Hydrochloric Acid → 4-Fluoro-N-[(3R,4S)-3-hydroxy-6-piperazin-1-yl-chroman-4-yl]benzamide hydrochloride

HRID 1516330Notes

Reaction equation

HRID 1516330 reaction equation
C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.BrC1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][C@H:19]([OH:25])[C@H:18]2[NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+].P(=O)(O)(O)O.[ClH:47]>CS(C)=O.CO.O1CCOCC1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(OCC)(=O)C>[ClH:47].[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]([NH:26][C@H:18]2[C:17]3[C:22](=[CH:23][CH:24]=[C:6]([N:8]4[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]4)[CH:16]=3)[O:21][CH2:20][C@@H:19]2[OH:25])=[O:35])=[CH:33][CH:32]=1

Participants

12

Reactant 5

HCID 313Hydrochloric AcidHCID 1004Phosphoric AcidHCID 143452tert-Butyl piperazine-1-carboxylateHCID 23676156Sodium t-butoxideHCID 67281102N-[(3R,4S)-6-Bromo-3-hydroxy-chroman-4-yl]-4-fluoro-benzamide

Product 1

HCID 672807314-Fluoro-N-[(3R,4S)-3-hydroxy-6-piperazin-1-yl-chroman-4-yl]benzamide hydrochlorideYield 73%

Reagents, catalysts & solvents 6

HCID 61538Palladium, di-mu-chlorobis(eta3-2-propenyl)di-CatalystHCID 2734635Tri-tert-butylphosphine tetrafluoroborateCatalystHCID 679Dimethyl SulfoxideSolventHCID 887MethanolSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

Degas (bubble nitrogen through the mixture) a suspension of tri-t-butylphosphonium tetrafluoroborate (16.0 g, 54.6 mmol) and allylpalladium(II) chloride dimer (5.07 g, 27.3 mmol) in DMSO (1.40 L) with stirring at room temperature. Add N-tert-butoxycarbonylpiperazine (315 g, 1.64 mol, 97% pure) and N-[(3R,4S)-6-bromo-3-hydroxy-chroman-4-yl]-4-fluoro-benzamide (200.0 g, 546 mmol). Stir the mixture for 15 min under nitrogen and then heat at 80° C. Add sodium tert-butoxide (179 g, 1.80 mol) and heat at 93-98° C. for 45 min. Pour the mixture over a solution of 1 M phosphoric acid (2.73 L, 2.73 mol, adjusted to pH=2.3 with 50% sodium hydroxide) and ethyl acetate (800 mL) and stir for 10 min. Separate the layers and extract the aqueous layer with ethyl acetate (3×300 mL). Wash the combined organic layer with semi-saturated brine (2×500 mL). Treat the organic layer with activated carbon (20 g) and silica gel (200 g) and stir for 30 min. Filter through a pad of diatomaceous earth and concentrate under reduced pressure to obtain a dark oil. Dissolve the oil in methanol (800 mL), add 4 M hydrogen chloride in dioxane (410 mL), and stir the solution at 40° C. for 1 hr. Evaporate the solvent in vacuo, suspend the residue in acetonitrile (1.6 L) and stir at room temperature for 1 hr. Collect the solid by filtration under nitrogen to avoid hydration of the salt. Wash the filtrate with acetonitrile (500 mL) and methyl tert-butyl ether (1 L), and dry under vacuum to obtain the title compound (262 g, 73%). LC-ES/MS m/z 372 [M+H]+.

Workup

  1. customDegas (
  2. custombubble nitrogen through the mixture)
  3. stirringStir the mixture for 15 min under nitrogen
  4. temperatureheat at 80° C
  5. stirringstir for 10 min
  6. customSeparate the layers
  7. extractionextract the aqueous layer with ethyl acetate (3×300 mL)
  8. washWash the combined organic layer with semi-saturated brine (2×500 mL)
  9. additionTreat the organic layer with activated carbon (20 g) and silica gel (200 g)
  10. stirringstir for 30 min
  11. filtrationFilter through a pad of diatomaceous earth
  12. concentrationconcentrate under reduced pressure
  13. customto obtain a dark oil
  14. stirringstir the solution at 40° C. for 1 hr
  15. customEvaporate the solvent in vacuo
  16. stirringstir at room temperature for 1 hr
  17. customCollect the solid
  18. filtrationby filtration under nitrogen
  19. washWash the filtrate with acetonitrile (500 mL) and methyl tert-butyl ether (1 L)
  20. customdry under vacuum

Sources & evidence

ORD record
ord-639b458d546643e78f29e546280cbf32
Source dataset
uspto-grants-2012_07
Patent number
US08227468B2

Reaction notes

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