3-(4-fluorophenyl)propanal

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 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 609 mg (4.0 mmol) of 3-(4-fluorophenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 4.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 0.88 g (64.2%, yellow oily substance) of the desired product. by refluxing for 4.5 hours After the reaction mixture was cooled the solvent was distilled off The residue was dissolved in dichloromethane washed with purified water dried after which the solvent was distilled off The residue was purified by column chromatography (eluent, chloroform/methanol=50/1)

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

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

Procedure: A mixture of 1-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-piperidin-3-ylmethylurea hydrochloride (35 mg, 100 μmol), 3-(4-fluorophenyl)-propionaldehyde (15 mg, 100 μmol), triethylamine (15 μL, 110 μmol), resin-bound cyanoborohydride (prepared according to Ley, S. V., et al., J. Chem. Soc. Perkin Trans. 1, 1998, 2239; 100 mg), toluene (1 mL) and methanol (1 mL) was agitated gently at room temperature for 65 hours. The mixture was filtered, the resin was washed with dichloromethane, and the filtrates were concentrated. The residue was purified by flash chromatography, eluting with 4% methanol in dichloromethane containing 0.4% aqueous ammonium hydroxide, to provide an amorphous white solid (29 mg, 64%). 1H NMR (300 MHz, CDCl3) δ7.88 (s, 1H), 7.79 (d, J=8 Hz, 1H), 7.44 (t, J=8 Hz, 1H), 7.27 (m, 1H), 7.11 (m, 2H), 6.93 (t, J=9 Hz, 2H), 4.18 (s, 3H), 3.2-3.0 (m, 4H), 2.59 (m, 4H), 2.3-1.8 (m, 8H), 1.10 (m, 1H). Mass Spec (ES+) m/z 452.4 (M+H+, 100%). The mixture was filtered the resin was washed with dichloromethane the filtrates were concentrated The residue was purified by flash chromatography eluting with 4% methanol in dichloromethane containing 0.4% aqueous ammonium hydroxide

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

Procedure: A mixture of 1-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-piperidin-3-ylmethylurea hydrochloride (35 mg, 100 μmol), 3-(4-fluorophenyl)-propionaldehyde (15 mg, 100 μmol), triethylamine (15 μL, 110 μmol), resin-bound cyanoborohydride (prepared according to Ley, S. V., et al., J. Chem. Soc. Perkin Trans. 1, 1998, 2239; 100 mg), toluene (1 mL) and methanol (1 mL) was agitated gently at room temperature for 65 hours. The mixture was filtered, the resin was washed with dichloromethane, and the filtrates were concentrated. The residue was purified by flash chromatography, eluting with 4% methanol in dichloromethane containing 0.4% aqueous ammonium hydroxide, to provide an amorphous white solid (29 mg, 64%). 1H NMR (300 MHz, CDCl3) δ7.88 (s, 1H), 7.79 (d, J=8 Hz, 1H), 7.44 (t, J=8 Hz, 1H), 7.27 (m, 1H), 7.11 (m, 2H), 6.93 (t, J=9 Hz, 2H), 4.18 (s, 3H), 3.2-3.0 (m, 4H), 2.59 (m, 4H), 2.3-1.8 (m, 8H), 1.10 (m, 1H). Mass Spec (ES+) m/z 452.4 (M+H+, 100%). The mixture was filtered the resin was washed with dichloromethane the filtrates were concentrated The residue was purified by flash chromatography eluting with 4% methanol in dichloromethane containing 0.4% aqueous ammonium hydroxide

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of oxalyl chloride (1.32 mL, 15.1 mmol) in dichloromethane (40 mL) was stirred at −78° C. and treated dropwise with dimethyl sulfoxide (2.21 mL, 31.1 mL) over 5 minutes. The resulting solution was stirred for 35 minutes at −78° C. A solution of 3-(4-fluorophenyl)-propan-1-ol (1.50 g, 9.73 mmol) in dichloromethane (12 mL) was added over 5 minutes, and stirring continued at the same temperature for 50 minutes. Triethylamine (4.41 mL, 31.6 mmol) was added, and the cooling bath was replaced by an ice-water bath. The resulting slurry was stirred for one hour, then was diluted with dichloromethane. The resulting mixture was washed with half-saturated aqueous ammonium chloride, then with saturated sodium chloride, dried over sodium sulfate, and concentrated under vacuum. The resulting orange oil was distilled in a short-path apparatus at 50° C. and 0.2 Torr pressure to provide a colorless liquid (764 mg, 50%). 1H NMR (300 MHz, CDCl3) δ9.83 (t, J=1 Hz, 1H), 7.17 (m, 2H), 6.99 (t, J=9 Hz, 2H), 2.95 (t, J=7 Hz, 2H), 2.79 (tt, J=7, 1 Hz, 2H). stirring continued at the same temperature for 50 minutes the cooling bath was replaced by an ice-water bath The resulting slurry was stirred for one hour The resulting mixture was washed with half-saturated aqueous ammonium chloride with saturated sodium chloride, dried over sodium sulfate concentrated under vacuum The resulting orange oil was distilled in a short-path apparatus at 50° C.

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

Procedure: 71.7 g (0.51 mol) of 2-chlorobenzaldehyde are added to a solution of 4 g of 50% strength sodium hydroxide solution in 300 ml of methanol while cooling, at a rate such that the temperature does not exceed 20° C. 70.0 g (0.46 mol) of p-fluorodihydrocinnamaldehyde are then added dropwise at 25°-30° C. in the course of 4 hours. Stirring is continued for one hour at 30° C., the mixture is neutralized with dilute sulfuric acid and evaporated down and the residue is distilled. while cooling, at a rate such that the temperature does not exceed 20° C evaporated down the residue is distilled

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

Procedure: To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 609 mg (4.0 mmol) of 3-(4-fluorophenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 4.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 0.88 g (64.2%, yellow oily substance) of the desired product. by refluxing for 4.5 hours After the reaction mixture was cooled the solvent was distilled off The residue was dissolved in dichloromethane washed with purified water dried after which the solvent was distilled off The residue was purified by column chromatography (eluent, chloroform/methanol=50/1)

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

Procedure: To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 609 mg (4.0 mmol) of 3-(4-fluorophenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 4.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 0.88 g (64.2%, yellow oily substance) of the desired product. by refluxing for 4.5 hours After the reaction mixture was cooled the solvent was distilled off The residue was dissolved in dichloromethane washed with purified water dried after which the solvent was distilled off The residue was purified by column chromatography (eluent, chloroform/methanol=50/1)

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

Procedure: Reaction of 3-(4-fluorophenyl)-propionaldehyde (Dickinson, R. P.; Dack, K. N.; Steele, J.; Tute, M. S. Bioorg. Med. Chem. Lett., 6, 14, 1996, 1691-1696) with methoxylamine hydrochloride as described in the preparation of compound 1-A gave the title oxime ether as a clear oil (97% yield), bp 65-75° C./1.5 torr (bulb to bulb distillation, air bath temperature). 1HNMR indicated a 6:4 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.51 and 2.65 (2H, 2 m, CH2), 2.8 (2H, m, CH2), 3.84 and 3.88 (3H, 2 s, OCH3), 6.67 (t, J=5.5 Hz, CH), 7.0 (2H, m, aromatics), 7.16 (2H, m, aromatics), 7.40 (t, J=4.2 Hz, CH). gave

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

Procedure: Reaction of 3-(4-fluorophenyl)-propionaldehyde (Dickinson, R. P.; Dack, K. N.; Steele, J.; Tute, M. S. Bioorg. Med. Chem. Lett., 6, 14, 1996, 1691-1696) with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (97% yield), bp 65-75° C./1.5 torr (bulb to bulb distillation, air bath temperature). 1HNMR indicated a 6:4 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.51 and 2.65 (2H, 2 m, CH2), 2.8 (2H, m, CH2), 3.84 and 3.88 (3H, 2 s, OCH3), 6.67 (t, J=5.5 Hz, CH), 7.0 (2H, m, aromatics), 7.16 (2H, m, aromatics), 7.40 (t, J=4.2 Hz, CH). gave

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

Procedure: A solution of 3-(4-fluorophenyl)propanal (7.0 g) in ether (50 ml) was addedto a stirred suspension of 4-nitrophenylhydrazine (7.0 g) in ether (1 50 ml), followed by sufficient ethyl acetate to achieve a clear solution. Thesolution was filtered and evaporated and the residue was crystallised from ethyl acetate/hexane to give the title compound (5.48 g), m.p. 125°-127° C. Found: C,62.81; H,4.87; N,14.44. C15 H14FN3O2 requires: C,62.71; H,4.91; N,14.63%. Thesolution was filtered evaporated the residue was crystallised from ethyl acetate/hexane