合成路线1

FCE 22891 in the ester prodrug formulation of FCE 22101. Reaction of the latter (sodium salt) with acetoxymethyl bromide (DMF) is the traditional synthetic route to FCE 22891. This route is also the preferred one as long as manufacturing involves both compounds (the reverse process, conversion of FCE 22891 into the parent acid FCE 22101, can be conveniently realized by enzymic hydrolysis catalyzed by porcine liver esterase or lipase A6 from Aspergillus niger). Direct synthesis of FCE 22891 can be performed using two major strategies. The total synthetic approaches start from chiral amino or hydroxy acids (threonine, 3-hydroxybutyric acid) and have (3R,4R)-4-acetoxy-3-[(R)-1-hydroxyethyl]-2-oxo-1H-azetidine (Ia) or its 4-benzoyloxy analogue (Ib), usually protected as the tert-butyldimethylsilyl ethers, as common intermediates. These compounds, in particular (Ia), can also be found on the market (Kaneka). Reaction of either (Ia) or (Ib) with the sodium salt of 2-carbamoyloxyethanethioic acid gives the azetidinone thiolester (II), which is condensed with acetoxymethyl oxalyl chloride. Reductive carbonyl condensation (triethyl phosphite, refluxing toluene) and desilylation (tetrabutylammonium fluoride buffered with acetic acid) affords FCE 22891. The hemisynthetic route utilizes 6-APA as a chiral template. Introduction of the alpha-hydroxyethyl chain on the penam nucleus is satisfactorily achieved by deaminative bromination, metal exchange with EtMgBr, aldol reaction (acetaldehyde, THF, -70 C) and reductive dehalogenation (Zn-AcOH), MeOH, -10 C). During this process, the acetoxymethyl promoiety characterizing the final product is conveniently introduced. According to an original procedure, beta-eliminative ring opening of the thiazolidine ring (AgCl/DBN) and in situ acylation of the intermediate silver mercaptide with carbamoyloxyacetyl chloride affords the key azetidone thioester (VII). Ozonolysis (CH2Cl2, -50 C) and reductive carbonyl condensation completes the sequence, without resorting to protective groups other than trimethylsilyl, which is removed at the end by simple acidic work-up.