Triethylamine → 2-(4-Chloro-phenyl)-5-[3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one

HRID 601534Notes

Reaction equation

HRID 601534 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C[Al](C)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]3[C:36](=O)[O:35][CH2:34][CH2:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[H-].[Na+]>C(Cl)Cl.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]3[C:36](=[O:35])[N:16]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]5[CH2:12][CH2:13][CH2:14][CH2:15]5)=[C:2]([Cl:1])[CH:3]=4)[CH2:34][CH2:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1

Participants

9

Reactant 6

HCID 8471TriethylamineHCID 24758Sodium hydrideHCID 31297Methanesulfonyl chlorideHCID 16682925TrimethylaluminumHCID 196269953-Chloro-4-[2-(pyrrolidin-1-yl)ethoxy]anilineHCID 574214852-(4-Chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one

Product 1

HCID 114973602-(4-Chloro-phenyl)-5-[3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-oneYield 37%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent

Procedure

Dissolve 3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.20 g, 0.83 mmol) in CH2Cl2 (10.0 mL) and treat with trimethylaluminum (2.0M in hexanes, 0.6 mL, 1.20 mmol). Stir at room temperature for 15 min and add 2-(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (0.22 g, 0.83 mmol) neat and stir the reaction at room temperature for 2 h. Carefully quench the mixture with saturated Rochelles salt solution and stir at room temperature for 1 h. Dilute with water and extract with CH2Cl2 (2×). Combine the organic portions and dry, filter and concentrate. Dissolve the residue in CH2Cl2, and treat with triethylamine (0.50 mL, 3.56 mmol) followed by methanesulfonyl chloride (0.05 mL, 0.65 mmol). Stir for 1 h at room temperature, dilute with water and extract with CH2Cl2 (2×). Combine the organic portions and dry, filter, and concentrate. Dissolve the residue in THF and treat with NaH (0.03 g, 0.75 mmol) and stir at room temperature for 18 h. Dilute the reaction with water and extract with CH2Cl2 (2×). Combine the organic portions, dry, filter, and concentrate. Purify the crude material by flash chromatography, using a gradient of 0% to 10% 2N NH3/MeOH in CH2Cl2, to give the title compound (80 mg, 37%). MS (ES+) 488.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 2H, J=8.3 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.39 (d, 1H, J=2.2 Hz), 7.22 (dd, 1H, J=8.8, 2.6 Hz), 6.97 (d, 1H, J=9.2 Hz), 4.22 (t, 2H, J=5.9 Hz), 4.07 (t, 2H, J=7.0 Hz), 3.28 (t, 2H, J=7.0 Hz), 3.01 (t, 2H, J=5.9 Hz), 2.73 (m 4H), 1.84 (m 4H).

Workup

  1. stirringstir
  2. customthe reaction at room temperature for 2 h
  3. customCarefully quench the mixture with saturated Rochelles salt solution
  4. stirringstir at room temperature for 1 h
  5. additionDilute with water
  6. extractionextract with CH2Cl2 (2×)
  7. customCombine the organic portions and dry
  8. filtrationfilter
  9. concentrationconcentrate
  10. dissolutionDissolve the residue in CH2Cl2
  11. stirringStir for 1 h at room temperature
  12. extractionextract with CH2Cl2 (2×)
  13. customCombine the organic portions and dry
  14. filtrationfilter
  15. concentrationconcentrate
  16. dissolutionDissolve the residue in THF
  17. stirringstir at room temperature for 18 h
  18. additionDilute
  19. extractionextract with CH2Cl2 (2×)
  20. customCombine the organic portions, dry
  21. filtrationfilter
  22. concentrationconcentrate
  23. customPurify the crude material by flash chromatography

Sources & evidence

ORD record
ord-e8fa0b4ceaeb45ea8a1e7ca4a845c02b
Source dataset
uspto-grants-2011_03
Patent number
US07902356B2

Reaction notes

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