| 80% |
With sodium hydride; In tetrahydrofuran; at 0℃; for 1h; |
a. 2-Cyclobutoxy-5-nitro-pyridine A mixture of 2-chloro-5-nitropyridine (7.12 g, 45.0 mmol) and <strong>[2919-23-5]cyclobutanol</strong> (3.40 g, 47.2 mmol) in THF (30 mL) was vigorously stirred at 0 C. while NaH (1.18 g, 46.7 mmol) was added in three portions over ~10-20 s under air (Caution: Extensive gas evolution). Reaction residue was rinsed down with additional THF (5 mL), followed by stirring under positive argon pressure in the ice bath for 1-2 more minutes. The ice bath was then removed and the brown homogeneous solution was stirred for 1 h. The reaction mixture was concentrated under reduced pressure at 80 C., taken up in 0.75 M EDTA (tetrasodium salt) (150 mL), and extracted with CH2Cl2 (1*100 mL, 1*50 mL). The combined organic layers were dried (Na2SO4), concentrated, taken up in MeOH (2*100 mL) and concentrated under reduced pressure at 60 C. to provide the title compound as a thick dark amber oil that crystallized upon standing (7.01 g, 80%). 1H NMR (CDCl3) delta 9.04 (dd, J=2.84 and 0.40 Hz, 1H), 8.33 (dd, J=9.11 and 2.85 Hz, 1H), 6.77 (dd, J=9.11 and 0.50 Hz, 1H), 5.28 (m, 1H), 2.48 (m, 2H), 2.17 (m, 2H), 1.87 (m, 1H), 1.72 (m, 1H). |
| 80% |
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 1.03611 - 1.05556h; |
A mixture of 2-chloro-5-nitropyridine (7.12 g, 45.0 mmol) and <strong>[2919-23-5]cyclobutanol</strong> (3.40 g, 47.2 mmol) in THF (30 mL) was vigorously stirred at 0 C. while NaH (1.18 g, 46.7 mmol) was added in three portions over ~10-20 s under air (Caution: Extensive gas evolution). Reaction residue was rinsed down with additional THF (5 mL), followed by stirring under positive argon pressure in the ice bath for 1-2 more minutes. The ice bath was then removed and the brown homogeneous solution was stirred at "rt" for 1 h. The reaction was concentrated under reduced pressure at 80 C., taken up in 0.75 M EDTA (tetrasodium salt) (150 mL), and extracted with DCM (1*100 mL, 1*50 mL). The combined organic layers were dried (Na2SO4), concentrated, taken up in MeOH (2*100 mL) and concentrated under reduced pressure at 60 C. to provide the title compound as a thick dark amber oil that crystallized upon standing (7.01 g, 80%). 1H NMR (300 MHz, CDCl3) delta 9.04 (dd, J=2.84 and 0.40 Hz, 1H), 8.33 (dd, J=9.11 and 2.85 Hz, 1H), 6.77 (dd, J=9.11 and 0.50 Hz, 1H), 5.28 (m, 1H), 2.48 (m, 2H), 2.17 (m, 2H), 1.87 (m, 1H), 1.72 (m, 1H). |
| 80% |
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 1.03611 - 1.05556h; |
A mixture of 2-chloro-5-nitropyridine (7.12 g, 45.0 mmol) and <strong>[2919-23-5]cyclobutanol</strong> (3.40 g, 47.2 mmol) in THF (30 mL) was vigorously stirred at 0 C. while NaH (1.18 g, 46.7 mmol) was added in three portions over ~10-20 s under air (Caution: Extensive gas evolution). Reaction residue was rinsed down with additional THF (5 mL), followed by stirring under positive argon pressure in the ice bath for 1-2 more minutes. The ice bath was then removed and the brown homogeneous solution was stirred at RT for 1 h. The reaction was concentrated under reduced pressure at 80 C., taken up in 0.75 M EDTA (tetrasodium salt) (150 mL), and extracted with DCM (1*100 mL, 1*50 mL). The combined organic layers were dried (Na2SO4), concentrated, taken up in MeOH (2*100 mL) and concentrated under reduced pressure at 60 C. to provide the title compound as a thick dark amber oil that crystallized upon standing (7.01 g, 80%). 1H NMR (300 MHz, CDCl3) delta 9.04 (dd, J=2.84 and 0.40 Hz, 1H), 8.33 (dd, J=9.11 and 2.85 Hz, 1H), 6.77 (dd, J=9.11 and 0.50 Hz, 1H), 5.28 (m, 1H), 2.48 (m, 2H), 2.17 (m, 2H), 1.87 (m, 1H), 1.72 (m, 1H). |
| 80% |
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 1.01944 - 1.03889h; |
EXAMPLE 17; 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (6-cyclobutoxy-pyridin-3-yl)-amide; a. 2-Cyclobutoxy-5-nitro-pyridine; A mixture of 2-chloro-5-nitropyridine (7.12 g, 45.0 mmol) and <strong>[2919-23-5]cyclobutanol</strong> (3.40 g, 47.2 mmol) in THF (30 mL) was vigorously stirred at 0 C. while NaH (1.18 g, 46.7 mmol) was added in three portions over 10-20 s under air (Caution: Extensive gas evolution). Reaction residue was rinsed down with additional THF (5 mL), followed by stirring under positive argon pressure in the ice bath for 1-2 more minutes. The ice bath was then removed and the brown homogeneous solution was stirred at ?rt? for 1 h. The reaction was concentrated under reduced pressure at 80 C., taken up in 0.75 M EDTA (tetrasodium salt) (150 mL), and extracted with DCM (1×100 mL, 1×50 mL). The combined organic layers were dried (Na2SO4), concentrated, taken up in MeOH (2×100 mL) and concentrated under reduced pressure at 60 C. to provide the title compound as a thick dark amber oil that crystallized upon standing (7.01 g, 80%). 1H NMR (300 MHz, CDCl3) delta 9.04 (dd, J=2.84 and 0.40 Hz, 1H), 8.33 (dd, J=9.11 and 2.85 Hz, 1H), 6.77 (dd, J=9.11 and 0.50 Hz, 1H), 5.28 (m, 1H), 2.48 (m, 2H), 2.17 (m, 2H), 1.87 (m, 1H), 1.72 (m, 1H). |
| 80% |
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 1.01933 - 1.03883h; |
b. 2-Cyclobutoxy-5-nitro-pyridine A mixture of 2-chloro-5-nitropyridine (7.12 g, 45.0 mmol) and <strong>[2919-23-5]cyclobutanol</strong> (3.40 g, 47.2 mmol) in THF (30 mL) was vigorously stirred at 0 C. while NaH (1.18 g, 46.7 mmol) was added in three portions over ~10-20 s under air (Caution: Extensive gas evolution). Reaction residue was rinsed down with additional THF (5 mL), followed by stirring under positive argon pressure in the ice bath for 1-2 more minutes. The ice bath was then removed and the brown homogeneous solution was stirred at RT for 1 h. The reaction was concentrated under reduced pressure at 80 C., taken up in 0.75 M EDTA (tetrasodium salt) (150 mL), and extracted with DCM (1*100 mL, 1*50 mL). The combined organic layers were dried (Na2SO4), concentrated, taken up in MeOH (2*100 mL) and concentrated under reduced pressure at 60 C. to provide the title compound as a thick dark amber oil that crystallized upon standing (7.01 g, 80%). 1H NMR (300 MHz, CDCl3) delta 9.04 (dd, J=2.84 and 0.40 Hz, 1H), 8.33 (dd, J=9.11 and 2.85 Hz, 1H), 6.77 (dd, J=9.11 and 0.50 Hz, 1H), 5.28 (m, 1H), 2.48 (m, 2H), 2.17 (m, 2H), 1.87 (m, 1H), 1.72 (m, 1H). |
| 80% |
With sodium hydride; In tetrahydrofuran; at 0℃; for 1.01944 - 1.02222h; |
EXAMPLE 6; 4-[6-Amino-5-(methoxyimino-methyl)-pyrimidin-4-yl]-piperazine-l-carboxylic acid (beta-cyclobutoxy-pyridin-B-y^-amide; a. 2-Cyclobutoxy-5-nitro-pyridineA mixture of 2-chloro-5-nitropyridine (7.12 g, 45.0 mmol) and <strong>[2919-23-5]cyclobutanol</strong> (3.40 g, 47.2 mmol) in THF (30 mL) was vigorously stirred at 0 C while NaH (1.18 g, 46.7 mmol) was added in three portions over -10-20 s under air (Caution: Extensive gas evolution). Reaction residue was rinsed down with additional THF (5 mL), followed by stirring under positive argon pressure in the ice bath for 1-2 more minutes. The ice bath was then removed and the brown homogeneous solution was stirred for 1 h. The reaction mixture was concentrated under reduced pressure at 80 C, taken up in 0.75 M EDTA (tetrasodium salt) (150 mL), and extracted with CH2Cl2 (1 X 100 mL, 1 X 50 mL). The combined organic layers were dried (Na2SO4), concentrated, taken up in MeOH (2 x 100 mL) and concentrated under reduced pressure at 60 C to provide the title compound as a thick dark amber oil that crystallized upon standing (7.01 g, 80%). 1H NMR (CDCl3) delta 9.04 (dd, J = 2.84 and 0.40 Hz, IH), 8.33 (dd, J = 9.11 and 2.85 Hz, IH), 6.77 (dd, J = 9.11 and 0.50 Hz, IH), 5.28 (m, IH), 2.48 <m, 2H), 2.17 (m, 2H), 1.87 (m, IH), 1.72 (m, IH). |
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