Diethyl Malonate → 3-Methyl-2-nitropyridine
反応式
Cl[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Na].[K].[Li].[C:14](OCC)(=O)CC(OCC)=O.C(OC)(=O)CC(OC)=O>>[CH3:14][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1Cl[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Na].[K].[Li].[C:14](OCC)(=O)CC(OCC)=O.C(OC)(=O)CC(OC)=O>>[CH3:14][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1In Scheme 1, step a, chloro-nitropyridine 1 is added in portions to an alkali metal salt of a malonic acid diester in excess malonic diester, such as for example the sodium, potassium or lithium salt of the malonic acid diester in an excess of the malonic acid diester, such as for example diethyl malonate or dimethyl malonate, at a temperature of about 50° C. to about 70° C. The alkali metal salt of the malonic acid diester may be prepared, for example, by adding an alkali metal, such as for example sodium metal, to an excess of the malonic acid diester as is well known to one skilled in the art. After about three hours at about 50° C. to about 70° C., the mixture is allowed to stand at ambient temperature for about 12 to about 24 hours. If the reaction is incomplete, the mixture is heated to about 80° C. for about 2 hours to about 4 hours, then concentrated to remove excess malonic acid diester, and then treated with a concentrated mineral acid such as for example hydrochloric acid or sulfuric acid and water. The mixture is heated at about 100° C. to about 110° C. for about 5 hours to about 9 hours to effect decarboxylation. After standing about 12 to about 24 hours at ambient temperature the mixture is washed with a suitable solvent, such as for example ethyl ether and ethyl acetate, basified to about pH 8 to about pH 9 with an alkali metal hydroxide, such as for example sodium hydroxide or potassium hydroxide, and extracted with a suitable organic solvent, such as for example ethyl acetate. The organic extract is filtered and concentrated under reduced pressure to afford the desired methyl-nitropyridine 2. Preparation of 2 by this “step a” procedure is referred to as a “two step, one pot synthesis”.
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