Efficient synthesis method of pebiprofen

Abstract

The invention discloses a high-efficiency synthesis method of pebiprofen, and relates to the technical field of drug synthesis, the high-efficiency synthesis method of pebiprofen comprises the following steps: (1) under the action of a catalyst, carrying out an alkylation reaction on p-bromobenzyl cyanide and dimethyl carbonate to obtain an intermediate 1; (2) the intermediate 1, an organic lithium reagent and N, N-dimethylformamide are subjected to a Bouveault aldehyde synthesis reaction, and an intermediate 2 is obtained; (3) carrying out condensation reaction on the intermediate 2 and 1-morpholinyl-1-cyclohexene to obtain an intermediate 3; and (4) carrying out hydrolysis reaction on the intermediate 3 to obtain the pebiprofen. The synthetic method of the pebiprofen, provided by the invention, has the characteristics of easily available raw materials, simple post-treatment, high yield of intermediates and products and the like, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to an efficient synthesis method of pelubiprofen. Background Art

[0002] Pelubiprofen is an orally active non-steroidal anti-inflammatory drug and belongs to the members of the 2-arylpropionic acid family, which has a relatively selective effect on the activity of COX-2. Pelubiprofen can inhibit the COX activity and the TGF-β-activated kinase 1-IκB kinase β-NF-κB pathway, and has significant anti-inflammatory and analgesic effects.

[0003]

[0004] Currently, there are few reports and clinical uses of pelubiprofen in China. However, its excellent targeting properties and anti-inflammatory and analgesic effects will attract the attention of domestic generic drug companies in the future and may further replace flurbiprofen. Therefore, the research on pelubiprofen has important market value and economic value.

[0005] At present, the synthesis of pelubiprofen mainly adopts the following method:

[0006]

[0007] This method uses 2-phenylpropionic acid as the starting material, but the presence of the free carboxyl group has a great influence on the subsequent purification of the intermediate and the purity of pelubiprofen, resulting in a low yield. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide an efficient synthesis method of pelubiprofen, which has the characteristics of easily available raw materials, simple post-treatment, high yields of intermediates and products, and is suitable for industrial production.

[0009] The technical problem to be solved by the present invention is achieved by adopting the following technical solutions:

[0010] The present invention provides an efficient synthesis method of pelubiprofen, comprising the following steps:

[0011] (1) Under the action of a catalyst, p-bromophenylacetonitrile and dimethyl carbonate undergo an alkylation reaction to obtain intermediate 1;

[0012] (2) Intermediate 1, an organolithium reagent, and N,N-dimethylformamide undergo a Bouveault aldehyde synthesis reaction to obtain intermediate 2;

[0013] (3) Intermediate 2 and 1-morpholin-1-cyclohexene undergo a condensation reaction to obtain intermediate 3;

[0014] (4) Intermediate 3 undergoes a hydrolysis reaction to obtain beprifene.

[0015] The synthesis route is as follows:

[0016]

[0017] Furthermore, the catalyst includes but is not limited to one or more of sodium bromide, potassium bromide, sodium iodide, and potassium iodide, preferably sodium bromide. Under the action of the catalyst, dimethyl carbonate hydrolyzes to form carbonate ions, and the carbonate ions undergo a nucleophilic substitution reaction with p-bromophenylacetonitrile to introduce a methyl group into p-bromophenylacetonitrile.

[0018] Furthermore, the molar ratio of p-bromophenylacetonitrile to dimethyl carbonate and the catalyst is 1:(5 - 10):(1 - 2), preferably 1:(5 - 8):(1 - 1.5). Dimethyl carbonate not only participates in the reaction but also acts as a solvent, and the unreacted dimethyl carbonate can be recovered from the waste liquid by vacuum distillation.

[0019] Furthermore, the alkylation reaction is carried out under nitrogen protection, and the reaction pressure is 0.1 - 2 MPa, preferably 0.5 - 2 MPa.

[0020] Furthermore, the temperature of the alkylation reaction is 120 - 180 °C, preferably 140 - 160 °C. The alkylation reaction needs to be carried out under specific temperature and pressure conditions, and nitrogen is used as a protective gas to prevent impurities such as moisture and oxygen from contacting the reactants to form by-products, thereby improving the purity of Intermediate 1.

[0021] Furthermore, the organolithium reagent includes but is not limited to one or more of n-butyllithium and tert-butyllithium, preferably n-butyllithium. Intermediate 1 and N,N-dimethylformamide undergo a Bouveault aldehyde synthesis reaction under the action of the organolithium reagent to convert the bromo substituent into an aldehyde group, obtaining Intermediate 2.

[0022] Furthermore, the molar ratio of Intermediate 1 to the organolithium reagent and N,N-dimethylformamide is 1:(1 - 2):(1 - 2), preferably 1:(1 - 1.5):(1 - 1.5).

[0023] Furthermore, the temperature of the Bouveault aldehyde synthesis reaction is -90 - 0 °C, preferably -78 - -30 °C. Since the molecular movement of the organolithium reagent is slow at low temperatures, it is easier to react with the reactants.

[0024] Furthermore, the molar ratio of Intermediate 2 to 1-morpholin-1-cyclohexene is 1:(1 - 3), preferably 1:(1 - 2).

[0025] Further, the temperature of the condensation reaction is 20-90°C, preferably 30-80°C. 1-Morpholin-1-cyclohexene is a complex of cyclohexanone and morpholine. The carbanion of 1-morpholin-1-cyclohexene and the aldehyde group of intermediate 2 undergo an aldol-like condensation reaction, and the morpholinyl group is eliminated to form intermediate 3.

[0026] Further, the hydrolysis reaction is carried out under alkaline conditions, and the base includes but is not limited to one or more of sodium hydroxide, potassium hydroxide, and potassium carbonate, preferably sodium hydroxide. Of course, the hydrolysis of the cyano group can also be carried out under acidic conditions.

[0027] Further, the molar ratio of intermediate 3 to the base is 1:(1-3), preferably 1:(1-2).

[0028] Further, the temperature of the hydrolysis reaction is 60-120°C, preferably 80-110°C. Carrying out the hydrolysis reaction under heating conditions can increase the reaction rate and make the reaction more complete.

[0029] The beneficial effects of the present invention are as follows: Using 4-bromophenylacetonitrile as the starting material, the target product bepridil is obtained through alkylation reaction, Bouveault aldehyde synthesis reaction, condensation reaction, and hydrolysis reaction. This synthesis method has the characteristics of easily available raw materials, simple post-treatment, high product yield and purity, and is suitable for industrial production. Description of the Drawings

[0030] Figure 1 It is the 1H NMR spectrum of bepridil. Detailed Embodiments

[0031] In order to make the technical means, creative features, achieved purposes, and functions of the present invention easy to understand, the present invention will be further described below in conjunction with specific embodiments and illustrations.

[0032] Example 1

[0033] Synthesis of Intermediate 1:

[0034] Under nitrogen protection, 4-bromophenylacetonitrile (120 g, 0.61 mol), dimethyl carbonate (549 g, 6.1 mol), and sodium bromide (62.8 g, 0.61 mol) were added to an autoclave. After sealing, it was heated to 140°C and reacted for 5 h under a pressure of 0.5 MPa. After the reaction was completed, the reaction solution was cooled to room temperature, filtered by suction, washed with n-heptane, and the filtrate was concentrated to obtain Intermediate 1 with a yield of 93.6%.

[0035] Synthesis of Intermediate 2:

[0036] Intermediate I (0.97 g, 4.1 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran. n-Butyl lithium (3.4 mL, 8.2 mmol) was added under nitrogen and stirred for 1 h. Anhydrous N,N-dimethylformamide (448 mg, 6.15 mmol) was then added dropwise at -78°C. The mixture was allowed to react at -78°C for 1 h. After the addition was complete, the reaction solution was allowed to warm to room temperature and acidified with hydrochloric acid (2 mol / L) to a pH of 5. The solution was extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by n-hexane / ethyl acetate column chromatography to obtain Intermediate 2 in a yield of 88.6%.

[0037] Synthesis of intermediate 3:

[0038] Intermediate 2 (14.08 g, 0.084 mol) and 1-morpholino-1-cyclohexene (14.03 g, 0.084 mol) were dissolved in 100 mL of dichloromethane and heated to 40°C for 6 h. After the reaction, hydrochloric acid (50 mL, 6 mol / L) was added to the reaction solution, stirred at room temperature for 1 h, and extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to precipitate crystals, which were recrystallized from ethyl acetate / hexane to obtain Intermediate 3 in a yield of 81.4%.

[0039] Synthesis of Pebiprofen:

[0040] Under nitrogen, intermediate 3 (4.78 g, 0.02 mmol), aqueous sodium hydroxide solution (0.02 mmol, 1.5 mol / L), and water (8 mL) were added to ethanol (25 mL) and refluxed for 5 h. After completion of the reaction, the reaction solution was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by petroleum ether / ethyl acetate column chromatography to obtain pebiprofen in a yield of 77.8% and a purity of 99.7%. 1 H NMR (400MHz, DMSO) δ7.44-7.27(m,5H),3.47(q,J=7.1Hz,1H),2.80(td,J=6.6 ,2.0Hz,2H),2.45(t,J=6.6Hz,2H),1.92-1.64(m,4H),1.30(d,J=7.1Hz,3H).

[0041] Example 2

[0042] Synthesis of intermediate 1:

[0043] Under nitrogen protection, p-bromophenylacetonitrile (120 g, 0.61 mol), dimethyl carbonate (274.5 g, 3.05 mol) and potassium bromide (72.6 g, 0.61 mol) were added to an autoclave. After sealing, it was heated to 160 °C and reacted at a pressure of 1 MPa for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered by suction, washed with n-heptane, and the filtrate was concentrated to obtain Intermediate 1 with a yield of 75.6%.

[0044] Synthesis of Intermediate 2:

[0045] Intermediate I (0.97 g, 4.1 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran. Under nitrogen protection, n-butyllithium (1.7 mL, 4.1 mmol) was added, and the mixture was stirred for 1 h. Then, anhydrous N,N-dimethylformamide (448 mg, 6.15 mmol) was added dropwise at -78 °C. After the addition was completed, the reaction was carried out at -78 °C for 1 h. After the reaction was completed, the reaction solution was allowed to warm to room temperature naturally, acidified with hydrochloric acid (2 mol / L) to a solution pH of 5, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. It was separated by column chromatography of n-hexane / ethyl acetate to obtain Intermediate 2 with a yield of 65.1%.

[0046] Synthesis of Intermediate 3:

[0047] Intermediate 2 (14.08 g, 0.084 mol) and 1-morpholino-1-cyclohexene (28.06 g, 0.168 mol) were dissolved in 100 mL of dichloromethane and heated to 50 °C for reaction for 5 h. After the reaction was completed, hydrochloric acid (50 mL, 6 mol / L) was added to the reaction solution, and the mixture was stirred at room temperature for 1 h, extracted with dichloromethane, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to precipitate crystals. It was recrystallized with ethyl acetate / hexane to obtain Intermediate 3 with a yield of 83.5%.

[0048] Synthesis of bepiprunox:

[0049] Under nitrogen protection, Intermediate 3 (4.78 g, 0.02 mmol), aqueous sodium hydroxide solution (0.04 mmol, 1.5 mol / L) and water (8 mL) were added to ethanol (25 mL), and the mixture was refluxed for 5 h. After the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. It was separated by column chromatography of petroleum ether / ethyl acetate to obtain bepiprunox with a yield of 78.4% and a purity of 99.7%.

[0050] Example 3

[0051] Synthesis of Intermediate 1:

[0052] Under nitrogen protection, p-bromophenylacetonitrile (120 g, 0.61 mol), dimethyl carbonate (439 g, 4.88 mol) and sodium bromide (94.7 g, 0.92 mol) were added to an autoclave. After sealing, it was heated to 150 °C and reacted at a pressure of 2 MPa for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered by suction, washed with toluene, and the filtrate was concentrated to obtain Intermediate 1 with a yield of 94.2%.

[0053] Synthesis of Intermediate 2:

[0054] Intermediate I (0.97 g, 4.1 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran. Under nitrogen protection, n-butyllithium (3.4 mL, 8.2 mmol) was added, and the mixture was stirred for 1 h. Then, anhydrous N,N-dimethylformamide (258.3 mg, 4.1 mmol) was added dropwise at -78 °C. After the addition was completed, the reaction was carried out at -78 °C for 1 h. After the reaction was completed, the reaction solution was allowed to rise to room temperature naturally, acidified to pH = 5 with hydrochloric acid (2 mol / L), extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and separated by silica gel column chromatography with n-hexane / ethyl acetate to obtain Intermediate 2 with a yield of 88.6%.

[0055] Synthesis of Intermediate 3:

[0056] Intermediate 2 (14.08 g, 0.084 mol) and 1-morpholino-1-cyclohexene (14.03 g, 0.084 mol) were dissolved in 100 mL of dichloromethane and heated to 80 °C for reaction for 3 h. After the reaction was completed, hydrochloric acid (50 mL, 6 mol / L) was added to the reaction solution, and the mixture was stirred at room temperature for 1 h, extracted with dichloromethane, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, crystals were precipitated, and recrystallized with ethyl acetate / hexane to obtain Intermediate 3 with a yield of 81.9%.

[0057] Synthesis of beprofen:

[0058] Under nitrogen protection, Intermediate 3 (4.78 g, 0.02 mmol), aqueous sodium hydroxide solution (0.06 mmol, 1.5 mol / L) and water (8 mL) were added to ethanol (25 mL), and the mixture was refluxed for 5 h. After the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and separated by silica gel column chromatography with petroleum ether / ethyl acetate to obtain beprofen with a yield of 78.9% and a purity of 99.7%.

[0059] The present invention also provides a high-efficiency synthesis method of beprofen, comprising the following steps:

[0060] (1) Under the action of Catalyst 1, p-bromophenylacetonitrile and dimethyl carbonate undergo an alkylation reaction to obtain Intermediate 1;

[0061] (2) Intermediate 1 undergoes a Bouveault aldehyde synthesis reaction with an organolithium reagent and N,N-dimethylformamide to obtain Intermediate 2;

[0062] (3) Under the action of Catalyst 2, Intermediate 2 undergoes a condensation reaction with 1-morpholinocyclohexene to obtain Intermediate 3;

[0063] (4) Intermediate 3 undergoes a hydrolysis reaction to obtain febuprofene.

[0064] The synthesis route is as follows:

[0065]

[0066] Furthermore, the Catalyst 1 includes, but is not limited to, one or several of sodium bromide, potassium bromide, sodium iodide, and potassium iodide, preferably sodium bromide. Under the action of the catalyst, dimethyl carbonate is hydrolyzed to generate carbonate ions, and the carbonate ions undergo a nucleophilic substitution reaction with p-bromophenylacetonitrile to introduce a methyl group into p-bromophenylacetonitrile.

[0067] Furthermore, the molar ratio of p-bromophenylacetonitrile to dimethyl carbonate and Catalyst 1 is 1:(5 - 10):(1 - 2), preferably 1:(5 - 8):(1 - 1.5). Dimethyl carbonate not only participates in the reaction but also acts as a solvent, and the unreacted dimethyl carbonate can be recovered from the waste liquid by vacuum distillation.

[0068] Furthermore, the alkylation reaction is carried out under nitrogen protection, and the reaction pressure is 0.1 - 2 MPa, preferably 0.5 - 2 MPa.

[0069] Furthermore, the temperature of the alkylation reaction is 120 - 180 °C, preferably 140 - 160 °C. The alkylation reaction needs to be carried out under specific temperature and pressure conditions, and nitrogen is used as a protective gas to prevent impurities such as moisture and oxygen from contacting the reactants to generate by-products, thereby improving the purity of Intermediate 1.

[0070] Furthermore, the organolithium reagent includes, but is not limited to, one or several of n-butyllithium and tert-butyllithium, preferably n-butyllithium. Intermediate 1 and N,N-dimethylformamide undergo a Bouveault aldehyde synthesis reaction under the action of the organolithium reagent to convert the bromo substituent into an aldehyde group to obtain Intermediate 2.

[0071] Furthermore, the molar ratio of Intermediate 1 to the organolithium reagent and N,N-dimethylformamide is 1:(1 - 2):(1 - 2), preferably 1:(1 - 1.5):(1 - 1.5).

[0072] Further, the temperature of the Bouveault aldehyde synthesis reaction is -90 to 0 °C, preferably -78 to -30 °C. Since the molecular movement of organolithium reagents is slow at low temperatures, it is easier for them to react with reactants.

[0073] Further, the catalyst 2 is aluminum boride (AlB2), preferably nano-aluminum boride. The catalyst 2 can promote the formation of carbanions of 1-morpholino-1-cyclohexene, accelerate the reaction rate, increase the yield of intermediate 3, and thus further increase the total yield of perbinofel.

[0074] Further, the molar ratio of the intermediate 2 to 1-morpholino-1-cyclohexene and the catalyst 2 is 1:(1 - 3):(0.1 - 0.3), preferably 1:(1 - 2):(0.1 - 0.2).

[0075] Further, the temperature of the condensation reaction is 20 to 90 °C, preferably 30 to 80 °C.

[0076] Further, the hydrolysis reaction is carried out under alkaline conditions, and the base includes but is not limited to one or more of sodium hydroxide, potassium hydroxide, and potassium carbonate, preferably sodium hydroxide. Of course, the hydrolysis of the cyano group can also be carried out under acidic conditions.

[0077] Further, the molar ratio of the intermediate 3 to the base is 1:(1 - 3), preferably 1:(1 - 2).

[0078] Further, the temperature of the hydrolysis reaction is 60 to 120 °C, preferably 80 to 110 °C. Carrying out the hydrolysis reaction under heating conditions can increase the reaction rate and make the reaction more complete.

[0079] Example 4

[0080] Synthesis of intermediate 3:

[0081] Dissolve intermediate 2 (14.08 g, 0.084 mol) and 1-morpholino-1-cyclohexene (14.03 g, 0.084 mol) in 100 mL of dichloromethane, then add nano-aluminum boride with an average particle size of 30 nm (0.41 g, 0.0084 mol), and react at 80 °C for 3 h. After the reaction is completed, add hydrochloric acid (50 mL, 6 mol / L) to the reaction solution, stir at room temperature for 1 h, extract with dichloromethane, wash the organic phase with water, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, precipitate crystals, and recrystallize with ethyl acetate / hexane to obtain intermediate 3 with a yield of 89.7%.

[0082] Example 5

[0083] Synthesis of intermediate 3:

[0084] Intermediate 2 (14.08 g, 0.084 mol) and 1-morpholino-1-cyclohexene (14.03 g, 0.084 mol) were dissolved in 100 mL of dichloromethane, and then nano-aluminum boride with an average particle size of 20 nm (0.82 g, 0.0168 mol) was added. The mixture was heated to 80 °C and reacted for 2 h. After the reaction was completed, hydrochloric acid (50 mL, 6 mol / L) was added to the reaction solution, and the mixture was stirred at room temperature for 1 h. It was extracted with dichloromethane, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, crystals were precipitated, and recrystallized with ethyl acetate / hexane to obtain Intermediate 3 with a yield of 93.5%.

[0085] Example 6

[0086] Synthesis of Intermediate 3:

[0087] Intermediate 2 (14.08 g, 0.084 mol) and 1-morpholino-1-cyclohexene (14.03 g, 0.084 mol) were dissolved in 100 mL of dichloromethane, and then nano-aluminum boride with an average particle size of 30 nm (1.22 g, 0.0252 mol) was added. The mixture was heated to 80 °C and reacted for 2 h. After the reaction was completed, hydrochloric acid (50 mL, 6 mol / L) was added to the reaction solution, and the mixture was stirred at room temperature for 1 h. It was extracted with dichloromethane, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, crystals were precipitated, and recrystallized with ethyl acetate / hexane to obtain Intermediate 3 with a yield of 94.2%.

[0088] It can be seen from Examples 4 - 6 that adding nano-aluminum boride as a catalyst for the condensation reaction of synthesizing Intermediate 3 from Intermediate 2 can not only substantially improve the yield of Intermediate 3, but also shorten the reaction time. At the same time, the amount of nano-aluminum boride needs to be controlled. Excessive nano-aluminum boride will not further effectively improve the yield of Intermediate 3, but will increase the cost.

[0089] The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What is described in the above embodiments and the specification only illustrates the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of the present invention claimed. The scope of protection claimed by the present invention is defined by the appended claims and their equivalents.

Claims

1. An efficient synthesis method of bepridilol, characterized in that, It includes the following steps: (1) Under the action of a catalyst, bromophenylacetonitrile reacts with dimethyl carbonate in an alkylation reaction to obtain intermediate 1; (2) Intermediate 1 undergoes a Bouveault aldehyde synthesis reaction with an organolithium reagent and N,N-dimethylformamide to obtain intermediate 2; (3) Intermediate 2 undergoes a condensation reaction with 1-morpholino-1-cyclohexene to obtain intermediate 3; (4) Intermediate 3 undergoes a hydrolysis reaction to obtain beprifene; The synthesis route is as follows:

2. The high-efficiency synthesis method of peribuprofen according to claim 1, wherein: The catalyst is selected from one or more of sodium bromide, potassium bromide, sodium iodide, and potassium iodide; Preferably, the molar ratio of bromophenylacetonitrile to dimethyl carbonate and the catalyst is 1:(5-10):(1-2).

3. The high-efficiency synthesis method of pebrofenn according to claim 1, characterized in that: The alkylation reaction is carried out under nitrogen protection, and the reaction pressure is 0.1-2 MPa; Preferably, the temperature of the alkylation reaction is 120-180 °C.

4. The high-efficiency synthesis method of perbuprofen according to claim 1, wherein: The organolithium reagent is selected from one or more of n-butyllithium and tert-butyllithium; Preferably, the molar ratio of intermediate 1 to the organolithium reagent and N,N-dimethylformamide is 1:(1-2):(1-2).

5. The high-efficiency synthesis method of pebrofenn according to claim 1, wherein: The temperature of the Bouveault aldehyde synthesis reaction is -90-0 °C.

6. The high-efficiency synthesis method of pebrofen according to claim 1, characterized in that: The molar ratio of intermediate 2 to 1-morpholino-1-cyclohexene is 1:(1-3).

7. The high-efficiency synthesis method of perbuprofen according to claim 1, characterized in that: The temperature of the condensation reaction is 20-90 °C.

8. The highly efficient synthesis method of perbuprofen according to claim 1, characterized in that: The hydrolysis reaction is carried out under alkaline conditions, and the base is selected from one or more of sodium hydroxide, potassium hydroxide, and potassium carbonate.

9. The high-efficiency synthesis method of peribuprofen according to claim 8, characterized in that: The molar ratio of intermediate 3 to the base is 1:(1-3).

10. The high-efficiency synthesis method of peribuprofen according to claim 1, wherein: The temperature of the hydrolysis reaction is 60-120 °C.

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