Morpholine → (+/-)-N-((3R,4R)-3-((tert-butyldimethyls ilyl)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)morpholine-4-carboxamide

HRID 921654Notes

Reaction equation

HRID 921654 reaction equation
[NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:41])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH:33]4[CH2:35][CH2:34]4)[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:20]4=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44].C1N=CN([C:55]([N:57]2[CH:61]=N[CH:59]=[CH:58]2)=[O:56])C=1.N1CC[O:65][CH2:64]C1>C1COCC1>[Si:43]([O:42][C@H:3]1[C@H:2]([NH:1][C:55]([N:57]2[CH2:58][CH2:59][O:65][CH2:64][CH2:61]2)=[O:56])[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]([N:23]([CH:33]4[CH2:34][CH2:35]4)[CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[C:20]4=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]4[N:18]=3)[C:9]=2[Cl:41])[CH2:4]1)([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]

Participants

5

Reactant 3

HCID 8083MorpholineHCID 682631,1'-CarbonyldiimidazoleHCID 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

Product 1

HCID 86708506(+/-)-N-((3R,4R)-3-((tert-butyldimethyls ilyl)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)morpholine-4-carboxamideYield 73.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of (+/−)-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 (40 mg, 0.057 mmol) in THF (1 mL) was added to CDI (37.1 mg, 0.229 mmol) in THF (1 mL) at 0° C. and the reaction mixture was stirred at room temperature overnight. Morpholine (39.9 mg, 0.458 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. LCMS showed completion of reaction. 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 2-6% 2 N ammonia in methanol/dichloromethane). (+/−)-N-((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)morpholine-4-carboxamide (34 mg) was obtained as a white solid.

Workup

  1. stirringthe reaction mixture was stirred at room temperature for 1 h
  2. customcompletion of reaction
  3. customSolvent was evaporated
  4. customthe residue was partitioned between dichloromethane and saturated sodium bicarbonate
  5. customThe layers were separated
  6. dry with materialthe organic layer was dried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by flash chromatography on silica gel using
  10. washan automated ISCO system (24 g column, eluting with 2-6% 2 N ammonia in methanol/dichloromethane)

Sources & evidence

ORD record
ord-5ac1b7ee386144cca36a79efa6c21a39
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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