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【结 构 式】 
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【分子编号】16075 【品名】4-methoxybenzyl (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 】C30H30NO9P 【 分 子 量 】579.543302 【元素组成】C 62.17% H 5.22% N 2.42% O 24.85% P 5.34% |
合成路线1
该中间体在本合成路线中的序号：(III)The reaction of (1R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-methoxybenzyl ester (I) with diphenyl chlorophosphate (II) and ethyl diisopropylamine in acetonitrile gives the corresponding penem diphenylphosphate (III), which is condensed with 1-(tert-butoxycarbonyl)-2(S)-sulfamoylaminomethyl)pyrrolidine-4(S)-thio l (IV) by means of ethyl diisopropylamine in the same solvent, yielding compound (V), which is finally treated with AlCl3 to eliminate the protecting groups to obtain S-4661.
| 【1】 Sendo, Y.; Kii, M.; Nishitani, Y.; Irie, T.; Nishino, Y. (Shionogi & Co., Ltd.); A production method for sulfamide. EP 0557122 . |
| 【2】 Castaner, J.; Mealy, N.; Rabasseda, X.; S-4661. Drugs Fut 1995, 20, 4, 367. |
| 【3】 Nishitani, Y.; Irie, T.; Nishino, Y. (Shionogi & Co. Ltd.); A pyrrolidylthiocarbapenem derivative. EP 0528678; JP 1993294970; US 5317016 . |
| 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) | 16073 | 4-methoxybenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C18H21NO6 | 详情 | 详情 | |
| (II) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (III) | 16075 | 4-methoxybenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C30H30NO9P | 详情 | 详情 | |
| (IV) | 16076 | tert-butyl (2S,4S)-2-[[(aminosulfonyl)amino]methyl]-4-sulfanyltetrahydro-1H-pyrrole-1-carboxylate | C10H21N3O4S2 | 详情 | 详情 | |
| (V) | 16077 | 4-methoxybenzyl (4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)amino]methyl]-1-(tert-butoxycarbonyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C28H40N4O9S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)A new synthesis of S-4661 has been reported: The esterification of trans-4-hydroxy-L-proline (I) with methanol/HCl gives the corresponding methyl ester (II), which is N-protected as trans-N-(4-methoxybenzyloxycarbonyl)-4-hydroxy-L-proline methyl ester (III). The mesylation of (III) with methanesulfonyl chloride and triethylamine in dichloromethane affords the 4-O-mesylate (IV), which is treated with sodium triphenylmethylsulfide giving cis-N-(4-methoxybenzyloxycarbonyl)-4-(triphenylmethylsulfanyl)-L-prolin e methyl ester (V). The reduction of (V) with LiBH4 in THF yields the corresponding methanol (VI), which is mesylated as before affording (VII). The reaction of (VII) with potassium phthalimide (VIII) gives the adduct (IX), which is cleaved with hydrazine yielding (2S,4S)-2-(aminomethyl)-1-(4-methoxybenzyloxycarbonyl)-4-(triphenylmeth ylsulfanyl)pyrrolidine (X). The condensation of (X) with N-(4-methoxybenzyl)sulfamoyl chloride (XI) by means of triethylamine affords the corresponding protected sulfamide (XII). Deprotection of the trityl group of (XII) by treatment with silver nitrate and pyridine affords compound (XIII) with a free SH group. The reaction of (XIII) with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-methoxybenzyl ester (XIV) by means of diisopropylethylamine yields the protected final product (XV), which is finally treated with AlCl3 in anisole to eliminate the protecting groups.
| 【1】 Iso, Y.; Motokawa, K.; Nishitani, Y.; Nishino, Y.; Irie, T.; A novel 1beta-methylcarbapenem antibiotic, S-4661. Synthesis and structure-activity relationships of 2-(5-substituted pyrrolidin-3-ylthio)-1beta-methylcarbapenems. J Antibiot 1996, 49, 2, 199. |
| 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) | 16080 | 1-(4-methoxybenzyl) 2-methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate | C15H19NO6 | 详情 | 详情 | |
| (IV) | 16081 | 1-(4-methoxybenzyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C16H21NO8S | 详情 | 详情 | |
| (V) | 16082 | 1-(4-methoxybenzyl) 2-methyl (2S,4S)-4-(tritylsulfanyl)-1,2-pyrrolidinedicarboxylate | C34H33NO5S | 详情 | 详情 | |
| (VI) | 16083 | 4-methoxybenzyl (2S,4S)-2-(hydroxymethyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C33H33NO4S | 详情 | 详情 | |
| (VII) | 16084 | 4-methoxybenzyl (2S,4S)-2-[[(methylsulfonyl)oxy]methyl]-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C34H35NO6S2 | 详情 | 详情 | |
| (VIII) | 10926 | (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium | C8H4KNO2 | 详情 | 详情 | |
| (IX) | 16086 | 4-methoxybenzyl (2S,4S)-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C41H36N2O5S | 详情 | 详情 | |
| (X) | 16087 | 4-methoxybenzyl (2S,4S)-2-(aminomethyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C33H34N2O3S | 详情 | 详情 | |
| (XI) | 16088 | chloro([[(4-methoxybenzyl)oxy]carbonyl]amino)dioxo-lambda(6)-sulfane | C9H10ClNO5S | 详情 | 详情 | |
| (XII) | 16089 | 4-methoxybenzyl (2S,4S)-2-([[([[(4-methoxybenzyl)oxy]carbonyl]amino)sulfonyl]amino]methyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C42H43N3O8S2 | 详情 | 详情 | |
| (XIII) | 16090 | 4-methoxybenzyl (2S,4S)-2-([[([[(4-methoxybenzyl)oxy]carbonyl]amino)sulfonyl]amino]methyl)-4-sulfanyl-1-pyrrolidinecarboxylate | C23H29N3O8S2 | 详情 | 详情 | |
| (XIV) | 16075 | 4-methoxybenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C30H30NO9P | 详情 | 详情 | |
| (XV) | 16092 | 4-methoxybenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[[(3S,5S)-1-[[(4-methoxybenzyl)oxy]carbonyl]-5-([[([[(4-methoxybenzyl)oxy]carbonyl]amino)sulfonyl]amino]methyl)pyrrolidinyl]sulfanyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C41H48N4O13S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)
| 【1】 Nishino Y, Kobayashi M, Shinno T.2003.Practical large-scale synthesis of doripenem: a novel 1β-methylcarbapenem antibiotic. Orangic Process Research & Development, 7:846. |
| 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) | 67079 | (2S,4S)-4-nitrobenzyl 4-(acetylthio)-2-(((tert-butoxycarbonyl)(sulfamoyl)amino)methyl)pyrrolidine-1-carboxylate | 491878-06-9 | C20H28N4O9S2 | 详情 | 详情 |
| (II) | 67080 | (2R,4R)-4-nitrobenzyl 4-(acetylthio)-2-((sulfamoylamino)methyl)pyrrolidine-1-carboxylate | C15H20N4O7S2 | 详情 | 详情 | |
| (III) | 16075 | 4-methoxybenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C30H30NO9P | 详情 | 详情 | |
| (IV) | 67081 | nitro(phenyl)methyl 6-(1-hydroxyethyl)-4-methyl-3-((1-(((4-nitrobenzyl)oxy)carbonyl)-5-((sulfamoylamino)methyl)pyrrolidin-3-yl)thio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C30H34N6O12S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)
| 【1】 Tang ZJ, Zhang QW, Shi HL.2007.Preparation of pyrrolidinothiocarbapenem derivative and intermediate. CN 101007806. |
| 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) | 16075 | 4-methoxybenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C30H30NO9P | 详情 | 详情 | |
| (II) | 67086 | 4-nitrobenzyl 3-((diphenoxyphosphoryl)oxy)-4-methyl-7-oxo-6-(1-((trimethylsilyl)oxy)ethyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C32H35N2O10PSi | 详情 | 详情 | |
| (III) | 67087 | 4-nitrobenzyl 2-(hydroxymethyl)-4-mercaptopyrrolidine-1-carboxylate | C13H16N2O5S | 详情 | 详情 | |
| (IV) | 67088 | 4-nitrobenzyl 3-((5-(hydroxymethyl)-1-(((4-nitrobenzyl)oxy)carbonyl)pyrrolidin-3-yl)thio)-4-methyl-7-oxo-6-(1-((trimethylsilyl)oxy)ethyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C33H40N4O11SSi | 详情 | 详情 | |
| (V) | 16097 | tert-butyl 2,2-dioxo-2lambda(6)-diazathiane-1-carboxylate | 148017-28-1 | C5H12N2O4S | 详情 | 详情 |
| (VI) | 67089 | 4-nitrobenzyl 3-((5-(((tert-butoxycarbonyl)(sulfamoyl)amino)methyl)-1-(((4-nitrobenzyl)oxy)carbonyl)pyrrolidin-3-yl)thio)-4-methyl-7-oxo-6-(1-((trimethylsilyl)oxy)ethyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C38H50N6O14S2Si | 详情 | 详情 | |
| (VII) | 67090 | 4-nitrobenzyl 3-((5-(((tert-butoxycarbonyl)(sulfamoyl)amino)methyl)-1-(((4-nitrobenzyl)oxy)carbonyl)pyrrolidin-3-yl)thio)-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C35H42N6O14S2 | 详情 | 详情 | |
| (VIII) | 67081 | nitro(phenyl)methyl 6-(1-hydroxyethyl)-4-methyl-3-((1-(((4-nitrobenzyl)oxy)carbonyl)-5-((sulfamoylamino)methyl)pyrrolidin-3-yl)thio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C30H34N6O12S2 | 详情 | 详情 | |
| (IX) | 67085 | 4-nitrobenzyl 6-(1-hydroxyethyl)-4-methyl-7-oxo-3-((5-((sulfamoylamino)methyl)pyrrolidin-3-yl)thio)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C22H29N5O8S2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号： (I)
| 【1】 Tewari N, Meeran HNPN, Rai BP, et al. 2006. Aprocess for the preparation of doripenem. WO 2006117763 A2. |
| 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) | 16075 | 4-methoxybenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C30H30NO9P | 详情 | 详情 | |
| (II) | 67099 | 4-nitrobenzyl 4-mercapto-2-((sulfamoylamino)methyl)pyrrolidine-1-carboxylate | C13H18N4O6S2 | 详情 | 详情 | |
| (III) | 67098 | nitro(phenyl)methyl 6-(1-hydroxyethyl)-4-methyl-3-((1-(((4-nitrobenzyl)oxy)carbonyl)-5-(((((4-nitrobenzyl)oxy)carbonyl)(sulfamoyl)amino)methyl)pyrrolidin-3-yl)thio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C38H39N7O16S2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)
| 【1】 Kanamoto K.2007. Process for producing carbapenem derivatives through reactions without isolating intermediates. WO 2007020960 A1. |
| 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) | 67100 | 4-nitrobenzyl 2-diazo-4-(3-(1-hydroxyethyl)-4-oxoazetidin-2-yl)-3-oxopentanoate | C17H18N4O7 | 详情 | 详情 | |
| (II) | 37720 | 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (III) | 16075 | 4-methoxybenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C30H30NO9P | 详情 | 详情 | |
| (IV) | 67099 | 4-nitrobenzyl 4-mercapto-2-((sulfamoylamino)methyl)pyrrolidine-1-carboxylate | C13H18N4O6S2 | 详情 | 详情 | |
| (V) | 67098 | nitro(phenyl)methyl 6-(1-hydroxyethyl)-4-methyl-3-((1-(((4-nitrobenzyl)oxy)carbonyl)-5-(((((4-nitrobenzyl)oxy)carbonyl)(sulfamoyl)amino)methyl)pyrrolidin-3-yl)thio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C38H39N7O16S2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(III)
| 【1】 Tewari N, George V, Mane AS, et al.2007. A process for the preparation of carbapenem compounds. WO 2007029084 A2. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 67101 | 4-nitrobenzyl 2-(((tert-butoxycarbonyl)(sulfamoyl)amino)methyl)-4-mercaptopyrrolidine-1-carboxylate | C18H26N4O8S2 | 详情 | 详情 | |
| (I) | 67079 | (2S,4S)-4-nitrobenzyl 4-(acetylthio)-2-(((tert-butoxycarbonyl)(sulfamoyl)amino)methyl)pyrrolidine-1-carboxylate | 491878-06-9 | C20H28N4O9S2 | 详情 | 详情 |
| (III) | 16075 | 4-methoxybenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C30H30NO9P | 详情 | 详情 | |
| (IV) | 67090 | 4-nitrobenzyl 3-((5-(((tert-butoxycarbonyl)(sulfamoyl)amino)methyl)-1-(((4-nitrobenzyl)oxy)carbonyl)pyrrolidin-3-yl)thio)-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C35H42N6O14S2 | 详情 | 详情 |