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【结 构 式】 
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【药物名称】Tigemonam, SQ-30213 【化学名称】3beta(S)-[2-(2-Aminothiazol-4-yl)-2(Z)-(carboxymethoxyimino)acetamido]-1-hydroxy-2,2-dimethylazetidin-4-one hydrogen sulfate ester 【CA登记号】102507-71-1, 102916-21-2 (dicholine salt) 【 分 子 式 】C12H15N5O9S2 【 分 子 量 】437.40945 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】Monobactams |
合成路线1
The reaction of N-(tert-butoxycarbonyl)-3-hydroxyvaline (I) with O-benzylhydroxylamine (II) by means of hydroxybenzotriazole (HBT) and dicyclohexylcarbodiimide (DCC) in THF gives the corresponding benzyloxyamide (III), which is treated with the pyridine.SO3 complex (IV) in pyridine to yield N-(tert-butoxycarbonyl)-3-(sulfooxy)-N2-(benzyloxy)valinamide (V). The cyclization of (V) by means of K2CO3 in ethyl acetate - water affords 1-(benzyloxy)-3-(tert-butoxycarbonylamino)-4,4-dimethylazetidin-2-one (VI), which is debenzylated by hydrogenation with H2 over Pd/C in methanol to give the N-hydroxyazetidine (VII). The reaction of (VII) with the sulfonating complex (IV) affords the 1-azetidinyl sulfuric ester (VIII), which is deprotected by reaction with trifluoroacetic acid in anisole - dichloromethane yielding 3-amino-4,4-dimethyl-2-oxoazetidinyl-1-sulfate (IX). The condensation of (IX) with 2-(2-aminothiazol-4-yl)-2(Z)-(diphenylmethoxycarbonylmethoxyimino)acetic acid (X) by means of diphenyl chlorophosphate (PCP) and triethylamine in DMF gives the diphenylmethyl ester (XI) of the final product, which is finally deprotected by hydrolysis with trifluoroacetic acid and anisole.
| 【1】 Slusarchyk, W.A.; Dejneka, T.; Kostes, W.H. (Bristol-Myers Squibb Co.); Preparation of 4,4-dialkyl-2-azetidinones. AU 8652460; BE 090411; DE 3602347; ES 8706112; ES 8800897; FR 2576596; GB 2170201; US 4638061 . |
| 【2】 Gurney, J.D.; Prous, J.; Castaner, J.; TIGEMONAM < Rec INN >. Drugs Fut 1989, 14, 10, 966. |
| 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) | 21366 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-methylbutyric acid | C10H19NO5 | 详情 | 详情 | |
| (II) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (III) | 21368 | tert-butyl (1S)-1-[[(benzyloxy)amino]carbonyl]-2-hydroxy-2-methylpropylcarbamate | C17H26N2O5 | 详情 | 详情 | |
| (V) | 21369 | (5S)-9,9-dimethyl-5-[1-methyl-1-(sulfoperoxy)ethyl]-4,7-dioxo-1-phenyl-2,8-dioxa-3,6-diazadecane | C17H26N2O9S | 详情 | 详情 | |
| (VI) | 21370 | tert-butyl (3S)-1-(benzyloxy)-2,2-dimethyl-4-oxoazetidinylcarbamate | C17H24N2O4 | 详情 | 详情 | |
| (VII) | 21371 | tert-butyl (3S)-1-hydroxy-2,2-dimethyl-4-oxoazetidinylcarbamate | C10H18N2O4 | 详情 | 详情 | |
| (VIII) | 21372 | tert-butyl (3S)-2,2-dimethyl-4-oxo-1-(sulfoperoxy)azetidinylcarbamate | C10H18N2O8S | 详情 | 详情 | |
| (IX) | 21373 | (3S)-3-amino-4,4-dimethyl-1-(sulfoperoxy)-2-azetidinone | C5H10N2O6S | 详情 | 详情 | |
| (X) | 21374 | 2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(benzhydryloxy)-2-oxoethoxy]imino]acetic acid | C20H17N3O5S | 详情 | 详情 | |
| (XI) | 21375 | benzhydryl 2-[[((Z)-1-(2-amino-1,3-thiazol-4-yl)-2-[[(3S)-2,2-dimethyl-4-oxo-1-(sulfoperoxy)azetidinyl]amino]-2-oxoethylidene)amino]oxy]acetate | C25H25N5O10S2 | 详情 | 详情 |