Cesium carbonate → 1,1-Dimethylethyl 4-methoxybenzeneacetate

HRID 921894Notes

Reaction equation

HRID 921894 reaction equation
ClC1C(C2(F)CNC2)=CC(C#N)=CC=1NC1N=C(N(C2CC2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)C2=NC=C(C#N)N2N=1.NC1C(Cl)=C(C2(F)CN([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])C2)C=C(C#N)C=1.ClC1N=C(N(C2CC2)CC2C=CC(OC)=CC=2)C2=NC=C(C#N)N2N=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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].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:53]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 867084772-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileHCID 89922489HCID 89922489, compoundHCID 899229552-((2-Chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 123620391,1-Dimethylethyl 4-methoxybenzeneacetate

Reagents, catalysts & solvents 3

HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile A mixture of tert-butyl 3-(3-amino-2-chloro-5-cyanophenyl)-3-fluoroazetidine-1-carboxylate (21-D), (163 mg, 0.500 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (186 mg, 0.525 mmol), DPPF (27.7 mg, 0.050 mmol), Cs2CO3 (326 mg, 1.001 mmol), XANTPHOS (29.0 mg, 0.050 mmol), and palladium(f1) acetate (33.7 mg, 0.150 mmol) in a microwave vial in dioxane (4.5 mL) was evacuated and backfilled with nitrogen for three times, and then was heated in an oil bath at 100° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered through celite to remove insoluble material. The filtrate was washed with water, and brine. After drying with sodium sulfate, the solvents were removed and the product was purified by ISCO column (4 g) chromatography, eluting with hexane containing 0 to 35% EtOAc to afford 167 mg of the Boc-PMB-protected product which was dissolved in DCM (6 ml), added TFA (3 ml), and left stirring at room temperature for 30 min. Removal of the solvent. The crude was applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with a mixture of 2 N solution of ammonia in methanol and DCM (1:1). Removal of the solvents left 2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (143 mg) as a solid which was used on next step as such.

Workup

  1. customwas evacuated
  2. temperatureThe reaction mixture was cooled to room temperature
  3. additiondiluted with EtOAc
  4. filtrationfiltered through celite
  5. customto remove insoluble material
  6. washThe filtrate was washed with water, and brine
  7. dry with materialAfter drying with sodium sulfate
  8. customthe solvents were removed
  9. customthe product was purified by ISCO column (4 g) chromatography
  10. washeluting with hexane containing 0 to 35% EtOAc

Sources & evidence

ORD record
ord-fc05daf521d5408ba08cc3ff1b43627c
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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