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【结 构 式】

【药物名称】J-113863

【化学名称】1-(1-Cycloocten-1-ylmethyl)-4-(2,7-dichloroxanthen-9-ylcarboxamido)-1-ethylpiperidinium iodide

【CA登记号】202796-41-6 (cis-isomer), 202796-42-7 (trans-isomer)

【 分 子 式 】C30H37Cl2IN2O2

【 分 子 量 】655.45199

【开发单位】Banyu (Originator)

【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Chemokine CCR1 Antagonists

合成路线1

Coupling between 2,7-dichloroxanthene-9-carboxylic acid (I) and 4-amino-1-tert-butoxycarbonylpiperidine (II) in the presence of EDC and HOBt afforded amide (III). After acidic cleavage of the Boc protecting group of (III), the resulting amine (IV) was reductively condensed with 1-cyclooctene carbaldehyde (V) by means of NaBH(OAc)3 to yield the cyclooctenylmethyl amine (VI). Subsequent alkylation of the tertiary amine (VI) with iodoethane gave rise to the target ammonium salt. Separation of the geometric isomers was carried out by column chromatography.

1 Naya, A.; et al.; Design, synthesis, and discovery of a novel CCR1 antagonist. J Med Chem 2001, 44, 9, 1429.
2 Naya, A.; Owada, Y.; Saeki, T.; Ohwaki, K.; Iwasawa, Y. (Banyu Pharmaceutical Co., Ltd.); Chemokine receptor antagonists. EP 0916668; WO 9804554 .
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) 37972 2,7-dichloro-9H-xanthene-9-carboxylic acid C14H8Cl2O3 详情 详情
(II) 28414 4-Amino-1-N-Boc-piperidine; tert-butyl 4-amino-1-piperidinecarboxylate; N-Boc-4-aminopiperidine 87120-72-7 C10H20N2O2 详情 详情
(III) 37973 tert-butyl 4-[[(2,7-dichloro-9H-xanthen-9-yl)carbonyl]amino]-1-piperidinecarboxylate C24H26Cl2N2O4 详情 详情
(IV) 37974 2,7-dichloro-N-(4-piperidinyl)-9H-xanthene-9-carboxamide C19H18Cl2N2O2 详情 详情
(V) 37975 1-cyclooctene-1-carbaldehyde C9H14O 详情 详情
(VI) 37976 2,7-dichloro-N-[1-(1-cycloocten-1-ylmethyl)-4-piperidinyl]-9H-xanthene-9-carboxamide C28H32Cl2N2O2 详情 详情

合成路线2

Cyclooctanone tosylhydrazone was treated with n-BuLi and subsequently reacted with DMF to afford (II). Compound (III) was prepared from 4-tert-butoxycarbonylpiperidine by reductive alkylation with (II). Deprotection of (III) and condensation with 2,7-dichloroxanthen-9-carboxylic acid (IV) using 1,1'-carbonyldiimidazole (CDI) afforded (V). Compound (V) was quaternarized with iodoethane to provide a quaternary ammonium derivative as a mixture of two isomers (cis and trans) attributed to the 4-substituted piperidinium structure in a ratio of 2:1. Finally, the mixture was separated by silica gel column chromatography to give a major isomer, J-113863.

1 Naya, A.; et al.; Design, synthesis, and discovery of a novel CCR1 antagonist. J Med Chem 2001, 44, 9, 1429.
2 Saeki, T.; Naya, A.; J-113863. Drugs Fut 2001, 26, 2, 121.
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) 14209 Cyclooctanone 502-49-8 C8H14O 详情 详情
(II) 37975 1-cyclooctene-1-carbaldehyde C9H14O 详情 详情
(III) 41601 tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine 73874-95-0 C10H20N2O2 详情 详情
(IV) 44356 tert-butyl 1-(1-cycloocten-1-ylmethyl)-4-piperidinylcarbamate C19H34N2O2 详情 详情
(V) 37972 2,7-dichloro-9H-xanthene-9-carboxylic acid C14H8Cl2O3 详情 详情
(VI) 37976 2,7-dichloro-N-[1-(1-cycloocten-1-ylmethyl)-4-piperidinyl]-9H-xanthene-9-carboxamide C28H32Cl2N2O2 详情 详情
Extended Information