Cesium carbonate → (R)-tert-butyl 2-(4-(5-cyclopropylpyrimidin-2-ylamino)-2-fluorophenyl)morpholine-4-carboxylate

HRID 2403334Notes

Reaction equation

HRID 2403334 reaction equation
[NH2:1][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.Cl[C:23]1[N:28]=[CH:27][C:26]([CH:29]2[CH2:31][CH2:30]2)=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH:29]1([C:26]2[CH:25]=[N:24][C:23]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C@H:8]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]4)=[C:4]([F:21])[CH:3]=3)=[N:28][CH:27]=2)[CH2:31][CH2:30]1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 468640872-Chloro-5-cyclopropylpyrimidineHCID 68325616(R)-tert-butyl 2-(4-amino-2-fluorophenyl)morpholine-4-carboxylate

Product 1

HCID 68325663(R)-tert-butyl 2-(4-(5-cyclopropylpyrimidin-2-ylamino)-2-fluorophenyl)morpholine-4-carboxylateYield 43%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

(R)-tert-Butyl 2-(4-amino-2-fluorophenyl)morpholine-4-carboxylate (300 mg), 2-chloro-5-cyclopropylpyrimidine (188 mg, CAS 166740-44-9) and cesium carbonate (495 mg) were combined with dioxane (8 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (35.1 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (31.4 mg) were then added. The reaction mixture was then capped and stirred at 120° C. for 3 hours. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 55% EtOAc in hexanes) to afford (R)-tert-butyl 2-(4-(5-cyclopropylpyrimidin-2-ylamino)-2-fluorophenyl)morpholine-4-carboxylate (180 mg, 43%) as a yellow solid. MS (ISP): 415.2 ([M+H]+).

Workup

  1. customto give a yellow suspension
  2. customThe mixture was degassed
  3. customby bubbling argon into the mixture for several minutes
  4. additionXantphos (35.1 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (31.4 mg) were then added
  5. customThe reaction mixture was then capped
  6. customThe crude reaction mixture
  7. temperaturewas cooled to room temperature
  8. filtrationfiltered
  9. concentrationThe filtrate was concentrated in vacuo
  10. customthe residue was purified by flash column chromatography (silica gel; gradient: 0% to 55% EtOAc in hexanes)

Sources & evidence

ORD record
ord-01d298093f284a689c7c39dffab24bf9
Source dataset
uspto-grants-2014_08
Patent number
US08802673B2

Reaction notes

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