Triethylamine → (S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl-2,3,5-trifluorobenzoic acid ethyl ester

HRID 729368Notes

Reaction equation

HRID 729368 reaction equation
[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2].[C:16]([O:20][C:21](=[O:28])[NH:22][C@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:25]2[CH2:26][CH2:27][C@H:23]([NH:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:28])[CH2:24]2)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 1514396(3S)-(-)-3-(tert-Butoxycarbonylamino)pyrrolidineHCID 2774395Ethyl 2H-tetrafluorobenzoate

Product 1

HCID 58681883(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl-2,3,5-trifluorobenzoic acid ethyl esterYield 74.5%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A solution of 2,3,4,5-tetrafluorobenzoic acid ethyl ester (Example 1a, 4.03 g, 18.1 mmol), (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.02 g, 21.6 mmol) (Sanchez J. P., Domagala J. M., Heifetz C. L., Priebe S. R., Sesnie J. A., Trehan A. K., J. Med. Chem., 1992; 35(10):1764-1773), and triethylamine (18.0 mL, 129 mmol) in acetonitrile (50 mL) is heated at 50° C. under a nitrogen atmosphere for 4.5 hours. The yellow solution is concentrated in vacuo and poured into a saturated NaHCO3 solution. The mixture is then extracted with chloroform, and the combined organic extracts are washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The resulting residue is then purified by flash column chromatography (1:7 ethyl acetate/hexanes) to afford the title compound (5.24 g). 1H NMR (CDCl3): δ 7.35 (ddd, 1H), 4.70-4.65 (bs, 1H), 4.42-4.20 (m, 3H), 3.90-3.62 (m, 3H), 3.58-3.42 (m, 1H), 2.28-2.03 (m, 1H), 1.99-1.80 (m, 1H), 1.46 (s, 9H), 1.37 (t, 3H).

Workup

  1. concentrationThe yellow solution is concentrated in vacuo
  2. additionpoured into a saturated NaHCO3 solution
  3. extractionThe mixture is then extracted with chloroform
  4. washthe combined organic extracts are washed with brine
  5. dry with materialdried with Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe resulting residue is then purified by flash column chromatography (1:7 ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-3413e8669e6b4655aad5d0bc941c7e4c
Source dataset
uspto-grants-2009_09
Patent number
US07582627B2

Reaction notes

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