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【结 构 式】 
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【药物名称】Biapenem, CL-186815, L-627, LJC-10627, Omegacin 【化学名称】(1R,5S,6S)-2-[(6,7-Dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolio-6-yl)thio]-6-[(R)-1-hydroxyethyl]-1-methylcarbapenem-3-carboxylate 【CA登记号】120410-24-4 【 分 子 式 】C15H18N4O4S 【 分 子 量 】350.39911 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Treatment of Septic Shock, Carbapenems |
合成路线1
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).
| 【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
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.
| 【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
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.
| 【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 |