* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 15, p. 4792 - 4803
2
[ 609-71-2 ]
[ 390360-97-1 ]
Yield
Reaction Conditions
Operation in experiment
76%
With N-iodo-succinimide In N,N-dimethyl-formamide at 20 - 50℃; for 21 h; Darkness
A mixture of 2-hydroxynicotinic acid (24 g, 173 mmol), N-iodosuccinimide (50.5 g, 224 mmol) in DMF (300 mL) was stirred under shading at room temperature for 1 h and at 50 °C for 20 h. About 250 mL of DMF was removed in vacuo and water (400 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h and at 0 °C for 1 h, and then the resulting solid was filtered. The solid was suspended in MeOH (200 mL) and stirred at room temperature for 2 h, then the solid was filtered, washed with MeOH (40 mL) and dried in vacuo to give 19 as a pale yellow solid (38.4 g, 76percent). 1H NMR (400 MHz, CDCl3) δ = 8.41 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H); MS (ESI+) 265.9 (M+H)+.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 15, p. 4792 - 4803
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 17, p. 2674 - 2687
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20 - 50℃; for 21.0h;Darkness;
A mixture of 2-hydroxynicotinic acid (24 g, 173 mmol), N-iodosuccinimide (50.5 g, 224 mmol) in DMF (300 mL) was stirred under shading at room temperature for 1 h and at 50 C for 20 h. About 250 mL of DMF was removed in vacuo and water (400 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h and at 0 C for 1 h, and then the resulting solid was filtered. The solid was suspended in MeOH (200 mL) and stirred at room temperature for 2 h, then the solid was filtered, washed with MeOH (40 mL) and dried in vacuo to give 19 as a pale yellow solid (38.4 g, 76%). 1H NMR (400 MHz, CDCl3) delta = 8.41 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H); MS (ESI+) 265.9 (M+H)+.
With thionyl chloride; N,N-dimethyl-formamide; for 4.0h;Heating / reflux;
a) Ethyl 2-[(2-chloro-5-iodo-3-pyridinyl)carbonyl]-3-(ethylamino)-2-propenoate; 5-lodo-2-hydroxypyhdine-3-carboxylic acid (T. R. Elworthy et al., J.Med.Chem., 40, 17, 1997, 2674-2687) (7.95 g) was suspended in thionyl chloride (40 mL). DMF (4 drops) was added and the mixture refluxed for 4 h. The resultant solution was evaporated to dryness. EPO <DP n="38"/>This acid chloride was then dissolved in 1 ,4-dioxane (40 mL) and added dropwise to a solution of ethyl 3-(ethylamino)-2-propenoate (5.15 g) and triethylamine (10.5 mL) in 1 ,4- dioxane at 00C. After 1 h the cooling bath was removed, and the reaction stirred for 16 h. The mixture was then evaporated, saturated sodium hydrogen carbonate solution added, and extracted with EtOAc. The combined organic extracts were washed with brine, dried and concentrated in vacuo to give a dark oil which was purified by flash chromatography (silica gel, 33-45% Et2O in petroleum ether [b.p. 40-600C]) to give the title compound as a pale brown solid (5.35 g); ESMS m/z 409.1 [M+H]+.
5-iodo-2-hydroxypyridine-3-carboxylic acid chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thionyl chloride; In DMF (N,N-dimethyl-formamide); for 4.0h;Heating / reflux;
5-lodo-2-hydroxypyridine-3-carboxylic acid (T. R. Elworthy et al., J. Med. CHEM., 40,17, 1997,2674-2687) (7.95 g) was suspended in thionyl chloride (40 mL). DMF (4 drops) was added and the mixture REFLUXED for 4 h. The resultant solution was evaporated to dryness. This acid chloride was then dissolved in 1,4-dioxane (40 mL) and added dropwise to a solution of ethyl 3- (ethylamino)-2-propenoate (5.15 g) and triethylamine (10.5 mL) in 1,4- dioxane at 0oC. After 1 h the cooling bath was removed, and the reaction stirred at room temperature for 16 h. The mixture was then evaporated, saturated sodium hydrogen carbonate solution added, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated to give a dark oil. This was purified by chromatography on silica gel, eluting with 33-45% diethyl ether in petroleum ether, to give the title compound (5.35 g); ESMS M/Z 409 [M+H] +.
With thionyl chloride; In N,N-dimethyl-formamide; at 70℃; for 4.0h;
The mixture of 19 (29.8 g, 107 mmol), DMF (1.5 mL) and SOCl2 (78 mL, 10 eq.) was stirred at 70 C for 4 h. The mixture was concentrated in vacuo and diluted with DMF (6 mL). Water (90 mL) was slowly added to the mixture and then satd NaHCO3 aq (200 mL) was slowly added. The mixture was acidified to pH 4 by 1 N HCl (55 mL) and stirred at room temperature for 2 h and at 0 C overnight. After filtration, the solid was washed with water and dried in vacuo to yield a crude mixture of 2-chloro-5-iodonicotinic acid as a pale yellow solid (27 g). The solid was suspended in CHCl3 (135 mL) and SOCl2 (13.9 mL) and the suspension was stirred at reflux for 0.5 h. DMF (0.5 mL) and SOCl2 (27.8 mL) were added to make a clear solution and the mixture was stirred at reflux for 1.5 h, then cooled and concentrated in vacuo. EtOH (135 mL) was slowly added to the residue at 0 C and the mixture was stirred at 0 C for 15 min. and at room temperature for 30 min. The mixture was concentrated in vacuo and partitioned between AcOEt (270 mL) and satd NaHCO3 aq (135 mL). The aqueous phase was extracted with AcOEt (135 mL) and the combined organic phase was washed with brine, dried over Na2SO4 and filtered. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (AcOEt/n-hexane; 0:100 to 20:80) to yield 20 as a white solid (27.25 g, 95%).
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