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【结 构 式】 
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【药物名称】 【化学名称】2-(3,4-Dihydroxyphenyl)acetic acid (2R,3S,5R)-3-carboxy-2-methyl-1,1-dioxo-6-[(Z)-pyridin-2-ylmethylene]penam-2-ylmethyl ester sodium salt 【CA登记号】 【 分 子 式 】C22H19N2NaO9S 【 分 子 量 】510.45853 |
【开发单位】Research Corporation Technologies (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, beta-Lactam Enhancers, beta-Lactamase Inhibitors |
合成路线1
6-Aminopenicillanic acid benzhydryl ester (I) was protected as the carbamate (II) using allyl chloroformate. Subsequent oxidation of (II) with m-chloroperbenzoic acid provided sulfoxide (III). Opening of the thiazolidine ring of (III) by means of 2-mercaptobenzothiazole (IV) produced disulfide (V), which was further cyclized in the presence of arylacetic acid (VI) and silver acetate to furnish a 4:1 mixture of penicillanic ester (VII) and the cephalosporanic analogue (VIII). Deprotection of the required isomer (VII) employing Pd(PPh3)4 and Bu3SnH afforded amine (IX). Diazotization of (IX) with isopropyl nitrite, followed by treatment with propylene oxide and Rh2(OAc)4 gave rise to oxolactam (X). Wittig reaction of (X) with the ylide resulting from phosphonium salt (XI) and NaNH2 provided the (pyridylmethylene) derivative (XII). Finally, oxidation to the corresponding sulfone and cleavage of the protecting groups provided the title compound.
| 【1】 Buynak, J.D.; et al.; New beta-lactamase inhibitors of the class A and class C enzymes. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 194. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 35142 | benzhydryl (2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C21H22N2O3S | 详情 | 详情 | |
| (II) | 35143 | benzhydryl (2S,5R,6R)-6-[[(allyloxy)carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C25H26N2O5S | 详情 | 详情 | |
| (III) | 35144 | benzhydryl (2S,5R,6R)-6-[[(allyloxy)carbonyl]amino]-3,3-dimethyl-4,7-dioxo-4lambda(4)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C25H26N2O6S | 详情 | 详情 | |
| (IV) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (V) | 35145 | benzhydryl (2R)-2-[(2R,3R)-3-[[(allyloxy)carbonyl]amino]-2-(1,3-benzothiazol-2-yldisulfanyl)-4-oxoazetidinyl]-3-methyl-3-butenoate | C32H29N3O5S3 | 详情 | 详情 | |
| (VI) | 35146 | 2-[3,4-di(tert-butoxy)phenyl]acetic acid | C16H24O4 | 详情 | 详情 | |
| (VII) | 35147 | benzhydryl (2S,3R,5R,6R)-6-[[(allyloxy)carbonyl]amino]-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C41H48N2O9S | 详情 | 详情 | |
| (VIII) | 35148 | benzhydryl (2R,3S,7R)-7-[[(allyloxy)carbonyl]amino]-3-([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylate | C41H48N2O9S | 详情 | 详情 | |
| (IX) | 35149 | benzhydryl (2S,3R,5R,6R)-6-amino-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C37H44N2O7S | 详情 | 详情 | |
| (X) | 35150 | benzhydryl (2S,3R,5R)-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-6,7-dioxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C37H41NO8S | 详情 | 详情 | |
| (XI) | 35151 | triphenyl(2-pyridinylmethyl)phosphonium chloride; 2-picolyl triphenylphosphonium chloride | 73870-25-4 | C24H21ClNP | 详情 | 详情 |
| (XII) | 35152 | benzhydryl (2S,3R,5R)-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-6-[(Z)-2-pyridinylmethylidene]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C43H46N2O7S | 详情 | 详情 |