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Preparation of progestational hormone

A technology of dienogest and its compound, which is applied in the field of preparation of dienogest, can solve the problems of compound 1 difficult to obtain, harsh reaction conditions, difficult industrialization, etc., and achieve the effect of good effect, mild conditions, and easy industrialization

Active Publication Date: 2009-01-28
TIANJIN PHARMA GROUP CORP
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Problems solved by technology

However, this method also has some disadvantages: First, it is difficult to obtain compound 1, because it needs to obtain the aromatic ring A of estrone through Birch reduction, the reaction conditions are harsh, and the yield is also very low
However, on the current route of synthesizing dienogest, the main problem is that it is not easy to be industrialized

Method used

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  • Preparation of progestational hormone
  • Preparation of progestational hormone
  • Preparation of progestational hormone

Examples

Experimental program
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Effect test

Embodiment 1

[0070] The synthesis of embodiment one dienogest

[0071] (1) Estro-4,9(10)-diene-3,17-dione-3,3-ethylidene ketone thiol (formula VI):

[0072] Add 10g of estro-4,9-diene-3,17-dione (Pharmaceutical Industry, 1985, 16(9):15-18) and 100ml of methanol into the reaction flask, blow nitrogen, stir, add 4ml of hydroxyethylene dione Mercaptan and 5ml boron trifluoride etherate, react at 25±2°C for 2h, distill off methanol, dissolve the residue in dichloromethane, wash with saturated aqueous sodium bicarbonate, wash with water, concentrate the separated organic layer, and Crystallization in cyclohexane gave the expected product 11.9 g estra-4,9(10)-diene-3,17-dione-3,3-ethylidene ketone mercaptan; IR: 3033 (v=CH ), 2926 (vCH 3 ), 2881 (vCH 2 ), 1735(vC=O), 1638(vC=C), 1062(vC-O-C); H-NMR, 0.88(18-CH 3 ), 3.33 (-S-CH 2 ), 3.99 (-O-CH 2 ), 5.59(4-H);

[0073](2) 17β-spiro-1′, 2′-oxirane-estra-4,9(10)-diene-3-ketone-3,3-ethylidene ketone thiol (formula VII ): under nitrogen, add ...

Embodiment 2

[0081] The synthesis of embodiment two dienogest

[0082] (1) Estra-4,9(10)-diene-3,17-dione-3,3-ethanethiol ketal (formula IX):

[0083] Add 10g of estro-4,9-diene-3,17-dione and 50ml of dichloromethane into the reaction flask, blow nitrogen, stir, and add 10g of NaHSO 4 .SiO 2 (Synthesis 2005, 2, 250-254), add 8ml of ethanethiol, react at 25±2°C for 1h, filter, wash the filtrate with saturated aqueous sodium bicarbonate, wash with water, concentrate the separated organic layer, and Crystallization in the medium obtained the expected product 12.3g estro-4,9(10)-diene-3,17-dione-3,3-ethanethiol ketal;

[0084] IR: 3035 (v=CH), 2928 (vCH 3 ), 2885 (vCH 2 ), 1735 (vC=O), 1639 (vC=C);

[0085] H-NMR, 0.89 (18-CH 3 ), 0.97 (-CH on ethyl sulfide 3 ), 3.30 (-S-CH 2 ), 5.58(4-H);

[0086] (2) 17β-spiro-1′, 2′-oxirane-estro-4,9(10)-dien-3-one-3,3-ethanethiol ketal (Formula X):

[0087] Under nitrogen, add 6g of sodium methoxide to the reaction flask, add 70ml of tetrahydrofu...

Embodiment 3

[0098] The synthesis of embodiment three dienogest

[0099] (1) Estro-4,9(10)-diene-3,17-dione-3,3-ethylene ketone thiol:

[0100] Add 10g of estro-4,9-diene-3,17-dione and 70ml of dioxane into the reaction flask, blow nitrogen, stir, add 4ml of ethanedithiol and 5ml of boron trifluoride etherate, 25±2 React at ℃ for 2 h, distill out dioxane, dissolve the residue in dichloromethane, wash with saturated aqueous sodium bicarbonate solution, wash with water, concentrate the separated organic layer, and crystallize in cyclohexane to obtain 11.5 g of the expected product Estro-4,9(10)-diene-3,17-dione-3,3-ethylidene ketone thioketal;

[0101] IR: 3029 (v=CH), 2926 (vCH 3 ), 2879 (vCH 2 ), 1736 (vC=O), 1635 (vC=C);

[0102] H-NMR, 0.87 (18-CH 3 ), 3.20-3.40 (-S-CH 2 -CH 2 -S-), 5.59(4-H);

[0103] (2) 17β-spiro-1′, 2′-oxirane-estra-4,9(10)-dien-3-one-3,3-ethylidene thioketal:

[0104]Under nitrogen, add 7g of sodium ethoxide to the reaction flask, add 100ml of dimethylforma...

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Abstract

The invention relates to a method for preparing sterides progestational hormone compound, in particular to the preparation of dienogest. The invention provides a novel method for synthesizing the dienogest, wherein, the dienogest is obtained after female sterides-4,9-diene-3,17-diketone which is served as a starting material is subjected to a 3-ketone group protective reaction, a 17- ketone group epoxy ethide reaction, a cyanation and a deprotection reaction. In the process route, raw materials can be easily obtained, and the cost is lower. Therefore, the dienogest is easy to be industrially produced.

Description

technical field [0001] The present invention relates to a preparation method of steroid progesterone compound, especially relates to the preparation of dienogest. Background technique [0002] Dienogest is a very useful progestogenic compound that potently suppresses gonadotropin and testosterone levels in healthy men without side effects. "Possibly the best drug candidate in male contraceptive clinical trials". Dienogest 2mg+estradiol valerate 2mg compound product of German Schering Company can be used as a continuous compound hormone replacement therapy drug for the treatment of postmenopausal symptoms; another contraceptive product dienogest 2.mg and ethinyl estradiol Alcohol 50μg compound was also listed in Germany as early as 1995. [0003] Dienogest research and development began in the 1970s. So far, there are more than a dozen articles about its synthesis, and the main process routes are as follows: [0004] People such as Ponsold published many documents in the ...

Claims

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Application Information

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IPC IPC(8): C07J1/00
CPCY02P20/55
Inventor 丁丽李金禄陈立营
Owner TIANJIN PHARMA GROUP CORP
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