Trifluoroacetic acid → 5-(4-((4-Fluoropiperidin-4-yl)methylamino)-5-(4-methoxyphenyl)pyridin-2-ylamino)pyrazine-2-carbonitrile

HRID 556866Notes

Reaction equation

HRID 556866 reaction equation
FC(F)(F)C(O)=O.[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][C:25]3([F:38])[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:20]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[CH:19][N:18]=2)=[N:14][CH:15]=1)#[N:9]>ClCCl>[F:38][C:25]1([CH2:24][NH:23][C:21]2[C:20]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[CH:19][N:18]=[C:17]([NH:16][C:13]3[N:14]=[CH:15][C:10]([C:8]#[N:9])=[N:11][CH:12]=3)[CH:22]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 66745448Tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate

Product 1

HCID 596134635-(4-((4-Fluoropiperidin-4-yl)methylamino)-5-(4-methoxyphenyl)pyridin-2-ylamino)pyrazine-2-carbonitrileYield 82.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

5-Aminopyrazine-2-carbonitrile (5.45 mg, 0.045 mmol), Xantphos (1.749 mg, 3.02 μmol), tris(dibenzylideneacetone)dipalladium(0) (1.384 mg, 1.511 μmol), and cesium carbonate (24.62 mg, 0.076 mmol) were added to tert-butyl 44(2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (17 mg, 0.038 mmol) in a 0.2 mL microwave reaction vial. The vial was sealed and an inert atmosphere was introduced before dry dioxane (291 μL) was added. Nitrogen was bubbled through the mixture for 5 min. The mixture was heated at 150° C. for 1 hr by microwave irradiation. After cooling the mixture was diluted with 20% dichloromethane in MeOH and loaed onto a preparative thin layer chromatography plate. Elution with 50% EtOAc in hexane gave tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (1.5 mg, 2.81 μmol, 7% yield) as a light yellow powder. LCMS (4) Rt=2.35 min; m/z (ESI+) 534 (MH+). Trifluoroacetic acid (0.1 mL, 1.298 mmol) was added to tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (1.5 mg, 2.81 μmol) dissolved in dichloromethane (0.5 mL) and the solution was stirred for 1 hr. The volatiles were removed in vacuo and the crude product was purified by ion exchange on (solute SCX II acidic resin (1 g), followed by preparative thin layer chromatography, eluting with 10% MeOH/1% NH3/89% dichloromethane, to give 5-(4-((4-fluoropiperidin-4-yl)methylamino)-5-(4-methoxyphenyl)pyridin-2-ylamino)pyrazine-2-carbonitrile (1 mg, 2.307 μmol, 82% yield) as a yellow powder.

Workup

  1. customThe volatiles were removed in vacuo
  2. customthe crude product was purified by ion exchange on (solute SCX II acidic resin (1 g)
  3. washeluting with 10% MeOH/1% NH3/89% dichloromethane

Sources & evidence

ORD record
ord-aa95691abd634218b149472b19aeb77b
Source dataset
uspto-grants-2011_11
Patent number
US08058045B2

Reaction notes

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