4-Methylmorpholine → 1,4-dihydro-2,6-dimethyl-4-[3-[[2-(4-morpholinyl)ethyl]amino]-1H-indazol-5-yl]-3,5-pyridinedicarbonitrile

HRID 218498Notes

Reaction equation

HRID 218498 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]O)=[N:9]1)=O)(C)(C)C.C[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.S(Cl)(C)(=O)=O.N1CCOCC1>C1COCC1.C(N(CC)CC)C>[CH3:25][C:21]1[NH:20][C:19]([CH3:26])=[C:18]([C:27]#[N:28])[CH:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][N:9]=[C:10]3[NH:29][CH2:30][CH2:31][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:22]=1[C:23]#[N:24]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 8083MorpholineHCID 31297Methanesulfonyl chlorideHCID 690419115-(3,5-Dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-(2-hydroxy-ethylamino)-indazole-1-carboxylic acid tert-butyl ester

Product 1

HCID 692717941,4-dihydro-2,6-dimethyl-4-[3-[[2-(4-morpholinyl)ethyl]amino]-1H-indazol-5-yl]-3,5-pyridinedicarbonitrile

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
35 °C

Procedure

To a stirred and chilled (ice/water bath) solution of crude 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-(2-hydroxy-ethylamino)-indazole-1-carboxylic acid tert-butyl ester (1 g) in THF (157 mL), under argon, was added sequentially 4-methylmorpholine (5.2 mL) and mesyl chloride (MsCl, CH3SO2Cl, 0.89 mL) dropwise. The mixture was allowed to warm to room temperature overnight before morpholine (41 mL) was added. Stirring was continued overnight before heating to 35° C. On cooling, triethylamine was added, the mixture concentrated to ca. one third the volume and the residue cooled (ice/water bath). The mixture was quenched with ice and aqueous sodium carbonate solution and the extracted with EtOAc. The combined organic extracts were dried and concentrated. The residue was taken up in THF (15 mL), HCl (15 mL) was added and the mixture was heated for 1.5 h at 60° C. (bath temperature). On cooling, the mixture was poured carefully onto aqueous sodium hydrogencarbonate solution and extracted with EtOAc. The combined organic extracts were dried and concentrated. The residue was purified by preparative reverse phase HPLC to give 1,4-dihydro-2,6-dimethyl-4-[3-[[2-(4-morpholinyl)ethyl]amino]-1H-indazol-5-yl]-3,5-pyridinedicarbonitrile (60 mg) (Cpd. No. 307, Table 8). 1H-NMR (DMSO-D6, 300 MHz): δ=11.46 (br s, 1H), 9.50 (br s, 1H), 7.56 (s, 1H), 7.25 (d, 1H), 7.17 (dd, 1H), 5.93 (t, 1H), 4.40 (s, 1H), 3.60 (m, 4H), 3.40 (partially obscured by solvent, 2H), 2.59 (t, 2H), 2.44 (m, 4H), 2.05 (s, 6H) ppm.

Workup

  1. additionwas added
  2. stirringStirring
  3. temperatureOn cooling
  4. concentrationthe mixture concentrated
  5. temperaturethe residue cooled (ice/water bath)
  6. customThe mixture was quenched with ice and aqueous sodium carbonate solution
  7. extractionthe extracted with EtOAc
  8. customThe combined organic extracts were dried
  9. concentrationconcentrated
  10. additionHCl (15 mL) was added
  11. temperaturethe mixture was heated for 1.5 h at 60° C. (bath temperature)
  12. temperatureOn cooling
  13. additionthe mixture was poured carefully onto aqueous sodium hydrogencarbonate solution
  14. extractionextracted with EtOAc
  15. customThe combined organic extracts were dried
  16. concentrationconcentrated
  17. customThe residue was purified by preparative reverse phase HPLC

Sources & evidence

ORD record
ord-bd0e281591cb4132a19359b7d9a7e71a
Source dataset
uspto-grants-2012_06
Patent number
US08198456B2

Reaction notes

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