Alkylation of amino acids

Details Alkylation of amino acids Alkylation of amino acids

2000-05-05

2001-08-21

Shippen, Michael L. (Department: 1621)

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

Organic compounds

Carboxylic acids and salts thereof

Reexamination Certificate

active

06278020

ABSTRACT:

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
n
H
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
2
)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
2
)
n
— chain. Cyclohexyl groups used with or without a —(CH
2
)
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, tyrosine, serine, cystine, threonine, methionine, diiodotyrosine, thyroxine, dibromotyrosine, tryptophan, proline and hydroxyproline (which are all “neutral”), aspartic acid, glutamic acid and 3-hydroxyglutamic acid (which are all “acidic”) and ornithine, arginine, lysine and histidine (which are all “basic” and less preferred for the reasons stated below). All these acids have an &agr;-amino group but other amino acids e.g. phenylglycine or amino acids having a &bgr;-amino group such as &bgr;-alanine can be used. The preferred amino acids are those with two carboxyl groups and one amino group (preferably the “acidic” amino acids listed above). Aspartic and glutamic acid are the most preferred of the three. The “basic” amino acids have more potential for unwanted side reactions and are currently less preferred than the “neutral” amino acids. The presence of e.g. aryl groups is not significant; for example phenylalanine reacts satisfactorily. In the case of synthetic amino acids substituted hydrocarbyl groups e.g. of the various types outlined above may be present. Specific optical isomers, particularly the L-form, are desirable because they increase biodegradability and in some cases, may also improve the chelating effect.
The metal ion is desirably a divalent ion but ions of higher valencies can be used. The preferred ions are those of the alkaline-earth metals (Groups II/IIa) with Ca and Mg being preferred. Other preferred metals are transition metals, particularly Group IIb metals such as Zn and other metals of the first transition row (Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn). It is important however to select metals which do not precipitate out, e.g. as oxides or hydroxides, under the reaction conditions (normally an alkaline pH).
The metal ion will normally be provided by a water-soluble metal salt although a water-soluble oxide or hydroxide may be used to raise the pH. Ca(OH)
2
can for example be used for this purpose (though its solubility is limited). Examples of salts include the divalent metal salts CaCl
2
, CaBr
2
, MgCl
21
, and ZnCl
2
. The reaction proceeds at a pH in the range 7-14, generally in the range 8-13 and preferably in the range 9-12. The pH may be maintained with alkali (i.e. a base), typically aq. NaOH solution, though a wide variety of water-soluble inorganic and organic bases may be used. It is desirable to add alkali during the reaction such that the pH remains substantially constant.
The reaction medium is normally wholly aqueous but the presence of other solvents such as ethanol is not excluded. In some circumstances, alkali (base) may be provided wholly or in part by other components of the reaction medium, particularly when the amino acid starting material is in salt form and/or when the metal cation is provided by a basic compound.
The amounts of metal salt included in the reaction mixture may generally range from 0.2 to 2.0 moles, preferably 0.2 to 1.5 moles, especially 0.3 to 1.0 moles, of cation per mole of amino acid.
The remaining parameters for the reaction are generally:
General
Preferred
Range
Range
Amino acid:dihaloalkane
1:1 to 6:1
1.5:1 to 5:1
mole ratio
Reaction Temperature
70-120° C.
85-100° C.
Reaction Period
1-48 hours
1-12 hours
pH
7-14, e.g. 8-13
9-12
Particularly when using the more volatile dihaloalkanes, the reaction is desirably carried out under pressure e.g. 1-12 bar gauge, preferably 1-6 bar gauge.
The alkylated product is generally less soluble than the starting amino acid such that the reaction mixture can be diluted to a level at which remaining amino acid is soluble, followed by acidification and selective crystallisation of the desired product.
In the specific case of (S,S)-ethylenediaminedisuccinic acid prepared from L-aspartic acid and 1,2-dibromoethane, the reaction mixture is preferably held at boiling point for about 1 hour to reduce the level of unreacted 1,2-dibromoethane, diluted with water, acidified with an acid such as hydrochloric acid to a pH of from 2-5, preferably 2-3, and cooled to below about 50° C. to crystallise out the product acid. The crysta

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