Water → N-[3-Bromo-6-(methyloxy)-2-pyridinyl]-2,2-dimethylpropanamide

Temperature

0 °C

A solution of 2,2-dimethyl-N-[6-(methyloxy)-2-pyridinyl]propanamide (55.011 g, 264.467 mmol) in THF (450 ml) in a three necked 1 L flask with an internal thermometer under argon was cooled to −78° C. and treated with n-butyl lithium (232 ml, 581.847 mmol) over 15 minutes and then allowed to warm to 0° C. and stirred at 0° C. for 7 h. The mixture was then recooled to −78° C. and treated with 1,2-dibromoethane (27.3 ml, 317 mmol) over 10 minutes and then the solution was allowed warm to room temperature and stirred at room temperature for 30 minutes by which time all the solid which had formed dissolved again. Gas was evolved at this stage so a gas bubbler was placed on one of the flasks necks. Water (100 ml) was then carefully added over 10 minutes. Further water (500 ml) was then added and the mixture was extracted with diethyl ether (3×500 ml). The combined organic solvents were then dried (MgSO4), filtered, evaporated to give the crude product. This was then dissolved in warm ethyl acetate (100 ml) and allowed to stand in the freezer overnight. The resultant solid which crystallised out was filtered off, washed with ice-cooled diethyl ether (20 ml) and dried in vacuo to give product as a white solid (45.660 g, 159.011 mmol, 60% yield). The filtrate was evaporated and the residue was chromatographed (0-25% ethyl acetate/40-60 petroleum ether) to give recovered starting material (7.264 g, 34.9 mmol), and product as a white solid (8.038 g, 27.992 mmol, 10% yield). The product from recrystallisation and silica chromatography were identical by NMR and LC-MS and so were combined.

1. customwas then recooled to −78° C.
2. temperaturethe solution was allowed warm to room temperature
3. stirringstirred at room temperature for 30 minutes by which time all the solid which
4. customhad formed
5. dissolutiondissolved again
6. extractionthe mixture was extracted with diethyl ether (3×500 ml)
7. dry with materialThe combined organic solvents were then dried (MgSO4)
8. filtrationfiltered
9. customevaporated
10. customto give the crude product
11. customto stand in the freezer overnight
12. customThe resultant solid which crystallised out
13. filtrationwas filtered off
14. washwashed with ice-
15. temperaturecooled diethyl ether (20 ml)
16. customdried in vacuo

ORD record

ord-d0ccb358ae8e4ec198a965c641c7da8d

Source dataset

uspto-grants-2013_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08389524B2