Hydrochloric Acid → (1-{2-Fluoro-4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid

HRID 409397Notes

Reaction equation

HRID 409397 reaction equation
C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:6]([CH3:33])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[O:22][C:23]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=4[C:25]=3[CH3:26])=[O:20])=[CH:14][C:13]=2[F:32])[C:9]=1[CH3:10].[OH-].[Na+].Cl>O1CCOCC1.O.O>[F:32][C:13]1[CH:14]=[C:15]([NH:18][C:19]([C:21]2[O:22][C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[C:25]=2[CH3:26])=[O:20])[CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:9]([CH3:10])=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:6]([CH3:33])=[N:7]1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 68276373(1-(2-fluoro-4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester

Product 1

HCID 59054523(1-{2-Fluoro-4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acidYield 58.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 218864351,4-Dioxane--water (1/1)Solvent

Conditions

Temperature
60 °C

Procedure

To a solution of 5-fluoro-3-methyl-1-benzofuran-2-carboxylic acid (194 mg, 1 mmol) in 5 mL dimethylformamide is added diisopropylethylamine (0.516 mL, 3 mmol) and HATU (399 mg, 1.05 mmol) is added. After stirring at room temperature for 25 minutes dimethylformamide (1 mL) and then intermediate [1-(4-amino-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester (291 mg, 1 mmol) is added. Subsequently diisopropylethylamine (0.344 mL, 2 mmol) and dimethylformamide (2 mL) is added, and the mixture is stirred at room temperature for 48 hours. Then ethyl acetate and water are added and the precipitate is filtered off. The organic layer is extracted twice with acetic acid (1 N), once with an aqueous solution of NaHCO3 (5% by weight) and twice with water, dried over MgSO4. The solvent is removed by evaporation in vacuo. The residue is purified by MPLC (dichloromethane/methanol 96:4) to yield 120 mg of (1-(2-fluoro-4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+=468; TLC: Rf=0.72 (dichloromethane/methanol 9:1, silicagel 60 F254)). b) To a solution of (1-(2-fluoro-4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)-amino]-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (119 mg, 0.26 mmol) in dioxane/water (7 mL/7 mL) is added an aqueous solution of NaOH (1 M, 2.3 mL) and the mixture is stirred at room temperature for 12 hours and at 60° C. for 2 hours. The mixture is diluted with water, acidified with hydrochloric acid (1 M, 1 mL) and extracted with ethyl acetate. The organic layer is dried over MgSO4, the solvent evaporated in vacuo, the residue is crystallized with diisopropyl ether and the precipitate is isolated by filtration to yield 69 mg of the title compound (ESI mass spectrum: [M+H]+=454; Retention time HPLC: 0.90 min (method D)).

Workup

  1. extractionextracted with ethyl acetate
  2. dry with materialThe organic layer is dried over MgSO4
  3. customthe solvent evaporated in vacuo
  4. customthe residue is crystallized with diisopropyl ether
  5. customthe precipitate is isolated by filtration

Sources & evidence

ORD record
ord-be10a67a30f040e0a09fc5d35a6562a3
Source dataset
uspto-grants-2014_06
Patent number
US08759386B2

Reaction notes

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