| 78% |
With phosphorus pentachloride; trichlorophosphate; at 150℃; for 2h; |
Example 1153-((5-Amino-6-methylpyridin-2-yl)ethynyl)-7,7-dimethyl-7,8-dihydroquinoone[00319] A mixture of 6-methyl-5-nitropyridin-2-ol (500 mg, 3.24 mmol), POCI3 (0.5 mL) and PCI5 (200 mg) is stirred at 150 °C for 2 h, cooled to r.t, poured onto ice, and extracted with DCM (3x20 mL). The combined organic phases are washed with water to reach pH 7, dried over Na2S04 and concentrated at reduced pressure. The obtained residue is dried at reduced pressure to give 6-chloro-2-methyl-3-nitropyridine (430 mg, 78percent) as light brown solid.[00320]According to General Procedure 2, 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin- 5(6/-/)-one (199 mg, 1 .00 mmol) is reacted with 6-chloro-2-methyl-3-nitropyridine (172 mg, 1.00 mmol) in the presence of PdCI2(PPh3)2 (42 mg, 0.06 mmol), P(f-Bu)3 (16 mg, 0.08 mmol), and TEA (1 .5 mL) in DMF (3 mL) at 100 °C for 3 h. The crude product is purified by column chromatography (silica gel) to give the intermediate product 7,7- dimethyl-3-((6-methyl-5-nitropyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)-one (80 mg, 16percent) as yellow solid.[00321 ]7,7-dimethyl-3-((6-methyl-5-nitropyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6/-/)- one (194 mg, 0.58 mmol) is dissolved in EtOAc (10 mL) and cooled down to 0 °C. A solution of SnCl2*2H2O (650 mg, 2.90 mmol) in concentrated aqueous HCI solution (1 mL) is added dropwise. The reaction mixture is stirred at r.t. for 3 h, poured onto ice, treated with 15percent aqueous NaOH solution to reach pH 9-10, and extracted with EtOAc (3x25 mL). The combined organic phases are dried over Na2SO4 and concentrated at reduced pressure. The obtained residue is purified by preparative TLC (silica gel, DCM/EtOH, 40: 1 ) to provide the title compound (34 mg, 19percent).1H NMR (De-DMSO), deltaEta, 1 .05 (s, 6H), 2.29 (s, 3H), 2.59 (s, 2H), 3.03 (s, 2H), 5.51 (br s, 2H), 6.92 (d, 1 H), 7.24 (d, 1 H), 8.15 (s, 1 H), 8.83 (s, 1 H).LC/MS (M+H)+ = 306 |
| 62% |
With phosphorus pentachloride; trichlorophosphate; In DMF (N,N-dimethyl-formamide); at 110 - 115℃; for 8h; |
(c) To 6-Hydroxy-3-nitro-2-picoline (15.73 g, 0.102 mol) was added PCls (5.73 g, 0.027 mol) and POCh (2.9 ml, 0.032 mol). This mixture was heated at 110-115°C for 3 hrs. However, the amount of POCh added was only enough to moisten the starting material. More POC13 (3 ml) was added, the reaction mixture heated at 110-115°C but only sublination of PCls (100°C) was observed. DMF (5 ml) was added and the solution was heated at 115°C for 5 hrs, cooled and poured into a slush of ice and water. A beige product precipitated and the water suspension was stirred for 48 hrs. The brown precipitate was filtered off and washed with water. Purification by dry-flash dichloromethane yielded 10.93 g (62 percent) of 6-chloro-2-picoline. |
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