Iodoethane → 4-Isopropoxy-3-methylbenzaldehyde

Temperature

25 °C

A solution of [10-(5-fluoro-3-pyridyl)-8-hydroxy-11-oxa-3-azaspiro[5.5]undec-9-en-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (56 mg, 0.13 mmol) in ethanol (4.4 mL) was purged with nitrogen for 5 min and treated with 10% palladium on carbon (13 mg, 0.012 mmol). The mixture was evacuated and put under a hydrogen atmosphere (balloon). The reaction mixture was stirred for 12 h at 25° C. The reaction mixture was evacuated and put under an inert atmosphere and re-charged with 10% palladium on carbon (54 mg, 0.05 mmol). The mixture was evacuated and put under a hydrogen atmosphere (balloon) and stirred for 4 h. The reaction mixture was evacuated and put under an inert atmosphere. The Pd-catalyst was removed via filtration and was washed with ethyl acetate. The filtrate was concentrated to dryness and dissolved in DMF (2.4 mL). The mixture was cooled to 0° C. and treated with 60% NaH (28 mg, 1.19 mmol) and ethyl iodide (95 μL, 1.2 mmol). The reaction mixture was warmed to 25° C. and stirred for 2 h. The reaction mixture was quenched by the addition of methanol and partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organics were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by reverse phase HPLC (1-100% acetonitrile in water, no modifier) afforded cis-4-ethoxy-2-(5-fluoropyridin-3-yl)-1-oxa-9-azaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone (68 mg) ESI-MS m/z calc. 470.26, found 471.2 (M+1)+; Retention time: 1.453 minutes (3 min run).

1. customThe mixture was evacuated
2. customThe reaction mixture was evacuated
3. customThe mixture was evacuated
4. stirringstirred for 4 h
5. customThe reaction mixture was evacuated
6. customThe Pd-catalyst was removed via filtration
7. washwas washed with ethyl acetate
8. concentrationThe filtrate was concentrated to dryness
9. dissolutiondissolved in DMF (2.4 mL)
10. temperatureThe mixture was cooled to 0° C.
11. temperatureThe reaction mixture was warmed to 25° C.
12. stirringstirred for 2 h
13. customThe reaction mixture was quenched by the addition of methanol
14. custompartitioned between water and ethyl acetate
15. customThe layers were separated
16. extractionthe aqueous layer was extracted with ethyl acetate (3×50 mL)
17. washThe combined organics were washed with saturated aqueous sodium chloride
18. dry with materialdried over sodium sulfate
19. filtrationfiltered
20. concentrationconcentrated under reduced pressure
21. customPurification by reverse phase HPLC (1-100% acetonitrile in water

ORD record

ord-5d844270815e4d30be9a99ef96ee345f

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09403839B2