Sodium hydride → 4-((5-methyl-3-phenylisoxazol-4-yl)methyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide

HRID 528616Notes

Reaction equation

HRID 528616 reaction equation
COC1C=CC(C[N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=CC=1.[H-].[Na+].Br[CH2:32][C:33]1[C:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:35][O:36][C:37]=1[CH3:38]>CN(C=O)C>[CH3:38][C:37]1[O:36][N:35]=[C:34]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]=1[CH2:32][N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9]([NH:8][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]1=2

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 27761474-(Bromomethyl)-5-methyl-3-phenylisoxazoleHCID 89761436N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide2×

Product 1

HCID 897618614-((5-methyl-3-phenylisoxazol-4-yl)methyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamideYield 12.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

To a flask charged with N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE M) (0.104 g, 0.25 mmol) was added DMF (0.7 ml), and cooled in an ice water bath prior to the addition of NaH (60% in mineral oil) (10 mg, 0.25 mmol). The mixture was stirred for 45 min at 0° C., then 30 min at rt. To a separate vial charged with 4-(bromomethyl)-5-methyl-3-phenylisoxazole (Sigma Aldrich) (35 mg, 0.25 mmol) was added DMF (0.3 ml), then the solution of deprotonated amine. The resulting mixture was sealed and shaken at room temperature overnight. The mixture was quenched with the addition of MeOH, then concentrated under reduced pressure and purified with NH4OH modified reverse-phase-HPLC affording 4-((5-methyl-3-phenylisoxazol-4-yl)methyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (14.6 mg, 12%). 1H NMR (500 MHz, DMSO-d6) δ=12.50 (br. s., 1 H), 7.60 (dd, J=1.7, 7.7 Hz, 2 H), 7.48-7.40 (m, 3 H), 7.21 (d, J=4.6 Hz, 1 H), 7.15 (dd, J=2.1, 8.5 Hz, 1 H), 6.99 (d, J=2.2 Hz, 1 H), 6.82-6.75 (m, 2 H), 4.37 (s, 2 H), 4.03-3.95 (m, 2 H), 3.13-3.07 (m, 2 H), 2.47 (s, 3 H); m/z (ESI) 469.0 (M+H)+.

Workup

  1. temperaturecooled in an ice water bath
  2. custom30 min
  3. customat rt
  4. customThe resulting mixture was sealed
  5. stirringshaken at room temperature overnight
  6. customThe mixture was quenched with the addition of MeOH
  7. concentrationconcentrated under reduced pressure
  8. custompurified with NH4OH modified reverse-phase-HPLC

Sources & evidence

ORD record
ord-8969f2095f4d46d192327dc52aff95f7
Source dataset
uspto-grants-2016_05
Patent number
US09346798B2

Reaction notes

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