4-Hydroxybenzoic Acid → 4-hydroxy-benzoic acid, compd. with (2S,4E)-N-methyl-5-[5-(1-methylethoxy)-3-pyridinyl]-4-penten-2-amine (1:1)

Temperature

130 °C

A mixture of 3-bromo-5-isopropoxypyridine (21.0 g, 97.2 mmol), (S)—N-Methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (24.0 g, 120 mmol), DMF (53 mL), K2CO3 (22 g, 159 mmol), palladium(II) acetate (0.22 g, 0.98 mmol) and tri-o-tolylphosphine (0.57 g, 1.9 mmol) was degassed and placed under a nitrogen atmosphere. The stirred mixture was then heated at 130° C. for 2.5 h. To remove palladium salts, Smopex™ (20 g) and ethyl acetate (100 mL) were added. The stirred mixture was heated at 50° C. for 5 h and at ambient temperature for 16 h and then filtered. The filtrate was concentrated under reduced pressure, and the residue (83 g) was dissolved in methanol (25 mL), cooled in a cold water bath (<5° C.) and treated drop-wise with 6 M HCl (100 mL). This mixture was stirred 3 h at ambient temperature, and the methanol was removed by concentration under vacuum. The remaining aqueous mixture was washed with dichloromethane (100 mL), made basic by careful (with cooling) addition of 3 M NaOH, and extracted (2×200 mL) with dichloromethane. These latter extracts were washed with saturated aqueous NaCl and concentrated under vacuum. The residue was dissolved in acetone (150 mL), and p-hydroxybenzoic acid (14.0 g, 101 mmol) was added. After complete dissolution of the p-hydroxybenzoic acid, the solution was kept at ambient temperature, as a large amount of solid formed (several hours). After several hours of cooling at −15° C., the mixture was suction filtered. The resulting solid (24.8 g) was recrystallized from acetone (240 mL) to give 22.3 g (61.6%) of off-white crystals (97+% pure by GCMS and LCMS).

1. customwas degassed
2. customTo remove palladium salts, Smopex™ (20 g) and ethyl acetate (100 mL)
3. additionwere added
4. temperatureThe stirred mixture was heated at 50° C. for 5 h and at ambient temperature for 16 h
5. filtrationfiltered
6. concentrationThe filtrate was concentrated under reduced pressure
7. dissolutionthe residue (83 g) was dissolved in methanol (25 mL)
8. temperaturecooled in a cold water bath (<5° C.)
9. additiontreated drop-wise with 6 M HCl (100 mL)
10. customthe methanol was removed by concentration under vacuum
11. washThe remaining aqueous mixture was washed with dichloromethane (100 mL)
12. temperaturemade basic by careful (with cooling) addition of 3 M NaOH
13. extractionextracted (2×200 mL) with dichloromethane
14. washThese latter extracts were washed with saturated aqueous NaCl
15. concentrationconcentrated under vacuum
16. dissolutionThe residue was dissolved in acetone (150 mL)
17. customwas kept at ambient temperature, as a large amount of solid
18. customformed (several hours)
19. temperatureAfter several hours of cooling at −15° C.
20. filtrationfiltered
21. customThe resulting solid (24.8 g) was recrystallized from acetone (240 mL)

ORD record

ord-a9f258d90a58463ead3a2474aa5959b6

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08778978B2