Trifluoroacetic acid → HCID 178494716, compound

Temperature

70 °C

To a solution of 2-[3,4-bis(methyloxy)phenyl]-4-(methyloxy)-3-oxobutanenitrile (200 mg, 0.8 mmol) in ethanol (5 mL) was added hydrazine dihydrochloride (101 mg, 0.9 mmol). The resulting mixture was heated at reflux for 1 hour. It was cooled, pour into a saturated sodium bicarbonate solution (10 mL), and the mixture was extracted with ethyl acetate (3×10 mL). The combined extract was washed with water and brine (30 mL each), dried over sodium sulfate, filtered and concentrated to give oily residue. To this residue was added of 3-chloro-4-hydroxybenzaldehyde (189 mg, 1.2 mmol) and trifluoroacetic acid (3 mL), and the resulting mixture was heated at 70° C. for 18 hours. Then the reaction mixture was concentrated, dissolved in 10 mL of N,N-dimethylformamide and purified by preparatory reverse phase HPLC (Shimadzu LC-8A HPLC, Waters Xterra C18 30 mm×100 mm column, acetonitrile-water-trifluoroacetic buffer). After lyophillization of the pure fractions a yellow powder was obtained. The solid was dissolved in 4 mL of 1:1 methanol: 4N hydrogen chloride in dioxane, and evaporated to dryness (repeated three times) to give 4-{7,8-bis(methyloxy)-1-[(methyloxy)methyl]-3H-pyrazolo[3,4-c]isoquinolin-5-yl}-2-chlorophenol hydrochloride salt (101 mg, 0.23 mmol, 29% yield). 1H NMR (400 MHz, d6-DMSO): 10.64 (b, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.58-7.56 (d, 1H), 7.45 (s, 1H), 7.17-7.15 (d, 1H), 4.92 (s, 2H), 4.02 (s, 3H), 3.78 (s, 3H); MS (EI) for C20H18ClN3O4: 400 (MH+).

1. temperatureThe resulting mixture was heated
2. temperatureat reflux for 1 hour
3. temperatureIt was cooled
4. extractionthe mixture was extracted with ethyl acetate (3×10 mL)
5. extractionThe combined extract
6. washwas washed with water and brine (30 mL each)
7. dry with materialdried over sodium sulfate
8. filtrationfiltered
9. concentrationconcentrated
10. customto give oily residue
11. concentrationThen the reaction mixture was concentrated
12. dissolutiondissolved in 10 mL of N,N-dimethylformamide
13. custompurified by preparatory reverse phase HPLC (Shimadzu LC-8A HPLC, Waters Xterra C18 30 mm×100 mm column, acetonitrile-water-trifluoroacetic buffer)
14. customAfter lyophillization of the pure fractions a yellow powder was obtained
15. custom4N hydrogen chloride in dioxane, and evaporated to dryness (repeated three times)

ORD record

ord-61a2475eba244467b6229ba68d303d91

Source dataset

uspto-grants-2011_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07872014B2