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【结 构 式】 
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【分子编号】38597 【品名】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 【CA登记号】 |
【 分 子 式 】C23H22N6O4S 【 分 子 量 】478.53172 【元素组成】C 57.73% H 4.63% N 17.56% O 13.37% S 6.7% |
合成路线1
该中间体在本合成路线中的序号：(XIX)The partial hydrogenation of (VIII) with H2 over Pd/(CaCO3) in methanol gives the allyl ether (IX), which is epoxidized with MCPBA in dichloromethane yielding epoxide (X). Epoxide cleavage with the lithium salt of 1-methyltetrazole-5-thiol (XI) in THF affords the isopropanol derivative (XII), which is oxidized with CrO3/H2SO4 in acetone giving the ketone (XIII). The ozonolysis of the isopropylidene group of (XIII) with O3 in dichloromethane affords the alpha ketoester (XIV), which is reduced with Zn/AcOH to the alpha hydroxyester (XV). The reaction of (XV) with SOCl2 and pyridine affords the alpha chloroester (XVI), which by reaction with triphenylphosphine in refluxing dichloromethane gives the alpha triphenylphosphoranylidene acetate (XVII). Thermal cyclization of (XVII) in refluxing dioxane affords the oxacephem derivative (XVIII), which is deacylated by reaction with PCl5 and pyridine providing the 7-beta-amino oxacephem derivative (XIX).
| 【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 |
|---|---|---|---|---|---|---|
| (VIII) | 38586 | 1-phenylethyl 3-methyl-2-[(3S,4R)-2-oxo-3-[(2-phenylacetyl)amino]-4-(2-propynyloxy)azetidinyl]-2-butenoate | C27H28N2O5 | 详情 | 详情 | |
| (IX) | 38587 | benzhydryl 2-[(2R,3S)-2-(allyloxy)-4-oxo-3-[(2-phenylacetyl)amino]azetidinyl]-3-methyl-2-butenoate | C32H32N2O5 | 详情 | 详情 | |
| (X) | 38588 | benzhydryl 3-methyl-2-[(2R,3S)-2-(2-oxiranylmethoxy)-4-oxo-3-[(2-phenylacetyl)amino]azetidinyl]-2-butenoate | C32H32N2O6 | 详情 | 详情 | |
| (XI) | 38589 | C2H3LiN4S | 详情 | 详情 | ||
| (XII) | 38590 | benzhydryl 2-[(2R,3S)-2-[2-hydroxy-3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]propoxy]-4-oxo-3-[(2-phenylacetyl)amino]azetidinyl]-3-methyl-2-butenoate | C34H36N6O6S | 详情 | 详情 | |
| (XIII) | 38591 | benzhydryl 3-methyl-2-[(2R,3S)-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxo-3-[(2-phenylacetyl)amino]azetidinyl]-2-butenoate | C34H34N6O6S | 详情 | 详情 | |
| (XIV) | 38592 | benzhydryl 2-[(2R,3S)-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxo-3-[(2-phenylacetyl)amino]azetidinyl]-2-oxoacetate | C31H28N6O7S | 详情 | 详情 | |
| (XV) | 38593 | benzhydryl 2-hydroxy-2-[(2R,3S)-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxo-3-[(2-phenylacetyl)amino]azetidinyl]acetate | C31H30N6O7S | 详情 | 详情 | |
| (XVI) | 38594 | benzhydryl 2-chloro-2-[(2R,3S)-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxo-3-[(2-phenylacetyl)amino]azetidinyl]acetate | C31H29ClN6O6S | 详情 | 详情 | |
| (XVII) | 38595 | benzhydryl 2-[(2R,3S)-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxo-3-[(2-phenylacetyl)amino]azetidinyl]-2-(triphenylphosphoranylidene)acetate | C49H43N6O6PS | 详情 | 详情 | |
| (XVIII) | 38596 | benzhydryl (6R,7S)-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-7-[(2-phenylacetyl)amino]-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C31H28N6O5S | 详情 | 详情 | |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(XIX)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 |