Hydrochloric Acid → 3-(2-Fluoro-4-{[4-({[2-(4-fluorophenyl)ethyl][4-(4-fluorophenyl)-1,3-thiazol-2-yl]amino}methyl)benzyl]oxy}-phenyl)propanoic acid

HRID 732225Notes

Reaction equation

HRID 732225 reaction equation
Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[S:23])=[CH:15][CH:14]=1.[H-].[Na+].Cl[CH2:28][C:29]1[CH:50]=[CH:49][C:32]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])=[C:37]([F:48])[CH:36]=2)=[CH:31][CH:30]=1.Cl>C(O)C.O1CCCC1.[OH-].[Na+].CN(C)C=O>[F:48][C:37]1[CH:36]=[C:35]([O:34][CH2:33][C:32]2[CH:49]=[CH:50][C:29]([CH2:28][N:21]([CH2:20][CH2:19][C:16]3[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=3)[C:22]3[S:23][CH:2]=[C:3]([C:5]4[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=4)[N:24]=3)=[CH:30][CH:31]=2)[CH:40]=[CH:39][C:38]=1[CH2:41][CH2:42][C:43]([OH:45])=[O:44]

Participants

10

Reactant 5

HCID 313Hydrochloric Acid2×HCID 24758Sodium hydrideHCID 967492-Bromo-1-(4-fluorophenyl)ethan-1-oneHCID 23143241Ethyl 3-(4-([4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoateHCID 23143277N-[2-(4-fluorophenyl)ethyl]thiourea

Product 1

HCID 231433293-(2-Fluoro-4-{[4-({[2-(4-fluorophenyl)ethyl][4-(4-fluorophenyl)-1,3-thiazol-2-yl]amino}methyl)benzyl]oxy}-phenyl)propanoic acidYield 44%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 14798Sodium HydroxideSolvent

Procedure

A mixture of 2-bromo-1-(4-fluorophenyl)ethanone (217 mg, 1.0 mmol), N-[2-(4-fluorophenyl)ethyl]thiourea (198 mg, 1.0 mmol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hr. Sodium hydride (100 mg, in oil, 2.5 mmol) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 1 hr. Ethyl 3-(4-{[4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoate (350 mg, 1.0 mmol) was added, and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was poured into 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-3:2 in volume ratio) to give a yellow oil. The oil was dissolved in a mixed solvent of ethanol (5 mL) and tetrahydrofuran (5 mL), and 2N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (264 mg, yield 44%, 3 steps) as a pale-green oil.

Workup

  1. stirringthe mixture was stirred at room temperature for 1 hr
  2. stirringthe mixture was further stirred at room temperature for 2 hr
  3. extractionthe mixture was extracted with ethyl acetate
  4. concentrationThe organic layer was concentrated
  5. customThe residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-3:2 in volume ratio)
  6. customto give a yellow oil
  7. additionwas added
  8. stirringThe mixture was stirred at room temperature for 2 hr
  9. extractionthe mixture was extracted with ethyl acetate
  10. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-674d648921d6448792b665071b3a4598
Source dataset
uspto-grants-2009_09
Patent number
US07585880B2

Reaction notes

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