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【结 构 式】 
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【药物名称】CL-191983, OCA-983 【化学名称】(1R,5S,6S)-6-[1(R)-Hydroxyethyl]-1-methyl-2-[2(R)-(L-valylaminomethyl)tetrahydrofuran-3(R)-ylsulfanyl]-1-carba-2-penem-3-carboxylic acid 【CA登记号】161856-02-6 【 分 子 式 】C20H31N3O6S 【 分 子 量 】441.55057 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems |
合成路线1
Azetidineacetic acid derivative (I) was activated with 1,1'-carbonyldiimidazole and then condensed with p-nitrobenzyl malonate magnesium salt (II) to afford ketoester (III). Desilylation of (III) with methanolic HCl then gave alcohol (IV). Dodecylbenzenesulfonyl azide (VI) was prepared by treatment of sulfonyl chloride (V) with NaN3. Reaction of (IV) with sulfonyl azide (VI) provided diazo ester (VII). Ring closure of (VII) in the presence of rhodium diacetate in hot cyclohexane, followed by condensation with diphenylphosphoric chloride furnished carbapenem phosphate (VIII).
| 【1】 Lin, Y.-I.; Bitha, P.; Sakya, S.; Strohmeyer, T.W.; Bush, K. (American Cyanamid Co.); Novel 2-thiosubstd. carbapenems. CA 2118961; EP 0617036; JP 1994321948; US 5602118 . |
| 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) | 33039 | magnesium 2-(4-nitrobenzyl)malonate | C10H7MgNO6 | 详情 | 详情 | |
| (III) | 33040 | 4-nitrobenzyl (4R)-4-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-oxopentanoate | C23H34N2O7Si | 详情 | 详情 | |
| (IV) | 22573 | 4-nitrobenzyl 4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate | C17H20N2O7 | 详情 | 详情 | |
| (V) | 33041 | 4-dodecylbenzenesulfonyl chloride | C18H29ClO2S | 详情 | 详情 | |
| (VI) | 33042 | 4-dodecylbenzenesulfonyl azide | C18H29N3O2S | 详情 | 详情 | |
| (VII) | 30150 | (3S,4R)-3-((1R)-1-Hydroxyethyl)-4[(1R)-1-methyl-3-diazo-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one | 137391-68-5 | C17H18N4O7 | 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 |
合成路线2
1,2-Dideoxy-D-ribose (IX) was converted to bismesylate (X) upon treatment with methanesulfonyl chloride and pyridine. Displacement of the primary mesylate group of (X) with LiN3 in DMF gave azide (XI). The secondary mesylate group was further displaced with potassium thioacetate to provide (XII). Thiol (XIII) was then prepared by hydrolysis of the thioester function with NaOMe in THF.
| 【1】 Lin, Y.-I.; Bitha, P.; Sakya, S.; Strohmeyer, T.W.; Bush, K. (American Cyanamid Co.); Novel 2-thiosubstd. carbapenems. CA 2118961; EP 0617036; JP 1994321948; US 5602118 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 33043 | (2R,3S)-2-(hydroxymethyl)tetrahydro-3-furanol | C5H10O3 | 详情 | 详情 | |
| (X) | 33044 | (2R,3S)-2-[[(methylsulfonyl)oxy]methyl]tetrahydro-3-furanyl methanesulfonate | C7H14O7S2 | 详情 | 详情 | |
| (XI) | 33045 | (2R,3S)-2-(azidomethyl)tetrahydro-3-furanyl methanesulfonate | C6H11N3O4S | 详情 | 详情 | |
| (XII) | 33046 | S-[(2R,3R)-2-(azidomethyl)tetrahydro-3-furanyl] ethanethioate | C7H11N3O2S | 详情 | 详情 | |
| (XIII) | 33047 | (2R,3R)-2-(azidomethyl)tetrahydro-3-furanthiol; (2R,3R)-2-(azidomethyl)tetrahydro-3-furanylhydrosulfide | C5H9N3OS | 详情 | 详情 |
合成路线3
In an alternative procedure, deoxyribose (XIV) was reduced to 2-deoxy-D-erythropentitol (XV) with NaBH4. Acid-catalyzed cyclization of (XV) produced (IX), which was converted to triflate (XVI) using trifluoromethanesulfonic anhydride and pyridine. Displacement with tetrabutylammonium azide provided azido derivative (XVII). Further treatment with trifluoromethanesulfonic anhydride gave triflate (XVIII), which was then displaced with potassium thioacetate to yield thioester (XII). This was hydrolyzed with NaOMe as above to furnish thiol (XIII).
| 【1】 Lin, Y.-I.; Bitha, P.; Sakya, S.; Strohmeyer, T.W.; Bush, K. (American Cyanamid Co.); Novel 2-thiosubstd. carbapenems. CA 2118961; EP 0617036; JP 1994321948; US 5602118 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 33043 | (2R,3S)-2-(hydroxymethyl)tetrahydro-3-furanol | C5H10O3 | 详情 | 详情 | |
| (XII) | 33046 | S-[(2R,3R)-2-(azidomethyl)tetrahydro-3-furanyl] ethanethioate | C7H11N3O2S | 详情 | 详情 | |
| (XIII) | 33047 | (2R,3R)-2-(azidomethyl)tetrahydro-3-furanthiol; (2R,3R)-2-(azidomethyl)tetrahydro-3-furanylhydrosulfide | C5H9N3OS | 详情 | 详情 | |
| (XIV) | 33048 | (3S,4R)-3,4,5-trihydroxypentanal | 18546-37-7 | C5H10O4 | 详情 | 详情 |
| (XV) | 33049 | (2R,3S)-1,2,3,5-pentanetetrol | C5H12O4 | 详情 | 详情 | |
| (XVI) | 33050 | [(2R,3S)-3-hydroxytetrahydro-2-furanyl]methyl trifluoromethanesulfonate | C6H9F3O5S | 详情 | 详情 | |
| (XVII) | 33051 | (2R,3S)-2-(azidomethyl)tetrahydro-3-furanol | C5H9N3O2 | 详情 | 详情 | |
| (XVIII) | 33052 | (2R,3S)-2-(azidomethyl)tetrahydro-3-furanyl trifluoromethanesulfonate | C6H8F3N3O4S | 详情 | 详情 |
合成路线4
Coupling of carbapenem phosphate (VIII) with thiol (XIII) using diisopropylethylamine gave rise to sulfide (XIX). Hydrogenolysis of the p-nitrobenzyl group of (XIX) with simultaneous azide reduction in the presence of Pd/C provided (XX). Treatment of p-nitrobenzyl chloroformate (XXI) with p-nitrophenol (XXII) afforded the nitrophenyl carbonate (XXIII), which was coupled with L-valine (XXIV), yielding carbamate (XXV). Activation of (XXV) with N-hydroxy succinimide and DCC then produced the succinimidyl ester (XXVI). Amine (XX) was coupled with succinimidyl ester (XXVI) to furnish amide (XXVII). The p-nitrobenzyl ester was finally removed by hydrogenation over Pd/C to provide the title compound.
| 【1】 Lin, Y.-I.; et al.; Peptidic prodrugs of novel aminomethyl-THF 1beta-methylcarbapenems. Bioorg Med Chem Lett 1997, 7, 13, 1665. |
| 【2】 Lin, Y.-I.; Bitha, P.; Sakya, S.; Strohmeyer, T.W.; Bush, K. (American Cyanamid Co.); Novel 2-thiosubstd. carbapenems. CA 2118961; EP 0617036; JP 1994321948; US 5602118 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (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 |
| (XIII) | 33047 | (2R,3R)-2-(azidomethyl)tetrahydro-3-furanthiol; (2R,3R)-2-(azidomethyl)tetrahydro-3-furanylhydrosulfide | C5H9N3OS | 详情 | 详情 | |
| (XIX) | 33053 | 4-nitrobenzyl (4R,5S,6S)-3-[[(2R,3R)-2-(azidomethyl)tetrahydro-3-furanyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C22H25N5O7S | 详情 | 详情 | |
| (XX) | 33054 | (4R,5S,6S)-3-[[(2R,3R)-2-(aminomethyl)tetrahydro-3-furanyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid | C15H22N2O5S | 详情 | 详情 | |
| (XXI) | 33055 | 1-[[(chlorocarbonyl)oxy]methyl]-4-nitrobenzene | 4457-32-3 | C8H6ClNO4 | 详情 | 详情 |
| (XXII) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (XXIII) | 33056 | 4-nitrobenzyl 4-nitrophenyl carbonate | C14H10N2O7 | 详情 | 详情 | |
| (XXIV) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
| (XXV) | 33057 | (2S)-3-methyl-2-([[(4-nitrobenzyl)oxy]carbonyl]amino)butyric acid | C13H16N2O6 | 详情 | 详情 | |
| (XXVI) | 33058 | 4-nitrobenzyl (1S)-1-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-methylpropylcarbamate | C17H19N3O8 | 详情 | 详情 | |
| (XXVII) | 33059 | (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(2R,3R)-2-([[(2S)-3-methyl-2-([[(4-nitrobenzyl)oxy]carbonyl]amino)butanoyl]amino]methyl)tetrahydro-3-furanyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid | C28H36N4O10S | 详情 | 详情 |
合成路线5
A convergent synthesis was further developed. Azide (XII) was reduced to the corresponding amine (XXVIII) employing triethyl phosphite. Hydrolysis of the thioacetate ester of (XXVIII) then gave thiol (XXIX). Coupling of (XXIX) with protected valine succinimidyl ester (XXVI) produced amide (XXX). Condensation of (XXX) with carbapenem phosphate (VIII) yielded adduct (XXXI). The p-nitrobenzyl esters were finally deprotected by catalytic hydrogenation.
| 【1】 Lin, Y.I.; Li, Z.; Bitha, P.; Convergent synthesis of oral 1beta-methylcarbapenems. J Antibiot 1999, 52, 7, 643. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (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 |
| (XII) | 33046 | S-[(2R,3R)-2-(azidomethyl)tetrahydro-3-furanyl] ethanethioate | C7H11N3O2S | 详情 | 详情 | |
| (XXVI) | 33058 | 4-nitrobenzyl (1S)-1-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-methylpropylcarbamate | C17H19N3O8 | 详情 | 详情 | |
| (XXVIII) | 33060 | S-[(2R,3R)-2-(aminomethyl)tetrahydro-3-furanyl] ethanethioate | C7H13NO2S | 详情 | 详情 | |
| (XXIX) | 33061 | (2R,3R)-2-(aminomethyl)tetrahydro-3-furanylhydrosulfide; (2R,3R)-2-(aminomethyl)tetrahydro-3-furanthiol | C5H11NOS | 详情 | 详情 | |
| (XXX) | 33062 | 4-nitrobenzyl (1S)-2-methyl-1-[([[(2R,3R)-3-sulfanyltetrahydro-2-furanyl]methyl]amino)carbonyl]propylcarbamate | C18H25N3O6S | 详情 | 详情 | |
| (XXXI) | 33063 | 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(2R,3R)-2-([[(2S)-3-methyl-2-([[(4-nitrobenzyl)oxy]carbonyl]amino)butanoyl]amino]methyl)tetrahydro-3-furanyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C35H41N5O12S | 详情 | 详情 |