4-Methylpyridine → Disodium

Temperature

10 °C

To a stirred mixture of sodium 2-[3-(trifluoromethyl)phenyl]propanedioate (2:1) (i.e. the product from Example 3A, Step A) (5.0 g, 95.0 area %, 16 mmol) and dichloromethane (50 mL) in a 250-mL round bottom flask at −1° C. was added 1-formylpiperidine (0.09 g, 0.8 mmol). Oxalyl chloride (5.6 g, 98%, 43 mmol) was then added via addition funnel over 5 min while maintaining the internal temperature at between −3 and +1° C. The resulting reaction mixture was stirred at between −3 and +2° C. for 10 min, then at 20−22° C. for 2-3 h. Upon complete conversion to 2-[3-(trifluoromethyl)phenyl]propanedioyl dichloride, the reaction mixture was cooled to 0° C., then a mixture of N-[(5-pyrimidinyl)methyl]-2-pyridinamine (i.e. the product of Example 3, Step B) (3.2 g, 95.3%, 16.4 mmol) and 4-picoline (3.1 g, 98%, 32.6 mmol) in dichloromethane (20 mL) was added to the acid chloride mixture via syringe pump over 10 min at 0 to 3° C. Upon complete addition, the reaction mixture was warmed to 10° C. over 10 min and stirred at 9 to 12° C. for 30 min until complete conversion of the acid chloride intermediate was observed (by quenching with methanol and determining by HPLC the absence of 1,3-dimethyl 2-[3-(trifluoromethyl)phenyl]propanedioate). The reaction mixture was warmed to 18° C., then water (15 mL) was added to the reaction mixture at 18 to 20° C., and the two-phase mixture was stirred at 18 to 20° C. for 15 min. The mixture settled and the layers were separated. The aqueous layer was extracted with dichloromethane (2×25 mL). The organic layers were combined, and then i-propanol (30 mL) was added to the combined organic solution followed by water (1.25 mL). The resulting mixture was distilled with a pot temperature of 82° C. and with the head temperature at 42-82° C. under atmospheric pressure to remove dichloromethane and water. When the head temperature reached the boiling point of pure i-propanol, the distillation was stopped, and additional i-propanol (30 mL) was added to the hot concentrate, and the mixture was allowed to cool to room temperature and stirred at room temperature overnight during which time a solid crystallized. The mixture was then filtered and the wet solids washed with i-propanol (3×5 mL). The solid product was dried in a vacuum oven at 50-55° C. and ˜250 mm Hg to afford the title compound as a yellow solid (5.0 g, 99.0 HPLC area %, 98.3 wt %, 75.9% yield from the disodium salt (i.e. sodium 2-[3-(trifluoromethyl)phenyl]propanedioate (2:1)).

1. temperaturewhile maintaining the internal temperature at between −3 and +1° C
2. customThe resulting reaction mixture
3. waitat 20−22° C. for 2-3 h
4. additionUpon complete addition
5. customby quenching with methanol
6. temperatureThe reaction mixture was warmed to 18° C.
7. additionwater (15 mL) was added to the reaction mixture at 18 to 20° C.
8. stirringthe two-phase mixture was stirred at 18 to 20° C. for 15 min
9. customthe layers were separated
10. extractionThe aqueous layer was extracted with dichloromethane (2×25 mL)
11. additioni-propanol (30 mL) was added to the combined organic solution
12. distillationThe resulting mixture was distilled with a pot temperature of 82° C. and with the head temperature at 42-82° C. under atmospheric pressure
13. customto remove dichloromethane and water
14. distillationthe distillation
15. additionadditional i-propanol (30 mL) was added to the hot concentrate
16. temperatureto cool to room temperature
17. stirringstirred at room temperature overnight during which time a solid
18. customcrystallized
19. filtrationThe mixture was then filtered
20. washthe wet solids washed with i-propanol (3×5 mL)
21. customThe solid product was dried in a vacuum oven at 50-55° C.

ORD record

ord-37e3223e2eb149148c3117fcf78699cf

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09108965B2