JPS5820283B2 - Continuous optical resolution method for racemic organic compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is characterized in that when a racemic organic compound is optically resolved by a preferential crystallization method, seed crystals are self-supplied by crushing the growing active crystal using a mechanical crushing mechanism. The present invention relates to a method for continuous optical resolution of racemic organic compounds that can efficiently and successfully obtain active substances with high optical purity.

Various methods have been known for continuous optical resolution using preferential crystallization of racemic organic compounds.

For example, (1) a supersaturated solution of the racemate is allowed to flow in and rise from the bottom of the split column, seed crystals of the optically active compound are continuously supplied from the top of the column, and crystals of the active compound that settle as they grow are transferred to the bottom of the column. A method of extracting more continuously
(Refer to Publication No. 7710), (2) After suspending a seed crystal of an optically active substance in a supersaturated solution of a racemic substance, and growing the crystal while continuously flowing the solution together with the suspended crystal in the same direction. Method of solid-liquid separation (see Japanese Patent Publication No. 11728/1972 and Japanese Patent Publication No. 27841/1989), (3)
A racemic supersaturated solution is flowed in and raised from the bottom of a dividing tank equipped with an ultrasonic generator, and activated crystals are initially inoculated, and thereafter the grown active crystals are crushed by the ultrasonic generator, thereby seeding. A method of solid-liquid separation in which active crystals are self-replenished, and when the number of active crystals that can be grown increases, the active crystals are intermittently extracted from the side of the tower along with the solution (Japanese Patent Publication No. 46-32
(See Publication No. 402).

However, among these methods, method (1) and method (2) require continuous inoculation of extremely optically pure active seed crystals from outside the splitting system, and for this purpose, a large amount of seed crystals must be prepared. Moreover, there is a disadvantage that a continuous seed crystal inoculation device must be installed.

Method (3) has a seed crystal self-replenishment function, but since it uses ultrasonic waves, if the solvent is water, the split material is susceptible to oxidation. need to be used, and there are problems with versatility in industrial implementation.

Furthermore, the heat generated by the ultrasonic generator is significant, making thermal economy difficult and temperature control difficult.

. Furthermore, the grown active crystals have to be extracted intermittently in batches, which is a serious hindrance to the smooth continuity of the entire process when carried out industrially.

However, as a result of extensive research in order to solve the above-mentioned problems in the conventional optical resolution method based on the preferential crystallization method of racemic organic compounds, the present inventors have developed a continuous process for racemic organic compounds that is extremely advantageous industrially. We succeeded in solving the optical splitting method.

That is, the present invention relates to optical separation using a preferential crystallization method of racemic organic compounds, and provides a solution supply port provided at the bottom of the tank, an overflow port provided at the top of the tank, and a crystal suspension section occupying the upper part of the tank. and a divided tank equipped with a mechanical crushing mechanism consisting of a crystal crushing screen placed below the crystal suspension and a crystal crushing rotary blade placed close to the bottom of the screen. A certain racemic solution is supplied continuously or intermittently from the liquid supply port, seed crystals of the active substance are initially supplied into the tank, and after that, a part of the grown active substance crystals is crushed by the mechanical crushing mechanism. A racemic device that is self-replenishing by crushing, and a part of the grown active crystals is continuously or intermittently discharged from an overflow port together with a solution, and the active crystals are removed by solid-liquid separation. A method for continuous optical resolution of organic compounds is provided.

In the method of the present invention, seed crystals of the active substance need only be inoculated once at the initial stage, and thereafter, the seed crystals are self-supplied to the split system by crushing the growing active crystals using a mechanical crushing mechanism.

Therefore, the complexity of preparing a large amount of seed crystals in the conventional methods (1) and (2) in which seed crystals are continuously supplied from outside the splitting system is eliminated, and a continuous seed crystal inoculation device is not required. .

In addition, since self-replenishment of seed crystals is achieved by mechanically crushing the growing active crystals, water can be used as a solvent, which was not used in the conventional method (3) that uses ultrasonic crushing. Temperature control is easy because there is little heat generation.

Furthermore, in the method of the present invention, the active substance crystals that have grown sufficiently in the crystal suspension part are smoothly and continuously taken out from the splitting system together with the overflow solution, and by solid-liquid separation, highly pure active substance crystals are obtained. Crystals can be changed.

Therefore, the method of the present invention is industrially extremely advantageous since the entire process can be carried out smoothly and continuously.

FIG. 1 is a schematic longitudinal cross-sectional view showing a preferred embodiment of a continuous optical separation device that is advantageous for carrying out the method of the present invention. a liquid supply port 2 for a supersaturated solution of the body; an overflow port 3 provided at the top;
A crystal suspension part 4 occupying the upper part of the divided tank 1, a crystal crushing screen 5 provided below the crystal suspension part 4, and a crystal crushing rotary blade 6 installed close to the bottom of the screen 5. It becomes more.

To explain the operation of the method of the present invention using the above-mentioned apparatus,
While a supersaturated solution of the racemate to be separated is supplied from the liquid supply port 2 into the separation tank 1 at a desired flow rate, an appropriate amount of active substance crystals are inoculated into the separation tank.

The inoculated seed crystals are mechanically crushed by the crystal crushing screen 5 and the crystal crushing rotary blade 6, ascend within the dividing tank 1, and grow in the crystal suspension section 4.

A part of the grown active crystal 7 settles in the dividing tank 1 and is mechanically crushed by the crystal crushing screen 5 and the crystal crushing rotary blade 6 to become seed crystals, and a part of it settles in the dividing tank 1 along with the solution. The water rises and is discharged to the outside of the divided tank 1 through the overflow port 3.

The solution containing the discharged active substance crystals is subjected to an appropriate solid-liquid separation method,
For example, solid-liquid separation is performed using a continuous centrifuge to obtain active substance crystals.

The supersaturated solution of the racemate is normally supplied continuously, but it may also be supplied intermittently in fixed amounts.

When the racemic solution is continuously supplied, the growing active substance crystals are taken out continuously, and when it is intermittent, it is taken out intermittently.

The mechanical crushing mechanism for crystals in the above-mentioned apparatus consists of a combination of a crystal crushing screen 5 and a crystal crushing rotary blade 6, which mainly utilizes crushing by shearing force.

The screen 5 is usually fixed to the wall inside the divided tank 1, but
It may be rotated.

In this case, the direction of rotation of the screen 5 is preferably opposite to the direction of rotation of the rotary blades 6, and the number of rotations thereof is preferably smaller than the number of rotations of the rotary blades 6.

The gap between the screen 5 and the rotary blade 6 is an important factor in crystal crushing ability, and is usually selected from a range of 0.5 to 2.0 mm.

If the gap is less than 0.57ILrIL, a large amount of fine crushed crystals with small particle sizes are generated and are likely to be discharged out of the splitting system together with the overflowing solution.

Therefore, it becomes difficult to continue the seed crystal self-replenishment operation in the divided tanks.

On the other hand 2. If Omrrt is exceeded, the growing active crystals cannot be effectively crushed, resulting in a very inefficient operation.

That is, the number of crystals discharged outside the splitting system is not sufficiently replenished by the crushing operation, and the number of crystals in the splitting system gradually decreases, resulting in a decrease in splitting efficiency.

The shape of the screen 5 is not particularly limited, and various shapes may be employed, but for example, those shown in FIGS. 2 to 4 are preferably employed.

2 to 4 show top views of the screen 5,
Fig. 2 shows one with many circular holes, Fig. 3 shows a grid-like one, and Fig. 4 shows a slit-like one.

The shape of the rotating blade 6 is not particularly limited, and various shapes may be adopted, but for example, those shown in FIGS. 5A to 5B and 6A to 6B are preferably adopted.

Figure 5A shows the upper surface of a rotating blade with a mesh plate fixed on top of a simple rotary blade, such as a four-blade blade, and Figure 5B shows the
It is a cross-sectional view taken along the a-a line in figure A.

A screen having the shape shown in FIGS. 2 to 4 may be used instead of the mesh plate.

FIG. 6A is a top view of a rotary blade composed of a large number of blades.

FIG. 6B is a sectional view taken along line a-a of FIG. 6A.

In addition, in the screen 5 and the rotating blade 6, it is preferable that the opening gap of the rotating blade 6 is smaller than the opening gap of the screen 5.

In the above-mentioned apparatus, a stirring blade 8 for crystal discharge may be provided in the crystal suspension part 4 in order to smoothly discharge the grown active substance crystal.

Further, an auxiliary stirring blade 9 may be provided below the rotary blade 6 in order to smooth the flow of the racemic supersaturated solution introduced into the dividing tank 1 from the liquid supply port 2.

Note that 10 is a temperature regulating jacket.

Next, the method of the present invention will be explained in detail.

Since the method of the present invention is an optical resolution method using a preferential crystallization method, the substance to be resolved in the method of the present invention must be a racemic organic compound that forms a so-called congramate.

Examples of such racemic organic compounds include DL-threonine, DL-serine metaxylene-4-sulfonate, N-acetyl-DL-phenylalanine ammonium salt, N-acetyl-DL-41J butophane ammonium salt, and DL-lysine. - p-aminobenzenes/L'pho7 acid L DL-alanine p-chlorobenzenesulfonate, DL-glutamic acid and its salts, and the like.

The racemic organic compound to which the method of the present invention is applied preferably has an optically active substance having a so-called acicular or columnar crystal form.

If the crystal form is scale-like or thin plate-like, the splitting efficiency may decrease.

The seed crystals of the active substance to be inoculated are preferably ones that are close to the state of the active substance crystals present in the divided tank during steady operation when the seed crystals are inoculated into the divided tank.

For example, seed crystals that have been crushed in advance are suitable.

The amount of inoculation is also selected to achieve the set solids concentration during steady-state operation.

The grain size of the seed crystals is usually selected from the range of 16 to 65 mesh.

The particle size of the self-replenishing seed crystals is also preferably within this range, and therefore the crushing conditions for the growing crystals are selected to achieve this particle size range.

Various methods can be considered for crushing crystals to self-replenish seed crystals, but the points to consider when selecting a method are (
1) It is not mechanically complex; (ii) it does not apply stimuli that induce nucleation of dissolved enantiomers; it does not produce curved ultrafine crystals, etc.

Crushing force is usually classified into four forces: compressive force, impact force, frictional force, and shearing force, but considering the conditions (1) to (2) above, a crushing method that mainly uses shearing force is the most preferable. From this point of view, a mechanism consisting of a combination of a screen 5 and a rotating blade 6 as shown in FIG. 1 is preferably used.

Instead of the mechanism shown in FIG. 1, it is also possible to use a commercially available rotary shear type stirrer for emulsification operations.

The degree of supersaturation of the supersaturated solution of the racemate to be supplied is preferably selected so that the growth rate of the active substance crystals is maximized within a range in which nucleation of the dissolved enantiomer does not occur.

Since such conditions vary depending on the substance to be divided, the operating temperature, etc., it is preferable to determine each condition individually through preliminary experiments.

Incidentally, if the dividing operation is performed continuously for a long time while maintaining a certain degree of supersaturation, scales often adhere to the inner walls of the dividing tank.

As a means for preventing such scale adhesion, it is preferable to periodically bring the supersaturated solution of the racemate in the divided tank into an unsaturated state.

The period of unsaturated state is determined in consideration of the state of scale adhesion, such as once every hour, once every two hours, and once every four hours.

Such a periodic unsaturated state can be caused by periodically increasing the temperature of the racemic solution to be supplied above the saturation temperature (by raising the temperature), or by periodically raising the temperature of the divided tank above the saturation temperature of the racemic solution. achieved by.

The degree of unsaturation is preferably determined by preliminary experiments in the same way as the degree of supersaturation, but as a rough guide, the minimum degree of unsaturation at which fine crystals can be completely dissolved can be cited.

FIG. 7 schematically shows the means. In the same figure, curve A
indicates the temperature change of the racemic solution in the divided tank with respect to the operation time, and straight line B indicates the saturation temperature of the racemic solution.

Further, C shown in the figure represents an unsaturated temperature, and D represents a supersaturated temperature.

FIG. 8 shows the relationship between the scale amount and the operation time when the above-mentioned means is employed and when it is not employed.

In the same figure, curve E shows the change in scale amount when operated in a constant supersaturation state (Example 1 described later),
When the curve F is operated by periodically giving an unsaturated state (
It shows the change in scale amount in Example 2), which will be described later.

The above method of periodically imparting an unsaturated state also has the effect of preventing nucleation of dissolved enantiomers.

Although the dividing operation temperature may be limited depending on the physical properties of the substance to be divided, it is usually set in the range of 20 to 60°C from an industrial standpoint.

The higher the solid concentration in the divided tank, the more advantageous it is in terms of throughput, but on the other hand, the fluidity of the crystals deteriorates, scale adhesion is more likely to occur, and there are disadvantages such as a decrease in the optical purity of the obtained active substance crystals and contamination. It may occur in some cases.

Therefore, it is preferable to determine the optimum solids concentration by considering these factors, but it is usually 3 to 25% [(crystal weight/divided tank internal volume) x 100 (w/v%), the same applies hereinafter], especially 5 to 15%. A range is preferred.

If the rotation speed of the crystal discharge stirrer, solution flow rate, temperature inside the tank, etc. are carefully selected, the solid concentration can be maintained for about a day even when unattended, and it can be maintained for an even longer time if operated by a person. However, it is possible to maintain the solid concentration within a certain range for a long time, to create an unsaturated state by changing the temperature inside the tank, or when operating conditions are likely to change. etc., it is necessary to control the solid concentration.

As a method of controlling the solids concentration, the actual solids concentration in the divided tank is detected by some kind of detection means, and the output from the detection means is used to increase or decrease the amount of racemic solution supplied or to increase or decrease the rotational speed of a stirrer for discharging crystals. One method is to maintain the solids concentration at a set level by increasing the concentration of solids.

As the detection means in this method, a near-infrared photoelectric detector is preferable, and as shown in FIG.
A constant amount of near-infrared light pulsed at a high frequency is irradiated into the dividing tank 1 from 2, and the amount of reflected light from the active crystal suspended in the dividing tank 1 is received in synchronization with the irradiated light,
By calculating the average value, the average solids concentration in the divided tank 1 is detected.

When such a method is adopted, it becomes possible to maintain the solids concentration strictly within a certain range for a long period of time even when no one is present.

The device shown in Figure 1 has both a seed crystal self-replenishment function and a front high function, but it has a structure in which a tank for self-replenishment of seed crystals and a tank exclusively for front height are combined in series. A device may also be used.

Next, the present invention will be explained with reference to Examples.

Example 1 The apparatus shown in FIG. 1 was used.

The internal volume of the divided tank 1 is 200 m1, the screen 5 shown in FIG. 2 and the rotary blade 6 shown in FIGS. 5A and 5B are used, and the gap between the screen 5 and the rotary blade is 1. .3mm.

A saturated aqueous solution of DL-threonine at 43.0°C was
The solution was stored in a tank kept at 0°C, and the solution was led to a cooling tube and cooled to 36.0°C to make it supersaturated.
The liquid was introduced from the liquid supply port 2 into the divided tank 1 whose temperature was adjusted to 36.0° C. at a flow rate of min.

15 g of L-threonine (optical purity 99.8%) having a particle size of 28 to 35 mesh was added from the top of the divided tank 1 to the initial seed crystal.

By sequentially separating the crystal-containing liquid (slurry) discharged from the overflow port 3 into solid and liquid using a heated glass filter, L-threonine crystals were changed at an average rate of 0.06'5 g/min.

The average optical purity of this product was 97.5%.

After 25 hours, the operation was stopped, and the solution in separation tank 1 was subjected to solid-liquid separation to obtain 18.4 g of L-threonine crystals.

The optical purity of this product was 99.0%.

Note that the amount of scale in the divided tank 1 was relatively large at 10 g or more.

Example 2 The same apparatus as in Example 1 was used except that the divided tank 1 had an internal volume of 220 m1.

A saturated aqueous solution of DL-threonine at 44.0°C was
Stored in a tank kept at 0°C, the solution was led to a cooling tube and cooled to 36.5°C to make it supersaturated, for 140 yr.
tl/mi! The liquid was introduced from the liquid supply port 2 into the divided tank 1 whose temperature was adjusted to 36.5° C. at a flow rate of 1.

Note that the feed liquid was given an unsaturated temperature of 3.0° C. once every hour.

15 g of L-threonine (optical purity 99.8%) having a particle size of 28 to 35 mesh was added as an initial m crystal from the upper part of the divided tank 1.

The solid concentration was adjusted to 6.8% by automatically controlling the rotational speed of the stirring blade 8 for discharging crystals according to the output of the near-infrared photoelectric detector 12.

By sequentially separating the crystal-containing liquid discharged from the overflow port 3 into solid-liquid, L-threonine crystals (average optical purity 96.6%) were changed at an average speed of 0.112.9/mm.

After 72 hours, the operation was stopped, and the solution in the dividing tank 1 was separated into solid and liquid to form L-threonine crystals (optical purity 99.7%) 16
．． I got 8g.

The amount of scale in the divided tank 1 was as small as 1 g or less.

Example 3 The same apparatus as in Example 1 was used except that the divided tank 1 had an internal volume of 3201111.

A saturated aqueous solution of DL-threonine at 44.7°C was
The solution was stored in a tank kept at 0°C, and the solution was led to a cooling tube and cooled to 37.2°C to make it supersaturated. 195 ml
The liquid was introduced from the liquid supply port 2 into the divided tank 1 whose temperature was adjusted to 37.2° C. at a flow rate of /min.

Note that the feed liquid was given an unsaturated temperature of 4.2°C once every 2 hours.

As an initial seed crystal, 18 g of pre-crushed 35-48 mesh threonine (optical cotton v100%) was added from the upper part of the divided tank 1.

The solids concentration was adjusted to 5.6% in the same manner as in Example 2.

By sequentially separating the crystal-containing liquid discharged from the overflow port 3 into solid-liquid, an average of 0.214 g/lni! L at a speed of t
- Threonine crystal (average optical purity 94.0%) was changed.

After 168 hours, the operation was stopped, and the solution in the dividing tank 1 was separated into solid and liquid to obtain L-threonine crystals (optical purity 95.8%) 1
I got 7.5,9.

Although scale formation was observed in the dividing tank 1, the amount was small enough to cause no problem in continuing the dividing operation.

Example 4 The same apparatus as in Example 1 was used except that the divided tank 1 had an internal volume of 320 m1.

34 of DL-serine metaxylene-4-sulfonate
．． A saturated aqueous solution at 3°C was stored in a tank kept at 45°C, and the solution was introduced into a cooling tube and cooled to 31.3°C to become supersaturated, resulting in 63TLl/71u! 3 at a flow rate of t
The liquid was introduced from the liquid supply port 2 into the divided tank 1 whose temperature was adjusted to 1.3°C.

L-serine with a particle size of 16 to 20 mesh was used as the initial seed crystal.
Meta-xylene-4-sulfonate dihydrate (optical purity 9
9.5%) was added from the top of the divided tank 1.

6.3 by automatically controlling the supply amount of the racemic solution based on the output t of the near-infrared photoelectric detector 12 to determine the solid concentration.
%.

The crystal-containing liquid discharged from the overflow port 3 is separated into solid and liquid by using a small centrifuge kept warm while changing the temperature as appropriate, and L-serine meta-xylene-4-sulfonic acid is produced at an average rate of 1.25 g/=. Salt dihydrate (average optical purity 91
．． 0%) Changed.

After 18 hours, the operation was stopped, and the solution in the dividing tank 1 was separated into solid and liquid to obtain 21.1 g of L-serine metaxylene-4-sulfonate dihydrate (optical purity 92.9%).

Note that the amount of scale in divided tank 1 was relatively large.

Example 5 The same apparatus as in Example 1 was used except that the divided tank 1 had an internal volume of 320 m1.

34 of DL-serine metaxylene-4-sulfonate
．． A saturated aqueous solution at 2°C is stored in a tank kept at 45°C, and the solution is introduced into a cooling tube and cooled to 31.0°C to make it supersaturated.
The liquid was introduced from the liquid supply port 2 into the divided tank 1 whose temperature was adjusted to ℃.

Note that the feed liquid was given an unsaturated temperature of 0.5° C. once every 2 hours.

L-serine metaxylene-4-sulfonate 2 with a particle size of 16 to 48 mesh as initial seed crystals
20 g of hydrate (optical purity 99.5%) was added to the top of divided tank 1.

The solids concentration was adjusted to 6.3% in the same manner as in Example 4.

The crystal-containing liquid discharged from the overflow port 3 is separated into solid-liquid using a small centrifugal separator kept warm while changing the temperature as needed, and L-serine/meta-xylene-4- is separated at an average speed of 1,06 ji/mvt. The sulfonate dihydrate (average optical purity 97.4%) was converted.

After 20 hours, the operation was stopped, and the solution in the dividing tank 1 was separated into solid and liquid to form L-serine metaxylene-4-sulfonate 2.
18.1 g of hydrate (optical purity 99.1%) was obtained.

In addition, no scale was observed in the divided tank 1. Example 6 The divided tank 1 had an internal volume of 320 m1, and the gap between the screen 5 and the rotating blade 6 was 0.8 mm. The same apparatus as in Example 1 was used.

A saturated aqueous solution of N-acetyl-DL-phenylalanine ammonium salt at 50°C was stored in a tank kept at 60°C, and the solution was led to a cooling tube and cooled to 41.0°C to make it supersaturated. /min flow rate 4
The liquid was introduced from the liquid supply port 2 into the divided tank 1 whose temperature was adjusted to 1.0°C.

As an initial seed crystal, 20 g of N-acetyl-L-phenylalanine ammonium salt crystals (optical purity 100%) having a particle size of 20 to 65 mesh were added from the upper part of the divided tank 1.

The solids concentration was adjusted to 6.3% in the same manner as in Example 4.

By solid-liquid separation of the crystal-containing liquid discharged from the overflow port 3, N-acetyl-L-phenylalanine ammonium salt crystals (average optical purity 91.2%) were returned at an average rate of 0.059/yniyt.

After 24 hours, the operation was stopped, and the solution in the dividing tank 1 was subjected to solid-liquid separation to obtain 22.9.9 N-acetyl-L-phenylalanine ammonium salt crystals (optical purity 92.5%).

It should be noted that some scale was observed in the divided tank 1.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic vertical sectional view showing a preferred embodiment of the device used in the present invention, FIGS. 2 to 4 are top views of the screen used in the device, and FIGS. 5A and 6A are the A top view of the rotary vane used in the device, FIGS. 5B and 6B are cross-sectional views taken along line a-a of FIGS. 5A and 6A, respectively, and FIG. 7 shows the operation when periodically imparting an unsaturated state. A graph showing the temperature change of the racemic solution with respect to time. Figure 8 shows the change in the amount of scale with respect to the operation time when the operation is performed in a constant supersaturated state and in the case where the operation is performed in a periodically applied unsaturated state. It is a graph. Main symbols in the drawing: 1...Divided tank, 2...
・Liquid supply port, 3...Overflow port, 4...Crystal suspension part, 5...Crystal crushing screen, 6...
...Rotating blade for crystal crushing.

Claims (1)

[Scope of Claims] 1. In optical resolution by preferential crystallization of racemic organic compounds, a liquid supply port provided at the bottom of the tank, an overflow port provided at the top of the tank, and a suspended crystal suspension occupying the upper part of the tank. In a supersaturated state, Continuously or intermittently supplies a racemic solution from the liquid supply port, initially supplies seed crystals of the active substance into the tank, and thereafter part of the grown active crystals is passed through the mechanical crushing mechanism. Seed crystals are self-replenished by crushing the seed crystals, a part of the grown active crystals is continuously or intermittently discharged from the overflow port together with the solution, and the active crystals are removed by solid-liquid separation. Characterized method for continuous optical resolution of racemic organic compounds. 2. A patent claim in which the solid concentration in the divided tank is automatically maintained at a constant value by detecting the solid concentration in the divided tank by a detection means and increasing or decreasing the supply amount of the racemic solution based on the output from the detection means. The method described in item 1. 3 The solid concentration in the divided tank is detected by the detection means, and the solid concentration in the divided tank is automatically increased or decreased by increasing or decreasing the rotational speed of the stirring blade for discharging crystals provided in the crystal suspension part based on the output from the detection means. The method according to claim 1, wherein the concentration is maintained at a constant value. 4. The method according to claim 1, wherein scaling in the divided tank is prevented by periodically bringing the supersaturated racemic solution in the divided tank into an unsaturated state.