A new synthesis of loracarbef has been described: The reaction of L-(+)-phenylglycine (I) with ethyl chloroformate (II) and NaOH in dichloromethane gives L-N-(ethoxycarbonyl)phenylglycine (III), which is reduced with BH3 in THF to the alcohol (IV). The cyclization of (IV) by means of NaH in THF affords oxazolidinone (V), which by alkylation with ethyl bromoacetate and hydrolysis with NaOH is converted into the oxazolidinone-3-acetic acid (VI), and the corresponding acyl chloride (VII). The cyclization of (VII) with 2-[3-(benzylimino)-1-propenyl]furan (VIII) by means of triethylamine in dichloromethane yields the azetidinone (IX), which is purified from its enantiomer by crystallization. The reduction of (IX) with H2 over Pd/C in dichloromethane gives 1-benzyl-2-[2-(2-furyl)ethyl]-3-(2-oxo-4-phenyloxazolidin-3-yl)azetidin-4-one (X) with a 100% optical purity. The cleavage of (X) with Li/NH3 in tert-butanol - THF yields 3(S)-amino-2(R)-[2-(2-furyl)ethyl]azetidin-4-one (XI), which is acylated with phenoxyacetyl chloride (XII) and NaHCO3 to the amide (XIII). Ozonolysis of (XIII) with O3, H2O2 in dichloromethane-methanol affords 3-[4-oxo-3(S)-phenoxyacetamido)azetidin-2(R)-yl]propanoic acid (XIV), which is then condensed with the magnesium salt of the malonic derivative (XV) in THF to yield the ketoester (XVI).

Diazotization of (XVI) with dodecylsulfonyl azide and triethylamine in acetonitrile gives the diazo derivative (XVII), which is cyclized by means of rhodium octanoate in dichloromethane to afford the carbacephem derivative (XVIII). The reaction of (XVIII) with dichlorotriphenoxyphosphine - pyridine in dichloromethane, followed by hydrolysis in acidic medium gives (6R,7S)-7-amino-3-chloro-1-dethia-1-carba-3-cephem-4-carboxylic acid 4-nitrobenzyl ester (XIX). The acylation of (XIX) with the isobutyl anhydride of enamine-protected D-phenylglycine (XX) by means of triethylamine in DMF affords the fully protected compound (XXI), which is finally deprotected by a treatment with Zn and HCl.

The oxidation of 4-(benzyloxy)-1-butanol (I) with oxalyl chloride gives the corresponding aldehyde (II), which is condensed with the phosphonate (III) by means of DBU and LiCl in acetonitrile to yield the 2-hexenoate (IV). The asymmetric aminohydroxylation of (IV) by means of tert-butyl carbamate, K2[OsO2(OH)4] and a chiral catalyst ((DHQD)2PHAL) in propanol/water affords the desired regioisomer (V). The introduction of an azido group into the alpha-position with retention of the configuration was accomplished by two Mitsunobu reactions. The reaction of (V) with benzoic acid, PPh3 and DEAD in THF gives the benzoyloxy compound (VI) with inverted stereochemistry, which is hydrolyzed with K2CO3 in methanol to yield the corresponding alcohol (VII). Then the reaction of (VII) with HN3, DEAD and PPh3 in THF affords the azide (VIII) with the right stereochemistry. The hydrolysis of the ester group of (VIII) by means of K2CO3 in methanol/water, followed by cleavage of the protecting carbamate group with TFA, provides the carboxylic acid (IX). The cyclization of (IX) by means of 2-chloro-1-methylpyridinium iodide (CMPI) and TEA in acetonitrile gives the azetidinone (X), which is reduced with PPh3 in THF/water to yield the aminoazetidinone (XI). The acylation of the amino group of (XI) with 2-phenoxyacetyl chloride (A) and NaHCO3 in aqueous acetonitrile affords the amide (XII). The hydrogenation of (XII) with H2 over Pd/C in ethanol affords the primary alcohol (XIII), which is finally oxidized with the Jones reagent to provide the target carboxylic acid intermediate (XIV).