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【结 构 式】 
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【分子编号】38115 【品名】3-[(chlorocarbonyl)oxy]-1-propene 【CA登记号】2937-50-0 |
【 分 子 式 】C4H5ClO2 【 分 子 量 】120.5352 【元素组成】C 39.86% H 4.18% Cl 29.41% O 26.55% |
合成路线1
该中间体在本合成路线中的序号：(XLI)(S)-2-(Allyloxycarbonylamino)-3-[4-methoxy-3,5-bis(tert-butyldimethylsilyloxy)phenyl]propionic acid methyl ester (scheme 13922101a, cp. (IX)). The silylation of 3,5-dihydroxy-4-methoxybenzoic acid methyl ester (XXXII) with TBDMS-Cl, TEA and DMAP in dichloromethane gives the silylated compound (XXXIII), which is reduced with DIBAL in dichloromethane yielding the corresponding benzyl alcohol (XXXIV). The oxidation of (XXXIV) with pyridinium dichromate (PDC) in dichloromethane affords the benzaldehyde (XXXV), which is condensed with malonic acid monomethyl ester (XXXVI) by means of piperidine/AcOH in toluene providing the corresponding benzylidene derivative (XXXVII). The reaction of (XXXVII) with (PhO)2PO-N3 and benzyl alcohol in hot toluene affords the benzyloxycarbonylamino derivative (XXXVIII), which is enantioselectively reduced with H2 over a chiral Rh catalyst in methanol providing and (S)-2-(benzyloxycarbonylamino)-3-[4-methoxy-3,5-bis(tert-butyldimethylsilyloxy)phenyl]propionic acid methyl ester (XXXIX). Elimination of the benzyl protecting group of (XXXIX) with H2 over Pd/C in ethyl acetate gives the free aminoester (XL), which is finally reprotected with allyl chloroformate (XLI) and pyridine to furnish the desired intermediate (IX).
| 【1】 Gin, D.Y.; Corey, E.J.; Kania, R.S.; Enantioselective total synthesis of Ecteinascidin 743. J Am Chem Soc 1996, 118, 38, 9202-03. |
| 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) | 36457 | methyl (2S)-2-[[(allyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propanoate | C27H47NO7Si2 | 详情 | 详情 | |
| (XXXII) | 38107 | methyl 3,5-dihydroxy-4-methoxybenzoate | C9H10O5 | 详情 | 详情 | |
| (XXXIII) | 38108 | methyl 3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzoate | C21H38O5Si2 | 详情 | 详情 | |
| (XXXIV) | 38109 | (3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)methanol | C20H38O4Si2 | 详情 | 详情 | |
| (XXXV) | 38110 | 3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzaldehyde | C20H36O4Si2 | 详情 | 详情 | |
| (XXXVI) | 16198 | 3-Methoxy-3-oxopropionic acid; Malonic acid monomethyl ester | 16695-14-0 | C4H6O4 | 详情 | 详情 |
| (XXXVII) | 38111 | (E)-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)-2-(methoxycarbonyl)-2-propenoic acid | C24H40O7Si2 | 详情 | 详情 | |
| (XXXVIII) | 38112 | methyl (Z)-2-[[(benzyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)-2-propenoate | C31H47NO7Si2 | 详情 | 详情 | |
| (XXXIX) | 38113 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propanoate | C31H49NO7Si2 | 详情 | 详情 | |
| (XL) | 38114 | methyl (2S)-2-amino-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propanoate | C23H43NO5Si2 | 详情 | 详情 | |
| (XLI) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Swern oxidation of protected (hydroxymethyl)pyrrolidine (I), followed by Wittig condensation of the resulting aldehyde (II) with methylene triphenylphosphorane provided vinylpyrrolidine (III). Hydroboration of (III) with 9-borabicyclo[3.3.1]nonane and subsequent oxidative treatment with sodium perborate gave alcohol (IV). Interconversion of the N-benzyl protecting group for an allyloxycarbonyl group was achieved by catalytic hydrogenation and then treatment of the deprotected amine (V) with allyloxycarbonyl chloride (VI). Alcohol (VII) was activated as the corresponding mesylate (VIII), which was condensed with imidazole (IX) in the presence of t-BuOK to afford the N-alkylated imidazole (X). Acid deprotection of the silyl ether of (X) yielded the corresponding secondary alcohol, which was further converted to mesylate (XI). Subsequent displacement in (XI) by potassium thioacetate furnished the thioacetate ester (XII).
| 【1】 Barrett, D.; Azami, H.; Matsuda, K.; et al.; Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems. Part III: Novel 2-alkyl substituents containing cationic heteroaromatics linked via a C-N bond. Bioorg Med Chem 1999, 7, 8, 1665. |
| 【2】 Murata, M.; Tsutsumi, H.; Matsuda, K.; Hattori, K.; Nakajima, T. (Fujisawa Pharmaceutical Co., Ltd.); Substd. 3-pyrrolidinylthio-carbapenems as antimicrobial agents. EP 0636133; JP 1995505650; WO 9321186 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 | ||
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 32605 | ((2S,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]pyrrolidinyl)methanol | C18H31NO2Si | 详情 | 详情 | |
| (II) | 32606 | (2S,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]-2-pyrrolidinecarbaldehyde | C18H29NO2Si | 详情 | 详情 | |
| (III) | 32607 | (2S,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]-2-vinylpyrrolidine; (3S,5S)-1-benzyl-5-vinylpyrrolidinyl tert-butyl(dimethyl)silyl ether | C19H31NOSi | 详情 | 详情 | |
| (IV) | 32608 | 2-((2R,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]pyrrolidinyl)-1-ethanol | C19H33NO2Si | 详情 | 详情 | |
| (V) | 32609 | 2-((2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]pyrrolidinyl)-1-ethanol | C12H27NO2Si | 详情 | 详情 | |
| (VII) | 32610 | allyl (2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate | C16H31NO4Si | 详情 | 详情 | |
| (VIII) | 32611 | allyl (2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-[(methylsulfonyl)oxy]ethyl]-1-pyrrolidinecarboxylate | C17H33NO6SSi | 详情 | 详情 | |
| (IX) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (X) | 32612 | allyl (2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-(1H-imidazol-1-yl)ethyl]-1-pyrrolidinecarboxylate | C19H33N3O3Si | 详情 | 详情 | |
| (XI) | 32613 | allyl (2R,4S)-2-[2-(1H-imidazol-1-yl)ethyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C14H21N3O5S | 详情 | 详情 | |
| (XII) | 31614 | (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoic acid | C21H36ClNO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of 4(R)-hydroxy-L-proline (I) with allyl chloroformate (II) and NaOH gives the protected proline (III), which is esterified with MeOH and sulfuric acid to yield the methyl prolinate (IV). The reaction of (IV) with Ms-Cl and TEA affords the mesylate (V), which is reduced with NaBH4 to provide the prolinol derivative (VI). The Swern oxidation of alcohol (VI) gives the carbaldehyde (VII), which is condensed with the phosphorane (VIII) by means of NaOMe, yielding the acrylate (IX). The reduction of (IX) with DIBAL affords the substituted allyl alcohol (X), which is condensed with phthalimide (XI) by means of PPh3 and DIAD to provide the adduct (XII). The cleavage of the phthalimido group of (XII) with hydrazine gives the amino derivative (XIII), which is treated with Ms-Cl and TEA to yield the sulfonamide (XIV). The reaction of (XIV) with potassium thioacetate affords the acetylsulfanyl pyrrolidine (XV), which is hydrolyzed with HCl to provide the thiol (XVI). The condensation of the thiol (XVI) with the carbapenem derivative (XVII) by means of DIEA gives the protected adduct (XVIII), which is finally treated with Pd(II) and Bu3SnH in order to eliminate the allyl protecting groups. The intermediate carbapenem derivative (XVII) has been obtained from azetidinone (XIX) by known methods as indicated in the scheme.
| 【1】 Kwon, J.W.; Kim, W.B.; Kim, S.H.; Lee, M.G.; DA-1131. Drugs Fut 2001, 26, 11, 1040. |
| 【2】 Shin, H.C.; Kim, J.Y.; Kim, G.W.; Lee, C.W.; Lim, J.I.; Chang, M.S.; Kim, N.S.; Kim, D.S.; Im, W.B.; Rhee, J.K. (Dong-A Pharmaceutical Co., Ltd.); Carbapenem derivs. and processes for preparing the same. WO 9514692 . |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
| (III) | 47730 | (2S,4R)-1-[(allyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid | C9H13NO5 | 详情 | 详情 | |
| (IV) | 42200 | 1-allyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C10H15NO5 | 详情 | 详情 | |
| (V) | 42201 | 1-allyl 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate | C11H17NO7S | 详情 | 详情 | |
| (VI) | 42202 | allyl (2S,4R)-2-(hydroxymethyl)-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C10H17NO6S | 详情 | 详情 | |
| (VII) | 49446 | allyl (2S,4R)-2-formyl-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C10H15NO6S | 详情 | 详情 | |
| (VIII) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (IX) | 49447 | allyl (2S,4R)-2-[(E)-3-methoxy-3-oxo-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C13H19NO7S | 详情 | 详情 | |
| (X) | 49448 | allyl (2S,4R)-2-[(E)-3-hydroxy-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C12H19NO6S | 详情 | 详情 | |
| (XI) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (XII) | 49449 | allyl (2S,4R)-2-[(E)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C20H22N2O7S | 详情 | 详情 | |
| (XIII) | 49450 | allyl (2S,4R)-2-[(E)-3-amino-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C12H20N2O5S | 详情 | 详情 | |
| (XIV) | 50598 | allyl (2S,4R)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C13H22N2O7S2 | 详情 | 详情 | |
| (XV) | 49451 | allyl (2S,4S)-4-(acetylsulfanyl)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate | C14H22N2O5S2 | 详情 | 详情 | |
| (XVI) | 49452 | allyl (2S,4S)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C12H20N2O4S2 | 详情 | 详情 | |
| (XVII) | 32617 | allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C25H26NO8P | 详情 | 详情 | |
| (XVIII) | 49454 | allyl (4R,5S,6S)-3-[((3S,5S)-1-[(allyloxy)carbonyl]-5-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C25H35N3O8S2 | 详情 | 详情 | |
| (XIX) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (XX) | 50599 | C17H27N3O6Si | 详情 | 详情 | ||
| (XXI) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)In an alternative method, paclitaxel (I) was acylated with allyl chloroformate (V) to afford the bis-carbonate (VI). Dihydroxylation of both allyl groups of (VI) was accomplished by treatment with tert-butyl hydroperoxide producing (IV). The 2'-ester of (IV) was finally removed upon stirring in a NaHCO3-neutralized solution at room temperature.
| 【1】 Seligson, A.L.; et al.; A new prodrug of paclitaxel: Synthesis of Protaxel. Anti-Cancer Drugs 2001, 12, 4, 305. |
| 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) | 10595 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | 33069-62-4 | C47H51NO14 | 详情 | 详情 |
| (IV) | 56228 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-[((2R,3S)-3-(benzoylamino)-2-{[(2,3-dihydroxypropoxy)carbonyl]oxy}-3-phenylpropanoyl)oxy]-9-{[(2,3-dihydroxypropoxy)carbonyl]oxy}-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate | C55H63NO22 | 详情 | 详情 | |
| (V) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
| (VI) | 56229 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-9-{[(allyloxy)carbonyl]oxy}-15-{[(2R,3S)-2-{[(allyloxy)carbonyl]oxy}-3-(benzoylamino)-3-phenylpropanoyl]oxy}-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate | C55H59NO18 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)The selective silylation of azetidine (I) with TBDMSCl and Et3N in CH2Cl2 gives the fully silylated azetidine (II), which is condensed with 1-(trimethylsilyloxy) cyclohexene (III) by means of SnCl4 in CH3CN to yield the adduct (IV). The N-silylation of (IV) with TBDMSCl and Et3N in DMF affords the disilylated compound (V), which is condensed with diethyl chlorophosphate by means of LiHMDS in THF providing the phosphate ester (VI). The reaction of (VI) with MCPBA in CH2Cl2 gives the epoxide (VII), which is treated with methylamine and K2CO3 in ethyl acetate to yield the secondary amine (VIII). The acylation of (VIII) with allyl chloroformate (IX) and Et3N in CH2Cl2 affords the carbamate (X), which is cyclized with allyl chlorooxalate (XI) and Et3N in CH2Cl2 providing the tricyclic compound (XII). The desilylation of (XII) with TBAF and HOAc in THF gives the hydroxy diallyl ester (XIII), which is treated with Pd(PPh3)4 and 5,5-dimethylcyclohexane-1,3-dione (DMCHE) to yield the tricyclic aminoacid (XIV). Finally this compound is treated with benzyloxy formimidate (XV) in a pH 8 buffer to afford the target N-methylformamidino compound.
| 【1】 Perboni, A.; Donati, D.; Tarzia, G. (Glaxo Wellcome plc); Antibacterial condensed carbapenems. EP 0502468; EP 0575375; JP 1994505018; US 5426104; WO 9215288; WO 9215586 . |
| 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) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (II) | 41919 | (2R)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl acetate | C19H39NO4Si2 | 详情 | 详情 | |
| (III) | 15574 | 1-cyclohexen-1-yl trimethylsilyl ether; (1-cyclohexen-1-yloxy)(trimethyl)silane; 1-Cyclohexenyloxytrimethylsilane | 6651-36-1 | C9H18OSi | 详情 | 详情 |
| (IV) | 15575 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-oxocyclohexyl]-2-azetanone | C17H31NO3Si | 详情 | 详情 | |
| (V) | 41920 | (4R)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-oxocyclohexyl]-2-azetidinone | C23H45NO3Si2 | 详情 | 详情 | |
| (VI) | 41921 | (6R)-6-[(2R)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-1-cyclohexen-1-yl diethyl phosphate | C27H54NO6PSi2 | 详情 | 详情 | |
| (VII) | 41922 | (2R)-2-[(2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-7-oxabicyclo[4.1.0]hept-1-yl diethyl phosphate | C21H40NO7PSi | 详情 | 详情 | |
| (VIII) | 41923 | (4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-(methylamino)-2-oxocyclohexyl]-2-azetidinone | C18H34N2O3Si | 详情 | 详情 | |
| (IX) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
| (X) | 41924 | allyl (1S,3R)-3-[(2R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-2-oxocyclohexyl(methyl)carbamate | C22H38N2O5Si | 详情 | 详情 | |
| (XI) | 15585 | allyl 2-chloro-2-oxoacetate | C5H5ClO3 | 详情 | 详情 | |
| (XII) | 41925 | allyl (5S,8aS,8bR)-5-[[(allyloxy)carbonyl](methyl)amino]-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate | C27H42N2O6Si | 详情 | 详情 | |
| (XIII) | 41926 | allyl (5S,8aS,8bR)-5-[[(allyloxy)carbonyl](methyl)amino]-1-[(1R)-1-hydroxyethyl]-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate | C21H28N2O6 | 详情 | 详情 | |
| (XIV) | 41927 | (5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-(methylamino)-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylic acid | C14H20N2O4 | 详情 | 详情 | |
| (XV) | 41928 | 1-[[amino(imino)methoxy]methyl]benzene | C8H10N2O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XXI)Reaction of the carboxylic acid (XVI) with MsCl and TEA in THF yields the fully protected mixed anhydride (XVII). The chemo-selective ammonolysis of anhydride (XVII) gives amide (XVIII), which by displacement of the mesyloxy group with potassium thioacetate in hot DMF yields the thioacetate (XIX). Removal of the Boc protecting groups of (XIX) with HCl in ethyl acetate affords compound (XX), which is reprotected with allyl chloroformate (XXI) and TEA in dichloromethane to provide the bis(allyloxycarbonyl) compound (XXII). Hydrolysis of the thioacetate group of (XXII) with NaOH in methanol gives the thiol compound (XXIII), which is condensed with the carbape- nem diphenyl phosphate (XXIV) by means of DIEA in acetonitrile to provide the expected adduct (XXV). Finally, this compound is deprotected by a treatment with Bu3SnH and PdCl2(PPh3)2 in dichloromethane/water.
| 【1】 Yamada, K.; Miura, K.; Nishimura, I.; Shimizu, A.; Morishima, H.; Abe, S.; Nakajima, S.; Sakuraba, S.; Imamura, H.; Sato, H.; Sugimoto, Y.; Stereoselective synthesis of a broad spectrum 1 beta-methylcarbapenem, J-114,870. Tetrahedron 2000, 56, 39, 7705. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 32617 | allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C25H26NO8P | 详情 | 详情 | |
| (XVI) | 48235 | (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-[(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]phenyl]propionic acid | C23H34N2O7 | 详情 | 详情 | |
| (XVII) | 48238 | tert-butyl (2R,4R)-2-(4-[(1S)-1-[(tert-butoxycarbonyl)amino]-3-[(methylsulfonyl)oxy]-3-oxopropyl]phenyl)-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C25H38N2O11S2 | 详情 | 详情 | |
| (XVIII) | 48239 | tert-butyl (2R,4R)-2-(4-[(1S)-3-amino-1-[(tert-butoxycarbonyl)amino]-3-oxopropyl]phenyl)-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C24H37N3O8S | 详情 | 详情 | |
| (XIX) | 48240 | tert-butyl (2R,4S)-4-(acetylsulfanyl)-2-(4-[(1S)-3-amino-1-[(tert-butoxycarbonyl)amino]-3-oxopropyl]phenyl)-1-pyrrolidinecarboxylate | C25H37N3O6S | 详情 | 详情 | |
| (XX) | 48241 | S-((3S,5R)-5-[4-[(1S)-1,3-diamino-3-oxopropyl]phenyl]pyrrolidinyl) ethanethioate | C15H21N3O2S | 详情 | 详情 | |
| (XXI) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
| (XXII) | 48242 | allyl (2R,4S)-4-(acetylsulfanyl)-2-[4-((1S)-1-[[(allyloxy)carbonyl]amino]-3-amino-3-oxopropyl)phenyl]-1-pyrrolidinecarboxylate | C23H29N3O6S | 详情 | 详情 | |
| (XXIII) | 48243 | C21H27N3O5S | 详情 | 详情 | ||
| (XXV) | 48244 | allyl (4R,5S,6S)-3-([(3S,5R)-1-[(allyloxy)carbonyl]-5-[4-((1S)-1-[[(allyloxy)carbonyl]amino]-3-amino-3-oxopropyl)phenyl]pyrrolidinyl]sulfanyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C34H42N4O9S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：The title compound has been prepared by either solid-phase or solution-phase synthesis. In the first case, N(alpha)-Boc-N(omega)-nitro-L-arginine (I) was coupled with N,O-dimethylhydroxylamine, and the resulting N-methoxy-amide (II) was reduced with LiAlH4 to the corresponding aldehyde, isolated as the cyclic hemiaminal (III). Deprotection of the N-nitro group of (III) by hydrogenation over Pd/C afforded guanidine (IV), which was condensed with allyl chloroformate to give the allyl carbamate (V). Subsequent acid-catalyzed condensation with ethyl 6-hydroxyhexanoate (VI) at the aminal hydroxyl group provided ketal (VII). After hydrolysis of the ethyl ester of (VII), the resulting carboxylic acid (VIII) was coupled to amino-resin to produce the amide-resin (IX).
| 【1】 Cohen, C.R.; Weinhouse, M.I.; Roberts, C.; et al.; Synthesis and biological activity of transition-state urokinase inhibitors. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 090. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 29372 | N-alpha-(tert-butoxycarbonyl)-N-omega'-nitro-L-arginine | C11H21N5O6 | 详情 | 详情 | |
| (II) | 29373 | N-alpha-(tert-butoxycarbonyl)-N1-methoxy-N1-methyl-N-omega'-nitro-L-argininamide | C13H26N6O6 | 详情 | 详情 | |
| (III) | 29374 | 3(S)-(Tert-butoxycarbonylamino)-2-hydroxy-N2-nitropiperidine-1-carboxamidine | C11H21N5O5 | 详情 | 详情 | |
| (IV) | 29375 | tert-butyl (3S)-1-[amino(imino)methyl]-2-hydroxypiperidinylcarbamate | C11H22N4O3 | 详情 | 详情 | |
| (V) | 29376 | allyl (E)-amino[(3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxypiperidinyl]methylidenecarbamate | C15H26N4O5 | 详情 | 详情 | |
| (VI) | 29377 | ethyl 6-hydroxyhexanoate | C8H16O3 | 详情 | 详情 | |
| (VII) | 29378 | ethyl 6-([(3S)-1-[[[(allyloxy)carbonyl]imino](amino)methyl]-3-[(tert-butoxycarbonyl)amino]piperidinyl]oxy)hexanoate | C23H40N4O7 | 详情 | 详情 | |
| (VIII) | 29379 | 6-([(3S)-1-[[[(allyloxy)carbonyl]imino](amino)methyl]-3-[(tert-butoxycarbonyl)amino]piperidinyl]oxy)hexanoic acid | C21H36N4O7 | 详情 | 详情 | |
| (IX) | 29380 | allyl (E)-amino[(3S)-2-[(6-amino-6-oxohexyl)oxy]-3-[(tert-butoxycarbonyl)amino]piperidinyl]methylidenecarbamate | C21H37N5O6 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：6-Aminopenicillanic acid benzhydryl ester (I) was protected as the carbamate (II) using allyl chloroformate. Subsequent oxidation of (II) with m-chloroperbenzoic acid provided sulfoxide (III). Opening of the thiazolidine ring of (III) by means of 2-mercaptobenzothiazole (IV) produced disulfide (V), which was further cyclized in the presence of arylacetic acid (VI) and silver acetate to furnish a 4:1 mixture of penicillanic ester (VII) and the cephalosporanic analogue (VIII). Deprotection of the required isomer (VII) employing Pd(PPh3)4 and Bu3SnH afforded amine (IX). Diazotization of (IX) with isopropyl nitrite, followed by treatment with propylene oxide and Rh2(OAc)4 gave rise to oxolactam (X). Wittig reaction of (X) with the ylide resulting from phosphonium salt (XI) and NaNH2 provided the (pyridylmethylene) derivative (XII). Finally, oxidation to the corresponding sulfone and cleavage of the protecting groups provided the title compound.
| 【1】 Buynak, J.D.; et al.; New beta-lactamase inhibitors of the class A and class C enzymes. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 194. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 35142 | benzhydryl (2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C21H22N2O3S | 详情 | 详情 | |
| (II) | 35143 | benzhydryl (2S,5R,6R)-6-[[(allyloxy)carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C25H26N2O5S | 详情 | 详情 | |
| (III) | 35144 | benzhydryl (2S,5R,6R)-6-[[(allyloxy)carbonyl]amino]-3,3-dimethyl-4,7-dioxo-4lambda(4)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C25H26N2O6S | 详情 | 详情 | |
| (IV) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (V) | 35145 | benzhydryl (2R)-2-[(2R,3R)-3-[[(allyloxy)carbonyl]amino]-2-(1,3-benzothiazol-2-yldisulfanyl)-4-oxoazetidinyl]-3-methyl-3-butenoate | C32H29N3O5S3 | 详情 | 详情 | |
| (VI) | 35146 | 2-[3,4-di(tert-butoxy)phenyl]acetic acid | C16H24O4 | 详情 | 详情 | |
| (VII) | 35147 | benzhydryl (2S,3R,5R,6R)-6-[[(allyloxy)carbonyl]amino]-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C41H48N2O9S | 详情 | 详情 | |
| (VIII) | 35148 | benzhydryl (2R,3S,7R)-7-[[(allyloxy)carbonyl]amino]-3-([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylate | C41H48N2O9S | 详情 | 详情 | |
| (IX) | 35149 | benzhydryl (2S,3R,5R,6R)-6-amino-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C37H44N2O7S | 详情 | 详情 | |
| (X) | 35150 | benzhydryl (2S,3R,5R)-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-6,7-dioxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C37H41NO8S | 详情 | 详情 | |
| (XI) | 35151 | triphenyl(2-pyridinylmethyl)phosphonium chloride; 2-picolyl triphenylphosphonium chloride | 73870-25-4 | C24H21ClNP | 详情 | 详情 |
| (XII) | 35152 | benzhydryl (2S,3R,5R)-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-6-[(Z)-2-pyridinylmethylidene]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C43H46N2O7S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：The enantiopure diol (II) was prepared by the Sharpless asymmetric dihydroxylation of ethyl sorbate (I). Catalytic hydrogenation of (II) generated the gamma-lactone (III). After conversion of the hydroxyl group of (III) to the corresponding mesylate, displacement by NaN3 afforded azide (IV). Reduction of (IV) to amine gave rise to the formation of lactam (V). Sequential protection of alcohol and amide functions provided (VI), which was treated with lithium hexamethyldisilazide and Comin's reagent to furnish the aminovinyl triflate (VII). The enantiopure propargyl alcohol (X), prepared by treatment of (S)-glycidol pivalate (VIII) with lithium trimethylsilylacetylide (IX) followed by desilylation with tetrabutylammonium fluoride, was then coupled with triflate (VII) in the presence of Pd(PPh3)4 and CuI to yield adduct (XI), which was reduced to the trisubstituted piperidine (XII) by means of NaBH3CN and trifluoroacetic acid. Hydrogenation of the alkyne function of (XII) with concomitant removal of the benzyloxycarbonyl group gave (XIII). This was further protected as the allyl carbamate (XIV) by treatment with allyl chloroformate. The secondary alcohol of (XIV) was then protected as the tetrahydropyranyl ether (XV), and subsequent reductive cleavage of the pivaloyl ester with DIBAL liberated the primary alcohol (XVI).
| 【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 40236 | ethyl (2E,4E)-2,4-hexadienoate | 2396-84-1 | C8H12O2 | 详情 | 详情 |
| (II) | 40237 | ethyl (E,4R,5R)-4,5-dihydroxy-2-hexenoate | C8H14O4 | 详情 | 详情 | |
| (III) | 40238 | (5R)-5-[(1R)-1-hydroxyethyl]dihydro-2(3H)-furanone | C6H10O3 | 详情 | 详情 | |
| (IV) | 40239 | (5R)-5-[(1R)-1-azidoethyl]dihydro-2(3H)-furanone | C6H9N3O2 | 详情 | 详情 | |
| (V) | 40240 | (5R,6S)-5-hydroxy-6-methyl-2-piperidinone | C6H11NO2 | 详情 | 详情 | |
| (VI) | 40241 | benzyl (2S,3R)-2-methyl-6-oxo-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C23H37NO4Si | 详情 | 详情 | |
| (VII) | 40242 | benzyl (2S,3R)-2-methyl-6-[[(trifluoromethyl)sulfonyl]oxy]-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate | C24H36F3NO6SSi | 详情 | 详情 | |
| (VIII) | 12235 | (2S)oxiranylmethyl pivalate | C8H14O3 | 详情 | 详情 | |
| (IX) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (X) | 12236 | (2S)-2-hydroxy-4-pentynyl pivalate | C10H16O3 | 详情 | 详情 | |
| (XI) | 40243 | benzyl (2S,3R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate | C33H51NO6Si | 详情 | 详情 | |
| (XII) | 40244 | benzyl (2S,3R,6R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C33H53NO6Si | 详情 | 详情 | |
| (XIII) | 40245 | (2R)-2-hydroxy-5-[(2S,5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]pentyl pivalate | C25H51NO4Si | 详情 | 详情 | |
| (XIV) | 40246 | allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxypentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 | |
| (XV) | 40247 | allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C34H63NO7Si | 详情 | 详情 | |
| (XVI) | 40248 | allyl (2S,3R,6S)-6-[(4R)-5-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：The enantiopure diol (II) was prepared by the Sharpless asymmetric dihydroxylation of ethyl sorbate (I). Catalytic hydrogenation of (II) generated the gamma-lactone (III). After conversion of the hydroxyl group of (III) to the corresponding mesylate, displacement by NaN3 afforded azide (IV). Reduction of (IV) to amine gave rise to the formation of lactam (V). Sequential protection of alcohol and amide functions of (V) provided (VI), which was treated with lithium hexamethyldisilazide and Comin's reagent to furnish the aminovinyl triflate (VII). The enantiopure propargyl alcohol (X), prepared by treatment of (S)-glycidol pivalate (VIII) with lithium trimethylsilylacetylide (IX) followed by desilylation with tetrabutylammonium fluoride, was then coupled with triflate (VII) in the presence of Pd(PPh3)4 and CuI to yield adduct (XI), which was reduced to the trisubstituted piperidine (XII) by means of NaBH3CN and trifluoroacetic acid. Hydrogenation of the alkyne function of (XII) with concomitant removal of the benzyloxycarbonyl group gave (XIII). This was further protected as the allyl carbamate (XIV) by treatment with allyl chloroformate. The secondary alcohol of (XIV) was then protected as the tetrahydropyranyl ether (XV), and subsequent reductive cleavage of the pivaloyl ester with DIBAL liberated the primary alcohol (XVI).
| 【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 40236 | ethyl (2E,4E)-2,4-hexadienoate | 2396-84-1 | C8H12O2 | 详情 | 详情 |
| (II) | 40237 | ethyl (E,4R,5R)-4,5-dihydroxy-2-hexenoate | C8H14O4 | 详情 | 详情 | |
| (III) | 40238 | (5R)-5-[(1R)-1-hydroxyethyl]dihydro-2(3H)-furanone | C6H10O3 | 详情 | 详情 | |
| (IV) | 40239 | (5R)-5-[(1R)-1-azidoethyl]dihydro-2(3H)-furanone | C6H9N3O2 | 详情 | 详情 | |
| (V) | 40240 | (5R,6S)-5-hydroxy-6-methyl-2-piperidinone | C6H11NO2 | 详情 | 详情 | |
| (VI) | 40241 | benzyl (2S,3R)-2-methyl-6-oxo-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C23H37NO4Si | 详情 | 详情 | |
| (VII) | 40242 | benzyl (2S,3R)-2-methyl-6-[[(trifluoromethyl)sulfonyl]oxy]-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate | C24H36F3NO6SSi | 详情 | 详情 | |
| (VIII) | 12235 | (2S)oxiranylmethyl pivalate | C8H14O3 | 详情 | 详情 | |
| (IX) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (X) | 12236 | (2S)-2-hydroxy-4-pentynyl pivalate | C10H16O3 | 详情 | 详情 | |
| (XI) | 40243 | benzyl (2S,3R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-3,4-dihydro-1(2H)-pyridinecarboxylate | C33H51NO6Si | 详情 | 详情 | |
| (XII) | 40244 | benzyl (2S,3R,6R)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxy-1-pentynyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C33H53NO6Si | 详情 | 详情 | |
| (XIII) | 40245 | (2R)-2-hydroxy-5-[(2S,5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]pentyl pivalate | C25H51NO4Si | 详情 | 详情 | |
| (XIV) | 40246 | allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-hydroxypentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 | |
| (XV) | 40247 | allyl (2S,3R,6S)-6-[(4R)-5-[(2,2-dimethylpropanoyl)oxy]-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C34H63NO7Si | 详情 | 详情 | |
| (XVI) | 40248 | allyl (2S,3R,6S)-6-[(4R)-5-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)pentyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C29H55NO6Si | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VII)The nitration of the dimeric benzoic acid (I) with 70% HNO3 gives the dimeric nitrobenzoic acid (II), which is treated with oxalyl chloride in THF to yield the acid chloride (III). The reaction of (III) with the pyrrolidine (IV) by means of TEA in the same solvent affords the diamide (V). The reduction of the nitro groups of (V) with RaNI and hydrazine in methanol provides the diamino compound (VI), which is protected with allyloxycarbonyl chloride (VII) and pyridine in dichloromethane to give the bis carbamate (VIII). The oxidation of the OH groups of (VIII) with oxalyl chloride and TEA in DMSO/dichloromethane yields the bis-pyrrolidinone (IX), which is allowed to react with methyl triphenylphosphonium bromide (X) and tBu-OK in THF to afford the bis exomethylene derivative (XI).
| 【1】 Gregson, S.J.; Howard, P.W.; Corcoran, K.E.; Jenkins, T.C.; Kelland, L.R.; Thurston, D.E.; Synthesis of the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine dimer. Bioorg Med Chem Lett 2001, 11, 21, 2859. |
| 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) | 47736 | 4-[3-(4-carboxy-2-methoxyphenoxy)propoxy]-3-methoxybenzoic acid | C19H20O8 | 详情 | 详情 | |
| (II) | 47737 | 4-[3-(4-carboxy-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrobenzoic acid | C19H18N2O12 | 详情 | 详情 | |
| (III) | 47738 | 4-[3-[4-(chlorocarbonyl)-2-methoxy-5-nitrophenoxy]propoxy]-5-methoxy-2-nitrobenzoyl chloride | C19H16Cl2N2O10 | 详情 | 详情 | |
| (IV) | 62872 | (3R,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-pyrrolidinol | C11H25NO2Si | 详情 | 详情 | |
| (V) | 62873 | [(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]{4-[3-(4-{[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]carbonyl}-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrophenyl}methanone | C41H64N4O14Si2 | 详情 | 详情 | |
| (VI) | 62874 | {2-amino-4-[3-(5-amino-4-{[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]carbonyl}-2-methoxyphenoxy)propoxy]-5-methoxyphenyl}[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]methanone | C41H68N4O10Si2 | 详情 | 详情 | |
| (VII) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
| (VIII) | 62875 | allyl 5-[3-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]carbonyl}-2-methoxyphenoxy)propoxy]-2-{[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]carbonyl}-4-metho | C49H76N4O14Si2 | 详情 | 详情 | |
| (IX) | 62876 | allyl 5-[3-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-oxopyrrolidinyl]carbonyl}-2-methoxyphenoxy)propoxy]-2-{[(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-oxopyrrolidinyl]carbonyl}-4-methoxyphenylcarbam | C49H72N4O14Si2 | 详情 | 详情 | |
| (X) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XI) | 62877 | allyl 5-[3-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methylenepyrrolidinyl]carbonyl}-2-methoxyphenoxy)propoxy]-2-{[(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methylenepyrrolidinyl]carbonyl}-4-methoxy | C51H76N4O12Si2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(IV)The silylated 5-fluorocytosine (I) is coupled with D-ribofuranose tetraacetate (II) in the presence of SnCl4 in acetonitrile to afford the triacetyl 5-fluorocytidine (III). Acylation of (III) with allyl chloroformate (IV) yields carbamate (V). Then, methanolysis of the acetate ester groups of (V) provides 5-fluoro-N-(allyloxycarbonyl)cytidine (VI). Finally, selective oxidation of the primary alcohol group of (VI) with oxygen and PtO2 gives the target carboxylic acid
| 【1】 Kim, K.-H.; Kim, J.-Y; Lee, K-H; Noh, M.-J.; Kim, Y.-C.; Park, H.-J.; Synthesis and biological activity of the new 5-fluorocytosine derivatives, 5'-deoxy-N-alkyloxycarbonyl-5-fluorocytosine-5'-carboxylic acid. Bioorg Med Chem Lett 2002, 12, 3, 483. |
| 【2】 Lee, K.-H.; Kim, J.-Y.; Kim, Y.-C.; Kim, K.-H.; Park, H.-J.; Noh, M.-J.; Park, Y.-S.; Cho, S.-M. (Kolon Industries, Inc.); 5'-Deoxy-N-(substd. oxycarbonyl)-5-fluorocytosine and derivs. thereof, method of preparing same, and anticancer compsn. comprising same as active ingredients. WO 0211668 . |
| 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) | 36959 | 5-fluoro-N-(trimethylsilyl)-2-[(trimethylsilyl)oxy]-4-pyrimidinamine; N-[5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl]-N-(trimethylsilyl)amine | C10H20FN3OSi2 | 详情 | 详情 | |
| (II) | 33835 | (2R,3R,4R,5S)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-3-furanyl acetate | 13035-61-5 | C13H18O9 | 详情 | 详情 |
| (III) | 60387 | (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]tetrahydro-3-furanyl acetate | C15H18FN3O8 | 详情 | 详情 | |
| (IV) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
| (V) | 60388 | (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-[4-{[(allyloxy)carbonyl]amino}-5-fluoro-2-oxo-1(2H)-pyrimidinyl]tetrahydro-3-furanyl acetate | C19H22FN3O10 | 详情 | 详情 | |
| (VI) | 60389 | allyl 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-fluoro-2-oxo-1,2-dihydro-4-pyrimidinylcarbamate | C13H16FN3O7 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(A)Dynamic kinetic resolution of 3-acetyl-1-benzyl-2-pyrrolidinone (I) by Ru-BINAP catalyzed hydrogenation provides the (hydroxyethyl) pyrrolidinone (II). Subsequent reduction of lactam (II) employing NaBH4-BF3•Et2O affords pyrrolidine (III). After debenzylation of (III) by hydrogenation over Pd/C, the resultant pyrrolidine (IV) is protected as the corresponding N-Alloc derivative (V) upon treatment with allyl chloroformate. Subsequent Swern oxidation of the alcohol function of (V) leads to the optically pure ketone (VI). Treatment of ketone (VI) with Me3SiOTf and Et3N, followed by condensation with the acetoxyazetidinone (VII) affords adduct (VIII). Acylation of azetidinone (VIII) with allyl oxalyl chloride (IX), followed by cyclization of the intermediate oxalimide in the presence of triethyl phosphite, gives rise to the carbapenem system ( X). Desilylation of (X) with tetrabutylammonium fluoride leads to alcohol (XI). Further palladium-catalyzed deprotection of both the Alloc and allyl ester groups of (XI) provides the pyrrolidinyl carbapenem (XII). Finally, introduction of the desired N-methyl formimidoyl group into (XII) is accomplished by treatment with ethyl N-methyl formimidate.
| 【1】 Hattori, K.; et al.; Synthesis and antibacterial evaluation of novel 2-[N-imidoylpyrrolidinyl] carbapenems. Bioorg Med Chem Lett 2002, 12, 3, 383. |
| 【2】 Murata, M.; Chiba, T.; Tsutsumi, H.; Hattori, K.; Kuroda, S.; Ohtake, H.; Shirai, F. (Fujisawa Pharmaceutical Co., Ltd.); 1-Azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid cpds.. EP 0394991; JP 1990300187; US 5102877 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
| (B) | 60185 | ethyl methyliminoformate | C4H9NO | 详情 | 详情 | |
| (I) | 60175 | 3-acetyl-1-benzyl-2-pyrrolidinone | C13H15NO2 | 详情 | 详情 | |
| (II) | 60176 | (3S)-1-benzyl-3-[(1R)-1-hydroxyethyl]-2-pyrrolidinone | C13H17NO2 | 详情 | 详情 | |
| (III) | 60177 | (1R)-1-[(3R)-1-benzylpyrrolidinyl]-1-ethanol | C13H19NO | 详情 | 详情 | |
| (IV) | 60178 | (1R)-1-[(3R)pyrrolidinyl]-1-ethanol | C6H13NO | 详情 | 详情 | |
| (V) | 60179 | allyl (3R)-3-[(1R)-1-hydroxyethyl]-1-pyrrolidinecarboxylate | C10H17NO3 | 详情 | 详情 | |
| (VI) | 60180 | allyl (3R)-3-acetyl-1-pyrrolidinecarboxylate | C10H15NO3 | 详情 | 详情 | |
| (VII) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (VIII) | 60181 | allyl (3R)-3-{2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidinyl]acetyl}-1-pyrrolidinecarboxylate | C21H36N2O5Si | 详情 | 详情 | |
| (IX) | 15585 | allyl 2-chloro-2-oxoacetate | C5H5ClO3 | 详情 | 详情 | |
| (X) | 60182 | 2-propenyl 6-(1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-7-oxo-3-{1-[(2-propenyloxy)carbonyl]-3-pyrrolidinyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C26H40N2O6Si | 详情 | 详情 | |
| (XI) | 60183 | 2-propenyl 6-(1-hydroxyethyl)-7-oxo-3-{1-[(2-propenyloxy)carbonyl]-3-pyrrolidinyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C20H26N2O6 | 详情 | 详情 | |
| (XII) | 60184 | 6-(1-hydroxyethyl)-7-oxo-3-(3-pyrrolidinyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid | C13H18N2O4 | 详情 | 详情 |