【结 构 式】 |
【分子编号】68011 【品名】methyl 4-bromobutanoate 【CA登记号】4897-84-1 |
【 分 子 式 】C5H9BrO2 【 分 子 量 】181.02926 【元素组成】C 33.17% H 5.01% Br 44.14% O 17.68% |
合成路线1
该中间体在本合成路线中的序号:(XIIa)Reduction of 2-fluoro-6-(trifluoromethyl)benzonitrile (I) with BH3/THF in refluxing THF gives the benzylamine derivative (II), which by treatment with urea in the presence of HCl in refluxing water yields N-[2-fluoro-6-(trifluoromethyl)benzyl]urea (III). Cyclization of the urea (III) with diketene (IV) by means of NaI and TMSCl in acetonitrile provides the pyrimidine-2,4-dione derivative (V), which is then brominated with Br2 in AcOH to afford the 5-bromopyrimidine-2,4-dione derivative (VI). N-Alkylation of intermediate (VI) with N-Boc-D-phenylglycinol (VII) by means of PPh3 and DBAD in THF gives the 3-[2(R)-amino-2-phenylethyl]pyrimidine-2,4-dione derivative (VIII), which upon Suzuki condensation with 2-fluoro-3-methoxyphenylboronic acid (IX) in the presence of Na2CO3 and Pd(PPh3)4 in H2O/dioxane at 90 °C yields the 5-(2-fluoro-3-methoxyphenyl)pyrimidine-2,4-dione derivative (X). Deprotection of the N-protected benzylamine (X) by means of TFA in CH2Cl2 affords the benzylamine derivative (XI), which is finally N-alkylated with methyl (XIIa) or ethyl (XIIb) 4-bromobutyrate and DIEA or Et3N, respectively, in refluxing acetonitrile and the resulting methyl or ethyl esters, (XIIIa) or (XIIIb), saponified with NaOH or LiOH in THF/H2O or MeOH/H2O at 45-50 °C .
【1】 Chen, C., Wu, D., Guo, Z. et al. 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-phenylethylaminobutyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor. J Med Chem 2008, 51(23):7478-85. |
【2】 Guo, Z., Chen, Y., Chen, C. et al. (Neurocrine Biosciences, Inc.). Pyrimidine-2,4-dione derivatives as gonadotropin-releasing hormone receptor antagonists. EP 1646389, JP 2007521309, JP 2011088902, US 2005038057, US 7056927, WO 200500765. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XI) | 68008 | (R)-3-(2-amino-2-phenylethyl)-5- (2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6- (trifluoromethyl)benzyl)-6-methylpyrimidine-2,4 (1H,3H)-dione | C28H24F5N3O3 | 详情 | 详情 | |
(XIIa) | 68011 | methyl 4-bromobutanoate | 4897-84-1 | C5H9BrO2 | 详情 | 详情 |
(XIIb) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
(XIIIa) | 68009 | (R)-methyl 4-((2-(5-(2- fluoro-3-methoxyphenyl)-3-(2-fluoro-6- (trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3- dihydropyrimidin-1(6H)-yl)-1-phenylethyl)amino) butanoate | C33H32F5N3O5 | 详情 | 详情 | |
(XIIIb) | 68010 | (R)-ethyl 4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl) benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1 (6H)-yl)-1-phenylethyl)amino)butanoate | C34H34F5N3O5 | 详情 | 详情 | |
(I) | 67999 | 2-fluoro-6-(trifluoromethyl)benzonitrile | 133116-83-3 | C8H3F4N | 详情 | 详情 |
(II) | 68000 | (2-fluoro-6-(trifluoromethyl)phenyl)methanamine | 239087-06-0 | C8H7F4N | 详情 | 详情 |
(III) | 68001 | 1-(2-fluoro-6-(trifluoromethyl)benzyl)urea;N-[2-fluoro-6-(trifluoromethyl)benzyl]urea | 830346-46-8 | C9H8F4N2O | 详情 | 详情 |
(IV) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
(V) | 68002 | 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione | C13H10F4N2O2 | 详情 | 详情 | |
(VI) | 68003 | 5-bromo-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione | C13H9BrF4N2O2 | 详情 | 详情 | |
(VII) | 68004 | (R)-tert-butyl (2-hydroxy-1-phenylethyl)carbamate | 102089-74-7 | C13H19NO3 | 详情 | 详情 |
(VIII) | 68006 | (R)-tert-butyl (2-(5-bromo-3-(2-fluoro-6- (trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3- dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate | C26H26BrF4N3O4 | 详情 | 详情 | |
(IX) | 68005 | 2-fluoro-3-methoxyphenylboronic acid | 352303-67-4 | C7H8BFO3 | 详情 | 详情 |
(X) | 68007 | (R)-tert-butyl (2-(5-(2-fluoro-3- methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl) benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1 (6H)-yl)-1-phenylethyl)carbamate | C33H32F5N3O5 | 详情 | 详情 |