A process for the preparation of a phenylacetyl acetic acid compound

Abstract

The application discloses a preparation method of a phenylacetyl acetic acid compound, relates to the technical field of chemical synthesis, and the synthesis route of the phenylacetyl acetyl acid compound is as follows: an aniline compound connected with five groups of R1, R2, R3, R4 and R5 is used as a raw material, a diazotization reagent is added under acidic conditions to perform a diazotization reaction, a phase transfer catalyst, a copper catalyst and divinyl ketone are added to perform a reaction, and hydrolysis is performed under acidic conditions to obtain the phenylacetyl acetic acid compound; wherein R1, R2, R3, R4 and R5 are each independently selected from F, Cl, Br, -CH3, -OCH3, NO2, -C2H5, -C3H7, -CF3 or H, and are not H at the same time; when one or more of R1, R2, R3, R4 and R5 is F, the rest are not all H; and X is selected from Cl or Br. The raw material prepared by the application is easy to obtain, the operation is simple, the reaction condition is mild, the danger is low, the reaction step is short, the production cost and three waste emissions of enterprises are reduced, and large-scale industrial production can be easily realized.

Description

Technical Field

[0001] This application relates to the field of chemical synthesis, and in particular to a method for preparing a phenylacetoacetic acid compound. Background Technology

[0002] Phenylacetic acid compounds have a wide range of applications in medicine, pesticides, electronic materials and other fields.

[0003] Currently, the most commonly used industrial method for synthesizing phenylacetic acid is the sodium cyanide method. Phenylacetic acid is prepared into an acyl chloride, which is then condensed with Michaelis acid and subsequently decarboxylated to produce phenylacetic acid. The specific synthetic route is as follows:

[0004]

[0005] In the formula: R1, R2, R3, R4, and R5 are each independently selected from F, Cl, Br, -CH3, -OCH3, NO2, -C2H5, -C3H7, -CF3, or H, and not all of them are H at the same time; when one or more of R1, R2, R3, R4, and R5 are F, the rest are not all H.

[0006] The aforementioned technologies have long preparation routes, low overall yields, and are highly toxic due to sodium cyanide. The cyanide-containing wastewater causes serious environmental pollution, and the treatment of waste and production safety are difficult to manage. They are also costly, have complex processes, and are not suitable for stable industrial production. Summary of the Invention

[0007] In order to solve at least one of the above-mentioned technical problems and to develop a preparation method that does not generate cyanide-containing waste, this application provides a method for preparing a phenylacetoacetic acid compound.

[0008] On the one hand, this application provides a method for preparing a phenylacetoacetic acid compound, the synthetic route of which is as follows:

[0009]

[0010] In the formula: R1, R2, R3, R4, and R5 are each independently selected from F, Cl, Br, -CH3, -OCH3, NO2, -C2H5, -C3H7, -CF3, or H, and not all of them are H at the same time; when one or more of R1, R2, R3, R4, and R5 are F, the rest are not all H; X is selected from Cl or Br.

[0011] By adopting the above technical solution, the raw materials are simple and readily available, the route is short, the operation is convenient, the reaction conditions are mild, high-risk materials such as sodium cyanide are not used, the risk is low, the reaction steps are short, which helps enterprises reduce production costs and emissions of waste, and makes it easy to achieve large-scale industrial production.

[0012] Secondly, this application provides a method for preparing the above-mentioned phenylacetoacetic acid compound, comprising the following steps:

[0013] Step 1: Diazotization Coupling Reaction

[0014] Compound III and an acid solution were added to reaction flask 1, and the mixture was heated and stirred until the system was clear. Stirring was continued and the temperature was lowered to -30℃ to 5℃. An aqueous solution containing a diazotizing reagent was added dropwise. After the addition was complete, the temperature was maintained to obtain the diazonium salt.

[0015] Diketene, phase transfer catalyst and copper catalyst were added to reaction flask 2, stirred and cooled to -30℃ to 5℃, and slowly added dropwise to reaction flask 1 with the prepared diazonium salt. The temperature was kept constant during the addition, and stirring was continued after the addition was completed. The mixture was allowed to stand and separate into layers to obtain the organic phase.

[0016] In step one, compound III is used to prepare a diazonium salt in a system containing acid and a diazotizing reagent. The prepared diazonium salt is then reacted with diketene in the presence of a phase transfer catalyst and a copper-based catalyst to generate compound mixture II. The copper-based catalyst is used to accelerate the reaction rate. The phase transfer catalyst can transfer the negative ion X from the ionic phase to the organic phase, thereby improving the reactivity of the negative ion X and accelerating the reaction rate. The diazotization coupling reaction is favored by a slightly acidic medium.

[0017] Step 2: Hydrolysis reaction

[0018] The organic phase from step one was allowed to stand and then combined with the aqueous phase and stirred. An acid solution was added dropwise and stirred to obtain a mixture.

[0019] Compound IIb in compound mixture II is extremely unstable under acidic conditions and is easily converted into compound IIa. By adding acid solution dropwise, compound IIb in compound mixture II is converted into compound IIa. Compound IIa undergoes a hydrolysis reaction under acidic conditions to obtain a mixture, the main component of which is compound I.

[0020] Step 3: Crude product extraction. Add the extractant to the mixture from Step 2, cool and crystallize to obtain compound I;

[0021] Step two also includes any of the following reaction conditions:

[0022] A. Before adding the acid solution, add the phase transfer catalyst dropwise, and after adding the acid solution, stir at 0℃-100℃;

[0023] B. Do not add phase transfer catalyst before adding acid solution, and stir at 60℃-100℃ after adding acid solution.

[0024] By adding the above-mentioned reaction condition A in step two, the phase transfer catalyst transfers the negative ion X from the ionic phase to the organic phase, thereby improving the reactivity of the negative ion X and accelerating the reaction rate.

[0025] The reaction rate is increased by adding reaction condition B in step two, thereby raising the hydrolysis temperature, and the degree of hydrolysis is controlled by controlling the hydrolysis time.

[0026] Based on the number and type of groups (excluding amino groups) on the benzene ring of the raw material, in step two, either reaction condition A or B can be added:

[0027] When there are no other groups besides the amino group on the benzene ring, in step two, reaction condition B is selected: in the diazotization reaction, a phase transfer catalyst is added, but in the hydrolysis reaction, no phase transfer catalyst is added, and the hydrolysis reaction temperature is increased to 60℃-100℃. Adding a phase transfer catalyst in the hydrolysis reaction has a limited effect on increasing the yield of phenylacetoacetic acid. Increasing the hydrolysis reaction temperature can significantly increase both the reaction temperature and the yield. Therefore, it is chosen not to add a phase transfer catalyst in the hydrolysis reaction, and the yield is guaranteed while reducing costs by increasing the hydrolysis reaction temperature.

[0028] When the benzene ring contains at least one other group besides the amino group, a phase transfer catalyst is added in both the diazotization and hydrolysis reactions. The hydrolysis reaction temperature is between 0℃ and 100℃. The addition of a phase transfer catalyst in the hydrolysis reaction has a significant impact on improving the yield of phenylacetoacetic acid compounds. Increasing the hydrolysis temperature in the hydrolysis reaction reduces the hydrolysis reaction time. Considering the time and energy costs required to increase the hydrolysis temperature, conducting the reaction at room temperature results in lower time and energy costs.

[0029] Optionally, the phase transfer catalyst in reaction condition A of step one and step two is independently selected from one or more combinations of tetramethylammonium chloride, tetrabutylammonium chloride, tetraoctylammonium chloride, methyltrioctylammonium chloride, tetraoctylammonium bromide, tetrahexylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium bromide and tri-dodecylmethylammonium iodide.

[0030] Optionally, in step one, the molar ratio of compound III to the phase transfer catalyst is set to 1:0.01-0.1; in reaction condition A of step two, the molar ratio of compound mixture II to the phase transfer catalyst is set to 1:0.001-0.01.

[0031] Optionally, the acid used in steps one and two may be one or more of sulfuric acid, hydrochloric acid, hydrobromic acid, and fluoroboric acid.

[0032] Optionally, in step one, the molar ratio of compound III to acid is set to 1:1-2; in step two, the molar ratio of compound mixture II to acid is set to 1:2-10.

[0033] Optionally, in step one, the diazotizing agent is a nitrite and / or a nitrite ester; the molar ratio of compound III to the diazotizing agent is set at 1:1.1-5.

[0034] Optionally, in step one, the copper-based catalyst is one or more of the following: cuprous chloride, cuprous chloride, cuprous bromide, copper sulfate, basic copper carbonate, cuprous iodide, copper acetate, copper hydroxide, and cuprous oxide; the molar ratio of compound III to the copper-based catalyst is set at 1:0.01-0.1.

[0035] Optionally, in step one, the molar ratio of compound III to diketene is set at 1:2-20.

[0036] Optionally, in step three, the extractant is selected from one or more combinations of dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, toluene, acetone, acetic acid, and acetonitrile.

[0037] In summary, the present invention has at least one of the following beneficial technical effects:

[0038] 1. The raw materials are simple and readily available, the route is short, the operation is convenient, the reaction conditions are mild, and high-risk materials such as sodium cyanide are not used, so the risk is low. The reaction steps are short, which helps enterprises reduce production costs and emissions of waste, and makes it easy to achieve large-scale industrial production.

[0039] 2. Different phenylacetoacetic acid compounds were prepared, and different reaction conditions were selected in the hydrolysis reaction in step two to balance economic benefits and yield. Detailed Implementation

[0040] The present application will be further described in detail below with reference to the embodiments.

[0041] The synthetic route for the phenylacetoacetic acid compound described in this application is as follows:

[0042]

[0043] In the formula: R1, R2, R3, R4, and R5 are each independently selected from F, Cl, Br, -CH3, -OCH3, NO2, -C2H5, -C3H7, -CF3, or H, and not all of them are H at the same time; when one or more of R1, R2, R3, R4, and R5 are F, the rest are not all H; X is selected from Cl or Br.

[0044] In existing technologies, the synthetic route for phenylacetoacetic acid compounds requires the addition of sodium cyanide, which generates cyanide-containing wastewater, causing significant environmental impact and incurring high wastewater treatment costs. The applicant has abandoned existing synthetic routes and developed a novel one. While existing technologies require the sodium cyanide method to obtain phenylacetic acid, the applicant's synthetic route utilizes the diazotization reaction of the amino group on the benzene ring to generate a diazonium salt. Under the action of a phase transfer catalyst and a copper-based catalyst, the diazonium salt reacts with diketene to generate intermediates IIa and IIb, as well as a mixture of phenylacetoacetic acid compound I. It was discovered that intermediate IIb is extremely unstable under acidic conditions and readily converts to intermediate IIa, which then undergoes hydrolysis to yield phenylacetoacetic acid compound I. Therefore, the mixture of intermediates IIa, IIb, and phenylacetoacetic acid compound I is hydrolyzed under acidic conditions to obtain phenylacetoacetic acid compound I.

[0045] The present application discloses a method for preparing a phenylacetoacetic acid compound, comprising the following steps:

[0046] Step 1: Diazotization Coupling Reaction

[0047] Compound III and an acid solution were added to reaction flask 1, and the mixture was heated and stirred until the system was clear. Stirring was continued and the temperature was lowered to -30℃ to 5℃. An aqueous solution containing a diazotizing reagent was added dropwise. After the addition was complete, the temperature was maintained to obtain the diazonium salt.

[0048] Diketene, phase transfer catalyst and copper catalyst were added to reaction flask 2, stirred and cooled to -30℃ to 5℃, and slowly added dropwise to reaction flask 1 with the prepared diazonium salt. The temperature was kept constant during the addition, and stirring was continued after the addition was completed. The mixture was allowed to stand and separate into layers to obtain the organic phase.

[0049] Step 2: Hydrolysis reaction

[0050] The organic phase from step one was allowed to stand and then combined with the aqueous phase and stirred. An acid solution was added dropwise and stirred to obtain a mixture.

[0051] Step 3: Crude product extraction

[0052] Add the extractant to the mixture from step two, and cool to crystallize to obtain compound I.

[0053] When synthesizing phenylacetoacetic acid compounds using the above synthetic route, at least two methods were found to significantly improve the yield. One method is to add a phase transfer catalyst before adding the acid solution in step two, and then stir at 0℃-100℃ after adding the acid solution.

[0054] In preparing phenylacetoacetic acid compounds using the above synthetic route, the applicant discovered that the more groups other than amino groups on the benzene ring of starting material I, the greater the increase in product yield from adding a phase transfer catalyst during the hydrolysis reaction. After adding a phase transfer catalyst, increasing the hydrolysis temperature has a limited effect on yield improvement, but it can reduce reaction time. However, when the number of groups on the benzene ring of starting material I is small, the increase in yield from adding a phase transfer catalyst in step two is reduced, especially when the benzene ring of starting material I only has amino groups. In this case, the benefit of increasing the yield from adding a phase transfer catalyst is almost the same as the value of the phase transfer catalyst itself. At this point, increasing the hydrolysis reaction temperature has a significant effect on yield improvement. When the reaction temperature is further increased to 80°C, the increase in yield from adding a phase transfer catalyst in step two is almost zero. Therefore, when preparing different phenylacetoacetic acid compounds from different starting materials, the applicant improves product yield by selecting different reaction conditions in step two (i.e., selecting a phase transfer catalyst or increasing the hydrolysis reaction temperature), while also considering economic benefits in actual production. Specific Implementation

[0056] Example 1

[0057] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0058] Step 1: Diazotization Coupling Reaction

[0059] Add 1.0 mol of aniline and 1.8 mol of 30% hydrochloric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -5 to 0°C. Add 1.4 mol of a mixture of sodium nitrite and nitrite ester dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0060] Add 5.0 mol of diketene, 0.06 mol of tetrabutylammonium iodide and tri-dodecylmethylammonium iodide, and 0.08 mol of cuprous bromide to reaction flask 2. Stir and cool to -5℃ to 0℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture warm for 3 hours after the addition is complete. Continue stirring and keeping the mixture warm for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0061] Step 2: Hydrolysis reaction

[0062] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 1 mmol of trioctylmethylammonium chloride and tetrahexylammonium chloride were added dropwise, along with 7 mol of 30% hydrochloric acid. The mixture was stirred at 100°C for 13 hours to obtain the final mixture.

[0063] Step 3: Crude product extraction

[0064] Add 400 ml of toluene to the mixture from step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.782 mol of phenylacetoacetic acid, molar yield 78.2%, purity 99.1%. ¹H NMR (CDCl₃, 400 MHz) = 8.8 (s, ¹H), 7.19–7.38 (m, ⁵H), 3.82 (s, ⁻¹H), 3.53 (s, ⁻¹H).

[0065] Example 2

[0066] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0067] Step 1: Diazotization Coupling Reaction

[0068] Add 1.0 mol of aniline and 1.8 mol of 30% hydrochloric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -5 to 0°C. Add 1.4 mol of a mixture of sodium nitrite and nitrite ester dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0069] Add 5.0 mol of diketene, 0.06 mol of tetrabutylammonium bromide, and 0.08 mol of cuprous bromide to reaction flask 2. Stir and cool to -5℃ to 0℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture warm for 3 hours after the addition is complete. Continue stirring and keeping the mixture warm for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0070] Step 2: Hydrolysis reaction

[0071] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 1 mmol of trioctylmethylammonium chloride and tetrahexylammonium chloride were added dropwise, along with 7 mol of 30% hydrochloric acid. The mixture was stirred at 100°C for 13 hours to obtain the final mixture.

[0072] Step 3: Crude product extraction

[0073] Add 400 ml of toluene to the mixture from step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.766 mol of phenylacetoacetic acid, with a molar yield of 76.6% and a purity of 99.1%.

[0074] Example 3

[0075] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0076] Step 1: Diazotization Coupling Reaction

[0077] Add 1.0 mol of aniline and 1.2 mol of 30% hydrochloric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -25 to -15°C. Add 1.4 mol of a mixture of sodium nitrite and nitrite ester dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0078] Add 5.0 mol of diketene, 0.06 mol of tetrabutylammonium chloride and tetraoctylammonium chloride, and 0.08 mol of cuprous chloride and cupric chloride to reaction flask 2. Stir and cool to -25 to -15℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture warm for 3 hours after the addition is complete. Continue stirring and keeping the mixture warm for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0079] Step 2: Hydrolysis reaction

[0080] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 1 mmol of trioctylmethylammonium chloride and tetrahexylammonium chloride were added dropwise, along with 10 mol of 30% hydrochloric acid. The mixture was stirred at 60°C for 13 hours to obtain the final mixture.

[0081] Step 3: Crude product extraction

[0082] Add 400 ml of toluene to the mixture from step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.735 mol of phenylacetoacetic acid, with a molar yield of 73.5% and a purity of 99.1%.

[0083] Example 4

[0084] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0085] Step 1: Diazotization Coupling Reaction

[0086] Add 1.0 mol of aniline and 1.8 mol of 30% hydrochloric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -5 to 0°C. Add 1.4 mol of a mixture of sodium nitrite and nitrite ester dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0087] Add 5.0 mol of diketene, 0.06 mol of tetraoctylammonium bromide and tetrabutylammonium bromide, and 0.08 mol of cuprous bromide and cuprous iodide to reaction flask 2. Stir and cool to -5 to 0℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture warm for 3 hours after the addition is complete. Continue stirring and keeping the mixture warm for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0088] Step 2: Hydrolysis reaction

[0089] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 2 mol of 30% hydrochloric acid was added dropwise, and the mixture was stirred at 80°C for 18 hours to obtain the mixture.

[0090] Step 3: Crude product extraction

[0091] Add 400 ml of toluene to the mixture from step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.713 mol of phenylacetoacetic acid, with a molar yield of 71.3% and a purity of 99.1%.

[0092] Example 5

[0093] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0094] Step 1: Diazotization Coupling Reaction

[0095] Add 1.0 mol of p-fluoroaniline and 1.2 mol of 30% hydrochloric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool down to -5 to 0°C. Add an aqueous solution containing 1.1 mol of 40% nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0096] Add 5.0 mol of diketene, 0.055 mol of tetrabutylammonium bromide and 0.07 mol of cuprous bromide to reaction flask 2, stir and cool to -5℃ to 0℃, and slowly add it dropwise to reaction flask 1 with the prepared diazonium salt. Keep the reaction temperature for 3 hours after the addition is completed, and continue to keep the temperature and stir for 7 hours. Let it stand to separate the layers to obtain the organic phase.

[0097] Step 2: Hydrolysis reaction

[0098] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 3 mmol of tetraoctylammonium bromide and tetrabutylammonium bromide were added dropwise, along with 8.5 mol of 30% hydrochloric acid. The mixture was stirred at 60°C for 13 hours to obtain the final mixture.

[0099] Step 3: Crude product extraction

[0100] Add 400 ml of toluene to the mixture from step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.787 mol of p-fluorophenylacetoacetic acid, with a molar yield of 78.7% and a purity of 99.1%. ¹H NMR (CDCl₃, 400 MHz) δ = 9.8 (s, ¹H), 7.19 (m, 2H), 7.04 (m, 2H), 3.84 (s, 2H), 3.52 (s, 2H).

[0101] Example 6

[0102] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0103] Step 1: Diazotization Coupling Reaction

[0104] Add 1.0 mol of p-fluoroaniline and 2 mol of 30% hydrochloric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -25°C to -15°C. Add an aqueous solution containing 1.1 mol of 40% nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0105] Add 5.0 mol of diketene, 0.055 mol of tetrabutylammonium chloride and tetraoctylammonium chloride, and 0.07 mol of cuprous chloride and cupric chloride to reaction flask 2. Stir and cool to -25℃ to -15℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture warm for 3 hours after the addition is complete. Continue stirring and keeping the mixture warm for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0106] Step 2: Hydrolysis reaction

[0107] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 9 mmol of tetrabutylammonium chloride and tetraoctylammonium chloride were added dropwise, along with 4.5 mol of 30% hydrochloric acid. The mixture was stirred at 0°C for 12 hours to obtain the final mixture.

[0108] Step 3: Crude product extraction

[0109] Add 400 ml of toluene to the mixture in step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.764 mol of p-fluorophenylacetoacetic acid, with a molar yield of 76.4% and a purity of 99.1%.

[0110] Example 7

[0111] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0112] Step 1: Diazotization Coupling Reaction

[0113] Add 1.0 mol of p-fluoroaniline and 1.2 mol of 30% hydrochloric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -5°C to 0°C. Add an aqueous solution containing 1.1 mol of 40% nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0114] Add 5.0 mol of diketene, 0.055 mol of tetraoctylammonium bromide and tetrabutylammonium bromide, and 0.07 mol of cuprous bromide to reaction flask 2. Stir and cool to -5℃ to 0℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture warm for 3 hours after the addition is complete. Continue stirring and keeping the mixture warm for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0115] Step 2: Hydrolysis reaction

[0116] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 7 mol of 30% hydrochloric acid was added dropwise, and the mixture was stirred at 60°C for 24 hours to obtain the mixture.

[0117] Step 3: Crude product extraction

[0118] Add 400 ml of toluene to the mixture in step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.721 mol of p-fluorophenylacetoacetic acid, with a molar yield of 72.1% and a purity of 99.1%.

[0119] Example 8

[0120] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0121] Step 1: Diazotization Coupling Reaction

[0122] Add 1.0 mol of o-fluoroaniline and 1.6 mol of sulfuric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -30°C to -25°C. Add 1.3 mol of a mixture of sodium nitrite and nitrite ester dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0123] Add 5.0 mol of diketene, 0.01 mol of tetrabutylammonium bromide, and 0.03 mol of copper sulfate and copper acetate to reaction flask 2. Stir and cool to -30℃ to -25℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture warm for 3 hours after the addition is complete. Continue stirring and keeping the mixture warm for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0124] Step 2: Hydrolysis reaction

[0125] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 6 mmol of tetrabutylammonium iodide and tri-dodecylmethylammonium iodide were added dropwise, along with 2 mol of sulfuric acid. The mixture was stirred at 40°C for 11.5 hours to obtain the final mixture.

[0126] Step 3: Crude product extraction

[0127] Add 400 ml of toluene to the mixture from step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.759 mol of o-fluorophenylacetoacetic acid, molar yield 75.9%, purity 99.1%. ¹H NMR (CDCl₃, 400 MHz) δ = 9.7 (s, ¹H), 7.31 (m, ¹H), 6.98–7.04 (m, ³H), 3.86 (s, ²H), 3.52 (s, ²H).

[0128] Example 9

[0129] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0130] Step 1: Diazotization Coupling Reaction

[0131] Add 1.0 mol of m-fluoroaniline and 1.7 mol of sulfuric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to 0°C-5°C. Add an aqueous solution containing 1.2 mol of 40% sodium nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0132] Add 5.0 mol of diketene, 0.03 mol of tetrabutylammonium bromide and 0.02 mol of cuprous oxide to reaction flask 2, stir and cool to -30℃ to -25℃, and slowly add it dropwise to reaction flask 1 with the prepared diazonium salt. Keep the reaction temperature for 3 hours after the addition is completed, and continue to keep the temperature and stir for 7 hours. Let it stand to separate the layers to obtain the organic phase.

[0133] Step 2: Hydrolysis reaction

[0134] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 4 mmol of tetrabutylammonium iodide and tri-dodecylmethylammonium iodide were added dropwise, along with 8.5 mol of sulfuric acid. The mixture was stirred at 60°C for 12 hours to obtain the final mixture.

[0135] Step 3: Crude product extraction

[0136] Add 400 ml of toluene to the mixture from step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.762 mol of m-fluorophenylacetoacetic acid, molar yield 76.2%, purity 99.1%. ¹H NMR (CDCl₃, 400 MHz) δ = 10.1 (s, ¹H), 7.44 (m, ¹H), 7.06–7.12 (m, ³H), 3.81 (s, ²H), 3.48 (s, ²H).

[0137] Example 10

[0138] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0139] Step 1: Diazotization Coupling Reaction

[0140] Add 1.0 mol of 2,4,5-trifluoroaniline and 1.5 mol of 30% hydrochloric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -5°C to 0°C. Add an aqueous solution containing 1.2 mol of 40% sodium nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0141] Add 5.0 mol of diketene, 0.037 mol of tetrabutylammonium bromide and 0.06 mol of cuprous bromide to reaction flask 2, stir and cool to -5℃ to 0℃, and slowly add it dropwise to reaction flask 1 with the prepared diazonium salt. Keep the reaction temperature for 3 hours after the addition is completed, and continue to keep the temperature and stir for 7 hours. Let it stand to separate the layers to obtain the organic phase.

[0142] Step 2: Hydrolysis reaction

[0143] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 2 mmol of tetrabutylammonium bromide was added dropwise, followed by 7 mol of 30% hydrochloric acid. The mixture was stirred at 80°C for 12 hours to obtain the final mixture.

[0144] Step 3: Crude product extraction

[0145] Add 400 ml of toluene to the mixture from step two, and cool to crystallize to obtain a pale yellow to off-white solid, 0.812 mol of 2,4,5-trifluorophenylacetoacetic acid, with a molar yield of 81.2% and a purity of 99.1%. ¹H NMR (CDCl₃, 400 MHz) δ = 9.6 (s, ¹H), 7.26 (m, ¹H), 7.02 (m, ¹H), 3.82 (s, 2H), 3.46 (s, 2H).

[0146] Example 11

[0147] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0148] Step 1: Diazotization Coupling Reaction

[0149] Add 1.0 mol of 2,4,5-trifluoroaniline and 1.2 mol of 30% hydrochloric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -25°C to -15°C. Add an aqueous solution containing 1.2 mol of 40% sodium nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0150] Add 5.0 mol of diketene, 0.037 mol of tetrabutylammonium chloride and 0.06 mol of cuprous chloride to reaction flask 2, stir and cool to -25℃ to -15℃, and slowly add it dropwise to reaction flask 1 with the prepared diazonium salt. Keep the reaction temperature for 3 hours after the addition is completed, and continue to keep the temperature and stir for 7 hours. Let it stand to separate the layers to obtain the organic phase.

[0151] Step 2: Hydrolysis reaction

[0152] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 8 mmol of tetrabutylammonium chloride was added dropwise, followed by 10 mol of 30% hydrochloric acid. The mixture was stirred at 20°C for 9 hours to obtain the final mixture.

[0153] Step 3: Crude product extraction

[0154] Add 400 ml of toluene to the mixture from step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.795 mol of 2,4,5-trifluorophenylacetoacetic acid, with a molar yield of 79.5% and a purity of 98.8%.

[0155] Example 12

[0156] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0157] Step 1: Diazotization Coupling Reaction

[0158] Add 1.0 mol of 2,4,5-trifluoroaniline and 1.5 mol of 30% hydrochloric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -5°C to 0°C. Add an aqueous solution containing 1.2 mol of 40% sodium nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0159] Add 5.0 mol of diketene, 0.037 mol of tetrabutylammonium bromide and 0.06 mol of cuprous bromide to reaction flask 2, stir and cool to -5℃ to 0℃, and slowly add it dropwise to reaction flask 1 with the prepared diazonium salt. Keep the reaction temperature for 3 hours after the addition is completed, and continue to keep the temperature and stir for 7 hours. Let it stand to separate the layers to obtain the organic phase.

[0160] Step 2: Hydrolysis reaction

[0161] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 7 mol of 30% hydrochloric acid was added dropwise, and the mixture was stirred at 100°C for 15 hours to obtain the mixture.

[0162] Step 3: Crude product extraction

[0163] Add 400 ml of toluene to the mixture from step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.714 mol of 2,4,5-trifluorophenylacetoacetic acid, with a molar yield of 71.4% and a purity of 98.9%.

[0164] Example 13

[0165] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0166] Step 1: Diazotization Coupling Reaction

[0167] Add 1.0 mol of 2,4,5-trifluoroaniline and 1.6 mol of sulfuric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -30°C to -25°C. Add 1.2 mol of a mixture of sodium nitrite and nitrite ester dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0168] Add 5.0 mol of diketene, 0.01 mol of tetrabutylammonium bromide, and 0.03 mol of copper sulfate and copper acetate to reaction flask 2. Stir and cool to -30℃ to -25℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture at the temperature for 3 hours after the addition is complete. Continue stirring and keeping the mixture at the temperature for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0169] Step 2: Hydrolysis reaction

[0170] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 6 mmol of tetrabutylammonium bromide was added dropwise, followed by 8.5 mol of sulfuric acid. The mixture was stirred at 40°C for 11.5 hours to obtain the final mixture.

[0171] Step 3: Crude product extraction. Add 400 ml of a mixture of dichloromethane, acetone, and chloroform to the mixture from Step 2. Cool and crystallize to obtain a light yellow to off-white solid, 0.789 mol of 2,4,5-trifluorophenylacetoacetic acid, with a molar yield of 78.9% and a purity of 98.6%.

[0172] Example 14

[0173] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0174] Step 1: Diazotization Coupling Reaction

[0175] Add 1.0 mol of 2,4,5-trifluoroaniline and 1.7 mol of sulfuric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to 0°C-5°C. Add an aqueous solution containing 1.2 mol of 40% sodium nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0176] Add 5.0 mol of diketene, 0.03 mol of tetrabutylammonium chloride and 0.02 mol of cuprous oxide to reaction flask 2, stir and cool to 0℃-5℃, and slowly add it dropwise to reaction flask 1 with the prepared diazonium salt. Keep the reaction temperature for 3 hours after the addition is completed, and continue to keep the temperature and stir for 7 hours. Let it stand to separate the layers to obtain the organic phase.

[0177] Step 2: Hydrolysis reaction

[0178] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 4 mmol of tetramethylammonium chloride was added dropwise, followed by 4.5 mol of sulfuric acid. The mixture was stirred at 60°C for 12 hours to obtain the final mixture.

[0179] Step 3: Crude product extraction

[0180] Add 400 ml of 1,2-dichloroethane to the mixture in step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.764 mol of 2,4,5-trifluorophenylacetoacetic acid, with a molar yield of 76.4% and a purity of 98.5%.

[0181] Example 15

[0182] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0183] Step 1: Diazotization Coupling Reaction

[0184] Add 1.0 mol of 2,4,5-trifluoroaniline and 1.3 mol of sulfuric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -15°C to -5°C. Add 1.4 mol of nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0185] Add 5.0 mol of diketene, 0.07 mol of tetrabutylammonium bromide, and 0.1 mol of basic copper carbonate, copper hydroxide, and cuprous oxide to reaction flask 2. Stir and cool to -15℃ to -5℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture warm for 3 hours after the addition is complete. Continue stirring and keeping the mixture warm for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0186] Step 2: Hydrolysis reaction

[0187] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 2.5 mmol of tetrabutylammonium bromide was added dropwise, followed by 7 mol of sulfuric acid. The mixture was stirred at 80°C for 12.5 hours to obtain the final mixture.

[0188] Step 3: Crude product extraction

[0189] Add 400 ml of tetrahydrofuran to the mixture in step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.771 mol of 2,4,5-trifluorophenylacetoacetic acid, with a molar yield of 77.1% and a purity of 99.0%.

[0190] Example 16

[0191] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0192] Step 1: Diazotization Coupling Reaction

[0193] Add 1.0 mol of p-chloroaniline and 1.6 mol of 30% hydrochloric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -30°C to -25°C. Add 1.3 mol of a mixture of sodium nitrite and nitrite ester dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0194] Add 5.0 mol of diketene, 0.01 mol of tetrabutylammonium bromide, and 0.07 mol of copper sulfate and copper acetate to reaction flask 2. Stir and cool to -30℃ to -25℃. Slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture warm for 3 hours after the addition is complete. Continue stirring and keeping the mixture warm for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0195] Step 2: Hydrolysis reaction

[0196] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 6 mmol of tetrabutylammonium iodide and tri-dodecylmethylammonium iodide were added dropwise, along with 2 mol of 30% hydrochloric acid. The mixture was stirred at 40°C for 11.5 hours to obtain the final mixture.

[0197] Step 3: Crude product extraction

[0198] Add 400 ml of toluene to the mixture from step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.789 mol of p-chlorophenylacetoacetic acid, with a molar yield of 78.9% and a purity of 98.5%. ¹H NMR (CDCl₃, 400 MHz) δ = 10.01 (s, ¹H), 7.30 (m, ²H), 7.11 (m, ²H), 3.84 (s, ²H), 3.52 (s, ²H).

[0199] Example 17

[0200] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0201] Step 1: Diazotization Coupling Reaction

[0202] Add 1.0 mol of p-chloroaniline and 1.7 mol of 30% hydrochloric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to 0°C-5°C. Add an aqueous solution containing 1.2 mol of 40% sodium nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0203] Add 5.0 mol of diketene, 0.03 mol of tetrabutylammonium chloride, and 0.02 mol of cuprous chloride to reaction flask 2. Stir and cool to 0℃-5℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture at the temperature for 3 hours after the addition is complete. Continue stirring and keeping the mixture at the temperature for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0204] Step 2: Hydrolysis reaction

[0205] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 4 mmol of tetrabutylammonium iodide and tri-dodecylmethylammonium iodide were added dropwise, along with 8.5 mol of hydrobromic acid. The mixture was stirred at 60°C for 12 hours to obtain the final mixture.

[0206] Step 3: Crude product extraction

[0207] Add 400 ml of toluene to the mixture in step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.772 mol of p-chlorophenylacetoacetic acid, with a molar yield of 77.2% and a purity of 98.7%.

[0208] Example 18

[0209] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0210] Step 1: Diazotization Coupling Reaction

[0211] Add 1.0 mol of p-bromoaniline and 1.3 mol of fluoroboric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -15°C to -5°C. Add 1.4 mol of nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0212] Add 5.0 mol of diketene, 0.07 mol of tetrabutylammonium bromide, and 0.1 mol of basic copper carbonate, copper hydroxide, and cuprous oxide to reaction flask 2. Stir and cool to -15℃ to -5℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture warm for 3 hours after the addition is complete. Continue stirring and keeping the mixture warm for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0213] Step 2: Hydrolysis reaction

[0214] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 2.5 mmol of tetrabutylammonium iodide and tri-dodecylmethylammonium iodide were added dropwise, along with 7 mol of fluoroboric acid. The mixture was stirred at 80°C for 12.5 hours to obtain the final mixture.

[0215] Step 3: Crude product extraction

[0216] Add 400 ml of toluene to the mixture from step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.792 mol of p-bromophenylacetoacetic acid, with a molar yield of 79.2% and a purity of 98.3%. ¹H NMR (CDCl₃, 400 MHz) δ = 9.5 (s, ¹H), 7.33 (m, 2H), 7.16 (m, 2H), 3.79 (s, 2H), 3.48 (s, 2H).

[0217] Example 19

[0218] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0219] Step 1: Diazotization Coupling Reaction

[0220] Add 1.0 mol of p-bromoaniline and 1.8 mol of sulfuric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -10°C to -5°C. Add 1.5 mol of nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0221] Add 5.0 mol of diketene, 0.1 mol of tetrabutylammonium chloride and 0.09 mol of cuprous bromide to reaction flask 2, stir and cool to -10℃ to -5℃, and slowly add it dropwise to reaction flask 1 with the prepared diazonium salt. Keep the reaction temperature for 3 hours after the addition is completed, and continue to keep the temperature and stir for 7 hours. Let it stand to separate the layers to obtain the organic phase.

[0222] Step 2: Hydrolysis reaction

[0223] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 2 mmol of tetraoctylammonium bromide and 2 mmol of tetrabutylammonium bromide were added dropwise, and 10 mol of sulfuric acid was added dropwise. The mixture was stirred at 60°C for 14 hours to obtain the final mixture.

[0224] Step 3: Crude product extraction

[0225] Add 400 ml of toluene to the mixture in step two, cool and crystallize to obtain a pale yellow to off-white solid, 0.779 mol of p-bromophenylacetoacetic acid, with a molar yield of 77.9% and a purity of 98.4%.

[0226] Example 20

[0227] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0228] Step 1: Diazotization Coupling Reaction

[0229] Add 1.0 mol of 2,4-dichloro-5-fluoroaniline and 1.2 mol of 30% hydrochloric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -20°C to -15°C. Add an aqueous solution containing 1.4 mol of 40% sodium nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0230] Add 5.0 mol of diketene, 0.037 mol of tetrabutylammonium chloride, and 0.05 mol of cuprous chloride and cupric chloride to reaction flask 2. Stir and cool to -20℃ to -15℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture warm for 3 hours after the addition is complete. Continue stirring and keeping the mixture warm for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0231] Step 2: Hydrolysis reaction

[0232] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 1.5 mmol of tetrabutylammonium chloride and tetraoctylammonium chloride were added dropwise, along with 7 mol of 30% hydrochloric acid. The mixture was stirred at 100°C for 12.5 hours to obtain the final mixture.

[0233] Step 3: Crude product extraction

[0234] Add 400 ml of toluene to the mixture from step two, and cool to crystallize to obtain a pale yellow to off-white solid, 0.802 mol of 2,4-dichloro-5-fluorophenylacetoacetic acid, with a molar yield of 80.2% and a purity of 98.8%. ¹H NMR (CDCl₃, 400 MHz) δ = 9.9 (s, ¹H), 7.33 (m, ¹H), 7.07 (m, ¹H), 3.81 (s, 2H), 3.49 (s, 2H).

[0235] Example 21

[0236] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0237] Step 1: Diazotization Coupling Reaction

[0238] Add 1.0 mol of 2,4,5-tribromoaniline and 1.8 mol of hydrobromic acid and fluoroboric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -10°C to -5°C. Add 1.5 mol of nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0239] Add 5.0 mol of diketene, 0.1 mol of trioctylmethylammonium chloride and tetrahexylammonium chloride, and 0.09 mol of cuprous bromide to reaction flask 2. Stir and cool to -10℃ to -5℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture at the temperature for 3 hours after the addition is complete. Continue stirring and keeping the mixture at the temperature for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0240] Step 2: Hydrolysis reaction

[0241] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 2.5 mmol of tetramethylammonium chloride was added dropwise, along with 4.5 mol of a mixture of hydrobromic acid and fluoroboric acid. The mixture was stirred at 20°C for 15.5 hours to obtain the final mixture.

[0242] Step 3: Crude product extraction

[0243] Add 400 ml of toluene to the mixture from step two, and cool to crystallize to obtain a pale yellow to off-white solid, 0.815 mol of 2,4,5-tribromophenylacetoacetic acid, with a molar yield of 81.5% and a purity of 98.6%. ¹H NMR (CDCl₃, 400 MHz) δ = 9.8 (s, ¹H), 7.46 (m, ¹H), 7.08 (m, ¹H), 3.82 (s, 2H), 3.46 (s, 2H).

[0244] Example 22

[0245] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0246] Step 1: Diazotization Coupling Reaction

[0247] Add 1.0 mol of 2,4-difluoro-5-methylaniline and 1.2 mol of sulfuric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -20°C to -15°C. Add an aqueous solution containing 1.4 mol of 40% sodium nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0248] Add 5.0 mol of diketene, 0.02 mol of trioctylmethylammonium chloride and tetrahexylammonium chloride, and 0.05 mol of cuprous chloride to reaction flask 2. Stir and cool to -20℃ to -15℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture at the temperature for 3 hours after the addition is complete. Continue stirring and keeping the mixture at the temperature for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0249] Step 2: Hydrolysis reaction

[0250] The organic phase from step one was allowed to stand at room temperature, then mixed with the aqueous phase and stirred. 1 mmol of tetramethylammonium chloride was added dropwise, followed by 7 mol of sulfuric acid. The mixture was stirred at 0°C for 11.5 hours to obtain the final mixture.

[0251] Step 3: Crude product extraction

[0252] Add 400 ml of toluene to the mixture from step two, and cool to crystallize to obtain 0.798 mol of a pale yellow to off-white solid, 2,4-difluoro-5-methylphenylacetoacetic acid, with a molar yield of 79.8% and a purity of 98.3%. ¹H NMR (CDCl₃, 400 MHz) δ = 10.0 (s, 1H), 7.42 (m, 1H), 7.04 (m, 1H), 3.82 (s, 2H), 3.46 (s, 2H), 2.28 (s, 3H).

[0253] Example 23

[0254] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0255] Step 1: Diazotization Coupling Reaction

[0256] Add 1.0 mol of p-methoxyaniline and 1.2 mol of 30% hydrochloric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -20°C to -15°C. Add an aqueous solution containing 1.4 mol of 40% sodium nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0257] Add 5.0 mol of diketene, 0.01 mol of tetrabutylammonium chloride, and 0.09 mol of basic copper carbonate, copper hydroxide, and cuprous oxide to reaction flask 2. Stir and cool to -20℃ to -15℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture at the temperature for 3 hours after the addition is complete. Continue stirring and keeping the mixture at the temperature for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0258] Step 2: Hydrolysis reaction

[0259] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 1.5 mmol of tetrabutylammonium iodide and tri-dodecylmethylammonium iodide were added dropwise, followed by 2 mol of 30% hydrochloric acid. The mixture was stirred at 100°C for 12.5 hours to obtain a final mixture. Step three: Crude product extraction.

[0260] Add 400 ml of toluene to the mixture from step two, and cool to crystallize to obtain a pale yellow to off-white solid, 0.828 mol of 4-methoxyphenylacetoacetic acid, with a molar yield of 76.1% and a purity of 98.2%. ¹H NMR (CDCl₃, 400 MHz) δ = 9.8 (s, 1H), 7.28 (m, 2H), 7.02 (m, 2H), 3.77 (s, 2H), 3.41 (s, 2H), 2.28 (s, 3H).

[0261] Example 24

[0262] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0263] Step 1: Diazotization Coupling Reaction

[0264] Add 1.0 mol of p-methylaniline and 1.8 mol of sulfuric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -10°C to -5°C. Add 1.5 mol of nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0265] Add 5.0 mol of diketene, 0.01 mol of trioctylmethylammonium chloride and tetrahexylammonium chloride, and 0.05 mol of cuprous bromide to reaction flask 2. Stir and cool to -10℃ to -5℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture at the temperature for 3 hours after the addition is complete. Continue stirring and keeping the mixture at the temperature for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0266] Step 2: Hydrolysis reaction

[0267] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 1.5 mmol of tetrabutylammonium iodide and tri-dodecylmethylammonium iodide were added dropwise, along with 8.5 mol of sulfuric acid. The mixture was stirred at 20°C for 15.5 hours to obtain the final mixture.

[0268] Step 3: Crude product extraction. Add 400 ml of toluene to the mixture from Step 2, cool, and crystallize to obtain a pale yellow to off-white solid, 0.854 mol of 2,3,5,6-tetrafluoro-4-trifluoromethylphenylacetoacetic acid, with a molar yield of 77.0% and a purity of 99.2%. ¹H NMR (CDCl₃, 400 MHz) δ = 9.9 (s, 1H), 3.77 (s, 2H), 3.44 (s, 2H), 2.31 (s, 3H).

[0269] Example 25

[0270] A method for preparing a phenylacetoacetic acid compound includes the following steps:

[0271] Step 1: Diazotization Coupling Reaction

[0272] Add 1.0 mol of p-nitroaniline and 1.2 mol of hydrobromic acid and fluoroboric acid to reaction flask 1, heat to 90°C and stir until the system is clear, continue stirring for 1 hour, and cool to -20°C to -15°C. Add an aqueous solution containing 1.4 mol of 40% sodium nitrite dropwise over 2 hours. After the addition is complete, keep warm for 2 hours to prepare the diazonium salt.

[0273] Add 5.0 mol of diketene, 0.07 mol of trioctylmethylammonium chloride and tetrahexylammonium chloride, and 0.09 mol of cuprous chloride and cupric chloride to reaction flask 2. Stir and cool to -20℃ to -15℃, and slowly add the mixture dropwise to reaction flask 1, which has prepared the diazonium salt. Keep the mixture at the temperature for 3 hours after the addition is complete. Continue stirring and keeping the mixture at the temperature for 7 hours after the addition is complete. Allow the mixture to stand and separate into layers to obtain the organic phase.

[0274] Step 2: Hydrolysis reaction

[0275] The organic phase from step one was allowed to stand at room temperature and then mixed with the aqueous phase and stirred. 10 mmol of tetraoctylammonium bromide and tetrabutylammonium bromide were added dropwise, along with 7 mol of hydrobromic acid and fluoroboric acid. The mixture was stirred at 0°C for 11.5 hours to obtain the final mixture.

[0276] Step 3: Crude product extraction. Add 400 ml of toluene to the mixture from Step 2, cool, and crystallize to obtain a pale yellow to off-white solid, 0.852 mol of 4-nitrophenylacetoacetic acid, with a molar yield of 77.1% and a purity of 99.0%. ¹H NMR (CDCl₃, 400 MHz) δ = 10.2 (s, 1H), 7.42 (m, 2H), 7.17 (m, 2H), 3.91 (s, 2H), 3.53 (s, 2H).

[0277]

[0278]

[0279] As can be seen from Examples 2, 4, 5, 7, 10 and 12, as the number of groups on the benzene ring of raw material I increases, the effect of adding a phase transfer catalyst in step two on the yield becomes greater, while the effect of hydrolysis reaction temperature on the yield decreases.

[0280] Therefore, when aniline is used as the raw material I for preparing phenylacetoacetic acid, in step two, a phase transfer catalyst is not added, and the hydrolysis reaction temperature is increased to improve the yield and reduce the catalyst cost. Although the yield decreases accordingly, the cost saved on the phase transfer catalyst is higher than the product loss caused by the decrease in yield. Therefore, from an economic point of view, in the hydrolysis reaction of preparing phenylacetoacetic acid from aniline, a phase transfer catalyst is not added, and the hydrolysis reaction temperature is increased to 60℃-100℃.

[0281] When the benzene ring of the phenylacetoacetic acid compound to be prepared has at least one other group besides the acetoacetic acid group, the economic benefits of the increased yield resulting from the addition of the phase transfer catalyst in the hydrolysis reaction of step two are greater than those of the phase transfer catalyst itself, and the hydrolysis reaction temperature is also reduced, thus reducing energy costs.

[0282]

[0283] Examples 1, 2, and 3; Examples 5 and 6; Examples 10 and 11 show that the more groups (non-H) in R1-R5 (excluding the acetoacetic acid group) on the benzene ring of the desired phenylacetoacetic acid compound, the smaller the influence of the type of halogen group in the phase transfer catalyst added in step one on the yield. Specifically, the fewer groups in R1-R5, the greater the yield increase from adding a bromine-containing phase transfer catalyst in step one compared to adding a chlorine-containing phase transfer catalyst. For example, when preparing phenylacetoacetic acid using aniline, adding a bromine-containing phase transfer catalyst in step one increased the yield by 3.1% compared to adding a chlorine-containing catalyst; when preparing p-fluorophenylacetoacetic acid using p-fluoroaniline, adding a bromine-containing phase transfer catalyst in step one... The bromine-containing phase transfer catalyst increased the yield by 2.3% compared to the chlorine-containing catalyst. However, when preparing trifluorophenylacetoacetic acid using trifluoroaniline, adding a bromine-containing phase transfer catalyst in step one increased the yield by 1.7% compared to the chlorine-containing catalyst. Considering that the price of the bromine-containing phase transfer catalyst is 2-3 times that of the chlorine-containing phase transfer catalyst, when the number of groups on the benzene ring of the desired phenylacetoacetic acid compound, other than the acetoacetic acid group, is one, using a bromine-containing phase transfer catalyst can significantly improve the yield. Conversely, when the number of groups on the benzene ring of the desired phenylacetoacetic acid compound, other than the acetoacetic acid group, is more than two, adding a chlorine-containing phase transfer catalyst in step one reduces catalyst costs and improves economic efficiency without significantly changing the yield.

[0284] Comparing Example 1 and Example 2, adding an iodine-containing phase transfer catalyst in step 1 increased the yield by 1.6% compared to adding a bromine-containing phase transfer catalyst. However, the cost of the iodine-containing phase transfer catalyst is more than twice that of the bromine-containing phase transfer catalyst. Therefore, from an economic perspective, adding a bromine-containing phase transfer catalyst in step 1 is more cost-effective than adding an iodine-containing phase transfer catalyst.

[0285] Raw material I Phase transfer catalyst (Step 1) Yield (%) Example 5 p-Fluoroaniline Tetrabutylammonium bromide 78.7 Example 6 p-Fluoroaniline Tetrabutylammonium chloride, tetraoctylammonium chloride 76.4 Example 8 o-fluoroaniline Tetrabutylammonium bromide 75.9 Example 9 m-Fluoroaniline Tetrabutylammonium bromide 76.2

[0286] A comparison of Examples 5, 6, 8, and 9 shows that when there is only one group (excluding the acetoacetic acid group) on the benzene ring of the desired phenylacetoacetic acid compound, the position of this group relative to the acetoacetic acid group affects the yield. Specifically, the yield of the para position is higher than that of the meta position, which is higher than that of the ortho position. Furthermore, only in the synthetic route for preparing p-fluorophenylacetoacetic acid, the yield of adding a bromine-containing phase transfer catalyst in step one is higher than that of adding a chlorine-containing phase transfer catalyst. Therefore, when the number of groups R1-R5 on the benzene ring of the prepared phenylacetoacetic acid compound is one, and it is positioned para to the acetoacetic acid group, adding a bromine-containing phase transfer catalyst in step one when synthesizing the phenylacetoacetic acid compound using the synthetic route of this application improves the yield of the phenylacetoacetic acid compound.

[0287] When the number of groups R1-R5 on the benzene ring of the prepared phenylacetoacetic acid compound is one, but the position of this group is set in the ortho or meta position with the acetoacetic acid group, a chlorine-containing phase transfer catalyst is added in step one to reduce the cost of the phase transfer catalyst.

[0288] Raw material I Phase transfer catalyst (Step 1) Yield (%) Example 5 p-Fluoroaniline Tetrabutylammonium bromide 78.7 Example 6 p-Fluoroaniline Tetrabutylammonium chloride, tetraoctylammonium chloride 76.4 Example 16 p-Chloroaniline Tetrabutylammonium bromide 78.9 Example 17 p-Chloroaniline Tetrabutylammonium chloride 77.2 Example 18 p-Bromoaniline Tetrabutylammonium bromide 79.2 Example 19 p-Bromoaniline Tetrabutylammonium chloride 77.9 Example 23 p-Methoxyaniline Tetrabutylammonium chloride 76.1 Example 24 p-Toluidine Trioctylmethylammonium chloride, tetrahexylammonium chloride 77.0 Example 25 p-Nitroaniline Trioctylmethylammonium chloride, tetrahexylammonium chloride 77.1

[0289] A comparison of Examples 5, 6, 16, 17, 18 and 19 shows that when preparing a phenylacetoacetic acid compound with only one group other than the acetoacetic acid group on the benzene ring, and the group is a halogen group, the larger the molecular weight of the halogen group, the higher the yield. Furthermore, the addition of a bromine-containing phase transfer catalyst in step one has a smaller effect on yield improvement compared to a chlorine-containing phase transfer catalyst.

[0290] A comparison of Examples 5, 6, 16, 17, 18, 19, 23, 24, and 25 shows that in the preparation of phenylacetoacetic acid compounds with only one group other than the acetoacetic acid group on the benzene ring, the larger the molecular weight of this group, the higher the yield. Furthermore, the addition of a bromine-containing phase transfer catalyst in step one has a smaller increase in yield compared to a chlorine-containing phase transfer catalyst.

[0291]

[0292] A comparison of Examples 11, 20, 21, and 22 shows that, in the preparation of phenylacetoacetic acid compounds, the more groups other than acetoacetic acid groups on the benzene ring of the phenylacetoacetic acid compound, the higher the yield; when the number of groups is the same, the larger the molecular weight of the group, the higher the yield; and the different halogen groups in the phase transfer catalyst have a smaller impact on the yield.

[0293] Therefore, before preparing phenylacetoacetic acid compounds, the type of phase transfer catalyst in step one can be selected based on the type and number of groups on the benzene ring of the product, and whether to add a phase transfer catalyst or increase the hydrolysis reaction temperature in step two, thereby controlling costs in advance and achieving a balance between yield and economic benefits.

[0294] The above are all preferred embodiments of this application, and are not intended to limit the scope of protection of this application. Therefore, all equivalent changes made in accordance with the structure, shape and principle of this application should be covered within the scope of protection of this application.

Claims

1. A method for preparing a phenylacetoacetic acid compound, characterized in that, Includes the following steps: Step 1: Diazotization Coupling Reaction Compound III and an acid solution were added to reaction flask 1, and the mixture was heated and stirred until the system was clear. Stirring was continued and the temperature was lowered to -30℃ to 5℃. An aqueous solution containing a diazotizing reagent was added dropwise. After the addition was complete, the temperature was maintained to obtain the diazonium salt. Diketene, phase transfer catalyst and copper catalyst were added to reaction flask 2, stirred and cooled to -30℃ to 5℃, and slowly added dropwise to reaction flask 1 with the prepared diazonium salt. The temperature was kept constant during the addition, and stirring was continued after the addition was completed. The mixture was allowed to stand and separate into layers to obtain the organic phase. Step 2: Hydrolysis reaction The organic phase from step one is allowed to stand and then combined with the aqueous phase and stirred. An acid solution is added dropwise and stirred to obtain a mixture. Before adding the acid solution, a phase transfer catalyst is added dropwise, and after adding the acid solution, the mixture is stirred at 0℃-100℃. Step 3: Crude product extraction Add an extractant to the mixture in step two, cool and crystallize to obtain compound I. The extractant is selected from one or more combinations of dichloromethane, trichloromethane, 1,2-dichloroethane, and toluene. The chemical formula of compound III is: The chemical formula of compound I is In the formula: R1, R2, R3, R4, and R5 are each independently selected from F, Cl, Br, -CH3, -OCH3, NO2, -C2H5, -C3H7, -CF3, or H, and not all of them are H at the same time; when one or more of R1, R2, R3, R4, and R5 are F, the rest are not all H. Wherein, the phase transfer catalyst in step one and step two is independently selected from one or more combinations of tetramethylammonium chloride, tetrabutylammonium chloride, tetraoctylammonium chloride, methyltrioctylammonium chloride, tetraoctylammonium bromide, tetrahexylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium bromide and tri-dodecylmethylammonium iodide; The copper-based catalyst is one or more of the following: cuprous chloride, cuprous chloride, cuprous bromide, copper sulfate, basic copper carbonate, cuprous iodide, copper acetate, copper hydroxide, and cuprous oxide.

2. The method for preparing a phenylacetoacetic acid compound according to claim 1, characterized in that, In step one, the molar ratio of compound III to the phase transfer catalyst is set at 1:0.01-0.

1.

3. The method for preparing a phenylacetoacetic acid compound according to claim 1, characterized in that, The acids used in steps one and two can be sulfuric acid, hydrochloric acid, hydrobromic acid, and fluoroboric acid, or a combination of one or more of these.

4. The method for preparing a phenylacetoacetic acid compound according to claim 1, characterized in that, In step one, the molar ratio of compound III to acid is set at 1:1-2.

5. The method for preparing a phenylacetoacetic acid compound according to claim 1, characterized in that, In step one, the diazotizing agent is a nitrite and / or a nitrite ester; the molar ratio of compound III to the diazotizing agent is set at 1:1.1-5.

6. The method for preparing a phenylacetoacetic acid compound according to claim 1, characterized in that, In step one, the molar ratio of compound III to the copper catalyst is set at 1:0.01-0.

1.

7. The method for preparing a phenylacetoacetic acid compound according to claim 1, characterized in that, In step one, the molar ratio of compound III to diketene is set at 1:2-20.

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