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【结 构 式】 
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【分子编号】32617 【品名】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 【CA登记号】 |
【 分 子 式 】C25H26NO8P 【 分 子 量 】499.457142 【元素组成】C 60.12% H 5.25% N 2.8% O 25.63% P 6.2% |
合成路线1
该中间体在本合成路线中的序号：(XV)Cyclization of diazo azetidinone (XIII) by means rhodium(II) octanoate dimer produced the azabicyclo ketone (XIV), which was converted to the phosphorylated carbapenem (XV) employing diphenylphosphorochloridate. Hydrolysis of the thioacetate ester (XII) with NaOMe gave the intermediate thiol (XVI), which was condensed with phosphate (XV) to yield the (pyrrolidinylthio)carbapenem (XVII). Quaternization of the imidazole nucleus of (XVII) with methyl iodide afforded imidazolium salt (XVIII). Then, both allyl ester and allyloxycarbonyl groups of (XVIII) were deprotected using tributyltin hydride and a palladium catalyst. Finally, the iodide salt was exchanged for the corresponding chloride employing an ion exchange resin.
| 【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 |
|---|---|---|---|---|---|---|
| (XII) | 32614 | allyl (2R,4S)-4-(acetylsulfanyl)-2-[2-(1H-imidazol-1-yl)ethyl]-1-pyrrolidinecarboxylate | C15H21N3O3S | 详情 | 详情 | |
| (XIII) | 32615 | (4R)-1-(allyloxy)-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-1,3-dioxo-2-pentanediazonium | C13H18N3O5 | 详情 | 详情 | |
| (XIV) | 32616 | allyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C13H17NO5 | 详情 | 详情 | |
| (XV) | 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) | 32618 | allyl (2R,4S)-2-[2-(1H-imidazol-1-yl)ethyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C13H19N3O2S | 详情 | 详情 | |
| (XVII) | 32619 | allyl (4R,5S,6S)-3-([(3S,5R)-1-[(allyloxy)carbonyl]-5-[2-(1H-imidazol-1-yl)ethyl]pyrrolidinyl]sulfanyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C26H34N4O6S | 详情 | 详情 | |
| (XVIII) | 32620 | 3-[2-[(2R,4S)-1-[(allyloxy)carbonyl]-4-([(4R,5S,6S)-2-[(allyloxy)carbonyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]sulfanyl)pyrrolidinyl]ethyl]-1-methyl-1H-imidazol-3-ium iodide | C27H37IN4O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)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3
该中间体在本合成路线中的序号：(XIII)The condensation of the formyl pyrrolidine (I) with ethyl (triphenylphosphoranylidene)acetate (II) in dichloromethane gives acrylate (III), which is reduced with DIBAL in THF to yield the substituted allyl alcohol (IV). The condensation of (IV) with phthalimide (V) by means of PPh3 and DEAD in THF affords the adduct (VI), which is treated with hydrazine ethanol to provide the amino derivative (VII). The reaction of (VII) with Ms-Cl and TEA in dichloromethane gives the sulfonamide (VIII), which is desilylated by means of TBAF in THF, yielding the pyrrolidinol (IX). The reaction of (IX) with Ms-Cl and TEA in dichloromethane affords the sulfonate (X), which is treated with potassium thioacetate in refluxing acetonitrile to provide the acetylsulfanylpyrrolidine (XI). The hydrolysis of (XI) with NaOH in methanol gives the thiol (XII), which is condensed with the carbapenem derivative (XIII) by means of DIEA in acetonitrile to yield the protected adduct (XIV). Finally, this compound is treated with PdCl2(PPh3)2 and Bu3SnH in dichloromethane in order to eliminate the allyl protecting groups.
| 【1】 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) | 50600 | allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-formyl-1-pyrrolidinecarboxylate | C15H27NO4Si | 详情 | 详情 | |
| (II) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (III) | 50601 | allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-ethoxy-3-oxo-1-propenyl]-1-pyrrolidinecarboxylate | C19H33NO5Si | 详情 | 详情 | |
| (IV) | 50602 | allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-hydroxy-1-propenyl]-1-pyrrolidinecarboxylate | C17H31NO4Si | 详情 | 详情 | |
| (V) | 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 |
| (VI) | 50603 | allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-propenyl]-1-pyrrolidinecarboxylate | C25H34N2O5Si | 详情 | 详情 | |
| (VII) | 50604 | allyl (2S,4R)-2-[(E)-3-amino-1-propenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate | C17H32N2O3Si | 详情 | 详情 | |
| (VIII) | 50605 | allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate | C18H34N2O5SSi | 详情 | 详情 | |
| (IX) | 50606 | allyl (2S,4R)-4-hydroxy-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate | C12H20N2O5S | 详情 | 详情 | |
| (X) | 50598 | allyl (2S,4R)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C13H22N2O7S2 | 详情 | 详情 | |
| (XI) | 49451 | allyl (2S,4S)-4-(acetylsulfanyl)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate | C14H22N2O5S2 | 详情 | 详情 | |
| (XII) | 49452 | allyl (2S,4S)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C12H20N2O4S2 | 详情 | 详情 | |
| (XIII) | 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 | |
| (XIV) | 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 |
合成路线4
该中间体在本合成路线中的序号：(IV)MK-0826 can be synthesized as follows: The cyclization of 2-diazo-4-[3-(1-hydroxyethyl)-4-oxoazetidin-2-yl]-3-oxopentanoic acid allyl ester (I) by means of rhodium octanoate gives the 2-oxocarbapenam derivative (II), which by reaction with chlorophosphoric acid diphenyl ester (III) and DIEA in acetonitrile yields the enol phosphate (IV). Condensation of (IV) with the sulfanylpyrrolidine (V) by means of DIEA in acetonitrile affords the corresponding addition compound MK-0826 diallyl ester (VI), which is finally deprotected by means of Meldrum's acid and Pd(PPh3)4 in DMF/THF and converted to the sodium salt.
| 【1】 Betts, M.J.; Davies, G.M.; Swain, M.L. (AstraZeneca plc); Carbapenems containing a carboxy substd. phenyl group, processes for their preparation, intermediates and use as antibiotics. EP 0579826; JP 1994506704; US 5478820; US 5652233; US 5856321; WO 9315078 . |
| 【2】 Leeson, P.A.; Rabasseda, X.; Castañer, J.; Sorbera, L.A.; MK-0826. Drugs Fut 2000, 25, 8, 795. |
| 【3】 Houghton, P.; Williams, J.M.; Skerlj, R.; Brands, K.M.J. (Merck & Co., Inc.); Process for synthesizing carbapenem antibiotics. WO 9945010 . |
| 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) | 39645 | allyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate | C13H17N3O5 | 详情 | 详情 | |
| (II) | 32616 | allyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C13H17NO5 | 详情 | 详情 | |
| (III) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (IV) | 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 | |
| (V) | 39646 | allyl (2S,4S)-2-([3-[(allyloxy)carbonyl]anilino]carbonyl)-4-sulfanyl-1-pyrrolidinecarboxylate | C19H22N2O5S | 详情 | 详情 | |
| (VI) | 39647 | allyl (4R,5S,6S)-3-[[(3S,5S)-1-[(allyloxy)carbonyl]-5-([3-[(allyloxy)carbonyl]anilino]carbonyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C32H37N3O9S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XI)The Grignard condensation of the chiral pyrrolidinone (I) with 4-(dimethoxymethyl)phenylmagnesium bromide (II) in THF, followed by reduction with NaBH4, gives the aminoalcohol (III), which is cyclized to the pyrrolidine (IV) by means of MsCl and TEA in dichloromethane. Hydrolysis of the dimethyl acetal of (IV), followed by separation of the resulting diastereomeric mixture of aldehydes, yields the desired diastereomer (V). The reduction of (V) with NaBH4, followed by reaction with Ms-Cl in dichloromethane, affords the mesylate (VI), which by reaction with methylamine provides the secondary amine (VII). The protection of (VII) with allyl chloroformate and TEA, cleavage of the silyl-protecting group gives the hydroxy pyrrolidine (VIII), which is treated with MsCl and TEA to yield the mesylate (IX). The reaction of (IX) with potassium thioacetate in hot DMF affords the sulfanyl pyrrolidine (X), which is condensed with the penem diphenyl phosphate (XI) by means of DIEA in acetonitrile to provide the protected intermediate (XII). Finally, (XII) is converted into the target compound by reaction with PdCl2(PPh3)2 and Bu3SnH in dichloromethane/water.
| 【1】 Imamura, H.; et al.; A novel 1beta-methylcarbapenem, J-111,225: Effects of the C-3 and C-5 stereochemistry of the pyrrolidinylthio side chain on antibacterial activities. J Antibiot 2000, 53, 3, 314. |
| 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) | 30852 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate | C22H35NO4Si | 详情 | 详情 | |
| (II) | 30851 | bromo[4-(dimethoxymethyl)phenyl]magnesium | C9H11BrMgO2 | 详情 | 详情 | |
| (III) | 43977 | tert-butyl (2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-4-[4-(dimethoxymethyl)phenyl]-4-hydroxybutylcarbamate | C24H43NO6Si | 详情 | 详情 | |
| (IV) | 43978 | tert-butyl (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-(dimethoxymethyl)phenyl]-1-pyrrolidinecarboxylate | C24H41NO5Si | 详情 | 详情 | |
| (V) | 30852 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate | C22H35NO4Si | 详情 | 详情 | |
| (VI) | 30871 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)phenyl]-1-pyrrolidinecarboxylate | C25H43NO4SSi | 详情 | 详情 | |
| (VII) | 43979 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-[(methylamino)methyl]phenyl]-1-pyrrolidinecarboxylate | C23H40N2O3Si | 详情 | 详情 | |
| (VIII) | 43980 | allyl (2R,4R)-2-(4-[[[(allyloxy)carbonyl](methyl)amino]methyl]phenyl)-4-hydroxy-1-pyrrolidinecarboxylate | C20H26N2O5 | 详情 | 详情 | |
| (IX) | 43981 | allyl (2R,4R)-2-(4-[[[(allyloxy)carbonyl](methyl)amino]methyl]phenyl)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-pyrrolidinecarboxylate | C23H32N2O5S | 详情 | 详情 | |
| (X) | 43982 | allyl (2R,4S)-2-(4-[[[(allyloxy)carbonyl](methyl)amino]methyl]phenyl)-4-sulfanyl-1-pyrrolidinecarboxylate | C20H26N2O4S | 详情 | 详情 | |
| (XI) | 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 | |
| (XII) | 43983 | allyl (4R,5S,6S)-3-[[(3S,5R)-1-[(allyloxy)carbonyl]-5-(4-[[[(allyloxy)carbonyl](methyl)amino]methyl]phenyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C33H41N3O8S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIV)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：(XII)trans-4-Hydroxy-L-proline (I) was esterified with methanolic HCl, generated from acetyl chloride in MeOH, and the resulting 4-hydroxyproline methyl ester (II) was protected with allyl chloroformate to afford the allyl carbamate (III). Mesylation of the hydroxyl group of (III) with methanesulfonyl chloride, followed by reduction of the methyl ester with LiBH4, provided the alcohol (V). The mesylate group of (V) was then displaced by potassium thioacetate yielding thioacetate ester (VI). Iodo compound (VII) was obtained by mesylation of alcohol (VI) followed by substitution with NaI in acetone. 1-Methyl-5-mercaptotetrazole (IX), prepared by reaction of methyl isothiocyanate (VIII) with NaN3, was then condensed with iodide (VII) to give adduct (X). After deacetylation of thioacetate (X) with methanolic NaOH, the resulting pyrrolidinethiol (XI) was coupled with enol phosphate (XII) to give the protected carbapenem (XIII). The allyl ester and carbamate protecting groups of (XIII) were finally removed by treatment with Bu3SnH in the presence of palladium catalyst.
| 【1】 Kim, D.J.; Koo, K.D.; Shin, K.J.; Kim, C.; Park, S.W.; Yoo, K.H.; Synthesis and biological properties of new 1beta-methylcarbapenems having tetrazolothioether moiety. Bioorg Med Chem Lett 2000, 10, 13, 1421. |
| 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) | 15796 | methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate | C6H11NO3 | 详情 | 详情 | |
| (III) | 42200 | 1-allyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C10H15NO5 | 详情 | 详情 | |
| (IV) | 42201 | 1-allyl 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate | C11H17NO7S | 详情 | 详情 | |
| (V) | 42202 | allyl (2S,4R)-2-(hydroxymethyl)-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C10H17NO6S | 详情 | 详情 | |
| (VI) | 42203 | allyl (2S,4S)-4-(acetylsulfanyl)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C11H17NO4S | 详情 | 详情 | |
| (VII) | 42204 | allyl (2S,4S)-4-(acetylsulfanyl)-2-(iodomethyl)-1-pyrrolidinecarboxylate | C11H16INO3S | 详情 | 详情 | |
| (VIII) | 12092 | Methyl isothiocyanate; MITC; (Methylimino)(thioxo)methane | 556-61-6 | C2H3NS | 详情 | 详情 |
| (IX) | 28420 | 5-Mercapto-1-methyl-1H-tetrazole; 1-Methyl-1H-1,2,3,4-tetraazol-5-ylhydrosulfide | 13183-79-4 | C2H4N4S | 详情 | 详情 |
| (X) | 42205 | allyl (2S,4S)-4-(acetylsulfanyl)-2-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-1-pyrrolidinecarboxylate | C13H19N5O3S2 | 详情 | 详情 | |
| (XI) | 42206 | allyl (2S,4S)-2-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C11H17N5O2S2 | 详情 | 详情 | |
| (XII) | 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 | |
| (XIII) | 42207 | allyl (4R,5S,6S)-3-[((3S,5S)-1-[(allyloxy)carbonyl]-5-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C24H32N6O6S2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XIII)Propargyl alcohol (I) is oxidized with CrO3 under reduced pressure to give propynal (II), which is treated with sodium thiosulfate to afford the aldehyde dithionite (III). Subsequent cyclization of (III) in liquid ammonia gives rise to isothiazole (IV). The lithiated derivative of (IV) is formylated by means of DMF to provide aldehyde (V), which is further reduced to alcohol (VI) employing NaBH4 in THF (1). Bromination of alcohol (VI) in the presence of CBr4/PPh3 leads to 5-bromomethylisothiazole (VII). This is then converted into the phosphonium salt (VIII) upon treatment with triphenylphosphine in refluxing acetonitrile. Wittig condensation of (VIII) with the formyl pyrrolidine (IX) produces the ethenylpyrrolidine derivative (X). The mesylate group of (X) is displaced with potassium thioacetate to produce thioester (XI), which is subsequently hydrolyzed to thiol (XII) with methanolic NaOH. Condensation of thiol (XII) with the enol phosphate (XIII) in the presence of diisopropylethylamine affords the protected carbapenem derivative (XIV). This is finally deprotected with Bu3SnH and palladium catalyst to furnish the title compound (1,2)
| 【1】 Kang, Y.-K.; Lee, K.-S.; Yoo, K.-H.; Shin, K.-J.; Kim, D.-C.; Lee, C.-S.; Kong, J.Y.; Kim, D.J.; Synthesis and biological evaluation of novel 1beta-methylcarbapenems with isothiazoloethenyl side chains. Bioorg Med Chem Lett 2003, 13, 3, 463. |
| 【2】 Kim, D.J.; Yoo, K.H.; Kang, Y.K.; Park, S.W.; Shin, K.J.; Seo, K.J. (Korea Institute of Science and Technology); Novel 1beta-methylcarbapenem derivs. and process for preparation thereof. WO 0202561 . |
| 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) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (II) | 23544 | propiolaldehyde | C3H2O | 详情 | 详情 | |
| (III) | 63457 | sodium 1-{[oxido(dioxo)-lambda~6~-sulfanyl]sulfanyl}-3-oxo-1-propene | C3H3NaO4S2 | 详情 | 详情 | |
| (IV) | 63458 | isothiazole | C3H3NS | 详情 | 详情 | |
| (V) | 63459 | 5-isothiazolecarbaldehyde | C4H3NOS | 详情 | 详情 | |
| (VI) | 63460 | 5-isothiazolylmethanol | C4H5NOS | 详情 | 详情 | |
| (VII) | 63461 | 5-(bromomethyl)isothiazole | C4H4BrNS | 详情 | 详情 | |
| (VIII) | 63462 | (5-isothiazolylmethyl)(triphenyl)phosphonium bromide | C22H19BrNPS | 详情 | 详情 | |
| (IX) | 49446 | allyl (2S,4R)-2-formyl-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C10H15NO6S | 详情 | 详情 | |
| (X) | 63463 | 2-propenyl 2-[2-(5-isothiazolyl)ethenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C14H18N2O5S2 | 详情 | 详情 | |
| (XI) | 63464 | 2-propenyl 4-(acetylsulfanyl)-2-[2-(5-isothiazolyl)ethenyl]-1-pyrrolidinecarboxylate | C15H18N2O3S2 | 详情 | 详情 | |
| (XII) | 63465 | 2-propenyl 2-[2-(5-isothiazolyl)ethenyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C13H16N2O2S2 | 详情 | 详情 | |
| (XIII) | 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 | |
| (XIV) | 63466 | 2-propenyl 6-(1-hydroxyethyl)-3-({5-[2-(5-isothiazolyl)ethenyl]-1-[(2-propenyloxy)carbonyl]-3-pyrrolidinyl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C26H31N3O6S2 | 详情 | 详情 |