Racemic sorbinil (I) is hydrolyzed with barium hydroxide in refluxing water to give amino acid (II), which by reaction with potassium cyanate in water yields (RS)-6-fluoro-4-ureido-2,3-dihydro-4H-1-benzoyran-4-carboxylic acid (III). The optical resolution of (III) with D-(+)-(1-phenylethyl)amine or L-(-)-ephedrine affords 6-fluoro-4(S)-ureido-2,3-dihydro-4H-1-benzopyran-4-carboxylic acid (IV), which is finally cyclized to sorbinil by means of hot acetic acid.
A new method for the synthesis of sorbinil has been reported: The condensation of 2,3-dihydro-6-fluoro-4H-1-benzopyran-4-one (I) with methylbenzylamine (II) by means of TiCl4 in benzene gives 2,3-dihydro-6-fluoro-4-(1-phenylethylimino)-4H-1-benzopyran (III), which by reaction with HCN in ethanol is converted to 4-cyano-2,3-dihydro-6-fluoro-4-(1-phenylethylamino)-4H-1-benzopyran (IV). The cyclization of (IV) with chlorosulfonyl isocyanate (V) in methylene chloride affords 2,3-dihydro-6-fluoro-3'-(1-phenylethyl)spiro(4H-1-benzopyran-4,4'-imidazolidine)-2',5'-dione (VI), which is finally treated with 48% HBr in refluxing acetic acid.
The cyclization of 3-(p-fluorophenoxy)propionic acid (I) with polyphosphoric acid in boiling water gives 6-fluoro-4-chromanone (II), which is then treated with KCN and ammonium carbonate in hot ethanol-water.
The condensation of 4-fluorophenol (I) with 1,2-dibromoethane (II) in basic medium gives 2-(4-fluorophenyl)ethyl bromide (III), which by reaction with N-benzoyl-2-hydroxyglycine (IV) in methanesulfonic acid yields N-benzoyl-2-[2-(2-bromoethoxy)-5-fluorophenyl]glycine (V). The cyclization of (V) with acetic anhydride and triethylamine at 50 C affords 6-fluoro-2'-phenylspiro[2,3-dihydro-4H-1-benzopyran-4,4'-oxazolidine]-5'-one (VI), which is hydrolyzed with refluxing formic acid-HCl giving the amino acid (VII). The esterification of (VII) with SOCl2 and methanol in the usual way yields the methyl ester (VIII), which is submitted to optical resolution by selective hydrolysis with alpha-chymotrypsine affording methyl 4(S)-amino-6-fluoro-2,3-dihydro-4H-1-benzopyrano-4-carboxylate (IX). Finally, this compound is converted into sorbinil by cyclization with sodium cyanate in acetic acid at room temperature.
The synthesis of [2H]-, [3H]- and [14C]-radiolabeled sorbinil has been described: [2H]- and [3H]-sorbinil are prepared by chlorination of sorbinil (I) with Cl2 and FeCl2 in dry DMF to give the 8-chloro derivative (II), which is then reduced with deuterium or tritium over Pd/C in ethanol. [14C]-Labeled sorbinil is prepared by cyclization of 6-fluoro-3,4-dihydro-2H-benzo[b]pyran-4-one (III) with [14C]-potassium cyanide and ammonium carbonate in hot ethanol-water to give radiolabeled racemic sorbinil, which is then submitted to optical resolution with brucine in ethanol.