Preparation method of flurogestone acetate

A technology for fluprogesterone acetate and fluprogesterone acetate is applied in the field of preparation of three-step chemical reaction to synthesize fluprogesterone acetate, which can solve the problems of complex process operation, long synthesis route and high production cost, and achieves wide raw material sources and synthetic route. Short, low production cost effect

Inactive Publication Date: 2017-11-21
HUNAN KEREY BIOTECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The purpose of the present invention is to provide a new preparation method of fluorine progesterone acetate, which solves many problems such as the long synthesis route of the traditional production process of fluorine progesterone acetate, large investment in equipment, expensive production raw materials, difficult sewage treatment, complicated process operation, and high production cost. technical problem

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  • Preparation method of flurogestone acetate
  • Preparation method of flurogestone acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] A. Synthetic esters

[0019] In a 2000ml three-necked bottle, add 100g 9a-fluorocortisone, 600ml toluene, stir at room temperature to dissolve, then add 80g triethylamine, cool down to 10-15°C, slowly add dropwise 40g methanesulfonyl chloride and Add the solution made of 200ml toluene within about 0.5-1.0 hours, and then keep it warm at 20-25°C for 3-4 hours. TLC confirms the reaction end point. After the reaction, add 100g of 20% caustic soda aqueous solution, Continue to stir at 20-25°C for 1-2 hours to completely destroy the acid chloride, then separate the water layer, wash it twice with 800ml of tap water, dry it with 50g of anhydrous magnesium sulfate, recover toluene under reduced pressure until it is nearly dry, and then add 10 % ethanol aqueous solution 800ml, stirred and crystallized at 5-10°C for 4-6 hours, filtered, washed, and dried to obtain esterified product: 118g of 21-O-methylsulfonyl-9a-fluorocortisone, HPLC content 98.5%, weight The yield is 118%; ...

Embodiment 2

[0025] A. Synthetic esters

[0026]In a 2000ml three-necked flask, add 100g 9a-fluorocortisone and 600ml dichloromethane, stir at room temperature to dissolve, then add 80g triethylamine, raise the temperature to 40-45°C, and slowly add 40g p-toluene dropwise Add the solution of sulfonyl chloride and 200ml toluene within 0.5-1.0 hours, and then keep it at 40-45°C for 3-4 hours, then confirm the reaction end point by TLC. After the reaction, add 100g of 20% caustic soda aqueous solution , continue stirring at 40-45°C for 1-2 hours to completely destroy the acid chloride, then cool to 20-25°C, separate the water layer, then wash with 800ml of tap water twice, dry with 50g of anhydrous magnesium sulfate, and reduce pressure Recover toluene until nearly dry, then add 800ml of 10% ethanol aqueous solution, stir and crystallize at 5-10°C for 4-6 hours, filter, wash, and dry to obtain esterified product: 21-O-methylsulfonyl-9a-fluorocortisone 138g, HPLC content 98.3%, weight yield i...

Embodiment 3

[0032] A. Synthetic esters

[0033] In a 2000ml three-neck flask, add 100g 9a-fluorocortisone, 400ml glacial acetic acid, stir at room temperature to dissolve, then add 8g p-toluenesulfonic acid, 120g acetic anhydride, heat up to 40-45°C and keep warm for reaction After 5-6 hours, TLC confirms the end point of the reaction. After the reaction, cool to 20-25°C, add 1000g of 2% sodium carbonate aqueous solution, and continue to stir and crystallize for 3-4 hours, then filter, and the filtrate is discharged into waste water after recovering acetic acid In the treatment tank, add 800ml of 10% ethanol aqueous solution to the filter cake, stir and crystallize at 5-10°C for 4-6 hours, filter, wash, and dry to obtain esterified product: 21-O-methylsulfonyl-9a-hydrocortisone 108g , HPLC content 98.5%, weight yield is 108%;

[0034] B. Synthetic fluprogesterone

[0035] In a 1000ml three-neck flask, add 100g of the esterified product obtained above, 600ml of alcohol, stir at room temp...

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Abstract

The invention discloses a preparation method of flurogestone acetate. The preparation method comprises the following steps: using 9a-cortisone bifluoride as a raw material, dissolving 9a-cortisone bifluoride into an organic solvent, and reacting with acyl chloride under the existence of an acid-binding agent to obtain a 9a-cortisone bifluoride-21-O-ester; then reacting the ester with sodium iodide and a sulfur-containing reducing agent in the organic solvent for deesterification, and synthesizing flugestone; and finally reacting the flugestone with acetylchloride or acetic anhydride in the organic solvent, and synthesizing flurogestone acetate. According to the preparation method, 9a-cortisone bifluoride is used as the raw material, flurogestone acetate is synthesized through three-step reaction of 21-site esterification, then reduction and de-esterification and finally 17-site ethyl esterification, and compared with a traditional synthetic method for using a mold removal object acquired through diosgenin processing as a raw material, the preparation method has the advantages such as wide raw material source, short synthetic route, simple, convenient and environmentally-friendly process, few invested equipment and high product yield, and the production cost in the method is reduced by 25% to 30% as compared with a traditional method; and a solvent used in the production can be recycled and circularly used, and is easy for industrial production.

Description

technical field [0001] The invention belongs to the preparation process of steroid hormone drugs, and specifically refers to a preparation method for synthesizing fluprogesterone acetate through three-step chemical reactions. Background technique [0002] Fluprogesterone acetate (molecular formula C23H31O5), chemical name: 17a, 11-dihydroxy-pregna-4-ene-3,20-dione-17 acetate, melting point 267.5°C, is a pregnane substance. Clinically, it is mainly used as a progesterone drug, and at the same time, it can be used as a fertility regulating drug for animals, especially sheep. The traditional production method of fluorine progesterone acetate is to use the diosgenin extracted from the yam plant, through six steps of chemical reaction and one step of microbial fermentation to obtain the important hormone drug intermediate - mold oxide (referred to as mold oxygen) as raw material, after 11 Esterification at the 17th position, deesterification, bromination at the 16th and 17th pos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J7/00
CPCC07J7/0045
Inventor 胡爱国甘红星左前进吴来喜
Owner HUNAN KEREY BIOTECH
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