Diisopropylethylamine → 5-cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamide

HRID 1854329Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1854329
Br[C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]2[CH2:15][C@H:14]([C:16]3[N:20]4[C:21]5[CH:27]=[CH:26][N:25]([S:28]([C:31]6[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=6)(=[O:30])=[O:29])[C:22]=5[N:23]=[CH:24][C:19]4=[N:18][N:17]=3)[C:13]2([CH3:39])[CH3:38])(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:40]([NH:43][C@@H]1C[C@H](C(O)=O)C1(C)C)(=O)C.CCN(C(C)C)C(C)C.BrC1C=CC(S(Cl)(=O)=O)=NC=1.C([Zn]C#N)#N>CN(C=O)C.[OH-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)CCl>[C:40]([C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]2[CH2:15][C@H:14]([C:16]3[N:20]4[C:21]5[CH:27]=[CH:26][N:25]([S:28]([C:31]6[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=6)(=[O:30])=[O:29])[C:22]=5[N:23]=[CH:24][C:19]4=[N:18][N:17]=3)[C:13]2([CH3:39])[CH3:38])(=[O:9])=[O:10])=[N:6][CH:7]=1)#[N:43]

Komponenten

10

Edukt 5

HCID 81531DiisopropylethylamineHCID 11183048(1S,3R)-3-acetamido-2,2-dimethylcyclobutane-1-carboxylic acidHCID 445580975-Bromopyridine-2-sulfonyl chlorideHCID 580103065-bromo-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamideHCID 178514179HCID 178514179, Verbindung

Produkt 1

HCID 580102855-cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamideAusbeute 14 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 111,2-DichloroethaneLösungsmittelHCID 6228DimethylformamideLösungsmittelHCID 14798Sodium HydroxideLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

To a solution of 5-bromo-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamide (0.69 g, 1.1 mmol, prepared using A from (1S,3R)-3-acetamido-2,2-dimethylcyclobutanecarboxylic acid [Tetrahedron: Asymmetry 2008, 19, 302-308] and Preparation #9 with EDC, C with DIEA, JJ, N from 5-bromopyridine-2-sulfonyl chloride [Chem Impex]) in degassed DMF (1.5 mL) was added dicyanozinc (0.321 g, 2.74 mmol) followed by Pd(Ph3P)4 (0.063 g, 0.055 mmol, Strem). The reaction was heated at about 80° C. for about 16 h under a nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperature before it was diluted with aqueous NaOH (1N, 10 mL) and extracted with EtOAc (25 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (12 g) eluting with a gradient of 1-10% MeOH in DCM to give 5-cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamide (0.09 g, 14%) as a tan solid: LC/MS (Table 2, Method a) Rt=2.14 min; MS m/z: 577 (M+H)+.

Aufarbeitung

  1. temperatureto cool to ambient temperature before it
  2. extractionextracted with EtOAc (25 mL)
  3. washThe organic layer was washed with brine (20 mL)
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe product was purified by silica gel chromatography (12 g)
  8. washeluting with a gradient of 1-10% MeOH in DCM

Quellen und Nachweise

ORD-Eintrag
ord-8ebdba67acc84d92aea54b87a60342eb
Quelldatensatz
uspto-grants-2015_02
Patentnummer
US08962629B2

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