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【结 构 式】 
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【药物名称】 【化学名称】N-[4-Chloro-2-[N-(5-chloropyridin-2-yl)carbamoyl]phenyl]-1-isopropylpiperidine-4-carboxamide 【CA登记号】280771-57-5, 280769-08-6 (HCl) 【 分 子 式 】C21H24Cl2N4O2 【 分 子 量 】435.35703 |
【开发单位】Lilly (Originator) 【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Coagulation Factor Xa Inhibitors |
合成路线1
The condensation between 5-chloro-2-nitrobenzoyl chloride (I) and 2-amino-5-chloropyridine (II) produced the corresponding amide (III). Subsequent catalytic hydrogenation of the nitro group of (III) gave aniline (IV). Acid chloride (VI), prepared from N-Boc-isonipecotic acid (V) and oxalyl chloride, was then coupled to aniline (IV) to furnish amide (VII). Further trifluoroacetic acid-promoted cleavage of the Boc protecting group of (VII) yielded piperidine (VIII). Finally, reductive alkylation with acetone in the presence of sodium triacetoxyborohydride gave rise to the target N-isopropyl piperidine.
| 【1】 Kyle, J.A.; et al.; SAR investigations of N-aryl-2-[(piperidin-4-ylcarbonyl)amino]benzamide factor Xa inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 288. |
| 【2】 Aromatic amides. WO 0039118 . |
| 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) | 44133 | 5-chloro-2-nitrobenzoyl chloride | C7H3Cl2NO3 | 详情 | 详情 | |
| (II) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (III) | 44134 | 5-chloro-N-(5-chloro-2-pyridinyl)-2-nitrobenzamide | C12H7Cl2N3O3 | 详情 | 详情 | |
| (IV) | 44135 | 2-amino-5-chloro-N-(5-chloro-2-pyridinyl)benzamide | C12H9Cl2N3O | 详情 | 详情 | |
| (V) | 17404 | 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid; 1-BOC-piperidine-4-carboxylic acid; N-Boc-isonipecotic acid | 84358-13-4 | C11H19NO4 | 详情 | 详情 |
| (VI) | 44136 | tert-butyl 4-(chlorocarbonyl)-1-piperidinecarboxylate | C11H18ClNO3 | 详情 | 详情 | |
| (VII) | 44137 | tert-butyl 4-[(4-chloro-2-[[(5-chloro-2-pyridinyl)amino]carbonyl]anilino)carbonyl]-1-piperidinecarboxylate | C23H26Cl2N4O4 | 详情 | 详情 | |
| (VIII) | 44138 | N-(4-chloro-2-[[(5-chloro-2-pyridinyl)amino]carbonyl]phenyl)-4-piperidinecarboxamide | C18H18Cl2N4O2 | 详情 | 详情 |
合成路线2
An alternative preparation for the title compound consisted in the reductive alkylation of ethyl isonipecotate (IX) with acetone to afford the N-isopropyl isonipecotate (X). After basic hydrolysis of the ethyl ester group of (X), the resulting carboxylic acid (XI) was activated as the mixed anhydride (XII) with isobutyl chloroformate. Anhydride (XII) was finally coupled to aniline (IV) to generate the required amide.
| 【1】 Aromatic amides. WO 0039118 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 17410 | Ethyl isonipecotate; ethyl 4-piperidinecarboxylate | 1126-09-6 | C8H15NO2 | 详情 | 详情 |
| (X) | 44139 | ethyl 1-isopropyl-4-piperidinecarboxylate | C11H21NO2 | 详情 | 详情 | |
| (XI) | 44140 | 1-isopropyl-4-piperidinecarboxylic acid | C9H17NO2 | 详情 | 详情 | |
| (XII) | 44141 | C14H25NO4 | 详情 | 详情 | ||
| (XIII) | 44135 | 2-amino-5-chloro-N-(5-chloro-2-pyridinyl)benzamide | C12H9Cl2N3O | 详情 | 详情 |