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Preparation method of Elagolix

An amino and phenethyl technology, applied in the field of Elagolix preparation, can solve the problems of long Elagolix route and difficult purification, and achieve the effect of simple and convenient purification treatment, improved purity and less side reactions

Inactive Publication Date: 2019-04-19
安徽诺全药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is: the route of conventional method synthetic Elagolix is ​​longer, and is not easy to purify

Method used

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  • Preparation method of Elagolix
  • Preparation method of Elagolix
  • Preparation method of Elagolix

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] In the reactor, 1.0 g, 1.0 equiv. of (R)-3-(2-amino-2-phenethyl)-5-(2-fluoro-3-methoxybenzene represented by formula II Base)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione was dissolved in 10 mL of dichloromethane, and 1.2 Equiv. 4-oxobutanoic acid shown in formula V, 1.0equiv. acetic acid and 3.0equiv. sodium triacetoxyborohydride, stirred and reacted at 25°C for 18h; , and saturated brine to wash the reaction solution, then dried with sodium sulfate and spin-dried the solvent, and finally obtained 0.65 equiv. Elagolix as shown in formula I by column chromatography, and its yield was 65%. Using high-resolution mass spectrometry (ESI-) detection, the detection value is 630.2039; M-H + The calculated value of the high-resolution mass spectrum is 630.2033, and the structure of the product can be confirmed by comparison.

Embodiment 2

[0027] In the reactor, 1.0 g, 1.0 equiv. of (R)-3-(2-amino-2-phenethyl)-5-(2-fluoro-3-methoxybenzene represented by formula II Base)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione was dissolved in 15 mL of dichloromethane, and 1.5 Equiv. 4-oxobutanoic acid shown in formula V, 2.0equiv. acetic acid and 3.0equiv. sodium cyanoborohydride, stirred and reacted at 25°C for 18h; The reaction solution was washed with brine, then dried with sodium sulfate and spin-dried to dry the solvent, and finally obtained 0.62 equiv. Elagolix as shown in formula I by column chromatography, and the yield was 62%. It was detected by high-resolution mass spectrometry (ESI-), and the detected value was 630.2036.

Embodiment 3

[0029] In the reactor, 1.0 g, 1.0 equiv. of (R)-3-(2-amino-2-phenethyl)-5-(2-fluoro-3-methoxybenzene represented by formula II Base)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione was dissolved in 12 mL of 1,2-dichloroethane, Add 1.0 equiv. of 4-oxobutanoic acid represented by formula V, 1.0 equiv. hydrochloric acid and 1.0 equiv. of sodium triacetoxy borohydride, and stir the reaction at 0°C for 6 h; after the reaction, The reaction solution was washed successively with 1M aqueous hydrochloric acid solution and saturated brine, then dried with sodium sulfate and spin-dried to dry the solvent, and finally 0.41 equiv. Elagolix as shown in formula I was obtained by column chromatography, and the yield was 41%. It was detected by high-resolution mass spectrometry (ESI-), and the detected value was 630.2036.

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Abstract

The invention discloses a preparation method of Elagolix. The method is characterized in that (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-diketone as shown in the formula II and 4-oxobutyric acid as shown in the formula V are subjected to a reductive amination reaction, and Elagolix as shown in the formula I is obtained; the formulas are defined in the description. The method has the advantages that a target product can be obtained through a one-step reaction, the synthetic route is greatly shortened, and the preparation process is simplified; the route has fewer side reactions, introduction of impurities is reduced, subsequent passivating treatment can be easy and convenient, and the purity of the target product is effectively improved.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and pharmaceutical intermediates, in particular to a preparation method of Elagolix. Background technique [0002] The structure of Elagolix is ​​shown in formula I. It is an oral GnRH antagonist, which can treat endometriosis by inhibiting the pituitary gonadotropin receptor, and finally reducing the gonadal hormone level in the blood circulation. Pain caused by endometriosis. [0003] [0004] According to the records of US Patent WO2009062087, Elagolix can be synthesized by the following route: [0005] [0006] It is known from the above synthetic route that the prior art has the disadvantage of a long route when synthesizing Elagolix. The multi-step synthesis leads to the introduction of impurities that are difficult to remove during the synthesis process and the process parameters are not easy to control, which in turn affects the purity of the target product. Contents of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/54
CPCC07D239/54
Inventor 胡志刚许良志何大荣杜小鹏钱祝进何勇陈越磊
Owner 安徽诺全药业有限公司
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