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【结 构 式】 
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【分子编号】37712 【品名】(4R)-4-sulfanyl-2-pyrrolidinethione 【CA登记号】 |
【 分 子 式 】C4H7NS2 【 分 子 量 】133.23832 【元素组成】C 36.06% H 5.3% N 10.51% S 48.13% |
合成路线1
该中间体在本合成路线中的序号：(IV)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 |
合成路线2
该中间体在本合成路线中的序号：(IV)A new procedure suitable for the large-scale preparation of (IV) was further described. The chiral bromide (VI) was obtained by diazotization of L-aspartic acid beta-methyl ester (V) in the presence of KBr. Subsequent displacement of the bromide ion of (VI) by the potassium salt of benzyl mercaptan with inversion of the configuration yielded sulfide (VII). The carboxyl group of (VII) was then reduced to alcohol (VIII) using borane-dimethyl sulfide complex, and subsequent treatment with SOCl2 and pyridine afforded chloride (IX). Cyclization of (IX) with ammonia in MeOH generated pyrrolidinone (X), which was converted to the pyrrolidinethione (XI) by treatment with P2S5. Cleavage of the benzyl protecting group of (XI) with sodium in liquid ammonia then gave the required thiol (IV).
| 【1】 Seki, M.; et al.; Practical synthesis of (R)-4-mercaptopyrrolidine-2-thione from L-aspartic acid.Preparation of a novel orally active 1-beta-methylcarbapenem, TA-949. J Org Chem 2000, 65, 2, 517. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 37712 | (4R)-4-sulfanyl-2-pyrrolidinethione | C4H7NS2 | 详情 | 详情 | |
| (V) | 37713 | (2S)-2-amino-4-methoxy-4-oxobutyric acid | C5H9NO4 | 详情 | 详情 | |
| (VI) | 37714 | (2S)-2-bromo-4-methoxy-4-oxobutyric acid | C5H7BrO4 | 详情 | 详情 | |
| (VII) | 37715 | (2R)-2-(benzylsulfanyl)-4-methoxy-4-oxobutyric acid | C12H14O4S | 详情 | 详情 | |
| (VIII) | 37716 | methyl (3R)-3-(benzylsulfanyl)-4-hydroxybutanoate | C12H16O3S | 详情 | 详情 | |
| (IX) | 37717 | methyl (3R)-3-(benzylsulfanyl)-4-chlorobutanoate | C12H15ClO2S | 详情 | 详情 | |
| (X) | 37718 | (4R)-4-(benzylsulfanyl)-2-pyrrolidinone | C11H13NOS | 详情 | 详情 | |
| (XI) | 37719 | (4R)-4-(benzylsulfanyl)-2-pyrrolidinethione | C11H13NS2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Oxocarbapenam (XII) was converted into vinyl phosphate (XIII) by treatment with diphenylphosphoryl chloride and diisopropylethylamine. Displacement of the phosphate group of (XIII) by 4-mercaptopyrrolidine-2-thione (IV) yielded carbapenem sulfide (XIV). After hydrogenolytic cleavage of the p-nitrobenzyl ester of (XIV) in the presence of Pd/C and KHCO3, the resulting potassium carboxylate salt (XV) was condensed with isobutyryloxymethyl iodide (XVI) to furnish the title compound.
| 【1】 Horikawa, H.; Iwasaki, T.; Kondo, K. (Tanabe Seiyaku Co., Ltd.); Process for preparing beta-lactam deriv. and synthetic intermediate thereof. EP 0559533 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 37712 | (4R)-4-sulfanyl-2-pyrrolidinethione | C4H7NS2 | 详情 | 详情 | |
| (XII) | 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 | |
| (XIII) | 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 |
| (XIV) | 37721 | 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C21H23N3O6S2 | 详情 | 详情 | |
| (XV) | 37722 | potassium (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C14H17KN2O4S2 | 详情 | 详情 | |
| (XVI) | 37723 | iodomethyl 2-methylpropanoate | C5H9IO2 | 详情 | 详情 | |
| (XVII) | 37724 | (isobutyryloxy)methyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C19H26N2O6S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)Ring contraction of (XXIX) by desulfurizing treatment with triphenylphosphine produced oxocarbapenam (XXX). This was converted to vinyl phosphate (XXXI) and then condensed with mercapto pyrrolidinethione (IV) to give thioether (XXXII). Desilylation of (XXXII) to produce the title compound was carried out by treatment with a variety of fluoride reagents including KF, NH4F·HF and CaF2.
| 【1】 Horikawa, H.; Iwasaki, T.; Kondo, K. (Tanabe Seiyaku Co., Ltd.); Method for removing the protecting group for hydroxy group. EP 0567949 . |
| 【2】 Horikawa, H.; Iwasaki, T.; Kondo, K. (Tanabe Seiyaku Co., Ltd.); Process for preparing beta-lactam deriv. and synthetic intermediate thereof. EP 0559533 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 37712 | (4R)-4-sulfanyl-2-pyrrolidinethione | C4H7NS2 | 详情 | 详情 | |
| (XXIX) | 37733 | (isobutyryloxy)methyl (5R,6S,7S)-7-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methyl-4,8-dioxo-3-thia-1-azabicyclo[4.2.0]octane-2-carboxylate | C21H35NO7SSi | 详情 | 详情 | |
| (XXX) | 37734 | (isobutyryloxy)methyl (4R,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C21H35NO7Si | 详情 | 详情 | |
| (XXXI) | 37735 | (isobutyryloxy)methyl (4R,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-[(diphenoxyphosphoryl)oxy]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C33H44NO10PSi | 详情 | 详情 | |
| (XXXII) | 37736 | (isobutyryloxy)methyl (4R,5S,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-methyl-7-oxo-3-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C25H40N2O6S2Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)A new procedure based on the counterattack stategy was further developed. Azetidinonepropionic acid (XXXV) was available from acetoxy azetidinone (XXXIII) by coupling with benzoxazinone (XXXIV). After protection of (XXXV) with tert-butyldimethylsilyl chloride, alkylation with allyl bromoacetate yielded (XXXVI). DCC-mediated condensation of (XXXVI) with mercaptopyrrolidine (IV) produced thioester (XXXVII). Dieckman-type cyclization of (XXXVII) upon treatment with sodium bis(trimethylsilyl)amide produced carbapenem (XXXVIII) together with mercaptopyrrolidine (XXXIX). Treatment of the crude reaction mixture with chlorotrimethylsilane and subsequent addition of diphenylphosphoryl chloride generated the vinyl phosphate (XL) and the silylated mercaptopyrrolidine (XLI). The counterattack of the thiolate anion, liberated by desilylation of (XLI) with tetrabutylammonium fluoride, to the vinyl phosphate (XL) yielded the desired thioether (XLII). The hydroxyl protective group of (XLII) was removed by treatment with NH4F·HF to give (XLIII), and the allyl ester group of (XLIII) was further cleaved by means of palladium diacetate, producing carboxylic acid (XLIV). Finally, alkylation of the carboxylate group of (XLIV) with iodomethyl isobutyrate (XVI) gave rise to the title compound.
| 【1】 Seki, M.; et al.; Practical synthesis of (R)-4-mercaptopyrrolidine-2-thione from L-aspartic acid.Preparation of a novel orally active 1-beta-methylcarbapenem, TA-949. J Org Chem 2000, 65, 2, 517. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40728 | allyl 2-bromoacetate | C5H7BrO2 | 详情 | 详情 | ||
| (IV) | 37712 | (4R)-4-sulfanyl-2-pyrrolidinethione | C4H7NS2 | 详情 | 详情 | |
| (XVI) | 37723 | iodomethyl 2-methylpropanoate | C5H9IO2 | 详情 | 详情 | |
| (XXXIII) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (XXXIV) | 37738 | 3-(2-Bromo-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one | 158299-05-9 | C16H18BrNO3 | 详情 | 详情 |
| (XXXV) | 30029 | (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid | C14H27NO4Si | 详情 | 详情 | |
| (XXXVI) | 37739 | (2R)-2-[(2S,3S)-1-[2-(allyloxy)-2-oxoethyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid | C19H33NO6Si | 详情 | 详情 | |
| (XXXVII) | 37740 | allyl 2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-((1R)-1-methyl-2-oxo-2-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]ethyl)-4-oxoazetidinyl]acetate | C23H38N2O5S2Si | 详情 | 详情 | |
| (XXXVIII) | 37741 | C19H30NNaO5Si | 详情 | 详情 | ||
| (XXXIX) | 37742 | C4H5NNa2S2 | 详情 | 详情 | ||
| (XL) | 37743 | allyl (4R,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-[(diphenoxyphosphoryl)oxy]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C31H40NO8PSi | 详情 | 详情 | |
| (XLI) | 37744 | (4R)-1-(trimethylsilyl)-4-[(trimethylsilyl)sulfanyl]-2-pyrrolidinethione | C10H23NS2Si2 | 详情 | 详情 | |
| (XLII) | 37745 | allyl (4R,5S,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-methyl-7-oxo-3-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C23H36N2O4S2Si | 详情 | 详情 | |
| (XLIII) | 37746 | allyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C17H22N2O4S2 | 详情 | 详情 | |
| (XLIV) | 37747 | sodium (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C14H17N2NaO4S2 | 详情 | 详情 |