合成路线1

Lorcaserin hydrochloride can be prepared by several different procedures. 4-Chlorophenethylamine (I) is acylated with 2-chloropropionyl chloride (II) in the presence of pyridine in CH2Cl2 to give the chloropropionamide (III), which is cyclized to the benzazepinone (IV) upon heating with AlCl3. Subsequent reduction of (IV) with either BH3 or LiAlH4 in Et2O affords the racemic lorcaserin (V) (1-3). In a related method, chloropropionamide (III) is reduced with borane in THF to yield the chloro amine (VIa), which is then cyclized to benzazepine (V) in the presence of AlCl3 (3). Alternatively, condensation of 4-chlorophenethyl bromide (VII) with 1-amino-2-propanol (VIII) provides the aminoalcohol (IX), which is converted to either the chloro amine (VIa) or the analogous bromo amine (VIb) by treatment with SOCl2 or SOBr2, respectively (3). Optical resolution of tetrahydrobenzazepine (V) either employing chiral HPLC or by crystallization with D-tartaric acid furnishes the target (R)-enantiomer (X) (1-3). This is finally converted to the title hydrochloride salt by treatment with HCl in different solvent systems (4). In a further procedure, after protection of 4-chlorophenethylamine (I) as the corresponding trifluoroacetamide (XI) by means of trifluoroacetic anhydride and pyridine in CH2Cl2, iodination with bis(pyridine)iodonium tetrafluoroborate in the presence of trifluoromethanesulfonic acid furnishes (XII). Subsequent alkylation of trifluoroacetamide (XII) with allyl bromide under phase transfer conditions leads to the iodo olefin (XIII), which undergoes intramolecular Heck cyclization in the presence of Pd(OAc)2 and PPh3 to furnish the methylene benzazepine (XIV). After reduction of (XIV) to the methyl analogue (XV) by catalytic hydrogenation over Pd/C, the N-trifluoroacetyl group is hydrolyzed with NaOH in aqueous MeOH to give 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (V) (5). Scheme 1.