Dimethylformamide → 2-Methoxy-5-(methoxymethoxy)-4-pyridinecarboxaldehyde

Temperature

0 °C

To a mixture of 2-methoxy-5-(methoxymethoxy)pyridine (30 g, 0.178 mol) and diisopropylamine (507 uL, 3.6 mmol) in THF (500 mL) was added methyl lithium (1.6 M/THF, 200 mL, 0.32 mol) at −40° C. Upon the completion of addition, the mixture was warmed to 0° C. and continued to stir at 0° C. for 3 h. The reaction mixture was then cooled back down to −40° C. followed by addition of DMF (24.7 mL, 0.32 mol) slowly. The mixture was then stirred at −40° C. for 1 h and quenched with a mixture of HCl (12 N, 120 mL) and THF (280 mL). Water (200 mL) was added and the pH of the mixture was adjusted to pH 8-9 with solid K2CO3. The mixture was extracted with EtOAc (300 mL) twice. The organic layer was combined, dried over Na2SO4, and concentrated to give 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 95.7%) as a brown solid, which was used for next step without further purification. 1H NMR (400 MHz; CD3OD) 7.90 (s, 1H), 6.92 (s, 1H), 5.64 (s, 1H), 5.20 (s, 2H), 3.84 (s, 3H), 3.48 (s, 3H); MS (ESI) m/z 198.1 [M+H]+.

1. additionUpon the completion of addition
2. temperatureThe reaction mixture was then cooled back down to −40° C.
3. stirringThe mixture was then stirred at −40° C. for 1 h
4. customquenched with a mixture of HCl (12 N, 120 mL) and THF (280 mL)
5. additionWater (200 mL) was added
6. extractionThe mixture was extracted with EtOAc (300 mL) twice
7. dry with materialdried over Na2SO4
8. concentrationconcentrated

ORD record

ord-607c03afb88446aeb869e87ff11b4c91

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08952171B2