Acetic Acid → (4-Cyclobutyl-3,4-dihydro-2H-quinoxalin-1-yl)-[2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-methanone

HRID 1877410Notes

Reaction equation

HRID 1877410 reaction equation
[Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]([F:23])=[CH:7][N:6]=1.[C:29]1(=O)[CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:29]1([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]([C:11]([C:10]3[C:5]([O:4][C:3]4[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:2]=4[Cl:1])=[N:6][CH:7]=[C:8]([F:23])[CH:9]=3)=[O:12])[CH2:14][CH2:15]2)[CH2:32][CH2:31][CH2:30]1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 14496CyclobutanoneHCID 5003444Sodium cyanoborohydrideHCID 59294514[2-(2,5-Dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone

Product 1

HCID 59294475(4-Cyclobutyl-3,4-dihydro-2H-quinoxalin-1-yl)-[2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-methanoneYield 6%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of [2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (52.3 mg, 0.125 mmol, 1.0 equiv; Example 147) in methanol (0.5 mL) was added cyclobutanone (188 mg, 0.2 mL, 2.68 mmol, 21.4 equiv; [CAS RN 1191-95-3]), acetic acid (28 mg, 27 μL, 0.5 mmol, 4.0 equiv; [CAS RN 64-19-7]) and the reaction mixture stirred at rt. After 90 min, sodium cyanoborohydride (15.7 mg, 0.25 mmol, 2.0 equiv; [CAS RN 25895-60-7]) was added and stirring at rt continued for 18 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 3.3 mg (6%) of the title compound. MS (ISP): 474.1 [M+H]+.

Workup

  1. stirringstirring at rt
  2. waitcontinued for 18 h
  3. customRemoval of the solvent mixture
  4. customunder reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column
  5. customequipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps
  6. washa Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water

Sources & evidence

ORD record
ord-b0efe6333b304cd996b5aed1995e1dd4
Source dataset
uspto-grants-2012_11
Patent number
US08309734B2

Reaction notes

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