Goto, Shunsuke published the artcileThe Process Development of a Novel Aldose Reductase Inhibitor, FK366. Part 1. Improvement of Discovery Process and New Syntheses of 1-Substituted Quinazolinediones, Quality Control of 76283-09-5, the publication is Organic Process Research & Development (2003), 7(5), 700-706, database is CAplus.
The novel aldose reductase inhibitor FK366 I is prepared on multikilogram scale by an improved, practical and cost-effective process. Addition of base to a solution of 2-amino-4-chlorobenzoic acid followed by addition of sodium cyanate at pH 6-7 and a second treatment with aqueous sodium hydroxide yields the quinazoline II; the pH is carefully controlled in the cyanate addition step by addition of hydrochloric acid to the reaction mixture, preventing the decomposition of cyanate while allowing the cyclocondensation reaction to occur at a reasonable rate. Silylation of II with bis(trimethylsilyl)amide in the presence of sulfuric acid (with careful mixing of bis(trimethylsilyl)amide and sulfuric acid to avoid violent reaction) yields an intermediate bis(trimethylsilyloxy)quinazoline which undergoes regioselective alkylation in Et acetate to provide the intermediate III in good yield as a single regioisomer. Alkylation of the remaining free nitrogen of the quinazoline with 4-bromo-2-fluorobenzyl bromide followed by basic hydrolysis of the ethoxycarbonyl moiety yields I on 35 kg scale. The dibenzylated quinazoline IV, resulting from incomplete reaction of II in the regioselective alkylation reaction with Et bromoacetate followed by subsequent dibenzylation, acts as a initiator for the formation of an undesired polymorph of I which is difficult to filter and which forms thick slurries. Seeding solutions of I containing ≥1% of IV with either polymorph of I results in crystallization of the undesired polymorph of I from solution Solutions with 0.5% IV yield different polymorphs depending on the identity of the seed crystal; seeding the solution with a crystal of the undesired polymorph of I provides crystals of the undesired polymorph of I, while seeding the solution with a crystal of the desired polymorph of I results in crystallization of the desired polymorph of I. Monitoring of the initial silylation and regioselective alkylation step by HPLC is used to minimize the amount of IV present in the final product and thus to provide the desired polymorph of I upon recrystallization
Organic Process Research & Development published new progress about 76283-09-5. 76283-09-5 belongs to bromides-buliding-blocks, auxiliary class Fluoride,Bromide,Benzyl bromide,Benzene, name is 4-Bromo-1-(bromomethyl)-2-fluorobenzene, and the molecular formula is C7H5Br2F, Quality Control of 76283-09-5.
Referemce:
https://en.wikipedia.org/wiki/Bromide,
bromide – Wiktionary