(R)-4-((R)-1-(3-bromo-6-(1-tert-butyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one → example 6.09 on page 559 of WO15017610

HRID 2209239Notes

Reaction equation

HRID 2209239 reaction equation
BrC1C=NN2C=C(C3C=NN(C(C)(C)C)C=3)C=C(O[C@@H]([C@H]3CN([C@@H](C4C=CC(OC)=CC=4)C)C(=O)C3)C)C=12.C[Zn]C.[C:42]([N:46]1[CH:50]=[C:49]([C:51]2[CH:52]=[C:53]([O:61][C@@H:62]([C@H:64]3[CH2:68][N:67]([C@@H](C4C=CC(OC)=CC=4)C)[C:66](=[O:79])[CH2:65]3)[CH3:63])[C:54]3[N:55]([N:57]=[CH:58][C:59]=3[CH3:60])[CH:56]=2)[CH:48]=[N:47]1)([CH3:45])([CH3:44])[CH3:43]>Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:42]([N:46]1[CH:50]=[C:49]([C:51]2[CH:52]=[C:53]([O:61][C@@H:62]([C@H:64]3[CH2:68][NH:67][C:66](=[O:79])[CH2:65]3)[CH3:63])[C:54]3[N:55]([N:57]=[CH:58][C:59]=3[CH3:60])[CH:56]=2)[CH:48]=[N:47]1)([CH3:43])([CH3:44])[CH3:45]

Participants

6

Reactant 3

HCID 117843456(R)-4-((R)-1-(3-bromo-6-(1-tert-butyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-oneHCID 117843942(R)-4-((R)-1-(6-(1-tert-butyl-1H-pyrazol-4-yl)-3-methylpyrazolo[1,5-a]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-oneHCID 178477796HCID 178477796, compound

Product 1

HCID 117843683example 6.09 on page 559 of WO15017610

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 313Hydrochloric AcidSolvent

Conditions

Temperature
75 °C

Procedure

To an appropriate sized microwave vial, (R)-4-((R)-1-(3-bromo-6-(1-tert-butyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (60 mg, 0.10 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.7 mg, 0.010 mmol) were added. After evacuating and backfilling with nitrogen, dioxane (1 mL) was added followed by dimethylzinc (0.13 mL, 0.26 mmol, 2M solution in toluene). The mixture was heated at 75° C. for 18 h. After cooling to room temperature, the reaction was diluted with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford a mixture of dehalogenated starting material and title compound (R)-4-((R)-1-(6-(1-tert-butyl-1H-pyrazol-4-yl)-3-methylpyrazolo[1,5-a]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one. The mixture was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H37N5O3: 516.3; found: 516.2.

Workup

  1. customAfter evacuating
  2. additionwas added
  3. temperatureAfter cooling to room temperature
  4. extractionextracted with ethyl acetate
  5. washThe combined organic layers were washed with brine
  6. customdried
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by flash column chromatography on silica gel
  10. customto afford
  11. additiona mixture

Sources & evidence

ORD record
ord-83ab7550b096432497ea0bb056e5428e
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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