Sodium hydride → 3-[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-butyric acid

HRID 551507Notes

Reaction equation

HRID 551507 reaction equation
[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[CH:22][NH:23]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[H-].[Na+].C([O:32][C:33](=[O:37])/[CH:34]=[CH:35]/[CH3:36])C>CN(C)C=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[CH:22][N:23]4[CH:35]([CH3:36])[CH2:34][C:33]([OH:37])=[O:32])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 429065Ethyl trans-crotonate2×HCID 529398626-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole

Product 1

HCID 529397413-[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-butyric acidYield 6.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole (37 mg, 0.10 mmol, 1 eq.) was added dimethylformamide (1 ml), sodium hydride (8 mg of 60% dispersion, 0.2 mmol, 2 eq.) and (E)-but-2-enoic acid ethyl ester (0.025 ml, 0.2 mmol, 2 eq.). The reaction was stirred at room temperature for 18 hr and heated at 50° C. for 2 hr. To the reaction was added more (E)-but-2-enoic acid ethyl ester (0.050 ml, 0.4 mmol, 4 eq.) and the reaction heated at 80° C. for 22 hr. The reaction was partitioned between ethyl acetate (10 mL) and aqueous citric acid (10 mL), the organic layer separated and washed with brine (saturated NaCl), dried over magnesium sulfate, filtered, evaporated under reduced pressure. The crude material was dissolved in dimethylsulfoxide and purified by HPLC with a 50-100% acetonitrile in water gradient to yield 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-butyric acid as white solid (3 mg, 6%). LC-MS (ES) calculated for C26H23F2NO4, 451.2; found m/z 452 [M+H]+.

Workup

  1. temperatureheated at 50° C. for 2 hr
  2. temperaturethe reaction heated at 80° C. for 22 hr
  3. customThe reaction was partitioned between ethyl acetate (10 mL) and aqueous citric acid (10 mL)
  4. customthe organic layer separated
  5. washwashed with brine (saturated NaCl)
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. customevaporated under reduced pressure
  9. dissolutionThe crude material was dissolved in dimethylsulfoxide
  10. custompurified by HPLC with a 50-100% acetonitrile in water gradient

Sources & evidence

ORD record
ord-065c10e1cb464de1b41f85277527505a
Source dataset
uspto-grants-2011_05
Patent number
US07947728B1

Reaction notes

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