Dichloromethane → Diethyl (4-{[4-({7-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate

HRID 1947839Notes

Reaction equation

HRID 1947839 reaction equation
[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:40][O:41][CH2:42][CH2:43][N:44]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[N:45]1.C(=O)([O-])[O-].[K+].[K+].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[CH3:40][O:41][CH2:42][CH2:43][N:44]1[CH:48]=[C:47]([C:30]2[CH:31]=[CH:32][C:24]([NH:23][C:21]3[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([CH2:9][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:11][CH:12]=4)[N:22]=3)=[C:25]3[C:29]=2[CH2:28][N:27]([CH3:34])[C:26]3=[O:35])[CH:46]=[N:45]1

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 112304911-(2-Methoxyethyl)-1H-pyrazole-4-boronic acid, pinacol esterHCID 58292897Diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate

Product 1

HCID 58293052Diethyl (4-{[4-({7-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonateYield 19.6%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (10.0 mg, 0.0159 mmol), 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.02 mg, 0.0318 mmol), potassium carbonate (6.60 mg, 0.0477 mmol), 1,4-dioxane (0.4 mL), H2O (0.1 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (1.30 mg, 0.00159 mmol) was evacuated and purged with N2. The mixture was irradiated in a microwave reactor at 100° C. for 30 minutes. The crude mixture was passed through a Thiol-SPE column to remove Pd and purified by MDP to obtain the title compound (2.1 mg, 19.6% yield). 1H NMR (400 MHz, CD3OD) δ=1.25 (t, J=7.1 Hz, 6H), 3.21 (s, 3H), 3.30 (d, J=22.7 Hz), 3.35 (s, 3H), 3.79 (t, J=5.2 Hz, 2H), 4.01-4.13 (m, 4H), 4.37 (t, J=5.2 Hz, 2H), 4.60 (s, 2H), 7.37 (dd, J=8.6, 2.3 Hz, 2H), 7.57 (d, J=8.6 Hz, 2H), 7.72 (d, J=8.8 Hz, 1H), 7.94 (s, 1H), 8.08 (s, 1H), 8.36 (s, 1H), 8.68 (br. s., 1H). MS (ES+): m/z 674.34 (100) [MH+]; HPLC: tR=1.05 min (UPLC, purity).

Workup

  1. customwas evacuated
  2. custompurged with N2
  3. customThe mixture was irradiated in a microwave reactor at 100° C. for 30 minutes
  4. customto remove Pd
  5. custompurified by MDP

Sources & evidence

ORD record
ord-9a80379152fb4e96bdfbc033fb768dcf
Source dataset
uspto-grants-2013_03
Patent number
US08399433B2

Reaction notes

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