A method for converting a chiral compound racemate into a single enantiomer

Abstract

The present invention discloses a method for converting a chiral compound racemate into a single enantiomer, combining crystallization and SMB processes, while reducing the separation purity requirements of SMB, respectively, the chiral substance solution at the SMB extraction port and the raffinate port is crystallized and purified, and in addition, an equal mixture of the racemate raw material, the product of the racemization reaction of the single enantiomer derived from the non-target product in the racemization reactor, and the eutectic generated by the two crystallizers is used as the three sources of the racemate at the SMB feed port, which can not only ensure the purity of the target product, but also achieve high utilization of the racemate raw material and high yield of the target product, while significantly improving the overall equipment yield. It can be seen that using the method of the present invention, the chiral compound racemate can be converted into a single enantiomer, which can significantly improve the overall equipment yield while ensuring the purity and yield of the target product.

Description

Technical Field

[0001] The present invention relates to the fields of biology and chemical engineering, and in particular to a method for converting a chiral compound racemate into a single enantiomer. Background Art

[0002] Chiral drugs are drugs with chiral properties. Their physicochemical properties are essentially identical, differing only in optical rotation, hence the designations of dextrorotatory, levorotatory, and racemic. Chiral drugs account for over half of the current pharmaceuticals sold and used in the medical market. However, due to the difficulty of resolution, nearly 85%-90% of chiral drugs are produced, sold, and used as racemates (also known as racemates). Due to the differences in pharmacological activity between most enantiomers, the market demand for single-enantiomer drugs has rapidly increased, spurring the development of technologies for preparing single-enantiomer drugs. Many countries now have regulations governing the development and registration of chiral drugs, requiring the presentation of pharmacological activity and toxicity test data for each enantiomer. The preference is for production and sale of optically pure enantiomers. Unless the coexistence of both enantiomers has no effect on drug efficacy, harmful side effects of the chiral molecule should be avoided. Therefore, developing efficient methods for producing single enantiomers is of great significance.

[0003] Currently, single enantiomer compounds can be obtained through three main routes: the first is to directly produce single enantiomers using asymmetric synthesis technology, but this route often uses expensive chiral catalysts and chiral reagents, is highly targeted, and is currently not widely applicable to the production of most chiral drugs; the second is to first prepare the racemate using conventional chemical synthesis methods, and then use deracemization methods to convert the racemate into a single enantiomer (Huang et al., Science 2022, 375, 869-874). This route is an academic hot topic, but successful cases are limited and it has not yet reached the level of large-scale industrialization; the third is to resolve the racemate prepared by conventional chemical synthesis methods. Thanks to the development of chiral stationary phases in recent years, adsorption separation for chiral resolution, especially simulated moving bed (SMB) resolution, has become one of the most promising methods and has also been widely used in industry.

[0004] The simulated moving bed (SMB) separation device and method for chiral enantiomer resolution is well known (Traub HS, Preparative Chromatography, Weinheim, Germany, 2005; Nicoud RM, Chromatographic processes: modeling, simulation and design, Cambridge University Press, United Kingdom, 2015). However, SMB technology only resolves racemates into two distinct enantiomers. In many cases, only one enantiomer has pharmaceutical value, while the other is not. Therefore, using only SMB resolution can reduce the yield of the target product in the overall synthetic route. Furthermore, the accumulation of the unused enantiomer can also pose an environmental burden. Summary of the Invention

[0005] In view of this, the present invention proposes a method for converting a chiral compound racemate into a single enantiomer, which can ensure the purity of the target product while significantly improving the yield of the target product.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] A method for converting a chiral compound racemate into a single enantiomer comprises the following steps:

[0008] (1) dissolving the chiral compound racemate in a first mobile phase to form a solution, and entering the solution into a simulated moving bed separation system, collecting the enriched strongly adsorbed component at the extraction port of the simulated moving bed, with a purity of 80% to 95%; collecting the enriched weakly adsorbed component at the raffinate port of the simulated moving bed, with a purity of 80% to 95%;

[0009] (2) storing the outlet materials of the raffinate port and the extraction port in respective buffer tanks, and performing crystallization by removing the solvent through respective corresponding crystallizers, and then performing solid-liquid separation through corresponding filters, wherein the liquid phases obtained are respectively a high-purity single enantiomer solution of the weakly adsorbed component and a high-purity single enantiomer solution of the strongly adsorbed component, and the solid phases obtained are respectively a eutectic solid enriched in the weakly adsorbed component and a eutectic solid enriched in the strongly adsorbed component;

[0010] (3) evaporating the high-purity single enantiomer solution of the target product in the two high-purity single enantiomer solutions through an evaporator to obtain the target product and collecting it; evaporating the high-purity single enantiomer solution of the non-target product in the two high-purity single enantiomer solutions through an evaporator to obtain a non-target product single enantiomer solid, dissolving it in a second mobile phase, adjusting the temperature through a heat exchanger, and then passing it into a racemization reactor, where it is converted into a racemic solution;

[0011] (4) After evaporating the solvent of the racemic solution obtained from the racemization reactor, a recovered racemic solid is obtained; the eutectic solid enriched in the weakly adsorbed component and the eutectic solid enriched in the strongly adsorbed component obtained in step (2) are mixed in a weight ratio of 1:1 to obtain a recovered racemic solid; the recovered racemic solid obtained from the racemization reactor and the eutectic is mixed with a fresh racemic raw material, as the chiral compound racemate described in step (1), dissolved in the first mobile phase to form a solution, and then enters the simulated moving bed separation system again.

[0012] In a preferred technical solution, the strongly adsorbed component is collected and enriched at the extraction port of the simulated moving bed with a purity of 85% to 95%; the weakly adsorbed component is collected and enriched at the raffinate port of the simulated moving bed with a purity of 85% to 95%.

[0013] Wherein, the method of removing the solvent for crystallization includes: using drying or evaporation to crystallize. In a preferred technical solution, evaporation is used for crystallization.

[0014] Wherein, the racemization reaction is carried out under the conditions of enzyme catalysis and auxiliary heating.

[0015] A device for converting a racemate of a chiral compound into a single enantiomer, comprising:

[0016] (1) A simulated moving bed separation system comprising: an SMB filter, an SMB feed tank, an SMB heat exchanger, and a simulated moving bed, wherein a chiral filler is loaded in the fixed bed of the simulated moving bed for chiral separation of racemates and obtaining enriched strongly adsorbed components and weakly adsorbed components at the extraction port and the raffinate port of the simulated moving bed, respectively;

[0017] (2) a strongly adsorbed component crystallizer, a strongly adsorbed component filter, and a strongly adsorbed component evaporator, wherein the strongly adsorbed component crystallizer is used to crystallize the strongly adsorbed component enriched by the extraction port of the simulated moving bed separator by removing the solvent, and the strongly adsorbed component filter is used to perform solid-liquid separation on the crystallized product of the strongly adsorbed component crystallizer to obtain a high-purity single enantiomer solution of the strongly adsorbed component and a eutectic solid enriched in the strongly adsorbed component; the strongly adsorbed component evaporator is used to evaporate the high-purity single enantiomer solution of the strongly adsorbed component to obtain a high-purity single enantiomer solid of the strongly adsorbed component;

[0018] (3) a weakly adsorbed component crystallizer, a weakly adsorbed component filter, and a weakly adsorbed component evaporator, wherein the weakly adsorbed component crystallizer is used to crystallize the weakly adsorbed component enriched by the raffinate outlet of the simulated moving bed separator by removing the solvent, and the weakly adsorbed component filter is used to perform solid-liquid separation on the crystallized product of the weakly adsorbed component crystallizer to obtain a high-purity single enantiomer solution of the weakly adsorbed component and a eutectic solid enriched in the weakly adsorbed component; the weakly adsorbed component evaporator is used to evaporate the high-purity single enantiomer solution of the weakly adsorbed component to obtain a high-purity single enantiomer solid of the weakly adsorbed component;

[0019] Of the high-purity single strongly adsorbed component enantiomer and the high-purity single weakly adsorbed component enantiomer, one is a high-purity single enantiomer solid of the target product, i.e., the target product; and the other is a high-purity single enantiomer solid of a non-target product;

[0020] (4) a racemization reaction system, comprising: a high-purity single enantiomer dissolution tank for a non-target product, a high-purity single enantiomer buffer tank for a non-target product, a racemization heat exchanger, a racemization reactor, and a racemization evaporator, for dissolving the non-target high-purity single enantiomer solid in a second mobile phase and converting it into a racemic solid after temperature adjustment, racemization reaction, and evaporation;

[0021] (5) a racemate recovery tank for storing a racemate solid formed by a eutectic solid enriched in a strongly adsorbed component and a eutectic solid enriched in a weakly adsorbed component in a weight ratio of 1:1, and a racemate solid obtained from the racemization reaction system;

[0022] (6) a racemate dissolving tank, used to dissolve the racemate solid from the racemate recovery tank and the freshly fed racemate raw material in the first mobile phase and input them into the simulated moving bed separation system;

[0023] The separation purity of the simulated moving bed is set to 80% to 95%, preferably 85% to 95%. This means that the strongly adsorbed components collected and enriched at the extraction port of the simulated moving bed have a purity of 80% to 95%, preferably 85% to 95%, and the weakly adsorbed components collected and enriched at the raffinate port of the simulated moving bed have a purity of 80% to 95%, preferably 85% to 95%.

[0024] The simulated moving bed is composed of 4 to 10 fixed beds connected in series, and the fixed beds are filled with chiral fillers; the open-loop port, feed port, elution port, extraction port and raffinate port divide the fixed beds connected in series into several operating areas, including: a first area for desorbing strongly adsorbed components, located between the elution port and the extraction port; a second area for enriching strongly adsorbed components, located between the extraction port and the open-loop port; a third area for enriching weakly adsorbed components, located between the feed port and the raffinate port; and a fourth area for adsorbing weakly adsorbed components, located between the raffinate port and the elution port.

[0025] In the simulated moving bed, preferably, the number of the fixed beds is 4 to 8.

[0026] The first mobile phase solvent used in the simulated moving bed system and the second mobile phase solvent used in the racemization reaction system may have the same composition or different compositions.

[0027] The simulated moving bed can be operated in isocratic or gradient mode, and can be operated synchronously or asynchronously such as VeriCol (variable column SMB), SSMB (sequential SMB), or ISMB (intermittent SMB).

[0028] In the present invention, the separation purity requirement of SMB is lowered, so that it exceeds the purity corresponding to the eutectic point but is lower than the commercial single enantiomer purity requirement, which can greatly improve the production capacity of key SMB equipment; further, the characteristic process route of chiral crystallization with symmetrical eutectics is integrated, and the two streams of SMB are separately crystallized and purified. The two chiral substance solutions with chiral excess values exceeding the corresponding values of the eutectic are respectively crystallized by removing the solvent to obtain a eutectic and a high-purity single enantiomer; one of the two high-purity single enantiomers is used as the target product, and the other enters the racemization reactor to be converted into a racemate. At the same time, an equal mixture of the two eutectics is also a racemate; the product of the racemization reactor, the equal mixture of the eutectics produced by the two crystallizers, and the racemate raw material are used as sources to re-enter the SMB separation system for separation. It can be seen that if the addition and recovery of the solvent are not taken into account and only the chiral enantiomers are considered, the feed of the entire device contains only the racemate, and the product of the entire device contains only a high-purity single enantiomer of the target product. Moreover, the purity of the single enantiomer of the target product purified by the crystallizer exceeds 99%, meeting the product purity requirements.

[0029] Compared with the prior art, the present invention has the following beneficial technical effects:

[0030] The present invention combines the chiral resolution process with the racemization reaction, and can realize the conversion of the racemate into a single enantiomer.

[0031] The present invention combines crystallization and SMB processes, and uses two crystallizers to simultaneously crystallize and purify chiral substance solutions at the SMB extraction port and the raffinate port, thereby crystallizing both the target product and the non-target product, thereby ensuring the purity of the target product and facilitating the subsequent racemization reaction of the single enantiomer of the non-target product.

[0032] In the present invention, the racemate at the SMB feed port has three sources, namely, an equal mixture of the racemate raw material, the product of the racemization reactor (derived from a single enantiomer of a non-target product), and the eutectic generated by the two crystallizers, so the utilization rate of the raw materials is high and the yield is high.

[0033] The present invention reduces the separation purity requirement of SMB and significantly improves the production capacity of SMB separation. As a key device in the device of the present invention, the significant increase in the production capacity of SMB helps to significantly improve the overall device yield.

[0034] It can be seen that the use of the device and method of the present invention can convert the racemate of a chiral compound into a single enantiomer, which can greatly improve the overall equipment yield while ensuring the purity and yield of the target product. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1Schematic diagram of the apparatus for converting a racemic chiral compound into a single enantiomer according to the present invention.

[0036] Figure 2 Schematic diagram of the apparatus for converting a chiral compound racemate into a single enantiomer in a comparative example. DETAILED DESCRIPTION

[0037] In order to better illustrate the present invention and facilitate understanding of the technical solution of the present invention, the present invention is further described in detail below with reference to the accompanying drawings and specific embodiments.

[0038] For the convenience of description, the following will be explained using the weakly adsorbed component as the target product:

[0039] A device for converting a chiral compound racemate into a single enantiomer such as Figure 1 As shown, it includes: a racemate dissolution tank 1; an SMB filter 2; an SMB feed tank 3; an SMB heat exchanger 4; a simulated moving bed (SMB) 5; a weakly adsorbed component buffer tank 6; a strongly adsorbed component buffer tank 7; a weakly adsorbed component crystallizer 8; a strongly adsorbed component crystallizer 9; a weakly adsorbed component evaporator 10; a strongly adsorbed component evaporator 11; a strongly adsorbed component single enantiomer dissolution tank 12; a strongly adsorbed component single enantiomer buffer tank 13; a racemization heat exchanger 14; a racemization reactor 15; a racemate evaporator 16; and a racemate recovery tank 17.

[0040] The racemate dissolution tank 1 is connected to the SMB filter 2, the SMB feed tank 3, the SMB heat exchanger 4 and the simulated moving bed 5 in sequence.

[0041] The raffinate outlet of the simulated moving bed 5 is connected in sequence to the weakly adsorbed component buffer tank 6 and the weakly adsorbed component crystallizer 8 (with a filtering function for liquid-solid separation), the liquid phase outlet of the weakly adsorbed component crystallizer 8 is connected to the weakly adsorbed component evaporator 10, and the solid phase outlet of the weakly adsorbed component evaporator 10 collects the target product single enantiomer solid (i.e., target product VI); the solid phase outlet of the weakly adsorbed component crystallizer 8 is connected to the inlet of the racemate recovery tank 17.

[0042] The extraction port of the simulated moving bed 5 is connected to the strong adsorption component buffer tank 7 and the strong adsorption component crystallizer 9 (with a filtration function for liquid-solid separation) in sequence, the liquid phase outlet of the strong adsorption component crystallizer 9 is connected to the strong adsorption component evaporator 11, and the solid phase outlet of the strong adsorption component evaporator 11 is connected to the strong adsorption component single enantiomer dissolution tank 12, the strong adsorption component single enantiomer buffer tank 13, the racemization heat exchanger 14, the racemization reactor 15, the racemate evaporator 16 and the racemate recovery tank 17; the solid phase outlet of the strong adsorption component crystallizer 9 is connected to the inlet of the racemate recovery tank 17.

[0043] The outlet of the racemate recovery tank 17 is connected to the inlet of the racemate dissolution tank 1 .

[0044] At the same time, the input pipeline I of the first mobile phase solvent is connected to the racemate dissolution tank 1 and the simulated moving bed 5 respectively, and the input pipeline II of the second mobile phase solvent is connected to the strongly adsorbed component single enantiomer dissolution tank 12; the input end of the input pipeline I of the first mobile phase solvent is connected to the solvent I storage tank ( Figure 1 The input end of the second mobile phase solvent input pipeline II is connected to the solvent II storage tank ( Figure 1 not shown).

[0045] The gas phase outlet of the weak adsorption component crystallizer 8, the gas phase outlet of the strong adsorption component crystallizer 9, the gas phase outlet of the weak adsorption component evaporator 10 and the gas phase outlet of the strong adsorption component evaporator 11 are respectively passed through their respective condensers ( Figure 1 (not shown) and then enters the recovery pipeline III of the first mobile phase solvent, and the gas phase outlet of the racemic evaporator 16 passes through the corresponding condenser ( Figure 1 The output end of the first mobile phase solvent recovery pipeline III is connected to the solvent I recovery tank ( Figure 1 The output end of the recovery pipeline IV of the second mobile phase solvent is connected to the solvent II recovery tank ( Figure 1 not shown).

[0046] The simulated moving bed 5 may be an existing simulated moving bed, in which a chiral filler is loaded in the fixed bed. The screening and loading of the chiral filler may be performed by various existing known technologies.

[0047] For example, the simulated moving bed 5 may have the following structure:

[0048] The simulated moving bed 5 is composed of several fixed beds connected in series, which are filled with suitable chiral fillers. The number of fixed beds is 4 to 10, preferably 4 to 8; the simulated moving bed 5 has two inlets, namely the feed inlet and the elution inlet; the simulated moving bed 5 has two outlets, namely the extraction inlet and the raffinate inlet; these inlets and outlets divide the fixed beds connected in series into several operating areas, including: a first area for desorbing strongly adsorbed components, located between the elution inlet and the extraction inlet; a second area for enriching strongly adsorbed components, located between the extraction inlet and the open-loop inlet; a third area for enriching weakly adsorbed components, located between the feed inlet and the raffinate inlet; and a fourth area for adsorbing weakly adsorbed components, located between the raffinate inlet and the elution inlet.

[0049] The separation purity of the simulated moving bed 5 is set to 80% to 95%, preferably 85% to 95%. This separation purity exceeds the purity corresponding to the eutectic point, but is lower than the commercial single enantiomer purity requirement (commercial single enantiomer purity requirement is generally greater than 98%). This also means that the purity of the weakly adsorbed component obtained at the raffinate outlet is 80% to 95%, preferably 85% to 95%, and the purity of the strongly adsorbed component obtained at the extraction outlet is 80% to 95%, preferably 85% to 95%.

[0050] In each of the aforementioned crystallizers (including the weakly adsorbing component crystallizer 8 and the strongly adsorbing component crystallizer 9), a chiral substance solution having a chiral excess exceeding that of the eutectic is crystallized by removing the solvent to obtain a eutectic and a high-purity single enantiomer. This crystallization process can be achieved using various known techniques (e.g., crystallization by drying or evaporation).

[0051] For example, each of the above-mentioned crystallizers (including the component crystallizer 8 and the strong adsorption component crystallizer 9) can be a continuous crystallizer or a batch crystallizer, preferably a batch crystallizer. The crystallizer can be a crystallizer with a solid-liquid separation filtration function, or a single-function crystallizer can be selected, which only requires the corresponding filter to be equipped.

[0052] In the racemization reactor, a single enantiomer can be converted into a racemate by enzyme catalysis and auxiliary heating. The racemization reaction process can be achieved using various existing known techniques. For example, the racemization reactor 15 can be a batch reactor, a continuous reactor, a series of continuous reactors, or a fixed bed reactor, preferably a batch reactor or a fixed bed reactor.

[0053] The other heat exchangers, evaporators, buffer tanks and filters are all conventional equipment.

[0054] The method for converting a chiral compound racemate into a single enantiomer using the above-mentioned device comprises the following steps:

[0055] In racemate dissolution tank 1, the chiral compound racemate is dissolved in first mobile phase solvent 1 to form solution i. Solution i enters the simulated moving bed separation system: impurities are removed by SMB filter 2, then it enters SMB feed tank 3. After temperature adjustment by SMB heat exchanger 4, it enters simulated moving bed 5 for separation.

[0056] The enriched weakly adsorbed component ii is collected at the raffinate outlet of the simulated moving bed 5 and stored in a weakly adsorbed component buffer tank 6. The weakly adsorbed component then enters a weakly adsorbed component crystallizer 8, where it is crystallized by evaporating the solvent (the evaporated solvent I is recovered). Solid-liquid separation is performed through a built-in filter, resulting in a high-purity target product single enantiomer solution iv in the liquid phase and a mixture with a purity corresponding to the eutectic point (i.e., a eutectic solid ix enriched in the weakly adsorbed component). Subsequently, the liquid phase (i.e., the high-purity target product single enantiomer solution iv) enters a weakly adsorbed component evaporator 10 (the evaporated solvent I is recovered), yielding a high-purity target product (weakly adsorbed component) single enantiomer solid ⅷ, which is collected as the target product VI.

[0057] The enriched strongly adsorbed component iii is collected at the extraction port of the simulated moving bed 5 and stored in the strongly adsorbed component buffer tank 7, and then enters the strongly adsorbed component crystallizer 9, where crystallization is performed by evaporating the solvent (the evaporated solvent I is recovered), and solid-liquid separation is performed through the built-in filter to obtain a high-purity non-target product single enantiomer solution v in the liquid phase, and a mixture with a purity corresponding to the eutectic point (eutectic solid x rich in strongly adsorbed components) is obtained in the solid phase. Subsequently, the liquid phase (i.e., high-purity non-target product single enantiomer solution v) enters the strongly adsorbed component evaporator 11 (evaporated solvent I is recovered) to obtain a high-purity non-target product (strongly adsorbed component) single enantiomer solid vi, which enters the strongly adsorbed component single enantiomer dissolution tank 12 and is dissolved in the second mobile phase solvent II. The resulting solution vii enters the strongly adsorbed component single enantiomer buffer tank 13, is temperature-adjusted by the racemate heat exchanger 14, and is then passed into the racemization reactor 15 to be converted into a racemate solution xi. The solution enters the racemate evaporator 16 to evaporate the solvent (evaporated solvent II is recovered), thereby obtaining a racemate solid xii.

[0058] The eutectic solid ⅸ rich in weakly adsorbed components and the eutectic solid x rich in strongly adsorbed components are mixed in a weight ratio of 1:1, enter the racemate recovery tank 17, and after being mixed with the fresh racemate solid xii obtained from the racemate evaporator 16, return to the racemate dissolution tank 1, and are dissolved in the first mobile phase solvent I as a chiral compound racemate together with the newly added racemate solid raw material (V), and then enter the simulated moving bed separation system again.

[0059] The strongly adsorbed component enriched at the extraction port of the simulated moving bed 5 and the weakly adsorbed component enriched at the raffinate port have a purity of 80% to 95%, preferably 85% to 95%. This separation purity exceeds the purity corresponding to the eutectic point, but is lower than the commercial single enantiomer purity requirement. The commercial single enantiomer purity requirement is generally higher than 98% (actually higher than 99%). Purity is optimized and controlled by adjusting the operating parameters of the simulated moving bed.

[0060] The simulated moving bed 5 can be operated in isocratic or gradient mode, and can be operated in synchronous mode or in asynchronous mode such as VeriCol (variable column SMB), SSMB (sequential SMB), or ISMB (intermittent SMB).

[0061] The above-mentioned crystallization method for removing the solvent can be drying or evaporation, preferably vacuum evaporation.

[0062] The racemization reaction can be carried out under conditions of enzyme catalysis and auxiliary heating to convert a single enantiomer into a racemate. The racemization reaction process can be achieved by various existing known techniques.

[0063] Meanwhile, the first mobile phase solvent I is an SMB solvent. Generally speaking, the selection of this solvent should help improve the adsorption selectivity of the two enantiomers on the stationary phase. The second mobile phase solvent II is a racemization reaction solvent. Generally speaking, the selection of this solvent should help improve the rate of the enzyme-catalyzed reaction. The first mobile phase solvent I and the second mobile phase solvent II can be substances of the same composition or substances of different compositions.

[0064] As can be seen, the above-mentioned method for converting a chiral compound racemate into a single enantiomer includes the following three main unit operations: (1) preliminary separation of the racemate in the SMB; (2) further purification of the weakly adsorbed component and the strongly adsorbed component in two crystallizers; and (3) racemization of the high-purity single enantiomer of the non-target product in the racemization reactor to obtain the racemate. Of these three main unit operations, the racemization reaction and crystallization process can both be achieved with high efficiency based on existing technologies, while the slowest SMB separation is the key step that determines the production capacity of the entire process. Therefore, the following will use a specific chiral compound as an example to describe the parameters of the SMB process in detail, and based on this, an overall evaluation of the entire process will be conducted (in the following examples and comparative examples, the racemization reaction solvent is acetonitrile, the conversion rate of the racemization reactor exceeds 99%, and the solid-liquid separation is complete during the crystallization process).

[0065] Example 1

[0066] The following description will take the conversion of the N-2-methylbenzylidene-phenylglycine amide (NMPA) racemate into a single enantiomer as an example.

[0067] The devices used are as Figure 1 The SMB consists of four fixed beds, each 10 cm long and 1 cm in inner diameter, packed with ChiralPak AY (a normal phase chiral column derived from dacel polysaccharide) stationary phase, with a total porosity of 0.72.

[0068] The process parameters involved are described as follows:

[0069] The total concentration of the feed racemate was 15 mg / mL, and the maximum flow rate was 20 mL / min.

[0070] SMB operation: synchronous switching; isocratic operation, mobile phase ACN (acetonitrile), operating temperature 20 °C.

[0071] The target product is a weakly adsorbed component.

[0072] Under the following conditions, the adsorption satisfies the following isotherm equation:

[0073]

[0074] H1 = 0.95; H2 = 3.1; k1 = 0.03 mL / mg; k2 = 0.31 mL / mg. Here, H and k are adsorption equilibrium model parameters, c and q are mobile phase and stationary phase concentrations, respectively, both in mg / mL; i has a value of 1 and 2, representing weakly adsorbed and strongly adsorbed components, respectively.

[0075] In this example, the SMB was optimized to achieve a purity of 0.95 for the strongly and weakly adsorbed components enriched at the extraction and raffinate ports, respectively. The optimized operating parameters were: ts = 0.1 min; Q1 = 20 mL / min; Q2 = 9.94 mL / min; Q3 = 12.1 mL / min; and Q4 = 6.14 mL / min. Here, ts is the synchronous switching time; Qj is the volumetric flow rate of the mobile phase in zone j, where j = 1, 2, 3, or 4.

[0076] The goal is to achieve a purity of 0.99 (ee value 0.98) for the final target product single enantiomer. In this case, the total equipment yield is approximately 55 grams per hour, that is, 55 grams of racemate can be converted into the target product single enantiomer with an optical purity of 0.99 per hour.

[0077] When the purity requirement of the final target product single enantiomer is increased to 0.992, the total yield of the equipment is basically unchanged. It can be seen that the total yield of the device and method of the present invention is not greatly affected by the purity requirement of the target product.

[0078] Comparative Example 1

[0079] The following description will take the conversion of the N-2-methylbenzylidene-phenylglycine amide (NMPA) racemate into a single enantiomer as an example.

[0080] Devices such as Figure 2As shown, it includes: a racemate dissolution tank 1; an SMB filter 2; an SMB feed tank 3; an SMB heat exchanger 4; a simulated moving bed (SMB) 5; a weakly adsorbed component buffer tank 6; a strongly adsorbed component buffer tank 7; a weakly adsorbed component evaporator 10; a strongly adsorbed component evaporator 11; and a racemization reactor 15. It can be seen that the device used in Example 1 ( Figure 1 ) compared to the device in this comparative example, there is no crystallization device.

[0081] The racemate dissolution tank 1 is sequentially connected to an SMB filter 2, an SMB feed tank 3, an SMB heat exchanger 4, and a simulated moving bed 5. The raffinate outlet of the simulated moving bed 5 is sequentially connected to a weakly adsorbed component buffer tank 6 and a weakly adsorbed component evaporator 10. The solid phase outlet of the weakly adsorbed component evaporator 10 collects the target single enantiomer solid VI. The extraction port of the simulated moving bed 5 is sequentially connected to a strongly adsorbed component buffer tank 7 and a strongly adsorbed component evaporator 11. The solid phase outlet of the strongly adsorbed component evaporator 11 is connected to a racemization reactor 15. The outlet of the racemization reactor 15 is connected to the inlet of the racemate dissolution tank 1.

[0082] At the same time, the first mobile phase solvent input pipeline I is connected to the racemate dissolution tank 1, the simulated moving bed 5, and the racemization reactor 15 respectively; the input end of the first mobile phase solvent input pipeline I is connected to the solvent I storage tank ( Figure 2 not shown).

[0083] The gas phase outlet of the weak adsorption component evaporator 10 and the gas phase outlet of the strong adsorption component evaporator 11 are respectively passed through their respective condensers ( Figure 2 The output end of the first mobile phase solvent recovery pipeline III is connected to the solvent I recovery tank ( Figure 2 not shown).

[0084] Similarly, simulated moving bed 5 adopts the following structure: it consists of four fixed beds connected in series, each 10 cm long and 1 cm in inner diameter. The fixed beds are packed with ChiralPak AY stationary phase with a total porosity of 0.72. Simulated moving bed 5 has two inlets: a feed port and an elution port; and two outlets: an extraction port and a raffinate port. These inlets and outlets divide the series of fixed beds into several operating zones, including: a first zone for desorbing strongly adsorbed components, located between the elution port and the extraction port; a second zone for enriching strongly adsorbed components, located between the extraction port and the open-loop port; a third zone for enriching weakly adsorbed components, located between the feed port and the raffinate port; and a fourth zone for adsorbing weakly adsorbed components, located between the raffinate port and the elution port.

[0085] The total concentration of the feed racemate was 15 mg / mL, and the maximum flow rate was 20 mL / min.

[0086] SMB operation: synchronous switching; isocratic operation, mobile phase ACN (acetonitrile), operating temperature 20 °C.

[0087] The target product is a weakly adsorbed component.

[0088] Under the following conditions, the adsorption satisfies the following isotherm equation:

[0089]

[0090] H1 = 0.95; H2 = 3.1; k1 = 0.03 mL / mg; k2 = 0.31 mL / mg. Here, H and k are adsorption equilibrium model parameters, c and q are mobile phase and stationary phase concentrations, respectively, both in mg / mL; i has a value of 1 and 2, representing weakly adsorbed and strongly adsorbed components, respectively.

[0091] To achieve a single enantiomer purity of 0.99 (ee value 0.98) for the final target product, SMB was used directly in this comparative example to achieve this purity requirement. Based on this, the optimized SMB operating parameters were: ts = 0.093 min; Q1 = 20 mL / min; Q2 = 10.93 mL / min; Q3 = 11.88 mL / min; and Q4 = 6.86 mL / min. Here, ts is the synchronous switching time; Qj is the volumetric flow rate of the mobile phase in zone j, where j = 1, 2, 3, or 4.

[0092] In this case, the total plant productivity is about 25 g per hour, ie, 25 g of the racemate can be converted into the target product single enantiomer with an optical purity of 0.99 per hour.

[0093] Comparative Example 2

[0094] The process is essentially the same as Comparative Example 1, differing only in that the target product purity was increased to 0.992. Similarly, in this comparative example, SMB was used directly to achieve the required purity. Based on this, the optimized SMB operating parameters were: ts = 0.093 min; Q1 = 20 mL / min; Q2 = 11.02 mL / min; Q3 = 11.63 mL / min; and Q4 = 6.88 mL / min. Here, ts is the synchronous switching time; Qj is the volumetric flow rate of the mobile phase in zone j, with j = 1, 2, 3, or 4.

[0095] In this case, the total equipment productivity is about 17 g per hour, that is, 17 g of the racemate can be converted into the target product single enantiomer with an optical purity of 0.992 per hour.

[0096] Comparing Comparative Example 2 with Comparative Example 1, it can be found that as the purity requirement of the target product increases, the equipment yield decreases significantly.

[0097] Comparing Example 1 with Comparative Examples 1 and 2, it can be seen that the apparatus and method of the present invention, while ensuring conversion rate and product purity, can increase the yield of chiral racemates into single enantiomers by approximately 2-fold and 3-fold. As Example 1 demonstrates, the overall yield using the apparatus and method of the present invention is not significantly affected by the required purity of the target product. Therefore, the higher the required purity of the target product, the more significant the advantages of the apparatus and method of the present invention over the comparative examples.

[0098] The above is a specific description of the device and method of the present invention using a weakly adsorbed component as an example of the target product. Obviously, when the target product is a strongly adsorbed component, the device and method of the present invention can also be used.

[0099] It can be seen that in the present invention, the separation purity requirement of SMB is reduced, so that it exceeds the purity corresponding to the eutectic point but is lower than the commercial single enantiomer purity requirement, which can greatly improve the production capacity of key SMB equipment; and further, the characteristic integrated process route of chiral crystallization with symmetrical eutectic is utilized to integrate the process route, and the two streams of SMB are crystallized and purified separately, and the two chiral substance solutions whose chiral excess values of SMB separation exceed the corresponding values of the eutectic are crystallized by removing the solvent to obtain a eutectic and a high-purity single enantiomer respectively; after purification in the two crystallizers, one of the single enantiomers obtained is used as the target product, and the other enters the racemization reactor to be converted into a racemate. At the same time, an equal mixture of the two eutectics produced by the two crystallizers is also a racemate; the product of the racemization reactor, the equal mixture of the eutectics produced by the two crystallizers, and the racemate raw material are used as sources to re-enter the SMB separation system for separation. It can be seen that if the addition and recovery of the solvent are not taken into account and only the chiral enantiomers are considered, the feed of the entire device contains only the racemate, and the product of the entire device contains only a high-purity single enantiomer of the target product. Moreover, the purity of the single enantiomer of the target product purified by the crystallizer exceeds 99%, meeting the product purity requirements.

[0100] In summary, the present invention combines crystallization and SMB processes, and simultaneously crystallizes and purifies the chiral substance solution at the SMB extraction port and the raffinate port, crystallizing both the target product and the non-target product, thereby ensuring the purity of the target product and facilitating the subsequent racemization reaction of the single enantiomer of the non-target product. In the present invention, the racemate imported by the SMB has three sources, namely, an equal mixture of the racemate raw material, the product of the racemization reactor (derived from the single enantiomer of the non-target product), and the eutectic generated by the two crystallizers, which has high raw material utilization and high yield. The present invention reduces the separation purity requirements of SMB and significantly improves the production capacity of SMB separation. As a key device in the device of the present invention, the significant improvement in the production capacity of SMB helps to significantly improve the overall equipment yield. Therefore, using the device and method of the present invention, the chiral compound racemate can be converted into a single enantiomer, which can significantly improve the overall equipment yield while ensuring the purity and yield of the target product.

[0101] It should be noted that the embodiments described above are only used to illustrate the present invention and do not constitute any limitation of the present invention. The present invention has been described with reference to typical embodiments, but it should be understood that the words used therein are descriptive and explanatory words, rather than restrictive words. The present invention may be modified as specified within the scope of the claims of the present invention, and the present invention may be revised without departing from the scope and spirit of the present invention. Although the present invention described therein relates to specific methods, materials and embodiments, it does not mean that the present invention is limited to the specific examples disclosed therein. On the contrary, the present invention can be extended to all other methods and applications with the same function.

Claims

1. A method for converting a chiral compound racemate into a single enantiomer, comprising the following steps: (1) dissolving the chiral compound racemate in a first mobile phase to form a solution, and entering the solution into a simulated moving bed separation system, collecting the enriched strongly adsorbed component at the extraction port of the simulated moving bed, with a purity of 80% to 95%; collecting the enriched weakly adsorbed component at the raffinate port of the simulated moving bed, with a purity of 80% to 95%; (2) storing the outlet materials of the raffinate port and the extraction port in respective buffer tanks, and performing crystallization by removing the solvent through respective corresponding crystallizers, and then performing solid-liquid separation through corresponding filters, wherein the liquid phases obtained are respectively a high-purity single enantiomer solution of the weakly adsorbed component and a high-purity single enantiomer solution of the strongly adsorbed component, and the solid phases obtained are respectively a eutectic solid enriched in the weakly adsorbed component and a eutectic solid enriched in the strongly adsorbed component; (3) evaporating the high-purity single enantiomer solution of the target product in the two high-purity single enantiomer solutions through an evaporator to obtain the target product and collecting it; evaporating the high-purity single enantiomer solution of the non-target product in the two high-purity single enantiomer solutions through an evaporator to obtain a non-target product single enantiomer solid, dissolving it in a second mobile phase, adjusting the temperature through a heat exchanger, and then passing it into a racemization reactor, where it is converted into a racemic solution; (4) After evaporating the solvent of the racemic solution obtained from the racemization reactor, a recovered racemic solid is obtained; the eutectic solid enriched in the weakly adsorbed component and the eutectic solid enriched in the strongly adsorbed component obtained in step (2) are mixed in a weight ratio of 1:1 to obtain a recovered racemic solid; the recovered racemic solid obtained from the racemization reactor and the eutectic is mixed with a fresh racemic raw material, as the chiral compound racemate described in step (1), dissolved in the first mobile phase to form a solution, and then enters the simulated moving bed separation system again.

2. The method for converting a chiral compound racemate into a single enantiomer according to claim 1, wherein: The strongly adsorbed components are collected and enriched at the extraction port of the simulated moving bed, with a purity of 85% to 95%; the weakly adsorbed components are collected and enriched at the raffinate port of the simulated moving bed, with a purity of 85% to 95%.

3. The method for converting a chiral compound racemate into a single enantiomer according to claim 1, wherein: The method for removing the solvent to perform crystallization includes: performing crystallization by drying or evaporation.

4. The method for converting a chiral compound racemate into a single enantiomer according to claim 1, wherein: The racemization reaction is carried out under the conditions of enzyme catalysis and auxiliary heating.

5. A device for converting a chiral compound racemate into a single enantiomer, characterized in that: include: (1) A simulated moving bed separation system comprising: an SMB filter, an SMB feed tank, an SMB heat exchanger, and a simulated moving bed, wherein a chiral filler is loaded in the fixed bed of the simulated moving bed for chiral separation of racemates and obtaining enriched strongly adsorbed components and weakly adsorbed components at the extraction port and the raffinate port of the simulated moving bed, respectively; (2) a strongly adsorbed component crystallizer, a strongly adsorbed component filter, and a strongly adsorbed component evaporator, wherein the strongly adsorbed component crystallizer is used to crystallize the strongly adsorbed component enriched by the extraction port of the simulated moving bed separator by removing the solvent, and the strongly adsorbed component filter is used to perform solid-liquid separation on the crystallized product of the strongly adsorbed component crystallizer to obtain a high-purity single enantiomer solution of the strongly adsorbed component and a eutectic solid enriched in the strongly adsorbed component; the strongly adsorbed component evaporator is used to evaporate the high-purity single enantiomer solution of the strongly adsorbed component to obtain a high-purity single enantiomer solid of the strongly adsorbed component; (3) a weakly adsorbed component crystallizer, a weakly adsorbed component filter, and a weakly adsorbed component evaporator, wherein the weakly adsorbed component crystallizer is used to crystallize the weakly adsorbed component enriched by the raffinate outlet of the simulated moving bed separator by removing the solvent, and the weakly adsorbed component filter is used to perform solid-liquid separation on the crystallized product of the weakly adsorbed component crystallizer to obtain a high-purity single enantiomer solution of the weakly adsorbed component and a eutectic solid enriched in the weakly adsorbed component; the weakly adsorbed component evaporator is used to evaporate the high-purity single enantiomer solution of the weakly adsorbed component to obtain a high-purity single enantiomer solid of the weakly adsorbed component; Of the high-purity single strongly adsorbed component enantiomer and the high-purity single weakly adsorbed component enantiomer, one is a high-purity single enantiomer solid of the target product, i.e., the target product; and the other is a high-purity single enantiomer solid of a non-target product; (4) a racemization reaction system, comprising: a high-purity single enantiomer dissolution tank for a non-target product, a high-purity single enantiomer buffer tank for a non-target product, a racemization heat exchanger, a racemization reactor, and a racemization evaporator, for dissolving the non-target high-purity single enantiomer solid in a second mobile phase and converting it into a racemic solid after temperature adjustment, racemization reaction, and evaporation; (5) a racemate recovery tank for storing a racemate solid formed by a eutectic solid enriched in a strongly adsorbed component and a eutectic solid enriched in a weakly adsorbed component in a weight ratio of 1:1, and a racemate solid obtained from the racemization reaction system; (6) a racemate dissolving tank, used to dissolve the racemate solid from the racemate recovery tank and the freshly fed racemate raw material in the first mobile phase and input them into the simulated moving bed separation system; Wherein, the separation purity of the simulated moving bed is set to 80% to 95%.

6. The device according to claim 5, characterized in that The separation purity of the simulated moving bed is set to 85% to 95%.

7. The device according to claim 5, characterized in that The simulated moving bed separator adopts isocratic operation or gradient operation.

8. The device according to claim 5, wherein The simulated moving bed separator adopts synchronous operation or VeriCol, SSMB, ISMB asynchronous operation.

9. The device according to claim 5, wherein The simulated moving bed is composed of 4 to 10 fixed beds connected in series, and the fixed beds are filled with chiral fillers; wherein the open-loop port, feed port, elution port, extraction port and raffinate port divide the fixed beds connected in series into several operating zones, including: a first zone for desorbing strongly adsorbed components, located between the elution port and the extraction port; a second zone for enriching strongly adsorbed components, located between the extraction port and the open-loop port; a third zone for enriching weakly adsorbed components, located between the feed port and the raffinate port; and a fourth zone for adsorbing weakly adsorbed components, located between the raffinate port and the elution port.

10. The device according to claim 9, wherein The number of the fixed beds is 4 to 8.

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