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【结 构 式】 
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【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 |