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

HRID 732227Notes

Reaction equation

HRID 732227 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:15]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:29][C:30]1[CH:51]=[CH:50][C:33]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=[C:38]([F:49])[CH:37]=2)=[CH:32][CH:31]=1.Cl>CN(C)C=O.C(O)C.O1CCCC1.[OH-].[Na+]>[F:49][C:38]1[CH:37]=[C:36]([O:35][CH2:34][C:33]2[CH:50]=[CH:51][C:30]([CH2:29][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:11]3[S:12][CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=4)[N:15]=3)=[CH:31][CH:32]=2)[CH:41]=[CH:40][C:39]=1[CH2:42][CH2:43][C:44]([OH:46])=[O:45]

Participants

9

Reactant 4

HCID 313Hydrochloric Acid2×HCID 24758Sodium hydrideHCID 23143240N-[2-(4-fluorophenyl)ethyl]-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole-2-amineHCID 23143241Ethyl 3-(4-([4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoate

Product 1

HCID 231432873-[2-Fluoro-4-({4-[([2-(4-fluorophenyl)ethyl]{4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}amino)methyl]-benzyl}oxy)phenyl]propanoic acidYield 21.3%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 14798Sodium HydroxideSolvent

Procedure

To a solution of N-[2-(4-fluorophenyl)ethyl]-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole-2-amine (500 mg, 1.36 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (40 mg, in oil, 1.0 mmol) 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 1 hr. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:1 in volume ratio) 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 concentrated, and the residue was purified by preparative HPLC. The obtained fraction was concentrated, neutralized with 10% aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was filtered with a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.) and concentrated to give the title compound (139 mg, yield 21%, 2 steps) as a yellow oil.

Workup

  1. stirringthe mixture was further stirred at room temperature for 1 hr
  2. extractionextracted with ethyl acetate
  3. concentrationThe organic layer was concentrated
  4. customThe residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:1 in volume ratio)
  5. customgive a yellow oil
  6. additionwas added
  7. stirringThe mixture was stirred at room temperature for 2 hr
  8. extractionthe mixture was extracted with ethyl acetate
  9. concentrationThe organic layer was concentrated
  10. customthe residue was purified by preparative HPLC
  11. concentrationThe obtained fraction was concentrated
  12. extractionextracted with ethyl acetate
  13. filtrationThe ethyl acetate layer was filtered with a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.)
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-99fa99d144404c979e2d4db8f6f01dc1
Source dataset
uspto-grants-2009_09
Patent number
US07585880B2

Reaction notes

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