6-羟基-3A,4,6,6A-四氢吡咯并[3,4-C]吡唑-5(1H) - 羧酸叔丁酯

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate (47.0 kg, 207 mol) in dichloromethane (669 kg) at 0° C. was added a methanol solution of toluene-4-sulfonic acid monohydrate (3.7 kg, 20 mol in 38 kg MeOH) drop-wise over 2 h. The reaction was then aged for 4 h at this temperature. Then, 5% aqueous NaHCO3 (91 kg) was added and stirred at room temperature for 30 min. The layers were then separated and the aqueous extracted with dichloromethane (312 kg). The combined organics were washed with 5% brine (190 kg then 483 kg), treated with activated carbon (2.7 kg) and filtered. The resulting organics were dried with Na2SO4, filtered, and concentrated to 71-118 L. n-Heptane was then added (238 kg) and the batch further concentrated to 188-235 L. The slurry was cooled to 10-20° C., filtered, and the cake washed with n-heptane. The solids were dried under vacuum at 40-50° C. overnight to give tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate. The layers were then separated the aqueous extracted with dichloromethane (312 kg) The combined organics were washed with 5% brine (190 kg 483 kg), treated with activated carbon (2.7 kg) filtered The resulting organics were dried with Na2SO4 filtered concentrated to 71-118 L n-Heptane was then added (238 kg) the batch further concentrated to 188-235 L The slurry was cooled to 10-20° C. filtered the cake washed with n-heptane The solids were dried under vacuum at 40-50° C. overnight

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (58.2 kg, 242 mol) in toluene (251 kg) at 35-45° C. was added hydrazine hydrate (14.6 kg, 290 mol) via drop-wise addition over 2 h. The mixture was then stirred for 10 h at this temperature. The batch was then cooled to 0-10° C. and the slurry stirred for 6 h. This slurry was then filtered and the cake washed with n-heptane. The solids were then dried under vacuum overnight at 35-50° C. to give tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate. via drop-wise addition over 2 h the slurry stirred for 6 h This slurry was then filtered the cake washed with n-heptane The solids were then dried under vacuum overnight at 35-50° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate (47.0 kg, 207 mol) in dichloromethane (669 kg) at 0° C. was added a methanol solution of toluene-4-sulfonic acid monohydrate (3.7 kg, 20 mol in 38 kg MeOH) drop-wise over 2 h. The reaction was then aged for 4 h at this temperature. Then, 5% aqueous NaHCO3 (91 kg) was added and stirred at room temperature for 30 min. The layers were then separated and the aqueous extracted with dichloromethane (312 kg). The combined organics were washed with 5% brine (190 kg then 483 kg), treated with activated carbon (2.7 kg) and filtered. The resulting organics were dried with Na2SO4, filtered, and concentrated to 71-118 L. n-Heptane was then added (238 kg) and the batch further concentrated to 188-235 L. The slurry was cooled to 10-20° C., filtered, and the cake washed with n-heptane. The solids were dried under vacuum at 40-50° C. overnight to give tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate. The layers were then separated the aqueous extracted with dichloromethane (312 kg) The combined organics were washed with 5% brine (190 kg 483 kg), treated with activated carbon (2.7 kg) filtered The resulting organics were dried with Na2SO4 filtered concentrated to 71-118 L n-Heptane was then added (238 kg) the batch further concentrated to 188-235 L The slurry was cooled to 10-20° C. filtered the cake washed with n-heptane The solids were dried under vacuum at 40-50° C. overnight

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (58.2 kg, 242 mol) in toluene (251 kg) at 35-45° C. was added hydrazine hydrate (14.6 kg, 290 mol) via drop-wise addition over 2 h. The mixture was then stirred for 10 h at this temperature. The batch was then cooled to 0-10° C. and the slurry stirred for 6 h. This slurry was then filtered and the cake washed with n-heptane. The solids were then dried under vacuum overnight at 35-50° C. to give tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate. via drop-wise addition over 2 h the slurry stirred for 6 h This slurry was then filtered the cake washed with n-heptane The solids were then dried under vacuum overnight at 35-50° C.

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (58.2 kg, 242 mol) in toluene (251 kg) at 35-45° C. was added hydrazine hydrate (14.6 kg, 290 mol) via drop-wise addition over 2 h. The mixture was then stirred for 10 h at this temperature. The batch was then cooled to 0-10° C. and the slurry stirred for 6 h. This slurry was then filtered and the cake washed with n-heptane. The solids were then dried under vacuum overnight at 35-50° C. to give tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate. via drop-wise addition over 2 h the slurry stirred for 6 h This slurry was then filtered the cake washed with n-heptane The solids were then dried under vacuum overnight at 35-50° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate (47.0 kg, 207 mol) in dichloromethane (669 kg) at 0° C. was added a methanol solution of toluene-4-sulfonic acid monohydrate (3.7 kg, 20 mol in 38 kg MeOH) drop-wise over 2 h. The reaction was then aged for 4 h at this temperature. Then, 5% aqueous NaHCO3 (91 kg) was added and stirred at room temperature for 30 min. The layers were then separated and the aqueous extracted with dichloromethane (312 kg). The combined organics were washed with 5% brine (190 kg then 483 kg), treated with activated carbon (2.7 kg) and filtered. The resulting organics were dried with Na2SO4, filtered, and concentrated to 71-118 L. n-Heptane was then added (238 kg) and the batch further concentrated to 188-235 L. The slurry was cooled to 10-20° C., filtered, and the cake washed with n-heptane. The solids were dried under vacuum at 40-50° C. overnight to give tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate. The layers were then separated the aqueous extracted with dichloromethane (312 kg) The combined organics were washed with 5% brine (190 kg 483 kg), treated with activated carbon (2.7 kg) filtered The resulting organics were dried with Na2SO4 filtered concentrated to 71-118 L n-Heptane was then added (238 kg) the batch further concentrated to 188-235 L The slurry was cooled to 10-20° C. filtered the cake washed with n-heptane The solids were dried under vacuum at 40-50° C. overnight

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate (47.0 kg, 207 mol) in dichloromethane (669 kg) at 0° C. was added a methanol solution of toluene-4-sulfonic acid monohydrate (3.7 kg, 20 mol in 38 kg MeOH) drop-wise over 2 h. The reaction was then aged for 4 h at this temperature. Then, 5% aqueous NaHCO3 (91 kg) was added and stirred at room temperature for 30 min. The layers were then separated and the aqueous extracted with dichloromethane (312 kg). The combined organics were washed with 5% brine (190 kg then 483 kg), treated with activated carbon (2.7 kg) and filtered. The resulting organics were dried with Na2SO4, filtered, and concentrated to 71-118 L. n-Heptane was then added (238 kg) and the batch further concentrated to 188-235 L. The slurry was cooled to 10-20° C., filtered, and the cake washed with n-heptane. The solids were dried under vacuum at 40-50° C. overnight to give tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate. The layers were then separated the aqueous extracted with dichloromethane (312 kg) The combined organics were washed with 5% brine (190 kg 483 kg), treated with activated carbon (2.7 kg) filtered The resulting organics were dried with Na2SO4 filtered concentrated to 71-118 L n-Heptane was then added (238 kg) the batch further concentrated to 188-235 L The slurry was cooled to 10-20° C. filtered the cake washed with n-heptane The solids were dried under vacuum at 40-50° C. overnight

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (58.2 kg, 242 mol) in toluene (251 kg) at 35-45° C. was added hydrazine hydrate (14.6 kg, 290 mol) via drop-wise addition over 2 h. The mixture was then stirred for 10 h at this temperature. The batch was then cooled to 0-10° C. and the slurry stirred for 6 h. This slurry was then filtered and the cake washed with n-heptane. The solids were then dried under vacuum overnight at 35-50° C. to give tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate. via drop-wise addition over 2 h the slurry stirred for 6 h This slurry was then filtered the cake washed with n-heptane The solids were then dried under vacuum overnight at 35-50° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate (47.0 kg, 207 mol) in dichloromethane (669 kg) at 0° C. was added a methanol solution of toluene-4-sulfonic acid monohydrate (3.7 kg, 20 mol in 38 kg MeOH) drop-wise over 2 h. The reaction was then aged for 4 h at this temperature. Then, 5% aqueous NaHCO3 (91 kg) was added and stirred at room temperature for 30 min. The layers were then separated and the aqueous extracted with dichloromethane (312 kg). The combined organics were washed with 5% brine (190 kg then 483 kg), treated with activated carbon (2.7 kg) and filtered. The resulting organics were dried with Na2SO4, filtered, and concentrated to 71-118 L. n-Heptane was then added (238 kg) and the batch further concentrated to 188-235 L. The slurry was cooled to 10-20° C., filtered, and the cake washed with n-heptane. The solids were dried under vacuum at 40-50° C. overnight to give tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate. The layers were then separated the aqueous extracted with dichloromethane (312 kg) The combined organics were washed with 5% brine (190 kg 483 kg), treated with activated carbon (2.7 kg) filtered The resulting organics were dried with Na2SO4 filtered concentrated to 71-118 L n-Heptane was then added (238 kg) the batch further concentrated to 188-235 L The slurry was cooled to 10-20° C. filtered the cake washed with n-heptane The solids were dried under vacuum at 40-50° C. overnight

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (58.2 kg, 242 mol) in toluene (251 kg) at 35-45° C. was added hydrazine hydrate (14.6 kg, 290 mol) via drop-wise addition over 2 h. The mixture was then stirred for 10 h at this temperature. The batch was then cooled to 0-10° C. and the slurry stirred for 6 h. This slurry was then filtered and the cake washed with n-heptane. The solids were then dried under vacuum overnight at 35-50° C. to give tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate. via drop-wise addition over 2 h the slurry stirred for 6 h This slurry was then filtered the cake washed with n-heptane The solids were then dried under vacuum overnight at 35-50° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate (47.0 kg, 207 mol) in dichloromethane (669 kg) at 0° C. was added a methanol solution of toluene-4-sulfonic acid monohydrate (3.7 kg, 20 mol in 38 kg MeOH) drop-wise over 2 h. The reaction was then aged for 4 h at this temperature. Then, 5% aqueous NaHCO3 (91 kg) was added and stirred at room temperature for 30 min. The layers were then separated and the aqueous extracted with dichloromethane (312 kg). The combined organics were washed with 5% brine (190 kg then 483 kg), treated with activated carbon (2.7 kg) and filtered. The resulting organics were dried with Na2SO4, filtered, and concentrated to 71-118 L. n-Heptane was then added (238 kg) and the batch further concentrated to 188-235 L. The slurry was cooled to 10-20° C., filtered, and the cake washed with n-heptane. The solids were dried under vacuum at 40-50° C. overnight to give tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate. The layers were then separated the aqueous extracted with dichloromethane (312 kg) The combined organics were washed with 5% brine (190 kg 483 kg), treated with activated carbon (2.7 kg) filtered The resulting organics were dried with Na2SO4 filtered concentrated to 71-118 L n-Heptane was then added (238 kg) the batch further concentrated to 188-235 L The slurry was cooled to 10-20° C. filtered the cake washed with n-heptane The solids were dried under vacuum at 40-50° C. overnight

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (58.2 kg, 242 mol) in toluene (251 kg) at 35-45° C. was added hydrazine hydrate (14.6 kg, 290 mol) via drop-wise addition over 2 h. The mixture was then stirred for 10 h at this temperature. The batch was then cooled to 0-10° C. and the slurry stirred for 6 h. This slurry was then filtered and the cake washed with n-heptane. The solids were then dried under vacuum overnight at 35-50° C. to give tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate. via drop-wise addition over 2 h the slurry stirred for 6 h This slurry was then filtered the cake washed with n-heptane The solids were then dried under vacuum overnight at 35-50° C.