Diisopropylamine → (1-(2-fluoro-4-[(1H-indole-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester

HRID 409393Notes

Reaction equation

HRID 409393 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(NC(C)C)(C)C.[CH3:42][O:43][C:44](=[O:62])[CH2:45][C:46]1[C:47]([CH3:61])=[N:48][N:49]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][C:54]=2[F:60])[C:50]=1[CH3:51].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:42][O:43][C:44](=[O:62])[CH2:45][C:46]1[C:47]([CH3:61])=[N:48][N:49]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([NH:59][C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)=[O:12])=[CH:55][C:54]=2[F:60])[C:50]=1[CH3:51]

Participants

7

Reactant 5

HCID 7912DiisopropylamineHCID 11430Potassium CarbonateHCID 72899Indole-2-carboxylic acidHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 66707516[1-(4-amino-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester

Product 1

HCID 68276290(1-(2-fluoro-4-[(1H-indole-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl esterYield 46.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of indole-2-carboxylic acid (80 mg, 0.50 mmol) in N,N-dimethylformamide (1.5 mL) are added TBTU (139 mg, 0.43 mmol) and N,N-diisopropyl amine (0.126 mL, 0.74 mmol). Subsequently [1-(4-amino-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester (120 mg, 0.41 mmol) is added. The mixture is stirred at room temperature for 12 hours. After that an aqueous solution of K2CO3 (2 M, 0.5 mL) is added. The obtained mixture is flushed through Al2O3 with dichloromethane/methanol (9:1, 10 mL). The solvent is removed in vacuo to yield 82.3 mg of (1-(2-fluoro-4-[(1H-indole-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+=435; Retention time HPLC: 0.41 min (method N). b) (1-(2-Fluoro-4-[(1H-indole-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (82 mg, 0.19 mmol) is dissolved in methanol (0.5 mL). An aqueous solution of NaOH (4M, 0.3 mL) is added and the mixture is stirred at room temperature for 2 hours. The resulting mixture is diluted with methanol/water, the solid is filtered off and after evaporation the residue is purified by HPLC (Gilson, XRS Pursuit, methanol/H2O+0.1% conc. NH3). The fractions containing the title compound are concentrated and lyophilized to yield 15 mg of the title compound (ESI mass spectrum: [M+H]+=421; Retention time HPLC: 1.04 min (method G)).

Workup

  1. customThe obtained mixture is flushed through Al2O3 with dichloromethane/methanol (9:1, 10 mL)
  2. customThe solvent is removed in vacuo

Sources & evidence

ORD record
ord-0905736a0e0d48a3bbe738e4b5f1f515
Source dataset
uspto-grants-2014_06
Patent number
US08759386B2

Reaction notes

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