Trifluoroacetic acid → 2-((2-Chloro-5-cyano-3-(1-(3-(cyanomethyl)oxetan-3-yl)piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 1430918Notes

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.CCN(CC)CC.[O:48]1[CH2:51][C:50](=[CH:52][C:53]#[N:54])[CH2:49]1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>CO.C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][N:11]([C:50]3([CH2:52][C:53]#[N:54])[CH2:51][O:48][CH2:49]3)[CH2:12][CH2:13]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:33]2[CH2:34][CH2:35]2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1

Participants

Conditions

Temperature: 50 °C

Procedure

To a solution 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) (30 mg, 0.054 mmol) in a mixture solvent {CH2Cl2 (1 ml)/MeOH (0.5 mL)} was added Et3N (0.011 ml, 0.081 mmol) followed by 2-(oxetan-3-ylidene)acetonitrile (36.0 mg, 0.379 mmol). The reaction mixture was heated at 50° C. for 2 days. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, removal of the solvent and the crude PMB-protected product was purified by silica gel chromatography, eluting with DCM containing 0 to 2% MeOH. The PMB-protected product was dissolved in DCE (2 ml), and added anisole (0.059 ml, 0.541 mmol), followed by TFA (0.5 ml). The resulting mixture was stirred at rt overnight. Removal of the solvent, 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 permin, 20-100% B, over 20 min). The HPLC fractions containing the product were applied onto a cartridges of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with large amount of 2 N solution of ammonia in methanol/DCM (1:1). Removal of the solvents left 2-((2-chloro-5-cyano-3-(1-(3-(cyanomethyl)oxetan-3-yl)piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (10.6 mg) as a solid.

Workup

customThe reaction mixture was partitioned between EtOAc and water
washThe organic layer was washed with brine
dry with materialdried over Na2SO4, removal of the solvent
customthe crude PMB-protected product was purified by silica gel chromatography
washeluting with DCM containing 0 to 2% MeOH
dissolutionThe PMB-protected product was dissolved in DCE (2 ml)
customRemoval of the solvent
customthe crude material was purified by prep
customHPLC (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 permin, 20-100% B, over 20 min)
additionThe HPLC fractions containing the product
additionmixed-mode polymer
washThis was washed with methanol and product
washwas eluted with large amount of 2 N solution of ammonia in methanol/DCM (1:1)
customRemoval of the solvents
waitleft 2-((2-chloro-5-cyano-3-(1-(3-(cyanomethyl)oxetan-3-yl)piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (10.6 mg) as a solid

Sources & evidence

ORD record: ord-b6e470aea51642158dafd41fbdf08c23
Source dataset: uspto-grants-2015_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08940736B2

Reaction notes

Loading…