Diisopropylethylamine → 7-Fluoro-5-methyl-3-[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride

HRID 1798935Notes

Reaction equation

HRID 1798935 reaction equation
CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([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:12]=1[OH:32].[Cl:33][C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[ClH:33].[F:10][C:11]1[C:12]2[O:32][C:34](=[O:36])[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:13]=2[CH:14]=[C:15]([CH3:17])[CH:16]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 582873142-Fluoro-4-methyl-6-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}phenol

Product 1

HCID 672208297-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

DIPEA (0.14 mL, 0.79 mmol) was added to a solution of 2-fluoro-4-methyl-6-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}phenol (D17, 51 mg, 0.16 mmol) in DCM (5 mL) at room temperature under argon. The reaction was cooled to 0° C. and the triphosgene (19 mg, 0.07 mmol) was added. The mixture was stirred for 30 min at 0° C., followed by a further 15 min at room temperature. The reaction was quenched with sat. NaHCO3 (5 mL) and partitioned between DCM and H2O. The aqueous layer was extracted with DCM (2×) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give the crude product, which was purified via flash column chromatography (silica, DCM to 0.5% NH3/9.5% MeOH/90% DCM) to give the free base of the title compound as a white solid. The free base was dissolved in DCM (2 mL) at 25° C. HCl (0.24 mL, 0.24 mmol, 1 M in Et2O) was then added and the reaction was stirred for 15 min. The solvent was removed by rotary evaporation to give 7-fluoro-5-methyl-3-[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride (E4, 47 mg, 70%) as a white solid.

Workup

  1. waitfollowed by a further 15 min at room temperature
  2. customThe reaction was quenched with sat. NaHCO3 (5 mL)
  3. custompartitioned between DCM and H2O
  4. extractionThe aqueous layer was extracted with DCM (2×)
  5. dry with materialthe combined organics were dried (Na2SO4)
  6. concentrationconcentrated by rotary evaporation
  7. customto give the crude product, which
  8. customwas purified via flash column chromatography (silica, DCM to 0.5% NH3/9.5% MeOH/90% DCM)

Sources & evidence

ORD record
ord-5302e31ff9dc4f0897d998b4ab39228f
Source dataset
uspto-grants-2013_01
Patent number
US08344000B2

Reaction notes

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