Preparation method of sodium ozagrel impurity
The preparation of sodium ozagrel impurity compound I by irradiation with light of a specific wavelength and addition reaction solves the problem of lack of preparation methods in the prior art, realizes the acquisition of high-purity impurity standards, and supports the quality control of sodium ozagrel.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- TEAM ACAD OF PHARMA SCI
- Filing Date
- 2025-01-13
- Publication Date
- 2026-07-14
AI Technical Summary
The lack of existing methods for preparing sodium ozagrel impurity compound I makes it difficult to effectively control the quality of sodium ozagrel, especially the impurity content.
Compound II was reacted with a brominating agent and an initiator under irradiation with light of a specific wavelength. An addition reaction was achieved through photoexcitation of the double bond configuration change. The compound of formula I was then purified by column chromatography.
A low-cost and simple preparation method is provided to obtain high-purity ozagrel sodium impurity standards, supporting quality control.
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Abstract
Description
Technical Field
[0001] This invention relates to a method for preparing ozagrel sodium impurities, belonging to the field of pharmaceutical synthesis. Background Technology
[0002] Ozagrel sodium, chemically known as E-3-[4-(1H-imidazolyl-1-methylene)-phenyl]-2-acrylate sodium, was developed by Ono Pharmaceutical Co., Ltd. of Japan and officially launched in Japan in 1989 under the brand name Cataclot. It is a novel antiplatelet aggregation drug, an inhibitor of thromboxane A2 (TXA2) synthase, thus exhibiting antiplatelet aggregation and vasodilatory effects, and is suitable for the treatment of acute ischemic cerebrovascular diseases. Clinically, ozagrel sodium is mainly used to treat acute thrombotic cerebral infarction and motor disorders associated with cerebral infarction.
[0003] According to literature reports, among the several synthetic routes for ozagrel sodium, the most commonly used route is to first esterify p-methyl cinnamic acid, then bromine the methyl group, condense the brominated product with imidazole to obtain ozagrel ester products, and finally obtain ozagrel sodium by alkaline hydrolysis and salt formation. This route is relatively mature, yields high product yields, has low impurity content, and is suitable for large-scale commercial production, as shown in the figure below.
[0004]
[0005] Impurities are critical quality attributes of pharmaceuticals, affecting product safety and efficacy; therefore, impurity research is an important part of drug quality research. Any impurities in ozagrel sodium may originate from its degradation and manufacturing processes, including incompletely reacted materials, impurities and their chemical derivatives contained in reactants, synthetic byproducts, and degradation products. Recently, the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) reviewed our company's application for ozagrel sodium active pharmaceutical ingredient (API) and issued a supplemental application approval notice. The notice requires detailed research on the process impurity (E)-3-[4-[3-bromo-3-(4-bromomethylphenyl)-2-ethoxycarbonyl-propyl]phenyl]ethyl acrylate (structural formula shown in Formula I) and the development of a reasonable control strategy, demonstrating the critical importance of this impurity to the quality of the API.
[0006]
[0007] In the above-described synthetic route for ozagrel sodium, it is speculated that impurities of formula I may be generated during the synthesis process, for example, in the bromination step. To control the quality of ozagrel sodium, qualitative and quantitative analysis of impurities of formula I is necessary. Currently, there are no commercially available standards for impurities of formula I; therefore, it is necessary to synthesize standards for these impurities for analytical and quantitative purposes. However, a literature search revealed no reports on the preparation methods of compounds of formula I. Therefore, this invention provides a method for preparing compounds of formula I impurities, which is of great significance for impurity research and quality control of ozagrel sodium. Summary of the Invention
[0008] The technical problem to be solved by the present invention is to provide an ozagrel sodium impurity compound of type I and a method for its preparation, which is low in cost, uses readily available raw materials, is simple to operate and safe.
[0009] Through experiments, the inventors discovered that, following the general approach of addition reactions, directly reacting a compound of formula II with the brominating reagent bromosuccinimide (NBS) and the initiator azobisisobutyronitrile (AIBN) or benzoyl peroxide (BPO), even with heating, fails to yield the target product of formula I. The presumed reason is that the double bond of compound II is in a trans configuration, which is unfavorable for the participation of larger fragments in the addition reaction. However, the inventors unexpectedly discovered that under prolonged irradiation with light of a specific wavelength, compound II is excited, undergoing an electronic transition. The double bond changes from a trans configuration to a cis configuration, reducing steric hindrance on the other side of the double bond. Thus, under the action of bromosuccinimide (NBS), azobisisobutyronitrile (AIBN), or benzoyl peroxide (BPO), the double bond can undergo an addition reaction to obtain compound I. The reaction formula for the preparation method is shown below:
[0010]
[0011] Based on the above-mentioned unexpected discovery, the present invention provides a method for preparing a compound of formula I as described below, comprising the following steps:
[0012] Using compound II as a raw material, a solution was first prepared by dissolving compound II in a first solvent, and then irradiated under light of a specific wavelength for a certain period of time. After removing the light source, a suitable brominating reagent and initiator were added, and the reaction was carried out at a first temperature. After the reaction was completed, the solvent was removed by concentration, and then a second solvent was added while stirring at a second temperature to achieve crystallization and enrichment of the target product. The solid was filtered off, and the filtrate was concentrated to remove the solvent, yielding an oily product containing the target compound of formula I. After purification by column chromatography, the pure white solid of compound I was obtained.
[0013] In the preparation method described above, the first solvent is either chloroform or carbon tetrachloride, and the mass-to-volume ratio (m / V) of compound II to the added first solvent is 1:6 to 8.
[0014] In the preparation method described above, the wavelength of the specific wavelength light is 254 nm or 457 nm, preferably 254 nm. The irradiation time with the specific wavelength light is 15 to 30 days.
[0015] In the preparation method described above, the brominating reagent is bromosuccinimide, and the molar ratio of compound II to the brominating reagent is 1:1.0 to 1.5, preferably 1:1.0 to 1.3.
[0016] In the preparation method described above, the initiator is one of benzoyl peroxide and azobisisobutyronitrile.
[0017] In the preparation method described above, the first temperature is 50-70℃, preferably 60-70℃.
[0018] In the preparation method described above, the second solvent is any one of methanol, ethanol, and isopropanol, preferably methanol or ethanol.
[0019] In the preparation method described above, the second temperature is 5–30°C, preferably 20–30°C.
[0020] In the preparation method described above, when purifying the obtained oily substance by column chromatography, ethyl acetate-petroleum ether (ethyl acetate: petroleum ether = 1:30) is used as the eluent.
[0021] The beneficial effects of this invention are that it provides an ozagrel sodium impurity as a compound of formula I and a method for its preparation, providing a qualified standard for the quality study of ozagrel sodium. Using the above method, the reaction operation for synthesizing the impurity compound of formula I is convenient, the reaction conditions are mild and controllable, and the product has high purity.
[0022] Furthermore, the present invention also provides an HPLC method for determining the purity of sodium ozagrel impurities in compounds of formula I, as detailed below:
[0023] Column: Octadecylsilane-bonded silica gel (Agela Venusil MP-C18, 4.6 mm × 250 mm, 5 μm) was used as the packing material.
[0024] Mobile phase: 0.3% ammonium acetate solution (adjusted to pH 3.0 with phosphoric acid) - acetonitrile (40:60)
[0025] Wavelength: 280nm
[0026] Column temperature: 30℃
[0027] Flow rate: 1 ml / min
[0028] Injection volume: 30 μl
[0029] Sample solution preparation method: Accurately weigh the sample, use the mobile phase as solvent, dissolve and quantitatively dilute to prepare a solution containing approximately 30 mg per 1 ml, and shake well. Attached Figure Description
[0030] Figure 1 For ozagrel sodium impurity compound of formula I 1 H NMR spectrum.
[0031] Figure 2 The MS spectrum of sodium ozagrel impurity compound I is shown. Detailed Implementation
[0032] The present invention will be further described in detail below with reference to the embodiments, but it should be understood that the scope of the present invention is not limited to the scope of these embodiments. Experimental methods in the following embodiments that do not specify specific conditions are generally performed according to conventional methods.
[0033] Example 1
[0034] Compound II (5.0 g, 26.3 mmol) and 40 mL of carbon tetrachloride were added to the reaction flask and stirred until dissolved. The dissolved carbon tetrachloride solution was then placed under a 254 nm light source and irradiated continuously for 15 days. After the irradiation time was reached, the 254 nm UV light source was removed, and bromosuccinimide (5.6 g, 31.5 mmol) and benzoyl peroxide (1.3 g, 5.4 mmol) were added to the solution. The mixture was heated to 70 °C and reacted for 24 h. After cooling to room temperature, 25 mL of purified water was added, stirred, and the mixture was separated. The organic phase was collected and washed once more with 25 mL of purified water. Carbon tetrachloride was removed by concentration, and then 15 ml of anhydrous ethanol was added to the remaining concentrate. The mixture was stirred at 25 °C to induce crystallization, and a large amount of white solid precipitated. The solid was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, yielding an oily substance containing the target compound of formula I. The oily substance was purified by column chromatography using ethyl acetate-petroleum ether (ethyl acetate: petroleum ether = 1:30) as the eluent. The eluent from the target spot was collected, and the eluent was concentrated to dryness under reduced pressure to obtain 0.28 g of the target compound, with a yield of 4.0% and a purity of 92.32%.
[0035] The HPLC method for determining product purity is as follows:
[0036] Column: Octadecylsilane-bonded silica gel (Agela Venusil MP-C18, 4.6 mm × 250 mm, 5 μm) was used as the packing material.
[0037] Mobile phase: 0.3% ammonium acetate solution (adjusted to pH 3.0 with phosphoric acid) - acetonitrile (40:60)
[0038] Wavelength: 280nm
[0039] Column temperature: 30℃
[0040] Flow rate: 1 ml / min
[0041] Injection volume: 30 μl
[0042] Sample solution preparation method: Accurately weigh the sample, use the mobile phase as solvent, dissolve and quantitatively dilute to prepare a solution containing approximately 30 mg per 1 ml, and shake well.
[0043] MS (m / z): 537.0 [MH] - MS spectrum attached. Figure 2 .
[0044] 1 H NMR (600MHz, DMSO-d6): 1 The H NMR spectrum is attached. Figure 1 .
[0045] δ1.091~1.114(t,3H), δ1.298~1.322(t,3H), δ2.413~2.442(m,1H), δ2.603~2.644(m,1H), δ3.739~3.783(m,1H), δ4.076~4.115(m,2 H), δ4.183~4.224(m,2H), δ4.727(s,2H), δ5.380~5.398(d,1H), δ6.582~6.609(d,1H), δ7.087~7.100(d,2H), δ7.489~7.669(m,7H).
[0046] Example 2
[0047] Compound II (5.0 g, 26.3 mmol) and 40 mL of carbon tetrachloride were added to the reaction flask and stirred until dissolved. The dissolved carbon tetrachloride solution was then placed under a 457 nm light source and irradiated continuously for 17 days. After the irradiation time was reached, the 457 nm blue light source was removed, and bromosuccinimide (5.5 g, 30.9 mmol) and benzoyl peroxide (1.3 g, 5.4 mmol) were added to the solution. The mixture was heated to 70 °C and reacted for 24 h. After cooling to room temperature, 25 mL of purified water was added, stirred, and the mixture was separated. The organic phase was collected and washed once more with 25 mL of purified water. Carbon tetrachloride was removed by concentration, and then 15 ml of anhydrous ethanol was added to the remaining concentrate and stirred at 25 °C to induce crystallization. A large amount of white solid precipitated. The solid was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, yielding an oily substance containing the target compound of formula I. The oily substance was purified by column chromatography using ethyl acetate / petroleum ether (1:30) as the eluent. The eluent from the target spot was collected and concentrated under reduced pressure to dryness, yielding 0.11 g of the target compound, with a yield of 1.6% and a purity of 94.76%.
[0048] Example 3
[0049] Compound II (5.0 g, 26.3 mmol) and 60 mL of chloroform were added to a reaction flask and stirred until dissolved. The dissolved chloroform solution was then placed under a 254 nm light source and irradiated continuously for 20 days. After the irradiation time was reached, the 254 nm UV light source was removed, and bromosuccinimide (5.6 g, 31.6 mmol) and benzoyl peroxide (1.3 g, 5.4 mmol) were added to the solution. The mixture was heated to 60 °C and reacted for 24 h. After cooling to room temperature, 30 mL of purified water was added, and the mixture was stirred. The mixture was then separated, and the organic phase was collected. The organic phase was washed once with 20 mL of purified water. Chloroform was removed by concentration, and then 20 ml of anhydrous ethanol was added to the remaining concentrate and stirred at 30 °C to induce crystallization. A large amount of white solid precipitated. The solid was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, yielding an oily substance containing the target compound of formula I. The obtained oily substance was purified by column chromatography using ethyl acetate / petroleum ether (1:30) as the eluent. The eluent from the target spot was collected and concentrated under reduced pressure to dryness, yielding 0.33 g of the target compound, with a yield of 4.3% and a purity of 94.04%.
[0050] Example 4
[0051] Compound II (5.0 g, 26.3 mmol) and 60 mL of chloroform were added to the reaction flask and stirred until dissolved. The dissolved chloroform solution was then placed under a 457 nm light source and irradiated continuously for 17 days. After the irradiation time was reached, the 457 nm blue light source was removed, and bromosuccinimide (7.0 g, 39.5 mmol) and benzoyl peroxide (1.3 g, 5.4 mmol) were added to the solution. The mixture was heated to 60 °C and reacted for 24 h. After cooling to room temperature, 30 mL of purified water was added, and the mixture was stirred. The mixture was then separated, and the organic phase was collected. The organic phase was washed once with 20 mL of purified water. Carbon tetrachloride was removed by concentration, and then 20 ml of anhydrous ethanol was added to the remaining concentrate and stirred at 25 °C to induce crystallization. A large amount of white solid precipitated. The solid was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, yielding an oily substance containing the target compound of formula I. The oily substance was purified by column chromatography using ethyl acetate / petroleum ether (1:30) as the eluent. The eluent from the target spot was collected and concentrated under reduced pressure to dryness, yielding 0.09 g of the target compound, with a yield of 1.6% and a purity of 94.04%.
[0052] The experimental conditions and results of Examples 1-4 are compared as follows:
[0053] Example Light source wavelength Solvent types Brominated reagent ratio reaction temperature Yield % purity% Example 1 254nm Carbon tetrachloride 1.2 70℃ 4.0 92.32 Example 2 457nm Carbon tetrachloride 1.2 70℃ 1.6 94.76 Example 3 254nm Chloroform 1.2 60℃ 4.3 94.04 Example 4 457nm Chloroform 1.5 60℃ 1.3 96.12
[0054] By comparing the results of the above embodiments, under the same reaction conditions, the experimental results using a 254nm wavelength light source are better than those using a 457nm wavelength light source. This indicates that irradiation with a 254nm wavelength light source is more conducive to the formation of the target product, and therefore the 254nm wavelength light source is more effective.
[0055] Example 5
[0056] Compound II (10.0 g, 52.6 mmol) and 80 mL of carbon tetrachloride were added to a reaction flask and stirred until dissolved. The dissolved carbon tetrachloride solution was then placed under a 254 nm light source and irradiated continuously for 20 days. After the irradiation time was reached, the 254 nm UV light source was removed, and bromosuccinimide (12.2 g, 68.4 mmol) and azobisisobutyronitrile (1.7 g, 10.5 mmol) were added to the solution. The mixture was heated to 70 °C and reacted for 20 h. After cooling to room temperature, 60 mL of purified water was added, stirred, and the mixture was separated. The organic phase was collected and washed once with 30 mL of purified water. Carbon tetrachloride was removed by concentration, and then 40 ml of methanol was added to the remaining concentrate and stirred at 20 °C to induce crystallization. A large amount of white solid precipitated. The solid was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, yielding an oily substance containing the target compound of formula I. The oily substance was purified by column chromatography using ethyl acetate / petroleum ether (1:30) as the eluent. The eluent from the target spot was collected and concentrated under reduced pressure to dryness, yielding 0.65 g of the target compound, with a yield of 4.6% and a purity of 96.10%.
[0057] Example 6
[0058] Compound II (5.0 g, 26.3 mmol) and 40 mL of carbon tetrachloride were added to a reaction flask and stirred until dissolved. The dissolved carbon tetrachloride solution was then placed under a 254 nm light source and irradiated continuously for 20 days. After the irradiation time was reached, the 254 nm UV light source was removed, and bromosuccinimide (5.6 g, 31.5 mmol) and benzoyl peroxide (1.3 g, 5.4 mmol) were added to the solution. The mixture was heated to 50 °C and reacted for 24 h. After cooling to room temperature, 30 mL of purified water was added, stirred, and the mixture was separated. The organic phase was collected and washed once with 20 mL of purified water. Carbon tetrachloride was removed by concentration, and then 15 ml of anhydrous ethanol was added to the remaining concentrate. The mixture was stirred at 25 °C to induce crystallization, and a large amount of white solid precipitated. The solid was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, yielding an oily substance containing the target compound of formula I. The oily substance was purified by column chromatography using ethyl acetate-petroleum ether (1:30) as the eluent. The eluent from the target spot was collected, and the eluent was concentrated to dryness under reduced pressure to obtain 0.06 g of the target compound, with a yield of 0.8% and a purity of 95.88%.
[0059] Example 7
[0060] Compound II (5.0 g, 26.3 mmol) and 40 ml of carbon tetrachloride were added to the reaction flask and stirred until dissolved. The dissolved carbon tetrachloride solution was then placed under a 254 nm wavelength light source and irradiated continuously for 20 days. After the irradiation time was reached, the 254 nm UV light source was removed, and bromosuccinimide (5.6 g, 31.5 mmol) and benzoyl peroxide (1.9 g, 7.9 mmol) were added to the solution. The temperature was raised to 40 °C and the reaction was carried out for 24 h. The post-treatment procedure was the same as in Example 6 to obtain an oil containing the target compound of formula I. The obtained oil was purified by column chromatography using ethyl acetate-petroleum ether (1:30) as the eluent. The eluent from the target spot was collected, but no effective amount of the target compound was obtained.
[0061] The experimental results of the examples under different temperature conditions are compared as follows:
[0062]
[0063] Based on the experimental results under different reaction temperature conditions, the amount of product obtained was significantly reduced when the reaction temperature was lowered, indicating that a higher reaction temperature is beneficial to the reaction and improves the conversion rate of the target product.
[0064] Example 8
[0065] Compound II (5.0 g, 26.3 mmol) and 40 mL of chloroform were added to a reaction flask and stirred until dissolved. The dissolved chloroform solution was then placed under a 254 nm light source and irradiated continuously for 30 days. After the irradiation time was reached, the 254 nm UV light source was removed, and bromosuccinimide (5.6 g, 31.5 mmol) and benzoyl peroxide (1.3 g, 5.4 mmol) were added to the solution. The mixture was heated to 60 °C and reacted for 24 h. After cooling to room temperature, 60 mL of purified water was added, stirred, and the mixture was separated. The organic phase was collected and washed once with 30 mL of purified water. Chloroform was removed by concentration, and then 15 ml of isopropanol was added to the remaining concentrate and stirred at 20 °C to induce crystallization. A large amount of white solid precipitated. The solid was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, yielding an oily substance containing the target compound of formula I. The oily substance was purified by column chromatography using ethyl acetate-petroleum ether (1:30) as the eluent. The eluent from the target spot was collected and concentrated under reduced pressure to dryness, yielding 0.17 g of the target compound, with a yield of 2.4% and a purity of 93.19%.
[0066] The experimental results of the different crystallization solvents, i.e., the second solvent examples, are compared as follows:
[0067] Example Solvent types reaction temperature reaction time Second type of solvent Yield % purity% Example 1 Carbon tetrachloride 70℃ 24h ethanol 4.0 92.32 Example 5 Carbon tetrachloride 70℃ 20h methanol 4.6 96.10 Example 8 Carbon tetrachloride 60℃ 24h Isopropanol 2.4 93.19
[0068] As can be seen from the data in the table above, when methanol or ethanol is selected as the second solvent for impurity enrichment, the yield of the target product is not significantly different. However, when isopropanol is used, the yield is significantly reduced. Therefore, methanol or ethanol is preferred as the crystallization solvent.
[0069] Example 9
[0070] Compound II (8.0 g, 42.1 mmol) and 48 mL of carbon tetrachloride were added to the reaction flask and stirred until dissolved. The dissolved carbon tetrachloride solution was then placed under a 254 nm light source and irradiated continuously for 30 days. After the irradiation time was reached, the 254 nm UV light source was removed, and bromosuccinimide (5.6 g, 63.1 mmol) and benzoyl peroxide (3.1 g, 12.6 mmol) were added to the solution. The mixture was heated to 65 °C and reacted for 20 h. After cooling to room temperature, 64 mL of purified water was added, stirred, and the mixture was separated. The organic phase was collected and washed once with 32 mL of purified water. Carbon tetrachloride was removed by concentration, and then 32 ml of anhydrous ethanol was added to the remaining concentrate and stirred at 25 °C to induce crystallization. A large amount of white solid precipitated. The solid was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, yielding an oily substance containing the target compound of formula I. The oily substance was purified by column chromatography using ethyl acetate-petroleum ether (1:30) as the eluent. The eluent from the target spot was collected and concentrated under reduced pressure to dryness, yielding 0.26 g of the target compound, with a yield of 2.3% and a purity of 96.22%.
[0071] Example 10
[0072] Compound II (5.0 g, 26.3 mmol) and 40 mL of carbon tetrachloride were added to a reaction flask and stirred until dissolved. The dissolved carbon tetrachloride solution was then placed under a 254 nm light source and irradiated continuously for 30 days. After the irradiation time was reached, the 254 nm UV light source was removed, and bromosuccinimide (4.7 g, 26.3 mmol) and benzoyl peroxide (1.3 g, 5.4 mmol) were added to the solution. The mixture was heated to 70 °C and reacted for 20 h. After cooling to room temperature, 30 mL of purified water was added, stirred, and the mixture was separated. The organic phase was collected and washed once with 20 mL of purified water. Carbon tetrachloride was removed by concentration, and then 15 ml of anhydrous ethanol was added to the remaining concentrate. The mixture was stirred at 25 °C to induce crystallization, and a large amount of white solid precipitated. The solid was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, yielding an oily substance containing the target compound of formula I. The oily substance was purified by column chromatography using ethyl acetate-petroleum ether (1:30) as the eluent. The eluent from the target spot was collected, and the eluent was concentrated to dryness under reduced pressure to obtain 0.28 g of the target compound, with a yield of 4.0% and a purity of 92.09%.
[0073] The experimental results of different bromide reagent ratios are compared below:
[0074]
[0075]
[0076] Comparing the results of adding different ratios of brominating reagent, the yield tended to decrease when the ratio of brominating reagent was high. This is presumably because the presence of excessive brominating reagent would produce more polybrominated products, thus reducing the conversion rate of the target compound. Therefore, the preferred ratio of brominating reagent is 1:1.0 to 1:1.3.
[0077] Example 11
[0078] Compound II (5.0 g, 26.3 mmol) and 40 mL of carbon tetrachloride were added to a reaction flask and stirred until dissolved. The dissolved carbon tetrachloride solution was then placed under a 254 nm light source and irradiated continuously for 20 days. After the irradiation time was reached, the 254 nm UV light source was removed, and bromosuccinimide (4.7 g, 31.6 mmol) and benzoyl peroxide (1.3 g, 5.4 mmol) were added to the solution. The mixture was heated to 70 °C and reacted for 20 h. After cooling to room temperature, 30 mL of purified water was added, stirred, and the mixture was separated. The organic phase was collected and washed once with 20 mL of purified water. Carbon tetrachloride was removed by concentration, and then 15 ml of anhydrous ethanol was added to the remaining concentrate. The mixture was stirred at 5°C to induce crystallization, and a large amount of white solid precipitated. The solid was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, yielding an oily substance containing the target compound of formula I. The oily substance was purified by column chromatography using ethyl acetate-petroleum ether (ethyl acetate: petroleum ether = 1:30) as the eluent. The eluent from the target spot was collected, and the eluent was concentrated to dryness under reduced pressure to obtain 0.12 g of the target compound, with a yield of 1.8% and a purity of 95.11%.
[0079] Example 12
[0080] Compound II (5.0 g, 26.3 mmol) and 40 mL of carbon tetrachloride were added to a reaction flask and stirred until dissolved. The dissolved carbon tetrachloride solution was then placed under a 254 nm light source and irradiated continuously for 20 days. After the irradiation time was reached, the 254 nm UV light source was removed, and bromosuccinimide (4.7 g, 28.9 mmol) and benzoyl peroxide (1.9 g, 7.9 mmol) were added to the solution. The mixture was heated to 65 °C and reacted for 20 h. After cooling to room temperature, 30 mL of purified water was added, stirred, and the mixture was separated. The organic phase was collected and washed once with 20 mL of purified water. Carbon tetrachloride was removed by concentration, and then 15 ml of anhydrous ethanol was added to the remaining concentrate. The mixture was stirred at 15 °C to induce crystallization, and a large amount of white solid precipitated. The solid was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, yielding an oily substance containing the target compound of formula I. The oily substance was purified by column chromatography using ethyl acetate-petroleum ether (1:30) as the eluent. The eluent from the target spot was collected, and the eluent was concentrated to dryness under reduced pressure to obtain 0.18 g of the target compound, with a yield of 2.5% and a purity of 96.03%.
[0081] The experimental results of examples under different crystallization temperature conditions are compared as follows:
[0082]
[0083]
[0084] When adjusting the crystallization temperature of the enrichment process, the yield of the target compound tends to decrease when the temperature is low. Theoretically, this is because the target compound precipitates along with other components at lower temperatures, resulting in a reduction in the content of the target compound in the mother liquor. Therefore, the crystallization temperature is preferably 20-30°C.
[0085] Example 13
[0086] Compound II (5.0 g, 26.3 mmol) and 60 mL of chloroform were added to the reaction flask and stirred until dissolved. The dissolved chloroform solution was then placed under a 254 nm light source and irradiated continuously for 15 days. After the irradiation time was reached, the 254 nm UV light source was removed, and bromosuccinimide (5.6 g, 31.6 mmol) and benzoyl peroxide (1.3 g, 5.4 mmol) were added to the solution. The mixture was heated to 60 °C and reacted for 20 h. After cooling to room temperature, 30 mL of purified water was added, stirred, and the mixture was separated. The organic phase was collected and washed once with 20 mL of purified water. Chloroform was removed by concentration, and then 20 ml of anhydrous ethanol was added to the remaining concentrate. The mixture was stirred at 25 °C to induce crystallization, and a large amount of white solid precipitated. The solid was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, yielding an oily substance containing the target compound of formula I. The oily substance was purified by column chromatography using ethyl acetate / petroleum ether (1:30) as the eluent. The eluent from the target spot was collected and concentrated under reduced pressure to dryness, yielding 0.26 g of the target compound, with a yield of 3.7% and a purity of 94.81%.
[0087] Example 14
[0088] Compound II (5.0 g, 26.3 mmol) and 60 mL of chloroform were added to a reaction flask and stirred until dissolved. The dissolved chloroform solution was then placed under a 254 nm wavelength light source and irradiated continuously for 5 days. After the irradiation time was reached, the 254 nm UV light source was removed, and bromosuccinimide (5.6 g, 31.6 mmol) and benzoyl peroxide (1.3 g, 5.4 mmol) were added to the solution. The mixture was heated to 60 °C and reacted for 20 h. After cooling to room temperature, 30 mL of purified water was added, and the mixture was stirred and separated. The organic phase was collected and washed once with 20 mL of purified water. The chloroform was removed by concentration, and then 20 mL of anhydrous ethanol was added to the remaining concentrate and stirred at 25 °C to induce crystallization. A large amount of white solid precipitated. The solid was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, yielding an oily substance containing the target compound of formula I. The oily substance was purified by column chromatography, but no effective amount of the target compound was obtained.
[0089] The results of the examples with different light irradiation times are summarized below:
[0090]
[0091]
[0092] Based on the experimental results in the table above, the yield of the target compound was significantly reduced after shortening the light irradiation time, indicating that sufficient time is required under the irradiation of a specific light source to ensure that compound II is conducive to the reaction and to improve the conversion rate of the target compound during the reaction.
[0093] Example 15 (Comparative Example 1)
[0094] Compound II (2.5 g, 13.2 mmol) and 30 mL of carbon tetrachloride were added to the reaction flask and stirred until dissolved. Bromosuccinimide (3.1 g, 17.1 mmol) and azobisisobutyronitrile (0.43 g, 2.6 mmol) were then added to the solution, and the mixture was heated to 70 °C and reacted for 5 days. The reaction was monitored by TLC, and no target compound was observed. The reaction was continued for 3 days, and TLC monitoring again showed no target compound; the reaction was then discarded.
[0095] Example 16 (Comparative Example 2)
[0096] Compound II (2.5 g, 13.2 mmol) and 30 mL of carbon tetrachloride were added to a reaction flask and stirred until dissolved. Bromosuccinimide (3.1 g, 17.1 mmol) and benzoyl peroxide (0.65 g, 2.7 mmol) were then added to the solution, and the mixture was heated to 70 °C and reacted for 10 days. The reaction was monitored by TLC, and the absence of the target compound was confirmed. The reaction was then discarded.
[0097] As can be seen from Examples 15 and 16, it is difficult to obtain the target compound of Formula I by physical heating. The reason is presumably that physical heating cannot meet the high activation energy required for free radical addition reactions.
Claims
1. A method for preparing sodium ozagrel impurity compound of formula I, characterized in that: Using compound II as a raw material, compound II is first dissolved in a first solvent to prepare a solution, and then irradiated under light of a specific wavelength for a certain period of time. After removing the light source, a suitable brominating reagent and initiator are added and the reaction is carried out at a first temperature. After the reaction is completed, the solvent is removed by concentration, and then a second solvent is added and stirred at a second temperature to achieve crystallization to enrich the target product. The solid is filtered off, and the filtrate is concentrated to remove the solvent, yielding an oily product containing the target compound of formula I. After purification by column chromatography, the pure white solid of compound I is obtained.
2. The preparation method according to claim 1, characterized in that... The wavelength of the selected light source is 254nm or 457nm, preferably 254nm.
3. The preparation method according to claim 1, characterized in that... The duration of illumination using light of a specific wavelength is 15 to 30 days.
4. The preparation method according to claim 1, characterized in that... The selected initiator is either azobisisobutyronitrile or benzoyl peroxide.
5. The preparation method according to claim 1, characterized in that... The brominating reagent used is bromosuccinimide, and the ratio of compound II to the brominating reagent is between 1:1.0 and 1:1.5, preferably between 1:1.0 and 1:1.
3.
6. The preparation method according to claim 1, characterized in that, The first solvent used is either chloroform or carbon tetrachloride, and the mass-volume ratio of compound II to the added first solvent is 1:6 to 8.
7. The preparation method according to claim 1, characterized in that, The first temperature is 50-70℃, preferably 60-70℃.
8. The preparation method according to claim 1, characterized in that, The second solvent is any one of methanol, ethanol, and isopropanol, preferably methanol or ethanol.
9. The preparation method according to claim 1, characterized in that, The second temperature is 5–30°C, preferably 20–30°C.
10. The preparation method according to claim 1, characterized in that, When purifying the obtained oily substance by column chromatography, ethyl acetate-petroleum ether (ethyl acetate: petroleum ether = 1:30) was used as the eluent.