Crystallization process of famoxadone
By using a mixed lytic agent of n-hexane and benzene in the crystallization process of oxazomedone, the problem of oxazomedone clumping is solved, and the uniformity and purity of crystallization are improved.
Patent Information
- Application Number
- CN202411655350.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-19
- Publication Date
- 2025-02-25
AI Technical Summary
The crystalline products of oxazomedone are prone to agglomeration due to the large contact area between the crystals, which leads to inconvenient filtration, storage and transportation.
The crude oxazomedone product was dissolved in ethyl acetate at 45°C, cooled to 0°C, and then mixed solvating agent of n-hexane and benzene was added dropwise to perform lysis crystallization, followed by suction filtration, washing and vacuum drying to obtain uniform oxazomedone crystals.
This method effectively reduces the agglomeration rate of oxazomedone, improves the uniformity and purity of crystallization, and simplifies the subsequent processing process.
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of crystallization technology, and particularly relates to a crystallization technology of oxathiapiprolin. Background Art
[0002] Oxamethylenetetracycline is a new fungicide developed by DuPont in the United States. It is also known as Yibao. Its chemical name is 3-phenylamino-5-methyl-5-(4-phenoxyphenyl)-1,3-oxazoline-2,4-dione. Oxamethylenetetracycline is a white crystalline powder with a molecular formula of C 22 H 18 N204, relative molecular mass 374.39, melting point 140.3-141.8℃, flash point 250.9℃, solubility in 20℃ water is 52μg / L, soluble in organic solvents such as methanol, ethanol, acetone, chloroform, etc.
[0003] In the process of synthesizing oxathiapiprolin, due to the reaction yield and side reactions, unreacted raw materials such as carbonyldiimidazole and phenylhydrazine and other impurities remain in the synthesized oxathiapiprolin, and the method of rapid cooling spontaneous crystallization is generally used to separate and purify oxathiapiprolin. However, the crystalline product obtained by this method is prone to caking due to the large contact area between the crystals, which brings many inconveniences to the filtration, storage and transportation processes. Therefore, it is necessary to provide a crystallization process for oxathiapiprolin with uniform crystallization and low caking rate. Summary of the invention
[0004] The object of the present invention is to provide a crystallization process of oxathiapiprolin to solve the crystal agglomeration phenomenon caused by the large contact area between crystals in the background technology.
[0005] The purpose of the present invention can be achieved through the following technical solutions:
[0006] A crystallization process of oxathiapiprolin comprises the following steps:
[0007] The crude product of oxathiapiprolin is dissolved in a solvent at 45°C, filtered to obtain solution A; the solution A is cooled to 0°C; a solvent is added dropwise to perform dissolution and crystallization; after the addition of the solvent is completed, the solution is filtered, washed, and dried to obtain oxathiapiprolin.
[0008] Among them, the usage ratio of the crude product of oxathiapiprolin, the solvent and the dissolving agent is 5g:4mL:25mL.
[0009] Wherein, the solvent is a mixed solution of n-hexane and benzene.
[0010] Wherein, the volume ratio of n-hexane to benzene in the solvent is 1:0.2-0.5.
[0011] Wherein, the solvent is ethyl acetate.
[0012] Wherein, the washing is performed by using a solvent for 2-3 times.
[0013] Wherein, the drying is vacuum drying at 30°C.
[0014] Wherein, the crude product of oxathiapiprolin is prepared by the following method:
[0015] The intermediate 2-(4-oxyphenyl) ethyl lactate, carbonyldiimidazole and dichloromethane were mixed, reacted at room temperature for 9-12 hours, distilled water was added, and glacial acetic acid was added after stirring for 30 minutes. After stirring for 10 minutes, phenylhydrazine was added, the temperature was raised to 40°C, and the reaction was stirred for 16-24 hours. Distilled water was added, the pH was adjusted to 2, and the layers were allowed to stand. The aqueous phase was discarded, and the organic phase was filtered and evaporated to obtain a crude product of oxathiapiprolin.
[0016] Furthermore, the usage ratio of the 2-(4-oxyphenyl) ethyl lactate intermediate, carbonyldiimidazole, dichloromethane, distilled water, glacial acetic acid and phenylhydrazine is 4.4g:2g:10mL:26mL:4g:1.4g, and the mass ratio of the first addition and the second addition of distilled water is 6:20.
[0017] Furthermore, the pH is adjusted using a hydrochloric acid solution with a concentration of 0.1 mol / L.
[0018] Furthermore, the evaporation to dryness is performed by rotary evaporation using a rotary evaporator.
[0019] Furthermore, the evaporation temperature is 40° C. and the pressure is 1.325 kpa.
[0020] Furthermore, the preparation method of the 2-(4-oxyphenyl) ethyl lactate intermediate is as follows:
[0021] Ethyl pyruvate was added to dichloromethane to obtain a dichloromethane solution of ethyl pyruvate. Diphenyl ether, dichloromethane, aluminum chloride and sodium bicarbonate were mixed, stirred at 0°C, and the dichloromethane solution of ethyl pyruvate was added dropwise within 30 minutes. The mixture was stirred at 0°C for 3 hours, and the reaction solution was poured into 0°C water, extracted and separated, and the organic layer was distilled under reduced pressure for 15 minutes to remove dichloromethane to obtain 2-(4-oxyphenyl) lactic acid ethyl ester intermediate.
[0022] The dosage ratio of the diphenyl ether, dichloromethane, aluminum chloride, sodium bicarbonate and dichloromethane solution of ethyl pyruvate is 8.5 g: 20 mL: 8 g: 4.8 g: 15 mL.
[0023] The usage ratio of ethyl pyruvate to dichloromethane in the dichloromethane solution of ethyl pyruvate is 4.0 g:15 mL.
[0024] Wherein, the vacuum distillation has a temperature of 50°C and a pressure of 1 kPa.
[0025] Beneficial effects of the present invention:
[0026] 1. The present invention adds a dissolving agent composed of benzene and n-hexane, which is mutually soluble with ethyl acetate, and can adjust the polarity of the solution, so that the oxathiapiprolin dissolved in ethyl acetate is precipitated from the solution to achieve crystallization. The addition of benzene can adjust the polarity of n-hexane when the dissolving agent is added dropwise, further affecting the crystallization rate of oxathiapiprolin. Within a suitable addition amount, a part of the crystal seeds can be gradually dispersed in the solution to become crystal nuclei, and the growth of the crystal seeds and crystal nuclei can reduce the supersaturation of the system; by adjusting the crystals to grow slowly, a uniform and fully grown product is finally obtained, and agglomeration is reduced.
[0027] 2. The present invention adds a solvent composed of benzene and n-hexane. When the solvent is added to ethyl acetate, the benzene in the solvent can dissolve carbonyldiimidazole and phenylhydrazine precipitated from ethyl acetate, thereby separating the unreacted raw materials and improving the purity of oxathiapiprolin. DETAILED DESCRIPTION
[0028] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0029] Example 1
[0030] This embodiment provides a crude product of oxathiapiprolin, comprising the following preparation steps:
[0031] 4 g of ethyl pyruvate was added to 15 mL of dichloromethane to obtain a dichloromethane solution of ethyl pyruvate. 8.5 g of diphenyl ether, 20 mL of dichloromethane, 8 g of aluminum chloride, and 4.8 g of sodium bicarbonate were mixed, stirred at 0°C, and 15 mL of the dichloromethane solution of ethyl pyruvate was added dropwise within 30 min, and the mixture was stirred at 0°C for 3 h. The reaction solution was poured into 50 mL of 0°C water, and the mixture was separated by extraction. The organic layer was distilled under reduced pressure at 50°C and 1 kPa for 15 min to remove dichloromethane, and 2-(4-oxyphenyl) lactic acid ethyl ester intermediate was obtained.
[0032] 4.4 g of ethyl 2-(4-oxyphenyl) lactate intermediate, 2 g of carbonyldiimidazole and 10 mL of dichloromethane were mixed, reacted at room temperature for 9 h, distilled water was added, stirred for 30 min, 4 g of glacial acetic acid was added, stirred for 10 min, 1.4 g of phenylhydrazine was added, the temperature was raised to 40 ° C, stirred for 16 h, distilled water was added, the pH was adjusted to 2, the mixture was allowed to stand and the layers were separated, the aqueous phase was discarded, the organic phase was filtered, and the crude product of oxathiapiprolin was obtained after rotary evaporation at 40 ° C and 1.325 kpa.
[0033] Example 2
[0034] This embodiment provides a crude product of oxathiapiprolin, comprising the following preparation steps:
[0035] 8g of ethyl pyruvate was added to 30mL of dichloromethane to obtain a dichloromethane solution of ethyl pyruvate. 17g of diphenyl ether, 40mL of dichloromethane, 16g of aluminum chloride, and 9.6g of sodium bicarbonate were mixed, stirred at 0°C, and 30mL of the dichloromethane solution of ethyl pyruvate was added dropwise within 30min, and the mixture was stirred at 0°C for 3h. The reaction solution was poured into 50mL of 0°C water, and the mixture was separated by extraction. The organic layer was distilled under reduced pressure at 50°C and 1kPa for 15min to remove dichloromethane, and 2-(4-oxyphenyl) lactic acid ethyl ester intermediate was obtained.
[0036] 8.8 g of 2-(4-oxyphenyl) ethyl lactate intermediate, 4 g of carbonyldiimidazole and 20 mL of dichloromethane were mixed, reacted at room temperature for 10.5 h, distilled water was added, stirred for 30 min, 8 g of glacial acetic acid was added, stirred for 10 min, 2.8 g of phenylhydrazine was added, the temperature was raised to 40 ° C, stirred for 20 h, distilled water was added, the pH was adjusted to 2, the layers were allowed to stand, the aqueous phase was discarded, the organic phase was filtered, and the crude product of oxathiapiprolin was obtained after rotary evaporation at 40 ° C and 1.325 kpa.
[0037] Example 3
[0038] This embodiment provides a crude product of oxathiapiprolin, comprising the following preparation steps:
[0039] 12g of ethyl pyruvate was added to 45mL of dichloromethane to obtain a dichloromethane solution of ethyl pyruvate. 25.5g of diphenyl ether, 60mL of dichloromethane, 24g of aluminum chloride, and 14.4g of sodium bicarbonate were mixed, stirred at 0°C, and 45mL of dichloromethane solution of ethyl pyruvate was added dropwise within 30min, and the mixture was stirred at 0°C for 3h. The reaction solution was poured into 50mL of 0°C water, and the mixture was separated by extraction. The organic layer was distilled under reduced pressure at 50°C and 1kPa for 15min to remove dichloromethane, and 2-(4-oxyphenyl) ethyl lactate intermediate was obtained.
[0040] 13.2 g of ethyl 2-(4-oxyphenyl) lactate intermediate, 6 g of carbonyldiimidazole and 30 mL of dichloromethane were mixed, reacted at room temperature for 12 h, distilled water was added, stirred for 30 min, 12 g of glacial acetic acid was added, stirred for 10 min, 4.2 g of phenylhydrazine was added, the temperature was raised to 40 ° C, stirred and reacted for 24 h, distilled water was added, the pH was adjusted to 2, the layers were allowed to stand, the aqueous phase was discarded, the organic phase was filtered, and the crude product of oxathiapiprolin was obtained after rotary evaporation at 40 ° C and 1.325 kpa.
[0041] Example 4
[0042] This embodiment provides a kind of oxathiapiprolin, comprising the following preparation steps:
[0043] The n-hexane and benzene were mixed in a volume ratio of 1:0.2 to form a solvent.
[0044] 5 g of the crude product of oxathiapiprolin prepared in Example 1 was dissolved in 4 mL of ethyl acetate, heated to 45° C., maintained for 30 min to dissolve, and filtered to obtain solution A; solution A was cooled to 0° C., and 25 mL of a solvent was added dropwise for dissolution and crystallization. After the solvent was added dropwise within 30 minutes, the product was filtered by suction, and washed twice with the solvent; and dried in a vacuum drying oven at 30° C. for 12 h to obtain oxathiapiprolin.
[0045] Example 5
[0046] This embodiment provides a kind of oxathiapiprolin, comprising the following preparation steps:
[0047] The n-hexane and benzene were mixed in a volume ratio of 1:0.3 to form a solvent.
[0048] 10 g of the crude product of oxathiapiprolin prepared in Example 2 was dissolved in 8 mL of ethyl acetate, heated to 45° C., maintained for 30 min to dissolve, and filtered to obtain solution A; solution A was cooled to 0° C., and 50 mL of a solvent was added dropwise for dissolution and crystallization. After the solvent was added dropwise within 30 minutes, the solution was filtered by suction, and the product was washed with the solvent for 3 times; and dried in a vacuum drying oven at 30° C. for 12 h to obtain oxathiapiprolin.
[0049] Example 6
[0050] This embodiment provides a kind of oxathiapiprolin, comprising the following preparation steps:
[0051] The n-hexane and benzene were mixed in a volume ratio of 1:0.5 to form a solvent.
[0052] 20 g of the crude product of oxathiapiprolin prepared in Example 3 was dissolved in 16 mL of ethyl acetate, heated to 45°C, maintained for 30 min to dissolve, and filtered to obtain solution A; solution A was cooled to 0°C, and 100 mL of solvent was added dropwise for dissolution and crystallization. After the solvent was added dropwise within 30 minutes, the product was filtered by suction, and the product was washed twice with the solvent; and dried in a vacuum drying oven at 30°C for 12 h to obtain oxathiapiprolin.
[0053] Comparative Example 1
[0054] This embodiment provides a kind of oxathiapiprolin, comprising the following preparation steps:
[0055] Compared with Example 4, on the basis of Example 4, the solvent composed of a mixture of n-hexane and benzene in a volume ratio of 1:0.2 was replaced by a solvent containing only n-hexane, and other reagents and preparation steps were the same as those in Example 4.
[0056] Comparative Example 2
[0057] This embodiment provides a kind of oxathiapiprolin, comprising the following preparation steps:
[0058] Compared with Example 4, on the basis of Example 4, the solvent composed of a mixture of n-hexane and benzene in a volume ratio of 1:0.2 was replaced by a solvent composed of a mixture of n-hexane and tetrahydrofuran in a volume ratio of 1:0.2, and other reagents and preparation steps were the same as in Example 4.
[0059] Comparative Example 3
[0060] This embodiment provides a kind of oxathiapiprolin, comprising the following preparation steps:
[0061] Compared with Example 4, on the basis of Example 4, the solvent composed of a mixture of n-hexane and benzene in a volume ratio of 1:0.2 was replaced by a solvent composed of a mixture of n-hexane and benzene in a volume ratio of 1:0.15, and other reagents and preparation steps were the same as in Example 4.
[0062] Comparative Example 4
[0063] This embodiment provides a kind of oxathiapiprolin, comprising the following preparation steps:
[0064] Compared with Example 4, on the basis of Example 4, the solvent composed of a mixture of n-hexane and benzene in a volume ratio of 1:0.2 was replaced by a solvent composed of a mixture of n-hexane and benzene in a volume ratio of 1:0.55, and the other reagents and preparation steps were the same as those in Example 4.
[0065] Performance tests were performed on the oxathiapiprolins prepared in Examples 4 to 6 and Comparative Examples 1 to 4, wherein the caking rate was tested as follows:
[0066] Weigh 30 g of the oxathiapiprolin prepared in Examples 4-6 and Comparative Examples 1-4 respectively in a culture dish, press to the same thickness (1 cm) under the same environmental conditions, and then put it into a vacuum oven at 25° C. After 3 days, take it out and pass it through a 16-mesh sieve. The agglomeration rate is calculated using the formula: agglomeration rate % = (mass of crystals that have not passed / total mass) * 100%;
[0067] The purity of the oxathiapiprolin prepared in Examples 4-6 and Comparative Examples 1-4 was determined by high performance liquid chromatography, with a chromatographic column of C18 (150 mm×4.6 mm, 5 μm), a mobile phase of acetonitrile-water (20:80), and a flow rate of 1.0 ml / min. -1 , detection wavelength is 231nm, column temperature is room temperature, injection volume is 20μL. Take an appropriate amount of the sample to be tested, dissolve it completely with the mobile phase, prepare a test solution with a concentration of about 0.1mg / mL, take 20μL of the test solution, inject it into the chromatograph, record the chromatogram, and calculate the product purity by area normalization method.
[0068] According to the amount of ethyl pyruvate added, the theoretical yield of oxathiapiprolin was calculated at a ratio of n (ethyl pyruvate): n (oxathiapiprolin) = 1:1, and the actual yield of oxathiapiprolin obtained / theoretical yield of oxathiapiprolin was used to obtain the yield. The results are shown in Table 1:
[0069] Table 1
[0070] project Example 4 Example 5 Example 6 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Agglomeration rate (%) 1.34 1.31 1.28 3.75 1.33 1.73 1.33 purity(%) 99.1 99.2 99.4 97.9 98.1 98.3 99.4 Yield (%) 76.8 77.0 77.2 76.6 76.9 76.8 72.9
[0071] It can be seen from Table 1 that the agglomeration rates of Examples 4-6 are all lower than 1.34%, the purities are all greater than 99.1%, and the yields are all greater than 76.8%.
[0072] From the comparative example 1, it can be seen that when the solvent does not contain benzene, the agglomeration rate and purity of oxathiapiprolin are greatly reduced. This is because the benzene loses the effect of regulating the polarity of the solution and dissolving the impurities in the solute; from the comparative example 2, it can be seen that when the benzene in the solvent is replaced with tetrahydrofuran, it can be seen that the agglomeration rate of oxathiapiprolin is not greatly affected, but the purity is reduced. This is because the solubility of tetrahydrofuran in carbonyldiimidazole in the solute is too low; and from the comparative examples 3-4, it can be seen that when the n-hexane and benzene in the solvent are replaced with tetrahydrofuran, the agglomeration rate of oxathiapiprolin is greatly affected. When the volume ratio of n-hexane to benzene in the solvent is greater than 1:0.2, the agglomeration rate and yield of oxathiapiprolin will decrease. This is because the content of benzene in the solvent is too little, and the impurities in the solute cannot be completely dissolved and the polarity of the solvent cannot be adjusted. When the volume ratio of n-hexane to benzene in the solvent is less than 1:0.5, the agglomeration rate and purity of oxathiapiprolin are no different from those in the embodiment, but the yield of oxathiapiprolin will decrease significantly because benzene has a slight solubility in oxathiapiprolin. Once the proportion is too high, the yield of oxathiapiprolin will decrease.
[0073] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.
[0074] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.
Claims
1. A crystallization process for oxathiapiprolin, characterized in that: The steps include: The crude product of oxathiapiprolin is dissolved in a solvent at 45°C, filtered to obtain a solution A; the solution A is cooled to 0°C; a solvent is added dropwise to perform dissolution and crystallization; after the solvent is added dropwise, the solution is filtered, washed, and dried to obtain oxathiapiprolin; Wherein, the solvent is a mixed solution of n-hexane and benzene.
2. A crystallization process for oxathiapiprolin according to claim 1, characterized in that: The volume ratio of n-hexane to benzene in the solvent is 1:0.2-0.
5.
3. A crystallization process for oxathiapiprolin according to claim 1, characterized in that: The usage ratio of the crude product of oxathiapiprolin, the solvent and the dissolving agent is 5g:4mL:25mL.
4. A crystallization process for oxathiapiprolin according to claim 1, characterized in that: The solvent is ethyl acetate.
5. A crystallization process for oxathiapiprolin according to claim 1, characterized in that: The washing is performed by using a solvent for 2-3 times.
6. A crystallization process for oxathiapiprolin according to claim 1, characterized in that: The drying is vacuum drying at 30°C.