(-)-trans-1,2-Cyclohexanedicarboxylic anhydride

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

Procedure: 0.37 cm3 of N-methylpiperazine in solution in 5 cm3 of dioxane is added, under an argon atmosphere, to 0.50 g of (−)-trans-1,2-cyclohexanedicarboxylic anhydride in solution at −15° C. in 20 cm3 of dioxane. After 1.25 hours at 20° C., the reaction mixture is filtered, the solid is washed with 20 cm3 of diethyl ether, drained, and then dried under reduced pressure (2,7 kPa) at 20° C., to give 0.65 g of (1R, 2R)-2-[(4-methylpiperazin-1-yl)carbonyl]-1-cyclohexanecarboxylic acid in the form of a white solid. the reaction mixture is filtered the solid is washed with 20 cm3 of diethyl ether dried under reduced pressure (2,7 kPa) at 20° C.

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

Procedure: A solution containing 4.00 g (0.022 mole) of 4-amino-2,6-di-t-butylphenol in 50 ml of 1,2-dimethoxye-thane was added dropwise over a period of ten minutes to a solution of 3.35 g (0.022 mole) of trans-1,2-cyclohexanedi-carboxylic anhydride in 50 ml of 1,2-dimethoxyethane. The reaction mixture was stirred at room temperature for about seventy-two hours. The solvent was removed under vacuum and the residual solid was triturated with a mixture of diethyl ether and hexane. The resulting solid was recrys-tallized from a mixture of ethyl acetate and hexane to give 4.4 g of white solid 2-[N (3,5-di-t-butyl-4-hydroxyphenyl) carbamoyl]-trans-cyclohexanecarboxylic acid, m.p. 247°-252° C. Analysis: Calculated for C: HNO. %C, 70.4; %H, 8.9; %N, 3.7; Found: %C, 70.4; %H, 8.9; %N, 3.6. The solvent was removed under vacuum the residual solid was triturated with a mixture of diethyl ether and hexane The resulting solid was recrys-tallized from a mixture of ethyl acetate and hexane

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

Procedure: A solution of trans-1,2-cyclohexanedicarboxylic anhydride (10 g, 65 mmol) in ammonium hydroxide (conc., 30 ml) was hydrogenated by the method of EXAMPLE 168 to yield 7.4 g (80%) of the title material.

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

Procedure: A solution containing 4.00 g (0.022 mole) of 4-amino-2,6-di-t-butylphenol in 50 ml of 1,2-dimethoxyethane was added dropwise over a period of ten minutes to a solution of 3.35 g (0.022 mole) of trans-1,2-cyclohexanedicarboxylic anhydride in 50 ml of 1,2-dimethoxyethane. The reaction mixture was stirred at room temperature for about seventy-two hours. The solvent was removed under vacuum and the residual solid was triturated with a mixture of diethyl ether and hexane. The resulting solid was recrystallized from a mixture of ethyl acetate and hexane to give 4.4 g of white solid 2-[N-(3,5-di-t-butyl-4-hydroxyphenyl) carbamoyl]-trans-cyclohexanecarboxylic acid, m.p. 247°-252° C. Analysis: Calculated for C22H33NO4 : %C, 70.4; %H, 8.9; %N, 3.7; Found: %C, 70.4; %H, 8.9; %N, 3.6. The solvent was removed under vacuum the residual solid was triturated with a mixture of diethyl ether and hexane The resulting solid was recrystallized from a mixture of ethyl acetate and hexane

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

Procedure: Using, as starting materials, 2.3 g of 3,5-bistrifluoromethyl aniline, and 1.5 g (0.01 mole) of trans-cyclohexane-1,2-dicarboxylic anhydride, the title compound was obtained in the same manner as in Example 1.

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

Procedure: 0.37 cm3 of N-methylpiperazine in solution in 5 cm3 of dioxane is added, under an argon atmosphere, to 0.50 g of (−)-trans-1,2-cyclohexanedicarboxylic anhydride in solution at −15° C. in 20 cm3 of dioxane. After 1.25 hours at 20° C., the reaction mixture is filtered, the solid is washed with 20 cm3 of diethyl ether, drained, and then dried under reduced pressure (2,7 kPa) at 20° C., to give 0.65 g of (1R, 2R)-2-[(4-methylpiperazin-1-yl)carbonyl]-1-cyclohexanecarboxylic acid in the form of a white solid. the reaction mixture is filtered the solid is washed with 20 cm3 of diethyl ether dried under reduced pressure (2,7 kPa) at 20° C.

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

Procedure: (+)-trans-Cyclohexane-1,2-dicarboxylic anhydride (100 mg, 0.65 mmol) was weighed into a 10 mL round bottom flask and aminoacetonitrile hydrochloride (135 mg, 1.46 mmol) and 4-(dimethylamino)pyridine (7.5 mg, 61 μmol) added. After adding tetrahydrofuran (2.0 mL) and triethylamine (0.20 mL, 1.4 mmol), the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between 1 M aqueous hydrochloric acid (30 mL) and ethyl acetate (30 mL). The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to give (1R,2R)-2-{[(cyanomethyl)amino]carbonyl}cyclohexanecarboxylic acid (as a colorless solid. The reaction mixture was partitioned between 1 M aqueous hydrochloric acid (30 mL) and ethyl acetate (30 mL) The organic layer was separated washed with saturated sodium chloride aqueous solution dried over anhydrous sodium sulfate concentrated

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

Procedure: trans-1,2-Cyclohexanedicarboxylic anhydride (19.64 g, 127 mmol) and aminoacetonitrile hydrochloride (12.05 g, 130 mmol) were weighed into a dry 500 mL flask fitted with a stir bar and nitrogen inlet. After adding anhydrous dichloromethane (200 mL), triethylamine (39.1 mL, 281 mmol) was added at a moderate rate, allowing the reaction to warm the solution to near boiling point. The reaction mixture was allowed to cool to room temperature over 1 h, after which it was cooled to −10° C. and isobutyl chloroformate (18.2 mL, 140 mmol) was added dropwise, keeping the reaction temperature below 0° C. After the addition was complete, the reaction was allowed to warm to room temperature. After 1 h, the reaction mixture was diluted with anhydrous tetrahydrofuran (200 mL) and stired at 0° C. for 1 h. The precipitate were filtered and washed with cold anhydrous tetrahydrofuran (100 mL). The filtrate was taken in a 1000 mL flask and fitted with a stir bar and a 50 mL addition funnel. The solution was cooled to −25° C. and a solution of sodium borohydride (6.90 g, 182 mmol) in water (30 mL) was added at a slow dropping rate, keeping the reaction temperature below −15° C. After the addition was complete, the reaction mixture was stirred for 1 h between −20° C. and −10° C. After warming the reaction mixture to warm to room temperature and stirring for an additional 1 h, anhydrous magnesium sulfate was added and stirring was continured for additional 30 min, filtered and the filtrate was concentrated on a rotary evaporator. Product was purified from the residue by chromatography using 9:1 dichloromethane:methanol eluent. The product fractions were concentrated on a rotary evaporator and dried under high vacuum to give trans-N-cyanomethyl-2-hydroxymethyl-cyclohexanecarboxamide as a white solid. fitted with a stir bar and nitrogen inlet was added at a moderate rate the reaction to warm the solution after which it was cooled to −10° C. the reaction temperature below 0° C After the addition to warm to room temperature stired at 0° C. for 1 h The precipitate were filtered washed with cold anhydrous tetrahydrofuran (100 mL) The filtrate was taken in a 1000 mL flask fitted with a stir bar and a 50 mL addition funnel The solution was cooled to −25° C. the reaction temperature below −15° C After the addition After warming the reaction mixture to warm to room temperature stirring for an additional 1 h stirring was continured for additional 30 min filtered the filtrate was concentrated on a rotary evaporator Product was purified from the residue by chromatography The product fractions were concentrated on a rotary evaporator dried under high vacuum

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

Procedure: trans-1,2-Cyclohexanedicarboxylic anhydride (19.64 g, 127 mmol) and aminoacetonitrile hydrochloride (12.05 g, 130 mmol) were weighed into a dry 500 mL flask fitted with a stir bar and nitrogen inlet. After adding anhydrous dichloromethane (200 mL), triethylamine (39.1 mL, 281 mmol) was added at a moderate rate, allowing the reaction to warm the solution to near boiling point. The reaction mixture was allowed to cool to room temperature over 1 h, after which it was cooled to −10° C. and isobutyl chloroformate (18.2 mL, 140 mmol) was added dropwise, keeping the reaction temperature below 0° C. After the addition was complete, the reaction was allowed to warm to room temperature. After 1 h, the reaction mixture was diluted with anhydrous tetrahydrofuran (200 mL) and stired at 0° C. for 1 h. The precipitate were filtered and washed with cold anhydrous tetrahydrofuran (100 mL). The filtrate was taken in a 1000 mL flask and fitted with a stir bar and a 50 mL addition funnel. The solution was cooled to −25° C. and a solution of sodium borohydride (6.90 g, 182 mmol) in water (30 mL) was added at a slow dropping rate, keeping the reaction temperature below −15° C. After the addition was complete, the reaction mixture was stirred for 1 h between −20° C. and −10° C. After warming the reaction mixture to warm to room temperature and stirring for an additional 1 h, anhydrous magnesium sulfate was added and stirring was continured for additional 30 min, filtered and the filtrate was concentrated on a rotary evaporator. Product was purified from the residue by chromatography using 9:1 dichloromethane:methanol eluent. The product fractions were concentrated on a rotary evaporator and dried under high vacuum to give trans-N-cyanomethyl-2-hydroxymethyl-cyclohexanecarboxamide as a white solid. fitted with a stir bar and nitrogen inlet was added at a moderate rate the reaction to warm the solution after which it was cooled to −10° C. the reaction temperature below 0° C After the addition to warm to room temperature stired at 0° C. for 1 h The precipitate were filtered washed with cold anhydrous tetrahydrofuran (100 mL) The filtrate was taken in a 1000 mL flask fitted with a stir bar and a 50 mL addition funnel The solution was cooled to −25° C. the reaction temperature below −15° C After the addition After warming the reaction mixture to warm to room temperature stirring for an additional 1 h stirring was continured for additional 30 min filtered the filtrate was concentrated on a rotary evaporator Product was purified from the residue by chromatography The product fractions were concentrated on a rotary evaporator dried under high vacuum

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

Procedure: To a mixture of lithium aluminum hydride (2.85 g; 75 mmol) and diethyl ether (50 ml), a solution of trans-1,2-cyclohexanedicarboxylic acid anhydride (1) (7.71 g; 50 mmol) in diethyl ether (150 ml) is dropwise added, and the resultant mixture is allowed to react at room temperature for 3 hours and then heated under reflux for 2 hours. After cooling, wet ether is dropwise added to the reaction mixture, followed by addition of water. The organic layer is collected by decantation, followed by concentration to give trans-1,2-bis(hydroxymethyl)cyclohexane (2) (5.1 g). to react at room temperature for 3 hours heated under reflux for 2 hours After cooling The organic layer is collected by decantation followed by concentration

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

Procedure: Prepared from trans-cyclohexane-1,2-dicarboxylic anhydride and 1,2-dimethoxybenzene as described for compound A M.p. 202°-205° C.

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

Procedure: To a mixture of lithium aluminum hydride (2.85 g; 75 mmol) and diethyl ether (50 ml), a solution of trans-1,2-cyclohexanedicarboxylic acid anhydride (1) (7.71 g; 50 mmol) in diethyl ether (150 ml) is dropwise added, and the resultant mixture is allowed to react at room temperature for 3 hours and then heated under reflux for 2 hours. After cooling, wet ether is dropwise added to the reaction mixture, followed by addition of water. The organic layer is collected by decantation, followed by concentration to give trans-1,2-bis(hydroxymethyl)cyclohexane (2) (5.1 g). to react at room temperature for 3 hours heated under reflux for 2 hours After cooling The organic layer is collected by decantation followed by concentration