This contribution describes part 1 of process development of a novel aldose reductase inhibitor FK366 (1). The original process applied on a laboratory scale was improved from the safety viewpoint to manufacture materials on 500-L scale suitable for toxicological and pharmacological evaluations. A new process, including regioselective alkylation of silylated quinazolinedione, provided a practical and cost-effective synthesis of FK366 in a dramatically increased yield.

Abstract:4-(1-(2-(3-Methoxyphenethyl)phenoxy)-3-(dimethylamino)propan-2-yloxy)-4-oxobutanoic acid (MPPO), a serotonin receptor blocker, is known to have two polymorphs, Form A and Form B. Crystallization of MPPO was carried out from aqueous 2-butanone solutions by the further addition of 2-butanone as a poor solvent and by cooling to determine the operating conditions, in particular, the seeding effect under which polymorphic mixtures of desired compositions were produced. Seed particles were prepared by comminuting both polymorphs and mixing them at given compositions X As . The product polymorphic compositions (X Ap ) were well controlled by the seed composition as well as by the initial solvent composition (w) and seeding temperature in such a way that X Ap increased as the supersaturation at the moment of seeding decreased. In addition, size-dependent product compositions were analyzed to reveal the crystallization behavior of the polymorphs.

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