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【结 构 式】 
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【药物名称】 【化学名称】2-(Benzyloxycarboxamido)-3-[4-[2-[3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl]acetamidomethyl]piperidin-1-yl]propionic acid 【CA登记号】247254-24-6 【 分 子 式 】C34H41N5O7 【 分 子 量 】631.73517 |
【开发单位】Aventis Pharma (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Cell Adhesion Inhibitors, Integrin alpha4beta1 (VLA-4) Antagonists |
合成路线1
Selective protection of the secondary amino group of 4-(aminomethyl)piperidine (I) was achieved via conversion to imine (III) upon condensation with benzaldehyde (II), followed by treatment with di-tert-butyl dicarbonate to afford carbamate (IV). Subsequent acid hydrolysis of the imine function of (IV) furnished the mono-protected diamine (V). Coupling of amine (V) with 3-methoxy-4-(3-o-tolylureido)phenylacetic acid (VI) using HATU furnished amide (VII). Acidic cleavage of the N-Boc protecting group of (VII) gave piperidine (VIII). Aziridine (X) was prepared from ethyl 2,3-dibromopropionate (IX) by treatment with ammonia in acetonitrile. Condensation of (X) with N-(benzyloxycarbonyloxy)succinimide produced the benzyl carbamate (XI). Regioselective ring opening of the aziridine (XI) with piperidine (VIII) yielded adduct (XII). The ethyl ester group of (XII) was finally hydrolyzed to the target carboxylic acid under basic conditions.
| 【1】 Astles, P.C.; et al.; Diamine containing VLA-4 antagonists. Bioorg Med Chem 2001, 9, 8, 2195. |
| 【2】 McCarthy, C.; Morley, A.D.; Harris, N.V. (Rhone-Poulenc Rorer Ltd.); Substd. diamines and their use as cell adhesion inhibitors. WO 9954321 . |
| 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) | 19349 | 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine | 7144-05-0 | C6H14N2 | 详情 | 详情 |
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 19351 | N-[(E)-benzylidene]-N-(4-piperidinylmethyl)amine; N-[(E)-benzylidene](4-piperidinyl)methanamine | C13H18N2 | 详情 | 详情 | |
| (IV) | 49958 | tert-butyl 4-([[(E)-benzylidene]amino]methyl)-1-piperidinecarboxylate | C18H26N2O2 | 详情 | 详情 | |
| (V) | 19352 | 4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate | 144222-22-0 | C11H22N2O2 | 详情 | 详情 |
| (VI) | 39718 | 2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetic acid | C17H18N2O4 | 详情 | 详情 | |
| (VII) | 49959 | tert-butyl 4-[[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]methyl]-1-piperidinecarboxylate | C28H38N4O5 | 详情 | 详情 | |
| (VIII) | 49960 | 2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]-N-(4-piperidinylmethyl)acetamide | C23H30N4O3 | 详情 | 详情 | |
| (IX) | 18341 | ethyl 2,3-dibromopropanoate | 3674-13-3 | C5H8Br2O2 | 详情 | 详情 |
| (X) | 49961 | ethyl 2-aziridinecarboxylate | C5H9NO2 | 详情 | 详情 | |
| (XI) | 49962 | 1-benzyl 2-ethyl 1,2-aziridinedicarboxylate | C13H15NO4 | 详情 | 详情 | |
| (XII) | 49963 | ethyl 2-[[(benzyloxy)carbonyl]amino]-3-(4-[[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]methyl]-1-piperidinyl)propanoate | C36H45N5O7 | 详情 | 详情 |