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Synthesis method of elagolix intermediate

A synthetic method, the technology of Eragoli, which is applied in the field of medicine and chemical industry, can solve the problems of low industrialization value, low atomic economy, and high cost, and achieve high utilization of atomic economy, easy availability of raw materials, and reduced process costs Effect

Active Publication Date: 2020-02-07
SHANGHAI VASTPRO TECH DEV CO LTD
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0007] The construction of 6-methylpyrimidinedione in this route is the second step and the third step, the total yield is 60%, and the yield is low
Moreover, the reagents used in the ring-closing step are all at 15 equivalents, and the atom economy is low
After the construction of 6-methylpyrimidinedione is completed, the introduction of subsequent side chains requires heavy metal-catalyzed coupling reactions, which greatly increases the cost
However, the bromination step before it requires column chromatography preparation, so the industrial value of this route is not high

Method used

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  • Synthesis method of elagolix intermediate
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  • Synthesis method of elagolix intermediate

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preparation example Construction

[0077] The present invention provides a kind of synthetic method of elagolix intermediate compound X, and described method comprises steps:

[0078]

[0079] (a) in an inert solvent, compound VI is subjected to a cyclization reaction with 1-[1-(dimethylamino)ethylene]-2-methylthiourea salt to form compound VII;

[0080] (b) subjecting compound VII to a hydrolysis reaction to form compound VIII;

[0081] (c) in an inert solvent, compound VIII is subjected to an amino-protection reaction with an amino-protecting reagent, thereby forming compound IX;

[0082] (d) first in an inert solvent, in the presence of a base, compound IX and 2-trifluoromethyl-6-fluoro-benzyl bromide are subjected to a condensation reaction; after the condensation reaction is completed, the mixture containing the condensation product is subjected to acidic conditions The amino group deprotection reaction is carried out, thereby forming the elagolix intermediate compound X.

[0083] The present inventio...

Embodiment 1

[0121] Add 2-fluoroanisole (85.0 g, 0.67 mol), tetrahydrofuran (3540 mL), tetramethylethylenediamine (78.3 g, 0.67 mol) into a three-necked flask at room temperature, replace with nitrogen three times, start stirring, and cool down to -50 ~-78°C, add sec-butyllithium solution (870mL, 1.3M) dropwise, keep stirring for 2-3 hours after the dropwise addition, add N,N-dimethylformamide (67.5g, 0.92mol) dropwise, keep warm Stir for 1 hour, after the reaction is completed, add 13% acetic acid aqueous solution (1464g) dropwise at -50~-78°C, separate the layers, extract the aqueous phase with ethyl acetate (350mL*3), combine the organic phases, wash with water (500mL) and then 1N After washing with hydrochloric acid, the organic phase was concentrated until there was no liquid drop to obtain a light yellow mixture, which was crystallized from methyl tert-butyl ether (150 mL) to obtain a white solid, which was dried to obtain compound II (57.7 g, 57.3%). 1 HNMR-(300MHz, CDCl 3 )δ, 10.3...

Embodiment 2

[0123] Add compound II (104.8g, 0.68mol) and sodium borohydride (13.0g, 0.34mol) to a three-necked flask at room temperature, add methanol (1000mL), and stir at 15-50°C for 0.5-1.5 hours. After the reaction, 5% dilute hydrochloric acid aqueous solution was added dropwise to the system, extracted with ethyl acetate, separated, the organic phase was washed with saturated brine, and the organic phase was concentrated until no liquid was evaporated to obtain compound III (107.0 g, 100%). 1 HNMR-(300MHz, CDCl 3 )δ: 7.05-7.07 (m, 1H), 6.99-7.01 (s, 1H), 6.92-6.94 (m, 1H), 4.76 (s, 2H), 3.89 (s, 3H).

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Abstract

The invention relates to a synthesis method of an elagolix intermediate. Specifically, the invention provides a synthesis method of an elagolix intermediate compound X and an elagolix intermediate compound I. According to the method, 2-fluoro-3-methoxy-phenylacetic acid is used as a raw material, and the steps of cyclization, hydrolysis, amino protection, condensation, Mitsunobu reaction and the like are carried out in sequence, so that the elagolix intermediate compound X and the elagolix intermediate compound I are obtained. The method has the advantages of cheap and easily available reagents, high conversion rate, simple operation and low process cost, and is suitable for industrialization.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a synthesis method of a novel oral GnRH antagonist elagolix intermediate. Background technique [0002] Elagolix, chemical name: (R)-4-[[2-[5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoro Methyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl]amino]butanoic acid derived from Developed in collaboration with Abbvie and Neurocrine Biosciences. Is an oral gonadotropin-releasing hormone receptor antagonist, by inhibiting the pituitary gonadotropin-releasing hormone receptor, ultimately reducing the level of gonadal hormones in the blood circulation. AbbVie submitted the NDA for the drug in September 2017, obtained the FDA priority review qualification more than a month later, and was approved by the FDA on July 23, 2018. The trade name is Orilissa, which is used to treat the Pain caused by endometriosis, and it has become the f...

Claims

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Application Information

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IPC IPC(8): C07D239/54
CPCC07D239/54
Inventor 郭朋吉长友王俊张栋梁寿山朱文峰
Owner SHANGHAI VASTPRO TECH DEV CO LTD
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