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Preparation method of tibolone

A technology for tibolone and intermediates, applied in the field of preparation of tibolone, can solve the problems of high pollution in the production process, high cost of raw materials, long reaction route, etc., and achieve high production cost, few reaction steps, and low environmental pollution Effect

Inactive Publication Date: 2020-11-17
ZHEJIANG SHENZHOU PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] In order to solve the problems of high raw material cost, long reaction route, difficult purification, low total yield and large pollution in the production process in the above-mentioned existing tibolone preparation process, the present invention provides a simple purification, high yield and low pollution The preparation method of tibolone

Method used

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  • Preparation method of tibolone

Examples

Experimental program
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Effect test

Embodiment 1

[0034] The preparation of embodiment 1 tibolone

[0035] Step 1: Under nitrogen protection, add 2.5g of cuprous chloride and 1M methylmagnesium iodide to 500ml of tetrahydrofuran solution in 500ml of tetrahydrofuran, add 50g of 6,7-didehydronorethindrone (1) under low temperature stirring at -20°C Carry out the reaction, after thin-layer chromatographic analysis shows that the conversion of the raw materials is complete, the reaction solution is added to 750ml of 5% hydrochloric acid aqueous solution, 250ml of dichloromethane is added for extraction, the organic layer is washed with water until neutral, concentrated, filtered, and dried to obtain 42.5g of the intermediate (2);

[0036] Step 2: Under nitrogen protection, add 42.5g of the above-mentioned intermediate (2) to 600ml of methanol, add 0.5g of pyridinium hydrobromide and 42.5g of boron trifluoride diethyl ether, and stir at 40°C for reaction. TLC analysis shows that the raw material After the conversion was complete,...

Embodiment 2

[0038] The preparation of embodiment 2 tibolone

[0039]Step 1: Under the protection of argon, add 5g of copper chloride and 340ml of ether solution of 3M methylmagnesium bromide to 1500ml of ether, add 50g of 6,7-didehydronorethindrone (1) under low temperature stirring at -30°C to carry out Reaction, after thin-layer chromatographic analysis shows that raw material conversion is complete, reaction solution is joined in 1500ml10% sulfuric acid aqueous solution, adds 1000ml ethyl acetate to extract, washes organic layer to neutrality, concentrates, filters, oven dry, obtains 43.1g intermediate ( 2);

[0040] Step 2: Under nitrogen protection, add 43.1g of the above intermediate (2) to 400ml of methanol, add 8g of malonic acid and 25g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt Acetate (EDCI), stirred and reacted at 20°C, and after thin-layer chromatography analysis showed that the conversion of the raw materials was complete, 4.5ml of pyridine was added, cooled to -...

Embodiment 3

[0042] The preparation of embodiment 3 tibolone

[0043] Step 1: Under the protection of nitrogen, add 25g of copper acetate and 330ml of tetrahydrofuran solution of 5M methylmagnesium chloride to 2500ml of methyl tetrahydrofuran, and add 50g of 6,7-didehydronorethindrone (1) under low-temperature stirring at -40°C for reaction. Thin-layer chromatography analysis showed that the conversion of the raw materials was complete, the reaction solution was added to 1200ml of 30% acetic acid aqueous solution, 1500ml of toluene was added for extraction, the organic layer was washed with water until neutral, concentrated, filtered, and dried to obtain 42.7g of intermediate (2);

[0044] Step 2: Under nitrogen protection, add 42.7g of the above intermediate (2) to 50ml of methanol and 600ml of cyclohexane, add 1.3g of benzenesulfonic acid, reflux dehydration and stir the reaction, after thin-layer chromatography analysis shows that the conversion of the raw materials is complete, add 2ml...

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Abstract

The invention discloses a preparation method of tibolone, and belongs to the technical field of preparation and processing of steroid hormone drugs. According to the method, 6,7-didehydronorethindroneis used as an initial raw material, and tibolone is prepared through Grignard reaction, dietherification reaction and hydrolysis reaction. The 7-methyl introduction step is included in the Grignard reaction step in the synthesis route, so that special protection on 17-site hydroxyl is avoided, and the ratio of the 7-alpha methyl intermediate to the 7-beta methyl isomer obtained through the reaction is larger than 20:1; therefore, the single 7-alpha methyl intermediate can be obtained through simple treatment without chromatographic separation, the purification process is simple, and the purity of the final product reaches 99.0% or above, and the yield is higher than 60%; the raw materials are cheap and easily available, the reaction steps are few, the reaction conditions are mild and safe, and the control operation is easy; in addition, reagents used in the reaction are low in environmental pollution, and good economic and social benefits are achieved.

Description

technical field [0001] The invention relates to the technical field of preparation and processing of steroid hormone drugs, in particular to a preparation method of tibolone. Background technique [0002] Tibolone, chemical name 17β-hydroxy-7α-methyl-19-norpregna-5(10)-en-20-yn-3-one, has androgenic activity and weak progestational Hormone activity, has obvious anabolic effect, can prevent postmenopausal menopausal syndrome such as women's osteoporosis, relieve facial flushing, sweating and other menopausal symptoms, belongs to anabolic hormone and androgen drugs, and is used to treat menopause and postmenopause syndrome. [0003] Recl.Trav.Chim.Pays-Bas 105-111 (1986) has reported a kind of synthetic method of tibolone, is starting raw material with diester thing, through Grignard, hydrolysis, oxidation, chromatographic separation, dealdehyde, 3 - position protection, alkynylation, hydrolysis to obtain the final product tibolone, the synthetic route is as follows: [000...

Claims

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Application Information

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IPC IPC(8): C07J1/00
CPCC07J1/0096
Inventor 邵振平王荣王炳乾王洪福黄橙橙雷灵芝王友富
Owner ZHEJIANG SHENZHOU PHARMA
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