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【结 构 式】 
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【分子编号】18241 【品名】(2S,4S)-4-(acetylsulfanyl)-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C15H16N2O7S 【 分 子 量 】368.36732 【元素组成】C 48.91% H 4.38% N 7.6% O 30.4% S 8.7% |
合成路线1
该中间体在本合成路线中的序号：(XXI)The mercaptopyrrolidine (XIII) is prepared as follows: trans-4-hydroxy-L-proline (XV) is protected with 4-nitrobenzyl chloride (XVI) giving trans 4-hydroxy-N-(4-nitrobenzyloxycarbonyl)-L-proline (XVII), which is esterified with 4-methoxy benzyl chloride (XVIII) to the corresponding ester (XIX). The reaction of (XIX) with thioacetic acid by means of diethyl azodicarboxylate arid triphenyl-phosphine in THF affords the 4-acetylthio derivative (XX), which is partially hydrolyzed with trifluoroacetic acid and anisole to 4beta-(acetylthio)-N-(4-nitrobenzyloxycarbonyl)pyrrolidine-2beta-carboxylic acid (XXI). The condensation of (XXI) with dimethylamine by means of dicyclohexylcarbodiimide (DCC) gives the fully protected dimethylamide (XXII), which is deacetylated with NaOH in water to atford the desired product (XIII).
| 【1】 Fukasawa, M.; Inoue, T.; Kato, M.; Matsumura, H.; Sunagawa, M. (Sumitomo Pharmaceuticals Co., Ltd.); Thiopyrrolidinyl-beta-lactam derivs.. EP 0126587; ES 8600305; JP 1985001186; JP 1985019787; JP 1991041066; US 4933333; US 4943569; US 5122604 . |
| 【2】 Prous, J.; Castaner, J.; SM-7338. Drugs Fut 1988, 13, 6, 534. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 | ||
| (XIII) | 22578 | 4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C15H19N3O5S | 详情 | 详情 | |
| (XV) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (XVI) | 22580 | 1-(chloromethyl)-4-nitrobenzene | 100-14-1 | C7H6ClNO2 | 详情 | 详情 |
| (XVII) | 22581 | (2S,4R)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C13H14N2O7 | 详情 | 详情 | |
| (XVIII) | 11910 | 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether | 824-94-2 | C8H9ClO | 详情 | 详情 |
| (XIX) | 22583 | 2-(4-methoxybenzyl) 1-(4-nitrobenzyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C21H22N2O8 | 详情 | 详情 | |
| (XX) | 22584 | 2-(4-methoxybenzyl) 1-(4-nitrobenzyl) (2S,4S)-4-(acetylsulfanyl)-1,2-pyrrolidinedicarboxylate | C23H24N2O8S | 详情 | 详情 | |
| (XXI) | 18241 | (2S,4S)-4-(acetylsulfanyl)-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C15H16N2O7S | 详情 | 详情 | |
| (XXII) | 22586 | 4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[(dimethylamino)carbonyl]-1-pyrrolidinecarboxylate | C17H21N3O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Coupling of thioacetylproline derivative (I) with p-nitrobenzyl ester of ciprofloxacin (II) in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) provided amide (III). Treatment with pyrrolidine in acetonitrile gave thiol (IV), which was subsequently alkylated with the carbapenem phosphate (V) in the presence of diisopropylethylamine to give thioether (VI). Then, hydrogenolytical removal of p-nitrobenzyl protecting groups in the presence of Pd-C, followed by treatment with sodium 2-ethylhexanoate in acetone provided the target disodium salt.
| 【1】 Hershberger, P.M.; Switzer, A.G.; Yelm, K.E.; Coleman, M.C.; Devries, C.A.; Rourke, F.J.; Davis, B.W.; Kraft, W.G.; Twinem, T.L.; Koenigs, P.M.; Paule, S.M.; Siehnel, R.J.; Zoutendam, P.H.; Imbus, R.; Demuth, T.P. Jr.; Preparation and antimicrobial assessment of 2-thioether-linked quinolonyl-carbapenems. J Antibiot 1998, 51, 9, 857-871. |
| 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) | 18241 | (2S,4S)-4-(acetylsulfanyl)-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C15H16N2O7S | 详情 | 详情 | |
| (II) | 18242 | 4-nitrobenzyl 1-cyclopropyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylate | C24H23FN4O5 | 详情 | 详情 | |
| (III) | 18243 | 4-nitrobenzyl 7-[4-[((2S,4S)-4-(acetylsulfanyl)-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)carbonyl]-1-piperazinyl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C39H37FN6O11S | 详情 | 详情 | |
| (IV) | 18244 | 4-nitrobenzyl 1-cyclopropyl-6-fluoro-7-[4-[((2S,4S)-1-[[(4-nitrobenzyl)oxy]carbonyl]-4-sulfanylpyrrolidinyl)carbonyl]-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C37H35FN6O10S | 详情 | 详情 | |
| (V) | 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 |
| (VI) | 18246 | 4-nitrobenzyl 1-cyclopropyl-6-fluoro-7-[4-[((2S,4S)-4-[((4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-[[(4-nitrobenzyl)oxy]carbonyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl)sulfanyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)carbonyl]-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C54H51FN8O16S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)L-Tartaric acid (I) was converted to succinimimide (II) upon treatment with benzylamine in refluxing xylene with azeotropic removal of water. Subsequent reduction of (II) with borane, generated from NaBH4 and BF3, afforded pyrrolidine (III). Removal of the N-benzyl group of (III) was effected by hydrogenolysis over Pd/C, and the resulting secondary amine (IV) was coupled with the N-protected 3-thioacetylproline (V) to furnish amide (VI). Deacetylation of (VI) under basic conditions provided thiol (VII). Condensation of thiol (VII) with carbapenem enolphosphate (VIII) afforded thioether (IX). The 4-nitrobenzyl protecting groups of (IX) were finally removed by hydrogenolysis over Pd/C.
| 【1】 Park, S.W.; Park, S.Y.; Kim, D.J.; Shin, K.J.; Kang, Y.K.; Yoo, K.H.; Jae Seo, K.; Synthesis and biological evaluation of novel 1beta-methylcarbapenems having a new moiety at C-2. Bioorg Med Chem Lett 1999, 9, 16, 2385. |
| 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) | 16695 | (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid | 147-71-7 | C4H6O6 | 详情 | 详情 |
| (II) | 33017 | (3R,4R)-1-benzyl-3,4-dihydroxy-2,5-pyrrolidinedione | 75172-31-5 | C11H11NO4 | 详情 | 详情 |
| (III) | 33018 | (3S,4S)-1-benzyl-3,4-pyrrolidinediol | C11H15NO2 | 详情 | 详情 | |
| (IV) | 33019 | (3S,4S)-3,4-pyrrolidinediol | C4H9NO2 | 详情 | 详情 | |
| (V) | 18241 | (2S,4S)-4-(acetylsulfanyl)-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C15H16N2O7S | 详情 | 详情 | |
| (VI) | 33020 | 4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[[(3S,4S)-3,4-dihydroxypyrrolidinyl]carbonyl]-1-pyrrolidinecarboxylate | C19H23N3O8S | 详情 | 详情 | |
| (VII) | 33021 | 4-nitrobenzyl (2S,4S)-2-[[(3S,4S)-3,4-dihydroxypyrrolidinyl]carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C17H21N3O7S | 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) | 33022 | 4-nitrobenzyl (4R,5S,6S)-3-[((3S,5S)-5-[[(3S,4S)-3,4-dihydroxypyrrolidinyl]carbonyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C34H37N5O13S | 详情 | 详情 |