Cesium carbonate → Tert-butyl 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)benzyl)piperazine-1-carboxylate

HRID 921767Notes

Reaction equation

HRID 921767 reaction equation
[NH2:1][C:2]1[C:3]([Cl:24])=[C:4]([CH:19]=[C:20]([C:22]#[N:23])[CH:21]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.Cl[C:26]1[N:31]=[C:30]([N:32]([CH:42]2[CH2:44][CH2:43]2)[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:29]2=[N:45][CH:46]=[C:47]([C:48]#[N:49])[N:28]2[N:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>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:24][C:3]1[C:2]([NH:1][C:26]2[N:31]=[C:30]([N:32]([CH:42]3[CH2:44][CH2:43]3)[CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:29]3=[N:45][CH:46]=[C:47]([C:48]#[N:49])[N:28]3[N:27]=2)=[CH:21][C:20]([C:22]#[N:23])=[CH:19][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1

Participants

6

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-carbonitrile2×HCID 86708653Tert-butyl 4-(3-amino-2-chloro-5-cyanobenzyl)piperazine-1-carboxylate

Product 1

HCID 86708654Tert-butyl 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)benzyl)piperazine-1-carboxylateYield 41.6%

Reagents, catalysts & solvents 1

HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)Catalyst

Conditions

Temperature
100 °C

Procedure

A mixture of tert-butyl 4-(3-amino-2-chloro-5-cyanobenzyl)piperazine-1-carboxylate (28 mg, 0.079 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9)(28 mg, 0.079 mmol), Cs2CO3 (51.4 mg, 0.158 mmol), DPPF (4.4 mg, 7.9 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (4.6 mg, 7.9 μmol), and in a microwave vial was flushed with nitrogen. Dioxane (0.7 mL) was added and the vial was sealed and heated at 100° C. for 3 hr. The reaction was diluted with EtOAc and filtered through celite. The solvent was removed and radial silica gel chromatography with hexane containing 5 to 40% EtOAc afforded tert-butyl 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)benzyl)piperazine-1-carboxylate (22 mg) as an oil.

Workup

  1. customin a microwave vial was flushed with nitrogen
  2. additionDioxane (0.7 mL) was added
  3. customthe vial was sealed
  4. additionThe reaction was diluted with EtOAc
  5. filtrationfiltered through celite
  6. customThe solvent was removed

Sources & evidence

ORD record
ord-79f4dd228aae446a9b4ad5f5c494f096
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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