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【结 构 式】 
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【分子编号】17188 【品名】(S)-4-hydroxy-2-pyrrolidone; (4S)-4-hydroxytetrahydro-2H-pyrrol-2-one; (S)-4-hydroxypyrrolidone 【CA登记号】68108-18-9 |
【 分 子 式 】C4H7NO2 【 分 子 量 】101.10512 【元素组成】C 47.52% H 6.98% N 13.85% O 31.65% |
合成路线1
该中间体在本合成路线中的序号：(I)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)Protection of alcohol (I) with TBDMSCl and imidazole gives silyl compound (II) which is N-methylated by means of NaH and MeI and then deprotected with HCl to yield derivative (III). Mesylation of (III) with MsCl in presence of Et3N followed by thioacetylation with AcSK (A) affords thioacetate (IV) which is then hydrolyzed with NaOMe to yield (V). Treatment of (VI) with diphenylphosphoryl chloride (B) and DIEA in acetonitrile yields (VII), which is then condensed with mercaptan (V) by means of DIEA in the same solvent to provide carbapenem (VIII). Deprotection of the carboxyl moiety of (VIII) by hydrogenation with H2 over Pd/C affords carboxylate (IX), which is finally esterified with pivaloyloxymethyl iodide (X) 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) | 41642 | S-[(3R)-1-methyl-5-oxopyrrolidinyl] ethanethioate | C7H11NO2S | 详情 | 详情 | |
| (V) | 41643 | (4R)-1-methyl-4-sulfanyl-2-pyrrolidinone | C5H9NOS | 详情 | 详情 | |
| (VI) | 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 | |
| (VII) | 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 |
| (VIII) | 41644 | 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(3R)-1-methyl-5-oxopyrrolidinyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C22H25N3O7S | 详情 | 详情 | |
| (IX) | 41645 | sodium (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(3R)-1-methyl-5-oxopyrrolidinyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C15H19N2NaO5S | 详情 | 详情 | |
| (X) | 11159 | iodomethyl pivalate | C6H11IO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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 |
合成路线4
该中间体在本合成路线中的序号：(I)The original procedure for the synthesis of the intermediate (R)-4-mercaptopyrrolidine-2-thione (IV) started from (S)-4-hydroxy-2-pyrrolidinone (I). Mitsunobu coupling with thioacetic acid produced the (R)-thioacetate ester (II). Conversion of (II) to the thiolactam (III) was achieved by treatment with Lawesson's reagent. The thioester group of (III) was then hydrolyzed by means of methanolic ammonia.
| 【1】 Iwasaki, T.; Kondo, K.; Horikawa, H.; Yamaguchi, T.; Matsushita, T. (Tanabe Seiyaku Co., Ltd.); 1-Methylcarbapenem derivs. and process for preparation thereof. EP 0474243; JP 1992279588; US 5153187 . |
| 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) | 17191 | S-[(3R)-5-oxotetrahydro-1H-pyrrol-3-yl] ethanethioate | C6H9NO2S | 详情 | 详情 | |
| (III) | 37711 | S-[(3R)-5-thioxopyrrolidinyl] ethanethioate | C6H9NOS2 | 详情 | 详情 | |
| (IV) | 37712 | (4R)-4-sulfanyl-2-pyrrolidinethione | C4H7NS2 | 详情 | 详情 |