4-methyl-1,4lambda5-azaphosphinane 4-oxide;hydrochloride

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

実験手順: 2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (500 mg, 1.99 mmol), 4-methyl-1,4-azaphosphinane 4-oxide hydrochloride (406 mg, 2.39 mmol, prepared according to the method described in WO 2008/010985), and DIEA (522 μL, 2.99 mmol) were combined in DMF (5.0 mL) and stirred at room temperature overnight. The solvent was then evaporated in vacuo and the crude residue was purified by reverse phase HPLC (MeCN/water w/0.025% TFA) to afford the title compound as a colorless foam. The solvent was then evaporated in vacuo the crude residue was purified by reverse phase HPLC (MeCN/water w/0.025% TFA)

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

実験手順: 5-(4-(4-(6-methylpyridin-3-yloxy)-3-methylphenylamino)quinazolin-6-yl)furan-2-carbaldehyde, 4-methyl-1,4-azaphosphinane 4-oxide hydrogen chloride salt and DIPEA were suspended in dichloromethane (20 mL). Sequentially, acetic acid (3 drops) and sodium triacetoxyborohydride (2 equiv.) were added at room temperature. The mixture was stirred at room temperature until the starting material disappeared. The reaction was quenched with 2N NaOH aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as yellow crystalline solid. LCMS ESI(+) m/z: 554 (M+1). 1H NMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 8.47 (s, 1H), 8.18 (d, 1H), 8.12 (s, 1H), 7.77 (d, 1H), 7.69 (m, 1H), 7.60 (d, 1H), 7.28 (m, 2H), 6.99 (m, 2H), 6.51 (d, 1H), 3.83 (s, 2H), 3.73 (m, 2H), 3.24 (m, 2H), 2.95 (m, 2H), 2.51 (s, 3H), 2.27 (s, 3H), 2.04 (m, 2H), 1.58 (m, 3H). The reaction was quenched with 2N NaOH aqueous solution extracted with dichloromethane The combined organic layer and extracts were dried over anhydrous magnesium sulfate filtered concentrated The residue was purified by flash chromatography eluting with 20% methanol in dichloromethane

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

実験手順: To a mixture of 4-methyl-1,4-azaphosphinane 4-oxide hydrogen chloride salt (1.69 g), sodium iodide (150 mg) and Cs2CO3 (7.15 g) in acetone (50 mL) was added allyl chloride dropwise. The mixture was stirred at room temperature overnight, filtered and concentrated to provide the desired product as white solid (1.45 g). filtered concentrated

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

実験手順: A solution of 1-benzyl-4-methyl-1,4-azaphosphinane 4-oxide (5 g) in methanol (50 mL) and 3 M HCl (10 mL) with palladium on carbon (10%, 1.0 g) was hydrogenated on a Parr shaker for 24 hours at 60 psi. The mixture was filtered through Celite and all solvents were removed under reduced pressure to give a white crystalline solid, which was used without further purification. The mixture was filtered through Celite all solvents were removed under reduced pressure to give a white crystalline solid, which was used without further purification

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

実験手順: 1-Benzyl-4-methyl-[1,4]azaphosphinane 4-oxide was dissolved in ethanol (100 mL). 1 M HCl (100 mL) was added, along with palladium on carbon (10%, 2.6 g). The mixture was hydrogenated on a Parr shaker for 4 hours at 50 psi. The mixture was filtered through Celite and all solvents were removed under reduced pressure. The product was triturated in hot ethanol (50 mL) and cooled, and the solution was diluted with ether (300 mL). The white crystalline solid was filtered, washed with ether (2×50 mL), hexane (2×50 mL), and dried in vacuo. 4-methyl-[1,4]azaphosphinane 4-oxide hydrochloride was obtained as a white crystalline solid (9.46 g, 94%). 1H NMR (400 MHz, DMSO) δ 3.07 (m, 2H); 2.68 (m, 2H); 1.78 (m, 2H); 1.61 (m, 2H), 1.39 (3H, d, JH-C—P=13.6 Hz.); 31P NMR: δ 29 ppm; ESMS (m/z): (M+1)+ found, 134. The mixture was filtered through Celite all solvents were removed under reduced pressure The product was triturated in hot ethanol (50 mL) cooled the solution was diluted with ether (300 mL) The white crystalline solid was filtered washed with ether (2×50 mL), hexane (2×50 mL) dried in vacuo

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

実験手順: 1-Benzyl-4-methyl-[1,4]azaphosphinane 4-oxide was dissolved in ethanol (100 mL). 1 M HCl (100 mL) was added, along with palladium on carbon (10%, 2.6 g). The mixture was hydrogenated on a Parr shaker for 4 hours at 50 psi. The mixture was filtered through Celite and all solvents were removed under reduced pressure. The product was triturated in hot ethanol (50 mL) and cooled, and the solution was diluted with ether (300 mL). The white crystalline solid was filtered, washed with ether (2×50 mL), hexane (2×50 mL), and dried in vacuo. 4-methyl-[1,4]azaphosphinane 4-oxide hydrochloride was obtained as a white crystalline solid (9.46 g, 94%). 1H NMR (400 MHz, DMSO) δ 3.07 (m, 2H); 2.68 (m, 2H); 1.78 (m, 2H); 1.61 (m, 2H), 1.39 (3H, d, JH-C—P=13.6 Hz.); 31P NMR: δ 29 ppm; ESMS (m/z): (M+1)+ found, 134. The mixture was filtered through Celite all solvents were removed under reduced pressure The product was triturated in hot ethanol (50 mL) cooled the solution was diluted with ether (300 mL) The white crystalline solid was filtered washed with ether (2×50 mL), hexane (2×50 mL) dried in vacuo

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

実験手順: 2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (500 mg, 1.99 mmol), 4-methyl-1,4-azaphosphinane 4-oxide hydrochloride (406 mg, 2.39 mmol, prepared according to the method described in WO 2008/010985), and DIEA (522 μL, 2.99 mmol) were combined in DMF (5.0 mL) and stirred at room temperature overnight. The solvent was then evaporated in vacuo and the crude residue was purified by reverse phase HPLC (MeCN/water w/0.025% TFA) to afford the title compound as a colorless foam. The solvent was then evaporated in vacuo the crude residue was purified by reverse phase HPLC (MeCN/water w/0.025% TFA)

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

実験手順: 2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (500 mg, 1.99 mmol), 4-methyl-1,4-azaphosphinane 4-oxide hydrochloride (406 mg, 2.39 mmol, prepared according to the method described in WO 2008/010985), and DIEA (522 μL, 2.99 mmol) were combined in DMF (5.0 mL) and stirred at room temperature overnight. The solvent was then evaporated in vacuo and the crude residue was purified by reverse phase HPLC (MeCN/water w/0.025% TFA) to afford the title compound as a colorless foam. The solvent was then evaporated in vacuo the crude residue was purified by reverse phase HPLC (MeCN/water w/0.025% TFA)

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

実験手順: 1-Benzyl-4-methyl-[1,4]azaphosphinane 4-oxide was dissolved in ethanol (100 mL). 1 M HCl (100 mL) was added, along with palladium on carbon (10%, 2.6 g). The mixture was hydrogenated on a Parr shaker for 4 hours at 50 psi. The mixture was filtered through Celite and all solvents were removed under reduced pressure. The product was triturated in hot ethanol (50 mL) and cooled, and the solution was diluted with ether (300 mL). The white crystalline solid was filtered, washed with ether (2×50 mL), hexane (2×50 mL), and dried in vacuo. 4-methyl-[1,4]azaphosphinane 4-oxide hydrochloride was obtained as a white crystalline solid (9.46 g, 94%). 1H NMR (400 MHz, DMSO) δ 3.07 (m, 2H); 2.68 (m, 2H); 1.78 (m, 2H); 1.61 (m, 2H), 1.39 (3H, d, JH-C-P=13.6 Hz.); 31P NMR: δ 29 ppm; ESMS (m/z): (M+1)+ found, 134. The mixture was filtered through Celite all solvents were removed under reduced pressure The product was triturated in hot ethanol (50 mL) cooled the solution was diluted with ether (300 mL) The white crystalline solid was filtered washed with ether (2×50 mL), hexane (2×50 mL) dried in vacuo

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

実験手順: 5-(4-(4-(6-methylpyridin-3-yloxy)-3-methylphenylamino)quinazolin-6-yl)furan-2-carbaldehyde, 4-methyl-1,4-azaphosphinane 4-oxide hydrogen chloride salt and DIPEA were suspended in dichloromethane (20 mL). Sequentially, acetic acid (3 drops) and sodium triacetoxyborohydride (2 equiv.) were added at room temperature. The mixture was stirred at room temperature until the starting material disappeared. The reaction was quenched with 2N NaOH aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as yellow crystalline solid. LCMS ESI(+) m/z: 554 (M+1). 1H NMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 8.47 (s, 1H), 8.18 (d, 1H), 8.12 (s, 1H), 7.77 (d, 1H), 7.69 (m, 1H), 7.60 (d, 1H), 7.28 (m, 2H), 6.99 (m, 2H), 6.51 (d, 1H), 3.83 (s, 2H), 3.73 (m, 2H), 3.24 (m, 2H), 2.95 (m, 2H), 2.51 (s, 3H), 2.27 (s, 3H), 2.04 (m, 2H), 1.58 (m, 3H). The reaction was quenched with 2N NaOH aqueous solution extracted with dichloromethane The combined organic layer and extracts were dried over anhydrous magnesium sulfate filtered concentrated The residue was purified by flash chromatography eluting with 20% methanol in dichloromethane

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

実験手順: To a mixture of 4-methyl-1,4-azaphosphinane 4-oxide hydrogen chloride salt (1.69 g), sodium iodide (150 mg) and Cs2CO3 (7.15 g) in acetone (50 mL) was added allyl chloride dropwise. The mixture was stirred at room temperature overnight, filtered and concentrated to provide the desired product as white solid (1.45 g). filtered concentrated

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

実験手順: A solution of 1-benzyl-4-methyl-1,4-azaphosphinane 4-oxide (5 g) in methanol (50 mL) and 3 M HCl (10 mL) with palladium on carbon (10%, 1.0 g) was hydrogenated on a Parr shaker for 24 hours at 60 psi. The mixture was filtered through Celite and all solvents were removed under reduced pressure to give a white crystalline solid, which was used without further purification. The mixture was filtered through Celite all solvents were removed under reduced pressure to give a white crystalline solid, which was used without further purification