tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate

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

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 mixture of 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carbaldehyde (21.5 g, 70.24 mmol, 1.00 equiv), tert-butyl N-methyl-N-(2-(methylamino)ethyl)carbamate (20 g, 106.23 mmol, 1.51 equiv) and NaBH(OAc)3 (29.8 g, 137.98 mmol, 1.96 equiv) in dichloroethane (300 mL) was stirred for 1 h at room temperature. The reaction was diluted with 300 mL of dichloromethane and then washed with 3×300 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-7% methanol in dichloromethane to give 31 g (92%) of tert-butyl (2-(((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.62 (s, 1H), 5.34-5.30 (m, 1H), 4.06-4.02 (m, 1H), 3.68-3.62 (m, 1H), 3.42-3.38 (m, 4H), 2.85 (s, 4H), 2.62-2.53 (m, 2H), 2.47-2.46 (m, 2H), 2.13-1.97 (m, 3H), 1.74-1.69 (m, 3H), 1.46 (s, 9H) ppm. LCMS (method A, ESI): RT=1.17 min, m/z=479.0 [M+H]+. washed with 3×300 mL of brine The organic layer was dried over anhydrous sodium sulfate concentrated under vacuum The residue was purified on a silica gel column eluted with 0-7% methanol in dichloromethane

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

Procedure: To a solution of (R/S) 5-(4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (300 mg, 0.82 mmol, 1.00 equiv) and tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (170 mg, 0.90 mmol, 1.11 equiv) in 1,2-dichloroethane (40 mL) was added NaBH(OAc)3 (520 mg). The reaction was stirred at room temperature overnight and then quenched with 50 mL of water. The resulting mixture was extracted with 3×200 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-10% of ethyl acetate in petroleum ether to give 420 mg (95%) of (R/S) tert-butyl methyl(2-(methyl((5-(4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methyl)amino)ethyl)carbamate as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ 8.18 (m, 2H), 7.71-7.55 (m, 2H), 7.20-7.09 (m, 1H), 7.05-6.93 (m, 2H), 5.70-5.68 (m, 1H), 4.11-4.09 (m, 1H), 4.06-3.91 (m, 1H), 3.79-3.73 (m, 1H), 3.50-3.33 (m, 1H), 2.79 (s, 3H), 2.57-2.52 (m, 2H), 2.49-2.17 (m, 2H), 2.17-2.05 (m, 1H), 1.80-1.68 (m, 4H), 1.42 (s, 9H) ppm. quenched with 50 mL of water The resulting mixture was extracted with 3×200 mL of ethyl acetate The combined organic layers was dried over anhydrous sodium sulfate concentrated under vacuum The residue was purified on a silica gel column eluted with 0-10% of ethyl acetate in petroleum ether

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

Procedure: To a solution of (R/S) 5-(4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (300 mg, 0.82 mmol, 1.00 equiv) and tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (170 mg, 0.90 mmol, 1.11 equiv) in 1,2-dichloroethane (40 mL) was added NaBH(OAc)3 (520 mg). The reaction was stirred at room temperature overnight and then quenched with 50 mL of water. The resulting mixture was extracted with 3×200 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-10% of ethyl acetate in petroleum ether to give 420 mg (95%) of (R/S) tert-butyl methyl(2-(methyl((5-(4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methyl)amino)ethyl)carbamate as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ 8.18 (m, 2H), 7.71-7.55 (m, 2H), 7.20-7.09 (m, 1H), 7.05-6.93 (m, 2H), 5.70-5.68 (m, 1H), 4.11-4.09 (m, 1H), 4.06-3.91 (m, 1H), 3.79-3.73 (m, 1H), 3.50-3.33 (m, 1H), 2.79 (s, 3H), 2.57-2.52 (m, 2H), 2.49-2.17 (m, 2H), 2.17-2.05 (m, 1H), 1.80-1.68 (m, 4H), 1.42 (s, 9H) ppm. quenched with 50 mL of water The resulting mixture was extracted with 3×200 mL of ethyl acetate The combined organic layers was dried over anhydrous sodium sulfate concentrated under vacuum The residue was purified on a silica gel column eluted with 0-10% of ethyl acetate in petroleum ether

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

Procedure: tert-Butyl methyl(2-(methylamino)ethyl)carbamate was prepared as follows: N1,N2-dimethylethane-1,2-diamine (40 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0° C. A solution of di-tert-butylcarbonate (4.0 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0° C. over a period of 15 min. The resulting reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h. the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl methyl(2-(methylamino)ethyl)carbamate. This amine was subjected to the same reaction conditions outlined earlier in the preparation of (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate. The desired product, namely (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z) -N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)amino)-4-oxobut-2-enoate, was obtained after purification by silica gel chromatography. MS (EI) calcd for C31H46N2O4: 510.35; found 511 (M+1). tert-Butyl methyl(2-(methylamino)ethyl)carbamate was prepared The resulting reaction mixture warmed to room temperature After stirring at room temperature for 2 h. the reaction mixture The organic layer was washed with brine (3×25 mL) dried (Na2SO4) concentrated under reduced pressure

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

Procedure: tert-Butyl methyl(2-(methylamino)ethyl)carbamate was prepared as follows: N1,N2-dimethylethane-1,2-diamine (40 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0° C. A solution of di-tert-butylcarbonate (4.0 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0° C. over a period of 15 min. The resulting reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h. the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl methyl(2-(methylamino)ethyl)carbamate. This amine was subjected to the same reaction conditions outlined earlier in the preparation of (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate. The desired product, namely (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z) -N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)amino)-4-oxobut-2-enoate, was obtained after purification by silica gel chromatography. MS (EI) calcd for C31H46N2O4: 510.35; found 511 (M+1). tert-Butyl methyl(2-(methylamino)ethyl)carbamate was prepared The resulting reaction mixture warmed to room temperature After stirring at room temperature for 2 h. the reaction mixture The organic layer was washed with brine (3×25 mL) dried (Na2SO4) concentrated under reduced pressure

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

Procedure: tert-Butyl methyl(2-(methylamino)ethyl)carbamate was prepared as follows: N1,N2-dimethylethane-1,2-diamine (40 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0° C. A solution of di-tert-butylcarbonate (4.0 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0° C. over a period of 15 min. The resulting reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl methyl(2-(methylamino)ethyl)carbamate. This amine was subjected to the same reaction conditions outlined earlier in the preparation of (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate. The desired product, namely (E)-methyl 4-(methyl(2-((4Z,7Z,10Z,13Z,16Z,19Z)—N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)amino)-4-oxobut-2-enoate, was obtained after purification by silica gel chromatography. MS (EI) calcd for C31H46N2O4: 510.35. found 511 (M+1). tert-Butyl methyl(2-(methylamino)ethyl)carbamate was prepared The resulting reaction mixture warmed to room temperature After stirring at room temperature for 2 h The organic layer was washed with brine (3×25 mL) dried (Na2SO4) concentrated under reduced pressure

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

Procedure: To a solution of N-t-butoxycarbonyl-N,N'-dimethylethylenediamine (1.0 g) and triethylamine (537 mg) in methylene chloride (20 ml) which was cooled to 0° C., was added morpholinocarbonyl chloride (794 mg). The mixture was stirred at 0° C. for 1 hour. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml) and the solution was washed with 5% hydrochloric acid, 1 M sodium bicarbonate solution and water successively, and dried over magnesium sulfate. Evaporation of the solvent gave N-t-butoxycarbonyl-N'-(morpholinocarbonyl)-N,N'-dimethylethylenediamine (1.11 g) as an oil. After evaporation of the solvent the residue was dissolved in ethyl acetate (30 ml) the solution was washed with 5% hydrochloric acid, 1 M sodium bicarbonate solution and water successively dried over magnesium sulfate Evaporation of the solvent

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

Procedure: 3-Bromo-5-methylpyridine (350 mg, 2.035 mmol), tert-butyl N-methyl-N-(2-methylaminoethyl)carbamate (686 mg, 3.05 mmol), RuPhos (47.5 mg, 0.102 mmol) and sodium tert-butoxide (489 mg, 5.09 mmol) were combined in anhydrous toluene (15 ml). The mixture was purged with argon, tris(dibenzylideneacetone)dipalladium (0) chloroform complex (105 mg, 0.102 mmol) was added and the mixture was stirred at 100° C. overnight. The mixture was filtered through kieselguhr, concentrated under reduced pressure and the residue was purified by column chromatography (silica, gradient of 10 to 50% ethyl acetate in heptane) to yield 301 mg (1.078 mmol, 53%) MS(ESI) m/z=280.2 [M+1]+. was added The mixture was filtered through kieselguhr concentrated under reduced pressure the residue was purified by column chromatography (silica, gradient of 10 to 50% ethyl acetate in heptane) to yield 301 mg (1.078 mmol, 53%) MS(ESI) m/z=280.2 [M+1]+

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

Procedure: 3-Bromo-5-methylpyridine (350 mg, 2.035 mmol), tert-butyl N-methyl-N-(2-methylaminoethyl)carbamate (686 mg, 3.05 mmol), RuPhos (47.5 mg, 0.102 mmol) and sodium tert-butoxide (489 mg, 5.09 mmol) were combined in anhydrous toluene (15 ml). The mixture was purged with argon, tris(dibenzylideneacetone)dipalladium (0) chloroform complex (105 mg, 0.102 mmol) was added and the mixture was stirred at 100° C. overnight. The mixture was filtered through kieselguhr, concentrated under reduced pressure and the residue was purified by column chromatography (silica, gradient of 10 to 50% ethyl acetate in heptane) to yield 301 mg (1.078 mmol, 53%) MS(ESI) m/z=280.2 [M+1]+. was added The mixture was filtered through kieselguhr concentrated under reduced pressure the residue was purified by column chromatography (silica, gradient of 10 to 50% ethyl acetate in heptane) to yield 301 mg (1.078 mmol, 53%) MS(ESI) m/z=280.2 [M+1]+