• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【分子编号】16203

【品名】4-nitrobenzyl (2S,4R)-4-hydroxy-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-1-pyrrolidinecarboxylate

【CA登记号】

【 分 子 式 】C24H28N4O10

【 分 子 量 】532.50728

【元素组成】C 54.13% H 5.3% N 10.52% O 30.05%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

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:(VII)

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
Extended Information