The preparation method of megestrol

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

Active Publication Date: 2019-11-05
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

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  • The preparation method of megestrol
  • The preparation method of megestrol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] A, the preparation of bisketal

[0022] In a 1000ml three-necked flask, add 100g 6-ketone, 600ml dichloromethane, 50g ethylene glycol, 80ml triethyl orthoformate, 2g p-toluenesulfonic acid, stir and react at 25-30°C for 12-16 hours, TLC Detect the end point of the reaction, after the reaction, 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 and crystallize at 10-15°C 3 -4 hours, centrifuged, washed with water to get the crude bisketal product, the crude product was directly added to 800ml of 50% alcohol, first refluxed for 1-1.5 hours, then about 400ml of alcohol was evaporated under normal pressure, and then the system was cooled to -5- 0°C, stirred and crystallized for 2-3 hours, filtered with suction, washed with a small amount of ethanol, and dried the filter cake below 70°C to obtain 118.2g of bisketal, with an HPLC content of 99.4% and ...

Embodiment 2

[0026] A, the preparation of bisketal

[0027] In a 1000ml three-neck flask, add 100g of 6-ketone, 600ml of toluene, 50g of ethylene glycol, 80ml of triethyl orthoformate, 2g of 98% sulfuric acid, keep warm at 25-30°C and stir 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 to recover 90-95% of toluene, then add 600ml of tap water, stir and crystallize at 10-15°C for 3-4 hours, Centrifuge and wash with water to get the crude product of bisketal. Add the above crude product directly into 800ml of 50% alcohol, first reflux for 1-1.5 hours, then distill about 400ml of alcohol under normal pressure, and then cool the system to -5-0°C. Stir for crystallization for 2-3 hours, filter with suction, wash with a small amount of ethanol, and dry the filter cake below 70°C to obtain 117.4 g of bisketal, with an HPLC content of 99.5% and a weight yield o...

Embodiment 3

[0031] A, the preparation of bisketal

[0032] In a 1000ml three-necked flask, add 100g of 6 ketones, 600ml of dichloromethane, 50g of ethylene glycol, 80ml of triethyl orthoformate, and 10g of ethanol solution of hydrochloric acid, and keep warm at 25-30°C and stir for 12-16 After hours, TLC detects the end of the reaction. After the reaction, add 3ml of pyridine, stir for 20-25 minutes to neutralize the acid, then concentrate under reduced pressure to recover 90-95% of dichloromethane, then add 600ml of tap water, and stir at 10-15°C Crystallize for 3-4 hours, centrifuge, wash with water to get the crude product of bisketal, add the above crude product directly into 800ml of 50% alcohol, first reflux for 1-1.5 hours, then distill out about 400ml of alcohol under normal pressure, and then cool the system Stir to crystallize at -5-0°C for 2 to 3 hours, filter with suction, wash with a small amount of ethanol, and dry the filter cake below 70°C to obtain 116.8 g of bisketal, wi...

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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, and in particular relates to a preparation method of the progestin drug megestrol. Background technique [0002] Megestrol, commonly known as Hunan No. 1, chemically named 6-methyl-17a-acetoxy-pregna-4,6-diene-3,17-dione, is a progestin drug, clinically Used as oral contraceptives and family planning, the effect is good, the side effect is small, and the market prospect is broad. The traditional production method of megestrol is to extract diosgenin from the yam plant, after protection, oxidation, cracking and elimination, the key intermediate acetic acid gestational dienolone (referred to as diene) is obtained as raw material, which is epoxidized , Austenitic oxidation, bromination, debromination, 17-position esterification and other five-step reactions to obtain the key intermediate 17a acetoxy progesterone, and then use 17a acetoxy progesterone as raw material to undergo ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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