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To a stirred solution of N-methoxy-N,2-dimethylisonicotinamide (266c) (26 g,144.28Immol) in THF (520 rnL) was added MeLi (6.342 g, 288.562 mmoi, 1 M solution inTHF) under nitrogen atmosphere at -78°C. The reaction mixture was warmed to room temperature over a period of 1 h, quenched with saturated NH4CI solution at 0°C. The resulting reaction mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Theresidue obtained was purified by column chromatography to afford I -(2-methylpyridin-4-yl)ethanone (266d) (11 g, 56.4percent yield) as a reddish thick liquid; ‘H NMR (CDCI3) 3 8.6 1-8.59 (d, 1H), 7.51-7.45 (d, IH), 7.45-7.44 (m, lH), 2.56(s, 3H), 2.53 (s, 3H); MS (ES+)136. l(M+I).
56.4%
at -78 - 20℃; for 1 h; Inert atmosphere
Step-3 : Preparation of l-(2-methylpyridin-4-yl)ethanone (46d) To a stirred solution of N-methoxy-N,2-dimethylisonicotinamide (46c) (26 g, 144.28 lmmol) in THF (520 mL) was added MeLi (6.342 g, 288.562 mmol, 1 M solution in THF) under nitrogen atmosphere at -78°C. The reaction mixture was warmed to room temperature over a period of 1 h, quenched with saturated H4C1 solution at 0°C. The resulting reaction mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by column chromatography to afford l-(2-methylpyridin-4-yl)ethanone (46d) (11 g, 56.4percent yield) as a reddish thick liquid; 1H MR (CDC13) δ 8.61-8.59 (d, 1H), 7.51-7.45 (d, 1H), 7.45-7.44 (m, 1H), 4.05-4.02 (s, 3H); MS (ES+) 136.1(M+1).
51%
Stage #1: at -78 - 20℃; for 1.5 h; Inert atmosphere Stage #2: With ammonium chloride In tetrahydrofuran
Methyl lithium (3M, 1.7 mL, 3.48mmol) was added to a solution of N-methoxy-N2- dimethylisonicotinamide (314 mg, 1.74mmol) in dry THF (4 mL) at -78 °C under nitrogen protection. The mixture was stirred at -78 °C and slowly warm up to rt for 1.5h. After completion, 10 mL of NH4C1 solution (saturated) was added to the mixture, and it was extracted with EtOAc (10 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na2S04, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (CH2Cl2/MeOH=50/l) to obtain title compound (120mg, yield: 51percent). LCMS-AOIO: 136.1 [M+H]+; Rt = 0.585 min
51%
at -78 - 20℃; for 1.5 h; Inert atmosphere
(b) I -(2-methyipyridin-4-yl)ethanone: Methyl lithium (3M, 1.7 mL, 3.48inniol) was added to a solution of W-methoxy-X, 2-dimethyiisonieotinamide (314 ing, I .74mmol) in dry THE (4 mL) at -78 °C under nitrogen protection. The mixture was stirred at -78 °C and slowly warm up to it for l.5h. After completion, 10 niL of NI-LCI solution (saturated) was added to the mixture, and it was extracted with EtOAc (10 mLx3). The combined organic layers were washed with brine (20mL), dried over Na2SO4, and filtered. The filtrate was eoneeitmated, and the residue was purified by silica gel column chromatography (CH2C12/MeOH=50/i) to obtain title compound (120mg, yield: 51percent). LCMS-A0i0: 136.1 [M+H] R = 0.585 mm
Stage #1: at 0℃; Heating; Reflux Stage #2: With hydrogenchloride In tetrahydrofuran; hexane; water at 20℃;
[0352] l-(2-Methyl-4-pyridinyl)ethanone (143). A solution of MeMgBr (3 M in hexanes, 6.0 mL, 17.9 mmol) was added slowly to a stirred solution of nitrile 142 (1.76 g, 14.9 mmol) in dry THF (100 mL) at 0 0C and the mixture was stirred at reflux temperature for 16 h. The mixture was cooled to 20 0C and the reaction quenched with 6 M HCl (30 mL). The aqueous fraction was separated and the organic fraction extracted with 1 M HCl (30 mL). The combined acidic fraction was stirred at 80 0C for 1 h, cooled to 0 0C and made basic with cNH3 solution. The mixture was extracted with CHCl3 (3 x 50 mL), the combined organic fraction was washed with brine (50 mL), dried and the solvent evaporated. The residue was purified by column chromatography, eluting with 50percent EtO Ac/pet, ether, to give ketone 143 (0.50 g, 25percent) as an oil: 1H NMR (CDCl3) δ 8.68 (d, J= 5.1 Hz, 1 H, H-6'), 7.59 (br s, 1 H, H-3'), 7.52 (d, J= 5.1 Hz, 1 H, H-5'), 2.65 (s, 3 H, H-2), 2.61 (s, 3 H, CH3); MS m/z 136.5 (MH+, 100percent).
Reference：
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 2, p. 787 - 797
[2] Patent: WO2009/114552, 2009, A1, . Location in patent: Page/Page column 154
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 12, p. 5028 - 5037
3
[ 22282-99-1 ]
[ 97674-02-7 ]
[ 2732-28-7 ]
Yield
Reaction Conditions
Operation in experiment
44%
With tetrakis(triphenylphosphine) palladium(0) In toluene at 80℃; Inert atmosphere
To a solution of 4-bromo-2-methylpyridine (10.0 g, 58 mmol) in toluene (100 mL) was added tributyl(l-ethoxyvinyl)stannane (39.7 g, 110 mmol) and Pd(PPh3)4 (5.8 g, 5 mmol). The mixture was stirred at 80 °C under a nitrogen atmosphere overnight. IM HCl was added at 0 °C until the pH of the mixture was adjusted to 1-2. The mixture was stirred for 0.5 h. The pH was adjusted to 6-7 by adding IM NaOH. The mixture was extracted with ethyl acetate (150 mL*3). The organics layer was washed with brine and dried over sodium sulfate. Concentration and purification by column chromatography on silica gel (petroleum ether/ethyl acetate = 30/1-4/1) afforded l-(2-methylpyridin-4-yl)ethanone as light yellow solid (3.0 g, 44percent).
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