2-(4-fluorophenyl)-1-phenylethanone

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

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

Procedure: DIPEA (200 mg, 1.6 mmol) was added to a stirred solution of {[5-(4-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (120 mg, 0.45 mmol) (prepared by the method used for the synthesis of Intermediate 30, starting from (4′-fluorophenyl)acetophenone) in DMF (2 mL) followed by HOBt (65 mg, 0.48 mmol) and EDCI.HCl (92 mg, 0.48 mmol). After 2 minutes 3-chloro-5-(piperidin-4-yloxy)-pyridine hydrochloride (0.114 g, 0.00045 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by column chromatography (using 60-120 silica gel and 50% ethyl acetate in hexane as eluent) to afford 111 mg (55.5% Yield) of 5-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 458, 97.78%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.3 (m, 1H), 8.21 (m, 1H), 8.04 (m, 1H), 7.8 (m, 2H), 7.7 (m, 1H), 7.3 (m, 2H), 7.1 (s, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (m, 2H), 3.7 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H), 2.0 (m, 2H), 1.6 (m, 2H). prepared by the method was added to the reaction mixture extracted with ethyl acetate dried over sodium sulfate concentrated under reduced pressure The residue was purified by column chromatography (using 60-120 silica gel and 50% ethyl acetate in hexane as eluent)

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

Procedure: DIPEA (226 mg, 1.75 mmol) was added to a stirred solution of {[5-(4-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (130 mg, 0.5 mmol) (prepared by the method used for the synthesis of Intermediate 30, starting from (4-fluorophenyl)acetophenone) in DMF (2 mL) followed by HOBt (71 mg, 0.52 mmol) and EDCI.HCl (100 mg, 0.52 mmol). After 2 minutes 3-chloro-5-(piperidin-4-yloxy)-pyridine hydrochloride (125 mg, 0.5 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by column chromatography (using 60-120 silica gel and 40% ethyl acetate in hexane as eluent) to afford 134 mg (58.5% Yield) of 5-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 458, 93.27%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.0 (m, 2H), 7.8 (m, 2H), 7.7 (d, 1H), 7.4 (m, 1H), 7.25 (m, 2H), 7.1 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H). prepared by the method was added to the reaction mixture extracted with ethyl acetate dried over sodium sulfate concentrated under reduced pressure The residue was purified by column chromatography (using 60-120 silica gel and 40% ethyl acetate in hexane as eluent)

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

Procedure: DIPEA (226 mg, 1.75 mmol) was added to a stirred solution of {[5-(4-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (130 mg, 0.5 mmol) (prepared by the method used for the synthesis of Intermediate 30, starting from (4-fluorophenyl)acetophenone) in DMF (2 mL) followed by HOBt (71 mg, 0.52 mmol) and EDCI.HCl (100 mg, 0.52 mmol). After 2 minutes 3-chloro-5-(piperidin-4-yloxy)-pyridine hydrochloride (125 mg, 0.5 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by column chromatography (using 60-120 silica gel and 40% ethyl acetate in hexane as eluent) to afford 134 mg (58.5% Yield) of 5-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 458, 93.27%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.0 (m, 2H), 7.8 (m, 2H), 7.7 (d, 1H), 7.4 (m, 1H), 7.25 (m, 2H), 7.1 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H). prepared by the method was added to the reaction mixture extracted with ethyl acetate dried over sodium sulfate concentrated under reduced pressure The residue was purified by column chromatography (using 60-120 silica gel and 40% ethyl acetate in hexane as eluent)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(4-fluorophenyl)-1-phenyl-1-ethanone (5 g, 30 mmol) in 30 ml pyridine under nitrogen was added methoxylamine hydrochloride (3.8 g, 45 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 17 hours. The pyridine was removed in vacuo with heating. The residual solids were a mixture of the oxime geometrical isomers as a white syrup and it was used for the next step without further purification. Rf : 0.48, 0.70 (CH2Cl2). The pyridine was removed in vacuo with heating a mixture of the oxime geometrical isomers as a white syrup and it was used for the next step without further purification

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

Procedure: Following the procedure of example 1B, 13.8 g (0.0645 mol) of 2-(4-fluorophenyl)-1-phenylethanone was reacted with 20 mL of dimethyl formamide dimethyl acetal to yield 13.6 g of 3-(dimethylamino)-2-(4-fluorophenyl)-1-phenyl-2-propen-1-one, mp 115°-116° from isopropyl acetate. The enamine (10.5 g, 0.039 mol) was reacted with 6.03 g (0.039 mol) of ethyl hydrazinoacetate hydrochloride to yield 12.1 g of product mp 86°-87° C. from methyl-t-butyl ether.

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

Procedure: 5.27 ml. (42 mmoles) of 4-fluorobenzyl bromide (Compound CI) is slowly added to 928 mg. (38 mmoles) of magnesium turnings stirred in 38 ml. of anhydrous diethyl ether under nitrogen over a period of 45 minutes at a rate such that the reaction mixture gently refluxes. The reaction mixture is allowed to cool to 20°-25° C., 2.96 ml. (29 mmoles) of benzonitrile in 5 ml. of anhydrous diethyl ether is added over a period of 5 minutes, and the reaction mixture is stirred at 20°-25° C. for 3 hours, the reaction mixture being maintained under nitrogen throughout. The reaction mixture is slowly poured into ice cold 10% hydrochloric acid, and the organic phase is separated. The aqueous phase is extracted five times with diethyl ether and twice with ethyl acetate, and the organic phases are combined, washed once with saturated sodium bicarbonate solution, washed once with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated at reduced pressure. The residue is dissolved in 450 ml. of hot petroleum ether, and the solution is filtered and cooled to obtain the product as an off-white solid (3.5 g.), m.p. 109°-110° C. A second crop is also obtained (0.39 g.). to cool to 20°-25° C. the reaction mixture being maintained under nitrogen throughout the organic phase is separated The aqueous phase is extracted five times with diethyl ether washed once with saturated sodium bicarbonate solution washed once with saturated sodium chloride solution dried over anhydrous magnesium sulfate evaporated at reduced pressure The residue is dissolved in 450 ml of hot petroleum ether, and the solution is filtered cooled

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

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

Procedure: 5.27 ml. (42 mmoles) of 4-fluorobenzyl bromide (Compound CI) is slowly added to 928 mg. (38 mmoles) of magnesium turnings stirred in 38 ml. of anhydrous diethyl ether under nitrogen over a period of 45 minutes at a rate such that the reaction mixture gently refluxes. The reaction mixture is allowed to cool to 20°-25° C., 2.96 ml. (29 mmoles) of benzonitrile in 5 ml. of anhydrous diethyl ether is added over a period of 5 minutes, and the reaction mixture is stirred at 20°-25° C. for 3 hours, the reaction mixture being maintained under nitrogen throughout. The reaction mixture is slowly poured into ice cold 10% hydrochloric acid, and the organic phase is separated. The aqueous phase is extracted five times with diethyl ether and twice with ethyl acetate, and the organic phases are combined, washed once with saturated sodium bicarbonate solution, washed once with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated at reduced pressure. The residue is dissolved in 450 ml. of hot petroleum ether, and the solution is filtered and cooled to obtain the product as an off-white solid (3.5 g.), m.p. 109°-110° C. A second crop is also obtained (0.39 g.). to cool to 20°-25° C. the reaction mixture being maintained under nitrogen throughout the organic phase is separated The aqueous phase is extracted five times with diethyl ether washed once with saturated sodium bicarbonate solution washed once with saturated sodium chloride solution dried over anhydrous magnesium sulfate evaporated at reduced pressure The residue is dissolved in 450 ml of hot petroleum ether, and the solution is filtered cooled

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(4-fluorophenyl)-1-phenyl-1-ethanone (5 g, 30 mmol) in 30 ml pyridine under nitrogen was added methoxylamine hydrochloride (3.8 g, 45 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 17 hours. The pyridine was removed in vacuo with heating. The residual solids were a mixture of the oxime geometrical isomers as a white syrup and it was used for the next step without further purification. Rf : 0.48, 0.70 (CH2C12). The pyridine was removed in vacuo with heating a mixture of the oxime geometrical isomers as a white syrup and it was used for the next step without further purification

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(4-fluorophenyl)-1-phenyl-1-ethanone (5 g, 30 mmol) in 30 ml pyridine under nitrogen was added methoxylamine hydrochloride (3.8 g, 45 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 17 hours. The pyridine was removed in vacuo with heating. The residual solids were a mixture of the oxime geometrical isomers as a white syrup and it was used for the next step without further purification. Rf : 0.48, 0.70 (CH2C12). The pyridine was removed in vacuo with heating a mixture of the oxime geometrical isomers as a white syrup and it was used for the next step without further purification

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

Procedure: Following the procedure of example 1B, 13.8 g (0.0645 mol) of 2-(4-fluorophenyl)-1-phenylethanone was reacted with 20 mL of dimethyl formamide dimethyl acetal to yield 13.6 g of 3-(dimethylamino)-2-(4-fluorophenyl)-1-phenyl-2-propen-1-one, mp 115°-116° from isopropyl acetate. The enamine (10.5 g, 0.039 mol) was reacted with 6.03 g (0.039 mol) of ethyl hydrazinoacetate hydrochloride to yield 12.1 g of product mp 86°-87° C. from methyl-t-butyl ether.