Hydrochloric Acid → 3-(4-(5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxamido)phenyl)-2-methylpropanoic acid

HRID 1876442Notes

Reaction equation

HRID 1876442 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])=[CH:18][CH:17]=2)=[O:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.CO.[OH-].[Li+].Cl>O1CCCC1.CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:29])[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)=[O:14])[C:5]2[O:9][C:8]([CH3:10])([CH3:11])[CH2:7][C:6]=2[CH:12]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 887MethanolHCID 3939Lithium HydroxideHCID 67405616Ethyl 3-(4-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxamido)phenyl)-2-methylpropanoate

Product 1

HCID 468367693-(4-(5-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxamido)phenyl)-2-methylpropanoic acid

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (803) (Compound was prepared in a similar manner as that described for the synthesis of (735) (101.3 mg, 0.482 mmol) was dissolved in dichloromethane (4 mL) and ethyl 3-(4-aminophenyl)-2-methylpropanoate (646) (100 mg, 0.482 mmol), triethyl amine (0.4 mL, 2.89 mmol), and 1-propanephosphonic acid cyclic anhydride (0.34 mL, 0.58 mmol, 50% in ethyl acetate) were added and stirred overnight at room temperature. The reaction was purified in vacuo and purified by flash column chromatography on silica gel with hexanes and EtOAc to give ethyl 3-(4-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxamido)phenyl)-2-methylpropanoate. The ester was dissolved in tetrahydrofuran (1.0 mL), methanol (1.0 mL) and water (3 mL). Lithium hydroxide was added and the reaction was stirred at room temperature for 4 h. The mixture was acidified with 1M HCl and diluted with EtOAc (3 mL). The organic layer was washed with brine (3 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 3-(4-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxamido)phenyl)-2-methylpropanoic acid (97). 1H NMR (400 MHz, CDCl3) δ 9.53 (br, 1H), 7.66 (dd, J=9.9, 2.6 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.02 (dd, J=9.9, 2.6 Hz, 1H), 3.13-3.00 (m, 3H), 2.72 (m, 2H), 1.60 (s, 6H), 1.19 (d, J=8.0 Hz, 3H).

Workup

  1. washThe organic layer was washed with brine (3 mL)
  2. dry with materialdried over sodium sulfate
  3. filtrationfiltered
  4. concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-073366c00fb24c93b81bb414413a7a23
Source dataset
uspto-grants-2012_11
Patent number
US08309600B2

Reaction notes

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