A method for preparing a cyclohexane ester
By controlling the particle size of the acid-binding agent and the reaction conditions, the degradation of gaticycl esters under alkaline and high-temperature conditions was avoided, the problem of impurity A generation was solved, and the preparation of high-purity gaticycl esters was achieved, which is suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- HEILONGJIANG ZBD PHARMA
- Filing Date
- 2023-11-22
- Publication Date
- 2026-06-30
AI Technical Summary
During the preparation of gaticycline esters, the generation of impurity A leads to unstable quality of the final product. In particular, when reacting under alkaline and high-temperature conditions, impurity A can transform into impurity E in moxifloxacin hydrochloride, affecting product quality.
Using acid-binding agents with a particle size ≤48μm, such as potassium carbonate, sodium carbonate, and potassium bicarbonate, combined with N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide solvent, the reaction is carried out at 25–60℃ for 0.5–4h, followed by crystallization treatment with water at 5–15℃. This avoids the degradation of cyclohexane esters under high-temperature alkaline conditions, which would otherwise generate impurity A.
It has achieved the preparation of cyclohexane esters with high yield and high purity (≥99.9%), simplified the operation process, is suitable for industrial production, and ensures the quality stability of downstream products.
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Figure CN117658911B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical chemistry, and in particular to a method for preparing a gaticycline ester. Background Technology
[0002] Gaticycloesters are the core of the synthesis of various antibiotics such as gatifloxacin and moxifloxacin hydrochloride, and are a key intermediate with a wide range of applications.
[0003] Currently, impurity A is unavoidably generated during the preparation of gaticyclates. The preparation of gaticyclates generally uses ethyl (2Z)-3-(cyclopropylamino)-2-[(2,4,5-trifluoro-3-methoxyphenyl)carbonyl]prop-2-enoate (compound I) as a starting material, reacting under alkaline and high-temperature conditions to obtain the gaticyclate. Due to the harsh reaction conditions, the generated gaticyclate undergoes degradation and demethylation under alkaline and high-temperature conditions, reverting to impurity A. The structural formula of impurity A is: In the preparation of moxifloxacin hydrochloride using gaticycline ester as the starting material, impurity A will transform into impurity E in moxifloxacin hydrochloride. The structural formula of impurity E is: Impurity E is a known impurity in moxifloxacin hydrochloride as specified in the pharmacopoeia, and it can have a significant impact on the quality of the final product.
[0004] In view of this, this invention is hereby proposed. Summary of the Invention
[0005] The purpose of this invention is to provide a method for preparing cyclopentadiene esters, which avoids the generation of impurity A during the preparation process and can obtain cyclopentadiene esters with high yield and high purity, with the purity of cyclopentadiene esters reaching over 99.9%.
[0006] In order to achieve the above-mentioned objectives of the present invention, the following technical solution is adopted:
[0007] This invention provides a method for preparing a cyclohexane ester, comprising the following steps:
[0008] Compound I, an acid-binding agent, and a solvent react to yield the cyclohexane ester;
[0009] The structural formula of compound I is:
[0010] The particle size of the acid-binding agent is ≤48μm.
[0011] Furthermore, the acid-binding agent includes at least one of potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate.
[0012] Furthermore, the molar ratio of the acid-binding agent to compound I is (2-3.5):1.
[0013] Furthermore, the solvent includes at least one of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.
[0014] Furthermore, the mass ratio of the solvent to compound I is (3-6):1.
[0015] Furthermore, the reaction temperature is 25–60°C.
[0016] Furthermore, the reaction time is 0.5 to 4 hours.
[0017] Furthermore, after the reaction, the method further includes: performing a crystallization treatment on the reaction solution and water obtained after the reaction at 5-15°C.
[0018] Furthermore, the crystallization treatment time is 0.5 to 1.5 hours.
[0019] Furthermore, the volume ratio of the water to the solvent is (2-5):1.
[0020] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0021] The method for preparing cyclohexane esters provided by this invention has mild reaction conditions, short reaction time, simple operation, high product yield, and high purity. The purity of the product can reach more than 99.9%, and there is no impurity A in the product, making it suitable for large-scale industrial production. Detailed Implementation
[0022] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. However, those skilled in the art will understand that the embodiments described below are some embodiments of the present invention, but not all embodiments, and are only used to illustrate the present invention, and should not be regarded as limiting the scope of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall be followed. Where the manufacturers of reagents or instruments are not specified, they are all conventional products that can be purchased commercially.
[0023] In some embodiments of the present invention, a method for preparing a cyclohexane ester is provided, comprising the following steps:
[0024] Compound I, an acid-binding agent, and a solvent react to give a cyclohexane ester;
[0025] The structural formula of compound I is: The chemical name is (2Z)-3-(cyclopropylamino)-2-[(2,4,5-trifluoro-3-methoxyphenyl)carbonyl]prop-2-enoic acid ethyl ester;
[0026] The particle size of the acid-binding agent is ≤48μm.
[0027] During the preparation of cyclopentadiene esters, under alkaline high-temperature conditions, the generated cyclopentadiene esters will degrade and demethylate to produce impurity A;
[0028] Impurity A: Its chemical name is ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-4-oxo-3-quinolinecarboxylate, and its structural formula is:
[0029] The reaction process is as follows:
[0030]
[0031] The present invention provides a method for preparing cyclohexane esters, using compound I as a raw material to generate cyclohexane esters through a cyclization reaction. During the reaction, by using an acid-binding agent with a particle size ≤48μm, cyclohexane esters can be generated under mild reaction conditions and short reaction time, avoiding the degradation and demethylation reaction of the generated cyclohexane esters under alkaline and high temperature conditions, thereby avoiding the generation of impurity A. Cyclohexane esters can be obtained in high yield and with high purity, and the purity of the product can reach over 99.9%.
[0032] The method for preparing gaticycline provided by this invention avoids the presence of impurity A in the obtained gaticycline, thereby ensuring the stability and reliability of downstream products, such as moxifloxacin hydrochloride.
[0033] The particle size of the acid-binding agent has a significant impact on the reaction process. Larger particle sizes result in longer reaction times and higher reaction temperatures. As the particle size of the acid-binding agent decreases, both the reaction temperature and reaction time decrease accordingly. Because the reaction temperature becomes milder and the reaction time is reduced, the probability of generating impurity A decreases. When the particle size of the acid-binding agent is less than 48 μm, impurity A disappears in the cyclohexane.
[0034] In some embodiments of the present invention, the acid-binding agent includes at least one of potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate.
[0035] In some specific embodiments of the present invention, the acid-binding agent includes potassium carbonate.
[0036] In some embodiments of the invention, the molar ratio of the acid binder to compound I is (2 to 3.5):1; typically, but not limitingly, for example, the molar ratio of the acid binder to compound I can be a range of 2:1, 2.5:1, 3:1, 3.5:1, or any combination thereof.
[0037] In some embodiments of the present invention, the solvent includes at least one of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), and dimethyl sulfoxide (DMSO).
[0038] In some specific embodiments of the present invention, the solvent includes N,N-dimethylformamide (DMF).
[0039] In some embodiments of the invention, the mass ratio of solvent to compound I is (3 to 6):1; typically, but not limitingly, the mass ratio of solvent to compound I can be a range of 3:1, 4:1, 5:1, 6:1, or any combination thereof.
[0040] In some embodiments of the invention, the reaction temperature is 25–60°C; typically, but not limitingly, for example, the reaction temperature can be a range of 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, or any combination thereof.
[0041] In some embodiments of the present invention, the reaction time is 0.5 to 4 hours; typically, but not limitingly, for example, the reaction time can be a range of 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, or any combination thereof.
[0042] In some specific embodiments of the present invention, the reaction temperature is 40-50°C and the reaction time is 1-1.5 h.
[0043] The method for preparing cyclohexane esters of the present invention has short reaction conditions, temperature, and time, and high reaction yield, making it suitable for large-scale industrial production.
[0044] In some embodiments of the present invention, after the reaction, the reaction solution and water are subjected to crystallization treatment at 5 to 15°C.
[0045] In some embodiments of the present invention, the crystallization treatment time is 0.5 to 1.5 hours.
[0046] In some embodiments of the invention, the volume ratio of water to solvent is (2 to 5):1; typically, but not limitingly, for example, the volume ratio of water to solvent can be a range of 2:1, 3:1, 4:1, 5:1, or any combination thereof.
[0047] In some embodiments of the present invention, after the reaction is completed, the reaction solution is cooled to below 15°C, purified water (pre-cooled to 0-5°C) is slowly added to the reaction solution, and after stirring at 5-15°C for 0.5-1.5 hours, solid-liquid separation is performed to obtain filter cake.
[0048] In some embodiments of the present invention, the filter cake is washed with water and dried in sequence to obtain a cyclohexane ester.
[0049] In some embodiments of the present invention, drying includes vacuum drying; preferably, the drying temperature is 50–70°C.
[0050] The method for preparing cyclohexane provided by this invention requires only a simple post-processing step after the reaction to obtain high-purity cyclohexane.
[0051] The cyclohexane prepared by the method of the present invention has high purity after drying. Impurity A was not detected in multiple batches of tests, so no further purification step is required.
[0052] Compound I: Batch number 101P20230301S2; Supplier: Jiangxi Chenyang Pharmaceutical Co., Ltd.
[0053] N,N-Dimethylformamide: Batch number 20190801; Supplier: Tianjin Guangfu Reagent Co., Ltd.
[0054] Anhydrous potassium carbonate: batch number 20210802; supplier: Tianjin Fuchen Chemical Reagent Factory.
[0055] Example 1
[0056] The preparation route of the cyclohexane provided in this embodiment is as follows:
[0057]
[0058] The method for preparing the cyclohexane ester provided in this embodiment includes the following steps:
[0059] S1. Add 322.5g of N,N-dimethylformamide (DMF), 70g of compound I and 70g of anhydrous potassium carbonate (particle size 48μm, 300 mesh) sequentially to a 2L glass round-bottom flask, start stirring, heat to 40-50℃ and react for 1h, and monitor the reaction endpoint.
[0060] The method for monitoring the reaction endpoint was: TLC; thin-layer plate: silica gel GF254; developing solvent: n-heptane: ethyl acetate = 1:1; colorimetric method: observation under ultraviolet light (254nm) after development.
[0061] S2. After the reaction is complete, the reaction solution is cooled to below 15°C. 1L of purified water (pre-cooled to 0-5°C) is slowly added to the reaction solution and stirred at 5-15°C for 1 hour. The filter cake is obtained by filtration. The filter cake is washed with purified water and collected. The filter cake is dried under vacuum at 60°C to obtain the cyclohexane ester.
[0062] The yield of the cyclohexane ester in this embodiment was 95%, the purity was over 99.9%, and impurity A was not detected.
[0063] Example 2
[0064] The preparation method of the cyclohexane ester provided in this embodiment is the same as that in Example 1, except that 70g of anhydrous potassium carbonate is replaced with 51g of potassium bicarbonate.
[0065] The yield of the cyclohexane ester in this embodiment was 93%, the purity was over 99.9%, and impurity A was not detected.
[0066] Example 3
[0067] The preparation method of the gaticyclate provided in this embodiment is the same as that in Example 1, except that 70g of anhydrous potassium carbonate is replaced with 42.85g of sodium bicarbonate.
[0068] The yield of the cyclohexane ester in this embodiment was 91.3%, the purity was over 99.9%, and impurity A was not detected.
[0069] Example 4
[0070] The preparation method of the gaticyclate provided in this embodiment is the same as that in Example 1, except that 70g of anhydrous potassium carbonate is replaced with 54g of sodium carbonate.
[0071] The yield of the cyclohexane ester in this embodiment was 89%, the purity was over 99.9%, and impurity A was not detected.
[0072] Example 5
[0073] The preparation method of the gaticyclate provided in this embodiment is the same as that in Example 1, except that the particle size of anhydrous potassium carbonate is 30 μm.
[0074] The yield of the cyclohexane ester in this embodiment was 95%, the purity was over 99.9%, and impurity A was not detected.
[0075] Example 6
[0076] The preparation method of the cyclohexane provided in this embodiment is the same as that in Example 1, except that the reaction temperature is 25-35°C and the reaction time is 1 hour.
[0077] The yield of the cyclohexane ester in this embodiment was 95.7%, the purity was over 99.9%, and impurity A was not detected.
[0078] Example 7
[0079] The method for preparing the cyclohexane ester provided in this embodiment includes the following steps:
[0080] S1. Add 400g of N,N-dimethylformamide (DMF), 70g of compound I and 80g of anhydrous potassium carbonate (particle size 48μm, 300 mesh) sequentially to a 2L glass round-bottom flask, start stirring, heat to 25-35℃ and react for 1.5h, and monitor the reaction endpoint.
[0081] The method for monitoring the reaction endpoint was: TLC; thin-layer plate: silica gel GF254; developing solvent: n-heptane: ethyl acetate = 1:1; colorimetric method: observation under ultraviolet light (254nm) after development.
[0082] S2. After the reaction is complete, the reaction solution is cooled to below 15°C. 1.2L of purified water (pre-cooled to 0-5°C) is slowly added to the reaction solution and stirred at 5-15°C for 1 hour. The filter cake is obtained by filtration. The filter cake is washed with purified water and collected. The filter cake is dried under vacuum at 60°C to obtain the cyclohexane ester.
[0083] The yield of the cyclohexane ester in this embodiment was 95%, the purity was over 99.9%, and impurity A was not detected.
[0084] Comparative Example 1
[0085] The method for preparing the cyclohexane ester provided in this comparative example includes the following steps:
[0086] S1. Add 322.5g of N,N-dimethylformamide (DMF), 70g of compound I and 70g of anhydrous potassium carbonate (particle size 60μm) to a 2L glass round-bottom flask in sequence, start stirring, heat to 40-50℃ and react for 1h, and monitor the reaction endpoint.
[0087] The method for monitoring the reaction endpoint was: TLC; thin-layer plate: silica gel GF254; developing solvent: n-heptane: ethyl acetate = 1:1; colorimetric method: observation under ultraviolet light (254nm) after development.
[0088] S2. After the reaction is complete, the reaction solution is cooled to below 15°C. 1L of purified water (pre-cooled to 0-5°C) is slowly added to the reaction solution and stirred at 5-15°C for 1 hour. The filter cake is obtained by filtration. The filter cake is washed with purified water and collected. The filter cake is dried under vacuum at 60°C to obtain the cyclohexane ester.
[0089] The yield of the cyclohexane ester in this comparative example was 89%, the purity was over 98.3%, and the impurity A was 0.12%.
[0090] Comparative Example 2
[0091] The method for preparing the cyclohexane ester provided in this comparative example includes the following steps:
[0092] S1. Add 322.5g of N,N-dimethylformamide (DMF), 70g of compound I and 70g of anhydrous potassium carbonate (particle size 48μm, 300 mesh) sequentially to a 2L glass round-bottom flask, start stirring, heat to 70-80℃ and react for 8h, and monitor the reaction endpoint.
[0093] The method for monitoring the reaction endpoint was: TLC; thin-layer plate: silica gel GF254; developing solvent: n-heptane: ethyl acetate = 1:1; colorimetric method: observation under ultraviolet light (254nm) after development.
[0094] S2. After the reaction is complete, the reaction solution is cooled to below 15°C. 1L of purified water (pre-cooled to 0-5°C) is slowly added to the reaction solution and stirred at 5-15°C for 1 hour. The filter cake is obtained by filtration. The filter cake is washed with purified water and collected. The filter cake is dried under vacuum at 60°C to obtain the cyclohexane ester.
[0095] The yield of the cyclohexane ester in this comparative example was 83%, the purity was over 97.7%, and the impurity A was 0.53%.
[0096] This description is intended to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for preparing a cyclohexane ester, characterized in that, Includes the following steps: Compound I, an acid-binding agent, and a solvent react to yield the cyclohexane ester; The structural formula of compound I is: ; The particle size of the acid-binding agent is 30~48μm; The acid-binding agent is at least one of potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate. The solvent is N,N-dimethylformamide; The reaction temperature is 25~50℃.
2. The method for preparing the cyclohexane ester according to claim 1, characterized in that, The molar ratio of the acid-binding agent to compound I is (2~3.5):
1.
3. The method for preparing the cyclohexane ester according to claim 1, characterized in that, The mass ratio of the solvent to compound I is (3~6):
1.
4. The method for preparing the cyclohexane ester according to claim 1, characterized in that, The reaction time is 0.5 to 4 hours.
5. The method for preparing the cyclohexane ester according to claim 1, characterized in that, The reaction process further includes: crystallizing the resulting reaction solution and water at 5-15°C.
6. The method for preparing the cyclohexane ester according to claim 5, characterized in that, The crystallization treatment time is 0.5~1.5h.
7. The method for preparing the cyclohexane ester according to claim 5, characterized in that, The volume ratio of water to solvent is (2~5):1.