4-Methylmorpholine → (R)-tert-butyl 2-((N-methoxy-N-methylcarbamoyl)methyl)-4,4-difluoropyrrolidine-1-carboxylate

HRID 1754402Notes

Reaction equation

HRID 1754402 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[CH2:15][C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.NO.CCN=C=NCCC[N:30]([CH3:32])C.Cl.CN1CC[O:38][CH2:37]C1>C(Cl)Cl>[CH3:37][O:38][N:30]([CH3:32])[C:16]([CH2:15][C@@H:9]1[CH2:10][C:11]([F:13])([F:14])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:18]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 443297Hydroxyamine hydrochlorideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 867044572-[(2R)-1-Tert-butoxycarbonyl-4,4-difluoro-pyrrolidin-2-YL]acetic acid

Product 1

HCID 86704456(R)-tert-butyl 2-((N-methoxy-N-methylcarbamoyl)methyl)-4,4-difluoropyrrolidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a CH2Cl2 (10 ml) solution of 2-((R)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)acetic acid and hydroxylamine hydrogen chloride (713.8 mg, 7.32 mmol), EDCI.HCl (1.64 g, 8.54 mmol) and NMM (1.5 ml, 13.4 mmol) were added, the reaction mixture was stirred at room temperature for 15 hours. The reaction went to completion monitored by LC-MS and was quenched by addition of saturated aqueous NaHCO3 solution (˜25 ml). Two layers were separated, aqueous layer was extracted with CH2Cl2 (˜20 ml). Organic layers were combined, dried (Na2SO4), filtered, solvent was removed in vacuo. Crude product was purified by silica gel chromatography (Hexane/EtOAc, gradient from 100:0 to 70:30). Compound (R)-tert-butyl 2-((N-methoxy-N-methylcarbamoyl)methyl)-4,4-difluoropyrrolidine-1-carboxylate was obtained as a light yellow oil: 1.20 g; additional product was obtained from recovered carboxylic acid: 0.2 g (53% combined overall yield over 2 steps).

Workup

  1. customwas quenched by addition of saturated aqueous NaHCO3 solution (˜25 ml)
  2. customTwo layers were separated
  3. extractionaqueous layer was extracted with CH2Cl2 (˜20 ml)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. customsolvent was removed in vacuo
  7. customCrude product was purified by silica gel chromatography (Hexane/EtOAc, gradient from 100:0 to 70:30)

Sources & evidence

ORD record
ord-6748edf8afa849b591f8df9ddfaf8802
Source dataset
uspto-grants-2015_10
Patent number
US09169249B2

Reaction notes

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