Reaction Steps
To a solution of (S)-1,2,3,4-Tetrahydroisoquinolone-3-carboxylic acid (5.00 g, 28.2 mmol) in sulfuric acid (20 mL) was at 0° C. dropwise added a solution of potassium nitrate (2.95 g, 29.2 mmol) in sulfuric acid (10 mL). When the addition was complete, the mixture was stirred for 5 min and the carefully diluted with water and neutralized with ammonium hydroxide (about 100 mL). The precipitate was filtered, washed with water and dried in vacuo to give (S)-7-nitro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (4.70 g, 75% yield) as a yellow solid. Acetyl chloride (20.0 mL, 22.1 g, 281 mmol) was added carefully to methanol (50 mL) at −20° C. The solution was allowed to reach room temperatureand stirred for 10 min. (S)-7-nitro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (4.70 g, 21.2 mmol) was then added and the resulting suspension was stirred at 50° C. for 5 h. The solvent was evaporated and the residue was dried in vacuo to give (S)-methyl 7-nitro-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (5.77 g, 100% yield) as a crude form. (S)-methyl 7-nitro-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (4.77 g, 17.5 mmol) was suspended in methylene chloride (50 mL). Triethylamine (2.93 mL, 2.12 g, 2.10 mmol) was added and then carefully trifluoroacetyl anhydride (2.92 mL, 4.41 g, 21.0 mmol). the mixture was stirred for 10 min. Water was added (100 mL) and the mixture was extracted with methylene chloride (3×100 mL), dried over magnesium sulfate and concentrated. Column chromatography (CV 120 mL, 10% ethyl acetate hexanes to 30% ethyl acetate in hexanes, 20 (CV) gave the desired product, (S)-methyl 7-nitro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (2.70 g, 47% yield), and 1.28 g of coeluting byproduct mixture. Rf (ethyl acetate) 0.89. To a solution of (S)-methyl 7-nitro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (2.70 g, 8.13 mmol) in methanol (50 mL) was added palladium on charcoal (10%, 0.432 g, 0.406 mmol) and the resulting suspension was stirred in an atmosphere of hydrogen overnight. The mixture was filtered, charged with conc. HCl (1 mL) and concentrated to give (S)-methyl 7-amino-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (2.60 g, 95% yield) as a grey solid. Rf (ethyl acetate)=0.82. Using general method M, (S)-methyl 7-amino-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (2.60 g, 7.68 mmol) and pivaloylacetonitrile (0.961 g, 7.68 mmol) were combined to yield (3S)-methyl 7-(5-amino-3-t-butyl-1H-pyrazol-1-yl)-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate which was used without purification.
