The preparation method of nomegestrol acetate

A technology of nomegestrol acetate and norgegestrel acetate, which is applied in the field of preparation of steroid hormone drugs, can solve the problems of low rearrangement reaction yield, harsh reaction conditions, high production cost, etc., and achieve low production cost and comprehensive synthetic route The effect of shortening and reducing production cost

Inactive Publication Date: 2020-04-21
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 solve the problems of existing nomegestrol acetate production technology with low efficiency, many side reactions, low rearrangement reaction yield, high production cost and environmental pollution, and avoid the reaction caused by Vickers reaction in the traditional production process. There are many disadvantages such as harsh conditions, especially avoiding many shortcomings such as many impurities, low efficiency, and high cost caused by the 6-position catalytic transposition reaction

Method used

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  • The preparation method of nomegestrol acetate
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Examples

Experimental program
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Effect test

Embodiment 1

[0033] A, the preparation of bisketal

[0034] In a 1000ml three-neck flask, add 100g norgestrel acetate, 600ml dichloromethane, 50g ethylene glycol, 80ml triethyl orthoformate, 2g p-toluenesulfonic acid, keep warm at 25-30°C and stir for 12-16 hours. TLC detects 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 to recover 90-95% of dichloromethane, then add 600ml of tap water, stir and crystallize at 10-15°C After 3-4 hours, centrifuge and wash with water to obtain the crude product of bisketal. The above-mentioned crude product is not baked, directly added to 800ml of 50% alcohol, first refluxed for 1-1.5 hours, and then about 400ml of alcohol is evaporated under normal pressure, and then The system was cooled to -5-0°C, stirred and crystallized for 2-3 hours, suction filtered, washed with a small amount of ethanol, and the filter cake was dried below 70°C to obtain 1...

Embodiment 2

[0042] A, the preparation of bisketal

[0043] In a 1000ml three-neck flask, add 100g norgestimate acetate, 600ml toluene, 50g ethylene glycol, 80ml triethyl orthoformate, 2g 98% sulfuric acid, keep warm at 25-30°C and stir for 12-16 hours, TLC detection At 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, recover 90-95% of toluene, then add 600ml of tap water, stir and crystallize at 10-15°C for 3-4 hours , centrifuged and washed with water to obtain the crude product of bisketal. The above crude product is not baked, directly added to 800ml of 50% alcohol, first refluxed for 1-1.5 hours, then steamed out about 400ml of alcohol at normal pressure, then cooled the system to -5-0°C, stirred and crystallized for 2-3 hours, Suction filtration, washing with a small amount of ethanol, and drying of the filter cake below 70°C yielded 116.8 g of bisketal product with an HPLC conte...

Embodiment 3

[0051] A, the preparation of bisketal

[0052] In a 1000ml three-necked flask, add 100g norgestrel acetate, 600ml dichloromethane, 50g ethylene glycol, 80ml triethyl orthoformate, 10g ethanol solution of hydrochloric acid, keep warm at 25~30℃ 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 and wash with water to obtain the crude product of bisketal. The above crude product is not baked, directly added to 800ml of 50% alcohol, first refluxed for 1-1.5 hours, then steamed out about 400ml of alcohol at normal pressure, then cooled the system to -5-0°C, stirred and crystallized for 2-3 hours, pumped Filter, wash with a small amount of ethanol, and dry the filter cake below 70°C to obtain 116.2 g of bisketal, wi...

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Abstract

The invention discloses a preparation method of nomegestrol acetate. The method comprises that gestonorone acetate as a raw material is dissolved in an organic solvent and then undergoes a reaction with ethylene glycol under acid catalysis in the presence of triethyl orthoformate to produce diketal, the diketal is dissolved in an organic solvent and undergoes a reaction with hydrogen peroxide under alkali catalysis to produce an epoxy compound, the epoxy compound is dissolved in an organic solvent and undergoes a Grignard addition reaction with methylmagnesium halide, the reaction product is hydrolyzed in a strong acid solution and is subjected to dehydration deprotection so that a methyl compound is obtained, and the methyl compound is dissolved in an organic solvent and undergoes a dehydrogenation reaction with tetrachloro-p-benzoquinone to produce nomegestrol acetate. The nomegestrol acetate has HPLC content of 99.0-99. 5% and a four-step synthesis total yield of 60-62%. Compared with the traditional method, the method has the advantages of simple and convenient operation, economy, environmental friendliness, high total synthesis yield and good product quality and reduces a costby 35-40%. The solvent used by the method can be recovered and recycled and is conducive to industrial production.

Description

technical field [0001] The invention belongs to the preparation process of steroid hormone drugs, and in particular relates to the preparation method of the progesterone drug nomegestrol acetate. Background technique [0002] Nomegestrol acetate, chemical name: 6-methyl-17a-acetoxy-19-nor-pregna-4,6-diene-3,20-dione, is a high-efficiency progestogen drug . Clinically, it is mainly used to treat female endometriosis, and is also used to produce female contraceptives. Its 2mg subcutaneous implant is used for female contraception. The validity period is as long as 6 months, and the effective rate is almost 100%. Its effect in treating female endometriosis is about 60 times that of progesterone. Due to its good curative effect and low side effects, it has broad market application prospects. The traditional production method of nomegestrol acetate, as described in USP4,544,555, uses norgestimate acetate as a raw material, undergoes etherification at the 3-position, Vickers reac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J7/00C07C53/08C07C51/41
Inventor 胡爱国甘红星谢来宾吴来喜
Owner HUNAN KEREY BIOTECH
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