4,4-difluorocyclohexan-1-one

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

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

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 3.8 g (15.56 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (Example 73, intermediate g) in 38 ml methanol, 2.54 g (17.12 mmol) 4,4-difluorocyclohexanone (commercially available) were added. After stirring for 5 min. at room temperature the solution was treated with 2.44 g (15.58 mmol) p-chlorobenzoic acid, followed by an addition of 1.9 ml (15.56 mmol) benzyl isocyanide (commercially available). To the viscous slurry 12 ml methanol were added and the reaction for 22.5 h. Then 19.45 ml (77.80 mmol) 4M hydrochloric acid in dioxane were added dropwise over 5 min. After 4.5 h another 19.45 ml (77.80 mmol) 4M hydrochloric acid in dioxane were added. After 24 h, the suspension was poured onto 300 ml aqueous saturated sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted three times with ethyl acetate and the organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 50:50). Light yellow solid (76%). MS (Turbo Spray): m/z=530.2 [M+H]. the reaction for 22.5 h After 24 h the phases were separated The aqueous layer was extracted three times with ethyl acetate the organic layers were washed with brine dried over magnesium sulfate filtered evaporated The residue was purified by silica gel chromatography eluting with a gradient of heptane:ethyl acetate (100:0 to 50:50)

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

Procedure: To a solution of 4-iodo-1-(methoxymethyl)-1H-pyrazole (Organic Letters, 2007, 9, 4947-4950; 1.40 g, 5.88 mmol) in THF (15 mL), isopropyl magnesium chloride (2.0 M solution in THF; 3.8 mL, 7.64 mmol) was added with cooling on ice. The reaction solution was stirred for 30 minutes with cooling on ice. Then, 4,4-difluorocyclohexanone (2.30 g, 17.6 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, an aqueous ammonium chloride solution (50 mL) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=7:3) to yield the title compound (0.95 g, 66%) as a colorless oil. with cooling on ice with cooling on ice the mixture was stirred at room temperature for 1 hour followed by extraction with ethyl acetate (50 mL) The thus obtained organic layer was dried over anhydrous sodium sulfate After vacuum concentration the residue was purified with silica gel chromatography (hexane/ethyl acetate=7:3)

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

Procedure: The reaction and aftertreatment were conducted in the same manner as in Example 8a by using 4-iodo-1H-pyrazole (5.82 g, 30.0 mmol), butyl lithium (2.69 M solution in hexane; 22.3 mL, 60.0 mmol), 4,4-difluorocyclohexanone (4.43 g, 33.0 mmol) and THF (120 mL), to yield the title compound (2.32 g, 55%) as a pale yellow solid. The reaction and aftertreatment

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

Procedure: The reaction and aftertreatment were conducted in the same manner as in Example 4a by using 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (J. Org. Chem., 2007, 72 (9), 3589-3591; 10.0 g, 35.9 mmol), N,N,N′,N′-tetramethylethylenediamine (5.38 mL, 35.9 mmol), t-butyl lithium (1.60 M solution in pentane; 26.2 mL, 43.2 mmol), 4,4-difluorocyclohexanone (4.82 g, 35.9 mmol) and THF (100 mL), to yield the title compound (1.10 g, 11%) as a colorless oil. The reaction and aftertreatment

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

Procedure: To a solution of N,N-diisopropylamine (3.30 g, 32.6 mmol) in THF (50 mL), n-butyl lithium (1.65 M solution in hexane (18.0 mL, 29.7 mmol) was added dropwise with cooling on ice. The reaction solution was stirred at 0° C. for 30 minutes. Then, 4,4-difluorocyclohexanone (3.60 g, 26.8 mmol) was added thereto at −78° C., and the reaction solution was stirred at −78° C. for 1 hour. To the reaction solution, chlorotrimethylsilane (4.4 mL, 34.8 mmol) and triethylamine (8.0 mL, 57.4 mmol) were added, and the mixture was stirred at −78° C. for 2 hours. To the reaction solution, a saturated aqueous solution of sodium hydrogencarbonate (20 mL) was added, followed by extraction with ethyl acetate (20 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=98:2) to yield the title compound (2.10 g, 56%) as a colorless oil. with cooling on ice at −78° C., and the reaction solution was stirred at −78° C. for 1 hour the mixture was stirred at −78° C. for 2 hours followed by extraction with ethyl acetate (20 mL) The thus obtained organic layer was dried over anhydrous sodium sulfate After vacuum concentration the residue was purified with silica gel chromatography (hexane/ethyl acetate=98:2)

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

Procedure: 1.045 ml (13.57 mmol) of trifluoroacetic acid, 1 g (7.46 mmol) of 4,4-difluorocyclohexanone and 2.158 g (8.20 mmol) of tetramethylammonium triacetoxyborohydride are added to 1.521 g (5.22 mmol) of tert-butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate dissolved in 60 ml of dichloromethane. The reaction is left under stirring at room temperature for 24 hours. The solvent is evaporated and then the crude reaction product is redissolved in 30 ml of ethyl acetate. The solution is successively washed with 0.5 M HCl solution, 0.5 M soda solution and finally with saturated NaHCO3 solution. The organic phase is dried on sodium sulfate, filtered and concentrated to obtain 2.2 g of tert-butyl 2-(4,4-difluorocyclohexylamino)-4-(4-methylpiperazin-1-yl)benzoate in the form of a light brown gum (yield=72%). The reaction is left The solvent is evaporated the crude reaction product The solution is successively washed with 0.5 M HCl solution, 0.5 M soda solution and finally with saturated NaHCO3 solution The organic phase is dried on sodium sulfate filtered concentrated

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

Procedure: To a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (2.00 g, 10 mmol) and 4,4-difluorocyclohexanone (1.61 g, 12 mmol) in N,N-dimethylformamide (50 mL), kept at room temperature, acetic acid (3 mL, 50 mmol) and tetramethylammonium triacetoxyborohydride (5.24 g, 20 mmol) were subsequently added. The reaction mixture was allowed to stir overnight then diluted with water (150 mL), extracted with diethyl ether and the organic layer was discarded. The aqueous phase was made basic with ammonia and extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over sodium sulfate, evaporated to dryness and the residue was purified by column chromatography, using dichloromethane/ethanol/concentrated aqueous ammonia: 97.5/2.5/0.25 as the mobile phase. Tert-butyl [1-(4,4-difluorocyclohexyl)-piperidin-4-yl]-carbamate was obtained in fairly good yield as a white solid (2.5 g, 78%). kept at room temperature extracted with diethyl ether extracted with ethyl acetate (3×100 mL) The combined organic phases were dried over sodium sulfate evaporated to dryness the residue was purified by column chromatography

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

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

Procedure: 1.045 ml (13.57 mmol) of trifluoroacetic acid, 1 g (7.46 mmol) of 4,4-difluorocyclohexanone and 2.158 g (8.20 mmol) of tetramethylammonium triacetoxyborohydride are added to 1.521 g (5.22 mmol) of tert-butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate dissolved in 60 ml of dichloromethane. The reaction is left under stirring at room temperature for 24 hours. The solvent is evaporated and then the crude reaction product is redissolved in 30 ml of ethyl acetate. The solution is successively washed with 0.5 M HCl solution, 0.5 M soda solution and finally with saturated NaHCO3 solution. The organic phase is dried on sodium sulfate, filtered and concentrated to obtain 2.2 g of tert-butyl 2-(4,4-difluorocyclohexylamino)-4-(4-methylpiperazin-1-yl)benzoate in the form of a light brown gum (yield=72%). The reaction is left The solvent is evaporated the crude reaction product The solution is successively washed with 0.5 M HCl solution, 0.5 M soda solution and finally with saturated NaHCO3 solution The organic phase is dried on sodium sulfate filtered concentrated