3-Pyridinecarboxylic acid, 2,6-dichloro-, ethyl ester

Esterification of 2, 6-dichloronicotinic acid (25.5 g, 0.1328 mmol) in EtOH (200 proof, 200 mL) catalyzed with 96percent HA mixture 2, 6-dichloronicotinic acid (5.0 g, 26.2 mmol) and concentrated HPreparation 30: ethyl 2-ethoxy-6-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- yl)nicotinate; Step 1 : ethyl 2, 6-dichloronjcotjnate; To a solution of 2, 6-dichloronicotinic acid (10 g, 52.08 mmol) in ethanol (50 mL) was added concentrated sulfuric acid (1.0 mL) and the mixture was heated to refluxed for 16 h. The reaction was concentrated. The solid residue was diluted with ethyl acetate (50 mL) and washed with water (50 mL), 1M aqueous sodium carbonate (50 mL) and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound (7.38 g, 65percent) as a light orange solid. 1 H NMR (500 MHz, DMSO-CfA round bottom flask was charged under nitrogen with ie/ -butyl-dimethyl- (lH-pyrazol-3-yloxymethyl)silane (160 mg, 0.7534 mmol), ethyl 2, 6-dichloropyridine- 3-carboxylate (170 mg, 0.7725 mmol), K2CO3 (160 mg, 1.158 mmol) (freshly ground in a mortar) and anhydrous DMF (1.5 mL). DABCO (15 mg, 0.1337 mmol) was added and the mixture was stirred at room temperature under nitrogen for 8 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and water (50 mL) and the two phases were separated. The aqueous phase was further extracted with ethyl acetate (2 x 30 mL), and the combined extracts were washed with brine and dried over sodium sulfate, after which the solvent was removed under reduced pressure. The material was subjected to flash chromatography on silica gel using an initially shallow gradient of 0-40% ethyl acetate in hexanes. The pure fractions were combined and the solvents removed under reduced pressure to provide a white solid; ethyl 6-[3 -[[tert- butyl(dimethyl)silyl]methoxy]pyrazol-l-yl]-2-chloro-pyridine-3-carboxylate (194 mg, 63%). 1H NMR (400 MHz, Chloroform-d) d 8.35 (dd, J = 2.9, 0.9 Hz, 1H), 8.27 (dd, J = 8.4, 0.8 Hz, 1H), 7.73 (dd, J = 8.5, 0.8 Hz, 1H), 5.97 (dd, J = 2.9, 0.8 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 4.05 (s, 2H), 1.42 (dd, J = 7.6, 6.8 Hz, 3H), 0.97 (d, J = 0.9 Hz, 9H), 0.10 (s, 6H). ESI-MS m/z calc. 395.1432, found 396.2 (M+l)+; Retention time: 0.88 minutes (LC method D).A round bottom flask was charged under nitrogen with /c/V-butyl -dim ethyl - (lH-pyrazol-3-yloxymethyl)silane (160 mg, 0.7534 mmol), ethyl 2, 6-dichloropyridine-3- carboxylate (170 mg, 0.7725 mmol), K2CO3 (160 mg, 1.158 mmol) (freshly ground in a mortar) and anhydrous DMF (1.5 mL). DABCO (15 mg, 0.1337 mmol) was added and the mixture was stirred at room temperature under nitrogen for 8 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and water (50 mL) and the two phases were separated. The aqueous phase was further extracted with ethyl acetate (2 x 30 mL), and the combined extracts were washed with brine and dried over sodium sulfate, after which the solvent was removed under reduced pressure. The material was subjected to flash chromatography on silica gel using an initially shallow gradient of 0-40% ethyl acetate in hexanes. The pure fractions were combined and the solvents removed under reduced pressure to provide a white solid; ethyl 6-[3-[[/er/- butyl(dimethyl)silyl]methoxy]pyrazol-l-yl]-2-chloro-pyridine-3-carboxylate (194 mg, 63%). NMR (400 MHz, Chloroform-d) d 8.35 (dd, J = 2.9, 0.9 Hz, 1H), 8.27 (dd, J = 8.4, 0.8 Hz, 1H), 7.73 (dd, J = 8.5, 0.8 Hz, 1H), 5.97 (dd, J = 2.9, 0.8 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 4.05 (s, 2H), 1.42 (dd, J = 7.6, 6.8 Hz, 3H), 0.97 (d, J = 0.9 Hz, 9H), 0.10 (s, 6H). ESI-MS m/z calc. 395.1432, found 396.2 (M+l)+; Retention time: 0.88 minutes (LC method D).Into a solution of tri mcthylt l /7-pyra/ol-3-yloxy methyl (germane (1.7 g, 7.12 mmol) and Into a solution of tri methyl ( l//-pyrazol -3 -yloxymethyl (germane p| 7 ^ 7 ] 2 mmol) and Into a solution of trimethyl-[1 -methylene-3-(l /7-pyrazol-3-yloxy)propyl]silane (1.367 g, 6.50 mmol) in anhydrous DMF (14 mL) was added ethyl 2, 6-dichloropyridine- 3-carboxylate (1.719 g, 7.81 mmol) and potassium carbonate (2.708 g, 19.59 mmol). A catalytic amount of DABCO (159 mg, 1.42 mmol) was added to the reaction mixture. The reaction was stirred for 24 hours. The reaction was diluted with brine (50 mL) and diethyl ether (50 mL). Two layers were separated and the aqueous layer was extracted with diethyl ether (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography using 0 to 15% diethyl ether in hexane to furnish ethyl 2-chloro-6-[3-(3-trimethylsilylbut-3-enoxy)pyrazol-l-yl]pyridine-3- carboxylate (2.066 g, 81%) as a clear oil. ESI-MS m/z calc. 393.1275, found 394.1 (M+l)+; Retention time: 8.32 minutes (LC method C).Into a solution of tri methyl -[ 1 -methylene-3-( l//-pyrazol-3-yloxy)propyl]silane (1.367 g, 6.50 mmol) in anhydrous DMF (14 mL) was added ethyl 2, 6-dichloropyridine- 3-carboxylate (1.719 g, 7.81 mmol) and potassium carbonate (2.708 g, 19.59 mmol). A catalytic amount of DABCO (159 mg, 1.42 mmol) was added to the reaction mixture. The reaction was stirred for 24 hours. The reaction was diluted with brine (50 mL) and diethyl ether (50 mL). Two layers were separated and the aqueous layer was extracted with diethyl ether (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography using 0 to 15% diethyl ether in hexane to furnish ethyl 2-chloro-6-[3-(3-trimethylsilylbut-3-enoxy)pyrazol-l-yl]pyridine-3- carboxylate (2.066 g, 81%) as a clear oil. ESI-MS m/z calc. 393.1275, found 394.1 (M+l)+; Retention time: 8.32 minutes (LC method C).To a solution of trimethyl-[3-(l//-pyrazol-3-yloxy)propyl]silane (590 mg, 2.98 mmol), To a solution of trimethyl-[3-(li7-pyrazol-3-yloxy)propyl]silane (590 mg, 2.98 mmol) , Into a solution of tri methyl- [2-(l /7-pyrazol-3-yloxy)cthyl] si lane (2.919 g, 14.25 mmol) in anhydrous DMF (30 mL) were added ethyl 2, 6-dichloropyridine-3- carboxylate (3.147 g, 14.30 mmol) and potassium carbonate (5.909 g, 42.75 mmol). A catalytic amount of DABCO (321 mg, 2.86 mmol) was added to the reaction mixture. The reaction was stirred at rt for 16 hours. The reaction was diluted with water (100 mL) and diethyl ether (50 mL). The aqueous layer was extracted with diethyl ether (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography using 0 to 5% diethyl ether. The desired fractions were combined and concentrated to form a white solid. The crude product was then triturated with ethanol (20 mL) to furnish ethyl 2-chloro-6-[3-(2-trimethylsilylethoxy)pyrazol-l- yl]pyridine-3-carboxylate (3.783 g, 72%) as a white solid. ESI-MS m/z calc. 367.1119, found 368.1 (M+l)+; Retention time: 8.04 minutes (LC method C).Into a solution of trimethyl-[2-(liT-pyrazol-3-yloxy)ethyl]silane (2.919 g, 14.25 mmol) in anhydrous DMF (30 mL) were added ethyl 2, 6-dichloropyridine-3- carboxylate (3.147 g, 14.30 mmol) and potassium carbonate (5.909 g, 42.75 mmol). A catalytic amount of DABCO (321 mg, 2.86 mmol) was added to the reaction mixture. The reaction was stirred at rt for 16 hours. The reaction was diluted with water (100 mL) and diethyl ether (50 mL). The aqueous layer was extracted with diethyl ether (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography using 0 to 5% diethyl ether. The desired fractions were combined and concentrated to form a white solid. The crude product was then triturated with ethanol (20 mL) to furnish ethyl 2-chloro-6-[3-(2-trimethylsilylethoxy)pyrazol-l- yl]pyridine-3-carboxylate (3.783 g, 72%) as a white solid. ESI-MS m/z calc. 367.1 1 19, found 368.1 (M+l)+; Retention time: 8.04 minutes (LC method C).

Molecular Weight:220.05
XLogP3:3
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:218.9853839
Monoisotopic Mass:218.9853839
Topological Polar Surface Area:39.2
Heavy Atom Count:13
Complexity:189
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes