Hydrazine hydrate (1:1) → 4-[3-[(2-aminoethyl)amino]-1H-indazol-5-yl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile

HRID 218500Notes

Reaction equation

HRID 218500 reaction equation
C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH2:31][N:32]2C(=O)C3C(=CC=CC=3)C2=O)=[N:9]1)=O)(C)(C)C.O.NN>C(O)C>[NH2:32][CH2:31][CH2:30][NH:29][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])[CH:12]=2)[NH:8][N:9]=1

Participants

4

Reactant 2

HCID 24654Hydrazine hydrate (1:1)HCID 690436475-(3,5-Dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-indazole-1-carboxylic acid tert-butyl ester

Product 1

HCID 690467214-[3-[(2-aminoethyl)amino]-1H-indazol-5-yl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrileYield 58.4%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A mixture of crude 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-indazole-1-carboxylic acid tert-butyl ester (110 mg), hydrazine hydrate (80%, 0.039 mL, 0.62 mmol) and ethanol (1 mL), was heated at reflux for 2 hours. On cooling the reaction mixture was concentrated and the residue taken up in THF and aqueous HCl (4M) and heated at reflux for 1 hour. On cooling the reaction mixture was concentrated and the residue purified by preparative reverse phase HPLC to give 4-[3-[(2-aminoethyl)amino]-1H-indazol-5-yl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (38 mg) (Cpd. No. 308, Table 8). 1H-NMR (DMSO-D6, 300 MHz): δ=11.38 (br s, 1H), 9.46 (br s, 1H), 7.52 (s, 1H), 7.20 (d, 1H), 7.12 (dd, 1H), 5.93 (t, 1H), 4.34 (s, 1H), 3.21 (m, 2H), 2.75 (t, 2H), 2.01 (s, 6H) ppm.

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 2 hours
  3. temperatureOn cooling the reaction mixture
  4. concentrationwas concentrated
  5. temperatureaqueous HCl (4M) and heated
  6. temperatureat reflux for 1 hour
  7. temperatureOn cooling the reaction mixture
  8. concentrationwas concentrated
  9. customthe residue purified by preparative reverse phase HPLC

Sources & evidence

ORD record
ord-5f405d63df144355b245bc62a31372a0
Source dataset
uspto-grants-2012_06
Patent number
US08198456B2

Reaction notes

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