Acetic Acid → HCID 86708597, compound

HRID 921719Notes

Reaction equation

HRID 921719 reaction equation
[NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([Cl:38])=[C:7]([NH:13][C:14]3[N:19]=[C:18]([N:20]([CH:30]4[CH2:32][CH2:31]4)CC4C=CC(OC)=CC=4)[C:17]4=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]4[N:15]=3)[CH:8]=[C:9]([C:11]#[N:12])[CH:10]=2)[CH2:2]1.C(OC)(OC)OC.[CH3:46][N:47]1[CH2:52][CH2:51][C:50](=O)[CH2:49][CH2:48]1.C(O)(=O)C.C([BH3-])#N.[Na+].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>CO.ClCCCl>[Cl:38][C:6]1[C:5]([CH:3]2[CH2:4][N:1]([CH:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]3)[CH2:2]2)=[CH:10][C:9]([C:11]#[N:12])=[CH:8][C:7]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH:30]2[CH2:31][CH2:32]2)[C:17]2=[N:33][CH:34]=[C:35]([C:36]#[N:37])[N:16]2[N:15]=1

Participants

10

Reactant 7

HCID 176Acetic AcidHCID 6422Trifluoroacetic acidHCID 7519AnisoleHCID 9005Trimethyl orthoformateHCID 740491-Methyl-4-piperidoneHCID 5003444Sodium cyanoborohydrideHCID 86708598HCID 86708598, compound

Product 1

HCID 86708597HCID 86708597, compoundYield 83.3%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 887MethanolSolvent

Procedure

To a solution of 2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (53 mg, 0.084 mmol) in methanol (1.2 ml) was added trimethyl orthoformate (0.6 mL, 5.43 mmol), 1-methylpiperidin-4-one (0.1 ml, 0.866 mmol) and acetic acid (10 μL, 0.175 mmol). The mixture was stirred at room temperature for 40 min and then sodium cyanoborohydride (42.0 mg, 0.669 mmol) was added. After 4 h, the reaction mixture was partitioned between EtOAc and dilutes aq. NaHCO3 solution. The organic layer was washed with brine, and dried over Na2SO4. Removal of the solvent left the crude intermediate. To this was added DCE (1 ml), anisole (0.046 ml, 0.418 mmol), and TFA (0.5 ml). The resulting mixture was heated at 50° C. for 3 h. the solvents were removed and the crude material was purified by prep-HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; solvent B=90% Methanol, 10% H2O, 0.1% TFA, Flow rate 42 ml/min, 20-100% B, over 20 min). The HPLC fractions containing the product were 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 a mixture of 2 N solution of ammonia in methanol and dichloromethane (1:1). Removal of the solvents afforded 2-((2-chloro-5-cyano-3-(1-(1-methylpiperidin-4-yl)azetidin-3-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (35.2 mg) as a white solid.

Workup

  1. waitAfter 4 h
  2. customthe reaction mixture was partitioned between EtOAc
  3. washThe organic layer was washed with brine
  4. dry with materialdried over Na2SO4
  5. customRemoval of the solvent
  6. waitleft the crude intermediate
  7. temperatureThe resulting mixture was heated at 50° C. for 3 h. the solvents
  8. customwere removed
  9. customthe crude material was purified by prep-HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; solvent B=90% Methanol, 10% H2O, 0.1% TFA, Flow rate 42 ml/min, 20-100% B, over 20 min)
  10. additionThe HPLC fractions containing the product
  11. additionmixed-mode polymer
  12. washThis was washed with methanol and product
  13. washwas eluted with a mixture of 2 N solution of ammonia in methanol and dichloromethane (1:1)
  14. customRemoval of the solvents

Sources & evidence

ORD record
ord-ad44b7afc12c41d98e1bfc78382f6846
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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