1,2-Dimethoxyethane → 4-Fluoro-N-(2-{4-[2-(4-methoxymethyl-phenyl)-pyridin-3-yl]-piperazin-1-yl}-ethyl)-N-methyl-benzenesulfonamide hydrochloride

HRID 553517Notes

Reaction equation

HRID 553517 reaction equation
[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:27])[S:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].B(O)O.[CH3:37][O:38][CH2:39][CH2:40]OC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[ClH:1].[F:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:7]3[C:2]([C:6]4[CH:7]=[CH:2][C:40]([CH2:39][O:38][CH3:37])=[CH:4][CH:5]=4)=[N:3][CH:4]=[CH:5][CH:6]=3)[CH2:9][CH2:10]2)[CH3:27])(=[O:19])=[O:18])=[CH:21][CH:22]=1

Participants

6

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 11430Potassium CarbonateHCID 61668Boronic AcidHCID 86640209N-{2-[4-(2-Chloro-pyridin-3-yl)-piperazin-1-yl]-ethyl}-4-fluoro-N-methyl-benzenesulfonamide

Product 1

HCID 673678684-Fluoro-N-(2-{4-[2-(4-methoxymethyl-phenyl)-pyridin-3-yl]-piperazin-1-yl}-ethyl)-N-methyl-benzenesulfonamide hydrochloride

Reagents, catalysts & solvents 1

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalyst

Conditions

Temperature
80 °C

Procedure

Dissolve N-{2-[4-(2-chloro-pyridin-3-yl)-piperazin-1-yl]-ethyl}-4-fluoro-N-methyl-benzenesulfonamide (0.160 g, 0.387 mmol) in DME (5 mL, previously degassed with nitrogen). Add 4-(methoxymethyl)boronic acid (0.096 g, 0.581 mmol), 2N aqueous potassium carbonate (0.464 mL, 0.129 g, 0.930 mmol), and tetrakis(triphenylphosphine)-palladium (0.022 g, 0.022 mmol). Stir the reaction mixture at 80° C. for 18 hr. Increase the temperature to 95° C. and stir an additional 8 hr. Add fresh catalyst (0.015 g) and boronic acid (0.050 g). Stir 18 hr. at 95° C. Cool to room temperature and concentrate to remove DME. Dilute with ethyl acetate and brine. Extract the aqueous layer with ethyl acetate. Combine the organic phases, dry over sodium sulfate, filter, and concentrate. Purify by silica gel chromatography eluting with dichloromethane:methanol 98:2 to 90:10 to afford the free base of the title compound (0.075 g). Prepare the hydrochloride salt by dissolving the free base (0.075 g) in acetone (2 mL) and adding 1N HCl in diethyl ether (0.165 mL, 0.165 mmol). Stir for 20 min. at room temperature and then add diethyl ether to precipitate the salt. Wash the salt with diethyl ether and dry to afford the title compound (0.079 g, 38% yield). MS ES: m/z=499 [M+H]+.

Workup

  1. custompreviously degassed with nitrogen)
  2. temperatureIncrease the temperature to 95° C.
  3. stirringstir an additional 8 hr
  4. stirringStir 18 hr
  5. customat 95° C
  6. temperatureCool to room temperature
  7. concentrationconcentrate
  8. customto remove DME
  9. additionDilute with ethyl acetate and brine
  10. extractionExtract the aqueous layer with ethyl acetate
  11. dry with materialdry over sodium sulfate
  12. filtrationfilter
  13. concentrationconcentrate
  14. customPurify by silica gel chromatography
  15. washeluting with dichloromethane:methanol 98:2 to 90:10

Sources & evidence

ORD record
ord-9c9625af9c6a4db8b99bc2aae8dd9b77
Source dataset
uspto-grants-2011_11
Patent number
US08048884B2

Reaction notes

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