Sodium t-butoxide → N-Methyl-6-[6-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-nicotinamide

HRID 467561Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 467561
[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[C:28]([C:29]([NH:31][CH3:32])=[O:30])=[CH:27][N:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][NH:31][C:29](=[O:30])[C:28]1[CH:23]=[CH:24][C:25]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[N:26][CH:27]=1

Komponenten

7

Edukt 3

HCID 23676156Sodium t-butoxideHCID 674693264-Bromo-N-methyl-nicotinamideHCID 674693316-((2S,3'S)-2-Methyl-[1,3']bipyrrolidinyl-1'-yl)-1,2,3,4-tetrahydro-isoquinoline

Produkt 1

HCID 54669914N-Methyl-6-[6-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-nicotinamideAusbeute 68 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 634876Binap, (A+-)-KatalysatorHCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 1140TolueneLösungsmittel

Reaktionsbedingungen

Temperatur
85 °C

Versuchsvorschrift

6-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline (1.81 g, 6.35 mmol, 1 eq) was dissolved in 77 mL of dry toluene and purged with nitrogen. 4-Bromo-N-methyl-nicotinamide (1.49 g, 6.99 mmol, 1.1 eq), sodium tert-butoxide (885 mg, 9.2 mmol, 1.45 eq), Pd2(dba)3 (59 mg, 0.064 mmol, 0.01 eq) and BINAP (119 mg, 0.19 mmol, 0.03 eq) were sequentially added followed by an additional degassing with nitrogen. The reaction mixture was heated to 85° C. and stirred overnight. The reaction mixture was cooled to rt, transferred to a separatory funnel, diluted with water and brine and extracted with ethyl acetate (2×100 mL). The combined organics were dried over Na2SO4, concentrated under vacuum and purified by column chromatography on silica gel (200 g column; 50 mL/min; 10% MeOH in CH2Cl2). This resulted in 1.8 g (68%) of the title compound as a light orange solid.

Aufarbeitung

  1. custompurged with nitrogen
  2. customan additional degassing with nitrogen
  3. temperatureThe reaction mixture was cooled to rt
  4. customtransferred to a separatory funnel
  5. additiondiluted with water and brine
  6. extractionextracted with ethyl acetate (2×100 mL)
  7. dry with materialThe combined organics were dried over Na2SO4
  8. concentrationconcentrated under vacuum
  9. custompurified by column chromatography on silica gel (200 g column; 50 mL/min; 10% MeOH in CH2Cl2)

Quellen und Nachweise

ORD-Eintrag
ord-a39a355f3267412586f7fb3ba903c882
Quelldatensatz
uspto-grants-2014_01
Patentnummer
US08623877B2

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