Deuterated drug impurity norfloxacin-d5 and preparation method therefor

Description

Deuterated drug impurity norfloxacin-d5 and preparation method thereof TECHNICAL FIELD

[0001] The present application relates to the technical field of deuterated drug impurity norfloxacin-d5, in particular to a preparation method of deuterated drug impurity norfloxacin-d5. BACKGROUND

[0002] Norfloxacin-d5 is a deuterated product of norfloxacin, and norfloxacin is a fluoroquinolone antibiotic that can inhibit the growth of gram-positive bacteria and gram-negative bacteria. Norfloxacin-d5 also has the antibacterial properties of norfloxacin, and as a deuterated product, it has unique value in drug research and development, especially as a quantitative tracer. However, the traditional preparation method of deuterated drug impurity norfloxacin-d5 still has some shortcomings. First, in the traditional preparation process of deuterated drug impurity norfloxacin-d5, TLC is generally used to detect the reaction degree and purity, which has insufficient accuracy and affects the quality of the product. Second, in the traditional preparation process of deuterated drug impurity norfloxacin-d5, the preparation of intermediates and subsequent reactions are relatively slow, which affects the preparation efficiency. Third, in the traditional purification process, column chromatography is used, but the elution effect is not good, which affects the yield. Therefore, it is necessary to design a preparation method of deuterated drug impurity norfloxacin-d5. SUMMARY

[0003] The present application aims to provide a preparation method of deuterated drug impurity norfloxacin-d5 to solve the problems in the background art.

[0004] To achieve the above-mentioned purpose, the present application provides the following technical scheme: a preparation method of deuterated drug impurity norfloxacin-d5, comprising the following steps: step one, preparing materials; step two, preparing intermediates; step three, tritium substitution reaction; step four, removing impurities; step five, preparing semi-finished products; and step six, purification detection.

[0005] In step one, 50-60 parts of norfloxacin raw material, 10-15 parts of deuterated raw material, and 5-8 parts of solvent are taken according to the proportions of each component for standby use.

[0006] In step two, 3-chloro-4-fluoroaniline and ethoxymethylenemalonate (EMME) are subjected to a condensation reaction to form a primary intermediate, the primary intermediate is subjected to a cyclization reaction to obtain a cyclized fat, the cyclized fat is subjected to an ethylation reaction to obtain a secondary intermediate, the secondary intermediate is subjected to a hydrolysis reaction to obtain a hydrolysis product, and the hydrolysis product is subjected to a piperazine condensation reaction with anhydrous piperazine to obtain an intermediate of norfloxacin.

[0007] Wherein the above step three, in the solvent, the deuterium raw material and norfloxacin intermediate mixture, add the palladium-based catalyst, during the close monitoring of the reaction process;

[0008] Wherein the above step four, the product obtained in step three is post-treated, distilled, extracted, washed, etc. to remove unreacted raw materials and by-products;

[0009] Wherein the above step five, the product obtained in step four is subjected to further chemical reactions to obtain the crude product of norfloxacin-d5;

[0010] Wherein the above step six, using column chromatography, recrystallization and other purification techniques, the crude product of norfloxacin-d5 is purified to obtain high-purity product, the purified product is detected by high performance liquid chromatography (HPLC) for purity and structure, to ensure that it meets the standards.

[0011] As a further technical solution of the present application, in step one, when preparing materials, high performance liquid chromatography (HPLC) is used to detect the purity of the raw materials to ensure high-purity quality of the raw materials.

[0012] As a further technical solution of the present application, in step two, it is necessary to heat to 120℃ under rapid stirring and carry out condensation reaction at 120-130℃ for 2 hours.

[0013] As a further technical solution of the present application, in step two, trimethyl borate is added as a catalyst in the piperazine condensation reaction.

[0014] As a further technical solution of the present application, in step three, the reaction temperature is 70±5℃, and the reaction is carried out under stirring for 3-5 hours.

[0015] As a further technical solution of the present application, in step three, high performance liquid chromatography (HPLC) is used to detect whether the reaction is complete.

[0016] As a further technical solution of the present application, in step four, the obtained reaction mixture is heated during distillation to vaporize the volatile components, and the liquid is collected through a condenser to obtain a relatively pure product.

[0017] As a further technical solution of the present application, in step five, the reaction steps to obtain the crude product of norfloxacin-d5 include cyclization, hydrolysis, etc.

[0018] As a further technical solution of the present application, in step six, methanol and water are used as eluent to purify norfloxacin-d5, the ratio of methanol and water is adjusted to optimize the solubility difference, and gradient elution method is used for elution.

[0019] As a further technical scheme of the present application, in step six, the target component is collected according to the separation of each component on the chromatographic column, and the collected component is treated by concentration, drying and the like to obtain the purified norfloxacin-d5.

[0020] Compared with the prior art, the present application has the beneficial effects that: the preparation method of the deuterated drug impurity norfloxacin-d5 uses high performance liquid chromatography (HPLC) to detect whether the reaction is complete in step three, and uses high performance liquid chromatography (HPLC) to detect the purity and structure of the purified product in step six, to ensure that it meets the standard, instead of the traditional TLC detection method, which can quickly separate the components in a complex mixture and accurately quantify the analysis through the detector, improving the accuracy; by adding trimethyl borate as a catalyst in the piperazine condensation reaction, and adding a palladium-based catalyst during the mixing of the deuterated raw material and the norfloxacin intermediate, the yield of piperazine and the reaction rate are selectively improved, and the preparation efficiency is improved; by using methanol and water as eluents to purify norfloxacin-d5 in step six, adjusting the ratio of methanol and water to optimize the solubility difference, and using gradient elution to elute, the elution effect and yield are improved. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 is a flow chart of the method of the present application. DETAILED DESCRIPTION

[0022] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the accompanying drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, not all. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0023] Please refer to Figure 1, the present application provides a technical scheme: a preparation method of deuterated drug impurity norfloxacin-d5, comprising the following steps: step one, material preparation; step two, preparation of intermediate; step three, tritium exchange reaction; step four, impurity removal; step five, preparation of semi-finished product; step six, purification and detection;

[0024] In the above step one, 50-60 parts of norfloxacin raw material, 10-15 parts of deuterated raw material and 5-8 parts of solvent are taken according to the proportion of each component, the norfloxacin raw material is composed of 3-chloro-4-fluoroaniline, ethoxymethylenemalonate (EMME) and anhydrous piperazine, and the ratio of 3-chloro-4-fluoroaniline, ethoxymethylenemalonate (EMME) and anhydrous piperazine is 3:2:1, the deuterated raw material is composed of deuterated ethylamine and deuterated toluene, and the composition ratio of deuterated ethylamine and deuterated toluene is 1:1, and the deuterated raw material is composed of DMSO and water, and the composition ratio of DMSO and water is 2:3, when preparing, high performance liquid chromatography (HPLC) is used to detect the purity of the raw material to ensure the high purity quality of the raw material;

[0025] In the above step two, under rapid stirring, heating to 120℃, and at 120-130℃, 3-chloro-4-fluoroaniline and ethoxymethylenemalonate (EMME) are subjected to condensation reaction for 2 hours to form a first intermediate, the first intermediate is subjected to cyclization reaction to obtain a cyclized fat, the cyclized fat is subjected to ethylation reaction to obtain a second intermediate, the second intermediate is subjected to hydrolysis reaction to obtain a hydrolysis product, and the hydrolysis product is subjected to piperazine condensation reaction with anhydrous piperazine, and trimethyl borate is added as a catalyst in the piperazine condensation reaction to obtain an intermediate of norfloxacin;

[0026] In the above step three, under the condition that the reaction temperature is 70±5℃, the deuterated raw material and the norfloxacin intermediate are mixed and stirred in the solvent for 3-5 hours, and a palladium-based catalyst is added, and high performance liquid chromatography (HPLC) is used to detect whether the reaction is complete, and the reaction progress is closely monitored during the period;

[0027] In the above step four, the product obtained in step three is subjected to post-treatment, such as distillation, extraction and washing, to remove unreacted raw materials and by-products, wherein in the distillation process, the obtained reaction mixture is heated to vaporize the volatile components, and the liquid is collected through a condenser to obtain a relatively pure product;

[0028] In the above step five, the product obtained in step four is subjected to further chemical reactions, including cyclization and hydrolysis, to obtain a crude product of norfloxacin-d5;

[0029] In the above step six, purification technology such as column chromatography and recrystallization is used to purify the crude product of norfloxacin-d5, column chromatography is used, methanol and water are used as eluents to purify norfloxacin-d5, the ratio of methanol and water is adjusted to optimize the solubility difference, and gradient elution is used for elution, the target component is collected according to the separation of each component on the chromatographic column, and the collected component is treated by concentration and drying to obtain purified norfloxacin-d5, and the purity and structure of the purified product are detected by high performance liquid chromatography (HPLC) to ensure that it meets the standard.

[0030] Based on the above, the advantages of the present application are that, by using high performance liquid chromatography (HPLC) instead of the traditional TLC detection method, by using high performance liquid chromatography (HPLC) in step three to detect whether the reaction is complete, and by using high performance liquid chromatography (HPLC) to detect the purity and structure of the purified product in step six, it can ensure that it meets the standard, can quickly separate the components in the complex mixture, and through the detector, accurate quantitative analysis is carried out, which improves the accuracy; by adding trimethyl borate as a catalyst in the piperazine condensation reaction, and adding a palladium-based catalyst during the mixing of deuterated raw materials and norfloxacin intermediates, the selectivity of the piperazine yield and the reaction rate are selectively improved, and the preparation efficiency is improved; by using gradient elution in step six, methanol and water are used as eluents to purify norfloxacin-d5, and the proportion of methanol and water is adjusted to optimize the solubility difference, which improves the elution effect and yield.

[0031] It is obvious to those skilled in the art that the present application is not limited to the details of the above exemplary embodiments, and can be implemented in other specific forms without departing from the spirit or essential characteristics of the present application. Therefore, the embodiments should be regarded as exemplary and non-limiting, and the scope of the present application is defined by the appended claims rather than the above description, and therefore all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be included in the present application. Any reference signs in the claims should not be regarded as limiting the claims involved.

Claims

1. A process for the preparation of a deuterated pharmaceutical impurity norfloxacin-d5, comprising the steps of: The method comprises the following steps: step one, preparation; step two, preparation of an intermediate; step three, tritium substitution reaction; step four, impurity removal; step five, preparation of a semi-finished product; and step six, purification and detection; and the method is characterized in that: In step one, 50-60 parts of norfloxacin raw material, 10-15 parts of deuterium-substituted raw material, and 5-8 parts of solvent are taken according to the proportions of the components, and are prepared for use. In step two, 3-chloro-4-fluoroaniline and ethoxymethylenemalonate (EMME) are subjected to a condensation reaction to form a primary intermediate, the primary intermediate is subjected to a cyclization reaction to obtain a cyclized product, the cyclized product is subjected to an ethylation reaction to obtain a secondary intermediate, the secondary intermediate is subjected to a hydrolysis reaction to obtain a hydrolysis product, and the hydrolysis product is subjected to a piperazine condensation reaction with anhydrous piperazine to obtain an intermediate of norfloxacin. In step three, the deuterium-substituted raw material and the intermediate of norfloxacin are mixed in a solvent, and a palladium-based catalyst is added, and the reaction progress is closely monitored during the reaction. In step four, the product obtained in step three is subjected to post-treatment, such as distillation, extraction, and washing, to remove unreacted raw materials and by-products. In step five, the product obtained in step four is subjected to further chemical reactions to obtain a crude product of norfloxacin-d5. In step six, purification techniques such as column chromatography and recrystallization are used to purify the crude product of norfloxacin-d5 to obtain a high-purity product, and the purified product is subjected to purity and structure detection by high-performance liquid chromatography (HPLC) to ensure that it meets the standards.

2. The method for preparing deuterated drug impurity norfloxacin-d5 according to claim 1, characterized in that: In step one, the purity of the raw materials is detected by high-performance liquid chromatography (HPLC) to ensure high-purity quality.

3. The method for preparing deuterated drug impurity norfloxacin-d5 according to claim 1, characterized in that: In step two, the condensation reaction is carried out at 120℃ under rapid stirring for 2 hours.

4. The method for preparing deuterated drug impurity norfloxacin-d5 according to claim 1, characterized in that: In step two, trimethyl borate is added as a catalyst in the piperazine condensation reaction.

5. The method for preparing deuterated drug impurity norfloxacin-d5 according to claim 1, characterized in that: In step three, the reaction temperature is 70±5℃, and the reaction is carried out under stirring for 3-5 hours.

6. The method for preparing deuterated drug impurity norfloxacin-d5 according to claim 1, characterized in that: In step three, high-performance liquid chromatography (HPLC) is used to detect whether the reaction is complete.

7. The method for preparing deuterated drug impurity norfloxacin-d5 according to claim 1, characterized in that: In step four, the obtained reaction mixture is heated to vaporize the volatile components, and the liquid is collected through a condenser to obtain a relatively pure product.

8. The method for preparing deuterated drug impurity norfloxacin-d5 according to claim 1, characterized in that: In step five, the reaction steps for obtaining the crude product of norfloxacin-d5 include cyclization and hydrolysis.

9. The method for preparing deuterated drug impurity norfloxacin-d5 according to claim 1, characterized in that: In step six, methanol and water are used as eluents to purify norfloxacin-d5, the ratio of methanol and water is adjusted to optimize the solubility difference, and gradient elution is used for elution.

10. The method for preparing deuterated drug impurity norfloxacin-d5 according to claim 1, characterized in that: In step six, the target components are collected according to the separation of the components on the chromatographic column, and the collected components are subjected to concentration and drying to obtain the purified norfloxacin-d5.

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