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 1430829Notes

Reaction equation

HRID 1430829 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)[CH2:46][C:47]4[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=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>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]([N:45]([CH:55]4[CH2:56][CH2:57]4)[CH2:46][C:47]4[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=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])([CH3:10])[CH3:9].[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 2

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-carbonitrileHCID 86708507(+/-)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethyl silyl)oxy) piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

TFA (25% in 1,2-dichloroethane, 3 mL, 9.73 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 (Example 20B, 180 mg, 0.225 mmol) and anisole (0.098 mL, 0.901 mmol) in dichloromethane (1 mL) and the resulting reaction mixture was stirred at room temperature for 1 h. LCMS showed consumption of starting material and formation of two product (desired product and loss of Boc and PMB by-product). The reaction mixture was diluted with dichloromethane, washed cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10). The layers were separated and aqueous layer was extracted with dichloromethane two more times. The combined organic layer was 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 1-3% methanol/dichloromethane) to give (+/−)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (114 mg) and (+/−)-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 (30 mg).

Workup

  1. customthe resulting reaction mixture
  2. customconsumption of starting material and formation of two product (desired product and loss of Boc and PMB by-product)
  3. additionThe reaction mixture was diluted with dichloromethane
  4. washwashed cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10)
  5. customThe layers were separated
  6. extractionaqueous layer was extracted with dichloromethane two more times
  7. dry with materialThe combined organic layer was dried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customthe crude product was purified by flash chromatography on silica gel using
  11. washan automated ISCO system (40 g column, eluting with 1-3% methanol/dichloromethane)

Sources & evidence

ORD record
ord-f6d74f9c50244ec6ae1340e38be159f2
Source dataset
uspto-grants-2015_01
Patent number
US08940736B2

Reaction notes

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