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

HRID 1749045Notes

Reaction equation

HRID 1749045 reaction equation
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

Participants

4

Reactant 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

Product 1

HCID 76685059Azd-8835Yield 85%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
60 °C

Procedure

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.

Workup

  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)

Sources & evidence

ORD record
ord-c444e4c9538440e4aec6263ef097a9f7
Source dataset
uspto-grants-2015_10
Patent number
US09155727B2

Reaction notes

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