A method for synthesizing indobufen intermediate 2-(4-nitrophenyl)butyric acid

Abstract

The invention discloses a method for synthesizing indobufen intermediate 2 (4-nitrophenyl) butyric acid, the present invention relates to the field of compound synthesis technology, specifically including following synthesis step: step one, raw material preparation: 4-nitrobenzaldehyde, butyric acid and reducing agent, standby;Step 2, reaction: butyric acid is added into 4-nitrobenzaldehyde, then reducing agent is added, and reduction reaction is carried out. The method for synthesizing indobufen intermediate 2 (4-nitrophenyl) butyric acid, in the preparation process of 4-nitrobenzaldehyde, by using 2 (2,2,6,6-tetramethyl-4-piperidinyl-1-oxide) acetic acid aqueous solution as catalyst, its price is low and by-product is water, so that the technique is more environmentally friendly;And by adding hydrogen into 4-nitrobenzaldehyde and butyric acid, it is reduced and prepared 2 (4-nitrophenyl) butyric acid, not only improves the yield of 2 (4-nitrophenyl) butyric acid, its quality is also improved, while also effectively reducing the generation of spent acid.

Description

Technical Field

[0001] The present invention relates to the technical field of compound synthesis, in particular to a method for synthesizing 2-(4-nitrophenyl)butyric acid, an indobufen intermediate. Background Art

[0002] With the progress of society and the improvement of people's living standards, the incidence of cardiovascular and cerebrovascular diseases is increasing. Indobufen is an isoindolinylphenylbutyric acid derivative with the chemical name 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid. It is a racemic mixture developed by Pfizer in the United States. It can selectively act on circulating platelets, block thrombosis, inhibit the release of platelet factors and exert an anti-platelet aggregation effect. This inhibition is reversible, does not change plasma parameters, does not damage platelet function, and restores abnormal platelet function to normal. Compared with similar drugs, indobufen inhibits platelet factors and has an anti-platelet aggregation effect that is 2 to 5 times that of salicylic acid. It has a shorter bleeding time than salicylic acid and is the only reversible, selective multi-target antithrombotic drug currently available. It is used for the treatment and prevention of ischemic cardiovascular, cerebrovascular and peripheral vascular diseases and thrombosis caused by arteriosclerosis, with rapid onset and few side effects. The synthetic routes of indobufen or indobufen intermediates disclosed by Gao Xuepin et al. in "Synthesis of Anticoagulant Indobufen" (China Pharmaceutical Industry Journal, 1989.20(11)), Zheng Nanxiu et al. in "Preparation Process of Indobufen" (China Pharmaceutical Industry Journal, 1991.22(7)), and invention patent CN 10631974B all use 2-(4-nitrophenyl)butyric acid as the starting material. Currently, there are very few synthetic routes for 2-(4-nitrophenyl)butyric acid.

[0003] Chinese patent publication number CN114516799B discloses a method for synthesizing 2-(4-nitrophenyl)butyric acid, a key intermediate of indobufen. The method comprises reacting a compound represented by Formula I with bromoethane in an organic solvent under the action of an alkaline substance to obtain a compound represented by Formula II, and then hydrolyzing the compound represented by Formula II under acidic conditions to obtain a target product represented by Formula III. The method described in the present invention has simple steps, convenient operation, no nitration process, high safety, low pollution, and high product yield. The above-mentioned prior art solutions have the following shortcomings: during the hydrolysis reaction, sulfuric acid is required for hydrolysis, which easily has a significant impact on the reaction environment, and the reaction safety factor is low, the reaction time is long, the temperature is high, and the yield is poor. Finally, waste acid and pollutants such as organic solvents are generated, which are harmful to the environment. Therefore, the present invention provides a method for synthesizing 2-(4-nitrophenyl)butyric acid, an intermediate of indobufen, to address the above-mentioned problems. Summary of the Invention

[0004] In view of the shortcomings of the prior art, the present invention provides a method for synthesizing 2-(4-nitrophenyl)butyric acid, an intermediate of indobufen, which solves the problems mentioned in the above background technology.

[0005] To achieve the above objectives, the present invention is implemented by the following technical scheme: a method for synthesizing 2-(4-nitrophenyl)butyric acid, an indobufen intermediate, specifically comprising the following synthesis steps:

[0006] Step 1: Prepare raw materials: 4-nitrobenzaldehyde, butyric acid and reducing agent, set aside;

[0007] Step 2, reaction: adding butyric acid to 4-nitrobenzaldehyde, and then adding a reducing agent to carry out a reduction reaction;

[0008] Step 3, crystallization: crystallizing the reaction solution to obtain crystals of 2-(4-nitrophenyl)butyric acid;

[0009] Step 4: Purification: The crystals obtained in step 3 are washed, filtered, and dried to obtain the purified final product.

[0010] Preferably, the reducing agent is hydrogen.

[0011] Preferably, the molar ratio of the 4-nitrobenzaldehyde, butyric acid and reducing agent is 1:(0.5-1.5):(0.5-2).

[0012] Preferably, the reaction is carried out at room temperature and the reaction time is 6 to 9 hours.

[0013] Preferably, the preparation method of the 4-nitrobenzaldehyde is:

[0014] S1. Add 10-15 mL of dichloromethane to 1.53-1.61 g of p-nitrobenzyl alcohol and stir until the solid is completely dissolved.

[0015] S2, then add 1.2-1.5mL of 2-(2,2,6,6-tetramethyl-4-piperidinyl-1-oxide) acetic acid aqueous solution and 10-12mL of saturated sodium bicarbonate solution, and cool in a water bath;

[0016] S3. Add 10-12 mL of sodium hypochlorite solution dropwise while stirring. After the addition is complete, react at a constant temperature for 30-40 minutes.

[0017] Preferably, in S2, the water bath temperature is 15-20°C; in S3, the constant temperature is 15-20°C.

[0018] Preferably, in S3, the dripping time of the sodium hypochlorite solution is controlled to be 10 to 20 minutes.

[0019] Beneficial effects

[0020] The present invention provides a method for synthesizing 2-(4-nitrophenyl)butyric acid, an indobufen intermediate. Compared with the prior art, the method has the following advantages: In the preparation process of 4-nitrobenzaldehyde, an aqueous solution of 2-(2,2,6,6-tetramethyl-4-piperidinyl-1-oxide)acetic acid is used as a catalyst. This low-cost, water-based byproduct makes the process more environmentally friendly. Furthermore, hydrogen is added to 4-nitrobenzaldehyde and butyric acid to reduce them to produce 2-(4-nitrophenyl)butyric acid. This method not only increases the yield of 2-(4-nitrophenyl)butyric acid but also improves its quality, while effectively reducing the generation of waste acid, making the process more environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Purity analysis provided for a method of synthesizing 2-(4-nitrophenyl)butyric acid, an intermediate of indobufen, according to the present invention;

[0022] Figure 2 The invention provides a yield detection method for synthesizing the indobufen intermediate 2-(4-nitrophenyl)butyric acid. DETAILED DESCRIPTION

[0023] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0024] Example 1

[0025] A method for synthesizing the indobufen intermediate 2-(4-nitrophenyl)butyric acid specifically comprises the following synthesis steps:

[0026] Step 1: Prepare raw materials: 4-nitrobenzaldehyde, butyric acid, and a reducing agent, wherein the molar ratio of 4-nitrobenzaldehyde, butyric acid, and the reducing agent is 1:0.5:0.5, and set aside;

[0027] Wherein, the preparation method of 4-nitrobenzaldehyde is:

[0028] S1. Add 15 mL of dichloromethane to 1.53 g of p-nitrobenzyl alcohol and stir until the solid is completely dissolved;

[0029] S2, then add 11.5 mL of 2-(2,2,6,6-tetramethyl-4-piperidinyl-1-oxide) acetic acid aqueous solution and 12 mL of saturated sodium bicarbonate solution, and cool to 15 ° C in a water bath;

[0030] S3, add 12 mL of sodium hypochlorite solution dropwise while stirring. After 100 min of addition, react at a constant temperature of 15 ° C for 30 min;

[0031] Step 2, reaction: adding butyric acid to 4-nitrobenzaldehyde, then adding hydrogen, and reacting at room temperature for 6 hours;

[0032] Step 3, crystallization: crystallizing the reaction solution to obtain crystals of 2-(4-nitrophenyl)butyric acid;

[0033] Step 4: Purification: The crystals obtained in step 3 are washed, filtered, and dried to obtain the purified final product.

[0034] Example 2

[0035] A method for synthesizing the indobufen intermediate 2-(4-nitrophenyl)butyric acid specifically comprises the following synthesis steps:

[0036] Step 1: Prepare raw materials: 4-nitrobenzaldehyde, butyric acid, and a reducing agent, wherein the molar ratio of 4-nitrobenzaldehyde, butyric acid, and the reducing agent is 1:1:1, and set aside;

[0037] Wherein, the preparation method of 4-nitrobenzaldehyde is:

[0038] S1. Add 10 mL of dichloromethane to 1.55 g of p-nitrobenzyl alcohol and stir until the solid is completely dissolved;

[0039] S2, then add 1.2 mL of 2-(2,2,6,6-tetramethyl-4-piperidinyl-1-oxide) acetic acid aqueous solution and 11 mL of saturated sodium bicarbonate solution, and cool to 20 ° C in a water bath;

[0040] S3, add 11 mL of sodium hypochlorite solution dropwise while stirring. After 15 minutes of addition, react at a constant temperature of 20°C for 35 minutes;

[0041] Step 2, reaction: add butyric acid to 4-nitrobenzaldehyde, then add hydrogen, and react at room temperature for 7 hours;

[0042] Step 3, crystallization: crystallizing the reaction solution to obtain crystals of 2-(4-nitrophenyl)butyric acid;

[0043] Step 4: Purification: The crystals obtained in step 3 are washed, filtered, and dried to obtain the purified final product.

[0044] Example 3

[0045] A method for synthesizing the indobufen intermediate 2-(4-nitrophenyl)butyric acid specifically comprises the following synthesis steps:

[0046] Step 1: Prepare raw materials: 4-nitrobenzaldehyde, butyric acid, and a reducing agent, wherein the molar ratio of 4-nitrobenzaldehyde, butyric acid, and the reducing agent is 1:1.2:1.5, and set aside;

[0047] Wherein, the preparation method of 4-nitrobenzaldehyde is:

[0048] S1. Add 13 mL of dichloromethane to 1.60 g of p-nitrobenzyl alcohol and stir until the solid is completely dissolved;

[0049] S2, then add 1.4 mL of 2-(2,2,6,6-tetramethyl-4-piperidinyl-1-oxide) acetic acid aqueous solution and 12 mL of saturated sodium bicarbonate solution, and cool to 18 ° C in a water bath;

[0050] S3, add 12 mL of sodium hypochlorite solution dropwise while stirring. After 18 minutes of addition, react at a constant temperature of 20°C for 40 minutes;

[0051] Step 2, reaction: adding butyric acid to 4-nitrobenzaldehyde, then adding hydrogen, and reacting at room temperature for 8 hours;

[0052] Step 3, crystallization: crystallizing the reaction solution to obtain crystals of 2-(4-nitrophenyl)butyric acid;

[0053] Step 4: Purification: The crystals obtained in step 3 are washed, filtered, and dried to obtain the purified final product.

[0054] Example 4

[0055] A method for synthesizing the indobufen intermediate 2-(4-nitrophenyl)butyric acid specifically comprises the following synthesis steps:

[0056] Step 1: Prepare raw materials: 4-nitrobenzaldehyde, butyric acid, and a reducing agent, wherein the molar ratio of 4-nitrobenzaldehyde, butyric acid, and the reducing agent is 1:1.5:0.5, and set aside;

[0057] Wherein, the preparation method of 4-nitrobenzaldehyde is:

[0058] S1. Add 10 mL of dichloromethane to 1.61 g of p-nitrobenzyl alcohol and stir until the solid is completely dissolved;

[0059] S2, then add 1.2 mL of 2-(2,2,6,6-tetramethyl-4-piperidinyl-1-oxide) acetic acid aqueous solution and 10 mL of saturated sodium bicarbonate solution, and cool to 20 ° C in a water bath;

[0060] S3, add 10 mL of sodium hypochlorite solution dropwise while stirring. After 20 minutes of addition, react at a constant temperature of 20°C for 40 minutes;

[0061] Step 2, reaction: adding butyric acid to 4-nitrobenzaldehyde, then adding hydrogen, and reacting at room temperature for 9 hours;

[0062] Step 3, crystallization: crystallizing the reaction solution to obtain crystals of 2-(4-nitrophenyl)butyric acid;

[0063] Step 4: Purification: The crystals obtained in step 3 are washed, filtered, and dried to obtain the purified final product.

[0064] Comparative Example 1

[0065] A method for synthesizing the indobufen intermediate 2-(4-nitrophenyl)butyric acid specifically comprises the following synthesis steps:

[0066] Step 1: Place 120 mL of concentrated sulfuric acid and 46 g of 68% concentrated nitric acid in a reaction flask and mix;

[0067] Step 2: After cooling to 5°C in an ice bath, 60g of α-phenylbutyronitrile was added dropwise. After the addition was complete, the reaction was continued at this temperature for 1h.

[0068] Step 3: Then slowly cool to room temperature, add 120 mL of water, stir and reflux for 4 h, and cool;

[0069] Step 4: Finally, pour into 360 mL of cold water, stir to precipitate solid, filter to obtain a crude product, and then refine with toluene-petroleum ether to obtain a refined product of 2-(4-nitrophenyl)butyric acid.

[0070] Comparative Example 2

[0071] Step 1: adding p-nitrohalobenzene and alkyl acetoacetate to a solvent, reacting them under the action of sodium alkoxide or sodium hydride to obtain 2-(4-nitrophenyl)alkyl acetoacetate;

[0072] Step 2: Add the 2-(4-nitrophenyl) alkyl acetoacetate obtained in step 1 to a solvent, reduce it with hydrazine hydrate under alkaline conditions, then adjust the pH to 6, and crystallize to obtain 2-(4-nitrophenyl) butyric acid.

[0073] Purity analysis: The sample was dissolved in a chromatographic grade mixed solvent and the purity of the product was analyzed by high performance liquid chromatography (HPLC). The analysis conditions were: the chromatographic column was Luna 5μm Silica (2) The column temperature was 40°C, the flow rate was 1.0 mL / min, the detection wavelength was 254 nm, the sample weight was 1.0 mg, and the results were as follows: Figure 1 shown.

[0074]

[0075] in, is the yield of 2-(4-nitrophenyl)butyric acid, %; ω0 is the actual production amount of 2-(4-nitrophenyl)butyric acid, mg; ω1 is the theoretical production amount of 2-(4-nitrophenyl)butyric acid, mg.

[0076] like Figure 1 and Figure 2 As shown, the purity and yield of 2-(4-nitrophenyl)butyric acid prepared in Example 1-3 are significantly improved compared to those prepared in Comparative Example 1-2.

[0077] Meanwhile, the contents not described in detail in this specification belong to the prior art known to those skilled in the art.

[0078] It should be noted that, in this document, relational terms such as first and second, etc., are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "comprises," "comprising," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a list of elements includes not only those elements but also other elements not explicitly listed, or elements inherent to such process, method, article, or apparatus.

[0079] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing 2-(4-nitrophenyl)butyric acid, an indobufen intermediate, characterized by: Specifically comprising the following synthesis steps: Step 1: Prepare raw materials: 4-nitrobenzaldehyde, butyric acid and reducing agent, set aside; Step 2, reaction: adding butyric acid to 4-nitrobenzaldehyde, and then adding a reducing agent to carry out a reduction reaction; Step 3, crystallization: crystallizing the reaction solution to obtain crystals of 2-(4-nitrophenyl)butyric acid; Step 4: Purification: The crystals obtained in step 3 are washed, filtered, and dried to obtain a purified final product; The reducing agent is hydrogen.

2. A method for synthesizing 2-(4-nitrophenyl)butyric acid, an indobufen intermediate, according to claim 1, characterized in that: The molar ratio of the 4-nitrobenzaldehyde, butyric acid and reducing agent is 1:(0.5-1.5):(0.5-2).

3. A method for synthesizing 2-(4-nitrophenyl)butyric acid, an indobufen intermediate, according to claim 1, characterized in that: The reaction is carried out at room temperature and the reaction time is 6 to 9 hours.

4. A method for synthesizing 2-(4-nitrophenyl)butyric acid, an indobufen intermediate, according to claim 1, characterized in that: The preparation method of the 4-nitrobenzaldehyde: S1. Add 10-15 mL of dichloromethane to 1.53-1.61 g of p-nitrobenzyl alcohol and stir until the solid is completely dissolved. S2. Then, 1.2-1.5 mL of 2-(2,2,6,6-tetramethyl-4-piperidinyl-1-oxide)acetic acid aqueous solution and 10-12 mL of saturated sodium bicarbonate solution were added in sequence, and the mixture was cooled in a water bath; S3. Add 10-12 mL of sodium hypochlorite solution dropwise while stirring. After the addition is complete, react at a constant temperature for 30-40 minutes.

5. A method for synthesizing 2-(4-nitrophenyl)butyric acid, an indobufen intermediate, according to claim 4, characterized in that: In the S2, the water bath temperature is 15-20°C; in the S3, the constant temperature is 15-20°C.

6. A method for synthesizing 2-(4-nitrophenyl)butyric acid, an indobufen intermediate, according to claim 4, characterized in that: In the step S3, the dripping time of the sodium hypochlorite solution is controlled to be 10 to 20 minutes.

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