Sodium Bicarbonate → (R)-2-[(3-chloro-benzyl)-(3-methoxycarbonyl-propyl)-carbamoyl]-2-methyl-azetidine-1-carboxylic acid tert-butyl ester

HRID 408623Notes

Reaction equation

HRID 408623 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@:9]1([CH3:15])[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC(C(N2CC[C@]2(C)C(O)=O)=O)=CC=1.ClC(N(C)C)=C(C)C.Cl.[CH3:42][O:43][C:44](=[O:57])[CH2:45][CH2:46][CH2:47][NH:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@@:9]1([C:12](=[O:14])[N:48]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=1)[CH2:47][CH2:46][CH2:45][C:44]([O:43][CH3:42])=[O:57])[CH3:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 5

HCID 516892Sodium BicarbonateHCID 6407921-Chloro-N,N-2-trimethylpropenylamineHCID 20599252(2R)-1-[(tert-Butoxy)carbonyl]-2-methylazetidine-2-carboxylic acidHCID 70557656(R)-1-(4-bromo-benzoyl)-2-methyl-azetidine-2-carboxylic acidHCID 70558726HCID 70558726, compound

Product 1

HCID 70556400(R)-2-[(3-chloro-benzyl)-(3-methoxycarbonyl-propyl)-carbamoyl]-2-methyl-azetidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
20 °C

Procedure

To a solution of (R)-2-methyl-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester, Intermediate 33 (13 g, 1 eq.) in 300 mL of dry DCM under nitrogen was added dropwise a solution of 1-chloro-N,N,2-trimethylpropenylamine (16 mL, 2 eq.) in 50 mL of DCM. The solution was stirred at 20° C. for 30 min, then cooled to −5° C. A solution of 4-(3-chloro-benzylamino)-butyric acid methyl ester hydrochloride, Intermediate 80 (18.5 g, 1.1 eq.) and TEA (25 mL, 3 eq.) in 200 mL of DCM was added slowly to the previous mixture. The reaction was stirred at 20° C. for 2.5 h. The mixture was added to 500 mL of a saturated aqueous solution of NaHCO3. The crude was extracted three times with DCM. The organic layers were combined, washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 90/10 to 50/50) to afford (R)-2-[(3-chloro-benzyl)-(3-methoxycarbonyl-propyl)-carbamoyl]-2-methyl-azetidine-1-carboxylic acid tert-butyl ester (27 g, yield=quantitative).

Workup

  1. temperaturecooled to −5° C
  2. stirringThe reaction was stirred at 20° C. for 2.5 h
  3. extractionThe crude was extracted three times with DCM
  4. washwashed with brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 90/10 to 50/50)

Sources & evidence

ORD record
ord-c6530e84fd33448c904fbb0c01b89704
Source dataset
uspto-grants-2014_06
Patent number
US08759334B2

Reaction notes

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