Process for the preparation of pyroglutamyl-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn

The process for the preparation of the peptide having the structure,

• <
• Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn,
• which comprises condensing the blocked heptapeptide active ester having the structure,
• <
• Glu-Ala-(.epsilon.-R.sub.3)Lys-(O-R.sub.4 ')Ser-Gln-Gly-Gly-R.sub.6
• with the hydroxy blocked or unblocked dipeptide,
• (O-R.sub.5)Ser-Asn
• wherein
• R.sub.3 is the protecting group for the .epsilon.-amino of the lysyl moiety selected from the group consisting of INOC, trifluoroacetyl, phthaloyl, tosyl, p-nitrobenzyloxycarbonyl, TROC and FMOC;
• R.sub.4 ' is hydrogen, p-nitrobenzyl or benzoyl,
• R.sub.5 is hydrogen or a protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzyl, substituted benzyl wherein the substituent is o-chloro or p-nitro;
• t-butyl and benzoyl,
• R.sub.6 is an active ester selected from the group consisting of 1-hydroxybenzotriazole ester, N-hydroxysuccinimide ester and p-nitrophenyl ester, to obtain the blocked nonapeptide having the structure,
• <
• Glu-Ala-(.epsilon.-R.sub.3)Lys-(O-R.sub.4 ')Ser-Gln-Gly-Gly-(O-R.sub.5)Ser-Asn,
• and removing said blocking groups.

The compounds having the structure, Glu-Ala-(.epsilon.-R.sub.8)Lys-(O-R.sub.9)Ser-Gln-Gly-Gly-(O-R.sub.10)Ser- Asn

• wherein
• R.sub.8 is the protecting group for the .epsilon.-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl;
• 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl;
• 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC,
• R.sub.9 and R.sub.10 are independently hydrogen or
• R.sub.9 and R.sub.10 are protecting groups for the hydroxy group of the seryl moieties, independently selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro.

The compounds having the structure,

• <
• Glu-Ala-(.epsilon.-R.sub.8)Lys-(O-R.sub.9)Ser-Gln-Gly-Gly-R.sub.7
• wherein
• R.sub.8 is the protecting group for the .epsilon.-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl;
• 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl;
• 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC,
• R.sub.9 is hydrogen or the protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro,
• R.sub.7 is --NH--NH.sub.2, OH, 1-oxybenzotriazole, N-oxysuccinimide, p-nitrophenoxy or OCH.sub.3.

The compounds having the structure,

• <
• Glu(or BOC-Gln)-Ala-(.epsilon.-R.sub.8)Lys-(O-R.sub.9)Ser-Gln-Gly-Gly-O-CH.sub.2 -.phi.-resin
• wherein
• R.sub.8 is the protecting group for the .epsilon.-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl;
• 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl;
• 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC,
• R.sub.9 is hydrogen or the protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro.

The compounds having the structure,

• <
• Glu-Ala-(.epsilon.-R.sub.8)Lys-(O-R.sub.9)Ser-Gln-Gly-R.sub.7
• wherein
• R.sub.8 is the protecting group for the .epsilon.-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl;
• 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl;
• 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC,
• R.sub.9 is hydrogen or the protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro,
• R.sub.7 is --NH--NH.sub.2, OH, 1-oxybenzotriazole, N-oxysuccinimide, p-nitrophenoxy or OCH.sub.3.

The compounds having the structure,

• <
• Glu(or BOC-Gln)-Ala-(.epsilon.-R.sub.8)Lys-(O-R.sub.9)Ser-Gln-Gly-O-CH.sub.2 -.phi.-resin
• wherein
• R.sub.8 is the protecting group for the .epsilon.-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl;
• 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl;
• 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC,
• R.sub.9 is hydrogen or the protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro.