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【结 构 式】 
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【分子编号】50387 【品名】methyl (2S)-2-azetidinecarboxylate 【CA登记号】 |
【 分 子 式 】C5H9NO2 【 分 子 量 】115.132 【元素组成】C 52.16% H 7.88% N 12.17% O 27.79% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Reduction of the phenyl ring of N-(tert-butoxycarbonyl)-(R)-phenylglycine (VI) with H2 over Rh/Al2O3 in methanol gives the protected (R)-cyclohexylglycine (VII), which is condensed with azetidine (VIII) by means of EDC in acetonitrile to yield the dipeptide (IX). Hydrolysis of the ester group of (IX) affords the carboxylic acid (X), which is condensed with the amino group of the previous intermediate (V) by means of EDC and DMAP in acetonitrile or ethyl acetate/acetonitrile to provide adduct (XI). Cleavage of the Boc-protecting group of (XI) with HCl or methanesulfonic acid gives (XII) with a terminal amino group that is condensed with benzyl 2-(2-nitrophenylsulfonyloxy)acetate (XIII) or benzyl 2-bromoacetate (XIV) by means of K2CO3 in the same solvent to yield the melagatran precursor (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol.
| 【1】 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Melagatran and Ximelagatran. Drugs Fut 2001, 26, 12, 1155. |
| 【2】 Antonsson, K.T.; Bylund, R.E.; Gustafsson, N.D.; Nilsson, N.O.I. (AstraZeneca plc); New peptide derivs.. EP 0701568; JP 1996511018; JP 2001322974; US 5602253; US 5723444; WO 9429336 . |
| 【3】 Hedstrom, L.; Lundblad, A.; Nagard, S. (AstraZeneca AB); A substantially crystalline form of melagatran. WO 0102426 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 50386 | benzyl [4-(aminomethyl)phenyl](imino)methylcarbamate | C16H17N3O2 | 详情 | 详情 | |
| (VI) | 22613 | (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid | 2900-27-8 | C13H17NO4 | 详情 | 详情 |
| (VII) | 35619 | (2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoic acid | C13H23NO4 | 详情 | 详情 | |
| (VIII) | 50387 | methyl (2S)-2-azetidinecarboxylate | C5H9NO2 | 详情 | 详情 | |
| (IX) | 50388 | tert-butyl (1R)-1-cyclohexyl-2-[(2S)-2-[(methylamino)carbonyl]azetidinyl]-2-oxoethylcarbamate | C18H31N3O4 | 详情 | 详情 | |
| (X) | 50389 | (2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]-2-azetidinecarboxylic acid | C17H28N2O5 | 详情 | 详情 | |
| (XI) | 50376 | benzyl [4-([[((2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]azetidinyl)carbonyl]amino]methyl)phenyl](imino)methylcarbamate | C33H43N5O6 | 详情 | 详情 | |
| (XII) | 50390 | benzyl (4-[[([(2S)-1-[(2R)-2-amino-2-cyclohexylethanoyl]azetidinyl]carbonyl)amino]methyl]phenyl)(imino)methylcarbamate | C28H35N5O4 | 详情 | 详情 | |
| (XIII) | 50391 | benzyl 2-[[(2-nitrophenyl)sulfonyl]oxy]acetate | C15H13NO7S | 详情 | 详情 | |
| (XIV) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XV) | 50392 | benzyl 2-[((1R)-2-[(2S)-2-[([4-[[[(benzyloxy)carbonyl]amino](imino)methyl]benzyl]amino)carbonyl]azetidinyl]-1-cyclohexyl-2-oxoethyl)amino]acetate | C37H43N5O6 | 详情 | 详情 |