IE42673B1 - Production of amino acids - Google Patents

Abstract

The technical problem of preparing amino acids from carbamyl derivatives thereof is solved by reacting such a derivative, which may have been converted to a salt, with an oxidising agent such as nitrous acid in the presence of a cation resin in the acid form.

Description

This invention relates to a process for producing amino acids starting from the corresponding carbamoyl derivative of the amino acids.

Our British Patent Specification No. 1,452,591 describes and claims a process for producing optically active carbamoyl derivatives of amino acids from the corresponding racemic hydantoins by stereo-selective enzymic hydrolysis. The carbamoyl derivatives thus obtained can then be converted into the corresponding amino acid merely by boiling the derivative in an aqueous solution.

However, the hydrolysis of the carbamoyl derivatives to the amino acid under such conditions can be slow and can require a strict control of the operating conditions, and can sometimes give rise to by-products with a resulting lowering of the yield and even partial racemization.

The present invention provides a process for producing an «-amino acid, which comprises reacting the N-carbamoyl derivative of the desired amino acid, or a salt of such a derivative, with an oxidizing agent in the presence of an acid-group-containing ion-exchange resin.

By means of the present invention, the conversion of the carbamoyl derivative to the corresponding amino acid, can take place under mild conditions such that the resulting amino acid retains the optical purity of the starting carbamoyl derivative. - 2 4 ««7 3 The results which can be obtained by the present invention are surprising inasmuch as it is known that by merely reacting the carbamoyl derivative of an amino acid with an oxidizing substance, the desired amino acid is produced, but the amino group of the amino acid is immediately converted to a hydroxy group to give the corresponding hydroxy acid, thus making it impossible satisfactorily to convert the carbamoyl derivative to its amino acid.

In contrast, it has been observed that, when operating in the presence of cationic resins, in accordance with the present invention, under appropriate pH and temperature conditions, surprisingly high yields can be achieved inasmuch as the aminoacid is completely exempt from attack by the oxidizing reactant.

The process of the present invention can be carried out by dissolving the carbamoyl derivative, or a salt thereof, in water at a suitable concentration, preferably near saturation. The solution is supplemented by a quantity of a cationic resin in its acidic form preferably having such an exchange capacity as to bind from 100 to 500% of the amino acid product. During this step, the pH is generally lowered and the carbamoyl derivative, in an excess amount relative to its solubility, is precipitated. There are generally added from 1 to 1.5 equivalents of oxidizing agent per mole of carbamoyl derivative, the whole operation generally being conducted at a temperature in the range from 0°C to 40°C.

As cationic resins, there can be used resins with various acidic groups, although sulphonic type resins are preferably used. Also, the oxidizing agent can be any suitable oxidizing agent, although the use of nitrous acid or a salt thereof is preferred.

On completion of the reaction, the amino acid can be eluted from the resin with a base, after which the resin can be brought to its acidic form again; from the eluate, the amino acid can be isolated by simple concentration and crystallization operations. - 3 . 5 Ι«·?3 The present invention will now be illustrated by the following Examples 2 to 6, Example 1 being included for comparative purposes.

EXAMPLE 1 (Comparative) Millilitres of a 25 mM solution of N-carbamoyl-alpha-alanine were treated at 0°C with 5 ml of a 50 mM solution of NaNOg in water. The concentration of the amino acid (i.e. alanine) in the solution was occasionally measured. The concentration reached a maximum of 5 mM in the first hour of the reaction, and after that slowly diminished so that after 5 hours it had fallen to 3.2 mM.

Chromatographic analysis of the mixture showed the presence of a considerable quantity of lactic acid.

EXAMPLE 2. 194 Grams (1 mole) of D-N-carbamoyl-phenylglycine having an optical purity of 99% were slurried in 10 litres of deionized water, in the presence of 8 litres Amberlite I.R. 120 (H+), which is a phenol-methylene sulphonic resin.

The word '‘Amberlite is a Registered Trade Mark. The solution was stirred at room temperature and to it were added 83 grams (1.2 mole) of sodium nitrite.

After about 2 hours, the resin was filtered off, washed twice with 10 litres of demineralized water and then transferred to a column having a diameter of 11 centimetres and a height of 1 metre. The resin was then eluted with 2 mM ammonia; the amino acid was present in its entirety in the fraction from 10 to 15 litres of eluate.

The resulting solution of the ammonium salt of D-phenylglycine, in volume 5 litres, was evaporated under reduced pressure to dryness. There were ΟΛ thus obtained 150 grams (99% of theory) of D(-)phenylglycine having an (« )D = 157° (C = 0.5; HCl IN), that is an optical purity higher than 98% by taking as ?n the («t)D the data of the technical literature (Org. Synth. 22, 23, 1942). EXAMPLE 3.

By adopting the same procedure as set forth in Example 2, but starting from 132 grams (1 mole) of L-N-carbamoyl-alpha-alanine having an optical purity of on 98% there were obtained 87 grams (0.98 mole) of L-alpha-alanine with an ( D = - 4 4***3. 14.3° (c = 2, HCl IN); from the literature ( ο<· )θ15 = + 14.7°, according to J. Chem. Soc. 113, 526, 1918, for the pure compound.

EXAMPLE 4.

Following the same procedure as described in Example 2, but starting from 160 grams (1 mole) of L-N-carbamoyl valine with an optical purity of 97%, there were obtained 110 grams (0.94 mole) of L-valine; ( ot )^20 = 28.2° (c 3; HC1 6 NJ: according to Ber. 39, 2320, 1906, ( «* )θ2θ = 28.8° for the pure isomer.

EXAMPLE 5.

By following the same procedure as described in Example 2, from 192 grams (1 mole) of L-N-carbamoyl methionine, having an optical purity as high as 99%, there were obtained 145 grams (0.97 mole) of L-methionine; ( -)n^ ~ minus 8.01° (c - 0.8, water); according to J. Am. Chem. Soc., 53, u 25 3490, 1931, ( « )D = minus 8.01° for the pure isomer.

EXAMPLE 6.

Following the same procedure as described in Example 2, from 190 grams (1 mole) of L-N-carbamoyl glutamic acid having an optical purity of 98%, there were obtained about 141 grams (about 0.96 mole) of L-glutamic acid; ( « )D20 = 31° (c = 1; HC1 6N); according to Ber., 40, 3717, 1907, ( « )Q12 = + 31,2°, for the pure isomer.

Claims (8)

1. A process for producing an «-amino acid, which comprises reacting the N-carbamoyl derivative of the desired amino acid, or a salt of such a derivative, with an oxidizing agent in the presence of an acid-group-containing ion-exchange 25 resin.

2. A process according to Claim 1, wherein the reaction is conducted in the presence of an amount of oxidizing agent in the range from 1 to 1.5 equivalents per mole of carbamoyl derivative.

3. A process according to Claim 1 or 2, wherein the reaction is conducted 30 at a temperature in the range from 0°C to 40°C. - 5 4»t*3

4. A process according to any preceding claim, wherein the resin used is of the sulphonic type.

5. A process according to any preceding claim, wherein the oxidizing agent is nitrous acid or a salt thereof.

6. A process according to any preceding claim, where the acid-groupcontaining ion-exchange resin is used in an amount sufficient to absorb from 100 to 500% of the amino acid produced in the reaction.

7. A process according to Claim 1, substantially as described iri any one of the foregoing Examples 2 to 6.

8. An amino acid whenever produced by a process according to any preceding claim.