Process for the preparation of mixed anhydrides

Details Process for the preparation of mixed anhydrides Process for the preparation of mixed anhydrides

2001-12-06

2003-05-13

Seaman, D. Margaret (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S167000, C546S168000

Reexamination Certificate

active

06562977

ABSTRACT:

FIELD OF THE INVENTION
The present invention is in the field of the manufacture of mixed anhydrides.
BACKGROUND OF THE INVENTION
The manufacture of mixed anhydrides is known per se and is based on the reaction of an acid with a reactive acid derivative, for example an acid halide or acid anhydride in the presence of an adjuvant base. The production of mixed anhydrides has been described, for example, by Bodansky in “Principles of Peptide Synthesis”, 2nd ed., published by Springer Berlin, 1993, pages 21-29 and in “The Practice of Peptide Synthesis”, 2nd ed., published by Springer, Berlin, 1994 as well as by Stelzel in Houben-Weyl, volume XV/2, “Methoden der organischen Chemie: “Synthese von Peptiden”, part II.
Mixed anhydrides play a role primarily in activating and coupling reactions. Thus, Bodansky (loc.cit.) describes the synthesis of mixed anhydrides with pivaloyl chloride for use in the synthesis of peptides. For example, for the production of benzyloxycarbonyl-&agr;-methylalanyl-&agr;-methylalanine methyl ester, acid and adjuvant base are provided and the acid chloride is added. The mixture is stirred at −5° C. for 2 hours and subsequently at room temperature for 1 hour. The production of benzyloxycarbonyl-N
&egr;
-&agr;-p-toluenesulphonyl-L-lysylglycine ethyl ester proceeds analogously.
Stelzel (loc. cit.) describes the synthesis of N-benzyloxycarbonyl-L-prolyl-L-leucylglycine ethyl ester based on the addition of isovaleroyl chloride to a mixture of Z-Pro-OH and triethylamine in toluene.
However, these and other known processes for the production of mixed anhydrides have considerable disadvantages. Thus, the reaction does not proceed quantitatively by a long way. This is primarily due to the formation of byproducts, e.g. by disproportionation to the corresponding symmetrical anhydrides. Consequently, it is necessary to subject the reaction mixture to a costly working-up and purification.
SUMMARY OF THE INVENTION
This invention provides a process for producing an anhydride of two different carboxylic acids, comprising forming a mixture of a first carboxylic acid and a reactive acid derivative of a second carboxylic acid other than the first carboxylic acid, and reacting said mixture in the presence of a base to produce said anhydride, said base being added to said mixture to initiate the reaction.
By first mixing a carboxylic acid and the reactive acid derivative of a different carboxylic acid, and only afterwards combining the mixture with the base, it has surprisingly been found that the formation of unwanted byproducts including the symmetrical anhydrides can be largely avoided. Consequently, the yield of the desired mixed anhydride is increased. Because of the increased yield this invention provides a more efficient reaction for producing mixed anhydrides. Additionally, the production of mixed anhydrides is rendered more economical since the reaction product is more pure and therefore requires less post-reaction purification.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a process for producing an anhydride of two different carboxylic acids, comprising forming a mixture of a first carboxylic acid and a reactive acid derivative of a second carboxylic acid other than the first carboxylic acid, and reacting said mixture in the presence of a base to produce said anhydride, said base being added to said mixture to initiate the reaction.
In accordance with this invention any of the conventional conditions for forming an anhydride by reacting a carboxylic acid, a reactive acid derivative, and a base, can be used. What is important is that the base is not added until a mixture of the first carboxylic acid and the reactive acid derivative is formed.
Preferably the first carboxylic acid and the reactive acid derivative are present in the mixture in a molar ratio of about 1:1, however either the first carboxylic acid or the reactive acid derivative can be present in excess. Preferably the base is present in the mixture in an amount which is at least about one mole per mole of the first carboxylic acid. More preferably, the base is present in an amount which is from about one mole to about two moles per mole of the first carboxylic acid. Still more preferably the base is present in an amount which is about one mole per mole of the first carboxylic acid. Preferably the base is present in the mixture in an amount which is at least about one mole per mole of the reactive acid derivative. More preferably, the base is present in an amount which is from about one mole to about two moles per mole of the reactive acid derivative. Still more preferably, the base is present in an amount which is about one mole per mole of the reactive acid derivative.
This reaction is generally applicable and can be used for making any mixed anhydride. The first carboxylic acid and the second carboxylic acid can be any carboxylic acid provided that they are different from each other. The term “carboxylic acid” means any compound having a —COOH moiety. These can be e.g. unsubstituted and substituted aliphatic, aromatic, aromatic-aliphatic, heteroaromatic or heteroaromatic-aliphatic carboxylic acids or protected aminocarboxylic acids, e.g. N-acylated aminocarboxylic acids such as natural N-acylated &agr;-amino acids having the L-configuration or corresponding non-natural N-acylated &agr;-amino acids having the D-configuration as well as the corresponding racemates of the L- and D-amino acids. Moreover, homologues of such amino acids can be used, e.g. amino acids in which the amino acid side-chain is lengthened or shortened by one or two methylene groups and/or in which a methyl group is replaced by hydrogen. Furthermore, there can be used substituted aromatic N-acylated &agr;-amino acids, e.g. substituted phenylanine or phenylglycine, which can carry one or more of the following substituents—independently of one another—: alkyl, e.g. methyl, halogen, a protected hydroxy group, alkoxy, e.g. methoxy, alkanoyloxy, e.g. acetoxy, a protected amino or alkylamino group, alkyanoylamino, e.g. acetylamino or pivaloylamino, alkoxycarbonylamino, e.g. t-butoxycarbonylamino, arylmethoxycarbonylamino, e.g. benzyloxycarbonylamino or 9-fluorenylmethoxycarbonyl, and/or nitro. Moreover, benz-fused phenylalanine or phenylglycine, such as &agr;-naphthylamine, or hydrogenated phenylalanine or phenyglycine, such as cyclohexylalanine or cyclohexylglycine, a 5- or 6-membered cyclic benz-fused N-acylated &agr;-amino acid, e.g. indoline-2-carboxylic acid or 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, also come into consideration. Furthermore, natural or homologous N-acylated &agr;-amino acids in which a carboxy group in the side-chain is present in a esterified or amidated form, e.g. as an alkyl ester group, such as methoxycarbonyl or t-butoxycarbonyl, or as a carbamoyl group, an alkylcarbamoyl group, such as methylcarbamoyl, or a dialkylcarbamoyl group, such as dimethylcarbamoyl, and in which the amino group in the side-chain is present in acylated form, e.g. as an alkanoylamino group, such as acetylamino or pivaloylamino, as an alkoxycarbonylamino group, such as t-butoxycarbonylamino, can be used. In addition, amino acids in which a carboxy group in the side-chain is present as an arylmethoxycarbonylamino group, such as benzyloxycarbonylamino, can be used. A hydroxy group in the side-chain can be present in a etherified or esterified form, e.g. as an alkoxy group, such as methoxy, and also as an arylalkoxy group, such as benzyloxy, or as a lower-alkanoyloxy group, such as acetoxy. Suitable N-acyl groups are alkanoyl, such as acetyl or pivaloyl, alkoxycarbonyl, such as t-butoxycarbonyl and arylalkoxycarbonyl, such as benzyloxycarbonyl.
Examples of suitable unsubstituted and substituted aliphatic, aromatic and aromatic-aliphatic carboxylic acids, which can optionally be used in the form of their protected derivatives, are propionic acid, isobutyric acid, (R)- and (S)-lactic acid as well as the corresponding racemates, 2-phthalimidoxy-isobutyric acid and benzoic acid, 3,4-dihydroxybenzoic acid, salicylic ac

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