Diisopropylethylamine → tert-Butyl N-{6-[({[(5-amino-2-bromophenyl)methyl](methyl)carbamoyl}[4-(1,1-difluoro-2-hydroxyethyl)-3,5-dimethylphenyl]methyl)amino]isoquinolin-1-yl}-N-[(tert-butoxy)carbonyl]carbamate

HRID 708820Notes

Reaction equation

HRID 708820 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:7][CH:6]=[CH:5]2.[F:27][C:28]([C:32]1[C:37]([CH3:38])=[CH:36][C:35](B(O)O)=[CH:34][C:33]=1[CH3:42])([F:31])[CH2:29][OH:30].O.[C:44]([OH:48])(=O)[CH:45]=O.Cl.[Br:50][C:51]1[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][C:52]=1[CH2:58][NH:59][CH3:60].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(#N)C>[NH2:55][C:54]1[CH:56]=[CH:57][C:51]([Br:50])=[C:52]([CH2:58][N:59]([CH3:60])[C:44]([CH:45]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([N:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:7][CH:6]=[CH:5]3)[C:35]2[CH:36]=[C:37]([CH3:38])[C:32]([C:28]([F:31])([F:27])[CH2:29][OH:30])=[C:33]([CH3:42])[CH:34]=2)=[O:48])[CH:53]=1

Participants

9

Reactant 6

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 15620607Glyoxylic acid, monohydrateHCID 58717298tert-butyl N-(6-aminoisoquinolin-1-yl)-N-[(tert-butoxy)carbonyl]carbamateHCID 1180929794-bromo-3-((methylamino)methyl)aniline HCl saltHCID 123574365(4-(1,1-Difluoro-2-hydroxyethyl)-3,5-dimethylphenyl)boronic acid

Product 1

HCID 118098688tert-Butyl N-{6-[({[(5-amino-2-bromophenyl)methyl](methyl)carbamoyl}[4-(1,1-difluoro-2-hydroxyethyl)-3,5-dimethylphenyl]methyl)amino]isoquinolin-1-yl}-N-[(tert-butoxy)carbonyl]carbamateYield 16.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 6342AcetonitrileSolvent

Conditions

Temperature
75 °C

Procedure

To a vial charged with Intermediate 1 (781 mg, 2.174 mmol) and Intermediate 7 (500 mg, 2.174 mmol) was added glyoxylic acid monohydrate (230 mg, 2.500 mmol) followed by acetonitrile (12 mL) and DMF (4 mL). The suspension was heated at 75° C. overnight. After it cooled to rt, 4-bromo-3-((methylamino)methyl)aniline HCl salt (751 mg, 2.61 mmol) was added, followed by additional DMF (8.000 mL) and DIEA (1.519 mL, 8.70 mmol). The reaction mixture was cooled to 0° C. HATU (909 mg, 2.391 mmol) was added. The reaction was stirred for 0.5 h then the cooling bath was removed and the reaction stirred for 2.5 h. The reaction was poured into 10% LiCl (100 mL) and extracted with EtOAc (3×100 mL). The combined organics were washed with 10% LiCl (100 mL), dried (Na2SO4), filtered and concentrated. The residue was chromatographed on Isco (120 g) eluting with 5 to 80% EtOAc/dichloromethane. Fractions containing desired material were rechromatographed using 0 to 10% MeOH/dichloromethane to give 4A (289 mg, 0.362 mmol, 16.64% yield) as a pale orange solid. MS and 1H NMR are consistent with the desired product.

Workup

  1. temperatureAfter it cooled to rt
  2. temperatureThe reaction mixture was cooled to 0° C
  3. customthe cooling bath was removed
  4. stirringthe reaction stirred for 2.5 h
  5. additionThe reaction was poured into 10% LiCl (100 mL)
  6. extractionextracted with EtOAc (3×100 mL)
  7. washThe combined organics were washed with 10% LiCl (100 mL)
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was chromatographed on Isco (120 g)
  12. washeluting with 5 to 80% EtOAc/dichloromethane
  13. additionFractions containing desired material
  14. customwere rechromatographed

Sources & evidence

ORD record
ord-704105dd71f0415d95224268cca4410e
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

Loading…