Synthesis method of pyriproxyfen key intermediate 1-(4-phenoxy phenoxy)-2-propanol
By optimizing reaction conditions and catalyst selection, the problem of high isomer ratio in the synthesis of pyriproxypropane was solved, and the synthesis of 1-(4-phenoxyphenoxy)-2-propanol with high yield and high purity was achieved, reducing production costs and improving safety.
Patent Information
- Application Number
- CN202511284031.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-09
- Publication Date
- 2025-11-07
AI Technical Summary
In the existing pyriproxypropyl ether synthesis process, the proportion of isomer byproducts of the key intermediate 1-(4-phenoxyphenoxy)-2-propanol is high, which leads to a decrease in intermediate yield and purity, increases production costs and operational complexity, and poses safety hazards.
In a specific catalyst and solvent system, the reaction conditions were optimized by controlling the reaction temperature, time, and the rate of propylene oxide addition, thereby achieving highly selective synthesis of PPP isomers. Magnesium-based catalysts such as magnesium oxide, magnesium hydroxide, and magnesium carbonate were used, the reaction temperature was controlled at 40-80℃, the reaction time at 12-36 hours, propylene oxide was added dropwise over 30 minutes, and toluene was used as the solvent.
The isomer ratio is reduced from 10% to 1-2%, the yield is increased to over 70%, the purity is increased to 98-99%, the production process is simplified, costs are reduced and safety is improved.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of organic synthesis and pesticide intermediate preparation, and particularly relates to a synthesis method of a key intermediate 1-(4-phenoxyphenoxy)-2-propanol of pyriproxyfen. BACKGROUND
[0002] Pyriproxyfen, as a highly effective insect growth regulator, has a huge market demand, with an annual output of thousands of tons, showing its important position and broad application prospect in the market. This compound can effectively block the normal physiological functions of insects by precisely interfering with their growth and development process, thereby exerting a significant insecticidal effect. Pyriproxyfen not only has the characteristics of high efficiency, but also has the advantages of low toxicity and environmental friendliness, making it popular in various application scenarios. In the agricultural field, pyriproxyfen is widely used to control various pests and protect crops from healthy growth; in the field of health and epidemic prevention, it also plays an important role in effectively controlling the reproduction and spread of disease vector insects and ensuring public health safety. Therefore, pyriproxyfen has indispensable application value in multiple fields.
[0003] Agricultural field: This technology or product performs well in the field of agricultural pest control, and can effectively control and eliminate a variety of common agricultural pests, including but not limited to whitefly, aphid, scale insect, mosquito, fly and diamondback moth, etc. These pests often cause serious damage to crops, affecting yield and quality. This technology or product has a wide range of applications and is suitable for a variety of different crops, such as various vegetables, various fruit trees, cotton and rice, etc. Whether it is leafy vegetables or root vegetables, whether it is deciduous fruit trees or evergreen fruit trees, whether it is a fiber crop such as cotton or a food crop such as rice, the use of this technology or product can achieve good pest control effect, thereby ensuring the healthy growth and final yield of crops.
[0004] In the field of health and epidemic prevention, the application of WPSAI is particularly important. It is widely used to control mosquitoes, flies, cockroaches and other common health pests. These pests not only affect people's quality of life, but also can spread diseases, so it is crucial to control their reproduction. WPSAI can accurately identify and handle the breeding sites of pests, such as sewage pits, garbage dumps and other environments, through intelligent analysis and data processing. By scientifically and effectively treating these breeding sites, WPSAI can effectively block the reproduction chain of pests, thereby significantly reducing the number of pests and ensuring public health safety. In addition, WPSAI can also provide control strategies and suggestions to help relevant departments develop more scientific and efficient prevention and control measures, further improving the overall effect of health and epidemic prevention work.
[0005] Pyriproxyfen has a production of thousands of tons per year based on the above uses, and there are reports that 4-phenoxyphenol (abbreviation: POP) is used as a raw material to add isopropyl alcohol to generate products from acetone and propylene oxide, which are abbreviated as PPP. However, in the current synthesis process, the synthesis of the key intermediate 1-(4-phenoxyphenoxy)-2-propanol has a large isomer produced in the chemical reaction mechanism, and there is a problem of a high proportion of isomer by-products, which leads to a decrease in the yield and purity of the intermediate, resulting in a large waste of raw materials for the next step of producing pyriproxyfen and a large waste of product purification, and increasing the cost of subsequent synthesis of pyriproxyfen. The existing acetone route needs to add acetone at a high temperature of 100-150℃, which is complex to operate and has safety hazards; while the propylene oxide route is mild in conditions, but the proportion of isomers is as high as 10% without catalyst, which is still not conducive to industrial production.
[0006] Therefore, how to accurately control the reaction conditions to achieve high selectivity synthesis of PPP isomers, while effectively reducing the proportion of by-products, and simplifying the entire production process, has become a core technical problem that researchers in the field urgently need to solve. The solution to this problem not only relates to the improvement of product quality, but also significantly improves production efficiency and reduces cost, which has important significance for promoting the development of related industries. SUMMARY
[0007] The purpose of the present application is to provide a synthesis method of pyriproxyfen key intermediate 1-(4-phenoxyphenoxy)-2-propanol to solve the problems raised in the above background art.
[0008] To achieve the above purpose, the present application provides the following technical solutions:
[0009] The synthesis method of pyriproxyfen key intermediate 1-(4-phenoxyphenoxy)-2-propanol realizes high selectivity synthesis of PPP by controlling reaction temperature and reaction time and other parameters in a specific catalyst and solvent system, and the specific steps are as follows:
[0010] Comprising the following steps:
[0011] S1: using 4-fluorophenyl fluoride (POP) as a raw material to react in a reaction solution, wherein the reaction system further comprises a catalyst;
[0012] S2: controlling the reaction temperature to be 100-150℃, the reaction time to be 12-36 hours, and the reaction temperature to be 40-80 degrees to effectively control the PPP isomer;
[0013] Preferably, the catalyst is a magnesium-based catalyst, and the base is a reactant.
[0014] Preferably, the magnesium-based catalyst includes magnesium oxide, magnesium hydroxide, and magnesium carbonate.
[0015] Preferably, the base is sodium hydroxide, and the equivalent amount is 0.3-0.6 equivalents.
[0016] Preferably, step S2 further comprises the following operation: cooling the system to 0-5℃ before the reaction, and slowly adding propylene oxide drop by drop, with a drop time of 30 minutes, to inhibit side reactions.
[0017] Preferably, the equivalent amount of propylene oxide is 2-5 equivalents.
[0018] Preferably, the reaction solution in step S1 comprises one or more of DMF, toluene, xylene or acetonitrile.
[0019] Preferably, the reaction solution is preferably a toluene solution, and the amount of toluene solution is 2-5 times, preferably 3 times, the equivalent amount of POP.
[0020] Preferably, the purity of the target product in step S2 is ≥98% (determined by HPLC), the proportion of by-products is ≤1%, and the product can be stored stably under light-proof and dry conditions for ≥6 months.
[0021] Compared with the prior art, the present application has the following beneficial effects:
[0022] The proportion of isomers is significantly reduced, from about 10% to only 1-2%, which significantly improves the product quality. At the same time, the yield of PPP is also greatly improved, from about 50% to more than 70%, greatly improving the production efficiency. More importantly, the purity of PPP is also significantly improved, from 91-93% to as high as 98-99%, ensuring the quality of the product. In addition, the process conditions are relatively mild, not only the energy consumption is low, but also the safety in the production process is effectively guaranteed. More importantly, the product produced can directly enter the synthesis link of piperonyl ether, without the need for expensive separation and purification process, thereby greatly reducing the production cost and improving the overall economic benefit. DETAILED DESCRIPTION
[0023] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.
[0024] The content of the present application is as follows:
[0025] Embodiment 1
[0026] Preparation of 1-(4-phenoxyphenoxy)-2-propanol (abbreviation: PPP): 180 grams of toluene was added into a 500ml autoclave, 60 grams of POP was added and dispersed by stirring, 13 grams of sodium hydroxide solid was added, 1.5 grams of catalyst A was added, 56.2 grams of propylene oxide was added at 0-5 degrees, the reaction device was sealed, heated to 70 degrees and reacted for 15 hours, the remaining raw material was detected by central control to be less than 3%, the reaction was cooled to room temperature, 50 grams of water was added for washing, and the organic phase was dried and crystallized to obtain solid product, with a yield of 76%. HPLC detection showed a purity of 99.2%.
[0027] Example 2 (comparative group)
[0028] The same conditions were used without adding a catalyst, with a yield of 52%, an isomer ratio of 9.9%, and a purity of 91%.
[0029] Example 3
[0030] The same conditions were used with magnesium hydroxide as the catalyst, with a yield of 53%, an isomer ratio of 9.9%, and a purity of 91%.
[0031] Example 4
[0032] Magnesium carbonate was used as the catalyst, with a yield of 54%, an isomer ratio of 8.9%, and a purity of 92%.
[0033] The specific reaction data list is as follows:
[0034]
[0035]
[0036] PPP synthesis path:
[0037]
[0038] There are relevant literature reports that 4-phenoxyphenol (hereinafter referred to as POP) is used as the basic raw material, and isopropyl alcohol is introduced into it through a specific chemical reaction path, and the source of isopropyl alcohol can be traced back to acetone and propylene oxide, and the final target product is simply called PPP. In the existing patent literature, the specific process of acetone participating in the reaction has been reported, but it is worth noting that this reaction process needs to be carried out at a relatively high temperature range, i.e. between 100 and 150 degrees Celsius, and needs to be slowly added dropwise. The reaction under such high temperature conditions not only has a particularly slow conversion rate, but also makes it extremely difficult to accurately control the amount of acetone, which undoubtedly increases the complexity and uncertainty of the operation in actual production. More importantly, such a high reaction temperature raises extremely strict requirements for the safety of the production process, and any slight negligence may cause a safety accident.
[0039] In view of this, the inventors decided to take a different approach and focus their research on propylene oxide as the raw material. Through extensive experimental exploration and data analysis, it was found that without adding any catalyst, the isomer ratio generated by the reaction remained around 10%; however, once a suitable catalyst was introduced, the isomer ratio could be significantly reduced to around 2%, which was of crucial importance for improving product purity and yield. Specifically, under the optimized reaction conditions, the yield after purification could be stabilized at more than 75%, and the purity of the product could reach more than 99%, fully meeting the requirements of high-quality products.
[0040] In terms of reaction condition optimization, the inventors also conducted systematic and in-depth research. First, the reaction temperature was controlled between 40 and 80 degrees Celsius. After multiple experimental comparisons, it was found that 50 degrees Celsius was the optimal reaction temperature, which could ensure the best balance between reaction rate and product quality. Second, the amount of catalyst was strictly controlled within the range of 0.1 to 0.5 equivalents, with 0.15 equivalents being confirmed as the optimal choice. In addition, the length of reaction time also directly affected the quality and yield of the final product. After repeated testing, 12 to 36 hours was determined as the appropriate reaction time range, and 15 hours was the optimal reaction time. In terms of base selection, sodium hydroxide was adopted due to its good reaction performance, and its amount was controlled between 0.5 and 1.5 equivalents, with 1.0 equivalent being proven to be the best amount. As for the equivalent of propylene oxide, it was set within the range of 1 to 5 equivalents, with 3 equivalents being able to maximize the promotion of the reaction.
[0041] In terms of reaction solvent selection, the inventors compared and screened several feasible solvent options, including DMF, toluene, xylene, and acetonitrile, etc. Considering factors such as solvent solubility, reaction stability, and subsequent processing convenience, toluene was selected as the main reaction solvent, with its amount ratio controlled between 1 and 5 times the mass ratio, and 3 times the mass ratio being confirmed as the optimal ratio, which could provide an ideal solvent environment for the reaction, thereby ensuring efficient reaction and high-quality product output.
[0042] Formula 1
[0043]
[0044] Reaction mechanism: formula 1 reaction formula, POP under the action of base to produce oxygen anion, attack 2-methyl oxirane (propylene oxide) ring on the carbon atom to open ring to get product, because the carbon atom steric hindrance of 3 position is smaller, preferentially or mostly reaction occurs in 3 position, but 2 position will also react, produce isomer, under general conditions, the proportion is relatively fixed about 10%, however, magnesium ion on oxygen atom due to complexation further increases the steric hindrance of 2 position, so that the reaction is more conducive to occur in 3 carbon atom; Through the above experimental data can prove that, catalyst magnesium oxide greatly reduces the isomer ratio, from 10% to 2%.
[0045] The product PPP is a key intermediate for synthesizing pesticide pyriproxyfen, and its reaction formula is as formula two:
[0046] Formula two
[0047]
[0048] If the isomer ratio cannot be well controlled, according to the data shown in table one, not only will the yield of intermediate product PPP be significantly reduced, but also its purity will be reduced, thereby greatly increasing the production cost. More seriously, the intermediate with low purity, as shown in formula two, when it is docked with 2-chloropyridine to generate pyriproxyfen, the isomer impurities will inevitably be transferred to the final pesticide product, resulting in the pesticide containing high isomer impurities, which not only seriously affects the purity of the pesticide, but also has a very adverse effect on its production cost. On the contrary, if the intermediate product PPP with a purity of 99% is used for subsequent production, and each process link is strictly controlled, the pyriproxyfen product meeting the quality standard can be directly obtained. Through the comparison of the two cases, the economic benefits are obvious, and there is no need to say more.
[0049] NMR data are as follows:
[0050] HNMR (DMSO) δ 1.1-1.25 (dd, 3H), 3.7-3.8 (m, 2H), 3.8-4.0 (m, 1H), 4.75-4.9 (s, 1H), 6.8-7.1 (m, 6H), 3.7-3.8 (m, 2H), 7.1-7.2 (t, 1H), 7.3-7.4 (t, 2H), MS: M+1 = 245.
[0051] It will be obvious to a person skilled in the art that the application is not limited to the details of the above-described exemplary embodiments, but that the application can be implemented in other embodiments without departing from the scope of the application. The embodiments are therefore to be seen as exemplary and in no way restrictive, the scope of the application being defined by the claims below rather than by the above description, and all variations falling within the meaning and range of equivalency of the essential characteristics of the claims are therefore intended to be embraced therein.
[0052] Furthermore, it should be understood that although the description is made according to embodiments, not every embodiment contains only one independent technical solution, and the description is made in this way only for the sake of clarity, and a person skilled in the art should consider the description as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by a person skilled in the art.
Claims
1. A process for the synthesis of a piprofylline key intermediate, 1-(4-phenoxyphenoxy)-2-propanol, characterized by, The method comprises the following steps: S1: reacting in a reaction solution with 4-fluorophenyl fluoride (POP) as a raw material, wherein the reaction system further comprises a catalyst; S2: controlling the reaction temperature to be 100-150 DEG C, the reaction time to be 12-36 hours, and the reaction temperature to be 40-80 DEG C, so as to effectively control the PPP isomer.
2. The process for synthesis of piproxan key intermediate 1-(4-phenoxyphenoxy)-2-propanol as claimed in claim 1, wherein, The catalyst is a magnesium-based catalyst.
3. The process for synthesis of pifithrin key intermediate 1-(4-phenoxyphenoxy)-2-propanol as claimed in claim 2, wherein, The magnesium-based catalyst comprises magnesium oxide, magnesium hydroxide and magnesium carbonate.
4. The method for synthesizing the key intermediate 1-(4-phenoxyphenoxy)-2-propanol according to claim 2, characterized in that, The base is sodium hydroxide, and the equivalent is 0.3-0.6 equivalents.
5. The process for synthesis of pifithrin key intermediate 1-(4-phenoxyphenoxy)-2- propanol as claimed in claim 1, wherein, The step S2 further comprises the following operation: before the reaction, the system is cooled to 0-5 DEG C, and propylene oxide is slowly added dropwise, and the dropwise adding time is 30 minutes, so as to inhibit the side reaction.
6. The process for synthesis of pifithrin key intermediate 1-(4-phenoxyphenoxy)-2-propanol as claimed in claim 5, wherein, The equivalent of propylene oxide is 2-5 equivalents.
7. The process for synthesis of pifithrin key intermediate 1-(4-phenoxyphenoxy)-2- propanol as claimed in claim 1, wherein, The reaction solution in step S1 comprises one or more of DMF, toluene, xylene or acetonitrile.
8. The process for synthesis of pifithrin key intermediate 1-(4-phenoxyphenoxy)-2- propanol as claimed in claim 6 wherein, The reaction solution is preferably a toluene solution, and the amount of the toluene solution is 2-5 times, preferably 3 times, the equivalent of POP. 9. The process for synthesis of pifithrin key intermediate 1-(4-phenoxyphenoxy)-2- propanol as claimed in claim 1, wherein, In step S2, the purity of the target product is ≥98% (determined by HPLC), the proportion of by-products is ≤1%, and the product can be stably stored for ≥6 months under light-proof and dry conditions.