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With Ki; sodium thiosulfate In 1,2-dimethoxyethane; acetonitrile; pentane
19b. 2-Chloro-5-iodo-3-methylpyridine 5-Amino-2-chloro-3-methylpyridine (2.3 g, 16.3 mmol) in DME (9.0 mL) was added dropwise to a solution of boron trifluoride diethyl etherate (3.0 mL, 24.4 mmol) in DME (30.5 mL) at -17° C. After stirring for 15 min, t-butyl nitrite (442 μL, 3.7 mmol) in DME (30.5 mL) was carefully added to the reaction mixture while maintaining the temperature below -5° C. After complete addition the temperature was allowed to gradually warm to 5° C. over 1 hr. The mixture was recooled to -17° C., pentane was added and then decanted. The solid was triturated with pentane (3*) and Et2 O (3*) and then solvent was removed via positive N2 pressure. The crude diazonium tetrafluoroborate salt was dissolved in acetonitrile (15 mL) and KI (3.0 g, 17.9 mmol) was added at -10° C. The reaction was allowed to gradually warm to ambient temperature and stir overnight. A solution of 10percent sodium thiosulfate was carefully added to the reaction mixture which was then poured over Et2 O and the phases separated. The organic phase was dried (MgSO4), concentrated and the residue chromatographed (silica gel; EtOAc/hexane, 1:50) to afford a white solid (3.42 g, 83percent): 1 H NMR (CD3 OD, 300 MHz) δ2.34 (s, 3H),), 8.09 (d, J=2.2 Hz, 1H), 8.42 (d, J=2.2 Hz, 1H).
The product from Example 15B and 2-chloro-5-iodo-3-methylpyridine, prepared as described in (U.S. Pat. No. 5,733,912) were processed as described in Example 15C to provide the title compound. MS (DCI/NH3) m/z 324 (M+H)+.
Example 2 Preparation of 2-chloro-3-methyl-5-iodopyridine At -10 C., 21.3 g of chlorine gas were introduced into a suspension of 146 g of 10% strength by weight hydrochloric acid and 23.4 g of <strong>[166266-19-9]2-amino-3-methyl-5-iodopyridine</strong> [J. Org. Chem. (1995), p. 5356]. At about -50 C., a solution of 48.3 g of sodium nitrite in 120 ml of water was subsequently added dropwise. After about 2 hours of stirring at 0 C., the mixture was diluted with 1 l of water and extracted with methyl tert-butyl ether (MtBE). The organic phases were washed with NaHCO3 solution and water and then dried. Distillative removal of the solvent under reduced pressure and silica gel chromatography (cyclohexane/MtBE=1:10) gave 3.6 g of the product in the form of dark crystals. 1H-NMR (CDCl3, ppm): delta=8.4 (1H); 7.9 (1H); 2.3 (3H).
With Ki; sodium thiosulfate; In 1,2-dimethoxyethane; acetonitrile; pentane;
19b. 2-Chloro-5-iodo-3-methylpyridine <strong>[38186-82-2]5-Amino-2-chloro-3-methylpyridine</strong> (2.3 g, 16.3 mmol) in DME (9.0 mL) was added dropwise to a solution of boron trifluoride diethyl etherate (3.0 mL, 24.4 mmol) in DME (30.5 mL) at -17 C. After stirring for 15 min, t-butyl nitrite (442 muL, 3.7 mmol) in DME (30.5 mL) was carefully added to the reaction mixture while maintaining the temperature below -5 C. After complete addition the temperature was allowed to gradually warm to 5 C. over 1 hr. The mixture was recooled to -17 C., pentane was added and then decanted. The solid was triturated with pentane (3*) and Et2 O (3*) and then solvent was removed via positive N2 pressure. The crude diazonium tetrafluoroborate salt was dissolved in acetonitrile (15 mL) and KI (3.0 g, 17.9 mmol) was added at -10 C. The reaction was allowed to gradually warm to ambient temperature and stir overnight. A solution of 10% sodium thiosulfate was carefully added to the reaction mixture which was then poured over Et2 O and the phases separated. The organic phase was dried (MgSO4), concentrated and the residue chromatographed (silica gel; EtOAc/hexane, 1:50) to afford a white solid (3.42 g, 83%): 1 H NMR (CD3 OD, 300 MHz) delta2.34 (s, 3H),), 8.09 (d, J=2.2 Hz, 1H), 8.42 (d, J=2.2 Hz, 1H).
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