Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1990-07-17
1992-10-20
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
544408, C07C22926, C07C22936
Patent
active
051571455
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
The present invention relates to a process for preparing dipeptides derived from non-proteinogenous amino acids.
The specific synthesis of peptides which contain non-proteinogenous amino acids entails stepwise synthesis of the desired peptides employing the unnatural amino acids and using conventional protective groups and activation methods.
In this strategy, the unnatural amino acids employed are obtained either by non-enantioselective synthesis and subsequent racemate resolution or by enantioselective synthesis using optically active auxiliaries.
Difficulties in forming the peptide linkage can occur especially when the .alpha. position of the unnatural amino acid is substituted by two sterically demanding radicals (Helv. Chim. Acta 69, (1986) 1153, J. Amer. Chem. Soc. 103 (1981) 6127).
It has now been found that certain dipeptides can be prepared in a straightforward manner.
The invention relates to a process for preparing dipeptides with C-terminal non-proteinogenous amino acids, of the formula I ##STR1## in which R.sup.1 is a C.sub.1 -C.sub.8 -alkyl, phenyl or benzyl group, R.sup.2 denotes a C.sub.1 -C.sub.8 -alkyl group which can be interrupted by --O--, --S--, --CO-- or --CO--O--, or a phenyl or benzyl group, R.sup.3 is a hydrogen atom or a C.sub.1 -C.sub.8 -alkyl group or represents together with R.sup.2 the radicals --(CH.sub.2).sub.3 --, --(CH.sub.2).sub.4 -- or --CH.sub.2 --CH.dbd.CH--CH.sub.2 --, and R.sup.4 denotes a methyl, isopropyl, isobutyl, 2-butyl, t-butyl or benzyl radical, R.sup.5 is a methyl or ethyl group, which comprises hydrolyzing a compound of the formula II ##STR2## in which R.sup.1 to R.sup.5 have the stated meaning.
The hydrolysis of the compounds II to give the final products takes place especially well in dilute aqueous mineral acids in the presence of organic cosolvents such as methanol, ethanol, tetrahydrofuran, acetonitrile or dioxane. The mineral acids which are preferably used are HCl, HBr and HI. The reaction is normally carried out at from 0.degree. to 40.degree. C. The reaction takes 15 min to 6 h.
The compounds II can be obtained by selective partial acid-catalyzed cleavage of the compounds III ##STR3## The selective partial acid-catalyzed cleavage is carried out by reacting the compounds III with one equivalent of acid in an inert aprotic solvent. Acids which should be particularly mentioned are HCl, HBr and HI, and Lewis acids such as trialkylsilyl halides or dialkoxyboron halides. Suitable solvents are diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, dichloromethane, tetrachloromethane, toluene, cyclohexane and ethylene glycol dimethyl ether. The reaction is usually carried out at from 0.degree. to 40.degree. C. The reaction takes 15 min to 6 h.
The compounds II in which R.sup.3 is hydrogen can be converted by base-induced alkylation with alkyl halides or alkyl sulfates into the compounds II in which R.sup.3 is a C.sub.1 -C.sub.8 -alkyl group.
The compounds of the formula II in which R.sup.3 is a hydrogen atom and R.sup.5 is an ethyl group can be prepared especially well from the compounds of the formula IV ##STR4## by demethylation with a trialkylsilyl iodide with 1-4 carbon atoms in the alkyl radicals. The reaction is expediently carried out at from 0.degree. to -20.degree. C. in an anhydrous halohydrocarbon as solvent and under an inert gas. The trialkylsilyl iodides which are preferably used are those of the formula ##STR5## in which R.sup.6 -R.sup.8 are C.sub.1-4 alkyl radicals.
Because some of the compounds I in the form of the free bases readily form the corresponding diketopiperazines by ring closure, the salts of I produced in the hydrolysis are preferably converted by reaction with the acylating agents customary in peptide chemistry, such as benzyloxycarbonyl chloride, 9-fluorenylmethoxycarbonyl chloride or di-tert-butyl carbonate into the N-protected derivatives (cf. Houben-Weyl, Methoden der organischen Chemie, Vol. 15/1, G. Thieme Verlag, Stuttgart 1974) or reacted with activated amino-acid derivatives (cf. Houben-Weyl, Methoden d
REFERENCES:
Chemical Abstracts, vol. 108, No. 9, Feb. 29,1988, (Columbus, Ohio, US), U. Schoellkopf et al.: "Asymmetric syntheses via heterocyclic intermediates, XXXVI. Asymmetric synthesis of dimethyl (R)-4-amino-4-methyl-2-penetendioates(dimethyl B, y-didehydro-d-methyl-D-glutamates) or methyl (R)-2, 5-dihydro-2-methyl-5-oxo-2-pyrrolecarboxylates by the bislactim ether method. Studies on the asymmetric synthesis of B,y-didehydroglutamic acids", see p. 726, abstract 75801u, & Liebigs Ann, Chem. 1988, (1) 87-92.
Chemical Abstracts, vol. 109, No. 17, Oct. 24, 1988, (Columbus, Ohio, US), U. Schoellkopf et al.: "Asymmetric synthesis via heterocyclic intermediates. XL. Studies on the acylation of lithiated bislactim ethers of cyclo-(L-Val-Ala-) and cyclo (L-Val-Gyl-)", see p. 785, abstract 150014r, & Liebigs Ann. chem. 1988, (8), 781-6.
Tetrahedron, vol. 39, No. 12, 1983, Pergamon Press, (Oxford, GB), U. Schollkopf, "Enantioselective synthesis of non-proteinogenic amino acids via metallated bis-lactim ethers of 2,5-diketopiperazines", pp. 2085-2091.
Liebags Annalen der Chemie, issue 11, Nov. 1988, VCH Verlagsgesellschaft mbH, (Weinheim, DE), U. Schollkopf et al: "Asymmetric synthesis of Boc-L-Val-(R)-MePro-OMe, Boc-L-Val-(R)--Pro OMe, and of Boc-L-Val-(R)--MePhe-OMe and their analogues. A new stratgey for the synthesis of non-proteinogenic bipeptides", pp. 1025-1031.
Helvetica Chimica Acta, vol. 69, pp. 749-1534, Peter Wipf et al. "124. Kupplung von Peptiden mit C-terminalen x,x-disubstituierten x-Aminosauren via Oxazol-5 (4H)-one".
Journal of the American Chemical Society, vol 103, 1981, pp. 5991-7040, T. M. Balasubramanian, et al. "Synthesis and Acharacterization of the Major Component of Alamethicin", pp. 6127-6232.
Groth Ulrich
Lange Meinolf
Schoellkopf Ulrich
BASF - Aktiengesellschaft
Dees Jos,e G.
Frazier B.
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