There have been many reports on the production of optically active α-amino acid through chemical synthesis and biological synthesis.
For example, a process for optically resolving racemic α-amino acid amide using microorganisms and the like which has an ability to asymmetrically hydrolyse α-amino acid amide is a known process of biological synthesis. This process is useful as a general process for producing optically active α-amino acid because: α-amino acid with high optical purity can be easily produced by obtaining microorganisms with high stereoselectivity; starting racemic α-amino acid amide can be easily produced; this process can be applied for the production of both natural-type and non-natural-type optically active α-amino acids; and the like.
In the process for optically resolving racemic α-amino acid or optically impure α-amino acid amide using microorganisms and the like which has an ability to asymmetrically hydrolyse α-amino acid amide, however, both the optically active α-amino acid and the optically active α-amino acid amide of interest are present in the solution after the completion of the reaction. Thus, the optically active α-amino acid needs to be separated from the optically active α-amino acid amide.
One separation process can be carried out as follows: after the enzymatic asymmetric hydrolysis is carried out in an aqueous medium, the reaction solution is concentrated, a poor solvent for amino acid (i.e., an organic solvent such as alcohol) is added, the crystallized amino acid is taken, and unreacted amino acid amide is obtained as a filtrate in a dissolved state in a water-alcohol mixed solvent. Further, a process for producing optically active amino acid and amino acid amide in combination with racemization has been reported as a more efficient production process.
Examples of reported processs are: a process in which α-amino acid amide is removed by solvent extraction, followed by the collection of α-amino acid at the isoelectric point (see JP Patent Application Laying Open (Kokai) Nos. 58-209989 and 57-13000); a process in which ethanol is added and amino acid is preferentially crystallized (see JP Patent Application Laying Open (Kokai) Nos. 63-87998, 61-274690, 60-184392, and 59-159789); a process in which adsorption separation is carried out using an ion-exchange resin (see JP Patent Application Laying Open (Kokai) No. 1-226482); and a process in which α-amino acid amide is adsorbed on a cation-exchange resin, the cation-exchange resin is brought into contact with an enzyme to perform stereospecific hydrolysis, and a reaction is simultaneously conducted with the separation process, thereby producing the optically active amino acid (see JP Patent Application Laying Open (Kokai) No. 8-23996).
A process has been also reported in which, after the optical resolution, water which is contained in an aqueous solution of the obtained optically active α-amino acid, is removed under reduced pressure, the residue is washed with a heated organic solvent to selectively remove α-amino acid amide, and the remaining optically active α-amino acid is then recovered (see JP Patent Application Laying Open (Kokai) No. 61-293394).
This report also describes that a strongly basic compound is added to the organic solvent of the washed and recovered optically active α-amino acid amide, racemization of α-amino acid amide is carried out by heating, and the resulting mixture of D- and L-α-amino acid amide is recycled in asymmetric hydrolysis.
A process for racemizing α-amino acid amide by heating in the presence of alkali in an organic solvent is also described in JP Patent Application Laying Open (Kokai) No. 62-252751).
Further, JP Patent Application Laying Open (Kokai) No. 61-197530 describes that racemization efficiently proceeds under alkali conditions in an organic solvent.
In all these reports, the water content in the solution of the optically active α-amino acid amide should be kept low in order to inhibit the hydrolysis of α-amino acid amide, which is a side reaction during racemization. For example, the water content in an organic solvent has been specified at 10% or lower in JP Patent Application Laying Open (Kokai) No. 62-252751.
However, the process for separating the optically active α-amino acid from α-amino acid amide has various drawbacks, and it is not an industrially efficient production process.
In the process for collecting α-amino acid at the isoelectric point after separating α-amino acid from α-amino acid amide by solvent extraction, a large quantity of solvent is required for extraction. Accordingly, it is disadvantageous in terms of apparatus and cost. In the process for performing adsorption separation using an ion-exchange resin, many steps, such as adsorption, elimination, and recovery, are required. This process is unfavorable from the industrial point of view since it may bring about increased equipment investment, lowered recovery efficiency, contamination with impurities, and the like.
In contrast, in the process for preferentially crystallizing α-amino acid with the addition of ethanol to the concentrated reaction solution, operation is simpler and equipment investment is smaller than other processs since, for example, the process of concentration-crystallization can be carried out in the same tank. In this process, however, required ethanol volume should be several times that of the concentrate. This is one factor for the increased cost. Regarding this technique, there is a report concerning the limited use of this process for natural-type amino acids only, and the description on the purity of the obtained amino acid is available for valine only. Whether or not high purity amino acid can be efficiently obtained is not clear at all for other amino acids. Therefore, this process cannot be said to be versatile.
When the separated optically active α-amino acid amide is to be racemized and re-used in optical resolution in the above-mentioned process, it is obvious that ethanol has a low boiling point and is not suitable as a solvent for racemization. For example, JP Patent Application Laying Open (Kokai) No. 62-252751 describes an example of racemization using an ethanol solution, wherein the reaction is carried out by heating a vessel between 110 to 120° C. after sealing the reaction vessel in order to increase the reaction temperature. This process requires a particular apparatus for an industrial scale. Accordingly, without any equipment investment, it would be difficult to perform the ethanol-based reaction at normal pressure.
Further, since the water content of the separated and collected ethanol solution containing optically active α-amino acid amide is high, and the like, racemization of the optically active α-amino acid amide requires the dehydration of solution, substitution of solvents, and the like or the isolation and drying of the optically active α-amino acid amide crystals. These, therefore, complicate the processes.
In addition, the above process cannot always completely crystallize amino acid only, and amino acid could be contaminated with amino acid amide.
When only one optically active substance is needed, for example, it is very favorable if the optically active amino acid amide can be racemized and re-used as a starting material for asymmetric hydrolysis. However, the optical purity could be lowered by the contamination by amino acid.
In one process, which is carried out by removing water and washing the residue with a heated organic solvent, followed by selective washing and removal of α-amino acid amide, racemization can be carried out without isolating the optically active α-amino acid amide from the solution. However, it becomes technically difficult to completely dehydrate the solution and concentrate to dryness in the industrial scale production. This production process is impractical considering operability, equipment investment, and the like.
Accordingly, the processs for producing optically active α-amino acid and purifying racemized α-amino acid amide by the known technique are either inefficient or impractical for the collection of optically active α-amino acid and α-amino acid amide after the reaction, and are not industrially advantageous processs.
The present invention provides an effective and efficient process for producing optically active α-amino acid and optically active α-amino acid amide, which overcomes the above-mentioned disadvantages.