Diisopropylethylamine → (S)-6-Trifluoromethyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid [1-(1H-indazol-5-yl)-ethyl]-amide

HRID 1697472Notes

Reaction equation

HRID 1697472 reaction equation
O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH:16]([NH2:18])[CH3:17])=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:33]=[CH:32][C:24]2[O:25][C@H:26]([C:29](O)=[O:30])[CH2:27][O:28][C:23]=2[CH:22]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.CN(C=O)C>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([CH:16]([NH:18][C:29]([C@H:26]3[O:25][C:24]4[CH:32]=[CH:33][C:21]([C:20]([F:35])([F:19])[F:34])=[CH:22][C:23]=4[O:28][CH2:27]3)=[O:30])[CH3:17])=[CH:13][CH:14]=2)[CH:9]=[N:8]1

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58125484(S)-6-trifluoromethyl-2,3-dihydrobenzo[1,4]dioxine-2-carboxylic acidHCID 581255011-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethanamine

Product 1

HCID 44194585(S)-6-Trifluoromethyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid [1-(1H-indazol-5-yl)-ethyl]-amideYield 23.5%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Procedure

To a solution of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethanamine (66 mg, 0.27 mmol), (5)-6-trifluoromethyl-2,3-dihydrobenzo[1,4]dioxine-2-carboxylic acid (60.6 mg, 0.25 mmol), 4-dimethylaminopyridine (2.5 mg, 0.02 mmol) and N,N-diisopropylethylamine (153 μL, 0.88 mmol) in anhydrous DMF (4 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (102 mg, 0.27 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was poured into saturated NaHCO3 solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated. The residue was dissolved in methanol (20 mL) and 2N HCl (5 mL) was added. The reaction mixture was heated at 60° C. for 2 hours, then cooled and the methanol removed under vacuum. The remaining aqueous product was poured into saturated NaHCO3 solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (0 to 3% MeOH in DCM over 30 minutes) gave the product (23 mg) as a solid.

Workup

  1. extractionextracted with EtOAc (3×30 mL)
  2. washThe combined organics were washed with brine (3×30 mL)
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. dissolutionThe residue was dissolved in methanol (20 mL)
  7. addition2N HCl (5 mL) was added
  8. temperatureThe reaction mixture was heated at 60° C. for 2 hours
  9. temperaturecooled
  10. customthe methanol removed under vacuum
  11. additionThe remaining aqueous product was poured into saturated NaHCO3 solution (30 mL)
  12. extractionextracted with EtOAc (3×30 mL)
  13. washThe combined organics were washed with brine (3×30 mL)
  14. dry with materialdried (MgSO4)
  15. filtrationfiltered
  16. concentrationconcentrated

Sources & evidence

ORD record
ord-e702034c9a37404d9ce232903dda7fff
Source dataset
uspto-grants-2012_04
Patent number
US08163901B2

Reaction notes

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