Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1994-06-28
1997-08-19
Shippen, Michael L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C07C26100
Patent
active
056590717
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a process for the production of guanidino protected aminoalkyl guanidines, especially alkoxycarbonyl or aralkoxycarbonyl protected .omega.-aminoalkyl guanidines, such as N-t-butoxycarbonyl-N'-(.omega.-aminoalkyl) guanidines and N-benzyloxycarbonyl-N'-(.omega.-aminoalkyl) guanidines. Representatives of this group of compounds are useful or potentially useful as peptide building blocks as mimics to the arginine residue. In particular the invention relates to a novel, one step process comprising reacting a diamine selectively at one amino-group with an alkoxycarbonyl or aralkoxycarbonyl protected electrophilic guanylation reagent. More specifically, the invention relates to a process reacting a symmetric 1,n-diamino alkane with a alkoxycarbonyl or aralkoxycarbonyl isourea or isothiourea giving an guanidino protected .omega.-aminoalkyl guanidine. The invention further relates to some compounds that are novel compounds per se. These novel compounds were produced by using the process of the invention. Furthermore the invention relates to some novel compounds, useful in the process of the invention.
BACKGROUND OF THE INVENTION
Protected guanidines having an important role in the synthesis of peptides having arginine residues. Various mimics to arginine have been used as peptide building blocks. From a synthetical and commercial point of view, arginine-mimics having a simplified structure compared to arginine are of particular interest. Perhaps the most attractive structural simplification of arginine is replacing the carboxylic group in arginine with a hydrogen giving a non-chiral molecule. The most important arginine derivatives in this context are noragmatine (N-(3-aminopropyl)-guanidine) and agmatine (N-(4-aminobutyl)-guanidine). More generally, .omega.-aminoalkyl guanidines of varying chain length are interesting as peptide building blocks, particularly as a substitute for an arginine terminus in a peptide.
Previously known examples of applications of peptide building blocks, of the general type --NH--C(.dbd.NH)--NH--[CH.sub.2 ].sub.n --NH-- are, see for example:
A free guanidino group [--NH--C(.dbd.NH)--NH.sub.2 ] provides synthetic complications and to be synthetically useful the building block requires a protective group (PC) which may be removed from the guanidino group at a desired stage of the synthesis.
Frequently used protective groups for the guanidino group in arginine are for example alkoxycarbonyls such as t-butoxycarbonyl (Boc) and aralkoxycarbonyls such as benzyloxycarbonyl (Z), See for example: Wunsch E. "Methoden der Organischen Chemie (Houben Weyl), Syntheses yon Peptiden", 1974, 15/1, 506 ff. and Rzeszotarska Masiukiewicz Org. Prep. Proc. Int. 1988, 20, 427 ff. The expressions Boc and Z are used in the following description as abbreviates for t-butoxycarbonyl and benzyloxycarbonyl, respectively.
Guanidino protected .omega.-aminoalkyl guanidines, PG.sub.2 --NH--C(.dbd.NH)--NH--[CH.sub.2 ].sub.n --NH.sub.2 (3), are generally prepared starting from a mono-protected diaminoalkane (1) in which the free amino group is reacted with an electrophilic guanylation reagent, HN.dbd.C(L)--NH.sub.2 where L is a leaving group, commonly used in guanidine syntheses. The reaction produces an amino protected .omega.-aminoalkyl guanidine (2) which after protection of the guanidino group with a second protective group (PG.sub.2) and deprotection of the amino protective group (PG.sub.1) gives the desired PG.sub.2 --NH--C(.dbd.NH)--NH--[CH.sub.2 ].sub.n --NH.sub.2 (3). In this method the protective groups have to be orthogonal. Examples of guanylation reagents that may be used are L.dbd.OMe, SMe, pyrazol-1-yl, 3,5-dimethyl-pyrazo-1-yl, and SO.sub.3 H. Recent developments have proposed introduction of the second protective group, PG.sub.2, in the guanylation reagent. Such a method simplifies the linear synthesis and shortens it with one step, (13), see scheme 1. ##STR1##
Previously proposed guanylation reagents [PG.sub.2 --NH--C(L).dbd.NH], carrying a prote
REFERENCES:
patent: 4346078 (1982-08-01), Sandor et al.
patent: 4387049 (1983-06-01), Pfeiffer
patent: 5498724 (1996-03-01), Nystrom
Tian et al., Int. J. Peptide Protein Res. 37: pp. 425-429 (1991).
Mattingly, P., Synthesis pp. 366-368 (Apr. 1990).
Rzeszotarska et al., Org. Prep. and Proc. Int. vol. 20, No. 5: pp. 427-464 (1988).
Hegarty et al., Chemical Society, Perkin transactions II, vol. 15: pp. 2054-2060 (1973).
Greene, "Protective Groups in Organic Synthesis", pp. 218-287 1981.
Nystrom Jan-Erik
Sjobom Hans Fredrik
Astra Aktiebolag
Shippen Michael L.
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