Sodium Carbonate → N-(2-(2-methoxyphenyl)propyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine

HRID 2207709Notes

Reaction equation

HRID 2207709 reaction equation
Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH3:11])[CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=C(S(O[Na])(=O)=O)C=CC=2OC)CCCCC1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:10]([CH3:11])[CH2:9][NH:8][C:4]1[CH:3]=[C:2]([C:30]2[CH:29]=[N:28][C:27]([N:24]3[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]3)=[CH:32][CH:31]=2)[N:7]=[CH:6][N:5]=1

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 27696181-Methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine2×HCID 866996526-chloro-N-(2-(2-methoxyphenyl)propyl)pyrimidin-4-amineHCID 178492906HCID 178492906, compound

Product 1

HCID 73214432N-(2-(2-methoxyphenyl)propyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amineYield 42%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
90 °C

Procedure

As shown in step 4-vi of Scheme 4, a mixture of 6-chloro-N-(2-(2-methoxyphenyl)propyl)pyrimidin-4-amine (75.0 mg, 0.270 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine (Compound 2007, 90.1 mg, 0.297 mmol), Pd(OAc)2 (1.21 mg, 0.00540 mmol), [3-(2-dicyclohexylphosphanylphenyl)-2,4-dimethoxy-phenyl]sulfonyloxysodium (VPhos, 11.1 mg, 0.0216 mmol), and Na2CO3 (405 μL of 2 M, 0.810 mmol) in IPA (2 mL) was degassed and back-filled with N2 (repeated 2×), then heated to 90° C. for 4 hours. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by medium pressure chromatography on silica gel (90-100% EtOAc in hexanes) to give N-(2-(2-methoxyphenyl)propyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine as a clear, yellow oil (Compound 2013, 48.0 mg, 42% yield): 1H NMR (CDCl3) δ 8.77 (d, J=2.2 Hz, 1H), 8.56 (s, 1H), 8.15 (dd, J=9.0, 2.5 Hz, 1H), 7.28-7.21 (m, 2H), 7.01-6.89 (m, 2H), 6.72 (d, J=9.0 Hz, 1H), 6.60 (s, 1H), 5.09 (bs, 1H), 3.87 (s, 3H), 3.76-3.65 (m, 4H), 3.65-3.46 (m, 3H), 2.62-2.48 (m, 4H), 2.38 (s, 3H), 1.36 (d, J=6.7 Hz, 3H).

Workup

  1. customwas degassed
  2. additionback-filled with N2 (repeated 2×)
  3. filtrationThe reaction mixture was filtered through diatomaceous earth
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified by medium pressure chromatography on silica gel (90-100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-1ff1346a08804ae8b10a85c5f9c7c3b5
Source dataset
uspto-grants-2016_06
Patent number
US09376448B2

Reaction notes

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