- Method for preparing intermediate of elagolix
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The invention relates to a method for preparing an intermediate of elagolix. In particular, the invention discloses a method for preparing a key intermediate compound E8 of elagolix, and compounds such as a compound E4 for preparing the intermediate compound E8. The method is simple and convenient in operation, mild in condition and very applicable to industrial production.
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- Method for preparing agomelatine intermediate (by machine translation)
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The invention relates to a method for preparing an intermediate of agomelatine. The method is simple and convenient to E8 operate, mild E8 in condition and very suitable for industrial production C. (by machine translation)
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- Synthetic method of elagolix
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The invention discloses a synthetic method of elagolix. The synthetic method comprises the following steps that (1) (R)-(2-(5-(2-fluoro-3-methoxyphenyl))-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-diox-3,6-dihydropyrimidin-1(2H)-yl)-1-phenethyl)tert-butyl carbamate shown in a formula II is N-alkylated with ethyl 4-bromobutyrate shown in a formula IV to obtain an intermediate shown in a formula VI; (please see the specification for the formulae); and (2) the intermediate shown in the formula VI is subjected to de-N-BOC and O-Et to obtain Elagolix shown in the formula (I).(Please see the specification for the formula). The synthetic method of Elagolix has the advantages that the synthesis route is simple, by-products are few, and purification is easy.
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Page/Page column 7-11
(2019/06/11)
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- Preparation method of Elagolix
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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.
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Paragraph 0023-0035
(2019/05/02)
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- Elagolix synthesis method
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The invention provides an elagolix synthesis method. The elagolix synthesis method comprises enabling a compound 5 and a compound 10 to participate in a condensation reaction to finish N-alkylation reaction to obtain a compound 11, and then implementing alkaline hydrolysis to obtain elagolix 12. The invention further discloses two synthesis methods of the compound 5: the method I comprises enabling a 5-bromine-6-methylpyrimidine-2,4(1H,3H)-diketone compound 1 and a 2-(brooethyl)-1-fluorin-3-(trifluoromethyl) benzene compound 2 to have a condensation reaction to obtain an intermediate 3, and then having a coupling reaction; the method II comprises enabling 1-halide-3-fluorin-2-anisole and acetoacetate 7 to have a coupling reaction to obtain a compound 8, and then having a condensation cyclization reaction with a compound 9; the improvements greatly shorten the route steps, the route efficiency is improved, the use of a noble metal catalyst is avoided, and the process cost is greatly lowered. The operation of the route is simple, the total yield is high, the purity of an obtained product is also relatively high, and the method is suitable for the enlarged production.
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- Deuterated elagolix derivative and use thereof
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The invention discloses a method for preparing a deuterated elagolix derivative. When being used as a GnRH receptor antagonist, the deuterated elagolix derivative has the use of treating disease states relevant to male and female sex hormone. The invention also discloses a composition containing the compound combined with a medicine acceptable carrier, and a method for antagonizing intraindividualgonadotropin to release hormone by using the composition.
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- PROCESSES FOR THE PREPARATION OF URACIL DERIVATIVES
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The present invention relates to processes and intermediates for preparing Gonadotropin-Releasing Hormone (GnRH) receptor antagonists of structure (VI); and stereoisomers and pharmaceutically acceptable salts thereof.
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Page/Page column 17, 18
(2009/06/27)
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- Discovery of sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6- [trifluoromethyl]-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl] -1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor
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The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl) -4-methyl-2,6-dioxo-3,6-dihy-dro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.
- Chen, Chen,Wu, Dongpei,Guo, Zhiqiang,Xie, Qiu,Reinhart, Greg J.,Madan, Ajay,Wen, Jenny,Chen, Takung,Huang, Charles Q.,Chen, Mi,Chen, Yongsheng,Tucci, Fabio C.,Rowbottom, Martin,Pontillo, Joseph,Zhu, Yun-Fei,Wade, Warren,Saunders, John,Bozigian, Haig,Struthers, R. Scott
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experimental part
p. 7478 - 7485
(2009/12/07)
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- PYRIMIDINE-2, 4-DIONE DERIVATIVES AS GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS
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GnRH receptor antagonists are disclosed that have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: wherein R1a, R1b, R1c, R2a, R2b, R3, R4, R5, R6 and X are as defined herein, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.
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