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【结 构 式】 
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【分子编号】17189 【品名】(3S)-5-oxotetrahydro-1H-pyrrol-3-yl methanesulfonate 【CA登记号】 |
【 分 子 式 】C5H9NO4S 【 分 子 量 】179.1968 【元素组成】C 33.51% H 5.06% N 7.82% O 35.71% S 17.89% |
合成路线1
该中间体在本合成路线中的序号：(II)1) The mesylation of 4(S)-hydroxypyrrolidin-2-one (I) with mesyl chloride and triethylamine in pyridine gives the corresponding ester (II), which is treated with potassium thioacetate (III) in refluxing acetonitrile yielding 4(R)-(acetylsulfanyl)pyrrolidin-2-one (IV). The hydrolysis of (IV) with sodium methoxide in methanol followed by acidification with aqueous HCl affords 4(R)-sulfanylpyrrolidin-2-one (V), which is condensed with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (VI) by means of ethyldiisopropylamine in acetonitrile to give (1R,5S,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[5-oxopyrrolidin-3(R)-ylsulfanyl]-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (VII). The hydrogenolysis of (VII) with H2 over Pd/C in THF/aqueous phosphate buffer yields the sodium salt (VIII), which is finally esterified with pivaloyloxymethyl iodide (IX) in dimethylacetamide.
| 【1】 Yasuda, H.; Kuwahara, S.; Kawamoto, I.; Miyauchi, M.; Endo, R.; Hisaoka, M.; CS-834, a new oral carbapenem: I. Structure-activity relationships of 2-substituted 1beta-methylcarbapenems. 36th Intersci Conf Antimicrob Agents Chemother (Sept 15-18, New Orleans) 1996, Abst F105. |
| 【2】 Endo, R.; Yasuda, H.; Kawamoto, I.; Hisaoka, M.; Miyauchi, M.; Synthesis and structure-activity relationships of a novel oral carbapenem, CS-834. J Antibiot 1997, 50, 5, 429-39. |
| 【3】 Graul, A.; Castañer, R.M.; Castañer, J.; Leeson, P.; CS-834. Drugs Fut 1998, 23, 3, 261. |
| 【4】 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 . |
| 【5】 Kawamoto, I.; Miyauchi, M.; Endo, R. (Sankyo Co., Ltd.); Crystalline carbapenem deriv. EP 0599512; JP 1995165759 . |
| 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) | 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) | 17189 | (3S)-5-oxotetrahydro-1H-pyrrol-3-yl methanesulfonate | C5H9NO4S | 详情 | 详情 | |
| (III) | 17190 | potassium ethanethioate | 10387-40-3 | C2H3KOS | 详情 | 详情 |
| (IV) | 17191 | S-[(3R)-5-oxotetrahydro-1H-pyrrol-3-yl] ethanethioate | C6H9NO2S | 详情 | 详情 | |
| (V) | 17192 | (4R)-4-sulfanyltetrahydro-2H-pyrrol-2-one | 157429-42-0 | C4H7NOS | 详情 | 详情 |
| (VI) | 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 |
| (VII) | 17194 | 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-oxotetrahydro-1H-pyrrol-3-yl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C21H23N3O7S | 详情 | 详情 | |
| (VIII) | 17195 | sodium (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-oxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C14H17N2NaO5S | 详情 | 详情 | |
| (IX) | 11159 | iodomethyl pivalate | C6H11IO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of 2-bromo-5-methoxybenzoic acid (I) with ethyl 2-amino-4-chlorobenzoate (II) by means of Cu(OAc)2 and 1-methyl-2-pyrrolidone in DIEA, followed by cyclization by means of polyphosphoric acid ethyl ester in refluxing chloroform gives the acridone (III), which is hydrolyzed with NaOH in refluxing ethanol yielding the carboxylic acid (IV). The condensation of (IV) with N,N-dimethylethylenediamine (V) by means of CDI in DMF affords the corresponding amide (VI), which is cyclized with phosgene in chloroform to provide the pyrimidoacridinetrione (VII). The reaction of (VII) with N,N-dimethyleythylenediamine (V) gives the final intermediate (VIII), which is demethylated with refluxing 48% HBr.
| 【1】 Polucci, P.; Antonini, I.; Kelland, L.R.; Menta, E.; Pescalli, N.; Martelli, S.; 2,3-Dihydro-1H,7H-pyrimido[5,6,1-de]acridine-1,3,7-trione derivatives, a class of cytotoxic agents active on multidrug-resistant cell lines: Synthesis, biological evaluation, and structure-activity relationships. J Med Chem 1999, 42, 14, 2535. |
| 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) | 17189 | (3S)-5-oxotetrahydro-1H-pyrrol-3-yl methanesulfonate | C5H9NO4S | 详情 | 详情 | |
| (II) | 31887 | ethyl 2-amino-4-chlorobenzoate | C9H10ClNO2 | 详情 | 详情 | |
| (III) | 31888 | ethyl 1-chloro-7-methoxy-9-oxo-9,10-dihydro-4-acridinecarboxylate | C17H14ClNO4 | 详情 | 详情 | |
| (IV) | 31889 | 1-chloro-7-methoxy-9-oxo-9,10-dihydro-4-acridinecarboxylic acid | C15H10ClNO4 | 详情 | 详情 | |
| (V) | 14881 | N-(2-aminoethyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,2-ethanediamine; 2-Dimethylaminoethylamine | 108-00-9 | C4H12N2 | 详情 | 详情 |
| (VI) | 31890 | 1-chloro-N-[2-(dimethylamino)ethyl]-7-methoxy-9-oxo-9,10-dihydro-4-acridinecarboxamide | C19H20ClN3O3 | 详情 | 详情 | |
| (VII) | 31891 | 6-chloro-2-[2-(dimethylamino)ethyl]-9-methoxy-1H,7H-pyrimido[5,6,1-de]acridine-1,3,7(2H)-trione | C20H18ClN3O4 | 详情 | 详情 | |
| (VIII) | 31892 | 2-[2-(dimethylamino)ethyl]-6-[[2-(dimethylamino)ethyl]amino]-9-methoxy-1H,7H-pyrimido[5,6,1-de]acridine-1,3,7(2H)-trione | C24H29N5O4 | 详情 | 详情 |