Benzocaine → HCID 10647511, compound

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Reaction Steps

Reaction Scheme 6A discloses a synthetic route to specific preferred dihydronaphthalene compounds of the invention where with reference to Formula 1 the Z group is CONH (amide derivatives). Although the nature of the reagents utilized in this specific synthetic route is indicated in the scheme itself, and is described in detail in the description of the specific examples, the following explanation is also provided here. 3,4-Dihydro-4,4-dimethyl-1(2H)-naphthalenone is brominated in the presence of aluminum chloride to give 3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound B) which is the first compound shown in the scheme. Compound B is reacted with a Grignard reagent obtained from 4-bromotoluene to give 1,2,3,4-tetrahydro-1-hydroxy-1-(4-methylphenyl)-4,4-dimethyl-7-bromonaphthalene (Compound C) that is dehydrated by heating with para-toluene sulfonic acid to provide 3,4-dihydro-1-(4-methylphenyl)-4,4-dimethyl-7-bromonaphthalene (Compound D). Compound D is treated with t-butyllithium to cause a metal halogen exchange, and the resulting organolithium compound is quenched with carbon dioxide to yield 5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenecarboxylic acid (Compound K). Compound K is condensed with ethyl 4-aminobenzoate, ethyl 2-fluoro-4-aminobenzoate or ethyl 2,6-difluoro-4-aminobenzoate, respectively, in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)and of 4-dimethylaminopyridine (DMAP) to provide ethyl 4-[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 35), ethyl 2-fluoro-4-[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 40) and ethyl 2,6-difluoro-4-[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 212), respectively. Saponification of these ethyl esters, provided the free carboxylic acids, 4-[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoic acid (Compound 36), 2-fluoro-4-[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoic acid (Compound 41) and 2,6-difluoro-4-[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoic acid (Compound 203), respectively. ##STR13##

Provenance & Evidence