- AN IMPROVED PROCESS FOR THE PREPARATION OF 4-({(1 R)-2-[5-(2-FLUORO-3METHOXYPHENYL)-3-{[2-FLUORO-6-(TRIFLUORO METHYL) PHENYL]METHYL}-4-METHYL-2,6-DIOXO-3,6DIHYDROPYRIMIDIN-1(2 H)-YL]-1-PHENYLETHYL}AMINO)BUTANOIC ACID OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention relates to an improved process for the preparation of 4- ({(1R) -2- [5- (2-fluoro- 3- methoxy phenyl) – 3 - {[ 2-fluoro- 6-(trifluoro methyl) phenyl] methyl} -4-methyl- 2,6-dioxo- 3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino) butanoic acid of formula (I) or its pharmaceutically acceptable salts. The compound of formula (I) is represented by the following structural formula.
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- Preparation method of oxlagrel intermediate
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The invention relates to a preparation method of an oxlagrel intermediate. The preparation method comprises the following steps: dissolving a 2-fluoro-6-(trifluoromethyl)benzyl bromide compound 7 in an aprotic polar solvent, then adding alkali carbonate and urea, carrying out a heating reaction under stirring, and after the reaction is finished, carrying out post-treatment and recrystallization toobtain a compound 4, the yield being 89-95 wt%; and dissolving the compound 4 prepared in the step (1) into the aprotic polar solvent; then, adding a 2-bromoacetoacetic acid ethyl ester compound 9, and cooling to 3 DEG C or below, adding bromo-organosilane while stirring, then continuing to stir and react at 80 DEG C or below, and after the reaction is finished, carrying out aftertreatment and recrystallization to obtain the target product 5-bromo-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methylpyrimidine (1H, 3H)-2,4-diketone compound 1, the yield being 75-88 wt%. The method is simple in synthetic route and simple and convenient in post-treatment mode.
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Paragraph 0055-0064
(2020/12/10)
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- Substituted pyrimidine-2, 4(1H, 3H)-dione derivative and uses thereof
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The invention belongs to the technical field of medicines, and relates to a substituted pyrimidine-2, 4(1H, 3H)-dione derivative and uses thereof, and a pharmaceutical composition containing the compound. The derivative and the pharmaceutical composition can be used as gonadotropin releasing hormone receptor antagonists. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and uses of the compound and the pharmaceutical composition in prevention or treatment of sex hormone dependent diseases including but not limited to prostate cancer, endometriosis, hysteromyoma, precocious puberty and the like.
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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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Paragraph 0042; 0043; 0044
(2018/10/11)
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- PROCESS FOR THE PREPARATION OF ELAGOLIX AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention relates to a process for the preparation of Elagolix of formula (I) and its pharmaceutically acceptable salts. The present invention also relates to an intermediate of formula (VIII) and its use in preparation of Elagolix and its pharmaceutically acceptable salts.
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Page/Page column 12; 13
(2018/11/22)
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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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- 5-Aryluracils as potent GnRH antagonists-Characterization of atropisomers
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Optimization of a series of uracils bearing a 2-fluoro- or 2-chloro-3-methoxyphenyl group at the 5-position resulted in compounds such as 3d and 3f with subnanomolar binding affinity at the human GnRH receptor. While the 2-fluoro-3-methoxyphenyl compound 3a was characterized as a mixture of interchangeable atropisomers, the diastereoisomers of 2-chloro-3-methoxyphenyl analogs were separated. It was found that the aR-atropisomer was much more potent than the aS-isomer based on the X-ray crystal structure of 3h-II.
- Zhao, Liren,Guo, Zhiqiang,Chen, Yongsheng,Hu, Tao,Wu, Dongpei,Zhu, Yun-Fei,Rowbottom, Martin,Gross, Timothy D.,Tucci, Fabio C.,Struthers, R. Scott,Xie, Qiu,Chen, Chen
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scheme or table
p. 3344 - 3349
(2009/04/11)
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- URACIL-TYPE GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS AND METHODS RELATED THERETO
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Compounds having utility as GnRH receptor antagonists and for treatment of a variety of sex-hormone related conditions in both men and women. Such compounds have the following structure (I): (I) wherein R1a, R1b, R1c, R2a, R2b, R3, R4, R5, R6, R7, n and X are as defined herein, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of structure (I) 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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- 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 formula (I) wherein R1a, R1b, R2a, R2b, R3, R4, R5, R6, R7 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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- 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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- GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS AND METHODS RELATING THERETO
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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 n, 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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