Water → (3R)-[1,4']Bipiperidinyl-3,1'-dicarboxylic acid 1'-tert-butyl ester 3-ethyl ester

HRID 489886

Reaction equation

HRID 489886 reaction equation
O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH:15]1[CH2:25][CH2:24][CH2:23][C@@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16]1.C([BH3-])#N.[Na+].O>C(O)C.ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:21]([O:20][C:18]([C@@H:17]1[CH2:23][CH2:24][CH2:25][N:15]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:16]1)=[O:19])[CH3:22]

Participants

8

Reactant 4

HCID 962WaterHCID 185582ethyl (3R)-piperidine-3-carboxylateHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 5003444Sodium cyanoborohydride

Product 1

HCID 69694282(3R)-[1,4']Bipiperidinyl-3,1'-dicarboxylic acid 1'-tert-butyl ester 3-ethyl ester

Reagents, catalysts & solvents 3

HCID 11026Titanium isopropoxideCatalystHCID 702EthanolSolvent2×HCID 6344DichloromethaneSolvent

Procedure

To a mixture of tert-butyl 4-oxo-1-piperidinecarboxylate (12.40 g, 62.2 mmol) and (R)-ethyl nipecotate (1.05 eq, 65.3 mmol, 10.27 g) was added titanium tetraisopropoxide (1.25 eq, 23 mL) under nitrogen. A viscous, clear golden yellow solution was formed. After 1 h a solution of sodium cyanoborohydride (0.7 eq, 2.74 g) in anhydrous ethanol (65 mL) was added. An exothermic reaction took place and some gas evolution occurred. The solution was stirred overnight at ambient temperature then water (13 mL) was added slowly, along with additional ethanol as necessary to permit stirring to continue. The mixture was stirred for 30 minutes then filtered through a large pad of Celite®, washing through with ethanol. The filtrate was evaporated to dryness, toluene added and again evaporated to dryness. The residue was purified by chromatography on 150 g silica gel eluting with 5% methanol-dichloromethane. Fractions containing product were combined and evaporated to dryness to give an oil which became semi-solid on standing. The product was dissolved in dichloromethane, washed with dilute sodium hydroxide solution to remove titanium-containing impurities, dried over anhydrous sodium sulfate and evaporated to yield the title compound as a colorless oil, 21.14 g (containing a small amount of the isopropyl ester from transesterification).

Workup

  1. customA viscous, clear golden yellow solution was formed
  2. customAn exothermic reaction
  3. stirringto permit stirring
  4. stirringThe mixture was stirred for 30 minutes
  5. filtrationthen filtered through a large pad of Celite®
  6. washwashing through with ethanol
  7. customThe filtrate was evaporated to dryness, toluene
  8. additionadded
  9. customagain evaporated to dryness
  10. customThe residue was purified by chromatography on 150 g silica gel eluting with 5% methanol-dichloromethane
  11. additionFractions containing product
  12. customevaporated to dryness
  13. customto give an oil which
  14. washwashed with dilute sodium hydroxide solution
  15. customto remove titanium-
  16. additioncontaining impurities
  17. dry with materialdried over anhydrous sodium sulfate
  18. customevaporated

Sources & evidence

ORD record
ord-48a9183595e748deba4a0bba93a9af30
Source dataset
uspto-grants-2005_12
Patent number
US06979741B2

Linked notes

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