Diisopropylethylamine → (S)-(4-(5-methoxypyridin-2-yl)-8-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methanol

HRID 912435Notes

Reaction equation

HRID 912435 reaction equation
[OH:1][CH2:2][C@H:3]1[CH2:8][O:7][C:6]2[C:9]([C:13](O)=O)=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=1.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[CH:30][CH:31]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OC(=O)C)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:4]2[C@@H:3]([CH2:2][OH:1])[CH2:8][O:7][C:6]3[C:9]([C:13]4[NH:33][C:28]5[CH:27]=[C:26]([C:25]([F:24])([F:34])[F:35])[CH:31]=[CH:30][C:29]=5[N:32]=4)=[CH:10][CH:11]=[CH:12][C:5]2=3)=[N:17][CH:18]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 5208224-Trifluoromethyl-1,2-phenylenediamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67412020(S)-3-(hydroxymethyl)-4-(5-methoxypyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid

Product 1

HCID 67411729(S)-(4-(5-methoxypyridin-2-yl)-8-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methanolYield 89.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (S)-3-(hydroxymethyl)-4-(5-methoxypyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid 3.2 g (10 mmol) of step 7 in dimethylformamide 50 mL were 4-(trifluoromethyl)benzen-1,2-diamine 1.9 g (11 mmol), diisopropylethylamine 3.5 mL (20 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate 5.7 g (15 mmol), followed by stirring at room temperature for 3 hrs. The reaction mixture was diluted with ethylacetate, washed with a saturated sodium bicarbonate solution and a saturated NaCl solution, dried over magnesium sulfate and concentrated in a vacuum. The concentrate was dissolved in acetic acid/toluene (90 mL/10 mL), heated at 75° C. for 4 hrs with stirring, cooled to room temperature and concentrated in a vacuum. The concentrate was dissolved in ethylacetate, washed with a saturated sodium bicarbonate solution and a saturated NaCl solution, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by column chromatography (developing solvent: ethylacetate/hexane=2/3) afforded 4.1 g of the title compound (yield 82%).

Workup

  1. washwashed with a saturated sodium bicarbonate solution
  2. dry with materiala saturated NaCl solution, dried over magnesium sulfate
  3. concentrationconcentrated in a vacuum
  4. dissolutionThe concentrate was dissolved in acetic acid/toluene (90 mL/10 mL)
  5. temperatureheated at 75° C. for 4 hrs
  6. stirringwith stirring
  7. temperaturecooled to room temperature
  8. concentrationconcentrated in a vacuum
  9. dissolutionThe concentrate was dissolved in ethylacetate
  10. washwashed with a saturated sodium bicarbonate solution
  11. dry with materiala saturated NaCl solution, dried over magnesium sulfate
  12. concentrationconcentrated under reduced pressure
  13. customPurification by column chromatography (developing solvent: ethylacetate/hexane=2/3)

Sources & evidence

ORD record
ord-552b7738996244f4a7ca1597e3b15524
Source dataset
uspto-grants-2011_09
Patent number
US08026235B1

Reaction notes

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