tert-butyl N-(2-aminooxyethyl)-N-methylcarbamate

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (3.11 g, 7.91 mmol) in tetrahydrofuran (20 mL) was cooled with a −40° C. bath and treated with N-methylmorpholine (0.87 mL, 7.9 mmol). Diphenylphosphinic chloride (2.00 mL, 10.5 mmol) was added dropwise over 5 min and the reaction mixture was stirred for 90 min, during which time the temperature of the cooling bath slowly warmed to 0° C. The reaction mixture was again cooled to −40° C. and (2-aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (2.00 g, 10.5 mmol) was added as a solution in tetrahydrofuran (6 mL). After an additional 10 min, N-methylmorpholine (1.33 mL, 12.1 mmol) was added. The temperature of the cooling bath was allowed to warm to ambient temperature over 4 h and the reaction mixture was further stirred overnight. The reaction was diluted with ethyl acetate (40 mL) and washed with saturated aqueous ammonium chloride (2×10 mL). The organics were dried over magnesium sulfate, concentrated and purified by silica gel chromatography. Elution with 35% ethyl acetate-hexanes afforded [2-({1-[3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl ester (3.28 g, 73% yield) as an off-white foam: 1H NMR (400 MHz, DMSO-d6) δ 11.84 and 11.75 (br s, 1H total), 8.66 (br s, 1H), 7.54 (dd, J=10.9, 1.6 Hz, 1H), 7.36 (br t, J=8.8 Hz, 1H), 7.33 (br d, J=8.8 Hz), 7.20 (m, 1H), 6.64 (m, 1H), 3.85 (t, J=5.2 Hz, 2H), 3.34 (br s, 2H), 2.81 and 2.79 (br s, 3H total), 1.34 and 1.32 (s, 9H total); 19F NMR (376 MHz, DMSO-d6) δ −128.0 (d, J=32.9 Hz), −133.0, −144.2 (d, J=17.7 Hz); MS (APCI−)=564.1. The reaction mixture was again cooled to −40° C. After an additional 10 min to warm to ambient temperature over 4 h the reaction mixture was further stirred overnight washed with saturated aqueous ammonium chloride (2×10 mL) The organics were dried over magnesium sulfate concentrated purified by silica gel chromatography Elution with 35% ethyl acetate-hexanes

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

Procedure: To a solution of (2-aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (0.63 g, 3.31 mmol) and diisopropylethylamine (0.6 mL, 3.44 mmol) in dimethylformamide (10 mL) was added 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid pentafluorophenyl ester (1.66 g, 2.99 mmol). The resultant reaction mixture was stirred 5 h at ambient temperature and concentrated under reduced pressure. The residue was diluted with ether (100 mL), washed with water (2×25 mL) and brine (2×25 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography. Elution with dichloromethane afforded [2-({1-[3,4-difluoro-2-(4iodo-2-methyl-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl ester (1.05 g, 62%) as a white foam: 1H NMR (400 MHz, DMSO-d6) δ 11.85 and 11.80 (br s, 1H), 8.49 (br s, 1H), 7.50 (s, 1H), 7.39 (m, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.14 (m, 1H), 6.46 (dd, J=7.8, 5.9 Hz, 1H), 3.85 (br s, 2H), 3.35 (br s, 2H), 2.79 (br s, 3H), 2.21 (s, 3H), 1.36 and 1.33 (s, 9H); 19F NMR (376 MHz, DMSO-d6) δ −132.9, −143.3 (d, J=17.7 Hz); MS (APCI+)=562.1. The resultant reaction mixture concentrated under reduced pressure The residue was diluted with ether (100 mL) washed with water (2×25 mL) and brine (2×25 mL) dried over magnesium sulfate concentrated in vacuo The residue was purified by silica gel chromatography Elution with dichloromethane

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

Procedure: A solution of [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (4.50 g, 14.0 mmol) in dichloromethane (40 mL) was treated with methylhydrazine (0.78 mL, 14.7 mmol) and the reaction mixture was stirred 6 h at ambient temperature. Diethyl ether (80 mL) was added and the heterogeneous solution was allowed to stand overnight. The precipitate was removed by filtration and was washed with ether (80 mL). The filtrate was further concentrated and the resultant precipitate was filtered and the second filtrate concentrated to afford (2-Aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (2.83 g) as a viscous oil: 1H NMR (400 MHz, CDCl3) δ 3.73 (t, J=5.2 Hz, 2H), 5.45 (br s, NH2), 3.46 and 3.42 (br s, 2H), 2.86 br s, 3H), 1.25 (br s, 9H); MS (APCI+)=191.1. to stand overnight The precipitate was removed by filtration was washed with ether (80 mL) The filtrate was further concentrated the resultant precipitate was filtered the second filtrate concentrated

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

Procedure: Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tert-butyl(2-(aminooxy)ethyl)(methyl)carbamate (436 mg) described in Reference Example 16, 347.8 mg of the title compound was afforded (yield 55%).

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (3.11 g, 7.91 mmol) in tetrahydrofuran (20 mL) was cooled with a −40° C. bath and treated with N-methylmorpholine (0.87 mL, 7.9 mmol). Diphenylphosphinic chloride (2.00 mL, 10.5 mmol) was added dropwise over 5 min and the reaction mixture was stirred for 90 min, during which time the temperature of the cooling bath slowly warmed to 0° C. The reaction mixture was again cooled to −40° C. and (2-aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (2.00 g, 10.5 mmol) was added as a solution in tetrahydrofuran (6 mL). After an additional 10 min, N-methylmorpholine (1.33 mL, 12.1 mmol) was added. The temperature of the cooling bath was allowed to warm to ambient temperature over 4 h and the reaction mixture was further stirred overnight. The reaction was diluted with ethyl acetate (40 mL) and washed with saturated aqueous ammonium chloride (2×10 mL). The organics were dried over magnesium sulfate, concentrated and purified by silica gel chromatography. Elution with 35% ethyl acetate-hexanes afforded [2-({1-[3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl ester (3.28 g, 73% yield) as an off-white foam: 1 H NMR (400 MHz, DMSO-d6) δ 11.84 and 11.75 (br s, 1 H total), 8.66 (br s, 1 H), 7.54 (dd, J=10.9, 1.6 Hz, 1 H), 7.36 (br t, J=8.8 Hz, 1 H), 7.33 (br d, J=8.8 Hz), 7.20 (m, 1 H), 6.64 (m, 1 H), 3.85 (t, J=5.2 Hz, 2 H), 3.34 (br s, 2 H), 2.81 and 2.79 (br s, 3 H total), 1.34 and 1.32 (s, 9 H total); 19F NMR (376 MHz, DMSO-d6) δ −128.0 (d, J=32.9 Hz), −133.0, −144.2 (d, J=17.7 Hz); MS (APCI−)=564.1. The reaction mixture was again cooled to −40° C. After an additional 10 min to warm to ambient temperature over 4 h the reaction mixture was further stirred overnight washed with saturated aqueous ammonium chloride (2×10 mL) The organics were dried over magnesium sulfate concentrated purified by silica gel chromatography Elution with 35% ethyl acetate-hexanes

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

Procedure: To a solution of (2-aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (0.63 g, 3.31 mmol) and diisopropylethylamine (0.6 mL, 3.44 mmol) in dimethylformamide (10 mL) was added 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid pentafluorophenyl ester (1.66 g, 2.99 mmol). The resultant reaction mixture was stirred 5 h at ambient temperature and concentrated under reduced pressure. The residue was diluted with ether (100 mL), washed with water (2×25 mL) and brine (2×25 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography. Elution with dichloromethane afforded [2-({1-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl ester (1.05 g, 62%) as a white foam: 1 H NMR (400 MHz, DMSO-d6) δ 11.85 and 11.80 (br s, 1 H), 8.49 (br s, 1 H), 7.50 (s, 1 H), 7.39 (m, 1H), 7.35 (d, J=8.3 Hz, 1 H), 7.14 (m, 1 H), 6.46 (dd, J=7.8, 5.9 Hz, 1 H), 3.85 (br s, 2 H), 3.35 (br s, 2 H), 2.79 (br s, 3 H), 2.21 (s, 3 H), 1.36 and 1.33 (s, 9 H); 19F NMR (376 MHz, DMSO-d6) δ −132.9, −143.3 (d, J=17.7 Hz); MS (APCI+)=562.1. The resultant reaction mixture concentrated under reduced pressure The residue was diluted with ether (100 mL) washed with water (2×25 mL) and brine (2×25 mL) dried over magnesium sulfate concentrated in vacuo The residue was purified by silica gel chromatography Elution with dichloromethane

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

Procedure: A solution of [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (4.50 g, 14.0 mmol) in dichloromethane (40 mL) was treated with methylhydrazine (0.78 mL, 14.7 mmol) and the reaction mixture was stirred 6 h at ambient temperature. Diethyl ether (80 mL) was added and the heterogeneous solution was allowed to stand overnight. The precipitate was removed by filtration and was washed with ether (80 mL). The filtrate was further concentrated and the resultant precipitate was filtered and the second filtrate concentrated to afford (2-Aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (2.83 g) as a viscous oil: 1H NMR (400 MHz, CDCl3) δ 3.73 (t, J=5.2 Hz, 2 H), 5.45 (br s, NH2), 3.46 and 3.42 (br s, 2 H), 2.86 br s, 3 H), 1.25 (br s, 9 H); MS (APCI+)=191.1. to stand overnight The precipitate was removed by filtration was washed with ether (80 mL) The filtrate was further concentrated the resultant precipitate was filtered the second filtrate concentrated

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

Procedure: A solution of [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (4.50 g, 14.0 mmol) in dichloromethane (40 mL) was treated with methylhydrazine (0.78 mL, 14.7 mmol) and the reaction mixture was stirred 6 h at ambient temperature. Diethyl ether (80 mL) was added and the heterogeneous solution was allowed to stand overnight. The precipitate was removed by filtration and was washed with ether (80 mL). The filtrate was further concentrated and the resultant precipitate was filtered and the second filtrate concentrated to afford (2-Aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (2.83 g) as a viscous oil: 1H NMR (400 MHz, CDCl3) δ 3.73 (t, J=5.2 Hz, 2 H), 5.45 (br s, NH2), 3.46 and 3.42 (br s, 2 H), 2.86 br s, 3 H), 1.25 (br s, 9 H); MS (APCI+)=191.1. to stand overnight The precipitate was removed by filtration was washed with ether (80 mL) The filtrate was further concentrated the resultant precipitate was filtered the second filtrate concentrated