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Megestrol acetate preparation method

A megestrol and ketone-based technology is applied in the field of preparation of steroid hormone drugs, can solve the problems of complex process operation, many impurities in the composition, and high production cost, and achieves simple and convenient process operation, high synthesis yield and production cost. low effect

Active Publication Date: 2017-12-26
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The purpose of the present invention is to overcome many deficiencies in the traditional production process, such as expensive reaction raw materials, many impurities in the compound, complicated process operation, difficult environmental protection treatment, high production cost, etc., and provide a new preparation method of megestrol

Method used

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Experimental program
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Effect test

Embodiment 1

[0021] A. Preparation of diketals

[0022] In a 1000ml three-necked flask, add 100g 6 ketone base, 600ml dichloromethane, 50g ethylene glycol, 80ml triethyl orthoformate, 2g p-toluenesulfonic acid, and stir the reaction at 25~30 ℃ for 12~16 hours, TLC Detect the end point of the reaction, after the reaction is completed, add 3 ml of pyridine, stir for 20-25 minutes to neutralize the acid, then concentrate under reduced pressure, recover 90-95% of dichloromethane, then add 600 ml of tap water, stir and crystallize at 10-15 ° C for 3 -4 hours, centrifuged, washed with water to get the crude diketal product, the crude product was directly added to 800ml of 50% alcohol, refluxed for 1-1.5 hours, then steamed out about 400ml of alcohol at atmospheric pressure, and then cooled the system to -5-0 ℃, stirring for crystallization for 2-3 hours, suction filtration, washing with a small amount of ethanol, and drying the filter cake below 70 ℃ to obtain 118.2 g of diketal, HPLC content 99...

Embodiment 2

[0026] A. Preparation of diketals

[0027] In a 1000ml three-necked flask, add 100g of 6-ketone base, 600ml of toluene, 50g of ethylene glycol, 80ml of triethyl orthoformate, 2g of 98% sulfuric acid, keep the temperature at 25~30°C and stir the reaction for 12~16 hours, TLC detection At the end of the reaction, add 3ml of pyridine after the reaction, stir for 20-25 minutes to neutralize the acid, then concentrate under reduced pressure, recover 90-95% toluene, then add 600ml of tap water, stir and crystallize at 10-15°C for 3-4 hours, Centrifuge and wash with water to obtain the crude diketal product. The crude product is directly added to 800ml of 50% alcohol, first refluxed for 1-1.5 hours, then steamed out about 400ml of alcohol at normal pressure, and then the system is cooled to -5-0°C, The crystallization was stirred for 2 to 3 hours, suction filtered, washed with a small amount of ethanol, and the filter cake was dried below 70° C. to obtain 117.4 g of diketal, the HPLC...

Embodiment 3

[0031] A. Preparation of diketals

[0032] In a 1000ml three-necked flask, add 100g 6 ketone base, 600ml dichloromethane, 50g ethylene glycol, 80ml triethyl orthoformate, 10g ethanol solution of hydrochloric acid, keep the temperature at 25~30 ℃ and stir to react for 12~16 After the reaction is completed, add 3ml of pyridine, stir for 20-25 minutes to neutralize the acid, then concentrate under reduced pressure, recover 90-95% of dichloromethane, then add 600ml of tap water, stir at 10-15°C Crystallize for 3-4 hours, centrifuge, wash with water to obtain the crude diketal product, which is directly added to 800ml of 50% alcohol, refluxed for 1-1.5 hours, then steamed out about 400ml of alcohol at normal pressure, and then the system is cooled At -5-0°C, stirring for crystallization for 2 to 3 hours, suction filtration, washing with a small amount of ethanol, and drying the filter cake below 70°C to obtain 116.8 g of diketal, HPLC content of 99.6%, and weight yield of 116.8%. ...

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Abstract

The invention provides a megestrol acetate preparation method. The method comprises the steps that 6-keto-17a-acetoxy progesterone serves as the raw material, the raw material is dissolved into an organic solvent, in the presence of triethyl orthoformate, a catalytic reaction is conducted with glycolic acid, and double ketals are obtained; the double ketals are dissolved into an organic solvent, a Grignard reaction is conducted with a Grignard reagent, after the reaction is completed, under the strong acid effect, Grignard hydrolysis is conducted, deprotection and dehydration are conducted simultaneously, and a crude megestrol acetate product is synthesized through a two-step reaction; the crude product is subjected to decoloration and recrystallization through activated carbon, and a megestrol acetate product is obtained, wherein the HPLC content ranges from 99.0% to 99.5%, the melting point ranges from 213 DEG C to 220 DEG C, and the two-step synthetic weight total yield ranges from 80% to 85%. Accordingly, compared with a traditional method, the synthetic route is short, the technological operation is easy and convenient, production is economical and environmentally friendly, the synthetic total yield is increased by 30% or above compared with that of the traditional method, and the production cost is lowered by 30%-35%; the solvents used in the technology can be recycled and applied mechanically, economy and environmental friendliness are achieved, and the method is very beneficial to industrial production.

Description

technical field [0001] The invention belongs to the preparation technology of steroid hormone drugs, in particular to a preparation method of progesterone drug megestrol. Background technique [0002] Megestrol, commonly known as Hunan No. 1, its chemical name is 6-methyl-17a-acetoxy-pregne-4,6-diene-3,17-dione, is a progestogen drug, clinically Used as oral contraceptives and family planning, the effect is good, the side effects are small, and the market prospect is broad. The traditional production method of megestrol is to extract diosgenin from the diosgenous plant, and after protection, oxidation, cracking and elimination, the key intermediate acetate gestational dienolone (referred to as diene) is obtained as raw material, and epoxidized , Ostrich oxidation, bromination, debromination, 17-position esterification and other five-step reactions, the key intermediate 17a acetoxy progesterone is obtained, and then 17a acetoxy progesterone is used as a raw material, through...

Claims

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Application Information

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IPC IPC(8): C07J7/00
CPCC07J7/0045
Inventor 胡爱国甘红星谢来宾吴来喜
Owner HUNAN KEREY BIOTECH
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