2,6-Dichloro-5-fluoronicotinic acid → 6-Chloro-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid

Temperature

-78 °C

To a cold (−78° C.) solution of 2-fluoro-4-trimethylsilanyl-phenylamine (19.2 g, 105 mmol) in anhydrous THF (50 mL) was added a solution of LHMDS (160 mL, 1 M in hexanes, 160 mmol) dropwise over 45 minutes under a nitrogen atmosphere. After 2 hours at −78° C., a solution of 2,6-dichloro-5-fluoro-nicotinic acid (10.5 g, 50 mmol) in anhydrous THF (30 mL) was added. The mixture was stirred at −78° C. for 1 hour then allowed to warm to ambient temperature. After 18 hours stirring at ambient temperature the reaction was quenched with water and adjusted to pH 2 by the addition of concentrated HCl. The solution was extracted with ethyl acetate and the organic layer was isolated, washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was triturated with methanol and filtered to afford the title compound as a yellow solid (8.7 g, 49%). LCMS (method B): RT=4.92 min, [M+H]+=357.

1. temperatureto warm to ambient temperature
2. stirringAfter 18 hours stirring at ambient temperature the reaction
3. customwas quenched with water
4. additionadjusted to pH 2 by the addition of concentrated HCl
5. extractionThe solution was extracted with ethyl acetate
6. customthe organic layer was isolated
7. washwashed with water
8. dry with materialdried (Na2SO4)
9. filtrationfiltered
10. customevaporated in vacuo
11. customThe resultant residue was triturated with methanol
12. filtrationfiltered

ORD record

ord-e605645a42004ec8b5dea8a73ef1919e

Source dataset

uspto-grants-2011_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07923456B2