2) The cyclization of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV) with KCN and ammonium carbonate in hot water (80-90 C) gives 6-fluoro-2',5'-dioxospiro[3,4-dihydro-2H-1-benzopyran-4,4'-imidazolidine]-2-carboxylic acid (X) as a (5:1)-mixture of the (RS,RS)- and (RS,SR)-diastereomers. This mixture is treated with SiCl4 and dry ammonia in pyridine, yielding the corresponding (5:1)-mixture of amides (XI), which is separated by recrystallization, affording the (RS,RS)-diastereomer (XII) as a pure compound. The optical resolution of (XII) with N-methylquininium hydroxide (XIII) and crystallization gives the (2S,4S)-isomer as the N-methylquininium salt (XIV), which is finally treated with 1N aqueous HCl in ethanol/water.
1) The condensation of 4-fluoroanisole (I) with maleic anhydride (II) by means of AlCl3 in hot 1,2-dichloroethane gives (E)-4-(5-fluoro-2-hydroxyphenyl)-4-oxo-2-butenoic acid (III), which is cyclized by means of NaHCO3 in boiling water to yield racemic 6-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV). The reaction of (IV) with refluxing SOCl2 affords the corresponding acyl chloride (V), which is condensed with (S)-(-)-1-phenylethylamine (VI) affording the amide (VII) as a diastereomeric mixture (R,S + S,S), which is submitted to a fractional crystallization to give the suitable isomer (S,S)-(VII). The hydrolysis of (S,S)-(VII) with concentrated HCl in refluxing dioxane yields the corresponding acid (S)-(IV) as a pure enantiomer. The cyclization of (S)-(IV) with KCN and (NH4)2CO3 in hot water affords the acidic spiro compound (VIII), again as a diastereomeric mixture (2S,4R + 2S,4S), which is separated by fractional crystallization to obtain the desired (2S,4S)-(VIII) compound. The esterification of (2S,4S)-(VIII) with propanol/sulfuric acid affords the corresponding propyl ester (IX), which is finally treated with dry ammonia in methanol.