KR20040028303A - Recovery method of optical isomer and solvent in optical resolution by a simulated moving bed type chromatography, and method for utilizing circulation of solvent - Google Patents

Abstract

PURPOSE: To separate optical isomers and solvent in high efficiency by using a simulated moving bed chromatography using a filler adequate for separation of the optical isomers and to provide a method for reusing the recovered solvent. CONSTITUTION: In a method for separating optical isomers by introducing an optical isomer mixture containing solution and an elutant into a packed bed containing a filler for separating optical isomers having at least 23 weight % of the optically active high molecular weight compound supported on a carrier based on the weight of the filler and simultaneously extracting a solution containing one side optical isomer and a solution containing the other side optical isomer separated from the packed bed, the packed bed has an inlet port of elutant, an extraction port for a liquid(extract) containing an optical isomer easily adsorbable to the filler, an introducing port for a liquid containing a mixture of optical isomers and an extraction port for a liquid (raffinate) containing an optical isomer scarcely adsorbable to the filter and the positions of the ports are intermittently and successively moved in the flowing direction of the fluid in the packed beds. Solvents and optical isomers are recovered from the extract and/or the raffinate obtained by using the above simulated-moving bed method.

Description

Recovery method of optical isomers and solvents in optical separation by pseudo mobile floor chromatography and circulating use method of solvent METHOD FOR UTILIZING CIRCULATION OF SOLVENT}

The present invention relates to a method for recovering an optical isomer and a solvent in optical separation by pseudo mobile floor chromatography and a method for circulating the solvent. More specifically, it is possible to efficiently separate the optical isomers and at the same time efficiently recover the solvents used for the optical separation, and to recover the solvents by reusing the solvents recovered by the recovery method of the present invention. The circular use method which aimed at effective use of this invention is related.

Conventionally, chromatographic methods, in particular liquid chromatography methods, have been widely adopted as industrial methods for separating necessary components from raw materials such as isomer mixed solutions containing two or more kinds of components.

This method is a method of separating using an adsorbent such as ion exchange resin, zeolite, silica gel, etc. as a filler and using the difference in adsorption performance for the adsorbent between the components contained in the raw material mixture. In this method, water, an organic solvent or a mixture thereof is used as the eluent. And the high purity target component can be obtained by concentrating the eluate containing a target component.

As this liquid chromatography method, a batch method and a pseudo moving floor method are known.

The batch liquid chromatography method has an advantage that a target component can be obtained in a short time because chromatographic fractionation can be performed by scaling up by a similar type from the result of the chromatogram of the analysis level. However, since the amount of the eluent used is large and the use efficiency of the adsorbent is low, productivity is low. For this reason, the chromatographic fractionation by a batch liquid chromatography method is generally expensive. On the other hand, in the pseudo mobile floor chromatography, since the amount of eluent used is smaller than that of the batch method and the components can be separated continuously, the preparative productivity is higher than that of the batch chromatography, and the separation of isomers on an industrial scale It is an extremely valid separation method.

As a specific example of using pseudo mobile floor chromatography for optical separation of an optical isomeric mixture, as described in Japanese Patent Application Laid-Open No. 4-211021 and Japanese Patent Laid-Open No. 6-239767, a polysaccharide derivative is added to a silica gel as a carrier. The method of using the filler for optical division carried out is mentioned.

On the other hand, in the optical division using the pseudo moving floor method, the effort which lowers a driving cost is performed. For example, in the optical segmentation using the pseudo moving floor method disclosed in US Pat. Nos. 5,518 and 625, a cost reduction by operating under the condition of 0.1 < k '< 1.0 is attempted. In addition, this k 'shows the maintenance capacity ratio. However, the savings are so small that it is difficult to say that it is a fundamental solution.

Therefore, an optical isomer separation filler excellent in preparative productivity and a method for separating the optical isomers have been strongly desired.

In addition, in the optical separation using the pseudo moving floor method, a large amount of eluent is required, and since the concentration of the target in the eluate is low, there is a problem that enormous energy and complicated processes are required for recovery of the eluent.

This invention is made | formed based on the said situation. That is, an object of the present invention is to further separate the separation of optical isomers having higher preparative productivity by using pseudo mobile floor chromatography using an optical isomer separation filler which is more suitable for separation of optical isomers. At the same time, there is provided a novel method capable of efficiently separating each of the optical isomers and the solvent from a large amount of mixture containing the optical isomers. Another object of the present invention is to provide a method of efficiently separating each of the optical isomers and the solvent from a large amount of the mixture containing the optical isomers and at the same time reusing the recovered solvent.

BRIEF DESCRIPTION OF THE DRAWINGS Explanatory drawing which shows an example of the pseudo mobile floor chromatographic separation apparatus which implements this invention.

It is explanatory drawing which shows the other example of the pseudo mobile floor chromatographic separation apparatus which implements this invention.

It is explanatory drawing which shows the other example of the pseudo mobile floor chromatographic separation apparatus which implements this invention.

4 is a chromatogram obtained in Example 1. FIG.

5 is a chromatogram obtained in Example 2. FIG.

6 is a chromatogram obtained in Comparative Example 1. FIG.

7 is a chromatogram obtained in Example 3.

8 is a chromatogram obtained in Comparative Example 2. FIG.

<Explanation of symbols for main parts of drawing>

1-12: unit column 13: eluent supply line

14: extract extraction line 15: isomer mixed solution supply line

16: raffinate extraction line 17: recycling line

18: circulating pump 19: evaporator

20: second flow type thin film evaporator 21: second flow type thin film evaporator

22: recovery tank 23: storage tank

24: racemization tank 25: distillation apparatus

As a result of intensive studies to solve the above problems, the present inventors have described the amount of the optically active high molecular compound in the optical isomer separation filler formed by supporting the optically active high molecular compound on a carrier, for example, US5 described above. Although the amount of the polysaccharide derivative supported in the conventional commercial filler described in Japanese Patent No. 518,625 is 10-20% by mass, the amount is at least 23% by mass, or the filler is used for pseudo moving floor chromatography. When dividing, by setting the values of the holding capacity ratios kl 'and / or k2' to at least 1, the productivity of the optical dividing of the optical isomer mixture is improved, and the recovery of the solvent and the optical isomer is also found to be easy. Completed.

That is, the means of the present invention for solving the above problems is to accommodate therein an optical dividing filler formed by supporting an optically active polymer compound on a carrier at a ratio of at least 23% by mass relative to the weight of the optical isomer separation filler. In addition, as long as the front end and the rear end are joined in the fluid passage and are endless, the optical isomer mixture-containing liquid and the release liquid are introduced into the filling floor where the liquid circulates in one direction, and at the same time separated from the filling floor. Extracting the liquid containing the optical isomer of one side and the liquid containing the other optical isomer, and the extraction floor of the liquid (extract) containing the extraction liquid introduction opening, the optical isomer which is easy to adsorb | sucking on the filling floor, The liquid inlet port of the liquid mixture containing the optical isomer mixture and the extraction port of the liquid (rapinate) containing the optical isomer which is hard to be adsorbed. Solvents from the extract and / or raffinate, which are obtained in this order along the flow direction of and which can be obtained using a pseudo moving floor method, which is achieved by intermittently sequentially moving their positions in the flow direction of the fluid in the floor. And an optical isomer is collect | recovered, It is a collection method of the optical isomer and a solvent in the optical division characterized by the above-mentioned.

In a very suitable aspect in the method which concerns on this invention, an optically active high molecular compound is a polysaccharide derivative,

In another very suitable embodiment in the method according to the present invention, the polysaccharide derivative is at least one selected from the group consisting of esters and carbamate derivatives of cellulose and esters and carbamate derivatives of amylose,

In another very suitable aspect in the method which concerns on this invention, optical segmentation is performed on condition that the value of the retention capacitance ratio k1 'and / or k2' computed by following formula (1) and formula (2) is at least 1. Do it,

k1 '= (v1-vO) /v0...(1), k2' = (v2-v0) /v0...(2),

(However, each of v1 and v2 represents a holding capacity of each optical isomer that is a solute component, and v0 represents a dead volume.)

Another means of the present invention for solving the above problems is a circulating use method of a solvent, characterized in that the solvent recovered by the recovery method of the optical isomer and the solvent in the optical separation is returned in the fluid passage.

[Embodiment of the Invention]

EMBODIMENT OF THE INVENTION Hereinafter, embodiment in this invention is described in detail.

In the present invention, the amount of the optically active polymer compound-supported filler is at least 23% by mass relative to the mass of the optical isomer separation filler. If the supported amount is less than 23% by mass, the load amount is small, so that the efficiency of separating the optical isomers decreases and is not industrial. In consideration of the productivity, the amount of the optically active polymer compound supported on the carrier is preferably at least 27% by mass relative to the weight of the optical isomer separation filler. Although there is no upper limit in particular of a supporting amount, when the supporting amount becomes 60 mass%, since the fall of separation efficiency by a decrease of a number of steps occurs, it is unpreferable. The supported amount herein is expressed by the ratio of the mass of the optically active polymer compound to the mass of the optical isomer separation filler.

As an optically active high molecular compound, it is the (meth) acrylic acid ester or (meth) acrylamide which does not have an optically active substituent, for example, the (meth) acrylic acid ester or (meth) acrylamide, styrene, and acetylene which have an optically active substituent Polymers or copolymers, polysaccharides and polymers thereof, peptides, proteins and the like. Polymer compounds having asymmetric discriminating ability with respect to the compound to be separated are preferable, and polymers or copolymers of (meth) acrylic acid esters or (meth) acrylamides known to have asymmetric discriminating ability, polysaccharides and polymers thereof and proteins are preferable. Do. In addition, in this specification, an (meth) acrylic acid ester means an acrylic acid ester or a methacrylic acid ester, and an acrylamide or methacrylic amide means a (meth) acrylamide. Among these optically active high molecular compounds, polymers or copolymers of (meth) acrylic acid esters or (meth) acrylamides having an optically active substituent in the side chain, polysaccharides and derivatives thereof are preferable, and polysaccharide derivatives are particularly preferable. As the polysaccharide, any of synthetic polysaccharides, natural polysaccharides, and natural modified polysaccharides is not particularly limited as long as it is optically active.

Illustrating the polysaccharide, α-1, 4-glucan (amylose, amylopectin), β-1, 4-glucan (cellulose), α-1, 6-glucan (dextran), β-1, 4-glucan ( Pstran), α-1, 3-glucan, β-1, 3-glucan (cadlan, disopyran, etc.), β-1, 2-glucan (Crawn Ga1 polysaccharide), β-1, 4- Galactan, α-1, 6-Mann, β-1, 4-Mann, β-1, 2-Flictan (Inulin), β-2, 6-Flictan (Levan), β-1, 4-K Silane, β-1, 3-xsilane, β-1, 4-N-acetyl chitosan (kitchen), pullulan, agarose, alginic acid, cyclodextrin and the like.

Among them, cellulose, amylose, β--1, 4-mannan, inulin, cyanlan and the like, which can easily obtain high-purity polysaccharides, are preferable, and cellulose and amylose are particularly preferable.

The number average degree of polymerization (average number of pyranose or furanos ring contained in one molecule) of these polysaccharides is usually at least 5, preferably at least 10. On the other hand, although there is no upper limit in particular, it is preferable in the ease of handling that it is 1,000 or less, Especially preferably, it is 500 or less. In other words, a very suitable number average degree of polymerization of polysaccharides is from 5 to 1000, in particular from 10 to 1000, even more from 10 to 500.

As a polysaccharide derivative which can be used suitably, a polysaccharide ester derivative, a polysaccharide carbamate derivative, etc. are mentioned.

Among them, particularly preferred polysaccharide ester derivatives or polysaccharide carbamate derivatives include some or all of the hydrogen atoms on the hydroxyl or amino groups of the polysaccharides of the following formulas (1), (2), (3) and (4) The compound formed by substituting with at least 1 sort (s) of the atom group represented by either can be mentioned.

In the formula, R is an aromatic hydrocarbon group which may contain a hetero atom, and may be unsubstituted or a C1-C12 alkyl group, a C1-C12 alkoxy group, a C1-C12 alkyl thi group, a cyano group, or a halogen At least one group selected from the group consisting of an atom, an acyl group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 1 to 8 carbon atoms, a nitro group, an amino group, and an alkyl amino group having 1 to 8 carbon atoms may be substituted. Among these, particularly preferred groups include, as the aromatic hydrocarbon group, a phenyl group, naphthyl group, phenanthryl group, anthracyl group, indenyl group, prill group, thionyl group, pyryl group, benzofuryl group, benzthionyl group, indyru group, A pyridyl group, a pyrimidyl group, a quinolyl group, an ishiquinolyl group etc. are mentioned. Among these, preferable are a phenyl group, a naphthyl group, a pyridyl group, etc. Especially preferable are a halogenated phenyl group and an alkyl phenyl group.

X is a C1-C4 hydrocarbon group and may contain a double bond or a triple bond. Examples of X include methylene group, methyl methylene group, ethylene group, ethylidene group, ethenylene group, ethynylene group, 1, 2- or 1, 3-propylene group, 1,1- or 2, 2-propyridine group and the like. Can be mentioned.

Carbamate derivatives of polysaccharides that can be suitably employed as polysaccharide derivatives in the present invention are reacted with isocyanates represented by the following formulas (5) or (6) and polysaccharides, so that the ester derivatives of the polysaccharides are represented by the following formulas (7) or (8): By reacting an acid chloride and a polysaccharide, all can be manufactured by a well-known method.

In the formulae, R and X represent the same meanings as described above.

In the present invention, the introduction ratio of the substituent in the polysaccharide derivative is usually 10% to 100%, preferably 30% to 100%, and more preferably 80% to 100%. When the introduction ratio is less than 10%, since the optical dividing ability is rarely displayed, it is not preferable. Moreover, when the said introduction ratio is less than 30%, since separation may become inadequate depending on the kind and density | concentration of the optical isomer mixture which are going to optically divide, it is not preferable. When the said introduction ratio exceeds 80%, since the particle | grains which are especially excellent in the separation ability of an optical isomer can be obtained, it is preferable. The introduction rate of the said substituent can be calculated | required, for example by examining the change of carbon, hydrogen, and nitrogen before and after substituent addition by elemental analysis.

Examples of the carrier in the present invention include a porous organic carrier and a porous inorganic carrier, and a porous inorganic carrier is preferable. Suitable porous organic carriers are polymer materials selected from the group consisting of polystyrene, polyacrylamide, polyacrylates, and the like. Suitable porous inorganic carriers include silica, alumina, magnesia, glass, kaolin, titanium oxide, silicate, And hydroxy apatite. Particularly preferred carriers are silica gels. The average particle diameter of a silica gel is 5-70 micrometers, Preferably it is 10-50 micrometers. If this average particle diameter is smaller than 5 micrometers, an operating pressure will rise and if an average particle diameter is larger than 70 micrometers, since productivity will fall, it is unpreferable. The average pore diameter of the silica gel is 10 mm 3 to 100 μm, preferably 50 mm to 50,000 mm. Although the surface is preferably subjected to surface treatment in order to remove the influence of residual silanol and to improve affinity with the optically active polymer compound, it is not a problem even if the surface treatment is not performed at all.

As a very suitable method of surface treatment, the silanization process using an organic silane compound, the surface treatment method by plasma polymerization, are mentioned, for example.

The optical isomer separation filler according to the present invention is a method of chemically bonding an optically active polymer compound such as a polysaccharide derivative directly to a carrier, and applying a solvent to the carrier by applying an optically active polymer compound such as a polysaccharide derivative solution to the carrier. It can be obtained by any method of distillation removal. In this case, the solvent used for dissolving an optically active high molecular compound, for example, a polysaccharide derivative, may be any of an organic solvent which is usually used as long as it can dissolve an optically active high molecular compound, for example, a polysaccharide derivative. .

In addition, a chemical bond between the carrier and the applied optically active high molecular compound such as a polysaccharide derivative, an optically active high molecular compound such as a polysaccharide derivative between the carrier, a chemical bond using a third component, and an optical on the carrier It is optically active by forming new chemical bonds, for example, by irradiation with active polymer compounds such as polysaccharide derivatives, radiation by γ-rays, reaction by electromagnetic radiation such as microwaves, reaction by radical generation by radical initiators, and the like. Further solidification of a high molecular compound such as a polysaccharide derivative on a carrier may be achieved.

The separation method of the present invention using pseudo mobile floor chromatography is very suitable for separation of optical isomeric mixtures. Here, as an optical isomer mixture, various optical isomer mixtures, such as disopyramide and Warfarin, can be used as a raw material of the method of this invention, for example. According to the separation method of the optical isomer using pseudo mobile floor chromatography, both a pure phase system using an organic solvent as a mobile phase and a reverse phase system using a water-soluble solvent as a mobile phase can be employed depending on the compound to be separated. In addition, in order to separate the optical isomeric mixture, supercritical fluid chromatography using a supercritical fluid as a mobile phase may be used.

Next, an example of a method for separating optical isomers using pseudo mobile floor chromatography is shown. However, the separation method of the present invention using pseudo mobile floor chromatography is not limited to this method, for example, W000 / 25885. As disclosed in the publication, conditions such as cycle time may be arbitrarily set for optimization of operation.

Adsorptive separation by the optical isomer separation method using pseudo moving floor chromatography is carried out by continuously circulating the following adsorption operation, concentration operation, desorption operation and escape recovery operation as basic operations.

(1) adsorption operation

The optical isomer mixture is brought into contact with the filler, the optical isomers (strong adsorption components) that are easily adsorbed are adsorbed, and other optical isomers (weak adsorption components) that are less likely to be adsorbed are recovered together with the leaving solution by the raffinate flow.

(2) Concentration operation

The filler adsorbing the strong adsorption component is brought into contact with a part of the extract described later, and the weak adsorption component remaining on the filler is expelled to concentrate the strong adsorption component.

(3) Desorption operation

The filler containing the concentrated strong adsorption component is brought into contact with the leaving solution such that the strong adsorption component is expelled from the filler and recovered as an extract stream with the leaving solution.

(4) Departure collection operation

The filler, which adsorbs only the leachate, is in contact with a portion of the raffinate stream and a portion of the leachate contained in the filler is recovered as the leachate recovery stream.

EMBODIMENT OF THE INVENTION Hereinafter, the method in this invention is demonstrated based on drawing. FIG. 1: is a schematic diagram which shows an example of the pseudo mobile floor chromatograph apparatus used by this invention, and FIG. 2 is a schematic diagram which shows another example of the pseudo mobile floor chromatograph apparatus used by this invention.

In Fig. 1, the interior of the filling floor, which is the main part of the pseudo mobile floor chromatographic apparatus, is divided into 12 unit floors, and in Fig. 2, the floors are divided into 8 unit floors, but the number and size thereof are optical isomers. It is determined by such factors as the composition, the flow rate, the pressure loss, the size of the apparatus, and the like, but is not limited thereto.

In FIG. 1, (1-12) is a chamber (adsorption chamber) in which the filler entered, and is connected mutually. (13) the extraction liquid supply line, (14) the extract extraction line, (15) the optical isomer mixed solution supply line, (16) the raffinate extraction line, (17) the recycling line, and (18) the pump Display.

In the state of arrangement of the adsorption chambers 1 to 12 and the lines 13 to 16 shown in FIG. 1, the desorption operation in the adsorption chambers 1 to 3, the concentration operation in the adsorption chambers 4 to 6, and the adsorption chamber 7 The adsorption operation in ˜9) and the removal liquid recovery operation are performed in the adsorption chambers 10 to 12, respectively. In such a pseudo moving floor, each feed liquid and an extraction line are moved by the suction chamber one chamber minute each in the liquid flow direction by valve operation at fixed time intervals. Therefore, in the arrangement state of the following adsorption chamber, desorption operation in the adsorption chambers 2-4, concentration operation in the adsorption chambers 5-7, adsorption operation in the adsorption chambers 8-10, and adsorption chambers 11-1. ), The withdrawal liquid collection operation is performed respectively. By performing these operations sequentially, the separation treatment of the mixture of optical isomers is continuously and efficiently achieved.

Moreover, in the state of arrangement | positioning of the adsorption chambers 1-8 and each line 13-16 shown in FIG. 2, the removal liquid collection operation in the adsorption chamber 1, the adsorption operation in the adsorption chambers 2-5, The concentration operation in the adsorption chambers 6 to 7 and the desorption operation in the adsorption chamber 8 are performed respectively. In such a pseudo moving floor, each feed liquid and an extraction line are moved by the suction chamber one chamber minute each in the liquid flow direction by valve operation at fixed time intervals. Therefore, in the arrangement state of the following adsorption chamber, the desorption operation in the adsorption chamber 2, the concentration operation in the adsorption chambers 3 to 6, the adsorption operation in the adsorption chambers 7 to 8, and the leaving liquid in the adsorption chamber 1 are performed. Each recovery operation is performed. By performing these operations sequentially, the separation treatment of the mixture of optical isomers is continuously and efficiently achieved.

In the separation method of the present invention using pseudo mobile floor chromatography, it is preferable to perform chromatographic fractionation under the condition that the holding capacity ratio k 'is at least 1 (in other words, at least 1). K1 'and k2' here are holding capacity ratios computed by the following formula.

kl '= (v1-vO) / v0 (1), k2' = (v2-v0) / v0 ... (2)

At this time, each of v1 and v2 represents a holding capacity of each optical isomer as an elution component, and v0 represents a dead volume.

When all the maintenance capacity ratios k1 'and k2' are less than 1, since productivity falls, it is unpreferable. It is preferable that either of the storage capacity ratios k1 'and k2' is at least one, but it is more preferable that both of the storage capacity ratios k1 'and k2' are at least one in terms of productivity improvement.

In the present invention, either or both of the extract and the raffinate obtained by using the above-described pseudo moving floor method are provided in the solvent recovery step.

Recovery of the solvent from the extract and / or raffinate and separation of the optical isomers can be carried out using an evaporator and / or a distiller. The evaporator and the distillation unit preferably use a pressure reducing device. The evaporator of the pressure reducing system can be prevented from being oxidized and the evaporation temperature can be lowered. Thus, the evaporator can be separated without deteriorating the optical isomers by heating.

As the evaporator, a thin film type evaporator can be suitably used, and specifically, a forced thin film evaporator, a rising thin film evaporator, a flow type thin film evaporator, a stirred liquid film evaporator, and the like can be used. These various evaporators may be used individually by 1 group, and may be used combining the 2 or more types of the same kind or a different apparatus. As a still, a molecular distillation apparatus is preferable, and a batch molecular distillation apparatus, a flow-type thin film type molecular distillation apparatus, a centrifugal thin film type molecular distillation apparatus, etc. are mentioned specifically ,. The molecular distillation apparatus of these pressure-sensitive systems may be used individually by 1 group, and may be used combining the 2 or more types of the same kind or a different apparatus.

In the method of the present invention, it is preferable that the extract and / or raffinate extracted from the pseudo moving floor are separated as a separator in which two or three kinds of the flow-type thin film evaporator and the forced thin film evaporator are combined. It is because there exists an advantage that by combining these 2 types or 3 types of apparatus, the residence time in these apparatus can be shortened and racemization can be prevented. Moreover, you may combine two or more homogeneous apparatuses in series, and it is also preferable to combine molecular distillation apparatuses.

Specifically, as shown in FIG. 3, the extract is concentrated to about 30-50% with the first flow-type thin film evaporator 19, and then the concentrate is concentrated on the second flow-type thin film evaporator 20. To about 40 to 70%, and the concentrate is concentrated to about 60 to 99% with a forced thin film evaporator (21).

The solvent recovered by the evaporator is usually stored in the recovery tank once. In FIG. 3, what is represented by (22) is a collection tank which temporarily stores the collect | recovered solvent. The optical isomer-containing concentrated liquid concentrated by the evaporator is once stored in a storage tank. In FIG. 3, it is the storage tank represented by (23).

On the other hand, raffinate contains the other optical isomer and solvent which are large objects of the optical isomer contained in an extract. Recovery of the solvent from this raffinate can also be carried out similarly to recovery of the solvent from the extract.

In the method of this invention, the solvent collect | recovered as mentioned above is recycled as a leaving liquid. Moreover, it can also reuse in order to prepare the liquid containing an optical isomer mixture. In this case, the purity of the solvent to be reused may be 98% or more. For that purpose, it is preferable to use a distillation apparatus. In FIG. 3, the concentration of the solvent stored in the recovery tank 22 is increased to the required purity by the distillation apparatus 25. If the above-mentioned purity can be maintained, the optical isomer can be separated efficiently by the pseudo moving floor method.

EXAMPLE

Synthesis Example 1

Preparation of an HPLC Column Comprising Celluloseless (4-Chrophenyl Carbamate) Supported Filler with Supported Mass of 24 Mass%

① silica gel surface treatment

Aminopropylsilane treatment (APS treatment) was carried out by reacting the porous silica gel (average particle diameter 20 mu m) with 3-aminopropyltriethoxysilane by a known method. The obtained APS treated silica gel was subjected to 3,5- By reacting with dimethyl phenyl isocyanate, a silica gel subjected to carbamoyl surface treatment was obtained. Table 1 shows the carbon content (C%) obtained as a result of elemental analysis of this carbamoyl surface-treated silica gel.

② Synthesis of Celluloseless (4-Chlorophenylcarbamate)

In a nitrogen atmosphere, 10 g of cellulose was heated and stirred at 714 L of 4-chlorophenyl isocyanate (2.5 equivalents) and pyridine reflux temperature for 60 hours in 3.8 L of dry pyridine, and then injected into 40 L of 2-propanol. The precipitated solid was filtered with a glass filter and vacuum-dried (80 ° C, 15 hours) after washing several times with 2-propanol. As a result, 287 g (75%) of a slightly yellowish white solid was obtained. Table 1 shows the carbon content (C%) obtained as a result of performing elemental analysis of this cellulose tris (4-chlorophenylcarbamate).

(3) Preparation of silica gel-supported filler of cellulose tris (4-chlorophenylcarbamate) having a loading amount of 24% by mass

120 g of cellulose tris (4-chlorophenylcarbamate) obtained in the above ② was dissolved in 600 ml of acetone, and this polymer

Half the amount of dope was uniformly applied to 380 g of silica gel of ①. After coating, the acetone was distilled off under reduced pressure for 45 minutes under the conditions of 40 ° C and 40 KPa. In addition, the remaining half of the polymer dope was uniformly applied to the silica gel and subjected to reduced pressure distillation under the same conditions to prepare a cellulose-free (4-chlorophenylcarbamate) supported filler having a target mass of 24 mass%. Got it. Table 1 shows the supported amount of the cellulose-less (4-chlorophenylcarbamate) filler calculated from the carbon content (C%) and the carbon content obtained as a result of the elemental analysis of the filler.

④ Preparation of packed column for HPLC from preparation filler

The cellulose-free (4-chlorophenylcarbamate) -supported filler prepared in the above ③ was packed into a stainless column having a length of 25 cm and an internal diameter of 0.46 cm by slurry filling to prepare a separation column for optical isomers. .

Synthesis Example 2

Preparation of an HPLC Column Comprising Celluloseless (4-Chrophenyl Carbamate) Supported Filler with a Supported Weight of 30% by Mass

① silica gel surface treatment

The surface treatment was performed by the same method as ① of the synthesis example 1.

② Synthesis of Celluloseless (4-Chlorophenylcarbamate)

Cellulostris (4-chlorophenylcarbamate) was synthesize | combined by the method similar to (2) of the said synthesis example 1.

(3) Preparation of silica gel-supported filler of cellulose tris (4-chlorophenylcarbamate) having a loading amount of 30% by mass

150 g of cellulose tris (4-chlorophenylcarbamate) obtained in the above ② was dissolved in 800 ml of acetone, and this polymer dope was uniformly applied to 350 g of the silica gel of ①. After coating, the acetone was distilled off under reduced pressure for 30 minutes under the conditions of 40 ° C. and 40 KPa to obtain a cellulose-less (4-chlorophenylcarbamate) supported filler having a desired 30 mass% loading. Table 1 shows the supported amount of the cellulose-less (4-chlorophenylcarbamate) filler calculated from the carbon content (C%) and the carbon content obtained as a result of the elemental analysis of the filler.

④ Preparation of packed column for HPLC from preparation filler

The cellulose-free (4-chlorophenylcarbamate) supported filler prepared in the above ③ was packed into a stainless column having a length of 25 cm and an internal diameter of 0.46 cm by slurry filling to prepare a separation column for optical isomers.

Synthesis Example 3

Preparation of HPLC Columns Comprising Celluloseless (4-Chrophenyl Carbamate) Supported Fillers with a Supported Amount of 20 Mass%

① silica gel surface treatment

The surface treatment was performed by the method similar to (1) of the synthesis example 1.

② Synthesis of Celluloseless (4-Chlorophenylcarbamate)

Cellulostris (4-chlorophenylcarbamate) was synthesize | combined by the method similar to (2) of the said synthesis example 1.

③ Preparation of silica gel-supported filler of cellulostris (4-chlorophenylcarbamate) having a loading amount of 20% by mass

100 g of cellulose tris (4-chlorophenylcarbamate) obtained in the above ② was dissolved in 600 ml of acetone, and this polymer dope was uniformly applied to 400 g of silica gel of ①. After application, conditions of 40 ° C. and 40 KPa The acetone was distilled off under reduced pressure for 30 minutes under the following to obtain a cellulose tris (4-chlorophenylcarbamate) supported filler having a target 20 mass% loading. Table 1 shows the supported amount of the cellulose-less (4-chlorophenylcarbamate) filler calculated from the carbon content (C%) and the carbon content obtained as a result of the elemental analysis of the filler.

④ Preparation of packed column for HPLC from preparation filler

The cellulose-free (4-chlorophenylcarbamate) -supported filler prepared in the above ③ was packed into a stainless column having a length of 25 cm and an internal diameter of 0.46 cm by a slurry packing method to prepare a separation column for optical isomers. .

C% Output Carrying Amount (%) Synthesis Example 1 ① Carbamoylated Silica Gel 1.10 - Synthesis Example 1 ② Celluloseless (Chloro-Petyl Carbamate) 51.38 - Synthesis Example 1 Celluloseless (Chloro-Petyl Carbamate) Supporting Filler 13.21 23.9 Synthesis Example 1 Celluloseless (Chloro-Petyl Carbamate) Supporting Filler 15.79 29.2 Synthesis Example 1 Celluloseless (Chloro-Petyl Carbamate) Supporting Filler 11.10 19.9

In addition, the calculation formula which calculates a support amount from the carbon content (C%) calculated | required from elemental analysis is as follows.

{[C% (Cellulostris (4-Chlorophenylcarbamate) Supported Filler) -C% (Carbamoylated Silica Gel)] / [C% (Cellulostris (4-chlorophenylcarbamate) -C % (Carbamoyl silica gel))] × 100

Example 1

Synthesis Example 1 Measurement of Maintenance Capacity Ratio Using Preparative Column and Filler

The disopyramide represented by following formula (9) was analyzed by the HPLC column produced by the synthesis example 1 using the liquid chromatograph apparatus. Table 2 shows the analysis conditions and the maintenance capacity ratios obtained as a result of the analysis. The chromatogram is shown in FIG.

The fillers prepared in Synthesis Example 1 were charged by slurry filling into eight Ф 1.0 cm × L 10 cm stainless columns, and were mounted on a small pseudo moving floor chromatograph preparative device having the configuration shown in FIG. did. The operating conditions are described below. Table 3 shows the optical purity of the obtained Raffinate, the optical purity of the Extract and the productivity of the whole component as a result of operating the small pseudo mobile floor chromatographic preparative device. In addition, the solvent recovered by each of the evaporators 19 to 21 shown in FIG. 3 is stored in the storage tank 22 once, and when the predetermined amount of solvent is stored in the storage tank 22, the solvent is stored in the storage tank 22. The stored solvent was returned to the circulation flow path in the small pseudo mobile floor chromatographic fractionator and reused.

Mobile phase: n-hexane / 2-propanol / diethyl amine = 25/75/0. 1 (v / v)

Column temperature: 40 ℃

Feed flow rate: 1.79 ㎖ / min.

Raffinate flow rate: 3.12 ml / min.

Extract flow rate: 9.63 ml / min.

Eluent flow rate: 10. 96 ml / min.

Step time: 2.5 min.

Feed concentration: 50 (mg / ml mobile phase)

Example 2

Synthesis Example 2 Measurement of Maintenance Capacity Ratio Using Fabrication Column and Filler and Pseudochromatography Separation

The compound represented by said formula (9) was analyzed by the column for HPLC produced by the synthesis example 2 using the liquid chromatograph apparatus. Table 2 shows the analysis conditions and the maintenance capacity ratios obtained as a result of the analysis. The chromatogram is shown in FIG.

The filler prepared in Synthesis Example 2 was filled into eight columns of 1.0 mm × L10 cm stainless steel by slurry filling, and mounted on a small pseudo moving floor chromatograph preparative apparatus shown in FIG. The operating conditions are described below. Table 3 shows the optical purity of the obtained Raffinate, the optical purity of the Extract and the productivity of the whole component as a result of operating a small pseudo moving floor chromatographic fractionator. In addition, the solvent recovered by each of the evaporators 19 to 21 shown in FIG. 3 is stored in the storage tank 22 once, and when the predetermined amount of solvent is stored in the storage tank 22, the solvent is stored in the storage tank 22. The stored solvent was returned to the circulation flow path in the small pseudo mobile floor chromatographic fractionator and was reused.

Mobile phase: n-hexane / 2-propanol / diethylamine = 25/75 / 0.1 (v / v)

Column temperature: 40 ℃

Feed flow rate: 1.83 ㎖ / min.

Raffinate flow rate: 4.24 mL / min.

Extract flow rate: 14.55 ml / min.

Eluent flow rate: 16.96 ml / min.

Step time: 2.5 min.

Feed concentration: 50 (mg / ml mobile phase)

Remarks Example 1

Synthesis Example 3 Measurement of Maintenance Capacity Ratio Using Preparative Column and Filler and Pseudochromatographic Chromatography Separation

The compound shown in 9) was analyzed by the HPLC column produced by the synthesis example 3 using the liquid chromatograph apparatus. Table 2 shows the analysis conditions and the maintenance capacity ratios obtained as a result of the analysis. The chromatogram is shown in FIG.

The filler produced in Synthesis Example 3 was charged to eight Φ1.0 cm x L10 cm stainless columns by slurry filling method, and was attached to a small pseudo-floor chromatograph preparative device shown in FIG. The operating conditions are described below. Table 3 shows the optical purity of the obtained Raffinate, the optical purity of the Extract and the productivity of the whole component as a result of operating a small pseudo moving floor chromatographic fractionator. Moreover, once the solvent collect | recovered by each evaporator 19-21 shown in FIG. 3 is stored in the storage tank 22, and a predetermined amount of solvent is stored in this storage tank 22, it will be stored in the storage tank 22. As shown in FIG. The stored solvent was returned to the circulation flow path in the small pseudo mobile floor chromatographic fractionator and reused.

Mobile phase: n-hexane / 2-propanol / diethyl amine = 25/75 / 0.1 (v / v)

Column temperature: 40 ℃

Feed flow rate: 1.60 ㎖ / min.

Raffinate flow rate: 2.90 mL / min.

Extract flow rate: 7.93 ml / min.

ErlUent flow rate: 9.22 ml / min.

Step time: 2.5 min.

Feed concentration: 50 (mg / ml mobile phase)

column Support amount (mass%) Analysis condition K1 ', k2' Chromatogram Example Synthesis Example 1 24 ① 1.02, 2.57 Figure 3 Example Synthesis Example 2 30 ① 1.73, 15.43 Figure 4 Comparative example Hamseong Example 3 Production 20 ① 0.86, 2.19 Figure 5

Analysis condition in Table 2

① mobile phase: n-hexane / 2-propanol / diethylamine = 25/75 / 0.1 (v / v / v),

Flow rate: 1.0 ml / min, temperature: 40 ° C., detection: 254 nm,

Injection amount: 1.5mg / mL (mobile phase) × 2.5μl

② mobile phase: 2-propanol = 100 / 0.1 (v / v), flow rate: 1.0ml / min,

Temperature: 40 ℃, Detection: 254nm, Injection amount: 1.5mg / mL (mobile phase) × 2.5μl

kl 'and k2' were computed from the following formula.

kl '= (v1-v0) / v0, k2' = (v2-v0) / v0, v0 are the retention capacities of tri-tert-benzyl benzene, and v1 and v2 are the retention capacities of each optical isomer.

Example 1 Example 2 Comparative Example 1 Mobile phase ① ① ① Raffinate * 1 Optical Purity (% ee) 99.5 99.4 99.5 Extract * 2 Optical Purity (% ee) 94.7 94.8 94.6 Productivity * 3 (kg-rac./kg-CSP/day) 3.42 3.49 3.05

Kind of mobile phase in table 3

1: n-hexane / 2-propanol / diethylamine = 25/75 / 0.1 (v / v / v),

②: 2-propanol / diethylamine = 100 / 0.1 (v / v)

* 1: all components, * 2: post components

* 3: Racemic body mass (kg) per day per kg of filler

Synthesis Example 4

Preparation of an HPLC column consisting of a loading of 30 mass% amylostries (3,5-dimethylphenylcarbamate)

① silica gel surface treatment

Carbamoyl surface-treated silica gel was obtained in the same manner as in Synthesis Example 1

② Synthesis of Amylostries (3,5-dimethylphenylcarbamate)

In a nitrogen atmosphere, 50 g of amylose was heat-crossed at 340.7 g (2.5 equivalents) of 3,5-dimethyl isocyanate and pyridine reflux temperature in 3.8 L of dry pyridine for 60 hours, and then injected into 40 L of methanol. The precipitated solid was filtered with a glass filter, and washed several times with methanol, followed by vacuum drying (80 ° C., 15 hours). As a result, 177 g (95%) of a slightly yellowish white solid was obtained.

③ Preparation of a silica gel-supported filler of amine lostly (3,5-dimethylphenylcarbamate) having a loading amount of 30% by mass

15.0 g of amylostris (3,5-dimethylphenylcarbamate) obtained in the above ② was dissolved in 120 ml of ethyl acetate, and the polymer dope was applied to 35.0 g of silica gel. After application, reduced pressure distillation of ethyl acetate was carried out to obtain an amylostasis (3,5-dimethylphenylcarbamate) supported filler having a target mass of 30% by mass. Table 4 shows the supported amount of the amylolesse (3,5-dimethylphenylcarbamate) filler calculated from the carbon content (C%) and the carbon content obtained as a result of the elemental analysis of this filler.

④ Preparation of packed column for HPLC from preparation filler

A slurry column was filled in a stainless column having a length of 25 cm and an inner diameter of 0.46 cm using the amylolesse (3,5-dimethylphenylcarbamate) supported filler prepared in the above ③, to prepare a separation column for optical isomers. .

Synthesis Example 5

Preparation of HPLC Columns Comprising a Supported Amount of 20 O by Mass Amylostress (3,5-dimethylphenylcarbamate)

① silica gel surface treatment

The surface treatment was performed by the method similar to (1) of the synthesis example 1.

② Synthesis of Amylostries (3,5-dimethylphenylcarbamate)

Amylostris (3,5-dimethylphenyl carbamate) was synthesize | combined by the method similar to (2) of the synthesis example 1.

③ Preparation of silica gel-supported filler of amylostris (3,5-dimethylphenylcarbamate) having a loading amount of 20% by mass

10.0 g of amylostris (3,5-dimethylphenylcarbamate) obtained in the above ② was dissolved in 70 ml of ethyl acetate, and this polymer dope was uniformly applied to 40.0 g of the silica gel of ①. After coating, ethyl acetate was distilled off under reduced pressure to obtain an amylostasis (3,5-dimethylphenyl carbamate) supported filler having a desired 20% by mass loading.

④ Preparation of packed column for HPLC from preparation filler

Using a amylolesse (3,5-dimethylphenyl carbamate) supported filler prepared in the above ③, a stainless column having a length of 25 cm and an internal diameter of 0.46 cm was filled by slurry filling method to prepare a separation column for optical isomers. did.

Example 3

Synthesis Example 4 Measurement of Maintenance Capacity Ratio Using Preparative Column and Filler, and Pseudochromatographic Chromatography Separation

The Warfarin (II) shown by following formula (II) was analyzed by the HPLC column produced by the synthesis example 1 using the liquid chromatograph apparatus. Table 5 shows the analysis conditions and the maintenance capacity ratios obtained as a result of the analysis.

The filler produced in Synthesis Example 4 was packed into eight Φ1.0 cm x L10 cm stainless columns by slurry filling method, mounted on a small pseudo moving floor chromatograph preparative device shown in FIG. The operating conditions are described below. Table 5 shows the optical purity of the obtained Raffinate, the optical purity of the Extract component, and the total component productivity as a result of operating the small pseudo moving floor chromatographic fractionator. Moreover, once the solvent recovered by each evaporator 19-21 shown in FIG. 3 is stored in the storage tank 22, when the predetermined amount of solvent is stored in this storage tank 22, it will be stored in the storage tank 22. As shown in FIG. The stored solvent was returned to the circulation flow path in the small pseudo mobile floor chromatographic fractionator and reused.

Mobile phase: Ethanol / Acetic acid = 100 / 0.1 (v / v)

Column temperature: 25 ℃

Feed flow rate: 3.15 ㎖ / min.

Raffinate flow rate: 5.20 ml / min.

Extract flow rate: 19.20 ml / min.

Eluent flow rate: 21.25 ml / min.

Step time: 2.5 min.

Feed concentration: 20 (mg / ml-mobile phase)

Comparative Example 2

Synthesis Example 5 Measurement of holding capacity ratio using production column and filler and pseudo mobile floor chromatography separation

War farin (II) was analyzed by the HPLC column produced in Synthesis Example 2 using a liquid chromatograph. Table 4 shows the analysis conditions and the maintenance capacity ratios obtained as a result of the analysis.

The filler produced in Synthesis Example 5 was charged to eight Φ1.0 cm x L10 cm stainless columns by slurry filling method, mounted on a small pseudo moving floor chromatographic fractionator, and fractionated. The operating conditions are described below. As a result of operating a small pseudo moving floor chromatographic fractionator, Table 5 shows the obtained Raffinate optical purity, Extract optical purity, and total component productivity.

Mobile phase: Ethanol / Acetic acid = 100 / 0.1 (v / v)

Column temperature: 25 ℃

Feed flow rate: 2.14 ㎖ / min.

Raffinate flow rate: 4.14 ml / min.

Extract flow rate: 15.37 ml / min.

Eluent flow rate: 17.34 ml / min.

Step time: 2.5 min.

Feed Concentration: 50 (mg / ml-mobile phase)

column Support amount (mass%) Analysis condition k1 ', k2' Chromatogram Example 3 Synthesis Example 1 30 ① 0.43, 1.07 Figure 6 Comparative Example 2 Synthesis Example 5 20 ① 0.34, 0.74 Figure 7

Analysis conditions in table 4

Mobile phase: ethanol / acetic acid = 100 / 0.1 (v / v / v), flow rate: 0.5 ml / min,

Temperature: 25 ° C, detection: 254 nm, injection amount: 5.0 mg / mL (mobile phase) × 2.0 μl

kl 'and k2' are the same as above.

Example Comparative example Mobile phase ① ① Raffinate * 1 Optical Purity (% ee) 99.7 99.6 Extract * 2 Optical Purity (% ee) 94.8 94.3 Productivity * 3 (kg-rac./kg-CSP/day) 2.40 1.64

Mobile phase ①: Ethanol / Acetic acid = 100/0. 1 (v / v / v)

* 1: all components,

* 2: after ingredients

* 3: Racemic body mass (kg) which can be processed in 1 day per kg of filler

According to the present invention, by using a filler having an excellent optical dividing ability as a filler for optical dividing, it is possible to continuously and optically divide the optical isomer with high productivity.

According to the present invention, the mixture of the optical isomers can be continuously separated efficiently and efficiently, and the used solvent can be recovered. Since the recovered solvent is reused in the solvent circulating the pseudo moving floor, there is no waste of the solvent and the amount of the leaving solution is small. Thus, the solvent can be a closed system having good efficiency.

Claims (5)

The optically divided filler formed by carrying an optically active polymer compound in a carrier at a ratio of at least 23% by weight relative to the weight of the isomer separation filler is contained therein. A liquid containing a mixture of one isomer and a liquid containing another optical isomer is introduced into the filling floor where the liquid is circulated in one direction, and the liquid isomer containing one optical isomer separated from the filling floor at the same time. It is made by extracting the containing liquid, and the filling floor contains the extraction liquid introduction port, the extraction port of the liquid (extract) containing the optical isomer that is easy to be adsorbed, the optical isomer mixture containing liquid introduction port, and the optical isomer which is difficult to adsorb. The extraction port of the liquid (raffinate) to be disposed in this order along the flow direction of the liquid, A method for separating optical isomers by pseudo moving floor chromatography that intermittently sequentially moves their positions in the direction of the flow of fluid in the floor, wherein the solvent and optical isomers are extracted from the extract and / or raffinate. A method of recovering an optical isomer and a solvent in the optical separation, wherein the optical isomer is recovered. The method for recovering an optical isomer and a solvent in the optical separation according to claim 1, wherein the optically active high molecular compound is a polysaccharide derivative. The method for recovering an optical isomer and a solvent in optical separation according to claim 2, wherein the polysaccharide derivative is at least one selected from the group consisting of esters of cellulose and carbamate derivatives, and esters and carbamate derivatives of amylose. The optical segmentation according to any one of claims 1 to 3, wherein the optical division is performed under the condition that the values of the storage capacitance ratios k1 'and / or k2' calculated by the formulas (1) and (2) are at least one. The recovery method of the optical isomer and a solvent in the optical division which are used. k1 '= (v1-vO) /v0...(1) k2 '= (v2-v0) /v0...(2) (However, each of v1 and v2 represents a holding capacity of each optical isomer that is a solute component, and v0 represents a dead volume.) A solvent used in the fluid passage of claim 1 is returned to the solvent recovered by the method of claim 1.