Cesium carbonate → 4-{1-[1-(4-acetylphenyl)-ethyl]-piperidin-4-ylamino}-6-chlorochromen-2-One

HRID 897223

Reaction equation

HRID 897223 reaction equation
Br[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)[CH3:3].[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][C:19](=[O:24])[CH:18]=[C:17]2[NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:2]([N:29]2[CH2:30][CH2:31][CH:26]([NH:25][C:17]3[C:16]4[C:21](=[CH:22][CH:23]=[C:14]([Cl:13])[CH:15]=4)[O:20][C:19](=[O:24])[CH:18]=3)[CH2:27][CH2:28]2)[CH3:3])=[CH:5][CH:6]=1)(=[O:12])[CH3:11]

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 116376956-Chloro-4-(piperidin-4-ylamino)chromen-2-oneHCID 141568041-[4-(1-Bromoethyl)-phenyl]-ethanone

Product 1

HCID 208177264-{1-[1-(4-acetylphenyl)-ethyl]-piperidin-4-ylamino}-6-chlorochromen-2-OneYield 4.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 1-[4-(1-bromoethyl)-phenyl]-ethanone (0.35 g, 1.54 mmol) and 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one (0.42 g, 1.50 mmol) in dry THF (15 mL) was added Cs2CO3 (2.44 g, 7.50 mmol). The reaction mixture was allowed to stir at room temperature for 12 h, after which time THF was removed in vacuo and the white residue was partitioned between H2O (250 mL) and ethyl acetate (250 mL). After removal of the organic layer, the aqueous layer was washed with an addition portion of ethyl acetate (250 mL), and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to provide a yellow oil. The crude product was purified by flash chromatography through a silica gel column with dichloromethane and methanol (95: 5 v/v). The resulting yellow residue was then treated with 4 M HCl in dioxane, solvent was removed in vacuo to provide a yellow solid. Crystallization from dichloromethane provided the HCl salt of the desired compound (0.027 g, 4%) as a white solid MS (ESI(+)Q1MS) m/z 425 (M+H)+; 1H NMR (300 MHz, DMSO) δ ppm 10.84-10.97 (m, 1H), 8.32-8.38 (m, 1H), 8.00-8.08 (m, 2H), 7.75-7.84 (m, 2H), 7.58-7.63 (m, 1H), 7.48-7.54 (m, 1H), 7.30-7.35 (m, 1H), 5.39 (s, 1H), 4.51-4.63 (m, 1H), 3.60-3.77 (m, 2H), 3.24-3.40 (m, 1H), 2.73-2.95 (m, 2H), 2.59 (s, 3H), 1.95-2.14 (m, 4H), 1.72 (d, 3H). The pure racemic mixture was separated into enantiomers by prep HPLC chiral chromatography using a CHIRALPAK AD column: 7.5/7.5/85 MeOH/EtOH/Hexanes at 0.8 ml/min. Enantiomers had retention times of 4.2 and 6.4 minutes.

Workup

  1. customafter which time THF was removed in vacuo
  2. customthe white residue was partitioned between H2O (250 mL) and ethyl acetate (250 mL)
  3. customAfter removal of the organic layer
  4. washthe aqueous layer was washed with an addition portion of ethyl acetate (250 mL)
  5. dry with materialthe combined organic layers were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto provide a yellow oil
  9. customThe crude product was purified by flash chromatography through a silica gel column with dichloromethane and methanol (95: 5 v/v)
  10. additionThe resulting yellow residue was then treated with 4 M HCl in dioxane, solvent
  11. customwas removed in vacuo
  12. customto provide a yellow solid
  13. customCrystallization from dichloromethane

Sources & evidence

ORD record
ord-a7ce7b2293ea43f9bf69ed04b16ff979
Source dataset
uspto-grants-2005_07
Patent number
US06921821B2

Linked notes

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