tert-Butanol → 2-Amino-4-Methoxypyridine

Temperature

0 °C

To a cooled (0° C.) suspension of 4-methoxypyridine-2-carboxylic acid hydrazide (10.0 g, 59.9 mmol) and trifluoroacetic acid (6.83 g, 59.9 mmol) in tetrahydrofuran (120 ml) was added tert-butylnitrite (18.52 g, 179.6 mmol) at such a rate to keep the internal temperature below 5° C. (ca. 45 min). Once addition was complete the mixture was allowed to stir at 0° C. for 30 min and then the solvent was removed in vacuo. Toluene (100 ml) was added and the mixture heated under reflux for 1 h before adding tert-butanol (15 ml, 155.7 mmol). After heating at reflux for a further 10 h the reaction was cooled and the solvent evaporated in vacuo. The residue was suspended in toluene (100 ml), trifluoroacetic acid (5 ml) was added and the mixture heated at reflux for 5 h. The solvent was removed on a rotary evaporator and the residue purified by flash column chromatography on silica eluting with dichloromethane/methanol/conc. ammonia (97:3:0.3) to furnish 4-methoxypyridin-2-ylamine (4.50 g, 61%) as a pale brown solid. 1H NMR (400 MHz, CDCl3) δH 3.90 (3H, s), 6.12 (1H, s), 6.32 (1H, d, J 7), 7.52 (1H, d, J 7), 7.75 (1H, br s).

1. temperatureTo a cooled
2. customthe internal temperature below 5° C. (ca. 45 min)
3. additionOnce addition
4. customthe solvent was removed in vacuo
5. additionToluene (100 ml) was added
6. temperaturethe mixture heated
7. temperatureunder reflux for 1 h
8. temperatureAfter heating
9. temperatureat reflux for a further 10 h the reaction
10. temperaturewas cooled
11. customthe solvent evaporated in vacuo
12. additiontrifluoroacetic acid (5 ml) was added
13. temperaturethe mixture heated
14. temperatureat reflux for 5 h
15. customThe solvent was removed on a rotary evaporator
16. customthe residue purified by flash column chromatography on silica eluting with dichloromethane/methanol/conc

ORD record

ord-a98317f63cc64be9b21371482179a4d8

Source dataset

uspto-grants-2005_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06872731B2