1,10-Phenanthroline → 7-(1-Ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine

HRID 1044666Notes

Reaction equation

HRID 1044666 reaction equation
[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:16])[C:14](I)=[C:10]2[N:9]=[C:8]([CH3:17])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[Cl:18][C:19]1[S:20][CH:21]=[C:22]([Cl:24])[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.CC1OCCC1>CC(N(C)C)=O>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:16])[C:14]([C:21]3[S:20][C:19]([Cl:18])=[N:23][C:22]=3[Cl:24])=[C:10]2[N:9]=[C:8]([CH3:17])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]

Participants

7

Reactant 5

HCID 13181,10-PhenanthrolineHCID 73012-Methyltetrahydrofuran2×HCID 10796Cesium carbonateHCID 123331552,4-DichlorothiazoleHCID 248985233-Iodo-2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidine

Product 1

HCID 452757037-(1-Ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidineYield 95.88%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
70 °C

Procedure

7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (10 g, 29.17 mmoles), 2,4-dichlorothiazole (5.2 g, 33.76 mmoles), cesium carbonate (19.9 g, 61.07 mmoles) and 1,10-phenanthroline (1 g, 5.5 mmoles) are charged into a 250 mL 3-necked round bottomed flask, followed by 2-MeTHF (36 mL, 3.6 volumes). The reaction mixture is degassed with nitrogen and then evacuated. Cuprous chloride (0.57 g, 5.7 mmoles), DMAC (10 mL, 1 volume) and 2-MeTHF (4 mL, 0.4 volumes) are added in succession. The reaction mixture is degassed with nitrogen and then evacuated. The contents are refluxed for 20 hr. The reaction mixture is cooled to ˜70° C. and 2-MeTHF (100 mL, 10 volumes) is added. The contents are filtered at ˜70° C. and the residual cake is washed with 2-MeTHF (80 mL, 8 volumes) at about 65-72° C. The filtrate is transferred into a separatory funnel and extracted with water. The organic layer is separated and washed with dilute HCl. The resulting organic layer is treated with Darco G60, filtered hot (60° C.). The filtrate is concentrated at atmospheric pressure to ˜2.8 volumes. 25 mL 2-propanol is added, followed by re-concentration to ˜2.8 volumes. An additional 25 mL 2-propanol is added, followed again by re-concentration to ˜2.8 volumes. Finally, 48 mL 2-propanol is added. The contents are cooled to −7° C., maintained at −7° C. for 1 hr., filtered and rinsed with 20 mL chilled 2-propanol. Product is suction dried and then vacuum dried at 60° C. to afford 9.41 g 7-(1-ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (purity of product by HPLC assay is 95.88%). MS (ES)=369 (M+1).

Workup

  1. customThe reaction mixture is degassed with nitrogen
  2. customevacuated
  3. customThe reaction mixture is degassed with nitrogen
  4. customevacuated
  5. temperatureThe contents are refluxed for 20 hr
  6. addition2-MeTHF (100 mL, 10 volumes) is added
  7. filtrationThe contents are filtered at ˜70° C.
  8. washthe residual cake is washed with 2-MeTHF (80 mL, 8 volumes) at about 65-72° C
  9. customThe filtrate is transferred into a separatory funnel
  10. extractionextracted with water
  11. customThe organic layer is separated
  12. washwashed with dilute HCl
  13. additionThe resulting organic layer is treated with Darco G60
  14. filtrationfiltered hot (60° C.)
  15. concentrationThe filtrate is concentrated at atmospheric pressure to ˜2.8 volumes
  16. addition25 mL 2-propanol is added
  17. concentrationfollowed by re-concentration to ˜2.8 volumes
  18. additionAn additional 25 mL 2-propanol is added
  19. concentrationfollowed again by re-concentration to ˜2.8 volumes
  20. additionFinally, 48 mL 2-propanol is added
  21. temperatureThe contents are cooled to −7° C.
  22. temperaturemaintained at −7° C. for 1 hr
  23. filtration, filtered
  24. washrinsed with 20 mL
  25. temperaturechilled 2-propanol
  26. customdried
  27. customvacuum dried at 60° C.

Sources & evidence

ORD record
ord-23ec9969d3894b36ac4922697c9aaa10
Source dataset
uspto-grants-2013_10
Patent number
US08563718B2

Reaction notes

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