2-(5-BROMO-3-NITROPYRIDIN-2-YL)MALONIC ACID DIETHYL ESTER synthesis

Yield:911434-04-3 99%

Reaction Conditions:

Stage #1: diethyl malonatewith sodium hydride in N,N-dimethyl-formamide;mineral oil at 5 - 20; for 0.833333 h;
Stage #2: 5-bromo-2-chloro-3-nitropyridine in N,N-dimethyl-formamide;mineral oil at 5 - 40;

Steps:

7.1

Example 7: Synthesis of 2-{[5-(3-aminopropyl)-2-methylpyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6Η-pyrimido[5,4-d][l]benzazepin-6-one; Step 1 : Diethyl (5-bromo-3-nitropyridin-2-yl)malonate; To a suspension of NaH (60% in mineral oil, 27.9 g, 0.69 mol) in DMF (300 mL) at 5-10 ⁰C was slowly added ethyl malonate (125 mL, 0.69 mol) over 30 min. The mixture was allowed to stir for 20 min at rt, during which time the suspension became a solution. A solution of 5-bromo-2-chloro-3- nitropyridine (75 g, 0.32 mol) in DMF (75 mL) was added slowly at 5-10 ⁰C. The resulting dark red mixture was allowed to stir at 40 ⁰C for 2 h. The reaction mixture was then poured into IM AcOH (0.75 L) and extracted with DCM (3 x 250 mL). The organic solutions were combined, washed with water and brine, dried over MgSO₄, filtered and concentrated. The residue was purified by column chromatography to give diethyl (5-bromo-3-nitropyridin-2-yl)malonate (260 g, 99%) as a yellow oil.

References:

WO2010/65134,2010,A1 Location in patent:Page/Page column 89