Acetic Acid → HCID 86707747, compound

To a solution of Compound 46b (100 mg, 0.25 mmol) in DMF (3 mL) at 0° C. was added 1M NaHMDS in THF (0.55 mL, 0.55 mmol) and the mixture stirred for 10 min. Methanesulfonyl chloride (0.025 mL, 0.32 mmol) was added and the mixture stirred for 5 min then 2M iodomethane in tert-butyl methyl ether (0.22 mL, 0.45 mmol) was added and the reaction stirred for 1 h. Additional 2M iodomethane in tert-butyl methyl ether (0.080 mL, 0.16 mmol) was added and the reaction stirred for 1 h then quenched with acetic acid (0.043 mL, 0.75 mmol). The mixture was diluted with MeOH and purified by prep HPLC (Method B, gradient elution of 10-100% solvent B). Fractions containing product were made basic by the addition of 1.5 M phosphate buffer, evaporated under reduced pressure to remove most of the ACN, acidified by the addition of satd. NH4Cl and extracted with DCM (3×), dried (Na2SO4), filtered and concentrated under reduced pressure to afford the racemic product. The material was further purified by silica gel chromatography eluting with 0-100% EtOAc/hexane to afford the racemic product. The enantiomers were separated by chiral preparative chiral HPLC (Whelko 4.6×250 mm ID, 10 μm, 20 mL/min, 25% MeOH/EtOH (1:1) in heptane) to afford Reference 1, Isomer A (RT=14.3 min, 22 mg, 36% yield), LCMS=0.90 min using analytical method (M), 493.9 (M+H), 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=8.5 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.68 (dd, J=8.8, 1.8 Hz, 1H), 7.56 (d, J=7.0 Hz, 2H), 7.47-7.40 (m, 2H), 7.39-7.31 (m, 1H), 5.73 (br. s., 2H), 4.67 (s, 2H), 3.20 (s, 3H), 2.44 (s, 3H), EL IC50=3751 nM; and Reference 1, Isomer B (RT=15.5 min, 23 mg, 37% yield), LCMS=0.90 min using analytical method (M), 493.9 (M+H), 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=8.8 Hz, 1H), 8.00 (d, J=1.3 Hz, 1H), 7.67 (dd, J=8.5, 1.5 Hz, 1H), 7.56 (d, J=7.0 Hz, 2H), 7.47-7.39 (m, 2H), 7.37-7.32 (m, 1H), 5.61 (br. s., 2H), 4.67 (s, 2H), 3.20 (s, 3H), 2.44 (s, 3H), EL IC50=5202 nM.

1. stirringthe mixture stirred for 5 min
2. stirringthe reaction stirred for 1 h
3. stirringthe reaction stirred for 1 h
4. custompurified by prep HPLC (Method B, gradient elution of 10-100% solvent B)
5. additionFractions containing product
6. additionwere made basic by the addition of 1.5 M phosphate buffer
7. customevaporated under reduced pressure
8. customto remove most of the ACN
9. additionacidified by the addition of satd
10. extractionNH4Cl and extracted with DCM (3×)
11. dry with materialdried (Na2SO4)
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure
14. customto afford the racemic product
15. customThe material was further purified by silica gel chromatography
16. washeluting with 0-100% EtOAc/hexane
17. customto afford the racemic product
18. customThe enantiomers were separated by chiral preparative chiral HPLC (Whelko 4.6×250 mm ID, 10 μm, 20 mL/min, 25% MeOH/EtOH (1:1) in heptane)
19. customto afford Reference 1, Isomer A (RT=14.3 min, 22 mg, 36% yield), LCMS=0.90 min
20. customReference 1, Isomer B (RT=15.5 min, 23 mg, 37% yield), LCMS=0.90 min

ORD record

ord-898c4c288b0e440887db6e4e1b4feccf

Source dataset

uspto-grants-2014_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08680090B2