2-(Dimethylamino)ethanol → (+/-)-2-(dimethylamino)ethyl ((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate

HRID 921651Notes

Reaction equation

HRID 921651 reaction equation
[NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:32])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)[C:20]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].C1N=CN([C:46](N2C=NC=C2)=[O:47])C=1.[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][OH:57].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Si:34]([O:33][C@H:3]1[C@H:2]([NH:1][C:46](=[O:47])[O:57][CH2:56][CH2:55][N:54]([CH3:58])[CH3:53])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH:24]4[CH2:25][CH2:26]4)[C:20]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]4[N:18]=3)[C:9]=2[Cl:32])[CH2:4]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36]

Participants

6

Reactant 4

HCID 79022-(Dimethylamino)ethanolHCID 682631,1'-CarbonyldiimidazoleHCID 2733832Lithium HexamethyldisilazideHCID 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-carbonitrile

Product 1

HCID 89922746(+/-)-2-(dimethylamino)ethyl ((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamateYield 89%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

A solution of (+/−)-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 (32 mg, 0.055 mmol) in THF (1 mL) was added to CDI (35.8 mg, 0.221 mmol) in THF (1 mL) at 0° C. and the reaction mixture was stirred at room temperature overnight. In a 1-dram vial charged with 2-(dimethylamino)ethanol (44.6 mg, 0.500 mmol) in THF (1 mL) was added lithium bis(trimethylsilyl)amide (1M in THF, 0.884 mL, 0.884 mmol) at 0° C. and the resulting reaction solution was stirred at room temperature for 10 min before added to the above intermediate. The reaction mixture was stirred at room temperature for 1 h Solvent was evaporated and the residue was partitioned between dichloromethane and saturated sodium bicarbonate. The layers were separated and the 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 (24 g column, eluting with 1-8% methanol/dichloromethane). (+/−)-2-(dimethylamino)ethyl ((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (34 mg) was obtained as a white solid.

Workup

  1. customthe resulting reaction solution
  2. stirringwas stirred at room temperature for 10 min
  3. additionbefore added to the above intermediate
  4. stirringThe reaction mixture was stirred at room temperature for 1 h Solvent
  5. customwas evaporated
  6. customthe residue was partitioned between dichloromethane and saturated sodium bicarbonate
  7. customThe layers were separated
  8. dry with materialthe organic layer was dried over magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customthe crude product was purified by flash chromatography on silica gel using
  12. washan automated ISCO system (24 g column, eluting with 1-8% methanol/dichloromethane)

Sources & evidence

ORD record
ord-81d41d12563a4c84ad39034776e34eef
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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