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【结 构 式】 
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【分子编号】16205 【品名】4-nitrobenzyl (2S,4S)-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-4-sulfanyl-1-pyrrolidinecarboxylate 【CA登记号】 |
【 分 子 式 】C24H28N4O9S 【 分 子 量 】548.57388 【元素组成】C 52.55% H 5.14% N 10.21% O 26.25% S 5.85% |
合成路线1
该中间体在本合成路线中的序号：(X)The hydrolysis of N-(tert-butoxycarbonyl)-4(R)-(tert-butyldimethylsilyloxy)-L-proline methyl ester (I) with NaOH gives the corresponding protected amino acid (II), which is condensed with malonic acid monomethyl ester (II) by means of carbonyldiimidazole (CDI) in THF to afford the L-prolylacetate (IV). The reduction of (IV) with NaBH4 in refluxing THF-methanol gives (2S,4R)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-(1,3-dihydroxypropyl)pyrrolidine (V), which is acylated with tosyl chloride to the primary monotosylate (VI). The chromatographic separation of (VI) over SiO2 yields the [2S(1'R),4R]-enantiomer (VII), which by treatment first with methylamine followed by 4,6-dimethyl-2-(4-nitrobenzyloxycarbonylthio)pyrimidine (PNZ-Pym) affords the N-protected methylamino derivative (VIII). The mesylation of (VIII) with methanesulfonyl chloride followed by reaction with potassium thioacetate gives (2S,4S)-4-acetylthio-2-[1(R)-hydroxy-3-(4-nitrobenzyloxycarbonylamino) propyl]-1-(4-nitrobenzyl)pyrrolidine (IX), which is treated with NaOH in methanol-water to afford the corresponding thiol (X). The condensation of (X) with (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester (XI) by means of diisopropylethylamine in acetonitrile yields the protected compound (XII), which is finally hydrolyzed and deprotected by hydrogenation with H2 over Pd/C and treatment with HCl.
| 【1】 Nakagawa, S.; Kato, S.; Murase, S.; Okamoto, O.; Mitomo, R.; Yamamoto, K.; Yamada, K.; Fukatsu, H. (Banyu Pharmaceutical Co., Ltd.); Aminoalkylpyrrolidinylthiocarbapenem derivs. EP 0545290; JP 1994087858; US 5550121; WO 9311128 . |
| 【2】 Graul, A.; Rabasseda, X.; Castaner, J.; Prous, J.; BO-2727. Drugs Fut 1994, 19, 8, 731. |
| 【3】 Rabasseda, X.; Prous, J.; Castaner, J.; Biapenem. Drugs Fut 1994, 19, 7, 631. |
| 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) | 16196 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C17H33NO5Si | 详情 | 详情 | |
| (II) | 16197 | (2S,4R)-1-(tert-butoxycarbonyl)-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-1H-pyrrole-2-carboxylic acid | C16H31NO5Si | 详情 | 详情 | |
| (III) | 16198 | 3-Methoxy-3-oxopropionic acid; Malonic acid monomethyl ester | 16695-14-0 | C4H6O4 | 详情 | 详情 |
| (IV) | 16199 | tert-butyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-methoxy-3-oxopropanoyl)tetrahydro-1H-pyrrole-1-carboxylate | C19H35NO6Si | 详情 | 详情 | |
| (V) | 16200 | tert-butyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(1,3-dihydroxypropyl)tetrahydro-1H-pyrrole-1-carboxylate | C18H37NO5Si | 详情 | 详情 | |
| (VI) | 16201 | tert-butyl (2S,4R)-2-[3-[(benzylsulfonyl)oxy]-1-hydroxypropyl]-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-1H-pyrrole-1-carboxylate | C25H43NO7SSi | 详情 | 详情 | |
| (VII) | 16202 | tert-butyl (2S,4R)-2-[(1R)-3-[(benzylsulfonyl)oxy]-1-hydroxypropyl]-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-1H-pyrrole-1-carboxylate | C25H43NO7SSi | 详情 | 详情 | |
| (VIII) | 16203 | 4-nitrobenzyl (2S,4R)-4-hydroxy-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-1-pyrrolidinecarboxylate | C24H28N4O10 | 详情 | 详情 | |
| (IX) | 16204 | 4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-1-pyrrolidinecarboxylate | C26H30N4O10S | 详情 | 详情 | |
| (X) | 16205 | 4-nitrobenzyl (2S,4S)-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C24H28N4O9S | 详情 | 详情 | |
| (XI) | 16206 | (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-[2-(4-nitrobenzyloxy)acetyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl diphenylphosphinate | C29H27N2O8P | 详情 | 详情 | |
| (XII) | 16207 | 4-nitrobenzyl (2S,4S)-4-([(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-[2-(4-nitrophenyl)acetyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]sulfanyl)-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-1-pyrrolidinecarboxylate | C41H44N6O14S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)A new synthesis of BO-2727 has been described: The condensation of (2S,4R)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-2-carbaldehyde (I) with ethyl acetate (II) by means of butyllithium and hexa-methyldisylazane (HMSA) in THF gives 3-[1-(tert-butoxycarbonyl)-4(R)-(tert-butyldimethylsilyloxy) pyrrolidin-2(S)-yl]-3-hydroxypropionic acid ethyl ester (III), which was submitted to column chromatography over silicagel yielding the pure 3(R)-hydroxypropionic acid (IV). The reduction of (IV) with NaBH4 in THF afforded the expected diol (V), which was treated with tosyl chloride and triethylamine to give the monotosylate (VI). The reaction of (VI) first with methylamine in methanol, and then with p-nitrobenzyloxycarbonyl chloride (PNZ-Cl) in the same solvent yielded (2S,4R)-2-[1(R)-hydroxy-3-[N-methyl-N-(p-nitrobenzyloxycarbonyl)amino]propyl] pyrrolidin-4-ol (VII). The reaction of (VII) first with SOCl2 and then with potassium thioacetate afforded the 4(R)-acetylsulfanyl derivative (VIII), which was hydrolyzed with NaOH in methanol/water to the corresponding thiol (IX). The condensation of (IX) with the carbapenem intermediate (X) by means of diisopropylethylamine (DIEA) in acetonitrile gave the precursor (protected) of BO-2727 (XI), which was finally deprotected by hydrogenation with H2 over Pd/C in THF/ethanol/pH-7 buffer.
| 【1】 Ohtake, N.; Okamoto, O.; Mitomo, R.; Kato, Y.; Yamamoto, K.; Haga, Y.; Fukatsu, H.; Nakagawa, S.; 1ß-Methyl-2-(5-substituted pyrrolidin-3-ylthio)carbapenems; 3. Synthesis and antibacterial activity of BO-2727 and its related compounds. J Antibiot 1997, 50, 7, 598. |
| 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) | 17490 | tert-butyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-formyl-1-pyrrolidinecarboxylate | C16H31NO4Si | 详情 | 详情 | |
| (II) | 17491 | ethyl acetate | 141-78-6 | C4H8O2 | 详情 | 详情 |
| (III) | 17492 | tert-butyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-ethoxy-1-hydroxy-3-oxopropyl)-1-pyrrolidinecarboxylate | C20H39NO6Si | 详情 | 详情 | |
| (IV) | 17493 | tert-butyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(1R)-3-ethoxy-1-hydroxy-3-oxopropyl]-1-pyrrolidinecarboxylate | C20H39NO6Si | 详情 | 详情 | |
| (V) | 17494 | tert-butyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(1R)-1,3-dihydroxypropyl]-1-pyrrolidinecarboxylate | C18H37NO5Si | 详情 | 详情 | |
| (VI) | 17495 | tert-butyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-((1R)-1-hydroxy-3-[[(4-methylphenyl)sulfonyl]oxy]propyl)-1-pyrrolidinecarboxylate | C25H43NO7SSi | 详情 | 详情 | |
| (VII) | 16203 | 4-nitrobenzyl (2S,4R)-4-hydroxy-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-1-pyrrolidinecarboxylate | C24H28N4O10 | 详情 | 详情 | |
| (VIII) | 16204 | 4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-1-pyrrolidinecarboxylate | C26H30N4O10S | 详情 | 详情 | |
| (IX) | 16205 | 4-nitrobenzyl (2S,4S)-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C24H28N4O9S | 详情 | 详情 | |
| (X) | 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 |
| (XI) | 16207 | 4-nitrobenzyl (2S,4S)-4-([(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-[2-(4-nitrophenyl)acetyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]sulfanyl)-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-1-pyrrolidinecarboxylate | C41H44N6O14S | 详情 | 详情 |