Dichloromethane → 5-(4-Morpholino-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidin-2-yl)pyrimidin-2-amine

HRID 528451Notes

Reaction equation

HRID 528451 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[O:11][CH2:10][CH2:9][O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[O:15]1[CH2:16][CH2:17][N:12]([C:4]2[C:5]3[O:11][CH2:10][CH2:9][O:8][C:6]=3[N:7]=[C:2]([C:26]3[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=3)[N:3]=2)[CH2:13][CH2:14]1

Participants

7

Reactant 4

HCID 6344Dichloromethane2×HCID 10796Cesium carbonateHCID 177502122-Aminopyrimidine-5-boronic acid, pinacol ester2×HCID 867117372-Chloro-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine

Product 1

HCID 867117385-(4-Morpholino-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidin-2-yl)pyrimidin-2-amine

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 2-chloro-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (114 mg, 0.44 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (196 mg, 0.88 mmol), PdCl2dppf.DCM (36 mg, 0.04 mmol) and cesium carbonate (430 mg, 1.32 mmol) in dioxane (5 mL) and water (0.5 mL) was degassed and then heated at 100° C. for 2 hours. Further 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (100 mg, 0.44 mmol), PdCl2dppf.DCM (36 mg, 0.04 mmol) were added and the mixture heated at 100° C. for a further 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-10% methanol in DCM) then triturated with diethyl ether affording 101 (37 mg, 27%). LCMS: RT=2.75 min, [M+H]+=317. 1H NMR (400 MHz, DMSO): δ 8.90 (2H, s), 7.01 (2H, s), 4.42-4.36 (2H, m), 4.25-4.18 (2H, m), 3.70 (8H, s).

Workup

  1. temperaturethe mixture heated at 100° C. for a further 2 hours
  2. extractionextracted with ethyl acetate
  3. dry with materialThe combined organic extracts were dried (Na2SO4)
  4. concentrationconcentrated in vacuo
  5. washwas washed with methanol
  6. washthe product eluted with 2M ammonia in methanol
  7. concentrationconcentrated in vacuo
  8. customThe resulting residue was purified by column chromatography (SiO2, gradient 0-10% methanol in DCM)
  9. customthen triturated with diethyl ether affording 101 (37 mg, 27%)

Sources & evidence

ORD record
ord-92d2dcec0a0c4b3d9c9bb5b6aa66f9a7
Source dataset
uspto-grants-2016_05
Patent number
US09346817B2

Reaction notes

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