Sodium Hydroxide → HCID 87304286, Verbindung

HRID 547780Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 547780
[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[O:38][CH2:39][C@@H:40]1[CH2:44][CH2:43][C@@H:42]([CH2:45][O:46]C)[NH:41]1.[OH-].[Na+].B(Br)(Br)Br>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.ClCCl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[OH:38][CH2:39][C@H:40]1[CH2:44][CH2:43][C@@H:42]([CH2:45][OH:46])[N:41]1[C:21]1[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:34])[CH3:33])=[C:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH:22]=1.[OH:38][CH2:39][C@@H:40]1[CH2:44][CH2:43][C@@H:42]([CH2:45][OH:46])[N:41]1[C:21]1[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:34])[CH3:33])=[C:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH:22]=1

Komponenten

10

Edukt 4

HCID 14798Sodium HydroxideHCID 25134Boron tribromideHCID 7019262(S,S)-(+)-2,5-Bis(methoxymethyl)pyrrolidineHCID 235027842-(3,5-Bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyrid-3-yl)-N,2-dimethylpropanamide

Produkt 2

HCID 87304286HCID 87304286, VerbindungAusbeute 2 %HCID 87304714HCID 87304714, VerbindungAusbeute 2 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 5974Hexadecyltrimethylammonium BromideKatalysatorHCID 178418851HCID 178418851, VerbindungKatalysatorHCID 1140TolueneLösungsmittelHCID 6344DichloromethaneLösungsmittel2×

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

A mixture of 0.30 g (0.56 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.11 g (0.68 mmol) (2S,5S)-(−)-2,5-bis(methoxymethyl)pyrrolidine, 5 mg (0.01 mmol) cetyltrimethylammonium bromide, 0.014 g (0.027 mmol) bis(tri-t-butylphosphine)palladium(0), 0.07 ml NaOH 50% and 2 ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated under argon at 90° C. over night. After cooling to room temperature the mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 0.09 g of the crude coupling product. This material was dissolved in 2 ml dichloromethane and treated with 1.1 ml (1.1 mmol) of a 1 M solution of boron tribromide in dichloromethane at 0° C. After 15 min. the reaction was quenched by the addition of water, followed by extraction with three portions of dichloromethane. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 7 mg (2%) of (2R,5S)—N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light brown solid and 6 mg (2%) of (2S,5S)—N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light brown solid.

Aufarbeitung

  1. customwas degassed by two freeze-thaw cycles
  2. temperatureAfter cooling to room temperature the mixture
  3. additionwas diluted with water
  4. extractionextracted with three portions of tert-butyl methyl ether
  5. dry with materialThe combined organic layers were dried over sodium sulphate
  6. concentrationconcentrated in vacuo
  7. customFlash column chromatography gave 0.09 g of the crude coupling product
  8. customAfter 15 min. the reaction was quenched by the addition of water
  9. extractionfollowed by extraction with three portions of dichloromethane
  10. dry with materialThe combined organic layers were dried over sodium sulphate
  11. concentrationconcentrated in vacuo

Quellen und Nachweise

ORD-Eintrag
ord-33c7a87dfc824fb89282d60d0ee11454
Quelldatensatz
uspto-grants-2011_05
Patentnummer
US07939533B2

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