4-Methylmorpholine → Benzyl 2-{3-[methoxy(methyl)carbamoyl]cyclobutylidene}acetate

HRID 2040657Notes

Reaction equation

HRID 2040657 reaction equation
[CH2:1]([O:8][C:9](=[O:18])[CH:10]=[C:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:35][O:36][NH:37][CH3:38]>C(Cl)Cl>[CH3:35][O:36][N:37]([CH3:38])[C:15]([CH:13]1[CH2:12][C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:18])[CH2:14]1)=[O:17]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 677753443-[2-(Benzyloxy)-2-oxoethylidene]cyclobutane-1-carboxylic acid

Product 1

HCID 86666117Benzyl 2-{3-[methoxy(methyl)carbamoyl]cyclobutylidene}acetateYield 65.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To an ice cold solution of 3-[2-(benzyloxy)-2-oxoethylidene]cyclobutane-1-carboxylic acid (2.0 g, 8.12 mmol), N-Methyl-morpholine (2.70 ml, 24.36 mmol) in DCM (50 ml) was added isobutyl chloroformate (1.70 ml, 12.99 mmol) drop-wise over 5 min. After an additional 5 min, methoxy(methyl)amine hydrochloride (1.58 g, 16.24 mmol) was added and the mixture was stirred overnight whilst allowing to warm to RT. The reaction mixture was then diluted with DCM (30 ml), washed with 0.1N HCl (50 ml) then sat. NaHCO3 (50 ml), dried over Na2SO4, filtered and evaporated. Purification by silica gel column chromatography, eluting with EtOAc:heptanes from 1:9 to 3:7 gave the desired product (1.54 g, 65%); MS (ESI+) for C16H19NO4 m/z 290.10 [M+H]+; HPLC purity 100% (ret. time, 1.86 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm 2.96 (1 H, ddd, J=16.98, 8.79, 1.81 Hz), 3.17-3.30 (4 H, m), 3.30-3.48 (2 H, m), 3.51-3.63 (1 H, m), 3.64-3.75 (3 H, m), 5.15 (2 H, s), 5.73 (1 H, quirt, J=2.25 Hz), 7.29-7.42 (5 H, m).

Workup

  1. washwashed with 0.1N HCl (50 ml)
  2. dry with materialsat. NaHCO3 (50 ml), dried over Na2SO4
  3. filtrationfiltered
  4. customevaporated
  5. customPurification by silica gel column chromatography
  6. washeluting with EtOAc

Sources & evidence

ORD record
ord-512d466544b043f393b7172c54f53121
Source dataset
uspto-grants-2013_11
Patent number
US08580762B2

Reaction notes

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