1-(2-Hydroxyethyl)piperazine → 1-Cyclohexyl-3-{3,5-dichloro-4'-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-biphenyl-4-ylmethyl}-pyrrolidin-2-one hydrochloride salt

HRID 416007Notes

Reaction equation

HRID 416007 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].B([C:32]1[CH:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1)=O.[N:41]1([CH2:47][CH2:48][OH:49])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[ClH:1].[CH:14]1([N:11]2[CH2:12][CH2:13][CH:9]([CH2:8][C:7]3[C:2]([Cl:1])=[CH:3][C:4]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:44]5[CH2:45][CH2:46][N:41]([CH2:47][CH2:48][OH:49])[CH2:42][CH2:43]5)=[O:39])=[CH:34][CH:33]=4)=[CH:5][C:6]=3[Cl:21])[C:10]2=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1

Participants

8

Reactant 5

HCID 76771-(2-Hydroxyethyl)piperazineHCID 10340Sodium CarbonateHCID 14798Sodium HydroxideHCID 27733384-(Oxoboranyl)benzoyl chlorideHCID 592994213,5-Dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate

Product 1

HCID 666218421-Cyclohexyl-3-{3,5-dichloro-4'-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-biphenyl-4-ylmethyl}-pyrrolidin-2-one hydrochloride saltYield 74%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

Combine Preparation 10 (trifluoro-methanesulfonic acid 3,5-dichloro-4-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-phenyl ester) (250 mg, 0.53 mmol), 4-chlorocarbonylphenylboronic anhydride (263 mg, 0.53 mmol) and Pd(PPh3)4 (61 mg, 0.053 mmol) and purge with nitrogen. Add 2-(piperazin-1-yl)ethanol (0.32 mL, 2.6 mmol) followed quickly by dimethoxyethane (5 mL) and 2M sodium carbonate (1 mL) and heat to 80° C. for 1 hour. Cool to room temperature and pour into 1N sodium hydroxide. Extract with ethyl acetate and wash the organic layer twice with water, followed by brine. Dry over sodium sulfate and concentrate in vacuo. Purify on SCX column (load and wash with methanol, elute with 2M ammonia in methanol). Dissolve resultant oil in methylene chloride. Add 2M hydrochloric acid in ether (1 mL) and concentrate under vacuum. Re-dissolve in small amount of methylene chloride and add dropwise to vigorously stirred ether. Filter precipitate and dry in vacuum oven to afford 231 mg (74%) of the title compound: MS (m/z): 558 (M+).

Workup

  1. custompurge with nitrogen
  2. temperatureCool to room temperature
  3. extractionExtract with ethyl acetate
  4. washwash the organic layer twice with water
  5. dry with materialDry over sodium sulfate
  6. concentrationconcentrate in vacuo
  7. customPurify on SCX column (load and wash with methanol, elute with 2M ammonia in methanol)
  8. dissolutionDissolve resultant oil in methylene chloride
  9. additionAdd 2M hydrochloric acid in ether (1 mL)
  10. concentrationconcentrate under vacuum
  11. additionRe-dissolve in small amount of methylene chloride and add dropwise to vigorously stirred ether
  12. filtrationFilter precipitate
  13. customdry in vacuum oven

Sources & evidence

ORD record
ord-273fdd49580746f498895554e4bc5bf1
Source dataset
uspto-grants-2012_01
Patent number
US08088776B2

Reaction notes

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