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Stage #1: With hydrogenchloride; sodium nitrite In water at -5 - 5℃; for 0.166667 h; Stage #2: With potassium iodide In water at -5 - 10℃;
Step 1: 5-iodo-2-(trifluoromethyl)pyridine [0251] A solution of 6-(trifluoromethyl)pyridin-3-amine (9.96 g, 0.062 mol) in 5N HC1 (70 mL) was cooled to -5°C and sodium nitrite (6.39 g, 0.093 mol) in 30 mL of water was added dropwise while maintaining the internal temperature below 5°C. After 10 min, KI (22.5 g, 0.136 mol) in 30 mL of water was added dropwise at -5°C while maintaining the internal temperature below 10°C over the course of the addition. The reaction mixture was warmed to rt and 250 mL of EtOAc was added. The pH of the aqueous layer was adjusted to 11 by the addition of 50 mL of 6N NaOH, the layers were separated, and the organic layer was washed with 120 mL of 0.3M Na2S203. The EtOAc layer was concentrated and the concentrate was purified by column chromatography over silica gel (hexane/ EtOAc =25/1) to afford the title compound as a white solid (14.6 g, 87percent). MS (ESI) calcd for C6H3F3IN: 273.0; found: 274.0[M+H]. 1H NMR (400 MHz, CDC13) δ 8.96 (s, 1H), 8.22 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H).
87%
Stage #1: With hydrogenchloride; sodium nitrite In water at -5 - 5℃; for 0.166667 h; Stage #2: With potassium iodide In water at -5 - 20℃;
A solution of 6—(triflucron’iethyi)pyridin—3—arnine (c.96 g. 0.062 moi) in sN HCI (70 mL) was cooled to -5°C and sodium nitrite (6.39 g, 0.093 mol) in 30 niL of water was added dtopwise \percent bile rnamtaanrng the internal temper ilure helms 5 C. \ftei 10 mm K (22 5 g 0 1 o mol) in 30 niL of water uac added dropi 1st at —5°C while inarntauung the inttrnaltemperature below 10 °C over the course of the addition. [he reaction mixture was warmed to rt and 250 mL of EtOAc was added. The pH of the aqueous layer was adjusted to 11 by the addition of So ml of ON ‘4aOH Ihe oiganic laser ws sepaiated and ashed ;kith 120 mL of 0 M \&S2O, Tin. EtOc laser was oncntrated and the onc,.entratc was purifitd b Lolumo chronwogiaphy O\ ei sdica gel he,.ane 1 ii) .c 2 I) to aifoid the title compound as a white solid (14.6 g, 87percent). MS (ES) ealcd for C6H3F31N: 273.0; found: 274.0 [M±HJ. ‘H NMR (400 MHz. CDCL) ii 8.96 (s. iS). 8.22 (d. J:::: 8.2 Hz, JHI, 7.47 (d. J 8.2 Hz, iii).
With iodine; silver sulfate In ethanol at 20℃; for 24 h;
PREPARATION IV 3-Amino-2-iodo-6-(trifluoromethyl)pyridine 3.85 g (12.3 mM) of silver sulfate are added, with stirring and at room temperature, to a solution of 2 g (12.3 mM) of 5-amino-2-(trifluoromethyl)pyridine in 100 ml of ethanol. 3.13 g of iodine are then added and the reaction mixture is stirred at room temperature for 24 hours. The solid in suspension in the medium is removed by filtration and the filtrate is concentrated under reduced pressure. The evaporation residue is taken up in 200 ml of dichloromethane and washed with 5percent sodium hydroxide solution, and then with water and dried over magnesium sulfate. The solution obtained is concentrated under reduced pressure and 3.42 g of the expected compound are thus obtained in the form of a pink solid (yield=96percent). m.p.=127° C.
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