Hydrochloric Acid → Azd-9496

7.5M Sodium hydroxide (32.9 ml, 247.10 mmol) was added to a solution of (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (11.28 g, 24.71 mmol) in THF (143 ml) and methanol (71.4 m). The reaction was stirred at room temperature for 4 h. The pH of the aqueous was adjusted to ˜6.5 by addition of 2N HCl solution, then the solution was extracted with diethyl ether (3×150 ml). The combined organics were dried over Na2SO4 and concentrated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% methanol in DCM which afforded a yellow solid. Attempted trituration with acetone/heptane failed due to higher than expected solubility. The solvents were removed to give a yellow solid which was triturated in isohexane (50 ml) with a few drops of diethyl ether, the resulting solid was filtered off and dried to give crude product (11.14 g) as a yellow powder. The solid was dissolved in ethanol (100 ml), under nitrogen and in the dark. The solution was then evaporated to 5 mBar using a vacuum pump at 62° C. in the dark. This procedure was repeated twice and the resulting resulting yellow glass scratched with a spatula into a fine powder and subjected to 5 mBar using a vacuum pump at 62° C. for 60 min, to afford a yellow powder. The powder was then left in a vacuum oven over P2O5 at 62° C. at 300 mBar overnight to afford the title product (9.77 g, 89%) as a pale yellow solid. 1H NMR (400 MHz, DMSO, 27° C.) δ 1.07-1.16 (3H, m) 1.18-1.29 (6H, m), 2.39 (1H, dd), 2.62 (1H, dd), 2.92 (2H, dd), 3.56 (1H, d), 5.26 (1H, s), 6.70 (1H, d), 7.02 (2H, dd), 7.22 (1H, d), 7.47 (3H, dd), 7.58 (1H, d), 10.60 (1H, s), 12.60 (1H, s). m/z: ES+ (ElectroSpray+) [M+H]+ 443.

1. extractionthe solution was extracted with diethyl ether (3×150 ml)
2. dry with materialThe combined organics were dried over Na2SO4
3. concentrationconcentrated
4. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 20% methanol in DCM which
5. customafforded a yellow solid
6. customThe solvents were removed
7. customto give a yellow solid which
8. customwas triturated in isohexane (50 ml) with a few drops of diethyl ether
9. filtrationthe resulting solid was filtered off
10. customdried
11. customto give crude product (11.14 g) as a yellow powder
12. customThe solution was then evaporated to 5 mBar
13. customat 62° C.
14. customthe resulting resulting yellow glass
15. customat 62° C.
16. customfor 60 min
17. customto afford a yellow powder

ORD record

ord-72d4b3e2e7c243198a37a5a31fbdf2dd

Source dataset

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09155727B2