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【结 构 式】 
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【药物名称】 【化学名称】(1R,5S,6S)-6-[1(R)-Hydroxyethyl]-1-methyl-2-[1-methyl-5-oxopyrrolidin-3(S)-ylsulfanyl]-1-carba-2-penem-3-carboxylic acid pivaloyloxymethyl ester 【CA登记号】162599-64-6, 127423-15-8 (undefined isomer) 【 分 子 式 】C21H30N2O7S 【 分 子 量 】454.54645 |
【开发单位】Sankyo (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, Carbapenems |
合成路线1
Alcohol (I) is protected with TBDMSCl and imidazole to give silyl compound (II), which is N-methylated by means of NaH and MeI and then deprotected with HCl to yield derivative (III). Mitsunobu reaction of (III) with 4-nitrobenzoic acid in presence of PPh3 and DEAD, followed by ester hydrolysis with K2CO3, provides alcohol (IV). Mesylation of (IV) with MsCl in presence of Et3N, followed by thioacetylation with AcSK (A), affords thioacetate (V), which is then hydrolyzed with NaOMe to yield (VI). Treatment of (VII) with diphenylphosphoryl chloride (B) in CH3CN and DIEA in CH3CN yields (VIII), which is then condensed with mercaptan (VI) by means of DIEA in the same solvent to provide carbapenem (IX). Deprotection of the carboxyl moiety of (IX) by hydrogenation with H2 over Pd/C affords carboxylate (X), which is finally esterified with pivaloyloxymethyl iodide (XI) in N,N-dimethylacetamide or DMF.
| 【1】 Miyauchi, M.; Ohya, S.; Kawamoto, I.; Shibayama, T.; Kanno, O.; Synthesis and biological evaluation of new oral carbapenems with 1-methyl-5-oxopyrrolidin-3-ylthio moiety. J Antibiot 1999, 52, 10, 900. |
| 【2】 Kawamoto, I.; Tanaka, T.; Endo, R.; Miyauchi, M.; Iwata, M. (Sankyo Co., Ltd.); 2-(Heterocyclylthio)carbapenem derivs. their preparation and their use as antibiotics. AU 8932386; EP 0337637; EP 0597821; JP 1990028180; JP 1990049783; US 5104867; US 5242914 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (A) | 17190 | potassium ethanethioate | 10387-40-3 | C2H3KOS | 详情 | 详情 |
| (I) | 17188 | (S)-4-hydroxy-2-pyrrolidone; (4S)-4-hydroxytetrahydro-2H-pyrrol-2-one; (S)-4-hydroxypyrrolidone | 68108-18-9 | C4H7NO2 | 详情 | 详情 |
| (II) | 41640 | (4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-pyrrolidinone | C10H21NO2Si | 详情 | 详情 | |
| (III) | 41641 | (4S)-4-hydroxy-1-methyl-2-pyrrolidinone | C5H9NO2 | 详情 | 详情 | |
| (IV) | 41648 | (4R)-4-hydroxy-1-methyl-2-pyrrolidinone | C5H9NO2 | 详情 | 详情 | |
| (V) | 41649 | S-[(3S)-1-methyl-5-oxopyrrolidinyl] ethanethioate | C7H11NO2S | 详情 | 详情 | |
| (VI) | 41650 | (4S)-1-methyl-4-sulfanyl-2-pyrrolidinone | C5H9NOS | 详情 | 详情 | |
| (VII) | 37720 | 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (VIII) | 13224 | 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | 90776-59-3 | C29H27N2O10P | 详情 | 详情 |
| (IX) | 41646 | 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(3S)-1-methyl-5-oxopyrrolidinyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C22H25N3O7S | 详情 | 详情 | |
| (X) | 41647 | sodium (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(3S)-1-methyl-5-oxopyrrolidinyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C15H19N2NaO5S | 详情 | 详情 | |
| (XI) | 11159 | iodomethyl pivalate | C6H11IO2 | 详情 | 详情 |