2-chloro-1-oxidopyridin-1-ium;hydrochloride

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

Procedure: Sodium hydride (0.68 g, 60% in mineral oil) was added to a solution of 2-ethyl-2-trifluoromethyl-6-nitro-3,4-dihydro-2H-1,4-benzoxazine (0.235 g), 2-chloropyridine-N-oxide hydrochloride (0.142 g), and dimethylsulfoxide (10 mL) and stirred at room temperature overnight. The mixture was quenched with saturated ammonium chloride/water and extracted into ethyl acetate. The organic extract was washed (water, brine) dried, decolorized (charcoal), filtered (celite) and evaporated. Chromatography, eluting successively with dichloromethane, ethyl acetate, and then methanol, gave the title compound as a yellow solid (0.11 g); mp 59°-62° C.; NMR: 0.95 (t,3), 2.04 (q), 4.05 (d,d), 7.01 (s,1), 7.25 (d) 7.45 (m,2), 7.63 (d), 7.76 (d), 8.41 (d,1); MS: m/z=370(M+1). Analysis for C16H14F3N3O4 : Calculated: C, 52.04; H, 3.82; N, 11.38; Found: C, 51.95; 3.98; N, 11.10. The mixture was quenched with saturated ammonium chloride/water extracted into ethyl acetate The organic extract was washed (water, brine) dried filtered (celite) evaporated Chromatography, eluting successively with dichloromethane, ethyl acetate

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

Procedure: A mixture of mono-Boc-1,2-ethylenediamine (5.83 g, 36.39 mmole), 2-chloropyridine-N-oxide hydrochloride (7.25 g, 43.67 mmole), NaHCO3 (15.29 g, 182 mmole), and tert-amyl alcohol (36 mL) was heated at reflux. After 47 hr, the dark brown mixture was cooled, diluted with CH2Cl2 (100 mL), and suction filtered to remove insoluble materials. The filtrate was concentrated and reconcentrated from toluene. Silica gel chromatography (10% MeOHICHCl3) gave impure title compound (8.23 g, 89%) as a yellow solid which was used without further purification: TLC (10% MeOH/CHCl3) Rf 0.42; 1H NMR (250, CDCl3) δ 8.16 (dd, J=6.5, 1.3 Hz, 1 H), 7.05-7.30 (m, 2 H), 6.68 (br d, J=8.6 Hz, 1 H), 6.50-6.65 (m, 1 H), 5.70-5.95 (m, 1 H), 3.25-3.60 (m, 4 H), 1.44 (s, 9 H); MS (ES) m/e 254 (M+H)+. was heated at reflux the dark brown mixture was cooled filtered to remove insoluble materials The filtrate was concentrated

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

Procedure: Ethyl 1-(2-aminoethyl)-1H-indazole-5-carboxylate (584 mg, 2.5 mmol, prepared as in step B), was added to dry n-butanol along with 2-chloropyridine-N-oxide hydrochloride (847 mg, 5.1 mmol) and anhydrous sodium bicarbonate (850 mg, 10.1 mmol). The reaction mixture was vigorously stirred and heated at 100C for 21 hr. Additional aliquots of 2-chloropyridine-N-oxide hydrochloride (847 mg, 5.1 mmol) and anhydrous sodium bicarbonate (850 mg, 10.1 mmol) were added and heating continued for 24 hours. The reaction was cooled and filtered and the filtrate concentrated. The residue was purified by flash chromatography (5% methanol-dichloromethane) and the product fractions concentrated to afford the product as an orange solid (358 mg, 44%). LRMS (ES): 327.1 ([M+H]+, 100%), 653.3 ([2M+H]+, 40%) 1HNMR (600.1343 MHz, CDCl3): 8.44 (s, 1H), 8.12 (s, 1H), 7.97 (d of t, 2H), 7.56 (bs, 1H), 7.45 (d, 1H), 7.06, (m, 1H), 6.45 (m, 1H), 6.35 (t, 1H), 4.68 (t, 2H), 4.37 (q, 2H), 3.90 (q, 2H), 1.39 (t, 3H). heating The reaction was cooled filtered the filtrate concentrated The residue was purified by flash chromatography (5% methanol-dichloromethane) the product fractions concentrated

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

Procedure: A mixture of 4-amino-1-butanol (2.0 mL, 21.7 mmole), 2-chloropyridine-N-oxide hydrochloride (3.00 g, g, 18.0 mmole), NaHCO3 (7.56 g, 90.0 mmole), and tert-amyl alcohol (22 mL) was heated at reflux. After 24 hr, the mixture was cooled and filtered, then the filtrate was concentrated under reduced pressure. Silica gel chromatography (10% MeOH/CHCl3) gave the title compound (2.08 g, 63%) as a yellow solid: MS (ES) m/e 183 (M+H)+. was heated at reflux the mixture was cooled filtered the filtrate was concentrated under reduced pressure

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

Procedure: A mixture of mono-Boc-1,2-ethylenediamine (5.83 g, 36.39 mmole), 2-chloropyridine-N-oxide hydrochloride (7.25 g, 43.67 mmole), NaHCO3 (15.29 g, 182 mmole), and tert-amyl alcohol (36 mL) was heated at reflux. After 47 hr, the dark brown mixture was cooled, diluted with CH2Cl2 (100 mL), and suction filtered to remove insoluble materials. The filtrate was concentrated and reconcentrated from toluene. Silica gel chromatography (10% MeOH/CHCl3) gave impure title compound (8.23 g, 89%) as a yellow solid which was used without further purification: TLC (10% MeOH/CHCl3) Rf 0.42; 1H NMR (250, CDCl3) δ 8.16 (dd, J=6.5, 1.3 Hz, 1H), 7.05-7.30 (m, 2H), 6.68 (br d, J=8.6 Hz, 1H), 6.50-6.65 (m, 1H), 5.70-5.95 (m, 1H), 3.25-3.60 (m, 4H), 1.44 (s, 9H); MS (ES) m/e 254 (M+H)+. was heated at reflux the dark brown mixture was cooled filtered to remove insoluble materials The filtrate was concentrated

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

Procedure: A mixture of mono-Boc-1,2-ethylenediamine (5.83 g, 36.39 mmole), 2-chloropyridine-N-oxide hydrochloride (7.25 g, 43.67 mmole), NaHCO3 (15.29 g, 182 mmole), and tert-amyl alcohol (36 mL) was heated at reflux. After 47 hr, the dark brown mixture was cooled, diluted with CH2Cl2 (100 mL), and suction filtered to remove insoluble materials. The filtrate was concentrated and reconcentrated from toluene. Silica gel chromatography (10% MeOH/CHCl3) gave impure title compound (8.23 g, 89%) as a yellow solid which was used without further purification: TLC (10% MeOH/CHCl3) Rf 0.42; 1H NMR (250, CDCl3) δ 8.16 (dd, J=6.5, 1.3 Hz, 1 H), 7.05-7.30 (m, 2 H), 6.68 (br d, J=8.6 Hz, 1 H), 6.50-6.65 (m, 1 H), 5.70-5.95 (m, 1 H), 3.35-3.60 (m, 4 H), 1.44 (s, 9 H); MS (ES) m/e 254 (M+H)+. was heated at reflux the dark brown mixture was cooled filtered to remove insoluble materials The filtrate was concentrated

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

Procedure: Sodium hydride (0.68 g, 60% in mineral oil) was added to a solution of 2-ethyl-2-trifluoromethyl-6-nitro-3,4-dihydro-2H-1,4-benzoxazine (0.235 g), 2-chloropyridine-N-oxide hydrochloride (0.142 g), and dimethylsulfoxide (10 mL) and stirred at room temperature overnight. The mixture was quenched with saturated ammonium chloride/water and extracted into ethyl acetate. The organic extract was washed (water, brine) dried, decolorized (charcoal), filtered (celite) and evaporated. Chromatography, eluting successively with dichloromethane, ethyl acetate, and then methanol, gave the title compound as a yellow solid (0.11 g); mp 59°-62° C.; NMR: 0.95 (t,3), 2.04 (q), 4.05 (d,d), 7.01 (s,1), 7.25 (d) 7.45 (m,2), 7.63 (d), 7.76 (d), 8.41 (d,1); MS: m/z=370(M+1). Analysis for C16H14F3N3O4 : Calculated: C, 52.04; H, 3.82; N, 11.38; Found: C, 51.95; 3.98; N, 11.10. The mixture was quenched with saturated ammonium chloride/water extracted into ethyl acetate The organic extract was washed (water, brine) dried filtered (celite) evaporated Chromatography, eluting successively with dichloromethane, ethyl acetate

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

Procedure: Ethyl 1-(2-aminoethyl)-1H-indazole-5-carboxylate (584 mg, 2.5 mmol, prepared as in step B), was added to dry n-butanol along with 2-chloropyridine-N-oxide hydrochloride (847 mg, 5.1 mmol) and anhydrous sodium bicarbonate (850 mg, 10.1 mmol). The reaction mixture was vigorously stirred and heated at 100 C for 21 hr. Additional aliquots of 2-chloropyridine-N-oxide hydrochloride (847 mg, 5.1 mmol) and anhydrous sodium bicarbonate (850 mg, 10.1 mmol) were added and heating continued for 24 hours. The reaction was cooled and filtered and the filtrate concentrated. The residue was purified by flash chromatography (5% methanol-dichloromethane) and the product fractions concentrated to afford the product as an orange solid (358 mg, 44%). LRMS (ES): 327.1 ([M+H]+, 100%), 653.3 ([2M+H]+, 40%) 1HNMR (600.1343 MHz, CDCl3): 8.44 (s, 1H), 8.12 (s, 1H), 7.97 (d of t, 2H), 7.56 (bs, 1H), 7.45 (d, 1H), 7.06, (m, 1H), 6.45 (m, 1H), 6.35 (t, 1H), 4.68 (t, 2H), 4.37 (q, 2H), 3.90 (q, 2H), 1.39 (t, 3H). heated at 100 C for 21 hr heating The reaction was cooled filtered the filtrate concentrated The residue was purified by flash chromatography (5% methanol-dichloromethane) the product fractions concentrated

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

Procedure: Ethyl 1-(2-aminoethyl)-1H-indazole-5-carboxylate (584 mg, 2.5 mmol, prepared as in step B), was added to dry n-butanol along with 2-chloropyridine-N-oxide hydrochloride (847 mg, 5.1 mmol) and anhydrous sodium bicarbonate (850 mg, 10.1 mmol). The reaction mixture was vigorously stirred and heated at 100 C for 21 hr. Additional aliquots of 2-chloropyridine-N-oxide hydrochloride (847 mg, 5.1 mmol) and anhydrous sodium bicarbonate (850 mg, 10.1 mmol) were added and heating continued for 24 hours. The reaction was cooled and filtered and the filtrate concentrated. The residue was purified by flash chromatography (5% methanol-dichloromethane) and the product fractions concentrated to afford the product as an orange solid (358 mg, 44%). LRMS (ES): 327.1 ([M+H]+, 100%), 653.3 ([2M+H]+, 40%) 1HNMR (600.1343 MHz, CDCl3): 8.44 (s, 1H), 8.12 (s, 1H), 7.97 (d of t, 2H), 7.56 (bs, 1H), 7.45 (d, 1H), 7.06, (m, 1H), 6.45 (m, 1H), 6.35 (t, 1H), 4.68 (t, 2H), 4.37 (q, 2H), 3.90 (q, 2H), 1.39 (t, 3H). heated at 100 C for 21 hr heating The reaction was cooled filtered the filtrate concentrated The residue was purified by flash chromatography (5% methanol-dichloromethane) the product fractions concentrated

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

Procedure: Sodium hydride (0.68 g, 60% in mineral oil) was added to a solution of 2-ethyl-2-trifluoromethyl-6-nitro-3,4-dihydro-2H-1,4-benzoxazine (0.235 g), 2-chloropyridine-N-oxide hydrochloride (0.142 g), and dimethylsulfoxide (10 mL) and stirred at room temperature overnight. The mixture was quenched with saturated ammonium chloride/water and extracted into ethyl acetate. The organic extract was washed (water, brine) dried, decolorized (charcoal), filtered (celite) and evaporated. Chromatography, eluting successively with dichloromethane, ethyl acetate, and then methanol, gave the title compound as a yellow solid (0.11 g); mp 59°-62 ° C.; NMR: 0.95 (t,3), 2.04 (q), 4.05 (d,d), 7.01 (s,1), 7.25 (d) 7.45 (m, 2), 7.63 (d), 7.76 (d), 8.41 (d,1); MS: m/z=370(M+1). Analysis for C16H14F3N3O4 : Calculated: C, 52.04; H, 3.82; N, 11.38; Found: C, 51.95; 3.98; N, 11.10. The mixture was quenched with saturated ammonium chloride/water extracted into ethyl acetate The organic extract was washed (water, brine) dried filtered (celite) evaporated Chromatography, eluting successively with dichloromethane, ethyl acetate

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

Procedure: A solution of 2-methyl-2-trifluoromethyl-6-phenylsulfonyl-3,4-dihydro-2H-1,4-benzoxazine (200 mg) and 2-chloropyridine N-oxide·HCl (121 mg;) in dimethylsulfoxide (8 mL) was treated with sodium hydride (60% dispersion in oil, 58 mg), and stirred under a nitrogen atmosphere for 18 hours. The mixture was then poured into a solution containing aqueous sodium hydroxide (0.5 N, 150 mL) and saturated sodium chloride (20 mL.) and extracted with ethyl acetate. (3×150 mL). The combined organic portions were washed with aqueous sodium hydroxide (0.5 N, 30 mL) and saturated sodium chloride (5 mL) and evaporated to yield a black semi-solid. Chromatography of this solid on silica gel eluting with ethyl acetate then ethyl acetate/methanol (97:3) yielded the title compound (110 mg) as a white solid; mp 192°-193° C.; NMR (250 MHz, d6-DMSO): 1.55 (s,3), 3.98 (dd,2), 6.8.1 (s,1), 7.20 (d,1), 7.40 (dd, 1), 7.45 (m,2), 7.62 (m,4) 7.85 (dd,2), 8.42 (d, 1); MS: m/z=451(M+1). Analysis for C21H17F3N2O4S: Calculated: C, 56.00; H, 3.78; N, 6.22; Found: C, 56.10; H, 3.88; N, 6.02. The mixture was then poured into a solution extracted with ethyl acetate The combined organic portions were washed with aqueous sodium hydroxide (0.5 N, 30 mL) and saturated sodium chloride (5 mL) evaporated to yield a black semi-solid

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

Procedure: The moist crystals of 2-aminopyridine-1-oxide hydrochloride from Example 1, with or without drying and recrystallization, or the material of Example 2 after purification, can be used in this preparation without substantial difference in the results. A solution of 2-aminopyridine-1-oxide hydrochloride (110 g. dry weight) and 146 g. of concentrated hydrochloric acid (37.5%) in 158 g. of water was cooled to about 0° C and treated dropwise, with stirring, with 51.8 g. of sodium nitrite in 110 g. of water over a period of 1 hour with the temperature being maintained between -5° C and +5° C, to give a clear, orange solution of diazotized material. The orange solution was stirred for about 5 minutes at about 0° C, and was then immediately added by a cooled funnel, over a 40-minute period with stirring, to a hot solution of 110 g. 20% hydrochloric acid with the temperature of the reaction vessel being maintained at 95°-101° C. After 1/3 of the diazotized solution was added, 58.5 g. concentrated hydrochloric acid (37.5%) was poured into the hot reaction mixture. The addition of the remaining 2/3 of diazotized solution was then continued at the same rate and temperature, and stirring was then continued until nitrogen evolution ceased, about 7 minutes. This treatment yielded an aqueous solution of 2-chloropyridine-1-oxide hydrochloride, suitable for use as the solution in Examples 4 and 5. Isolation by vacuum evaporation, extraction from inorganic salts with absolute ethanol and recrystallization from ethanol-toluene gave purified material, m.p. 135°-137° C. The moist crystals of 2-aminopyridine-1-oxide hydrochloride from Example 1, with or without drying recrystallization the material of Example 2 after purification can be used in this preparation without substantial difference in the results treated dropwise to give a clear, orange solution of diazotized material The orange solution was stirred for about 5 minutes at about 0° C was then immediately added by a cooled funnel, over a 40-minute period with stirring, to a hot solution of 110 g After 1/3 of the diazotized solution was added The addition of the remaining 2/3 of diazotized solution stirring