1,2-Dichloroethane → 1-[2-(4-Amino-3-chloro-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-amide

HRID 2363377Notes

Reaction equation

HRID 2363377 reaction equation
C([O:5][C:6](=O)[NH:7][CH:8]([CH3:33])[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:32])[NH:17][CH:18]1[CH2:22][C:21](=[O:23])[O:20][CH:19]1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[NH2:51][C:52]1[CH:60]=[CH:59][C:55](C(O)=O)=[CH:54][C:53]=1[Cl:61].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:25]([O:24][CH:19]1[CH:18]([NH:17][C:16]([CH:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:9](=[O:10])[CH:8]([NH:7][C:6](=[O:5])[C:55]2[CH:59]=[CH:60][C:52]([NH2:51])=[C:53]([Cl:61])[CH:54]=2)[CH3:33])=[O:32])[CH2:22][C:21](=[O:23])[O:20]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1

Participants

8

Reactant 6

HCID 111,2-DichloroethaneHCID 6422Trifluoroacetic acidHCID 172114-Amino-3-chlorobenzoic acidHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 22977790{2-[2-(2-Benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl}-carbamic acid tert-butyl ester

Product 1

HCID 229774991-[2-(4-Amino-3-chloro-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-amide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A 1.899 g (3.99 mmol) sample of 75 in CH2Cl2 (20 ml) was treated with anhydrous TFA (5 ml) then stirred at room temperature under N2 for 1 hour and evaporated to dryness. The residue was repeatedly concentrated from CH2Cl2 (3×) then dried under vacuum. The resulting residue was dissolved in CH2Cl2 (20 ml), cooled to 0° C., then treated with DIEA (5.6 ml, 8 eq, 32.1 mmol), 4-amino-3-chloro-benzoic acid (0.910 g, 5.3 mmol), HOBT (0.824 g, 6.1 mmol), and EDC (1.197 g, 6.23 mmol). The resulting mixture was warmed to room temperature and stirred for 18 hours. The solvent was removed in vacuo and the residue dissolved in EtOAc then washed with distilled water (3×), 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a residue that was purified by flash chromatography using CH2Cl2/MeOH (99/1 to 97/3%). The title compound was obtained as a white solid (1.221 g, 58% yield). 1H-NMR (500 MHz, CD3OD) δ 1.15 (d, 0.25H), 1.29-1.60 (m, 2.75H), 2.41-2.54 (m, 0.5H), 2.55-2.70 (m, 0.5H), 2.77 (dd, 0.5H), 3.03 (ddd, 0.5H), 3.59-3.75 (m, 1H), 3.75-3.98 (m, 1H), 4.26-5.01 (m, 5H), 5.41-5.57 (m, 1H). 5.60-5.76 (m, 0.5H), 6.70-6.92 (m, 0.5H), 7.15-7.48 (m, 5H), 7.48-7.68 (m, 1H), 7.68-7.88 (m, 1H), 8.15-8.34 (m, 1H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 14.44, 14.89 min. LC-MS (ES+) m/e=529.3 (M+H).

Workup

  1. customevaporated to dryness
  2. concentrationThe residue was repeatedly concentrated from CH2Cl2 (3×)
  3. customthen dried under vacuum
  4. dissolutionThe resulting residue was dissolved in CH2Cl2 (20 ml)
  5. temperaturecooled to 0° C.
  6. temperatureThe resulting mixture was warmed to room temperature
  7. stirringstirred for 18 hours
  8. customThe solvent was removed in vacuo
  9. dissolutionthe residue dissolved in EtOAc
  10. washthen washed with distilled water (3×), 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine
  11. dry with materialThe organic layer was dried over Na2SO4
  12. filtrationfiltered
  13. customevaporated
  14. customto give a residue that
  15. customwas purified by flash chromatography

Sources & evidence

ORD record
ord-4e4ccda704f84b54bda71c8813093e84
Source dataset
uspto-grants-2014_04
Patent number
US08691848B2

Reaction notes

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