Acetic Acid → 2-((2-chloro-5-cyano-3-(1-methylhexahydro-1H-pyrrolo[3,2-c]pyridin-5 (6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921815Notes

Reaction equation

HRID 921815 reaction equation
[C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:21]([N:22]2[CH2:27][CH2:26][CH:25]3[NH:28][CH2:29][CH2:30][CH:24]3[CH2:23]2)=[CH:20][C:19]([C:31]#[N:32])=[CH:18][C:17]=1[NH:33][C:34]1[N:39]=[C:38]([N:40]([CH:50]2[CH2:52][CH2:51]2)[CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:37]2=[N:53][CH:54]=[C:55]([C:56]#[N:57])[N:36]2[N:35]=1.C=O.C(O)(=O)C>ClCCl>[Cl:15][C:16]1[C:21]([N:22]2[CH2:27][CH2:26][CH:25]3[N:28]([CH3:1])[CH2:29][CH2:30][CH:24]3[CH2:23]2)=[CH:20][C:19]([C:31]#[N:32])=[CH:18][C:17]=1[NH:33][C:34]1[N:39]=[C:38]([N:40]([CH:50]2[CH2:52][CH2:51]2)[CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)[C:37]2=[N:53][CH:54]=[C:55]([C:56]#[N:57])[N:36]2[N:35]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 712Formaldehyde2×HCID 5049666Sodium triacetoxyborohydride2×HCID 899228312-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 899227532-((2-chloro-5-cyano-3-(1-methylhexahydro-1H-pyrrolo[3,2-c]pyridin-5 (6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 90.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Sodium triacetoxyborohydride (20.66 mg, 0.097 mmol) was added to a solution of 2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 442F, 29 mg, 0.049 mmol), paraformaldehyde (14.63 mg, 0.487 mmol) and acetic acid (5.58 μl, 0.097 mmol) in dichloromethane (2 mL) and the reaction mixture was stirred at room temperature for 5 hours. More paraformaldehyde (14.63 mg, 0.487 mmol) and sodium triacetoxyborohydride (20.66 mg, 0.097 mmol) were added and stirring continued overnight. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane 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 (80 g column, eluting with 5-30% ethyl acetate/hexanes). 2-((2-chloro-5-cyano-3-(1-methylhexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (27 mg) was obtained as a white solid.

Workup

  1. stirringstirring continued overnight
  2. washwashed with saturated sodium bicarbonate
  3. extractionThe aqueous layer was extracted with dichloromethane 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
  8. washan automated ISCO system (80 g column, eluting with 5-30% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-903149f7ea0747d3adc858de8202ca62
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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