sodium;2-(diethylamino)acetate

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

Procedure: A solution of 2-nitrobenzene-1,4-diamine (2.00 g; 13.1 mmol), di-tert-butyl dicarbonate (3.14 g, 14.4 mmol), and DIPEA (2.6 mL; 14.9 mmol) in dioxane (40 mL) was heated at reflux for 40 min, then allowed to cool to room temperature. The mixture was concentrated under reduced pressure and taken up in EA (100 mL). The EA solution was washed with water and the aqueous phase extracted with EA. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure to give tert-butyl 3-amino-4-nitrophenylcarbamate in quantitative yield as a brown solid. To a stirred solution of tert-butyl 3-amino-4-nitrophenylcarbamate (2.74 g; 10.8 mmol) in anhydrous THF (50 mL) was added sodium hydride (0.868 g of a 60 wt % dispersion in oil, 21.7 mmol) in portions over 10 min. The mixture was stirred for a further 5 min at room temperature and then iodoethane (950 μL; 11.9 mmol) was added. The solution was stirred for 20 hr, water (1 mL) was added, and the solution concentrated under reduced pressure. The residue was partitioned between EA and water and the phases separated. The aqueous phase was extracted twice with EA and the combined organic phases washed with water, saturated aqueous sodium bicarbonate and brine. The organic solution was dried over magnesium sulfate and concentrated under reduced pressure to give a mixture of mono- and di-ethylated products (2.18 g). This was purified by silica gel column chromatography eluting with 1:4 EA/hexanes to give tert-butyl 4-amino-3-nitrophenyl(ethyl)carbamate (0.534 g) as an orange solid. A solution of tert-butyl 4-amino-3-nitrophenyl(ethyl)carbamate (0.514 g; 1.83 mmol) in 4M hydrogen chloride in dioxane (10 mL) was stirred at ambient temperature for 3 hr. The solvent was removed under reduced pressure and the residue dissolved in water. The pH was adjusted to 10 with 1M aqueous sodium hydroxide and the aqueous phase was extracted three times with EA. The combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give N1-ethyl-3-nitrobenzene-1,4-diamine (0.311 g) as a purple solid. N1-Ethyl-3-nitrobenzene-1,4-diamine (0.208 g; 1.38 mmol) was dissolved in acetonitrile (10 mL) and N,N-diethylglycine sodium salt (0.192 g; 1.25 mmol) and DEPBT (0.375 g; 1.25 mmol) were added, followed by triethylamine (577 μL; 4.14 mmol). The mixture was stirred at room temperature for 8 hr; and then further quantities of N,N-diethylglycine sodium salt (0.192 g; 1.25 mmol), DEPBT (0.375 g; 1.25 mmol), and triethylamine (577 μL; 4.14 mmol) were added and stirring continued for 63 hr. Solids were removed by filtration and the filtrate concentrated under reduced pressure. Water was added to the residue and the pH was adjusted to 10 with saturated aqueous sodium bicarbonate. This solution was extracted three times with EA, and the organic extracts combined, washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to give N-(4-amino-3-nitrophenyl)-2-(diethylamino)-N-ethylacetamide (0.303 g) as a brown oil. A solution of N-(4-amino-3-nitrophenyl)-2-(diethylamino)-N-ethylacetamide (0.092 g; 0.31 mmol) in ethanol (5 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (11 mg) at room temperature for 22 hr. The mixture was filtered through diatomaceous earth, washing with ethanol, and the filtrate was concentrated under reduced pressure to give N-(3,4-diaminophenyl)-2-(diethylamino)-N-ethylacetamide in quantitative yield as a brown oil. stirring continued for 63 hr Solids were removed by filtration the filtrate concentrated under reduced pressure Water was added to the residue This solution was extracted three times with EA washed with water and brine dried over magnesium sulfate concentrated under reduced pressure

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

Procedure: 2-Nitrobenzene-1,4-diamine (1.55 g, 10.1 mmol), N,N-diethylglycine sodium salt (1.61 g, 10.6 mmol) and DEPBT (3.02 g, 10.0 mmol) were suspended in acetonitrile (75 mL). Triethylamine (2.8 mL, 20.0 mmol) was added and the solution stirred overnight at room temperature. The brown precipitate which was formed was filtered and discarded. The filtrate was concentrated and the residue partitioned between EA and saturated aqueous sodium bicarbonate. The organic phase was washed with water and then with brine, dried over sodium sulfate, and the solvent removed under reduced pressure. The residue was dissolved in ethanol (50 mL) and hydrogenated at atmospheric pressure with 10% palladium on charcoal (1.0 g, 0.9 mmol) at room temperature overnight. Filtration and concentration under reduced pressure gave N-(3,4-diaminophenyl)-2-(diethylamino)acetamide as a light brown semi-solid, which solidified and turned blue on standing. The brown precipitate which was formed was filtered The filtrate was concentrated the residue partitioned between EA and saturated aqueous sodium bicarbonate The organic phase was washed with water with brine, dried over sodium sulfate the solvent removed under reduced pressure Filtration and concentration under reduced pressure

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

Procedure: 2-Nitrobenzene-1,4-diamine (1.55 g, 10.1 mmol), N,N-diethylglycine sodium salt (1.61 g, 10.6 mmol) and DEPBT (3.02 g, 10.0 mmol) were suspended in acetonitrile (75 mL). Triethylamine (2.8 mL, 20.0 mmol) was added and the solution stirred overnight at room temperature. The brown precipitate which was formed was filtered and discarded. The filtrate was concentrated and the residue partitioned between EA and saturated aqueous sodium bicarbonate. The organic phase was washed with water and then with brine, dried over sodium sulfate, and the solvent removed under reduced pressure. The residue was dissolved in ethanol (50 mL) and hydrogenated at atmospheric pressure with 10% palladium on charcoal (1.0 g, 0.9 mmol) at room temperature overnight. Filtration and concentration under reduced pressure gave N-(3,4-diaminophenyl)-2-(diethylamino)acetamide as a light brown semi-solid, which solidified and turned blue on standing. The brown precipitate which was formed was filtered The filtrate was concentrated the residue partitioned between EA and saturated aqueous sodium bicarbonate The organic phase was washed with water with brine, dried over sodium sulfate the solvent removed under reduced pressure Filtration and concentration under reduced pressure

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

Procedure: Compound 6 (3.70 g) was dissolved in pyridine (100 mL), and N,N-diethylglycin sodium salt (7.66 g) was added to the solution, followed by stirring at room temperature for 1 hour. Subsequently, p-toluenesulfonyl chloride (9.43 g) was added to the mixture, followed by stirring under reflux for 12 hours. After completion of reaction, the solvent was evaporated under reduced pressure. Chloroform (1,000 mL) was added to the residue, and the mixture was washed with water three times. The pH of the aqueous layer was checked by use of a pH testpaper, and adjusted to 4 to 5 with 1N aqueous hydrochloric acid. The organic layer was dried over sodium sulfate anhydrate, and the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (CHCl3-Hexane), to thereby yield the target product (yield: 3.62 g, 75%). by stirring under reflux for 12 hours After completion of reaction the solvent was evaporated under reduced pressure Chloroform (1,000 mL) was added to the residue the mixture was washed with water three times The organic layer was dried over sodium sulfate anhydrate the solvent was evaporated to dryness The residue was purified by silica gel column chromatography (CHCl3-Hexane)

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

Procedure: Compound 6 (3.70 g) was dissolved in pyridine (100 mL), and N,N-diethylglycin sodium salt (7.66 g) was added to the solution, followed by stirring at room temperature for 1 hour. Subsequently, p-toluenesulfonyl chloride (9.43 g) was added to the mixture, followed by stirring under reflux for 12 hours. After completion of reaction, the solvent was evaporated under reduced pressure. Chloroform (1,000 mL) was added to the residue, and the mixture was washed with water three times. The pH of the aqueous layer was checked by use of a pH testpaper, and adjusted to 4 to 5 with 1N aqueous hydrochloric acid. The organic layer was dried over sodium sulfate anhydrate, and the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (CHCl3-Hexane), to thereby yield the target product (yield: 3.62 g, 75%). by stirring under reflux for 12 hours After completion of reaction the solvent was evaporated under reduced pressure Chloroform (1,000 mL) was added to the residue the mixture was washed with water three times The organic layer was dried over sodium sulfate anhydrate the solvent was evaporated to dryness The residue was purified by silica gel column chromatography (CHCl3-Hexane)

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

Procedure: Compound 6 (480 mg) was dissolved in toluene (100 mL), and N,N-diethylglycin sodium salt (296 mg) and p-toluenesulfonic acid monohydrate (490 mg) were added to the solution, followed by stirring under reflux for 5 hours. The solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (CHCl3-MeOH), to thereby yield the target product (yield: 237 mg, 37.7%). under reflux for 5 hours The solvent was evaporated to dryness the residue was purified by silica gel column chromatography (CHCl3-MeOH)

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

Procedure: Compound 6 (480 mg) was dissolved in toluene (100 mL), and N,N-diethylglycin sodium salt (296 mg) and p-toluenesulfonic acid monohydrate (490 mg) were added to the solution, followed by stirring under reflux for 5 hours. The solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (CHCl3-MeOH), to thereby yield the target product (yield: 237 mg, 37.7%). under reflux for 5 hours The solvent was evaporated to dryness the residue was purified by silica gel column chromatography (CHCl3-MeOH)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Powdery solid N,N-diethylglycine sodium salt (produced by Tokyo Kasei Kogyo K.K. Japan) was dissolved in deionized water. The solubility in water of the N,N-diethylglycine sodium salt was 34% by mass (20° C.). To 342 g of this aqueous 34% by mass solution, was added 98% by mass sulfuric acid to adjust the pH to 6.6. This aqueous solution was condensed at 90° C. under a reduced pressure until the N,N-diethylglycine sodium salt concentration in the solution reached 67% by mass. The condensed solution was cooled to 40° C. and was stirred for one hour. The deposited crystalline sodium sulfate was removed at 40° C. by using a Buchner vacuum filter. Thereby, an aqueous 67% by mass solution of N,N-diethylglycine was obtained in an amount of 125 g. The aqueous N,N-diethylglycine solution contained sodium sulfate at a concentration of 0.9% by mass. 34% by mass (20° C.) condensed at 90° C. under a reduced pressure until the N,N-diethylglycine sodium salt concentration in the solution The deposited crystalline sodium sulfate was removed at 40° C. filter

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

Procedure: A solution of 2-nitrobenzene-1,4-diamine (2.00 g; 13.1 mmol), di-tert-butyl dicarbonate (3.14 g, 14.4 mmol), and DIPEA (2.6 mL; 14.9 mmol) in dioxane (40 mL) was heated at reflux for 40 min, then allowed to cool to room temperature. The mixture was concentrated under reduced pressure and taken up in EA (100 mL). The EA solution was washed with water and the aqueous phase extracted with EA. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure to give tert-butyl 3-amino-4-nitrophenylcarbamate in quantitative yield as a brown solid. To a stirred solution of tert-butyl 3-amino-4-nitrophenylcarbamate (2.74 g; 10.8 mmol) in anhydrous THF (50 mL) was added sodium hydride (0.868 g of a 60 wt % dispersion in oil, 21.7 mmol) in portions over 10 min. The mixture was stirred for a further 5 min at room temperature and then iodoethane (950 μL; 11.9 mmol) was added. The solution was stirred for 20 hr, water (1 mL) was added, and the solution concentrated under reduced pressure. The residue was partitioned between EA and water and the phases separated. The aqueous phase was extracted twice with EA and the combined organic phases washed with water, saturated aqueous sodium bicarbonate and brine. The organic solution was dried over magnesium sulfate and concentrated under reduced pressure to give a mixture of mono- and di-ethylated products (2.18 g). This was purified by silica gel column chromatography eluting with 1:4 EA/hexanes to give tert-butyl 4-amino-3-nitrophenyl(ethyl)carbamate (0.534 g) as an orange solid. A solution of tert-butyl 4-amino-3-nitrophenyl(ethyl)carbamate (0.514 g; 1.83 mmol) in 4M hydrogen chloride in dioxane (10 mL) was stirred at ambient temperature for 3 hr. The solvent was removed under reduced pressure and the residue dissolved in water. The pH was adjusted to 10 with 1M aqueous sodium hydroxide and the aqueous phase was extracted three times with EA. The combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give N1-ethyl-3-nitrobenzene-1,4-diamine (0.311 g) as a purple solid. N1-Ethyl-3-nitrobenzene-1,4-diamine (0.208 g; 1.38 mmol) was dissolved in acetonitrile (10 mL) and N,N-diethylglycine sodium salt (0.192 g; 1.25 mmol) and DEPBT (0.375 g; 1.25 mmol) were added, followed by triethylamine (577 μL; 4.14 mmol). The mixture was stirred at room temperature for 8 hr; and then further quantities of N,N-diethylglycine sodium salt (0.192 g; 1.25 mmol), DEPBT (0.375 g; 1.25 mmol), and triethylamine (577 μL; 4.14 mmol) were added and stirring continued for 63 hr. Solids were removed by filtration and the filtrate concentrated under reduced pressure. Water was added to the residue and the pH was adjusted to 10 with saturated aqueous sodium bicarbonate. This solution was extracted three times with EA, and the organic extracts combined, washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to give N-(4-amino-3-nitrophenyl)-2-(diethylamino)-N-ethylacetamide (0.303 g) as a brown oil. A solution of N-(4-amino-3-nitrophenyl)-2-(diethylamino)-N-ethylacetamide (0.092 g; 0.31 mmol) in ethanol (5 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (11 mg) at room temperature for 22 hr. The mixture was filtered through diatomaceous earth, washing with ethanol, and the filtrate was concentrated under reduced pressure to give N-(3,4-diaminophenyl)-2-(diethylamino)-N-ethylacetamide in quantitative yield as a brown oil. stirring continued for 63 hr Solids were removed by filtration the filtrate concentrated under reduced pressure Water was added to the residue This solution was extracted three times with EA washed with water and brine dried over magnesium sulfate concentrated under reduced pressure

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

Procedure: 2-Nitrobenzene-1,4-diamine (1.55 g, 10.1 mmol), N,N-diethylglycine sodium salt (1.61 g, 10.6 mmol) and DEPBT (3.02 g, 10.0 mmol) were suspended in acetonitrile (75 mL). Triethylamine (2.8 mL, 20.0 mmol) was added and the solution stirred overnight at room temperature. The brown precipitate which was formed was filtered and discarded. The filtrate was concentrated and the residue partitioned between EA and saturated aqueous sodium bicarbonate. The organic phase was washed with water and then with brine, dried over sodium sulfate, and the solvent removed under reduced pressure. The residue was dissolved in ethanol (50 mL) and hydrogenated at atmospheric pressure with 10% palladium on charcoal (1.0 g, 0.9 mmol) at room temperature overnight. Filtration and concentration under reduced pressure gave N-(3,4-diaminophenyl)-2-(diethylamino)acetamide as a light brown semi-solid, which solidified and turned blue on standing. The brown precipitate which was formed was filtered The filtrate was concentrated the residue partitioned between EA and saturated aqueous sodium bicarbonate The organic phase was washed with water with brine, dried over sodium sulfate the solvent removed under reduced pressure Filtration and concentration under reduced pressure