Preparation method of 4-(3, 3-dichloroallyloxy) phenol

Abstract

The invention provides a preparation method of 4-(3, 3-dichloroallyloxy) phenol, which comprises the following steps: 1) under an alkaline condition, dropwise adding 1, 1, 3-trichloropropene into a first system containing p-nitrophenol, and carrying out etherification reaction to obtain 1-(3, 3-dichloroallyloxy)-4-nitrobenzene; (2) carrying out reduction reaction on the 1-(3, 3-dichloro allyloxy)-4-nitrobenzene, so as to obtain 4-(3, 3-dichloro allyloxy) aniline; (3) carrying out diazotization reaction on the 4-(3, 3-dichloro allyloxy) aniline to obtain 4-(3, 3-dichloro allyloxy) benzene diazonium salt; 4, the 4-(3, 3-dichloro allyloxy) benzene diazonium salt is subjected to a hydrolysis reaction, and the 4-(3, 3-dichloro allyloxy) phenol is obtained.The preparation method of the 4-(3, 3-dichloro allyloxy) phenol is high in reaction selectivity and easy to operate, a solvent is environmentally friendly, and the production cost can be reduced.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and particularly relates to a method for preparing 4-(3,3-dichloroallyloxy)phenol. Background Technology

[0002] Lepidoptera and Thysanoptera pests are major threats to agricultural production, posing a persistent challenge to global food security and cash crop production. For a long time, pest control has relied primarily on various chemical pesticides. However, the increasing resistance of pests to pesticides and the environmental and non-target organism impacts of many traditional pesticides have made the development of novel, highly effective, safe pesticides with unique mechanisms of action an urgent priority.

[0003] Trifluralin exhibits superior efficacy against various resistant lepidopteran pests (such as the tobacco shoot borer, diamondback moth, cotton bollworm, armyworm, and cabbage looper) and tsioptera (such as thrips), generally outperforming commercially available conventional pesticides. It provides a powerful tool for addressing the challenge of controlling resistant pests. 4-(3,3-dichloroallyloxy)phenol is the most crucial intermediate in the synthesis of this insecticide. The chemical structure of this intermediate forms the basis for the trifluralin molecular skeleton, requiring a series of subsequent reactions such as chlorination and etherification to obtain the final target product.

[0004] However, existing methods for preparing 4-(3,3-dichloroallyloxy)phenol generally suffer from low selectivity of raw material reactions, complex operation, and high production costs. Summary of the Invention

[0005] The main objective of this invention is to provide a method for preparing 4-(3,3-dichloroallyloxy)phenol, which has high selectivity of raw material reaction, is simple to operate, has low production cost, and uses environmentally friendly and safe solvents.

[0006] This invention provides a method for preparing 4-(3,3-dichloroallyloxy)phenol, comprising the following steps:

[0007] 1) Under alkaline conditions, 1,1,3-trichloropropene is added dropwise to a first system including p-nitrophenol, resulting in an etherification reaction to give 1-(3,3-dichloroallyloxy)-4-nitrobenzene;

[0008] 2) The 1-(3,3-dichloroallyloxy)-4-nitrobenzene is reduced to give 4-(3,3-dichloroallyloxy)aniline;

[0009] 3) The 4-(3,3-dichloroallyloxy)aniline is subjected to a diazotization reaction to obtain 4-(3,3-dichloroallyloxy)benzene diazonium salt;

[0010] 4) Hydrolyze the 4-(3,3-dichloroallyloxy)benzene diazonium salt to obtain the 4-(3,3-dichloroallyloxy)phenol.

[0011] In the preparation method described above, the etherification reaction is carried out at a temperature of 30-60°C for 8-24 hours.

[0012] And / or, the molar ratio of 1,1,3-trichloropropene to p-nitrophenol is (1.0~1.2):1;

[0013] And / or, the dropping rate of the 1,1,3-trichloropropene is 5~10 g / min.

[0014] The preparation method described above further includes a first solvent, which comprises at least one of N,N-dimethylformamide, methanol, acetonitrile, and dioxane.

[0015] And / or, the alkaline reagent used in the alkaline conditions includes at least one of potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, and triethylamine.

[0016] The preparation method described above, wherein the reduction reaction of 1-(3,3-dichloroallyloxy)-4-nitrobenzene comprises: adding a reducing agent dropwise to a second system comprising 1-(3,3-dichloroallyloxy)-4-nitrobenzene and a catalyst, thereby causing the reduction reaction to obtain 4-(3,3-dichloroallyloxy)aniline.

[0017] The preparation method described above further includes a second solvent, which includes at least one of methanol, ethanol, water, and acetonitrile.

[0018] And / or, the catalyst comprises at least one of Raney nickel, platinum, palladium, ferrous chloride, and ferric chloride;

[0019] And / or, the reducing agent includes at least one of hydrazine hydrate, ammonium acetate, iron powder, and Raney nickel (hydrogen);

[0020] And / or, the dropping rate of the reducing agent is 1~10 g / min;

[0021] And / or, the reduction reaction is carried out at a temperature of 40~60℃ for a time of 1~16h.

[0022] The preparation method described above, wherein the diazotization reaction of the 4-(3,3-dichloroallyloxy)aniline comprises: adding sodium nitrite solution dropwise to a third system comprising the 4-(3,3-dichloroallyloxy)aniline and a strong acid, thereby conducting the diazotization reaction to obtain the 4-(3,3-dichloroallyloxy)benzene diazonium salt.

[0023] In the preparation method described above, the third system further includes a third solvent, which includes at least one of water, methanol, ethyl acetate, and dichloromethane;

[0024] And / or, the diazotization reaction is carried out at a temperature of -10 to 10°C for a time of 1 to 16 hours;

[0025] And / or, the strong acid includes concentrated sulfuric acid and / or concentrated hydrochloric acid;

[0026] And / or, the dropping rate of the sodium nitrite solution is 1~10 g / min.

[0027] The preparation method described above, wherein the hydrolysis reaction of the 4-(3,3-dichloroallyloxy)benzene diazonium salt comprises: adding an inorganic acid to the 4-(3,3-dichloroallyloxy)benzene diazonium salt, and subjecting the hydrolysis reaction to obtain the 4-(3,3-dichloroallyloxy)phenol.

[0028] In the preparation method described above, the hydrolysis reaction is carried out at a temperature of 80-120°C for 1-16 hours.

[0029] And / or, the inorganic acid includes dilute sulfuric acid and / or dilute hydrochloric acid.

[0030] The preparation method described above, after the hydrolysis reaction is completed, further includes: adding a fourth solvent to the hydrolysis reaction system, extraction, separation, and obtaining the 4-(3,3-dichloroallyloxy)phenol;

[0031] The fourth solvent includes at least one of toluene, n-heptane, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0032] The method for preparing 4-(3,3-dichloroallyloxy)phenol provided by this invention uses p-nitrophenol as a raw material, exhibits high reaction selectivity, requires a small amount of raw material, and utilizes inexpensive and readily available p-nitrophenol, thereby reducing production costs. Furthermore, this preparation method eliminates the need for group protection, is simple to operate, and uses relatively safe and environmentally friendly solvents. Attached Figure Description

[0033] To more clearly illustrate the technical solutions in the embodiments of the present invention or related technologies, the accompanying drawings used in the description of the embodiments of the present invention or related technologies are briefly introduced below. Obviously, the drawings described below are merely some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0034] Figure 1The 1H NMR spectrum of 4-(3,3-dichloroallyloxy)phenol prepared in Example 1 of this invention (solvent CDCl3).

[0035] Figure 2 LC-MS spectrum of 4-(3,3-dichloroallyloxy)phenol prepared in Example 1 of this invention. Detailed Implementation

[0036] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions in the embodiments of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Obviously, the described embodiments are only some embodiments of this invention, not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0037] In agricultural production, pest control is a crucial link in ensuring crop yield and quality. For a long time, pesticides have played an irreplaceable role in agriculture as an important means of pest control. However, with the widespread and continuous use of pesticides, the problem of pesticide resistance has become increasingly prominent, and the effectiveness of many traditional pesticides has gradually decreased or even become ineffective, posing a significant challenge to agricultural production. At the same time, increasing public concern about environmental protection and agricultural product safety has placed higher demands on the safety of pesticides, making the development of new, highly effective, low-toxicity pesticides with unique mechanisms of action an urgent need in agricultural research.

[0038] Against this backdrop, Sumitomo Chemical Industries, Ltd. of Japan successfully developed trifluralin, a dichloropropylene ether insecticide, in 1997. Trifluralin possesses several significant advantages: it lacks optical isomers and cis-trans isomers; its structure, while novel, is not complex, containing only one trifluoromethylpyridine group. More importantly, although its biochemical mechanism of action is still under investigation, it has clearly demonstrated a mechanism of action different from existing insecticides. In practical applications, this compound has shown good control effects against pests such as the tobacco leafminer moth and diamondback moth. After application, the pests rapidly lose their mobility and generally die within 2-3 hours, a symptom distinct from other insecticides. At treatment doses of 80-300 g / hm²... 2 At the same time, its control efficacy against various lepidopteran and tsioptera pests, such as cotton bollworm, armyworm, cabbage looper, cabbage looper, and thrips, is superior to other commercially available pesticides, fully demonstrating its unique mechanism of action and significant application value.

[0039] 4-(3,3-Dichloroallyloxy)phenol is a key intermediate in the synthesis of the insecticide trifluralin, and its synthesis process is crucial. This intermediate requires a series of operations, including chlorination and etherification, to prepare trifluralin. Therefore, the level of research on the synthesis of this intermediate directly restricts the development and widespread application of trifluralin. In existing technologies, hydroquinone is mostly used as a raw material to prepare 4-(3,3-dichloroallyloxy)phenol, but this method suffers from low selectivity of the raw material reaction, complex operation, and high production costs.

[0040] The inventors of this application have discovered through research that using p-nitrophenol as a raw material to prepare 4-(3,3-dichloroallyloxy)phenol can improve the selectivity of raw materials, simplify the operation, and reduce production costs.

[0041] Based on this, the present invention provides a method for preparing 4-(3,3-dichloroallyloxy)phenol, comprising the following steps:

[0042] 1) Under alkaline conditions, 1,1,3-trichloropropene is added dropwise to a first system including p-nitrophenol, resulting in an etherification reaction to give 1-(3,3-dichloroallyloxy)-4-nitrobenzene;

[0043] 2) Reduce 1-(3,3-dichloroallyloxy)-4-nitrobenzene to give 4-(3,3-dichloroallyloxy)aniline;

[0044] 3) Diazotization of 4-(3,3-dichloroallyloxy)aniline yields 4-(3,3-dichloroallyloxy)benzene diazonium salt;

[0045] 4) Hydrolyze 4-(3,3-dichloroallyloxy)benzene diazonium salt to obtain 4-(3,3-dichloroallyloxy)phenol.

[0046] In step 1), the etherification reaction is essentially an SN2 nucleophilic substitution reaction, i.e., a bimolecular nucleophilic substitution reaction. p-Nitrophenol is deprotonated under alkaline conditions to generate a highly reactive nucleophile, namely the p-nitrobenzene anion. The nitro group on the benzene ring is a strong electron-withdrawing group, which, through conjugation and inductive effects, greatly stabilizes the phenoxide anion, making it more nucleophilic and easier to generate. The oxygen atom in the p-nitrobenzene anion is rich in electrons and, as a nucleophile, attacks the terminal carbon atom of 1,1,3-trichloropropene (an electrophile) molecule, which has less steric hindrance and stronger electron positive charge. The lone pair of electrons from the oxygen atom attacks the carbon atom, and simultaneously the carbon-chlorine bond breaks. The chlorine atom leaves as a chloride ion with a pair of electrons, yielding 1-(3,3-dichloroallyloxy)-4-nitrobenzene. The generated chloride ion reacts with ions in the solution (e.g., Na+). + K + They combine to form salt, which is a byproduct.

[0047] Specifically, p-nitrophenol can be added to a reaction flask and heated to a certain temperature. Then, alkali is added to the reaction flask to create an alkaline environment in the first system, and the mixture is kept at this temperature for 1-2 hours. Next, 1,1,3-trichloropropene is added dropwise to the system. After the addition is complete, an etherification reaction occurs. After the reaction is complete, the mixture is filtered while hot. A certain amount of water is added to the filtrate, and a large amount of solid precipitates out. Filtering this solution yields 1-(3,3-dichloroallyloxy)-4-nitrobenzene.

[0048] In step 2), 1-(3,3-dichloroallyloxy)-4-4-nitrobenzene undergoes a reduction reaction, reducing the nitro group on the benzene ring to an amino group, to obtain 4-(3,3-dichloroallyloxy)aniline.

[0049] In step 3), the amino group in 4-(3,3-dichloroallyloxy)aniline is activated by 3,3-dichloroallyloxy, which is a strong electron-donating group, making the benzene ring electron-rich and easy to diazotize, ultimately yielding 4-(3,3-dichloroallyloxy)benzene diazonium salt.

[0050] In step 4), 4-(3,3-dichloroallyloxy)benzenediazonium salt is generally used under acidic conditions, -N2 + The group is replaced by a hydroxyl group, and a hydrolysis reaction occurs to produce the final product 4-(3,3-dichloroallyloxy)phenol.

[0051] The above reaction process is illustrated below:

[0052]

[0053] In summary, the method for preparing 4-(3,3-dichloroallyloxy)phenol provided by this invention uses p-nitrophenol as a raw material, which has only one active site, thus avoiding the presence of dietherified components. This method exhibits high reaction selectivity, requires a small amount of raw material, and utilizes inexpensive and readily available p-nitrophenol, thereby reducing production costs. Furthermore, this preparation method does not require protection of the functional group, is simple to operate, and uses relatively safe and environmentally friendly solvents.

[0054] In some embodiments of the present invention, the temperature of the etherification reaction is 30~60°C, for example, it can be a range of 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C or any two of these; the time is 8~24h, for example, it can be a range of 8h, 12h, 16h, 20h, 22h, 24h or any two of these.

[0055] When the temperature of the etherification reaction is within the above range, the reactant molecules can obtain enough energy to collide effectively, promoting the etherification reaction, while avoiding the occurrence of side reactions due to excessively high temperatures.

[0056] The etherification reaction time is within the above range, allowing sufficient time for reactant molecules to collide and react with each other. Increasing the conversion rate of reactants allows more raw materials to be converted into the target product, thereby increasing the yield.

[0057] In some embodiments, the molar ratio of 1,1,3-trichloropropene to p-nitrophenol is (1.0~1.2):1, for example, it can be a range of 1.0:1, 1.05:1, 1.1:1, 1.15:1, 1.2:1 or any two of these.

[0058] Maintaining a molar ratio of 1,1,3-trichloropropene to p-nitrophenol within the aforementioned range ensures sufficient reaction of the reactants, avoids excess or deficiency of any one raw material, and optimizes raw material utilization. Furthermore, it allows the reaction to proceed more smoothly towards the formation of the target product, reduces side reactions, and improves product yield and purity.

[0059] In some embodiments, the dropping rate of 1,1,3-trichloropropene is 5 to 10 g / min, for example, it can be a range of 5 g / min, 6 g / min, 7 g / min, 8 g / min, 9 g / min, 10 g / min or any combination thereof.

[0060] By controlling the dropping rate of 1,1,3-trichloropropene within the aforementioned range, the rate at which 1,1,3-trichloropropene enters the reaction system can be controlled, thereby controlling the overall reaction rate. This avoids excessively rapid dropping, which could lead to a sudden increase in reactant concentration and a rapid reaction rate, potentially causing localized overheating and increasing the likelihood of side reactions. It also ensures a relatively uniform distribution of reactants within the reaction system, improving reaction repeatability and product quality stability.

[0061] In some embodiments of the present invention, the first system further includes a first solvent, which includes at least one of N,N-dimethylformamide, methanol, acetonitrile, and dioxane.

[0062] The first solvent has good solubility for both the raw materials and reactants during the reaction process, allowing the reactants to be uniformly dispersed in the solution. This increases the chances of molecular collisions, enabling the etherification reaction to proceed more fully and rapidly, thus improving reaction efficiency. Furthermore, this solvent does not react with the product; after the reaction, the solvent and product can be separated using a simple method, which is beneficial for product separation and purification.

[0063] In some embodiments, the alkaline reagent used under alkaline conditions includes at least one of potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, and triethylamine.

[0064] The aforementioned alkaline reagent can effectively maintain a suitable alkaline environment, which is conducive to the formation of p-nitrophenol anions, enhances its nucleophilicity, promotes the reaction with 1,1,3-trichloropropene, and improves the reaction conversion rate and selectivity.

[0065] In some embodiments of the present invention, the reduction reaction of 1-(3,3-dichloroallyloxy)-4-nitrobenzene includes: adding a reducing agent dropwise to a second system comprising 1-(3,3-dichloroallyloxy)-4-nitrobenzene and a catalyst to induce a reduction reaction and obtain 4-(3,3-dichloroallyloxy)aniline.

[0066] Specifically, 1-(3,3-dichloroallyloxy)-4-nitrobenzene can be added to a reaction flask, and then a catalyst and a catalyst support, such as activated carbon, can be added to the reaction flask to obtain a second system. After the second system is heated to a certain temperature, a reducing agent is added dropwise to the reaction flask. After the addition is complete, a reduction reaction is carried out. After the reaction is completed, the mixture is filtered while hot, and the filtrate is concentrated until there are no fractions to obtain 4-(3,3-dichloroallyloxy)aniline.

[0067] The dropwise addition of the reducing agent allows for precise control of its concentration and reaction rate within the reaction system. Compared to adding the reducing agent all at once, dropwise addition maintains a relatively low and stable concentration in the reaction system. Under these conditions, the reducing agent is more likely to selectively reduce nitro groups to amino groups, while reducing the reduction of other potentially easily reduced groups, thereby improving the selectivity of the target product, 4-(3,3-dichloroallyloxy)aniline.

[0068] Adding a reducing agent dropwise can also effectively prevent the reaction from becoming too violent. If a large amount of reducing agent is added at once, the reaction may release a large amount of heat instantly, causing the temperature of the reaction system to rise sharply. This could not only trigger side reactions but also pose safety hazards such as material spillage or explosion. By adding the reducing agent dropwise, the reaction can proceed smoothly, making it easier to control the reaction temperature and process, thus improving the safety and operability of the reaction.

[0069] In some embodiments of the present invention, the second system further includes a second solvent, which includes at least one of methanol, ethanol, water, and acetonitrile.

[0070] The second solvent mentioned above has good solubility for 4-(3,3-dichloroallyloxy)nitrobenzene and reducing agents, which can make the reactants uniformly dispersed in the solution, increase the contact area and collision opportunities between molecules, thereby improving the reaction rate and making the reduction reaction more complete and rapid.

[0071] In some embodiments, the catalyst includes at least one selected from Raney nickel, platinum, palladium, ferrous chloride, and ferric chloride.

[0072] The catalysts described above can lower the activation energy of the reduction reaction, making the reaction easier to proceed. Under the action of the catalyst, reactant molecules more easily reach the transition state, thereby accelerating the reaction rate and improving reaction efficiency. Furthermore, these catalysts can selectively promote the target reaction and inhibit the occurrence of side reactions.

[0073] In some embodiments, the reducing agent includes at least one of hydrazine hydrate, ammonium acetate, iron powder, and Raney nickel (hydrogen).

[0074] The reducing agent described above has a strong reducing ability and can efficiently reduce the nitro group in 1-(3,3-dichloroallyloxy)-4-nitrobenzene to an amino group, generating the target product 4-(3,3-dichloroallyloxy)aniline.

[0075] In some embodiments, the temperature of the reduction reaction is 40~60°C, for example, it can be a range of 40°C, 45°C, 50°C, 55°C, 60°C or any two of them; the time is 1~16h, for example, it can be a range of 1h, 4h, 8h, 12h, 16h or any two of them.

[0076] At the above temperature and time, the reduction reaction can proceed at a relatively fast rate while ensuring the selectivity of the reaction, so that 1-(3,3-dichloroallyloxy)-4-nitrobenzene is fully reduced to 4-(3,3-dichloroallyloxy)aniline, and the formation of by-products is reduced.

[0077] In some embodiments, the dropping rate of the reducing agent is 1 to 10 g / min, for example, it can be a range of 1 g / min, 3 g / min, 5 g / min, 7 g / min, 9 g / min, 10 g / min or any combination thereof.

[0078] By controlling the dropping rate of the reducing agent, the concentration of the reducing agent in the reaction system can be adjusted, thereby controlling the reaction rate. If the dropping rate is too fast, the concentration of the reducing agent in the reaction system will be too high, which may cause the reaction to be too violent, generate a large amount of heat, trigger side reactions, or even lead to a runaway reaction.

[0079] An appropriate dropping rate ensures thorough mixing of the reducing agent and reactants, guaranteeing a uniform reaction. This contributes to improved reaction selectivity and yield, resulting in high-quality target products.

[0080] In some embodiments of the present invention, the diazotization reaction of 4-(3,3-dichloroallyloxy)aniline includes: adding sodium nitrite solution dropwise to a third system comprising 4-(3,3-dichloroallyloxy)aniline and a strong acid to induce a diazotization reaction and obtain 4-(3,3-dichloroallyloxy)benzene diazonium salt.

[0081] Specifically, 4-(3,3-dichloroallyloxy)aniline can be added to a reaction flask and kept at 20-30°C. Then, strong acid is added dropwise to the system, and a large amount of solid precipitates out. After the addition is complete, the mixture is stirred for 1-2 hours to obtain a third system. Then, the third system is cooled to a certain temperature, and sodium nitrite solution is added dropwise to the third system. After the addition is complete, a diazotization reaction is carried out to obtain 4-(3,3-dichloroallyloxy)benzene diazonium salt.

[0082] Under acidic conditions, sodium nitrite reacts with acid to form nitrous acid. The resulting nitrous acid is unstable and undergoes further protonation and dehydration reactions to generate nitrosyl ions (NO). + Nitrosyl cations are highly electrophilic reactive intermediates carrying a positive charge. The amino group in the 4-(3,3-dichloroallyloxy)aniline molecule possesses a lone pair of electrons, exhibiting a certain degree of basicity. In a strongly acidic environment, the amino group accepts a proton, undergoing a protonation reaction to form a protonated amino group (-NH3). + ). Nitrosyl cation (NO) + As an electrophile, NO attacks the protonated nitrogen atom of the protonated 4-(3,3-dichloroallyloxy)aniline molecule at the site activated by protonation, resulting in an electrophilic substitution reaction. In this process, NO... + It undergoes electron rearrangement with the system containing the amino nitrogen atom, ultimately forming 4-(3,3-dichloroallyloxy)benzenediazonium salt.

[0083] The diazotization reaction is carried out by dropwise addition of sodium nitrite solution in a strong acid system, resulting in relatively mild reaction conditions. This reduces the requirements for reaction equipment, lowers equipment investment and operating costs, and also reduces safety risks caused by extreme conditions, such as explosions and leaks, making the reaction easier to control and operate. Furthermore, it can improve the selectivity of the reaction, increase the purity and yield of the target product 4-(3,3-dichloroallyloxy)benzene diazonium salt, and reduce the difficulty and cost of subsequent separation and purification.

[0084] In some embodiments of the present invention, the third system further includes a third solvent, which includes at least one of water, methanol, ethyl acetate, and dichloromethane.

[0085] The aforementioned third solvent can provide a good dissolution environment, effectively dissolve reactants and products, ensure sufficient contact between reactants, and improve reaction efficiency.

[0086] In some embodiments, the temperature of the diazotization reaction is -10 to 10°C, for example, it can be a range of -10°C, -5°C, 0°C, 5°C, 10°C or any two of these; the time is 1 to 16 hours, for example, it can be a range of 1 hour, 4 hours, 8 hours, 12 hours, 14 hours, 16 hours or any two of these.

[0087] The temperature of the diazotization reaction can effectively suppress the occurrence of side reactions, making the reaction proceed more smoothly, and the temperature is also conducive to improving the selectivity of the reaction.

[0088] In some embodiments, strong acids include concentrated sulfuric acid and / or concentrated hydrochloric acid.

[0089] The aforementioned strong acids provide the necessary acidic environment for the diazotization reaction. Under acidic conditions, the amino group of 4-(3,3-dichloroallyloxy)aniline is more readily protonated, thereby enhancing the positive charge of the nitrogen atom and making it more susceptible to nitrosyl ions (NO3-). + The attack of ) promotes the diazotization reaction.

[0090] In some embodiments, the dropping rate of the sodium nitrite solution is 1 to 10 g / min, for example, it can be a range of 1 g / min, 3 g / min, 5 g / min, 7 g / min, 9 g / min, 10 g / min or any combination thereof.

[0091] By controlling the dropping rate of the sodium nitrite solution, the concentration of nitrite ions in the reaction system can be adjusted, thereby controlling the rate of the diazotization reaction. If the dropping rate is too fast, the concentration of nitrite ions in the reaction system will be too high, which may lead to an overly vigorous reaction, generating a large amount of heat, triggering side reactions, or even causing the reaction to run away from control.

[0092] Furthermore, an appropriate dropping rate ensures thorough mixing of sodium nitrite with 4-(3,3-dichloroallyloxy)aniline and the strong acid, guaranteeing a uniform reaction. This contributes to improved reaction selectivity and yield, resulting in high-quality target products. Simultaneously, a uniform reaction process reduces localized excessively high or low concentrations, preventing uneven chemical reactions within the reaction system.

[0093] In some embodiments of the present invention, the hydrolysis reaction of 4-(3,3-dichloroallyloxy)benzene diazonium salt includes: adding an inorganic acid to 4-(3,3-dichloroallyloxy)benzene diazonium salt to conduct a hydrolysis reaction to obtain 4-(3,3-dichloroallyloxy)phenol.

[0094] When an inorganic acid is added to 4-(3,3-dichloroallyloxy)benzene diazonium salt and heated, water molecules in the inorganic acid act as nucleophiles, attacking the nitrogen atom in the diazonium group. Because the diazonium group carries a positive charge, the electron cloud density around the nitrogen atom is reduced, making it more susceptible to nucleophilic attack. After the water molecule attack, a series of electron rearrangements occur, and the diazonium group (−N2) departs as nitrogen gas, simultaneously forming a carbocation intermediate on the benzene ring. This carbocation intermediate then extracts a proton from surrounding water molecules or anions in the acid, ultimately generating 4-(3,3-dichloroallyloxy)phenol.

[0095] 3,3-Dichloroallyloxy is an ether substituent, which is stable under acidic conditions (not easily hydrolyzed) and therefore does not interfere with the reaction.

[0096] The hydrolysis of diazonium salts can conveniently convert 4-(3,3-dichloroallyloxy)aniline into 4-(3,3-dichloroallyloxy)phenol, providing an important raw material for subsequent synthesis reactions.

[0097] In some embodiments of the present invention, the temperature of the hydrolysis reaction is 80~120°C, for example, it can be a range of 80°C, 85°C, 90°C, 95°C, 100°C, 110°C, 120°C or any two of them; the time is 1~16h, for example, it can be a range of 1h, 4h, 8h, 12h, 14h, 16h or any two of them.

[0098] The temperature and time of the above hydrolysis reaction can effectively promote the hydrolysis reaction, accelerate the hydrolysis rate, make the hydrolysis reaction more complete, and convert more 4-(3,3-dichloroallyloxy)benzene diazonium salt into the target product 4-(3,3-dichloroallyloxy)phenol, thereby improving the conversion rate of the reaction.

[0099] In some embodiments, the inorganic acid includes dilute sulfuric acid and / or dilute hydrochloric acid.

[0100] In the hydrolysis reaction, the acidic environment plays a crucial role in the departure of the diazonium group and the nucleophilic attack of water molecules. Hydrogen ions can combine with anions in the diazonium salt, reducing the stability of the diazonium group and promoting its departure as nitrogen gas. At the same time, the acidic environment also facilitates the ionization of water molecules, enhancing their nucleophilicity and making them more likely to attack the nitrogen atom in the diazonium group, thereby driving the reaction forward.

[0101] In some embodiments of the present invention, after the hydrolysis reaction is completed, the process further includes: adding a fourth solvent to the hydrolysis reaction system, extraction, and separation to obtain 4-(3,3-dichloroallyloxy)phenol. The fourth solvent includes at least one selected from toluene, n-heptane, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0102] Specifically, a fourth solvent can be added to the hydrolysis system, the mixture is stirred and extracted, separated, and the upper organic phase is concentrated until no fraction remains to obtain 4-(3,3-dichloroallyloxy)phenol.

[0103] The fourth solvent mentioned above is immiscible with water and has a high boiling point, exceeding the temperature of the hydrolysis reaction, thus effectively dissolving 4-(3,3-dichloroallyloxy)phenol. Through extraction, the target product is transferred from the aqueous phase to the organic phase, achieving separation from inorganic acids and water-soluble impurities.

[0104] The technical solution of the present invention will be further described below with reference to specific embodiments.

[0105] Example 1

[0106] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment includes the following steps:

[0107] 1) Add 400 mL of N,N-dimethylformamide and 69.5 g of p-nitrophenol to a 1000 mL reaction flask. Heat the system to 60 °C, add 72.5 g of potassium carbonate, and maintain the temperature at 60 °C with stirring for 1 h to obtain the first system. Add 76.1 g of 1,1,3-trichloropropene dropwise to the first system at a rate of 5 g / min. After the addition is complete, maintain the temperature at 60 °C for etherification reaction for 8 h. Then filter while hot, add 150 g of water to the filtrate, and a large amount of solid precipitates out. Filter to obtain 120.0 g of 1-(3,3-dichloroallyloxy)-4-nitrobenzene, with an LC purity of 99.0% and a yield of 96.7%. The molar ratio of 1,1,3-trichloropropene to p-nitrophenol is 1:1.

[0108] 2) Add 400 mL of methanol and 49.6 g of 1-(3,3-dichloroallyloxy)-4-nitrobenzene to a 1000 mL reaction flask. Simultaneously add 2.5 g of ferrous chloride and 7.2 g of activated carbon to the system to obtain the second system. Heat the second system to 60 °C and add 24.0 g of hydrazine hydrate as a reducing agent at a rate of 1 g / min to the reaction flask. After the addition is complete, maintain the temperature at 60 °C for a reduction reaction for 16 h. Then filter while hot and concentrate the filtrate until there are no fractions to obtain 38.4 g of 4-(3,3-dichloroallyloxy)aniline with an LC purity of 99.5% and a yield of 88%.

[0109] 3) Add 200 mL of water and 21.8 g of 4-(3,3-dichloroallyloxy)aniline to a 1000 mL reaction flask. Maintain the system at 25 °C, and add 20.0 g of concentrated sulfuric acid dropwise. A large amount of solid precipitates out. After the addition is complete, stir the system for 1.5 h to obtain the third system. Cool the third system to 0 °C, and add 50.0 g of sodium nitrite aqueous solution dropwise to the reaction flask at a rate of 1 g / min. After the addition is complete, maintain the temperature at 0 °C for a diazotization reaction for 16 h to obtain 4-(3,3-dichloroallyloxy)benzene diazonium salt. Then add 200 g of dilute sulfuric acid to the system, heat the system to 100 °C for a hydrolysis reaction for 16 h, add 300.0 g of toluene, stir and extract, separate the layers, and concentrate the upper organic phase until no fraction remains to obtain 18.7 g of 4-(3,3-dichloroallyloxy)phenol, with an LC purity of 99.2% and a yield of 85.4%.

[0110] The obtained 4-(3,3-dichloroallyloxy)phenol was characterized by proton nuclear magnetic resonance spectroscopy. Figure 1 The 1H NMR spectrum of 4-(3,3-dichloroallyloxy)phenol prepared in Example 1 (solvent CDCl3) is shown. Figure 1 The assignment analysis of the proton NMR spectrum yielded the following proton NMR data for 4-(3,3-dichloroallyloxy)phenol:

[0111] 1 H NMR (300MHz, CDCl3) δ6.77 (d, J=1.2Hz, 4H), 6.13 (t, J=6.0Hz, 1H), 4.61 (d, J=6.0Hz, 2H).

[0112] The obtained 4-(3,3-dichloroallyloxy)phenol was characterized by liquid chromatography-mass spectrometry (LC-MS). Figure 2 The LC-MS spectrum of 4-(3,3-dichloroallyloxy)phenol prepared in Example 1 is shown.

[0113] Example 2

[0114] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment is basically the same as that in Example 1, except that the etherification reaction temperature is 30°C and the time is 24 hours.

[0115] In this example, 18.8 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.2%, and the yield was 85.8%.

[0116] Example 3

[0117] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment is basically the same as that in Example 1, except that the etherification reaction temperature is 40°C and the time is 12h.

[0118] In this example, 19.0 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.0%, and the yield was 86.8%.

[0119] Example 4

[0120] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment is basically the same as that in Example 1, except that 95.9g of 1,1,3-trichloropropene is added dropwise, so that the molar ratio of 1,1,3-trichloropropene to p-nitrophenol is 1.2:1, and the dropping rate of 1,1,3-trichloropropene is 10g / min.

[0121] In this example, 18.7 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.0%, and the yield was 85.4%.

[0122] Example 5

[0123] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment is basically the same as that in Example 1, except that 83.7g of 1,1,3-trichloropropene is added dropwise, so that the molar ratio of 1,1,3-trichloropropene to p-nitrophenol is 1.1:1, and the dropping rate of 1,1,3-trichloropropene is 7g / min.

[0124] In this example, 19.0 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.3%, and the yield was 86.8%.

[0125] Example 6

[0126] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment is basically the same as that in Example 1, except that the dropping rate of the reducing agent is 5 g / min.

[0127] In this example, 19.1 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.3%, and the yield was 87.2%.

[0128] Example 7

[0129] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment is basically the same as that in Example 1, except that the dropping rate of the reducing agent is 10 g / min.

[0130] In this example, 18.9 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.3%, and the yield was 86.3%.

[0131] Example 8

[0132] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment is basically the same as that in Example 1, except that the reduction reaction temperature is 40°C and the time is 12h.

[0133] In this example, 19.2 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.4%, and the yield was 87.7%.

[0134] Example 9

[0135] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment is basically the same as that in Example 1, except that the reduction reaction temperature is 50°C and the time is 1 hour.

[0136] In this example, 19.1 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.5%, and the yield was 87.2%.

[0137] Example 10

[0138] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment is basically the same as that in Example 1, except that the diazotization reaction temperature is -10℃ and the time is 2h.

[0139] In this example, 19.5 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.0%, and the yield was 89.0%.

[0140] Example 11

[0141] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment is basically the same as that in Example 1, except that the diazotization reaction is carried out at a temperature of 10°C for 1 hour.

[0142] In this example, 19.4 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.0%, and the yield was 88.6%.

[0143] Example 12

[0144] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment is basically the same as that in Example 1, except that the dropping rate of sodium nitrite aqueous solution is 10 g / min.

[0145] In this example, 19.5 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.0%, and the yield was 89.0%.

[0146] Example 13

[0147] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment is basically the same as that in Example 1, except that the dropping rate of sodium nitrite aqueous solution is 10 g / min.

[0148] In this example, 19.0 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.2%, and the yield was 86.8%.

[0149] Example 14

[0150] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment is basically the same as that in Example 1, except that the hydrolysis reaction temperature is 80°C and the time is 16h.

[0151] In this example, 19.0 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.6%, and the yield was 86.8%.

[0152] Example 15

[0153] The preparation method of 4-(3,3-dichloroallyloxy)phenol in this embodiment is basically the same as that in Example 1, except that the hydrolysis reaction temperature is 120°C and the time is 8 hours.

[0154] In this example, 19.1 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.5%, and the yield was 87.2%.

[0155] The 4-(3,3-dichloroallyloxy)phenol prepared in Examples 2-15 was characterized by 1H NMR spectroscopy and liquid chromatography-mass spectrometry. The peak positions and intensities were basically consistent with those of the 4-(3,3-dichloroallyloxy)phenol prepared in Example 1, proving that 4-(3,3-dichloroallyloxy)phenol was prepared in Examples 2-15.

[0156] Comparative Example 1

[0157] The preparation method of 4-(3,3-dichloroallyloxy)phenol in Comparative Example 1 includes the following steps:

[0158] 400 mL of N,N-dimethylformamide and 110.0 g of hydroquinone were added to a 1000 mL reaction flask. The system was heated to 60 °C, and 8.0 g of sodium hydroxide was added. The system was kept at 60 °C and stirred for 2 h to obtain the first system. 29.0 g of 1,1,3-trichloropropene was added dropwise to the first system at a rate of 1 g / min. After the addition was complete, the system was kept at 60 °C for etherification reaction for 16 h. Subsequently, the system was directly concentrated until no fraction was distilled off. 110 mL of toluene was added to the system, and 100.0 g of 10% sodium hydroxide solution was added to the filtrate. The mixture was stirred evenly, and the layers were separated. 36% hydrochloric acid solution was added to the lower aqueous phase until the pH reached 7.5. The lower layer was separated to obtain 22.0 g of 4-(3,3-dichloroallyloxy)phenol. The molar ratio of 1,1,3-trichloropropene to hydroquinone was 1:5.

[0159] The above reaction process is illustrated below:

[0160]

[0161] In this example, 22.0 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.0%, and the yield was 50.0%.

[0162] Comparative Example 2

[0163] The preparation method of 4-(3,3-dichloroallyloxy)phenol in Comparative Example 2 includes the following steps:

[0164] 1) In a 500 mL four-necked flask equipped with a mechanical stirrer and a thermometer, add 11.5 g of hydroquinone (0.1 mol, 1.05 eq) and 120 mL of 1,4-dioxane. Heat to 110 °C, and add 14.4 g of benzoyl chloride (0.1 mol, 1.0 eq) dropwise, controlling the dropping rate. After the addition is complete, continue the reaction for 1 h. Cool down to precipitate a white solid, filter, add 120 mL of methyl tert-butyl ether to the filter cake, stir at 25 °C for 30 minutes, and then filter. The filtrate is desolventized under reduced pressure to obtain the intermediate 4-hydroxybenzoic acid phenyl ester, with a weight of 12.8 g, yield 60.0%, and purity 99.2%.

[0165] 2) In a 500 mL four-necked flask equipped with a mechanical stirrer and a thermometer, 12.8 g of phenyl 4-hydroxybenzoate (0.06 mol, 1.0 eq) and 100 mL of N,N-dimethylformamide and 4.3 g of sodium hydroxide (0.11 mol, 1.8 eq) were added. The mixture was stirred at room temperature for 5 min, and then 9.6 g of 1,1,3-trichloropropene (0.066 mol, 1.1 eq) was added. The mixture was reacted at 20 °C for about 4 h. After the reaction was completed, the mixture was filtered, dissolved under reduced pressure, and then toluene and water were added. The mixture was extracted, washed with water, dried, and dissolved under reduced pressure to obtain the intermediate phenyl 4-(3,3-dichloro-2-allyloxy)benzoate, weighing 17.0 g, with a yield of 87.6% and a purity of 99.3%.

[0166] 3) In a 500 mL four-necked flask equipped with a mechanical stirrer and thermometer, add 17.0 g of phenyl 4-(3,3-dichloro-2-allyloxy)benzoate (0.05 mol, 95.0%, 1.0 eq), 10 mL of methanol, and 20 mL of water. Stir, and slowly add 40 mL of 10% sodium hydroxide solution (0.1 mol, 2.0 eq). Incubate the reaction for 8 h until phenyl 4-(3,3-dichloro-2-allyloxy)benzoate is completely reacted. After the reaction is complete, adjust the pH to 5.5 with 10% hydrochloric acid solution, add toluene for extraction, separate the layers, wash the organic layer with 10% sodium bicarbonate solution, wash with water, and remove solvent under reduced pressure to obtain 11.1 g of 4-(3,3-dichloroallyloxy)phenol, with a purity of 95.3% and a yield of 96.2%.

[0167] The above reaction process is illustrated below:

[0168]

[0169] In this example, 11.1 g of 4-(3,3-dichloroallyloxy)phenol was prepared. The LC purity of 4-(3,3-dichloroallyloxy)phenol was 99.0%, and the overall yield was 50.0%.

[0170] Comparative Example 2 has a longer route and lower selectivity for hydroquinone, with nearly 30% of the components under dual protection. Subsequent recovery is more complicated, and subsequent routes require deprotection operations, increasing the workload. Furthermore, it uses benzoyl chloride with a larger molecular weight, resulting in lower atom utilization and higher production costs.

[0171] Finally, it should be noted that other embodiments of the invention will readily occur to those skilled in the art upon consideration of the specification and practice of the invention disclosed herein. This invention is intended to cover any variations, uses, or adaptations of the invention that follow the general principles of the invention and include common knowledge or customary techniques in the art not disclosed herein, and is not limited to the precise structures described above and shown in the accompanying drawings, and various modifications and changes can be made without departing from its scope. The scope of the invention is limited only by the appended claims.

Claims

1. A process for the preparation of 4-(3,3-dichloroallyloxy)phenol, characterized in that, The method comprises the following steps: 1) adding 1,1,3-trichloropropene dropwise to a first system comprising p-nitrophenol under alkaline conditions to perform etherification to obtain 1-(3,3-dichloroallyloxy)-4-nitrobenzene; 2) performing reduction on the 1-(3,3-dichloroallyloxy)-4-nitrobenzene to obtain 4-(3,3-dichloroallyloxy)aniline; 3) performing diazotization on the 4-(3,3-dichloroallyloxy)aniline to obtain 4-(3,3-dichloroallyloxy)benzenediazonium salt; 4) performing hydrolysis on the 4-(3,3-dichloroallyloxy)benzenediazonium salt to obtain the 4-(3,3-dichloroallyloxy)phenol.

2. The production method according to claim 1, characterized by, The temperature of the etherification is 30-60°C, and the time is 8-24h; And / or, the molar ratio of the 1,1,3-trichloropropene to the p-nitrophenol is (1.0-1.2):1; And / or, the dropping speed of the 1,1,3-trichloropropene is 5-10g / min.

3. The production method according to claim 1 or 2, characterized by, The first system further comprises a first solvent, and the first solvent comprises at least one of N,N-dimethylformamide, methanol, acetonitrile, dioxane; And / or, the alkaline reagent used in the alkaline conditions comprises at least one of potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, and triethylamine.

4. The production method according to any one of claims 1 to 3, characterized by, The reduction on the 1-(3,3-dichloroallyloxy)-4-nitrobenzene comprises adding a reducing agent dropwise to a second system comprising the 1-(3,3-dichloroallyloxy)-4-nitrobenzene and a catalyst to perform the reduction to obtain the 4-(3,3-dichloroallyloxy)aniline.

5. The preparation method according to claim 4, characterized in that, The second system further comprises a second solvent, and the second solvent comprises at least one of methanol, ethanol, water, and acetonitrile; And / or, the catalyst comprises at least one of Raney nickel, metallic platinum, metallic palladium, ferrous chloride, and ferric chloride; And / or, the reducing agent comprises at least one of hydrazine hydrate, ammonium acetate, iron powder, and Raney nickel (hydrogen); And / or, the dropping speed of the reducing agent is 1-10g / min; And / or, the temperature of the reduction is 40-60°C, and the time is 1-16h.

6. The method of any one of claims 1-5, wherein, The diazotization on the 4-(3,3-dichloroallyloxy)aniline comprises adding a sodium nitrite solution dropwise to a third system comprising the 4-(3,3-dichloroallyloxy)aniline and a strong acid to perform the diazotization to obtain the 4-(3,3-dichloroallyloxy)benzenediazonium salt.

7. The production method according to claim 6, wherein The third system further comprises a third solvent, and the third solvent comprises at least one of water, methanol, ethyl acetate, and dichloromethane; And / or, the temperature of the diazotization is -10-10°C, and the time is 1-16h; And / or, the strong acid comprises concentrated sulfuric acid and / or concentrated hydrochloric acid; And / or, the dropping speed of the sodium nitrite solution is 1-10g / min.

8. The method of any one of claims 1-7, wherein, The hydrolysis reaction of the 4-(3,3-dichloroallyloxy)benzenediazonium salt comprises: adding an inorganic acid to the 4-(3,3-dichloroallyloxy)benzenediazonium salt, and the hydrolysis reaction is carried out to obtain the 4-(3,3-dichloroallyloxy)phenol.

9. The production method according to claim 8, characterized by, The temperature of the hydrolysis reaction is 80-120 DEG C, and the time is 1-16 hours. And / or, the inorganic acid comprises dilute sulfuric acid and / or dilute hydrochloric acid.

10. The method of any one of claims 1-9, wherein, After the hydrolysis reaction is completed, further comprising: adding a fourth solvent to the hydrolysis reaction system, extracting, separating, and obtaining the 4-(3,3-dichloroallyloxy)phenol. The fourth solvent comprises at least one of toluene, n-heptane, N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone.

Images