Cesium carbonate → (+/-)-2-((2-chloro-5-cyano-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921805Notes

Reaction equation

HRID 921805 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([N:36]2[CH2:41][CH2:40][N:39]3[CH2:42][C@H:43]([OH:45])[CH2:44][C@H:38]3[CH2:37]2)[C:34]=1[Cl:35])[C:30]#[N:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:35][C:34]1[C:33]([N:36]2[CH2:41][CH2:40][N:39]3[CH2:42][C@H:43]([OH:45])[CH2:44][C@H:38]3[CH2:37]2)=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 867084772-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileHCID 131734934HCID 131734934, compound

Product 1

HCID 131734936(+/-)-2-((2-chloro-5-cyano-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 54.5%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (60.6 mg, 0.171 mmol), (+/−)-3-amino-4-chloro-5-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzonitrile (50 mg, 0.171 mmol), palladium(II) acetate (10.16 mg, 0.045 mmol), Xantphos (9.88 mg, 0.017 mmol), DPPF (9.47 mg, 0.017 mmol) and cesium carbonate (145 mg, 0.444 mmol) in dioxane (3 ml) was evacuated and back filled with nitrogen three time and was heated at 80° C. for 5 h. The reaction mixture was filtered through a celite pad, the filtrate was concentrated. And the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 0.5-5% 2 N ammonia in methanol/dichloromethane). It was further purified by prep-HPLC (Pursuit XRs 10 u C18 column, 30×250 mm, room temperature 13.171 min, 30-100% gradient aqueous methanol over 12 minutes containing 0.1% TFA, 40 ml/min at 254 rinm). (+/−)-2-((2-chloro-5-cyano-3-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (57 mg) was obtained as a brown solid.

Workup

  1. customwas evacuated
  2. additionback filled with nitrogen three time
  3. filtrationThe reaction mixture was filtered through a celite pad
  4. concentrationthe filtrate was concentrated
  5. customAnd the crude product was purified by flash chromatography on silica gel using
  6. washan automated ISCO system (24 g gold column, eluting with 0.5-5% 2 N ammonia in methanol/dichloromethane)
  7. customIt was further purified by prep-HPLC (Pursuit XRs 10 u C18 column, 30×250 mm, room temperature 13.171 min, 30-100% gradient aqueous methanol over 12 minutes containing 0.1% TFA, 40 ml/min at 254 rinm)

Sources & evidence

ORD record
ord-8986409d8e884e898be1b6fcd52c5c89
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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