Acetic Acid → 4-[2-(4-Bromo-2-methyl-phenylamino)-ethyl]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

HRID 1911074Notes

Reaction equation

HRID 1911074 reaction equation
[CH3:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([O:12][C:13]([C:15]1([CH2:28][CH:29]=O)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])[CH3:11].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].NC1C=CC=CC=1>ClCCCl.C(Cl)Cl.CO>[CH2:10]([O:12][C:13]([C:15]1([CH2:28][CH2:29][NH:4][C:3]2[CH:5]=[CH:6][C:7]([Br:9])=[CH:8][C:2]=2[CH3:1])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])[CH3:11]

Participants

9

Reactant 5

HCID 176Acetic AcidHCID 6115Aniline2×HCID 114234-Bromo-2-methylanilineHCID 5049666Sodium triacetoxyborohydrideHCID 584784234-(2-Oxoethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

Product 1

HCID 674216984-[2-(4-Bromo-2-methyl-phenylamino)-ethyl]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl esterYield 41%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolvent2×HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Procedure

2-Methyl-4-bromo-aniline (0.637 g, 3.427 mmol) was dissolved in DCE (15 mL); to this solution was transferred a solution of 4-(2-oxo-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.03 g, 3.425 mmol) in DCE (35 mL). The flask was submerged in a water bath at rt. To this clear solution was then added acetic acid (0.647 g, 10.8 mmol, 3.1 equiv), followed by addition of powder NaBH(OAc)3 (2.18 g, 10.3 mmol, 3 equiv.) under N2 at r.t. The yellowish milky suspension was stirred at r.t. overnight. LC/MS showed m/z 469/471 at t=4.930 min. along with small amount of aniline sm at 2.103 (186/188). TLC (5% of MeOH in DCM) showed no SM. of aldehyde, but aniline. The reaction was diluted with DCM (20 mL), cooled to ice-water bath, and quenched with 10 mL of 1N NH4OH. The two layers were separated, and the aqueous layer was extracted with DCM (15 mL×3). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (10 mL), dried (anhydrous potassium carbonate), filtered, and concentrated. The product was purified on a 40 g-silica gel column eluted with 0-2% of MeOH in DCM to get 0.65 g (41%) of the title compound as an oil.

Workup

  1. customThe flask was submerged in a water bath at rt
  2. customat t=4.930 min.
  3. temperaturecooled to ice-water bath
  4. customquenched with 10 mL of 1N NH4OH
  5. customThe two layers were separated
  6. extractionthe aqueous layer was extracted with DCM (15 mL×3)
  7. washThe combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (10 mL)
  8. dry with materialdried (anhydrous potassium carbonate)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe product was purified on a 40 g-silica gel column
  12. washeluted with 0-2% of MeOH in DCM

Sources & evidence

ORD record
ord-6af146f7f3cd4bc0b4e44627bf65070c
Source dataset
uspto-grants-2013_12
Patent number
US08604046B2

Reaction notes

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