ethyl 2-(1-benzylpiperidin-4-ylidene)acetate

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: 51.0 g of ethyl (1-benzylpiperidin-4-ylidene)acetate was dissolved in 200 ml of dichloroethane. After adding 36.5 g of 1-chloroethyl chloroformate under ice-cooling, the resulting mixture was heated under reflux for 2 hours. After adding 100 ml of methanol, the resulting mixture was further heated under reflux for 40 minutes and then allowed to stand at room temperature overnight. Then 60 g of triethylamine was added to the reaction mixture under ice-cooling. Further, 300 ml of methanol was added thereto and the system was made homogeneous. Next, 47.2 g of tert-butyl dicarbonate was added and the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium chloride and saturated sodium hydrogencarbonate and dried over anhydrous magnesium sulfate followed by filtration. After distilling off the solvent under reduced pressure, the crude crystals thus obtained were ground and washed with hexane to thereby give 15.2 g of the title compound. The filtrate was concentrated and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 37.8 g of the additional title compound as colorless crystals. cooling the resulting mixture was heated under reflux for 2 hours the resulting mixture was further heated under reflux for 40 minutes cooling The reaction mixture was concentrated under reduced pressure diluted with ethyl acetate washed successively with 1 N hydrochloric acid, water a saturated aqueous solution of sodium chloride and saturated sodium hydrogencarbonate and dried over anhydrous magnesium sulfate followed by filtration After distilling off the solvent under reduced pressure the crude crystals thus obtained washed with hexane

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

Procedure: 51.0 g of ethyl (1-benzylpiperidin-4-ylidene)acetate was dissolved in 200 ml of dichloroethane. After adding 36.5 g of 1-chloroethyl chloroformate under ice-cooling, the resulting mixture was heated under reflux for 2 hours. After adding 100 ml of methanol, the resulting mixture was further heated under reflux for 40 minutes and then allowed to stand at room temperature overnight. Then 60 g of triethylamine was added to the reaction mixture under ice-cooling. Further, 300 ml of methanol was added thereto and the system was made homogeneous. Next, 47.2 g of tert-butyl dicarbonate was added and the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium chloride and saturated sodium hydrogencarbonate and dried over anhydrous magnesium sulfate followed by filtration. After distilling off the solvent under reduced pressure, the crude crystals thus obtained were ground and washed with hexane to thereby give 15.2 g of the title compound. The filtrate was concentrated and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 37.8 g of the additional title compound as colorless crystals. cooling the resulting mixture was heated under reflux for 2 hours the resulting mixture was further heated under reflux for 40 minutes cooling The reaction mixture was concentrated under reduced pressure diluted with ethyl acetate washed successively with 1 N hydrochloric acid, water a saturated aqueous solution of sodium chloride and saturated sodium hydrogencarbonate and dried over anhydrous magnesium sulfate followed by filtration After distilling off the solvent under reduced pressure the crude crystals thus obtained washed with hexane

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (1.0 g, 3.6 mmol), ethyl 2-(1-benzylpiperidin-4-ylidene)acetate (1.1 g, 4.3 mmol) and K2CO3 (745 mg, 5.4 mmol) in DMF (20 mL) was heated to 80° C. for 16 hr under N2. The reaction was quenched with water (20 mL) and extracted with EA (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated and purified by chromatography column on silica gel using 30% of EA in PE as eluant to give the product (950 mg, 54.9%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.48-7.40 (m, 2H), 7.36-7.29 (m, 4H), 7.27-7.23 (m, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.15-7.07 (m, 4H), 3.55 (s, 2H), 3.01 (s, 2H), 2.81-2.73 (m, 2H), 2.39-2.27 (m, 2H), 2.26-2.16 (m, 2H), 1.83-1.74 (m, 2H). MS (ESI, m/e) [M+1]+ 489.9. The reaction was quenched with water (20 mL) extracted with EA (20 mL×3) The combined organic layers were dried over Na2SO4 concentrated purified by chromatography column on silica gel using 30% of EA in PE as eluant

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

Procedure: To a suspension of NaH (318 mg, 7.94 mmol) in THF (20 mL) was added a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.78 g, 7.94 mmol) in THF (5 mL) dropwise over 30 min at 0° C. After stirring for 10 min, a solution of 1-benzylpiperidin-4-one (1.0 g, 5.29 mmol) in THF (5 mL) was added dropwise at 0° C. over 20 min. The mixture was allowed to stir for 60 min. Then, the reaction was quenched with water (10 mL). The mixture was extracted with EA (10 mL×3). The combined organic layers were dried over Na2SO4, concentrated and purified by chromatography column on silica gel using 25% of EA in PE as eluant to give the product (1.2 g, 87.3%) as a yellow oil. MS (ESI, m/e) [M+1]+ 260.0. to stir for 60 min Then, the reaction was quenched with water (10 mL) The mixture was extracted with EA (10 mL×3) The combined organic layers were dried over Na2SO4 concentrated purified by chromatography column on silica gel using 25% of EA in PE as eluant

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

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (1.0 g, 3.6 mmol), ethyl 2-(1-benzylpiperidin-4-ylidene)acetate (1.1 g, 4.3 mmol) and K2CO3 (745 mg, 5.4 mmol) in DMF (20 mL) was heated to 80° C. for 16 hr under N2. The reaction was quenched with water (20 mL) and extracted with EA (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated and purified by chromatography column on silica gel using 30% of EA in PE as eluant to give the product (950 mg, 54.9%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.48-7.40 (m, 2H), 7.36-7.29 (m, 4H), 7.27-7.23 (m, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.15-7.07 (m, 4H), 3.55 (s, 2H), 3.01 (s, 2H), 2.81-2.73 (m, 2H), 2.39-2.27 (m, 2H), 2.26-2.16 (m, 2H), 1.83-1.74 (m, 2H). MS (ESI, m/e) [M+1]+ 489.9. The reaction was quenched with water (20 mL) extracted with EA (20 mL×3) The combined organic layers were dried over Na2SO4 concentrated purified by chromatography column on silica gel using 30% of EA in PE as eluant

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

Procedure: To a suspension of NaH (318 mg, 7.94 mmol) in THF (20 mL) was added a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.78 g, 7.94 mmol) in THF (5 mL) dropwise over 30 min at 0° C. After stirring for 10 min, a solution of 1-benzylpiperidin-4-one (1.0 g, 5.29 mmol) in THF (5 mL) was added dropwise at 0° C. over 20 min. The mixture was allowed to stir for 60 min. Then, the reaction was quenched with water (10 mL). The mixture was extracted with EA (10 mL×3). The combined organic layers were dried over Na2SO4, concentrated and purified by chromatography column on silica gel using 25% of EA in PE as eluant to give the product (1.2 g, 87.3%) as a yellow oil. MS (ESI, m/e) [M+1]+ 260.0. to stir for 60 min Then, the reaction was quenched with water (10 mL) The mixture was extracted with EA (10 mL×3) The combined organic layers were dried over Na2SO4 concentrated purified by chromatography column on silica gel using 25% of EA in PE as eluant

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ester 203 (8.06 g, 31.1 mmol) in THF (100 mL) was added an aqueous solution of LiOH (1.96 g, 46.6 mmol) in water (30 mL) and the reaction mixture was allowed to stir at 45° C. for 60 min. Then more LiOH (0.5 g, 11.9 mmol) was added to the heating solution. After further heating for 8 h, the reaction mixture was concentrated, extracted with AcOEt. The extract was concentrated and the residue was combined with the white solid which was collected by filtration from the aqueous phase. The combined solid materials were dissolved in DCM, treated with 2N HCl in diethyl ether (10 mL) and the mixture was diluted with benzene, evaporated and dried under vacuum to give (presumably) mono-hydrochloride salt of the acid 204 (8.23 g, 99% yield). After further heating for 8 h the reaction mixture was concentrated extracted with AcOEt The extract was concentrated was collected by filtration from the aqueous phase The combined solid materials were dissolved in DCM treated with 2N HCl in diethyl ether (10 mL) the mixture was diluted with benzene evaporated dried under vacuum

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

Procedure: 51.0 g of ethyl (1-benzylpiperidin-4-ylidene)acetate was dissolved in 200 ml of dichloroethane. After adding 36.5 g of 1-chloroethyl chloroformate under ice-cooling, the resulting mixture was heated under reflux for 2 hours. After adding 100 ml of methanol, the resulting mixture was further heated under reflux for 40 minutes and then allowed to stand at room temperature overnight. Then 60 g of triethylamine was added to the reaction mixture under ice-cooling. Further, 300 ml of methanol was added thereto and the system was made homogeneous. Next, 47.2 g of tert-butyl dicarbonate was added and the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium chloride and saturated sodium hydrogencarbonate and dried over anhydrous magnesium sulfate followed by filtration. After distilling off the solvent under reduced pressure, the crude crystals thus obtained were ground and washed with hexane to thereby give 15.2 g of the title compound. The filtrate was concentrated and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 37.8 g of the additional title compound as colorless crystals. cooling the resulting mixture was heated under reflux for 2 hours the resulting mixture was further heated under reflux for 40 minutes cooling The reaction mixture was concentrated under reduced pressure diluted with ethyl acetate washed successively with 1 N hydrochloric acid, water a saturated aqueous solution of sodium chloride and saturated sodium hydrogencarbonate and dried over anhydrous magnesium sulfate followed by filtration After distilling off the solvent under reduced pressure the crude crystals thus obtained washed with hexane