1-chloro-2-iodoethane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-(2-chloro-6-morpholino-9H-purin-9-yl)-2-methylbutan-2-ol (360 mg, 1.1 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.25 mL, 1.7 mmol) in THF (8.1 mL) was cooled to −42° C. and treated with a solution of 2.5M n-butyllithium in hexane (BuLi, 2.0 mL, 5.0 mmol) dropwise over 5 minutes. After 30 minutes at −42° C., 1-chloro-2-iodoethane (0.51 mL, 5.4 mmol) was added and the reaction mixture was slowly warmed to 0° C. over 1 hr. The mixture was quenched with a saturated solution of NH4Cl, and diluted with ethyl acetate. The aqueous layer was extracted into ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford 4-(2-chloro-8-iodo-6-morpholino-9H-purin-9-yl)-2-methylbutan-2-ol as a white foam (390 mg, 78%). LC/MS (ESI+): m/z 452 (M+H) The mixture was quenched with a saturated solution of NH4Cl diluted with ethyl acetate The aqueous layer was extracted into ethyl acetate (3×) the combined organics were dried over sodium sulfate filtered absorbed onto celite for purification by flash chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-(2-(2-chloro-6-morpholino-9H-purin-9-yl)ethyl)cyclopropanol (220 mg, 0.68 mmol) and N,N,N′,N′-tetramethylethylene-diamine (0.15 mL, 1.0 mmol) in THF (4.9 mL) was cooled to −42° C. and treated with a solution of 2.5M n-butyllithium in hexane (1.5 mL, 3.7 mmol) dropwise over 5 minutes. After 30 minutes at −42° C., 1-chloro-2-iodoethane (0.31 mL, 3.3 mmol) was added and the reaction mixture was slowly warmed to 0° C. over 1 hr. The mixture was quenched with a saturated solution of NH4Cl, and diluted with ethyl acetate. The aqueous layer was extracted into ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford 1-(2-(2-chloro-8-iodo-6-morpholino-9H-purin-9-yl)ethyl)cyclopropanol as a colorless oil (220 mg, 71%). LC/MS (ESI+): m/z 450 (M+H) The mixture was quenched with a saturated solution of NH4Cl diluted with ethyl acetate The aqueous layer was extracted into ethyl acetate (3×) the combined organics were dried over sodium sulfate filtered absorbed onto celite for purification by flash chromatography

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

Procedure: To a solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (1.0 g, 3.1 mmol) and N,N,N′,N′-tetramethylenediamine (0.7 mL, 4.6 mmol) in anhydrous THF (23 mL) at −42° C. was added 2.5 M n-butyllithium solution in hexane (4.3 mL, 11.0 mmol) dropwise down the side of the reaction flask. The reaction was stirred at cold temperature and maintained for 1 h before 1-chloro-2-iodoethane (1.4 mL, 15 mmol) was introduced. Stirring was continued for 1.5 h period. LC-MS indicated the reaction had reached complete conversion to the desired product. The reaction mixture was subsequently quenched and worked up with sat. NH4Cl aqueous solution which was extracted with EtOAc (3 times), dried over MgSO4, filtered and concentrated in vacuo to give 4-(2-chloro-8-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (1.4 g, 84% yield) determined by LC-MS to be >90% purity. MS (ESI+): m/z 450.1 (M+H+) was introduced Stirring

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

Procedure: A solution of 13 (124 mg, 0.49 mmol) in 2.0 mL anhydrous THF was cooled to −20° C. and treated with TMEDA (0.26 mL, 1.71 mmol) followed by n-BuLi (0.69 mL of a 2.5 M solution in hexanes, 1.71 mmol) in a slow dropwise manner. The resulting gold solution stirred for 4 h at −20° C. The reaction mixture was treated with 1-chloro-2-iodoethane (0.126 mL, 1.71 mmol) and stirred for 15 min at 25° C. The reaction was diluted with H2O (30 mL), extracted with Et2O (3×20 mL), and the combined organic extracts were washed with saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5×10 cm, 0-10% EtOAc/hexane gradient) yielded recovered 13 (51.8 mg, 41%) and 14 (85.5 mg, 46%) as a white solid: mp 82-84° C.; 1H NMR (CDCl3, 400 MHz) δ 7.72 (d, J=8.2 Hz, 1H), 7.21 (t, J=6.0 Hz, 1H), 7.01 (br s, 1H), 6.72 (dd, J=1.2, 8.2 Hz, 1H), 5.21 (s, 2H), 3.47 (s, 3H), 1.49 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 156.0, 152.5, 140.1, 129.5, 113.4, 108.9, 94.8, 82.4, 80.9, 54.4, 28.3; IR (film) νmax 3388, 2977, 1736, 1592, 1515, 1465, 1406, 1252, 1226, 1153, 1005 cm−1; FABHRMS (NBA/CsI) m/z 511.9351 (C13H18INO4+C+ requires 511.9335). Anal. Calcd for C13H18INO4: C, 41.18; H, 4.78; N, 3.69. Found: C, 41.19; H, 5.11; N, 3.79. extracted with Et2O (3×20 mL) the combined organic extracts were washed with saturated aqueous NaCl dried (Na2SO4) concentrated under reduced pressure Flash chromatography (SiO2, 2.5×10 cm, 0-10% EtOAc/hexane gradient) yielded recovered 13 (51.8 mg, 41%) and 14 (85.5 mg, 46%) as a white solid

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

Procedure: A solution of 23 (0.435 g 1.43 mmol) in 5.7 mL anhydrous THF was cooled to −25° C. and treated with TMEDA (0.758 mL, 5.0 mmol) followed by n-BuLi (2.29 mL of a 2.5 M solution in hexane, 5.0 mmol) in a slow dropwise manner. The resulting gold solution was stirred for 2 h at −25° C. The reaction mixture was treated with 1-chloro-2-iodoethane (0.37 mL, 5.0 mmol) and stirred for 15 min at 25° C. The reaction was diluted with H2O (40 mL), extracted with Et2O (3×20 mL), and the combined organic extracts were washed with saturated aqueous NaCl, dried Na2SO4) and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5×15 cm, 0-7% EtOAc/hexane gradient) yielded 24 (490 mg, 80%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.03 (d, J=12.8 Hz, 1H), 7.78 (d, J=12.5 Hz, 1H), 7.42 (m, 2H), 7.14 (br s, 1H), 5.20 (s, 2H), 3.74 (s, 3H), 1.56 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 154.7, 152.6, 135.1, 134.8, 127.6, 127.4, 125.1, 125.0, 122.2, 113.0, 100.5, 87.7, 81.1, 58.5, 28.4; IR (film) νmax 3391, 2977, 2933, 1732, 1524, 1367, 1340, 1276, 1228, 1157 cm−1; FABHRMS (NBA/NaI) m/z 430.0507 (C17H20INO4+H+ requires 430.0515). extracted with Et2O (3×20 mL) the combined organic extracts were washed with saturated aqueous NaCl, dried Na2SO4) and concentrated under reduced pressure

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

Procedure: A solution of 23 (0.435 g 1.43 mmol) in 5.7 mL anhydrous THF was cooled to −25° C. and treated with TMEDA (0.758 mL, 5.0 mmol) followed by n-BuLi (2.29 mL of a 2.5 M solution in hexane, 5.0 mmol) in a slow dropwise manner. The resulting gold solution was stirred for 2 h at −25° C. The reaction mixture was treated with 1-chloro-2-iodoethane (0.37 mL, 5.0 mmol) and stirred for 15 min at 25° C. The reaction was diluted with H2O (40 mL), extracted with Et2O (3×20 mL), and the combined organic extracts were washed with saturated aqueous NaCl, dried Na2SO4) and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5×15 cm, 0-7% EtOAc/hexane gradient) yielded 24 (490 mg, 80%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.03 (d, J=12.8 Hz, 1H), 7.78 (d, J=12.5 Hz, 1H), 7.42 (m, 2H), 7.14 (br s, 1H), 5.20 (s, 2H), 3.74 (s, 3H), 1.56 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 154.7, 152.6, 135.1, 134.8, 127.6, 127.4, 125.1, 125.0, 122.2, 113.0, 100.5, 87.7, 81.1, 58.5, 28.4; IR (film) νmax 3391, 2977, 2933, 1732, 1524, 1367, 1340, 1276, 1228, 1157 cm−1; FABHRMS (NBA/NaI) m/z 430.0507 (C17H20INO4+H+ requires 430.0515). extracted with Et2O (3×20 mL) the combined organic extracts were washed with saturated aqueous NaCl, dried Na2SO4) and concentrated under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine (10 g) in anhydrous dimethylformamide (150 ml), 55% NaH (1.75 g) was added at room temperature. After stirring for 1 hours, a solution of 2-chloro-1-iodo-ethane (7 g) in dimethylformamide (50 ml) was added all at one time. The temperature was maintained at 50° C. for 1 hour then Na2CO3 (5.82 g) was added and the whole was maintained at 50° C. for a further 3 hours. The whole was poured into water and extraction made with ethyl acetate. After a standard working up, procedure, 2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine (6.24 g; 57%) was obtained as a transparent oil .HCl m.p. 140°-170° C. the whole was maintained at 50° C. for a further 3 hours

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine (10 g) in anhydrous dimethylformamide (150 ml), 55% NaH (1.75 g) was added at room temperature. After stirring for 1 hours, a solution of 2-chloro-1-iodo-ethane (7 g) in dimethylformamide (50 ml) was added all at one time. The temperature was maintained at 50° C. for 1 hour then Na2CO3 (5.82 g) was added and the whole was maintained at 50° C. for a further 3 hours. The whole was poured into water and extraction made with ethyl acetate. After a standard working up, procedure, 2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine (6.24 g; 57%) was obtained as a transparent oil .HCl m.p. 140°-170° C. the whole was maintained at 50° C. for a further 3 hours

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

Procedure: 500 mg (1.01 mmol) of 2-[3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[2-(trifluoromethyl)benzyl]-acetamide from Example 243A are dissolved in 10 ml of toluene with 230 mg (1.01 mmol) of benzyltriethylammonium chloride. Next, a solution of 658 mg (2.02 mmol) of caesium carbonate, dissolved in 1.0 ml water, is added, and the mixture vigorously stirred at RT for 30 mins. After addition of 1.92 g (10.13 mmol) of 1-iodo-2-chloroethane, the mixture is heated for 7 hrs at 80° C. with vigorous stirring. The suspension is then diluted with ethyl acetate and washed once each with water, 10% sodium thiosulphate and saturated ammonium chloride solution. The organic phase is dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 9]. 195 mg (41% of theory) of the target compound are thus obtained. is added the mixture is heated for 7 hrs at 80° C. with vigorous stirring washed once each with water, 10% sodium thiosulphate and saturated ammonium chloride solution The organic phase is dried over sodium sulphate filtered concentrated in vacuo The crude product is purified by preparative HPLC [Method 9] 195 mg (41% of theory) of the target compound are thus obtained

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-(2-chloro-6-morpholino-9H-purin-9-yl)-2-methylbutan-2-ol (360 mg, 1.1 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.25 mL, 1.7 mmol) in THF (8.1 mL) was cooled to −42° C. and treated with a solution of 2.5M n-butyllithium in hexane (BuLi, 2.0 mL, 5.0 mmol) dropwise over 5 minutes. After 30 minutes at −42° C., 1-chloro-2-iodoethane (0.51 mL, 5.4 mmol) was added and the reaction mixture was slowly warmed to 0° C. over 1 hr. The mixture was quenched with a saturated solution of NH4Cl, and diluted with ethyl acetate. The aqueous layer was extracted into ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford 4-(2-chloro-8-iodo-6-morpholino-9H-purin-9-yl)-2-methylbutan-2-ol as a white foam (390 mg, 78%). LC/MS (ESI+): m/z 452 (M+H) The mixture was quenched with a saturated solution of NH4Cl diluted with ethyl acetate The aqueous layer was extracted into ethyl acetate (3×) the combined organics were dried over sodium sulfate filtered absorbed onto celite for purification by flash chromatography