2-(azetidin-3-yl)propan-2-ol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared in an analogous fashion to that described in Stage 128.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and 2-azetidin-3-yl-propan-2-ol (WO2010138589) to afford an off-white crystalline product. HPLC (Condition 4) tR=5.84 min, UPLC-MS (Condition 7) m/z=474.1 [M+H]+. to afford an off-white crystalline product

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared in an analogous fashion to that described in Stage 128.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and 2-azetidin-3-yl-propan-2-ol (WO2010138589) to afford an off-white crystalline product. HPLC (Condition 4) tR=5.84 min, UPLC-MS (Condition 7) m/z=474.1 [M+H]+. to afford an off-white crystalline product

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.075 g, 0.20 mmol), 2-azetidin-3-ylpropan-2-ol (0.023 g, 0.20 mmol) in DCE (2 mL), trimethoxymethane (0.215 mL, 2 mmol) and acetic acid (0.012 mL, 0.2 mmol) was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (0.042 g, 0.2 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between DCM and water, and the organic layer was separated, washed with brine, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give 315 as an off-white solid (0.020 g, 23%). LCMS (Method G): RT=5.61 min, [M+H]+ 477.2. 1H NMR (CDCl3, 400 MHz) δ 8.11-8.07 (m, 1 H); 7.72-7.69 (m, 1 H); 7.35-7.26 (m, 2 H); 4.42-4.31 (m, 4 H); 3.89-3.82 (m, 11 H); 3.62-3.12 (m, 2H); 2.94 (s, 3 H); 2.70-2.55 (m, 1 H); 1.18 (s, 6 H) the reaction mixture was stirred for 18 h at room temperature The reaction mixture was partitioned between DCM and water the organic layer was separated washed with brine dried over sodium sulphate concentrated The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (300 mg, 1.01 mmol) in DCE (20 mL) was added 2-azetidin-3-ylpropan-2-ol (118 mg, 1.02 mmol), trimethyl orthoformate (1.11 mL, 10.14 mmol) and acetic acid (0.06 mL, 1.01 mmol). The reaction mixture was stirred at room temperature for 6 h, sodium triacetoxyborohydride (323 mg, 1.52 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give the title compound as a pale yellow oil (90 mg, 23%). LCMS (Method A): RT=2.37 min, [M+H]+ 395.2 the resulting mixture stirred for a further 18 h the cartridge was washed with MeOH the desired product eluted with 2 M NH3 in MeOH The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.075 g, 0.20 mmol), 2-azetidin-3-ylpropan-2-ol (0.023 g, 0.20 mmol) in DCE (2 mL), trimethoxymethane (0.215 mL, 2 mmol) and acetic acid (0.012 mL, 0.2 mmol) was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (0.042 g, 0.2 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between DCM and water, and the organic layer was separated, washed with brine, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 10:90) to give 315 as an off-white solid (0.020 g, 23%). LCMS (Method G): RT=5.61 min, [M+H]+ 477.2. 1H NMR (CDCl3, 400 MHz) δ 8.11-8.07 (m, 1 H); 7.72-7.69 (m, 1 H); 7.35-7.26 (m, 2 H); 4.42-4.31 (m, 4 H); 3.89-3.82 (m, 11 H); 3.62-3.12 (m, 2 H); 2.94 (s, 3 H); 2.70-2.55 (m, 1H); 1.18 (s, 6 H) the reaction mixture was stirred for 18 h at room temperature The reaction mixture was partitioned between DCM and water the organic layer was separated washed with brine dried over sodium sulphate concentrated The residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 10:90)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (300 mg, 1.01 mmol) in DCE (20 mL) was added 2-azetidin-3-ylpropan-2-ol (118 mg, 1.02 mmol), trimethyl orthoformate (1.11 mL, 10.14 mmol) and acetic acid (0.06 mL, 1.01 mmol). The reaction mixture was stirred at room temperature for 6 h, sodium triacetoxyborohydride (323 mg, 1.52 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give the title compound as a pale yellow oil (90 mg, 23%). LCMS (Method A): RT=2.37 min, [M+H]+ 395.2 the resulting mixture stirred for a further 18 h the cartridge was washed with MeOH the desired product eluted with 2 M NH3 in MeOH The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared in an analogous fashion to that described in Stage 128.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and 2-azetidin-3-yl-propan-2-ol (WO2010138589) to afford an off-white crystalline product. HPLC (Condition 4) tR=5.84 min, UPLC-MS (Condition 7) m/z=474.1 [M+H]+. to afford an off-white crystalline product