Dimethylformamide → HCID 24803254, compound

HRID 2384903Notes

Reaction equation

HRID 2384903 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:25][C:26]([C:28]2[S:29][C:30]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[CH:31][C:32]=2C)=[O:27])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][C@@H:11]([O:14][Si](C(C)C)(C(C)C)C(C)C)[CH2:10]1.[Li][C:42](C)(C)[CH3:43].CN(C=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1.CCOC(C)=O>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C:30]2[S:29][C:28]3[C:26](=[O:27])[N:25]([C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:42]=[CH:43][C:32]=3[CH:31]=2)=[CH:35][CH:36]=1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 521998p-Toluenesulfonic acid monohydrateHCID 86629208HCID 86629208, compoundHCID 178418306HCID 178418306, compound

Product 1

HCID 24803254HCID 24803254, compoundYield 33.2%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

Dissolve 5-(4-chloro-phenyl)-3-methyl-thiophene-2-carboxylic acid [3-methoxy-4-((R)-3-triisopropylsilanyloxy-pyrrolidin-1-yl)-phenyl]-amide (0.573 g, 0.958 mmol) in THF (10 mL). Cool the mixture to −78° C. under argon. Add t-BuLi (1.2 mL, 2.11 mmol) dropwise and stir at −78° C. for 20 min. Add DMF (1.5 mL) and stir at −78° C. for 10 min, then warm gradually to 0° C. Quench the mixture with saturated NH4Cl (10 mL) then dilute with EtOAc (100 mL) and wash with water (2×30 mL). Dry the solution with Na2SO4, filter, and concentrate. Suspend the resulting crude material in toluene (40 mL) and treat with p-toluenesulfonic acid-H2O (0.45 g, 2.37 mmol). Reflux the mixture using a Dean-Stark trap. Dilute the mixture with EtOAc (150 mL) and wash with saturated NaHCO3 (2×50 mL). Dry the solution with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 100% EtOAc to give 0.144 g (33%) of 2-(4-chloro-phenyl)-6-[4-((R)-3-hydroxy-pyrrolidin-1-yl)-3-methoxy-phenyl]-6H-thieno[2,3-c]pyridin-7-one.

Workup

  1. temperaturewarm gradually to 0° C
  2. customQuench the mixture with saturated NH4Cl (10 mL)
  3. additionthen dilute with EtOAc (100 mL)
  4. washwash with water (2×30 mL)
  5. dry with materialDry the solution with Na2SO4
  6. filtrationfilter
  7. concentrationconcentrate
  8. temperatureReflux the mixture
  9. washwash with saturated NaHCO3 (2×50 mL)
  10. dry with materialDry the solution with Na2SO4
  11. filtrationfilter
  12. concentrationconcentrate
  13. customPurify the crude material by chromatography
  14. washeluting with 100% EtOAc

Sources & evidence

ORD record
ord-271d63c6a941419995c458cd67faa0b6
Source dataset
uspto-grants-2012_09
Patent number
US08263772B2

Reaction notes

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