2-chloro-N-(2-chloroethyl)-N-dichlorophosphorylethanamine

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: Cyclohexylammonium Hydrogen N,N-di-(2-chloroethyl)phosphorodiamidate synthesis. 25 g of bis(2-chloroethyl)amine hydrochloride in 65 ml of oxyphosphorus chloride was heated to reflux for 12 hours. The excess oxyphosphorus was removed by evaporation. Di(2-chloroethyl)phosphoramidic dichloride was crystallized from petroleum ether and acetone (1:1). It was recrystallized 3 times with the same solvent. 14.5 g of white crystals were obtained, m.p. 54°-56° C. This melting point was the same as that previously reported. 3 g of di(2-chloroethyl)phosphoramidic dichloride and 1.15 g of phenol were added to 20 ml of toluene and heated to reflux, 1.85 ml of triethylamine was then added over 2 minutes, the reflux continued for 4 hours and then left overnight. The suspension was filtered and the filtrate was submitted to SiO2 column chromatography (hexane:ethylacetate =7:3). Phenyl-di(2chloroethyl)phosphoramidic chloride was obtained as a yellow oil, 3.361 g, 92% NMR (CDCl3) 7.3 (s, 5 H, C6H5 ), 3.87-3.33 (m, 8 H, CH2CH2Cl). 2.115 g of Phenyldi(2-chloroethyl) phosphoramidic chloride in toluene was bubbled with ammonia for 30 minutes. The precipitate was filtered and the solvent was removed by evaporation. The residue was diluted to cloudiness with petroleum ether and left overnight. Phenyl N,N-di(2-chloroethyl)phosphorodiamidate was crystallized, filtered, and without further purification, it was added to 50 ml of 100% ethanol and 0.4 g of platinum(IV) oxide and hydrogenolized for 15 minutes under the pressure 11 lb/inch2. The mixture was filtered and 0.5 ml of cyclohexamine was added immediately. After the evaporation, the residue was washed onto a filter with ether. 0.501 g cyclohexylammonium hydrogen N,N-di(2-chloroethyl)phosphorodiamidate as an off-white powder was obtained, 23%, m.p. 124°-126° C. heated to reflux left overnight The suspension was filtered

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

Procedure: Di-(2-chloroethyl)amidophosphorodichloridate is prepared according to H. Brintzinger et al in Chemische Berichte 82, 389-99 (1949) from bis-(2-chloroethyl)amine hydrochloride and phosphoryl chloride in the presence of pyridine. 0.03 mol (7.8 g) of this material is dissolved in 100 ml of acetone and added to an acetone solution of 0.03 mole (6.3 g) of 2-cyanovinyl 4-aminophenyl sulfone. To the stirred mixture is added in 2-3 portions a 10% solution of 1,4-diazabicyclo[2.2.2.]octane in acetone. After a few minutes a yellow slurry forms which is stirred at room temperature for 30 minutes. After filtration to remove the amine hydrochlorides the filtrate is reduced to about half its volume by evaporation and then mixed with chloroform, washed with water and worked up. The light yellow solid is di-(2-chloroethyl)amido-di-4-(2-cyanoethenesulfonylanilido)phosphine oxide: ##SPC57## After filtration to remove the amine hydrochlorides the filtrate is reduced to about half its volume by evaporation mixed with chloroform washed with water

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

Procedure: Di-(2-chloroethyl)amidophosphorodichloridate is prepared according to H. Brintzinger et al in Chemische Berichte 82, 389-99 (1949) from bis-(2-chloroethyl)amine hydrochloride and phosphoryl chloride in the presence of pyridine. 0.03 mol (7.8 g) of this material is dissolved in 100 ml of acetone and added to an acetone solution of 0.03 mole (6.3 g) of 2-cyanovinyl 4-aminophenyl sulfone. To the stirred mixture is added in 2-3 portions a 10% solution of 1,4-diazabicyclo[2.2.2.]octane in acetone. After a few minutes a yellow slurry forms which is stirred at room temperature for 30 minutes. After filtration to remove the amine hydrochlorides the filtrate is reduced to about half its volume by evaporation and then mixed with chloroform, washed with water and worked up. The light yellow solid is di-(2-chloroethyl)amido-di-4-(2-cyanoethenesulfonylanilido)phosphine oxide: ##SPC57## After filtration to remove the amine hydrochlorides the filtrate is reduced to about half its volume by evaporation mixed with chloroform washed with water

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-[2-(diethylamino)ethylthio]ethanol (420 mg, 2.4 mmol) in tetrahydrofuran, cooled to −78° C., was added with stirring lithium bis(trimethylsilyl)amide (1.0M in tert-butyl methyl ether, 2.62 mL, 2.62 mmol), followed by a solution of N,N-bis(2-chloroethyl)phosphoramidic dichloride (680 mg, 2.62 mmol) in tetrahydrofuran (10 mL). The orange reaction mixture was stirred at −78° C. for 90 minutes, then allowed to warm to −20° C. and ammonia gas bubbled through it for 10 minutes. The reaction mixture was stirred for an additional 10 minutes, then poured into a separatory funnel containing water (200 mL) and dichloromethane (200 mL). The organic and aqueous layers were separated, and the aqueous layer washed with dichloromethane (3×200 mL). The organic layer and washings were combined, dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography on a 25 g silica column, eluting with 90% chloroform/10% (5% ammonium hydroxide in methanol), to give 2-{[2-(diethylamino)ethyl]thio}ethyl N,N-bis(2-chloroethyl)phosphorodiamidate as a clear oil, 97% pure by HPLC. MS (ES): m/z=380 [C12H28Cl2N3O2PS+H+]. to warm to −20° C. ammonia gas bubbled through it for 10 minutes The reaction mixture was stirred for an additional 10 minutes poured into a separatory funnel containing water (200 mL) and dichloromethane (200 mL) The organic and aqueous layers were separated the aqueous layer washed with dichloromethane (3×200 mL) dried over magnesium sulfate filtered the filtrate concentrated under reduced pressure to give a yellow oil The oil was purified by chromatography on a 25 g silica column eluting with 90% chloroform/10% (5% ammonium hydroxide in methanol)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-[2-(diethylamino)ethylthio]ethanol (420 mg, 2.4 mmol) in tetrahydrofuran, cooled to −78° C., was added with stirring lithium bis(trimethylsilyl)amide (1.0M in tert-butyl methyl ether, 2.62 mL, 2.62 mmol), followed by a solution of N,N-bis(2-chloroethyl)phosphoramidic dichloride (680 mg, 2.62 mmol) in tetrahydrofuran (10 mL). The orange reaction mixture was stirred at −78° C. for 90 minutes, then allowed to warm to −20° C. and ammonia gas bubbled through it for 10 minutes. The reaction mixture was stirred for an additional 10 minutes, then poured into a separatory funnel containing water (200 mL) and dichloromethane (200 mL). The organic and aqueous layers were separated, and the aqueous layer washed with dichloromethane (3×200 mL). The organic layer and washings were combined, dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography on a 25 g silica column, eluting with 90% chloroform/10% (5% ammonium hydroxide in methanol), to give 2-{[2-(diethylamino)ethyl]thio}ethyl N,N-bis(2-chloroethyl)phosphorodiamidate as a clear oil, 97% pure by HPLC. MS (ES): m/z=380 [C12H28Cl2N3O2PS+H+]. to warm to −20° C. ammonia gas bubbled through it for 10 minutes The reaction mixture was stirred for an additional 10 minutes poured into a separatory funnel containing water (200 mL) and dichloromethane (200 mL) The organic and aqueous layers were separated the aqueous layer washed with dichloromethane (3×200 mL) dried over magnesium sulfate filtered the filtrate concentrated under reduced pressure to give a yellow oil The oil was purified by chromatography on a 25 g silica column eluting with 90% chloroform/10% (5% ammonium hydroxide in methanol)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Bis(2-chloroethyl)amine hydrochloride (6.3 g, 35 mmol), suspended in 80 mL dichloromethane, was cooled to −78° C. under argon and stirred. A solution of phosphoryl chloride (5.41 g, 35 mmol) in 10 mL dichloromethane, followed by a solution of triethylamine (3.53 g, 70 mmol) in 10 mL dichloromethane, was added slowly by syringe. Stirring was continued while the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was washed with 0.01N hydrochloric acid (3×25 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give N,N-bis(2-chloroethyl)phosphoramidic dichloride as a light orange oil that solidified on standing (7.9 g, 87% yield). A 2.2 g aliquot of the crude N,N-bis(2-chloroethyl)phosphoramidic dichloride was purified by flash chromatography on a 12 g silica cartridge, eluting with a gradient of 100% hexane to 67% hexane/33% ethyl acetate over 10 minutes followed by 67% hexane/33% ethyl acetate for a further 10 minutes, to give 1.5 g pure N,N-bis(2-chloroethyl)phosphoramidic dichloride as a white solid after evaporation of the solvents. MS (ES): m/z=275 [C4H8Cl4NOP+NH4+]. was added slowly by syringe Stirring to warm to room temperature overnight The reaction mixture was washed with 0.01N hydrochloric acid (3×25 mL) dried over magnesium sulfate concentrated under reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Bis(2-chloroethyl)amine hydrochloride (6.3 g, 35 mmol), suspended in 80 mL dichloromethane, was cooled to −78° C. under argon and stirred. A solution of phosphoryl chloride (5.41 g, 35 mmol) in 10 mL dichloromethane, followed by a solution of triethylamine (3.53 g, 70 mmol) in 10 mL dichloromethane, was added slowly by syringe. Stirring was continued while the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was washed with 0.01N hydrochloric acid (3×25 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give N,N-bis(2-chloroethyl)phosphoramidic dichloride as a light orange oil that solidified on standing (7.9 g, 87% yield). A 2.2 g aliquot of the crude N,N-bis(2-chloroethyl)phosphoramidic dichloride was purified by flash chromatography on a 12 g silica cartridge, eluting with a gradient of 100% hexane to 67% hexane/33% ethyl acetate over 10 minutes followed by 67% hexane/33% ethyl acetate for a further 10 minutes, to give 1.5 g pure N,N-bis(2-chloroethyl)phosphoramidic dichloride as a white solid after evaporation of the solvents. MS (ES): m/z=275 [C4H8Cl4NOP+NH4+]. was added slowly by syringe Stirring to warm to room temperature overnight The reaction mixture was washed with 0.01N hydrochloric acid (3×25 mL) dried over magnesium sulfate concentrated under reduced pressure

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

Procedure: A solution of bis(2-chloroethyl)phosphoramidic dichloride (10 mmol) in ethyl acetate (100 mL) is added dropwise to a solution of commercial 3 methylamino-1-phenyl-1-propanol (10 mmol) and triethylamine (20 mmol) in ethyl acetate (100 mL) at rt. After stirring at rt for 3 days, the salts are filtered off and the combined filtrates are concentrated under vacuum. The crude product is purified by column chromatography on silica. the salts are filtered off the combined filtrates are concentrated under vacuum The crude product is purified by column chromatography on silica

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

Procedure: A solution of bis(2-chloroethyl)phosphoramidic dichloride (10 mmol) in ethyl acetate (100 mL) is added dropwise to a solution of commercial 3 methylamino-1-phenyl-1-propanol (10 mmol) and triethylamine (20 mmol) in ethyl acetate (100 mL) at rt. After stirring at rt for 3 days, the salts are filtered off and the combined filtrates are concentrated under vacuum. The crude product is purified by column chromatography on silica. the salts are filtered off the combined filtrates are concentrated under vacuum The crude product is purified by column chromatography on silica

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

Procedure: Phosphorous oxychloride (0.15 mol) in 100 ml. THF are mixed dropwise at 10° C. with bis-chloroethylamine (0.1 mol) in 100 ml. THF and triethylamine (0.15 mol). After ending of the reaction (TLC verification), triethylamine hydrochloride is filtered off and the filtrate, after the addition of 50 ml. toluene, evaporated. The oily residue is immediately further reacted. is filtered off the filtrate, after the addition of 50 ml toluene, evaporated The oily residue is immediately further reacted