Processes for the Preparation of 2-(1-Phenylethyl)isoindolin-1-one Compounds

A process for preparing a compound of formula:

• or a pharmaceutically acceptable salt, solvate, or polymorph thereof,
• comprising the step of reacting a primary amine of formula (II)
• or a salt thereof,
• with a 2-(bromomethyl)benzoic acid ester of formula (III).
• in the presence of an inorganic base, wherein:
• R is alkyl or aryl;
• each of R1 and R2 is independently hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy of 3 to 18 carbon atoms;
• R3 is hydroxyl, alkyl of 1 to 8 carbon atoms, phemyl, benzyl or NR4R5;
• each of X1, X2, X3 and X4 is independently hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxyl, or —NR4R5 ;
• or
• any two of X1, X2, X3 and X4 on adjacent carbon atoms, together with the depicted phenylene ring, form naphthylidiene;
• each of R4 and R5 is independently hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl;
• or
• one of R4 and R5 is hydrogen, and the other is —COR5, or —SO2R6;
• or
• R4 and R5 taken together are tetramethylene, pentamethylene, hexamethylene, or —CH2CH2X5CH2CH2— in which X5 is —O—, —S—, or —NH2—;
• each of R4′ and R5′ is independently hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl;
• or
• one of R4′ and R5′ is hydrogen and the other is —COR6′, or —SO2R6′;
• or
• R4′ and R5′ taken together are tetramethylene, pentamethylene, hexamethylene, or —CH2CH2X5CH2CH2— in which X5 is —O—, —S—, or —NH2—;
• and
• each of R6 and R6′ is independently hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or phenyl.