tert-butyl N-[2-(2-aminoethoxy)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:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 146 g of [2-{2-(t-butoxycarbonylamino)ethoxy}ethyl]methane sulfonate was dissolved in 500 ml DMF, was added 134 g of sodium azide. The reaction mixture was stirred at 70° C. for 20 h, and then concentrated under reduced pressure. The resulting residue was dissolved in 1,200 ml water and extracted with EA. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was dissolved in 2,000 ml THF, to which was added 162 g of triphenylphosphine. The reaction mixture was stirred at RT for 2 h, after which was added 200 ml water. The reaction mixture was stirred at RT for 18 h and concentrated to 500 ml under reduced pressure. Then the resulting precipitate was filtered off. The filtrate was further concentrated under reduced pressure to remove THF, and washed with MC. The aq layer was concentrated to obtain 86.2 g of compd 42 as a liquid. 1H NMR (400 MHz; CDCl3) δ 4.96 (br s, 1H), 3.54-3.48 (m, 4H), 3.34 (q, 2H), 2.88 (t, 2H), 1.48-1.46 (m, 11H). concentrated under reduced pressure The resulting residue was dissolved in 1,200 ml water extracted with EA The organic layer was dried over anhydrous sodium sulfate concentrated in vacuo The resulting residue was dissolved in 2,000 ml THF, to which was added 162 g of triphenylphosphine The reaction mixture was stirred at RT for 2 h after which was added 200 ml water The reaction mixture was stirred at RT for 18 h concentrated to 500 ml under reduced pressure Then the resulting precipitate was filtered off The filtrate was further concentrated under reduced pressure to remove THF washed with MC The aq layer was concentrated

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

Procedure: tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (420, 2.06 mmol) was then taken up in CH3CN (20 mL) along with nicotinic acid (253 mg, 2.06 mmol) and EDCI (434 mg, 2.3 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate (280 mg, 44%). MS calculated for C15H23N3O4: 309.17; found: [M+H]+310. The resulting reaction mixture washed with saturated aqueous NaHCO3, brine dried over Na2SO4 filtered concentrated under reduced pressure The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH)

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

Procedure: To 146 g of [2-{2-(t-butoxycarbonylamino)ethoxy}ethyl]methane sulfonate was dissolved in 500 ml DMF, was added 134 g of sodium azide. The reaction mixture was stirred at 70° C. for 20 h, and then concentrated under reduced pressure. The resulting residue was dissolved in 1,200 ml water and extracted with EA. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was dissolved in 2,000 ml THF, to which was added 162 g of triphenylphosphine. The reaction mixture was stirred at RT for 2 h, after which was added 200 ml water. The reaction mixture was stirred at RT for 18 h and concentrated to 500 ml under reduced pressure. Then the resulting precipitate was filtered off. The filtrate was further concentrated under reduced pressure to remove THF, and washed with MC. The aq layer was concentrated to obtain 86.2 g of compd 42 as a liquid. 1H NMR (400 MHz; CDCl3) δ 4.96 (br s, 1H), 3.54-3.48 (m, 4H), 3.34 (q, 2H), 2.88 (t, 2H), 1.48-1.46 (m, 11H). concentrated under reduced pressure The resulting residue was dissolved in 1,200 ml water extracted with EA The organic layer was dried over anhydrous sodium sulfate concentrated in vacuo The resulting residue was dissolved in 2,000 ml THF, to which was added 162 g of triphenylphosphine The reaction mixture was stirred at RT for 2 h after which was added 200 ml water The reaction mixture was stirred at RT for 18 h concentrated to 500 ml under reduced pressure Then the resulting precipitate was filtered off The filtrate was further concentrated under reduced pressure to remove THF washed with MC The aq layer was concentrated

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: Under a nitrogen purge, 10% palladium on carbon (9.2 g) was added to a solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (92.0 g, 399 mmol) in toluene (900 mL) in a pressure vessel. The vessel was placed under hydrogen pressure (30 psi, 2.0×105 Pa), and for the first 20 minutes, the hydrogen was replaced every five minutes and brought to a pressure of (20 psi, 1.4×105 Pa). The reaction was maintained under hydrogen pressure (20 psi, 1.4×105 Pa) overnight. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure to yield 77.4 g of tert-butyl 2-(2-aminoethoxy)ethylcarbamate as a light green oil. Under a nitrogen purge The reaction was maintained under hydrogen pressure (20 psi, 1.4×105 Pa) overnight The reaction mixture was filtered through a layer of CELITE filter aid the filter cake was washed with ethanol The filtrate was concentrated under reduced pressure

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

Procedure: Under a nitrogen atmosphere, a solution of tert-butyl 2-(2-aminoethoxy)ethylcarbamate (23.1 g, 113 mmol) in N,N-dimethylformamide (100 mL) was added over a 1 hour period to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (25.02 g, 113 mmol) in N,N-dimethylformamide (400 mL) containing triethylamine (24 mL, 175 mmol). The reaction mixture was allowed to stir at ambient temperature overnight. The N,N-dimethylformamide was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 mL), washed with water (3×100 ml), dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (450 g of silica gel eluting sequentially with 3/1 hexanes/ethyl acetate (1.2 L), 2/1 hexanes/ethyl acetate (1.2 L), and 1/1 hexanes/ethyl acetate (1 L)) to provide 20.67 g of tert-butyl 2-{2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethoxy}ethylcarbamate. The N,N-dimethylformamide was removed under reduced pressure The residue was dissolved in ethyl acetate (500 mL) washed with water (3×100 ml) dried over magnesium sulfate concentrated under reduced pressure The residue was purified by column chromatography (450 g of silica gel eluting sequentially with 3/1 hexanes/ethyl acetate (1.2 L), 2/1 hexanes/ethyl acetate (1.2 L), and 1/1 hexanes/ethyl acetate (1 L))

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

Procedure: A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (52 g, 226 mmol) in methanol (500 mL) was added to a Parr vessel containing 10% palladium on carbon (4 g) which had been wetted with toluene (30 mL). The mixture was placed under hydrogen pressure (30 psi; 2.0×105 Pa). After 18.5 hours analysis by thin layer chromatography indicated that the reaction was not complete. Catalyst (0.5 g) was added and the hydrogenation was continued for an additional 4 hours. The reaction mixture was filtered through a layer of Celite® filter aid and a glass wool filter pad. The filter cake was rinsed with a mixture of isopropanol and methanol. The filtrate was concentrated under reduced pressure to provide tert-butyl 2-(2-aminoethoxy)ethylcarbamate. the hydrogenation was continued for an additional 4 hours The reaction mixture was filtered through a layer of Celite® filter aid a glass wool filter pad The filter cake was rinsed with a mixture of isopropanol and methanol The filtrate was concentrated under reduced pressure

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

Procedure: tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (1.0 g, 4.90 mmol) was then taken up in 20 mL of CH3CN along with mono methyl fumarate (637 mg, 4.90 mmol) and EDCI (1.7 g, 5.39 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (9:1 CH2Cl2/MeOH) to afford 1.0 g of (E)-methyl 4-(2-(2-(tert-butoxycarbonyl)ethoxy)ethylamino)-4-oxobut-2-enoate (64% yield). MS (EI) called for C14H24 N2O6: 316.16; found 317 (M+1). The resulting reaction mixture washed with saturated aqueous NaHCO3, brine dried (Na2SO4) concentrated under reduced pressure The resulting residue was purified by chromatography (9:1 CH2Cl2/MeOH)