4-[4-(6-fluoro-5-methyl-2-oxo-1,3-benzoxazol-3(2H)-yl)-1-piperidinyl]tetrahydro-2H-pyran-4-carbonitrile → 5-Fluoro-4-methyl-2-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}phenol

HRID 1798920Notes

Reaction equation

HRID 1798920 reaction equation
C[Mg]I.[F:4][C:5]1[C:28]([CH3:29])=[CH:27][C:8]2[N:9]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]4([C:25]#N)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:15][CH2:14]3)C(=O)[O:11][C:7]=2[CH:6]=1>O1CCCC1>[F:4][C:5]1[C:28]([CH3:29])=[CH:27][C:8]([NH:9][CH:13]2[CH2:14][CH2:15][N:16]([C:19]3([CH3:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH2:17][CH2:18]2)=[C:7]([OH:11])[CH:6]=1

Participants

4

Reactant 2

HCID 582873204-[4-(6-fluoro-5-methyl-2-oxo-1,3-benzoxazol-3(2H)-yl)-1-piperidinyl]tetrahydro-2H-pyran-4-carbonitrileHCID 178418373HCID 178418373, compound

Product 1

HCID 582873015-Fluoro-4-methyl-2-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}phenolYield 17.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Methylmagnesium iodide (3 mL, 9 mmol, 3 M in diethyl ether) was added to a suspension of 4-[4-(6-fluoro-5-methyl-2-oxo-1,3-benzoxazol-3(2H)-yl)-1-piperidinyl]tetrahydro-2H-pyran-4-carbonitrile (D4, 681 mg, 0.852 mmol) in tetrahydrofuran (10 mL) at 0° C. under argon. The reaction was stirred for 1 h at rt before being cooled to 0° C. and quenched with saturated aqueous NH4Cl (5 mL). The mixture was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a brown oil, which was purified via chromatography (silica, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give a brown oil. This was further purified by high pH MDAP to give 5-fluoro-4-methyl-2-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]-amino}phenol (D5, 47 mg 17% yield) as a brown solid.

Workup

  1. temperaturebefore being cooled to 0° C.
  2. customquenched with saturated aqueous NH4Cl (5 mL)
  3. customThe mixture was partitioned between ethyl acetate and water
  4. extractionthe aqueous layer was extracted with ethyl acetate
  5. dry with materialThe combined organics were dried (Na2SO4)
  6. concentrationconcentrated by rotary evaporation
  7. customto give a brown oil, which
  8. customwas purified via chromatography (silica, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane)
  9. customto give a brown oil
  10. customThis was further purified by high pH

Sources & evidence

ORD record
ord-d01d8827c2854ca49086bcb155747afc
Source dataset
uspto-grants-2013_01
Patent number
US08344000B2

Reaction notes

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