Process for the separation of spirodiphenols by simulated moving bed chromatography

Abstract

The application discloses a method for separating spirodiphenol by using an analog moving bed chromatography. The method for separating spirodiphenol specifically disclosed comprises the following steps: separating left-handed spirodiphenol and right-handed spirodiphenol from a spirodiphenol racemate by using an analog moving bed chromatography system; and the analog moving bed chromatography system has the following conditions: a stationary phase: silica gel coated with chiral polymer; and a mobile phase: a mixed solution of n-hexane and ethanol. The application can realize complete separation of two single enantiomers, obtain high purity and high recovery rate, and is more suitable for industrial production while being continuously operated. The process has strong stability, constant product quality, high automation degree, higher yield and lower cost than batch chromatography. The method also has the advantages of high yield, low cost, recyclable elution phase, green environmental protection, automatic and continuous production, stable product quality and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the preparation and separation technology of chiral spiro compounds, in particular to a method for separating spirodiphenol by simulated moving bed chromatography. BACKGROUND

[0002] Asymmetric catalytic reaction is an important method for preparing chiral compounds, and has been widely used in the synthesis of chiral drugs, chiral natural products and functional materials. Chiral catalyst induces the generation and control of chirality in the reaction product, so the development of chiral catalyst is the core research direction of asymmetric catalytic reaction. The catalyst and ligand developed based on some specific structures often have more excellent selectivity and catalytic activity, and such structures are called "advantageous structure".

[0003] Axial chiral 1,1'-spirodihydroindene-7,7'-diol (chiral spirodiphenol or SPINOL) is a very important representative of advantageous structure. Since 2002, when Academician Zhou Qilin's group first introduced SPINOL structure into the field of asymmetric catalysis, a series of highly efficient chiral catalysts and ligands based on this structure have been developed and widely used in the field of asymmetric catalytic synthesis, becoming an indispensable tool in asymmetric synthesis. However, the synthesis of related chiral catalysts and ligands requires very high optical purity of SPINOL itself, and at present the acquisition of optically pure SPINOL mainly depends on the resolution of racemate, and the method of asymmetric synthesis of SPINOL is very limited. In view of the above reasons, the separation of spirodiphenol racemate is of great significance, and seeking a high-yield, low-cost, high-quality chromatographic resolution method has great commercial prospect.

[0004] In recent years, simulated moving bed (SMB) chromatography has been increasingly widely used in the field of separation of chiral compounds. SMB is a kind of multi-column continuous chromatography, which has the characteristics of continuous operation, high utilization rate of chiral stationary phase and automatic control, and is very suitable for large-scale production. Compared with batch chromatography HPLC, SMB has higher preparation efficiency, lower solvent consumption, internal circulation of solvent system, and can realize complete separation of low selectivity system, and is especially suitable for chiral compound resolution. At present, there is no report on the preparation and resolution of spirodiphenol racemate by simulated moving bed chromatography at home and abroad. SUMMARY

[0005] The present application aims to solve the problems of low efficiency and solvent recovery rate, high cost and poor stability of large-scale preparation of batch chromatographic resolution for spirodiphenol asymmetric catalysis, and provides a method for preparing and resolving spirodiphenol racemate by simulated moving bed chromatography. The present application uses simulated moving bed chromatography to prepare and resolve spirodiphenol racemate, and respectively performs vacuum low-temperature concentration and rotary evaporation drying on the collected left-handed and right-handed spirodiphenol solutions to obtain left-handed and right-handed spirodiphenol solid powder products.

[0006] The present application aims to achieve the above-mentioned technical problems by the following technical solutions.

[0007] The present application provides a separation method of spirodiphenol, comprising the following steps: separating left-handed spirodiphenol and right-handed spirodiphenol from spirodiphenol racemate by using a simulated moving bed chromatography system.

[0008] The conditions of the simulated moving bed chromatography system are as follows:

[0009] Stationary phase: silica gel coated with chiral polymers;

[0010] Mobile phase: a mixed solution of n-hexane and ethanol.

[0011] In an embodiment of the present application, the chiral polymers are amylose-tris(3,5-dimethylphenylcarbamate).

[0012] In an embodiment of the present application, the stationary phase is AD.

[0013] In an embodiment of the present application, the volume ratio of n-hexane to ethanol in the mobile phase is 50-90:50-10, for example, 70:30.

[0014] In an embodiment of the present application, the flow rate of the eluent can be adjusted as needed, for example, selecting a corresponding flow rate matched under different column sizes, preferably 60-150 mL / min, for example, 86.3 mL / min or 120.9 mL / min.

[0015] In an embodiment of the present application, the working temperature of the simulated moving bed chromatography system is 20-40℃, for example, 35℃.

[0016] In an embodiment of the present application, the separation method comprises the following steps:

[0017] (S1) dissolving spirodiphenol racemate in a mobile phase as a feed liquid;

[0018] (S2) separating a solution containing left-handed spirodiphenol and a solution containing right-handed spirodiphenol from the feed liquid by using a simulated moving bed chromatography system, wherein the solution containing left-handed spirodiphenol is an extract liquid, and the solution containing right-handed spirodiphenol is a raffinate liquid.

[0019] In an embodiment of the present application, the separation method further comprises the following step: (S3) separately concentrating and drying the solution containing left-handed spirodiphenol and the solution containing right-handed spirodiphenol to obtain left-handed spirodiphenol and right-handed spirodiphenol products.

[0020] In an embodiment of the present application, the concentration of the racemate of the spirodiphenol in the feed liquid can be selected as desired, preferably 10-150 g / L, for example 23.0 g / L.

[0021] In an embodiment of the present application, the flow rate of the feed liquid can be selected as desired, preferably 5-50 mL / min, for example 16.0 mL / min or 23.0 mL / min.

[0022] In an embodiment of the present application, the flow rate of the extract liquid can be selected as desired, preferably 20-100 mL / min, for example 49.8 mL / min or 70.4 mL / min.

[0023] In an embodiment of the present application, the circulation flow rate in the simulated moving bed chromatography system can be selected as desired, preferably 100-500 mL / min, for example 250 mL / min or 350 mL / min.

[0024] In an embodiment of the present application, the simulated moving bed chromatography system comprises 4-12 chromatography columns, which are connected in series to form a loop system, wherein, in the flow direction of the mobile phase, the loop system is sequentially provided with a mobile phase inlet, an extract liquid outlet, a feed liquid inlet and a raffinate liquid outlet;

[0025] There are at least 1 chromatography column between the mobile phase inlet and the extract liquid outlet, which is a stationary phase regeneration zone;

[0026] There are at least 1 chromatography column between the extract liquid outlet and the feed liquid inlet, which is a separation and enrichment zone;

[0027] There are at least 1 chromatography column between the feed liquid inlet and the raffinate liquid outlet, which is a separation and enrichment zone;

[0028] There are at least 1 chromatography column between the raffinate liquid outlet and the mobile phase inlet, which is a mobile phase regeneration zone.

[0029] In an embodiment of the present application, the number of chromatography columns used in the simulated moving bed chromatography system can be selected as desired, preferably 4-8, for example 8.

[0030] In an embodiment of the present application, there are 2 chromatography columns between the mobile phase inlet and the extract liquid outlet, 2 chromatography columns between the extract liquid outlet and the feed liquid inlet, 2 chromatography columns between the feed liquid inlet and the raffinate liquid outlet, and 2 chromatography columns between the raffinate liquid outlet and the mobile phase inlet.

[0031] In some embodiments of the present application, the mobile phase inlet, the extract outlet, the feed inlet and the raffinate outlet are switched at intervals along the direction of mobile phase flow by one column position; preferably, the switching time is 0.5-2 min, for example 0.91 min or 1.28 min.

[0032] Without departing from the common knowledge in the art, the above-mentioned preferred conditions can be adjusted and combined in any proportion according to the scale of the equipment, thus obtaining various preferred embodiments of the present application.

[0033] The reagents and raw materials used in the present application are commercially available.

[0034] The positive progress effects of the present application are as follows:

[0035] 1) The racemic spirodiphenol is prepared and separated by SMB chromatography, which can realize complete separation of two single enantiomers in continuous operation, obtain high purity and high recovery rate, and is more suitable for industrial production than asymmetric synthesis, enzyme method and diastereomeric crystallization at the present stage.

[0036] 2) The racemic spirodiphenol is prepared and separated by SMB chromatography, which has strong process stability, constant product quality, high automation degree, higher yield and lower cost than batch chromatography.

[0037] 3) The spirodiphenol enantiomers are subjected to loading test on a plurality of chiral packings, which shows that the nonlinear performance of sample adsorption equilibrium is prominent when the concentration is high, and the chromatographic peak tailing is obvious, and SMB chromatography is more suitable for the separation of this system.

[0038] 4) The product solution is dried to obtain two single enantiomer solid products with optical purity higher than 99%, which can be directly faced to the market.

[0039] 5) The method has the advantages of high yield, low cost, recyclable eluent, green environmental protection, automatic continuous production, stable product quality, etc. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 The figure is a schematic diagram of the SMB of the embodiments of the present application.

[0041] Explanation of reference signs:

[0042] 1-8: chromatographic column; 9: eluent pump; 10: extract pump; 11: feed pump; 12: raffinate pump; 13: circulation pump; 14: mass flow meter. DETAILED DESCRIPTION

[0043] The application will be further described in the following examples, but the application is not limited to the examples. The experimental methods in the following examples are not specified, and the methods are selected according to the conventional methods and conditions or the product instructions.

[0044] (1) Preparation equipment

[0045] The application adopts a closed-loop simulated moving bed chromatography system for preparation and separation. The system is composed of an eluent pump 9, an extract pump 10, a feed pump 11, a raffinate pump 12, a circulation pump 13, a mass flow meter 14, and chromatography columns 1-8. The system further includes a process control system composed of a pneumatic switching valve, an electrical cabinet, an industrial computer, and control software, and a constant-temperature water bath circulator for controlling the temperature of the chromatography columns.

[0046] Figure 1 The figure shows a process schematic diagram of an asynchronous switching closed-loop simulated moving bed chromatography system of eight chromatography columns. As can be seen from the figure, the connecting pipelines connect the eight chromatography columns 1-8, the circulation pump 13, and the mass flow meter 14 in series to form a closed loop system. The elution port, the extraction port, the sample inlet, and the raffinate port divide the closed loop system into four functional areas. The chromatography columns between the elution port and the extraction port function as a stationary phase regeneration area, which is area I. The chromatography columns between the extraction port and the sample inlet function as a separation and enrichment area, which is area II, used for enriching the left-handed spirodiphenol in the spirodiphenol system. The chromatography columns between the sample inlet and the raffinate port function as a separation and enrichment area, which is area III, used for enriching the right-handed spirodiphenol in the spirodiphenol system. The chromatography columns between the raffinate port and the elution port function as a mobile phase regeneration area, which is area IV. The mobile phase passing through area IV is directly used in area I. Every certain time, all the inlets and outlets switch one chromatography column position along the direction of the mobile phase flow, realizing the reverse movement of the stationary phase and the mobile phase relative to the positions of the inlets and outlets.

[0047] The feed liquid of the spirodiphenol system is pumped into the simulated moving bed chromatography system by the feed pump 11. The eluent inlet, the extract outlet, the feed inlet, and the raffinate outlet are periodically switched along the direction of the mobile phase. The left-handed and right-handed spirodiphenols are continuously separated and enriched in functional areas II and III, respectively. After a period of periodic steady state, the left-handed spirodiphenol solution with an optical purity higher than 99% is collected from the extract outlet, and the right-handed spirodiphenol solution with an optical purity higher than 99% is collected from the raffinate outlet.

[0048] (2) Detection method

[0049] The optical purity of the obtained left-handed and right-handed spirodiphenol solutions and the single enantiomer solid powder products is determined by high-performance liquid chromatography. The operating conditions are as follows:

[0050] Instrument: SHIMADZU LC-20AD

[0051] Chromatographic column: AD-H (4.6 mmΦ x 250 mm L, 5 μm)

[0052] Mobile phase: mixture of n-hexane, ethanol, volume ratio 70:30

[0053] Detection wavelength: 230 nm

[0054] Flow rate: 1.0 ml / min

[0055] Example 1

[0056] 1. Pretreatment

[0057] Filling with packing material Eight chromatographic columns were filled with AD (produced by Daicel Corporation, Japan, average particle size 20 μm, packing material is spherical silica gel with surface-coated chiral polymers (amylose-tris(3,5-dimethylphenylcarbamate)), isopropanol as homogenate solvent, length of packing layer of all chromatographic columns is 97 mm, deviation of length of packing layer is less than 5% of average length. Connect to simulated moving bed chromatographic system.

[0058] Prepare mobile phase by mixing n-hexane, ethanol in preparation grade according to volume ratio 70:30, filter with filter of pore size 0.1 μm, use as eluent; prepare solution of spirodiphenol racemate (ratio of two single enantiomers is 50:50) with concentration 23.0 g / L by using mobile phase as solvent, filter the solution with filter of pore size 0.1 μm, use as feed liquid; use eluent to transition and equilibrate simulated moving bed chromatographic system.

[0059] 2.8-column simulated moving bed chromatographic preparation of resolution

[0060] Process parameters are as follows:

[0061] Number and arrangement of chromatographic columns: 8 (50 mmΦ*92 mm L), 2 / 2 / 2 / 2;

[0062] Mobile phase: n-hexane: ethanol = 70:30 (v / v);

[0063] Concentration of feed liquid: C F = 23.0 g / l;

[0064] Flow rate of eluent: Q D = 86.3 mL / min;

[0065] Flow rate of extract: Q E = 49.8 mL / min;

[0066] Flow rate of feed liquid: Q F = 16.0 mL / min;

[0067] Circulation flow rate: Q R = 250 mL / min;

[0068] Switching time: t s = 1.28 min;

[0069] Chromatographic column control temperature: 35°C;

[0070] After 10 cycles, a periodic steady state is reached, and the levorotatory spirodiphenol solution is collected at the extract port, while the dextrorotatory spirodiphenol solution is collected at the raffinate port, and the preparation of the resolution is continued for 3 days (3*24h) under sufficient conditions of eluent and feed.

[0071] 3. Productization process

[0072] 3.1 Productization of the levorotatory spirodiphenol solution

[0073] The levorotatory spirodiphenol solution collected on the first day (24h) in step 2 is taken as the first batch, and is subjected to steps such as vacuum concentration, vacuum rotary evaporation, vacuum drying, etc., to obtain a white solid powder product, which is levorotatory spirodiphenol product batch 1, and is transferred for storage.

[0074] The levorotatory spirodiphenol solution collected on the second day (24h) in step 2 is taken as the second batch, and is subjected to steps such as vacuum concentration, vacuum rotary evaporation, vacuum drying, etc., to obtain a white solid powder product, which is levorotatory spirodiphenol product batch 2, and is transferred for storage.

[0075] The levorotatory spirodiphenol solution collected on the third day (24h) in step 2 is taken as the third batch, and is subjected to steps such as vacuum concentration, vacuum rotary evaporation, vacuum drying, etc., to obtain a white solid powder product, which is levorotatory spirodiphenol product batch 3, and is transferred for storage.

[0076] 3.2 Productization of the dextrorotatory spirodiphenol enantiomer:

[0077] The dextrorotatory spirodiphenol solution collected on the first day (24h) in step 2 is taken as the first batch, and is subjected to steps such as vacuum concentration, vacuum rotary evaporation, vacuum drying, etc., to obtain a white solid powder product, which is dextrorotatory spirodiphenol product batch 1, and is transferred for storage.

[0078] The dextrorotatory spirodiphenol solution collected on the second day (24h) in step 2 is taken as the second batch, and is subjected to steps such as vacuum concentration, vacuum rotary evaporation, vacuum drying, etc., to obtain a white solid powder product, which is dextrorotatory spirodiphenol product batch 2, and is transferred for storage.

[0079] The dextrorotatory spirodiphenol solution collected on day 3 (24 h) of step 2 was taken as the third batch, and was subjected to steps of concentration under reduced pressure, rotary evaporation under reduced pressure, vacuum drying, etc., to obtain a white solid powder product, which was the dextrorotatory spirodiphenol product batch 3, and was transferred for storage.

[0080] 4. Product detection

[0081] 4.1 Optical purity detection of the collected solutions of levorotatory and dextrorotatory spirodiphenols

[0082] The purity of the collected solutions of levorotatory and dextrorotatory spirodiphenols obtained in step 2 was detected by high performance liquid chromatography, and the operating conditions were as follows:

[0083] Instrument: SHIMADZU LC-20AD

[0084] Chromatographic column: AD-H (4.6 mmФ*250 mm L, 5 μm)

[0085] Mobile phase: n-hexane: ethanol = 70:30 (v / v)

[0086] Detection wavelength: 230 nm

[0087] Flow rate: 1.0 ml / min

[0088] The optical purity of the levorotatory spirodiphenol solution collected on day 1 was 99.89%, and the optical purity of the dextrorotatory spirodiphenol solution was 99.48%.

[0089] The optical purity of the levorotatory spirodiphenol solution collected on day 2 was 99.85%, and the optical purity of the dextrorotatory spirodiphenol solution was 99.49%.

[0090] The optical purity of the levorotatory spirodiphenol solution collected on day 3 was 99.86%, and the optical purity of the dextrorotatory spirodiphenol solution was 99.52%.

[0091] 4.2 Optical purity detection of the levorotatory and dextrorotatory spirodiphenol products

[0092] 10 mg of the levorotatory or dextrorotatory spirodiphenol product of batch 1 obtained in step 3 was accurately weighed, dissolved in 2 ml of the mobile phase (a mixed solution of n-hexane and ethanol) to prepare a sample solution, and sample solutions of the levorotatory or dextrorotatory spirodiphenol products of batches 2 and 3 were prepared in turn. The purity of the prepared sample solutions was detected by high performance liquid chromatography, and the detection conditions were the same as in 4.1.

[0093] The optical purity of the levorotatory spirodiphenol product of batch 1 was 99.85%, and the optical purity of the dextrorotatory spirodiphenol product was 99.43%.

[0094] The optical purity of the levorotatory spirodiphenol product of Batch 2 was 99.85%, and the optical purity of the dextrorotatory spirodiphenol product was 99.49%.

[0095] The optical purity of the levorotatory spirodiphenol product of Batch 3 was 99.85%, and the optical purity of the dextrorotatory spirodiphenol product was 99.43%.

[0096] 4.3 Material preparation accounting

[0097] The simulated moving bed chromatography was used to prepare and separate the spirodiphenol enantiomers, and was stably operated for 3 days. The optical purity of the levorotatory spirodiphenol solid product was greater than 99%, the recovery rate was greater than 96%, the optical purity of the dextrorotatory spirodiphenol product was greater than 99%, the recovery rate was greater than 96%, and the yield was 529 g of raw material per 24 hours.

[0098] Example 2

[0099] 1. Pretreatment

[0100] The 8 chromatographic columns prepared in Example 1 were used in Example 2.

[0101] The mobile phase was prepared by mixing n-hexane and ethanol in a certain volume ratio, filtered with a filter having a pore size of 0.1 μm, and used as an eluent. The spirodiphenol racemate solution with a concentration of 23.0 g / L was prepared using the mobile phase as a solvent, filtered with a filter having a pore size of 0.1 μm, and used as a feed solution. The eluent was used to transition and balance the simulated moving bed chromatography system.

[0102] 2.8-column simulated moving bed chromatography preparation and separation

[0103] The operating conditions were as follows:

[0104] Number and arrangement of chromatographic columns: 8 (50 mmΦ*92 mm L), 2 / 2 / 2 / 2;

[0105] Mobile phase: n-hexane: ethanol = 70:30 (v / v);

[0106] Feed solution concentration: C F = 23.0 g / L;

[0107] Eluent flow rate: Q D = 120.9 mL / min;

[0108] Extractant flow rate: Q E = 70.4 mL / min;

[0109] Feed solution flow rate: Q F = 23.0 mL / min;

[0110] Circulation flow rate: Q R= 350 mL / min;

[0111] Switching time: t s = 0.91 min;

[0112] Chromatographic column control temperature: 35 °C;

[0113] Periodic steady state was reached after 10 cycles, collecting the levorotatory spirodiphenol solution at the extract port and the dextrorotatory spirodiphenol solution at the raffinate port, under the condition that the eluent and the feed were sufficient to continue the preparation of the resolution for 3 days (3*24h).

[0114] 3. Productization process

[0115] 3.1 Productization of the levorotatory spirodiphenol solution:

[0116] The levorotatory spirodiphenol solution collected on the first day (24h) of step 2 was taken as the first batch, which was subjected to steps such as vacuum concentration, vacuum rotary evaporation, vacuum drying, etc., to obtain a white solid powder product, which was the levorotatory spirodiphenol product batch 4, and was transferred and stored.

[0117] The levorotatory spirodiphenol solution collected on the second day (24h) of step 2 was taken as the second batch, which was subjected to steps such as vacuum concentration, vacuum rotary evaporation, vacuum drying, etc., to obtain a white solid powder product, which was the levorotatory spirodiphenol product batch 5, and was transferred and stored.

[0118] The levorotatory spirodiphenol solution collected on the third day (24h) of step 2 was taken as the third batch, which was subjected to steps such as vacuum concentration, vacuum rotary evaporation, vacuum drying, etc., to obtain a white solid powder product, which was the levorotatory spirodiphenol product batch 6, and was transferred and stored.

[0119] 3.2 Productization of the dextrorotatory spirodiphenol enantiomer:

[0120] The dextrorotatory spirodiphenol solution collected on the first day (24h) of step 2 was taken as the first batch, which was subjected to steps such as vacuum concentration, vacuum rotary evaporation, vacuum drying, etc., to obtain a white solid powder product, which was the dextrorotatory spirodiphenol product batch 4, and was transferred and stored.

[0121] The dextrorotatory spirodiphenol solution collected on the second day (24h) of step 2 was taken as the second batch, which was subjected to steps such as vacuum concentration, vacuum rotary evaporation, vacuum drying, etc., to obtain a white solid powder product, which was the dextrorotatory spirodiphenol product batch 5, and was transferred and stored.

[0122] The dextrorotatory spirodiphenol solution collected on the third day (24h) of step 2 was taken as the third batch, which was subjected to steps such as vacuum concentration, vacuum rotary evaporation, vacuum drying, etc., to obtain a white solid powder product, which was the dextrorotatory spirodiphenol product batch 6, and was transferred and stored.

[0123] 4. Product detection

[0124] 4.1 Optical purity detection of the solution of the collected levorotatory and dextrorotatory spirodiphenol

[0125] The purity of the solution of the collected levorotatory and dextrorotatory spirodiphenol obtained in step 2 was detected by high performance liquid chromatography, and the operation conditions were as follows:

[0126] Instrument: SHIMADZU LC-20AD

[0127] Chromatographic column: AD-H (4.6 mmΦ*250 mm L, 5 μm)

[0128] Mobile phase: mixed solution of n-hexane and ethanol, volume ratio 70:30

[0129] Detection wavelength: 230 nm

[0130] Flow rate: 1.0 ml / min

[0131] It was detected that the optical purity of the levorotatory spirodiphenol solution collected on the first day was 99.59%, and the optical purity of the dextrorotatory spirodiphenol solution was 99.29%.

[0132] The optical purity of the levorotatory spirodiphenol solution collected on the second day was 99.65%, and the optical purity of the dextrorotatory spirodiphenol solution was 99.35%.

[0133] The optical purity of the levorotatory spirodiphenol solution collected on the third day was 99.44%, and the optical purity of the dextrorotatory spirodiphenol solution was 99.34%.

[0134] 4.2 Optical purity detection of the levorotatory and dextrorotatory spirodiphenol product

[0135] Accurately weigh 10 mg of the levorotatory or dextrorotatory spirodiphenol product of batch 1 obtained in step 3, dissolve it in 2 ml of the mobile phase (mixed solution of n-hexane and ethanol) to prepare a sample solution, and then prepare sample solutions of the levorotatory or dextrorotatory spirodiphenol products of batches 2 and 3 in turn. The purity of the prepared sample solutions was detected by high performance liquid chromatography, and the detection conditions were the same as those in 4.1.

[0136] It was detected that the optical purity of the levorotatory spirodiphenol product of batch 4 was 99.56%, and the optical purity of the dextrorotatory spirodiphenol product was 99.31%.

[0137] The optical purity of the levorotatory spirodiphenol product of batch 5 was 99.60%, and the optical purity of the dextrorotatory spirodiphenol product was 99.30%.

[0138] The optical purity of the levorotatory spirodiphenol product of batch 6 was 99.52%, and the optical purity of the dextrorotatory spirodiphenol product was 99.29%.

[0139] 4.3 Material Preparation Accounting

[0140] Simulated moving bed chromatography was used to prepare and separate spirocyclic diol enantiomers. After 3 days of stable operation, levospirocyclic diol solid product with optical purity greater than 99% and recovery rate greater than 97% was obtained, and dextrospirocyclic diol product with optical purity greater than 99% and recovery rate greater than 97% was obtained. The yield was 761 g raw material / 24hr.

[0141] Simulated moving bed chromatography was used to prepare and resolve spirocyclic diol enantiomers. Examples 1 and 2 are the optimal preparation process parameters. The yield was linearly scaled up under the same scale of preparation equipment, and products with the same optical purity and recovery rate were obtained. The preparation process is stable and reliable and has great commercial value.

[0142] Comparative Example 1: Screening of stationary and mobile phases

[0143] The stationary phase was screened using HPLC. A racemic solution of spirobiol at the corresponding concentration (two enantiomers in a 50:50 ratio) was accurately prepared using the mobile phase as the solvent. This solution was then filtered through a 0.1 μm filter and used as the feed solution. The chromatographic conditions were as follows:

[0144] Instrument: SHIMADZU LC-20AD

[0145] Chromatographic columns: see Table 1

[0146] Mobile phase: See Table 1

[0147] Detection wavelength: 254nm

[0148] Flow rate: 1.0 ml / min

[0149] Column temperature: 35℃

[0150] Injection volume: See Table 1

[0151] Sample concentration: See Table 1

[0152] Table 1

[0153]

[0154]

[0155]

[0156]

[0157] The results showed that, The separation effect is better when AD-H is used as the stationary phase and n-hexane and ethanol are used as the mobile phase.

Claims

1. A method for separating spirocyclic diol, comprising the following steps: Levospirocyclodiol and devospirocyclodiol were separated from the racemic mixture of spirocyclodiol using a simulated moving bed chromatography system; The conditions of the simulated moving bed chromatography system are as follows: Stationary phase: silica gel coated with a chiral polymer; the chiral polymer is amylose-tris(3,5-dimethylaminocarbamate); Mobile phase: a mixed solution of n-hexane and ethanol; the volume ratio of n-hexane to ethanol is 70:30; The separation method includes the following steps: (S1) Dissolve the racemic spirocyclic diol in the mobile phase and use it as the feed liquid; (S2) Using a simulated moving bed chromatography system, a solution containing levozygosylcyclohexanol and a solution containing dextrospirocyclohexanol are separated from the feed liquid, wherein the solution containing levozygosylcyclohexanol is used as the extract and the solution containing dextrospirocyclohexanol is used as the raffinate. The simulated moving bed chromatography system includes 8 chromatographic columns connected in series to form a loop system. The loop system is provided with a mobile phase inlet, an extract outlet, a feed inlet, and a raffinate outlet in sequence according to the direction of mobile phase flow. There are two chromatographic columns between the mobile phase inlet and the extract outlet, forming the stationary phase regeneration zone; There are two chromatographic columns between the extract outlet and the feed inlet, forming a separation and enrichment zone; There are two chromatographic columns between the feed liquid inlet and the raffinate outlet, forming a separation and enrichment zone; There are two chromatographic columns between the raffinate outlet and the mobile phase inlet, forming the mobile phase regeneration zone; The mobile phase inlet, the extract outlet, the feed inlet, and the raffinate outlet are switched along the mobile phase flow direction to one column position; the switching time is 0.5-2 min.

2. The method for separating spirocyclic diol as described in claim 1, characterized in that, The method for separating spirocycline satisfies one or two of the following conditions: (1) The flow rate of the eluent is 60-150 mL / min; (2) The operating temperature of the simulated moving bed chromatography system is 20-40℃.

3. The method for separating spirocyclic diol as described in claim 1, characterized in that, The method for separating spirobiol satisfies one or more of the following conditions: (1) The stationary phase is ; (2) The flow rate of the eluent is 86.3 mL / min or 120.9 mL / min; (3) The operating temperature of the simulated moving bed chromatography system is 35 ℃.

4. The method for separating spirocyclic diol as described in claim 3, characterized in that, The separation method further includes the following steps: (S3) concentrating and drying the solution containing levozygosylcyclohexanol and the solution containing dextrospirocyclohexanol respectively to obtain levozygosylcyclohexanol and dextrospirocyclohexanol products.

5. The method for separating spirocyclic diol as described in claim 1, characterized in that, The method for separating spirobiol satisfies one or more of the following conditions: (1) The concentration of the racemic spirocyclin in the feed liquid is 10-150 g / L; (2) The flow rate of the feed liquid is 5-50 mL / min; (3) The flow rate of the extract is 20-100 mL / min; (4) In the simulated moving bed chromatography system, the circulation flow rate is 100-500 mL / min.

6. The method for separating spirocyclic diol as described in claim 1, characterized in that, The method for separating spirobiol satisfies one or more of the following conditions: (1) The concentration of the racemic spirocyclin in the feed liquid is 23.0 g / L; (2) The flow rate of the feed liquid is 16.0 mL / min or 23.0 mL / min; (3) The flow rate of the extract is 49.8 mL / min or 70.4 mL / min; (4) In the simulated moving bed chromatography system, the circulation flow rate is 250 mL / min or 350 mL / min.

7. The method for separating spirocyclic diol as described in claim 1, characterized in that, The switching time is 0.91 min or 1.28 min.

Images