Ammonium Chloride → HCID 70944694, compound

HRID 1023335Notes

Reaction equation

HRID 1023335 reaction equation
Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[C:4](F)[CH:3]=1.[Li]CCCC.[NH4+].[Cl-].N1(C([O:38][C:39](C)(C)C)=O)CCNCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+].CCCC[N+](CCCC)(CCCC)CCCC.[F-:79]>CCOC(C)=O.O.C1COCC1.C(Cl)Cl.CN(C=O)C>[F:79][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:2]=1[CH2:39][OH:38])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1

Participants

13

Reactant 7

HCID 25517Ammonium ChlorideHCID 143452tert-Butyl piperazine-1-carboxylateHCID 516892Sodium BicarbonateHCID 2724141Tetrabutylammonium FluorideHCID 5049666Sodium triacetoxyborohydrideHCID 67328284HCID 67328284, compoundHCID 178418339Butyllithium

Product 1

HCID 70944694HCID 70944694, compound

Reagents, catalysts & solvents 5

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a THF (53 mL) solution of tert-butyl 4-(4-bromo-2-fluorobenzyl)piperazine-1-carboxylate (5.331 g) was added slowly n-BuLi (11.48 mL, 2.6 M in hexane) at −78° C., then the resultant mixture was stirred for 0.5 hour. To the mixture was added slowly DMF (1.681 mL) at −78° C., then the resultant mixture was stirred for 2 hours. The mixture was poured into saturated aqueous NH4Cl, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=95/5 to 67/33) to afford a colorless oil. To a CH2Cl2 (25 mL) solution of that colorless oil and tert-butyl 1-piperazinecarboxylate (3.42 g) were added NaBH(OAc)3 (5.310 g) at 0° C. The resultant mixture was stirred at room temperature over night. To the reaction mixture was added saturated aqueous NaHCO3, and extracted with CH2Cl2. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=67/33 to 33/67) to afford a colorless oil. To a THF (25 mL) solution of that colorless oil was added TBAF (25.05 mL, 1.0 M in THF) at 0° C. The resultant mixture was stirred at room temperature for 1 hour. After cooling to 0° C., the reaction mixture was diluted with AcOEt and water. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=67/33 to 1/4) to afford tert-butyl 4-[3-fluoro-4-(hydroxymethyl)benzyl]piperazine-1-carboxylate as a colorless oil (2.303 g).

Workup

  1. extractionextracted with AcOEt
  2. washThe organic layer was washed with water and saturated aqueous NaCl
  3. dry with materialdried over anhydrous Na2SO4
  4. customevaporated
  5. customThe residue was purified by silica gel column chromatography (n-hexane/AcOEt=95/5 to 67/33)
  6. customto afford a colorless oil
  7. extractionextracted with CH2Cl2
  8. washThe organic layer was washed with saturated aqueous NaCl
  9. dry with materialdried over anhydrous MgSO4
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified by silica gel column chromatography (n-hexane/AcOEt=67/33 to 33/67)
  12. customto afford a colorless oil
  13. washThe organic layer was washed with saturated aqueous NaCl
  14. dry with materialdried over anhydrous Na2SO4
  15. concentrationconcentrated under reduced pressure
  16. customThe residue was purified by silica gel column chromatography (n-hexane/AcOEt=67/33 to 1/4)

Sources & evidence

ORD record
ord-6ef082ad26f54c1d90599adcfc1fe302
Source dataset
uspto-grants-2014_05
Patent number
US08722663B2

Reaction notes

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