Diisopropylethylamine → 6-Fluoro-5-methyl-3-[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride

HRID 1798932Notes

Reaction equation

HRID 1798932 reaction equation
CCN(C(C)C)C(C)C.[F:10][C:11]1[C:12]([CH3:32])=[CH:13][C:14]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3([CH3:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[C:15]([OH:17])[CH:16]=1.[Cl:33][C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[ClH:33].[F:10][C:11]1[C:12]([CH3:32])=[CH:13][C:14]2[N:18]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]4([CH3:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:23][CH2:24]3)[C:34](=[O:36])[O:17][C:15]=2[CH:16]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 582873015-Fluoro-4-methyl-2-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}phenol

Product 1

HCID 672209236-Fluoro-5-methyl-3-[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Hünig's base (0.07 mL, 0.401 mmol) was added to a solution of 5-fluoro-4-methyl-2-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}phenol (D5, 47 mg, 0.146 mmol) in dichloromethane (5 mL) at rt under argon. The reaction was cooled to 0° C., the triphosgene (22.8 mg, 0.077 mmol) was added and the mixture was stirred for 1 h at 0° C. The reaction was quenched with saturated aqueous NaHCO3 (5 mL) and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a brown oil. The crude residue was purified via chromatography (amino-doped silica, iso-hexane-ethyl acetate) to give the free base of the title compound as a white solid. HCl (0.05 mL, 0.05 mmol, 1 M in diethyl ether) was added to a solution of the free base in dichloromethane (0.5 mL). The solvent was removed by rotary evaporation and the resulting residue was triturated with diethyl ether (2×) to give 6-fluoro-5-methyl-3-[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride (E1, 13.1 mg, 22% yield) as a white solid.

Workup

  1. customThe reaction was quenched with saturated aqueous NaHCO3 (5 mL)
  2. custompartitioned between dichloromethane and water
  3. extractionThe aqueous layer was extracted with dichloromethane (2×)
  4. dry with materialthe combined organics were dried (Na2SO4)
  5. concentrationconcentrated by rotary evaporation
  6. customto give a brown oil
  7. customThe crude residue was purified via chromatography (amino-doped silica, iso-hexane-ethyl acetate)

Sources & evidence

ORD record
ord-f7afe938b46e4b6aa7411ceae712f484
Source dataset
uspto-grants-2013_01
Patent number
US08344000B2

Reaction notes

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