| 52% |
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A.12.1. Synthesis of tert-butyl methyl (3-chloro-5-nitropyridin-4-yl)propanedioate a33. To a solution of sodium hydride (1.33 g, 33.42 mmol) in DMF (40 mL) at 0 °C was added dropwise <strong>[42726-73-8]tert-butyl methyl malonate</strong> (5.65 mL, 33.42 mmol) in DMF (10 mL). The reaction mixture was stirred at rt for 30 min, then 3,4-dichloro-5-nitropyridine (4.3 g, 22.28 mmol) in DMF (10 mL) was added dropwise at 0 °C. The reaction mixture was stirred at rt for 6 h, then acidified to pH 3 with a 2N aqueous solution of HCI. The reaction mixture was poured into ice water and extracted with Et20. The organic layer was dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by column chromatography using 20percent EtOAc in hexanes to afford 3.83 g of tert-butyl methyl (3-chloro-5-nitropyridin-4- yl)propanedioate a33 as pale yellow solid. Yield: 52percent. 1H NMR (400 MHz, CDCI3) delta 9.15 (s, 1 H), 8.88 (s, 1 H), 5.37 - 5.51 (m, 1 H), 3.79 (s, 3H), 1.46 (s, 9H). |
| 52% |
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To a solution of NaH (60percent in mineral oil, 1.33 g, 33.42 mmol) in DMF (40 mL) at 0 °C was added dropwise <strong>[42726-73-8]tert-butyl methyl malonate</strong> (5.65 mL, 33.42 mmol) in DMF (10 mL). The mixture was stirred at ft for 30 mm., then 3,4-dichloro-5-nitropyridmne (commercial, 4.3 g, 22.28 mmol) in DMF (10 mL) was added dropwise at 0 °C. The reaction mixture was stirred at rt for 6 h, then acidified to pH 3 with a 2N aqueous solution of HCI. The reaction mixture was poured onto ice water and the compound was extracted in Et20. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue waspurified by column chromatography using 20percent EtOAc in hexanes to afford 3.83 g of tertbutyl methyl (3-chloro-5-nitropyridin-4-yl)propanedioate a4 as pale yellow solid.Yield: 52percent.1H NMR (400 MHz, CDCI3) 6 9.15 (s, 1H), 8.88 (s, 1H), 5.37 - 5.51 (m, 1H), 3.79 (s, 3H),1.46 (s, 9H). |
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Step 3. tert-Buty\\ methyl (3-chloro-5-nitropyridin-4-yl)malonate; A solution of <strong>[42726-73-8]tert-butyl methyl malonate</strong> (2.37 mL, 14.0 mmol) in 10 mL of DMF is added dropwise to a stirred suspension of sodium hydride (60percent in oil, 560 mg, 14.0 mmol) in 30 ml of DMF at room temperature. The mixture is stirred for 30 min., and then a solution of 3,4- dichloro-5-nitropyridine (1.8 g, 9.33 mmol) in 10 mL of DMF is added slowly. The dark orange/brown reaction mixture is stirred at room temperature for 4 h, and then poured into water (75 mL). The resulting solution is acidified to pH=3 with 6N HCl and extracted with Et2O (2 x 100 mL). The combined ethereal extracts are dried (Na2SO4), filtered, and evaporated in vacuo to give a brown oil. Purification by column chromatography (gradient from hexane to 30percent EtOAc/hexane) affords the title compound as a light brown solid. 1H NMR (300 MHz, CDCl3) delta 9.14 (s, IH), 8.88 (s, IH), 5.41 (s, IH), 3.79 (s, 3H), 1.46 (s, 9H). |
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