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).

合成路线2

The cyclization of the diazo azetidinone (I) by means of a Rhodium catalyst in dichloromethane gives the -methyl-2-oxocarbapenam derivative (II), which is treated with methanesulfonic anhydride and TEA in dichloromethane yielding the enol triflate (II). The silylation of the OH group of (III) with triethylsilyl triflate and TEA affords the silyl ether (IV), which is condensed with the fluorenone boronic acid (V) by means of KOH and a Pd catalyst giving the adduct (VI) (1). The mesylation of (VI) with MsCl and TEA in dichloromethane, followed by reaction with NaI in acetone yields the iodomethyl compound (VII), which is condensed with 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide triflate (VIII) by means of silver triflate in THF/acetonitrile to afford the protected intermediate (IX). Finally, this compound is deprotected first with HCl in THF/water and then by hydrogenation with H2 over Rh/C. The intermediate 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide triflate (VIII) has been obtained as follows: The condensation of 1,4-diazabicyclo[2.2.2]octane (X) with 2-bromoacetamide (XI) in acetonitrile gives 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide bromide (XII), which is then treated with silver triflate in acetonitrile/methanol to yield (VIII).

合成路线3

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.

合成路线4

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.

合成路线5

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.

合成路线6

Cyclization of azetidinone (I) by means of catalyst Rh2(OAc)4 in toluol provides carbapenam (II), which is treated with SiO2 in EtOAc to produce epimerization to the alpha-methyl compound (III). Methylation of (III) with diazomethane in dioxane affords carbapenem (IV), which is hydrogenolyzed over Pd/C in EtOAc and finally saponified with KHCO3 in H2O to furnish the desired compound.

合成路线7