Pyridine 4-methylbenzene-1-sulfonate → Azd-8835

HRID 1749045Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1749045
CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.[NH2:18][C:19]1[N:20]=[CH:21][C:22]([C:34]2[N:38]([CH2:39][CH3:40])[N:37]=[C:36]([CH:41]3[CH2:46][CH2:45][N:44]([C:47](=[O:57])[CH2:48][CH2:49][O:50]C4CCCCO4)[CH2:43][CH2:42]3)[N:35]=2)=[N:23][C:24]=1[C:25]1[O:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[N:28][N:29]=1>CO>[NH2:18][C:19]1[N:20]=[CH:21][C:22]([C:34]2[N:38]([CH2:39][CH3:40])[N:37]=[C:36]([CH:41]3[CH2:42][CH2:43][N:44]([C:47](=[O:57])[CH2:48][CH2:49][OH:50])[CH2:45][CH2:46]3)[N:35]=2)=[N:23][C:24]=1[C:25]1[O:26][C:27]([C:30]([CH3:33])([CH3:31])[CH3:32])=[N:28][N:29]=1

Komponenten

4

Edukt 2

HCID 161440Pyridine 4-methylbenzene-1-sulfonateHCID 867276661-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-one

Produkt 1

HCID 76685059Azd-8835Ausbeute 85 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 887MethanolLösungsmittel

Reaktionsbedingungen

Temperatur
60 °C

Versuchsvorschrift

Pyridine 4-methylbenzenesulfonate (11.62 g, 46.24 mmol) was added to a suspension of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-one (128 g, 231.19 mmol) in methanol (1 L) under nitrogen. The mixture was stirred at 60° C. for 1.5 hours. The mixture was soluble after 5 minutes. The mixture was held at 50° C. overnight during which time a precipitate formed. The solid material was isolated by filtration and washed with water and acetonitrile. This material still contained minor impurities from the previous stage and required further purification. The material was dissolved in dichloromethane and purified by flash chromatography on silica gel (0% methanol/DCM to 10% methanol/DCM). The desired product, 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (Reference Example 1) (92 g, 85%), was thus isolated as a cream solid (Form A): 1H NMR Spectrum: (DMSO-d6) 1.4-1.51 (12H, m), 1.51-1.78 (2H, m), 1.89-2.05 (2H, n), 72-2.86 (1H, m), 2.91-3.05 (1H, m), 3.12-3.24 (1H, m), 3.64 (2H, q), 3.83-4.01 (1H, m), 4.29-4.41 (1H, m), 4.47 (1H, t), 4.58 (2H, q), 8.26 (2H, s), 8.85 (1H, s): Mass Spectrum [M+H]+=470.

Aufarbeitung

  1. waitThe mixture was soluble after 5 minutes
  2. waitThe mixture was held at 50° C. overnight during which time
  3. customa precipitate formed
  4. customThe solid material was isolated by filtration
  5. washwashed with water and acetonitrile
  6. customThis material still contained minor impurities from the previous stage and required further purification
  7. dissolutionThe material was dissolved in dichloromethane
  8. custompurified by flash chromatography on silica gel (0% methanol/DCM to 10% methanol/DCM)

Quellen und Nachweise

ORD-Eintrag
ord-c444e4c9538440e4aec6263ef097a9f7
Quelldatensatz
uspto-grants-2015_10
Patentnummer
US09155727B2

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