Diisopropylethylamine → tert-Butyl N-(6-{[({[5-amino-2-(cyclopropanesulfonyl)phenyl]methyl}(methyl)carbamoyl)({4-[(2R)-1-fluoro-3-hydroxypropan-2-yl]-3-methylphenyl})methyl]amino}isoquinolin-1-yl)-N-[(tert-butoxy)carbonyl]carbamate

HRID 708887Notes

Reaction equation

HRID 708887 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][CH2:28][C@H:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=1[CH3:41])[CH2:30][OH:31].O.[C:43]([OH:47])(=O)[CH:44]=O.Cl.[CH:49]1([S:52]([C:55]2[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][C:56]=2[CH2:62][NH:63][CH3:64])(=[O:54])=[O:53])[CH2:51][CH2:50]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(#N)C>[NH2:59][C:58]1[CH:60]=[CH:61][C:55]([S:52]([CH:49]2[CH2:51][CH2:50]2)(=[O:54])=[O:53])=[C:56]([CH2:62][N:63]([CH3:64])[C:43]([CH:44]([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]=[CH:37][C:32]([C@H:29]([CH2:30][OH:31])[CH2:28][F:27])=[C:33]([CH3:41])[CH:34]=2)=[O:47])[CH:57]=1

Participants

9

Reactant 6

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 15620607Glyoxylic acid, monohydrateHCID 58717298tert-butyl N-(6-aminoisoquinolin-1-yl)-N-[(tert-butoxy)carbonyl]carbamateHCID 123776672(R)-(4-(1-Fluoro-3-hydroxypropan-2-yl)-3-methylphenyl)boronic acidHCID 1317338614-(Cyclopropylsulfonyl)-3-((methylamino)methyl)aniline hydrochloride

Product 1

HCID 118098757tert-Butyl N-(6-{[({[5-amino-2-(cyclopropanesulfonyl)phenyl]methyl}(methyl)carbamoyl)({4-[(2R)-1-fluoro-3-hydroxypropan-2-yl]-3-methylphenyl})methyl]amino}isoquinolin-1-yl)-N-[(tert-butoxy)carbonyl]carbamateYield 60.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent

Procedure

A mixture of Intermediate 1 1080 (0.076 g, 0.212 mmol), 24D (0.045 g, 0.212 mmol) and glyoxylic acid monohydrate (0.020 g, 0.218 mmol) suspended in DMF (0.5 mL) and acetonitrile (1.5 mL) was heated at 80° C. in an oil bath for 2.0 h. After it was cooled to rt, Intermediate 8 (0.066 g, 0.212 mmol) and DIEA (0.185 mL, 1.061 mmol) was added, followed by BOP (0.094 g, 0.212 mmol). The mixture was left stirring at rt overnight. The solvent was removed under reduced pressure, the crude residue was redissolved in dichloromethane and washed with brine (3×) and dried over sodium sulfate. The crude product was purified by flash chromatography (0-100% EtOAc/hexanes) to give 24E (0.103 g, 0.128 mmol, 60.2% yield). MS (ESI) (m/z): 806.3 (M+H)+.

Workup

  1. waitThe mixture was left
  2. customThe solvent was removed under reduced pressure
  3. dissolutionthe crude residue was redissolved in dichloromethane
  4. washwashed with brine (3×)
  5. dry with materialdried over sodium sulfate
  6. customThe crude product was purified by flash chromatography (0-100% EtOAc/hexanes)

Sources & evidence

ORD record
ord-b08102ddca8b4b5a8068ca9cd318dda3
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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