Sodium Carbonate → 5-(7-Cyclopropyl-4-morpholino-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidin-2-yl)pyrimidin-2-amine

HRID 528494Notes

Reaction equation

HRID 528494 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][CH2:13]3)[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+]>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.C(#N)C>[CH:12]1([CH:9]2[O:8][C:6]3[N:7]=[C:2]([C:29]4[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=4)[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]=3[O:11][CH2:10]2)[CH2:14][CH2:13]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 734270355-(7-Cyclopropyl-4-morpholino-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidin-2-yl)pyrimidin-2-amine

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
120 °C

Procedure

A microwave vial was charged with 2-chloro-7-cyclopropyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (205 mg, 0.49 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (324 mg, 1.47 mmol), Pd(PPh3)2Cl2 (51 mg, 0.07 mmol), sodium carbonate (2.41 mL, 2.41 mmol, 1M aqueous solution) and acetonitrile (2.5 mL). The vessel was sealed then evacuated and back filled with argon (×3) before being heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was filtered and the filtrate concentrated in vacuo. The resultant residue was purified by column chromatography (SiO2, gradient 0-4% methanol in DCM), then triturated in diethyl ether/pentane. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient methanol 10-98%) affording 118 as an off white solid (4.5 mg, 3%). LCMS: RT=3.52 min, [M+H]+=357. 1H NMR (400 MHz, DMSO-d6): δ 8.91 (2H, s), 7.01 (2H, s), 4.40 (1H, dd, J=11.38, 2.41 Hz), 4.01 (1H, dd, J=11.41, 7.52 Hz), 3.80-3.60 (9H, m), 1.11-0.98 (1H, m), 0.69-0.41 (4H, m).

Workup

  1. customThe vessel was sealed
  2. customthen evacuated
  3. additionback filled with argon (×3)
  4. custommicrowave irradiation
  5. filtrationThe reaction mixture was filtered
  6. concentrationthe filtrate concentrated in vacuo
  7. customThe resultant residue was purified by column chromatography (SiO2, gradient 0-4% methanol in DCM)
  8. customtriturated in diethyl ether/pentane
  9. customThe resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient methanol 10-98%)

Sources & evidence

ORD record
ord-bcdafc3ea4e74647a9c08e26fb2b060b
Source dataset
uspto-grants-2016_05
Patent number
US09346817B2

Reaction notes

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