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【结 构 式】 
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【分子编号】39549 【品名】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 【CA登记号】 |
【 分 子 式 】C50H48N6O10S 【 分 子 量 】925.03156 【元素组成】C 64.92% H 5.23% N 9.09% O 17.3% S 3.47% |
合成路线1
该中间体在本合成路线中的序号：(X)The epoxidation of alpha-(3beta-benzamido-4beta-allyloxy-2-oxoazetidin-1-yl)-alpha-isopropylilideneacetic acid diphenylmethyl ester (I) with a peracid gives the corresponding epoxide in the allyl group (II), which is chlorinated with tert-butyl hypochlorite affording the chloro epoxide (III). The methoxylation of (III) with lithium methoxide yields the 3beta-benzamido-3alpha-methoxy derivative (IV), which is condensed with lithium 1-methyltetrazol-5-ylmercaptide (V) to afford the tetrazol derivative (VI). The oxidation of (VI) with CrO3 affords the ketonic compound (VII), which is debenzoylated by treatment with PCl5, MeOH and triethylamine giving alpha-[3beta-amino-3alpha-methoxy-4beta-[3-(1-methyltetrazol-5-yl)thiomethyl-2-oxopropoxy]-2-oxoazetidine-1-yl]-alpha-isopropylidieneacetic acid diphenylmethyl ester (VIII). The condensation of (VIII) with alpha-(p-benzyloxyphenyl)-alpha-(benzyloxycarbonyl)acetyl chloride (IX) by means of triethylamine affords the 3beta-[alpha-(benzyloxyphenyl)-alpha-(benzyloxycarbonyl)acetamido] derivative (XX).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 39541 | benzhydryl 2-[(2R,3S)-2-(allyloxy)-3-(benzoylamino)-4-oxoazetidinyl]-3-methyl-2-butenoate | C31H30N2O5 | 详情 | 详情 | |
| (II) | 39542 | benzhydryl 2-[(2R,3S)-3-(benzoylamino)-2-(2-oxiranylmethoxy)-4-oxoazetidinyl]-3-methyl-2-butenoate | C31H30N2O6 | 详情 | 详情 | |
| (III) | 39543 | benzhydryl 2-[(2R,3R)-3-(benzoylamino)-3-chloro-2-(2-oxiranylmethoxy)-4-oxoazetidinyl]-3-methyl-2-butenoate | C31H29ClN2O6 | 详情 | 详情 | |
| (IV) | 39544 | benzhydryl 2-[(2R,3R)-3-(benzoylamino)-3-methoxy-2-(2-oxiranylmethoxy)-4-oxoazetidinyl]-3-methyl-2-butenoate | C32H32N2O7 | 详情 | 详情 | |
| (V) | 39545 | C2H4LiN4S | 详情 | 详情 | ||
| (VI) | 39546 | benzhydryl 2-((2R,3R)-3-(benzoylamino)-2-[2-hydroxy-3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]propoxy]-3-methoxy-4-oxoazetidinyl)-3-methyl-2-butenoate | C34H36N6O7S | 详情 | 详情 | |
| (VII) | 39547 | benzhydryl 2-((2R,3R)-3-(benzoylamino)-3-methoxy-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxoazetidinyl)-3-methyl-2-butenoate | C34H34N6O7S | 详情 | 详情 | |
| (VIII) | 39548 | benzhydryl 2-((2R,3R)-3-amino-3-methoxy-2-[3-[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]-2-oxopropoxy]-4-oxoazetidinyl)-3-methyl-2-butenoate | C27H30N6O6S | 详情 | 详情 | |
| (IX) | 38602 | benzyl 2-[4-(benzyloxy)phenyl]-3-chloro-3-oxopropanoate | C23H19ClO4 | 详情 | 详情 | |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(X)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 |