3-Iodo-2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidine → 7-(1-Ethyl-propyl)-2,5-dimethyl-3-(3-methyl-thieno[3,2-b]pyridin-2-yl)-pyrazolo[1,5-a]pyrimidine

HRID 1639666Notes

Reaction equation

HRID 1639666 reaction equation
[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.C([Li])CCC.[CH2:16]([CH:18]([C:21]1[N:26]2[N:27]=[C:28]([CH3:31])[C:29](I)=[C:25]2[N:24]=[C:23]([CH3:32])[CH:22]=1)[CH2:19][CH3:20])[CH3:17]>[Cl-].[Zn+2].[Cl-].C1COCC1>[CH2:16]([CH:18]([C:21]1[N:26]2[N:27]=[C:28]([CH3:31])[C:29]([C:3]3[S:4][C:5]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[C:2]=3[CH3:1])=[C:25]2[N:24]=[C:23]([CH3:32])[CH:22]=1)[CH2:19][CH3:20])[CH3:17]

Participants

6

Reactant 3

HCID 248985233-Iodo-2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidineHCID 577526103-Methylthieno[3,2-b]pyridineHCID 178418339Butyllithium

Product 1

HCID 591614517-(1-Ethyl-propyl)-2,5-dimethyl-3-(3-methyl-thieno[3,2-b]pyridin-2-yl)-pyrazolo[1,5-a]pyrimidineYield 202.3%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

Charge an oven dried schrenk flask with 3-methylthieno[3,2-b]pyridine (0.213 g, 1.42 mmol) and anhydrous THF (5 mL) and cool to −78° C. under an inert atmosphere. Add n-butyl lithium (2.5 M hexane, 0.72 mL, 1.78 mmol) and stir at reduced temperature for 30 min. Add anhydrous zinc chloride (0.58 g, 4.26 mmol) in one aliquot and stir 15 min at reduced temperature. Allow the reaction to warm to room temperature and stir an additional 30 min. Dilute the reaction with anhydrous THF (5 mL) and add 7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (0.406 g, 0.08 mmol). Degas 15 min with positive argon pressure and add dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium (II) dichloromethane (0.093 g, 0.114 mmol). Reflux the reaction overnight in an oil bath (90° C.) under an inert atmosphere. Cool the reaction to room temperature, quench with saturated ammonium chloride, and dilute with ethyl acetate (75 mL). Separate and extract the aqueous portion with ethyl acetate (50 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify using flash chromatography, eluting with 100% hexane/0% (15% ethyl acetate/hexane) to 0% hexane/100% (15% ethyl acetate/hexane) in a step gradient of 10% increments to give a white foam (0.059 g, 14%). ES/MS m/z 365.0 (M+1)+.

Workup

  1. additionCharge an oven
  2. customthe reaction
  3. temperatureto warm to room temperature
  4. additionDilute
  5. customDegas 15 min with positive argon pressure
  6. temperatureReflux
  7. customthe reaction overnight in an oil bath (90° C.) under an inert atmosphere
  8. temperatureCool
  9. customthe reaction to room temperature
  10. customquench with saturated ammonium chloride
  11. additiondilute with ethyl acetate (75 mL)
  12. customSeparate
  13. extractionextract the aqueous portion with ethyl acetate (50 mL)
  14. dry with materialCombine the organic phases, dry over anhydrous magnesium sulfate
  15. filtrationfilter
  16. concentrationconcentrate under reduced pressure
  17. customPurify
  18. washeluting with 100% hexane/0% (15% ethyl acetate/hexane) to 0% hexane/100% (15% ethyl acetate/hexane) in a step gradient of 10% increments

Sources & evidence

ORD record
ord-db833a9ae1c54c49a8e0f06d713b0f7a
Source dataset
uspto-grants-2012_02
Patent number
US08110580B2

Reaction notes

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