5-(Trifluoromethyl)pyrimidin-2-amine → (R)-tert-butyl 2-(2-fluoro-4-(5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate

HRID 2403336Notes

Reaction equation

HRID 2403336 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[C:4]([F:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1>O1CCOCC1>[F:21][C:4]1[CH:3]=[C:2]([NH:30][C:27]2[N:26]=[CH:25][C:24]([C:23]([F:32])([F:22])[F:31])=[CH:29][N:28]=2)[CH:7]=[CH:6][C:5]=1[C@H:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1

Participants

4

Reactant 2

HCID 152735745-(Trifluoromethyl)pyrimidin-2-amineHCID 68325672(+)-(R)-tert-butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate

Product 1

HCID 68325593(R)-tert-butyl 2-(2-fluoro-4-(5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylateYield 83%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a 25 ml glass vial was added (+)-(R)-tert-butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate (300 mg, example 192(f)) and 5-trifluoromethyl-pyrimidin-2-ylamine (156 mg, CAS 69034-08-8) in dioxane (5 ml). The reaction mixture was purged with argon for 5 min. 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (58.3 mg), tris(dibenzylideneacetone)dipalladium(0) (30.5 mg) and sodium tert-butoxide (89.8 mg) were then added. The vial was capped and heated at 100° C. for 2 h. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 60% EtOAc in heptane) to afford (R)-tert-butyl 2-(2-fluoro-4-(5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (304 mg, 83%) as an amorphous yellow solid. MS (ISP): 441.2 ([M−H]−).

Workup

  1. customThe reaction mixture was purged with argon for 5 min
  2. addition2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (58.3 mg), tris(dibenzylideneacetone)dipalladium(0) (30.5 mg) and sodium tert-butoxide (89.8 mg) were then added
  3. customThe vial was capped
  4. filtrationThe reaction mixture was then filtered through sintered glass
  5. concentrationthe filtrate was concentrated in vacuo
  6. customThe residue was purified by flash column chromatography (silica gel; gradient: 0% to 60% EtOAc in heptane)

Sources & evidence

ORD record
ord-c68b0b4f44084d0b992b5b830750030e
Source dataset
uspto-grants-2014_08
Patent number
US08802673B2

Reaction notes

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