Preparation method of 17beta-androst-4-ene-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 production cost and market price increase, saponin production cost increase, water consumption, energy consumption, etc., and achieve product High yield, beneficial to industrial production, and the effect of reducing production cost

Inactive Publication Date: 2016-02-03
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the extraction of diosgenin, oxidative cracking, diene hydrogenation, bromoform reaction and other processes produce more waste water, which is difficult to handle and easy to pollute the environment; the Oxide oxidation process used in production requires steam distillation, water consumption, High energy consumption; using active nickel or palladium carbon to catalyze hydrogenation, there are potential safety hazards
More importantly, with the depletion of wild yam plant resources, and the artificial planting of yam plants due to the increasing cost of labor and chemical fertilizers, the production costs of saponin and dienes have doubled, resulting in 17β-androst-4- The production cost and market price of en-3-one-17-carboxylic acid have increased significantly, which has had a significant impact on the global finasteride drug market

Method used

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  • Preparation method of 17beta-androst-4-ene-3-one-17-carboxylic acid
  • Preparation method of 17beta-androst-4-ene-3-one-17-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] A. Preparation of ether compounds

[0027] In a 1000ml three-necked 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 Pyridine, stir for 20-25 minutes to neutralize the acid, then cool the system to -5-0°C, stir and crystallize for 2-3 hours, filter with suction, wash with a small amount of ethanol, combine the lotion and filtrate, recover the solvent and use the crude product mechanically; filter cake Drying below 70°C yielded 101.6g of ether compound with an HPLC content of 99.2% and a weight yield of 101.6%.

[0028] B. Preparation of nitro compounds

[0029] In a 1000ml three-neck flask, add 100g of ether compound, 400ml of nitromethane, and 5ml of ethylenediamine, keep warm at 85-90°C and stir for 6-8 hours. TLC detects the end point of the reaction. After the reaction, concentrate under reduced pressure to ...

Embodiment 2

[0035] A. Preparation of ether compounds

[0036] In a 1000ml three-neck flask, add 100g4AD, 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. After 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, suction filter, a small amount Wash with ethanol, combine the lotion and filtrate, recover the solvent and reuse the crude product; dry the filter cake below 70°C to obtain 100.2 g of etherified compound, the HPLC content is 99.4%, and the weight yield is 100.2%.

[0037] B. Preparation of nitro compounds

[0038] In a 1000ml three-necked flask, add 100g of ether compound, 60ml of nitroethane, 600ml of toluene, and 5ml of ethylenediamine, keep warm at 85-90°C and...

Embodiment 3

[0044] A. Preparation of ether compounds

[0045] In a 1000ml three-neck flask, add 100g 4AD, 200ml ethanol, 80ml triethyl orthoformate, add 2g of HCl gas, seal it, keep it warm at 2025°C and stir for 12-16 hours. TLC detects the reaction end point. After the reaction, add 3ml Pyridine, stir for 20-25 minutes to neutralize the acid, then cool the system to -5-0°C, stir and crystallize for 2-3 hours, filter with suction, wash with a small amount of ethanol, combine the lotion and filtrate, recover the solvent and apply the crude product; filter cake Drying below 70°C yielded 103.2 g of ether compound with an HPLC content of 99.1% and a weight yield of 103.2%.

[0046] B. Preparation of nitro compounds

[0047] In a 1000ml three-neck flask, add 100g of ether compound, 400ml of nitroethane, and 5ml of N,N-tetramethylethylenediamine, keep warm at 85-90°C and stir for 6-8 hours. TLC detects the end point of the reaction. , concentrated under reduced pressure, and recovered nitrom...

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Abstract

The invention discloses a preparation method of 17beta-androst-4-ene-3-one-17-carboxylic acid. The preparation method comprises the following specific operation steps of performing acid catalyzed reaction on 4AD (Androstenedione) and triethyl orthoformate in low-carbon alcohol organic solvent to obtain etherate 3-ethyoxyl-androst-3,5-diene-17-one; performing 17-situ addition on the obtained etherate and nitromethane in the organic solvent under the catalysis of ethanediamine to obtain a nitro compound; reducing the obtained nitro compound in the organic solvent with zinc powder, and hydrolyzing with acid to obtain 17beta-androst-4-ene-3-one-17-formaldehyde; oxidizing an intermediate obtained by hydrolyzing in the organic solvent with hydrogen peroxide to obtain a 17beta-androst-4-ene-3-one-17-formic acid crude product; recrystallizing the crude product through methyl alcohol to obtain a finished product. According to the preparation method, total yield of synthesis weight is 70 to 72 percent, and the content of HPLC (High Performance Liquid Chromatography) is 99.0 percent or over 99.0 percent. The method disclosed by the invention has the advantages of high production yield, low cost, good purity, stable quality, high recovery rate of solvent, economy and environment friendliness.

Description

technical field [0001] The invention belongs to the preparation technology of steroid hormone drug intermediates, and in particular relates to a preparation method of finasteride intermediate 17β-androst-4-en-3-one-17-carboxylic acid of prostatic hypertrophy treatment drug. 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. Since finasteride can selectively inhibit the activity of 5α-reductase in the human body, thereby blocking the conversion of testosterone into dihydrotestosterone in the body, and causing the proliferated prostate to shrink due to lack of dihydrotestosterone, the side effects of this drug are small. The curative effect is definite, and the market potential is huge. The production of finasteride is made from the intermediate 17β-androst-4-en-3-one-17-carboxylic acid th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J3/00
Inventor 胡爱国谢来宾吴来喜
Owner HUNAN KEREY BIOTECH
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