8-fluoro-3-(3-hydroxypropyl)-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide → 1-[8-fluoro-3-(3-hydroxypropyl)-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazin-2-yl]ethanone

HRID 1867267Notes

Reaction equation

HRID 1867267 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[C:11]([CH2:26][CH2:27][CH2:28][OH:29])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14](N(OC)C)=[O:15])=[N:13][N:7]3[C:6]=2[CH:30]=1.[CH3:31][Li]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[C:11]([CH2:26][CH2:27][CH2:28][OH:29])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14](=[O:15])[CH3:31])=[N:13][N:7]3[C:6]=2[CH:30]=1

Participants

4

Reactant 2

HCID 729864628-fluoro-3-(3-hydroxypropyl)-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamideHCID 178418348HCID 178418348, compound

Product 1

HCID 684487931-[8-fluoro-3-(3-hydroxypropyl)-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazin-2-yl]ethanone

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

8-Fluoro-3-(3-hydroxypropyl)-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (5-7; a racemic mixture, 2.6 g, 6.29 mmol) was dissolved in anhydrous THF (50 mL) and cooled to −78° C. Methyllithium (11.8 mL, 3M in diethylether, 18.9 mmol) was added and the reaction stirred to 25° C. Upon completion the reaction was quenched by the addition of NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. Flash column chromatography (ISCO Redisep 0-100% EtOAc/hexanes gradient) provided 1-[8-fluoro-3-(3-hydroxypropyl)-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazin-2-yl]ethanone (5-8; a racemic mixture). 1H NMR (300 MHz, CDCl3) δ 7.28 (m, 4H), 7.07 (m, 2H), 6.78 (dd, J=8.9, 5.1 Hz, 1H), 6.58 (ddd, J=8.9, 8.2, 3.1 Hz, 1H), 4.15 (dd, J=10.5, 3.5 Hz, 1H), 3.75 (m, 2H), 3.71 (dd, J=10.8, 3.5 Hz, 1H), 2.95 (t, J=10.8 Hz, 1H), 2.55 (dt, J=13.0, 4.0 Hz, 1H), 2.55 (s, 3H), 2.37 (dt, J=13.0, 4.0 Hz, 1H), 1.74 (m, 1H), 1.42 (m, 1H); MS (M+H+, C21H21FN2O3) 369.3 found 369.4 required. This compound was resolved on the Chiracel OD column using MeOH as eluant into its separate enantiomers.

Workup

  1. customUpon completion the reaction was quenched by the addition of NH4Cl (50 mL)
  2. extractionextracted with EtOAc (3×50 mL)
  3. dry with materialThe combined organic extracts were dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-c7fbd8b4dc9b43a5bac23dc891131575
Source dataset
uspto-grants-2009_12
Patent number
US07632833B2

Reaction notes

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