Ethyl Acrylate → Ethyl (2E)-3-(6-aminopyridin-3-yl)prop-2-enoate

Temperature

100 °C

To a glass bomb were charged with 5-bromopyridin-2-amine (10.0 g, 57.8 mmol), ethyl acrylate (8.14 mL, 75 mmol) and DIEA (25.2 mL, 144 mmol) in DMF (40 mL). The mixture was purged with argon, followed by addition of Pd(OAc)2 (0.649 g, 2.89 mmol) and (o-Tol)3P (3.87 g, 12.72 mmol), and finally purged thoroughly with argon. The mixture was sealed, and heated with 100° C. oil bath overnight. The reaction mixture was cooled down to room temperature, and the precipitates were removed by filtering through a thin layer of Celite. The filtrate was concentrated as much as possible via rotavap, and the residue was partitioned between EtOAc/water (150 mL/100 mL). EtOAc layer was washed with water (2×100 mL), dried over Na2SO4, and concentrated. A brown slid was obtained as crude product. The crude product was triturated with EtOAc (40 mL) and the yellow solid was collected via filtration. The filter cake was rinsed with small amount of EtOAc and dried under vacuum as the first crop of product (5.0 g). The mother liquor from trituration was stripped by dilute aqueous 1 N HCl (30 mL) and water (70 mL). Aqueous layer was transferred to a clean separate funnel, basicified with 20 mL sat. Na2CO3, and extracted with EtOAc (60 mL). EtOAc layer was dried over Na2SO4, concentrated and provided the second portion of product (4.0 g). The two crops of product were combined to afford 81% yield. LCMS (m/z) 193.2 (MH+), 0.39 min.

1. customThe mixture was purged with argon
2. customfinally purged thoroughly with argon
3. customThe mixture was sealed
4. temperatureThe reaction mixture was cooled down to room temperature
5. customthe precipitates were removed
6. filtrationby filtering through a thin layer of Celite
7. concentrationThe filtrate was concentrated as much as possible via rotavap
8. customthe residue was partitioned between EtOAc/water (150 mL/100 mL)
9. washEtOAc layer was washed with water (2×100 mL)
10. dry with materialdried over Na2SO4
11. concentrationconcentrated
12. customA brown slid was obtained as crude product
13. customThe crude product was triturated with EtOAc (40 mL)
14. filtrationthe yellow solid was collected via filtration
15. washThe filter cake was rinsed with small amount of EtOAc
16. dry with materialdried under vacuum as the first crop of product (5.0 g)
17. customAqueous layer was transferred to a clean separate funnel
18. extractionextracted with EtOAc (60 mL)
19. dry with materialEtOAc layer was dried over Na2SO4
20. concentrationconcentrated

ORD record

ord-f65acde1215244cb9494c9028832511f

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09242996B2