one-17-carboxylic acid. The 17 beta-androst-4-ene-3-one-17-carboxylic acid has a melting point of 244-246 DEG C, HPLC content of 99.0% or more and a reaction weight total yield of 70-72%. Compared with the traditional method, the preparation method utilizes cheap and easily available raw materials, has simple and environmental friendly processes and a high synthesis yield, produces highquality products, reduces a cost by 30-40% and is conducive to industrial production.

Description

technical field [0001] The invention relates to the preparation technology of steroid hormone drug intermediates, in particular to the preparation method of finasteride intermediate 17β-androst-4-en-3-one-17-carboxylic acid. Background technique [0002] 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. Because finasteride can selectively inhibit the activity of 5α-reductase in the human body, thereby blocking the conversion of testosterone into dihydrotestosterone in the body, so that the proliferated prostate shrinks due to the lack of dihydrotestosterone. Indeed, the market potential is huge. The production of finasteride is made from the intermediate 17β-androst-4-en-3-one-17-carboxylic acid through five steps of ring opening, ring closing, hydrogenation, amidation and dehydrogenation. [0003] The traditional ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J3/00
Inventor 甘红星胡爱国吴来喜谢来宾
Owner HUNAN KEREY BIOTECH
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