Hydrochloric Acid → 1-(4-Isopropoxyphenyl)-5-(5-trifluoromethylpyridin-2-yl)indole-2,3-dicarb-oxylic acid diethyl ester

HRID 420975Notes

Reaction equation

HRID 420975 reaction equation
[Li]C(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[CH2:17]([O:19][C:20]([C:22]1[N:23]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH:44]([CH3:46])[CH3:45])=[CH:39][CH:38]=2)[C:24]2[C:29]([C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][C:27](Br)=[CH:26][CH:25]=2)=[O:21])[CH3:18].[NH4+].[Cl-].Cl>CCOCC.C1COCC1.[Cl-].[Cl-].[Zn+2].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].[Cu]I.CN1CCCC1=O>[CH2:17]([O:19][C:20]([C:22]1[N:23]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH:44]([CH3:46])[CH3:45])=[CH:39][CH:38]=2)[C:24]2[C:29]([C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][C:27]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1)=[CH:26][CH:25]=2)=[O:21])[CH3:18]

Participants

12

Reactant 5

HCID 313Hydrochloric AcidHCID 25517Ammonium ChlorideHCID 27364342-Bromo-5-(trifluoromethyl)pyridineHCID 57419918HCID 57419918, compoundHCID 178418306HCID 178418306, compound

Product 1

HCID 866288201-(4-Isopropoxyphenyl)-5-(5-trifluoromethylpyridin-2-yl)indole-2,3-dicarb-oxylic acid diethyl ester

Reagents, catalysts & solvents 6

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 3007855ZincchlorideCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 3283Diethyl EtherSolvent2×HCID 8028TetrahydrofuranSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

t-BuLi (1.5 M in pentane, 4.5 mL, 3 mmol) was added dropwise at −78° C. to Et2O (15 mL). 2-Bromo-5-trifluoromethylpyridine (762 mg, 3.37 mmol) in Et2O (5 mL) was added via syringe. After 20 min at −78° C. the cold mixture was cannulated to cooled (−78° C.) ZnCl2 (1 M in Et2O, 7.4 mL, 7.4 mmol). The mixture was allowed to warm to rt and was stirred at rt for 3 h. The mixture was diluted with THF (15 mL) and added to a mixture of 5-bromo-1-(4-isopropoxyphenyl)indole-2,3-dicarboxylic acid diethyl ester (800 mg 1.69 mmol, see step (c) above), Pd(dppf)Cl2 (165 mg, 0.20 mmol), CuI (77 mg, 0.40 mmol) and NT-methylpyrrolidin-2-one (5.3 mL). The mixture was heated at 80° C. for 6 h, poured into NH4Cl (aq, sat, 50 mL) and extracted with t-BuOMe (3×30 mL). The combined extracts were washed with brine, dried (Na2SO4) and filtered through Celite®. The solids were washed with t-BuOMe and the combined filtrates were concentrated. The residue was dissolved in anhydrous Et2O and HCl (4 M in dioxane, 500 μL, 2.0 mmol) was added. After 10 min the mixture was concentrated and the residue was treated with anhydrous Et2O to give the sub-title compound. Yield 900 mg (92%).

Workup

  1. temperatureThe mixture was heated at 80° C. for 6 h
  2. extractionextracted with t-BuOMe (3×30 mL)
  3. washThe combined extracts were washed with brine
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered through Celite®
  6. washThe solids were washed with t-BuOMe
  7. concentrationthe combined filtrates were concentrated
  8. dissolutionThe residue was dissolved in anhydrous Et2O
  9. concentrationAfter 10 min the mixture was concentrated
  10. additionthe residue was treated with anhydrous Et2O

Sources & evidence

ORD record
ord-3701c6698b484e18b2a329c5f36aa60c
Source dataset
uspto-grants-2012_01
Patent number
US08097623B2

Reaction notes

Loading…