Preparation method of methyltestosterone

A technology of methyl testosterone and ethoxy, which is applied in the field of preparation of steroid hormone drug intermediates, can solve the problems of complex process operation, difficult environmental protection treatment, high production cost, etc., and achieve process economy and environmental protection, production cost reduction, and synthetic The effect of short routes

Inactive Publication Date: 2017-02-15
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The purpose of the present invention is to provide a new method for preparing methyltestosterone, which overcomes many disadvantages of traditional production techn

Method used

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  • Preparation method of methyltestosterone
  • Preparation method of methyltestosterone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] A. Preparation of ether compounds

[0021] 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 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%.

[0022] B. Preparation of Grignard

[0023] In a 1000ml three-necked flask, add 35g of magnesium powder and 350ml of tetrahydrofuran, stir, keep warm at 45-50°C, and feed 120g of methyl bromide, and continue to stir for 4 to 6 hours until the magnesium powder basically disappears, and the Grignard reagent i...

Embodiment 2

[0027]A. Preparation of ether compounds

[0028] 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, cool down, 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%.

[0029] B. Preparation of Grignard

[0030] In a 1000ml three-neck flask, add 35g of magnesium powder and 350ml of ether, stir, keep warm at 35-40°C, and feed 120g of methyl chloride. After the passage, continue to stir and react for ...

Embodiment 3

[0034] A. Preparation of ether compounds

[0035] 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 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, 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 The filter cake was dried below 70°C to obtain 103.2g of etherified compound, the HPLC content was 99.1%, and the weight yield was 103.2%.

[0036] B. Preparation of Grignard

[0037] In a 1000ml three-neck flask, add 35g of magnesium powder and 350ml of tetrahydrofuran, stir, keep warm at 35-40°C, and feed 120g of methyl bromide. After passing through, continue to stir and react for 4 to 6 hours until the magnesium powder basically disappears, and the ...

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Abstract

The invention provides a preparation method of methyltestosterone. 4AD short for 4-androstenedione is taken as a raw material, and etherate is synthesized firstly as follows: 4AD and triethyl orthoformate are subjected to an acid catalyzed reaction in a low-carbon alcohol organic solvent, and 3-ethoxy-androst-3,5-diene-17-one as the etherate is obtained; then a Grignard product is synthesized as follows: a Grignard reagent methyl magnesium halide and the etherate are placed in an organic solvent, the 17-position ketone group of the etherate and the Grignard reagent are subjected to addition, and the Grignard product 3-ethoxy-17a-methyl-androst-3,5-diene-17-ol is obtained through hydrolysis; then the Grignard product is subjected to an acid catalyzed hydrolysis in an organic solvent, and crude methyltestosterone is obtained; the crude methyltestosterone is decolorized by activated carbon in C4-below low-carbon alcohol and recrystallized, the methyltestosterone is obtained, HPLC content is 99.0%-99.5%, and the total yield of synthesis weight is 75%-78%. According to the method, the raw materials are widely sourced, the process is simple and convenient to operate, the product yield is high, the purity is good, the solvent recovery rate is high in reaction and technological processing, and the method is economical and environment-friendly.

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 the androgen drug methyltestosterone. Background technique [0002] Methyltestosterone is a male hormone drug, which is mainly used clinically to promote the development of male sexual organs and secondary sexual characteristics and maintain their normal functions. It is also used for women's dysfunctional uterine bleeding and migratory breast cancer. Synthetic methyltestosterone propionate and other advanced androgen drugs have a huge market. The traditional production method of methyl testosterone is to extract diosgenin from yam plant, after protection, oxidative cracking, and elimination, the key intermediate obtained - acetic acid pregnant dienolone (referred to as diene) as raw material, after oximation , Beckmann rearrangement, acid hydrolysis, Grignard reaction, alkali hydrolysis, Osmanthus oxidation a...

Claims

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Application Information

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IPC IPC(8): C07J1/00
CPCC07J1/0037
Inventor 甘红星龙能吟胡爱国吴来喜
Owner HUNAN KEREY BIOTECH
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