Diisopropylamine → Methyl 2,6-bis(trifluoromethyl)-4-hydroxy-3-pyridinecarboxylate

Temperature

-78 °C

To a flame dried 3-liter, four-necked flask equipped with nitrogen inlet, low temperature thermometer, 500 ml addition funnel and mechanical stirrer is charged 147 ml (1.05 mol) of diisopropylamine and 600 ml of dry tetrahydrofuran. The resulting solution is cooled to -78° C. using an acetone-dry ice bath. To this is slowly added 618 ml (1.05 mol) of 1.7M n-BuLi in hexane at such a rate that the reaction temperature was kept below -60° C. After stirring at -78° C. for 1 hour, a solution of 106 g (0.50 mol) of methyl 2-acetyl-3-amino-4,4,4-trifluoro-2-butenoate from Step 1 in 400 ml of dry THF was added in such a rate that the reaction temperature was kept below -60° C. The reaction mixture turned yellow and a solid suspension formed. After 1 hour of stirring at -78° C., the reaction mixture was treated with 59.5 ml (0.50 mol) of ethyl trifluoroacetate in such rate that the reaction temperature was kept below -60° C. This reaction mixture was left at -78° C. for 1 hour, then warmed to room temperature (the yellow suspension disappeared and a yellow solution was formed) and stirred for 2 hours. The resulting solution was poured into 1 L of H2O and extracted with ether (3×700 ml). The combined ether layers were washed with H2O (2×800 ml) and the combined aqueous layers were acidified with concentrated HCl (pH ~2). The acidified aqueous layer was extracted with CHCl3 (3×1000 ml), dried (MgSO4) and reduced in vacuo affording 120.85 g of a yellow solid. The crude was recrystallized from ether/hexane to give 103.28 g (71%) of pyridine product; mp 62°-75° C.

1. customTo a flame dried 3-liter, four-necked flask
2. customequipped with nitrogen inlet
3. additionlow temperature thermometer, 500 ml addition funnel and mechanical stirrer
4. customwas kept below -60° C
5. customwas kept below -60° C
6. customa solid suspension formed
7. stirringAfter 1 hour of stirring at -78° C.
8. customwas kept below -60° C
9. waitThis reaction mixture was left at -78° C. for 1 hour
10. temperaturewarmed to room temperature (the yellow suspension
11. customa yellow solution was formed) and
12. stirringstirred for 2 hours
13. extractionextracted with ether (3×700 ml)
14. washThe combined ether layers were washed with H2O (2×800 ml)
15. extractionThe acidified aqueous layer was extracted with CHCl3 (3×1000 ml)
16. dry with materialdried (MgSO4)

ORD record

ord-b06b5b96a9594939ace2be26626de8a0

Source dataset

uspto-grants-1988_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04789395