Alkylation of amino acids

Abstract

This invention provides improvements in certain processes for alkylating amino acids whereby yields based on amino acid are improved. More specifically, 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, 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 and/or wherein the unreacted amino acid is recovered and recycled.

1 . 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, 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.  
     
     
         2 . A process according to  claim 1 , wherein the cations are divalent.  
     
     
         3 . A process according to  claim 2 , wherein the cations are of an alkaline earth metal or Group IIb metal.  
     
     
         4 . A process according to  claim 3 , wherein the cations are of calcium, magnesium or zinc.  
     
     
         5 . A process according to  claim 4 , wherein the cations are of calcium.  
     
     
         6 . A process according to any preceding claim, wherein the cations are introduced in the form of a water-soluble metal salt, oxide or hydroxide.  
     
     
         7 . A process according to any preceding claim, wherein the amino acid is an optionally substituted α- or β-amino acid.  
     
     
         8 . A process according to  claim 7 , wherein the amino acid is of a naturally-occurring type.  
     
     
         9 . A process according to  claim 8 , wherein the amino acid is neutral or acid.  
     
     
         10 . A process according to  claim 9 , wherein the amino acid is aspartic acid or glutamic acid.  
     
     
         11 . A process according to  claim 8 ,  9  or  10 , wherein the amino acid is in the form of a specific optical isomer.  
     
     
         12 . A process according to  claim 11 , wherein the amino acid is in the S-form and the product is in the S,S-form.  
     
     
         13 . A process according to any preceding claim, wherein X and Y are each chloro or bromo.  
     
     
         14 . A process according to any preceding claim, wherein A is of the general formula (CH 2 ) n  where n is 1 to 20, optionally substituted with groups which are unreactive under the reaction conditions.  
     
     
         15 . A process according to  claim 14 , wherein A is (CH 2 ) n  or cycloalkyl.  
     
     
         16 . A process according to  claim 15  wherein A is (CH 2 ) n  where n is 2, 3 or 4 or 1,2-, 1,3- or 1,4-cyclohexyl.  
     
     
         17 . A process according to  claim 16 , wherein X-A-Y is dibromoethane or dichloroethane.  
     
     
         18 . A process according to any preceding claim, wherein the reaction is carried out in aqueous alkali, preferably aqueous NaOH.  
     
     
         19 . A process according to any preceding claim, wherein alkali is added during the reaction.  
     
     
         20 . A process according to any preceding claim, wherein the reaction is carried out under pressure.  
     
     
         21 . A process according to  claim 20 , wherein the pressure is at least 1 bar gauge.  
     
     
         22 . A process according to any preceding claim, including the step of recovering the product from the reaction mixture.  
     
     
         23 . A process according to any preceding claim, including the step of recovering unreacted amino acid and recycling it to the process.  
     
     
         24 . A process according to any preceding claim, wherein there are 0.2 to 2.0, preferably 0.2 to 1.5, and more preferably 0.3 to 1.0 moles of cation per mole of amino acid.  
     
     
         25 . A process according to any preceding claim, wherein the mole ratio of amino acid to X-A-Y is from 1:1 to 6:1, preferably from 1.5:1 to 5:1.  
     
     
         26 . A process according to any preceding claim, wherein the pH is in the range 7-14, preferably 8-13, and more preferably 9-12.  
     
     
         27 . A process according to any preceding claim, wherein the product is (S,S)-ethylenediaminedisuccinic acid or a salt thereof.  
     
     
         28 . A process for the preparation of (S,S)-ethylenediaminedisuccinic acid, which comprises reacting a 1,2-dihaloethane with L-aspartic acid in aqueous alkali, and recovering the product (S,S)-ethylenediaminedisuccinic acid from the reaction mixture, wherein the reaction is carried out in the presence of a water-soluble salt of a Gp II/IIa or transition metal.  
     
     
         29 . 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, 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), including the step of recovering unreacted amino acid and recycling it to the process.  
     
     
         30 . A process according to  claim 29 , wherein the recovery step comprises acidification of the reaction mixture so that the desired product crystallises out, separating the crystallised product from the mother liquor, raising the pH of the mother liquor with alkali, passing it through a nanofiltration membrane and acidifying the retentate.  
     
     
         31 . A process according to  claim 29 , wherein the recovery step comprises acidification of the reaction mixture so that the desired product crystallises out, separating the crystallised product from the mother liquor, further acidifying the mother liquor and allowing the amino acid to crystallise out.  
     
     
         32 . A process according to  claim 29 , wherein the recovery step comprises acidification of the reaction mixture so that the desired product crystallises out, separating the crystallised product from the mother liquor, raising the pH of the mother liquor with alkali, evaporating part of it to reduce its volume, acidifying it and allowing the amino acid to crystallise out.  
     
     
         33 . A process according to any one of claims  29 - 32 , wherein the reaction is carried out a number of times, the final mother liquor from which amino acid has been separated in one stage being added, to the mother liquor from which the desired product has been separated in another stage to produce a combined mother liquor from which amino acid is recovered.  
     
     
         34 . A process according to any one of claims  29 - 33 , having the characterising features of one or more of claims  1 - 22  and  24 - 27 .  
     
     
         35 . An amino acid derivative, in free acid or salt form, in which the nitrogen atoms of two or more amino acids are linked by a hydrocarbyl or substituted hydrocarbyl group, when prepared by a process according to any one of claims  1 - 28 .  
     
     
         36 . An amino acid derivative, in free acid or salt form, in which the nitrogen atoms of two or more amino acids are linked by a hydrocarbyl or substituted hydrocarbyl group, when prepared by a process according to any one of claims  29 - 34 .