Acetic Acid → (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester

HRID 1794152Notes

Reaction equation

HRID 1794152 reaction equation
Br[C:2]1[C:3]([F:28])=[C:4]([C:24]([F:27])=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:22][CH3:23])=[O:8].C([Li])CCC.C(O)(=[O:36])C.OO>O1CCCC1>[F:28][C:3]1[C:2]([OH:36])=[CH:26][CH:25]=[C:24]([F:27])[C:4]=1[CH2:5][O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:22][CH3:23])=[O:8]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 784Hydrogen PeroxideHCID 69141503(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(3-bromo-2,6-difluoro-benzyl) esterHCID 178418339Butyllithium

Product 1

HCID 69142665(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(2,6-difluoro-3-hydroxy-benzyl)esterYield 28%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(3-bromo-2,6-difluoro-benzyl) ester (3.9 g, 8 mM) was dissolved in tetrahydrofuran (120 mL), trisopropylborate (3.1 g, 17 mM) was added and the mixture was cooled to −78° C. At this low temperature n-butyllithium (7.8 mL, 1.6N) was added drop by drop with stirring. The mixture was stirred for 45 min at −78° C., for another 45 min at −50° C. and for 15 min at 0° C. Acetic acid (4.4 mL, 50%) was added slowly with stirring (0–5° C.), followed by hydrogen peroxide (1.3 mL, 35%). Stirring continued with cooling for another 45 min and for 1 h at room temperature. The mixture was partitioned between water and diethylether, organic phases were pooled, washed with water, sodium thiosulfate solution (5%), brine and dried with Na2SO4 to yield after evaporation a light yellow oil (4.1 g). This residue was purified by column chromatography (silica gel; n-hexane/ethylacetate 1:1) to yield 0.93 g (28%) of the product as a colorless oil. MS (ISP): 418.2 (M+NH4)+.

Workup

  1. additiontrisopropylborate (3.1 g, 17 mM) was added
  2. stirringThe mixture was stirred for 45 min at −78° C., for another 45 min at −50° C. and for 15 min at 0° C
  3. stirringwith stirring (0–5° C.)
  4. stirringStirring
  5. temperaturewith cooling for another 45 min and for 1 h at room temperature
  6. customThe mixture was partitioned between water and diethylether, organic phases
  7. washwashed with water, sodium thiosulfate solution (5%), brine
  8. dry with materialdried with Na2SO4
  9. customto yield
  10. customafter evaporation a light yellow oil (4.1 g)
  11. customThis residue was purified by column chromatography (silica gel; n-hexane/ethylacetate 1:1)

Sources & evidence

ORD record
ord-58266b286d9b4a119b2163dbe8db1643
Source dataset
uspto-grants-2006_04
Patent number
US07022707B2

Reaction notes

Loading…