N-[(Z)-ethylideneamino]aniline

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 500 gallon reactor is charged with 61.1 pounds of tert-butanol (88/12 azeotrope with water) which is stirred and cooled to 5° C. To this is added 22.0 pounds (0.203 lb-mole) of acetaldehyde phenylhydrazone. While maintaining the temperature of the reaction mixture at 0° to 5° C., 15.6 pounds (0.240 lb-mole) of 85% pure sodium cyanate in 44.5 pounds of water is added during a five-minute period. The reaction mixture is maintained at 5° C. as it is stirred during a 30 minute period. While maintaining the reaction mixture at about 10° C., 14.8 pounds (0.247 lb-mole) of acetic acid is added during about a 30-45 minute period. Upon completion of the addition, the reaction mixture is stirred for three hours at about 10° C. until the reaction is complete. The reaction endpoint and the concentration of the phenyltriazolidinone intermediate are determined by gas chromatograph. At the end of this time, a solution of 12.6 pounds of sodium chloride in 35.8 pounds of water is stirred into the reaction mixture. The aqueous phase is separated when the reaction mixture temperature is about 15° C. After this time, 67.8 pounds of water is added to the reaction mixture and 73.4 pounds of tert-butanol/water (88/12) is removed by distillation at an overhead temperature of 80° C. The residue is cooled to 0° C., and a solid is collected by filtration. The solid is dried at 80° C./5 mm Hg for 24 hours to yield 3-methyl-1-phenyl-1,2,4-triazolidin-5-one. While maintaining the temperature of the reaction mixture at 0° to 5° C. The reaction mixture is maintained at 5° C. as it is stirred during a 30 minute period While maintaining the reaction mixture at about 10° C. Upon completion of the addition the reaction mixture is stirred for three hours at about 10° C. until the reaction The aqueous phase is separated when the reaction mixture temperature is about 15° C After this time, 67.8 pounds of water is added to the reaction mixture and 73.4 pounds of tert-butanol/water (88/12) is removed by distillation at an overhead temperature of 80° C The residue is cooled to 0° C. a solid is collected by filtration The solid is dried at 80° C./5 mm Hg for 24 hours

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 500 gallon reactor is charged with 61.1 pounds of tert-butanol (88/12 azeotrope with water) which is stirred and cooled to 5° C. To this is added 22.0 pounds (0.203 lb-mole) of acetaldehyde phenylhydrazone. While maintaining the temperature of the reaction mixture at 0° to 5° C., 15.6 pounds (0.240 lb-mole) of 85% pure sodium cyanate in 44.5 pounds of water is added during a five-minute period. The reaction mixture is maintained at 5° C. as it is stirred during a 30 minute period. While maintaining the reaction mixture at about 10° C., 14.8 pounds (0.247 lb-mole of acetic acid is added during about a 30-45 minute period. Upon completion of the addition, the reaction mixture is stirred for three hours at about 10° C. until the reaction is complete. The reaction endpoint and the concentration of the phenyltriazolidinone intermediate are determined by gas chromatograph. At the end of this time, a solution of 12.6 pounds of sodium chloride in 35.8 pounds of water is stirred into the reaction mixture. The aqueous phase is separated when the reaction mixture temperature is about 15° C. After this time, 67.8 pounds of water is added to the reaction mixture and 73.4 pounds of tert-butanol/water (88/12) is removed by distillation at an overhead temperature of 80° C. The residue is cooled to 0° C., and a solid is collected by filtration. The solid is dried at 80° C./5 mm Hg for 24 hours to yield 3-methyl-1-phenyl-1,2,4-triazolidin-5-one. While maintaining the temperature of the reaction mixture at 0° to 5° C. The reaction mixture is maintained at 5° C. as it is stirred during a 30 minute period While maintaining the reaction mixture at about 10° C. Upon completion of the addition the reaction mixture is stirred for three hours at about 10° C. until the reaction The aqueous phase is separated when the reaction mixture temperature is about 15° C After this time, 67.8 pounds of water is added to the reaction mixture and 73.4 pounds of tert-butanol/water (88/12) is removed by distillation at an overhead temperature of 80° C The residue is cooled to 0° C. a solid is collected by filtration The solid is dried at 80° C./5 mm Hg for 24 hours

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

Procedure: A solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 4.36 g, 20.3 mmol) in 1,2-dichloroethane (40 mL) was added over a period of one minute to a cooled (˜0° C.) solution of N-ethylidene-N′-phenyl-hydrazine (prepared according to A. R. Maguire et al. Bioorg. Med. Chem. 2001, 9, 745-762; 2.60 g, 19.4 mmol) and pyridine (2.5 mL, 30.9 mmol) in 1,2-dichloroethane (20 mL). The reaction mixture was stirred at room temperature for 15 min and then at 50° C. for 25 min. It was then cooled to room temperature and 4M HCl in dioxane (12 mL) was added. The reaction mixture was stirred for 5 min at room temperature, then glacial acetic acid (20 mL) was added and the mixture was heated in an oil bath at 100° C. for 20 min. The reaction mixture was cooled to room temperature and then evaporated. Dichloromethane (200 mL) was added, the solution was washed with 50% saturated brine (2×50 mL), and the combined aqueous layers were back-extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine (150 mL), dried (magnesium sulfate), filtered, evaporated and eluted through a plug of silica gel with 30% ethyl acetate/hexanes to give (4S,7R)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (5.04 g, 97%) as an orange foam. prepared at 50° C. for 25 min It was then cooled to room temperature The reaction mixture was stirred for 5 min at room temperature the mixture was heated in an oil bath at 100° C. for 20 min The reaction mixture was cooled to room temperature evaporated Dichloromethane (200 mL) was added the solution was washed with 50% saturated brine (2×50 mL) the combined aqueous layers were back-extracted with dichloromethane (2×100 mL) The combined organic layers were washed with brine (150 mL) dried (magnesium sulfate) filtered evaporated eluted through a plug of silica gel with 30% ethyl acetate/hexanes

Conditions: temp:0.00; pressure:0.00; stir: