6-Aminohexanoic Acid → (S)-6-[3-(1H-Indol-3-yl)-2-(4-phenyl-butyrylamino)-propionylamino]-hexanoic acid 2,5-dioxo-pyrrolidin-1-yl ester

HRID 1362580Notes

Reaction equation

HRID 1362580 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:15][C:16](=[O:26])[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([OH:14])=O)=[CH:2]1.[OH:27][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56](O)=[O:57].C([O-])(O)=O.[Na+]>C(#N)C.O>[O:34]=[C:29]1[CH2:30][CH2:31][C:32](=[O:33])[N:28]1[O:27][C:56](=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][NH:50][C:12](=[O:14])[C@@H:11]([NH:15][C:16](=[O:26])[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1

Participants

8

Reactant 5

HCID 5646-Aminohexanoic AcidHCID 10868Dicyclohexylcarbodiimide2×HCID 80170N-Hydroxysuccinimide2×HCID 516892Sodium BicarbonateHCID 57796817(S)-3-(1H-Indol-3-yl)-2-(4-phenyl-butyrylamino)-propionic acid

Product 1

HCID 57796858(S)-6-[3-(1H-Indol-3-yl)-2-(4-phenyl-butyrylamino)-propionylamino]-hexanoic acid 2,5-dioxo-pyrrolidin-1-yl esterYield 56%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Procedure

(Method J15C) A solution of 3-(1H-indol-3-yl)-2-(4-phenyl-butyrylamino)-propionic acid (16/95) (1.333 g, 4.01 mmol) and N-hydroxysuccinimide (0.461 g, 4.01 mmol) in acetonitrile (50 ml) was treated with N,N′-dicyclohexylcarbodiimide (0.828 g, 4.02 mmol) at 0° C. The resulting suspension was allowed to stand for 14 hours at 4° C., the precipitate was filtered off and washed with acetonitrile (2×10 ml). To the filtrate a solution of 6-aminohexanoic acid (0.526 g, 4.01 mmol) and NaHCO3 (0.672 g, 4.01 mmol) in water (20 ml) was added and the resulting mixture was stirred for 3 hours at room temperature. Acetonitrile was removed under reduced pressure, the residue was acidified with citric acid to pH 2 and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water (20 ml), brine (20 ml), and dried (MgSO4). The extract was filtered and to the filtrate successively N-hydroxysuccinimide ((0.461 g, 4.01 mmol) and N,N′-dicyclohexylcarbodiimide (0.828 g, 4.02 mmol) were added. The mixture was stirred for 6 hours at room temperature, the precipitate was filtered off and washed with ethyl acetate (3×20 ml). The filtrate was evaporated and the residue was chromatographed on silicagel with ethyl acetate-petroleum ether (1:1) as eluent to give the title product 18/95 (1.217 g, 56%) as a foam. 1H NMR (DMSO-d6, HMDSO) δ: 1.11-1.89 (8H, m); 1.96-2.23 (2H, m); 2.31-2.70 (4H, m, partially overlapped with a signal of DMSO); 2.79 (4H, s); 2.89-3.20 (4H, m); 4.40-4.72 (1H, m); 6.87-7.69 (10H, m); 7.75-8.07 (2H, m); 10.78 (1H, s).

Workup

  1. filtrationthe precipitate was filtered off
  2. washwashed with acetonitrile (2×10 ml)
  3. customAcetonitrile was removed under reduced pressure
  4. extractionthe mixture was extracted with ethyl acetate (100 ml)
  5. washThe organic layer was washed with water (20 ml), brine (20 ml)
  6. dry with materialdried (MgSO4)
  7. additionwere added
  8. stirringThe mixture was stirred for 6 hours at room temperature
  9. filtrationthe precipitate was filtered off
  10. washwashed with ethyl acetate (3×20 ml)
  11. customThe filtrate was evaporated
  12. customthe residue was chromatographed on silicagel with ethyl acetate-petroleum ether (1:1) as eluent

Sources & evidence

ORD record
ord-2b68ae2dcef94d4e9cd0e044549a9952
Source dataset
uspto-grants-2011_02
Patent number
US07880020B2

Reaction notes

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