Hydrochloric Acid → (R)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid

HRID 1482274Notes

Reaction equation

HRID 1482274 reaction equation
[NH:1]([C:16]([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[NH2:62][C@H:63]([C:71]([OH:73])=[O:72])[CH2:64][S:65][S:66][C:67]([CH3:70])([CH3:69])[CH3:68].Cl>ClCCl>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][C@@H:2]([C:13](=[O:14])[NH:62][C@H:63]([C:71]([OH:73])=[O:72])[CH2:64][S:65][S:66][C:67]([CH3:70])([CH3:68])[CH3:69])[NH:1][C:16](=[O:17])[O:18][CH2:19][CH:20]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:5]1

Participants

8

Reactant 6

HCID 313Hydrochloric AcidHCID 80170N-HydroxysuccinimideHCID 81531DiisopropylethylamineHCID 978343Fmoc-L-tryptophanHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 7006457s-tert-Butylmercapto-L-cysteine

Product 1

HCID 117735889(R)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acidYield 57.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of Fmoc-Trp-OH (5 g, 11.72 mmol) and N-hydroxysuccinimide (1.35 g, 11.72 mmol) in dichloromethane (23 ml) was cooled to 0° C., after which 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl, 2.25 g, 11.72 mmol) was added and the reaction solution was stirred at room temperature for 5.5 hours. The reaction solution was cooled to 0° C., after which N,N-diisopropylethylamine (2.05 ml, 11.72 mmol) and H-Cys(StBu)-OH (2.45 g, 11.72 mmol) were added and the reaction solution was stirred at room temperature for 14 hours. Dichloromethane and 1 M hydrochloric acid were added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with 25 wt % brine and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure, and the concentration residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (5S,8R)-5-((1H-indol-3-yl)methyl)-1-(9H-fluoren-9-yl)-12,12-dimethyl-3,6-dioxo-2-oxa-10,11-dithia-4,7-diazatridecane-8-carboxylic acid (Compound SP602, Fmoc-Trp-Cys(StBu)-OH) (4.15 g, 57%).

Workup

  1. temperatureThe reaction solution was cooled to 0° C.
  2. stirringthe reaction solution was stirred at room temperature for 14 hours
  3. extractionfollowed by extraction with dichloromethane
  4. washThe organic layer was washed with 25 wt % brine
  5. dry with materialdried over sodium sulfate
  6. concentrationThe resulting solution was concentrated under reduced pressure
  7. customthe concentration residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution)

Sources & evidence

ORD record
ord-5df1ef973abc4ca291a782f118874d0b
Source dataset
uspto-grants-2016_08
Patent number
US09409952B2

Reaction notes

Loading…