2-Fluorobenzohydrazide

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 suspension of 15.2 g (0.058 mol) 2-(phenylsulfonyl)-ethanimidic acid ethyl ester hydrochloride in 160 ml chloroform was treated with 57.7 ml 1N aqueous sodium hydoxide. 80 ml of a saturated aqueous sodiumbicarbonate solution was added and the mixture was extracted with chloroform. The extracts were combined and dried with sodium sulfate and the solvents were distilled off under reduced pressure. The resulting colorless oil was stirred together with 9.98 g (0.063 mol) 2-fluorobenzoic acid hydrazide in 65 ml chloroform over io night at 50° C. The resulting precipitate was filtered off and dried. A yield of 14.6 g 2-fluoro-benzoic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide was obtained as white solid. MS m/e (%): 336 (M+H+, 100). the mixture was extracted with chloroform dried with sodium sulfate the solvents were distilled off under reduced pressure The resulting precipitate was filtered off dried

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

Procedure: A suspension of 15.2 g (0.058 mol) 2-(phenylsulfonyl)-ethanimidic acid ethyl ester hydrochloride in 160 ml chloroform was treated with 57.7 ml 1N aqueous sodium hydoxide. 80 ml of a saturated aqueous sodiumbicarbonate solution was added and the mixture was extracted with chloroform. The extracts were combined and dried with sodium sulfate and the solvents were distilled off under reduced pressure. The resulting colorless oil was stirred together with 9.98 g (0.063 mol) 2-fluorobenzoic acid hydrazide in 65 ml chloroform over io night at 50° C. The resulting precipitate was filtered off and dried. A yield of 14.6 g 2-fluoro-benzoic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide was obtained as white solid. MS m/e (%): 336 (M+H+, 100). the mixture was extracted with chloroform dried with sodium sulfate the solvents were distilled off under reduced pressure The resulting precipitate was filtered off dried

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

Procedure: The product from step c) (10 g, 0.028 mol) was suspended in xylene (250 ml) with 2-fluorobenzoic hydrazide (4.7 g, 0.0231 mol) and heated under reflux for 3 h. After cooling, the reaction mixture was filtered and the solid produced was washed in the sinter funnel several times with dichloromethane then concentrated under vacuum to leave a solid (10.53 g). The product existed as a 1:1 mixture of 2 tautomers. 1H NMR (400 MHz, CDCl3) δ 2.37 (3H, s), 7.18-7.66 (12H, m), 8.06 (1H, s), 11.90 (0.5H, s), 13.78 (0.5H, s); MS (ES+) m/e 497 [MH]+. heated under reflux for 3 h After cooling the reaction mixture was filtered the solid produced was washed in the sinter funnel several times with dichloromethane then concentrated under vacuum

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of toluene-4-sulfonic acid 5-hydroxymethyl-1H-pyrazol-3-yl ester (25 g, 93 mmol) in chloroform (800 ml) was added manganese dioxide (40.3 g, 465 mmol) and the suspension was heated at 70° C. for 14 h. The reaction mixture was filtered through sand/silica and the plug of silica was then washed several times with 10% methanol/dichloromethane. The combined filtrates were concentrated under vacuum to give crude aldehyde (25 g). Some of the crude aldehyde (2 g, 7.6 mmol) and 2-fluorobenzoic hydrazide (1.16 g, 7.6 mmol) were suspended in xylene (60 ml) and heated together at reflux for 3 h. After cooling, the solid formed was collected by filtration and dried under vacuum at 80° C. to afford 2.7 g (94%) of the condensation product as a light brown solid. Some of this condensation product, which existed in nmr solution as a mixture of isomers (1 g, 2.5 mmol), was dissolved in Dowtherm A (100 ml) and heated at 180° C. for 72 h. The whole reaction solution was cooled and eluted through a silica gel column using 0 to 15% ethyl acetate/dichloromethane to give the title compound as a light tan solid (0.614 g, 64%); 1H NMR (360 MHz, CDCl3) δ 2.46 (3H, s), 6.73 (1H, s), 7.18-7.35 (4H, m), 7.61 (1H, m), 7.71 (1H, m), 7.82 (2H, d, J 8.3 Hz), 9.33 (1H, s). The reaction mixture was filtered through sand/silica the plug of silica was then washed several times with 10% methanol/dichloromethane The combined filtrates were concentrated under vacuum to give crude aldehyde (25 g) heated together at reflux for 3 h After cooling the solid formed was collected by filtration dried under vacuum at 80° C.

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of toluene-4-sulfonic acid 5-hydroxymethyl-1H-pyrazol-3-yl ester (25 g, 93 mmol) in chloroform (800 ml) was added manganese dioxide (40.3 g, 465 mmol) and the suspension was heated at 70° C. for 14 h. The reaction mixture was filtered through sand/silica and the plug of silica was then washed several times with 10% methanol/dichloromethane. The combined filtrates were concentrated under vacuum to give crude aldehyde (25 g). Some of the crude aldehyde (2 g, 7.6 mmol) and 2-fluorobenzoic hydrazide (1.16 g, 7.6 mmol) were suspended in xylene (60 ml) and heated together at reflux for 3 h. After cooling, the solid formed was collected by filtration and dried under vacuum at 80° C. to afford 2.7 g (94%) of the condensation product as a light brown solid. Some of this condensation product, which existed in nmr solution as a mixture of isomers (1 g, 2.5 mmol), was dissolved in Dowtherm A (100 ml) and heated at 180° C. for 72 h. The whole reaction solution was cooled and eluted through a silica gel column using 0 to 15% ethyl acetate/dichloromethane to give the title compound as a light tan solid (0.614 g, 64%); 1H NMR (360 MHz, CDCl3) δ 2.46 (3H, s), 6.73 (1H, s), 7.18-7.35 (4H, m), 7.61 (1H, m), 7.71 (1H, m), 7.82 (2H, d, J 8.3 Hz), 9.33 (1H, s). The reaction mixture was filtered through sand/silica the plug of silica was then washed several times with 10% methanol/dichloromethane The combined filtrates were concentrated under vacuum to give crude aldehyde (25 g) heated together at reflux for 3 h After cooling the solid formed was collected by filtration dried under vacuum at 80° C.

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

Procedure: A mixture of 3,6-dichloro-4-(1,1-dimethylethyl)pyridazine (20 g, 0.097 mol), 2-fluorobenzhydrazide (22.6 g, 0.145 mol) and triethylamine hydrochloride (20 g, 0.0145 mol) in dioxan (1.2 l) was stirred and heated at reflux under a stream of nitrogen for 4 days. Upon cooling the volatiles were removed in vacuo and the residue was triturated with dichloromethane (200 ml), filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel eluting with 0%→25% ethyl acetate/dichloromethane to give the title compound (12.95 g. 44%) as a white solid. Data for the title compound: 1H NMR (360 MHz, CDCl3) δ1.57 (9H, s), 7.26-7.35 (2H, m), 7.53-7.60 (1H, m), 7.89-7.93 (1H, m), 8.17 (1H, s); MS (ES+) m/e 305 [MH]+, 307 [MH]+. heated at reflux under a stream of nitrogen for 4 days Upon cooling the volatiles were removed in vacuo the residue was triturated with dichloromethane (200 ml) filtered concentrated under vacuum The residue was purified by chromatography on silica gel eluting with 0%→25% ethyl acetate/dichloromethane

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of toluene-4-sulfonic acid 5-acetyl-1H-pyrazol-3-yl ester (2.52 g, 8.99 mmol) and 2-fluorobenzhydrazide (1.53 g, 9.90 mmol) in xylene (110 ml) was heated at reflux for 17 h under nitrogen. The solvent was removed in vacuo, and the residue was heated in Dowtherm A at 180° C. for 18 h The mixture was poured directly onto a column of silica gel, which was eluted with dichloromethane, then 25% EtOAc/CH2Cl2, to give 3.40 g (95%) of the title compound as a brown solid: 1H NMR (360 MHz, CDCl3) δ 2.45 (3H, s), 2.83 (3H, s), 6.71 (1H, s), 7.18 (1H, t, J=9.5 Hz), 7.30 (2H, d, J=7.8 Hz), 7.31 (1H, m), 7.59 (1H, m), 7.66 (1H, m), 7.82 (2H, d, J=8.4 Hz); MS (ES+) m/e 399 [M+H]+. was heated at reflux for 17 h under nitrogen The solvent was removed in vacuo was poured directly onto a column of silica gel, which was eluted with dichloromethane

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Toluene-4-sulfonic acid 5-acetyl-4-cyclopentyl-1H-pyrazol-3-yl ester (0.65 g, 1.87 mmol) and 2-fluorobenzhydrazide (0.317 g, 1.1 molar eq) were stirred together in xylene (20 ml) at reflux for 2 h. The solvent was reduced to ˜5 ml and Dowtherm A (20 ml) was added and the reaction mixture was heated at 180° C. for 3 h. The mixture was cooled and poured directly onto a column of silica gel, and the Dowtherm was eluted off with dichloromethane before eluting the product off with 3-5% ethyl acetate in dichloromethane (UV detection). Toluene-4-sulfonic acid 3-cyclopentyl-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester was obtained as a light brown solid (0.5 g). 1H NMR (360 MHz, CDCl3) δ 1.72-2.06 (8H, m), 2.42 (8H, s), 2.91 (3H, 8), 3.46 (1H, m), 7.16-7.33 (4H, m), 7.58-7.65 (2H, m), 7.84 (2H, d, J=8.7 Hz); MS (ES+) m/e 467 [MH]+. at reflux for 2 h was added The mixture was cooled poured directly onto a column of silica gel the Dowtherm was eluted off with dichloromethane before eluting the product off with 3-5% ethyl acetate in dichloromethane (UV detection)

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Toluene-4-sulfonic acid 5-acetyl-4-cyclopentyl-1H-pyrazol-3-yl ester (0.65 g, 1.87 mmol) and 2-fluorobenzhydrazide (0.317 g, 1.1 molar eq) were stirred together in xylene (20 ml) at reflux for 2 h. The solvent was reduced to ˜5 ml and Dowtherm A (20 ml) was added and the reaction mixture was heated at 180° C. for 3 h. The mixture was cooled and poured directly onto a column of silica gel, and the Dowtherm was eluted off with dichloromethane before eluting the product off with 3-5% ethyl acetate in dichloromethane (UV detection). Toluene-4-sulfonic acid 3-cyclopentyl-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester was obtained as a light brown solid (0.5 g). 1H NMR (360 MHz, CDCl3) δ 1.72-2.06 (8H, m), 2.42 (8H, s), 2.91 (3H, 8), 3.46 (1H, m), 7.16-7.33 (4H, m), 7.58-7.65 (2H, m), 7.84 (2H, d, J=8.7 Hz); MS (ES+) m/e 467 [MH]+. at reflux for 2 h was added The mixture was cooled poured directly onto a column of silica gel the Dowtherm was eluted off with dichloromethane before eluting the product off with 3-5% ethyl acetate in dichloromethane (UV detection)

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Toluene-4-sulfonic acid 5-acetyl-4-(2-fluorophenyl)-1H-pyrazol-3-yl ester (8.26 g, 22.1 mmol) and 2-fluorobenzhydrazide (3.86 g, 25.0 mmol) were stirred together in xylene (250 ml) at reflux overnight. The solvent was removed in vacuo, and the residue was heated in Dowtherm A at 180° C. for 2 h. The mixture was poured directly onto a column of silica gel, and the Dowtherm was eluted off with dichloromethane before eluting the product off with 10% ethyl acetate in dichloromethane (UV detection). Toluene-4-sulfonic acid 3,7-bis(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester was obtained as a yellow solid (6.62 g). 1H NMR (400 MHz, CDCl3) δ 2.43 (3H, s), 2.53 (3H, s), 7.17-7.37 (6H, m), 7.41-7.51 (2H, m), 7.63 (1H, m), 7.69 (3H, m); MS (ES+) m/e 493 [MH]+. at reflux overnight The solvent was removed in vacuo The mixture was poured directly onto a column of silica gel the Dowtherm was eluted off with dichloromethane before eluting the product off with 10% ethyl acetate in dichloromethane (UV detection)