Hydrochloric Acid → 3-({[4-(Cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methoxy)phenyl]carbonyl}amino)propanoic acid

HRID 1876992Notes

Reaction equation

HRID 1876992 reaction equation
C1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[S:20][C:19]=2[CH2:33][CH3:34])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)CCCCC1.Cl.[NH2:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40].O.ON1[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+].[OH-].[Na+].Cl>C(O)C.O1CCCC1.CN(C)C=O.C(N(CC)CC)C>[CH:49]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)[S:20][C:19]=2[CH2:33][CH3:34])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:14])=[CH:16][CH:17]=2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1

Participants

12

Reactant 7

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 25517Ammonium ChlorideHCID 458475beta-Alanine, ethyl ester, hydrochlorideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 685145964-(Cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methoxy)benzoic acid

Product 1

HCID 595294123-({[4-(Cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methoxy)phenyl]carbonyl}amino)propanoic acidYield 40.7%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Procedure

To a mixture of 4-(cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methoxy)benzoic acid (251 mg) synthesized above, ethyl β-alaninate hydrochloride (94.8 mg), 1-hydroxybenzotriazole monohydrate (94.5 mg), triethylamine (86.0 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118 mg), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane to ethyl acetate:hexane=2:3, volume ratio) to give a colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (2.5 mL) was added to the reaction mixture, the organic solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a white solid. The solid was recrystallized from ethyl acetate-hexane to give the title compound (117 mg, 40%) as a colorless crystal.

Workup

  1. customto quench
  2. customthe reaction
  3. extractionthe mixture was extracted with ethyl acetate
  4. washThe extract was washed with brine
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography (hexane to ethyl acetate:hexane=2:3, volume ratio)
  8. customto give a colorless oil
  9. stirringthe mixture was stirred at room temperature for 1 hr
  10. customthe organic solvent was evaporated under reduced pressure
  11. extractionthe mixture was extracted with ethyl acetate
  12. washThe extract was washed with water and brine
  13. dry with materialdried over magnesium sulfate
  14. concentrationconcentrated under reduced pressure
  15. customto give a white solid
  16. customThe solid was recrystallized from ethyl acetate-hexane

Sources & evidence

ORD record
ord-d96e0378ce254e98a17a3cff64e325cd
Source dataset
uspto-grants-2012_11
Patent number
US08309580B2

Reaction notes

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