CN111925380A - Combined eutectic guest resolving agent causing chiral selective transformation and application thereof - Google Patents
Combined eutectic guest resolving agent causing chiral selective transformation and application thereof Download PDFInfo
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Abstract
The present invention relates to a combined eutectic guest resolving agent comprising dibenzoyltartaric acid and di-p-methylbenzyltartaric acid, which causes a chirally selective transition. The invention also relates to a method for resolving chiral drugs, in particular chiral ofloxacin, by using the combined eutectic guest resolving agent causing chiral selective transformation. The method is based on a method for inducing chiral selective transformation under the action of a combined eutectic guest resolving agent, and based on the process of drug eutectic resolving ofloxacin, two specific dibenzoyltartaric acid derivatives are used as the combined eutectic guest resolving agent, and a chiral ofloxacin solution is used as a water phase, so that the process of chiral selective transformation of the eutectic resolving chiral drug is realized. Compared with the single resolving agent, the phenomenon of chiral selective transformation can be generated when the two specific tartaric acid derivative eutectic objects are subjected to chiral ofloxacin resolution in a combined resolving agent mode, and the method has certain guiding significance for realizing control and optimization of a chiral resolution process.
Description
Technical Field
The invention belongs to the field of chiral drug resolution, and relates to a combined eutectic guest resolving agent causing chiral selectivity transition and application thereof, in particular to a combined eutectic guest resolving agent causing chiral selectivity transition and a method for causing chiral selectivity transition when ofloxacin is resolved.
Background
With the rapid development of the global pharmaceutical industry, the world chiral drug market has not developed rapidly before. Different stereo configurations of chiral drugs can show completely different biological activity, pharmacological action and toxicological action, so that the acquisition of high-purity single-enantiomer chiral drugs and the reduction of the drug dosage are the frontier and the trend of chiral drug research, and a chiral resolution method is one of important ways for acquiring single-enantiomer chiral drugs. At present, the traditional crystal salt resolution method is the chiral resolution technology with the most extensive industrial application, and the pharmaceutical cocrystal is a multi-component crystal formed by a pharmaceutical active component and a cocrystal object through non-covalent bond action, so that the method has more and more extensive application in the field of pharmaceutical research, and particularly has unique application advantages in the resolution of chiral compounds which can not form salts or are difficult to form salts. At present, the induction mode of chiral selective transformation in the process of crystal resolution can only be caused by solvent effect, and is called solvent switch method. As the dielectric properties of the solvent change, the preferred configuration of the resulting diastereomeric crystals will change, primarily the relative stability of the different configurations changes during the chiral transition. The induction mode of chiral selective transformation in the existing crystallization resolution process can only be caused by solvent effect, and the method has the defects of difficult solvent screening, large solvent consumption, difficult operation and the like.
Therefore, there is a need to develop a chiral resolving agent that has low solvent consumption, simple operation, and little environmental pollution, and can perform chiral resolution by an induced manner of chiral selective transformation.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a combined eutectic guest resolving agent causing chiral selectivity transformation aiming at the problems in the prior art. The combined eutectic guest resolving agent can efficiently resolve an enantiomer chiral drug in an induction mode of chiral selective transformation, has the advantages of low consumption in the using process, simplicity in operation and low environmental pollution, and can be widely used for resolving the chiral drug.
To this end, the present invention provides in a first aspect a combined co-crystal guest resolving agent comprising dibenzoyltartaric acid and di-p-methylbenzyltartaric acid.
According to some embodiments of the invention, the combined co-crystal guest resolving agent comprises D- (+) -dibenzoyltartaric acid (D-DBTA) and L- (-) -di-p-methylbenzoyltartaric acid (L-DTTA).
In some embodiments of the invention, the mass ratio of D- (+) -dibenzoyltartaric acid to L- (-) -di-p-methylbenzoyltartaric acid in the combined eutectic guest resolving agent is from 1:5 to 5: 1.
According to some embodiments of the invention, the combined eutectic guest resolving agent comprises L- (-) -dibenzoyltartaric acid (L-DBTA) and D- (+) -di-p-methylbenzoyltartaric acid (D-DTTA).
In some embodiments of the invention, the mass ratio of L- (-) -dibenzoyltartaric acid and D- (+) -di-p-methylbenzoyltartaric acid in the combined eutectic guest resolving agent is from 1:5 to 5: 1.
In a second aspect, the present invention provides the use of a combined co-crystal guest resolving agent causing chirality selective transformation for the resolution of a chiral drug, which comprises subjecting a chiral drug solution to a resolution process causing chirality selective transformation using a combined co-crystal guest resolving agent as described in the first aspect of the present invention to obtain a co-crystal to the chiral drug.
In some embodiments of the invention, the chiral drug comprises ofloxacin.
In a third aspect of the present invention, there is provided a use of a combined eutectic guest resolving agent for inducing chirality selective transformation in the resolution of chiral ofloxacin, which comprises subjecting a solution of chiral ofloxacin to a resolution treatment for inducing chirality selective transformation using a combined eutectic guest resolving agent according to the first aspect of the present invention to obtain a co-crystal of ofloxacin.
According to the invention, the method for resolving ofloxacin causing chiral selective transformation comprises the following steps: adding the combined eutectic object resolving agent into an ofloxacin aqueous solution, sealing the obtained solid-liquid mixture, placing the sealed solid-liquid mixture into a water bath for uniform oscillation, then carrying out centrifugal treatment, filtering and separating the obtained solid-liquid mixture, and drying the obtained solid phase to obtain the ofloxacin eutectic.
In some embodiments of the invention, the concentration of the ofloxacin aqueous solution is 0.5-1.0 g/L;
in some embodiments of the invention, the amount of the combined eutectic guest resolving agent added is 1.75-3.0 g/L based on the total volume of the ofloxacin aqueous solution.
In some embodiments of the invention, the rotation speed of the oscillation is 200-250 r/min, and the time of the oscillation is 30-50 min.
In some embodiments of the invention, the rotation speed of the centrifugation is 3000-5000 r/min, and the time of the centrifugation is 10-20 min.
According to some embodiments of the invention, the mass ratio of D- (+) -dibenzoyltartaric acid to L- (-) -di-p-methylbenzoyltartaric acid in the combined eutectic guest resolving agent is from 1:5 to 5: 1.
In some embodiments of the invention, the mass ratio of the total mass of D- (+) -dibenzoyltartaric acid and L- (-) -di-p-methylbenzoyltartaric acid to ofloxacin is from 7:4 to 3: 1.
According to some embodiments of the invention, the mass ratio of L- (-) -dibenzoyltartaric acid and D- (+) -di-p-methylbenzoyltartaric acid in the combined eutectic guest resolving agent is between 1:5 and 5: 1.
In some embodiments of the invention, the mass ratio of the total mass of L- (-) -dibenzoyltartaric acid and D- (+) -di-p-methylbenzoyltartaric acid to ofloxacin is between 7:4 and 3: 1.
At present, the induction mode of chiral selective transformation in the crystal resolution process can only be caused by a solvent effect, but the invention relates to a method for causing chiral selective transformation under the action of a combined resolving agent. When D-DBTA and L-DTTA are used as a combined resolving agent, the chiral selectivity of the D-DBTA and the L-DTTA is changed, the D-DBTA and the L-DTTA are preferentially combined with levofloxacin to form a eutectic, the maximum separation factor is 2.455, and the ee value is 41.15%; when the L-DBTA and the D-DTTA are used as the combined resolving agents, the chiral selectivity is changed, the L-DBTA and the D-DTTA are preferentially combined with the levofloxacin to form a eutectic, the maximum separation factor is 1.786, and the ee value is 27.10%. Compared with the single resolving agent, the phenomenon of chiral selective transformation can be generated when the two specific tartaric acid derivative eutectic objects are subjected to chiral ofloxacin resolution in a combined resolving agent mode, and compared with the chiral transformation caused by the traditional solvent effect, the method has the advantages of less solvent consumption, less environmental pollution, simplicity in operation and the like, has certain guiding significance for realizing the control and optimization of the chiral resolution process, and has great significance for the crystallization resolution method in scientific research and industrial application.
Drawings
The invention is described in further detail below with reference to the attached drawing figures:
fig. 1 is a schematic diagram of the process of chiral selective transformation of ofloxacin under the action of a combined eutectic guest resolving agent.
FIG. 2 is an X-ray diffraction pattern of the resulting co-crystal powder when D-DBTA and L-DTTA are used as the combined resolving agent.
FIG. 3 is an X-ray diffraction pattern of the resulting co-crystal powder when L-DBTA and D-DTTA are used as the combined resolving agent.
Detailed Description
In order that the invention may be readily understood, a more particular description thereof will be rendered by reference to the appended drawings. However, before the invention is described in detail, it is to be understood that this invention is not limited to particular embodiments described. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
Unless otherwise defined, all terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described.
I. Term(s) for
The term "cocrystal" is also referred to as "pharmaceutical cocrystal" and is a multicomponent crystal formed by non-covalent bond interactions such as intermolecular hydrogen bonding between a pharmaceutically active host (APl) and a cocrystal guest (coformer) at a certain stoichiometric ratio.
The term "eutectic guest" is compared with "eutectic host", the pharmaceutical eutectic consists of two components, namely a host and a guest, wherein one component is the eutectic host and is a pharmaceutical active component or a raw material medicine; the other ingredient is a co-crystal guest, essentially a safe and non-toxic food or pharmaceutical additive.
The term "eutectic object resolving agent" as used herein refers to a resolving agent as a eutectic object.
The term "pure eutectic" as used herein refers to a eutectic having a single melting point.
II. Detailed description of the preferred embodiments
As mentioned above, the induction mode of chiral selective transformation in the existing crystal resolution process can only be caused by solvent effect, and this method has the disadvantages of difficult solvent screening, large solvent consumption, difficult operation, etc. In view of this, the present inventors have conducted extensive studies on a chiral drug resolution method that causes chiral selective transformation.
The invention researches a chiral selective transformation process of an ofloxacin eutectic splitting process based on a method for inducing chiral selective transformation under the action of a combined resolving agent, a pharmaceutical eutectic technology and a mode of combining a eutectic object resolving agent. The inventor researches and discovers that when D-DBTA and L-DTTA are used as combined resolving agents, the chiral selectivity of the combined resolving agents is changed, and the combined resolving agents and levofloxacin are preferentially selected to form a eutectic crystal; when L-DBTA and D-DTTA are used as the combined resolving agent, the chiral selectivity is changed, and the L-DBTA and the D-DTTA are preferentially combined with the levofloxacin to form a eutectic crystal. The present invention has been made based on the above findings.
Accordingly, the combined co-crystal guest resolving agent according to the first aspect of the present invention comprises dibenzoyltartaric acid and di-p-methylbenzyltartaric acid.
In the invention, the combined eutectic guest resolving agent can be composed of D- (+) -dibenzoyl tartaric acid (D-DBTA) and L- (-) -di-p-methylbenzoyl tartaric acid (L-DTTA), and also can be composed of L- (-) -dibenzoyl tartaric acid (L-DBTA) and D- (+) -di-p-methylbenzoyl tartaric acid (D-DTTA).
In a combined eutectic guest resolving agent consisting of D- (+) -dibenzoyltartaric acid (D-DBTA) and L- (-) -di-p-methylbenzoyltartaric acid (L-DTTA), the mass ratio of D- (+) -dibenzoyltartaric acid to L- (-) -di-p-methylbenzoyltartaric acid is 1:5 to 5: 1.
In a combined eutectic guest resolving agent consisting of L- (-) -dibenzoyltartaric acid (L-DBTA) and D- (+) -di-p-methylbenzoyltartaric acid (D-DTTA), the mass ratio of the L- (-) -dibenzoyltartaric acid and the D- (+) -di-p-methylbenzoyltartaric acid is 1:5 to 5: 1.
The application of the combined eutectic guest resolving agent causing chirality selective transformation in the second aspect of the present invention to the resolution of chiral drugs can be understood as a method for resolving chiral drugs by using the combined eutectic guest resolving agent causing chirality selective transformation, which includes obtaining a co-crystal of chiral drugs by performing resolution treatment causing chirality selective transformation on a chiral drug solution by using the combined eutectic guest resolving agent according to the first aspect of the present invention.
In some specific embodiments of the invention, the chiral drug comprises ofloxacin (racemate).
The ofloxacin (ofloxacin) [ (+ -) -9-fluorine-2, 3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1, 2, 3-DE ] - [1, 4] benzoxazine-6-carboxylic acid ] is an antibacterial drug and has better antibacterial activity on aerobic gram-negative bacilli. Wherein, the antibacterial activity of the levofloxacin (S-OFLX) is 8 to 128 times of that of the levofloxacin (R-OFLX) and is 2 times of that of the ofloxacin raceme. The chemical structure of the ofloxacin (raceme) is shown as a formula (I):
the invention provides a method for inducing chiral selective transformation under the action of a combined eutectic guest resolving agent, which is based on the process of drug eutectic resolving ofloxacin, takes two specific dibenzoyltartaric acid derivatives as the combined eutectic guest resolving agent, and takes a water phase as a chiral ofloxacin solution, thereby realizing the process of chiral selective transformation of the eutectic resolving chiral drug. Fig. 1 is a schematic diagram of the process of chiral selective transformation of ofloxacin under the action of a combined eutectic guest resolving agent. As can be seen from FIG. 1, when D-DBTA and L-DTTA are taken as the combined resolving agents, the chiral selectivity of the combined resolving agents is changed, and the combined resolving agents and levofloxacin are preferentially selected to form a eutectic crystal; when L-DBTA and D-DTTA are used as the combined resolving agent, the chiral selectivity is changed, and the L-DBTA and the D-DTTA are preferentially combined with the levofloxacin to form a eutectic crystal. The traditional induction mode of the chiral selective transformation process can be only caused by solvent effect, and the invention opens up a new chiral transformation induction way.
Further, the third aspect of the present invention specifically provides the use of a combined eutectic guest resolving agent causing chirality selective transformation for resolving chiral ofloxacin, which can be understood as a method for resolving chiral ofloxacin by using the combined eutectic guest resolving agent causing chirality selective transformation, which comprises subjecting a solution of chiral ofloxacin to resolution treatment by using the combined eutectic guest resolving agent according to the first aspect of the present invention to cause chirality selective transformation to obtain a eutectic of ofloxacin.
In some embodiments of the invention, the method for resolving ofloxacin resulting in a chirally selective transition comprises: taking an ofloxacin aqueous solution as a water phase, adding a combined eutectic object resolving agent into the ofloxacin aqueous solution with the concentration of 0.5-1.0 g/L, sealing the obtained solid-liquid mixture, placing the sealed mixture in a water bath, uniformly oscillating for 30-50 min at the rotating speed of 200-250 r/min, then carrying out centrifugal treatment for 10-20 min at the rotating speed of 3000-5000 r/min, filtering and separating the obtained solid-liquid mixture, and drying the obtained solid phase to obtain the ofloxacin eutectic. In the preparation process, the addition amount of the combined eutectic object resolving agent is 1.75-3.0 g/L based on the total volume of the ofloxacin aqueous solution;
in a combined eutectic guest resolving agent consisting of D- (+) -dibenzoyltartaric acid (D-DBTA) and L- (-) -di-p-methylbenzoyltartaric acid (L-DTTA), the mass ratio of D- (+) -dibenzoyltartaric acid to L- (-) -di-p-methylbenzoyltartaric acid is 1:5 to 5: 1.
In some embodiments of the invention, the mass ratio of the total mass of D- (+) -dibenzoyltartaric acid and L- (-) -di-p-methylbenzoyltartaric acid to ofloxacin is from 7:4 to 3: 1.
In a combined eutectic guest resolving agent consisting of L- (-) -dibenzoyltartaric acid (L-DBTA) and D- (+) -di-p-methylbenzoyltartaric acid (D-DTTA), the mass ratio of the L- (-) -dibenzoyltartaric acid and the D- (+) -di-p-methylbenzoyltartaric acid is 1:5 to 5: 1.
In some embodiments of the invention, the mass ratio of the total mass of L- (-) -dibenzoyltartaric acid and D- (+) -di-p-methylbenzoyltartaric acid to ofloxacin is between 7:4 and 3: 1.
The X-ray powder diffraction pattern analysis has unique application in the compound structure identification process, and the results of structural characterization on the eutectic formed between the ofloxacin and the eutectic object resolving agent through PXRD patterns (figure 2 and figure 3) after chiral selective transformation experiments caused by the combined resolving agent show that when the D-DBTA and the L-DTTA are used as the combined resolving agent, pure eutectic is formed between the D-DBTA and the L-DTTA and the ofloxacin is accompanied with the process of chiral selective transformation; similarly, when L-DBTA and D-DTTA are used as the combined resolving agents respectively, pure eutectic crystals are formed between the L-DBTA and the D-DTTA and the ofloxacin, and the chiral selective transformation process is accompanied.
In the invention, an Ultima IV X-ray diffractometer (Rigaku) is adopted to carry out X-ray powder diffraction analysis on the eutectic formed between the ofloxacin and the eutectic object resolving agent, and the emission target is CuKa
The tube voltage and current were set to 40kV and 40mA, respectively, with a scanning step of 0.02 °.
In the invention, liquid chromatography (LC-20AT, Shimadzu corporation, Japan) is adopted to detect the effect of the combined eutectic object resolving agent in the invention in the process of eutectic resolution of ofloxacin: sampling from a lower clear liquid (mother liquid after eutectic resolution of ofloxacin) obtained by centrifugation and filtration during the resolution of the ofloxacin causing chiral selective transformation, and analyzing the composition by high performance liquid chromatography; the specific test method is that a 1mL disposable sterile syringe is used for absorbing the lower layer aqueous phase clear liquid in the centrifugal tube, the lower layer aqueous phase clear liquid is filtered by a 0.45 mu m filter head, and 10 mu L of sample injection is carried out in a high performance liquid chromatography for analysis and test.
III, examples
The present invention will be specifically described below with reference to specific examples. The experimental methods described below are, unless otherwise specified, all routine laboratory procedures. The experimental materials described below, unless otherwise specified, are commercially available.
Example 1: D-DBTA and L-DTTA are used as combined resolving agents to resolve ofloxacin through cocrystallization
Preparing 1.0g/L ofloxacin aqueous solution, weighing 0.025g D-DBTA and 0.025g L-DTTA (the mass ratio of the two is 1: 1) into a 100mL conical flask, and transferring 20mL of aqueous phase into the conical flask by a pipette. The conical flask is sealed and then placed in a digital display water bath constant temperature oscillator THZ-82A, oscillated at the rotating speed of 220r/min for 50min and then placed in a centrifuge tube and centrifuged at the rotating speed of 5000r/min in a centrifuge for 10 min. Filtering and drying the solid-liquid mixture after centrifugation to obtain the ofloxacin cocrystal.
The aqueous clear solution obtained by centrifugation was taken up by 1mL using a disposable sterile syringe, filtered through a 0.45 μm filter head, and introduced into 10 μ L high performance liquid chromatography (LC-20AT, Shimadzu, Japan). Experimental results show that when D-DBTA and L-DTTA are used as combined resolving agents, chiral selectivity of the combined resolving agents is changed, the combined resolving agents are preferentially combined with levofloxacin to form a eutectic, a separation factor is 2.455, and an ee value is 41.15%.
Example 2: experiment for co-crystallizing and splitting ofloxacin by using L-DBTA and D-DTTA as combined splitting agents
Preparing 1.0g/L ofloxacin aqueous solution, weighing 0.025g L-DBTA and 0.025g D-DTTA (the mass ratio of the two is 1: 1) into a 100mL conical flask, and transferring 20mL of aqueous phase into the conical flask by a pipette. The conical flask is sealed and then placed in a digital display water bath constant temperature oscillator THZ-82A, oscillated at the rotating speed of 220r/min for 50min and then placed in a centrifuge tube and centrifuged at the rotating speed of 5000r/min in a centrifuge for 10 min. Filtering and drying the solid-liquid mixture after centrifugation to obtain the ofloxacin cocrystal. The aqueous phase was analyzed in the same manner as in example 1. Experimental results show that when L-DBTA and D-DTTA are used as the combined resolving agents, chiral selectivity of the combined resolving agents is changed, the combined resolving agents are preferentially selected to be combined with the dexofloxacin to form a eutectic, a separation factor is 1.786, and an ee value is 27.10%. .
Example 3: resolution experiments when the mass ratio of D-DBTA to L-DTTA is 5: 4
A1.0 g/L ofloxacin aqueous solution is prepared, 0.025g D-DBTA and 0.020g L-DTTA are weighed into a 100mL conical flask, and 20mL of aqueous phase is transferred into the conical flask by a pipette. The conical flask is sealed and then placed in a digital display water bath constant temperature oscillator THZ-82A, oscillated at the rotating speed of 220r/min for 50min and then placed in a centrifuge tube and centrifuged at the rotating speed of 5000r/min in a centrifuge for 10 min. Filtering and drying the solid-liquid mixture after centrifugation to obtain the ofloxacin cocrystal. The aqueous clear solution was analyzed in the same manner as in example 1, and the results of the experiment showed that the separation factor was 2.17 and the ee value was 35.88% when the mass ratio of D-DBTA to L-DTTA was 5: 4.
Example 4: resolution experiments when the mass ratio of L-DBTA to D-DTTA is 5: 4
A1.0 g/L ofloxacin aqueous solution is prepared, 0.025g L-DBTA and 0.020g D-DTTA are weighed into a 100mL conical flask, and 20mL of aqueous phase is transferred into the conical flask by a pipette. The conical flask is sealed and then placed in a digital display water bath constant temperature oscillator THZ-82A, oscillated at the rotating speed of 220r/min for 50min and then placed in a centrifuge tube and centrifuged at the rotating speed of 5000r/min in a centrifuge for 10 min. Filtering and drying the solid-liquid mixture after centrifugation to obtain the ofloxacin cocrystal. The aqueous clear solution was analyzed by the same method as in example 1, and the results of the experiment showed that the separation factor was 1.26 and the ee value was 11.14% when the mass ratio of L-DBTA to D-DTTA was 5: 4.
Example 5: resolution experiments when the mass ratio of D-DBTA to L-DTTA is 5: 6
A1.0 g/L ofloxacin aqueous solution is prepared, 0.025g D-DBTA and 0.030g L-DTTA are weighed into a 100mL conical flask, and 20mL of aqueous phase is transferred into the conical flask by a pipette. The conical flask is sealed and then placed in a digital display water bath constant temperature oscillator THZ-82A, oscillated at the rotating speed of 220r/min for 50min and then placed in a centrifuge tube and centrifuged at the rotating speed of 5000r/min in a centrifuge for 10 min. Filtering and drying the solid-liquid mixture after centrifugation to obtain the ofloxacin cocrystal. The aqueous clear solution was analyzed by the same method as in example 1, and the results showed that the separation factor was 2.24 and the ee value was 37.50% when the mass ratio of D-DBTA to L-DTTA was 5: 6.
Example 6: resolution experiments when the mass ratio of L-DBTA to D-DTTA is 5: 6
A1.0 g/L ofloxacin aqueous solution is prepared, 0.025g L-DBTA and 0.030g D-DTTA are weighed into a 100mL conical flask, and 20mL of aqueous phase is transferred into the conical flask by a pipette. The conical flask is sealed and then placed in a digital display water bath constant temperature oscillator THZ-82A, oscillated at the rotating speed of 220r/min for 50min and then placed in a centrifuge tube and centrifuged at the rotating speed of 5000r/min in a centrifuge for 10 min. Filtering and drying the solid-liquid mixture after centrifugation to obtain the ofloxacin cocrystal. The aqueous clear solution was analyzed by the same method as in example 1, and the results of the experiment showed that when the mass ratio of L-DBTA to D-DTTA was 5: 6, the separation factor was 1.40, and the ee value was 16.00%.
Example 7: x-ray powder diffraction analysis (PXRD) of the resulting cocrystals when D-DBTA and L-DTTA are used as a combined resolving agent
The X-ray powder diffraction pattern analysis has unique application in the compound structure identification process, and after a chiral selective transformation experiment caused by the combination of the resolving agent, the structure of the eutectic formed between the ofloxacin and the eutectic object resolving agent is characterized by a PXRD pattern.
The ofloxacin cocrystal obtained by centrifugation, filtration and drying in example 1 was analyzed by X-ray powder diffraction. Using a Nippon Rigaku Ultima IV X-ray diffractometer with an emission target CuKa
The tube voltage and current were set to 40kV and 40mA, respectively, with a scanning step of 0.02 °. The obtained spectrum is shown in FIG. 2.
As can be seen from fig. 2, the obtained cocrystal after the chiral selective transformation is a mixture of multiple diastereomeric cocrystals, and both of them show significant differences compared with PXRD patterns of the original chiral drug host and guest resolvers, and a plurality of new characteristic peaks (such as the marked positions of the characteristic peaks with asterisks in the figure) appear, and meanwhile, a plurality of characteristic peaks of the cocrystal host and guest disappear or are obviously weakened, thereby confirming that a new eutectic phase is generated. When D-DBTA and L-DTTA are used as the combination resolving agent, new characteristic peaks appear in the eutectic obtained after the experiment is finished at the positions with 2 theta angles of 6.42 degrees, 9.92 degrees, 11.93 degrees, 15.89 degrees and 24.46 degrees. When D-DBTA and L-DTTA are used as a combined resolving agent, pure eutectic crystals are formed between the D-DBTA and the L-DTTA and ofloxacin is accompanied by the process of chiral selective transformation.
Example 8: x-ray powder diffraction analysis (PXRD) of the resulting co-crystals when L-DBTA and D-DTTA are used as a combined resolving agent
The X-ray powder diffraction pattern analysis has unique application in the compound structure identification process, and after a chiral selective transformation experiment caused by the combination of the resolving agent, the research carries out structural characterization on the eutectic formed between the ofloxacin and the eutectic object resolving agent through a PXRD pattern.
The ofloxacin cocrystal obtained by centrifuging, filtering and drying in example 2 was subjected to X-ray powder diffraction analysis by the same X-ray powder diffraction analysis test method as in example 7, and the obtained spectrum was shown in fig. 3.
As can be seen from fig. 3, the obtained cocrystal after the chiral selective transformation is a mixture of multiple diastereomeric cocrystals, and both of them show significant differences compared with PXRD patterns of the original chiral drug host and guest resolvers, and a plurality of new characteristic peaks (such as the marked positions of the characteristic peaks with asterisks in the figure) appear, and meanwhile, a plurality of characteristic peaks of the cocrystal host and guest disappear or are obviously weakened, thereby confirming that a new eutectic phase is generated. When L-DBTA and D-DTTA are used as the combination resolving agent, the eutectic crystal obtained after the experiment is finished has new characteristic peaks at the positions with 2 theta angles of 6.42 degrees, 9.92 degrees, 11.93 degrees and 14.69 degrees. When L-DBTA and D-DTTA are respectively used as combined resolving agents, pure eutectic crystals are formed between the L-DBTA and the D-DTTA and ofloxacin, and the chiral selective transformation process is accompanied.
It should be noted that the above-mentioned embodiments are only for explaining the present invention, and do not constitute any limitation to the present invention. The present invention has been described with reference to exemplary embodiments, but the words which have been used herein are words of description and illustration, rather than words of limitation. The invention can be modified, as prescribed, within the scope of the claims and without departing from the scope and spirit of the invention. Although the invention has been described herein with reference to particular means, materials and embodiments, the invention is not intended to be limited to the particulars disclosed herein, but rather extends to all other methods and applications having the same functionality.
Claims (10)
1. A combined co-crystal guest resolving agent that causes a chirally selective transition comprising dibenzoyltartaric acid and di-p-methylbenzyltartaric acid.
2. The combined eutectic guest resolving agent of claim 1, wherein the combined eutectic guest resolving agent comprises D- (+) -dibenzoyltartaric acid and L- (-) -di-p-methylbenzoyltartaric acid; preferably, the mass ratio of D- (+) -dibenzoyltartaric acid to L- (-) -di-p-methylbenzoyltartaric acid in the combined eutectic guest resolving agent is from 1:5 to 5: 1.
3. The combined eutectic guest resolving agent of claim 1, wherein the combined eutectic guest resolving agent comprises L- (-) -dibenzoyltartaric acid and D- (+) -di-p-methylbenzylformyl tartaric acid; preferably, the mass ratio of the L- (-) -dibenzoyltartaric acid and the D- (+) -di-p-methylbenzyltartaric acid in the combined eutectic guest resolving agent is 1:5 to 5: 1.
4. Use of a combined co-crystal guest resolving agent causing chirality selective shift for resolving a chiral drug, comprising subjecting a chiral drug solution to a resolution process causing chirality selective shift using a combined co-crystal guest resolving agent as defined in any of claims 1 to 3 to obtain a co-crystal to the chiral drug; preferably, the chiral drug comprises ofloxacin.
5. Use of a combined co-crystal guest resolving agent causing chirally selective transition for resolving chiral ofloxacin comprising subjecting a solution of chiral ofloxacin to a resolution process causing chirally selective transition using a combined co-crystal guest resolving agent as defined in any one of claims 1 to 3 to obtain a co-crystal to ofloxacin.
6. The method of claim 5, wherein the method comprises: adding the combined eutectic object resolving agent into an ofloxacin aqueous solution, sealing the obtained solid-liquid mixture, placing the sealed solid-liquid mixture into a water bath for uniform oscillation, then carrying out centrifugal treatment, filtering and separating the obtained solid-liquid mixture, and drying the obtained solid phase to obtain the ofloxacin eutectic.
7. The process according to claim 6, wherein the concentration of the ofloxacin aqueous solution is 0.5-1.0 g/L; preferably, the addition amount of the combined eutectic guest resolving agent is 1.75-3.0 g/L based on the total volume of the ofloxacin aqueous solution.
8. The method according to any one of claims 6 or 7, wherein the rotation speed of the oscillation is 200-250 r/min, and the time of the oscillation is 30-50 min; and/or the rotating speed of the centrifugation is 3000-5000 r/min, and the time of the centrifugation is 10-20 min.
9. The method of any one of claims 6-8, wherein the mass ratio of D- (+) -dibenzoyltartaric acid to L- (-) -di-p-methylbenzoyltartaric acid in the combined co-crystalline guest resolving agent is from 1:5 to 5: 1; the mass ratio of the total mass of the D- (+) -dibenzoyltartaric acid and the L- (-) -di-p-methylbenzoyltartaric acid to the mass of the ofloxacin is 7:4 to 3: 1.
10. The method of any one of claims 6-8, wherein the mass ratio of L- (-) -dibenzoyltartaric acid and D- (+) -di-p-methylbenzyltartaric acid in the combined co-crystalline guest resolving agent is from 1:5 to 5: 1; the mass ratio of the total mass of the L- (-) -dibenzoyltartaric acid and the D- (+) -di-p-methylbenzyltartaric acid to the mass of the ofloxacin is 7:4 to 3: 1.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101239913A (en) * | 2008-03-17 | 2008-08-13 | 广州辉宏生物医药科技有限公司 | Chiral tartaric acids derivatives and preparation method thereof |
| CN103664998A (en) * | 2013-10-28 | 2014-03-26 | 中建安装工程有限公司 | Split reagent and method for ofloxacin racemic mixture |
| CN105037387A (en) * | 2015-05-25 | 2015-11-11 | 北京化工大学 | Method for splitting ofloxacin chiral drug through liquid-liquid-solid extraction |
| CN108473418A (en) * | 2016-01-04 | 2018-08-31 | 株式会社爱茉莉太平洋 | Use the chiral separation method of N- [4- (1- amino-ethyls) phenyl] sulfamide derivative of polar non-solute |
-
2019
- 2019-05-13 CN CN201910395922.XA patent/CN111925380A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101239913A (en) * | 2008-03-17 | 2008-08-13 | 广州辉宏生物医药科技有限公司 | Chiral tartaric acids derivatives and preparation method thereof |
| CN103664998A (en) * | 2013-10-28 | 2014-03-26 | 中建安装工程有限公司 | Split reagent and method for ofloxacin racemic mixture |
| CN105037387A (en) * | 2015-05-25 | 2015-11-11 | 北京化工大学 | Method for splitting ofloxacin chiral drug through liquid-liquid-solid extraction |
| CN108473418A (en) * | 2016-01-04 | 2018-08-31 | 株式会社爱茉莉太平洋 | Use the chiral separation method of N- [4- (1- amino-ethyls) phenyl] sulfamide derivative of polar non-solute |
Non-Patent Citations (1)
| Title |
|---|
| LICHAO HE, ET AL.: "Green and Efficient Resolution of Racemic Ofloxacin Using Tartaric Acid Derivatives via Forming Cocrystal in Aqueous Solution", 《CRYSTAL GROWTH & DESIGN》 * |
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