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【结 构 式】 
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【分子编号】38604 【品名】benzhydryl (6R,7R)-7-([3-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-oxopropanoyl]amino)-7-methoxy-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 【CA登记号】 |
【 分 子 式 】C47H42N6O9S 【 分 子 量 】866.95152 【元素组成】C 65.12% H 4.88% N 9.69% O 16.61% S 3.7% |
合成路线1
该中间体在本合成路线中的序号：(XXVII)The reaction of the amino group of (XIX) with 3,5-di-tert-butyl-4-hydroxybenzaldehyde (XX) gives the imine (XXI), which is dehydrogenated with nickel peroxide to the quinomethane (XXII). Addition of methanol to (XXII) yields the 7-alpha-amino compound (XXIII), which is treated with Girard reagent T to afford the 7-beta-amino-7-alpha-methoxyoxacepehem compound (XXIV). The acylation of the NH2 group of (XXIV) with 2-(benzyloxycarbonyl)-2-[4-benzyloxy)phenyl)acetyl chloride (XXV) (obtained by reaction of the corresponding acid (XXVI) with oxalyl chloride) gives the expected amide (XXVII), which is finally deprotected with TFA/anisole or AlCl3/anisole.
| 【1】 Narisada, M.; et al.; Synthetic studies on beta-lactam antibiotics. Part 10. Synthesis of 7beta-[2-carboxy-2-(4-hydroxyphenyl)acetamido]-7alpha-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-1-oxa-1-dethia-3-cephem-4-carboxylic acid disodium salt (6059-S) and its related. J Med Chem 1979, 22, 7, 757. |
| 【2】 Nagata, W.; Narisada, M. (Shionogi & Co. Ltd.); Arylmalonamido-1-oxadethiacephalosporins. US 4180571 . |
| 【3】 Narisada, M.; Nagata, W. (Shionogi & Co. Ltd.); Arylmalonamido-1-oxadethiacephalosporins. DE 2713370; US 4138486 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 38597 | benzhydryl (6R,7S)-7-amino-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H22N6O4S | 详情 | 详情 | |
| (XX) | 14875 | 3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzaldehyde; 3,5-di(tert-butyl)-4-hydroxybenzaldehyde; 3,5-Di-tert-butyl-4-hydroxybenzaldehyde | 1620-98-0 | C15H22O2 | 详情 | 详情 |
| (XXI) | 38598 | benzhydryl (6R,7S)-7-([(E)-[3,5-di(tert-butyl)-4-hydroxyphenyl]methylidene]amino)-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C38H42N6O5S | 详情 | 详情 | |
| (XXII) | 38599 | benzhydryl (6R)-7-([[3,5-di(tert-butyl)-4-oxo-2,5-cyclohexadien-1-ylidene]methyl]imino)-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C38H40N6O5S | 详情 | 详情 | |
| (XXIII) | 38600 | benzhydryl (6R,7R)-7-([(E)-[3,5-di(tert-butyl)-4-hydroxyphenyl]methylidene]amino)-7-methoxy-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C39H44N6O6S | 详情 | 详情 | |
| (XXIV) | 38601 | benzhydryl (6R,7R)-7-amino-7-methoxy-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | 66510-99-4 | C24H24N6O5S | 详情 | 详情 |
| (XXV) | 38602 | benzyl 2-[4-(benzyloxy)phenyl]-3-chloro-3-oxopropanoate | C23H19ClO4 | 详情 | 详情 | |
| (XXVI) | 38603 | 3-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-oxopropionic acid | C23H20O5 | 详情 | 详情 | |
| (XXVII) | 38604 | benzhydryl (6R,7R)-7-([3-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-oxopropanoyl]amino)-7-methoxy-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C47H42N6O9S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)The isopropylidene group of (X) is oxidized with ozone affording the corresponding diketonic compound (XI), which is reduced selectively with Zn and acetic acid yielding the hydroxy ketone (XII). The reaction of (XII) with SOCl2 affords the corresponding chloro ketone (XIII), which is treated with triphenylphosphine in a basic medium to give alpha-[3beta-[alpha-(p-benzyloxyphenyl)-alpha-(benzyloxycarbonyl)acetamido]-3alpha-methoxy-4beta-[-3-(1-methyltetrazol-5-yl)thiomethyl-2-oxopropoxy]-2-oxoazetidine-1-yl]-alpha-triphenylphosphoranylideneacetic acid diphenylmethyl ester (XIV). Finally, this compound is treated with refluxing dioxane affording the protected 1-oxa-dethia-3-cephem compound (XV), which is deprotected with trifluoroacetic acid in anisole.
| 【1】 Serradell, M.N.; Blancafort, P.; Castaner, J.; S-6059. Drugs Fut 1979, 4, 9, 667. |
| 【2】 Narisada, M.; Nagata, W. (Shionogi & Co. Ltd.); Arylmalonamido-1-oxadethiacephalosporins. DE 2713370; US 4138486 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 39549 | benzhydryl 2-((2R,3R)-3-([3-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-oxopropanoyl]amino)-3-methoxy-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxoazetidinyl)-3-methyl-2-butenoate | C50H48N6O10S | 详情 | 详情 | |
| (XI) | 39550 | benzyl 3-[((2R,3R)-1-[2-(benzhydryloxy)-2-oxoacetyl]-3-methoxy-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxoazetidinyl)amino]-2-[4-(benzyloxy)phenyl]-3-oxopropanoate | C47H42N6O11S | 详情 | 详情 | |
| (XII) | 39551 | benzyl 3-[((2R,3R)-1-[2-(benzhydryloxy)-1-hydroxy-2-oxoethyl]-3-methoxy-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxoazetidinyl)amino]-2-[4-(benzyloxy)phenyl]-3-oxopropanoate | C47H44N6O11S | 详情 | 详情 | |
| (XIII) | 39552 | benzyl 3-[((2R,3R)-1-[2-(benzhydryloxy)-1-chloro-2-oxoethyl]-3-methoxy-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxoazetidinyl)amino]-2-[4-(benzyloxy)phenyl]-3-oxopropanoate | C47H43ClN6O10S | 详情 | 详情 | |
| (XIV) | 39553 | benzyl 3-[((2R,3R)-1-[2-(benzhydryloxy)-2-oxo-1-(triphenylphosphoranylidene)ethyl]-3-methoxy-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxoazetidinyl)amino]-2-[4-(benzyloxy)phenyl]-3-oxopropanoate | C65H57N6O10PS | 详情 | 详情 | |
| (XV) | 38604 | benzhydryl (6R,7R)-7-([3-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-oxopropanoyl]amino)-7-methoxy-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C47H42N6O9S | 详情 | 详情 |