Bicarbonate Ion → HCID 54674844, compound

HRID 2362711Notes

Reaction equation

HRID 2362711 reaction equation
F[C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)(O)[O-]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:32][N:33]1[CH:37]=[C:36]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[CH:2][C:3]([C:22]4[S:26][C:25]([C:27]5([OH:31])[CH2:28][CH2:29][CH2:30]5)=[N:24][CH:23]=4)=[C:4]3[CH:10]=2)[CH:35]=[N:34]1

Participants

6

Reactant 3

HCID 769Bicarbonate IonHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 670034821-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol

Product 1

HCID 54674844HCID 54674844, compound

Reagents, catalysts & solvents 2

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 107C) (150 mg, 0.272 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (85 mg, 0.408 mmol) in N,N-dimethylformamide (2.04 mL) was added saturated aqueous bicarbonate solution (680 μL) followed by bis(triphenylphosphine) palladium dichloride (13.37 mg, 0.019 mmol). The mixture was heated to 70° C. for 1.5 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane. A solution of the crude material in methanol (2.0 mL) and 2N aqueous sodium hydroxide solution (700 μL) was heated by microwave irradiation (Biotage, Initiator) to 120° C. for 30 minutes. The reaction was cooled to room temperature, and the pH adjusted to ˜3 with 10% aqueous HCl solution. The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.48 (bs, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 8.18 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.32 (d, J=5.1 Hz, 1H), 3.93 (s, 3H), 2.64-2.55 (m, 2H), 2.45-2.35 (m, 2H), 2.05-1.92 (m, 2H); MS ESI(+) m/z 352.7 [M+H]+.

Workup

  1. customwas quenched by the addition of water and dichloromethane
  2. customThe layers were separated
  3. extractionthe aqueous layer was extracted with additional dichloromethane
  4. dry with materialThe combined organics were dried with anhydrous magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customto give crude product
  8. customThe residue was purified by flash chromatography on silica gel
  9. washeluting with a gradient of 0 to 100% ethyl acetate in hexane
  10. temperatureA solution of the crude material in methanol (2.0 mL) and 2N aqueous sodium hydroxide solution (700 μL) was heated by microwave irradiation (Biotage, Initiator) to 120° C. for 30 minutes
  11. temperatureThe reaction was cooled to room temperature
  12. customThe resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC
  13. washeluting with a gradient of 5% B in A to 75% B in A over 25 minutes

Sources & evidence

ORD record
ord-33c84f1011814e08ba4e8393a6b37d07
Source dataset
uspto-grants-2014_04
Patent number
US08691810B2

Reaction notes

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