Preparation method of altrenogest

Abstract

The invention discloses a preparation method of altrenogest, and belongs to the technical field of preparation and processing of pharmaceutical compounds. The method comprises the following steps: firstly, dissolving 3-protected estrogen-delta<5, 10>, delta<9, 11>-diene-17-one (1) in an organic solvent, and carrying out Grignard reaction to obtain 3-protected 17beta-hydroxyl-17alpha-propenyl-estra-delta<5, 10>, delta<9, 11>-diene (2); then carrying out hydrolysis reaction to obtain a dichloromethane solution of 17 beta-hydroxyl-17 alpha-propenyl estra-3-one-delta<5, 10>, delta<9, 11>-diene (3), and finally carrying out dehydrogenation reaction to obtain altrenogest. The method has the advantages of complete reaction, clear reaction complete judgment standard and few byproducts; reaction products in each step are easy to purify, the total mass yield of a final product is higher than 75%, and the purity reaches 99% or above; the method has the advantages of cheap and accessible raw materials, low cost, high operability and extremely high commercial competitiveness, is suitable for industrial large-scale production, and has favorable economic benefits.

Description

technical field

[0001] The invention relates to the technical field of preparation and processing of pharmaceutical compounds, in particular to a preparation method of tetraenestrone. Background technique

[0002] Altrenogest, also known as allylgestrol, is an orally active synthetic steroidal progestogen, which has dual properties of 19-nortestosterone and progesterone, in order to be similar to natural progesterone Mode of action to inhibit the release of gonadotropins, with unique pharmacodynamic and pharmacokinetic properties.

[0003] Tetraenestrone was first developed by Intervet, Inc. The trade name is Regu-Mate. It is used to treat animals in estrus. It has reliable effects, low adverse reactions and good tolerance. It has become a relatively good veterinary drug in the animal market.

[0004] The method and deficiency of existing synthetic tetraenyl estradiol are as follows:

[0005] (1) The early route uses trenbolone as a raw material, protects the 3-position ca...

Examples

Embodiment 1

[0035] Example 1: Preparation of 17β-hydroxyl-17α-propenyl-3-ethylenedioxyestran-5,10-diene (2) 1

[0036] Add 10 g of 3-ethylenedioxyestr-5,10-dien-17-one (1) and 150 ml of methyl tetrahydrofuran into the reaction flask, under nitrogen protection, control the temperature at -5°C, add dropwise 3M bromine 25 ml of methyl tetrahydrofuran solution of propenylmagnesium, after the reaction is completed, add saturated ammonium chloride aqueous solution, concentrate the organic solvent, collect the precipitated solid by cooling and filtering, and dry to obtain 10.1 g of 17β-hydroxyl-17α-propenyl-3-ethylene Dioxyestra-5,10-diene (2).

Embodiment 2

[0037] Example 2: Preparation 2 of 17β-hydroxyl-17α-propenyl-3-ethylenedioxyestran-5,10-diene (2)

[0038] Add 10 grams of 3-ethylenedioxyestr-5,10-dien-17-one (1) and 100 milliliters of tetrahydrofuran into the reaction flask, and add 3M chloropropenyl dropwise under nitrogen protection at a controlled temperature of -10°C. Magnesium tetrahydrofuran solution 10.6 ml, after the reaction is completed, add saturated ammonium chloride aqueous solution, concentrate the organic solvent, cool down and filter to collect the precipitated solid, and dry to obtain 10.0 g of 17β-hydroxyl-17α-propenyl-3-ethylenedioxyestradiol Steta-5,10-diene (2).

Embodiment 3

[0039] Example 3: Preparation of 17β-hydroxyl-17α-propenyl-3-bismethoxyestra-5,10-diene (2) 3

[0040] Add 10 grams of 3-bismethoxyestr-5,10-dien-17-one (1) and 200 milliliters of ether into the reaction flask, under nitrogen protection, control the temperature at 20°C, add dropwise 3M bromopropenylmagnesium Diethyl ether solution was 52.7 ml. After the reaction was completed, saturated ammonium chloride aqueous solution was added, the organic solvent was concentrated, the precipitated solid was collected by cooling and filtration, and dried to obtain 10.2 g of 17β-hydroxyl-17α-propenyl-3-bismethoxyestr-5 ,10-diene (2).

technical field

[0001] The invention relates to the technical field of preparation and processing of pharmaceutical compounds, in particular to a preparation method of tetraenestrone. Background technique

[0002] Altrenogest, also known as allylgestrol, is an orally active synthetic steroidal progestogen, which has dual properties of 19-nortestosterone and progesterone, in order to be similar to natural progesterone Mode of action to inhibit the release of gonadotropins, with unique pharmacodynamic and pharmacokinetic properties.

[0003] Tetraenestrone was first developed by Intervet, Inc. The trade name is Regu-Mate. It is used to treat animals in estrus. It has reliable effects, low adverse reactions and good tolerance. It has become a relatively good veterinary drug in the animal market.

[0004] The method and deficiency of existing synthetic tetraenyl estradiol are as follows:

[0005] (1) The early route uses trenbolone as a raw material, protects the 3-position ca...

Examples

Embodiment 1

[0035] Example 1: Preparation of 17β-hydroxyl-17α-propenyl-3-ethylenedioxyestran-5,10-diene (2) 1

[0036] Add 10 g of 3-ethylenedioxyestr-5,10-dien-17-one (1) and 150 ml of methyl tetrahydrofuran into the reaction flask, under nitrogen protection, control the temperature at -5°C, add dropwise 3M bromine 25 ml of methyl tetrahydrofuran solution of propenylmagnesium, after the reaction is completed, add saturated ammonium chloride aqueous solution, concentrate the organic solvent, collect the precipitated solid by cooling and filtering, and dry to obtain 10.1 g of 17β-hydroxyl-17α-propenyl-3-ethylene Dioxyestra-5,10-diene (2).

Embodiment 2

[0037] Example 2: Preparation 2 of 17β-hydroxyl-17α-propenyl-3-ethylenedioxyestran-5,10-diene (2)

[0038] Add 10 grams of 3-ethylenedioxyestr-5,10-dien-17-one (1) and 100 milliliters of tetrahydrofuran into the reaction flask, and add 3M chloropropenyl dropwise under nitrogen protection at a controlled temperature of -10°C. Magnesium tetrahydrofuran solution 10.6 ml, after the reaction is completed, add saturated ammonium chloride aqueous solution, concentrate the organic solvent, cool down and filter to collect the precipitated solid, and dry to obtain 10.0 g of 17β-hydroxyl-17α-propenyl-3-ethylenedioxyestradiol Steta-5,10-diene (2).

Embodiment 3

[0039] Example 3: Preparation of 17β-hydroxyl-17α-propenyl-3-bismethoxyestra-5,10-diene (2) 3

[0040] Add 10 grams of 3-bismethoxyestr-5,10-dien-17-one (1) and 200 milliliters of ether into the reaction flask, under nitrogen protection, control the temperature at 20°C, add dropwise 3M bromopropenylmagnesium Diethyl ether solution was 52.7 ml. After the reaction was completed, saturated ammonium chloride aqueous solution was added, the organic solvent was concentrated, the precipitated solid was collected by cooling and filtration, and dried to obtain 10.2 g of 17β-hydroxyl-17α-propenyl-3-bismethoxyestr-5 ,10-diene (2).

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