Potassium Carbonate → tert-Butyl 4-{3-[4-(hydroxymethyl)phenyl]pyrazin-2-yl}piperazine-1-carboxylate

HRID 220560Notes

Reaction equation

HRID 220560 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.F[B-](F)(F)F.C(P(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1.O.C(=O)(O)[O-].[Na+].CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:32]3[CH:33]=[CH:34][C:29]([CH2:28][OH:27])=[CH:30][CH:31]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

11

Reactant 5

HCID 11430Potassium CarbonateHCID 25517Ammonium ChlorideHCID 27347064-(Hydroxymethyl)benzeneboronic acidHCID 11150691Tert-butyl 4-(3-chloropyrazin-2-yl)piperazine-1-carboxylateHCID 71317416Tributyl phosphine tetrafluoroborate

Product 1

HCID 68594684tert-Butyl 4-{3-[4-(hydroxymethyl)phenyl]pyrazin-2-yl}piperazine-1-carboxylateYield 35.1%

Reagents, catalysts & solvents 5

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 516892Sodium BicarbonateSolvent

Procedure

Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (1.29 g, 4.35 mmol) in tetrahydrofuran (12 mL) and water (6 mL). Add potassium carbonate (1.32 g, 9.56 mmol) then 4-hydroxymethylbenzeneboronic acid (0.924 g, 6.08 mmol) and degas with nitrogen for 15 min. Add tri-n-butylphosphine tetrafluoroborate (50 mg, 0.174 mmol) and tris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.0869 mmol) and reflux for 20 hr. Cool to room temperature then dilute with saturated aq. sodium bicarbonate and extract 3 times with ethyl acetate. Dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 3:97 methanol (with 2 M ammonia): DCM), to give a yellow oil. Dissolve the oil in methanol and add ammonium chloride then sonicate the mixture for 10 min. Evaporate the solution to give 3′-(4-hydroxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester as a yellow semisolid (0.565 g, 35%). MS (ES): m/z=371 [M+H]+.

Workup

  1. extractionextract 3 times with ethyl acetate
  2. dry with materialDry (sodium sulfate)
  3. filtrationfilter
  4. concentrationconcentrate
  5. custompurify
  6. wash(silica gel chromatography, eluting with 3:97 methanol (with 2 M ammonia): DCM)
  7. customto give a yellow oil
  8. customthen sonicate the mixture for 10 min
  9. customEvaporate the solution

Sources & evidence

ORD record
ord-cd4d2fa3be704d628ea518a6cf64c67b
Source dataset
uspto-grants-2012_06
Patent number
US08202873B2

Reaction notes

Loading…