2,5-dibromohexane

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

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

Procedure: Dibromoethane (3.0 mL, 0.035 mol) was added to a mechanically stirred suspension of Mg turnings (78 g, 3.21 mol) in THF (160 mL). After 30 min. most of the THF was removed via cannula and fresh THF (270 mL) was added. Then a solution of 2,5-dibromohexane (299 g, 1.24 mol) in THF (650 mL) was added at a rate that maintained the internal temperature at 30°-34° C. The resulting mixture was stirred overnight, filtered through glass wool and diluted with THF to a volume of 2 L. Hydrolysis of an aliquot and titration for total base showed the concentration of this solution to be 0.39M (63% yield, typically 60-65%). The Grignard solution was added to a cooled, magnetically stirred solution of N,N-diethylaminodichloroborane (124 g, 0.80 mol) in ether (1.0 L) at a rate that allowed maintenance of an internal temperature of -70° to -65° C. The resulting suspension was allowed to warm to 20° C. overnight. The solids were allowed to settle and the supernatant was removed via cannula. The solids were washed with pentane (four times) and the combined supernatants were concentrated by fractional distillation. The residue was vacuum transferred to a cold (dry ice-acetone) receiver by heating the residue to 120° C. at 0.1 torr. Distillation under reduced pressure gave the diethylaminoborolane 7 as a mixture of isomers (72.8 g, 0.44 mol) in 56% yield. On a small scale yields up to 70% were obtained. After 30 min. most of the THF was removed via cannula and fresh THF (270 mL) was added that maintained the internal temperature at 30°-34° C filtered through glass wool diluted with THF to a volume of 2 L Hydrolysis of an aliquot and titration for total base maintenance of an internal temperature of -70° to -65° C the supernatant was removed via cannula The solids were washed with pentane (four times) the combined supernatants were concentrated by fractional distillation by heating the residue to 120° C. at 0.1 torr Distillation under reduced pressure

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

Procedure: The title compound, MS: m/e=467.3 [(M+H)+], was prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 2,5-dibromohexane. The 3 diastereomers were not separated.

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

Procedure: The title compound, MS: m/e=467.3 [(M+H)+], was prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 2,5-dibromohexane. The 3 diastereomers were not separated.

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

Procedure: Dibromoethane (3.0 mL, 0.035 mol) was added to a mechanically stirred suspension of Mg turnings (78 g, 3.21 mol) in THF (160 mL). After 30 min. most of the THF was removed via cannula and fresh THF (270 mL) was added. Then a solution of 2,5-dibromohexane (299 g, 1.24 mol) in THF (650 mL) was added at a rate that maintained the internal temperature at 30°-34° C. The resulting mixture was stirred overnight, filtered through glass wool and diluted with THF to a volume of 2 L. Hydrolysis of an aliquot and titration for total base showed the concentration of this solution to be 0.39M (63% yield, typically 60-65%). The Grignard solution was added to a cooled, magnetically stirred solution of N,N-diethylaminodichloroborane (124 g, 0.80 mol) in ether (1.0 L) at a rate that allowed maintenance of an internal temperature of -70° to -65° C. The resulting suspension was allowed to warm to 20° C. overnight. The solids were allowed to settle and the supernatant was removed via cannula. The solids were washed with pentane (four times) and the combined supernatants were concentrated by fractional distillation. The residue was vacuum transferred to a cold (dry ice-acetone) receiver by heating the residue to 120° C. at 0.1 torr. Distillation under reduced pressure gave the diethylaminoborolane 7 as a mixture of isomers (72.8 g, 0.44 mol) in 56% yield. On a small scale yields up to 70% were obtained. After 30 min. most of the THF was removed via cannula and fresh THF (270 mL) was added that maintained the internal temperature at 30°-34° C filtered through glass wool diluted with THF to a volume of 2 L Hydrolysis of an aliquot and titration for total base maintenance of an internal temperature of -70° to -65° C the supernatant was removed via cannula The solids were washed with pentane (four times) the combined supernatants were concentrated by fractional distillation by heating the residue to 120° C. at 0.1 torr Distillation under reduced pressure

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

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

Procedure: To a solution of 3-[2-(t-butyloxycarbonylamino)ethyl]-5-hydroxy-1H-indole (1.34 g, 4.86 mmol) in acetonitrile (50 mL) were added 2,5-dibromohexane (2.4 g, 9.72 mmol) and potassium carbonate (1.3 g, 9.72 mmol) and the resulting mixture was stirred at reflux for 60 hours. After cooling to room temperature, the solution was poured into ethyl acetate (40 mL), washed with water (40 mL), dried over sodium sulfate and evaporated to dryness. Column chromatography on silica gel using hexane/ethyl acetate (4:1, 2:1 and 1:1) provided the title compound as a syrup (0.65 g, 30%). at reflux for 60 hours washed with water (40 mL) dried over sodium sulfate evaporated to dryness

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

Procedure: To a solution of 3-[2-(t-butyloxycarbonylamino)ethyl]-5-hydroxy-1H-indole (1.34 g, 4.86 mmol) in acetonitrile (50 mL) were added 2,5-dibromohexane (2.4 g, 9.72 mmol) and potassium carbonate (1.3 g, 9.72 mmol) and the resulting mixture was stirred at reflux for 60 hours. After cooling to room temperature, the solution was poured into ethyl acetate (40 mL), washed with water (40 mL), dried over sodium sulfate and evaporated to dryness. Column chromatography on silica gel using hexane/ethyl acetate (4:1, 2:1 and 1:1) provided the title compound as a syrup (0.65 g, 30%). at reflux for 60 hours washed with water (40 mL) dried over sodium sulfate evaporated to dryness

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

Procedure: To a solution of 3-[2-(t-butyloxycarbonylamino)ethyl]-5-hydroxy-1H-indole (1.34 g, 4.86 mmol) in acetonitrile (50 mL) were added 2,5-dibromohexane (2.4 g, 9.72 mmol) and potassium carbonate (1.3 g, 9.72 mmol) and the resulting mixture was stirred at reflux for 60 hours. After cooling to room temperature, the solution was poured into ethyl acetate (40 mL), washed with water (40 mL), dried over sodium sulfate and evaporated to dryness. Column chromatography on silica gel using hexane/ethyl acetate (4:1, 2:1 and 1:1) provided the title compound as a syrup (0.65 g, 30%). at reflux for 60 hours washed with water (40 mL) dried over sodium sulfate evaporated to dryness

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

Procedure: The title compound, MS: m/e=467.3 [(M+H)+], was prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 2,5-dibromohexane. The 3 diastereomers were not separated.

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

Procedure: Sodium metal (16 g, 0.7 mole) was dissolved in absolute ethanol (500 ml) under argon with cooling as necessary to maintain a temperature of <70° C. The solution was cooled and redistilled diethyl malonate (54.3 g, 0.362 mole) was added dropwise, with cooling as necessary, followed by 2,5-dibromohexane (85 g, 0.348 mole) in a single portion. The reaction mixture was stirred overnight at room temperature and then refluxed for 2 hours. The mixture was then concentrated to approximately half the volume under reduced pressure, water (500 ml) added and the mixture extracted with ether (3×200 ml). The combined extracts were dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was fractionated in vacuo to yield diethyl 2,5-dimethylcyclopentane-1,1-dicarboxylate (35 g), which was homogeneous by GC. with cooling as necessary to maintain a temperature of <70° C The solution was cooled was added dropwise with cooling as necessary, refluxed for 2 hours The mixture was then concentrated to approximately half the volume under reduced pressure, water (500 ml) added the mixture extracted with ether (3×200 ml) The combined extracts were dried (Na2SO4) filtered evaporated under reduced pressure

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

Procedure: The title compound, MS: m/e=467.3 [(M+H)+], was prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 2,5-dibromohexane. The 3 diastereomers were not separated.