1-Hydroxybenzotriazole → HCID 67973772, compound

HRID 880611Notes

Reaction equation

HRID 880611 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][N:10]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]4[CH2:25][CH2:24][CH2:23][N:22]4[C:26](=[O:39])[C@@H:27]([NH:31][C:32](OC(C)(C)C)=[O:33])[CH:28]([CH3:30])[CH3:29])[CH:20]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2].C[CH2:41][N:42]([CH:46]([CH3:48])C)[CH:43](C)C.C(N[C@H](C(O)=O)C(C)C)([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=O.CN(C([O:71]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(C)(OC(C)(C)C)=O.N[C@H](C(O)=O)C>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][N:10]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]4[CH2:25][CH2:24][CH2:23][N:22]4[C:26](=[O:39])[C@@H:27]([NH:31][C:32](=[O:33])[C@@H:46]([N:42]([C:43]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:71])[CH3:41])[CH3:48])[CH:28]([CH3:29])[CH3:30])[CH:20]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]

Participants

11

Reactant 6

HCID 757711-HydroxybenzotriazoleHCID 81531Diisopropylethylamine2×HCID 83693Boc-L-ValineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 67976898HCID 67976898, compoundHCID 131732636HCID 131732636, compound

Product 1

HCID 67973772HCID 67973772, compoundYield 62.3%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A solution of 1-{5-[(S)-1-((S)-2-tert-butoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-pyridin-3-yl}-1H-indole-4-carboxylic acid ethyl ester (I-1A-1c: 2.5 g, 4.7 mmol) in TFA (2 mL) and CH2Cl2 (2 mL) was stirred at room temperature for 18 hours. More TFA (3.6 mL) was added. The mixture was stirred for 3 hours and concentrated under reduced pressure. To the resulting oily residue was added anhydrous. DMF, DIEA (7.6 mL, 44 mmol), Boc-L-valine (0.89 g, 4.4 mmol), HBTU (1.8 g, 4.8 mmol), and HOBT (0.74 g, 4.9 mmol). The mixture was stirred at room temperature overnight. To the reaction mixture was added more HBTU (0.83 g, 2.2 mmol), Boc-Me-Alanine (0.18 g, 0.87 mmol), and DIEA (2.3 mL, 13.1 mmol). Stirring continued at room temperature overnight. The reaction mixture was then diluted with EtOAc (200 mL) and washed with water (2×100 mL). The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers were washed with water again (2×25 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give an oil. This oil was purified by silica gel column chromatography (0-100% EtOAc/heptane) to give the titled compound as a light yellow foam (1.7 g, 58% for 2 steps).

Workup

  1. concentrationconcentrated under reduced pressure
  2. additionTo the resulting oily residue was added anhydrous
  3. stirringThe mixture was stirred at room temperature overnight
  4. stirringStirring
  5. waitcontinued at room temperature overnight
  6. washwashed with water (2×100 mL)
  7. extractionThe aqueous layer was extracted with EtOAc (50 mL)
  8. washthe combined organic layers were washed with water again (2×25 mL)
  9. dry with materialThe organic layer was dried over anhydrous Na2SO4
  10. concentrationconcentrated under reduced pressure
  11. customto give an oil
  12. customThis oil was purified by silica gel column chromatography (0-100% EtOAc/heptane)

Sources & evidence

ORD record
ord-fdd76238b07542d68422e789c3ec5af5
Source dataset
uspto-grants-2015_03
Patent number
US08993523B2

Reaction notes

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