KR101808824B1 - Chromatographic separation of optical isomers using simulated moving bed chromatography from glycerol and hexitol - Google Patents

Abstract

The present invention relates to the separation of optical isomers from glycerol and hexitol by using a simulated moving bed chromatography. The optical isomer separation method or the purification method according to the present invention is characterized by using a simulated moving bed chromatography, And the C-3 optical isomer from the sorbitol can be purified at a high purity and a high yield of 99.9% or more, and there is a useful effect of obtaining a high value-added chiral synthon or the like from this.

Description

Separation of optical isomers from glycerol and hexitol using a simulated moving bed chromatography {Chromatographic separation of optical isomers using simulated moving bed chromatography from glycerol and hexitol}

The present invention relates to the separation of optical isomers using a simulated moving bed chromatograph from glycerol and hexitol.

Carbon sources from non-edible biological resources that can replace increasingly depleted fossil fuels are a demand of the era enabling sustainable chemical industries. Therefore, many researches on the catalysts and processes for conversion from non-edible biomass resources to basic substances that are the basis of the harmonization industry have been conducted all over the world.

For example, some attempts have been made to secure 5-HMF, levulinic acid, adipic acid, etc. through chemical reactions from biological sources. There is a big problem of completely eliminating one chirality.

In order to solve the above problems, it is necessary to secure a high-value-added chiral synthon from the biomass using a more sophisticated catalyst / reaction system.

On the other hand, since the invention of the early 20th century, the chromatography technique has been widely used in the industry as a representative separation and purification technique capable of separating various high efficiency of chromatography, but the first batch chromatography technique is inefficient consumption of the mobile phase, There are technical drawbacks such as low utilization and low raw material throughput, and attempts have been made to secure this.

Simulated moving-bed (SMB), which is a typical technique complemented with the above disadvantages, moves the mobile phase and the stationary phase in a counter-current direction in chromatography while a substance that can be easily adsorbed moves in a flow direction of a fixed phase. In the direction of the image plane.

Specifically, the SMB is a continuous chromatography process that simulates the movement of a fixed phase while organically turning on / off a valve of a port connected between each column. As a result, SMB can continuously produce a large amount of materials in high purity, and recently, there has been an increasing trend of application to high-purity low-molecular medicine or fine chemical products both domestically and externally.

For example, there has been known a method of synthesizing (R) -glyceraldehyde from D-mannitol by a method of obtaining a C ₃ -chiral building block by oxidative cleavage (Non-Patent Document 1), (S ) -Glyceraldehyde, there is a method of synthesizing from L-ascorbic acid. However, the synthesis method of (S) -glyceraldehyde has a yield of only about 27% by a three-step process, L-ascorbic acid is synthesized from D-glucose by chemical transformation and a Reichstein process through microorganisms. Since its yield is about ~ 60% and usually requires 3-4 steps of conversion, As a result, when the (S) -glyceraldehyde is to be obtained from glucose, a long reaction process of 7 to 8 steps in total is required, and the yield is as low as about 16%, which is inefficient and low in productivity One A.

Therefore, it is required to develop a process for obtaining C ₃ -chiral building blocks from glucose in high yield.

Accordingly, the present inventors have made efforts to develop a process for obtaining C ₃ -chiral building blocks in high yield. In the present invention, hexitol, that is, glucose succinic acid or glycerol, is used as a racemic-C ₃ precursor And the SMB process capable of separating the C ₃ alcoholic optical isomers with high purity, respectively, has been developed and the present invention has been completed.

Organic Syntheses, Coll. Vol. 9, p. 450 (1998); Vol. 72, p.6 (1995)

It is an object of the present invention to provide a process for the separation of (R, S) -enantiomers from hexitol or glycerol.

It is another object of the present invention to provide (R, S) -enantiomers separated by said separation process.

In order to achieve the above object,

The present invention provides a method for separating into (R) or (S) optical isomers, comprising the step of applying a (R, S) derivative represented by the following formula 1 to a simulated moving bed chromatography :

[Chemical Formula 1]

(In the formula 1,

R ¹ and R ² are independently C _1-10 alkyl, or R ¹ , R ² , and the carbon between R ¹ and R ² together can form a C _3-10 cycloalkyl;

이되,R ₃ is hydrogen, or

However,

Wherein R ⁴ is C _1-10 alkyl, C _1-10 alkoxy, C _6-10 aryl or C _{6-10 oxyaryl} .

In addition, the present invention provides an (R) or (S) optical isomer obtained from the above separation method.

The optical isomer separation or purification method according to the present invention can purify the C-3 optical isomer at a high purity and a high yield of 99.9% or more from glycerol and sorbitol using a simulated moving bed chromatography through a simpler process than before There is a useful effect of obtaining a high value-added chiral synthon or the like from this.

1 is a graph showing HPLC chromatogram of (1,4-dioxaspiro [4,5] decan-2-yl) methylbenzoate racemate.
2 is a graph comparing the results of computer simulation of adsorption equations determined using an elution experiment and PIM.
FIG. 3 is a graph showing adsorption amounts and adsorption lines of the measured optical isomers by concentration. FIG.
4 is a graph showing operating conditions in a triangular region for a pre-predictive computational simulation of a simulated moving bed chromatography operation.
5 is a graph showing the results of a pre-predictive computational simulation of the simulated moving bed chromatographic operation (concentration distribution curve in the SMB process).
6 is a schematic diagram of a simulated moving bed chromatography operation.
Figure 7 shows the separation of the (R, S) optical isomeric racemate obtained from sorbitol or glycerol by the separation method according to the invention, separating the (R) optical isomer as an extract and separating the optical isomer of the (S) form by raffinate It is an HPLC graph that confirms separation.

Hereinafter, the present invention will be described in detail.

The following description is provided to assist the understanding of the invention, and the present invention is not limited to the following description.

The present invention provides a method for separating into (R) or (S) optical isomers, comprising the step of applying a (R, S) derivative represented by the following formula 1 to a simulated moving bed chromatography :

[Chemical Formula 1]

In Formula 1,

R ¹ and R ² are independently C _1-10 alkyl, or R ¹ , R ² , and the carbon between R ¹ and R ² together can form a C _3-10 cycloalkyl;

이되,R ₃ is hydrogen, or

However,

Wherein R ⁴ is C _1-10 alkyl, C _1-10 alkoxy, C _6-10 aryl or C _{6-10 oxyaryl} .

Preferably,

R ¹ and R ² can be independently methyl or ethyl, or R ¹ , R ² , and the carbon between R ¹ and R ² together can form cyclopentyl or cyclohexyl.

(R, S) derivative (1,4-dioxaspiro [4,5] decan-2-yl) methyl benzoate represented by the above formula (1) is more preferable.

In addition, the step of applying the (R, S) derivative represented by the formula (1) to the simulated moving bed chromatography,

Calculating the adsorption rates of the (R) derivative and the (S) derivative in the adsorption column using the following formula (1) (step 1);

Calculating a process condition of a simulated moving bed chromatographic process by applying the adsorption rate calculated in the step 1 to a triangular theory (step 2); And

Separating each of the (R) derivative and the (S) derivative by supplying the (R, S) derivative raw material solution and eluent to the simulated moving bed chromatography and applying the process conditions calculated in the step 2 (step 3); . ≪ / RTI >

[Equation 1]

q _i represents the adsorption rate per volume of the adsorption column,

alpha represents the corrected retention factor,

V _{E, i} represents the retention volume of the substance _i in the adsorption column,

epsilon represents the porosity,

V _col represents the volume of the column,

c _i represents the concentration of the injected material.

Hereinafter, the separation method according to the present invention will be described in detail for each step.

In the method for separating the (R, S) derivative represented by the formula (1) according to the present invention, the step (1) is a step of separating the adsorption ratio of the (R) Respectively.

In the present invention, the (R, S) derivatives, which are optical isomers which are difficult to separate, are respectively separated and used for simulated moving bed chromatography to achieve high purity.

At this time, analyzing the adsorption rate is one of the main factors for designing the process conditions of the simulated moving bed chromatography process, and the adsorption constant value can be calculated from each adsorption rate. Based on this, The flow rate of the (R, S) derivative to be fed, and the like can be derived.

On the other hand, in the above step 1, the adsorption rate of the (R, S) derivative to the adsorption column is calculated using Equation (1). The adsorption rate analysis in step 1 is performed by high performance liquid chromatography (HPLC) using a solvent such as acetonitrile, isopropanol, ethanol, tetrahydrofuran, tert-butyl methyl ether, water, Preferably HPLC, consisting of a column comprising silica in the form of a fixed bed of silica coated with ethanol and amylose tris (5-chloro-2-methylphenylcarbamate). Most preferably, a column (CHIRALPAK-AY20 from Daicel, particle size 20 μm, total size 10 mm × 100 mm) used in the experimental example of the present invention can be used.

In the step 1, the adsorption rate is calculated by using Equation (1), which is advantageous for analyzing a small amount of material because the amount of sample to be injected is small as compared with general shear analysis, and the processing time can be shortened by quick analysis. Of course, a general shear analysis method is also included in the scope of the present invention.

Further, a more accurate adsorption rate can be calculated by applying the corrected retention factor derived from the concentration of the (R, S) derivative to the above equation (1).

In the method for separating the (R, S) derivative represented by the formula (1) according to the present invention, the adsorption rate calculated in the step (1) is applied to the triangular theory and the simulated moving bed chromatography This is the step of calculating the process conditions of the graphic process.

The Simulated Moving Bed (SMB) chromatography process is a process that simulates a TMB (True Moving Bed) process using a countercurrent flow for efficient separation.

The SMB chromatography process may include a plurality of adsorption columns and may include a regulator valve system for regulating the flow rate of the materials supplied into the adsorption columns. In addition, the eluent and the mixed raw material may be composed of two outlets into which the raw material is introduced and two outlets through which the separated material flows out respectively, and the two outlets and inlets are connected to the moving merchant And moves along the moving direction of the eluent to simulate the countercurrent of the mobile phase and the fixed phase.

At this time, the flow rate and exchange time of the mixed material supplied to the inlet, outlet, and adsorption columns constituting the SMB chromatography process are generally determined using a triangle theory, and the equation forming the triangle theory is expressed by the following equation 2 can be defined as follows.

&Quot; (2) "

(where a represents the corrected retention factor,

V _{E, i} represents the retention volume of each substance in the adsorption column,

epsilon represents the porosity,

V _col represents the volume of the column.)

The triangle theory calculates the operating conditions for operation of the simulated moving bed process using the isothermal adsorption equations and column characteristics of the two materials to be separated. In step 2, the adsorption rate calculated in step 1 is applied to the triangular theory The process conditions of the simulated moving bed (SMB) chromatography process, namely the flow rate of the (R, S) derivative and the exchange time, are determined.

The application of the adsorption rate to the triangular theory means that the adsorption constant value derived from the adsorption rate is applied to the equation of the triangle theory. The calculation of the process conditions can be performed using the chromatography simulation program, The simulation program is generally available by selecting the simulation program used for the SMB process.

(R, S) derivative according to the present invention is characterized in that the step (3) is a step of supplying the (R, S) derivative raw material solution and the eluent to the simulated moving bed chromatography, (R) and (S) derivatives, respectively, by applying the calculated process conditions.

In the step 2, the simulated moving bed chromatography apparatus is designed with the process conditions calculated through the triangle theory, and the raw material solution in which the (R, S) derivative represented by the formula (1) is mixed and the eluent are supplied to the designed apparatus , It can be separated into high purity.

At this time, the eluent may be a solvent such as acetonitrile, isopropanol, ethanol, tetrahydrofuran, tert-butyl methyl ether, water, etc. In some cases, they may be mixed and used, .

By using the simulated moving bed chromatography in step 3, a very small amount of eluent (solvent) is used as compared with general batch chromatography, high concentration and high purity can be separated, and the production can be improved .

According to the separation method of the present invention, the (R, S) derivative represented by the general formula (1) can be isolated at 70% or more, 80% or more, 90% or more or 99% It is possible to obtain a yield of 70% or more, 80% or more, 90% or more, or 99% or more, and thus mass production is possible, and the separation method is suitable for commercial use.

Meanwhile, the simulated moving bed chromatography is a method in which,

Using four-zone SMB chromatography with two inlets and two outlets, the extract outlet is closed within one exchange time and the substance separated from the first zone is transported to the next zone, the rate of the residue outlet being set to the initial set angle Adjusting the ratio value to a value to obtain a high purity residue material (step 1);

In step 1, after the residue is transported to the second zone, the extract outlet is opened, and the extract outlet flow rate is started to obtain a high purity extract at a rate calculated by the steps 1 and 3 (step 2); And

After performing steps 1 and 2 above, the residue outlet is closed within one exchange time and the substance separated from the third zone is transported to the fourth zone, and the rate of the extract outlet is adjusted to a value obtained by adding the initial value of angular rate, (Step 3) of obtaining the extract of the present invention (step 3).

At this time, the step 1 of the four-zone SMB chromatography according to the present invention is characterized in that the extract outlet is closed within one exchange time and the substance separated from the first zone is transported to the next zone and the rate of the residue outlet is set to the initial value And adjusting it to a value added.

The step 1 is to close the extract outlet to send the extract to the next zone without discharging the extract in which the residues separated from the first zone, which had conventionally been spilled out, are mixed, thereby preventing the residues from mixing with the extract, thereby increasing the purity of the extract have. In addition, when the extract outlet is closed as described above, the third zone rate can be increased by flowing the feed material between the second zone and the third zone. The residue outlet of step 1 is set at a rate that is the sum of the initial rate of each outlet to match the mass balance of the SMB chromatography while maintaining the increased rate, and then the residue is drained.

At this time, the fluid flowing out through the residue outlet does not contain the extract, and the high-purity residue can be separated.

In step 1, as the recycle rate flows through the column 2, the desorbent is injected into the desorbent inlet and the rate of the first zone is increased to 3. By closing the extract outlet according to the present invention, the rate of the second zone is 3 and the rate of the third zone is increased to 4 by feeding the feedstock through the feedstock inlet. Thereafter, the residue outlet according to the present invention is set to a rate of 2, which is the rate of addition of the rate of 1 of the extract outlet, to the initial residue outlet rate 1, and the residue is discharged at rate 2 so that the rate of recirculation is again 2 and circulated .

In step 1, the shufting ratio of the outlet of the extract is a ratio of closing time of the extract outlet within one exchange time. The ratio is preferably 0 to 0.4%. More preferably, the closing ratio is 0.1 to 0.3%. When the range of the closing ratio is out of the range, the separation condition of the extract is exceeded and the separation of the substance itself can not be performed.

Next, the step 2 is a step of opening the extract outlet after the residue is transported from the step 1 to the second zone, and starting to obtain a high purity extract at the rate calculated by the step 1 and the following step 3 .

Before the extract of the step 2 is opened and discharged, the rate of each of the outlets is changed to the rate set in the initial four-zone SMB chromatography, and the impurity residues are transported to the second zone, and then the extract outlet is opened to obtain a high purity extract Can be obtained.

Step 3 according to the present invention is also characterized in that after performing steps 1 and 2 above, the residue outlet is closed within one exchange time and the substance separated from the third zone is transported to the fourth zone, And the rate is adjusted to a value to obtain a high purity extract.

Further, in step 3, the high purity extract is discharged through steps 1 to 2, and then the residue outlet is closed to transport the material separated from the third area to the fourth area.

In step 3, as the recycle rate flows through the column 2, the desorbent is injected into the desorbent inlet to increase the rate of the first zone to 3. The extract is flowed out by setting the extract outlet according to the present invention to the initial residue outlet rate 1 and the rate 1 of the initial extract outlet to the rate 2. The rate of the second zone is then reduced to 1 and fed into the feed rate 1 through the feedstock inlet so that the rate of the third zone is 2 and is reduced from the rate 3 of the three zones of the conventional initial SMB chromatography , The recirculation rate can again be diverged and circulated.

At this time, the closing ratio of the residue outlet is a ratio of the time when the residue outlet closes the residual outlet within one exchange time as a ratio of the shouting ratio of the residue outlet. The ratio is preferably 0 to 0.594%. More preferably, the closing rate of the residue outlet is 0.4 to 0.594%. If the closing ratio is out of the range, the boundary condition of the residue is exceeded and SMB chromatography can not be implemented.

On the other hand, the (R, S) derivative represented by the above formula (1) can be prepared from hexitol or glycerol.

For example, the (R, S) -derivative represented by the above formula (1)

A step of preparing a compound represented by the formula (3) from the compound represented by the formula (2) (step 1);

Preparing a compound represented by the formula (4) from the compound represented by the formula (3) prepared in the step (1) (step 2);

A step of preparing a compound represented by the formula (5) from the compound represented by the formula (4) prepared in the step (2) (step 3); And

(상기 반응식 1에 이어서,
R¹, R² 및 R³는 제1항의 화학식 1에서 정의한 바와 같다).A step of preparing a compound represented by the general formula (1) from the compound represented by the general formula (5) prepared in the step (3); and a step of separating the compound represented by the general formula
[Reaction Scheme 1]

(Following Scheme 1 above,
R ¹ , R ² and R ³ are the same as defined in the formula (1).

delete

delete

As another example, the (R, S) -derivative represented by the above formula (1)

A step of preparing a compound represented by the formula (5) from a compound represented by the following formula (7) (step 1); And

(Step 2) of preparing a compound represented by the formula (6) from the compound represented by the formula (5) prepared in the step (1).

[Reaction Scheme 2]

.

.

The detailed description of each step can be understood as shown in the examples of the present invention, and is not limited and can be included in the scope of the present invention as long as the target compound of each step can be prepared by changing or modifying it.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

However, the following examples and experimental examples are illustrative of the present invention, and the present invention is not limited thereto.

< Example  1 > (1,4- Dioxaspiro [4.5] decane -2 days) methyl Benzoate  Produce

The method for the synthesis of racemic-glyceraldehyde from D-sorbitol was carried out by oxidative decomposition in the same manner as in the synthesis of (R) -glyceraldehyde from D-mannitol, and then the racemic-glyceraldehyde prepared was dissolved in NaBH ₄ , and then reacted with benzoyl chloride to obtain the target compound.

More specifically,

Step 1: ( 1S, 2S ) -1 - ((R) -1,4- Dioxaspiro [4.5] decane -2-yl) -2 - ((S) -1,4- Dioxaspiro [4.5] decane Yl) ethane-1,2-diol)

Sorbitol (18.2 g, 100 mmol) was dissolved in DMSO (50 mL) under argon gas and stirred in a 250 mm two-necked RB flask. To the stirred solution was added cyclohexanone (31.0 mL, 300 mmol), triethyl orthoformate (16.62 mL, 100 mmol) and BF ₃ . (Et) ₂ O (1.0 mL) was injected successively at room temperature into the syringe and stirred for 10 hours. It was poured into the resulting mixture in a 10% NaHCO ₃ (100 mL) ice-cooled solution. The organic layer was extracted with (Et) ₂ O (2 x 50 mL), and the organic extract was washed with water (1 x 50 mL). The combined organic extracts were washed with brine (1 x 10 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The crude product was purified by flash silica gel column chromatography with eluent EtOAc: hexane (40:60) to give the desired compound (24.6 g, 75.6%).

^{1 H NMR (300 MHz, CDCl} 3): δ 4.17 (t, j = 3.9 Hz, 1H), 4.07 (m, 4H), 3.8 (d, j = 6.6 Hz, 1H), 3.70 (m, 1H), 4.49 (d, J = 4.8 Hz, 1H), 2.45 (d, J = 6.6 Hz, 1H), 2.11 (s, 1H), 1.63 (d, J = 5.3 Hz, 16H), 1.39 ¹³ C NMR (75 MHz, CDCl ₃ ):? 110.1, 76.7, 76.3, 71.5, 66.7, 62.1, 36.9, 36.7, 36.6, 34.9, 25.2, 25.1, 24.1, 24.0, 23.9.

step 2: 1 ,4- Dioxaspiro [4.5] decane -2- Carbaldehyde  Produce

NaIO ₄ (2.50 g, 11.7 mmol) was added slowly to the cooled aqueous solution (CH ₃ CN, 15 mL, 60%) of the compound (2.0 g, 5.85 mmol) prepared in the above step 1 at 0 ° C for 1 hour do. The resulting two-phase reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched with ice water (5 mL) and the organic layer was extracted with CH ₂ Cl ₂ (2 x 10 mL). The combined organic extracts were washed with brine (1 x 10 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The crude product was purified by flash silica gel column chromatography with eluent EtOAC: hexane (30: 70) to give the desired compound as a colorless liquid (0.642 g, 64.5%).

^{1 H NMR (300 MHz, CDCl} 3): δ 9.72 (d, j = 1.7 Hz, 1H), 4.39 (m, 1H), 4.12 (m, 2H), 1.67 (d, j = 9.0 Hz, 8H), 1.43 (s, 2 H); ¹³ C NMR (75 MHz, CDCl ₃ ):? 202.3, 112.1, 79.7, 65.4, 35.9, 34.7, 25.1, 24.0, 23.9.

Step 3: (l, 4- Dioxaspiro [4,5] decane -2-yl) methanol

NaBH ₄ (0.734 g, 19.4 mmol) was added to a cold solution of THF / MeOH (15 mL, 3: 1) in which the compound prepared in Step 2 (1.65 g, 9.70 mmol) was dissolved in an argon atmosphere at 0 ° C for 1 hour Lt; / RTI &gt; The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated NH ₄ Cl (10 mL) and the organic layer was extracted with CH ₂ Cl ₂ (2 × 10 mL). The combined organic extracts were washed with brine (1 x 10 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The crude product was purified by flash silica gel column chromatography with an eluent EtOAC: hexane (25: 75) to give the desired compound as a colorless liquid (1.31 g, 78.2%).

^{1 H NMR (300 MHz, CDCl} 3): δ 4.24 (m, 1H), 4.03 (t, j = 8.1 Hz, 1H), 3.78 (m, 2H), 3.60 (m, 1H), 2.03 (t, j = 6.2 Hz, 1H), 1.61 (d, J = 8.6 Hz, 8H), 1.40 (brs, 2H); ^{13 C NMR (75 MHz, CDCl} 3): δ 110.1, 75.8, 65.4, 63.2, 36.5, 34.9, 25.2, 24.1, 23.9.

Step 4: (l, 4- Dioxaspiro [4.5] decane -2 days) methyl Benzoate  Produce

Et ₃ N (14.64 mL, 105.27 mmol) was added to a stirred solution of the compound prepared in Step 3 (6.0 g, 35.9 mmol) in CH ₂ Cl ₂ at 0 ° C. After 15 minutes, benzoyl chloride (6.09 mL, 52.63 mmol) was added to the RM via syringe under nitrogen gas. The resulting reaction mixture was stirred at room temperature for 5 hours. The reaction was quenched with saturated NaHCO ₃ (15 mL) and the organic layer was extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (1 x 10 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The desired product was prepared as a colorless liquid (8.022 g, 83%) which was purified by flash silica gel column chromatography with eluent CH ₂ Cl ₂ : hexane (15: 85) to give the crude product as a white solid. .

^{1 H NMR (300 MHz, CDCl} 3): δ 8.05 (d, j = 1.3 Hz, 2H), 7.56 (d, j = 7.3 Hz, 1H), 7.44 (t, j = 7.3 Hz, 1H), 4.45 ( J = 4.8 Hz, 1H), 4.37 (d, J = 1.0 Hz, 2H), 4.14 (q, , 1.63 (d, J = 8.6 Hz, 8H), 1.40 (brs, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ):? 166.3, 133.1, 129.9, 129.7, 128.4, 110.4, 73.3, 66.1, 65.1, 36.4, 34.9, 25.1, 23.9, 23.8.

< Example  2> (1,4- Dioxaspiro [4.5] decane -2 days) methyl Benzoate  Produce

Racemic - glyceraldehyde is also very easy and economical to synthesize from glycerol, ketalizing glycerol produces an alcohol containing asymmetric carbon. Followed by reaction with benzoyl chloride to give the desired compound.

The manufacturing method of Embodiment 2 is advantageous in that the reaction is easy, the number of reaction steps is small, and the total yield is also extremely high.

Specifically,

Step 1: (l, 4- Dioxaspiro [4,5] decane -2-yl) methanol

Cyclohexanone (155.0 mL, 1.5 mol), triethylorthoformate (83.2 mL, 0.50 mol) and BF ₃ were added to a stirred solution of DMSO (200 mL) in which glycerol (6, 46.04 g, 0.50 mol) do. Subsequently, Et ₂ O (5.0 mL) was injected into the syringe at room temperature, followed by stirring at the same temperature for 18 hours. The resulting RM (reaction mixture) was poured into an ice-cooled solution of NaHCO ₃ (200 mL). The organic layer was extracted with Et ₂ O (3 × 150 mL), and the extracted organic layer was washed with water (1 × 100 mL). Finally, the organic extracts were washed with brine (1 x 100 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the crude product. The obtained crude product was purified by silica gel column chromatography using an eluent EtOAc: hexane (40:60) to obtain the target compound as a colorless oil (84.4 g, 98.08%).

^{1 H NMR (300 MHz, CDCl} 3): δ 4.24 (m, 1H), 4.03 (t, j = 8.1 Hz, 1H), 3.78 (m, 2H), 3.60 (m, 1H), 2.03 (t, j = 6.2 Hz, 1H), 1.61 (d, J = 8.6 Hz, 8H), 1.40 (brs, 2H); ^{13 C NMR (75 MHz, CDCl} 3): δ 110.1, 75.8, 65.4, 63.2, 36.5, 34.9, 25.2, 24.1, 23.9.

Step 2: (l, 4- Dioxaspiro [4,5] decane -2 days) methyl Benzoate  Produce

Benzoyl chloride (12.73 mL, 100 mmol) was added to an ice-cooled stirring solution of the compound (17.21 g, 100 mmol) in CH ₂ Cl ₂ (100 mL) and Et ₃ N (30.60 mL, 220.0 mmol) 110.0 mmol) was added via syringe. The resulting reaction mixture was stirred at room temperature for 5 hours. The reaction was quenched with saturated NaHCO ₃ (20 mL) and the organic layer was extracted with CH ₂ Cl ₂ (2 x 50 mL). The combined organic extracts were washed with brine (1 x 20 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain the crude product, which was purified by flash silica gel column chromatography with eluent CH ₂ Cl ₂ : hexane (15: 85) to give the desired compound as a white solid (26.53 g, 96.12%).

^{1 H NMR (300 MHz, CDCl} 3): δ 8.05 (d, j = 1.3 Hz, 2H), 7.56 (d, j = 7.3 Hz, 1H), 7.44 (t, j = 7.3 Hz, 2H), 4.45 ( J = 4.8 Hz, 1H), 4.37 (d, J = 1.0 Hz, 2H), 4.14 (q, 1.63 (d, J = 8.6 Hz, 8H), 1.40 (br s, 2H); ₁₃ C NMR (75 MHz, CDCl ₃ ):? 166.3, 133.1, 129.9, 129.7, 128.4, 110.4, 73.3, 66.1, 65.1, 36.4, 34.9, 25.1, 23.9, 23.8.

< Experimental Example  1> HPLC  Chromatogram

In order to find optimal conditions for separating (1,4-dioxaspiro [4,5] decan-2-yl) methylbenzoate racemate prepared in Example 1 and Example 2 of the present invention Respectively.

Specifically, in order to select a column that can be used for the simulated moving bed chromatography separation, the best resolution (1,4-dioxaspiro [4,5] decan-2-yl) methylbenzoate racemate The results are shown in FIG. 1 below.

1 is a graph showing HPLC chromatogram of (1,4-dioxaspiro [4,5] decan-2-yl) methylbenzoate racemate.

1 shows that Chiralpak AY-3 exhibits the best solubility with respect to (1,4-dioxaspiro [4,5] decan-2-yl) methylbenzoate racemate, It was confirmed that separation was possible.

< Experimental Example  2> Simulation Mobile layer ( SMB ) Chromatography

< Experimental Example  2-1> HPLC  Data-driven SMB  simulation

Based on the results obtained in Experimental Example 1, SMB simulation was performed to perform the simulated moving bed chromatography of the present invention.

Specifically, the sample was injected while changing the concentration to 2.7, 4.6, 8.7, 10, and 21.4 mg / ml using an analytical column of ChiralPAK AY-20 (inner diameter: 0.46 cm, height: 25 cm) Adsorption behavior analysis was performed through the obtained elution curves. Based on this, adsorption behavior of the optical isomer, that is, adsorption formula was estimated by PIM (Pulse Input Method), and the results are shown in FIG. 2 and FIG.

2 is a graph comparing the results of computer simulation of adsorption equations determined using an elution experiment and PIM.

FIG. 3 is a graph showing adsorption amounts and adsorption lines of the measured optical isomers by concentration. FIG.

Referring to FIG. 2, the estimated adsorption equation was compared with the existing experimental results through a commercial computer simulation program and its accuracy was confirmed.

Referring to FIG. 3, it can be seen that the determined adsorption formula shows a very high level of accuracy through the linear model.

< Experimental Example  2-2> Predictive computational simulation

Based on the adsorption formula verified in Experimental Example 2-1, predictive computational simulation was performed to determine the SMB separation possibility, and the results are shown in FIG. 4 and FIG.

4 is a graph showing operating conditions in a triangular region for a pre-predictive computational simulation of a simulated moving bed chromatography operation.

5 is a graph showing the results of a pre-predictive computational simulation of the simulated moving bed chromatographic operation (concentration distribution curve in the SMB process).

Referring to FIG. 4, a triangle area where the SMB operation condition can be set can be confirmed through the triangle theory.

In this simulation, we set the operating conditions near the center of the triangle to minimize the various disturbances that may occur during operation in the triangle area.

FIG. 5 shows the concentration distribution curves of the SMB equipment obtained from the predictive computational simulation. In the chromatogram using HPLC, the material rapidly eluting was named A and the material slowly eluted was named B.

< Experimental Example  3> Simulation Mobile layer  Separation / purification using chromatography

Dioxaspiro [4,5] decan-2-yl) methyl benzoate racemate prepared in Example 1 and Example 2 of the present invention was tested as follows.

Specifically, 8 samples of column (inner diameter 1 cm, height 10 cm) for producing AY-20 HPLC type of Daicel Co. were used for bench scale SMB equipments held by Korea Research Institute of Chemical Technology, -Dioxaspiro [4,5] decan-2-yl) methyl benzoate racemate (see FIG. 6).

At this time, the SMB operating condition was a stationary phase in which amylose tris (5-chloro-2-methylphenylcarbamate) was coated on silica with CHIRALPAK-AY20 manufactured by Daicel Co. The particle size was 20 μm and the total size was 10 mm × 100 mm . Ethanol was used as a mobile phase as a separation solvent.

In order to select the operating conditions of the simulated moving bed chromatography, the triangle area can be shown through the triangle theory, and the operating conditions of the simulated moving bed chromatography near the center in the triangle area were selected.

The resulting product was continuously separated in high purity using a simulated moving bed chromatography apparatus with (1,4-dioxaspiro [4,5] decan-2-yl) methylbenzoate racemate. The results are shown in Table 1 .

6 is a schematic diagram of a simulated moving bed chromatography operation.

Attempted order Run Purity (%) Excess enrichment ratio (e.e.%) yield(%) Raffinate extract Raffinate extract Raffinate extract R S R S R S Primary Run 1 61.54 42.95 23.08 14.10 51.89 52.76 Secondary Run 1 50.19 0.000 0.380 100.0 33.42 0.000 Run 2 47.45 6.710 51.00 86.58 33.71 11.32 Run 3 65.48 69.64 30.96 39.28 68.32 66.86 Run 4 70.41 74.08 40.82 48.16 73.09 71.46 Third Run 1 99.90 99.99 99.80 99.98 99.99 99.90 Fourth Run 1 0.000 40.52 100 18.96 0.000 28.84 Run 2 2.122 40.07 95.76 19.86 3.419 29.05 Run 3 51.51 98.35 3.020 96.70 96.89 66.98 Run 4 51.14 98.23 2.280 96.46 96.65 66.78 Run 5 58.81 86.35 17.62 72.70 81.16 67.70 Run 6 67.63 51.48 35.26 2.960 58.23 61.39 5th Run 1 32.96 40.23 34.08 19.54 35.54 37.50 Run 2 35.51 35.51 28.98 22.26 36.74 37.61 Run 3 98.15 98.15 96.30 98.94 99.46 98.17 6th Run 1 80.83 80.83 61.66 81.34 89.65 82.54 Run 2 96.17 96.17 92.34 98.98 99.47 96.29

As can be seen in Table 1, the R foam, which is a relatively low adsorptive substance as a result of the SMB operation, was eluted from the Rafffinate port in Zone 3 and the S foam, which is a highly adsorbing substance, eluted in Zone 1, (Extract) port. Particularly, according to the results of the third run 1, R foam was confirmed to have 99.9% purity at the Raffinate port and 99.9% purity at the extract port at the simulated moving bed chromatography.

In particular, if the operation conditions of the third run 1 are more clearly shown,

Feed concentration: 10 mg / ml

Total feed consumption: 150 ml

Total desorbent consumption: 643 ml

Port exchange time: 380 seconds

Total driving time: 296 minutes

The respective column flow rates were suitably adjusted at: 0.05 to 8 ml / min.

In addition, the extracts and raffinates isolated from the run conditions of the third Run 1 were analyzed by the following HPLC analysis conditions, and the results are shown in FIG. 7:

HPLC analysis conditions: Chiralcel AD-H column (0.46 cm x 25 cm), Hex / EtOH = 20/80, 0.8 mL / min, 215 nm

Figure 7 shows the separation of the (R, S) optical isomeric racemate obtained from sorbitol or glycerol by the separation method according to the invention, separating the (R) optical isomer as an extract and separating the optical isomer of the (S) form by raffinate It is an HPLC graph that confirms separation.

7, it can be confirmed that the separation method using the simulated moving bed chromatography of the present invention completely separated the (S) optical isomer from the (R) optical isomer and the raffinate as the extract.

Thus, using the simulated moving bed chromatography of the present invention, it can be confirmed that the C-3 optical isomer can be separated at a high purity of 99.9%, and the purification method (or separation method) Can be a useful separation / purification method for obtaining a high value-added chiral synthon from a high yield purity.

Claims (10)

(R) or (S) optical isomers, comprising the step of applying a (R, S) derivative represented by the following formula (1) to a simulated Moving bed chromatography:
[Chemical Formula 1]

(In the formula 1,
R ¹ and R ² are independently C _1-10 alkyl, or R ¹ , R ² , and the carbon between R ¹ and R ² together can form a C _3-10 cycloalkyl;
R ₃ is hydrogen, or

However,
Wherein R ⁴ is C _1-10 alkyl, C _1-10 alkoxy, C _6-10 aryl or C _{6-10 oxyaryl} .
The method according to claim 1,
Wherein the (R, S) derivative represented by the formula (1) is prepared from hexitol or glycerol.
The method according to claim 1,
Wherein the step
Calculating the adsorption rates of the (R) derivative and the (S) derivative in the adsorption column using the following formula (1) (step 1);
Calculating a process condition of a simulated moving bed chromatographic process by applying the adsorption rate calculated in the step 1 to a triangular theory (step 2); And
Separating each of the (R) derivative and the (S) derivative by supplying the (R, S) derivative raw material solution and eluent to the simulated moving bed chromatography and applying the process conditions calculated in the step 2 (step 3); Separating method comprising:
[Equation 1]

(q _i represents the adsorption rate per volume of the adsorption column,
alpha represents the corrected retention factor,
V _{E, i} represents the retention volume of the substance _i in the adsorption column,
epsilon represents the porosity,
V _col represents the volume of the column,
c _i represents the concentration of the injected material).
The method according to claim 1,
The simulated Moving bed chromatography can be carried out in the following manner:
Using four-zone SMB chromatography with two inlets and two outlets, the extract outlet is closed within one exchange time and the substance separated from the first zone is transported to the next zone, the rate of the residue outlet being set to the initial set angle Adjusting the ratio value to a value to obtain a high purity residue material (step 1);
In step 1, after the residue is transported to the second zone, the extract outlet is opened, and the extract outlet flow rate is started to obtain a high purity extract at a rate calculated by the steps 1 and 3 (step 2); And
After performing steps 1 and 2 above, the residue outlet is closed within one exchange time and the substance separated from the third zone is transported to the fourth zone, and the rate of the extract outlet is adjusted to a value obtained by adding the initial value of angular rate, (Step 3) to obtain an extract of the four-zone SMB chromatograph.
The method according to claim 1,
Wherein each of the (R) -derived and (S) -divided by the separation method has a purity of 99% or more.
The method according to claim 1,
The (R, S) - derivative represented by the above formula (1)
A step of preparing a compound represented by the formula (3) from the compound represented by the formula (2) (step 1);
Preparing a compound represented by the formula (4) from the compound represented by the formula (3) prepared in the step (1) (step 2);
A step of preparing a compound represented by the formula (5) from the compound represented by the formula (4) prepared in the step (2) (step 3); And
A step of preparing a compound represented by the general formula (1) from the compound represented by the general formula (5) prepared in the step (3); and a step of separating the compound represented by the general formula
[Reaction Scheme 1]

(Following Scheme 1 above,
R ¹ , R ² and R ³ are the same as defined in the formula (1).
The method according to claim 1,
The (R, S) - derivative represented by the above formula (1)
A step of preparing a compound represented by the formula (5) from a compound represented by the following formula (7) (step 1); And
A step of preparing a compound represented by the formula (1) from the compound represented by the formula (5) prepared in the step (1) (step 2);
[Reaction Scheme 2]

(Following Scheme 2 above,
R ¹ , R ² and R ³ are the same as defined in the formula (1).
The method of claim 3,
Characterized in that said adsorption column comprises silica in the form of a bed coated with amylose tris (5-chloro-2-methylphenylcarbamate).
The method of claim 3,
Wherein said eluent is at least one solution selected from the group consisting of acetonitrile, isopropanol, ethanol, tetrahydrofuran, tertbutyl methyl ether and water.
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