Hydrochloric Acid → 3-Chloro-1-(4-isopropoxyphenyl)-5-(5-trifluoromethylpyridin-2-yl)indole-2-carboxylic acid ethyl ester

HRID 646140Notes

Reaction equation

HRID 646140 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:33]2[CH:38]=[CH:37][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[CH:35][CH:34]=2)[C:24]2[C:29]([C:30]=1[Cl:31])=[CH:28][C:27](Br)=[CH:26][CH:25]=2)=[O:21])[CH3:18].[NH4+].[Cl-].Cl>CCOCC.[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.C1COCC1>[CH2:17]([O:19][C:20]([C:22]1[N:23]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH:40]([CH3:41])[CH3:42])=[CH:37][CH:38]=2)[C:24]2[C:29]([C:30]=1[Cl:31])=[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 686966545-Bromo-3-chloro-1-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl esterHCID 178418306HCID 178418306, compound

Product 1

HCID 684751033-Chloro-1-(4-isopropoxyphenyl)-5-(5-trifluoromethylpyridin-2-yl)indole-2-carboxylic acid ethyl esterYield 75.3%

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 EtherSolvent3×HCID 8028TetrahydrofuranSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
-78 °C

Procedure

t-BuLi (3.25 mL of 1.5M solution in pentane) was added dropwise at −78° C. to Et2O (5 mL). To the resulting solution was added, via syringe, a solution of 2-bromo-5-(trifluoromethyl)pyridine (550 mg, 2.43 mmol) in Et2O (2.5 mL). Stirring at −78° C. was continued for 20 min after which the cold reaction mixture was transferred via cannula to a cooled (−78° C.) 1M solution of ZnCl2 in Et2O (5.25 mL, 5.35 mmol). The reaction was allowed to warm to room temperature and left to stir for 3 h. THF (10 mL) was then added and the resulting solution was transferred via cannula to a mixture of 5-bromo-3-chloro-1-(4-isopropoxyphenyl)-1H-indole-2-carboxylic acid ethyl ester (see Example 35, Method 1, step (b)) (531 mg, 1.22 mmol), Pd(dppf)Cl2 (118.4 mg, 0.145 mmol), CuI (56.2 mg, 0.295 mmol) and N-methylpyrrolidine-2-one (2.5 mL) under argon. The reaction was heated at 80° C. for 6 h, poured into NH4Cl (aq. sat., 50 mL) and extracted with t-BuOMe (3×25 mL). The combined organic extracts were washed with brine, dried (Na2SO4), then filtered through a Celite® pad and the filter cake was washed with t-BuOMe. The solvent was removed and the residue dissolved in dry Et2O and HCl (4M in dioxane; 360 μL, 1.4 mmol) was added. After stirring for 10 min, solvents were removed by evaporation and the residue was twice recrystallised from EtOH to yield the sub-title compound (462 mg, 75%).

Workup

  1. additionTo the resulting solution was added, via syringe
  2. customafter which the cold reaction mixture
  3. temperatureto warm to room temperature
  4. waitleft
  5. stirringto stir for 3 h
  6. temperatureThe reaction was heated at 80° C. for 6 h
  7. extractionextracted with t-BuOMe (3×25 mL)
  8. washThe combined organic extracts were washed with brine
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered through a Celite® pad
  11. washthe filter cake was washed with t-BuOMe
  12. customThe solvent was removed
  13. dissolutionthe residue dissolved in dry Et2O
  14. stirringAfter stirring for 10 min
  15. customsolvents were removed by evaporation
  16. customthe residue was twice recrystallised from EtOH

Sources & evidence

ORD record
ord-68c83e52446e4d70a4911ee6079623ad
Source dataset
uspto-grants-2010_04
Patent number
US07705023B2

Reaction notes

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