Acetamide, N-(trimethylsilyl)- → N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-beta-alanine methyl ester

HRID 1862525Notes

Reaction equation

HRID 1862525 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:34][O:35][C:36](=[O:51])[C@@H:37]([NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH2:38][NH2:39].C[Si](C)(C)NC(=O)C>ClCCl.CN(C)C=O>[CH3:34][O:35][C:36](=[O:51])[C@@H:37]([NH:40][C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[CH2:38][NH:39][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25]

Participants

7

Reactant 4

HCID 25989Acetamide, N-(trimethylsilyl)-HCID 65578Oxalyl chlorideHCID 13756825Methyl 2-(S)-[N-carbobenzyloxy]amino-3-aminopropionate, hydrochlorideHCID 54408184(R)-1-(3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidinecarboxylic acid

Product 1

HCID 11307948N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-beta-alanine methyl esterYield 54.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidine carboxylic acid (1.0 g) and N,N-dimethylformamide (210 μl) in dichloromethane (10 ml) was added dropwise oxalyl chloride (240 μl) at 4° C. under a nitrogen atmosphere. To an ice cooled solution of 2(S)-benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (940 mg) and N-(trimethylsilyl)-acetamide (2.85 g) in N,N-dimethylformamide (10 ml) was added dropwise the above solution with stirring under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature, and stirred for 2 hours, which was partitioned between a mixture of ethyl-acetate and n-hexane and water. The organic layer was separated, washed in turn with water, aqueous 5% NaHCO3 solution and brine, and dried over MgSO4. Evaporation of the solvent gave a residue, which was purified by silica-gel column chromatography eluting with n-hexane-ethyl acetate (from 1:6 to ethyl acetate only) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alanine methyl ester (0.89 g) as a foam, which is the same compound obtained in Preparation 15.

Workup

  1. stirringstirred for 2 hours
  2. customwhich was partitioned between a mixture of ethyl-acetate and n-hexane and water
  3. customThe organic layer was separated
  4. washwashed in turn with water, aqueous 5% NaHCO3 solution and brine
  5. dry with materialdried over MgSO4
  6. customEvaporation of the solvent
  7. customgave a residue, which
  8. customwas purified by silica-gel column chromatography
  9. washeluting with n-hexane-ethyl acetate (from 1:6 to ethyl acetate only)

Sources & evidence

ORD record
ord-963d4a8024e741d496ccb672bc39db7f
Source dataset
uspto-grants-2003_03
Patent number
US06538007B1

Reaction notes

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