Sodium Bicarbonate → 4-[3-(5-chloro-2-thienyl)-5-cyclopropyl-1H-pyrazol-4-yl]pyridine

HRID 2359053Notes

Reaction equation

HRID 2359053 reaction equation
C(=O)([O-])O.[Na+].Br[C:7]1[N:11](CC2C=CC(OC)=CC=2)[N:10]=[C:9]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:8]=1[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.Br[C:34]1[C:38]([C:39]2C=CN=CC=2)=C(C2SC(Cl)=CC=2)N(CC2C=CC(OC)=CC=2)N=1.C1(B(O)O)CC1>C(COC)OC.O.C(OCC)(=O)C>[Cl:26][C:23]1[S:22][C:21]([C:9]2[C:8]([C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)=[C:7]([CH:39]3[CH2:38][CH2:34]3)[NH:11][N:10]=2)=[CH:25][CH:24]=1

Participants

8

Reactant 4

HCID 516892Sodium BicarbonateHCID 2760897Cyclopropylboronic acid2×HCID 67260634HCID 67260634, compoundHCID 67261945HCID 67261945, compound

Product 1

HCID 672602794-[3-(5-chloro-2-thienyl)-5-cyclopropyl-1H-pyrazol-4-yl]pyridineYield 25%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

To a mixture of sodium hydrogen carbonate (2.0 mmol) and PdCl2dppf:CH2Cl2 1:1 (0.05 eq, 0.03 mmol) under argon, was added a degassed solution of 4-[5-bromo-3-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine and 4-[3-bromo-5-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine (mixture of isomers 2:1, 0.65 mmol) in 10.5 mL dimethoxyethane and 3 mL of water. Cyclopropylboronic acid (1.3 mmol) was then added and the mixture was stirred at 90° C. for 3 h. Further cyclopropylboronic acid was then added (1.3 mmol), and the mixture was stirred overnight at 65° C. After cooling to room temperature, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in 3 mL of trifluoroacetic acid and stirred at 65° C. for 2 h. Water and ethyl acetate were added. And the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with a saturated solution of sodium hydrogen carbonate, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC (Column WATERS Sunfire C18.5 μm 50*150 mm, eluent:water/methanol/0.1% formic acid) to afford 49 mg of 4-[3-(5-chloro-2-thienyl)-5-cyclopropyl-1H-pyrazol-4-yl]pyridine (25% yield).

Workup

  1. stirringthe mixture was stirred overnight at 65° C
  2. temperatureAfter cooling to room temperature
  3. extractionThe aqueous layer was extracted with ethyl acetate
  4. washthe combined organic extracts were washed with brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. dissolutionThe residue was dissolved in 3 mL of trifluoroacetic acid
  9. stirringstirred at 65° C. for 2 h
  10. additionWater and ethyl acetate were added
  11. extractionAnd the aqueous layer was extracted with ethyl acetate
  12. washThe combined organic extracts were washed with a saturated solution of sodium hydrogen carbonate
  13. dry with materialdried over MgSO4
  14. filtrationfiltered
  15. concentrationconcentrated
  16. customThe residue was purified by preparative HPLC (Column WATERS Sunfire C18.5 μm 50*150 mm, eluent:water/methanol/0.1% formic acid)

Sources & evidence

ORD record
ord-b0af24417b8346be89cb493922558605
Source dataset
uspto-grants-2014_04
Patent number
US08685974B2

Reaction notes

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