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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).

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4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analogue (XVI) but without optical resolution. 5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV), the compound also obtained by hydrolysis of (XXIII) with LiOH. This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV), which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI).

合成路线3

6) The reaction of 5-(4-fluorophenyl)-4-pentenoic acid (XXVI) with oxalyl chloride gives the acyl chloride (XXVII), which is condensed with the chiral oxazolidinone (XXI) by means of DMAP and DIEA in dichloromethane, yielding the acyloxazolidinone (XXVIII). Condensation of (XXVIII) with the benzylideneimine (II) by means of TiCl4 affords adduct (XXIX), which is cyclized to the chiral azetidinone (XXX). The oxidation of the double bond of (XXX) with benzoquinone and HClO4 catalyzed by Pd(OAc)2 in acetonitrile/water provides the previously reported trans-(3R,4S)-azetidinone (XX), which is worked up to give azetimibe as described before.

合成路线4

The activation of 5-(4-fluorophenyl)-5-oxopentanoic acid (I) with pivaloyl chloride (II) gives the mixed anhydride (III), which is condensed with the chiral oxazolidinone (IV) by means of DMAP to yield the acylated oxazolidine (V) (1). The asymmetric reduction of (V) by means of BH3/Me2S catalyzed by the chiral boron catalyst (VI) affords the chiral alcohol (VII) (1-3), which is condensed with the imine (VIII) by means of Tms-Cl, DIEA and TiCl4 to provide the adduct (IX). The cyclization of (IX) by means of bis(trimethylsilyl)acetamide and TBAF gives the protected azetidinone (X), which is finally desilylated by means of sulfuric acid in isopropanol

合成路线5

The condensation of 4(R)-phenyloxazolidin-2-one (I) with 2(E)-pentenoyl chloride (II) by means of BuLi in THF gives 3-[2(E)-pentenoyl]-3(R)-phenyloxazolidin-2-one (III), which is treated with 3-[bis(trimethylsilyl)amino]phenylmagnesium bromide (IV) and CuBr in DMSO/THF regioselectively yielding the addition product (V). Elimination of the silyl groups of (VII) in mild acidic conditions and treatment of the resulting amine with benzyl bromide affords the dibenzylated amine derivative (VI), which is regioselectively acylated with 2-methoxy-2-methyl-1,3-dioxolane (V) and TiCl4 in dichloromethane under basic conditions giving the dione (VIII). The condensation of (VIII) with 1-phenyl-3-hexanone (IX) by means of Ti(OBu)Cl3 in dichloromethane as before yields the hydroxy-dione (X), which is cyclized by means of potassium tert-butoxide in THF to afford the dihydropyrone (XI). The debenzylation of (XI) by hydrogenation with H2 over Pd/C in methanol/ethyl acetate gives the free amine (XII), which is finally sulfonated with 5-(trifluoromethyl)pyridine-2-sulfonyl chloride (XIII) in pyridine/dichloromethane

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