Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate → Methyl 4-{4-[({[5-amino-2-(cyclopropylsulfanyl)phenyl]methyl}(methyl)carbamoyl)[(1 {bis[(tert-butoxy)carbonyl]amino}-4-fluoroisoquinolin-6-yl)amino]methyl]-2,6-dimethylphenyl}-3-hydroxybutanoate

HRID 708814Notes

Reaction equation

HRID 708814 reaction equation
[OH:1][CH:2]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7](B(O)O)=[CH:6][C:5]=1[CH3:14].[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:26][CH:25]=[C:24]2[F:46].O.[C:48]([OH:52])(=O)[CH:49]=O.Cl.[CH:54]1([S:57][C:58]2[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][C:59]=2[CH2:65][NH:66][CH3:67])[CH2:56][CH2:55]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C.CN(C=O)C.CCOC(C)=O>[NH2:62][C:61]1[CH:63]=[CH:64][C:58]([S:57][CH:54]2[CH2:56][CH2:55]2)=[C:59]([CH2:65][N:66]([CH3:67])[C:48]([CH:49]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[C:27]([N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])=[N:26][CH:25]=[C:24]3[F:46])[C:7]2[CH:8]=[C:9]([CH3:10])[C:4]([CH2:3][CH:2]([OH:1])[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([CH3:14])[CH:6]=2)=[O:52])[CH:60]=1

Participants

9

Reactant 5

HCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 15620607Glyoxylic acid, monohydrateHCID 1177499146-Amino-1-(di-tert-butoxycarbonylamino)-4-fluoroisoquinolineHCID 1180930774-(Cyclopropylthio)-3-((methylamino)methyl)aniline hydrochlorideHCID 123401472(4-(2-Hydroxy-4-methoxy-4-oxobutyl)-3,5-dimethylphenyl)boronic acid

Product 1

HCID 118093103Methyl 4-{4-[({[5-amino-2-(cyclopropylsulfanyl)phenyl]methyl}(methyl)carbamoyl)[(1 {bis[(tert-butoxy)carbonyl]amino}-4-fluoroisoquinolin-6-yl)amino]methyl]-2,6-dimethylphenyl}-3-hydroxybutanoateYield 66.1%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

2C (100 mg, 0.376 mmol), Intermediate 3 (142 mg, 0.376 mmol), and glyoxylic acid monohydrate (34.6 mg, 0.376 mmol) were dissolved in acetonitrile (1.5 mL)/DMF (1.500 mL) and heated at 80° C. for 2 h. A solution of Intermediate 6 (106 mg, 0.376 mmol)) and TEA (0.157 mL, 1.127 mmol) in DMF (1.500 mL) was added followed by BOP (183 mg, 0.413 mmol) as a solid. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography (0 to 100% EtOAc in hexanes then elute with 20% MeOH in dichloromethane) to yield 2D (210 mg, 0.248 mmol, 66.1% yield) as a yellow solid. MS (ESI) m/z: 846.7 (M+H)+.

Workup

  1. washwashed with water and brine
  2. dry with materialdried over Na2SO4
  3. concentrationconcentrated
  4. customThe crude material was purified by column chromatography (0 to 100% EtOAc in hexanes
  5. washthen elute with 20% MeOH in dichloromethane)

Sources & evidence

ORD record
ord-e4fe56208696483088229575e4a08e35
Source dataset
uspto-grants-2015_11
Patent number
US09174974B2

Reaction notes

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