O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate → (R)-N-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-4-yl}-2-methylamino-propionamide

HRID 1842007

Reaktionsgleichung

Reaktionsgleichung von HRID 1842007
[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.C(O[C:30]([N:32](C)[C@H:33]([CH3:37])[C:34](O)=[O:35])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[CH2:17][CH2:18][CH:19]([NH:22][C:34](=[O:35])[C@H:33]([NH:32][CH3:30])[CH3:37])[CH2:20][CH2:21]3)=[CH:23][CH:24]=2)[CH2:2]1

Komponenten

6

Edukt 3

HCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 16211306N-(tert-Butoxycarbonyl)-N-methyl-D-alanineHCID 866953541-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-4-ylamine

Produkt 1

HCID 71737328(R)-N-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-4-yl}-2-methylamino-propionamide

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

A solution of Intermediate M (100 mg, 0.276 mmol), (R)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid (67 mg, 0.33 mmol), TEA (0.115 mL, 0.828 mmol), and TBTU (106 mg, 0.331 mmol) in DMF (2 mL) is heated at 60° C. overnight. The reaction is diluted with EtOAc, rinsed with sat. NaHCO3, and the organics dried and concentrated. The residue is purified by silica gel chromatography eluting with 0-10% MeOH/DCM. The pooled and concentrated product fractions are treated with 4M HCl in 1,4-dioxane (5 mL) and stirred overnight. The reaction is concentrated and purified by reverse phase HPLC eluting with 10-90% MeCN in water (0.1% TFA). The concentrated product fractions are dissolved in MeOH and eluted through a carbonate resin cartridge to afford the title compound 261. (LC/MS method 16: ES+ m/z 411.4 [M+H]+, Rt=0.33 min)

Aufarbeitung

  1. washrinsed with sat. NaHCO3
  2. customthe organics dried
  3. concentrationconcentrated
  4. customThe residue is purified by silica gel chromatography
  5. washeluting with 0-10% MeOH/DCM
  6. additionThe pooled and concentrated product fractions are treated with 4M HCl in 1,4-dioxane (5 mL)
  7. concentrationThe reaction is concentrated
  8. custompurified by reverse phase HPLC
  9. washeluting with 10-90% MeCN in water (0.1% TFA)
  10. dissolutionThe concentrated product fractions are dissolved in MeOH
  11. washeluted through a carbonate resin cartridge

Quellen und Nachweise

ORD-Eintrag
ord-17d1abc48f9b4733bdc1296c6bd42177
Quelldatensatz
uspto-grants-2015_02
Patentnummer
US08946203B2

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