Dimethylformamide → (S)-7-(cyclopropylethynyl)-3-(2-fluoro-2-methylpropoxy)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine

HRID 335732Notes

Reaction equation

HRID 335732 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[N:10][CH:11]=[C:12]([O:21][CH2:22][C:23]([F:26])([CH3:25])[CH3:24])[CH:13]=3)[O:8][C:5]2=[CH:6][CH:7]=1.CN(C=O)C.C(NC(C)C)(C)C.[CH:39]1([C:42]#[CH:43])[CH2:41][CH2:40]1>O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I.C(OCC)(=O)C>[CH:39]1([C:42]#[C:43][C:2]2[CH:3]=[C:4]3[C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[N:10][CH:11]=[C:12]([O:21][CH2:22][C:23]([F:26])([CH3:25])[CH3:24])[CH:13]=4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH2:41][CH2:40]1

Participants

10

Reactant 4

HCID 6228DimethylformamideHCID 7912Diisopropylamine2×HCID 138823Cyclopropylacetylene2×HCID 67241788(S)-7-bromo-3-(2-fluoro-2-methylpropoxy)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine

Product 1

HCID 58466210(S)-7-(cyclopropylethynyl)-3-(2-fluoro-2-methylpropoxy)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 83717Copper iodideCatalystHCID 178418397HCID 178418397, compoundCatalyst2×HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

A sealable tube was charged with (S)-7-bromo-3-(2-fluoro-2-methylpropoxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (75 mg, 0.178 mmol), copper(i) iodide (3.38 mg, 0.018 mmol), tetrakis(triphenylphosphine)palladium (20.53 mg, 0.018 mmol). Added DMF (355 μL, 0.178 mmol), diisopropylamine (498 μL, 3.55 mmol) and cyclopropylacetylene (75 μL, 0.888 mmol) and the tube was flushed with argon, sealed and heated to 110° C. for 2 hours. More copper iodide (3.38 mg, 0.018 mmol), tetrakis(triphenylphosphine)palladium (20.53 mg, 0.018 mmol), diisopropylamine (498 μL, 3.55 mmol) and cyclopropylacetylene (75 μL, 0.888 mmol) were added and the black mixture was heated at 110° C. for 3 hours. The reaction was diluted with water (100 mL) and poured into a separatory funnel containing ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-7-(cyclopropylethynyl)-3-(2-fluoro-2-methylpropoxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a tan solid.

Workup

  1. customsealed
  2. temperaturethe black mixture was heated at 110° C. for 3 hours
  3. additionpoured into a separatory funnel
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with ethyl acetate (2×50 mL)
  6. washThe combined organic layers were washed with water
  7. dry with materialbrine, dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customto provide a brown oil that
  11. customwas purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide)

Sources & evidence

ORD record
ord-744924b2d0154e2990d8debff7ec9a0e
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Reaction notes

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