Reaktion #363297

Reaktionsgleichung

N,N-diisopropylethylamine

O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

N,N-diisopropylethylamine

piperidine dimethylformamide

potassium thioacetate

trifluoroacetic acid acetonitrile

Fmoc-(L)-homophenylalanine

(R)-2-bromo-3-methylbutyric acid

1,3-diisopropylcarbodiimide

→

title compound

(S)-2-Mercapto-3-methylbutyroyl-(L)-homo-phenylalanyl-(L)-phenylalanine

Lösungsmittel

dimethylformamide

water

dimethylformamide

water

N-methylpyrrolidinone

N-methylpyrolidinone

acetonitrile

Reaktionsbedingungen

Aufarbeitung

1. 1
   Filtrationfilter
2. 2
   workup.ADDITIONadd dimethylformamide (3 mL) and 50% piperidine/dimethylformamide (3 mL)
3. 3
   Sonstigebubble for 10 minutes
4. 4
   Filtrationfilter
5. 5
   WaschenRinse the resin with dimethylformamide (10 times 5 mL), dichloromethane (3 times 5 mL)
6. 6
   workup.WAITAfter 15 hours
7. 7
   Filtrationfilter
8. 8
   Waschenrinse the resin with dimethylformamide (9 times 5 mL), dichloromethane (3 times 5 mL)
9. 9
   SonstigeAdd dimethylformamide (3 mL) and 50% piperidine/dimethylformamide (3 mL), bubble for 10 minutes
10. 10
    Filtrationfilter
11. 11
    WaschenRinse the resin with dimethylformamide (10 times 5 mL), dichloromethane (3 times 5 mL)
12. 12
    workup.WAITAfter 15 hours
13. 13
    Filtrationfilter
14. 14
    Waschenrinse the resin with dimethylformamide (9 times 5 mL), dichloromethane (3 times 5 mL)
15. 15
    workup.WAITAfter 3 hours
16. 16
    Filtrationfilter
17. 17
    Waschenrinse the resin with dimethylformamide (9 times 5 mL)
18. 18
    workup.WAITAfter 5 minutes
19. 19
    Filtrationfilter
20. 20
    Waschenrinse the resin with methanol (5 times 5 mL)
21. 21
    workup.WAITAfter 3 hours
22. 22
    Filtrationfilter
23. 23
    Waschenrinse with 50% trifluoroacetic acid/dichloromethane (2 times 10 mL)
24. 24
    EinengenConcentrate the filtrate in vacuo
25. 25
    Sonstigeto give a residue
26. 26
    Sonstigeevaporate under a stream of nitrogen
27. 27
    Sonstigeto give a residue
28. 28
    Sonstigeto give a residue
29. 29
    Sonstigeto give a residue
30. 30
    SonstigePurify by HPLC

Vorschrift

Combine Fmoc-(L)-phenylalanine-NovaSyn® TGT resin (1.0 g, 0.15 mmol/g, Nova Biochem), dimethylformamide (3 mL) and 50% piperidine/dimethylformamide (3 mL). After 5 minutes, filter, add dimethylformamide (3 mL) and 50% piperidine/dimethylformamide (3 mL), bubble for 10 minutes, and filter. Rinse the resin with dimethylformamide (10 times 5 mL), dichloromethane (3 times 5 mL), and then dimethylformamide (5 mL). Kaiser (ninhydrin) test indicates complete deprotection. Add Fmoc-(L)-homophenylalanine (0.240 g, 0.5 mmol), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.228 g, 0.60 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.20 mmol), and dimethylformamide (5 mL). After 15 hours, filter, rinse the resin with dimethylformamide (9 times 5 mL), dichloromethane (3 times 5 mL), and then dimethylformamide (5 mL). Add dimethylformamide (3 mL) and 50% piperidine/dimethylformamide (3 mL), bubble for 10 minutes, and filter. Rinse the resin with dimethylformamide (10 times 5 mL), dichloromethane (3 times 5 mL), and then dimethylformamide (5 mL). Kaiser (ninhydrin) test indicates complete deprotection. Add (R)-2-bromo-3-methylbutyric acid (0.145 g, 0.6 mmol), 1,3-diisopropylcarbodiimide (0.076 g, 0.60 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.20 mmol) in N-methylpyrrolidinone (5 mL). After 15 hours, filter, rinse the resin with dimethylformamide (9 times 5 mL), dichloromethane (3 times 5 mL), and then dimethylformamide (5 mL). Combine the resin with a degassed solution of potassium thioacetate (0.137 g, 1.2 mmol) in N-methylpyrolidinone (5 mL). After 3 hours, filter and rinse the resin with dimethylformamide (9 times 5 mL). Combine the resin with a degassed saturated methanolic ammonia solution (5 mL). After 5 minutes, filter and rinse the resin with methanol (5 times 5 mL). Combine the resin and a degassed 95% trifluoroacetic acid/4% water/1% 2-mercaptoethanol solution (10 mL). After 3 hours, filter, rinse with 50% trifluoroacetic acid/dichloromethane (2 times 10 mL). Concentrate the filtrate in vacuo to give a residue. Combine the residue with 1% trifluoroacetic acid/acetonitrile solution and evaporate under a stream of nitrogen to give a residue. Combine the residue and water (about 4 mL) and lyophilize to give a residue. Combine the residue and acetonitrile and water and again lyophilize to give a residue. Purify by HPLC to give the title compound: retention time=4:24 minutes, YMC Inc. 4.0 mm×50 mm ODS-A column, flow rate 1.0 mL/minute, initial conditions 70% A (95% water/5% acetonitrile/0.1% trifluoroacetic acid) and 30% B (5% water/95% acetonitrile/0.085% trifluoracetic acid) and a linear gradient over 5 minutes to 100% B. Mass Spectrum (MH+=443).

Quelle