Friedel-Crafts reaction between 4-hydroxyphenylacetic acid (I) and resorcinol (II) by means of BF3.Et2O provides trihydroxydeoxy benzoin (III), which is then protected with dihydropyran (IV) in the presence of TsOH to give the bis-THP ether (V). Knoevenagel reaction of (V) with 4-hydroxybenzaldehyde (VI) in the presence of piperidine in refluxing benzene, followed by alkylation with 1-(2-chloroethyl)piperidine (VII) in the presence of Cs2CO3 in refluxing acetone:H2O to yield chromanone (VIII). Alternatively, (VIII) can be synthesized by reaction of (V) with compound (IX) (obtained in turn from reaction between aldehyde (VI) and chloro derivative (VII) with K2CO3 in DMF) by means of piperidine in refluxing toluene, followed by treatment with NaOAc in refluxing MeOH. Chromanone (VIII) is then alkylated either with MeLi or with methylmagnesium bromide in THF and then dehydrated and deprotected in HOAc furnishing chromene (X). Racemic compound (X) is then resolved to afford enantiomer (XI) either by preparative chiral HPLC or by chemical resolution of the corresponding diastereomeric salt obtained by reaction with (+)-CSA in DMF/CH2Cl2, and treatment of the resulting salt with saturated K2CO3 . Finally, the target product is obtained by acylation of (XI) by reaction with pivaloyl chloride (XII) and Et3N in CH2Cl2.
The reaction of 1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-ethanone (I) with DHP and Ts-OH in ethyl acetate gives the bis-tetrahydropyranyl ether (II), which is condensed with the benzaldehyde (III) by means of piperidine in 2-butanol to yield a mixture of the propenone (IV) and the benzopyranone (V). This mixture, without isolation, is treated with DBU to convert (IV) into (V). The methylation of (V) with MeLi in tert-butyl methyl ether affords the benzopyran-4-ol (VI), which is treated with (S)-(+)-camphorsulfonic acid (VII) to provide the dehydrated benzopyran camphorsulfonate (VIII) as a diastereomeric mixture that is separated by crystallization. The desired isomer (IX) is treated with TEA to give the title compound (X) as free base that is finally treated with HCl in EtOH/water to yield the desired hydrochloride.
The condensation of radiolabeled resorcinol (I) with 2-(4-hydroxyphenyl)acetic acid (II) by means of BF3/Et2O in hot toluene gives the diphenylethanone (III), which is treated with dihydropyran and TsOH in dichloromethane to yield the bis tetrahydropyranyl ether (IV). The cyclization of (IV) with 4-hydroxybenzaldehyde (V) by means of piperidine in hot benzene affords the dihydro benzopyran (VI), which is alkylated with 1-(2-chloroethyl)piperidine (VII) and Cs2CO3 in hot water to provide the adduct (VIII). The methylation of the ketonic group of (VIII) with MeLi in THF gives the tertiary alcohol (IX), which is dehydrated by means of hot AcOH (80 C) to yield the methylated benzopyran (X) as a racemic mixture. This mixture is submitted to optical resolution through formation of the diastereomeric salt with (+)-CSA, crystallization and treatment with Na2CO3 to afford the radiolabeled dihydroxy benzopyran (XI), which is finally acylated with pivaloyl chloride to provide the target dipivalate.
The condensation of radiolabeled resorcinol (I) with 2-(4-hydroxyphenyl)acetic acid (II) by means of BF3/Et2O in hot toluene gives the diphenylethanone (III), which is treated with dihydropyran and TsOH in dichloromethane to yield the bis tetrahydropyranyl ether (IV). The cyclization of (IV) with 4-hydroxybenzaldehyde (V) by means of piperidine in hot benzene affords the dihydro benzopyran (VI), which is alkylated with 1-(2-chloroethyl)piperidine (VII) and Cs2CO3 in hot water to provide the adduct (VIII). The methylation of the ketonic group of (VIII) with MeLi in THF gives the tertiary alcohol (IX), which is dehydrated by means of hot AcOH (80 C) to yield the methylated benzopyran (X) as a racemic mixture. Finally, this compound is submitted to; optical resolution through formation of the diastereomeric salt with (+)-CSA, crystallization and treatment with Na2CO3 to afford the target radiolabeled benzopyran.