2-methylsulfonylethanol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:70.01; pressure:0.00; stir:

実験手順: Dilution of the aliquot (2 uL) with DMSO (200 uL).

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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: 4-Fluoro-3-(morpholine-4-sulfonyl)-benzoic acid (Example 6, 5.36 g, 19 mmol) was dissolved in DMF and commercially available 2-methylsulfonyl ethanol (4.8 g, 39 mmol) was added. After five minutes of stirring, sodium hydride (2.4 g of 60% dispersion in mineral oil, 61 mmol) was added. The solution immediately turned black. After 15 min, the reaction was complete. The DMF solution was partitioned between ethyl acetate (150 mL) and brine/HCl (200 mL). The brine solution was discarded, and this was repeated two additional times. All ethyl acetate was dried with magnesium sulfate, and removed under reduced pressure to provide the title compound as a white solid (4.0 g, 74%): 1HNMR (DMSO-d6) δ8.23 (d, J=2 Hz, 1H), 8.02 (dd , J=9 Hz, 2 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 3.62 (m, 4H), 3.12 (m, 4H); MS (−APCI):[M−H]−286; Anal.Calc. for C11H13NO6S: C, 44.99; H, 4.56; N, 4.88. Found: C, 45.45; H, 4.41; N, 4.74. After 15 min The DMF solution was partitioned between ethyl acetate (150 mL) and brine/HCl (200 mL) All ethyl acetate was dried with magnesium sulfate removed under reduced pressure

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

実験手順: 4-Fluoro-3-(morpholine-4-sulfonyl)-benzoic acid (Example 6, 5.36 g, 19 mmol) was dissolved in DMF and commercially available 2-methylsulfonyl ethanol (4.8 g, 39 mmol) was added. After five minutes of stirring, sodium hydride (2.4 g of 60% dispersion in mineral oil, 61 mmol) was added. The solution immediately turned black. After 15 min, the reaction was complete. The DMF solution was partitioned between ethyl acetate (150 mL) and brine/HCl (200 mL). The brine solution was discarded, and this was repeated two additional times. All ethyl acetate was dried with magnesium sulfate, and removed under reduced pressure to provide the title compound as a white solid (4.0 g, 74%): 1HNMR (DMSO-d6) δ8.23 (d, J=2 Hz, 1H), 8.02 (dd , J=9 Hz, 2 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 3.62 (m, 4H), 3.12 (m, 4H); MS (−APCI):[M−H]−286; Anal.Calc. for C11H13NO6S: C, 44.99; H, 4.56; N, 4.88. Found: C, 45.45; H, 4.41; N, 4.74. After 15 min The DMF solution was partitioned between ethyl acetate (150 mL) and brine/HCl (200 mL) All ethyl acetate was dried with magnesium sulfate removed under reduced pressure

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

実験手順: To a solution of 1-bromo-3,5-difluorobenzene (30.6 mL, 0.266 mole) and 2-(methylsulfonyl)ethanol (66 g, 0.531 mole) in DMSO (240 mL) was added potassium tert-butoxide (76.6 g, 0.682 mole) at 0° C. The resulting mixture was stirred at room temperature for 3 h and quench with 4N HCl slowly to pH≦1. The desired product was extracted with Et2O (12 L) until no product was detected in the aqueous layer. The Et2O was evaporated under reduced pressure to one third the amount of the solvent and washed with 1N NaOH (12 L). Then, the NaOH solution was adjusted to pH=3 and extracted with Et2O until no desired product was detected in the aqueous layer. The Et2O was evaporated under reduced pressure and passed through an Al2O3 column eluted with Et2O to afford 3-bromo-5-fluorophenol as a colorless oil (48 g, 94% yield). LC-MS 190.33 (M+H); Analytical HPLC=2.26 minutes (0-100% CH3CN in H2O with 0.1% TFA in a 4-min run); 1H NMR (400 MHz, CD3OD) δ ppm 6.88-6.64 (m, 2H), 6.58-6.30 (m, 1H), 4.99 (s, 1H). quench with 4N HCl slowly to pH≦1 The desired product was extracted with Et2O (12 L) until no product The Et2O was evaporated under reduced pressure to one third the amount of the solvent washed with 1N NaOH (12 L) extracted with Et2O until no desired product The Et2O was evaporated under reduced pressure eluted with Et2O

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

実験手順: To a solution of methanesulfonyl chloride (484 mg, 4.23 mmol) in 15 mL of DCM at 0° C. was added 2-methanesulfonyl-ethanol (500 mg, 4.03 mmol) in 10 mL of DCM followed by DIEA (1.05 mL, 6.05 mmol) under Ar. The mixture was warmed to RT and stirred for 20 h under Ar. The mixture was treated with 100 mL of EtOAc and washed with H2O (3×20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent in vacuo gave 534 mg (66%) of the title compound as a brown oil. 1H-NMR (CDCl3; 400 MHz): δ 4.67 (d, 2H, J=5.5 Hz), 3.46 (d, 2H, J=5.5 Hz), 3.11 (s, 3H), 3.04 (s, 3H). washed with H2O (3×20 mL), brine (20 mL) dried (Na2SO4) Removal of the solvent in vacuo

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

実験手順: To a solution of methanesulfonyl chloride (484 mg, 4.23 mmol) in 15 mL of DCM at 0° C. was added 2-methanesulfonyl-ethanol (500 mg, 4.03 mmol) in 10 mL of DCM followed by DIEA (1.05 mL, 6.05 mmol) under Ar. The mixture was warmed to RT and stirred for 20 h under Ar. The mixture was treated with 100 mL of EtOAc and washed with H2O (3×20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent in vacuo gave 534 mg (66%) of the title compound as a brown oil. 1H-NMR (CDCl3; 400 MHz): δ 4.67 (d, 2H, J=5.5 Hz), 3.46 (d, 2H, J=5.5 Hz), 3.11 (s, 3H), 3.04 (s, 3H). washed with H2O (3×20 mL), brine (20 mL) dried (Na2SO4) Removal of the solvent in vacuo

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: General procedure of coupling alcohol to aryl halides: A mixture of 4-[6-(2-fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (103 mg, 0.2 mmole), cesium carbonate (130 mg, 0.4 mmole), copper iodide (8 mg, 0.04 mmole), and 1,10-phenanthroline (14 mg, 0.08 mmole) in 2-methanesulfonyl-ethanol (3 mL) was heated under microwave irradiation at 150° C. for 1 hour. The crude mixture was purified by HPLC to provide The crude mixture was purified by HPLC to provide

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

実験手順: Sodium hydride (40 mg, 1 mmol, 60%) was added to a solution of 2-(methansulphonyl)ethanol (124 mg, 1 mmol) in DMF (5 mL, anhydrous) and stirred at room temperature for 10 min. This mixture (0.6 mL) was added to a solution of 7-(3-chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-4-amine (50 mg, 0.1 mmol) in DMF (1 mL) and was heated in a sealed tube via microwave at 150° C. for 20 min. Solvent was removed in vacuo and the residue was purified by column chromatography to yield the product as a light brown solid (5 mg). was heated in a sealed tube via microwave at 150° C. for 20 min Solvent was removed in vacuo the residue was purified by column chromatography