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【结 构 式】 
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【药物名称】 【化学名称】3(S)-Amino-N-methyl-6-(1-methylguanidino)-N-(4-oxo-2-ureido-1,4,5,6-tetrahydropyrimidin-5-yl)hexanamide dihydrochloride 【CA登记号】 【 分 子 式 】C14H29Cl2N9O3 【 分 子 量 】442.35173 |
【开发单位】Bayer (Originator) 【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY |
合成路线1
The N-Boc group of the orthogonally protected beta-lysine (I) is removed by acidic treatment to provide amine (II), which is further reprotected as the trifluoroacetamide (III) by reaction with methyl trifluoroacetate. Transesterification of acid (III) with t-butyl acetate in the presence of HClO4 gives rise to the corresponding t-butyl ester (IV). Selective methylation of the trifluoroacetamide N of (IV) furnishes the N-methyl amide (V), which is subsequently hydrolyzed to the N-methyl amine (VI) under alkaline conditions. Guanidylation of amine (VI) with N,N'-bis-carbobenzoxy-1-amidinopyrazole (VII) leads to the protected guanidine (VIII). Then, acidic cleavage of the tert-butyl ester group of (VIII) provides carboxylic acid (IX)
| 【1】 Brands, M.; Endermann, R.; Gahlmann, R.; et al.; Novel antibiotics for the treatment of gram-positive bacterial infections. J Med Chem 2002, 45, 19, 4246. |
| 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) | 62268 | (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoic acid | C19H28N2O6 | 详情 | 详情 | |
| (II) | 62269 | (3S)-6-amino-3-{[(benzyloxy)carbonyl]amino}hexanoic acid | C14H20N2O4 | 详情 | 详情 | |
| (III) | 62270 | (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(2,2,2-trifluoroacetyl)amino]hexanoic acid | C16H19F3N2O5 | 详情 | 详情 | |
| (IV) | 62271 | tert-butyl (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(2,2,2-trifluoroacetyl)amino]hexanoate | C20H27F3N2O5 | 详情 | 详情 | |
| (V) | 62272 | tert-butyl (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[methyl(2,2,2-trifluoroacetyl)amino]hexanoate | C21H29F3N2O5 | 详情 | 详情 | |
| (VI) | 62273 | tert-butyl (3S)-3-{[(benzyloxy)carbonyl]amino}-6-(methylamino)hexanoate | C19H30N2O4 | 详情 | 详情 | |
| (VII) | 60787 | C6H10N4 | 详情 | 详情 | ||
| (VIII) | 62274 | tert-butyl (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[({[(benzyloxy)carbonyl]amino}{[(benzyloxy)carbonyl]imino}methyl)(methyl)amino]hexanoate | C36H44N4O8 | 详情 | 详情 | |
| (IX) | 62275 | (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[({[(benzyloxy)carbonyl]amino}{[(benzyloxy)carbonyl]imino}methyl)(methyl)amino]hexanoic acid | C32H36N4O8 | 详情 | 详情 |
合成路线2
Acid (IX) is coupled with the amino pyrimidinone derivative (X) using HATU to produce amide (XI). Finally, hydrogenolysis of the carbobenzoxy groups of (XI) in the presence of PdCl2 gives rise to the title compound
| 【1】 Brands, M.; Endermann, R.; Gahlmann, R.; et al.; Novel antibiotics for the treatment of gram-positive bacterial infections. J Med Chem 2002, 45, 19, 4246. |
| 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) | 62275 | (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[({[(benzyloxy)carbonyl]amino}{[(benzyloxy)carbonyl]imino}methyl)(methyl)amino]hexanoic acid | C32H36N4O8 | 详情 | 详情 | |
| (X) | 62276 | N-[5-(methylamino)-4-oxo-1,4,5,6-tetrahydro-2-pyrimidinyl]urea | C6H11N5O2 | 详情 | 详情 | |
| (XI) | 62277 | benzyl (E)-[((4S)-6-[{2-[(aminocarbonyl)amino]-4-oxo-1,4,5,6-tetrahydro-5-pyrimidinyl}(methyl)amino]-4-{[(benzyloxy)carbonyl]amino}-6-oxohexyl)(methyl)amino]{[(benzyloxy)carbonyl]amino}methylidenecarbamate | C38H45N9O9 | 详情 | 详情 |