3-hydroxybenzohydrazide

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: 3-hydroxybenzoic acid hydrazide (2.98 g, 19.58 mmol) and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl]isothiourea hydroiodide (7.78 g, 19.63 mmol) were suspended in 40 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours, during which time it changed color from yellow into dark-red. Then it was cooled down to ambient temperature and poured with stirring into 250 mL of ice-water. The aqueous solution was decanted and the oily residue was purified by silica gel chromatography on Isco column using 0=>50% gradient of ethyl acetate in hexane. Solvent was removed in vacuo to give the title product as a white solid (2.176 g). 31.3% yield. The reaction mixture was refluxed for 18 hours, during which time it poured The aqueous solution was decanted the oily residue was purified by silica gel chromatography on Isco column Solvent was removed in vacuo

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (Preparation 5(B) (177 mg, 0.466 mmol) in glacial acetic acid (4 mL) was added 3-hydroxy benzhydrazide (90 mg, 0.591 mmol). The reaction was heated to 120° C. for 3 hours, was cooled to room temperature, and was concentrated in vacuo. The residue was triturated with 50% Et2O in hexanes and the solids were filtered. The solids were dissolved in CH2Cl2 and the organic solution was washed with aqueous NaHCO3, dried (MgSO4) and concentrated to provide 244 mg of 2-[1-(3-hydroxy-phenyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD3OD) δ7.74 (s, 2H), 7.56-7.18 (m, 10H), 6.91 (m, 1H), 4.86 (m, 1H), 4.30-4.10 (m, 2H), 3.98 (d, 1H), 3.71 (d, 1H), 1.06 (m, 6H). was cooled to room temperature was concentrated in vacuo The residue was triturated with 50% Et2O in hexanes the solids were filtered The solids were dissolved in CH2Cl2 the organic solution was washed with aqueous NaHCO3 dried (MgSO4) concentrated

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (Preparation 5(B) (177 mg, 0.466 mmol) in glacial acetic acid (4 mL) was added 3-hydroxy benzhydrazide (90 mg, 0.591 mmol). The reaction was heated to 120° C. for 3 hours, was cooled to room temperature, and was concentrated in vacuo. The residue was triturated with 50% Et2O in hexanes and the solids were filtered. The solids were dissolved in CH2Cl2 and the organic solution was washed with aqueous NaHCO3, dried (MgSO4) and concentrated to provide 244 mg of 2-[1-(3-hydroxy-phenyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD3OD) δ7.74 (s, 2H), 7.56-7.18 (m, 10H), 6.91 (m, 1H), 4.86 (m, 1H), 4.30-4.10 (m, 2H), 3.98 (d, 1H), 3.71 (d, 1H), 1.06 (m, 6H). was cooled to room temperature was concentrated in vacuo The residue was triturated with 50% Et2O in hexanes the solids were filtered The solids were dissolved in CH2Cl2 the organic solution was washed with aqueous NaHCO3 dried (MgSO4) concentrated

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (Preparation 5(B) (177 mg, 0.466 mmol) in glacial acetic acid (4 mL) was added 3-hydroxy benzohydrazide (90 mg, 0.591 mmol). The reaction was heated to 120° C. for 3 hours, was cooled to room temperature, and was concentrated in vacuo. The residue was triturated with 50% Et2O in hexanes and the solids were filtered. The solids were dissolved in CH2Cl2 and the organic solution was washed with aqueous NaHCO3, dried (MgSO4) and concentrated to provide 244 mg of 2-[1-(3-hydroxy-phenyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD3OD) δ 7.74 (s, 2H), 7.56-7.18 (m, 10H), 6.91 (m, 1H), 4.86 (m, 1H), 4.30-4.10 (m, 2H), 3.98 (d, 1H), 3.71 (d, 1H), 1.06 (m, 6H). was cooled to room temperature was concentrated in vacuo The residue was triturated with 50% Et2O in hexanes the solids were filtered The solids were dissolved in CH2Cl2 the organic solution was washed with aqueous NaHCO3 dried (MgSO4) concentrated

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

Procedure: 3-hydroxybenzoic acid hydrazide (2.98 g, 19.58 mmol) and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl]isothiourea hydroiodide (7.78 g, 19.63 mmol) were suspended in 40 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours, during which time it changed color from yellow into dark-red. Then it was cooled down to ambient temperature and poured with stirring into 250 mL of ice-water. The aqueous solution was decanted and the oily residue was purified by silica gel chromatography on Isco column using 0=>50% gradient of ethyl acetate in hexane. Solvent was removed in vacuo to give the title product as a white solid (2.176 g). 31.3% yield. The reaction mixture was refluxed for 18 hours, during which time it poured The aqueous solution was decanted the oily residue was purified by silica gel chromatography on Isco column Solvent was removed in vacuo

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3-hydroxybenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 133 mg of the title compound (65%) as a yellow solid in 99.4% purity by HPLC (Rt: 4.83, gradient of 10 min, MaxPlot detection between 230 and 400 nm). the reaction mixture was cooled to rt a yellow solid precipitated out Filtration on a fritté washing with AcOH, water drying under vacuo at 60° C. overnight

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

Procedure: (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (663 mg, 2.5 mmol) (intermediate 3a) and 3-hydroxy-benzohydrazide (376 mg, 2.5 mmol) were coupled similarly to the procedure used for intermediate 1b. After column chromatography (5% methanol/EtOAc) the title compound was isolated as a white solid (615 mg, 62%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.79 (br s, 1H), 8.81 (br s, 1H), 7.45 (ad, J=8.7 Hz, 1H), 7.38 (m, 2H), 7.27 (t, J=7.87 Hz, 1H), 7.02 (m, 1H), 6.71 (d, J=8.7 Hz, 1H), 5.61 (m, 1H), 4.23 (m, 1H), 4.14 (m, 1H), 2.29 (s, 3H), 1.37 (d, J=6.5 Hz, 3H).

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

Procedure: (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (663 mg, 2.5 mmol) (intermediate 3a) and 3-hydroxy-benzohydrazide (376 mg, 2.5 mmol) were coupled similarly to the procedure used for intermediate 1b. After column chromatography (5% methanol/EtOAc) the title compound was isolated as a white solid (615 mg, 62%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.79 (br s, 1H), 8.81 (br s, 1H), 7.45 (ad, J=8.7 Hz, 1H), 7.38 (m, 2H), 7.27 (t, J=7.87 Hz, 1H), 7.02 (m, 1H), 6.71 (d, J=8.7 Hz, 1H), 5.61 (m, 1H), 4.23 (m, 1H), 4.14 (m, 1H), 2.29 (s, 3H), 1.37 (d, J=6.5 Hz, 3H).

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

Procedure: Intermediate 7a was synthesized similarly to the procedure outlined for intermediate 1b described above using (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (522 mg, 1.9 mmol) and 3-hydroxy-benzohydrazide (296 mg, 1.9 mmol). After column chromatography (EtOAc), the title compound was isolated as a white solid (407 mg, 52%). 1H NMR (400 MHz, acetone-d6, δ in ppm) δ 9.80 (br s, 1H), 9.52 (br s, 1H), 8.76 (br s, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.40 (m, 1H), 7.29 (at, J=8.1 Hz, 1H), 7.04 (m, 1H), 6.66 (d, J=8.7 Hz, 1H), 5.55 (d, J=7.1 Hz, 1H), 4.89 (br s, 1H), 4.39 (m, 1H), 4.11 (dd, J=3.3, 7.0 Hz, 1H), 2.35 (s, 3H), 1.34 (d, J=6.5 Hz, 3H). Intermediate 7a was synthesized similarly to the procedure