Cesium carbonate → Methyl (3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate

HRID 921747Notes

Reaction equation

HRID 921747 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([N:16]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:17](=[O:20])[O:18][CH3:19])[CH:5]=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:7]=1[F:8].[CH:30]1([N:33]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[C:34]2[C:39]3=[N:40][CH:41]=[C:42]([C:43]#[N:44])[N:38]3[N:37]=[C:36](S(C)(=O)=O)[N:35]=2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:43]([C:42]1[N:38]2[C:39]([C:34]([N:33]([CH:30]3[CH2:32][CH2:31]3)[CH2:49][C:50]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=3)=[N:35][C:36]([NH:1][C:2]3[CH:3]=[C:4]([N:16]([CH2:21][C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[C:17](=[O:20])[O:18][CH3:19])[CH:5]=[C:6]([N:9]4[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]4)[C:7]=3[F:8])=[N:37]2)=[N:40][CH:41]=1)#[N:44]

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 86708519HCID 86708519, compoundHCID 86708629Methyl (3-amino-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate

Product 1

HCID 86708630Methyl (3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carbamateYield 103.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

methyl (3-amino-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (50 mg, 0.093 mmol), 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (44.6 mg, 0.112 mmol) and Cs2CO3 (91 mg, 0.280 mmol) in DMF (1 ml) were heated at 45° C. for 14 hours. LCMS showed product formation (m/e+=721, [M+H]+). The mixture was poured onto a Phenomenex Strata XC cation exchange resin (2 g adsorbent). The cartridge was washed with MeOH and CH3CN. The product was eluted with a 1:1 mixture of CH3CN and a 2 molar solution of NH3 in MeOH. Evaporation to dryness gave crude methyl (3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (69.5 mg). The material was used in the following PMB deprotection reaction without further purification.

Workup

  1. additionThe mixture was poured onto a Phenomenex Strata XC cation exchange resin (2 g adsorbent)
  2. washThe cartridge was washed with MeOH and CH3CN
  3. washThe product was eluted with a 1:1 mixture of CH3CN
  4. customEvaporation to dryness

Sources & evidence

ORD record
ord-638de265f3c1434c9e6c5a901269fe2f
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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