Picolinic acid → HCID 44199929, compound

Temperature

100 °C

To a solution of picolinic acid (1.35 g, 11 mmol), HATU (4.18 g, 11 mmol) and DIPEA (2.09 mL, 12 mmol) in dry DMF (50 mL) at rt in the presence of anhydrous Na2SO4 (7 g, 50 mmol) was added 17 (3.37 g, 10 mmol) slowly. The consumption of 17 was determined to be completed by LC/MS. Additional anhydrous DMF (50 mL) was added and the mixture was heated at 100° C. for 16 h. Solid was filtered off and most of DMF was removed under vacuum. The residue was partitioned between a mixture of water (200 mL), aqueous Na2CO3 (2 M, 20 mL), EtOAc (300 mL) and MeOH (30 mL). The organic phase was washed further with water (2×50 mL). After drying and removal of EtOAc, the residue was treated with mixtures of DCM/MeOH (30 mL/3 mL) and washed with DCM to yield A52 as a solid precipitate (1.4 g). The mother liquor was purified by silica gel chromatography (8% MeOH in DCM) to remove most impurities. Most fractions containing product were combined to obtain solid product which was further trituated in ACN (60 mL) and washed several time with ACN to give 0.9 g of product A52. Fractions containing some product but more impurities were combined to get a crude residue which was purified with preparative HPLC to recover an additional 0.3 g A52. All three batches of 1,7-dimethyl-3-(2-methyl-5-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A52) had identical NMR and LC/MS. 1H NMR (400 MHz, d6-DMSO) δ 10.1 (s, 1H), 8.83 (m, 2H), 8.18 (dt, J=8.8, 1 Hz, 1H), 8.1 (td, J=7.7, 1.7 Hz, 1H), 7.97 (s, 1H), 7.71 (ddd, J=7.6, 4.8, 1.2 Hz, 1H), 7.47 (dd, J=8.3, 2.4 Hz, 1H), 7.44 (s, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 3.66 (s, 3H), 3.34 (s, 3H), 2.01 (s, 3H). MS m/z 425.1 (M+1).

1. customThe consumption of 17
2. additionAdditional anhydrous DMF (50 mL) was added
3. filtrationSolid was filtered off and most of DMF
4. customwas removed under vacuum
5. customThe residue was partitioned between a mixture of water (200 mL), aqueous Na2CO3 (2 M, 20 mL), EtOAc (300 mL) and MeOH (30 mL)
6. washThe organic phase was washed further with water (2×50 mL)
7. customAfter drying
8. customremoval of EtOAc
9. additionthe residue was treated with mixtures of DCM/MeOH (30 mL/3 mL)
10. washwashed with DCM

ORD record

ord-9b0cc65b632e40a4abeb25b6125f22ab

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08278452B2