p-Toluenesulfonic acid → HCID 24803256, compound

HRID 2384906Notes

Reaction equation

HRID 2384906 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[S:25][C:26]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)=[CH:27][C:28]=3C)=[O:23])=[CH:17][C:16]=2[O:37][CH3:38])[CH2:9]1)=O)(C)(C)C.[C:39]([Li])(C)(C)[CH3:40].CCCCC.CN(C)C=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>O1CCCC1.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:26]2[S:25][C:24]3[C:22](=[O:23])[N:21]([C:18]4[CH:19]=[CH:20][C:15]([O:14][C@@H:10]5[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]5)=[C:16]([O:37][CH3:38])[CH:17]=4)[CH:39]=[CH:40][C:28]=3[CH:27]=2)=[CH:31][CH:32]=1

Participants

9

Reactant 6

HCID 6101p-Toluenesulfonic acidHCID 6228DimethylformamideHCID 8003PentaneHCID 14798Sodium HydroxideHCID 68952355HCID 68952355, compoundHCID 178418306HCID 178418306, compound

Product 1

HCID 24803256HCID 24803256, compoundYield 35%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

Dissolve (R)-3-(4-{[5-(4-chloro-phenyl)-3-methyl-thiophene-2-carbonyl]-amino}-2-methoxy-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (2.63 g, 4.72 mmol) in tetrahydrofuran (35 mL) under argon and cool to −78° C. Add 1.7 M tert-butyllithium in pentane (6.1 mL, 10.38 mmol) while maintaining the temperature below −70° C. Stir the solution at −78° C. for 20 min. Add N,N-dimethylformamide (2.68 mL, 34.46 mmol) to the solution maintaining temperature below −70° C. Remove the cooling bath after 5 min and stir the reaction for 30 min. Quench the reaction with saturated aqueous ammonium chloride (20 mL). Dilute the mixture with water (10 mL) and extract with ethyl acetate (3×30 mL). Dry the combined organics (Na2SO4), filter, and concentrate in vacuo. Dissolve the residue in 30 mL of ethyl acetate and add p-toluenesulfonic acid (1.41 g, 7.08 mmol). Heat the mixture at reflux overnight, cool, and dilute with water (30 mL). Make the mixture basic with 1 N NaOH and extract with ethyl acetate (3×40 mL). Dry the combined organics (Na2SO4), filter, and concentrate in vacuo. Purify by chromatography (dichloromethane to 7% 2 M ammonia in methanol/dichloromethane) to afford 0.77 g (35%) of 2-(4-chloro-phenyl)-6-[3-methoxy-4-((R)-piperidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridine-7-one.

Workup

  1. temperaturewhile maintaining the temperature below −70° C
  2. customRemove the cooling bath after 5 min
  3. stirringstir
  4. customthe reaction for 30 min
  5. customQuench
  6. customthe reaction with saturated aqueous ammonium chloride (20 mL)
  7. extractionextract with ethyl acetate (3×30 mL)
  8. dry with materialDry the combined organics (Na2SO4)
  9. filtrationfilter
  10. concentrationconcentrate in vacuo
  11. dissolutionDissolve the residue in 30 mL of ethyl acetate
  12. temperatureHeat the mixture
  13. temperatureat reflux overnight
  14. temperaturecool
  15. extractionextract with ethyl acetate (3×40 mL)
  16. dry with materialDry the combined organics (Na2SO4)
  17. filtrationfilter
  18. concentrationconcentrate in vacuo
  19. customPurify by chromatography (dichloromethane to 7% 2 M ammonia in methanol/dichloromethane)

Sources & evidence

ORD record
ord-8eae7a59ff594b13b31c705682130528
Source dataset
uspto-grants-2012_09
Patent number
US08263772B2

Reaction notes

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