Hydrochloric Acid → 4-(((Benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid

HRID 1062696Notes

Reaction equation

HRID 1062696 reaction equation
[NH2:1][C:2]1([C:15]([OH:17])=[O:16])[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.Cl.[CH2:19]([O:26][C:27](ON1C(=O)CCC1=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[OH-].[Na+].COCCOC>[CH2:19]([O:26][C:27]([NH:1][C:2]1([C:15]([OH:17])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 83172Benzyl succinimido carbonate2×HCID 6937974-Amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid

Product 1

HCID 27566404-(((Benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acidYield 82.5%

Reagents, catalysts & solvents 2

HCID 80711,2-DimethoxyethaneSolvent2×HCID 14798Sodium HydroxideSolvent2×

Procedure

4-Amino-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (18.0 g) was dissolved in 0.03M aqueous sodium hydroxide (750 mL), and 1,2-dimethoxyethane (100 mL). The pH was adjusted to 9.5 with dilute hydrochloric acid, and the suspension was added to an ice-cold solution of N-(benzyloxycarbonyloxy)succinimide (28.8 g) in 1,2-dimethoxyethane (100 mL). The pH was kept at 9.5 by addition of aq. sodium hydroxide, and the mixture was stirred at room temperature. More N-(benzyloxycarbonyloxy)succinimide (3 g) was added after 7 h, then stirring continued overnight. After evaporation to remove the 1,2-dimethoxyethane, the aqueus residue was extracted with ether then acidified to pH 4 and extracted with ethyl acetate. This extract was washed with dilute hydrochloric acid, water and brine, dried and evaporated. Trituration of the oily residue gave 4-benzyloxycarbonylamino-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (23 g). This acid (9.62 g) was esterified by treatment with alkyl bromide (2.2 mL), potassium carbonate (7.04 g) and potassium iodide (catalytic) in acetone (100 mL) under reflux for 20 h. Evaporation, partitioning of the residue between dichloromethane and water and evaporation of the organic phase gave the alkyl ester (10.2 g). This was then treated with trifluoroacetic acid in dichloromethane (1.5 h, room temp.) to give, after basification of the triflate salt and extraction with dichloromethane/methanol, the piperidine free base (6.58 g).

Workup

  1. stirringstirring continued overnight
  2. customAfter evaporation
  3. customto remove the 1,2-dimethoxyethane
  4. extractionthe aqueus residue was extracted with ether
  5. extractionextracted with ethyl acetate
  6. washThis extract was washed with dilute hydrochloric acid, water and brine
  7. customdried
  8. customevaporated

Sources & evidence

ORD record
ord-7426dc4dc8af48169f350ae522d413fd
Source dataset
uspto-grants-2005_11
Patent number
US06962917B2

Reaction notes

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