Alkylation of amino acids

Details Alkylation of amino acids Alkylation of amino acids

1996-01-11

1998-12-15

Shippen, Michael L.

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

Organic compounds

Carboxylic acids and salts thereof

C07C22900

Patent

active

058499482

DESCRIPTION:

BRIEF SUMMARY
This invention relates to a process for alkylation of amino acids, and particularly though not exclusively a process for preparing (S,S)-ethylenediaminedisuccinic acid or a salt thereof.
Certain compounds having amino acid moieties linked by a group joining their nitrogen atoms have a variety of uses mainly based on their metal chelating properties e.g. as corrosion inhibitors, and in detergents, photographic developing solutions, rubber and resin formulations and metal treatments. One particular example is ethylenediaminedisuccinic acid which has two chiral centres, the S,S-enantiomer being preferred because of its biodegradability and its better chelating properties. It can be manufactured by a variety of different routes, e.g. the reaction of NaOH with L-aspartic acid and dibromoethane c.f. Neal, J. A. and Rose, N. J., Inorganic Chemistry, Vol. 7, No. 11, November 1968, pages 2405-2412, particularly page 2406, but whichever route is chosen it is usually difficult to obtain economic yields and a high purity product.
We have now found that the overall yield in alkylation reactions of this general type can be improved by the presence of certain metal ions. While we do not wish to be bound by any theory, it is likely that the amino acid starting material, the final product or both forms a complex with the metal ion which facilitates the desired reaction. The amino acid is relatively expensive but any which is unreacted can normally be recycled. Thus from the point of view of economic operation, reduction of by-product formation is highly significant.
More generally stated, one aspect of the invention provides a process for the preparation of amino acid derivatives in free acid or salt form, in which the nitrogen atoms of two or more amino acid molecules are linked by a hydrocarbyl or substituted hydrocarbyl group, which comprises reacting, in an aqueous medium at a pH in the range 7-14 and preferably in aqueous alkali, a compound of the formula X--A--Y where X and Y are halo atoms which may be the same or different and A is a hydrocarbyl or substituted hydrocarbyl group in which X and Y are attached to aliphatic or cycloaliphatic carbon atoms, with an amino acid (or salt thereof), wherein the reaction is carried out in the presence of dissolved cations of an alkaline earth metal or of a transition metal.
In the simplest cases A will have the formula --C.sub.n H.sub.2n -- where n can be from 1 to 20, particularly 1 to 5, more especially 2, 3 or 4. Preferably it will be straight-chained i.e. --(CH.sub.2).sub.n -- but branched chain compounds can be used (e.g. compounds with alkyl substituents on the chain), as also can compounds with aryl groups such as phenyl (provided that X and Y are attached to an aliphatic or cycloaliphatic carbon atom) and cycloalkyl groups such as cyclohexyl in the main chain or in a side chain (as a monovalent, divalent or polyvalent group). A can also be divalent cycloalkyl without a --(CH.sub.2).sub.n -- chain. Cyclohexyl groups used with or without a --(CH.sub.2).sub.n -- chain can be 1,2-cyclohexyl, 1,3-cyclohexyl or 1,4-cyclohexyl, for example. Possible non-hydrocarbyl substituents include ether and thioether linkages, and hydroxy groups; they can be in a main chain or a side chain. Further halo atoms can also be present particularly if more than two amino acid molecules are to be linked. The substituents should basically not be groups which encourage unwanted side reactions. Olefinic unsaturation may also be present.
The term halo embraces chloro, bromo and iodo; in practice iodo compounds are undesirable for cost reasons. Bromo is preferred and chloro less preferred; one bromo atom and one chloro atom is another satisfactory possibility. The preferred X--A--Y compounds are dibromoethane and dichloroethane.
The amino acids will normally be one of the 26 or so naturally occurring amino acids listed in standard textbooks (except cysteine because of its --SH group which would undergo unwanted side reactions) viz. glycine, alanine, valine, leucine, norleucine, phenylalanine, tyrosin

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