反应详情

Activated magnesium powder (19.2 g, 0.792 moles) is added to a dry 3 L flask fitted with a condensor and a drop funnel. The entire apparatus is heated with a gun dry under vacuum and allowed to cool. Enough ether is added to cover the magnesium. 3-Bromopentane (100 g, 0.662 mmol) is added to the addition funnel in 175 ml of diethyl ether. A ⅓ of the bromopentane solution is added to the magnesium and the reaction mixture is stirred under nitrogen until bubbling occurs. Then, the rest is dripped in at such a rate that the bubbling continues gently. The reaction is stirred for 30 minutes after bubbling ceases. Next, 2,2-dimethyl-N-(6-methyl-pyridazine-3-yl)-propionamide (21.3 g, 0.110 mmol) dissolved in 225 ml of dry THF is added dropwise. The reaction mixture is stirred for 1 hour. Saturated sodium tartrate (1 L) is carefully added, and the reaction is stirred for 30 minutes. The reaction mixture is transferred to a larger flask, 2 L of ethyl acetate is added, and the reaction is stirred 1 hour more. The layers are separate and the aqueous layer is extracted several times with ethyl acetate. The organic extracts are combined, and the solvents are evaporated. The residue is taken up in 600 mL of dichloromethane, and iodine (28 g, 0.110 mol) is added. The reaction is stirred for 2 hours. The organic layer is washed once with aqueous solution of sodium sulfite and then with water. The organic layer is dried over sodium sulfate, filtered, and evaporated to red oil. The crude product is purified via silica gel chromatography using a hexanes:ethyl acetate gradient. The product fractions are combined and evaporated. The residue is triturated in ethyl acetate and a light tan solid is filtered to obtain 12.0 g (45.6 mmol, 41%) of the title compound. 1H-NMR (DMSO-d6), δ 9.88 (s, 1H); 7.59 (s, 1H); 2.60 (s, 3H); 2.39-2.42 (m, 1H); 1.21-1.37 (m, 2H); 1.38-1.43 (m, 2H); 1.23 (s, 9H); 0.71 (t, J=7.49 Hz, 6H) ppm. MS/ES+=264.

1. customfitted with a condensor and a drop funnel
2. temperatureThe entire apparatus is heated with a gun
3. customdry under vacuum
4. temperatureto cool
5. additionEnough ether is added
6. customuntil bubbling
7. stirringThe reaction is stirred for 30 minutes
8. customafter bubbling ceases
9. additionis added dropwise
10. stirringThe reaction mixture is stirred for 1 hour
11. stirringthe reaction is stirred for 30 minutes
12. customThe reaction mixture is transferred to a larger flask
13. stirringthe reaction is stirred 1 hour more
14. customThe layers are separate
15. extractionthe aqueous layer is extracted several times with ethyl acetate
16. customthe solvents are evaporated
17. stirringThe reaction is stirred for 2 hours
18. washThe organic layer is washed once with aqueous solution of sodium sulfite
19. dry with materialThe organic layer is dried over sodium sulfate
20. filtrationfiltered
21. customevaporated to red oil
22. customThe crude product is purified via silica gel chromatography
23. customevaporated
24. customThe residue is triturated in ethyl acetate
25. filtrationa light tan solid is filtered