Hydrochloric Acid → (5S,8R)-5-benzyl-1-(9H-fluoren-9-yl)-12,12-dimethyl-3,6-dioxo-2-oxa-10,11-dithia-4,7-diazatridecane-8-carboxylic acid

HRID 1482294Notes

Reaction equation

HRID 1482294 reaction equation
[NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[C:59]([S:63][S:64][CH2:65][C@@H:66]([C:68]([OH:70])=[O:69])[NH2:67])([CH3:62])([CH3:61])[CH3:60].Cl>ClCCl.C(OCC)(=O)C>[CH2:3]([C@@H:2]([C:10](=[O:11])[NH:67][C@H:66]([C:68]([OH:70])=[O:69])[CH2:65][S:64][S:63][C:59]([CH3:62])([CH3:60])[CH3:61])[NH:1][C:13](=[O:14])[O:15][CH2:16][CH:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 80170N-HydroxysuccinimideHCID 81531DiisopropylethylamineHCID 978331Fmoc-phenylalanineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 7006457s-tert-Butylmercapto-L-cysteine

Product 1

HCID 117735693(5S,8R)-5-benzyl-1-(9H-fluoren-9-yl)-12,12-dimethyl-3,6-dioxo-2-oxa-10,11-dithia-4,7-diazatridecane-8-carboxylic acidYield 71%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of Fmoc-Phe-OH (4 g, 10.32 mmol) and N-hydroxysuccinimide (1.19 g, 10.32 mmol) in dichloromethane (20 ml) was cooled to 0° C., after which 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl, 1.98 g, 10.32 mmol) was added and the reaction solution was stirred at room temperature for 6 hours. The reaction solution was cooled to 0° C., after which N,N-diisopropylethylamine (1.80 ml, 10.23 mmol) and S-(t-butylthio)-L-cysteine (H-Cys(StBu)-OH) (2.16 g, 10.32 mmol) were added and the reaction solution was stirred at room temperature for 12 hours. Ethyl acetate and 2 M hydrochloric acid were added to the reaction mixture, followed by extraction with ethyl acetate. 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-benzyl-1-(9H-fluoren-9-yl)-12,12-dimethyl-3,6-dioxo-2-oxa-10,11-dithia-4,7-diazatridecane-8-carboxylic acid (Compound SP663, Fmoc-Phe-Cys(StBu)-OH) (4.22 g, 71%).

Workup

  1. temperatureThe reaction solution was cooled to 0° C.
  2. stirringthe reaction solution was stirred at room temperature for 12 hours
  3. extractionfollowed by extraction with ethyl acetate
  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-5bd90351c4c04f369ac0deb5dc1d677d
Source dataset
uspto-grants-2016_08
Patent number
US09409952B2

Reaction notes

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