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 1430918노트

반응식

HRID 1430918 반응식
[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

참가 물질

8

반응물 5

HCID 6422Trifluoroacetic acidHCID 7519AnisoleHCID 8471TriethylamineHCID 533465742-(3-Oxetanylidene)acetonitrileHCID 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

생성물 1

HCID 867086232-((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

시약·촉매·용매 2

HCID 887Methanol용매HCID 6344Dichloromethane용매

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온도
50 °C

실험 절차

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.

후처리

  1. customThe reaction mixture was partitioned between EtOAc and water
  2. washThe organic layer was washed with brine
  3. dry with materialdried over Na2SO4, removal of the solvent
  4. customthe crude PMB-protected product was purified by silica gel chromatography
  5. washeluting with DCM containing 0 to 2% MeOH
  6. dissolutionThe PMB-protected product was dissolved in DCE (2 ml)
  7. customRemoval of the solvent
  8. customthe crude material was purified by prep
  9. 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)
  10. additionThe HPLC fractions containing the product
  11. additionmixed-mode polymer
  12. washThis was washed with methanol and product
  13. washwas eluted with large amount of 2 N solution of ammonia in methanol/DCM (1:1)
  14. customRemoval of the solvents
  15. 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

출처 및 근거

ORD 기록
ord-b6e470aea51642158dafd41fbdf08c23
출처 데이터셋
uspto-grants-2015_01
특허 번호
US08940736B2

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