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【结 构 式】

【分子编号】31629

【品名】2-bromo-2-cyclopropylacetonitrile

【CA登记号】

【 分 子 式 】C5H6BrN

【 分 子 量 】160.01338

【元素组成】C 37.53% H 3.78% Br 49.94% N 8.75%

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:(VI)

The reaction of 3-chlorotetrafluoropyridine (I) with sodium tert-butoxide in THF gives 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine (II), which is dechlorinated with H2 over Pearlman's catalyst in methanol yielding 4-(tert-butoxy)-2,3,6-trifluoropyridine (III). The methylation of (III) with methyl iodide and lithium diethylamide (LDA) in THF affords 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine (IV), which is treated with hydrazine in refluxing propanol to give 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine (V). The condensation of (V) with 2-bromo-2-cyclopropylacetopnitrile (VI) by means of LDA in THF yields the expected condensation product (VII), which is treated with TFA to eliminate the tert-butyl protecting group and with POCl3 in DMF to afford the 4-chloropyridyl derivative (VIII). The hydrolysis of the nitrile group of (VIII) with HCl in ethanol gives the corresponding acetate ester (IX), which is reduced with LiAlH4 in THF to the alcohol (X). The oxidation of (X) with oxalyl chloride in DMSO/dichloromethane yields the aldehyde (XI), which is cyclized with diethyl malonate (XII) by means of piperidine in refluxing acetic acid, followed by heating at 220 C C in Dowtherm to afford 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (XIII). The condensation of (XIII) with 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XIV) by means of triethylamine in DMF gives the expected condensation product (XV), which is methylated with methyl iodide and sodium hexamethyldisylazane (Na-HMDS) in THF yielding the N-methyl derivative (XVI). The hydrolysis of the ester group of (XVI) with LiOH in THF/water provides the corresponding free acid (XVII), which is finally deprotected with HCl in acetic acid. The synthesis of the intermediate 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XIV) has already been described in the first synthesis of compound no. 268134 (see scheme 26813401a).

1 Or, Y.S.; Armiger, Y.-L.; Fung, A. (Abbott Laboratories Inc.); Pyridone antibiotic with improved safety profile. US 5977133; WO 0010998 .
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) 16189 (2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoic acid C10H8O3S 详情 详情
(II) 16820 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine; tert-butyl 3-chloro-2,5,6-trifluoro-4-pyridinyl ether C9H9ClF3NO 详情 详情
(III) 16821 4-(tert-butoxy)-2,3,6-trifluoropyridine; tert-butyl 2,3,6-trifluoro-4-pyridinyl ether C9H10F3NO 详情 详情
(IV) 16822 tert-butyl 2,3,6-trifluoro-5-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine C10H12F3NO 详情 详情
(V) 16823 tert-butyl 2,5-difluoro-3-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine C10H13F2NO 详情 详情
(VI) 31629 2-bromo-2-cyclopropylacetonitrile C5H6BrN 详情 详情
(VII) 16825 2-[4-(tert-butoxy)-5-fluoro-3-methyl-2-pyridinyl]-2-cyclopropylacetonitrile C15H19FN2O 详情 详情
(VIII) 16826 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile C11H10ClFN2 详情 详情
(IX) 16827 ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetate C13H15ClFNO2 详情 详情
(X) 31627 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropyl-1-ethanol C11H13ClFNO 详情 详情
(XI) 16828 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde C11H11ClFNO 详情 详情
(XII) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XIII) 16831 ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate C16H15ClFNO3 详情 详情
(XIV) 15193 tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate C11H20N2O2 详情 详情
(XV) 26950 ethyl 8-[(7S)-7-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate C27H34FN3O5 详情 详情
(XVI) 16951 (1R)-1-[(4S,5R)-2,2-dimethyl-5-[(E)-1-tetradecenyl]-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanol C40H54O4 详情 详情
(XVII) 31628 8-[(7S)-7-[(tert-butoxycarbonyl)(methyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid C26H32FN3O5 详情 详情
Extended Information