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

HRID 1862524Notes

Reaction equation

HRID 1862524 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].ClC(OCC(C)C)=O.CN1CCOCC1.Cl.[CH3:43][O:44][C:45](=[O:60])[C@@H:46]([NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:47][NH2:48].C[Si](C)(C)NC(=O)C>O1CCCC1>[CH3:43][O:44][C:45](=[O:60])[C@@H:46]([NH:49][C:50]([O:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:51])[CH2:47][NH:48][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 5

HCID 79724-MethylmorpholineHCID 25989Acetamide, N-(trimethylsilyl)-HCID 62365Isobutyl chloroformateHCID 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 83.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred solution of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidine carboxylic acid (1.0 g) in tetrahydrofuran (20 ml) was added dropwise isobutyl chloroformate (356 μl) and 4-methylmorpholine (300 μl) at −15° C. under a nitrogen atmosphere. To an ice cooled solution of 2(S)-benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (783 mg) and N-(trimethylsilyl)acetamide (1.78 g) in tetrahydrofuran (30 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 ethyl acetate and water. The organic layer was separated, washed in turn with water, aqueous 5% KHSO4, aqueous 5% NaHCO3 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 (1.36 g) as a foam, which is the same compound obtained in Preparation 7.

Workup

  1. stirringstirred for 2 hours
  2. customwhich was partitioned between ethyl acetate and water
  3. customThe organic layer was separated
  4. washwashed in turn with water, aqueous 5% KHSO4, aqueous 5% NaHCO3 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-a71df9fe8b7f4979a1e34651794e1f91
Source dataset
uspto-grants-2003_03
Patent number
US06538007B1

Reaction notes

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