2-hydroxy-3-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:0.00; pressure:0.00; stir:

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

Procedure: A 1.04 M THF solution of t-BuOK (3.7 mL, 3.9 mmol) was added to a THF solution (0.5 mL) of 2-hydroxy-3-methylbenzaldehyde (500 mg, 3.7 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (1.16 g, 3.9 mmol) and the reaction was stirred at room temperature. After 30 min the temperature was increased to 40° C. After 5 min the resulting mixture was partitioned with DCM and water, and the aqueous layer was extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated to yield a 4:1 w/w mixture of the title compound and starting material, which mixture was used in the next step without further purification. After 30 min the temperature was increased to 40° C After 5 min the resulting mixture was partitioned with DCM and water the aqueous layer was extracted with DCM The combined organic layers were dried (Na2SO4) concentrated to yield

Conditions: temp:177.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The suspension of 2-Hydroxy-3-methyl benzaldehyde (30 gm, 0.220 mole) and anhydrous Sodium acetate (45 gm, 0.55 mole) in Acetic anhydride (45 gm, 0.44 mole) was heated at 175-180° C. for 6 hours. The reaction mixture was cooled; water (150 ml) and Hexane (60 ml) were added. It was stirred for an hour and filtered. The obtained solid was stirred with Diethyl ether (30 ml). Finally the suspension was filtered and dried to give 19 gm desired product. The reaction mixture was cooled filtered The obtained solid was stirred with Diethyl ether (30 ml) Finally the suspension was filtered dried

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

Procedure: To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 2-hydroxy-3-methylbenzaldehyde (0.25 mmol), methanol (1.0 mL), and acetic acid (0.040 mL) was added NaBH3CN (0.40 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. The resulting material was dissolved into ethyl acetate/methanol=5:1 (1 mL), loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=5:1 (5 mL), and concentrated. The residue was dissolved in methanol (2 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. Preparative TLC afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(2-hydroxy-3-methylbenzyl)piperidine (Compound No. 2106): The purity was determined by RPLC/MS (97%); ESI/MS m/e 447.0 (M++H, C23H28F2N4O3). The mixture was cooled to room temperature washed with CH3OH (5 mL×2) Product was eluted off concentrated The resulting material was dissolved into ethyl acetate/methanol=5:1 (1 mL) eluted off concentrated The residue was dissolved in methanol (2 mL) 4 N HCl in dioxane (0.50 mL) was added The solution was stirred at room temperature overnight concentrated The residue was dissolved in methanol washed with CH3OH (5 mL×2) Product was eluted off concentrated

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

Procedure: To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 2-hydroxy-3-methylbenzaldehyde (0.25 mmol), methanol (1.0 mL), and acetic acid (0.040 mL) was added NaBH3CN (0.40 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. The resulting material was dissolved into ethyl acetate/methanol=5:1 (1 mL), loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=5:1 (5 mL), and concentrated. The residue was dissolved in methanol (2 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. Preparative TLC afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(2-hydroxy-3-methylbenzyl)piperidine (Compound No. 2106): The purity was determined by RPLC/MS (97%); ESI/MS m/e 447.0 (M++H, C23H28F2N4O3). The mixture was cooled to room temperature washed with CH3OH (5 mL×2) Product was eluted off concentrated The resulting material was dissolved into ethyl acetate/methanol=5:1 (1 mL) eluted off concentrated The residue was dissolved in methanol (2 mL) 4 N HCl in dioxane (0.50 mL) was added The solution was stirred at room temperature overnight concentrated The residue was dissolved in methanol washed with CH3OH (5 mL×2) Product was eluted off concentrated

Conditions: temp:177.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The suspension of 2-Hydroxy-3-methyl benzaldehyde (30 gm, 0.220 mole) and anhydrous Sodium acetate (45 gm, 0.55 mole) in Acetic anhydride (45 gm, 0.44 mole) was heated at 175-180° C. for 6 hours. The reaction mixture was cooled; water (150 ml) and Hexane (60 ml) were added. It was stirred for an hour and filtered. The obtained solid was stirred with Diethyl ether (30 ml). Finally the suspension was filtered and dried to give 19 gm desired product. The reaction mixture was cooled filtered The obtained solid was stirred with Diethyl ether (30 ml) Finally the suspension was filtered dried

Conditions: temp:177.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The suspension of 2-Hydroxy-3-methyl benzaldehyde (30 gm, 0.220 mole) and anhydrous Sodium acetate (45 gm, 0.55 mole) in Acetic anhydride (45 gm, 0.44 mole) was heated at 175-180° C. for 6 hours. The reaction mixture was cooled; water (150 ml) and Hexane (60 ml) were added. It was stirred for an hour and filtered. The obtained solid was stirred with Diethyl ether (30 ml). Finally the suspension was filtered and dried to give 19 gm desired product. The reaction mixture was cooled filtered The obtained solid was stirred with Diethyl ether (30 ml) Finally the suspension was filtered dried

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-hydroxy-3-methylbenzaldehyde (10.2 g, 75.0 mmoles, Aldrich), bromoacetonitrile (5.70 mL, 82.5 mmoles), and potassium carbonate (11.4 g, 82.5 mmoles) in DMF (150 mL) is heated to 55° C. for 3 hours, cooled, then diluted with ether. The mixture is washed with distilled water, saturated NaCl solution, then the organic layer dried over MgSO4 and concentrated to give the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 10.20 (s, 1H), 7.70 (d, 1H), 7.53 (d, 1H), 7.29 (m, 1H), 4.81 (s, 2H), 2.42 (s, 3H). cooled The mixture is washed with distilled water, saturated NaCl solution the organic layer dried over MgSO4 concentrated