N-[2-(4-bromophenyl)ethyl]formamide

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound of formula II can be made as outlined in Scheme I and as specifically exemplified in Example 1. Referring to Scheme I, 2-(4-bromophenyl)ethylamine hydrobromide is reacted with ethyl formate in the presence of a base to make N-[2-(4-bromophenyl)ethyl]formamide. The fornamide is then treated with phosphorus pentoxide in polyphosphoric acid to cyclize, followed by treatment with hydrogen halide (e.g., HCl) gas to form the hydrohalide salt of 7-bromo-3,4-dihydroisoquinoline hydrohalide. The hydrohalide salt is then reduced to afford 7-bromo-1,2,3,4-tetrahydroisoquinoline. The reduced material is then nitrated by treatment with potassium nitrate in concentrated sulfuric acid and the appropriate fraction separated to yield 7-bromo6-nitro-1,2,3,4-tetrahydroisoquinoline. The nitrated material is then reacted with di-tert-butyl dicarbonate in the presence of a base to block the ring tetrahydroisoquinoline nitrogen, thereby affording 7-bromo-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester. The ester is then hydrogenated in the presence of palladium-on-calcium carbonate to form the corresponding 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid ester. The amine is then reacted with 4'-trifluoromethylbiphenyl-2-carboxylic acid to form 6-[4'-trifluoromethylbiphenyl-2-carbonyl)amino]3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester. This product can then be deblocked conventionally to make compound II, 4'-trifluoromethylbiphenyl-2-carboxylic acid (1,2,3,4tetrahydroisoquinolin-6-yl)amide. ##STR6##

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-phenethylamine (4.45 g, 22.25 mmol) was dissolved in ethyl formate (100 mL). 5 mg of TsOH was added. The clear colorless solution was heated in an oil bath to reflux for 16 h. The reaction solution was cooled to r.t, passed through a short silica gel plug, rinsed with ethyl acetate. The filtrate was evaporated to yield 5.1 g (100%) of the title compound as a liquid which became a solid on standing. MS: 230 (M+H+). The clear colorless solution was heated in an oil bath to reflux for 16 h The reaction solution was cooled rinsed with ethyl acetate The filtrate was evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 500 g (1.78 mol) of 2-(4-Bromo-phenyl)ethylamine hydrobromide, 1 liter (12.4 mol) of ethyl formate and 248 mL (1.78 mol) of triethylamine were combined and heated to reflux for 3 hrs. The reaction was treated with 1 liter each of deionized water and ethyl acetate. The organic layer was separated and washed with 1 liter each of water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to yield 378 g of a solid. heated to reflux for 3 hrs The organic layer was separated washed with 1 liter each of water and brine The organic layer was dried over anhydrous magnesium sulfate filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound of formula II can be made as outlined in Scheme I and as specifically exemplified in Example 1. Referring to Scheme I, 2-(4-bromophenyl)ethylamine hydrobromide is reacted with ethyl formate in the presence of a base to make N-[2-(4-bromophenyl)ethyl]formamide. The fornamide is then treated with phosphorus pentoxide in polyphosphoric acid to cyclize, followed by treatment with hydrogen halide (e.g., HCl) gas to form the hydrohalide salt of 7-bromo-3,4-dihydroisoquinoline hydrohalide. The hydrohalide salt is then reduced to afford 7-bromo-1,2,3,4-tetrahydroisoquinoline. The reduced material is then nitrated by treatment with potassium nitrate in concentrated sulfuric acid and the appropriate fraction separated to yield 7-bromo6-nitro-1,2,3,4-tetrahydroisoquinoline. The nitrated material is then reacted with di-tert-butyl dicarbonate in the presence of a base to block the ring tetrahydroisoquinoline nitrogen, thereby affording 7-bromo-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester. The ester is then hydrogenated in the presence of palladium-on-calcium carbonate to form the corresponding 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid ester. The amine is then reacted with 4'-trifluoromethylbiphenyl-2-carboxylic acid to form 6-[4'-trifluoromethylbiphenyl-2-carbonyl)amino]3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester. This product can then be deblocked conventionally to make compound II, 4'-trifluoromethylbiphenyl-2-carboxylic acid (1,2,3,4tetrahydroisoquinolin-6-yl)amide. ##STR6##

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-phenethylamine (4.45 g, 22.25 mmol) was dissolved in ethyl formate (100 mL). 5 mg of TsOH was added. The clear colorless solution was heated in an oil bath to reflux for 16 h. The reaction solution was cooled to r.t, passed through a short silica gel plug, rinsed with ethyl acetate. The filtrate was evaporated to yield 5.1 g (100%) of the title compound as a liquid which became a solid on standing. MS: 230 (M+H+). The clear colorless solution was heated in an oil bath to reflux for 16 h The reaction solution was cooled rinsed with ethyl acetate The filtrate was evaporated