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【结 构 式】 
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【药物名称】SM-197436 【化学名称】(1R,5S,6S)-2-[4-(2,5-Dihydro-1H-pyrrol-3-yl)thiazol-2-ylsulfanyl]-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 【CA登记号】 【 分 子 式 】C17H19N3O4S2 【 分 子 量 】393.48668 |
【开发单位】Roche (Originator), Sumitomo Pharmaceuticals (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems |
合成路线1
Michael addition of ethyl acrylate (I) to glycine ethyl ester (II) produces the amino diester (III), which is protected as the allyl carbamate (IV) by treatment with allyl chloroformate. Dieckmann cyclization of diester (IV) in the presence of NaH leads to pyrrolidinone (V). After reduction of (V) to the corresponding alcohol (VI) with NaBH4, dehydration by means of methanesulfonyl chloride and pyridine furnishes the conjugated ester (VII). Acid (VIII), obtained by alkaline hydrolysis of (VII), is then condensed with magnesium tert-butyl malonate in the presence of CDI to produce keto ester (IX). Chlorination of (IX) with sulfuryl chloride, followed by acidic decarboxylation gives rise to chloro ketone (X). This is then condensed with ammonium dithiocarbamate to generate the 2-mercapto thiazole (XI)
| 【1】 Sunagawa, M.; Itoh, M.; Kubota, K.; et al.; New anti-MRSA and anti-VRE carbapenems; synthesis and structure-activity relationships of 1beta-methyl-2-(thiazol-2-ylthio)carbapenems. J. Antibiot. 2002, 55, 8, 722. |
| 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) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (II) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (III) | 61451 | ethyl 3-[(2-ethoxy-2-oxoethyl)amino]propanoate | C9H17NO4 | 详情 | 详情 | |
| (IV) | 61452 | ethyl 3-[[(allyloxy)carbonyl](2-ethoxy-2-oxoethyl)amino]propanoate | C13H21NO6 | 详情 | 详情 | |
| (V) | 61453 | 1-allyl 3-ethyl 4-oxo-1,3-pyrrolidinedicarboxylate | C11H15NO5 | 详情 | 详情 | |
| (VI) | 61454 | 1-allyl 3-ethyl 4-hydroxy-1,3-pyrrolidinedicarboxylate | C11H17NO5 | 详情 | 详情 | |
| (VII) | 61455 | 1-allyl 3-ethyl 2,5-dihydro-1H-pyrrole-1,3-dicarboxylate | C11H15NO4 | 详情 | 详情 | |
| (VIII) | 61456 | 1-[(allyloxy)carbonyl]-2,5-dihydro-1H-pyrrole-3-carboxylic acid | C9H11NO4 | 详情 | 详情 | |
| (IX) | 61457 | allyl 3-[3-(tert-butoxy)-3-oxopropanoyl]-2,5-dihydro-1H-pyrrole-1-carboxylate | C15H21NO5 | 详情 | 详情 | |
| (X) | 61458 | allyl 3-(2-chloroacetyl)-2,5-dihydro-1H-pyrrole-1-carboxylate | C10H12ClNO3 | 详情 | 详情 | |
| (XI) | 61459 | allyl 3-(2-sulfanyl-1,3-thiazol-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate | C11H12N2O2S2 | 详情 | 详情 |
合成路线2
Coupling of the carbapenem phosphate (XII) with mercaptothiazole (XI) furnishes thioether (XIII). Finally, desilylation of (XIII), followed by palladium-catalyzed removal of the allyl ester and carbamate groups provides the title compound
| 【1】 Sunagawa, M.; Itoh, M.; Kubota, K.; et al.; New anti-MRSA and anti-VRE carbapenems; synthesis and structure-activity relationships of 1beta-methyl-2-(thiazol-2-ylthio)carbapenems. J. Antibiot. 2002, 55, 8, 722. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 61459 | allyl 3-(2-sulfanyl-1,3-thiazol-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate | C11H12N2O2S2 | 详情 | 详情 | |
| (XII) | 61460 | allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C28H34NO8PSi | 详情 | 详情 | |
| (XIII) | 61461 | allyl (4R,5S,6S)-3-[(4-{1-[(allyloxy)carbonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C27H35N3O6S2Si | 详情 | 详情 |