CN114805355A - Doxofylline isomer impurity and method for separating isomer impurity from doxofylline reaction liquid - Google Patents
Doxofylline isomer impurity and method for separating isomer impurity from doxofylline reaction liquid Download PDFInfo
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- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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Abstract
The invention relates to the technical field of chemical synthesis, and particularly discloses doxofylline isomer impurities and a method for separating the isomer impurities from a doxofylline reaction solution. The structure of the doxofylline isomer impurity is shown as a formula (I). The impurity is obtained from the doxofylline reaction liquid by a specific separation method, the purity of the impurity obtained by separation is higher and can reach more than 98.5%, the impurity can be used as a reference substance for impurity detection to detect the content of the isomer impurity in the doxofylline product, so that the safety and the effectiveness of the doxofylline product are ensured, the method has very important significance for quality control of doxofylline raw materials and improvement of controllability of a synthesis process, and the quality standard of doxofylline raw material medicines or preparations thereof is favorably perfected.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to doxofylline isomer impurities and a method for separating the isomer impurities from a doxofylline reaction solution.
Background
Doxofylline belongs to the latest generation of theophylline drugs, belongs to xanthine derivatives, and is a bronchodilator. The research on the action mechanism of the polyphylline shows that the relaxation effect of the polyphylline on bronchial smooth muscle is 10-15 times that of aminophylline, the polyphylline has the cough relieving effect which is not possessed by aminophylline, the side effects of the central nervous system, the gastrointestinal tract system and other extrapulmonary systems which are caused by the aminophylline are not caused, and the cardiac function is not influenced. Clinical researches show that compared with aminophylline, doxofylline has shorter relieving time for cough, expectoration and asthmatic symptoms in the aspect of treating diseases such as chronic obstructive pulmonary disease, bronchial asthma, child bronchitis and the like, and the total effective rate is obviously higher than that of aminophylline.
Various impurities are generated in the process of synthesizing doxofylline, and if the content of the impurities is high, the purity and yield of the doxofylline product are reduced, so that the quality of the doxofylline preparation is reduced, and even the safety and the effectiveness of the medicine in clinical use are affected. In order to ensure and improve the quality of doxofylline products and ensure the safety and effectiveness of medicaments, detailed research and monitoring on impurities in the synthesis process and the preparation process of doxofylline are needed. Although the prior literatures and data report some related impurities of doxofylline, the research on the impurities with novel structures generated in the processes of synthesis and preparation of doxofylline is a dynamically developed and continuously promoted process, and can be applied to the impurity analysis and process control of doxofylline.
Disclosure of Invention
In view of the above, the invention provides doxofylline isomer impurities and a method for separating and removing the isomer impurities from a doxofylline reaction solution, which has the advantages of short steps and simple operation, is beneficial to improving the purity of doxofylline and improving the medication safety of doxofylline, and can also obtain doxofylline isomer impurities with higher purity, be used as a reference substance for doxofylline impurity analysis, monitor and adjust the synthesis process of doxofylline, and improve the controllability of the process.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
the doxofylline isomer impurity has a structure shown in a formula (I):
the inventor finds a new process impurity unexpectedly in the research and development process of synthesizing doxofylline, and the inventor determines through multi-aspect analysis that the structure of the new process impurity is shown as a formula (I). The existence of the impurities may affect the safety and effectiveness of the doxofylline drug, and in order to more effectively control the quality of the doxofylline product and improve the controllability of the doxofylline synthesis process, it is necessary to monitor whether the impurities shown in formula (I) are generated in the process of preparing the doxofylline product, so that a reference substance of the new process impurities is also required to be obtained.
The impurities are obtained by a specific separation method, the purity of the impurities obtained by separation is higher and can reach more than 98.5%, and the impurities can be used as a reference substance for impurity detection to detect the content of the isomer impurities in the doxofylline product, so that the safety and the effectiveness of the doxofylline product are ensured, and the method has very important significance for quality control of doxofylline raw materials and improvement of controllability of a synthesis process.
The invention also provides a method for separating the doxofylline isomer impurities from the doxofylline reaction liquid, which comprises the following steps:
step a, cooling the doxofylline reaction solution to 15-30 ℃, and filtering to obtain doxofylline and primary filtrate;
step b, spin-drying the obtained primary filtrate to remove the solvent, then adding ethanol water solution with volume concentration of more than or equal to 90%, cooling to 10-20 ℃ after the solid is dissolved, and filtering to obtain the doxofylline and secondary filtrate;
c, repeating the operation of the step b for 2-3 times on the secondary filtrate to obtain doxofylline and a final filtrate;
and d, adding the final-stage filtrate into a silica gel chromatographic column for elution, monitoring by using thin-layer chromatography, collecting eluent, concentrating and drying to obtain the doxofylline isomer impurities.
The doxofylline isomer impurity with the purity of more than 98.5 percent shown in the formula (I) is prepared by a specific separation process, can be used as a reference substance for impurity detection, increases the control type detection of the doxofylline impurity, provides a research basis for monitoring the production quality of doxofylline and improving the production process of doxofylline, is favorable for improving the quality of doxofylline products and reducing the adverse reaction of doxofylline, and has very important significance for improving the medication safety of doxofylline products.
Preferably, in step d, the elution specifically comprises the following steps: adding the final-stage filtrate into a silica gel chromatographic column, eluting with ethyl acetate and n-hexane in a volume ratio of 1: 900-1100, monitoring by thin-layer chromatography, eluting with ethyl acetate and n-hexane in a volume ratio of 1:90-110 after doxofylline is completely eluted, monitoring by thin-layer chromatography, collecting eluent, concentrating and drying to obtain doxofylline isomer impurities.
Preferably, in step d, the filler particle size of the silica gel chromatographic column is 200-400 meshes.
The preferable elution sequence and the selection of the silica gel chromatographic column are favorable for promoting the separation of doxofylline and doxofylline isomer impurities with lower content shown in formula (I), thereby being favorable for improving the purity of the doxofylline isomer prepared.
Preferably, the preparation method of the doxofylline reaction solution comprises the following steps:
adding theophylline, a compound shown as a formula (II) and an acid-binding agent into N, N-dimethylformamide, uniformly mixing, heating to 130-150 ℃, and reacting for 2-3 h to obtain a doxofylline reaction solution;
wherein X is Cl or Br.
Taking X as Br as an example, the production mechanism of doxofylline isomer impurities shown in formula (I) in the invention in the preparation process of doxofylline is as follows:
further preferably, the acid-binding agent is potassium carbonate.
More preferably, the molar ratio of the theophylline to the compound represented by the formula (II) is 1: 1-2.
More preferably, the mol ratio of the theophylline to the acid binding agent is 1: 0.5-1.1.
More preferably, the volume-mass ratio of the N, N-dimethylformamide to the theophylline is 2-6: 1, wherein the volume unit is milliliter, and the mass unit is gram.
The preferred ratio of the reaction substances can ensure that the forward reaction is promoted under the condition of small usage amount, and the yield and the purity of the target product are improved.
Preferably, in the step b, the volume-to-mass ratio of the ethanol aqueous solution to the theophylline is 4-8: 1, wherein the volume unit is milliliter, and the mass unit is gram.
Optionally, in step c, when the operation of step b is repeated on the secondary filtrate, the amount of the ethanol aqueous solution added each time is gradually reduced, and then the volume of the ethanol aqueous solution added each time is approximately 0.2-0.8 times of the mass of theophylline, wherein the unit of the volume is milliliter, and the unit of the mass is gram.
The novel doxofylline isomer impurity is prepared by a specific separation method, the purity of the prepared doxofylline isomer impurity can reach more than 98.5%, the doxofylline isomer impurity can be used as an impurity reference substance, the purity of the impurity reference substance and the accuracy of analysis work are effectively guaranteed, a qualified, cheap and easily-obtained reference substance is provided for quality control of doxofylline raw material medicines and preparations thereof, the quality standard of the doxofylline raw material medicines or the preparations thereof is favorably further perfected, and the clinical medication safety of the doxofylline preparations is further improved.
Drawings
FIG. 1 is a LC-MS spectrum of doxofylline isomer impurities of formula (I) prepared according to the present invention;
FIG. 2 shows the preparation of doxofylline isomer impurity of formula (I) according to the present invention 1 H NMR spectrum;
FIG. 3 shows the preparation of doxofylline isomer impurity of formula (I) according to the present invention 1 C NMR spectrum.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In order to better illustrate the invention, the following examples are given by way of further illustration.
Example 1
A method for separating doxofylline isomer impurities comprises the following steps:
step a, adding 200g of theophylline, 800mLN, N-dimethylformamide, 250g of 2-bromomethyl-1, 3-dioxolane and 150g of potassium carbonate into a 2L three-necked bottle, stirring and mixing uniformly, heating to 140 ℃, reacting for 2 hours, cooling to 15 ℃, and filtering to obtain a doxofylline solid and a first filtrate;
step b, after the solvent is dried by spinning, adding 1000mL of 95% ethanol water solution to dissolve the substrate, then cooling to 15 ℃ and filtering to obtain a doxofylline solid and a second filtrate;
step c, after the solvent is dried by spinning, adding 100mL of 95% ethanol water solution to dissolve the substrate, then cooling to 15 ℃ and filtering to obtain a doxofylline solid and a third filtrate;
d, after the solvent is dried by spinning, adding 50mL of 95% ethanol water solution to dissolve the substrate, then cooling to 15 ℃ and filtering to obtain a doxofylline solid and a fourth filtrate;
and e, adding the obtained fourth filtrate into a 200-mesh silica gel chromatographic column, and adding ethyl acetate: and (2) completely eluting doxofylline with 5L of a mixed solvent of n-hexane and 1:1000, and then adding ethyl acetate: eluting with 2L mixed solvent (1: 100) of n-hexane, monitoring by thin layer chromatography, collecting eluate, and spin-drying filtrate to obtain doxofylline isomer impurity 0.5g, yield 0.17%, and purity 98.5%; and combining the doxofylline solids obtained in each step, and drying to obtain 280g of doxofylline, wherein the yield is 94.7%, and the purity is 99.91%.
The doxofylline isomer impurity prepared in this example was structurally characterized and confirmed to have the following structure:
the mass spectrometry spectrum of the doxofylline isomer impurity prepared in the example is shown in fig. 1, and the detected molecular weight of the doxofylline isomer impurity is 267.4 (theoretical molecular weight is 266.26) according to the mass spectrometry spectrum.
Preparation of doxofylline isomer impurity from this example 1 The H NMR is shown in FIG. 2, and the results of hydrogen spectroscopy are shown in Table 1.
TABLE 1
| Chemical shift (ppm) | Number of protons | Peak shape | Attribution |
| 7.295-7.390 | 1 | s | H-N |
| 5.226-5.229 | 1 | s | H-3 |
| 4.493-4.496 | 2 | s | H-4 |
| 3.829-3.844 | 2 | d | H-2 |
| 3.800 | 3 | s | H-10 |
| 3.611-3.629 | 2 | d | H-1 |
| 3.434 | 3 | s | H-11 |
Preparation of doxofylline isomer impurity from this example 13 C NMR is shown in FIG. 3, and the results of hydrogen spectrum analysis are shown in Table 2.
TABLE 2
Example 2
A method for separating doxofylline isomer impurities comprises the following steps:
step a, adding 200g of theophylline, 400ml of N-dimethylformamide, 190g of 2-bromomethyl-1, 3-dioxolane and 85g of potassium carbonate into a 1L three-necked bottle, stirring and mixing uniformly, heating to 150 ℃, reacting for 2 hours, cooling to 20 ℃, and filtering to obtain a doxofylline solid and a first filtrate;
step b, after the solvent is dried by spinning, adding 800mL of 95% ethanol water solution to dissolve the substrate, then cooling to 20 ℃ and filtering to obtain doxofylline solid and second filtrate;
step c, after the solvent is dried by spinning, adding 50mL of 95% ethanol water solution to dissolve the substrate, then cooling to 20 ℃ and filtering to obtain a doxofylline solid and a third filtrate;
and e, adding the obtained third filtrate into a 200-mesh silica gel chromatographic column, and adding ethyl acetate: and (3) completely eluting doxofylline with 5L of a mixed solvent of n-hexane and 1:1100, and then adding ethyl acetate: eluting with 2L mixed solvent of n-hexane 1:110, monitoring by thin layer chromatography, collecting eluate, and spin-drying filtrate to obtain doxofylline isomer impurity 0.4g, yield 0.14%, and purity 96.8%; and combining the doxofylline solids obtained in each step, and drying to obtain 240g of doxofylline, wherein the yield is 81.17%, and the purity is 99.01%.
The doxofylline isomer impurity prepared in this example was confirmed to be identical in structure to example 1.
Example 3
A method for separating doxofylline isomer impurities comprises the following steps:
step a, adding 200g of theophylline, 1200mL of N, N-dimethylformamide, 369g of 2-bromomethyl-1, 3-dioxolane and 168g of potassium carbonate into a 3L three-necked bottle, stirring and mixing uniformly, heating to 130 ℃, reacting for 3 hours, cooling to 30 ℃, and filtering to obtain a doxofylline solid and a first filtrate;
step b, after the solvent is dried by spinning, 1600mL of 95% ethanol water solution is added to dissolve the substrate, and then the temperature is reduced to 10 ℃ for filtration, so that the doxofylline solid and the second filtrate are obtained;
step c, after the solvent is dried by spinning, adding 150mL of 95% ethanol water solution to dissolve the substrate, then cooling to 10 ℃ and filtering to obtain doxofylline solid and third filtrate;
d, after the solvent is dried by spinning, adding 50mL of 95% ethanol water solution to dissolve the substrate, then cooling to 10 ℃ and filtering to obtain a doxofylline solid and a fourth filtrate;
and e, adding the obtained fourth filtrate into a 200-mesh silica gel chromatographic column, and adding ethyl acetate: and (3) completely eluting doxofylline with 5L of a mixed solvent of n-hexane and 900: then adding ethyl acetate: eluting with 2L mixed solvent of n-hexane 1:90, monitoring by thin layer chromatography, collecting eluate, and spin-drying filtrate to obtain doxofylline isomer impurity 0.35g, yield 0.12%, and purity 99.5%; and (3) mixing the doxofylline solid obtained in each step, and drying to obtain 290g of doxofylline, wherein the yield is 97.5%, and the purity is 98.6%.
The doxofylline isomer impurity prepared in this example was confirmed to be identical in structure to example 1.
The 2-bromomethyl-1, 3-dioxolane in the examples 1-3 of the present invention can be replaced by 2-chloromethyl-1, 3-dioxolane, and the filler particle size of the silica gel column can be replaced by other particle sizes defined by the present invention, all of which can achieve the technical effects basically equivalent to those in the examples 1-3.
Comparative example 1
The comparative example provides a separation method of doxofylline isomer impurities, the specific process steps are completely the same as those of example 1, the difference is only that the temperature reduction temperature after solid is dissolved clearly in the step b and the step c is different, and the temperature reduction temperature after solid is dissolved clearly is changed to 25 ℃.
0.2g of the prepared doxofylline isomer impurity, 0.07% of yield and 89.5% of purity; and combining the doxofylline solids obtained in each step, and drying to obtain 240g of doxofylline, wherein the yield is 81.17%, and the purity is 99.01%.
Comparative example 2
The comparative example provides a separation method of doxofylline isomer impurities, the specific process steps are completely the same as those of example 1, the difference is only that the temperature reduction temperature after solid is dissolved clearly in the step b and the step c is different, and the temperature reduction temperature after solid is dissolved clearly is changed to 5 ℃.
0.10g of doxofylline isomer impurity, 0.03% of yield and 99.5% of purity; and combining the doxofylline solids obtained in each step, and drying to obtain 290g of doxofylline, wherein the yield is 97.5%, and the purity is 98.6%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. The doxofylline isomer impurity is characterized by having a structure shown as a formula (I):
2. a method for separating doxofylline isomer impurities of claim 1 from a doxofylline reaction solution, comprising the steps of:
step a, cooling the doxofylline reaction solution to 15-30 ℃, and filtering to obtain doxofylline and primary filtrate;
step b, spin-drying the obtained primary filtrate to remove the solvent, then adding ethanol water solution with volume concentration of more than or equal to 90%, cooling to 10-20 ℃ after the solid is dissolved, and filtering to obtain the doxofylline and secondary filtrate;
c, repeating the operation of the step b for 2-3 times on the secondary filtrate to obtain the doxofylline and the final filtrate;
and d, adding the final-stage filtrate into a silica gel chromatographic column for elution, monitoring by using thin-layer chromatography, collecting eluent, concentrating and drying to obtain the doxofylline isomer impurities.
3. The method for separating the doxofylline isomer impurities from the doxofylline reaction solution according to claim 2, wherein the specific steps of step d are: adding the final-stage filtrate into a silica gel chromatographic column, eluting with ethyl acetate and n-hexane in a volume ratio of 1: 900-1100, monitoring by thin-layer chromatography, eluting with ethyl acetate and n-hexane in a volume ratio of 1:90-110 after doxofylline is completely eluted, monitoring by thin-layer chromatography, collecting eluent, concentrating and drying to obtain doxofylline isomer impurities.
4. The method for separating the doxofylline isomer impurities from the doxofylline reaction solution according to claim 2 or 3, wherein in step d, the filler particle size of the silica gel chromatography column is 200 mesh to 400 mesh.
5. The method of separating the doxofylline isomer impurities from the doxofylline reaction solution of claim 2, wherein said doxofylline reaction solution is prepared by a process comprising the steps of:
adding theophylline, a compound shown as a formula (II) and an acid-binding agent into N, N-dimethylformamide, uniformly mixing, heating to 130-150 ℃, and reacting for 2-3 h to obtain a doxofylline reaction solution;
wherein X is Cl or Br.
6. The method of claim 5, wherein the acid scavenger is potassium carbonate.
7. The method for separating doxofylline isomer impurities from a doxofylline reaction solution according to claim 5, wherein the molar ratio of theophylline to the compound of formula (II) is 1:1 to 2.
8. The method for separating doxofylline isomer impurities from a doxofylline reaction solution according to claim 5, wherein the molar ratio of theophylline to acid-binding agent is 1:0.5 to 1.1.
9. The method according to claim 5, wherein the volume to mass ratio of N, N-dimethylformamide to theophylline is 2-6: 1, wherein the volume is ml and the mass is g.
10. The method for separating the doxofylline isomer impurities from the doxofylline reaction solution according to claim 5, wherein in step b, the volume to mass ratio of the ethanol aqueous solution to theophylline is 4-8: 1, wherein volume is in milliliters and mass is in grams.
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