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

HRID 528465Notes

Reaction equation

HRID 528465 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[O:11][CH2:10][CH:9]([C:12]([F:15])([F:14])[F:13])[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=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:19]1[CH2:20][CH2:21][N:16]([C:4]2[C:5]3[O:11][CH2:10][CH:9]([C:12]([F:15])([F:14])[F:13])[O:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=3)[N:3]=2)[CH2:17][CH2:18]1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 177502122-Aminopyrimidine-5-boronic acid, pinacol esterHCID 867117492-Chloro-4-morpholin-4-yl-7-trifluoromethyl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine

Product 1

HCID 732119285-[4-Morpholino-7-(trifluoromethyl)-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidin-2-yl]pyrimidin-2-amineYield 49%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
120 °C

Procedure

A microwave vial was charged with 2-chloro-4-morpholin-4-yl-7-trifluoromethyl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (105 mg, 0.32 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (143 mg, 0.64 mmol), Pd(PPh3)2Cl2 (23 mg, 0.03 mmol) and sodium carbonate (1.06 mL, 1.06 mmol, 1M aqueous solution) in acetonitrile (1.6 mL) before the vessel was evacuated and back filled with argon (×3). The mixture was heated at 120° C. for 30 minutes using microwaves. The reaction mixture was diluted with H2O/DCM/methanol then absorbed onto diatomaceous earth before being purified by column chromatography (SiO2, gradient 0-4% methanol in DCM then SiO2 then gradient 0-90% ethyl acetate in cyclohexane) followed by trituration in diethyl ether to give 105 as a white solid (60 mg, 49%). LCMS: RT=3.52 min, [M+H]+=385. 1H NMR (400 MHz, DMSO): δ 8.92 (2H, s), 7.08 (2H, s), 5.51-5.41 (1H, m), 4.53-4.41 (2H, m), 3.78-3.65 (8H, m)

Workup

  1. customwas evacuated
  2. additionback filled with argon (×3)
  3. additionThe reaction mixture was diluted with H2O/DCM/methanol
  4. customthen absorbed onto diatomaceous earth
  5. custombefore being purified by column chromatography (SiO2, gradient 0-4% methanol in DCM

Sources & evidence

ORD record
ord-214da57c49e84269b34956b5a0e621ee
Source dataset
uspto-grants-2016_05
Patent number
US09346817B2

Reaction notes

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