반응 #61633

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Benzyl 4-[2-(4-fluorophenyl)-3-(pyrimidin-4-yl)imidazo[1,2-a]pyridin-7-yl]-piperidine-1-carboxylate

thiophenol

iodotrimethylsilane

→

2-(4-fluorophenyl)-3-(pyrimidin-4-yl)-7-piperidin-4-ylimidazo[1,2-a]pyridine

수율 94.6%

용매

acetonitrile

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후처리

1. 1
   농축The reaction was concentrated under reduced pressure
2. 2
   workup.DISSOLUTIONdissolved in a minimum volume of methylene chloride
3. 3
   세척eluted with a gradient that
4. 4
   workup.ADDITIONFractions containing desired product
5. 5
   농축concentrated under reduced pressure

실험 절차

Benzyl 4-{3-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-(4-fluorophenyl)imidazo-[1,2-a]pyridin-7-yl}piperidin-1-carboxylate (Example 1, Step 5, 0.570 mmol, 300 mg) was charged with 1-propanol (5 mL), formamidine HCl (2.28 mmol, 183 mg), and sodium methoxide (2.28 mmol, 0.521 mL of a 25% w/w solution in methanol). This reaction was heated to 100° C. for 12 hours. The reaction was then poured into a separatory funnel, diluted with methylene chloride (100 mL), washed with 50 mL saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered, concentrated under reduced pressure, then dissolved in a minimum volume of methylene chloride and injected onto an Isco RediSep 40 g normal phase cartridge, and eluted with a gradient that started with 100% heptane and ended with 100% ethyl acetate. Fractions containing desired product were pooled and concentrated under reduced pressure to provide benzyl 4-[2-(4-fluorophenyl)-3-(pyrimidin-4-yl)imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate (191 mg, 66%). MS (ESI+) 508.4. Step 2. Benzyl 4-[2-(4-fluorophenyl)-3-(pyrimidin-4-yl)imidazo[1,2-a]pyridin-7-yl]-piperidine-1-carboxylate (Step 1, 0.368 mmol, 187 mg) was diluted with acetonitrile, then charged with thiophenol (0.553 mmol, 61 mg, 57 μL), and iodotrimethylsilane (3.68 mmol, 737 mg, 524 μL), and the reaction stirred at room temperature for 12 hours. The reaction was concentrated under reduced pressure, then dissolved in a minimum volume of methylene chloride and injected onto an Isco RediSep 40 g normal phase cartridge, and eluted with a gradient that started with 100% methylene chloride and ended with 100% 90:9:1 methylene chloride:methanol:concentrated ammonium hydroxide. Fractions containing desired product were pooled and concentrated under reduced pressure to provide 2-(4-fluorophenyl)-3-(pyrimidin-4-yl)-7-piperidin-4-ylimidazo[1,2-a]pyridine (130 mg, 94%). MS (ESI+) 374.3. Step 3. 2-(4-fluorophenyl)-3-(pyrimidin-4-yl)-7-piperidin-4-ylimidazo[1,2-a]pyridine (Step 2, 0.348 mmol, 130 mg) was diluted in methanol (5.0 mL), then charged with acetic acid (130 μL), 37% w/w formaldehyde in water (0.383 mmol, 31 mg, 29 μL), and NaBH3CN (0.418 mmol, 418 μL of a 1.0M solution in THF). After stirring at room temperature for 30 minutes, the reaction was quenched with 1.0 mL concentrated ammonium hydroxide, then purified via 6×1.0 mL injections onto a reverse phase HPLC column using a gradient that started with 50% methanol:50% 0.1% Et3N in water and ended with 100% methanol. Fractions containing desired product were pooled and concentrated under reduced pressure to provide the title compound (96 mg, 71%). 1H NMR (400 MH, CDCl3) δ 1.91 (m, 4H), 2.10 (m, 2H), 2.35 (s, 3H), 2.59 (m, 1H), 3.02 (m, 2H), 6.89 (dd, J=7.3, 1.9 Hz, 1H), 7.14 (m, 3H), 7.58 (s, 1H), 7.60 (m, 2H), 8.45 (d, 3=5.5 Hz, 1H), 9.25 (s, 1H), 9.65 (dd, J=7.3, 0.7 Hz, 1H). MS (ESI+) 388.3.

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