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【结 构 式】

【分子编号】42003

【品名】N-(5-bromo-2-pyridinyl)-N'-[(1S,2S)-2-(6-fluoro-2-methoxy-3-propionylphenyl)cyclopropyl]urea

【CA登记号】

【 分 子 式 】C19H19BrFN3O3

【 分 子 量 】436.2806832

【元素组成】C 52.31% H 4.39% Br 18.31% F 4.35% N 9.63% O 11%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XIV)

3-Fluorophenol (I) was converted into propionic ester (II) by treatment with propionyl chloride and pyridine. Fries rearrangement of (II) in the presence of AlCl3 furnished propiophenone (III). The phenolic hydroxyl group of (III) was then protected as the methyl ether (IV) using iodomethane and K2CO3. The keto group of (IV) was subsequently protected as the ethylene ketal (V) by treatment with ethylene glycol and p-toluenesulfonic acid. Lithiation of (V) with n-butyllithium in THF at -65 C, followed by formylation with N,N-dimethylformamide yielded aldehyde (VI). Styrene derivative (VII) was obtained by Wittig reaction of aldehyde (VI) with methylene triphenylphosphorane. Asymmetric cyclopropanation of (VII) with ethyl diazoacetate in the presence of cuprous triflate and the chiral auxiliary (VIII) gave the desired (1S,2R)-cis ester (IX) along with some trans isomer, that was separated by column chromatography. After ketal (IX) hydrolysis with HCl, the resulting keto ester (X) was saponified with LiOH to provide cyclopropanecarboxylic acid (XI). Curtius rearrangement of acid (XI) employing diphenylphosphoryl azide produced isocyanate (XII), which was subsequently condensed with 2-amino-5-bromopyridine (XIII) to afford urea (XIV). The methyl ether group of (XIV) was finally cleaved to the title phenol by means of boron trichloride in CH2Cl2.

1 Sahlberg, C.; Engelhardt, P.; Hogberg, M.; et al.; Urea-PETT compounds as a new class of HIV-1 reverse transcriptase inhibitors.3.Synthesis and further structure-activity relationship studies of PETT analogues. J Med Chem 1999, 42, 20, 4150.
2 Noreen, R.; Hogberg, M.; Engelhardt, P.; Sahlberg, C. (Medivir AB); Antivirals. WO 9936406 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 23809 3-fluorophenol 372-20-3 C6H5FO 详情 详情
(II) 41992 3-fluorophenyl propionate C9H9FO2 详情 详情
(III) 41993 1-(4-fluoro-2-hydroxyphenyl)-1-propanone C9H9FO2 详情 详情
(IV) 41994 1-(4-fluoro-2-methoxyphenyl)-1-propanone C10H11FO2 详情 详情
(V) 41995 2-ethyl-2-(4-fluoro-2-methoxyphenyl)-1,3-dioxolane; 2-(2-ethyl-1,3-dioxolan-2-yl)-5-fluorophenyl methyl ether C12H15FO3 详情 详情
(VI) 41996 3-(2-ethyl-1,3-dioxolan-2-yl)-6-fluoro-2-methoxybenzaldehyde C13H15FO4 详情 详情
(VII) 41997 6-(2-ethyl-1,3-dioxolan-2-yl)-3-fluoro-2-vinylphenyl methyl ether; 2-ethyl-2-(4-fluoro-2-methoxy-3-vinylphenyl)-1,3-dioxolane C14H17FO3 详情 详情
(VIII) 41998 (4R)-4-(tert-butyl)-2-[1-[(4R)-4-(tert-butyl)-4,5-dihydro-1,3-oxazol-2-yl]-1-methylethyl]-4,5-dihydro-1,3-oxazole C17H30N2O2 详情 详情
(IX) 41999 ethyl (1S,2R)-2-[3-(2-ethyl-1,3-dioxolan-2-yl)-6-fluoro-2-methoxyphenyl]cyclopropanecarboxylate C18H23FO5 详情 详情
(X) 42000 ethyl (1S,2R)-2-(6-fluoro-2-methoxy-3-propionylphenyl)cyclopropanecarboxylate C16H19FO4 详情 详情
(XI) 42001 (1S,2R)-2-(6-fluoro-2-methoxy-3-propionylphenyl)cyclopropanecarboxylic acid C14H15FO4 详情 详情
(XII) 42002 1-[4-fluoro-3-[(1S,2S)-2-isocyanatocyclopropyl]-2-methoxyphenyl]-1-propanone C14H14FNO3 详情 详情
(XIII) 12123 5-Bromo-2-pyridinylamine; 5-Bromo-2-pyridinamine; 2-Amino-5-bromopyridine 1072-97-5 C5H5BrN2 详情 详情
(XIV) 42003 N-(5-bromo-2-pyridinyl)-N'-[(1S,2S)-2-(6-fluoro-2-methoxy-3-propionylphenyl)cyclopropyl]urea C19H19BrFN3O3 详情 详情
Extended Information