JPH05310781A - Improved production of crystal of l-alpha-aspartyl-l-phenylalanine methyl ester - Google Patents

Abstract

PURPOSE:To obtain crystal of L-alpha-aspartyl-L-phenylalanine methyl ester having excellent filtering characteristics and dehydrating properties in high yield, economically and advantageously by using a crystallizing device equipped with a cooler, an agitating element of specific constitution and baffle plats of specific constitution. CONSTITUTION:First, a first member 1 composed of a flat plate to sweet the bottom part of a crystallizing tank 5 is fixed to a revolving shaft 4 at one end in the horizontal direction of the plate and a member 2 which is a bar second member 2 extending from the revolving shaft 4 toward the inner wall of the tank and has one end fixed to the revolving shaft 4 is arranged above the first member 1. Further, a stirring rod or laminar third member 3 which extends in the vertical direction in a liquid and stirs a solution is attached to the first member 1 and/or the second member 2 to constitute an agitating element 6. By using a crystallizing device equipped with a cooler, the agitating element 6 and plural baffle plates 8 set on the side wall face of the crystallizing tank 5 from the bottom to the top along the axial direction at intervals, a solution of L-alpha-aspartyl-L-phenylalanine methyl ester is continuously treated at <= its crystallization temperature.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to α-L-aspartyl-
The present invention relates to a crystallization separation method of L-phenylalanine methyl ester (hereinafter abbreviated as APM).

[0002]

APM is widely known as a dipeptide sweetener having a sweetness about 200 times that of sugar. AP
M is synthesized by various methods, but in any method, a step of purifying a crude APM is indispensable when finally isolating APM to obtain a final product. This purification step is usually performed with water or a water-containing lower alcohol (hereinafter,
APM solution of water and a solvent containing water is referred to as an aqueous medium) is generally purified by recrystallization by cooling. The obtained crystals are separated by a solid-liquid separator such as a centrifuge, dehydrated, and dried to obtain a product.

Usually, cooling crystallization is carried out in a stirring type crystallization tank having a cooling heat transfer surface or a crystallization tank having an external circulation type heat exchanger. Forced flow devised for the purpose of improving crystal properties. It is known that the cooling is performed by a crystallization tank that cools only by conduction heat transfer that does not give heat (Japanese Patent Laid-Open No. Sho 5).
8-177952). In addition, as a method of giving forced flow, a method of performing crystallization by mixing a hot aqueous solution and a cold aqueous solution of APM is also known (JP-A-3-7).
2497).

[0004]

The conventional method of cooling and crystallization of APM in a crystallization tank accompanied by forced flow such as normal stirring and external circulation gives fine crystals having poor filtration and dehydration properties. Further, according to this method, there is a drawback that crystals are easily deposited on the cooling heat transfer surface to cause scaling, and the heat transfer efficiency is rapidly deteriorated.

As a method for avoiding such a problem, A is achieved by conduction heat transfer without giving forced flow such as mechanical stirring.
A method has been proposed in which the PM aqueous solution is cooled to form a pseudo-solid phase and then further cooled if necessary. According to this method, crystals having improved filterability and dehydration property in the solid-liquid separation step are obtained. Although it can be obtained, cooling by conduction heat transfer is performed without stirring and after forming the pseudo-solid phase, the cooling efficiency is extremely poor. However, it takes a very long time to cool, and there is a limit industrially. Therefore, in this prior art, in order to shorten the cooling time, the maximum distance from the cooling surface to the object to be cooled is defined, and a special device suitable for it is proposed. As described above,
The method described in Japanese Patent No. 77952 cannot be an industrial method unless a special crystallization apparatus is used.

Further, a method has been proposed in which a hot aqueous solution and a cold aqueous solution of APM are mixed under forced flow to perform crystallization, and further, if necessary, cooled to improve the crystal properties. However, it is true that the crystals obtained by mixing the hot aqueous solution and the cold aqueous solution of APM have good filterability, but when the aqueous medium is water, the amount of crystals obtained is extremely high. It is a little and not economically advantageous in terms of economy.

In addition, after mixing the hot aqueous solution and the cold aqueous solution, in order to increase the yield of APM crystals, it is necessary to carry out the cooling crystallization which is conventionally performed under mechanical stirring.
The crystals obtained by mixing the hot aqueous solution and the cold aqueous solution and then cooling and crystallizing are fine crystals having poor filterability as long as an ordinary stirring blade is used. In addition to that, even crystals obtained by mixing a hot aqueous solution and a cold aqueous solution may become fine due to mechanical stirring during cooling crystallization,
Expected enough. From this fact, JP-A-3-72497
The APM crystallization method described in the publication cannot be said to be an industrially advantageous method.

[0008]

The inventors of the present invention have conducted extensive studies to solve the above-mentioned problems in the crystallization of APM, and as a result, gave crystals excellent in filterability and dehydration, and were industrially used. The present inventors have found a crystallization method of APM that is advantageous for

That is, surprisingly, in the method for crystallizing APM from the solution, the APM solution is continuously supplied to the crystallizer by using the cooling device and the crystallizer having a specific constitution. Crystals obtained by continuously cooling the inside of the crystallizer to a temperature not higher than the crystal crystallization temperature of the APM solution and continuously extracting the slurry liquid containing the crystallized crystals are very excellent in filterability and dehydration. It was also found that crystallization can be performed with almost no scaling on the wall surface of the crystallization tank. The method for cooling the inside of the crystallizer is not particularly limited, and cooling by decompression or external forced cooling by circulating a refrigerant through the jacket of the crystallizer may be used. It suffices if the temperature can be maintained below the crystal precipitation temperature of the solution.

A crystallizer having a specific structure in the preamble is claimed in claim 1.
However, roughly speaking, it is composed of a plate for sweeping the tank and the bottom of the tank, a rod-shaped member provided on the plate for extending in the vertical direction or the horizontal direction, and a baffle plate.

The stirring blade used in the present invention will be described. The stirring blade is attached to a rotating shaft provided at the center of the tank on one side of the blade. The first member of the blade is essentially a plate and sweeps the bottom of the bath. It is preferable that the distance between the lower end of the plate and the bottom of the tank is narrow. Although the reason is not clear, it seems preferable that the liquid flow toward the bottom of the tank is not large. The end facing the inner wall of the tank is preferably spaced to some extent from the inner wall.
This is for forming a liquid flow toward the inner wall.

The second member is a substantially rod-shaped member member extending from the rotary shaft provided on the first member to the inner wall of the tank,
In other words, it is an arm extending from the rotation axis. This member is not limited to one, and a plurality of members may be arranged vertically. The limitation of the length is the same as that of the length of the first member, and it may be shorter. The extending direction of the rod-shaped member is not particularly required to be parallel to the liquid surface, and may be provided so as to substantially cut the liquid laterally even if it is inclined.

The third member is a rod-shaped or plate-shaped member that extends substantially vertically in the liquid and stirs the liquid. If the mechanical strength of stirring the liquid can be maintained, the first member or the second member. It may be fixed to only one of the above.
The direction of this member is also not required to be strict, and it is sufficient that the member is oriented substantially in the vertical direction. It may be provided via the. This member may be plural.

Most commonly, the above three members are provided in the same plane to form a lattice-like one having a space with one plate as a whole, but one plate as a whole is twisted. It does not matter even if one curved surface is formed. As a matter of course, the number of baffle plates may be one or more as long as it is ensured that the shaft can be smoothly rotated, but for facilitating the work, two baffles are provided symmetrically.

An example of the shape of the blade that can be used in the present invention is as shown in FIGS. 2 to 6, and FIGS. 7 to 9 are not used in the present invention. The second member and the third member will be described. In the above explanation, words such as parallel to the liquid surface or cutting the liquid horizontally are used, but this is expressed on the assumption that the liquid surface is intentionally assumed to be easy to understand. is doing. However, if the blades rotate in the tank, the liquid at the bottom of the tank inevitably causes a flow from the center to the outer circumference in the tank, and in response to this, the liquid inside the tank rises at the outer circumference and descends at the center. Circulation occurs due to convection. If the circulating flow becomes violent, the liquid surface will form a parabolic surface with the central part down. Therefore, the second member and the third member are shown in FIG. 2 when they are oriented parallel to the paraboloid, but this is not a problem. Furthermore, the second member and the third member may be integrated into a single curved rod as shown in FIG.

In the present invention, the above-mentioned stirring blade is set to 0.2
Thus, by rotating at a peripheral speed of 1.5 m / sec, it was possible to obtain APM crystals excellent in filterability and dehydration in a high yield with almost no crushing of the precipitated crystals. Further, when using a normal stirring blade, for example, a paddle type or turbine type, compared to conventional cooling crystallization,
In terms of filterability and dewaterability, some good crystals are obtained, but in order to prevent scaling on the inner wall of the crystallizer, it is necessary to rotate at a considerable peripheral speed,
Since the precipitated crystals are crushed by the shearing force, there is a limit in obtaining crystals having excellent filterability and dehydratability. This is a surprising new fact in view of the peculiar crystallization behavior of APM, which was said to be unable to improve the properties of crystals under forced flow conditions such as stirring.

That is, the present invention relates to an aqueous solution of α-L-aspartyl-L-phenylalanine methyl ester from A
In obtaining the PM crystal, crystallization is continuously performed using the crystallizer having the above-mentioned specific structure.
The present invention provides a crystallization method of -L-aspartyl-L-phenylalanine methyl ester.

An embodiment of the present invention will be described based on the schematic diagram shown in FIG. APM dissolution tank # 1 is a storage tank for a solution in which about 2 to 4% by weight of APM is dissolved at a temperature of 60 ° C. or lower,
The solution is continuously supplied to crystallization tank # 2 by pump # 4. Crystallization tank # 2 has two or more baffles in the tank,
It is equipped with a stirring blade and a cooling device as shown in FIGS. The crystallization tank # 2 is continuously supplied with the APM solution from the dissolution tank # 1, and is cooled to a temperature below the crystallization temperature of the APM solution by a cooling device to continuously crystallize APM crystals.

The temperature at which APM crystals are precipitated is closely related to the concentration of the solvent and its solution. In the present invention, for example, the solubility of APM in water is about 5% at 60 ° C. and 20 ° C.
It is about 1% at 5 ° C. and about 0.5% at 5 ° C., and crystals can be precipitated by cooling to a temperature below the solubility. The crystallized crystal slurry is continuously precipitated from the bottom of the crystallization tank, and the crystal part and the liquid are separated by a separator such as a centrifuge.

[0020]

EFFECTS OF THE INVENTION According to the present invention, since crystals having good filterability and dehydration can be obtained in good yield, not only the economical efficiency of the crystallization step but also economically after the crystallization step is achieved. Provide an advantageous industrial process. That is, 5-benzyl-3,6-dioxo-2, which does not have a sweet taste, is obtained because crystallization is performed in a short time by continuing the crystallization process.
-The production of piperazine acetic acid methyl ester (DKP) can be suppressed. In addition, the equipment can be downsized, and the equipment cost can be reduced because there is no need to use a special equipment, and the equipment can be rationalized by improving the filterability even in the solid-liquid separation process. The cleaning effect of impurities such as DKP is significantly improved. Further, the improvement of the dehydration property makes it possible to reduce the drying load in the drying process.

Further, according to the present invention, since scaling hardly occurs in the crystallization tank, there is almost no need to perform a complicated operation such as removal of scaling. As is clear from the above, the present invention provides various industrially advantageous crystallization methods that improve various drawbacks in the conventional crystallization operation and provide crystals with excellent filterability and dehydration in high yield. To do.

[0022]

EXAMPLES The present invention will now be described in more detail with reference to Examples. Example 1 A test was conducted using the apparatus shown in FIG. In the figure, # 1 is AP
M dissolution tank (300 l, with jacket and Faudler stirring blade), # 2 crystallizer (300 l, with jacket and stirring blade), # 3 is filter (centrifugal separator), # 4 and # 5 are transfer pumps, # 6 is a condenser, and # 7 is a vacuum pump.

Hot water is circulated in the jacket of the # 1 raw material tank so that the 4% APM aqueous solution is always maintained at 60 ° C., and the required amount of APM and hot water are constantly supplied. A # 2 crystallizer was charged with 250 kg of APM aqueous solution, and crystallized up to 5 ° C. by external cooling from the jacket. Supply the APM aqueous solution from # 1 to # 2
It was carried out continuously so that the internal temperature was always kept at 5 ° C. In # 2, the refrigerant circulated through the jacket during crystallization. The stirring blade of the # 2 crystallizer was as shown in FIG. 2, and the rotation speed was 40 rpm. The same amount of A supplied from # 1 from the bottom of # 2
The PM crystal slurry was continuously deposited. 250 kg of the crystallization mass of the # 2 crystallizer after this operation was continuously performed for 5 hours was filtered and dehydrated by a # 5 centrifuge.
After only 20 minutes, the water content of the cake was 32%. still,
The APM recovery rate was 86%. In addition, almost no scaling was observed on the inner wall of each crystallizer.

Example 2 A stirring blade (FIG. 2) of the # 2 crystallizer was rotated at 30 rpm, and the same operation as in Example 1 was carried out.
Was filtered and dehydrated with a centrifuge.
The water content of the cake after 0 minutes was 30%, and the APM recovery rate was 86%. Almost no scaling was observed on the inner wall of the crystallizer.

Example 3 A test was conducted in the same manner as in Example 1 by setting the rotation speed of the stirring blade (FIG. 2) of the # 2 crystallizer to 50 rpm and performing cooling using both reduced pressure cooling and external cooling. After filtration and dehydration, the water content of the cake after 20 minutes was 30%, and the recovery rate of APM was 87.
%Met. Almost no scaling was observed on the inner wall of the crystallizer.

Example 4 Using the stirring blade of the # 2 crystallizer as shown in FIG. 5, the same operation as in Example 1 was carried out. 250 kg of the crystallization mass was filtered and dehydrated by a centrifugal separator, and after 20 minutes. Had a water content of 32% and an APM recovery rate of 85%. Almost no scaling was observed on the inner wall of the crystallizer.

Example 5 Using the stirring blade of the # 2 crystallizer as shown in FIG. 6, the same operation as in Example 1 was performed, and 250 kg of the crystallization mass was filtered and dehydrated by a centrifugal separator, and after 20 minutes. Had a water content of 31% and an APM recovery rate of 86%. Almost no scaling was observed on the inner wall of the crystallizer.

Comparative Example 1 250 kg of a 4% APM aqueous solution was charged into a # 2 crystallizer using the stirring blade shown in FIG. 7, and a cooling crystallization was performed by circulating a refrigerant through the crystallizer jacket from 60 ° C. to 5 ° C. I went. The rotation speed of the stirring blade at this time was 200 rpm.
During the crystallization, there was a portion where the slurry did not flow, and a large amount was attached to the inner wall when discharged. 2 for subsequent filtration and dehydration
The water content was 60% or more over time. In addition, there was a filtration leak, and the recovery rate was 60%.

Comparative Example 2 A stirring blade of a # 2 crystallizer is shown in FIG.
The same operation as in Example 1 was performed. During crystallization, #
There was a portion where the slurry did not flow in the No. 3 and No. 4 crystallizers, and there was considerable adhesion to the inner wall when discharged. The water content in the cake was 55% even after 1 hour of filtration and dehydration. In addition, there was a leakage of filtration, and the recovery rate was 70%.

[Brief description of drawings]

FIG. 1 is a schematic diagram for explaining the present invention.

FIG. 2 is a cross-sectional view of a crystallizer provided with a specific stirring blade used for implementing the present invention.

FIG. 3 is a cross-sectional view of a crystallizer provided with a specific stirring blade used for carrying out the present invention.

FIG. 4 is a cross-sectional view of a crystallizer provided with a specific stirring blade used for carrying out the present invention.

FIG. 5 is a cross-sectional view of a crystallizer provided with a specific stirring blade used for carrying out the present invention.

FIG. 6 is a cross-sectional view of a crystallizer provided with a specific stirring blade used for carrying out the present invention.

FIG. 7 is a view showing a shape of a stirring blade that is not used for carrying out the present invention.

FIG. 8 is a view showing a shape of a stirring blade that is not used for carrying out the present invention.

FIG. 9 is a view showing a shape of a stirring blade which is not used for carrying out the present invention.

[Explanation of symbols]

 1. First member 2. Second member 3. Third member 4. Rotation axis 5. Crystallizer 6. Stirrer 7. Jacket 8. Baffle

Claims (2)

[Claims] 1. A method for crystallizing L-α-aspartyl-L-phenylalanine methyl ester from its solution, using a crystallizer equipped with a cooling device and blades and baffles having the configurations specified below. -Α-Aspartyl-L-phenylalanine methyl ester solution is continuously fed to the crystallizer, and L-α-aspartyl-
L-α-aspartyl-L-phenylalanine methyl ester, in which the inside of the crystallizer is kept cooled to a temperature not higher than the crystal crystallization temperature of the L-phenylalanine methyl ester solution, and the slurry liquid containing the crystallized crystals is continuously extracted. Improved crystal manufacturing method. (A) At least one blade is fixed to the rotating shaft so that the liquid in the crystallization tank can be stirred. (B) The wing is provided with the following three members (c), (d) and (e). (C) It is a substantially flat plate, and is fixed to the rotary shaft at one end in the lateral direction of the plate, and the end facing the fixed end and facing the inner wall of the tank extends until an arbitrary long distance is maintained from the inner wall, The first member in the downward direction maintains a constant short distance from the bottom of the tank. (D) Provided on the liquid surface side of the first member and extending in a direction substantially parallel to the liquid surface between the rotary shaft and the inner wall of the tank in a plane substantially parallel to the first member, the rotary shaft at one end And a second member that is fixed to the other end and extends from the inner wall of the tank until an arbitrary long distance is maintained. (E) It is provided on the liquid surface side of the first member and is always fixed to either one of the first member and the second member, and is substantially vertical in a plane substantially orthogonal to the liquid surface. A third member having a plurality of rods or plates extending to the. (F) A plurality of baffle plates are arranged on the side wall surface of the crystallization tank from the lower part to the upper part along the axial direction at intervals. 2. The method according to claim 1, wherein the wing is a member that is a single rod including a curve in which the second member and the third member are integrated and substantially substantially an arc. thing.