Ethyl bromoacetate → 2-(4-(5-(2-Cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)acetic acid

HRID 2278783Notes

Reaction equation

HRID 2278783 reaction equation
[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:32][C:33]([O:35]CC)=[O:34]>CN(C=O)C>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:32][C:33]([OH:35])=[O:34])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1

Participants

5

Reactant 3

HCID 7748Ethyl bromoacetateHCID 24758Sodium hydrideHCID 1363910154-[5-(2-Cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol

Product 1

HCID 575243792-(4-(5-(2-Cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)acetic acidYield 62.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (203 mg, 0.535 mmol) in DMF (5 mL), NaH (43 mg, 1.07 mmol, 60% in mineral oil) is added at 0° C. The mixture is stirred at 0° C. and ethyl bromoacetate (98 mg, 0.588 mmol) is added. Stirring is continued at 0° C. for 30 min, then at rt for 72 h. The reaction is quenched by adding water (2 mL) and the mixture is concentrated. The residue is dissolved in THF (10 mL), methanol (10 mL) and 2 N aq. LiOH (10 mL). The mixture is stirred at 60° C. for 2 h before it is cooled to rt, acidified by adding 2 N aq. HCl and extracted three times with EA (3×20 mL). The combined org. extracts are concentrated and the crude product is purified by prep. HPLC to give the title compound (146 mg) as a white solid; LC-MS: tR=1.14 min, [M+H]+=438.07; 1H NMR (CDCl3): δ 7.90 (s, 1H), 7.88 (s, 1H), 7.79 (s br, 1H), 7.50 (s, 1H), 7.29 (s, 1H), 4.57 (s, 2H), 4.01 (s, 3H), 3.20-3.29 (m, 1H), 2.79 (q, J=7.5 Hz, 2H), 2.42 (s, 3H), 2.04-2.16 (m, 2H), 1.82-1.95 (m, 4H), 1.68-1.80 (m, 2H), 1.34 (t, J=7.5 Hz, 3H).

Workup

  1. stirringStirring
  2. waitat rt for 72 h
  3. customThe reaction is quenched
  4. additionby adding water (2 mL)
  5. concentrationthe mixture is concentrated
  6. dissolutionThe residue is dissolved in THF (10 mL)
  7. stirringThe mixture is stirred at 60° C. for 2 h before it
  8. temperatureis cooled to rt
  9. additionby adding 2 N aq. HCl
  10. extractionextracted three times with EA (3×20 mL)
  11. concentrationextracts are concentrated
  12. customthe crude product is purified by prep

Sources & evidence

ORD record
ord-c3a70b2ea917497ab9998fa5c46d0c07
Source dataset
uspto-grants-2015_09
Patent number
US09133179B2

Reaction notes

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