Toluene → HCID 59321570, compound

To a solution of 2,6-dichlorobenzaldehyde oxime (26.4 g, 139 mmol) in N,N-dimethylformamide (70 mL) at 5° C. was added solid N-chlorosuccinimide (18.6 g, 139 mmol) in portions. The mixture was allowed to stir and warm to ambient temperature (with occasional cooling when warming was noted) over approximately 1.5 hour and then poured into ether. The ether layer containing the crude imidoyl chloride was washed twice with water followed by brine, dried over magnesium sulfate and concentrated. To a separate solution of ethyl 4-methyl-3-oxohexanoate (28.8 g, 167 mmol) in tetrahydrofuran (50 mL) at 0° C. was added sodium ethoxide (21 wt % in ethanol, 62.3 mL, 167 mmol) quickly. Then the above imidoyl chloride was added dropwise in tetrahydrofuran (100 mL). The solution was allowed to stir while warming to ambient temperature overnight. The mixture was then poured into ether, washed twice with water followed by brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 1.25% acetone in hexanes) to afford an oil which was dissolved in tetrahydrofuran (75 mL) at 0° C. Then a 1.5 M solution of diisobutylaluminum hydride in toluene (100 mL, 150 mmol) was added slowly. The solution was allowed to warm slightly while stirring for approximately 2.5 hours and then was re-cooled to 0° C. and stirred for 1.5 hours. Then aqueous Rochelle's salt (20 mL) was added carefully followed by ethyl acetate and the mixture was stirred overnight. Then the layers were separated and the aqueous layer was extracted two more times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 20% ethyl acetate in hexanes) to afford a white solid. The enantiomers were resolved by supercritical fluid chromatography (Chiralpak AD, 10% methanol in supercritical carbon dioxide) and the resulting solid was taken up with dichloromethane, dried over magnesium sulfate and concentrated to afford {3-(2,6-dichlorophenyl)-5-[(1S)-1-methylpropyl]-4-isoxazolyl}methanol (1.53 g, 7%) 1H-NMR (400 MHz, DMSO-d6) δ 7.61-7.51 (m, 3H), 4.85 (t, J=5 Hz, 1H), 4.20-4.06 (m, 2H), 3.15-3.10 (m, 1H), 1.69-1.62 (m, 2H), 1.29 (d, J=7 Hz, 3H), 0.79 (t, J=7 Hz, 3H).

1. temperature(with occasional cooling when warming was noted) over approximately 1.5 hour
2. washwas washed twice with water
3. dry with materialdried over magnesium sulfate
4. concentrationconcentrated
5. stirringto stir
6. temperaturewhile warming to ambient temperature overnight
7. washwashed twice with water
8. dry with materialdried over magnesium sulfate
9. concentrationconcentrated
10. custompurified by chromatography (silica gel, 1.25% acetone in hexanes)
11. customto afford an oil which
12. temperatureto warm slightly
13. stirringwhile stirring for approximately 2.5 hours
14. temperaturewas re-cooled to 0° C.
15. stirringstirred for 1.5 hours
16. stirringthe mixture was stirred overnight
17. customThen the layers were separated
18. extractionthe aqueous layer was extracted two more times with ethyl acetate
19. washThe combined organic layers were washed with brine
20. dry with materialdried over magnesium sulfate
21. concentrationconcentrated
22. custompurified by chromatography (silica gel, 20% ethyl acetate in hexanes)
23. customto afford a white solid
24. dry with materialdried over magnesium sulfate
25. concentrationconcentrated

ORD record

ord-e6fcf1b4a21f411aa324b27391a48b5d

Source dataset

uspto-grants-2011_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07960552B2