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

HRID 1877261Notes

Reaction equation

HRID 1877261 reaction equation
[CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:26])=[CH:28][CH:29]=2)[C:8]2[CH:12]=[C:11]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 458475beta-Alanine, ethyl ester, hydrochlorideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 685154374-({Cyclohexyl[2-ethyl-5-(2-methylpropanoyl)thiophen-3-yl]methyl}amino)benzoic acid

Product 1

HCID 595293783-({[4-({Cyclohexyl[2-ethyl-5-(2-methylpropanoyl)thiophen-3-yl]methyl}amino)phenyl]carbonyl}amino)propanoic acidYield 70.7%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Procedure

To a mixture of 4-({cyclohexyl[2-ethyl-5-(2-methylpropanoyl)thiophen-3-yl]methyl}amino)benzoic acid (140 mg) synthesized above, ethyl β-alaninate hydrochloride (62.5 mg), 1-hydroxybenzotriazole monohydrate (62.3 mg) and triethylamine (57 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78.0 mg), and the mixture was stirred at room temperature for 2.5 days. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate/hexane), and then purified by NH-silica gel column chromatography (ethyl acetate) 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 (1 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (116 mg, 70%) as a white solid.

Workup

  1. customto quench
  2. customthe reaction
  3. extractionthe mixture was extracted with ethyl acetate
  4. washThe extract was washed with saturated brine
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography (40% ethyl acetate/hexane)
  8. custompurified by NH-silica gel column chromatography (ethyl acetate)
  9. customto give a colorless oil
  10. stirringthe mixture was stirred at room temperature for 1 hr
  11. concentrationconcentrated under reduced pressure
  12. dissolutionThe residue was dissolved in water (10 mL)
  13. addition1N hydrochloric acid (1 mL) was added at 0° C
  14. filtrationThe resulting precipitate was collected by filtration

Sources & evidence

ORD record
ord-686a2bf3396a4adf868926a0f54ee7da
Source dataset
uspto-grants-2012_11
Patent number
US08309580B2

Reaction notes

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