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Ethanolamine → (e)-3-(5-Bromo-2-methoxy-phenyl)-n-{2-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethyl}-acrylamide

HRID 854606
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 854606
N[CH2:2][CH2:3][OH:4].C(O[BH-](O[C:15](=[O:17])[CH3:16])OC(=O)C)(=O)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:38]1C=CN=C1.II.C(OC1(C[C:56]2[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=2)CCNCC1)(=O)C.[CH:63]([N:66]([CH:69]([CH3:71])C)[CH2:67][CH3:68])([CH3:65])C.[Br:72][C:73]1[CH:74]=[CH:75][C:76]([O:84][CH3:85])=[C:77](/[CH:79]=C/C(O)=O)[CH:78]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>COC(OC)OC.ClCCl.CN(C=O)C.CO>[Br:72][C:73]1[CH:74]=[CH:75][C:76]([O:84][CH3:85])=[C:77](/[CH:79]=[CH:2]/[C:3]([NH:38][CH2:71][CH2:69][N:66]2[CH2:63][CH2:65][C:15]([CH2:16][C:56]3[CH:57]=[CH:58][C:59]([F:62])=[CH:60][CH:61]=3)([OH:17])[CH2:68][CH2:67]2)=[O:4])[CH:78]=1
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

13

Edukt 9

HCID 700EthanolamineHCID 795ImidazoleHCID 807IodineHCID 11776TriphenylphosphineHCID 81531Diisopropylethylamine2×HCID 676162trans-5-Bromo-2-methoxycinnamic acidHCID 2733207
O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
HCID 5049666Sodium triacetoxyborohydride
HCID 694266924-(4-Fluoro-benzyl)-piperidin-4-ol acetate

Produkt 1

HCID 10117306(e)-3-(5-Bromo-2-methoxy-phenyl)-n-{2-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethyl}-acrylamide

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 887MethanolLösungsmittelHCID 6228DimethylformamideLösungsmittel3×HCID 87981187Trimethylorthoformate dichloromethaneLösungsmittel

Reaktionsbedingungen

Temperatur
20 °C

Versuchsvorschrift

To a suspension of 2-(formyl-3-methoxyphenoxy)ethyl polystyrene (AMEBA) resin (ex Novabiochem) (1.5 g, 1.05 mmol) in a mixture of trimethylorthoformate/dichloromethane (15 ml, 1:1 v/v) is added 2-amino ethanol (0.317 ml, 5.25 mmol), sodium triacetoxyborohydride (1.113 g, 5.25 mmol) followed by methanol (2 ml) and the mixture shaken for 8 hours at 20° C., then filtered. The resin is washed with methanol, dichloromethane and THF. The dried resin is suspended in THF/acetonitrile (40 ml, 9:1 v/v) and treated with triphenylphosphine (2.75 g, 10.5 mmol), imidazole (0.715 g, 10.5 mmol) and iodine (2.66 g, 10.5 mmol). The suspension obtained is, shaken for 6 hours at 20° C., then filtered. The resin is washed with THF followed by DMF and dried under vacuum. To the freshly prepared resin (1.0 g, 0.7 mmol) suspended in DMF (3 ml) is added 4-(4-fluoro-benzyl)-piperidin-4-ol acetate (0.399 g, 1.4 mmol) and diisopropylethylamine (0.36 g, 2.8 mmol). The mixture is heated at 50° C. for 16 hours and then filtered. The resin is washed with DMF. To the washed resin (0.5 g, 0.35 mmol ) suspended in DMF (3 ml) is added a solution of (E)-3-(5-bromo-2-methoxy-phenyl)-acrylic acid (0.27 g, 1.05 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate (0.34 g, 1.05 mmol), diisopropylethylamine (0.29 g, 1.05 mmol) in DMF (2 ml) and the mixture is shaken at 20° C. for 4 hours, then washed with DMF, methanol and dichloromethane after which it is treated with trifluoroacetic acid/dichloromethane (6 ml, 1:1 v/v) at 20° C. for 1 hour to remove the product from the resin. The resulting mixture is filtered and the filtrate evaporated under vacuum to give the crude product which is purified by preparative HPLC to afford (E)-3-(5-Bromo-2-methoxy-phenyl)-N-{2-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethyl}-acrylamide, as the trifluoroacetate salt, [MH]+ 490.9, 492.8

Aufarbeitung

  1. filtrationfiltered
  2. washThe resin is washed with methanol, dichloromethane and THF
  3. customThe suspension obtained
  4. stirringshaken for 6 hours at 20° C.
  5. filtrationfiltered
  6. washThe resin is washed with THF
  7. customdried under vacuum
  8. temperatureThe mixture is heated at 50° C. for 16 hours
  9. filtrationfiltered
  10. washThe resin is washed with DMF
  11. stirringthe mixture is shaken at 20° C. for 4 hours
  12. washwashed with DMF, methanol and dichloromethane after which it
  13. additionis treated with trifluoroacetic acid/dichloromethane (6 ml, 1:1 v/v) at 20° C. for 1 hour
  14. customto remove the product from the resin
  15. filtrationThe resulting mixture is filtered
  16. customthe filtrate evaporated under vacuum
  17. customto give the crude product which
  18. customis purified by preparative HPLC

Quellen und Nachweise

ORD-Eintrag
ord-6a406733cb7243afaf0b4454b6639712
Quelldatensatz
uspto-grants-2007_08
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US07259173B2

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