N-(2-bromoethyl)methanesulfonamide

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

Procedure: A stirred solution of N-(4-piperidylmethyl) 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxarnide (E21, 220 mg, 0.70 mmole) in acetonitrile (8 ml) was treated with diisopropylethylamine (0.24 ml, 1.4 mmole) and N-(2-bromoethyl)methanesulphonamide (D14, 160 mg, 0.77 mmole) and the mixture heated under reflux for 2.5 h. The reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel eluting with dichloromethane/methanol/0.88 ammonia solution (200:10:1). The colourless oil obtained was dissolved in chloroform (30 ml) and washed with water (2×20 ml), then dried (Na2SO4) and concentrated in vacuo. The residue was passed through a short plug of basic alumina eluting with ethyl acetate to afford the title compound as a colourless oil (34 mg, 11%). This was converted to its oxalate salt and crystallised from acetone to give a white solid mp 80-85° C. the mixture heated under reflux for 2.5 h The reaction mixture was concentrated in vacuo the residue chromatographed on silica gel eluting with dichloromethane/methanol/0.88 ammonia solution (200:10:1) The colourless oil obtained washed with water (2×20 ml) dried (Na2SO4) concentrated in vacuo

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

Procedure: A stirred solution of N-(4-piperidylmethyl) 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxarnide (E21, 220 mg, 0.70 mmole) in acetonitrile (8 ml) was treated with diisopropylethylamine (0.24 ml, 1.4 mmole) and N-(2-bromoethyl)methanesulphonamide (D14, 160 mg, 0.77 mmole) and the mixture heated under reflux for 2.5 h. The reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel eluting with dichloromethane/methanol/0.88 ammonia solution (200:10:1). The colourless oil obtained was dissolved in chloroform (30 ml) and washed with water (2×20 ml), then dried (Na2SO4) and concentrated in vacuo. The residue was passed through a short plug of basic alumina eluting with ethyl acetate to afford the title compound as a colourless oil (34 mg, 11%). This was converted to its oxalate salt and crystallised from acetone to give a white solid mp 80-85° C. the mixture heated under reflux for 2.5 h The reaction mixture was concentrated in vacuo the residue chromatographed on silica gel eluting with dichloromethane/methanol/0.88 ammonia solution (200:10:1) The colourless oil obtained washed with water (2×20 ml) dried (Na2SO4) concentrated in vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8-((6-iodobenzo[d][1,3]dioxol-5-yl)thio)-9H-purin-6-amine (100 mg, 0.24 mmol) in 5 mL of dry DMF was added N-(2-bromoethyl)methanesulfonamide (150 mg, 0.7 mmol) and Cs2CO3 (150 mg, 0.46 mmol). The resulting mixture was stirred at a temperature of about 25° C. for 3 hrs, condensed under reduced pressure and purified by flash chromatography to provide compound WS35 as white solid (35 mg, 27% yield). condensed under reduced pressure purified by flash chromatography

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8-((6-iodobenzo[d][1,3]dioxol-5-yl)thio)-9H-purin-6-amine (100 mg, 0.24 mmol) in 5 mL of dry DMF was added N-(2-bromoethyl)methanesulfonamide (150 mg, 0.7 mmol) and Cs2CO3 (150 mg, 0.46 mmol). The resulting mixture was stirred at a temperature of about 25° C. for 3 hrs, condensed under reduced pressure and purified by flash chromatography to provide compound WS35 as white solid (35 mg, 27% yield). condensed under reduced pressure purified by flash chromatography

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

Procedure: 4-Piperidine methanol (1.60 g) was dissolved in dry acetonitrile (40 ml), N,N-diisopropylethylamine (5 ml) was added, followed by N-(2-bromoethyl)methanesulphonamide (2.95 g) in acetonitrile (10 ml), and the resulting mixture heated at reflux for 2 h. The solvent was removed in vacuo to leave a gum. This was purified by FCC eluting with System A (75:8:1) to give the title compound (1.80 g) as a solid, m.p. 81°-82°. the resulting mixture heated at reflux for 2 h The solvent was removed in vacuo to leave a gum This was purified by FCC eluting with System A (75:8:1)

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

Procedure: 4-Piperidine methanol (1.60 g) was dissolved in dry acetonitrile (40 ml), N,N-diisopropylethylamine (5 ml) was added, followed by N-(2-bromoethyl)methanesulphonamide (2.95 g) in acetonitrile (10 ml), and the resulting mixture heated at reflux for 2 h. The solvent was removed in vacuo to leave a gum. This was purified by FCC eluting with System A (75:8:1) to give the title compound (1.80 g) as a solid, m.p. 81°-82°. the resulting mixture heated at reflux for 2 h The solvent was removed in vacuo to leave a gum This was purified by FCC eluting with System A (75:8:1)

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

Procedure: A stirred solution of N-(4-piperidylmethyl) 3,4-dihydro-2 H-[1,3]oxazino[3,2-a]indole-10-carboxamide (E21, 220 mg, 0.70 mmole) in acetonitrile (8 ml) was treated with diisopropylethylamine (0.24 ml, 1.4 mmole) and N-(2-bromoethyl)methanesulphonamide (D14, 160 mg, 0.77 mmole) and the mixture heated under reflux for 2.5 h. The reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel eluting with dichloromethane/methanol/0.88 ammonia solution (200:10:1). The colourless oil obtained was dissolved in chloroform (30 ml) and washed with water (2×20 ml), then dried (Na2SO4) and concentrated in vacuo. The residue was passed through a short plug of basic alumina eluting with ethyl acetate to afford the title compound as a colourless oil (34 mg, 11%). This was converted to its oxalate salt and crystallised from acetone to give a white solid mp 80°-85° C. the mixture heated under reflux for 2.5 h The reaction mixture was concentrated in vacuo the residue chromatographed on silica gel eluting with dichloromethane/methanol/0.88 ammonia solution (200:10:1) The colourless oil obtained washed with water (2×20 ml) dried (Na2SO4) concentrated in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of compound (AFD) (0.40 mmol) in dry DMF was added triethylamine (0.45), followed by the alkylating agent Br(CH2)2NHSO2CH3 (0.45 mmol). The resulting mixture was stirred at 80° C. overnight. After completion of the reaction, the cooled mixture was poured into 1M NaOH (150 mL) and extracted with ethyl acetate (2×100 mL). The organic extracts were dried (MgSO4) and the solvent evaporated at the rotary evaporator to leave a gum. Flash chromatography of the residue (SiO2, ether:methanol:ammonium hydroxide (200:10:1)) provided compound (AFV) as a colorless gum: (yield:26%); purity >97% (HPLC); MS: m/z 616.3 (M+1); 1H NMR (DMSO d6): δ 2.1–2.2 (br s, 3H), 2.3–2.4 (m, 5H), 2.75 (s, 3H) 2.9–2.10 (br s, 3H), 3.3–3.4 (m, 6H), 3.5 (m, 3H), 4.65 (m, 2H), 7.15–7.5 (m, 16H). After completion of the reaction extracted with ethyl acetate (2×100 mL) The organic extracts were dried (MgSO4) the solvent evaporated at the rotary evaporator to leave a gum

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

Procedure: A stirred solution of N-(4-piperidylmethyl) 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxarnide (E21, 220 mg, 0.70 mmole) in acetonitrile (8 ml) was treated with diisopropylethylamine (0.24 ml, 1.4 mmole) and N-(2-bromoethyl)methanesulphonamide (D14, 160 mg, 0.77 mmole) and the mixture heated under reflux for 2.5 h. The reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel eluting with dichloromethane/methanol/0.88 ammonia solution (200:10:1). The colourless oil obtained was dissolved in chloroform (30 ml) and washed with water (2×20 ml), then dried (Na2SO4) and concentrated in vacuo. The residue was passed through a short plug of basic alumina eluting with ethyl acetate to afford the title compound as a colourless oil (34 mg, 11%). This was converted to its oxalate salt and crystallised from acetone to give a white solid mp 80-85° C. the mixture heated under reflux for 2.5 h The reaction mixture was concentrated in vacuo the residue chromatographed on silica gel eluting with dichloromethane/methanol/0.88 ammonia solution (200:10:1) The colourless oil obtained washed with water (2×20 ml) dried (Na2SO4) concentrated in vacuo