Dichloromethane → HCID 11952881, compound

HRID 1354073Notes

Reaction equation

HRID 1354073 reaction equation
Br[CH2:2][CH2:3][C:4](Cl)=[O:5].ClCCl.C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[Al+3].[Cl-].[Cl-].[Cl-].[F:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][CH2:42][CH2:41]2.[OH-].[Na+]>C(#N)C>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][C:4]([N:43]2[C:44]3[C:40](=[CH:39][C:38]([F:37])=[CH:46][CH:45]=3)[CH2:41][CH2:42]2)=[O:5])[CH2:29][CH2:28]1

Participants

9

Reactant 7

HCID 6344DichloromethaneHCID 14798Sodium HydroxideHCID 81531Diisopropylethylamine2×HCID 84944Propanoyl chloride, 3-bromo-HCID 8518331-(2,3-Dichlorophenyl)piperazineHCID 27744635-FluoroindolineHCID 6451240Aluminum(III) Chloride

Product 1

HCID 11952881HCID 11952881, compound

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent3×

Procedure

3-Bromopropanoyl chloride (1 g in 10 ml dry dichloromethane) was added with stirring at 0° C. to a suspension of 1 g Wang resin (Rapp polymere, loading 0.95 mmol/g) in 10 ml dry dichloromethane containing 5 equivalents of diisopropylethyl amine. The mixture was stirred overnight at room temperature, filtered and washed with dry dichloromethane (6×100 ml). A solution of 1-(2,3-dichlorophenyl)piperazine (2.5 equivalents) in dry acetonitrile containing diisopropylethyl amine (5 equivalents) was added to the dried resin and the mixture heated to 70° C. for 3 hours. The mixture was cooled to room temperature and the resin washed with dry acetonitrile and dichloromethane and dried. A solution of AlCl3 (1.1 equivalent) in dry acetonitrile (5 ml) was added to the resin followed by a solution of 5-fluoro-2,3-dihydro-1H-indole (3 equivalents) in dry acetonitrile (5 ml) and the mixture agitated for 3 hours. The reaction was quenched by addition of 2N NaOH (1.2 equivalent), filtrated and the product purified by solid phase ion exchange chromatography (Varian SCX columns) using Gilson ASPEC 232 XL. Further purification was performed on a PE Sciex API 150EX instrument equipped with IonSpray source and Shimadzu LC-8A/SLC-10A LC system. The LC conditions (50×20 mm YMC ODS-A with 5 μm particle size) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (80:20:0.05) to water/acetonitrile/trifluoroacetic acid (10:90:0.03) in 7 min at 22.7 mL/min. Fraction collection was performed by split-flow MS detection. Purity was determined by integration of the UV trace (254 nm). The retention times RT are expressed in minutes.

Workup

  1. filtrationfiltered
  2. washwashed with dry dichloromethane (6×100 ml)
  3. additionwas added to the dried resin
  4. temperaturethe mixture heated to 70° C. for 3 hours
  5. temperatureThe mixture was cooled to room temperature
  6. washthe resin washed with dry acetonitrile and dichloromethane
  7. customdried
  8. stirringthe mixture agitated for 3 hours
  9. filtrationfiltrated
  10. customthe product purified by solid phase ion exchange chromatography (Varian SCX columns)
  11. customFurther purification
  12. customequipped with IonSpray source and Shimadzu LC-8A/SLC-10A LC system
  13. washgradient elution with water/acetonitrile/trifluoroacetic acid (80:20:0.05) to water/acetonitrile/trifluoroacetic acid (10:90:0.03) in 7 min at 22.7 mL/min
  14. customFraction collection
  15. customby split-flow MS detection
  16. waitThe retention times RT are expressed in minutes

Sources & evidence

ORD record
ord-b7c1ddcb41ae47448f7fefd933483706
Source dataset
uspto-grants-2007_05
Patent number
US07223765B2

Reaction notes

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