(2S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol

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

Procedure: A solution of (S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)aniline (4.42 g, 15.3 mmol), 1,1′-carbonyl diimidazole and toluene (50 mL) was stirred at room temperature for 10 minutes. The reaction was quenched with ice-water (10 mL). The two layers were separated, ethyl acetate (10 mL) was added to the toluene layer and the mixture was washed with brine (2×30 mL) and the two layers were separated. The organic layer was evaporated to dryness to give an orange oil and further crystallized with hexanes to give (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white or off-white solid. 1H NMR (CDCl3) δ 9.64 (s, 1H), 7.49 (a, s, 1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 1.43-1.36 (m, 1H), 0.97-0.91 (m, 2H), 0.88-0.86 (m, 2H). The reaction was quenched with ice-water (10 mL) The two layers were separated ethyl acetate (10 mL) was added to the toluene layer the mixture was washed with brine (2×30 mL) the two layers were separated The organic layer was evaporated to dryness to give an orange oil further crystallized with hexanes

Conditions: temp:92.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10, 1 g, 2.13 mmol) and 40% NaOH aqueous solution (20 mL) was stirred at 90-95° C. for 20 hours. Toluene (20 mL) was added and the layers were separated. The organic layer was washed with water (20 mL) and evaporated to dryness to give (S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl) aniline (8). the layers were separated The organic layer was washed with water (20 mL) evaporated to dryness

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude (S)-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2-(4'-methoxyphenyl) -3, 1-benzoxazine (71 kg calculated dry weight) was charged to a mixture of methanol (301 kg), 30% NaOH (121 kg) and water (61L). The mixture was heated to 60° C. to give a clear solution then cooled to 30° C. A solution of sodium borohydride (3.2 kg, 84.2 mol) in 0.2 N NaOH (29L) was added to the methanolic solution over 20 min, keeping the temperature below 35° C. After 30 min, excess borohydride was quenched with acetone (5.8 kg) and the solution diluted with water (175L) then neutralized to pH 8 to 9 with acetic acid. The resulting slurry was cooled to about 0° C., filtered and the product washed with water then dried in vacuo at 40° C. The crude product was reslurried with a mixture of toluene (133 kg) and heptanes (106 kg) initially at 25° C., then with cooling below -10° C. The product was filtered, washed with heptanes (41 kg) and dried in vacuo at 40° C. to give 44.5 kg (88%) as an off-white/pale yellow crystalline solid. An analytical sample was recrystallized from t-butyl methyl ether/heptane: mp 141-143° C.; [a]25D -28.3° (c 0.106, MeOH); 1H NMR (300 MHz, CDCl3) δ7.54 (d, J=2 Hz, 1H), 7.13 (dd, J=9, 2 Hz, 1H), 6.61 (d, J=9 Hz, 1H), 4.61 (brs, 1H), 4.40 (brs, 1H), 1.44-135 (m, 1H), 0.94-0.78 (m, 2H): 13C NMR (75 MHz, DMSO-d6) δ146.7, 129.4, 129.0, 124.3, 118.4, 118.07, 118.05, 92.3, 72.6, 71.0, 8.2, 8.1, -1.1; 19F NMR (282 MHz CDCl3) δ-80.5. to give a clear solution then cooled to 30° C the temperature below 35° C excess borohydride was quenched with acetone (5.8 kg) the solution diluted with water (175L) The resulting slurry was cooled to about 0° C. filtered the product washed with water then dried in vacuo at 40° C The crude product was reslurried with a mixture of toluene (133 kg) and heptanes (106 kg) initially at 25° C. with cooling below -10° C The product was filtered washed with heptanes (41 kg) dried in vacuo at 40° C. to give 44.5 kg (88%) as an off-white/pale yellow crystalline solid An analytical sample was recrystallized from t-butyl methyl ether/heptane

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

Procedure: A solution of (S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)aniline (4.42 g, 15.3 mmol), 1,1′-carbonyl diimidazole and toluene (50 mL) was stirred at room temperature for 10 minutes. The reaction was quenched with ice-water (10 mL). The two layers were separated, ethyl acetate (10 mL) was added to the toluene layer and the mixture was washed with brine (2×30 mL) and the two layers were separated. The organic layer was evaporated to dryness to give an orange oil and further crystallized with hexanes to give (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-ben zoxazin-2-one as a white or off-white solid. 1H NMR (CDCl3) δ 9.64 (s, 1H), 7.49 (a, s, 1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 1.43-1.36 (m, 1H), 0.97-0.91 (m, 2H), 0.88-0.86 (m, 2H). The reaction was quenched with ice-water (10 mL) The two layers were separated ethyl acetate (10 mL) was added to the toluene layer the mixture was washed with brine (2×30 mL) the two layers were separated The organic layer was evaporated to dryness to give an orange oil further crystallized with hexanes

Conditions: temp:92.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10, 1 g, 2.13 mmol) and 40% NaOH aqueous solution (20 mL) was stirred at 90-95° C. for 20 hours. Toluene (20 mL) was added and the layers were separated. The organic layer was washed with water (20 mL) and evaporated to dryness to give (S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)aniline (8). 1H NMR (CDCl3) δ 7.54 (s, 1H), 7.12 (dd, J=8.5, 1.5 Hz, 1H), 6.62 (d, J=8.6 Hz, 1H), 4.47 (br. s, 3H), 1.44-1.35 (m, 1H), 0.93-0.88 (m, 2H), 0.83-0.80 (m, 2H). the layers were separated The organic layer was washed with water (20 mL) evaporated to dryness

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-5-Chloro-α-(cyclopropylethynyl)-2-amino-α-(trifluoromethyl)benzenemethanol (15.7 kg, 54.3 mol) was dissolved in a mixture of heptanes (32 kg) and THF (52 kg) below -10° C. Phosgene (~8.0 kg, 80 mol) was directly fed below the surface over about 1 h, keeping the temperature below 0° C. The resulting slurry was warmed to 20-25° C. and held 1 hour. Methanol (6.5 kg, 203 mol) was added and the solution stirred about 30 min. Heptanes (97 kg) was added and ~140 L of solvent was distilled under reduced pressure. Heptanes (97 kg) and THF (22 kg) were added and the solution washed with 5% aqueous sodium bicarbonate (15 L), followed by water (15 L). The solution was warmed to 50° C. and filtered into a clean reactor, followed by a 40 kg heptanes rinse. The solution was concentrated under reduced pressure, diluted with heptanes (22 kg) and cooled below -10° C. The product was filtered, washed with heptanes (37 kg) and dried in vacuo at 90-100° C. to give 16.0 kg (95%) as an off-white to slightly pinkish solid. HPLC: 99.8 area %: mp 139-141° C.; [a]25D -94.1° (c 0.300, MeOH); 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.54 (dd, J 32 2.5, 7 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 6.99 (d, J=7 Hz, 1H), 1.58 (m, 1H), 0.92 (m, 2H), 0.77 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 146.23, 134.71, 132.04, 126.93, 126.57, 122.24, 116.83, 114.08, 95.63, 77.62, 65.85, 8.48, 8.44, -1.32; 19F NMR (282 MHz, DMSO-d6) δ -81.1. the temperature below 0° C ~140 L of solvent was distilled under reduced pressure Heptanes (97 kg) and THF (22 kg) were added the solution washed with 5% aqueous sodium bicarbonate (15 L) The solution was warmed to 50° C. filtered into a clean reactor rinse The solution was concentrated under reduced pressure diluted with heptanes (22 kg) cooled below -10° C The product was filtered washed with heptanes (37 kg) dried in vacuo at 90-100° C. to give 16.0 kg (95%) as an off-white to slightly pinkish solid

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-5-Chloro-α-(cyclopropylethynyl)-2-amino-α-(trifluoromethyl)benzenemethanol (15.7 kg, 54.3 mol) was dissolved in a mixture of heptanes (32 kg) and THF (52 kg) below -10° C. Phosgene (~8.0 kg, 80 mol) was directly fed below the surface over about 1 h, keeping the temperature below 0° C. The resulting slurry was warmed to 20-25° C. and held 1 hour. Methanol (6.5 kg, 203 mol) was added and the solution stirred about 30 min. Heptanes (97 kg) was added and ~140 L of solvent was distilled under reduced pressure. Heptanes (97 kg) and THF (22 kg) were added and the solution washed with 5% aqueous sodium bicarbonate (15 L), followed by water (15 L). The solution was warmed to 50° C. and filtered into a clean reactor, followed by a 40 kg heptanes rinse. The solution was concentrated under reduced pressure, diluted with heptanes (22 kg) and cooled below -10° C. The product was filtered, washed with heptanes (37 kg) and dried in vacuo at 90-100° C. to give 16.0 kg (95%) as an off-white to slightly pinkish solid. HPLC: 99.8 area %: mp 139-141° C.; [a]25D -94.1° (c 0.300, MeOH); 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.54 (dd, J 32 2.5, 7 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 6.99 (d, J=7 Hz, 1H), 1.58 (m, 1H), 0.92 (m, 2H), 0.77 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 146.23, 134.71, 132.04, 126.93, 126.57, 122.24, 116.83, 114.08, 95.63, 77.62, 65.85, 8.48, 8.44, -1.32; 19F NMR (282 MHz, DMSO-d6) δ -81.1. the temperature below 0° C ~140 L of solvent was distilled under reduced pressure Heptanes (97 kg) and THF (22 kg) were added the solution washed with 5% aqueous sodium bicarbonate (15 L) The solution was warmed to 50° C. filtered into a clean reactor rinse The solution was concentrated under reduced pressure diluted with heptanes (22 kg) cooled below -10° C The product was filtered washed with heptanes (37 kg) dried in vacuo at 90-100° C. to give 16.0 kg (95%) as an off-white to slightly pinkish solid

Conditions: temp:58.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a slurry of DDQ (9.42 g, 41.5 mmol) in t-butyl methyl ether (33 ml) at 10° C. was added a solution of (S)-5-chloro-α-(cyclopropylethynyl)-2-[(4-methoxyphenyl)methyl]-amino!-α-(trifluoromethyl) benzenemethanol (16.38 g, 40 mmol). After 5 minutes the resulting slurry was filtered at 30° C. and the resulting solids washed with 5 ml t-butyl methyl ether. The filtrate was washed with 5% aqueous sodium bicarbonate then partially concentrated by distilling 70 ml solvent. Methanol (25 ml) was added followed by distilling 25 ml of solvent. Methanol (25 ml) and 6N NaOH (4 ml) were added followed by distillation of 20 ml of solvent. 4N NaOH (26 ml) was added and the mixture heated briefly to 58° C. then cooled to 30° C. A solution of sodium borohydride (0.60 g, 15.9 mmol) in 0.5 N NaOH (6 mL) was added. After 15 minutes, water (45 ml) was added followed by acetone (1 ml). After 0.5 hours, acetic acid (12 ml, 210 mmol) was added to a pH of 7.5. The resulting slurry was cooled to about 0° C., filtered and the product was washed with water then dried in vacuo at 40° C. The crude product was reslurried at room temperature with methylcyclohexane, cooled to about 0° C. and filtered. This material was further purified by recrystallization from t-butyl methyl ether/hexanes to give 9.95 g (86%) as a white solid. The physical characteristics were identical with product prepared by the two step (p-chloranil/NaBH4) process. (Example 6, above) After 5 minutes the resulting slurry was filtered at 30° C. the resulting solids washed with 5 ml t-butyl methyl ether The filtrate was washed with 5% aqueous sodium bicarbonate then partially concentrated by distilling 70 ml solvent Methanol (25 ml) was added by distilling 25 ml of solvent Methanol (25 ml) and 6N NaOH (4 ml) were added followed by distillation of 20 ml of solvent 4N NaOH (26 ml) was added then cooled to 30° C After 0.5 hours The resulting slurry was cooled to about 0° C. filtered the product was washed with water then dried in vacuo at 40° C was reslurried at room temperature with methylcyclohexane cooled to about 0° C. filtered This material was further purified by recrystallization from t-butyl methyl ether/hexanes to give 9.95 g (86%) as a white solid

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

Procedure: A solution of (S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)aniline (4.42 g, 15.3 mmol), 1,1′-carbonyl diimidazole and toluene (50 mL) was stirred at room temperature for 10 minutes. The reaction was quenched with ice-water (10 mL). The two layers were separated, ethyl acetate (10 mL) was added to the toluene layer and the mixture was washed with brine (2×30 mL) and the two layers were separated. The organic layer was evaporated to dryness to give an orange oil and further crystallized with hexanes to give (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white or off-white solid. 1H NMR (CDCl3) δ 9.64 (s, 1H), 7.49 (a, s, 1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 1.43-1.36 (m, 1H), 0.97-0.91 (m, 2H), 0.88-0.86 (m, 2H). The reaction was quenched with ice-water (10 mL) The two layers were separated ethyl acetate (10 mL) was added to the toluene layer the mixture was washed with brine (2×30 mL) the two layers were separated The organic layer was evaporated to dryness to give an orange oil further crystallized with hexanes

Conditions: temp:92.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10, 1 g, 2.13 mmol) and 40% NaOH aqueous solution (20 mL) was stirred at 90-95° C. for 20 hours. Toluene (20 mL) was added and the layers were separated. The organic layer was washed with water (20 mL) and evaporated to dryness to give (S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl) aniline (8). the layers were separated The organic layer was washed with water (20 mL) evaporated to dryness

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

Procedure: A solution of (S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)aniline (4.42 g, 15.3 mmol), 1,1′-carbonyl diimidazole and toluene (50 mL) was stirred at room temperature for 10 minutes. The reaction was quenched with ice-water (10 mL). The two layers were separated, ethyl acetate (10 mL) was added to the toluene layer and the mixture was washed with brine (2×30 mL) and the two layers were separated. The organic layer was evaporated to dryness to give an orange oil and further crystallized with hexanes to give (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white or off-white solid. 1H NMR (CDCl3) δ 9.64 (s, 1H), 7.49 (a, s, 1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 1.43-1.36 (m, 1H), 0.97-0.91 (m, 2H), 0.88-0.86 (m, 2H). The reaction was quenched with ice-water (10 mL) The two layers were separated ethyl acetate (10 mL) was added to the toluene layer the mixture was washed with brine (2×30 mL) the two layers were separated The organic layer was evaporated to dryness to give an orange oil further crystallized with hexanes

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude (S)-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2-(4'-methoxyphenyl) -3, 1-benzoxazine (71 kg calculated dry weight) was charged to a mixture of methanol (301 kg), 30% NaOH (121 kg) and water (61L). The mixture was heated to 60° C. to give a clear solution then cooled to 30° C. A solution of sodium borohydride (3.2 kg, 84.2 mol) in 0.2 N NaOH (29L) was added to the methanolic solution over 20 min, keeping the temperature below 35° C. After 30 min, excess borohydride was quenched with acetone (5.8 kg) and the solution diluted with water (175L) then neutralized to pH 8 to 9 with acetic acid. The resulting slurry was cooled to about 0° C., filtered and the product washed with water then dried in vacuo at 40° C. The crude product was reslurried with a mixture of toluene (133 kg) and heptanes (106 kg) initially at 25° C., then with cooling below -10° C. The product was filtered, washed with heptanes (41 kg) and dried in vacuo at 40° C. to give 44.5 kg (88%) as an off-white/pale yellow crystalline solid. An analytical sample was recrystallized from t-butyl methyl ether/heptane: mp 141-143° C.; [a]25D -28.3° (c 0.106, MeOH); 1H NMR (300 MHz, CDCl3) δ7.54 (d, J=2 Hz, 1H), 7.13 (dd, J=9, 2 Hz, 1H), 6.61 (d, J=9 Hz, 1H), 4.61 (brs, 1H), 4.40 (brs, 1H), 1.44-135 (m, 1H), 0.94-0.78 (m, 2H): 13C NMR (75 MHz, DMSO-d6) δ146.7, 129.4, 129.0, 124.3, 118.4, 118.07, 118.05, 92.3, 72.6, 71.0, 8.2, 8.1, -1.1; 19F NMR (282 MHz CDCl3) δ-80.5. to give a clear solution then cooled to 30° C the temperature below 35° C excess borohydride was quenched with acetone (5.8 kg) the solution diluted with water (175L) The resulting slurry was cooled to about 0° C. filtered the product washed with water then dried in vacuo at 40° C The crude product was reslurried with a mixture of toluene (133 kg) and heptanes (106 kg) initially at 25° C. with cooling below -10° C The product was filtered washed with heptanes (41 kg) dried in vacuo at 40° C. to give 44.5 kg (88%) as an off-white/pale yellow crystalline solid An analytical sample was recrystallized from t-butyl methyl ether/heptane