Sodium Iodide → 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)-N-methylacetamide

HRID 921888노트

반응식

HRID 921888 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.Cl[CH2:42][C:43]([NH:45][CH3:46])=[O:44].[I-].[Na+].CCN(CC)CC.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>CN(C=O)C.CCOC(C)=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:16][C:17]2[N:22]=[C:21]([NH:23][CH:33]3[CH2:34][CH2:35]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[CH2:9][CH2:10][N:11]([CH2:42][C:43]([NH:45][CH3:46])=[O:44])[CH2:12][CH2:13]1

참가 물질

10

반응물 6

HCID 5238Sodium IodideHCID 6422Trifluoroacetic acidHCID 7519AnisoleHCID 8471TriethylamineHCID 667732-chloro-N-methylacetamideHCID 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 899224082-(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)-N-methylacetamide

시약·촉매·용매 3

HCID 6228Dimethylformamide용매HCID 6344Dichloromethane용매HCID 8857Ethyl Acetate용매

반응 조건

온도
100 °C

실험 절차

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 (in 12163-US-psp), (25 mg, 0.045 mmol), 2-chloro-n-methylacetamide (97 mg, 0.090 mmol), sodium iodide (13.53 mg, 0.090 mmol) and Et3N (0.024 mL, 0.135 mmol) in DMF (1.2 mL) in a microwave vial was heated at 100° C. in a microwave reactor for 2 h. The reaction mixture was diluted with EtOAc, washed with water, brine, and dried over Na2SO4. Removal of the solvent followed by silica gel chromatography eluting with DCM containing 0 to 2% MeOH to afford the PMB-protected product which was dissolved in DCM (0.7 ml), and TFA (0.7 ml) and anisole (0.025 mL, 0.226 mmol) were added. The resulting mixture was heated at 50° C. for 3 h. After removal of solvent the residue was taken in MeOH/DCM and 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 (5 CV) of mixture of 2 N solution of ammonia in methanol and DCM (1:1). Removal of the solvents 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)-N-methylacetamide (15.6 mg).

후처리

  1. washwashed with water, brine
  2. dry with materialdried over Na2SO4
  3. customRemoval of the solvent
  4. washeluting with DCM containing 0 to 2% MeOH
  5. customto afford the PMB-protected product which
  6. temperatureThe resulting mixture was heated at 50° C. for 3 h
  7. customAfter removal of solvent the residue
  8. additionmixed-mode polymer
  9. washThis was washed with methanol and product
  10. washwas eluted with large amount (5 CV) of mixture of 2 N solution of ammonia in methanol and DCM (1:1)
  11. customRemoval of the solvents

출처 및 근거

ORD 기록
ord-7f6ef1a665c246f594c3c3cdd3a6472c
출처 데이터셋
uspto-grants-2016_03
특허 번호
US09273057B2

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