Cesium carbonate → 7-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one

HRID 1045929Notes

Reaction equation

HRID 1045929 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([N:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]2)=[C:15]2[C:19]=1[C:18](=[O:20])[N:17]([CH3:21])[CH2:16]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:22]3[CH2:23][CH2:24][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:26][CH2:27]3)=[C:15]3[C:19]=2[C:18](=[O:20])[N:17]([CH3:21])[CH2:16]3)[C:5]([Cl:9])=[CH:4][N:3]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 534009652,5-Dichloro-4-iodopyridineHCID 598492047-amino-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one

Product 1

HCID 866551407-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-oneYield 99.3%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 2,5-dichloro-4-iodopyridine (0.40 g, 1.46 mmol), 7-amino-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one (0.421 g, 1.46 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.051 g, 0.09 mmol), cesium carbonate (0.952 g, 2.92 mmol) and palladium(II) acetate (0.013 g, 0.06 mmol) was suspended in DMA (15 mL). The mixture was heated at 100° C. for 1 hour in a microwave reactor and then allowed to cool to room temperature. The mixture was loaded onto an SCX column and the product eluted first with MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated to afford 7-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one (0.630 g, 99% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 1.01-1.18 (3H, d), 2.60-2.64 (4H, m), 3.04-3.09 (5H, m), 4.51 (2H, s), 7.16 (1H, d), 7.29 (1H, s), 7.50 (1H, d), 8.28 (1H, s), 9.59 (1H, s); Mass spectrum: m/z (ESI+) (M+H)=434.0 and 436.0 and 438.0.

Workup

  1. temperatureto cool to room temperature
  2. washthe product eluted first with MeOH
  3. additionFractions containing product
  4. customevaporated

Sources & evidence

ORD record
ord-4a365807627049f89416a951affb167c
Source dataset
uspto-grants-2013_10
Patent number
US08569298B2

Reaction notes

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