Trifluoroacetic acid → (+/-) 2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 1430825Notes

Reaction equation

HRID 1430825 reaction equation
C(O)(C(F)(F)F)=O.[Si:8]([O:15][C@H:16]1[C@H:21]([NH:22]C(=O)OC(C)(C)C)[CH2:20][CH2:19][N:18]([C:30]2[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([NH:38][C:39]3[N:44]=[C:43]([N:45]([CH:55]4[CH2:57][CH2:56]4)CC4C=CC(OC)=CC=4)[C:42]4=[N:58][CH:59]=[C:60]([C:61]#[N:62])[N:41]4[N:40]=3)[C:31]=2[Cl:63])[CH2:17]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C1(OC)C=CC=CC=1>ClCCCl.ClCCl>[NH2:22][C@@H:21]1[CH2:20][CH2:19][N:18]([C:30]2[C:31]([Cl:63])=[C:32]([NH:38][C:39]3[N:44]=[C:43]([NH:45][CH:55]4[CH2:56][CH2:57]4)[C:42]4=[N:58][CH:59]=[C:60]([C:61]#[N:62])[N:41]4[N:40]=3)[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=2)[CH2:17][C@H:16]1[O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:10]

Participants

6

Reactant 3

HCID 6422Trifluoroacetic acidHCID 7519AnisoleHCID 131732386(+/-)-tert-butyl ((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate

Product 1

HCID 86708502(+/-) 2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 60.8%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
30 °C

Procedure

TFA (25% in 1,2-dichloroethane, 4 mL, 12.98 mmol) was added to a solution of (+/−)-tert-butyl ((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (270 mg, 0.338 mmol) and anisole (0.148 mL, 1.351 mmol) in 1,2-dichloroethane (2 mL) and the resulting solution was heated at 30° C. overnight The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10), the layers were separated and aqueous layer was extracted with dichloromethane/methanol (4/1) two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 1-7% methanol/dichloromethane to afford (+/−)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (119 mg,) and then 6-16% 2 N ammonia in methanol/dichloromethane to give (+/−)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (8 mg,).

Workup

  1. washwashed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10)
  2. customthe layers were separated
  3. extractionaqueous layer was extracted with dichloromethane/methanol (4/1) two more times
  4. dry with materialThe combined organic layers were dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customthe crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column
  8. washeluting with 1-7% methanol/dichloromethane

Sources & evidence

ORD record
ord-adb5ffdfa17d4614a03cd00da22e2c79
Source dataset
uspto-grants-2015_01
Patent number
US08940736B2

Reaction notes

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