Triethylamine → (R)-Tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate

HRID 579569Notes

Reaction equation

HRID 579569 reaction equation
[C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:39][NH:40][O:41][CH3:42].C(N(CC)CC)C>C(Cl)Cl>[CH3:42][O:41][N:40]([CH3:39])[C:13]([C@@H:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:9]1)=[O:15]

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 1512491(3R)-1-[(tert-butoxy)carbonyl]pyrrolidine-3-carboxylic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride

Product 1

HCID 58507551(R)-Tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

In a 500 mL round-bottomed flask under a positive pressure of nitrogen, was added a methylene chloride (125 mL) solution of (R)—N-Boc-pyrroldine-3-carboxylic acid (7.00 g, 0.0325 mol). This solution was cooled to 0° C. using an ice/water bath and treated sequentially with, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.48 g, 0.0390 mol) and 1-hydroxybenzotriazole (5.29 g, 0.0391 mol) in single portions. Following the addition of the coupling agents, the reaction mixture became cloudy, but upon further stirring a clear solution was obtained. The reaction mixture was stirred at 0° C. for 20 min then charged with N,O-dimethylhydroxylamine hydrochloride (4.78 g, 0.0490 mol) and triethylamine (13.5 mL, 0.0968 mol). The cooling bath was removed and the reaction mixture was allowed to warm to room temperature with stirring over a period of 1 h. The resulting solution was diluted with dichloromethane (600 mL) and 1 N HCl (1000 mL), mixed thoroughly and separated. The organic layer was washed with saturated aqueous sodium bicarbonate (300 mL) and saturated aqueous sodium chloride (300 mL), then dried over Na2SO4, filtered and concentrated to give tert-butyl (3R)-3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate as a colorless oil (7.00 g; 83%). 1H NMR (400 MHz, CDCl3) δ 3.73 (s, 3H), 3.60-3.37 (m, 4H), 3.21 (s, 3H), 2.35-2.09 (m, 3H) 1.47 (s, 9H); ESI MS found for C12H22N2O4 m/z [159.1 (M+1-Boc)]

Workup

  1. additionthe addition of the coupling agents
  2. customwas obtained
  3. stirringThe reaction mixture was stirred at 0° C. for 20 min
  4. customThe cooling bath was removed
  5. temperatureto warm to room temperature
  6. stirringwith stirring over a period of 1 h
  7. additionThe resulting solution was diluted with dichloromethane (600 mL) and 1 N HCl (1000 mL)
  8. additionmixed thoroughly
  9. customseparated
  10. washThe organic layer was washed with saturated aqueous sodium bicarbonate (300 mL) and saturated aqueous sodium chloride (300 mL)
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-a06a47f5cafb46cebd71cbedd8db80b4
Source dataset
uspto-grants-2015_05
Patent number
US09040703B2

Reaction notes

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