Potassium Carbonate → 4-[7-Chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindol-5-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester

HRID 2427537Notes

Reaction equation

HRID 2427537 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.Br[C:25]1[CH:26]=[C:27]2[C:31](=[C:32]([Cl:34])[CH:33]=1)[C:30](=[O:35])[N:29]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:39][CH:38]=1)[CH2:28]2.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:25]2[CH:26]=[C:27]3[C:31](=[C:32]([Cl:34])[CH:33]=2)[C:30](=[O:35])[N:29]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]([F:46])([F:47])[F:45])=[CH:39][CH:38]=2)[CH2:28]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

9

Reactant 5

HCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 789669-Borabicyclo(3.3.1)nonaneHCID 27568081-Boc-4-MethylenepiperidineHCID 117044755-Bromo-7-chloro-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one

Product 1

HCID 579496974-[7-Chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindol-5-ylmethyl]-piperidine-1-carboxylic acid tert-butyl esterYield 44%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a purged (Argon) sample of 4-Methylene-piperidine-1-carboxylic acid tert-butyl ester (51.6 mg, 0.26 mmol) was added 9-BBN. The mixture was stirred at 60° C. for one hour. After cooling to room temperature this solution was added to 5-bromo-7-chloro-2-(4 trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (100.0 mg, 0.24 mmol), Pd(dppf)Cl2 (5.9 mg, 0.0072 mmol), DMF (2.0 mL), potassium carbonate 943.1 mg, 0.31 mmol) and water (0.2 mL). The mixture was allowed to stir at 75° C. overnight. The mixture was then cooled to room temperature and poured into water (3 mL). The pH was adjusted to 11 with aqueous sodium hydroxide (3N). The product was extracted with ethyl acetate. The combined organic layers were washed with water three times, brine, dried over sodium sulphate, filtered and concentrated. Column chromatography (30% Ethyl acetate/hexanes) provided the title compound (54.9 mg, 44%).

Workup

  1. temperatureAfter cooling to room temperature this solution
  2. stirringto stir at 75° C. overnight
  3. temperatureThe mixture was then cooled to room temperature
  4. extractionThe product was extracted with ethyl acetate
  5. washThe combined organic layers were washed with water three times, brine
  6. dry with materialdried over sodium sulphate
  7. filtrationfiltered
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-3a2117995ada4bef9e3e4aabf1fe4095
Source dataset
uspto-grants-2011_06
Patent number
US07968570B2

Reaction notes

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