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【结 构 式】

【分子编号】58738

【品名】(1S,5S,6R)-7,7-dichloro-5-methyl-2-azabicyclo[4.1.0]heptan-3-one

【CA登记号】

【 分 子 式 】C7H9Cl2NO

【 分 子 量 】194.06

【元素组成】C 43.33% H 4.67% Cl 36.54% N 7.22% O 8.24%

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:(IX)

The condensation between methyl (R)-5-hydroxy-3-methylpentanoate (I) and 4-methoxybenzylamine (II) afforded amide (III). Swern oxidation of the alcohol function led to the corresponding aldehyde, which spontaneously evolved to the cyclic hemiaminal form (IV). Dehydration of (IV) to the tetrahydropyridinone (V) was accomplished by either heating in toluene, or by treatment with phosphoric acid in refluxing dimethyl carbonate. The bicyclic derivative (VI) was then obtained by addition of dichlorocarbene, generated from either ethyl trichloroacetate or chloroform and a base, to tetrahydropyridinone (V). Mono-dehalogenation of dichloro compound (VI) employing zinc dust and ethylenediamine provided a mixture of diastereomeric mono-chloro derivatives (VIIa-b) . After acid-promoted cleavage of the p-methoxybenzyl group, the major isomer (VIII) was isolated by selective crystallization from the reaction mixture. Alternatively, dichloro compound (VI) was first subjected to acidic p-methoxybenzyl group cleavage yielding (IX). Then, radical dehalogenation with triphenyltin hydride and AIBN produced a mixture of mono-chloro compounds, which were separated by column chromatography. Lactam (VIII) was converted to imidate (X) upon treatment with trimethyloxonium tetrafluoroborate. Optionally, the analogous ethyl imidate (XI) was prepared by a similar procedure. Treatment of imidates (X) or (XI) with either ammonia or ammonium acetate furnished the target amidine, which was finally isolated as the corresponding hydrochloride salt.

1 Kobayashi, K.; Taniguchi, N.; Naka, M. (Ono Pharmaceutical Co., Ltd.); Condensed piperidine derivs. used as a nitrogen monoxide synthase inhibitors. EP 0870763; JP 1999171866; US 6110930; US 6228866 .
2 Hashimoto, S.; Kusuda, S.; Kuwabe, S. (Ono Pharmaceutical Co., Ltd.); Process for the preparation of intermediate cpds. of drugs. EP 1188749; WO 0078722 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIIa) 58739 (1S,5S,6R,7S)-7-chloro-2-(4-methoxybenzyl)-5-methyl-2-azabicyclo[4.1.0]heptan-3-one C15H18ClNO2 详情 详情
(VIIa) 58740 (1S,5S,6R,7R)-7-chloro-2-(4-methoxybenzyl)-5-methyl-2-azabicyclo[4.1.0]heptan-3-one C15H18ClNO2 详情 详情
(I) 57410 methyl (3R)-5-hydroxy-3-methylpentanoate C7H14O3 详情 详情
(II) 15098 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine 2393-23-9 C8H11NO 详情 详情
(III) 57411 (3R)-5-hydroxy-N-(4-methoxybenzyl)-3-methylpentanamide C14H21NO3 详情 详情
(IV) 58412 N-[(E)-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-5-methylphenyl)methylidene]-N-(3-pyridinyl)amine; N-[(E)-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-5-methylphenyl)methylidene]-3-pyridinamine C20H28N2O2Si 详情 详情
(V) 57406 (4S)-1-(4-methoxybenzyl)-4-methyl-3,4-dihydro-2(1H)-pyridinone C14H17NO2 详情 详情
(VI) 57407 (1S,5S,6R)-7,7-dichloro-2-(4-methoxybenzyl)-5-methyl-2-azabicyclo[4.1.0]heptan-3-one C15H17Cl2NO2 详情 详情
(VIII) 57408 (1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]heptan-3-one C7H10ClNO 详情 详情
(IX) 58738 (1S,5S,6R)-7,7-dichloro-5-methyl-2-azabicyclo[4.1.0]heptan-3-one C7H9Cl2NO 详情 详情
(X) 57415 (1S,5S,6R,7R)-7-chloro-3-methoxy-5-methyl-2-azabicyclo[4.1.0]hept-2-ene; (1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]hept-2-en-3-yl methyl ether C8H12ClNO 详情 详情
(XI) 58741 (1S,5S,6R,7R)-7-chloro-3-ethoxy-5-methyl-2-azabicyclo[4.1.0]hept-2-ene; (1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]hept-2-en-3-yl ethyl ether C9H14ClNO 详情 详情
Extended Information