Acetic Acid → 3-Benzylamino-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

HRID 2174963Notes

Reaction equation

HRID 2174963 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[CH2:7][CH2:8][N:9]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:10][CH:11]1[NH:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:5])[CH3:2]

Participants

5

Reactant 3

HCID 176Acetic Acid2×HCID 5049666Sodium triacetoxyborohydrideHCID 670868445-Benzylamino-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

Product 1

HCID 670866753-Benzylamino-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl esterYield 45%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
0 °C

Procedure

To a mixture of 5-benzylamino-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (10.2 g, 28.9 mmol) in toluene (110 mL) was added NaBH(OAc)3 (30 g, 141.5 mmol) and freshly activated 4A0 powder molecular sieve (24 g) with vigorous stirring. The reaction mixture was cooled to 0° C., then acetic acid (32.5 mL, 566 mmol) was added drop-wise in such a way that reaction mixture temperature remained below 5° C. After the addition of acetic acid was complete, the mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was filtered and concentrated to remove most of the acetic acid. The crude residue was dissolved in ethyl acetate (125 mL) and saturated aqueous NaHCO3 solution (100 mL) was slowly added to neutralize the residual acid under stirring. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure (11.25 g, crude). The residue was purified (FCC, SiO2, ethyl acetate/hexanes, gradient 0-40%) to yield the title compound (4.59 g, 45%). MS (ESI) mass calcd. for C20H30N2O2, 362.46; m/z found, 363.3 [M+H]+. 1H NMR (DMSO-d6): 7.53-6.76 (m, 5H), 4.10-3.96 (m, 3H), 3.89-3.87 (m, 1H), 3.66 3.54 (m, 1H), 3.05-2.60 (m, 4H), 1.80-1.65 (m, 2H), 1.60-1.45 (m, 1H), 1.40 (s, 9H), 1.14 (t, J=7.1, 3H).

Workup

  1. customthat reaction mixture temperature
  2. customremained below 5° C
  3. temperatureto warm to ambient temperature
  4. filtrationThe reaction mixture was filtered
  5. concentrationconcentrated
  6. customto remove most of the acetic acid
  7. dissolutionThe crude residue was dissolved in ethyl acetate (125 mL)
  8. additionsaturated aqueous NaHCO3 solution (100 mL) was slowly added
  9. stirringunder stirring
  10. customThe layers were separated
  11. extractionthe aqueous layer was extracted with ethyl acetate (2×100 mL)
  12. dry with materialThe combined organics were dried over Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated under reduced pressure (11.25 g, crude)
  15. customThe residue was purified (FCC, SiO2, ethyl acetate/hexanes, gradient 0-40%)

Sources & evidence

ORD record
ord-753e94a31eef43cebaf701d6a4096227
Source dataset
uspto-grants-2015_06
Patent number
US09062044B2

Reaction notes

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