3-Fluoro-4-methylbenzaldehyde

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:

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1S,2R,3S,4R)-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 300 mg, 1.637 mmol) was suspended in ethanol (5 mL). 3-Fluoro-4-methyl-benzaldehyde (0.2 mL, 1.637 mmol) was added followed by glacial acetic acid (0.1 mL, 3.724 mmol) and 4 Å powdered molecular sieves (0.6 g). Sodium cyanoborohydride (0.593 g, 9.406 mmol) was added and the mixture was stirred under nitrogen at 50° C. for 18 h. Upon cooling, the mixture was filtered through Celite. The filtrate was diluted with half-saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2×75 mL). The layers were separated and the organic layer was washed with saturated aqueous brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Further purification by flash column chromatography (Teledyne Isco RediSep column; 1st column: 0 to 25% ethyl acetate in hexanes; 2nd column: 0 to 20% ethyl acetate in hexanes) afforded the desired product, (1S,2R,3S,4R)-3-(3-fluoro-4-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (221 mg, 0.724 mmol, 44%), as a clear thick oil. 1H NMR (400 MHz, CDCl3) δ: 1.04-1.15 (2H, m), 1.21 (1H, d, J=10.1 Hz), 1.29 (3H, t, J=7.1 Hz), 1.42-1.63 (4H, m), 1.94 (1H, dt, J1=10.2 Hz, J2=2.0 Hz), 2.25 (3H, s), 2.43 (1H, d, J=3.5 Hz), 2.59 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 2.93 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 3.65 (1H, d, J=13.4 Hz), 3.79 (1H, d, J=14.2 Hz), 4.15 (2H, q, J=7.1 Hz), 6.94 (1H, d, J=7.9 Hz), 6.98 (1H, d, J=10.9 Hz), 7.08 (1H, t, J=7.8 Hz). LC-MS (ESI) calcd for C18H24FNO2 305.18, found 305.9 [M+H+]. Upon cooling the mixture was filtered through Celite The filtrate was diluted with half-saturated aqueous sodium bicarbonate solution (50 mL) extracted with ethyl acetate (2×75 mL) The layers were separated the organic layer was washed with saturated aqueous brine solution dried over sodium sulfate filtered concentrated in vacuo Further purification by flash column chromatography (Teledyne Isco RediSep column; 1st column: 0 to 25% ethyl acetate in hexanes; 2nd column: 0 to 20% ethyl acetate in hexanes)

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

Procedure: To a suspension of 0.22 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride in 7 mL of methanol, 66 mg of sodium cyanoborohydride, 64 μL of 3-fluoro-4-methylbenzaldehyde, 0.30 g of a 28% sodium methoxide/methanol solution and 30 μL of acetic acid were added, and the mixture was stirred at room temperature for 3 hours. Thereto was added 22 mg of 3-fluoro-4-methylbenzaldehyde, and the mixture was stirred at the same temperature for 1 hour. Thereto was further added 33 mg of sodium cyanoborohydride, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added thereto, and the solvent was distilled off under reduced pressure. Thereto was added chloroform, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=9:1 to obtain 20 mg of 1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as a colorless oily substance. were added the mixture was stirred at the same temperature for 1 hour the mixture was stirred at the same temperature for 1 hour the solvent was distilled off under reduced pressure Thereto was added chloroform the organic layer was separated the aqueous layer was extracted with chloroform the resultant solution was washed sequentially with water a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate the solvent was distilled off under reduced pressure The resultant residue was purified by basic silica gel column chromatography

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1S,2R,3 S,4R)-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 300 mg, 1.637 mmol) was suspended in ethanol (5 mL). 3-Fluoro-4-methyl-benzaldehyde (0.2 mL, 1.637 mmol) was added followed by glacial acetic acid (0.1 mL, 3.724 mmol) and 4 Å powdered molecular sieves (0.6 g). Sodium cyanoborohydride (0.593 g, 9.406 mmol) was added and the mixture was stirred under nitrogen at 50° C. for 18 h. Upon cooling, the mixture was filtered through Celite. The filtrate was diluted with half-saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2×75 mL). The layers were separated and the organic layer was washed with saturated aqueous brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Further purification by flash column chromatography (Teledyne Isco RediSep column; 1st column: 0 to 25% ethyl acetate in hexanes; 2nd column: 0 to 20% ethyl acetate in hexanes) afforded the desired product, (1S,2R,3S,4R)-3-(3-fluoro-4-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (221 mg, 0.724 mmol, 44%), as a clear thick oil. 1H NMR (400 MHz, CDCl3) δ: 1.04-1.15 (2H, m), 1.21 (1H, d, J=10.1 Hz), 1.29 (3H, t, J=7.1 Hz), 1.42-1.63 (4H, m), 1.94 (1H, dt, J1=10.2 Hz, J2=2.0 Hz), 2.25 (3H, s), 2.43 (1H, d, J=3.5 Hz), 2.59 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 2.93 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 3.65 (1H, d, J=13.4 Hz), 3.79 (1H, d, J=14.2 Hz), 4.15 (2H, q, J=7.1 Hz), 6.94 (1H, d, J=7.9 Hz), 6.98 (1H, d, J=10.9 Hz), 7.08 (1H, t, J=7.8 Hz). LC-MS (ESI) calcd for C18H24FNO2 305.18. found 305.9 [M+H+]. Upon cooling the mixture was filtered through Celite The filtrate was diluted with half-saturated aqueous sodium bicarbonate solution (50 mL) extracted with ethyl acetate (2×75 mL) The layers were separated the organic layer was washed with saturated aqueous brine solution dried over sodium sulfate filtered concentrated in vacuo Further purification by flash column chromatography (Teledyne Isco RediSep column; 1st column: 0 to 25% ethyl acetate in hexanes; 2nd column: 0 to 20% ethyl acetate in hexanes)

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

Procedure: To an ice-cold solution of 3-fluoro-4-methylbenzaldehyde (50 mg, 0.36 mmol) in THF (0.5 mL) was added dropwise a 0.93 M solution (0.47 mL) of methylmagnesium bromide (0.44 mmol) in THF. The temperature of the reaction mixture was allowed to rise back to room temperature, at which the reaction mixture was stirred for 1 hour. Then, 2 mol/L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to yield title compound as a pale yellow oil (55.8 mg, quantitative). to rise back to room temperature, at which the mixture was extracted with ethyl acetate The extract was washed with brine dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure

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

Procedure: To an ice-cold solution of 3-fluoro-4-methylbenzaldehyde (50 mg, 0.36 mmol) in THF (0.5 mL) was added dropwise a 0.93 M solution (0.47 mL) of methylmagnesium bromide (0.44 mmol) in THF. The temperature of the reaction mixture was allowed to rise back to room temperature, at which the reaction mixture was stirred for 1 hour. Then, 2 mol/L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to yield title compound as a pale yellow oil (55.8 mg, quantitative). to rise back to room temperature, at which the mixture was extracted with ethyl acetate The extract was washed with brine dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1S,2R,3S,4R)-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 300 mg, 1.637 mmol) was suspended in ethanol (5 mL). 3-Fluoro-4-methyl-benzaldehyde (0.2 mL, 1.637 mmol) was added followed by glacial acetic acid (0.1 mL, 3.724 mmol) and 4 Å powdered molecular sieves (0.6 g). Sodium cyanoborohydride (0.593 g, 9.406 mmol) was added and the mixture was stirred under nitrogen at 50° C. for 18 h. Upon cooling, the mixture was filtered through Celite. The filtrate was diluted with half-saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2×75 mL). The layers were separated and the organic layer was washed with saturated aqueous brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Further purification by flash column chromatography (Teledyne Isco RediSep column; 1st column. 0 to 25% ethyl acetate in hexanes; 2nd column: 0 to 20% ethyl acetate in hexanes) afforded the desired product, (1S,2R,3S,4R)-3-(3-fluoro-4-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (221 mg, 0.724 mmol, 44%), as a clear thick oil. 1H NMR (400 MHz, CDCl3) δ: 1.04-1.15 (2H, m), 1.21 (1H, d, J=10.1 Hz), 1.29 (3H, t, J=7.1 Hz), 1.42-1.63 (4H, m), 1.94 (1H, dt, J1=10.2 Hz, J2=2.0 Hz), 2.25 (3H, s), 2.43 (1H, d, J=3.5 Hz), 2.59 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 2.93 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 3.65 (1H, d, J=13.4 Hz), 3.79 (1H, d, J=14.2 Hz), 4.15 (2H, q, J=7.1 Hz), 6.94 (1H, d, J=7.9 Hz), 6.98 (1H, d, J=10.9 Hz), 7.08 (1H, t, J=7.8 Hz). LC-MS (ESI) calcd for C18H24FNO2 305.18, found 305.9 [M+H+]. Upon cooling the mixture was filtered through Celite The filtrate was diluted with half-saturated aqueous sodium bicarbonate solution (50 mL) extracted with ethyl acetate (2×75 mL) The layers were separated the organic layer was washed with saturated aqueous brine solution dried over sodium sulfate filtered concentrated in vacuo Further purification by flash column chromatography (Teledyne Isco RediSep column; 1st column. 0 to 25% ethyl acetate in hexanes; 2nd column: 0 to 20% ethyl acetate in hexanes)

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

Procedure: To ethanol (200 ml) was added portionwise 6.7 g sodium metal in such a way that the temperature stayed below 50° C. After all sodium had dissolved, the temperature was brought to −5° C. and a solution of 3-fluoro-4-methylbenzaldehyde (10.0 g, 0.072 mol) and azido acetic acid ethyl ester (37.4 g, 0.29 mol) in 100 ml ethanol was added while maintaining the temperature below 5° C. After 3 h the orange-red solution was poured on saturated aqueous ammonium chloride solution and ethyl acetate (300 ml) and water (100 ml) was added. The phases were separated, the aqueous phase was reextracted three times with ethyl acetate (300 ml each) and the combined organic layers were washed with brine (400 ml) and dried over magnesium sulfate. The crude reaction product was purified by column chromatography over silical gel (0.030–0.063 mm) with n-hexane/tert-butyl methyl ether (50/1) as eluent to yield the title product as a yellow oil (9.8 g, 54.2%). EI-MS: m/e=249.1 (M) stayed below 50° C was brought to −5° C. while maintaining the temperature below 5° C was added The phases were separated the combined organic layers were washed with brine (400 ml) dried over magnesium sulfate The crude reaction product was purified by column chromatography over silical gel (0.030–0.063 mm) with n-hexane/tert-butyl methyl ether (50/1) as eluent

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

Procedure: To ethanol (200 ml) was added portionwise 6.7 g sodium metal in such a way that the temperature stayed below 50° C. After all sodium had dissolved, the temperature was brought to −5° C. and a solution of 3-fluoro-4-methylbenzaldehyde (10.0 g, 0.072 mol) and azido acetic acid ethyl ester (37.4 g, 0.29 mol) in 100 ml ethanol was added while maintaining the temperature below 5° C. After 3 h the orange-red solution was poured on saturated aqueous ammonium chloride solution and ethyl acetate (300 ml) and water (100 ml) was added. The phases were separated, the aqueous phase was reextracted three times with ethyl acetate (300 ml each) and the combined organic layers were washed with brine (400 ml) and dried over magnesium sulfate. The crude reaction product was purified by column chromatography over silical gel (0.030–0.063 mm) with n-hexane/tert-butyl methyl ether (50/1) as eluent to yield the title product as a yellow oil (9.8 g, 54.2%). EI-MS: m/e=249.1 (M) stayed below 50° C was brought to −5° C. while maintaining the temperature below 5° C was added The phases were separated the combined organic layers were washed with brine (400 ml) dried over magnesium sulfate The crude reaction product was purified by column chromatography over silical gel (0.030–0.063 mm) with n-hexane/tert-butyl methyl ether (50/1) as eluent