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Preparation method of oxragolian sodium

A technology of elagolix sodium and compounds, applied in the field of drug synthesis, which can solve the problems of low purity of intermediates, many base toxic impurities, and large amount of three wastes

Active Publication Date: 2021-04-20
ZHEJIANG LEPU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] What the present invention aims to solve is the technical problems such as complex operation, low purity of intermediates, many potential base toxic impurities, and large amount of three wastes in the existing synthesis route of elagolix sodium, and provides a simple operation, low cost and green Environmentally friendly synthetic route, suitable for large-scale production

Method used

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  • Preparation method of oxragolian sodium
  • Preparation method of oxragolian sodium
  • Preparation method of oxragolian sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The preparation of embodiment 1 compound 4

[0044] Add 10.28 g of compound 1, 18.26 g of compound 2, 9.73 g of tetramethylguanidine, and 7.6 g of DMF into the flask, raise the temperature to 50-60° C., and spot the plate to confirm the completion of the reaction. Evaporate the solvent to dryness, cool down to room temperature, add 80g of toluene, and wash with 50mL*2 1mol / L dilute hydrochloric acid. Separate layers, add 35g of concentrated hydrochloric acid to the organic phase, stir vigorously, react at 100°C until the organic phase spot plate confirms that the reaction is complete, and then slowly lower to room temperature. After stirring and crystallizing for 1 h, the filter cake was rinsed with 10 g of pre-cooled toluene and dried at 50° C. to obtain compound 4 with a yield of 95% and a purity of 99.3%.

[0045] 1 H NMR (CDCl 3)δ2.08(s, 3H), 3.90(s, 3H), 4.12(m, 1H), 4.28(m, 1H), 4.40(dd, 1H), 5.50(s, 2H), 6.75-6.85(m , 1H), 6.95-6.99(dd, 1H), 7.12(m, 1H), 7.21...

Embodiment 2

[0046] The preparation of embodiment 2 compound 4

[0047] Add 10.28g of compound 1, 18.26g of compound 2, 11.66g of potassium carbonate, and 50g of acetone into the flask, raise the temperature to 50-60°C, and spot the plate to confirm the completion of the reaction. Evaporate the solvent to dryness, cool down to room temperature, add 80g of toluene, and wash with 50mL*2 1mol / L dilute hydrochloric acid. Separate layers, add 35g of concentrated hydrochloric acid to the organic phase, stir vigorously, react at 100°C until the organic phase spot plate confirms that the reaction is complete, and then slowly lower to room temperature. After stirring and crystallizing for 1 h, the filter cake was rinsed with 10 g of pre-cooled toluene and dried at 50° C. to obtain compound 4 in a yield of 90% and a purity of 98.1%.

Embodiment 3

[0048] The preparation of embodiment 3 compound 4

[0049] Add 10.28 g of compound 1, 18.26 g of compound 2, 9.73 g of tetramethylguanidine, and 50 g of acetonitrile into the flask, raise the temperature to 50-60° C., and spot plate to confirm the completion of the reaction. Evaporate the solvent to dryness, cool down to room temperature, add 80g of toluene, and wash with 50mL*2 1mol / L dilute hydrochloric acid. Separate layers, add 35g of concentrated hydrochloric acid to the organic phase, stir vigorously, react at 100°C until the organic phase spot plate confirms that the reaction is complete, and then slowly lower to room temperature. After stirring and crystallizing for 1 h, the filter cake was rinsed with 10 g of pre-cooled toluene and dried at 50° C. to obtain compound 4 in a yield of 92% and a purity of 99.1%.

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Abstract

The invention provides a preparation method of oxagolide sodium. According to the method, the synthetic route of the oxogoliride sodium is improved, Boc protecting groups are removed by using concentrated hydrochloric acid, and then the oxogoliride sodium is salified and separated out, so that the operation is greatly simplified, and the yield is increased. When a 4-ester butyl segment is introduced, water is used as a reaction solvent, inorganic base is used as an acid-binding agent, the reaction conditions are mild and controllable, and less ammonia nitrogen wastewater is generated. The final product is obtained in an isopropanol crystallization mode, the operation is simple, and the product purity is high. The method is simple and convenient to operate, low in cost, environment-friendly and suitable for large-scale production.

Description

technical field [0001] The invention relates to a preparation method of elagolix sodium, which belongs to the technical field of medicine synthesis. Background technique [0002] Elagolix sodium is an oral GnRH antagonist jointly developed by Abbvie and its partner Neurocrine Biosciences. It inhibits the pituitary gonadotropin receptor and ultimately reduces the level of circulating gonadal hormones. On July 23, 2018, the U.S. Food and Drug Administration (FDA) approved the listing of elagolix sodium, with a trade name of Elagolix sodium is the first FDA-approved drug for the treatment of endometriosis by oral administration in more than a decade. In addition, a Phase III clinical study of the compound for the control of heavy menstrual bleeding associated with uterine fibroids is also underway. It is estimated that by 2022, the sales of elagolix sodium will reach 1.152-1.358 billion US dollars, so the development of elagolix sodium API has a good market prospect. [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/54
CPCY02P20/55
Inventor 金从阳林义颜剑波任重
Owner ZHEJIANG LEPU PHARMA CO LTD