O-(2-methylpropyl)hydroxylamine;hydrochloride

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: O-iso-Butylhydroxylamine hydrochloride (380 mg, 3.0 mmol, 2.0 equiv) and 4-(dimethylamino)pyridine (740 mg, 6.0 mmol, 4.0 equiv) were sequentially added to a stirred suspension of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (prepared as in Balko et al., U.S. Pat. No. 7,314,849 B2; 500 mg, 1.5 mmol, 1.0 equiv) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.2 g, 6.0 mmol, 4.0 equiv) in 1,2-dichloroethane (5.0 mL) at 23° C. The resulting tan suspension was stirred at 23° C. for 18 h. The reaction mixture was quenched with glacial acetic acid (430 μL, 7.5 mmol, 5.0 equiv) and concentrated by a nitrogen stream. The residue was directly subjected to silica gel column chromatography (50% EtOAc in hexane) to afford a white powder (370 mg, 61%): mp 145-148° C.; 1H NMR (300 MHz, CDCl3) δ 9.87 (br s, 1H), 7.53 (t, J=8 Hz, 1H), 7.26 (m, 1H), 7.18 (d, J=2 Hz, 1H), 4.95 (br s, 2H), 3.99 (d, J=1 Hz, 3H), 3.83 (d, J=7 Hz, 2H), 2.07 (m, 1H), 1.01 (d, J=6 Hz, 6H); IR (neat film) 3221 (m), 2941 (w), 2878 (w), 1653 (s) cm−1; ESIMS m/z 402.2 ([M+H]+). prepared as in Balko et al., U.S at 23° C concentrated by a nitrogen stream

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

Procedure: A mixture of 1-[2-methyl-8-2,4,6-trimethyl-phenyl)quinolin4-yl]-propan-1-one (52 mg), iso-butoxylamine hydrochloride (300 mg), potassium carbonate (50 mg) and sodium acetate (40 mg) in ethanol (2 ml) was stirred at room temperature for 48 hr. The mixture was concentrated to dryness, then diluted with water, brine, and extracted with chloroform. The organic layer was separated, dried (Na2SO4) and concentrated to dryness to give a mixture of the title (Z) and (E)-isomer, respectively. The crude mixture was purified by preparative thin layer chromatography with 7% ethyl acetate in hexane as solvent to give a 6:4 mixture of isomers. The mixture was concentrated to dryness diluted with water, brine extracted with chloroform The organic layer was separated dried (Na2SO4) concentrated to dryness to give The crude mixture was purified by preparative thin layer chromatography with 7% ethyl acetate in hexane as solvent to give a 6:4 mixture of isomers

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

Procedure: A mixture of 1-[2-methyl-8-2,4,6-trimethyl-phenyl)quinolin4-yl]-propan-1-one (52 mg), iso-butoxylamine hydrochloride (300 mg), potassium carbonate (50 mg) and sodium acetate (40 mg) in ethanol (2 ml) was stirred at room temperature for 48 hr. The mixture was concentrated to dryness, then diluted with water, brine, and extracted with chloroform. The organic layer was separated, dried (Na2SO4) and concentrated to dryness to give a mixture of the title (Z) and (E)-isomer, respectively. The crude mixture was purified by preparative thin layer chromatography with 7% ethyl acetate in hexane as solvent to give a 6:4 mixture of isomers. The mixture was concentrated to dryness diluted with water, brine extracted with chloroform The organic layer was separated dried (Na2SO4) concentrated to dryness to give The crude mixture was purified by preparative thin layer chromatography with 7% ethyl acetate in hexane as solvent to give a 6:4 mixture of isomers

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

Procedure: (3-Chloro-4-methanesulfonyl-phenyl)-oxo-acetic acid methyl ester (prepared as in Example 1, 90 mg, 3.26 mmol) was stirred in methanol (7 mL) and warmed in a 70° C. oil bath. O-Isobutylhydroxylamine hydrochloride (511 mg, 4.07 mmol) was added. After 3 h, the reaction mixture was allowed to cool and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) afforded (E)-(3-chloro-4-methanesulfonyl-phenyl)-isobutoxyimino-acetic acid methyl ester as a white solid (395 mg, 35%): H1-NMR (400 MHz, CDCl3) δ=0.91 (6H, d, J=6.8 Hz), 2.04 (1H, m), 3.30 (3H, s), 3.91 (3H, s), 4.10 (2H, d, J=6.8 Hz), 7.50 (1H, dd, J=8.2 Hz, J=1.6 Hz), 7.61 (1H, d, J=1.6 Hz), 8.18 (1H, d, J=8.2 Hz). to cool concentrated in vacuo Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes to 30% ethyl acetate/hexanes)

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

Procedure: (3-Chloro-4-methanesulfonyl-phenyl)-oxo-acetic acid methyl ester (prepared as in Example 1, 90 mg, 3.26 mmol) was stirred in methanol (7 mL) and warmed in a 70° C. oil bath. O-Isobutylhydroxylamine hydrochloride (511 mg, 4.07 mmol) was added. After 3 h, the reaction mixture was allowed to cool and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) afforded (E)-(3-chloro-4-methanesulfonyl-phenyl)-isobutoxyimino-acetic acid methyl ester as a white solid (395 mg, 35%): H1-NMR (400 MHz, CDCl3) δ=0.91 (6H, d, J=6.8 Hz), 2.04 (1H, m), 3.30 (3H, s), 3.91 (3H, s), 4.10 (2H, d, J=6.8 Hz), 7.50 (1H, dd, J=8.2 Hz, J=1.6 Hz), 7.61 (1H, d, J=1.6 Hz), 8.18 (1H, d, J=8.2 Hz). to cool concentrated in vacuo Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes to 30% ethyl acetate/hexanes)

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: O-iso-Butylhydroxylamine hydrochloride (380 mg, 3.0 mmol, 2.0 equiv) and 4-(dimethylamino)pyridine (740 mg, 6.0 mmol, 4.0 equiv) were sequentially added to a stirred suspension of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (prepared as in Balko et al., U.S. Pat. No. 7,314,849 B2; 500 mg, 1.5 mmol, 1.0 equiv) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.2 g, 6.0 mmol, 4.0 equiv) in 1,2-dichloroethane (5.0 mL) at 23° C. The resulting tan suspension was stirred at 23° C. for 18 h. The reaction mixture was quenched with glacial acetic acid (430 μL, 7.5 mmol, 5.0 equiv) and concentrated by a nitrogen stream. The residue was directly subjected to silica gel column chromatography (50% EtOAc in hexane) to afford a white powder (370 mg, 61%): mp 145-148° C.; 1H NMR (300 MHz, CDCl3) δ 9.87 (br s, 1H), 7.53 (t, J=8 Hz, 1H), 7.26 (m, 1H), 7.18 (d, J=2 Hz, 1H), 4.95 (br s, 2H), 3.99 (d, J=1 Hz, 3H), 3.83 (d, J=7 Hz, 2H), 2.07 (m, 1H), 1.01 (d, J=6 Hz, 6H); IR (neat film) 3221 (m), 2941 (w), 2878 (w), 1653 (s) cm−1; ESIMS m/z 402.2 ([M+H]+). prepared as in Balko et al., U.S at 23° C concentrated by a nitrogen stream

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: O-iso-Butylhydroxylamine hydrochloride (380 mg, 3.0 mmol, 2.0 equiv) and 4-(dimethylamino)pyridine (740 mg, 6.0 mmol, 4.0 equiv) were sequentially added to a stirred suspension of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (prepared as in Balko et al., U.S. Pat. No. 7,314,849 B2; 500 mg, 1.5 mmol, 1.0 equiv) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.2 g, 6.0 mmol, 4.0 equiv) in 1,2-dichloroethane (5.0 mL) at 23° C. The resulting tan suspension was stirred at 23° C. for 18 h. The reaction mixture was quenched with glacial acetic acid (430 μL, 7.5 mmol, 5.0 equiv) and concentrated by a nitrogen stream. The residue was directly subjected to silica gel column chromatography (50% EtOAc in hexane) to afford a white powder (370 mg, 61%): mp 145-148° C.; 1H NMR (300 MHz, CDCl3) δ 9.87 (br s, 1H), 7.53 (t, J=8 Hz, 1H), 7.26 (m, 1H), 7.18 (d, J=2 Hz, 1H), 4.95 (br s, 2H), 3.99 (d, J=1 Hz, 3H), 3.83 (d, J=7 Hz, 2H), 2.07 (m, 1H), 1.01 (d, J=6 Hz, 6H); IR (neat film) 3221 (m), 2941 (w), 2878 (w), 1653 (s) cm−1; ESIMS m/z 402.2 ([M+H]+). prepared as in Balko et al., U.S at 23° C concentrated by a nitrogen stream

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (E)-tert-butyl (4-acetamido-3,5-dichlorobenzylamino)(3-(4-methoxyphenyl)-3-oxopropanamido)methylenecarbamate (6 mg) and O-isobutylhydroxylamine hydrochloride (3 mg) in ethanol (0.1 mL) was heated at 80° C. for 2 h. Ethanol was removed in vacuo and the crude mixture was purified by reverse phase HPLC (30×100 mm PHENOMENEX-LUNA S10 column, 10-90% methanol/H2O/0.1% TFA) to give the title compound as a clear sticky oil. Ethanol was removed in vacuo the crude mixture was purified by reverse phase HPLC (30×100 mm PHENOMENEX-LUNA S10 column, 10-90% methanol/H2O/0.1% TFA)

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: O-iso-Butylhydroxylamine hydrochloride (380 mg, 3.0 mmol, 2.0 equiv) and 4-(dimethylamino)pyridine (740 mg, 6.0 mmol, 4.0 equiv) were sequentially added to a stirred suspension of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (prepared as in Balko et al., U.S. Pat. No. 7,314,849 B2; 500 mg, 1.5 mmol, 1.0 equiv) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.2 g, 6.0 mmol, 4.0 equiv) in 1,2-dichloroethane (5.0 mL) at 23° C. The resulting tan suspension was stirred at 23° C. for 18 h. The reaction mixture was quenched with glacial acetic acid (430 μL, 7.5 mmol, 5.0 equiv) and concentrated by a nitrogen stream. The residue was directly subjected to silica gel column chromatography (50% EtOAc in hexane) to afford a white powder (370 mg, 61%): mp 145-148° C.; 1H NMR (300 MHz, CDCl3) δ 9.87 (br s, 1H), 7.53 (t, J=8 Hz, 1H), 7.26 (m, 1H), 7.18 (d, J=2 Hz, 1H), 4.95 (br s, 2H), 3.99 (d, J=1 Hz, 3H), 3.83 (d, J=7 Hz, 2H), 2.07 (m, 1H), 1.01 (d, J=6 Hz, 6H); IR (neat film) 3221 (m), 2941 (w), 2878 (w), 1653 (s) cm−1; ESIMS m/z 402.2 ([M+H]+). prepared as in Balko et al., U.S at 23° C concentrated by a nitrogen stream

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

Procedure: Isobutoxyamine hydrochloride (7.96 mmol, 1.0 g), 4-methoxybenzenesulfonyl chloride (7.24 mmol, 1.5 g), diisopropylethylamine (18.09 mmol, 3.15 mL) and anhydrous THF (15 mL) were combined under nitrogen. The reaction stirred at room temperature for 15 hours. The reaction solution was concentrated to a white solid and partitioned between ethyl acetate and 1N HCl. The organic layer was separated and washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated under vacuum to yield an off-white colored solid. Rf: 0.5 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.84 (2H,d), 6.99 (2H,d), 6.81 (1H,s), 3.87 (3H,s), 3.74 (2H,d), 1.90 (1H, septet), 0.86 (6H,d). The reaction solution was concentrated to a white solid partitioned between ethyl acetate and 1N HCl The organic layer was separated washed with saturated aqueous sodium bicarbonate and brine dried over magnesium sulfate concentrated under vacuum to yield an off-white colored solid

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (E)-tert-butyl (4-acetamido-3,5-dichlorobenzylamino)(3-(4-methoxyphenyl)-3-oxopropanamido)methylenecarbamate (6 mg) and O-isobutylhydroxylamine hydrochloride (3 mg) in ethanol (0.1 mL) was heated at 80° C. for 2 h. Ethanol was removed in vacuo and the crude mixture was purified by reverse phase HPLC (30×100 mm PHENOMENEX-LUNA S10 column, 10-90% methanol/H2O/0.1% TFA) to give the title compound as a clear sticky oil. Ethanol was removed in vacuo the crude mixture was purified by reverse phase HPLC (30×100 mm PHENOMENEX-LUNA S10 column, 10-90% methanol/H2O/0.1% TFA)

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: O-iso-Butylhydroxylamine hydrochloride (380 mg, 3.0 mmol, 2.0 equiv) and 4-(dimethylamino)pyridine (740 mg, 6.0 mmol, 4.0 equiv) were sequentially added to a stirred suspension of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (prepared as in Balko et al., U.S. Pat. No. 7,314,849 B2; 500 mg, 1.5 mmol, 1.0 equiv) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.2 g, 6.0 mmol, 4.0 equiv) in 1,2-dichloroethane (5.0 mL) at 23° C. The resulting tan suspension was stirred at 23° C. for 18 h. The reaction mixture was quenched with glacial acetic acid (430 μL, 7.5 mmol, 5.0 equiv) and concentrated by a nitrogen stream. The residue was directly subjected to silica gel column chromatography (50% EtOAc in hexane) to afford a white powder (370 mg, 61%): mp 145-148° C.; 1H NMR (300 MHz, CDCl3) δ 9.87 (br s, 1H), 7.53 (t, J=8 Hz, 1H), 7.26 (m, 1H), 7.18 (d, J=2 Hz, 1H), 4.95 (br s, 2H), 3.99 (d, J=1 Hz, 3H), 3.83 (d, J=7 Hz, 2H), 2.07 (m, 1H), 1.01 (d, J=6 Hz, 6H); IR (neat film) 3221 (m), 2941 (w), 2878 (w), 1653 (s) cm−1; ESIMS m/z 402.2 ([M+H]+). prepared as in Balko et al., U.S at 23° C concentrated by a nitrogen stream