Cesium carbonate → HCID 58292935, compound

HRID 511501Notes

Reaction equation

HRID 511501 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31]CC)=[CH:27][C:26]=3[O:40][CH3:41])[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.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]>[CH3:41][O:40][C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][C:25]=1[NH:24][C:16]1[N:15]=[C:14]([NH:13][C:5]2[CH:4]=[CH:3][C:2]([N:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)=[C:10]3[C:6]=2[C:7](=[O:12])[N:8]([CH3:11])[CH2:9]3)[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:17]=1)[CH2:29][P:30](=[O:37])([OH:31])[O:34][CH2:35][CH3:36]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 531671-MethylpiperazineHCID 58293036HCID 58293036, compound

Product 1

HCID 58292935HCID 58292935, compoundYield 1.2%

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)-3-methoxybenzyl]phosphonate (200.0 mg, 0.3038 mmol), 1-methylpiperazine (202 uL, 1.82 mmol), bis(dibenzylideneacetone)palladium(0) (34.9 mg, 0.0608 mmol), Cs2CO3 (297 mg, 0.911 mmol) in 1,4-dioxane (20 mL) was evacuated and purged with nitrogen three times and allowed to stir at 100° C. overnight. The reaction mixture was passed through a Thiol-SPE cartridge to remove Pd and the crude material was purified by MDP. The resulting material, diethyl (3-methoxy-4-{[4-{[2-methyl-7-(4-methylpiperazin-1-yl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl) phosphonate, was taken up in conc. HCl (2.0 mL) and heated at 80° C. for 2 hours. The crude material was again purified by MDP to obtain the title compound (2.3 mg, 1.2% yield). 1H NMR (400 MHz, methanol-d4) δ=1.26 (t, J=6.9 Hz, 3 H), 2.99 (s, 3 H), 3.17 (s, 3 H), 3.18 (d, J=20.7 Hz, 2 H), 3.24-3.29 (m, 2 H), 3.33-3.36 (m, 2 H), 3.38-3.46 (m, 2 H), 3.58 (br. s., 2H), 3.88 (s, 3 H), 4.03 (quin, J=7.1 Hz, 2 H), 4.48 (s, 2 H), 7.00 (d, J=8.1 Hz, 1 H), 7.10 (s, 1H), 7.21 (d, J=8.8 Hz, 1 H), 7.60 (d, J=7.6 Hz, 1 H), 8.32 (s, 1 H), 8.39 (br. s., 1 H). MS (ES+): m/z 650.29 (100) [MH+]; HPLC: tR=0.63 min (UPLC, purity).

Workup

  1. customwas evacuated
  2. custompurged with nitrogen three times
  3. customto remove Pd
  4. customthe crude material was purified by MDP
  5. temperatureheated at 80° C. for 2 hours
  6. customThe crude material was again purified by MDP

Sources & evidence

ORD record
ord-e102fe2b28404dfca2b6fbe0522fc569
Source dataset
uspto-grants-2015_08
Patent number
US09096624B2

Reaction notes

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