Hydrochloric Acid → 4-({cyclohexyl[2-ethyl-5-(tetrahydro-2H-pyran-4-yl)thiophen-3-yl]methyl}amino)benzoic acid

HRID 1877212Notes

Reaction equation

HRID 1877212 reaction equation
Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:6][C:7]=1[CH2:8][CH3:9].[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C(=O)C>[CH:16]1([CH:2]([NH:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)[C:3]2[CH:4]=[C:5]([CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:6][C:7]=2[CH2:8][CH3:9])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 5238Sodium IodideHCID 10340Sodium CarbonateHCID 12082Methyl 4-aminobenzoateHCID 14798Sodium HydroxideHCID 685142684-{4-[chloro(cyclohexyl)methyl]-5-ethylthiophen-2-yl}tetrahydro-2H-pyran

Product 1

HCID 685112004-({cyclohexyl[2-ethyl-5-(tetrahydro-2H-pyran-4-yl)thiophen-3-yl]methyl}amino)benzoic acidYield 75%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 8028TetrahydrofuranSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of 4-{4-[chloro(cyclohexyl)methyl]-5-ethylthiophen-2-yl}tetrahydro-2H-pyran (725 mg) synthesized above, methyl 4-aminobenzoate (671 mg), sodium iodide (666 mg) and N,N-dimethylacetamide (15 mL) was added sodium carbonate (471 mg), and the mixture was stirred overnight at 100° C. under an argon atmosphere. To the reaction mixture was added 1N hydrochloric acid to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7, volume ratio) to give a white solid. To a mixture of the obtained solid, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 50° C. for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (10 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (710 mg, 75%) 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 1N hydrochloric acid and saturated brine
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7, volume ratio)
  8. customto give a white solid
  9. stirringthe mixture was stirred at 50° C. for 5 hr
  10. concentrationconcentrated under reduced pressure
  11. dissolutionThe residue was dissolved in water (20 mL)
  12. addition1N hydrochloric acid (10 mL) was added at 0° C
  13. filtrationThe resulting precipitate was collected by filtration

Sources & evidence

ORD record
ord-820292060dfb4bf3b65ff55c5ebbf51a
Source dataset
uspto-grants-2012_11
Patent number
US08309580B2

Reaction notes

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