【结 构 式】 |
【分子编号】34568 【品名】tert-butyl (Z)-[(tert-butoxycarbonyl)amino][4-[1-[(tert-butoxycarbonyl)amino]-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1-piperidinyl]methylidenecarbamate 【CA登记号】 |
【 分 子 式 】C26H41N5O7S 【 分 子 量 】567.70704 【元素组成】C 55.01% H 7.28% N 12.34% O 19.73% S 5.65% |
合成路线1
该中间体在本合成路线中的序号:(X)The condensation of 1-(benzyloxycarbonyl)piperidin-4-one with N-(tert-butoxycarbonyl)-2-phosphonoglycine trimethyl ester (II) by means of DBU in dichloromethane gives 2-[1-(benzyloxycarbonyl)piperidin-4-ylidene]-N-(tert-butoxycarbonyl)glycine methyl ester (III), which is selectively deprotected and reduced by hydrogenation with H2 over Pd/C in methanol yielding N-(tert-butoxycarbonyl)-2-(4-piperidyl)glycine methyl ester (IV). The reaction of (IV) with N,N'-di(tert-butoxycarbonyl)pyrazole-1-carboxamidine (V) by means of DIEA in dichloromethane gives the protected piperidine-1-carboxamidine (VI), which is treated with LiOH in methanol/water to obtain (VII) with a free carboxy group. The reaction of (VII) with O,N-dimethylhydroxylamine affords the hydroxamic ester (VIII), which is condensed with thiazole (IX) by means of butyllithium in THF yielding the fully protected intermediate (X). The deprotection of (X) with HCl in dioxane gives (XI) with free amino and amidino groups. The conddensation of (XI) with chiral acid (XII) by means of BOP and DIEA in acetonitrile yields amide (XIII) as a diastereomeric mixture that is resolved by preparative reverse-phase HPLC.
【1】 Plummer, J.S.; Berryman, K.A.; Cai, C.; Cody, W.L.; DiMaio, J.; Doherty, A.M.; Edmunds, J.J.; He, J.X.; Holland, D.R.; Levesque, S.; Kent, D.R.; Narasimhan, L.S.; Rubin, J.R.; Rapundalo, S.T.; Siddiqui, M.A.; Susser, A.J.; St-Denis, Y.; Winocour, P.D.; Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications. Bioorg Med Chem Lett 1998, 8, 23, 3409. |
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) | 26947 | benzyl 4-oxo-1-piperidinecarboxylate; N-Benzyloxycarbonyl-4-piperidone | 19099-93-5 | C13H15NO3 | 详情 | 详情 |
(II) | 34562 | methyl 2-[(tert-butoxycarbonyl)amino]-2-(dimethoxyphosphoryl)acetate | C10H20NO7P | 详情 | 详情 | |
(III) | 34563 | benzyl 4-[1-[(tert-butoxycarbonyl)amino]-2-methoxy-2-oxoethylidene]-1-piperidinecarboxylate | C21H28N2O6 | 详情 | 详情 | |
(IV) | 34564 | methyl 2-[(tert-butoxycarbonyl)amino]-2-(4-piperidinyl)acetate | C13H24N2O4 | 详情 | 详情 | |
(V) | 29482 | N,N-bis-Boc-1-guanylpyrazole; tert-butyl (E)-[(tert-butoxycarbonyl)amino](1H-pyrazol-1-yl)methylidenecarbamate | 152120-54-2 | C14H22N4O4 | 详情 | 详情 |
(VI) | 34565 | methyl 2-[(tert-butoxycarbonyl)amino]-2-(1-[[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]-4-piperidinyl)acetate | C24H42N4O8 | 详情 | 详情 | |
(VII) | 34566 | 2-[(tert-butoxycarbonyl)amino]-2-(1-[[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]-4-piperidinyl)acetic acid | C23H40N4O8 | 详情 | 详情 | |
(VIII) | 34567 | tert-butyl (Z)-[(tert-butoxycarbonyl)amino](4-[1-[(tert-butoxycarbonyl)amino]-2-[methoxy(methyl)amino]-2-oxoethyl]-1-piperidinyl)methylidenecarbamate | C25H45N5O8 | 详情 | 详情 | |
(IX) | 23000 | 1,3-thiazole | 288-47-1 | C3H3NS | 详情 | 详情 |
(X) | 34568 | tert-butyl (Z)-[(tert-butoxycarbonyl)amino][4-[1-[(tert-butoxycarbonyl)amino]-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1-piperidinyl]methylidenecarbamate | C26H41N5O7S | 详情 | 详情 | |
(XI) | 34569 | 4-[1-amino-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1-piperidinecarboximidamide | C11H17N5OS | 详情 | 详情 | |
(XII) | 34570 | (6S,8aS)-4-oxo-2-(3-phenylpropanoyl)octahydropyrrolo[1,2-a]pyrazine-6-carboxylic acid | C17H20N2O4 | 详情 | 详情 | |
(XIII) | 34571 | (6S,8aS)-N-[1-[1-[amino(imino)methyl]-4-piperidinyl]-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-4-oxo-2-(3-phenylpropanoyl)octahydropyrrolo[1,2-a]pyrazine-6-carboxamide | C28H35N7O4S | 详情 | 详情 |