cyclohexanecarbonitrile

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

Procedure: Solid KHMDS (4.36 g, 22.0 mmol) is dissolved in THF (80.0 mL) and cooled to 0° C. Cyclohexanecarbonitrile (2.38 g, 22.0 mmol) is added, and the resulting solution is stirred for 40 minutes. A solution of 4-fluorobenzonitrile (1.33 g, 10.95 mmol) in THF (10.0 mL) is added, and the mixture is stirred for 2 hours at 0° C. and 10 hours at room temperature. 1N HCl (50.0 mL) is added, and the aqueous phase is extracted with EtOAc (4×50.0 mL). The combined organic phases are dried over MgSO4, filtered and concentrated on the rotovaporator. The product is purified by flash chromatography (CombiFlash), eluting with mixtures of heptanes and EtOAc (0% EtOAc to 30% EtOAc) (1.55 g, 7.38 mmol, 67%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.23-1.38 (m, 1H) 1.52-1.68 (m, 2H) 1.68-1.78 (m, 1H) 1.78-1.93 (m, 4H) 2.00-2.11 (m, 2H) 7.75 (d, J=8.79 Hz, 2H) 7.91 (d, J=8.79 Hz, 2H). the mixture is stirred for 2 hours at 0° C. and 10 hours at room temperature the aqueous phase is extracted with EtOAc (4×50.0 mL) The combined organic phases are dried over MgSO4 filtered concentrated on the rotovaporator The product is purified by flash chromatography (CombiFlash)

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

Procedure: To a solution of cyclohexanecarbonitrile (0.913 g, 8.36 mmol) in toluene (25 ml) at 0° C. was added sodium bis(trimethylsilyl)amide (1M solution in THF, 10.0 ml, 10.0 mmol) and the resulting mixture was stirred for 1 hr at 0° C. 2-Chlorothiazole (1 g, 8.36 mmol) was then added dropwise as a solution in toluene (0.5 mL) over a period of 5 minutes and the resulting mixture was allowed to warm up from 0° C. to room temperature over 16 hrs. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (60 mL, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (gradient elution 2% to 12% EtOAc in Hexanes) to afford 1-(1,3-thiazol-2-yl)cyclohexanecarbonitrile (686 mg, 3.57 mmol, 42.7% yield) as a pale yellow oil which solidified upon standing. MS ESI: [M+H]+ m/z 193. to warm up from 0° C. to room temperature over 16 hrs The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) extracted with EtOAc (2×50 mL) The combined organic layers were washed with brine (60 mL dried (Na2SO4) filtered concentrated under reduced pressure The residue was purified by column chromatography on silica (gradient elution 2% to 12% EtOAc in Hexanes)

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture maintained under nitrogen, of 5.6 g (54.9 mmoles) of diisopropylamine and 92 ml of dry tetrahydrofuran, cooled to -40° C., there is added dropwise 34.2 ml (54.7 mmoles) of a 1.6M solution of n-butyllithium in hexane, then 8.2 g of 1,3-dimethylimidazolidin-2-one. The mixture is thereafter cooled to -78° C. and is stirred 1/4 hour before adding 5.45 g (50 mmoles) of commercial cyclohexanecarbonitrile in solution in 82 ml of dry tetrahydrofuran. After having stirred 1 hour, at -78° C., 14.3 g (50 mmoles) of the compound prepared in example 26a is added. The temperature is kept for an additional 3 hours at -78° C., before being allowed to rise and the mixture is stirred 19 hours at room temperature. Waster is then added, the mixture is acidified with HCl and is stirred again for 1 hour, before diluting it with water and extracting the reaction mixture with ether. The organic phase, washed with water, dried over Na2SO4 is concentrated. The liquid obtained is purified by distillation to give 7.5 g (yield= 61.6%) of a yellow liquid. b.p.0.5 =130°-80° C. The mixture is thereafter cooled to -78° C. After having stirred 1 hour, at -78° C. the mixture is stirred 19 hours at room temperature Waster is then added is stirred again for 1 hour extracting the reaction mixture with ether The organic phase, washed with water dried over Na2SO4 is concentrated The liquid obtained is purified by distillation

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture maintained under nitrogen, of 5.6 g (54.9 mmoles) of diisopropylamine and 92 ml of dry tetrahydrofuran, cooled to -40° C., there is added dropwise 34.2 ml (54.7 mmoles) of a 1.6M solution of n-butyllithium in hexane, then 8.2 g of 1,3-dimethylimidazolidin-2-one. The mixture is thereafter cooled to -78° C. and is stirred 1/4 hour before adding 5.45 g (50 mmoles) of commercial cyclohexanecarbonitrile in solution in 82 ml of dry tetrahydrofuran. After having stirred 1 hour, at -78° C., 14.3 g (50 mmoles) of the compound prepared in example 26a is added. The temperature is kept for an additional 3 hours at -78° C., before being allowed to rise and the mixture is stirred 19 hours at room temperature. Waster is then added, the mixture is acidified with HCl and is stirred again for 1 hour, before diluting it with water and extracting the reaction mixture with ether. The organic phase, washed with water, dried over Na2SO4 is concentrated. The liquid obtained is purified by distillation to give 7.5 g (yield= 61.6%) of a yellow liquid. b.p.0.5 =130°-80° C. The mixture is thereafter cooled to -78° C. After having stirred 1 hour, at -78° C. the mixture is stirred 19 hours at room temperature Waster is then added is stirred again for 1 hour extracting the reaction mixture with ether The organic phase, washed with water dried over Na2SO4 is concentrated The liquid obtained is purified by distillation

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

Procedure: Under a nitrogen atmosphere, to a solution of diisopropylamine (0.13 mL) in THF (7 mL) was added a solution (1.6 M, 0.58 mL) of butyllithium in hexane at 0° C., and the mixture was stirred at 0° C. for 10 min. The reaction mixture was cooled to −78° C., and cyclohexanecarbonitrile (0.12 mL) was added. The mixture was stirred at −78° C. for 1 hr, and a solution of ethyl 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-carboxylate (201 mg) in THF (3 mL) was added. The mixture was stirred at −78° C. for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (168 mg) as a colorless oil. The reaction mixture was cooled to −78° C. The mixture was stirred at −78° C. for 1 hr The mixture was stirred at −78° C. for 1 hr the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous sodium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)

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

Procedure: To a solution of cyclohexanecarbonitrile (0.913 g, 8.36 mmol) in toluene (25 ml) at 0° C. was added sodium bis(trimethylsilyl)amide (1M solution in THF, 10.0 ml, 10.0 mmol) and the resulting mixture was stirred for 1 hr at 0° C. 2-Chlorothiazole (1 g, 8.36 mmol) was then added dropwise as a solution in toluene (0.5 mL) over a period of 5 minutes and the resulting mixture was allowed to warm up from 0° C. to room temperature over 16 hrs. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (60 mL, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (gradient elution 2% to 12% EtOAc in Hexanes) to afford 1-(1,3-thiazol-2-yl)cyclohexanecarbonitrile (686 mg, 3.57 mmol, 42.7% yield) as a pale yellow oil which solidified upon standing. MS ESI: [M+H]+ m/z 193. to warm up from 0° C. to room temperature over 16 hrs The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) extracted with EtOAc (2×50 mL) The combined organic layers were washed with brine (60 mL dried (Na2SO4) filtered concentrated under reduced pressure The residue was purified by column chromatography on silica (gradient elution 2% to 12% EtOAc in Hexanes)

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 51.7 ml (0.5 mol) of anhydrous diethylamine are added dropwise, under protective gas at -10° C., to 312.5 ml (0.5 mol) of a 15% strength solution of n-butyllithium in hexane. The mixture is stirred for 20 minutes and then cooled to -70° C. 54.6 g of cyclohexanecarbonitrile are added dropwise over the course of 30 minutes and, after a further 30 minutes, 98.5 g of bromoacetaldehyde diethyl acetal are added within 1 hour and the mixture is left at low temperature for 24 hours. It is then warmed to room temperature, 100 g of ice are added, and the mixture is extracted twice with 500 ml of ethyl acetate, and the organic phase is dried over sodium sulfate, evaporated in vacuo and the residue is subjected to vacuum distillation. Yield: 90 g (about 80% of theory), boiling point 78°-79° C. at 8 torr (10.7 mbar). the mixture is left at low temperature for 24 hours It is then warmed to room temperature the mixture is extracted twice with 500 ml of ethyl acetate the organic phase is dried over sodium sulfate evaporated in vacuo the residue is subjected to vacuum distillation

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 51.7 ml (0.5 mol) of anhydrous diethylamine are added dropwise, under protective gas at -10° C., to 312.5 ml (0.5 mol) of a 15% strength solution of n-butyllithium in hexane. The mixture is stirred for 20 minutes and then cooled to -70° C. 54.6 g of cyclohexanecarbonitrile are added dropwise over the course of 30 minutes and, after a further 30 minutes, 98.5 g of bromoacetaldehyde diethyl acetal are added within 1 hour and the mixture is left at low temperature for 24 hours. It is then warmed to room temperature, 100 g of ice are added, and the mixture is extracted twice with 500 ml of ethyl acetate, and the organic phase is dried over sodium sulfate, evaporated in vacuo and the residue is subjected to vacuum distillation. Yield: 90 g (about 80% of theory), boiling point 78°-79° C. at 8 torr (10.7 mbar). the mixture is left at low temperature for 24 hours It is then warmed to room temperature the mixture is extracted twice with 500 ml of ethyl acetate the organic phase is dried over sodium sulfate evaporated in vacuo the residue is subjected to vacuum distillation

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

Procedure: Combine cyclohexanecarbonitrile (1.0 g, 9.20 mmol), ethanol (0.4 g, 9.20 mmol) and 4N hydrogen chloride in dioxane (8 mL) and stir the reaction mixture for 17 h at ambient temperature. Evaporate the solvent and triturate the residue with diethyl ether to obtain the desired intermediate as a white solid (1.4 g, 80%). Evaporate the solvent triturate the residue with diethyl ether

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

Procedure: Cyclohexanecarbonitrile (1.0 g, 9.2 mmol) was dissolved in anhydrous ethanol under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl cyclohexanecarbimidate hydrochloride (1.8 g, 100%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6): δ 11.66 (m, 1H), 11.03 (m, 1H), 4.39 (q, J=7.0 Hz, 2H), 2.62 (m, 1H), 1.84 (d, J=12.6 Hz, 2H), 1.70-1.65 (m, 3H), 1.40-1.38 (m, 2H), 1.33 (t, J=7.0 Hz, 3H), 1.23-1.19 (m, 3H). stirred for 6 h The solvent was removed in vacuo

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

Procedure: Cyclohexanecarbonitrile (1.0 g, 9.2 mmol) was dissolved in anhydrous ethanol under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl cyclohexanecarbimidate hydrochloride (1.8 g, 100%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6): δ 11.66 (m, 1H), 11.03 (m, 1H), 4.39 (q, J=7.0 Hz, 2H), 2.62 (m, 1H), 1.84 (d, J=12.6 Hz, 2H), 1.70-1.65 (m, 3H), 1.40-1.38 (m, 2H), 1.33 (t, J=7.0 Hz, 3H), 1.23-1.19 (m, 3H). stirred for 6 h The solvent was removed in vacuo

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 51.7 ml (0.5 mol) of anhydrous diethylamine are added dropwise, under protective gas at -10° C., to 312.5 ml (0.5 mol) of a 15% strength solution of n-butyllithium in hexane. The mixture is stirred for 20 minutes and then cooled to -70° C. 54.6 g of cyclohexanecarbonitrile are added dropwise over the course of 30 minutes and, after a further 30 minutes, 98.5 g of bromoacetaldehyde diethyl acetal are added within 1 hour and the mixture is left at low temperature for 24 hours. It is then warmed to room temperature, 100 g of ice are added, and the mixture is extracted twice with 500 ml of ethyl acetate, and the organic phase is dried over sodium sulfate, evaporated in vacuo and the residue is subjected to vacuum distillation. the mixture is left at low temperature for 24 hours It is then warmed to room temperature the mixture is extracted twice with 500 ml of ethyl acetate the organic phase is dried over sodium sulfate evaporated in vacuo the residue is subjected to vacuum distillation