Nitrogen → N-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine

HRID 2207703Notes

Reaction equation

HRID 2207703 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[C:19]3[O:18][CH2:17][C:16]([CH3:21])([CH3:20])[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=C(S(O[Na])(=O)=O)C=CC=2OC)CCCCC1.N#N>CC(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:20][C:16]1([CH3:21])[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:10][CH2:9][NH:8][C:6]3[CH:5]=[C:4]([C:32]4[CH:31]=[N:30][C:29]([N:26]5[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]5)=[CH:34][CH:33]=4)[N:3]=[CH:2][N:7]=3)[C:19]=2[O:18][CH2:17]1

Participants

8

Reactant 5

HCID 947NitrogenHCID 10340Sodium CarbonateHCID 27696181-Methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineHCID 86699650chloro-N-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)pyrimidin-4-amineHCID 178492906HCID 178492906, compound

Product 1

HCID 86699649N-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amineYield 37%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
90 °C

Procedure

As shown in step 3-vii of Scheme 3, a solution of -chloro-N-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)pyrimidin-4-amine (60 mg, 0.197 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine (71.86 mg, 0.237 mmol), Na2CO3 (296.2 μL of 2M, 0.592 mmol), and [3-(2-dicyclohexylphosphanylphenyl)-2,4-dimethoxy-phenyl]sulfonyloxysodium (VPhos, 8.1 mg, 0.0158 mmol) in i-PrOH (1.6 mL) was degassed using a stream of N2 for 30 minutes. Pd(OAc)2 (0.88 mg, 0.0039 mmol) was added and the solution was heated to 90° C. for 2 hours. The solution was concentrated under reduced pressure and purified by medium pressure chromatography on silica gel (0 to 100% (10% MeOH/EtOAc) in hexanes) to give N-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine (Compound 68, 32.4 mg, 36%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.49 (s, 1H), 8.07 (d, J=8.1 Hz, 1H), 6.94-6.90 (m, 2H), 6.77 (t, J=7.3 Hz, 1H), 6.62 (d, J=8.9 Hz, 1H), 6.55 (s, 1H), 5.30 (s, 1H), 4.20 (s, 2H), 3.60 (s, 6H), 2.86 (t, J=6.4 Hz, 2H), 2.45 (s, 4H), 2.28 (s, 3H) and 1.27 (s, 6H) ppm; ESMS (M+H)=445.09.

Workup

  1. customfor 30 minutes
  2. concentrationThe solution was concentrated under reduced pressure
  3. custompurified by medium pressure chromatography on silica gel (0 to 100% (10% MeOH/EtOAc) in hexanes)

Sources & evidence

ORD record
ord-500b46fbdfdf4090b0c49548f35477a8
Source dataset
uspto-grants-2016_06
Patent number
US09376448B2

Reaction notes

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