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【结 构 式】

【分子编号】13224

【品名】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

【CA登记号】90776-59-3

【 分 子 式 】C29H27N2O10P

【 分 子 量 】594.514622

【元素组成】C 58.59% H 4.58% N 4.71% O 26.91% P 5.21%
与该中间体有关的原料药合成路线共 24 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23合成路线24

合成路线1

该中间体在本合成路线中的序号：(XIX)

Reaction of 3-(benzyloxy)propionic acid (I) with 4(R)-isopropyl-1,3-thiazolidine-2-thione (II) in the presence of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and DMAP gives 3-[3-(benzyloxy)propanoyl]-4(R)-isopropyl-1,3-thiazolidine-2-thione (III), which by treatment with tin(II) trifluoromethanesulfonate and excess acetaldehyde affords 3-[(2S,3R)-2-(benzyloxymethyl)-3-hydroxybutanoyl]-4(R)-isopropyl-1,3-thiazolidine-2-thione (IV). Protection of the hydroxy group of (IV) with tert-butyldimethylsilyl chloride in the presence of imidazole yields 3-[(2S,3R)-2-(benzyloxymethyl)-3-(tert-butyldimethylsilyloxy)butanoyl]-4(R)-isopropyl-1,3-thiazolidine-2-thione (V), which is treated with p-anisidine to afford (2S,3R)-2-(benzyloxymethyl)-3-(tert-butyldimethylsilyloxy)-N-(4-methoxyphenyl)butylamide (VI). Deprotection of (VI) by hydrogenation with Pd/C in methanol-acetic acid gives (2S,3R)-3-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)-N-(4-methoxyphenyl)butylamide (VII), which is mesylated with methanesulfonyl chloride in the presence of triethylamine to yield (2S,3R)-3-(tert-butyldimethylsilyloxy)-2-[(methanesulfonyloxy)methyl]-N-(4-methoxyphenyl)butylamide (VIII). Cyclization of (VIII) with sodium hydride in CH2Cl2-DMF affords 3(S)-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-1-(4-methoxyphenyl) azetidin-2-one (IX), the nitrogen atom of which is deprotected with cerium ammonium nitrate (CAN) in a mixture of acetonitrile-water to yield 3(S)-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (X). Compound (X) is stereoselectively converted to (3S,4R)-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-acetoxyazetidin-2-one (XI) on treatment with peracetic acid and ruthenium(III) chloride. Compound (XI) and 4(S)-ethyl-3-propionyl-1,3-thiazolidine-2-thione (XII) give, on treatment with tin(II) trifluoromethanesulfonate, (3S,4R)-3-[1(R)-(tert-butyldimethysilyloxy)methyl]-4-[1(R)-[4(S)-ethyl-2-thioxo-1,3-thiazolidin-3-ylcarbonyl]ethyl]azetidin-2-one (XIII) as the major diastereoisomer. Reaction of (XIII) with imidazole in acetonitrile gives (3S,4R)-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-[1(R)-(imidazol-1-ylcarbonyl)ethyl]azetidin-2-one (XIV), which is treated with Mg(O2CH2CO2PNB)2 in acetonitrile to yield (3S,4R)-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-[1(R)-methyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one (XV). Compound (XV) is deprotected with hydrochloric acid in methanol to give (3S,4R)-3-[1(R)-hydroxyethyl]-4-[1(R)-methyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one (XVI), which on diazotization with dodecylbenzenesulfonyl azide in acetonitrile yields (3S,4R)-4-[3-diazo-1(R)-methyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-3-[1(R)-hydroxyethyl]azetidin-2-one (XVII). Treatment of compound (XVII) with rhodium(II) octanoate in ethylacetate gives p-nitrobenzyl (1R,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-oxocarbapenam-3-carboxylate (XVIII), which is reacted with diphenylchlorophosphate and diisopropylethylamine to afford p-nitrobenzyl (1R,5R,6S)-2-[(diphenylphosphono)oxy]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (XIX).

参考文献 中间体
合成目标
【1】 Kumagai, T.; Matsunaga, H.; Machida, Y.; Nagase, Y.; Hikida, M.; Nagao, Y. (Lederle (Japan), Ltd.); (1R,5S,6S)-2-(Substd. thio)-6-[(R)-1-hydroxy-ethyl]-1-methyl-carbapenem-3-carboxylic-acid derivatives. AU 8814428; EP 0289801; JP 1989025779; US 4925836 .
【2】 Abe, T.; Matsunaga, H.; Kumagai, T.; Nagase, Y. (Lederle (Japan), Ltd.); Method of preparation of carbapenem cpds. JP 1990088578 .
【3】 Rabasseda, X.; Prous, J.; Castaner, J.; Biapenem. Drugs Fut 1994, 19, 7, 631.
【4】 Hayashi, T.; Shimada, O.; Inoue, Y.; Nagao, Y.; Matsunaga, H.; Nagase, Y.; Kumagai, T.; Abe, T.; beta-Lactams. 3. Asymmetric total synthesis of new non-natural 1beta-methylcarbapenems exhibiting strong antimicrobial activities and stability against human renal dehydropeptidase-. J Org Chem 1992, 57, 15, 4243-9.
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) 13189 3-(Benzyloxy)propionic acid C10H12O3 详情 详情
(II) 13190 (4R)-4-Isopropyl-1,3-thiazolidine-2-thione C6H11NS2 详情 详情
(III) 13191 3-(Benzyloxy)-1-[(4R)-4-isopropyl-2-thioxo-1,3-thiazolidin-3-yl]-1-propanone C16H21NO2S2 详情 详情
(IV) 13192 (2S,3R)-2-[(Benzyloxy)methyl]-3-hydroxy-1-[(4R)-4-isopropyl-2-thioxo-1,3-thiazolidin-3-yl]-1-butanone C18H25NO3S2 详情 详情
(V) 13193 (2S,3R)-2-[(Benzyloxy)methyl]-3-[[tert-butyl(dimethyl)silyl]oxy]-1-[(4R)-4-isopropyl-2-thioxo-1,3-thiazolidin-3-yl]-1-butanone C24H39NO3S2Si 详情 详情
(VI) 13194 (2S,3R)-2-[(Benzyloxy)methyl]-3-[[tert-butyl(dimethyl)silyl]oxy]-N-(4-methoxyphenyl)butanamide C25H37NO4Si 详情 详情
(VII) 13195 (2S,3R)-3-[[tert-Butyl(dimethyl)silyl]oxy]-2-(hydroxymethyl)-N-(4-methoxyphenyl)butanamide C18H31NO4Si 详情 详情
(VIII) 13196 (2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[(4-methoxyanilino)carbonyl]butyl methanesulfonate C19H33NO6SSi 详情 详情
(IX) 13197 (3S)-3-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]ethyl)-1-(4-methoxyphenyl)-2-azetidinone C18H29NO3Si 详情 详情
(X) 13198 (3S)-3-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]ethyl)-2-azetidinone C11H23NO2Si 详情 详情
(XI) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(XII) 13200 1-[(4S)-4-Ethyl-2-thioxo-1,3-thiazolidin-3-yl]-1-propanone C8H13NOS2 详情 详情
(XIII) 13201 (3S,4S)-3-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-[(4S)-4-ethyl-2-thioxo-1,3-thiazolidin-3-yl]-1-methyl-2-oxoethyl]-2-azetidinone C19H34N2O3S2Si 详情 详情
(XIV) 13202 (3S,4S)-3-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-(1H-imidazol-1-yl)-1-methyl-2-oxoethyl]-2-azetidinone C17H29N3O3Si 详情 详情
(XV) 33040 4-nitrobenzyl (4R)-4-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-oxopentanoate C23H34N2O7Si 详情 详情
(XVI) 22573 4-nitrobenzyl 4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate C17H20N2O7 详情 详情
(XVII) 38749 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate C17H18N4O7 详情 详情
(XVIII) 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
(XIX) 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

合成路线2

该中间体在本合成路线中的序号：(XIX)

Compound (XIX) reacts with 4-mercapto-N,N-bis(p-nitrobenzyloxycarbonyl)pyrazolidine (XX) in the presence of diisopropylethylamine to give p-nitrobenzyl (1R,5R,6S)-2-[[N,N-bis(p-nitrobenzyloxycarbonyl)pyrazolidin-4-yl]thio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (XXIII). Compound (XXIII) is reduced with H2 over Pd/C to give (1R,5R,6S)-2-[[N,N-bis(p-nitrobenzyloxycarbonyl)pyrazolidin-4-yl]thio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (XXIV), which is finally reacted with ethylformimidate hydrochloride (XXV). Compound (XX) is obtained from epichlorohydrin (XXI) by treatment with hydrazine monohydrate followed by reaction with p-nitrobenzyloxycarbonyl chloride to give 4-hydroxy-N,N-bis(p-nitrobenzyloxycarbonyl)pyrazolidine (XXII), which is subsequently treated with methanesulfonyl chloride and triethylamine in dichloromethane, potassium acetate in acetone and sodium methoxide in methanol-THF. Compound (XX) can also be obtained from hydrazine hydrate using a longer alternative procedure.

参考文献 中间体
合成目标
【1】 Kumagai, T.; Matsunaga, H.; Machida, Y.; Nagase, Y.; Hikida, M.; Nagao, Y. (Lederle (Japan), Ltd.); (1R,5S,6S)-2-(Substd. thio)-6-[(R)-1-hydroxy-ethyl]-1-methyl-carbapenem-3-carboxylic-acid derivatives. AU 8814428; EP 0289801; JP 1989025779; US 4925836 .
【2】 Abe, T.; Matsunaga, H.; Kumagai, T.; Nagase, Y. (Lederle (Japan), Ltd.); Method of preparation of carbapenem cpds. JP 1990088578 .
【3】 Hayashi, T.; Shimada, O.; Inoue, Y.; Nagao, Y.; Matsunaga, H.; Nagase, Y.; Kumagai, T.; Abe, T.; beta-Lactams. 3. Asymmetric total synthesis of new non-natural 1beta-methylcarbapenems exhibiting strong antimicrobial activities and stability against human renal dehydropeptidase-. J Org Chem 1992, 57, 15, 4243-9.
【4】 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
(XIX) 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
(XX) 13208 bis(4-nitrobenzyl) 4-sulfanyl-1,2-pyrazolidinedicarboxylate C19H18N4O8S 详情 详情
(XXI) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(XXII) 13210 bis(4-nitrobenzyl) 4-hydroxy-1,2-pyrazolidinedicarboxylate C19H18N4O9 详情 详情
(XXIII) 13211 bis(4-nitrobenzyl) 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)-1,2-pyrazolidinedicarboxylate C36H34N6O13S 详情 详情
(XXIV) 13212 (4R,5S,6S)-3-[(1,2-bis[[(4-Nitrobenzyl)oxy]carbonyl]-4-pyrazolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid C29H29N5O12S 详情 详情
(XXV) 13213 ethyl iminoformate C3H7NO 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XII)

2) The acylation of hydrazine (I) with di-tert-butyl dicarbonate (II) gives 1,2-di(tert-butyloxycarbonyl)hydrazine (III), which is cyclized with 1,3-dibromo-2-(tert-butyldimethylsilyloxy)propane (IV) by means of NaH in DMF yielding the pyrazolidine (V). The desilylation of (V) with tetrabutylammonium fluoride in THF affords 1,2-di(tert-butoxycarbonyl)-4-hydroxypyrazolidine (VI). Acylation of (VI) with methanesulfonyl chloride in dichloromethane gives the corresponding mesylate (VII), which is condensed with 4-methoxybenzyl mercaptane (VIII) by means of butyllithium in hexane to yield the benzyl ether (IX). The cyclization of (IX) with methyl formimidate hydrochloride in methanol-water affords 6-(4-methoxybenzylthio)-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride (X), which is deprotected with trifluoroacetic acid giving 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride (XI). Finally, this compound is condensed with (1R,5R,6S)-2-(diphenylphosphonooxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester (XII) by means of diisopropylethylamine in DMF followed by hydrogenolysis with H2 over Pd/C in butanol-EtOAc-potassium phosphate buffer.

参考文献 中间体
合成目标
【1】 Ratcliffe, R.W.; Wildonger, K.J.; Heteroaryliumthio substituted carbapenem derivatives: Synthesis and in vitro activity of 1beta-methyl-2-(dihydropyrrolotriazoliumthio)carbapenems. J Antibiot 1993, 46, 12, 1866-82.
【2】 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
(II) 13214 Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate 24424-99-5 C10H18O5 详情 详情
(III) 13215 di(tert-butyl) 1,2-hydrazinedicarboxylate; Di-tert-butyl hydrazodicarboxylate 16466-61-8 C10H20N2O4 详情 详情
(IV) 13216 [2-Bromo-1-(bromomethyl)ethoxy](tert-butyl)dimethylsilane; 2-Bromo-1-(bromomethyl)ethyl tert-butyl(dimethyl)silyl ether C9H20Br2OSi 详情 详情
(V) 13217 di(tert-butyl) 4-[[tert-butyl(dimethyl)silyl]oxy]-1,2-pyrazolidinedicarboxylate C19H38N2O5Si 详情 详情
(VI) 13218 di(tert-butyl) 4-hydroxy-1,2-pyrazolidinedicarboxylate C13H24N2O5 详情 详情
(VII) 13219 di(tert-butyl) 4-[(methylsulfonyl)oxy]-1,2-pyrazolidinedicarboxylate C14H26N2O7S 详情 详情
(VIII) 13220 4-Methoxybenzylhydrosulfide; (4-Methoxyphenyl)methanethiol; 4-Methoxy-alpha-toluenethiol 6258-60-2 C8H10OS 详情 详情
(IX) 13221 di(tert-butyl) 4-[(4-methoxybenzyl)sulfanyl]-1,2-pyrazolidinedicarboxylate C21H32N2O5S 详情 详情
(X) 13222 6-[(4-Methoxybenzyl)sulfanyl]-5H,6H,7H-pyrazolo[1,2-a][1,2,4]triazol-4-ium chloride C13H16ClN3OS 详情 详情
(XI) 13223 6-Sulfanyl-5H,6H,7H-pyrazolo[1,2-a][1,2,4]triazol-4-ium chloride 153851-71-9 C5H8ClN3S 详情 详情
(XII) 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

合成路线4

该中间体在本合成路线中的序号：(X)

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.

参考文献 中间体
合成目标
【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

合成路线5

该中间体在本合成路线中的序号：(XVI)

Condensation of (phosphoryloxy)carbapenem (XVI) with 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (XI) gave thioether (XVII). The p-nitrobenzyl ester group of (XVII) was then deprotected with Zn powder to afford the target carboxylic acid.

参考文献 中间体
合成目标
【1】 Satoh, C.; Mihira, A.; Yamamoto, S.; Hayashi, K.; Kitamura, M.; Tamai, S.; Abe, T.; Kumagai, T.; Hikida, M.; L-084, a new oral carbapenem: Synthesis and structure-activity relationships of C2-substituted 1beta-methylcarbapenems. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-64.
【2】 Abe, T.; Isoda, T.; Sato, C.; Mihira, A.; Tamai, S.; Kumagai, T. (Lederle (Japan), Ltd.); 2-(1-(1,3-Thiazolin-2-yl)azetidin-3-yl)thio-carbapenem derivs.. EP 0632039; EP 0717042; JP 1996053453; US 5534510; US 5659043; US 5783703 .
【3】 Abe, T.; Kumagai, T. (Lederle (Japan), Ltd.); Carbapenem-3-carboxylic acid ester derivs.. EP 0808315; JP 1999504039; US 5886172; WO 9721712 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 31404 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinylhydrosulfide; 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinethiol 179337-57-6 C6H10N2S2 详情 详情
(XVI) 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
(XVII) 31408 4-nitrobenzyl (4R,5S,6S)-3-[[1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C23H26N4O6S2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(I)

The condensation of the enolphosphate (I) (1) and the thiol (II) in the presence of diisopropylethylamine gives the protected compound (III), which is deprotected by hydrogenolysis with H2 over Pd(OH)2 on carbon, purified by reverse-phase silica gel chromatography and treated with HCl to afford ER-35786 (2), as shown in Scheme 22662001a.

参考文献 中间体
合成目标
【1】 Kaneda, S.; Hayasi, K.; Kumagai, T.; Crystalline 1-methyl-2-diphenylphosphoryloxy-carbapenem compounds. JP 92330085 .
【2】 Sato, N.; Ohba, F.; ER-35786. Drugs Fut 1996, 21, 4, 361.
【3】 Sato, N.; Sasho, M.; Kamada, A.; Suzuki, T.; Ashizawa, K.; Sugiyama, I.; ER-35786, a new antipseudomonal carbapenem: I. Synthesis and structure-activity relations of 2-substituted 1beta-methyl carbapenems. 35th Intersci Conf Antimicrob Agents Chemother (Sept 17-20, San Francisco) 1995, Abst F151.
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) 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
(II) 17113 (R)-[(2S,4S)-1-methyl-4-sulfanyltetrahydro-1H-pyrrol-2-yl][(3R)-1-methyltetrahydro-1H-pyrrol-3-yl]methanol C11H22N2OS 详情 详情
(III) 17114 methyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[((3S,5S)-5-[(R)-hydroxy[(3R)-1-methylpyrrolidinyl]methyl]-1-methylpyrrolidinyl)sulfanyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C22H35N3O5S 详情 详情

合成路线7

该中间体在本合成路线中的序号：(VI)

1) The mesylation of 4(S)-hydroxypyrrolidin-2-one (I) with mesyl chloride and triethylamine in pyridine gives the corresponding ester (II), which is treated with potassium thioacetate (III) in refluxing acetonitrile yielding 4(R)-(acetylsulfanyl)pyrrolidin-2-one (IV). The hydrolysis of (IV) with sodium methoxide in methanol followed by acidification with aqueous HCl affords 4(R)-sulfanylpyrrolidin-2-one (V), which is condensed with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (VI) by means of ethyldiisopropylamine in acetonitrile to give (1R,5S,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[5-oxopyrrolidin-3(R)-ylsulfanyl]-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (VII). The hydrogenolysis of (VII) with H2 over Pd/C in THF/aqueous phosphate buffer yields the sodium salt (VIII), which is finally esterified with pivaloyloxymethyl iodide (IX) in dimethylacetamide.

参考文献 中间体
合成目标
【1】 Yasuda, H.; Kuwahara, S.; Kawamoto, I.; Miyauchi, M.; Endo, R.; Hisaoka, M.; CS-834, a new oral carbapenem: I. Structure-activity relationships of 2-substituted 1beta-methylcarbapenems. 36th Intersci Conf Antimicrob Agents Chemother (Sept 15-18, New Orleans) 1996, Abst F105.
【2】 Endo, R.; Yasuda, H.; Kawamoto, I.; Hisaoka, M.; Miyauchi, M.; Synthesis and structure-activity relationships of a novel oral carbapenem, CS-834. J Antibiot 1997, 50, 5, 429-39.
【3】 Graul, A.; Castañer, R.M.; Castañer, J.; Leeson, P.; CS-834. Drugs Fut 1998, 23, 3, 261.
【4】 Kawamoto, I.; Tanaka, T.; Endo, R.; Miyauchi, M.; Iwata, M. (Sankyo Co., Ltd.); 2-(Heterocyclylthio)carbapenem derivs. their preparation and their use as antibiotics. AU 8932386; EP 0337637; EP 0597821; JP 1990028180; JP 1990049783; US 5104867; US 5242914 .
【5】 Kawamoto, I.; Miyauchi, M.; Endo, R. (Sankyo Co., Ltd.); Crystalline carbapenem deriv. EP 0599512; JP 1995165759 .
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) 17188 (S)-4-hydroxy-2-pyrrolidone; (4S)-4-hydroxytetrahydro-2H-pyrrol-2-one; (S)-4-hydroxypyrrolidone 68108-18-9 C4H7NO2 详情 详情
(II) 17189 (3S)-5-oxotetrahydro-1H-pyrrol-3-yl methanesulfonate C5H9NO4S 详情 详情
(III) 17190 potassium ethanethioate 10387-40-3 C2H3KOS 详情 详情
(IV) 17191 S-[(3R)-5-oxotetrahydro-1H-pyrrol-3-yl] ethanethioate C6H9NO2S 详情 详情
(V) 17192 (4R)-4-sulfanyltetrahydro-2H-pyrrol-2-one 157429-42-0 C4H7NOS 详情 详情
(VI) 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
(VII) 17194 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-oxotetrahydro-1H-pyrrol-3-yl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C21H23N3O7S 详情 详情
(VIII) 17195 sodium (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-oxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C14H17N2NaO5S 详情 详情
(IX) 11159 iodomethyl pivalate C6H11IO2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(V)

Coupling of thioacetylproline derivative (I) with p-nitrobenzyl ester of ciprofloxacin (II) in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) provided amide (III). Treatment with pyrrolidine in acetonitrile gave thiol (IV), which was subsequently alkylated with the carbapenem phosphate (V) in the presence of diisopropylethylamine to give thioether (VI). Then, hydrogenolytical removal of p-nitrobenzyl protecting groups in the presence of Pd-C, followed by treatment with sodium 2-ethylhexanoate in acetone provided the target disodium salt.

参考文献 中间体
合成目标
【1】 Hershberger, P.M.; Switzer, A.G.; Yelm, K.E.; Coleman, M.C.; Devries, C.A.; Rourke, F.J.; Davis, B.W.; Kraft, W.G.; Twinem, T.L.; Koenigs, P.M.; Paule, S.M.; Siehnel, R.J.; Zoutendam, P.H.; Imbus, R.; Demuth, T.P. Jr.; Preparation and antimicrobial assessment of 2-thioether-linked quinolonyl-carbapenems. J Antibiot 1998, 51, 9, 857-871.
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) 18241 (2S,4S)-4-(acetylsulfanyl)-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid C15H16N2O7S 详情 详情
(II) 18242 4-nitrobenzyl 1-cyclopropyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylate C24H23FN4O5 详情 详情
(III) 18243 4-nitrobenzyl 7-[4-[((2S,4S)-4-(acetylsulfanyl)-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)carbonyl]-1-piperazinyl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C39H37FN6O11S 详情 详情
(IV) 18244 4-nitrobenzyl 1-cyclopropyl-6-fluoro-7-[4-[((2S,4S)-1-[[(4-nitrobenzyl)oxy]carbonyl]-4-sulfanylpyrrolidinyl)carbonyl]-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate C37H35FN6O10S 详情 详情
(V) 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
(VI) 18246 4-nitrobenzyl 1-cyclopropyl-6-fluoro-7-[4-[((2S,4S)-4-[((4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-[[(4-nitrobenzyl)oxy]carbonyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl)sulfanyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)carbonyl]-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate C54H51FN8O16S 详情 详情

合成路线9

该中间体在本合成路线中的序号：(VIII)

Azetidineacetic acid derivative (I) was activated with 1,1'-carbonyldiimidazole and then condensed with p-nitrobenzyl malonate magnesium salt (II) to afford ketoester (III). Desilylation of (III) with methanolic HCl then gave alcohol (IV). Dodecylbenzenesulfonyl azide (VI) was prepared by treatment of sulfonyl chloride (V) with NaN3. Reaction of (IV) with sulfonyl azide (VI) provided diazo ester (VII). Ring closure of (VII) in the presence of rhodium diacetate in hot cyclohexane, followed by condensation with diphenylphosphoric chloride furnished carbapenem phosphate (VIII).

参考文献 中间体
合成目标
【1】 Lin, Y.-I.; Bitha, P.; Sakya, S.; Strohmeyer, T.W.; Bush, K. (American Cyanamid Co.); Novel 2-thiosubstd. carbapenems. CA 2118961; EP 0617036; JP 1994321948; US 5602118 .
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) 30029 (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid C14H27NO4Si 详情 详情
(II) 33039 magnesium 2-(4-nitrobenzyl)malonate C10H7MgNO6 详情 详情
(III) 33040 4-nitrobenzyl (4R)-4-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-oxopentanoate C23H34N2O7Si 详情 详情
(IV) 22573 4-nitrobenzyl 4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate C17H20N2O7 详情 详情
(V) 33041 4-dodecylbenzenesulfonyl chloride C18H29ClO2S 详情 详情
(VI) 33042 4-dodecylbenzenesulfonyl azide C18H29N3O2S 详情 详情
(VII) 30150 (3S,4R)-3-((1R)-1-Hydroxyethyl)-4[(1R)-1-methyl-3-diazo-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one 137391-68-5 C17H18N4O7 详情 详情
(VIII) 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

合成路线10

该中间体在本合成路线中的序号：(VIII)

Coupling of carbapenem phosphate (VIII) with thiol (XIII) using diisopropylethylamine gave rise to sulfide (XIX). Hydrogenolysis of the p-nitrobenzyl group of (XIX) with simultaneous azide reduction in the presence of Pd/C provided (XX). Treatment of p-nitrobenzyl chloroformate (XXI) with p-nitrophenol (XXII) afforded the nitrophenyl carbonate (XXIII), which was coupled with L-valine (XXIV), yielding carbamate (XXV). Activation of (XXV) with N-hydroxy succinimide and DCC then produced the succinimidyl ester (XXVI). Amine (XX) was coupled with succinimidyl ester (XXVI) to furnish amide (XXVII). The p-nitrobenzyl ester was finally removed by hydrogenation over Pd/C to provide the title compound.

参考文献 中间体
合成目标
【1】 Lin, Y.-I.; et al.; Peptidic prodrugs of novel aminomethyl-THF 1beta-methylcarbapenems. Bioorg Med Chem Lett 1997, 7, 13, 1665.
【2】 Lin, Y.-I.; Bitha, P.; Sakya, S.; Strohmeyer, T.W.; Bush, K. (American Cyanamid Co.); Novel 2-thiosubstd. carbapenems. CA 2118961; EP 0617036; JP 1994321948; US 5602118 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 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
(XIII) 33047 (2R,3R)-2-(azidomethyl)tetrahydro-3-furanthiol; (2R,3R)-2-(azidomethyl)tetrahydro-3-furanylhydrosulfide C5H9N3OS 详情 详情
(XIX) 33053 4-nitrobenzyl (4R,5S,6S)-3-[[(2R,3R)-2-(azidomethyl)tetrahydro-3-furanyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C22H25N5O7S 详情 详情
(XX) 33054 (4R,5S,6S)-3-[[(2R,3R)-2-(aminomethyl)tetrahydro-3-furanyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid C15H22N2O5S 详情 详情
(XXI) 33055 1-[[(chlorocarbonyl)oxy]methyl]-4-nitrobenzene 4457-32-3 C8H6ClNO4 详情 详情
(XXII) 11236 4-Nitrophenol; p-Nitrophenol 100-02-7 C6H5NO3 详情 详情
(XXIII) 33056 4-nitrobenzyl 4-nitrophenyl carbonate C14H10N2O7 详情 详情
(XXIV) 21056 (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid 640-68-6 C5H11NO2 详情 详情
(XXV) 33057 (2S)-3-methyl-2-([[(4-nitrobenzyl)oxy]carbonyl]amino)butyric acid C13H16N2O6 详情 详情
(XXVI) 33058 4-nitrobenzyl (1S)-1-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-methylpropylcarbamate C17H19N3O8 详情 详情
(XXVII) 33059 (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(2R,3R)-2-([[(2S)-3-methyl-2-([[(4-nitrobenzyl)oxy]carbonyl]amino)butanoyl]amino]methyl)tetrahydro-3-furanyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid C28H36N4O10S 详情 详情

合成路线11

该中间体在本合成路线中的序号：(VIII)

A convergent synthesis was further developed. Azide (XII) was reduced to the corresponding amine (XXVIII) employing triethyl phosphite. Hydrolysis of the thioacetate ester of (XXVIII) then gave thiol (XXIX). Coupling of (XXIX) with protected valine succinimidyl ester (XXVI) produced amide (XXX). Condensation of (XXX) with carbapenem phosphate (VIII) yielded adduct (XXXI). The p-nitrobenzyl esters were finally deprotected by catalytic hydrogenation.

参考文献 中间体
合成目标
【1】 Lin, Y.I.; Li, Z.; Bitha, P.; Convergent synthesis of oral 1beta-methylcarbapenems. J Antibiot 1999, 52, 7, 643.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 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
(XII) 33046 S-[(2R,3R)-2-(azidomethyl)tetrahydro-3-furanyl] ethanethioate C7H11N3O2S 详情 详情
(XXVI) 33058 4-nitrobenzyl (1S)-1-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-methylpropylcarbamate C17H19N3O8 详情 详情
(XXVIII) 33060 S-[(2R,3R)-2-(aminomethyl)tetrahydro-3-furanyl] ethanethioate C7H13NO2S 详情 详情
(XXIX) 33061 (2R,3R)-2-(aminomethyl)tetrahydro-3-furanylhydrosulfide; (2R,3R)-2-(aminomethyl)tetrahydro-3-furanthiol C5H11NOS 详情 详情
(XXX) 33062 4-nitrobenzyl (1S)-2-methyl-1-[([[(2R,3R)-3-sulfanyltetrahydro-2-furanyl]methyl]amino)carbonyl]propylcarbamate C18H25N3O6S 详情 详情
(XXXI) 33063 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(2R,3R)-2-([[(2S)-3-methyl-2-([[(4-nitrobenzyl)oxy]carbonyl]amino)butanoyl]amino]methyl)tetrahydro-3-furanyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C35H41N5O12S 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XII)

The protection of 4(R)-hydroxypyrrolidin-2-one (I) first with TBDMS-Cl and then with Boc2O gives the fully protected compound (II), which is condensed with the Grignard reagent of the 4-bromobenzaldehyde dimethyl acetal (III) yielding after working up the substituted benzaldehyde (IV). The reduction of (IV) with NaBH4 affords the benzyl alcohol (V), which is treated with methanesulfonyl chloride to give the corresponding mesylate (VI). The reaction of (VI) with methylamine, followed by protection with Boc2O yields the protected secondary amine (VII), which is desilylated with tetrabutylammonium fluoride to afford the pyrrolidinol (VIII). The reaction of (VIII) with MsCl gives the mesylate (IX), which is treated with potassium thioacetate to provide the acetylsulfanyl derivative (X). The hydrolysis and deprotection of (X) with HCl yields the pyrrolidinethiol (XI), which is condensed with the carbapenem phosphoric ester (XII) to afford the final 4-nitrobenzyl ester intermediate (XIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C.

参考文献 中间体
合成目标
【1】 Sato, H.; Morishima, H.; Sakuraba, S.; Yamada, K.; Imamura, H.; Shimizu, A.; Sugimoto, Y.; Practical synthesis of a 1beta-methylcarbapenem, J-111,225, using 4-mercapto-2-[4-(N-methylaminomethyl)phenyl]pyrrolidine as a precursor. Chem Pharm Bull 2001, 49, 4, 476.
【2】 Imamura, H.; et al.; Discovery of novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems. Bioorg Med Chem 2000, 8, 8, 1969.
【3】 Sato, H.; Shimizu, A.; Imamura, H.; et al.; J-111,225, a novel trans-3,5-disubstituted pyrrolidinylthio 1beta-methylcarbapenem; synthesis and physicochemical properties. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-61.
【4】 Imamura, H.; Ohtake, N.; Shimizu, A.; et al.; Structure-activity relationships of trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems. Part 2: J-111,225, J-114,870, J-114,871 and related compounds. Bioorg Med Chem Lett 2000, 10, 2, 115.
【5】 Ushijima, R.; Sugimoto, Y.; Shimizu, A.; Kiyonaga, H.; Nagano, R.; Nakagawa, S.; Sakuraba, S.; Sato, H.; Hashizume, T.; Nakano, M.; Imamura, H.; Fukatsu, H. (Banyu Pharmaceutical Co., Ltd.); Carbapenem derivs.. EP 1048669; JP 2000143512; WO 9931106 .
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) 30864 N-Benzyl-N-(1(R)-phenylethyl)amide lithium salt C15H16LiN 详情 详情
(II) 30850 tert-butyl (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-oxo-1-pyrrolidinecarboxylate C15H29NO4Si 详情 详情
(III) 30851 bromo[4-(dimethoxymethyl)phenyl]magnesium C9H11BrMgO2 详情 详情
(IV) 30852 tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate C22H35NO4Si 详情 详情
(V) 30870 tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-(hydroxymethyl)phenyl]-1-pyrrolidinecarboxylate C22H37NO4Si 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) 30872 tert-butyl (2R,4R)-2-(4-[[(tert-butoxycarbonyl)(methyl)amino]methyl]phenyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate C28H48N2O5Si 详情 详情
(VIII) 30873 tert-butyl (2R,4R)-2-(4-[[(tert-butoxycarbonyl)(methyl)amino]methyl]phenyl)-4-hydroxy-1-pyrrolidinecarboxylate C22H34N2O5 详情 详情
(IX) 30874 tert-butyl (2R,4R)-2-(4-[[(tert-butoxycarbonyl)(methyl)amino]methyl]phenyl)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-pyrrolidinecarboxylate C25H40N2O5S 详情 详情
(X) 30875 tert-butyl (2R,4R)-4-(acetylsulfanyl)-2-(4-[[(tert-butoxycarbonyl)(methyl)amino]methyl]phenyl)-1-pyrrolidinecarboxylate C24H36N2O5S 详情 详情
(XI) 30876 (3S,5R)-5-[4-[(methylamino)methyl]phenyl]pyrrolidinylhydrosulfide; (3S,5R)-5-[4-[(methylamino)methyl]phenyl]-3-pyrrolidinethiol C12H18N2S 详情 详情
(XII) 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
(XIII) 30877 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[((3S,5R)-5-[4-[(methylamino)methyl]phenyl]pyrrolidinyl)sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C29H34N4O6S 详情 详情

合成路线13

该中间体在本合成路线中的序号：(XII)

(R)-4-hydroxy-2-pyrrolidinone (I) was protected as the tert-butyldimethylsilyl ether, and then converted to tert-butyl carbamate (II) by means of Boc2O. Subsequent condensation of (II) with Grignard reagent (III), followed by reduction with NaBH4, and acetal hydrolysis yielded the pyrrolidinyl benzaldehyde (IV). Horner-Emmons reaction of (IV) with phosphonate (V) produced the cinnamic acid derivative (VI), and further Michael addition of the chiral lithium amide (VII) furnished aminoester (VIII). After hydrogenolysis of both N-benzyl groups of (VIII), the resulting primary amine (IX) was protected with Boc2O, and the silyl ether was then cleaved by means of tetrabutylammonium fluoride to give the hydroxypyrrolidine derivative (X). This was converted to the required thiol (XI), which was then coupled with the carbapenem phosphate (XII). Finally, hydrogenolysis of the 4-nitrobenzyl ester of (XII) provided the title compound.

参考文献 中间体
合成目标
【1】 Imamura, H.; et al.; Discovery of novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems. Bioorg Med Chem 2000, 8, 8, 1969.
【2】 Sato, H.; Shimizu, A.; Imamura, H.; et al.; J-111,225, a novel trans-3,5-disubstituted pyrrolidinylthio 1beta-methylcarbapenem; synthesis and physicochemical properties. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-61.
【3】 Imamura, H.; Sato, H.; Shimizu, A.; et al.; J-114,870 and J-114,871, novel trans-3,5-disubstituted pyrrolidinylthio 1beta-methylcarbapenems: Synthesis and physicochemical properties. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-56.
【4】 Imamura, H.; Ohtake, N.; Shimizu, A.; et al.; Structure-activity relationships of trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems. Part 2: J-111,225, J-114,870, J-114,871 and related compounds. Bioorg Med Chem Lett 2000, 10, 2, 115.
【5】 Ushijima, R.; Sugimoto, Y.; Shimizu, A.; Kiyonaga, H.; Nagano, R.; Nakagawa, S.; Sakuraba, S.; Sato, H.; Hashizume, T.; Nakano, M.; Imamura, H.; Fukatsu, H. (Banyu Pharmaceutical Co., Ltd.); Carbapenem derivs.. EP 1048669; JP 2000143512; WO 9931106 .
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) 30864 N-Benzyl-N-(1(R)-phenylethyl)amide lithium salt C15H16LiN 详情 详情
(II) 30850 tert-butyl (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-oxo-1-pyrrolidinecarboxylate C15H29NO4Si 详情 详情
(III) 30851 bromo[4-(dimethoxymethyl)phenyl]magnesium C9H11BrMgO2 详情 详情
(IV) 30852 tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate C22H35NO4Si 详情 详情
(VI) 30853 tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-[(E)-3-ethoxy-3-oxo-1-propenyl]phenyl]-1-pyrrolidinecarboxylate C26H41NO5Si 详情 详情
(VII) 30864 N-Benzyl-N-(1(R)-phenylethyl)amide lithium salt C15H16LiN 详情 详情
(VIII) 30865 tert-butyl (2R,4R)-2-[4-((1S)-1-[benzyl[(1R)-1-phenylethyl]amino]-3-ethoxy-3-oxopropyl)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate C41H58N2O5Si 详情 详情
(IX) 30866 tert-butyl (2R,4R)-2-[4-[(1S)-1-amino-3-ethoxy-3-oxopropyl]phenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate C26H44N2O5Si 详情 详情
(X) 30867 tert-butyl (2R,4R)-2-(4-[(1S)-1-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]phenyl)-4-hydroxy-1-pyrrolidinecarboxylate C25H38N2O7 详情 详情
(XI) 30868 (3S)-3-amino-3-[4-[(2R,4S)-4-sulfanylpyrrolidinyl]phenyl]propanamide C13H19N3OS 详情 详情
(XII) 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

合成路线14

该中间体在本合成路线中的序号：(XII)

(R)-4-hydroxy-2-pyrrolidinone (I) was protected as the tert-butyldimethylsilyl ether, and then converted to tert-butyl carbamate (II) by means of Boc2O. Subsequent condensation of (II) with Grignard reagent (III), followed by reduction with NaBH4, and acetal hydrolysis yielded the pyrrolidinyl benzaldehyde (IV). Horner-Emmons reaction of (IV) with phosphonate (V) produced the cinnamic acid derivative (VI), and further Michael addition to (VI) of the chiral lithium amide (VII) furnished aminoester (VIII). After hydrogenolysis of both N-benzyl groups of (VIII), the resulting primary amine (IX) was protected with Boc2O, and the silyl ether was then cleaved by means of tetrabutylammonium fluoride to give the hydroxypyrrolidine derivative (X). This was converted to the required thiol (XI), which was then coupled with the carbapenem phosphate (XII). Finally, hydrogenolysis of the 4-nitrobenzyl ester of (XII) provided the title compound.

参考文献 中间体
合成目标
【1】 Imamura, H.; et al.; Discovery of novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems. Bioorg Med Chem 2000, 8, 8, 1969.
【2】 Imamura, H.; Sato, H.; Shimizu, A.; et al.; J-114,870 and J-114,871, novel trans-3,5-disubstituted pyrrolidinylthio 1beta-methylcarbapenems: Synthesis and physicochemical properties. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-56.
【3】 Sato, H.; Shimizu, A.; Imamura, H.; et al.; J-111,225, a novel trans-3,5-disubstituted pyrrolidinylthio 1beta-methylcarbapenem; synthesis and physicochemical properties. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-61.
【4】 Imamura, H.; Ohtake, N.; Shimizu, A.; et al.; Structure-activity relationships of trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems. Part 2: J-111,225, J-114,870, J-114,871 and related compounds. Bioorg Med Chem Lett 2000, 10, 2, 115.
【5】 Ushijima, R.; Sugimoto, Y.; Shimizu, A.; Kiyonaga, H.; Nagano, R.; Nakagawa, S.; Sakuraba, S.; Sato, H.; Hashizume, T.; Nakano, M.; Imamura, H.; Fukatsu, H. (Banyu Pharmaceutical Co., Ltd.); Carbapenem derivs.. EP 1048669; JP 2000143512; WO 9931106 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(I) 30864 N-Benzyl-N-(1(R)-phenylethyl)amide lithium salt C15H16LiN 详情 详情
(II) 30850 tert-butyl (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-oxo-1-pyrrolidinecarboxylate C15H29NO4Si 详情 详情
(III) 30851 bromo[4-(dimethoxymethyl)phenyl]magnesium C9H11BrMgO2 详情 详情
(IV) 30852 tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate C22H35NO4Si 详情 详情
(VI) 30853 tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-[(E)-3-ethoxy-3-oxo-1-propenyl]phenyl]-1-pyrrolidinecarboxylate C26H41NO5Si 详情 详情
(VII) 30854 N-Benzyl-N-(1(S)-phenylethyl)amide lithium salt C15H16LiN 详情 详情
(VIII) 30855 tert-butyl (2R,4R)-2-[4-((1R)-1-[benzyl[(1S)-1-phenylethyl]amino]-3-ethoxy-3-oxopropyl)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate C41H58N2O5Si 详情 详情
(IX) 30856 tert-butyl (2R,4R)-2-[4-[(1R)-1-amino-3-ethoxy-3-oxopropyl]phenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate C26H44N2O5Si 详情 详情
(X) 30857 tert-butyl (2R,4R)-2-(4-[(1R)-1-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]phenyl)-4-hydroxy-1-pyrrolidinecarboxylate C25H38N2O7 详情 详情
(XI) 30858 (3R)-3-amino-3-[4-[(2R,4S)-4-sulfanylpyrrolidinyl]phenyl]propanamide C13H19N3OS 详情 详情
(XII) 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

合成路线15

该中间体在本合成路线中的序号：(XVI)

Condensation of (phosphoryloxy)carbapenem (XVI) with 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (XI) gave thioether (XVII). The p-nitrobenzyl ester group of (XVII) was then deprotected with Zn powder to afford carboxylic acid. Finally, treatment of (XVIII) with either iodo or chloromethyl pivalate (XIX) produced the target compound.

参考文献 中间体
合成目标
【1】 Satoh, C.; Mihira, A.; Yamamoto, S.; Hayashi, K.; Kitamura, M.; Tamai, S.; Abe, T.; Kumagai, T.; Hikida, M.; L-084, a new oral carbapenem: Synthesis and structure-activity relationships of C2-substituted 1beta-methylcarbapenems. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-64.
【2】 Abe, T.; Isoda, T.; Sato, C.; Mihira, A.; Tamai, S.; Kumagai, T. (Lederle (Japan), Ltd.); 2-(1-(1,3-Thiazolin-2-yl)azetidin-3-yl)thio-carbapenem derivs.. EP 0632039; EP 0717042; JP 1996053453; US 5534510; US 5659043; US 5783703 .
【3】 Abe, T.; Kumagai, T. (Lederle (Japan), Ltd.); Carbapenem-3-carboxylic acid ester derivs.. EP 0808315; JP 1999504039; US 5886172; WO 9721712 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIXa) 11159 iodomethyl pivalate C6H11IO2 详情 详情
(XIXb) 16166 chloromethyl pivalate 18997-19-8 C6H11ClO2 详情 详情
(XI) 31404 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinylhydrosulfide; 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinethiol 179337-57-6 C6H10N2S2 详情 详情
(XVI) 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
(XVII) 31408 4-nitrobenzyl (4R,5S,6S)-3-[[1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C23H26N4O6S2 详情 详情
(XVIII) 31409 (4R,5S,6S)-3-[[1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid C16H21N3O4S2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(VI)

Mercaptoproline derivative (I) was condensed with protected piperazine (II) via activation with carbonyl diimidazole to afford amide (III). The 4-methoxybenzyl group of (III) was then removed with trifluoromethanesulfonic acid in the presence of anisole and trifluoroacetic acid, and the resulting mercaptan (IV) was condensed with carbapenem phosphate (VI), (prepared from ketone (V) and diphenylphosphorochloridate), to afford thioether (VII). N-Methylation was carried out using methyl fluorosulfonate to yield quaternary ammonium salt (VIII). Finally, the 4-nitrobenzyl ester and carbamate groups of (VIII) were eliminated by hydrogenation in the presence of Pd/C, and the target product was isolated by ion-exchange chromatography.

参考文献 中间体
合成目标
【1】 Ishikawa, K.; Kojima, K.; Miyauchi, M.; Endo, R.; Yasuda H; Kawamoto I.; Synthesis and structure-activity relationships of 1beta-methylcarbapenems with quaternary ammonium side chains. J Antibiot 1998, 51, 8, 757.
【2】 Kawamoto, I.; Miyauchi, M.; Nakayama, E.; Endo, R.; Ohya, S.; Utsui, Y. (Sankyo Co., Ltd.); Carbapenem derivs. having antibiotic activity, their preparation and their use. EP 0443883; JP 1992211083; US 5310735 .
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) 26808 (2S,4S)-4-[(4-methoxybenzyl)sulfanyl]-1-methyl-2-pyrrolidinecarboxylic acid C14H19NO3S 详情 详情
(II) 26809 4-nitrophenyl 1-piperazinecarboxylate C11H13N3O4 详情 详情
(III) 26810 4-nitrobenzyl 4-([(2S,4S)-4-[(4-methoxybenzyl)sulfanyl]-1-methylpyrrolidinyl]carbonyl)-1-piperazinecarboxylate C26H32N4O6S 详情 详情
(IV) 26811 4-nitrobenzyl 4-[[(2S,4S)-1-methyl-4-sulfanylpyrrolidinyl]carbonyl]-1-piperazinecarboxylate C18H24N4O5S 详情 详情
(V) 22575 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate C17H18N2O7 详情 详情
(VI) 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
(VII) 26812 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-([(3S,5S)-1-methyl-5-[(4-[[(4-nitrobenzyl)oxy]carbonyl]-1-piperazinyl)carbonyl]pyrrolidinyl]sulfanyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C35H40N6O11S 详情 详情
(VIII) 26813 (1R,5S,6S)-6-(1(R)-Hydroxyethyl)-2-[1,1-dimethyl-5(S)-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-ylcarbonyl]pyrrrolidinium-3(S)-ylsulfanyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester fluorosulfonate; (1R,5S,6S)-6-(1(R)-Hydroxyethyl)-2-[1,1-dimethyl-5(S)-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-ylcarbonyl]pyrrrolidinium-3(S)-ylsulfanyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester fluorosulfonate C36H43FN6O14S2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VI)

Mercaptoproline derivative (I) was condensed with N-(carbamoylmethyl)homopiperazine (II) via activation with carbonyl diimidazole to afford amide (III). The 4-methoxybenzyl group of (III) was then removed with trifluoromethanesulfonic acid in the presence of anisole and trifluoroacetic acid, and the resulting mercaptan (IV) was condensed with carbapenem phosphate (VI), (prepared from ketone (V) and diphenylphosphorochloridate), to afford thioether (VII). N-Methylation of (VII) was carried out using methyl fluorosulfonate to yield quaternary ammonium salt (VIII). Finally, the 4-nitrobenzyl ester and carbamate groups of (VIII) were eliminated by hydrogenation in the presence of Pd/C, and the target product was isolated by ion-exchange chromatography.

参考文献 中间体
合成目标
【1】 Ishikawa, K.; Kojima, K.; Miyauchi, M.; Endo, R.; Yasuda H; Kawamoto I.; Synthesis and structure-activity relationships of 1beta-methylcarbapenems with quaternary ammonium side chains. J Antibiot 1998, 51, 8, 757.
【2】 Kawamoto, I.; Miyauchi, M.; Nakayama, E.; Endo, R.; Ohya, S.; Utsui, Y. (Sankyo Co., Ltd.); Carbapenem derivs. having antibiotic activity, their preparation and their use. EP 0443883; JP 1992211083; US 5310735 .
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) 26814 (2S,4S)-4-[(4-methoxybenzyl)sulfanyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid C21H22N2O7S 详情 详情
(II) 26815 2-(1,4-diazepan-1-yl)acetamide C7H15N3O 详情 详情
(III) 26816 4-nitrobenzyl (2S,4S)-2-[[4-(2-amino-2-oxoethyl)-1,4-diazepan-1-yl]carbonyl]-4-[(4-methoxybenzyl)sulfanyl]-1-pyrrolidinecarboxylate C28H35N5O7S 详情 详情
(IV) 26817 4-nitrobenzyl (2S,4S)-2-[[4-(2-amino-2-oxoethyl)-1,4-diazepan-1-yl]carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate C20H27N5O6S 详情 详情
(V) 22575 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate C17H18N2O7 详情 详情
(VI) 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
(VII) 26818 4-nitrobenzyl (4R,5S,6S)-3-[((3S,5S)-5-[[4-(2-amino-2-oxoethyl)-1,4-diazepan-1-yl]carbonyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C37H43N7O12S 详情 详情
(VIII) 26819 (1R,5S,6S)-2-[5(S)-[4-(carbamoylmethyl)-4-methylperhydro-1,4-diazepinium-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-(S)-ylsulfanyl]-6-(1(R)-hydroxyethyl)-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester fluorosulfonate; (1R,5S,6S)-2-[5(S)-[4-(carbamoylmethyl)-4-methylperhydro-1,4-diazepinium-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-(S)-ylsulfanyl]-6-(1(R)-hydroxyethyl)-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester fluorosulfonate C38H46FN7O15S2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(VIII)

L-Tartaric acid (I) was converted to succinimimide (II) upon treatment with benzylamine in refluxing xylene with azeotropic removal of water. Subsequent reduction of (II) with borane, generated from NaBH4 and BF3, afforded pyrrolidine (III). Removal of the N-benzyl group of (III) was effected by hydrogenolysis over Pd/C, and the resulting secondary amine (IV) was coupled with the N-protected 3-thioacetylproline (V) to furnish amide (VI). Deacetylation of (VI) under basic conditions provided thiol (VII). Condensation of thiol (VII) with carbapenem enolphosphate (VIII) afforded thioether (IX). The 4-nitrobenzyl protecting groups of (IX) were finally removed by hydrogenolysis over Pd/C.

参考文献 中间体
合成目标
【1】 Park, S.W.; Park, S.Y.; Kim, D.J.; Shin, K.J.; Kang, Y.K.; Yoo, K.H.; Jae Seo, K.; Synthesis and biological evaluation of novel 1beta-methylcarbapenems having a new moiety at C-2. Bioorg Med Chem Lett 1999, 9, 16, 2385.
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) 16695 (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid 147-71-7 C4H6O6 详情 详情
(II) 33017 (3R,4R)-1-benzyl-3,4-dihydroxy-2,5-pyrrolidinedione 75172-31-5 C11H11NO4 详情 详情
(III) 33018 (3S,4S)-1-benzyl-3,4-pyrrolidinediol C11H15NO2 详情 详情
(IV) 33019 (3S,4S)-3,4-pyrrolidinediol C4H9NO2 详情 详情
(V) 18241 (2S,4S)-4-(acetylsulfanyl)-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid C15H16N2O7S 详情 详情
(VI) 33020 4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[[(3S,4S)-3,4-dihydroxypyrrolidinyl]carbonyl]-1-pyrrolidinecarboxylate C19H23N3O8S 详情 详情
(VII) 33021 4-nitrobenzyl (2S,4S)-2-[[(3S,4S)-3,4-dihydroxypyrrolidinyl]carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate C17H21N3O7S 详情 详情
(VIII) 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
(IX) 33022 4-nitrobenzyl (4R,5S,6S)-3-[((3S,5S)-5-[[(3S,4S)-3,4-dihydroxypyrrolidinyl]carbonyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C34H37N5O13S 详情 详情

合成路线19

该中间体在本合成路线中的序号：(I)

Carbapenem-2-diphenylphosphate (I) was condensed with the sodium salt of 2-mercaptobenzothiophene (II) to give thioether (III). The p-nitrobenzyl group of (III) was then deprotected by hydrogenation over Pd/C in the presence of NaHCO3 to afford the corresponding carboxylic acid sodium salt.

参考文献 中间体
合成目标
【1】 Szumiloski, S.P.; Ratcliffe, R.W.; Waddell, S.T.; et al.; Benzothiazolylthio carbapenems: Potent anti-MRSA agents. Bioorg Med Chem Lett 1995, 5, 13, 1427.
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) 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
(II) 37709 sodium 1-benzothiophen-2-ylsulfide C8H5NaS2 详情 详情
(III) 37710 4-nitrobenzyl (4R,5S,6S)-3-(1-benzothiophen-2-ylsulfanyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C25H22N2O6S2 详情 详情

合成路线20

该中间体在本合成路线中的序号：(VII)

Protection of alcohol (I) with TBDMSCl and imidazole gives silyl compound (II) which is N-methylated by means of NaH and MeI and then deprotected with HCl to yield derivative (III). Mesylation of (III) with MsCl in presence of Et3N followed by thioacetylation with AcSK (A) affords thioacetate (IV) which is then hydrolyzed with NaOMe to yield (V). Treatment of (VI) with diphenylphosphoryl chloride (B) and DIEA in acetonitrile yields (VII), which is then condensed with mercaptan (V) by means of DIEA in the same solvent to provide carbapenem (VIII). Deprotection of the carboxyl moiety of (VIII) by hydrogenation with H2 over Pd/C affords carboxylate (IX), which is finally esterified with pivaloyloxymethyl iodide (X) in N,N-dimethylacetamide or DMF.

参考文献 中间体
合成目标
【1】 Miyauchi, M.; Ohya, S.; Kawamoto, I.; Shibayama, T.; Kanno, O.; Synthesis and biological evaluation of new oral carbapenems with 1-methyl-5-oxopyrrolidin-3-ylthio moiety. J Antibiot 1999, 52, 10, 900.
【2】 Kawamoto, I.; Tanaka, T.; Endo, R.; Miyauchi, M.; Iwata, M. (Sankyo Co., Ltd.); 2-(Heterocyclylthio)carbapenem derivs. their preparation and their use as antibiotics. AU 8932386; EP 0337637; EP 0597821; JP 1990028180; JP 1990049783; US 5104867; US 5242914 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 16074 Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate 2524-64-3 C12H10ClO3P 详情 详情
(A) 17190 potassium ethanethioate 10387-40-3 C2H3KOS 详情 详情
(I) 17188 (S)-4-hydroxy-2-pyrrolidone; (4S)-4-hydroxytetrahydro-2H-pyrrol-2-one; (S)-4-hydroxypyrrolidone 68108-18-9 C4H7NO2 详情 详情
(II) 41640 (4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-pyrrolidinone C10H21NO2Si 详情 详情
(III) 41641 (4S)-4-hydroxy-1-methyl-2-pyrrolidinone C5H9NO2 详情 详情
(IV) 41642 S-[(3R)-1-methyl-5-oxopyrrolidinyl] ethanethioate C7H11NO2S 详情 详情
(V) 41643 (4R)-1-methyl-4-sulfanyl-2-pyrrolidinone C5H9NOS 详情 详情
(VI) 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
(VII) 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
(VIII) 41644 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(3R)-1-methyl-5-oxopyrrolidinyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C22H25N3O7S 详情 详情
(IX) 41645 sodium (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(3R)-1-methyl-5-oxopyrrolidinyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C15H19N2NaO5S 详情 详情
(X) 11159 iodomethyl pivalate C6H11IO2 详情 详情

合成路线21

该中间体在本合成路线中的序号：(VIII)

Alcohol (I) is protected with TBDMSCl and imidazole to give silyl compound (II), which is N-methylated by means of NaH and MeI and then deprotected with HCl to yield derivative (III). Mitsunobu reaction of (III) with 4-nitrobenzoic acid in presence of PPh3 and DEAD, followed by ester hydrolysis with K2CO3, provides alcohol (IV). Mesylation of (IV) with MsCl in presence of Et3N, followed by thioacetylation with AcSK (A), affords thioacetate (V), which is then hydrolyzed with NaOMe to yield (VI). Treatment of (VII) with diphenylphosphoryl chloride (B) in CH3CN and DIEA in CH3CN yields (VIII), which is then condensed with mercaptan (VI) by means of DIEA in the same solvent to provide carbapenem (IX). Deprotection of the carboxyl moiety of (IX) by hydrogenation with H2 over Pd/C affords carboxylate (X), which is finally esterified with pivaloyloxymethyl iodide (XI) in N,N-dimethylacetamide or DMF.

参考文献 中间体
合成目标
【1】 Miyauchi, M.; Ohya, S.; Kawamoto, I.; Shibayama, T.; Kanno, O.; Synthesis and biological evaluation of new oral carbapenems with 1-methyl-5-oxopyrrolidin-3-ylthio moiety. J Antibiot 1999, 52, 10, 900.
【2】 Kawamoto, I.; Tanaka, T.; Endo, R.; Miyauchi, M.; Iwata, M. (Sankyo Co., Ltd.); 2-(Heterocyclylthio)carbapenem derivs. their preparation and their use as antibiotics. AU 8932386; EP 0337637; EP 0597821; JP 1990028180; JP 1990049783; US 5104867; US 5242914 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 16074 Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate 2524-64-3 C12H10ClO3P 详情 详情
(A) 17190 potassium ethanethioate 10387-40-3 C2H3KOS 详情 详情
(I) 17188 (S)-4-hydroxy-2-pyrrolidone; (4S)-4-hydroxytetrahydro-2H-pyrrol-2-one; (S)-4-hydroxypyrrolidone 68108-18-9 C4H7NO2 详情 详情
(II) 41640 (4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-pyrrolidinone C10H21NO2Si 详情 详情
(III) 41641 (4S)-4-hydroxy-1-methyl-2-pyrrolidinone C5H9NO2 详情 详情
(IV) 41648 (4R)-4-hydroxy-1-methyl-2-pyrrolidinone C5H9NO2 详情 详情
(V) 41649 S-[(3S)-1-methyl-5-oxopyrrolidinyl] ethanethioate C7H11NO2S 详情 详情
(VI) 41650 (4S)-1-methyl-4-sulfanyl-2-pyrrolidinone C5H9NOS 详情 详情
(VII) 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
(VIII) 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
(IX) 41646 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(3S)-1-methyl-5-oxopyrrolidinyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C22H25N3O7S 详情 详情
(X) 41647 sodium (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(3S)-1-methyl-5-oxopyrrolidinyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C15H19N2NaO5S 详情 详情
(XI) 11159 iodomethyl pivalate C6H11IO2 详情 详情

合成路线22

该中间体在本合成路线中的序号：(XIII)

Oxocarbapenam (XII) was converted into vinyl phosphate (XIII) by treatment with diphenylphosphoryl chloride and diisopropylethylamine. Displacement of the phosphate group of (XIII) by 4-mercaptopyrrolidine-2-thione (IV) yielded carbapenem sulfide (XIV). After hydrogenolytic cleavage of the p-nitrobenzyl ester of (XIV) in the presence of Pd/C and KHCO3, the resulting potassium carboxylate salt (XV) was condensed with isobutyryloxymethyl iodide (XVI) to furnish the title compound.

参考文献 中间体
合成目标
【1】 Horikawa, H.; Iwasaki, T.; Kondo, K. (Tanabe Seiyaku Co., Ltd.); Process for preparing beta-lactam deriv. and synthetic intermediate thereof. EP 0559533 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 37712 (4R)-4-sulfanyl-2-pyrrolidinethione C4H7NS2 详情 详情
(XII) 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
(XIII) 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
(XIV) 37721 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C21H23N3O6S2 详情 详情
(XV) 37722 potassium (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C14H17KN2O4S2 详情 详情
(XVI) 37723 iodomethyl 2-methylpropanoate C5H9IO2 详情 详情
(XVII) 37724 (isobutyryloxy)methyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-thioxopyrrolidinyl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C19H26N2O6S2 详情 详情

合成路线23

该中间体在本合成路线中的序号：(XV)

Displacement of the mesylate group of (XII) with potassium thioacetate gave thioester (XIII), which was further hydrolyzed to thiol (XIV). This was condensed with enol phosphate (XV) to afford the protected 1-methylcarbapenem (XVI). Finally, deprotection of the p-nitrobenzyl groups of (XVI) by zinc powder in the presence of phosphate buffer (pH 6.0) provided the title compound.

参考文献 中间体
合成目标
【1】 Park, S.W.; Yoo, K.H.; Shin, K.J.; Kang, Y.K.; Hong, C.Y.; Seo, K.J.; Park, S.Y.; Lee, C.-S.; Kim, D.J.; Synthesis and antibacterial activity of new carbapenems containing isoxazole moiety. Bioorg Med Chem Lett 2000, 10, 2, 95.
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) 44930 4-nitrobenzyl (2S,4R)-2-[(5R)-3-(hydroxymethyl)-4,5-dihydro-5-isoxazolyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C17H21N3O9S 详情 详情
(XIII) 44931 4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[(5R)-3-(hydroxymethyl)-4,5-dihydro-5-isoxazolyl]-1-pyrrolidinecarboxylate C18H21N3O7S 详情 详情
(XIV) 44932 4-nitrobenzyl (2S,4S)-2-[(5R)-3-(hydroxymethyl)-4,5-dihydro-5-isoxazolyl]-4-sulfanyl-1-pyrrolidinecarboxylate C16H19N3O6S 详情 详情
(XV) 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
(XVI) 44933 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[((3S,5S)-5-[(5R)-3-(hydroxymethyl)-4,5-dihydro-5-isoxazolyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)sulfanyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C33H35N5O12S 详情 详情

合成路线24

该中间体在本合成路线中的序号：(XIII)

The reaction of the hydroxyproline 4-methoxybenzyl ester (VIII) with Ms-Cl and DIEA in THF gives the mesylate (IX), which is treated with thioacetic acid and Cs2CO3 in DMA to yield the acetylsulfanyl derivative (X). The Boc deprotection of (X) with 4N HCl in ethyl acetate, followed by methylation with HCHO/HCOOH and simultaneous ester hydrolysis, affords the methylated proline (XI), which is activated with pivaloyl chloride and DIEA in acetonitrile to the mixed anhydride (XII). The condensation of (XII) with the intermediate pyrrolidine (VII) by means of DIEA in acetonitrile provides the adduct (XIII), which is further condensed with the carbapenem (XIV) by means of NaOMe in methanol to give the intermediate (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in THF/water to furnish the target 1-beta-methyl carbapenem.

参考文献 中间体
合成目标
【1】 Kanno, O.; Shibayama, T.; Ohya, S.; Shimoji, Y.; Kuwahara, S.; Ishikawa, K.; Kojima, K.; Kawamoto, I.; R-115685, a novel parenteral carbapenem: Synthesis and structure-activity relationships. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1229.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 53608 2-({imino[(4-nitrobenzoyl)amino]methyl}amino)-N-[(3S)pyrrolidinyl]acetamide n/a C14H18N6O4 详情 详情
(VIII) 53609 1-(tert-butyl) 2-(4-methoxybenzyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate n/a C18H25NO6 详情 详情
(IX) 53610 1-(tert-butyl) 2-(4-methoxybenzyl) (2S,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate n/a C19H27NO8S 详情 详情
(X) 53611 1-(tert-butyl) 2-(4-methoxybenzyl) (2S,4S)-4-(acetylsulfanyl)-1,2-pyrrolidinedicarboxylate n/a C20H27NO6S 详情 详情
(XI) 53612 (2S,4S)-4-(acetylsulfanyl)-1-methyl-2-pyrrolidinecarboxylic acid n/a C8H13NO3S 详情 详情
(XII) 53613 (2S,4S)-4-(acetylsulfanyl)-1-methyl-2-pyrrolidinecarboxylic 1,1-dimethylpropanoic anhydride n/a C13H21NO4S 详情 详情
(XIII) 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
(XIV) 53614 S-{(3S,5S)-5-[((3S)-3-{[2-({imino[(4-nitrobenzoyl)amino]methyl}amino)acetyl]amino}pyrrolidinyl)carbonyl]-1-methylpyrrolidinyl} ethanethioate n/a C22H29N7O6S 详情 详情
(XV) 53615 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-({(3S,5S)-5-[((3S)-3-{[2-({imino[(4-nitrobenzoyl)amino]methyl}amino)acetyl]amino}pyrrolidinyl)carbonyl]-1-methylpyrrolidinyl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate n/a C37H43N9O11S 详情 详情
Extended Information