Azetidone

Successive treatment with propanol and then acid serves in effect to hydrolyze the amide linkage. [Note particularly that this sequence is selective for the exocyclic amide over the azetidone.) Reaction of the protected 6-APA derivative (32) with the acid chloride from 24 affords the pivaloylmethylenedioxy derivative, pivampicillin (33) This last is a drug in its own right,... 

Four different synthetic methods leading to azetidones and condensed analogs have been described. These are discussed below in relation to the types of organometallic complexes used as reactants or envisaged as intermediates. 

Solvent CH.CLMeCN (19 1). Solvent CH.Cl,r 5% azetidone and 58% Af-phenylacrylamide under liquid liquid two-phase conditions.4 Using Duolite A-109 (Cl- form). 64% piperazine-2,5-dione after 18 h. I 88% piperazine-2,5-dione. Solvent THF. 63% yield in CH,Cl, MeCN. > Solvent PhH. Using TEBA-CI. 

Azetidones (p-lactams) are generally obtained in high yield from (3-halopropion-amides (Table 5.18) and the low yield from the reaction of N-phenyl (3-chloropropi-onamide can be reconciled with the isolation of A-phenyl acrylamide in 58% yield [34]. The unwanted elimination reaction can be obviated by conducting the cyclization in a soliddiquid system under high dilution [35, 36]. Azetidones are also formed by a predominant intramolecular cyclization of intermolecular dimerization to yield piperazine-2,5-diones, or intramolecular alkylation to yield aziridones. Aone-pot formation of azetidones in 45-58% yield from the amine and P-bromocarboxylic acid chloride has also been reported [38]. 

Method A Using procedure 5.2.12.A, the 3-bromo-(2-bromomethyl)propionamide is stirred in aqueous NaOH (40%) and CCl4 (or CH2Cl2) in the presence of TEB A-Br or TEPA-Br for 18 h at room temperature to produce the azetidone. 

Azacyclonol, 47 Azaphenothiazine, 429 Azepinamide, 137 Azetidone, synthesis, 419 Aziridinium salt, 79 Azlactone, 96 Azomycin, 238... 

The presence of an internal salt, a zwitterion or betaine, in cephalosporins enhances their solubity in water, making such agents particularly suitable for parenteral administration. The preparation of one such dmg first involves the replacement of allyl oxygen in the tert-butylcarbonyloxy protected 7-ACA derivative (23-1) by nitrogen in azaindan (23-2) to afford the betaine (23-3). The protecting group is then removed so as to free the amine on the azetidone (23-4) by treatment with trifluoroacetic acid. Reaction with the thiazole free acid (23-5) in the presence of DCC then affords cefpirone (23-6) [26]. 

The beta lactam moiety is formed by the 2-1-2 cycloaddition of a ketene with an imine. Thus reaction of the acid chloride (37-7) with the benzylimine from 3-fiirylacrolein (38-2) in the presence of triethylamine goes directly to the azetidone (38-3),... 

One of the first compounds to be introduced to the clinic, aztreonam (40-9), has been produced by total synthesis. Constmction of the chiral azetidone starts with amide formation of L-threonine (40-1) via its acid chloride treatment with ammonia leads to the corresponding amide (40-2). The primary amino group in that product is then protected as its carbobenzyloxy derivative (40-3). Reaction of that product with methanesulfonyl chloride affords the mesylate (40-4). Treatment of that intermediate with the pyridine sulfur trioxide complex leads to the formation of the A -sulfonated amide (40-5). Potassium bicarbonate is sufficiently basic to ionize the very acidic proton on the amide the resulting anion then displaces the adjacent mesylate to form the desired azetidone the product is isolated as its tetrabutyl ammonium salt (40-6). Catalytic hydrogenation over palladium removes the carbobenzyloxy protecting group to afford the free primary amine (40-7). The... 

Therefore, some conclusions have been generally accepted and have been summarized as follows the cycloaddition reaction is a stepwise reaction rather than a concerted one the reaction is initiated by nucleophihc attack of an imine to a ketene, giving rise to a zwitterionic intermediate a conrotatory eleclrocyclic ring-closure of the zwitterionic intermediate produces the final 2-azetidone product [85], As the stereochemistry of the structure of the P-lactams strongly affects their biological activity, the stereoselectivity of the process must be carefully considered. Uncatalysed as well as catalysed processes have been reported organometallic and organic catalysts have been utilized in procedures oriented to the syntheses of enantiopure P-lactams [90-92],... 

Another example of how ene reductases can work in tandem with the ADHs to give valuable products is represented by the microbial reduction of the doubly activated substrate 76 (Scheme 3.20). Indeed, the (2S,3S)-hydroxyester 77, one of the products of this biotransformation, was converted after a few chemical manipulations to the chiral azetidone 78, precursor of several P-lactam antibiotics [93]. 

The core structure of ezetimibe molecule 87 consists of an azetidone moiety that could be constructed in the following way (Scheme 39.23). 

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