4-Methylmorpholine → Tert-butyl 3,3-difluoro-4-{[3-(methylsulfonyl)propanoyl]amino}pyrrolidine-1-carboxylate

HRID 928202Notes

Reaction equation

HRID 928202 reaction equation
[NH2:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C:3]1([F:15])[F:14].[CH3:16][S:17]([CH2:20][CH2:21][C:22](O)=[O:23])(=[O:19])=[O:18].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:14][C:3]1([F:15])[CH:2]([NH:1][C:22](=[O:23])[CH2:21][CH2:20][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:4]1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 757711-HydroxybenzotriazoleHCID 1203083-(Methylsulfonyl)propanoic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 72207756Tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate

Product 1

HCID 118073705Tert-butyl 3,3-difluoro-4-{[3-(methylsulfonyl)propanoyl]amino}pyrrolidine-1-carboxylateYield 76%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a reaction flask was added tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (1.36 g, 6.12 mmol), 3-(methylsulfonyl)propanoic acid (1.02 g, 6.73 mmol, 1.1 mol eq), DCM (31 mL, 0.4 M), NMM (1.35 mL, 12.2 mmol, 2 mol eq), HOBt (1.31 g, 9.2 mmol, 1.5 mol eq) and EDC-HCl (1.85 g, 9.2 mmol, 1.5 mol eq). The resulting suspension was stirred at ambient temperature under a nitrogen atmosphere for 2 hr. The reaction was diluted with DCM (80 mL), washed with aqueous NaHCO3 (2×30 mL) and the organic layer was dried over Na2SO4 and evaporated to give a residue that was purified via silica flash chromatography eluting with gradients from 100% heptane to 100% ethyl acetate to give the title product as a white foamy solid (1.65 g, 76% yield, >95% purity). 1H NMR (400 MHz, chloroform-d) δ ppm 6.45 (br. s., 1 H) 4.68-4.89 (m, 1 H) 3.94 (dd, J=10.70, 8.62 Hz, 1 H) 3.62-3.86 (m, 2 H) 3.43 (t, J=7.15 Hz, 2 H) 3.18 (br. s., 1 H) 2.97 (s, 3 H) 2.84 (td, J=7.15, 1.96 Hz, 2 H) 1.47 (s, 9 H). 19F NMR (376 MHz, chloroform-d) δ ppm −112.79-−110.52 (m, 1 F) −114.51-−113.30 (m, 1 F). m/z (APCI+) for C13H22F2N2O5S 257.1 (M+H)+.

Workup

  1. washwashed with aqueous NaHCO3 (2×30 mL)
  2. dry with materialthe organic layer was dried over Na2SO4
  3. customevaporated
  4. customto give a residue that
  5. customwas purified via silica flash chromatography
  6. washeluting with gradients from 100% heptane to 100% ethyl acetate

Sources & evidence

ORD record
ord-c3e1b052e92a417e8cde17f451e78e11
Source dataset
uspto-grants-2016_03
Patent number
US09290496B2

Reaction notes

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