Water → 3-[4-(3-Amino-1h-indazol-5-yl)-1h-pyrazol-1-yl]propanenitrile

HRID 1752566Notes

Reaction equation

HRID 1752566 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[NH2:11].C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][C:33]#[N:34])[CH:30]=2)O1.O>COCCOC.C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH2:32][C:33]#[N:34])[CH:30]=3)[CH:3]=2)[NH:7][N:6]=1

Participants

8

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 8179103-Amino-5-bromo-1H-indazoleHCID 569657334-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-propanenitrile

Product 1

HCID 689900873-[4-(3-Amino-1h-indazol-5-yl)-1h-pyrazol-1-yl]propanenitrile

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 6342AcetonitrileSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
150 °C

Procedure

To a microwave vial was added 5-bromo-1H-indazol-3-amine (0.14 g, 0.66 mmol), tetrakis(triphenylphosphine)palladium(0) (0.076 g, 0.066 mmol), and sodium carbonate (0.147 g, 1.39 mmol) followed by a solution of Example 267A (0.212 g, 0.858 mmol) in 1,2-dimethoxyethane (2.50 mL) and then water (1.25 mL). The mixture was heated in a CEM microwave at about 150° C. for about 20 minutes (275 psi maximum pressure, about 2 minutes ramp, 200 maximum watts) and then the mixture was concentrated under reduced pressure. Methanol (20 mL) was added and the resulting mixture was stirred for about 1 hour. The insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure onto silica gel and purified via silica gel chromatography eluting with a stepwise gradient of dichloromethane/methanol/ammonium hydroxide (990:9:1 to 985:13.5:1.5 to 980:18:2) to afford a solid. This solid was dissolved in a minimum amount of hot acetonitrile (˜2 mL), filtered to remove minor amount of insolubles, while washing with methanol (<0.5 mL), and left to sit at ambient temperature. The resulting solid that formed overnight was collected by filtration, while washing with additional acetonitrile, and dried in a vacuum oven at about 60° C. for about 2 hours to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.35 (s, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.84 (s, 1H), 7.44 (dd, J=8.54, 1.26 Hz, 1H), 7.23 (d, J=8.62 Hz, 1H), 5.32 (s, 2H), 4.42 (t, J=6.36 Hz, 2H), 3.10 (t, J=6.43 Hz, 2H). MS (ESI+) m/z 253.2 (M+H)+.

Workup

  1. concentrationthe mixture was concentrated under reduced pressure
  2. additionMethanol (20 mL) was added
  3. customThe insoluble material was removed by filtration
  4. concentrationThe filtrate was concentrated under reduced pressure onto silica gel
  5. custompurified via silica gel chromatography
  6. washeluting with a stepwise gradient of dichloromethane/methanol/ammonium hydroxide (990:9:1 to 985:13.5:1.5 to 980:18:2)
  7. customto afford a solid
  8. filtrationfiltered
  9. customto remove minor amount of insolubles
  10. washwhile washing with methanol (<0.5 mL)
  11. waitleft
  12. customto sit at ambient temperature
  13. customThe resulting solid that formed overnight
  14. filtrationwas collected by filtration
  15. washwhile washing with additional acetonitrile
  16. customdried in a vacuum oven at about 60° C. for about 2 hours

Sources & evidence

ORD record
ord-93d124d4db254a9eb01b892a257f8425
Source dataset
uspto-grants-2015_10
Patent number
US09163007B2

Reaction notes

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