Sodium Bicarbonate → tert-butyl methyl 2-{(S)-amino[3-(benzyloxy)phenyl]methyl}propanedioate

HRID 526324Notes

Reaction equation

HRID 526324 reaction equation
[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:15]([NH:28]C(OC(C)(C)C)=O)[CH:16]([C:24]([O:26][CH3:27])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+]>C(O)=O>[NH2:28][C@H:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH:16]([C:24]([O:26][CH3:27])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]

Participants

4

Reactant 2

HCID 516892Sodium BicarbonateHCID 117653877tert-butyl methyl 2-{(1S)-[3-(benzyloxy)phenyl][(tert-butoxycarbonyl)amino]methyl}propanedioate

Product 1

HCID 71259832tert-butyl methyl 2-{(S)-amino[3-(benzyloxy)phenyl]methyl}propanedioateYield 81.6%

Reagents, catalysts & solvents 1

HCID 284Formic AcidSolvent

Procedure

To tert-butyl methyl 2-{(1S)-[3-(benzyloxy)phenyl][(tert-butoxycarbonyl)amino]methyl}propanedioate (600 mg, 1.24 mmol) was added 0° C. cold formic acid (13.8 mL) and the solution was stored at 5° C. for 20 hours. Ice was added and pH was adjusted to 8 by addition of aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with ethyl acetate. The combined extracts were washed with aqueous sodium hydrogen carbonate solution and brine and dried over sodium sulfate. Concentration under reduced pressure yields 390 mg of raw tert-butyl methyl 2-{(1S)-amino[3-(benzyloxy)phenyl]methyl}propanedioate. (3R)-1-{3-[1-(Tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidine-3-carboxylic acid (447 mg, 1.21 mmol) were suspended in N,N-dimethylformamide (14 mL) and cooled to 0° C. HATU (646 mg, 1.7 mmol), a solution of the raw tert-butyl methyl 2-{(1S)-amino[3-(benzyloxy)phenyl]methyl}propanedioate (780 mg, 1.21 mmol) in N,N-dimethylformamide (14 mL) and N-ethyl-diisopropylamine (350 μL, 3.64 mmol) were added. The mixture was stirred at 0° C. for 2 hours. Ice water and saturated ammonium chloride solution was added, the mixture extracted with ethyl acetate and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on an amino phase column (Separtis® Flash-NH2, ethyl acetate in hexane 0 to 100%) to yield 700 mg of tert-butyl methyl-[(S)-[3-(benzyloxy)phenyl]({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)methyl]propanedioate.

Workup

  1. additionIce was added
  2. extractionThe aqueous phase was extracted with ethyl acetate
  3. washThe combined extracts were washed with aqueous sodium hydrogen carbonate solution and brine
  4. dry with materialdried over sodium sulfate
  5. concentrationConcentration under reduced pressure

Sources & evidence

ORD record
ord-73f23ae731524269b83f8ba44eca48d0
Source dataset
uspto-grants-2016_05
Patent number
US09345793B2

Reaction notes

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