Sodium Iodide → HCID 89923218, compound

HRID 921887Notes

Reaction equation

HRID 921887 reaction equation
[Cl:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:35][CH2:34]2)CC2C=CC(OC)=CC=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1.Br[C:42]([CH3:47])([CH3:46])[C:43]([NH2:45])=[O:44].[I-].[Na+].C([O-])([O-])=O.[Cs+].[Cs+].C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>CC#N.C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:16][C:17]2[N:22]=[C:21]([NH:23][CH:33]3[CH2:35][CH2:34]3)[C:20]3=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]3[N:18]=2)=[CH:4][C:5]([C:14]#[N:15])=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:42]([CH3:47])([CH3:46])[C:43]([NH2:45])=[O:44])[CH2:10][CH2:9]1

Participants

9

Reactant 6

HCID 5238Sodium IodideHCID 6422Trifluoroacetic acidHCID 7519AnisoleHCID 10796Cesium carbonateHCID 1012352-Bromo-2-methylpropanamideHCID 867085292-((2-Chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 89923218HCID 89923218, compound

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, (Example 208D) (25 mg, 0.045 mmol), 2-bromo-2-methylpropanamide (37.5 mg, 0.226 mmol), sodium iodide (33.8 mg, 0.226 mmol) and Cs2CO3 (58.8 mg, 0.180 mmol) in CH3CN (1.2 mL) was heated at 120° C. for 2 h using microwave irradiation. The reaction mixture was diluted with DCM, filtered to remove insoluble material. The filtrate was concentrated. The residue was dissolved in DCE (1 mL). To this was added TFA (0.5 ml), anisole (0.1 ml, 0.918 mmol), and then heated at 50° C. for 3 h. Solvent was removed. The residue was applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with large amount (3 CV) of mixture of 2 N solution of ammonia in methanol/DCM (1:1). Removal of the solvents left 23 mg material which was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 methanol: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with 10-mM ammonium acetate; Gradient: 50-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-1-yl)-2-methylpropanamide (3.6 mg).

Workup

  1. custommicrowave irradiation
  2. filtrationfiltered
  3. customto remove insoluble material
  4. concentrationThe filtrate was concentrated
  5. dissolutionThe residue was dissolved in DCE (1 mL)
  6. temperatureheated at 50° C. for 3 h
  7. customSolvent was removed
  8. additionmixed-mode polymer
  9. washThis was washed with methanol and product
  10. washwas eluted with large amount (3 CV) of mixture of 2 N solution of ammonia in methanol/DCM (1:1)
  11. customRemoval of the solvents
  12. waitleft 23 mg material which
  13. customwas further purified via preparative LC/MS with the following conditions
  14. customa 5-minute hold
  15. additionFractions containing the desired product
  16. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-823daaa22ee846e5ab4ad161e613d8ae
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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