Chloramphenicol hemisuccinate

Carboxylic half-esters (e.g. hemisuccinates) of phenols are easily hydrolyzed in aqueous solution and are therefore not recommended for the solubilization of phenolic compounds. Even hemisuccinates of alcohols suffer somewhat from stability problems and must be supplied as lyophi-lized (freeze-dried) powders for reconstitution in water and used within 48 h (see, for example, the monographies chloramphenicol sodium succinate or hydrocortisone sodium succinate in The Handbook on Injectable Drugs,see also Anderson et... 

An additional difficulty occurring with hemisuccinates was discovered by Sandman et al These authors, in studying the stability of chloramphenicol succinate, found an unusual partial acyl transfer reaction of the succinyl group to give a cyclic hemi-orthoester (Figure 38.6). 

From the point of view of importance and chemical feasibility, chloramphenicol (Figure 9) presented an excellent subject for structural modification. It was the first truly broad-spectrum antibiotic isolated, and its structure and total synthesis were both reported two years after the discovery was announced (40, 41, 42). The synthesis of chloramphenicol analogs proved to be one of the great disappointments of early chemical research in the antibiotic field. Hundreds of analogs were synthesized, but none was found superior to the parent drug in terms either of antimicrobial activity or therapeutic index (43). The palmitate and hemisuccinate esters have provided superior dosage forms for oral and parenteral use. One synthetic analog, thiamphenicol (44) has achieved limited use in human and veterinary medicine. 

Figure 6-26. The lincosaminides and chloramphenicol. Chiral centers or hemisuccinate.

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