Propionic Acid → Benzyl (2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxylate oxalate

HRID 925519Notes

Reaction equation

HRID 925519 reaction equation
C(O)(=O)CC.[BH4-].[Na+].[CH2:8]([O:15][C:16]([C@@H:18]1[CH2:23][CH2:22][C:21](=[N:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20][N:19]1CC1C=CC=CC=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.S(=O)(=O)(O)O.O.O.[C:47]([OH:52])(=[O:51])[C:48]([OH:50])=[O:49]>C(OCC)(=O)C.CO>[C:47]([OH:52])(=[O:51])[C:48]([OH:50])=[O:49].[CH2:26]([O:25][NH:24][C@H:21]1[CH2:20][NH:19][C@H:18]([C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:17])[CH2:23][CH2:22]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1

Participants

8

Reactant 5

HCID 1032Propionic AcidHCID 1118Sulfuric AcidHCID 61373Oxalic acid dihydrateHCID 4311764Sodium borohydrideHCID 86675003benzyl (2S)-5-[(benzyloxy)imino]piperidine-2-carboxylic acid benzyl ester

Product 1

HCID 70673933Benzyl (2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxylate oxalate

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
45 °C

Procedure

Propanoic acid (140.6 ml, 1878.6 mmol, 6 eq) was added to a suspension of sodium borohydride (23.2 g, 626.2 mmol, 2 eq) in ethyl acetate (600 ml) and held until the reaction was deemed to be complete. The resulting solution was added to a solution of benzyl (2S)-5-[(benzyloxy)imino]piperidine-2-carboxylic acid benzyl ester in ethyl acetate (600 ml total volume) and sulphuric acid (83.4 ml, 1565 mmol, 5 eq) at −20° C. and held until reaction was deemed to be complete. The reaction was quenched by the addition of water (1000 ml), then neutralized with aqueous ammonia solution. The organic layer was washed with water and concentrated in vacuo to 400 ml. The solution was warmed to 45° C. and held at this temperature. Methanol (200 ml) at 40° C. was added, followed by a freshly prepared solution of oxalic acid dihydrate (39.5 g, 313.1 mmol) in methanol (100 ml). The mixture was cooled and the product was isolated by filtration. The solid was washed with an ethyl acetate/methanol mixture, then with ethyl acetate. The solid was dried to give benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) as a single isomer (79.4 g, 185 mmol, 59%).

Workup

  1. customheld until reaction
  2. customThe reaction was quenched by the addition of water (1000 ml)
  3. washThe organic layer was washed with water
  4. concentrationconcentrated in vacuo to 400 ml
  5. additionMethanol (200 ml) at 40° C. was added
  6. temperatureThe mixture was cooled
  7. customthe product was isolated by filtration
  8. washThe solid was washed with an ethyl acetate/methanol mixture
  9. customThe solid was dried

Sources & evidence

ORD record
ord-725219fc251b4577a4562479ae7246b4
Source dataset
uspto-grants-2016_03
Patent number
US09284314B2

Reaction notes

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