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Delmadinone acetate preparation method

A technology of equigesterone acetate and dimaprogesterone, which is applied in the fields of organic chemistry methods, steroids, organic chemistry, etc., and can solve the problems of many side reactions, many impurities, and high production costs

Inactive Publication Date: 2019-02-22
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When preparing Dimagestrol acetate at last, adopt DDQ to make Dimagestrol acetate 1-position dehydrogenation in dioxane, environmental protection is also difficult to handle, there is side effect in the whole process. There are many problems such as many reactions, many impurities, low product purity, difficult environmental protection treatment, high production cost, etc.

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0052] A: Preparation of Hydroxycyanide

[0053] In a 1000ml three-necked flask, add 100g of starting material IDD and 250ml of acetone cyanohydrin, control the temperature to 40~45℃, stir to completely dissolve the IDD, then control the temperature at 20~25℃, slowly add 2% carbonic acid dropwise Sodium-alkali aqueous solution, drip for about 2-2.5 hours, and then keep it at 25~30℃ to react for 2~3 hours. TLC confirms the end of the reaction. After the reaction, concentrate under reduced pressure to recover 90-95% of the solvent acetone cyanohydrin. The temperature of the substance is lowered to 20-25℃, and then 500ml of tap water is added for water analysis, filtered, and the filtrate is sent to the wastewater treatment station for treatment. The filter cake is crystallized with 500ml of 40% alcohol aqueous solution to obtain 98.6g of cyanide, HPLC content of 98.2%, weight yield 98.6%.

[0054] B: Preparation of 1,6-didehydro-17a-hydroxyprogesterone

[0055] In a 1000ml three-neck...

Embodiment 2

[0064] A: Preparation of Hydroxycyanide

[0065] In a 1000ml three-necked flask, add 100g starting materials IDD, 50ml acetone cyanohydrin, 500ml methanol, control the temperature to 40~45℃, stir to completely dissolve the IDD, then control the temperature at 20~25℃, slowly add 2 % Sodium hydroxide aqueous solution, drip in about 2-2.5 hours, then keep at 25~30℃ and react for 2-3 hours. TLC confirms the end of the reaction. After the reaction, concentrate under reduced pressure to recover 90-95% methanol and acetone The mixed solvent of cyanohydrin is used, the residue is cooled to 20~25℃, and then 500ml of tap water is added for water precipitation, filtered, and the filtrate is sent to the wastewater treatment station for treatment. The filter cake is crystallized with 500ml of 40% alcoholic water solution to obtain 97.8g of hydroxycyanide. The HPLC content is 98.5%, and the weight yield is 97.8%.

[0066] B: Preparation of 1,6-didehydro-17a-hydroxyprogesterone

[0067] In a 1000...

Embodiment 3

[0076] A: Preparation of Hydroxycyanide

[0077] In a 1000ml three-necked flask, add 100g starting materials IDD, 50ml acetone cyanohydrin, 500ml DME, control the temperature to 40~45℃, stir to completely dissolve the IDD, then control the temperature at 20~25℃, slowly add 2% dropwise The solution of triethylamine alkali solution is dripped in about 2-2.5 hours, and then kept at 25~30℃ to react for 2~3 hours. TLC confirms the end of the reaction. After the reaction, concentrate under reduced pressure to recover 90-95% of DME and acetone cyanide Alcohol mixed solvent is used, the residue is cooled to 20~25℃, and then 500ml tap water is added for precipitation, filtered, and the filtrate is sent to the wastewater treatment station for treatment. The filter cake is crystallized with 500ml 40% alcohol aqueous solution to obtain 96.2g of hydroxycyanide, HPLC The content is 98.2%, and the weight yield is 96.2%.

[0078] B: Preparation of 1,6-didehydro-17a-hydroxyprogesterone

[0079] In ...

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Abstract

The invention provides a delmadinone acetate preparation method which comprises the following steps: by taking 1,4-androstadienedione, that is, IDD, as a raw material, firstly, enabling 17-site ketonein IDD molecules to react with acetone cyanohydrins in a first organic solvent under catalysis of an alkali, and introducing beta-hydroxyl and alpha-cyan into the 17-site so as to obtain hydroxyl cyanogens; preparing 1,6-bidehydrogenation-17a-hydroxyl progesterone from the hydroxyl cyanogens in the presence of methyl magnesium halide, a second organic solvent and an acid; and further synthesizinga 6-site epoxy substance, further synthesizing 6-site chloride so as to obtain delmadinone, and finally carrying out 17-site esterification, thereby obtaining delmadinone acetate. Compared with a conventional synthesis method, the delmadinone acetate preparation method provided by the invention has multiple advantages of being simple and convenient in process operation, economic and environmental-friendly in production, high in total synthesis yield, high in product quality, low in production cost, and the like.

Description

Technical field [0001] The invention belongs to the preparation process of a steroid hormone medicine, and specifically relates to a preparation method of a progesterone medicine dimagestrol acetate and its intermediate dimagestrol. Background technique [0002] Dimagestrol acetate, chemical name: 6-chloro-17a-acetoxy-pregnant-1,4,6-,triene-3,20-dione, is a highly effective progesterone drug with It has a strong milk-promoting effect and is mainly used clinically to promote milk-ejection during breastfeeding for fertile women with poor milk-ejection. It is most widely used in cattle and sheep breeding to promote milk cows and sheep milk. Because of its good effect and low side effects, it has a broad market application prospect. The traditional production method of dimagestrone acetate is based on 17a hydroxyprogesterone as raw material, diacetylated with acetic anhydride, chlorinated with bleaching powder, etherified with triethyl orthoformate, and DDQ (or tetrachlorobenzoquino...

Claims

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Application Information

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IPC IPC(8): C07J7/00C07J41/00C07J71/00
CPCC07B2200/07C07J7/0045C07J41/0094C07J71/001
Inventor 吴来喜胡爱国甘红星
Owner HUNAN KEREY BIOTECH
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