Sodium Carbonate → 5-(4-morpholinospiro[6H-[1,4]dioxino[2,3-d]pyrimidine-7,1'-cyclopropane]-2-yl)pyrimidin-2-amine

HRID 528471Notes

Reaction equation

HRID 528471 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:11][CH2:10][CH:9]([CH:12]3[CH2:14]C3)[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:18]1[CH2:17][CH2:16][N:15]([C:4]2[C:5]3[O:11][CH2:10][C:9]4([CH2:12][CH2:14]4)[O:8][C:6]=3[N:7]=[C:2]([C:29]3[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=3)[N:3]=2)[CH2:20][CH2:19]1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 177502122-Aminopyrimidine-5-boronic acid, pinacol esterHCID 867117542-Chloro-7-cyclopropyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine

Product 1

HCID 734271355-(4-morpholinospiro[6H-[1,4]dioxino[2,3-d]pyrimidine-7,1'-cyclopropane]-2-yl)pyrimidin-2-amineYield 35.2%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 2-chloro-7-cyclopropyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (98 mg, 0.34 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (144 mg, 0.65 mmol), Pd(PPh3)2Cl2 (25 mg, 0.035 mmol) and sodium carbonate (1.0 mL, 1.0 mmol, 1M aqueous solution) in acetonitrile (4 mL) was degassed then heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture 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 reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 106 as a white solid (41 mg, 35%). LCMS: RT=3.24 min, [M+H]+=343. 1H NMR (400 MHz, CDCl3): δ 9.12 (2H, s), 5.20 (2H, broad s), 4.16 (2H, s), 3.82 (8H, s), 1.29 (2H, t, J=6.89 Hz), 0.88 (2H, t, J=6.88 Hz).

Workup

  1. customwas degassed
  2. custommicrowave irradiation
  3. washwas washed with methanol
  4. washthe product eluted with 2M ammonia in methanol
  5. concentrationconcentrated in vacuo
  6. customThe resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%)

Sources & evidence

ORD record
ord-1208f11cab76467f9fa291a27b30a35b
Source dataset
uspto-grants-2016_05
Patent number
US09346817B2

Reaction notes

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