环磷酰胺杂质10

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of bis(2-chloroethyl)amine hydrochloride (4.68 g, 26.2 mmol) in dry THF (50 mL) was added Et3N (18.3 mL, 131 mmol) at 0° C. and the mixture was stirred for 15 min. p-Toluenesulfonyl chloride (5.00 g, 26.25 mmol) and DMAP (a spatula pinch) were added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. When TLC analysis showed complete conversion, the mixture was filtered to remove the Et3N.HCl and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography to afford N,N-bis(2′-chloroethyl)-4-methylbenzenesulfonamide (6.22 g, 80% yield). were added the mixture was filtered to remove the Et3N.HCl extracted with EtOAc The combined organic phases were washed with brine dried (Na2SO4) filtered concentrated The residue was purified by flash column chromatography

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 66 g of the product obtained in Step 1 above are added to a suspension of 38.6 g of N,N-bis(2-chloroethyl)amine hydrochloride in 265 ml of xylene heated to 100° C. The reaction mixture is heated at 140° C. for 12 hours and, after cooling, filtered over a frit. The filtrate is concentrated and then purified by flash chromatography (eluant CH2Cl2/AcOEt: 95/5) to yield the expected product. The reaction mixture is heated at 140° C. for 12 hours after cooling filtered over a frit The filtrate is concentrated purified by flash chromatography (eluant CH2Cl2/AcOEt: 95/5)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The solution of the product of example 13 (1.50 g, 0.010 mol) and bis(2-chloroethyl)amine hydrochloride (1.77 g 0.01 mol) in chlorobenzene (20 ml) was heated under reflux for 24 h, cooled to room temperature and evaporated in vacuo. The white solid was dissolved in aqueous sodium hydroxide (100 ml) and extracted into ethyl acetate (3×50 ml). The extracts were dried (MgSO4) and evaporated in vacuo to give the product (2.00 g). under reflux for 24 h evaporated in vacuo The white solid was dissolved in aqueous sodium hydroxide (100 ml) extracted into ethyl acetate (3×50 ml) The extracts were dried (MgSO4) evaporated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: bis-(2-Chloroethyl)amine hydrochloride 26 (200 mg, 1.1 mmol) was dissolved in dichloromethane (15 mL) and triethylamine (0.45 mL, 3.3 mmol) was added. The mixture was stirred for 5 minutes at ambient temperature and methyl chlorothioformate (1.32 mmol) was added. The mixture was stirred until no bis-(2-chloroethyl)amine remained by TLC (ethyl acetate). Tyrosine methyl ester (411 mg, 2.1 mmol) was added and the mixture was heated under reflux for 4 hours. The mixture was allowed to cool purified by dry flash column chromatography (silica gel, dichloromethane 200 mL) and concentrated in vacuo to yield prodrug 30 as an orange/brown oil (278 mg, 60%). νmax 3400, 1740, 1660, 1444, 1380, 1145/cm−1; δ 1H (400 MHz, CDCl3) 2.32 (3H, s, CH3) 2.60 (2H, t, J 3.72 Hz, CH2Ar), 2.64 (3H, s, CH3) 3.12–3.25 (9H, m, ArCH2CH, 2×CH2CH2Cl), 6.67 (2H, d, J 5.7 Hz, 2×ArH), 6.9 (2H, d, J 5.7 Hz, 2×ArH), 7.82 (1H, brs, NH);. 13C (100 MHz, CDCl3) 29.8 (CH2), 43.3 (CH2), 44.1 (CH2), 44.2 (CH2), 45.2 (CH2), 46.6 (CH2), 47.1 (CH3) 115.9 (2×CH), 130 (2×CH), 130.1 (C), 155.6 (C), 160.3 (C) 161.5 (C). m/z (Cl) 242 (72%), 227 (45), 183 (75) 152 (100), 121 (45), 108 (35). the mixture was heated under reflux for 4 hours to cool purified by dry flash column chromatography (silica gel, dichloromethane 200 mL) concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: bis-(2-Chloroethyl)amine hydrochloride 26 (200 mg, 1.1 mmol) was dissolved in dichloromethane (15 mL) and triethylamine (0.45 mL, 3.3 mmol) was added. The mixture was stirred for 5 minutes at ambient temperature and methyl chlorothioformate (1.32 mmol) was added. The mixture was stirred until no bis-(2-chloroethyl)amine remained by TLC (ethyl acetate). N-mehty tyramine (322 mg, 2.1 mmol) was added and the mixture was heated under reflux for 4 hours. The mixture was allowed to cool, purified by dry flash column chromatography (silica gel, dichloromethane 200 mL) and concentrated in vacuo to yield prodrug 29 as an orange/brown oil (68 mg, 18%). νmax 3400, 1660, 1444, 1380, 1145/cm−1; δ 1H (400 MHz, CDCl3) 2.32 (3H, s, CH3) 2.60 (2H, t, J 3.72 Hz, CH2Ar), 3.17–3.22 (10H, m, ArCH2CH2, 2×CH2CH2Cl), 6.67 (2H, d, J 5.7 Hz, 2×ArH), 6.9 (2H, d, J 5.7 Hz, 2×ArH), 7.82 (1H, brs, NH); 13C (100 MHz, CDCl3) 30.1 (CH2), 43.3 (CH2), 44.1 (CH2), 44.2 (CH2), 45.2 (CH2), 46.5 (CH3) 46.6 (CH2), 115.9 (2×CH), 130 (2×CH), 130.1 (C), 155.6 (C), 161.5 (C). m/z (Cl) 283 (87%), 238 (50) 152 (100), 121 (45), 108 (35). the mixture was heated under reflux for 4 hours to cool purified by dry flash column chromatography (silica gel, dichloromethane 200 mL) concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: One pot method. bis-(2-Chloroethyl)amine hydrochloride 26 (200 mg, 1.1 mmol) was dissolved in dichloromethane (15 mL) and triethylamine (0.45 mL, 3.3 mmol) was added. The mixture was stirred for 5 minutes at ambient temperature and ethyl chloroformate or methyl chlorothioformate (1.32 mmol) was added. The mixture was stirred until no bis-(2-chloroethyl)amine remained by TLC (ethyl acetate). Tyramine (300 mg, 2.2 mmol) was added and the mixture was heated under reflux for 4 hours. the mixture was allowed to cool, purified by dry flash column chromatography (silica gel, dichloromethane 200 cm3) and concentrated in vacuo to yield prodrug 28 as an orange/brown oil (234 mg, 67% for methyl chlorothioformate and 229 mg, 64% for ethyl chloroformate). the mixture was heated under reflux for 4 hours to cool purified by dry flash column chromatography (silica gel, dichloromethane 200 cm3) concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 500 ml of water are added 50.0 g of 2-amino-5-n-propylbenzenesulfonic acid and 6.28 g of sodium carbonate and the mixture was dissolved by heating. To the solution was added 88.13 g of bis(2-chloroethyl)amine hydrochloride and the mixture was refluxed by heating for 3 hours, And then, a suspension containing 26.25 g of sodium carbonate suspended in 63 ml of water was added thereto, and the mixture was refluxed by heating for 12 hours. The reaction mixture was condensed under reduced pressure, extracted with methyl alcohol and then methyl alcohol was removed under reduced pressure. To the residue was added 200 ml of water, and after a pH of the mixture was adjusted to about 8.0 with sodium carbonate, 500 ml of chloroform was added thereto and the mixture was stirred. Precipitated crystals were collected by filtration, washed with chloroform and dried to give 44.83 g (yield: 67.9%) of the above title product. the mixture was dissolved by heating the mixture was refluxed by heating for 3 hours was added the mixture was refluxed by heating for 12 hours condensed under reduced pressure extracted with methyl alcohol methyl alcohol was removed under reduced pressure To the residue was added 200 ml of water was added Precipitated crystals were collected by filtration washed with chloroform dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2-(2,2,2-trifluoroethoxy)aniline (2.85 g, 14.9 mmol), bis(2-chloroethyl)amine hydrochloride (2.66 g, 14.9 mmol), potassium carbonate (2.06 g, 14.9 mmol), sodium iodide (0.45 g, 3 mmol) and bis(2-methoxyethyl) ether (7.3 mL) was heated 8 hours at reflux. The reaction mixture then was cooled, treated with concentrated ammonium hydroxide, poured into water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with water (2×30 mL) and brine (1×30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (95:5) to give 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine (2.93 g, 11.2 mmol), m.p. 107°-108° C. was heated 8 hours at reflux The reaction mixture then was cooled extracted with ethyl acetate (3×30 mL) The combined extracts were washed with water (2×30 mL) and brine (1×30 mL) dried (MgSO4) concentrated in vacuo The residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (95:5)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 3-chloro-2-methylaniline (21.6 g, 0.15 mol) in n-butanol (200 ml) was added bis(2-chloroethyl)amine hydrochloride (30 g, 0.17 mol) at room temperature and allowed to refluxed temperature for 2 days. After cooled to room temperature Na2CO3 (9 g, 0.08 mol) was added and then reaction mixture was refluxed 30 min. The resulting mixture was filtered with n-butanol (100 ml) and collected solid was dried under reduced pressure to be obtained title compound (24.8 g, 81%) as white solid. to refluxed temperature for 2 days was added reaction mixture was refluxed 30 min The resulting mixture was filtered with n-butanol (100 ml) collected solid was dried under reduced pressure

反应条件: temp:155.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Aminobenzonitrile (6.1 g, 52 mmol) and bis(2-chloroethyl)amine hydrochloride (10 g, 57 mmol) were dissolved in xylene (100 ml), and the resulting solution was stirred at 150 to 160° C. for 5 hours. Supernatant fluid of the reaction solution was discarded, the remaining residue was dissolved in sodium hydroxide aqueous solution (1 N) and then the reaction product was extracted therefrom with ethyl acetate. The extract was washed with saturated brine, and then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 3.2 g of the title compound (17 mmol, 34% in yield). A portion of the thus obtained compound was made into hydrochloric acid salt by treating it with hydrochloric acid-saturated methanol. the reaction product was extracted The extract was washed with saturated brine the compound obtained by the evaporation of the solvent under a reduced pressure was separated purified by a silica gel column chromatography

反应条件: temp:155.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Aminobenzonitrile (6.1 g, 52 mmol) and bis(2-chloroethyl)amine hydrochloride (10 g, 57 mmol) were dissolved in xylene (100 ml), and the resulting solution was stirred at 150 to 160° C. for 5 hours. Supernatant fluid of the reaction solution was discarded, the remaining residue was dissolved in sodium hydroxide aqueous solution (1 N) and then the reaction product was extracted therefrom with ethyl acetate. The extract was washed with saturated brine, and then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 3.2 g of the title compound (17 mmol, 34% in yield). A portion of the thus obtained compound was made into hydrochloric acid salt by treating it with hydrochloric acid-saturated methanol. the reaction product was extracted The extract was washed with saturated brine the compound obtained by the evaporation of the solvent under a reduced pressure was separated purified by a silica gel column chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Bromo-aniline (2 g, 1.162 mmol) was taken in dry nBuOH (25 mL) and dry potassium carbonate (4.8 g, 34.8 mmol) was added to it and stirred at rt for 1 h under nitrogen. Bis-(2-chloroethyl) amine hydrochloride 2 (2.49 g, 13.9 mmol) in nBuOH (10 mL) was then added to the mixture through a syringe. The reaction mass was then heated at 100° C. for 12 h. nBuOH was evaporated in vacuo and the residue was extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration afforded the crude product that on purification silica gel column (chloroform/methanol) afforded the title compound. was evaporated in vacuo the residue was extracted with ethyl acetate Drying of the organic layer with Na2SO4 followed by concentration afforded the crude product that on purification silica gel column (chloroform/methanol)