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

HRID 1697471노트

반응식

HRID 1697471 반응식
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

참가 물질

8

반응물 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 581255011-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethanamineHCID 58125504(R)-6-trifluoromethyl-2,3-dihydrobenzo[1,4]dioxine-2-carboxylic acid

생성물 1

HCID 44194584(R)-6-Trifluoromethyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid [1-(1H-indazol-5-yl)-ethyl]-amide수율 44%

시약·촉매·용매 2

HCID 142844-(Dimethylamino)pyridine촉매HCID 6228Dimethylformamide용매

실험 절차

To a solution of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethanamine (66 mg, 0.27 mmol), (R)-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 (43 mg) as a solid. m/z=391.8 (M+1), r.t.=2.96 and 3.04 mins. 1H NMR (400 MHz; DMSO-d6) δ 12.99 (1H, d), 8.68-8.60 (1H, m), 8.04 (0.5H, s), 7.94-7.87 (0.5H, m), 7.69 (0.5H, s), 7.53-7.16 (5H, m), 7.08-7.04 (0.5H, m), 5.12-4.90 (2H, m), 4.47-4.30 (2H, m), 1.46-1.41 (3H, m).

후처리

  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

출처 및 근거

ORD 기록
ord-5ef43bf3aa9c4f2997213f5328319f72
출처 데이터셋
uspto-grants-2012_04
특허 번호
US08163901B2

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