Hydrochloric Acid → 2-(4-Chloro-phenyl)-6-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride

HRID 2384919Notes

Reaction equation

HRID 2384919 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:26][CH:11]3[C:12](=[O:25])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=4)[CH:14]=[CH:15][CH:10]3[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.Cl>C(#N)C.CCOC(C)=O.C(Cl)Cl.CCO>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:26][C:11]3[C:12](=[O:25])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:34][CH2:35][N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[C:18]([O:23][CH3:24])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 816691-(2-Chloroethyl)pyrrolidineHCID 689502812-(4-Chloro-phenyl)-6-(4-hydroxy-3-methoxy-phenyl)-3a,7a-dihydro-6H-thieno[2,3-c]pyridin-7-one

Product 1

HCID 248035832-(4-Chloro-phenyl)-6-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochlorideYield 59%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 6342AcetonitrileSolvent2×HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

Suspend 2-(4-chloro-phenyl)-6-(4-hydroxy-3-methoxy-phenyl)-3 a,7a-dihydro-6H-thieno[2,3-c]pyridin-7-one (0.233 g, 0.61 mmol) in acetonitrile (12 mL). Add Cs2CO3 (0.40 g, 1.22 mol) and reflux for 1 h. Add a solution of 1-(2-chloro-ethyl)-pyrrolidine hydroloride salt (114 mg, 0.67 mmol) in acetonitrile (5 mL) dropwise over a period of 5 min. Reflux the reaction for 2.5 h. Allow to cool to RT and dilute with EtOAc (50 mL). Wash with water (2×30 mL), dry over Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 2% NH3—H2O, 50% CH3OH/EtOAc to give 0.164 g. Dissolve the material in CH2Cl2 (5 mL) and treat with 1.0 M HCl in EtOH (340 μL). Stir at RT for 5 min and concentrate to give 0.172 g, (59%) of the title compound. LC-MS/ES m/z (37Cl) 482.0 [M+]. 1H NMR (DMSO-d6) δ 1.82-1.96 (m, 2H), 1.98-2.12 (m, 2H), 3.08-3.23 (m, 2H), 3.58-3.70 (m, 4H), 3.82 (s, 3H), 4.04 (t, J=4.8 Hz, 2H), 6.82 (d, J=7.1 Hz, 1H), 7.02 (dd, J=8.3, 2.4 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.56 (d, J=7.1 Hz, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.84-7.89 (m, 3H), 10.69 (bs, 1H).

Workup

  1. temperatureReflux
  2. customthe reaction for 2.5 h
  3. washWash with water (2×30 mL)
  4. dry with materialdry over Na2SO4
  5. filtrationfilter
  6. concentrationconcentrate
  7. customPurify the crude material by chromatography
  8. washeluting with 2% NH3—H2O, 50% CH3OH/EtOAc
  9. customto give 0.164 g
  10. concentrationconcentrate

Sources & evidence

ORD record
ord-fb9f370c4c3243b581504aa3bc4c5415
Source dataset
uspto-grants-2012_09
Patent number
US08263772B2

Reaction notes

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