cyclopentylhydrazine;hydrochloride

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred mixture of 3-methoxy-1-(3-methoxyphenyl)-2-oxo-4-propionyl-1,2,5,6-tetrahydro-pyridine (0.49 grams, 1.7 mmole), cyclopentylhydrazine hydrochloride (0.40 grams) and sodium methoxide (46 mg, 0.85 mmole) in anhydrous ethanol was heated to reflux. After 16 hours, the mixture was concentrated under reduced pressure and chromatographed on a silica gel column using 1:4 ethyl acetate/hexane as eluent to give a white solid. Recrystallization from ether gave white needles. M.P. 64.65° C.; MS m/z [M+] 340.2025; HRMS [M+] 340.2046. was heated to reflux the mixture was concentrated under reduced pressure chromatographed on a silica gel column to give a white solid Recrystallization from ether gave white needles

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred mixture of 3-methoxy-1-(3-methoxyphenyl)-2-oxo-4-propionyl-1,2,5,6-tetrahydro-pyridine (0.49 grams, 1.7 mmole), cyclopentylhydrazine hydrochloride (0.40 grams) and sodium methoxide (46 mg, 0.85 mmole) in anhydrous ethanol was heated to reflux. After 16 hours, the mixture was concentrated under reduced pressure and chromatographed on a silica gel column using 1:4 ethyl acetate/hexane as eluent to give a white solid. Recrystallization from ether gave white needles. M.P. 64.65° C.; MS m/z [M+] 340.2025; HRMS [M+] 340.2046. was heated to reflux the mixture was concentrated under reduced pressure chromatographed on a silica gel column to give a white solid Recrystallization from ether gave white needles

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of cyclopentyl hydrazine hydrochloride (1.4 g, 10.2 mmol), sodium methoxide (0.55 g, 10.2 mmol) and ethanol (30 ml) was heated to reflux and then (1-methoxyphenylethylidene)malononitrile (2.0 g, 10.2 mmol) in ethanol (15 ml) was added dropwise over 1 hour. The reaction mixture was refluxed for 6.5 hours and the solvent was removed in vacuo. The residue was partitioned between chloroform and water, the organic layer was separated and the aqueous layer was extracted with chloroform (3×75 ml). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to afford 0.7 g (26%) of 1-cyclopentyl-3-phenylmethyl-5-amino-1H-pyrazole-4-carbonitrile as white flakes, m.p. 180°-182° C. when recrystallized from ethyl acetate and dried for 18 hours at 90° C. in high vacuum. was heated to reflux The reaction mixture was refluxed for 6.5 hours the solvent was removed in vacuo The residue was partitioned between chloroform and water the organic layer was separated the aqueous layer was extracted with chloroform (3×75 ml) The combined organic layers were washed with brine dried over anhydrous MgSO4 concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of cyclopentyl hydrazine hydrochloride (1.4 g, 10.2 mmol), sodium methoxide (0.55 g, 10.2 mmol) and ethanol (30 ml) was heated to reflux and then (1-methoxyphenylethylidene)malononitrile (2.0 g, 10.2 mmol) in ethanol (15 ml) was added dropwise over 1 hour. The reaction mixture was refluxed for 6.5 hours and the solvent was removed in vacuo. The residue was partitioned between chloroform and water, the organic layer was separated and the aqueous layer was extracted with chloroform (3×75 ml). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to afford 0.7 g (26%) of 1-cyclopentyl-3-phenylmethyl-5-amino-1H-pyrazole-4-carbonitrile as white flakes, m.p. 180°-182° C. when recrystallized from ethyl acetate and dried for 18 hours at 90° C. in high vacuum. was heated to reflux The reaction mixture was refluxed for 6.5 hours the solvent was removed in vacuo The residue was partitioned between chloroform and water the organic layer was separated the aqueous layer was extracted with chloroform (3×75 ml) The combined organic layers were washed with brine dried over anhydrous MgSO4 concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Cyclopentylhydrazine hydrochloride (20.9 g, 0.1 moles), 97% sodium methoxide (5.6 g, 0.1 moles) and ethanol (100 ml) were combined and stirred at room temperature under argon for 2.5 hours. (1-Ethoxypropylidene)malononitrile was added to the reaction mixture and the mixture was refluxed for 21 hours. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was treated with water (150 ml) and the obtained precipitate was collected by filtration, washed with water and dried in a vacuum oven for 24 hours to afford 14.2 g (70%) of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carbonitrile as a brown powder, m.p. 171°-173° C. the mixture was refluxed for 21 hours The reaction mixture was cooled the solvent was removed in vacuo The residue was treated with water (150 ml) the obtained precipitate was collected by filtration washed with water dried in a vacuum oven for 24 hours

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared in the same manner as described for intermediate 19 using cyclopentylhydrazine hydrochloride (2 g, 14.64 mmol), (2Z)-3-amino-2-butenenitrile (1.202 g, 14.64 mmol) and ethanol (20 mL). The final product was collected as 0.57 g (24%). LCMS E-S (M+H)=166.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.60-1.69 (m, 2H), 1.86-1.95 (m, 2H), 1.99-2.09 (m, 4H), 2.19 (s, 3H), 3.46 (br. s., 2H), 4.38 (quin, J=7.89 Hz, 1H), 5.36 (s, 1H). The final product was collected as 0.57 g (24%)

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Cyclopentyl-hydrazine hydrochloride (0.250 g, 1.83 mmol, Example 64, Step 2), 2-dimethylaminomethylene-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (0.403 g, 1.68 mmol) and anhydrous sodium acetate (0.163 g, 1.99 mmol) were combined in ethanol (2.5 mL) and heated at 70° C. for 17 hours. After cooling to room temperature, the reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with water and brine. Each aqueous phase was back extracted with a second portion of methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography, eluting with a 10-40% ethyl acetate-hexanes gradient, yielded 1-cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.244 g, 52%). Mass spectrum: m/z: 277.1 (M+H). After cooling to room temperature the reaction mixture was partitioned between methylene chloride and water The organic phase was washed with water and brine Each aqueous phase was back extracted with a second portion of methylene chloride dried over sodium sulfate concentrated in vacuo Purification by flash chromatography eluting with a 10-40% ethyl acetate-hexanes

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Cyclopentyl-hydrazine hydrochloride (1.000 g; 7.32 mmol), ethyl (ethoxymethylene)-cyanoacetate (1.026 g, 6.61 mmol) and anhydrous sodium acetate (0.644 g, 7.85 mmol) were combined in ethanol (10 mL) and heated at 70° C. for 20 hours. After cooling to room temperature, ethanol was removed in vacuo and the residue was partitioned between methylene chloride and water. The organic phase was washed sequentially with water and brine. Each aqueous phase was back extracted with a single portion of methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated. Purification by flash chromatography, eluting with 10-40% EtOAc/hexanes yielded 5-amino-1-cyclopentyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.170 g, 73%). Mass spectrum: m/z: 224.1 (M+H). After cooling to room temperature ethanol was removed in vacuo the residue was partitioned between methylene chloride and water The organic phase was washed sequentially with water and brine Each aqueous phase was back extracted with a single portion of methylene chloride dried over sodium sulfate concentrated Purification by flash chromatography eluting with 10-40% EtOAc/hexanes

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Cyclopentyl-hydrazine hydrochloride (0.250 g, 1.83 mmol, Example 64, Step 2), 2-dimethylaminomethylene-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (0.403 g, 1.68 mmol) and anhydrous sodium acetate (0.163 g, 1.99 mmol) were combined in ethanol (2.5 mL) and heated at 70° C. for 17 hours. After cooling to room temperature, the reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with water and brine. Each aqueous phase was back extracted with a second portion of methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography, eluting with a 10-40% ethyl acetate-hexanes gradient, yielded 1-cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.244 g, 52%). Mass spectrum: m/z: 277.1 (M+H). After cooling to room temperature the reaction mixture was partitioned between methylene chloride and water The organic phase was washed with water and brine Each aqueous phase was back extracted with a second portion of methylene chloride dried over sodium sulfate concentrated in vacuo Purification by flash chromatography eluting with a 10-40% ethyl acetate-hexanes

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Cyclopentyl-hydrazine hydrochloride (1.000 g; 7.32 mmol), ethyl (ethoxymethylene)-cyanoacetate (1.026 g, 6.61 mmol) and anhydrous sodium acetate (0.644 g, 7.85 mmol) were combined in ethanol (10 mL) and heated at 70° C. for 20 hours. After cooling to room temperature, ethanol was removed in vacuo and the residue was partitioned between methylene chloride and water. The organic phase was washed sequentially with water and brine. Each aqueous phase was back extracted with a single portion of methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated. Purification by flash chromatography, eluting with 10-40% EtOAc/hexanes yielded 5-amino-1-cyclopentyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.170 g, 73%). Mass spectrum: m/z: 224.1 (M+H). After cooling to room temperature ethanol was removed in vacuo the residue was partitioned between methylene chloride and water The organic phase was washed sequentially with water and brine Each aqueous phase was back extracted with a single portion of methylene chloride dried over sodium sulfate concentrated Purification by flash chromatography eluting with 10-40% EtOAc/hexanes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4-iodo-2-methoxynicotinic acid (1.95 g) obtained in Step C of Example 6, cyclopentylhydrazine hydrochloride (1.05 g), EDCI hydrochloride (0.58 g), HOBt (2.01 g) and triethylamine (1.06 g) in DMF (30 mL) was stirred at room temperature for 3 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (697 mg). the mixture was extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4-iodo-2-methoxynicotinic acid (1.95 g) obtained in Step C of Example 6, cyclopentylhydrazine hydrochloride (1.05 g), EDCI hydrochloride (0.58 g), HOBt (2.01 g) and triethylamine (1.06 g) in DMF (30 mL) was stirred at room temperature for 3 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (697 mg). the mixture was extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)