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【结 构 式】 
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【分子编号】17192 【品名】(4R)-4-sulfanyltetrahydro-2H-pyrrol-2-one 【CA登记号】157429-42-0 |
【 分 子 式 】C4H7NOS 【 分 子 量 】117.17172 【元素组成】C 41% H 6.02% N 11.95% O 13.65% S 27.37% |
合成路线1
该中间体在本合成路线中的序号：(V)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：(V)2) The esterification of 2(R)-[4-oxo-3(S)-[1(R)-(trimethylsilyloxy)ethyl]azetidin-2(S)-yl]propionic acid (X) with the previously obtained pyrrolidinone (V) gives the expected thiopropionic ester (XI), which is acylated with oxalic acid monochloride monopivaloyloxymethyl ester (XII) by means of trimethylsilylchloride and triethylamine yielding the condensation product (XIII). The cyclization of (XIII) by means of methylphosphonic acid diethyl ester affords silylated CS-834 (XIV), which is finally deprotected with 1N HCl.
| 【1】 Graul, A.; Castañer, R.M.; Castañer, J.; Leeson, P.; CS-834. Drugs Fut 1998, 23, 3, 261. |
| 【2】 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. |
| 【3】 Oita, S.; Mori, M. (Sankyo Co., Ltd.); Carbapenem ester preparation. JP 1996059663 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 17192 | (4R)-4-sulfanyltetrahydro-2H-pyrrol-2-one | 157429-42-0 | C4H7NOS | 详情 | 详情 |
| (X) | 17197 | (2R)-2-[(2S,3R)-3-isopropyl-4-oxoazetidinyl]propionic acid | C9H15NO3 | 详情 | 详情 | |
| (XI) | 17198 | S-[(3R)-5-oxopyrrolidinyl] (2R)-2-[(2S,3R)-3-isopropyl-4-oxoazetidinyl]propanethioate | C13H20N2O3S | 详情 | 详情 | |
| (XII) | 17199 | [(2-chloro-2-oxoacetyl)oxy]methyl pivalate | C8H11ClO5 | 详情 | 详情 | |
| (XIII) | 17200 | ([2-[(2S,3R)-3-isopropyl-2-((1R)-1-methyl-2-oxo-2-[[(3R)-5-oxopyrrolidinyl]sulfanyl]ethyl)-4-oxoazetidinyl]-2-oxoacetyl]oxy)methyl pivalate | C21H30N2O8S | 详情 | 详情 | |
| (XIV) | 17201 | [(2,2-dimethylpropanoyl)oxy]methyl (4R,5S,6R)-6-isopropyl-4-methyl-7-oxo-3-[[(3R)-5-oxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C21H30N2O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)A short-step synthesis of CS-834 has been described: The condensation of azetidinone (I) with pyrrolidinone (II) by means of CDI gives the thioester (III), which is desilylated with BF3/Et2O to the alcohol (IV). In order to have a more labile protecting group, alcohol (IV) is resilylated with TMS-Cl (or TES-Cl) and triethylamine affording the silyl ether (V), which is protected again at the pyrrolidine nitrogen with TES-Cl, affording the disilylated azetidinone (VI). The condensation of (VI) with the oxalyl chloride (VII) by means of triethylamine in dichloromethane gives the expected oxalylazetidinone (VIII), which is treated with diethyl ethylphosphonite in toluene yielding the ylide (IX). This compound, without isolation, is cyclized in refluxing mesitylene to afford the protected carbapenem intermediate (X), which is finally desilylated with HCl in acetonitrile. The cyclization of azetidinone (VIII) to carbapenem (X) can also be performed with triethyl phosphite instead of diethyl ethylphosphonite. The oxalyl chloride (VII) is obtained by monoesterification of oxalic acid (XI) with pivaloyloxymethyl iodide (XII) by means of triethylamine yielding monoester (XIII), which is finally converted to intermediate (VII) by treatment with oxalyl chloride in dichloromethane.
| 【1】 Oida, S.; Mori, M.; A short-step synthesis of orally active carbapenem antibiotic CS-834. Chem Pharm Bull 2000, 48, 1, 126. |
| 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) | 30029 | (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid | C14H27NO4Si | 详情 | 详情 | |
| (II) | 17192 | (4R)-4-sulfanyltetrahydro-2H-pyrrol-2-one | 157429-42-0 | C4H7NOS | 详情 | 详情 |
| (III) | 33402 | S-[(3R)-5-oxopyrrolidinyl] (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanethioate | C18H32N2O4SSi | 详情 | 详情 | |
| (IV) | 33403 | S-[(3R)-5-oxopyrrolidinyl] (2R)-2-[(2S,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]propanethioate | C12H18N2O4S | 详情 | 详情 | |
| (V) | 33404 | S-[(3R)-5-oxopyrrolidinyl] (2R)-2-((2S,3S)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)propanethioate | C15H26N2O4SSi | 详情 | 详情 | |
| (VI) | 33405 | S-[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl] (2R)-2-((2S,3S)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)propanethioate | C21H40N2O4SSi2 | 详情 | 详情 | |
| (VII) | 17199 | [(2-chloro-2-oxoacetyl)oxy]methyl pivalate | C8H11ClO5 | 详情 | 详情 | |
| (VIII) | 33406 | [[2-((2S,3S)-2-((1R)-1-methyl-2-oxo-2-[[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl]sulfanyl]ethyl)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)-2-oxoacetyl]oxy]methyl pivalate | C29H50N2O9SSi2 | 详情 | 详情 | |
| (IX) | 33407 | [[2-[diethoxy(ethyl)phosphoranylidene]-2-((2S,3S)-2-((1R)-1-methyl-2-oxo-2-[[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl]sulfanyl]ethyl)-4-oxo-3-[(1R)-1-[(trimethylsilyl)oxy]ethyl]azetidinyl)acetyl]oxy]methyl pivalate | C35H65N2O10PSSi2 | 详情 | 详情 | |
| (X) | 33408 | [(2,2-dimethylpropanoyl)oxy]methyl (4R,5S,6S)-4-methyl-7-oxo-3-[[(3R)-5-oxo-1-(triethylsilyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-[(trimethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C29H50N2O7SSi2 | 详情 | 详情 | |
| (XI) | 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 |
| (XII) | 11159 | iodomethyl pivalate | C6H11IO2 | 详情 | 详情 | |
| (XIII) | 33409 | 2-[[(2,2-dimethylpropanoyl)oxy]methoxy]-2-oxoacetic acid | C8H12O6 | 详情 | 详情 |