2,6-Dibromo-3-pyridinecarboxylic acid synthesis

Yield:-

Reaction Conditions:

Stage #1:2,6-Dibromopyridine with n-butyllithium;diisopropylamine in tetrahydrofuran;hexane at -78; for 3.66667 h;
Stage #2:carbon dioxide in tetrahydrofuran;hexane at 20;
Stage #3: with hydrogenchloride in water;ethyl acetate

Steps:

2.2A
EXAMPLE 2 7-(2,6-dichlorobenzyl)-5-{ [2-methoxy-4-(piperazin-l -yl)phenyl]amino}pyrido[3,4- d]pyridazin-4-ol EXAMPLE 2A 2,6-dibromonicotinic acid and 2,6-dibromoisonicotinic acid To a solution of diisopropylamine (7.5 g, 74.3 mmol) in tetrahydrofuran (50 mL) at - 78°C was added «-butyllithium (27.8 mL. 2.5 M solution in hexane, 69.6 mmol). The mixture was stirred at -78 °C for 30 minutes and a solution of 2. 6-dibromopyridine (16.0 g, 67.6 mmol) in tetrahydrofuran (50 mL) was added over a period of 40 minutes. The mixture was stirred at -78 °C for 3 hours. Dry carbon dioxide was bubbled into the reaction mixture and the mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of ethyl acetate (50 mL) and 10% aqueous sodium hydroxide (100 mL). The aqueous phase was made acidic with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated to afford the title compound, which was used in the next step without further purification. MS: 282 (M+ l).

References:

ABBOTT LABORATORIES;ABBOTT LABORATORIES TRADING (SHANGHAI) COMPANY, LTD.;VASUDEVAN, Anil;PENNING, Thomas Dale;CHEN, Huanming;LIANG, Bo;WANG, Shaohui;ZHAO, Zhongqiang;CHAI, Dikun;YANG, Leifu;GAO, Yingxiang WO2012/97682, 2012, A1 Location in patent:Page/Page column 69-70