Hydrochloric Acid → trans-8-Fluoro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide

HRID 1867264Notes

Reaction equation

HRID 1867264 reaction equation
Cl.[CH3:2][O:3][NH:4][CH3:5].C[Al](C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]2[O:19][CH2:18][C@@H:17]3[C@H:20]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:21]([C:23](OCC)=[O:24])=[N:22][N:16]3[C:15]=2[CH:34]=1>C(Cl)Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]2[O:19][CH2:18][C@@H:17]3[C@H:20]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:21]([C:23]([N:4]([O:3][CH3:2])[CH3:5])=[O:24])=[N:22][N:16]3[C:15]=2[CH:34]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 14232N,O-DimethylhydroxylamineHCID 16682925TrimethylaluminumHCID 91552591trans-Ethyl 8-fluoro-3-phenyl-3a,4-dihydro-3h-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxylate

Product 1

HCID 86624795trans-8-Fluoro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

The HCl salt of N-methoxy-N-methylamine (4.47 g, 15.3 mmol) in anhydrous CH2Cl2 was cooled to −10° C. and treated with Me3Al (22.9 mL, 2.0M in hexanes, 45.8 mmol) and stirred 30 min. Trans-ethyl 8-fluoro-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxylate (5-4, 5.2 g, 15.3 mmol) was added as a solution in CH2Cl2 and the reaction was warmed to 25° C. for 1 h. Upon completion, the reaction was carefully quenched by the addition of 0.5 N tartaric acid, and stirred an additional 30 min. The solution was extracted with CH2Cl2, dried with MgSO4, filtered and concentrated under reduced pressure to give trans-8-Fluoro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (5-5). This material was used crude in the subsequent transformation. MS (M+H+, C19H18FN3O3) 356.3 found 356.4 required. 1H NMR (300 MHz, CDCl3) δ 7.32 (m, 5H), 7.19 (dd, J=8.9, 2.9 Hz, 1H), 6.86 (dd, J=9.2, 5.2 Hz, 1H), 6.64 (app dt, J=8.2, 3.1 Hz, 1H), 4.51 (d, J=5.1 Hz, 1H), 4.28 (dd, J=10.7, 2.6 Hz, 1H), 4.08 (ddd, J=10.7, 5.2, 3.6 Hz, 1H), 3.79 (s, 3H), 3.57 (t, J=10.7 Hz, 1H), 3.29 (s, 3H).

Workup

  1. customUpon completion, the reaction was carefully quenched by the addition of 0.5 N tartaric acid
  2. stirringstirred an additional 30 min
  3. extractionThe solution was extracted with CH2Cl2
  4. dry with materialdried with MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-1c31cf1fa0824e00a6056afa1454fc07
Source dataset
uspto-grants-2009_12
Patent number
US07632833B2

Reaction notes

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