2-chloro-N-(2-chloroethyl)-N-methylethanamine;hydrochloride

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

Procedure: To a stirring solution of 8-amino-2-naphthol (3.28 g, 20 mmol, Aldrich Chem. Co.) in 100 mL of acetonitrile was added sodium bicarbonate (7.42 g, 88 mmol), sodium iodide (6.72 g, 44 mmol) and mechlorethamine hydrochloride (4.32 g, 22 mmol). Under nitrogen, the reaction was heated to reflux and stirred for another 2 hr. The reaction mixture was then allowed to cool to room temperature and was stirred overnight. A thin layer chromatography (tlc) using methylene chloride: methanol: conc. ammonium hydroxide (90:10:1) showed the more polar product (Rf 0.25) with only a trace of the starting naphthol. Silica gel (4.5 g) was added and the reaction mixture was concentrated in vacuo to a dry purple solid. This was added to a column of silica gel (ca. 400 g) and eluted with 2 L volumes of CH2Cl2, CH2Cl2 :CH3OH (40:1), CH2Cl2 :CH3OH:conc. NH4OH (20:1:0.1) and finally 4 L of CH2Cl2 :CH3OH:conc. NH4CH (10:1:0.1). The appropriate fractions were combined to yield a purple-black solid, 5.26 g, mp 184°-185° C. Under nitrogen, the reaction was heated to reflux was stirred overnight Silica gel (4.5 g) was added the reaction mixture was concentrated in vacuo to a dry purple solid This was added to a column of silica gel (ca. 400 g) eluted with 2 L volumes of CH2Cl2, CH2Cl2 :CH3OH (40:1), CH2Cl2 to yield a purple-black solid, 5.26 g, mp 184°-185° C.

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 25 ml flask are added 0.5 g of 2-aminothiazole-5-carboxaldehyde, 1.35 g of K2CO3 in 5 ml of DMF. After dissolution, 0.901 g of 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride are added. The mixture is left at room temperature for 1 h then heated to 90° C. for 5 h. Next, the mixture is evaporated, dissolved in 100 ml of water, and the aqueous phase is extracted three times with ethyl acetate. The organic phases are combined, washed with sodium chloride saturated solution, dried over sodium sulfate, filtered, and evaporated to yield 420 mg (50%) of 2-(4-methylpiperazin-1-yl)thiazole-5-carboxaldehyde. are added Next, the mixture is evaporated dissolved in 100 ml of water the aqueous phase is extracted three times with ethyl acetate washed with sodium chloride saturated solution dried over sodium sulfate filtered evaporated

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

Procedure: A solution of 8-amino-3-phenylsulfonylquinoline (D5) (38.8 g, 137 mmol) in n-butanol (360 ml) was treated with bis-(2-chloroethyl)-methyl-amine hydrochloride (40 g, 138 mmol) and sodium carbonate (72 g, 0.68 mol). The mixture was heated to a vigorous reflux (˜100° C.) for 16 h then a further portion of bis-(2-chloroethyl)-methyl-amine hydrochloride (25 g, 86 mmol) introduced and heating continued for a further 4 h. The solution was cooled and a 1:1 mixture of saturated aqueous sodium bicarbonate and aqueous 10% sodium thiosulphate solution (2 L) added. Stirring was continued at ambient temperature for 16 h then the aqueous phase was extracted with dichloromethane (3×500 ml), the combined organic phase dried over magnesium sulphate, evaporated in vacuo and subjected to chromatography on a Biotage Flash 75 apparatus (1 kg Silica gel) to afford the title compound (E1) as the free base form (11.6 g), identical spectroscopically to that prepared by the first method. The mixture was heated to heating The solution was cooled added was continued at ambient temperature for 16 h the aqueous phase was extracted with dichloromethane (3×500 ml) the combined organic phase dried over magnesium sulphate evaporated in vacuo

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

Procedure: A solution of 8-amino-3-phenylsulfonylquinoline (D5) (38.8 g, 137 mmol) in n-butanol (360 ml) was treated with bis-(2-chloroethyl)-methyl-amine hydrochloride (40 g, 138 mmol) and sodium carbonate (72 g, 0.68 mol). The mixture was heated to a vigorous reflux (˜100° C.) for 16 h then a further portion of bis-(2-chloroethyl)-methyl-amine hydrochloride (25 g, 86 mmol) introduced and heating continued for a further 4 h. The solution was cooled and a 1:1 mixture of saturated aqueous sodium bicarbonate and aqueous 10% sodium thiosulphate solution (2 L) added. Stirring was continued at ambient temperature for 16 h then the aqueous phase was extracted with dichloromethane (3×500 ml), the combined organic phase dried over magnesium sulphate, evaporated in vacuo and subjected to chromatography on a Biotage Flash 75 apparatus (1 kg Silica gel) to afford the title compound (E1) as the free base form (11.6 g), identical spectroscopically to that prepared by the first method. The mixture was heated to heating The solution was cooled added was continued at ambient temperature for 16 h the aqueous phase was extracted with dichloromethane (3×500 ml) the combined organic phase dried over magnesium sulphate evaporated in vacuo

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

Procedure: bis-(2-Chloro-ethyl)-methyl-amine hydrochloride (3.7 g, 19.2 mmol) and sodium carbonate (9.0 g, 85 mmol) were added to a suspension of 3-bromo-quinolin-8-ylamine (3.9 g, 17.5 mmol) (for synthesis see Gershon et al., Monatsh. Chem., 1991, 122, 935) in n-butanol (70 ml). The stirred suspension was heated at reflux for 72 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (300 ml) and the solution washed with water (300 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane to afford the title compound (D1) as an oil (2.6 g, 8.5 mmol, 49%); The stirred suspension was heated at reflux for 72 h the solution washed with water (300 ml) dried (MgSO4) concentrated in vacuo to an oil The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane

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

Procedure: bis-(2-Chloro-ethyl)-methyl-amine hydrochloride (3.7 g, 19.2 mmol) and sodium carbonate (9.0 g, 85 mmol) were added to a suspension of 3-bromo-quinolin-8-ylamine (3.9 g, 17.5 mmol) (for synthesis see Gershon et al., Monatsh. Chem., 1991, 122, 935) in n-butanol (70 ml). The stirred suspension was heated at reflux for 72 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (300 ml) and the solution washed with water (300 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane to afford the title compound (D1) as an oil (2.6 g, 8.5 mmol, 49%); The stirred suspension was heated at reflux for 72 h the solution washed with water (300 ml) dried (MgSO4) concentrated in vacuo to an oil The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane

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

Procedure: A solution of 8-amino-3-phenylsulfonylquinoline (D5) (38.8 g, 137 mmol) in n-butanol (360 ml) was treated with bis-(2-chloroethyl)-methyl-amine hydrochloride (40 g, 138 mmol) and sodium carbonate (72 g, 0.68 mol). The mixture was heated to a vigorous reflux (˜100° C.) for 16 h then a further portion of bis-(2-chloroethyl)-methyl-amine hydrochloride (25 g, 86 mmol) introduced and heating continued for a further 4 h. The solution was cooled and a 1:1 mixture of saturated aqueous sodium bicarbonate and aqueous 10% sodium thiosulphate solution (2 L) added. Stirring was continued at ambient temperature for 16 h then the aqueous phase was extracted with dichloromethane (3×500 ml), the combined organic phase dried over magnesium sulphate, evaporated in vacuo and subjected to chromatography on a Biotage Flash 75 apparatus (1 kg Silica gel) to afford the title compound (E1) as the free base form (11.6 g), identical spectroscopically to that prepared by the first method. The mixture was heated to heating The solution was cooled added was continued at ambient temperature for 16 h the aqueous phase was extracted with dichloromethane (3×500 ml) the combined organic phase dried over magnesium sulphate evaporated in vacuo

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

Procedure: bis-(2-Chloro-ethyl)-methyl-amine hydrochloride (3.7 g, 19.2 mmol) and sodium carbonate (9.0 g, 85 mmol) were added to a suspension of 3-bromo-quinolin-8-ylamine (3.9 g, 17.5 mmol) (for synthesis see Gershon et al., Monatsh. Chem., 1991, 122, 935) in n-butanol (70 ml). The stirred suspension was heated at reflux for 72 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (300 ml) and the solution washed with water (300 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane to afford the title compound (D1) as an oil (2.6 g, 8.5 mmol, 49%); The stirred suspension was heated at reflux for 72 h the solution washed with water (300 ml) dried (MgSO4) concentrated in vacuo to an oil The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane

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

Procedure: Methyl 4-fluorophenylacetate (24.4 g) was dissolved in dry dimethyl sulphoxide (150 ml) and added dropwise to sodium hydride (15.7 g of an 80% dispersion in oil) under nitrogen. After 20 minutes mechlorethamine hydrochloride (24 g) in dry dimethyl sulphoxide (125 ml) was added over a period of 20 minutes. The reaction was poured onto ice (200 ml) and left overnight. The mixture was extracted with diethyl ether (50×250 ml) and the combined organic solutions were extracted with 5N HCl (100 ml). The aqueous solution was treated with potassium carbonate and extracted with ethyl acetate (3×250 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford a brown oil. The oil was purified by flash chromatography eluting with ethyl acetate graduated to 8% methanol in ethyl acetate, to afford the title compound (9.5 g). 1H NMR (360 MHz, CDCl3) δ 1.9-2.03 (2H, m), 2.07-2.19 (2H, m), 2.27 (3H, s), 2.51-2.62 (2H, m), 2.72-2.86 (2H, m), 3.65 (3H, s), 6.98-7.06 (2H, m), 7.27-7.39 (2H, m). MS (Cl+) 224 [M+H]+. The reaction was poured onto ice (200 ml) The mixture was extracted with diethyl ether (50×250 ml) the combined organic solutions were extracted with 5N HCl (100 ml) The aqueous solution was treated with potassium carbonate extracted with ethyl acetate (3×250 ml) The combined organic extracts were dried (MgSO4) concentrated in vacuo to afford a brown oil The oil was purified by flash chromatography eluting with ethyl acetate

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

Procedure: A solution of 8-amino-3-phenylsulfonylquinoline (D5) (38.8 g, 137 mmol) in n-butanol (360 ml) was treated with bis-(2-chloroethyl)-methyl-amine hydrochloride (40 g, 138 mmol) and sodium carbonate (72 g, 0.68 mol). The mixture was heated to a vigorous reflux (˜100° C.) for 16 h then a further portion of bis-(2-chloroethyl)-methyl-amine hydrochloride (25 g, 86 mmol) introduced and heating continued for a further 4 h. The solution was cooled and a 1:1 mixture of saturated aqueous sodium bicarbonate and aqueous 10% sodium thiosulphate solution (2 L) added. Stirring was continued at ambient temperature for 16 h then the aqueous phase was extracted with dichloromethane (3×500 ml), the combined organic phase dried over magnesium sulphate, evaporated in vacuo and subjected to chromatography on a Biotage Flash 75 apparatus (1 kg Silica gel) to afford the title compound (E1) as the free base form (11.6 g), identical spectroscopically to that prepared by the first method. The mixture was heated to heating The solution was cooled added was continued at ambient temperature for 16 h the aqueous phase was extracted with dichloromethane (3×500 ml) the combined organic phase dried over magnesium sulphate evaporated in vacuo

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

Procedure: A solution of 8-amino-3-phenylsulfonylquinoline (D5) (38.8 g, 137 mmol) in n-butanol (360 ml) was treated with bis-(2-chloroethyl)-methyl-amine hydrochloride (40 g, 138 mmol) and sodium carbonate (72 g, 0.68 mol). The mixture was heated to a vigorous reflux (˜100° C.) for 16 h then a further portion of bis-(2-chloroethyl)-methyl-amine hydrochloride (25 g, 86 mmol) introduced and heating continued for a further 4 h. The solution was cooled and a 1:1 mixture of saturated aqueous sodium bicarbonate and aqueous 10% sodium thiosulphate solution (2 L) added. Stirring was continued at ambient temperature for 16 h then the aqueous phase was extracted with dichloromethane (3×500 ml), the combined organic phase dried over magnesium sulphate, evaporated in vacuo and subjected to chromatography on a Biotage Flash 75 apparatus (1 kg Silica gel) to afford the title compound (E1) as the free base form (11.6 g), identical spectroscopically to that prepared by the first method. The mixture was heated to heating The solution was cooled added was continued at ambient temperature for 16 h the aqueous phase was extracted with dichloromethane (3×500 ml) the combined organic phase dried over magnesium sulphate evaporated in vacuo

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

Procedure: bis-(2-Chloro-ethyl)-methyl-amine hydrochloride (3.7 g, 19.2 mmol) and sodium carbonate (9.0 g, 85 mmol) were added to a suspension of 3-bromo-quinolin-8-ylamine (3.9 g, 17.5 mmol) (for synthesis see Gershon et al., Monatsh. Chem., 1991, 122, 935) in n-butanol (70 ml). The stirred suspension was heated at reflux for 72 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (300 ml) and the solution washed with water (300 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane to afford the title compound (D1) as an oil (2.6 g, 8.5 mmol, 49%); The stirred suspension was heated at reflux for 72 h the solution washed with water (300 ml) dried (MgSO4) concentrated in vacuo to an oil The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane