合成路线1

The reaction of 5-chloro-2-hydroxybenzoic acid (I) with 2-methyl-2-propenyl chloride (II) by means of K2CO3 and KI in hot DMF gives 5-chloro-2-(2-methyl-2-propenyloxy)benzoic acid 2-methyl-2-propenyl ester (III), which is rearranged by heating at 190 C yielding 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid 2-methyl-2-propenyl ester (IV). The cyclization of (IV) with refluxing 90% formic acid affords 5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (V), which is treated with SOCl2 in DMF and condensed with endo-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (VI). The acid intermediate (V) can also be obtained by hydrolysis of the ester (III) with NaOH and tetrabutylammonium bisulfate in refluxing water to give 5-chloro-2-(2-methyl-2-propenyloxy)benzoic acid (VII), which is rearranged by heating at 170 C yielding 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid (VIII). Finally, (VIII) is cyclized to acid intermediate (V) by a treatment with aqueous refluxing 2.7N HCl. The intermediate endo-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (VI) has been obtained as follows: 2,5-dihydroxytetrahydrofuran (IX) or 2,5-dimethoxytetra-hydrofuran (X) with HCl give butanedialdehyde (XI), which, without isolation, is cyclized with 3-oxoglutaric acid (XII) and methylamine by means of NaOAc and HCl in hot water yielding 8-methyl-8-azabicyclo[3.2.1]octan-3-one (XIII). The reductocondensation of (XIII) with benzylamine by means of NaBH(OAc)3, followed by hydrogenolysis with H2 over Pd/C in basic water gives directly the amine (VI). The intermediate amine (VI) can also be obtained by condensation of bicyclooctanone (XIII) with benzylamine(A) to give the imine (XIV), which is reduced to the benzylamine (XV) with H2 over PtO2 in ethanol. Finally, this compound is debenzylated by hydrogenation over Pd/C in the same solvent yielding amine (VI).