Methylhydrazine → 1-methyl-4-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-1H-pyrazolo[3,4-c]pyridin-3-amine

HRID 1910093Notes

Reaction equation

HRID 1910093 reaction equation
Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19](=[O:31])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH2:14][CH2:13]3)[C:7]=1[C:8]#[N:9].[CH3:32][NH:33][NH2:34]>C(O)C>[CH3:32][N:33]1[C:2]2=[CH:3][N:4]=[CH:5][C:6]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([C:19](=[O:31])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:14][CH2:13]4)=[C:7]2[C:8]([NH2:9])=[N:34]1

Participants

4

Reactant 2

HCID 6061Methylhydrazine2×HCID 668238663-chloro-5-(1-([3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-pyridinecarbonitrile

Product 1

HCID 534692631-methyl-4-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-1H-pyrazolo[3,4-c]pyridin-3-amineYield 41.6%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
100 °C

Procedure

To 3-chloro-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-pyridinecarbonitrile (80 mg, 0.181 mmol) was added Methyl hydrazine (0.286 mL, 5.43 mmol) to a 5 mL sealable vial with Ethanol (3 mL). The reaction was then capped and heated at 100° C. overnight. Observed incomplete conversion. Additional Methyl hydrazine (0.286 mL, 5.43 mmol) was added and heating was continued overnight. The reaction was concentrated, dissolved in 3 mL of DMSO and purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 17% ACN/H2O, 0.1% TFA to 42% ACN/H2O, 0.1% TFA) with UV detection at 220 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and the mixture was extracted with EtOAc (3×15 mL). The organics were combined, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The product was transferred into a 40 mL vial with MeCN then water was added and the solution was freeze-dried to give 1-methyl-4-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-1H-pyrazolo[3,4-c]pyridin-3-amine (34 mg, 41.6% yield) as a light yellow solid. LC/MS (ES) m/z=452.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.17 (d, J=8.34 Hz, 1H), 7.94 (s, 1H), 7.69 (s, 1H), 7.56-7.66 (m, 3H), 7.43 (s, 1H), 7.32 (d, J=8.08 Hz, 1H), 4.67 (br. s., 2H), 4.30 (t, J=8.46 Hz, 2H), 4.05 (s, 2H), 3.92 (s, 3H), 3.29 (t, 2H).

Workup

  1. customThe reaction was then capped
  2. temperatureheating
  3. concentrationThe reaction was concentrated
  4. dissolutiondissolved in 3 mL of DMSO
  5. custompurified by HPLC
  6. custom7.3-minute
  7. customto remove most of the MeCN
  8. waitTo the water left behind
  9. additionwas added saturated NaHCO3
  10. extractionthe mixture was extracted with EtOAc (3×15 mL)
  11. washwashed with saturated NaCl solution
  12. dry with materialdried over MgSO4
  13. filtrationfiltered
  14. concentrationconcentrated
  15. additionwater was added
  16. customthe solution was freeze-dried

Sources & evidence

ORD record
ord-b980b81afb024617bebbd34280ba41ac
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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