Cesium carbonate → Diethyl (4-{[4-{[7-(4-acetyl piperazin-1-yl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate

HRID 1948002Notes

Reaction equation

HRID 1948002 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].[C:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])[CH3:41].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[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]([N:46]4[CH2:47][CH2:48][N:43]([C:40](=[O:42])[CH3:41])[CH2:44][CH2:45]4)=[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]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 837951-AcetylpiperazineHCID 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 58293044Diethyl (4-{[4-{[7-(4-acetyl piperazin-1-yl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonateYield 20%

Reagents, catalysts & solvents 2

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

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 (50.0 mg, 0.0796 mmol), 1-acetylpiperazine (0.510 g, 3.98 mmol), bis(dibenzylideneacetone)palladium(0) (9.15 mg, 0.0159 mmol), and Cs2CO3 (77.8 mg, 0.239 mmol) in 1,4-dioxane (5 mL) was evacuated and purged with N2 three times and stirred at 100° C. overnight. The crude mixture was passed through a Thiol-SPE cartridge to remove Pd and subsequently purified by MDP to isolate the title compound (10.5 mg, 20% yield). 1H NMR (400 MHz, CD3OD) δ=1.28 (t, J=7.1 Hz, 6H), 2.17 (s, 3H), 3.04-3.10 (m, 2H), 3.11-3.15 (m, 2H), 3.19 (s, 3H), 3.23 (d, J=21.5 Hz, 2H), 3.68-3.73 (m, 2H), 3.73-3.79 (m, 2H), 4.02-4.14 (m, 4H), 4.54 (s, 2H), 7.15 (d, J=8.8 Hz, 1H), 7.38 (dd, J=8.6, 2.5 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 8.34 (s, 1H), 8.52 (br. s., 1H).

Workup

  1. customwas evacuated
  2. custompurged with N2 three times
  3. customto remove Pd
  4. customsubsequently purified by MDP

Sources & evidence

ORD record
ord-820691eb1ce848678b1675831d392a08
Source dataset
uspto-grants-2013_03
Patent number
US08399433B2

Reaction notes

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