US 4,761,495 A · Method relating to preparation of aspartyl peptides · patentgrep

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Abstract

The present invention is directed to a composition and method relating to the preparation of aspartyl peptides having the general formula: ##STR1## where the radical-NHR represents an amino acid or peptide group. In the method, a .beta.-monoester of aspartic acid having the general formula: ##STR2## where R.sub.1 represents a hydrocarbon-containing radical, is reacted with a .beta.-dicarbonyl compound, preferably ethylacetoacetate to protect the aspartyl amino group and form an enamine. The enamine is then coupld to an amino acid or peptide, following which any protecting groups are removed to yield .alpha.-aspartyl peptides without any .beta.-isomer. In its composition aspects, the present invention is directed to novel enamines resulting from reaction of the .beta.-monoester of aspartic acid with a .beta.-dicarbonyl compound.

Claims33

Dependent claims

A method for preparing an .alpha.-aspartyl peptide having the general formula:

##STR8## where --NHR represents an alanine, phenylalanine, or phenylalaninamide residue, the method comprising the steps of:
(a) reacting a .beta.-monoester of aspartic acid having the general formula:
##STR9## where R.sub.1 denotes a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, a phenyl radical substituted by a methyl radical, a methoxy radical or a halogen atom, a benzyl radical, or a benzyl radical substituted by a methyl radical, a methoxy radical or a nitro group, with a .beta.-dicarbonyl compound having the general formula:
##STR10## wherein:
(i) R.sub.2 is a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical, a carbomethoxymethyl radical, or a carboethoxymethyl radical;
R.sub.3 is a hydrogen atom;
and X is a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical, or an alkoxy radical having the formula --OR.sub.4 where R.sub.4 is a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical, or a radical having the formula --NR.sub.a R.sub.b where R.sub.a and R.sub.b represent a hydrogen atom or a linear or brached alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical, or where R.sub.a, R.sub.b and N constitute a 5- or 6-member ring;
or
(ii) R.sub.2 and R.sub.3 are bonded to one another and constitute a single alkyl chain portion of said .beta.-dicarbonyl compound, said alkyl chain portion having the general formula --(CH.sub.2).sub.n -- where n is 3 or 4;
and X has the meaning ascribed in (i) above;
or
(iii) R.sub.2 and X are bonded to one another and constitute a single three-carbon chain portion of said .beta.-dicarbonyl compound, said chain portion being unsubstituted or substituted by one or two methyl groups;
and R.sub.3 is hydrogen;
in the presence of a secondary or tertiary amine to obtain an aspartyl enamine having the general formula:
##STR11## where R.sub.1, R.sub.2, R.sub.3, and X have the meanings given in (i), (ii), and (iii) above;
and
(b) reacting said aspartyl enamine with an amino acid or amino acid derivative selected from the group consisting of phenylalanine, alanine, phenylalaninamide, and salts or esters thereof to obtain an .alpha.-aspartyl peptide.

14 more elements

A method for preparing an .alpha.-aspartyl peptide having the general formula:

##STR12## where --NHR represents an alanine, phenylalanine, or phenylalaninamide residue, the method comprising the steps of:
(a) reacting a .beta.-monoester of aspartic acid having the general formula:
##STR13## where R.sub.1 denotes a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, a phenyl radical substituted by a methyl radical, a methoxy radical or a halogen atom, a benzyl radical, or a benzyl radical substituted by a methyl radical, a methoxy radical or a nitro group, with a .beta.-dicarbonyl compound having the general formula:
##STR14## wherein R.sub.2 is a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical, a carbomethoxymethyl radical, or a carboethoxymethyl radical;
R.sub.3 is a hydrogen atom;
and X is a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical, or an alkoxy radical having the formula --OR.sub.4 where R.sub.4 is a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical, or a radical having the formula --NR.sub.a R.sub.b where R.sub.a and R.sub.b represent a hydrogen atom or a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical, or where R.sub.a, R.sub.b and N constitute a 5- or 6-member ring;
in the presence of a secondary or tertiary amine to obtain an aspartyl enamine having the general formula:
##STR15## where R.sub.1, R.sub.2, R.sub.3, and X have the meanings given above;
and (b) reacting said aspartyl enamine with an amino acid or amino acid derivative selected from the group consisting of phenylalanine, alanine, phenylalaninamide, and salts or esters thereof to obtain an .alpha.-aspartyl peptide.

6 more elements

A method for preparing an .alpha.-aspartyl peptide having the general formula:

##STR16## where --NHR represents an alanine, phenylalanine, or phenylalaninamide residue, the method comprising the steps of:
(a) reacting a .beta.-monoester of aspartic acid having the general formula:
##STR17## where R.sub.1 denotes a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, a phenyl radical substituted by a methyl radical, a methoxy radical or a halogen atom, a benzyl radical, or a benzyl radical substituted by a methyl radical, a methoxy radical or a nitro group, with a .beta.-dicarbonyl compound having the general formula:
##STR18## wherein R.sub.2 and R.sub.3 are bonded to one another and together constitute a single alkyl chain portion of said .beta.-dicarbonyl compound, said alkyl chain portion having the general formula --(CH.sub.2).sub.n -- where n is 3 or 4;
and X is a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical, or an alkoxy radical having the formula --OR.sub.4 where R.sub.4 is a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical, or a radical having the formula --NR.sub.a R.sub.b where R.sub.a and R.sub.b represent a hydrogen atom or a linear or brached alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical, or where R.sub.a, R.sub.b and N constitute a 5- or 6-member ring, in the presence of a secondary or tertiary amine to obtain an aspartyl enamine having the general formula:
##STR19## where R.sub.1, R.sub.2, R.sub.3, and X have the meanings given above;
and (b) reacting said aspartyl enamine with an amino acid or amino acid derivative selected from the group consisting of phenylalanine, alanine, phenylalaninamide, and salts or esters thereof to obtain an .alpha.-aspartyl peptide.

4 more elements

A method for preparing an .alpha.-aspartyl peptide having the general formula:

##STR20## where --NHR represents an alanine, phenylalanine, or phenylalaninamide residue, the method comprising the steps of:
(a) reacting a .beta.-monoester of aspartic acid having the general formula:
##STR21## where R.sub.1 denotes a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, a phenyl radical substituted by a methyl radical, a methoxy radical or a halogen atom, a benzyl radical, or a benzyl radical substituted by a methyl radical, a methoxy radical or a nitro group, with a .beta.-dicarbonyl compound having the general formula:
##STR22## wherein R.sub.2 and X are bonded to one another and together constitute a single three-carbon chain portion of said .beta.-dicarbonyl compound, said chain portion being unsubstituted or substituted by one or two methyl groups;
and R.sub.3 is hydrogen, in the presence of a secondary or tertiary amine to obtain as aspartyl enamine having the general formula:
##STR23## where R.sub.1, R.sub.2, R.sub.3, and X have the meanings given above;
and (b) reacting said aspartyl enamine with an amino acid or amino acid derivative selected from the group consisting of phenylalanine, alaline, phenylalaninamide, and salts or esters thereof to obtain an .alpha.-aspartyl peptide.

4 more elements

A method for preparing an .alpha.-aspartyl peptide having the general formula:

##STR24## where --NHR represents an alanine, phenylalanine, or phenylalaninamide residue, the method comprising the steps of:
(a) reacting a .beta.-monoester of aspartic acid having the general formula:
##STR25## where R.sub.1 denotes a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, a phenyl radical substituted by a methyl radical, a methoxy radical or a halogen atom, a benzyl radical, or a benzyl radical substituted by a methyl radical, a methoxy radical or a nitro group, with a .beta.-dicarbonyl compound having the general formula:
##STR26## wherein:
(i) R.sub.2 is a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical, a carbomethoxymethyl radical, or a carboethoxymethyl radical;
R.sub.3 is a hydrogen atom;
and X is a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical, or an alkoxy radical having the formula --OR.sub.4 where R.sub.4 is a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical, or a radical having the formula --NR.sub.a R.sub.b where R.sub.a and R.sub.b represent a hydrogen atom or a linear or branched alkyl radical with 1 to 5 carbon atoms, a phenyl radical, or a benzyl radical;
or
(ii) R.sub.2 and R.sub.3 are bonded to one another and constitute a single alkyl chain portion of said .beta.-dicarbonyl compound, said alkyl chain portion having the general formula --(CH.sub.2).sub.n -- where n is 3 or 4;
and X has the meaning ascribed in (i) above;
or
(iii) R.sub.2 and X are bonded to one another and constitute a single three-carbon chain portion of said .beta.-dicarbonyl compound, said chain portion being unsubstituted or substituted by one or two methyl groups;
and R.sub.3 is hydrogen;
in the presence of a secondary or tertiary amine to obtain an aspartyl enamine having the general formula:
##STR27## where R.sub.1, R.sub.2, R.sub.3, and X have the meanings given in (i), (ii), and (iii) above;
and
(b) reacting said aspartyl enamine with an amino acid or amino acid derivative selected from the group consisting of phenylalanine, alanine, phenylalaninamide, and salts or esters thereof to obtain an .alpha.-aspartyl peptide.

14 more elements

Dependencies are inferred from the claim text.