(3aR,7aS)-2,3,3a,4,5,6,7,7a-octahydro-1H-isoindole

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cis-4-cyclohexene-1,2-dicarboximide (10.9 g) was hydrogenated over 10% palladium on carbon (1 g) in absolute ethanol (420 ml) at 50 psi for 10 minutes. The mixture was filtered then evaporated to give cis-cyclohexane-1,2-dicarboximide (10.6 g). To anhydrous diethyl ether (200 ml) was cannulated under nitrogen a 1M diethyl ether solution (200 ml) of lithium aluminium hydride. To the foregoing solution, under reflux, was added cis-cyclohexane-1,2-dicarboximide (10.6 g) portionwise over 10 minutes. The reaction mixture was heated to reflux for 3 hours. After cooling to 0° C., water (7 ml) was added followed by 4N sodium hydroxide (7.6 ml) and water (23 ml). The white suspension was stirred whilst warming to room temperature. The solid was removed by filtration then the filtrate dried (sodium sulphate) and evaporated to give a cream oil. To the foregoing solution, under reflux The reaction mixture was heated to reflux for 3 hours whilst warming to room temperature The solid was removed by filtration the filtrate dried (sodium sulphate) evaporated to give a cream oil

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cis-4-cyclohexene-1,2-dicarboximide (10.9 g) was hydrogenated over 10% palladium on carbon (1 g) in absolute ethanol (420 ml) at 50 psi for 10 minutes. The mixture was filtered then evaporated to give cis-cyclohexane-1,2-dicarboximide (10.6 g). To anhydrous diethyl ether (200 ml) was cannulated under nitrogen a 1M diethyl ether solution (200 ml) of lithium aluminium hydride. To the foregoing solution, under reflux, was added cis-cyclohexane-1,2-dicarboximide (10.6 g) portionwise over 10 minutes. The reaction mixture was heated to reflux for 3 hours. After cooling to 0° C., water (7 ml) was added followed by 4N sodium hydroxide (7.6 ml) and water (23 ml). The white suspension was stirred whilst warming to room temperature. The solid was removed by filtration then the filtrate dried (sodium sulphate) and evaporated to give a cream oil. To the foregoing solution, under reflux The reaction mixture was heated to reflux for 3 hours whilst warming to room temperature The solid was removed by filtration the filtrate dried (sodium sulphate) evaporated to give a cream oil

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cis-4-cyclohexene-1,2-dicarboximide (10.9 g) was hydrogenated over 10% palladium on carbon (1 g) in absolute ethanol (420 ml) at 50 psi for 10 minutes. The mixture was filtered then evaporated to give cis-cyclohexane-1,2-dicarboximide (10.6 g). To anhydrous diethyl ether (200 ml) was cannulated under nitrogen a 1M diethyl ether solution (200 ml) of lithium aluminium hydride. To the foregoing solution, under reflux, was added cis-cyclohexane-1,2-dicarboximide (10.6 g) portionwise over 10 minutes. The reaction mixture was heated to reflux for 3 hours. After cooling to 0° C., water (7 ml) was added followed by 4N sodium hydroxide (7.6 ml) and water (23 ml). The white suspension was stirred whilst warming to room temperature. The solid was removed by filtration then the filtrate dried (sodium sulphate) and evaporated to give a cream oil. To the foregoing solution, under reflux The reaction mixture was heated to reflux for 3 hours whilst warming to room temperature The solid was removed by filtration the filtrate dried (sodium sulphate) evaporated to give a cream oil

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

Procedure: To a slurry of lithium aluminium hydride (17.1 g) in dry diethyl ether (375 ml) under a nitrogen atmosphere, cis-hexahydrophthalimide (23.0 g) in dry tetrahydrofuran (300 ml) was added over a two-hour period. The mixture was refluxed for 2.5 hours, cooled and treated very slowly with excess of water. The precipitate was filtered off and the filtrate was evaporated to yield the title compound as a viscous oil, which was used in the next step without purification. The mixture was refluxed for 2.5 hours cooled The precipitate was filtered off the filtrate was evaporated

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

Procedure: cis-Octahydro-1H-isoindole (1.81 g, 14.5 mmol), which is the compound described in Tetrahedron, 55 (1999) 9439-9454, was dissolved in 1N hydrochloric acid (16 ml), and the mixture was stirred under ice-cooling, sodium nitrite (6.22 g, 90.1 mmol) dissolved in water (20 ml) was gradually added, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was extracted with diethyl ether, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. Me insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (1.22 g, yield 55%) as a bistered oil. cooling was gradually added the mixture was stirred at the same temperature for 3 hr The reaction mixture was extracted with diethyl ether the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine dried over anhydrous magnesium sulfate Me insoluble material was filtered off the solution was concentrated under reduced pressure

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-3-benzyloxycarbonyl-4-phenylbutyric acid (671 mg) in anhydrous tetrahydrofuran (15 ml) were added N-methylmorpholine (0.5 ml) and isobutyl chloroformate (0.38 ml) with stirring at -20° C. for 20 minutes. To the mixture was added a solution of cis-hexahydroisoindoline (313 mg) in anhydrous tetrahydrofuran (5 ml) with stirring at -10 - -20° C. After 1 hour, the deposit was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 0.5N hydrochloric acid, saturated sodium bicarbonate solution, and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was recrystallized from dichloromethane-hexane to give 772 mg of benzyl (S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate. with stirring at -10 - -20° C After 1 hour the deposit was filtered off the solvent was evaporated under reduced pressure The residue was dissolved in ethyl acetate washed successively with 0.5N hydrochloric acid, saturated sodium bicarbonate solution, and brine dried over MgSO4 After the solvent was evaporated under reduced pressure the residue was recrystallized from dichloromethane-hexane

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

Procedure: To a suspension of (Z)-benzylidenesuccinic anhydride (139 mg) in dichloromethane (30 ml) was added cis-hexahydroisoindoline (120 mg) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 2N sodium hydroxide solution and the mixture was extracted with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was crystallized from ethyl acetate to give 190 mg of (Z)-2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid. the mixture was extracted with diethyl ether extracted with dichloromethane The organic layer was washed with brine dried over MgSO4 After the solvent was evaporated under reduced pressure the residue was crystallized from ethyl acetate

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

Procedure: To a suspension of (E)-benzylidenesuccinic anhydride (13.9 g) in dichloromethane (120 ml) was added cis-hexahydroisoindoline (12.0 g) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed successively with 1N hydrochloric acid and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was crystallized from ethyl acetate to give 19.5 g of (E)-2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid. The reaction mixture was washed successively with 1N hydrochloric acid and brine dried over MgSO4 After the solvent was evaporated under reduced pressure the residue was crystallized from ethyl acetate

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

Procedure: In a 3-liter GL autoclave fitted with a electromagnetic stirrer are added 226.5 g of N-benzylisoindoline, 545 g of 7.2% hydrochloric acid aqueous solution (pH 4.0) and 26 g of 5% palladium-carbon catalyst (50% water-containing). The reaction mixture is subjected to a hydrogen-pressure of 20 kg/cm2 and a temperature of 130° C. After a 10 hour hydrogen introduction, the drop in the rate of the hydrogen-absorption is observed, at this point the introduction of hydrogen is ceased to terminate the reaction. After the termination of reaction, the catalyst is filtered out from the reacted solution. By the result of the capillary chromatographic analysis, the yield of cis-hexahydroisoindoline is 83.8%. In addition, 0.1% of trans-hexahydroisoindoline and 0.7% of 2-methylcyclohexylmethylamine is formed. After cooling the reacted solution, 240 g of 20% sodium hydroxide aqueous solution is added to neutralize, and it is extracted with toluene. After concentrating the organic phase, the residue is purified by distillation to give 99.7 g of cis-hexahydroisoindoline (yield 79.6%). In a 3-liter GL autoclave fitted with a electromagnetic stirrer a temperature of 130° C the drop in the rate of the hydrogen-absorption to terminate the reaction After the termination of reaction the catalyst is filtered out from the reacted solution By the result of the capillary chromatographic analysis

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

Procedure: In a 3-liter GL autoclave fitted with a electromagnetic stirrer are added 129 g of isoindoline, 516 g of 50% water-containing tert-butyl alcohol and 26 g of 5% ruthenium-carbon catalyst (50% water-containing). The reaction mixture is subjected to a hydrogen-pressure of 30 kg/cm2 and a temperature of 130° C. After a 6 hour hydrogen introduction, the drop in the rate of the hydrogen-absorption is observed, at this point the introduction of hydrogen is ceased to terminate the reaction. After the termination of reaction, the catalyst is filtered out from the reacted solution. By the result of the capillary chromatographic analysis, the yield of cis-hexahydroisoindoline is 96.0%. In addition, 0.1% of trans-hexahydroisoindoline and 3.8% of 2-methylcyclohexylmethylamine is formed. After concentrating the reacted solution, the residue is purified by distillation to give 123.2 g of cis-hexahydroisoindoline (yield 91%). In a 3-liter GL autoclave fitted with a electromagnetic stirrer a temperature of 130° C the drop in the rate of the hydrogen-absorption to terminate the reaction After the termination of reaction the catalyst is filtered out from the reacted solution By the result of the capillary chromatographic analysis

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

Procedure: In a 3-liter GL autoclave fitted with a electromagnetic stirrer are added 129 g of isoindoline, 545 g of 7.2% hydrochloric acid aqueous solution (pH 4.0) and 2.6 g of 5% rhodium-carbon catalyst (50% water-containing). The reaction mixture is subjected to a hydrogen-pressure of 20 kg/cm2 and a temperature of 130° C. After a 1 hour hydrogen introduction, the drop in the rate of the hydrogen-absorption is observed, at this point the introduction of hydrogen is ceased to terminate the reaction. After the termination of reaction, the catalyst is filtered out from the reacted solution. By the result of the capillary chromatographic analysis, the yield of cis-hexahydroisoindoline is 98.7%. In addition, 0.4% of trans-hexahydroisoindoline and 0.4% of 2-methylcyclohexylmethylamine is formed. After cooling the reacted solution, 240 g of 20% sodium hydroxide aqueous solution is added to neutralize, and it is extracted with toluene. After concentrating the organic phase, the residue is purified by distillation to give 130.0 g of cis-hexahydroisoindoline (yield 95.9%). In a 3-liter GL autoclave fitted with a electromagnetic stirrer a temperature of 130° C the drop in the rate of the hydrogen-absorption to terminate the reaction After the termination of reaction the catalyst is filtered out from the reacted solution By the result of the capillary chromatographic analysis

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

Procedure: In a 3-liter GL (Glass Lining) autoclave fitted with a electromagnetic stirrer are added 129 g of isoindoline, 545 g of 7.2% hydrochloric acid aqueous solution (pH 4.0) and 26 g of 5% ruthenium-carbon catalyst (50% water-containing). The reaction mixture is subjected to a hydrogen-pressure of 20 kg/cm2 and a temperature of 130° C. After a 2 hour hydrogen introduction, the drop in the rate of the hydrogen-absorption is observed, at this point the introduction of hydrogen is ceased to terminate the reaction. After the termination of reaction, the catalyst is filtered out from the reacted solution. By the result of the capillary chromatographic analysis, the yield of cis-hexahydroisoindoline is 98.3%. In addition, 0.3% of trans-hexahydroisoindoline and 0.4% of 2-methylcyclohexylmethylamine is formed. After cooling the reacted solution, 240 g of 20% sodium hydroxide aqueous solution is added to neutralize, and it is extracted with toluene. After concentrating the organic phase, the residue is purified by distillation to give 128.0 g of cis-hexahydroisoindoline (yield 94.5%). In a 3-liter GL (Glass Lining) autoclave fitted with a electromagnetic stirrer a temperature of 130° C the drop in the rate of the hydrogen-absorption to terminate the reaction After the termination of reaction the catalyst is filtered out from the reacted solution By the result of the capillary chromatographic analysis