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

HRID 420975ノート

反応式

HRID 420975 の反応式
[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]

参加物

12

反応物 5

HCID 313Hydrochloric AcidHCID 25517Ammonium ChlorideHCID 27364342-Bromo-5-(trifluoromethyl)pyridineHCID 57419918HCID 57419918、化合物HCID 178418306HCID 178418306、化合物

生成物 1

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

試薬・触媒・溶媒 6

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)触媒HCID 3007855Zincchloride触媒HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 3283Diethyl Ether溶媒2 回HCID 8028Tetrahydrofuran溶媒HCID 13387N-methyl-2-pyrrolidone溶媒

実験手順

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%).

後処理

  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

出典と根拠

ORDレコード
ord-3701c6698b484e18b2a329c5f36aa60c
出典データセット
uspto-grants-2012_01
特許番号
US08097623B2

反応ノート

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