Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → 3-(3,5-Difluoro-phenyl)-2-[(2-isoquinolin-3-yl-1h-benzoimidazole-4-carbonyl)-amino]-propionic acid methyl ester

HRID 1910113Notes

Reaction equation

HRID 1910113 reaction equation
[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20](O)=[O:21])[C:13]=3[N:12]=2)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:48][O:49][C:50](=[O:62])[CH:51]([NH2:61])[CH2:52][C:53]1[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([F:60])[CH:54]=1>C(OCC)(=O)C>[CH3:48][O:49][C:50](=[O:62])[CH:51]([NH:61][C:20]([C:19]1[C:13]2[N:12]=[C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)[NH:15][C:14]=2[CH:16]=[CH:17][CH:18]=1)=[O:21])[CH2:52][C:53]1[CH:54]=[C:55]([F:60])[CH:56]=[C:57]([F:59])[CH:58]=1

Participants

5

Reactant 3

HCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66940454Methyl 2-amino-3-(3,5-difluorophenyl)propanoate hydrochlorideHCID 669406062-isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid

Product 1

HCID 669403573-(3,5-Difluoro-phenyl)-2-[(2-isoquinolin-3-yl-1h-benzoimidazole-4-carbonyl)-amino]-propionic acid methyl esterYield 50%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

145 mg (0.5 mmol) of 2-isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid (synthesized in Example 1, Step 3)) was reacted with 280 mg (0.75 mmol) of HBTU and 2-amino-3-(3,5-difluoro-phenyl)-propionic acid methyl ester HCl salt (126 mg, 0.5 mmol) as described in general procedure A. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL). The organic phase was washed with 1% NaOH aq. solution, then dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography (DCM/EtOAc=1:1 then DCM/EtOAc/MeOH=15:15:1) to give 3-(3,5-difluoro-phenyl)-2-[(2-isoquinolin-3-yl-1H-benzoimidazole-4-carbonyl)-amino]-propionic acid methyl ester (120 mg, 50%). LCMS: 487 (M+1)+.

Workup

  1. washThe organic phase was washed with 1% NaOH aq. solution
  2. dry with materialdried over Na2SO4
  3. concentrationconcentrated under vacuum
  4. customThe residue was purified by flash column chromatography (DCM/EtOAc=1:1

Sources & evidence

ORD record
ord-861dd41bce3248d38985dddda92ef247
Source dataset
uspto-grants-2013_12
Patent number
US08598353B2

Reaction notes

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