2,6-Lutidine → 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

HRID 921813Notes

Reaction equation

HRID 921813 reaction equation
[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[Cl:13][C:14]1[C:19]([NH:20][C:21]2[N:26]=[C:25]([N:27]([CH:37]3[CH2:39][CH2:38]3)[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:24]3=[N:40][CH:41]=[C:42]([C:43]#[N:44])[N:23]3[N:22]=2)=[CH:18][C:17]([C:45]#[N:46])=[CH:16][C:15]=1[N:47]1[CH2:52][CH2:51][CH:50]2[N:53](C(OC(C)(C)C)=O)[CH2:54][CH2:55][CH:49]2[CH2:48]1.N1C(C)=CC=CC=1C>ClCCl>[Cl:13][C:14]1[C:15]([N:47]2[CH2:52][CH2:51][CH:50]3[NH:53][CH2:54][CH2:55][CH:49]3[CH2:48]2)=[CH:16][C:17]([C:45]#[N:46])=[CH:18][C:19]=1[NH:20][C:21]1[N:26]=[C:25]([N:27]([CH:37]2[CH2:39][CH2:38]2)[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[C:24]2=[N:40][CH:41]=[C:42]([C:43]#[N:44])[N:23]2[N:22]=1

Participants

5

Reactant 3

HCID 79372,6-LutidineHCID 65367Trimethylsilyl triflateHCID 118253319tert-butyl 5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

Product 1

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-carbonitrileYield 93.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

TMS-OTf (0.281 ml, 1.553 mmol) was added to a solution of tert-butyl 5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (360 mg, 0.518 mmol) and 2,6-lutidine (0.181 ml, 1.553 mmol) in dichloromethane (3 ml) and the reaction mixture was stirred at room temperature for 2 hours. 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 (40 g column, eluting with 5-40% ethyl acetate/hexanes). 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 (288 mg) was obtained as an off-white solid.

Workup

  1. washwashed with saturated sodium bicarbonate
  2. extractionThe aqueous layer was extracted with dichloromethane two more times
  3. dry with materialThe combined organic layers were dried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude product was purified by flash chromatography on silica gel using
  7. washan automated ISCO system (40 g column, eluting with 5-40% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-b8559ea7b8f24aaa9424ab0596ec17c8
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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