A coupled separation method for efficient crystallization resolution of propranolol enantiomers and in-situ regeneration and application of its mother liquor

Abstract

The present invention discloses a coupled separation system and method for efficient crystallization separation of propranolol enantiomers and in-situ regeneration and application of mother liquor. The method utilizes crystallization and liquid-liquid extraction or membrane extraction, and couples them in a specific manner. Compared with the traditional diastereomeric crystallization method for separation of propranolol, the present invention has better separation effect, and realizes in-situ regeneration of mother liquor and repeated application. By adding raw materials, two high-purity enantiomers can be continuously produced. Compared with liquid-liquid extraction coupling, membrane extraction and crystallization are coupled, which has better stability and reduces physical banding and mixing between mother liquors. The present invention solves the problems of low yield and mother liquor treatment in the traditional crystallization method for separation of propranolol.

Description

Technical Field

[0001] The invention relates to a method for efficiently splitting a chiral drug propranolol and in-situ regeneration and application of its crystallization mother liquor, belonging to the technical field of chemical and pharmaceutical separation engineering. Background Art

[0002] Propranolol (chemical name: 1-isopropylamino-3-(naphthalene-1-oxy)propan-2-ol, foreign name: Propranolol, molecular formula: C 16 H 21 NO2, CAS No.: 525-66-6) is a chiral drug and a commonly used β-receptor blocker in clinical practice for the treatment of cardiovascular diseases. Although it is currently used as a racemate in clinical practice, its (S)-enantiomer is about 100 times more potent than its (R)-enantiomer, and the (R)-configuration may also produce some side effects (Wang Debin. Preparation of (S)-propranolol by chemical resolution [D]. Hebei University of Science and Technology, 2011). Since the pharmacological activities and metabolic mechanisms of the two enantiomers of propranolol are significantly different, studying its chiral resolution is of great significance for its further scientific use.

[0003] The diastereomeric salt crystallization resolution method is a mature chiral resolution technology that has been widely industrialized. However, the type of resolving agent or crystallization solvent has a great influence on the chiral resolution effect of the diastereomeric salt crystallization method. When the type of resolving agent or crystallization solvent is changed, the ee value of the crystal generally drops directly from about 100% to about 0%. In other words, there is either a chiral resolution effect or almost no effect or no crystallization. This is mainly because the two diastereomeric salts formed by the racemate and the resolving agent are also isomers, and their physicochemical properties are very similar. Therefore, for a specific racemate, a large number of experiments are required to find the type of resolving agent or crystallization solvent that has a chiral resolution effect on it. However, there have been studies reporting that the diastereomeric salt crystallization resolution method can be used to resolve racemic propranolol to obtain a single enantiomer of propranolol with high optical purity (Wang Debin. Preparation of (S)-propranolol by chemical resolution method [D]. Hebei University of Science and Technology, 2011). Propranolol is an organic amine alkaline drug that can react with an acidic resolving agent such as optically pure tartaric acid or its derivatives to produce two diastereomeric salts. Since the solubility of these two diastereomeric salts in certain solvents is significantly different, a crystallization method can be used to efficiently perform chiral separation, thereby obtaining a single enantiomer of propranolol with high optical purity. However, although the above-mentioned method for crystallizing and resolving propranolol by diastereomeric salts has the advantages of strong chiral separation ability, simple operation and low equipment investment, there are still some problems to be solved. Among them, the mother liquor remaining after crystallization still retains a part of the target enantiomer of propranolol, a part of the resolving agent and most of the non-target enantiomer of propranolol. Since the non-target enantiomer content in the mother liquor is too high, if the propranolol racemate and the resolving agent raw material are directly added to continue crystallization, the non-target enantiomer may also crystallize out. Therefore, it is difficult to apply the mother liquor multiple times. If the existing separation technology is used to extract each component in the mother liquor one by one for recovery, the steps will be cumbersome; while direct disposal will lead to practical problems such as low yield of propranolol single enantiomer product, great environmental pollution hazard of waste liquid and high cost of harmless treatment.

[0004] In response to the technical problems of mother liquor treatment and repeated application in the traditional diastereomeric salt crystallization separation method, the inventors established a new coupled separation system suitable for propranolol, which is expected to solve practical problems such as the low yield of single enantiomer products in its crystallization process, the great environmental pollution hazard of waste liquid and the high cost of its harmless treatment. Summary of the invention

[0005] The present invention is based on the concept of a previously disclosed separation method of coupled cyclic extraction and diastereomeric crystallization. By studying the physicochemical properties of propranolol, a new coupled separation system and method suitable for propranolol are established, which is expected to solve practical problems such as low yield of single enantiomer products in its crystallization process, great environmental pollution hazard of waste liquid and high cost of harmless treatment.

[0006] The idea of ​​the present invention is: add the racemate to be separated and the (R)-propranolol resolving agent to the (R)-propranolol crystallizer solvent, add the racemate to be separated and the (S)-propranolol resolving agent to the (S)-propranolol crystallization-extraction coupler solvent, and crystallize and separate to obtain crystalline salts containing (R)-propranolol and (S)-propranolol. In addition, the extraction phase first enters the (R)-propranolol crystallizer in sequence to perform liquid-liquid extraction with its crystallization solution to extract the uncrystallized (S)-propranolol; then flows out and enters the (S)-propranolol crystallization-extraction coupler to release the (S)-propranolol, and performs liquid-liquid extraction with its crystallization solution to extract the uncrystallized (R)-propranolol; then flows back to the (R)-propranolol crystallizer to release the (R)-propranolol and form a circulation flow. Thus, the uncrystallized enantiomers of the two mother liquors of the two crystallization systems are exchanged with each other, and the two mother liquors can gradually approach the racemic state to achieve regeneration. According to the crystal output and the operation loss, a certain amount of racemate and the respective resolving agent are added to the two mother liquors, so that the above operation can be repeated. In addition, the use of membrane extraction instead of liquid-liquid extraction is expected to solve the problem of mixing and band loss of the two mother liquors caused by the physical banding of the mother liquors.

[0007] To achieve the purpose of the present invention, the technical solution of the present invention is:

[0008] An extraction and crystallization coupling separation method for propranolol crystal splitting and in-situ regeneration and application of its crystallization mother liquor, characterized in that: the system of the method consists of three parts: a levorotatory crystallization solution, a dextrorotatory crystallization solution and an extraction phase, wherein the levorotatory crystallization solution contains two enantiomers of propranolol, an L-tartaric acid derivative splitting agent and a solvent, the dextrorotatory crystallization solution contains two enantiomers of propranolol, a D-tartaric acid derivative splitting agent and a solvent, and the extraction phase contains an alkane solvent; the levorotatory crystallization solution is in interface contact with the extraction phase, the dextrorotatory crystallization solution is in interface contact with the extraction phase, and the levorotatory crystallization solution and the dextrorotatory crystallization solution are not in interface contact;

[0009] Alternatively, the system of the method consists of four parts: a levorotatory crystallization solution, a dextrorotatory crystallization solution, an extraction phase and a membrane extraction component, wherein the levorotatory crystallization solution contains two enantiomers of propranolol, an L-tartaric acid derivative resolving agent and a solvent, the dextrorotatory crystallization solution contains two enantiomers of propranolol, a D-tartaric acid derivative resolving agent and a solvent, and the extraction phase contains an alkane solvent; the levorotatory crystallization solution and the extraction phase are in contact through the porous membrane interface in the membrane extraction component, the dextrorotatory crystallization solution and the extraction phase are in contact through the porous membrane interface in the membrane extraction component, and the levorotatory crystallization solution and the dextrorotatory crystallization solution are not in contact.

[0010] In the above technical scheme, preferably, the L-tartaric acid derivative resolving agent is dibenzoyl-L-tartaric acid, di-p-methylbenzoyl-L-tartaric acid or a mixture of the above two resolving agents; the D-tartaric acid derivative resolving agent is dibenzoyl-D-tartaric acid, di-p-methylbenzoyl-D-tartaric acid or a mixture of the above two resolving agents.

[0011] Preferably in the above technical solution, the solvent of the levorotatory crystallization solution or the dextrorotatory crystallization solution is methanol, dimethyl sulfoxide, N,N-dimethylformamide or a mixture of the above solvents and water.

[0012] Preferably in the above technical solution, the extraction phase is an alkane solvent, which is one of n-heptane, n-hexane, isooctane or n-octane, or a mixed solvent of two or more thereof.

[0013] Preferably in the above technical scheme, the usage ratio of propranolol, tartaric acid derivative resolving agent and crystallization solvent in the levorotatory crystallizer or the dextrorotatory crystallizer is 1mmol:0.25mmol~1mmol:10mL~20mL; the usage ratio of propranolol and the hydrocarbon solvent of the extraction phase alkane is 1mmol:20mL~200mL.

[0014] Preferably in the above technical scheme, the usage ratio of propranolol, tartaric acid derivative resolving agent and crystallization solvent in the levorotatory crystallizer or the dextrorotatory crystallizer is 1mmol:0.3mmol~0.7mmol:10mL~15mL; the usage ratio of propranolol and the hydrocarbon solvent of the extraction phase alkane is 1mmol:20mL~50mL.

[0015] Preferably in the above technical solution, an extractant capable of extracting the left-handed enantiomer and the right-handed enantiomer may be added to the extraction phase; the extractant is an organic phosphoric acid, phosphonic acid, carboxylic acid or sulfonic acid extractant.

[0016] In the above technical scheme, preferably, the solvent is pure methanol, or a mixed solvent with a volume ratio of methanol to water of 9:1 to 3:1, and the extraction phase flow rate is 5 to 11 mL / min; the preferred condition is that the solvent is a mixed solvent with a volume ratio of methanol to water of 9:1, and the extraction phase flow rate is 11 mL / min.

[0017] Preferably in the above technical solution, the membrane material of the membrane extraction is polyvinylidene fluoride, polytetrafluoroethylene, cellulose and its derivatives, polycarbonate, polyvinyl chloride, polysulfone, polyacrylonitrile, polyamide or sulfonated polysulfone porous hollow fiber membrane or flat membrane.

[0018] In the above technical scheme, preferably, in the propranolol levorotatory crystallizer, the levorotatory crystallization solution selectively crystallizes to precipitate the levorotatory propranolol enantiomer crystal salt; in the propranolol dextrorotatory crystallizer, the dextrorotatory crystallization solution selectively crystallizes to precipitate the dextrorotatory propranolol enantiomer crystal salt; the extraction phase first enters the levorotatory crystallizer to perform liquid-liquid extraction with its crystallization solution and then flows out, and then flows into the dextrorotatory crystallizer to perform liquid-liquid extraction with its crystallization solution and then flows out, and then flows back to the levorotatory crystallizer to form a circular flow; the uncrystallized propranolol enantiomers are mutually transferred between the crystallization solutions in the two crystallizers through the circular flow and liquid-liquid extraction of the extraction phase; after the crystals in the two crystallizers are taken out, the racemate and the respective resolving agent are continuously added to the two mother liquors, and the above operation is repeated; the positions of the levorotatory crystallizer and the dextrorotatory crystallizer can be interchanged;

[0019] Alternatively, in the propranolol levorotatory crystallizer, the levorotatory crystallization solution selectively crystallizes to precipitate the levorotatory propranolol enantiomer crystal salt; in the propranolol dextrorotatory crystallizer, the dextrorotatory crystallization solution selectively crystallizes to precipitate the dextrorotatory propranolol enantiomer crystal salt; the extraction phase first enters the levorotatory crystallization liquid-membrane extractor to perform membrane extraction with its crystallization solution and then flows out, and then flows into the dextrorotatory crystallization liquid-membrane extractor to perform membrane extraction with its crystallization solution and then flows out, and then flows back to the levorotatory crystallization liquid-membrane extractor to form a circulating flow; two crystallization processes are achieved through the circulating flow of the extraction phase and the membrane extraction. The uncrystallized propranolol enantiomers are transferred between the crystallization solutions in the crystallization devices; the dextrorotatory crystallization solution circulates between the dextrorotatory crystallization liquid-membrane extractor and the dextrorotatory crystallizer; the levorotatory crystallization solution circulates between the levorotatory crystallization liquid-membrane extractor and the levorotatory crystallizer; after the crystals in the two crystallizers are taken out, the racemate and the respective resolving agents are continuously added to the two mother liquors, and the above operation is repeated; the positions of the levorotatory crystallizer and the matching levorotatory crystallization liquid-membrane extractor can be interchanged with the positions of the dextrorotatory crystallizer and the matching levorotatory crystallization liquid-membrane extractor.

[0020] The positive and beneficial effects of the present invention are: the method of the present invention simultaneously crystallizes to obtain (S)-propranolol crystals and (R)-propranolol crystals, and utilizes the coupling of liquid-liquid extraction or membrane extraction and crystallization process to realize the transfer of non-crystallized enantiomers between two mother liquors, so that the mother liquor is restored to the racemic state to realize regeneration and can be continuously applied, thereby solving the problem that the mother liquor cannot be applied when propranolol is separated by the traditional diastereomeric crystallization method. The present invention mainly has the following improvements.

[0021] Compared with the traditional diastereomeric crystallization method, the crystallization mother liquor of the method of the present invention can be regenerated in situ and directly reused: in the traditional diastereomeric crystallization method, after the (S)-propranolol (or (R)-propranolol) crystals are filtered from the mother liquor, the remaining mother liquor, in addition to the solvent, also contains most of the non-target enantiomer (R)-propranolol (or (S)-propranolol), part of the target enantiomer (S)-propranolol (or (R)-propranolol) and part of the chiral resolving agent. At this time, since the concentration of the non-target enantiomer in the mother liquor is much greater than that of the target enantiomer, it is difficult to obtain a high-purity target enantiomer by cooling, and even the non-target enantiomer will crystallize in large quantities. If the raw material racemic propranolol and the resolving agent are forcibly added, and the mother liquor is reused, the non-target enantiomer in the mother liquor will further accumulate. A current treatment method is to add another chiral resolving agent that selectively crystallizes the non-target enantiomer to obtain a high-purity non-target enantiomer crystal. However, this results in a mixture of two chiral resolving agents in the mother liquor, and the splitting effect will also deteriorate if it is continued to be applied. Even if it is separated and recovered, the mixed chiral resolving agent can basically only be discarded. In summary, the traditional diastereomeric crystallization method is unable to apply its mother liquor because the non-target enantiomer is not removed from the system and continues to accumulate. In the method of the present invention, the non-target enantiomer of the mother liquor is continuously removed by the extraction phase, and the target enantiomer is continuously brought in from another crystallizer. Thus, both mother liquors can always be close to the racemic state. Only racemate and chiral resolving agent need to be continuously added to the mother liquor, and the mother liquor can be continuously reused. Therefore, the method of the present invention can realize the in-situ regeneration of the mother liquor (the in-situ racemization of the mother liquor produced by the cyclic extraction transfer) and direct repeated application, which is a green splitting method.

[0022] Compared with the traditional diastereomeric crystallization method for resolving propranolol, the yield and purity of propranolol crystals obtained by the coupled crystallization and resolving method of the present invention are higher: in the process of the traditional crystallization and resolving method, the concentration of a certain target enantiomer (such as (S)-propranolol enantiomer) in the mother liquor gradually decreases as its selective crystallization continues; and the concentration of the non-target enantiomer (such as (R)-propranolol enantiomer) remains basically unchanged or slightly decreases, and its relative concentration compared with (S)-propranolol increases. As a result, the non-target enantiomer (R)-propranolol in the mother liquor can gradually enter the (S)-propranolol crystal structure as an impurity due to the increase in relative concentration, so that the chiral resolution effect becomes worse. The greater the solute supersaturation concentration in the crystallization solution, the greater the possibility of impurity precipitation. In the method described in the present invention, the non-target (S)-propranolol in the (R)-propranolol crystallization-extraction coupler is continuously extracted and transferred to the (S)-propranolol crystallizer by the extraction phase. Thus, non-target (S)-propranolol is prevented from crystallizing in the (R)-propranolol crystallization-extraction coupler as an impurity. Similarly, the non-target (R)-propranolol in the (S)-propranolol crystallizer is continuously extracted and transferred to the (R)-propranolol crystallization-extraction coupler by the extraction phase, thereby preventing the non-target (R)-propranolol from crystallizing in the (S)-propranolol crystallizer as an impurity. Therefore, the purity of the crystals of the method of the present invention is improved. In addition, the (R)-propranolol in the (S)-propranolol crystallizer is transferred to the (R)-propranolol crystallization-extraction coupler by the extraction phase and crystallized, thereby improving the crystallization yield of the (R)-propranolol crystallization-extraction coupler; the (S)-propranolol in the (R)-propranolol crystallization-extraction coupler is transferred to the (S)-propranolol crystallizer by the extraction phase and crystallized, thereby improving the crystallization yield of the (S)-propranolol crystallizer.

[0023] Compared with the traditional diastereomeric crystallization method, the method of the present invention can simultaneously obtain two high-purity enantiomeric crystals: in the traditional diastereomeric crystallization method, only a part of the target enantiomer is precipitated as a high-purity crystal, and almost all of the non-target enantiomers, the remaining part of the target enantiomers and the remaining part of the chiral resolving agent are still left in the mother liquor. At this time, the post-processing problem of the mother liquor with complex components is relatively troublesome, and it is generally directly discarded. In the method described in the present invention, with the racemate as the raw material, the (R)-propranolol crystallization-extraction coupler and the (S)-propranolol crystallizer can continuously obtain high-purity (R)-propranolol crystals and (S)-propranolol crystals respectively. In addition, the mother liquor is not discarded, does not need to be treated, can be regenerated in situ and directly reused, and the racemate raw materials are all converted into high-purity (R)-propranolol crystals and (S)-propranolol crystals. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1It is a schematic diagram of the method of the present invention.

[0025] Figure 2 1 is a schematic diagram of a liquid-liquid extraction and crystallization coupling device according to an embodiment of the present invention, wherein: 1-(R)-propranolol crystallization-extraction coupler; 2-(S)-propranolol crystallization-extraction coupler; 3-(R)-propranolol crystallization-extraction buffer stabilizer; 4-(S)-propranolol crystallization-extraction buffer stabilizer; 5-extraction phase storage tank; 6-extraction phase pump; 7-agitator; 8-gauze; 9-feeding port; 10-(R)-propranolol crystallization solution; 11-(S)-propranolol crystallization solution; 12-extraction phase; 13-(R)-propranolol salt crystals; 14-(S)-propranolol salt crystals.

[0026] Figure 3 1 is a schematic diagram of a membrane extraction and crystallization coupling device according to an embodiment of the present invention, wherein: 15-(R)-propranolol crystallizer; 16-(S)-propranolol crystallizer; 17-(R)-propranolol crystallization liquid-membrane extractor; 18-(S)-propranolol crystallization liquid-membrane extractor; 19-(R)-propranolol crystallization liquid-buffer stabilizer after membrane extraction; 20-(S)-propranolol crystallization liquid-buffer stabilizer after membrane extraction; 21-(R)-propranolol crystallization liquid pump; 22-(S)-propranolol crystallization liquid pump; 23-filter; 24-feeding port; 25-discharging port.

[0027] Figure 4 1 is a graph showing the yield Y of crystals and mother liquor and the enantiomeric excess purity ee value after the 15th repeated crystallization in an embodiment of the present invention (a: crystals of the (R)-propranolol crystallizer using (D)-DBTA as a resolving agent; b: mother liquor of the (R)-propranolol crystallizer using (D)-DBTA as a resolving agent; c: crystals of the (S)-propranolol crystallizer using (L)-DBTA as a resolving agent; b: mother liquor of the (S)-propranolol crystallizer using (L)-DBTA as a resolving agent).

[0028] Figure 5 1 is a liquid phase diagram of (R)-propranolol and (S)-propranolol crystals obtained after repeated crystallization for the 15th time in an embodiment of the present invention, wherein a: liquid phase diagram of (R)-propranolol crystals; b: liquid phase diagram of (S)-propranolol crystals.

[0029] Figure 6 1 is a liquid phase diagram of two crystallization-extraction coupler mother liquors obtained after repeated crystallization for the 15th time in an embodiment of the present invention, wherein a: a liquid phase diagram of (R)-propranolol crystal mother liquor; b: a liquid phase diagram of (S)-propranolol crystal mother liquor.

[0030] Figure 7The results of directly applying the mother liquor of the conventional diastereomeric salt crystallization method using dibenzoyl-(D)-tartaric acid as a resolving agent, wherein a: the result of the crystals of the (R)-propranolol crystallizer using (D)-DBTA as a resolving agent; b: the result of the mother liquor of the (R)-propranolol crystallizer using (D)-DBTA as a resolving agent.

[0031] Figure 8 The results of directly applying the mother liquor of the conventional diastereomeric salt crystallization method using dibenzoyl-(L)-tartaric acid as a resolving agent, wherein a: the result of the crystals of the (S)-propranolol crystallizer using (L)-DBTA as a resolving agent; b: the result of the mother liquor of the (S)-propranolol crystallizer using (L)-DBTA as a resolving agent.

[0032] Fig. 9 The effect of the molar ratio of propranolol to dibenzoyl-D / L-tartaric acid on the crystallization process of PC-CE, where a: the effect on yield; b: the effect on ee value.

[0033] Fig.10 The effect of propranolol dosage in the crystallizer on the PC-CE crystallization process, where a: the effect on yield; b: the effect on ee value.

[0034] Fig.11 The influence of the volume ratio of methanol and water as crystallization solvents on the PC-CE crystallization process, where a: the influence on the yield; b: the influence on the ee value.

[0035] Fig.12 The influence of the circulating extraction flow rate on the PC-CE crystallization process, where a: the influence on the yield; b: the influence on the ee value.

[0036] In the accompanying drawings, PRO is propranolol and DBTA is dibenzoyl tartaric acid. DETAILED DESCRIPTION

[0037] The embodiments of the present invention are further described below in conjunction with the accompanying drawings, embodiments and comparative examples, but are not limited to the described contents.

[0038] Example 1: A new system of liquid-liquid extraction and crystallization coupling is used to separate propranolol and its crystallization mother liquor. Figure 1 Coupling principle diagram and Figure 2 As shown in the schematic diagram of the device, methanol-water solvent (12 mL, v:v = 9:1), chiral acid resolving agent (0.62 mmol) and propranolol base racemate (2.12 mmol) were added to the (R)-propranolol crystallization-extraction coupler and the (S)-propranolol crystallization-extraction coupler, respectively. Figure 2As shown, the (R)-propranolol crystallization-extraction coupler (1) is charged with dibenzoyl-(D)-tartaric acid, a chiral resolving agent for selective crystallization of (R)-propranolol, while the (S)-propranolol crystallization-extraction coupler (2) is charged with dibenzoyl-(L)-tartaric acid, a chiral resolving agent for selective crystallization of (S)-propranolol. The crystallization-extraction coupler is a sealed cylindrical tank body containing an extraction phase inlet and outlet, which can accommodate a crystallization solution and an extraction phase, and the two phases are divided into upper and lower layers due to the density difference. The inlet of the extraction phase is at the bottom of the tank body, and the outlet is at the top of the tank body. The temperature and stirring conditions are controlled to first dissolve the components of the crystallization solution in the two crystallizers to form a supersaturated solution. Then, the extraction phase (12) is introduced, so that the extraction phase (12) contacts and circulates with the supersaturated solution in the two crystallizers in turn. That is, the extraction phase (12) first enters the (R)-propranolol crystallization-extraction coupler (1) to contact the supersaturated crystallization solution (10) in the lower layer, then fills the upper space of the (R)-propranolol crystallization-extraction coupler (1) and overflows; then enters the (S)-propranolol crystallization-extraction coupler (2) to contact the supersaturated crystallization solution (11) therein, and then flows out of the (S)-propranolol crystallization-extraction coupler (2); and the outflowing extraction phase (12) enters the (R)-propranolol crystallization-extraction coupler (1) again, thereby forming a circulating liquid-liquid extraction. The flow of the extraction phase (12) is forced to flow by the action of a pump. In addition, the extraction phase intercepts a small amount of mother liquor droplets in the belt through a buffer stabilizer. Therefore, the whole device is mainly composed of two crystallizers-extractors (1 and 2), buffer stabilizers (3 and 4), an extract phase storage tank (5), a pump (6), an agitator (7), a filter component (8), a feed port (9) and pipelines. Among them, the extract phase (12) is a n-heptane solution (70mL). Then, the temperature (such as room temperature 25°C) is controlled to make the (R)-propranolol crystallization-extraction coupler (1) and the (S)-propranolol crystallization-extraction coupler (2) crystallize respectively. Circular extraction is performed at a flow rate of 11mL / min, and the (S)-propranolol in the (R)-propranolol crystallization-extraction coupler (1) is extracted by the extraction phase and transferred to the (S)-propranolol crystallization-extraction coupler (2) by back extraction; the (R)-propranolol in the (S)-propranolol crystallization-extraction coupler (2) is extracted by the extraction phase and transferred to the (R)-propranolol crystallization-extraction coupler (1) by back extraction. After a certain period of crystallization, (R)-propranolol crystals (13) and (S)-propranolol crystals (14) are taken out respectively. The reduction of propranolol, chiral resolving agent and solvent caused by crystallization and operation loss is calculated, and racemic propranolol, chiral resolving agent dibenzoyl-(D)-tartaric acid or dibenzoyl-(L)-tartaric acid and solvent are added to the two crystallizers respectively before the next crystallization.Then, the above steps are repeated to carry out the next crystallization, i.e., the mother liquor is reused to obtain the next batch of (R)-propranolol crystals and (S)-propranolol crystals.

[0039] To investigate and analyze the efficiency of chiral separation, the chiral purity of each phase after crystallization, i.e., the enantiomeric excess, was calculated using formula (i). The yield of each phase after crystallization was calculated using formulas (ii) and (iii).

[0040]

[0041]

[0042]

[0043] Wherein, X represents O1, O2 mother liquor or crystal. O1 is (R)-propranolol crystal mother liquor, and O2 is (S)-propranolol crystal mother liquor. R,X (mol / kg or mol / L) and n S,X (mol / kg or mol / L) corresponds to the molar amount of (R)-propranolol and (S)-propranolol in a certain crystal or solution. R,X (kg) and m S,X (kg) are the masses of (R)-propranolol and (S)-propranolol in phase X in a crystal or solution, respectively.

[0044] There may be an unstable state in the process of crystallization and extraction coupling, that is, the two crystallization mother liquors are mixed by the extraction phase, and the two splitting agents in the two mother liquors are mixed, which will reduce the chiral splitting effect and affect the application of the mother liquor. In order to investigate and analyze the stability of the chiral splitting process, the tracer method is used to determine the mixing degree of the two mother liquors caused by the cross-banding. The calculation is as follows:

[0045]

[0046] Where h is the degree of mixing of the two mother liquors. sz is the concentration of the tracer, and V is the volume. At the same time, the volume of the mother liquid droplets trapped by the buffer stabilizer is measured. The loss of the trapped volume is calculated as follows:

[0047]

[0048]

[0049] Where H is the volume loss of the belt. jd The volume of mother liquor droplets retained by the buffer stabilizer.

[0050] The yield Y and purity ee value of the crystals and mother liquor obtained by repeating the crystallization operation for 15 times are shown in the following table: Figure 4 As shown. The ee values ​​of (R)-propranolol crystals (i.e. (R)-propranolol-dibenzoyl-(D)-tartrate, referred to as RD salt) and (S)-propranolol crystals (i.e. (S)-propranolol-dibenzoyl-(L)-tartrate, referred to as SL salt) are between 94.73% and 98.44% and 93.80% and 97.97%, respectively. These results show that the enantiomeric resolution effect of the method of the present invention is good, and two optically pure crystals can be obtained. At the same time, the individual yields of RD salt and SL salt crystals are between 20.58% and 36.66% and 19.35% and 29.94%, respectively. The yields of these crystals fluctuate greatly, which is mainly caused by the accuracy of the amount added during the crystallization operation and the inaccurate amount of water added when the solvent methanol water is added. As Figure 4 As shown in Figures 4b and 4d, after each crystallization extraction for 10 hours (h), the ee value of the mother liquor of the RD salt crystallizer is between 0.22% and 9.56%, and the ee value of the mother liquor of the SL salt crystallizer is between 0.73% and 8.49%. The ee value of the mother liquor is close to the racemic state, so the mother liquor is regenerated and can be reused multiple times. Based on the above results, the method of the present invention is proven to be an efficient method for splitting propranolol, because it solves the problem of in-situ regeneration and reuse of its crystallization mother liquor, and realizes the green and efficient splitting of propranolol. As an example, Figure 5 This is the liquid phase diagram of (R)-propranolol and (S)-propranolol crystals obtained after repeated crystallization for the 15th time. Figure 6 This is the phase diagram of the two crystallization-extraction coupling mother liquors obtained after repeated crystallization for the 15th time. The enantiomer content is close to the racemic state. Based on the experimental conditions of the mother liquor reuse, the stability of the chiral separation process was further determined. The results show that the mixing degree h of the two mother liquors measured by this method is 7.15% to 9.53%, and the volume loss is and The results show that the tracer method can be used to measure the mixing degree of the mother liquors and the actual crystallization process. Figure 3 The device shown is operated because there is still a certain instability in the band of the extraction relative to the crystallization mother liquor droplets, which will have a certain impact on the total number of mother liquor utilizations.

[0051] Comparative Example-1: The traditional diastereomeric crystallization method was used to separate racemic propranolol and its crystallization mother liquor was applied to the (R)-propranolol crystallizer, and the solvent methanol (20mL), the chiral resolving agent dibenzoyl-(D)-tartaric acid (1.35mmol) and racemic propranolol (5.4mmol) were added. In the (S)-propranolol crystallizer, the solvent methanol (20mL), the chiral resolving agent dibenzoyl-(L)-tartaric acid (1.35mmol) and racemic propranolol (5.4mmol) were added. After 10 hours of crystallization, the (R)-propranolol crystals and (S)-propranolol crystals were taken out respectively. According to the crystals taken out and the operating loss, the additional amount was calculated, and the racemic propranolol, the chiral resolving agent dibenzoyl-(D)-tartaric acid or dibenzoyl-(L)-tartaric acid and the solvent were continued to be added to the two crystallizers. Repeat the above steps to conduct a stock solution replication study. Figure 7 and Figure 8 As shown, due to the accumulation of non-target enantiomers (i.e., (S)-propranolol in the (R)-propranolol crystallizer and (R)-propranolol in the (S)-propranolol crystallizer), the ee value and yield of the crystals vary greatly, and the resolution effect is poor. Figure 7 The ee value of the crystals shown fluctuates greatly after the mother liquor is applied for the fourth time, and the resolution effect is poor; Figure 8 The ee value of the crystals shown in the figure decreased after the fourth application of the mother liquor. Although the ee value of the crystals increased again after the fifth application, the yield of the crystals gradually decreased and the resolution effect was also poor. These were all caused by the accumulation of non-target enantiomers and the mother liquor composition gradually approaching the eutectic point.

[0052] Examples 2 to 5 disclose the effects of several major factors on the single-batch separation of propranolol by a new system of liquid-liquid extraction and crystallization coupling. Single-batch operation means that only one extraction and crystallization coupling operation is performed in order to optimize the separation conditions, and the mother liquor is not reused.

[0053] Example 2: Separation of propranolol by a new system of liquid-liquid extraction and crystallization under different molar ratios of propranolol to resolving agent

[0054] The effect of the molar ratio of propranolol to resolving agent on the separation of propranolol by liquid-liquid extraction and crystallization was investigated. Figure 1 and 2As shown, refer to the coupling method described in Example 1, but only a single batch of liquid-liquid extraction and crystallization coupling separation of propranolol operation is performed. In the crystallization-extraction coupler, the molar ratio of propranolol racemate to the chiral separation agent dibenzoyl-(D)-tartaric acid or dibenzoyl-(L)-tartaric acid is changed to 1:0.25, 1:0.375, 1:0.5, 1:0.625 and 1:0.75, and other conditions are kept unchanged, that is, the amount of propranolol racemate added is 0.9g (3.47mmol), the crystallization solvent is 12mL methanol, the extraction phase is 70mL n-heptane, the extraction phase flow rate is 5mL / min, and the operation time is 10 hours. The results are shown in Fig. 9 The amount of splitting agent used has a significant effect on the crystallization process. The crystal yield of the two crystallizers is Y RS The ee value of the crystal increases with the increase of the amount of the splitting agent, and decreases with the increase of the amount of the splitting agent. Among them, the left crystallizer is RD salt crystal, and its crystal yield increases from 29.63% to 64.55%, and the right crystallizer is SL salt crystal, and its crystal yield increases from 29.7% to 66.85%. When the molar ratio is higher than 1:0.375, the ee value of the crystal decreases rapidly, and the ee value of the mother liquor increases rapidly. This is because a large amount of non-target enantiomer salt is crystallized in the crystallizer, resulting in a decrease in the content of non-target enantiomers in the mother liquor, thereby reducing the recycling extraction efficiency. Among them, the best molar ratio of propranolol to splitting agent is 1:0.375, the crystal yield in the (R)-propranolol crystallization-extraction coupler is 46.8%, the crystal ee value is 83.7% (R), and the mother liquor ee value is -18.6% (S); the crystal yield in the (S)-propranolol crystallization-extraction coupler is 47.9%, the crystal ee value is -82.6% (S), and the mother liquor ee value is 13.2% (R). At the same time, the stability of the chiral resolution process under different molar ratios was also determined. The results show that the mixing degree h of the two mother liquors is 7.66%~8.94%, and the volume loss is and The proportions were 8.46% to 10.13% and 10.72% to 13.27% respectively. Under different molar ratios of propranolol to resolving agent, the mixing degree of mother liquor and the volume loss of the cross-zone did not change much.

[0055] Example 3: Separation of propranolol by a new system of liquid-liquid extraction and crystallization coupling under different propranolol dosage conditions The effect of propranolol dosage on the separation of propranolol by liquid-liquid extraction and crystallization coupling was investigated. Figure 1 and 2As shown, refer to the method described in Example 1, but only perform a single batch of liquid-liquid extraction and crystallization coupled resolution of propranolol. In the crystallization-extraction coupler, the propranolol dosage is changed to 0.9g, 0.7g, 0.55g, 0.45g and 0.35g, and other conditions are kept unchanged, that is, the molar ratio of propranolol racemate to the resolution agent is 1:0.375, the crystallization solvent is 12mL methanol, the extraction phase is 70mL n-heptane, and the extraction phase flow rate is 5mL / min. The operation time is 10 hours. The results are shown in Fig.10 As shown, the crystal yield Y of the two crystallizers in this process RS The ee value fluctuates slightly, among which the crystal yield of RD salt crystallizer is Y RS Between 35.79% and 46.83%, when the dosage decreased from 0.9g to 0.7g, the crystal ee value increased from 83.70% to 88.75%. As the dosage of propranolol gradually decreased to 0.35g, the crystal ee value slowly increased to 90.33%. At this time, the change in the dosage of propranolol had little effect on the crystal ee value. From the perspective of the mother liquor results, when the dosage of propranolol decreased from 0.9g to 0.7g, the ee value of the crystallization mother liquor in the RD salt crystallizer decreased from 18.64% to 2.46%, and the ee value of the crystallization mother liquor in the SL salt crystallizer decreased from 13.21% to 5.44%. This is because when the dosage of propranolol is 0.7g, the cyclic extraction within 10h can make the mother liquors of the two crystallizers reach extraction equilibrium, and when the dosage is higher than 0.7g, the mother liquor in the crystallizer cannot reach extraction equilibrium, so the mother liquor ee value is higher. When the dosage of propranolol is further reduced to 0.45g, the ee value of the mother liquor of the two crystallizers in the process remains basically unchanged, both below 4% and close to the racemic state. As the dosage of propranolol continues to decrease to 0.35g, the ee value of the crystallization mother liquor in the RD salt crystallizer increases to 6.12%, and the ee value of the crystallization mother liquor in the SL salt crystallizer increases to 5.39%. At this time, the enantiomer concentration in the two crystallizers decreases, thereby reducing the extraction efficiency of the mother liquor. Among them, the optimal propranolol dosage is 0.55g, the crystal yield in the (R)-propranolol crystallization-extraction coupler is 46.53%, the crystal ee value is 88.00% (R), and the mother liquor ee value is -3.77% (S); the crystal yield in the (S)-propranolol crystallization-extraction coupler is 42.64%, the crystal ee value is -81.91% (S), and the mother liquor ee value is 3.98% (R). At the same time, the stability of the chiral resolution process under different propranolol dosage conditions was also determined. The results show that the mixing degree of the two mother liquors is 7.81% to 9.07%, and the volume loss of the belt is and The percentages were 9.38% to 11.37% and 11.18% to 13.64% respectively. Under different propranolol dosage conditions, the mixing degree of mother liquor and the volume loss of the cross-zone did not change much.

[0056] Example 4: Separation of propranolol by a new system of liquid-liquid extraction and crystallization coupling under different methanol-water volume ratios The effect of the methanol-water volume ratio in the crystallization solvent on the separation of propranolol by liquid-liquid extraction and crystallization coupling was investigated. Figure 1 and 2 As shown, refer to the method described in Example 1, but only perform a single batch of liquid-liquid extraction and crystallization coupled resolution of propranolol. In the crystallization-extraction coupler, the volume ratio of methanol to water is changed to pure methanol, 9:1, 7:1, 5:1 and 3:1, and other conditions are kept unchanged, that is, the molar ratio of propranolol racemate to the resolution agent is 1:0.375, the propranolol dosage is 0.55g, the extraction phase is 70mL n-heptane, and the extraction phase flow rate is 5mL / min. The operation time is 10 hours. In the results of the above Examples 2-4, it was found that the crystal ee values ​​were all lower than the crystal ee values ​​of the conventional diastereomeric salt crystallization process. The reason was found to be due to partial miscibility between the extraction phase n-heptane and the crystallization solvent methanol, which causes the resolution agent in the two crystallizers to be transferred to another crystallizer, crystallizing a small amount of non-target enantiomers. For this reason, consider adding a certain amount of water to the crystallization solvent methanol to avoid the miscibility of n-heptane and methanol. The results are as follows Fig.11 As shown, when the crystallization solvent is pure methanol, the crystal yield Y RS The ee values ​​of the crystals were 88.00% and 81.91% respectively, and the ee values ​​of the mother liquors were 3.77% and 3.98% respectively. At this time, the solubility of the crystals in methanol is low and easy to crystallize. Due to the mutual solubility of methanol and n-heptane, a small amount of cross-band transfer of the resolving agent reduces the ee value of the crystals, but the extraction efficiency of the enantiomers is high at this time, and the mother liquor is close to the racemic state. When the volume ratio of methanol to water is 9:1, the crystal yield is Y RS The ee values ​​of the crystals were increased to 95.38% and 93.89%, and the ee values ​​of the mother liquor were increased to 17.17% and 16.55%, respectively. This is because the addition of water increases the solubility of the resolution agent and the RD salt crystals or SL salt crystals. At the same time, the addition of water also increases the immiscibility of methanol and n-heptane, preventing the cross-banding of the resolution agent, but reduces the extraction transfer efficiency of the enantiomers. As the volume ratio of methanol to water is further reduced to 5:1, the crystal yield Y RS Then it slowly decreased, with the RD salt crystal yield decreasing from 27.51% to 23.29%, and the SL salt crystal yield decreasing from 27.62% to 22.89%. This is because the solubility of the crystal in methanol gradually increases with the increase in the proportion of water, and the ee value of the crystal and the mother liquor remains basically unchanged. When the methanol-water volume ratio drops to 3:1, the crystal yield Y RSThe crystal ee value increased by 5.46% and 4.22% respectively, the crystal ee value decreased by 1.48% to 2.79%, and the mother liquor ee value changed slightly. The proportion of water in methanol was relatively high and propranolol was poorly soluble in water. At this time, the solubility of the target enantiomer and the non-target enantiomer under the methanol-water volume ratio condition was reduced. Among them, the optimal methanol-to-water volume ratio was 9:1, the crystal yield in the (R)-propranolol crystallization-extraction coupler was 27.51%, the crystal ee value was 95.38% (R), and the mother liquor ee value was -17.17% (S); the crystal yield in the (S)-propranolol crystallization-extraction coupler was 27.62%, the crystal ee value was -93.89% (S), and the mother liquor ee value was 16.55% (R). At the same time, the stability of the chiral separation process under different methanol-to-water volume ratios was also determined. The results show that the mixing degree h of the two mother liquors is 5.65% to 8.16%, and the volume loss of the band is 1. and The ratios of methanol to water were 7.38% to 10.64% and 9.33% to 12.76% respectively. Under different methanol to water volume ratios, the mixing degree of the mother liquor and the volume loss of the cross-zone changed significantly. The higher the water content, the higher the h, and The smaller the value, the smaller the degree of banding. This is because the addition of water reduces the miscibility of methanol and n-heptane.

[0057] Example 5: Separation of propranolol by a new system of liquid-liquid extraction and crystallization coupling under different extraction phase flow rates The effect of the extraction phase flow rate on the separation of propranolol by liquid-liquid extraction and crystallization coupling was investigated. Figure 1 and 2 As shown, refer to the method described in Example 1, but only perform a single batch of liquid-liquid extraction and crystallization coupled resolution of propranolol. In the crystallization-extraction coupler, the extraction phase flow rate is changed to 5mL / min, 8mL / min, 11mL / min, 14mL / min and 17mL / min, and other conditions are kept unchanged, that is, the molar ratio of propranolol racemate to the resolution agent is 1:0.375, the propranolol dosage is 0.55g, the volume ratio of methanol to water is 9:1, and the extraction phase is 70mL of n-heptane. The operation time is 10 hours. The results are shown in Fig.12 As shown in Figure 2, the flow rate of the extraction process has a significant effect on the transfer rate of the enantiomers. As the flow rate increases, the crystal yield Y RSThe ee values ​​of the mother liquor fluctuated between 26.57% and 29.14% and 24.61% and 29.01%, respectively, and the ee values ​​of the crystals were all above 93.3%. The ee value of the mother liquor decreased with the increase of the flow rate from 5mL / min to 11mL / min, and the transfer rate of the enantiomers in this stage increased with the increase of the flow rate. With the continuous increase of the flow rate, the ee value of the mother liquor did not change significantly, and the volume of the mother liquor carried to the stabilization bottle and the extraction phase bottle increased. Among them, the optimal extraction phase flow rate was 11mL / min, the crystal yield in the (R)-propranolol crystallization-extraction coupler was 26.57%, the crystal ee value was 93.37% (R), and the mother liquor ee value was -3.86% (S); the crystal yield in the (S)-propranolol crystallization-extraction coupler was 28.96%, the crystal ee value was -94.89% (S), and the mother liquor ee value was 4.67% (R). At the same time, the stability of the chiral separation process under different extraction phase flow conditions was also determined. The results show that the mixing degree of the two mother liquors is 6.47% to 13.24%, and the volume loss is and The ratios of h and h are 8.57% to 26.86% and 10.34% to 28.54% respectively. Under different flow conditions, the mixing degree of mother liquor and the volume loss of the cross-band change significantly. The larger the flow rate, the higher the h, and The larger it is, the greater the degree of banding.

[0058] Example-6: Separation of propranolol by a new system coupled with membrane extraction and crystallization

[0059] like Figure 1 and 3 As shown, methanol-water solvent (50 mL, v:v = 9:1), chiral acid resolving agent 0.7921 g (0.7921 / 358.3 = 2.21 mmol) and propranolol base racemate 2.2915 g (2.2915 / 259.343 = 8.836 mmol) were added to the (R)-propranolol crystallizer and the (S)-propranolol crystallizer, respectively. Among them, the chiral resolving agent dibenzoyl-(D)-tartaric acid that selectively crystallizes with (R)-propranolol was added to the (R)-propranolol crystallizer (15), while the chiral resolving agent dibenzoyl-(L)-tartaric acid that selectively crystallizes with (S)-propranolol was added to the (S)-propranolol crystallizer (16). Figure 3 As shown, the extract phase (12) is a n-heptane solution (300 mL). Figure 3It can be seen that the (R)-propranolol crystallizer (15) and the (S)-propranolol crystallizer (16) are both sealed cylindrical tanks containing an inlet and outlet for circulating the crystallization solution, wherein the outlet is connected to a filter (23). The temperature and stirring are controlled to first dissolve the components of the crystallization solution in the two crystallizers to form supersaturated solutions (10 and 11). Then, the extraction phase (12) is extracted from the extraction phase storage tank (5) by using an extraction phase pump (6) and passed into the tube path of the (R)-propranolol crystallization liquid-membrane extractor (17). Next, the extraction phase (12) flows into the (R)-propranolol crystallization liquid-membrane extraction buffer stabilizer (19), the tube side of the (S)-propranolol crystallization liquid-membrane extraction device (18) and the (S)-propranolol crystallization liquid-membrane extraction buffer stabilizer (20) in sequence, and the extraction phase (12) will expel the air in the above-mentioned containers and pipelines and flow back to the extraction phase storage tank (5), forming a circular flow, and allowing the membrane filament micropores to be fully infiltrated by the extraction phase (12). The temperature is controlled (e.g., room temperature 25°C), and after the two crystallizers are crystallized, the (R)-propranolol crystallization solution (10) is injected into the shell side of the (R)-propranolol crystallization liquid-membrane extractor (17) by the (R)-propranolol crystallization liquid pump (21); and the (S)-propranolol crystallization solution (11) is injected into the shell side of the (S)-propranolol crystallization liquid-membrane extractor (18) by the (S)-propranolol crystallization liquid pump (22). Thus, the extraction phase (12) is contacted with the two crystallization solutions in sequence at the membrane filament interface of the two membrane extractors to form a membrane extraction, thereby realizing the mutual transfer of non-target enantiomers between the two crystallization solutions. In addition, the extraction phase (12) intercepts a small amount of mother liquor droplets that may be carried over after the membrane extraction through the buffer stabilizer (19 and 20). Therefore, the whole device mainly consists of two crystallizers (15 and 16), two membrane extractors (17 and 18), buffer stabilizers (19 and 20), an extract phase storage tank (5), pumps (6, 21 and 22), a stirrer (7), a filter (23), a feed port (24) and pipelines, etc. The flow rates of the extract phase (12), the (R)-propranolol crystal solution (10) and the (S)-propranolol crystal solution (11) are 30 mL / min, respectively. The (S)-propranolol that has not been crystallized in the (R)-propranolol crystallization solution (10) is extracted by the extraction phase (12) in the (R)-propranolol crystallization liquid-membrane extractor (17), and is back-extracted by the (S)-propranolol crystallization solution (11) in the (S)-propranolol crystallization liquid-membrane extractor (18); while the (R)-propranolol that has not been crystallized in the (S)-propranolol crystallization solution (11) is extracted by the extraction phase (12) in the (S)-propranolol crystallization liquid-membrane extractor (18), and is back-extracted by the (S)-propranolol crystallization solution (10) in the (R)-propranolol crystallization liquid-membrane extractor (17). After a certain crystallization period, the (R)-propranolol crystals (13) and the (S)-propranolol crystals (14) are taken out respectively.The membrane material used is a PVDF hollow fiber membrane, the inner diameter and outer diameter of the PVDF membrane are 0.8mm and 1.5mm, and the micropore diameter is 0.1um. The effective length of the PVDF membrane in the homemade experimental membrane assembly is 32cm, the number of roots is 40, the inner diameter and outer diameter of the membrane assembly shell are 18mm and 20mm, and the length is 41cm. When the flow rate of the extraction phase and the crystallization solution is 30mL / min, and the operation time is 5h, the crystal yield in the (R)-propranolol crystallization-extraction coupler is 17.11%, the crystal ee value is 91.26% (R), and the mother liquor ee value is -4.90% (S); the crystal yield in the (S)-propranolol crystallization-extraction coupler is 15.94%, the crystal ee value is -96.38% (S), and the mother liquor ee value is 1.28% (R). At the same time, the stability of the chiral separation process under the crystallization and membrane extraction coupling conditions of this embodiment is also determined. The results show that the mixing degree of the two mother liquors is 2.25%, with a volume loss of 1. and The values ​​of 2.26% and 3.19% were respectively. This indicates that the band loss of membrane extraction is less than that of liquid-liquid extraction, and the stability is better.

[0060] Example-7: Separation of propranolol by a new system coupled with membrane extraction and crystallization

[0061] Referring to the operating conditions of Example 6, when the effective length of the PVDF membrane in the homemade experimental membrane assembly is changed to 16 cm and the operating time is 10 h, the crystal yield in the (R)-propranolol crystallization-extraction coupler is 23.13%, the crystal ee value is 90.28% (R), and the mother liquor ee value is -1.90% (S); the crystal yield in the (S)-propranolol crystallization-extraction coupler is 21.55%, the crystal ee value is -93.02% (S), and the mother liquor ee value is 1.66% (R). At the same time, the stability of the chiral resolution process under the crystallization and membrane extraction coupling conditions of this embodiment was also determined. The results show that the mixing degree h of the two mother liquors is 4.62%, and the volume loss of the band is 0.1%. and 3.74% and 4.35% respectively.

[0062] Example-8: Separation of propranolol by a new system coupled with membrane extraction and crystallization

[0063] Referring to the operating conditions of Example 6, when the effective length of the PVDF membrane in the homemade experimental membrane assembly is changed to 16 cm and the number of roots is changed to 10, the crystal yield in the (R)-propranolol crystallization-extraction coupler is 18.75%, the crystal ee value is 95.90% (R), and the mother liquor ee value is -10.92% (S); the crystal yield in the (S)-propranolol crystallization-extraction coupler is 17.54%, the crystal ee value is -91.46% (S), and the mother liquor ee value is 10.70% (R). At the same time, the stability of the chiral resolution process under the conditions of crystallization and membrane extraction coupling in this embodiment was also determined. The results show that the mixing degree h of the two mother liquors is 1.02%, and the volume loss of the band is 0.1%. and 1.01% and 1.13% respectively.

[0064] Example-9: Separation of propranolol by a new system coupled with membrane extraction and crystallization

[0065] Referring to the operating conditions of Example 6, when the effective length of the PVDF membrane in the homemade experimental membrane assembly is changed to 16 cm, the flow rate of the extraction phase (12) is 50 mL / min, and the flow rates of the crystallization solutions (10) and (11) are 50 mL / min, the crystal yield in the (R)-propranolol crystallization-extraction coupler is 22.84%, the crystal ee value is 96.52% (R), and the mother liquor ee value is -9.88%% (S); the crystal yield in the (S)-propranolol crystallization-extraction coupler is 18.96%, the crystal ee value is -92.98% (S), and the mother liquor ee value is 0.32% (R). At the same time, the stability of the chiral separation process under the conditions of crystallization and membrane extraction coupling of this embodiment is also determined. At the same time, the stability of the chiral separation process under the conditions of crystallization and membrane extraction coupling of this embodiment is also determined. The results show that the mixing degree h of the two mother liquors is 3.17%, and the volume loss of the band is 0.1%. and 3.73% and 5.56% respectively. Example 10: Reuse of the crystallization mother liquor after propranolol separation by coupling membrane extraction and crystallization with the new system. Referring to the operating conditions of Example 6, in order to investigate the reusability of the crystallization mother liquor, the amount reduced by the system due to crystallization and operation loss was calculated, and racemic propranolol and chiral resolving agent dibenzoyl-(D)-tartaric acid or dibenzoyl-(L)-tartaric acid were added to the two crystallizers respectively. Repeat the operating steps described in Example 6 to obtain the next batch of (R)-propranolol crystals and (S)-propranolol crystals. Similar to Example 1, the crystallization operation of reusing the mother liquor for 15 times was performed. The ee values ​​of the (R)-propranolol crystals (i.e., RD ​​salt) and (S)-propranolol crystals (i.e., SL salt) crystals are between 89.46% and 99.21% and 90.33% and 99.76%, respectively. These results show that the enantiomeric separation effect of the method of the present invention is good, and two optically pure crystals can be obtained. At the same time, the individual yields of RD salt and SL salt crystals are between 17.63% and 35.74% and 16.22% and 33.76%, respectively. After 5 hours of crystallization extraction each time, the ee value of the mother liquor of the RD salt crystallizer is between 0.53% and 11.23%, and the ee value of the mother liquor of the SL salt crystallizer is between 0.97% and 11.43%. The ee value of the mother liquor is close to the racemic state, so the mother liquor is regenerated and good application is achieved. Based on the above-mentioned mother liquor reuse experimental conditions, the stability of the analytical chiral separation process was further determined. The results show that the method measured the mixing degree h of the two mother liquors to be 1.34% to 3.56%, and the volume loss of the band and The results show that the band loss of membrane extraction is less than that of liquid-liquid extraction.

[0066] Table 1 summarizes the stability parameter comparison of the extraction methods in the above-mentioned embodiments in different coupling separation methods. The results show that the degree of mixing of the two mother liquors and the amount of cross-band volume loss are significantly lower than those of the liquid-liquid extraction method when the membrane extraction method is used for coupling. The mixing of the mother liquors will lead to the mixing of two different splitting agents in the two mother liquors, thereby reducing the chiral splitting effect and reducing the number of times the mother liquors are used. Therefore, the membrane extraction method is significantly more stable than the liquid-liquid extraction method.

[0067] Table 1 Comparison of stability parameters of extraction methods in different coupled separation methods

[0068]

[0069]

[0070] Example 10: A new system of liquid-liquid extraction and crystallization coupling containing an extractant is used to separate propranolol and its crystallization mother liquor. The method described in Example 1 was used to examine the extraction effect by using different alkane solvents as extraction solvents. The results in Table 2 show that cyclohexane and cyclopentane cannot be used as extraction solvents because their density is slightly different from that of methanol (0.79 g / cm3), resulting in poor phase separation effect. Organic extractants such as di(2-ethylhexyl) phosphate (P204), 2-ethylhexyl phosphate-2-ethylhexyl ester (P-507), TBP or n-octanoic acid are added to the extraction phase. On the basis of the original, the extraction rate is reduced. The stability can be basically maintained with little change.

[0071] Table 2 Extraction effects of different extraction solvents*

[0072] Extraction solvent Density g / cm3 Partition coefficient D Extraction rate Remark Cyclohexane 0.78 - - Difficult to separate Cyclopentane 0.75 - - Difficult to separate n-Hexane 0.66 0.145 21.44％ Normal phase Isooctane 0.71 0.146 22.25％ Normal phase n-Heptane 0.68 0.091 17.21％ Normal phase

[0073] *The mother solution is a solution containing 0.35 g of propranolol and 5 mL of methanol, and the volume of the extraction solvent is 17.5 mL. The distribution coefficient D is the concentration of propranolol in n-heptane divided by the concentration of propranolol in methanol.

[0074] Table 3 Extraction effect of different extractants*

[0075] Extraction agent type Extraction agent dosage / mL Partition coefficient D Extraction rate P204 0.64 0.10483 14.70％ P507 0.62 0.16301 16.38％ TBP 0.525 0.13436 20.46％ Octanoic acid 0.305 0.03469 4.37％ blank 0 0.13901 25.11％

[0076] *The mother liquor is a solution containing 0.45 g of propranolol and 5 mL of methanol, and the volume of the extraction solvent is 17.5 mL. The molar ratio of propranolol:extraction agent is 1:1.11.

[0077] Example 11: Effect of the Types of Resolving Agent and Solvent Used in the Separation of Propranolol and Its Crystallization Mother Solution by a New System of Liquid-Liquid Extraction and Crystallization

[0078] Referring to the method described in Example 1, the type of splitting agent is changed. For example, the type of splitting agent is changed to di-p-methylbenzoyl-(L)-tartaric acid ((L)-DTTA) or a mixture thereof with dibenzoyl-(L)-tartaric acid; di-p-methylbenzoyl-(D)-tartaric acid or a mixture thereof with dibenzoyl-(D)-tartaric acid. Alternatively, other tartaric acid splitting agents such as di-p-methoxybenzoyl-(L)-tartaric acid (or di-p-methoxybenzoyl-(D)-tartaric acid) can also be used to achieve coupled separation. The change in the type of the above-mentioned splitting agent has a certain improvement in the crystallization splitting effect. The ee value of propranolol crystals is 90% to 99%, and the yield can be increased by about 5% to 10%. Referring to the method described in Example 1, the solvent is changed. For example, the extraction phase n-heptane is changed to other alkane solvents, such as one or more mixed solvents of n-hexane, isooctane or n-octane. Due to differences in density, boiling point or difficulty in obtaining, while maintaining or optimizing the existing enantiomer separation effect, further improvements have been made in the separation of the extraction phase, solvent volatilization and reduction of usage costs. The stability can be basically maintained with little change.

[0079] Example 12: Comparison of crystallization resolution effects of other different crystallization resolution agents or crystallization solvents

[0080] In order to illustrate that the chiral resolution by crystallization method cannot be achieved by simple analogy replacement of the resolving agent or solvent. Table 4 lists the crystallization resolution effects of some different resolving agents. The results show that although the different resolving agents used are all optically pure, only (L)-DBTA crystals have a resolution effect. It is difficult to crystallize with propranolol in methanol using (L)-tartaric acid and (L)-camphorsulfonic acid as resolving agents. The chiral resolution effect is poor using (L)-DTTA as a resolving agent. Table 5 lists the crystallization resolution effects of some different crystallization solvents. The results show that although the different resolving agents used are all optically pure, only (L)-DBTA crystals have a resolution effect. It is difficult to crystallize with propranolol using DMF and DMAc as crystallization solvents. Using H2O as a crystallization solvent, (L)-DBTA is difficult to dissolve and needs to be heated to about 70°C to dissolve, and the resolution effect is also poor. The above results show that the type of resolving agent or crystallization solvent has a great influence on the chiral resolution effect of the diastereomeric salt crystallization method. When the resolving agent or crystallization solvent is replaced, the ee value of the crystal generally drops directly from about 100% to about 0%, that is, there is either a chiral resolution effect, or almost no effect or no crystallization. This is mainly because the two diastereomeric salts formed by the racemate and the resolving agent are also isomers, and their physical and chemical properties are very similar.

[0081] Table 4 Crystallization resolution effects of different resolution agents

[0082]

[0083]

[0084] Table 5 Crystallization separation effect of different crystallization solvents

[0085]

[0086] The above is a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, can make equivalent replacements or changes according to the technical solutions and concepts of the present invention, which should be covered by the protection scope of the claims of the present invention.

Claims

1. An extraction and crystallization coupled separation method for propranolol crystal splitting and in-situ regeneration and application of its crystallization mother liquor, characterized in that: The system of the method consists of three parts: a levorotatory crystallization solution, a dextrorotatory crystallization solution and an extraction phase, wherein the levorotatory crystallization solution contains two enantiomers of propranolol, L - Tartaric acid derivative resolving agent and solvent, the right-handed crystal solution contains two enantiomers of propranolol, D - a tartaric acid derivative resolving agent and a solvent, the extract phase contains an alkane solvent; the levorotatory crystallization solution is in contact with the extract phase interface, the dextrorotatory crystallization solution is in contact with the extract phase interface, and the levorotatory crystallization solution and the dextrorotatory crystallization solution are not in contact; Alternatively, the system of the method consists of four parts: a levorotatory crystallization solution, a dextrorotatory crystallization solution, an extraction phase and a membrane extraction component, wherein the levorotatory crystallization solution contains two enantiomers of propranolol, L - Tartaric acid derivative resolving agent and solvent, the right-handed crystal solution contains two enantiomers of propranolol, D - a tartaric acid derivative resolving agent and a solvent, the extraction phase contains an alkane solvent; the levorotatory crystal solution and the extraction phase are in contact through the porous membrane interface in the membrane extraction component, the dextrorotatory crystal solution and the extraction phase are in contact through the porous membrane interface in the membrane extraction component, and the levorotatory crystal solution and the dextrorotatory crystal solution are not in contact; Said L -Tartaric acid derivative resolving agent is dibenzoyl- L -Tartaric acid, di-p-methylbenzoyl- L - tartaric acid or a mixture of the two above-mentioned resolving agents; D -Tartaric acid derivative resolving agent is dibenzoyl- D -Tartaric acid, di-p-methylbenzoyl- D - tartaric acid or a mixture of the two above-mentioned resolving agents; The solvent of the levorotatory crystal solution or the dextrorotatory crystal solution is methanol or a mixture of the above solvent and water; The extraction phase is an alkane solvent, which is one of n-heptane, n-hexane, isooctane or n-octane, or a mixed solvent of two or more thereof.

2. The extraction and crystallization coupled separation method for propranolol crystal splitting and in-situ regeneration and application of its crystallization mother liquor as claimed in claim 1, characterized in that: The usage ratio of propranolol, tartaric acid derivative resolving agent and crystallization solvent in the levorotatory crystallizer or the dextrorotatory crystallizer is 1 mmol: 0.25 mmol~1 mmol: 10 mL~20 mL; the usage ratio of propranolol and hydrocarbon solvent of the extraction phase alkane is 1 mmol: 20 mL~200 mL.

3. The extraction and crystallization coupled separation method for propranolol crystal splitting and in-situ regeneration and application of its crystallization mother liquor as claimed in claim 2, characterized in that: The usage ratio of propranolol, tartaric acid derivative resolving agent and crystallization solvent in the levorotatory crystallizer or the dextrorotatory crystallizer is 1 mmol: 0.3 mmol~0.7 mmol: 10 mL~15 mL; the usage ratio of propranolol and the hydrocarbon solvent of the extraction phase alkane is 1 mmol: 20 mL~50 mL.

4. The extraction and crystallization coupled separation method for propranolol crystallization resolution and in-situ regeneration and application of its crystallization mother liquor as claimed in claim 1, characterized in that: An extractant capable of extracting the left-handed enantiomer and the right-handed enantiomer may also be added to the extraction phase; the extractant is an organic phosphoric acid, phosphonic acid, carboxylic acid or sulfonic acid extractant.

5. The extraction and crystallization coupled separation method for propranolol crystal splitting and in-situ regeneration and application of its crystallization mother liquor as claimed in claim 1, characterized in that: The solvent is pure methanol, or a mixed solvent with a volume ratio of methanol to water of 9:1 to 3:1, and the flow rate of the extraction phase is 5 to 11 mL / min.

6. The extraction and crystallization coupled separation method for propranolol crystal splitting and in-situ regeneration and application of its crystallization mother liquor as claimed in claim 5, characterized in that: The solvent is a mixed solvent of methanol and water in a volume ratio of 9:1, and the flow rate of the extraction phase is 11 mL / min.

7. The extraction and crystallization coupled separation method for propranolol crystallization resolution and in-situ regeneration and application of its crystallization mother liquor as claimed in claim 1, characterized in that: The membrane material of the membrane extraction is polyvinylidene fluoride, polytetrafluoroethylene, cellulose and its derivatives, polycarbonate, polyvinyl chloride, polysulfone, polyacrylonitrile, polyamide or sulfonated polysulfone porous hollow fiber membrane or flat membrane.

8. The extraction and crystallization coupled separation method for propranolol crystallization resolution and in-situ regeneration and application of its crystallization mother liquor as claimed in any one of claims 1 to 7, characterized in that: In the propranolol levorotatory crystallizer, the levorotatory crystallization solution selectively crystallizes to precipitate the levorotatory propranolol enantiomer crystal salt; in the propranolol dextrorotatory crystallizer, the dextrorotatory crystallization solution selectively crystallizes to precipitate the dextrorotatory propranolol enantiomer crystal salt; the extraction phase first enters the levorotatory crystallizer to perform liquid-liquid extraction with its crystallization solution and then flows out, and then flows into the dextrorotatory crystallizer to perform liquid-liquid extraction with its crystallization solution and then flows out, and then flows back to the levorotatory crystallizer to form a circular flow; The uncrystallized propranolol enantiomers are transferred to each other between the crystallization solutions in the two crystallizers by circulating the extraction phase and liquid-liquid extraction; after the crystals in the two crystallizers are taken out, the racemates and the respective resolving agents are continuously added to the two mother liquors, and the above operation is repeated; the positions of the left-handed crystallizer and the right-handed crystallizer can be interchanged; Alternatively, in a propranolol levorotatory crystallizer, a levorotatory crystallization solution selectively crystallizes to precipitate a levorotatory propranolol enantiomer crystal salt; in a propranolol dextrorotatory crystallizer, a dextrorotatory crystallization solution selectively crystallizes to precipitate a dextrorotatory propranolol enantiomer crystal salt; the extraction phase first enters the levorotatory crystallization liquid-membrane extractor to perform membrane extraction with its crystallization solution and then flows out, and then flows into the dextrorotatory crystallization liquid-membrane extractor to perform membrane extraction with its crystallization solution and then flows out, and then flows back to the levorotatory crystallization liquid-membrane extractor to form a circular flow; The mutual transfer of the non-crystallized propranolol enantiomers between the crystallization solutions in the two crystallizers is achieved by circulating the extraction phase and membrane extraction. The dextrorotatory crystallization solution circulates between the dextrorotatory crystallization liquid-membrane extractor and the dextrorotatory crystallizer; the levorotatory crystallization solution circulates between the levorotatory crystallization liquid-membrane extractor and the levorotatory crystallizer; after the crystals in the two crystallizers are taken out, the racemate and the respective resolving agents are continuously added to the two mother liquors, and the above operation is repeated; the positions of the levorotatory crystallizer and the matching levorotatory crystallization liquid-membrane extractor can be interchanged with the positions of the dextrorotatory crystallizer and the matching levorotatory crystallization liquid-membrane extractor.

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