Cyclobutanone → Gsk-189254

HRID 222689Notes

Reaction equation

HRID 222689 reaction equation
[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4].[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.C(O)(=O)C>[CH:23]1([N:18]2[CH2:19][CH2:20][C:14]3[CH:13]=[C:12]([O:11][C:8]4[CH:9]=[CH:10][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:6][N:7]=4)[CH:22]=[CH:21][C:15]=3[CH2:16][CH2:17]2)[CH2:26][CH2:25][CH2:24]1

Participants

7

Reactant 4

HCID 14496CyclobutanoneHCID 14798Sodium HydroxideHCID 5049666Sodium triacetoxyborohydrideHCID 57440288N-Methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide

Product 1

HCID 9798547Gsk-189254

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of N-methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) (1.04 g, 3.5 mmol) in dichloromethane (12 ml) containing acetic acid (240 μL) at 0° C. was treated dropwise with cyclobutanone (400 μL, 5.3 mmol) and then stirred at room temperature for 1 hour. The mixture was then cooled to 0° C. and treated portionwise with sodium triacetoxyborohydride (1.11 g, 5.3 mmol) and stirred at room temperature for 16 hours. The solution was carefully basified with 2N sodium hydroxide, stirred for 30 minutes and then extracted with dichloromethane. The combined extracts were washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude material was purified by column chromatography eluting with dichloromethane then a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title compound (E121); MS (ES+) m/e 352 [M+H]+.

Workup

  1. temperatureThe mixture was then cooled to 0° C.
  2. stirringstirred at room temperature for 16 hours
  3. stirringstirred for 30 minutes
  4. extractionextracted with dichloromethane
  5. washThe combined extracts were washed with brine
  6. dry with materialdried over anhydrous sodium sulphate
  7. concentrationconcentrated in vacuo
  8. customThe crude material was purified by column chromatography
  9. washeluting with dichloromethane
  10. additiona mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90)

Sources & evidence

ORD record
ord-c3b85fb1f06443e186df0e65486358df
Source dataset
uspto-grants-2012_06
Patent number
US08207331B2

Reaction notes

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