Preparation method of 2-[4-(1-oxo-2-isoindolinyl) phenyl] butyric acid

Abstract

The invention discloses a preparation method of 2-[4-(1-oxo-2-isoindolinyl) phenyl] butyric acid, which belongs to the technical field of drug synthesis, and is characterized by comprising the following steps: (1) in an organic solvent, heating 2-(4-aminophenyl) butyric acid and o-phthalaldehyde to directly react; and (2) carrying out vacuum concentration and ethanol-water reflux pulping treatment to obtain the 2-[4-(1-oxo-2-isoindolinyl) phenyl] butyric acid. The method has the beneficial effects that the 2-[4-(1-oxo-2-isoindolinyl) phenyl] butyric acid is obtained by direct reaction without adding a catalyst under a heating condition, so that the method is more environment-friendly, more economical and more suitable for industrial production.

Description

Technical field:

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for preparing 2-[4-(1-oxo-2-isoindolyl)phenyl]butyric acid. Background technology:

[0002] 2-[4-(1-oxo-2-isoindolyl)phenyl]butyric acid, also known as indobufen, is a racemic mixture developed by Pfizer in the United States. It was first successfully developed by Farmfalia Carlo Erba S.PA in Italy and first launched in Italy (ICH member country) in August 1984. It is currently the only reversible, selective multi-target anti-thrombotic exclusive new drug in the world. It can be a platelet aggregation inhibitor and has anti-inflammatory and analgesic effects. In the current production process of indobufen, most processes undergo multiple reduction reactions or high-temperature reactions.

[0003] In the synthesis process of 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid introduced in Chinese patent CN106631974, 2-(4-aminophenyl)butyric acid and phthalic anhydride are used for cyclization reaction to obtain 2-[4-(1,3-dioxo-2-isoindolinyl)phenyl]butyric acid, and then zinc powder-hydrogen chloride reduction is used to obtain 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid. The raw materials used in this route are widely available and of controllable quality, reagents and solvents are easily available, and the reaction and post-treatment are simple, but zinc powder reduction is used in the reduction process, which increases environmental pressure.

[0004]

[0005] In Japanese patents JP51068563, JP52017463 and German patent DE2154525, in the synthesis process of 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid, isoindolin-1-one and ethyl 2-(4-aminophenyl)butyrate are reacted at high temperature to generate ethyl 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyrate, which is then hydrolyzed under potassium carbonate to generate 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid. The reaction conditions of this route are relatively harsh and the reaction temperature is too high.

[0006]

[0007] Therefore, there is an urgent need for a preparation method of indobufen that is simple in preparation process, environmentally friendly, and suitable for industrial production. The present invention directly reacts 2-(4-aminophenyl)butyric acid with o-phthalaldehyde, does not require the addition of a catalyst, does not require a high-temperature reaction, and is more suitable for industrial production. Summary of the invention:

[0008] In order to solve the above problems and overcome the shortcomings of the prior art, the present invention provides a preparation method of indobufen which is simple in preparation process, environmentally friendly and suitable for industrial production, and can effectively solve the problem that the existing preparation method of 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid requires a catalyst, high temperature and produces a large number of by-products, resulting in greater difficulty in subsequent processing.

[0009] The specific technical solution of the present invention to solve the above technical problem is: a method for preparing 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid, characterized by comprising the following steps:

[0010]

[0011] (1) In an organic solvent, 2-(4-aminophenyl)butyric acid and o-phthalaldehyde are directly reacted by heating;

[0012] (2) removing the remaining o-phthalaldehyde and other impurities by vacuum concentration and ethanol-water reflux beating;

[0013] High-purity 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid is obtained.

[0014] Furthermore, in the embodiment, the molar ratio of 2-(4-aminophenyl)butyric acid to o-phthalaldehyde is 1:1.09-1.3.

[0015] Furthermore, in the embodiment, the reaction temperature is 55-75°C.

[0016] Furthermore, in the embodiment, the solvent for the reaction is tetrahydrofuran or N,N-dimethylformamide.

[0017] The beneficial effects of the present invention are:

[0018] By controlling the molar ratio of 2-(4-aminophenyl)butyric acid to o-phthalaldehyde, tetrahydrofuran is used as a reaction solvent, and under heating conditions, no catalyst needs to be added, and 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid is directly obtained by reaction, which is more environmentally friendly, more economical, and more suitable for industrial production. Description of the drawings:

[0019] Attached Figure 1 The HPLC spectrum of the product 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid obtained according to the conditions of the present invention is schematic;

[0020] Attached Figure 2 The figure is the H NMR spectrum of the product 2-[4-(1-oxo-2-isoindolyl)phenyl]butyric acid obtained according to the conditions of the present invention. Specific implementation method:

[0021] In the description of the present invention, specific details are only for a full understanding of the embodiments of the present invention, but those skilled in the art should know that the implementation of the present invention is not limited to these details. In addition, well-known structures and functions are not described or shown in detail to avoid blurring the key points of the embodiments of the present invention. For those of ordinary skill in the art, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0022] Specific implementation of the present invention:

[0023] In order to better understand the present invention, a specific embodiment is used for illustration. It is worth emphasizing that the effect of this embodiment is not substantially different from the various embodiments within the protection scope of the present invention, including the respective reagents and the content ratio of the reagents, and all of them can achieve the effects described in the present invention and solve the above-mentioned problems. Other combinations are not described here.

[0024] Embodiment 1:

[0025] Add 54mL of tetrahydrofuran and o-phthalaldehyde (10.71g, 79.85mmol, 1.10eq) to a 250ml three-necked flask, stir, heat to an internal temperature of 55°C, and start dripping a solution of 2-(4-aminophenyl)butyric acid (13.01g, 72.59mmol, 1.0eq) and 130mL of tetrahydrofuran. After dripping, control the reaction temperature to 65°C for 4 hours. TLC detects that the reaction is complete, stop heating, remove the solvent under reduced pressure to obtain a dark red solid, until no liquid drops, add 95% ethanol, control the temperature to 75-80°C, reflux and slurry for 0.5 hours. After cooling to room temperature, filter, rinse with anhydrous ethanol, and dry under reduced pressure. The material is collected to obtain 16.08g of 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid, with a yield of 75.00% and a HPLC purity of 99.35%.

[0026] Embodiment 2:

[0027] Add 56mL of tetrahydrofuran and o-phthalaldehyde (11.20g, 83.50mmol, 1.15eq) to a 250ml three-necked flask, stir, heat to an internal temperature of 55°C, and start dripping a solution of 2-(4-aminophenyl)butyric acid (13.01g, 72.59mmol, 1.0eq) and 130mL of tetrahydrofuran. After dripping, control the reaction temperature to 75°C for 4 hours. TLC detects that the reaction is complete, stop heating, remove the solvent under reduced pressure to obtain a dark red solid, until no liquid drops, add 95% ethanol, control the temperature to 75-80°C, reflux and slurry for 0.5 hours. After cooling to room temperature, filter, rinse with anhydrous ethanol, and dry under reduced pressure. The material is collected to obtain 16.16g of 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid, with a yield of 75.38% and a HPLC purity of 99.29%.

[0028] Embodiment 3:

[0029] Add 58mL of tetrahydrofuran and o-phthalaldehyde (11.68g, 87.08mmol, 1.20eq) to a 250ml three-necked flask, stir, heat to an internal temperature of 55°C, and start dripping a solution of 2-(4-aminophenyl)butyric acid (13.01g, 72.59mmol, 1.0eq) and 130mL of tetrahydrofuran. After dripping, control the reaction temperature to 55°C for 4 hours. TLC detects that the reaction is complete, stop heating, remove the solvent under reduced pressure to obtain a dark red solid, until no liquid drops, add 95% ethanol, control the temperature to 75-80°C, reflux and slurry for 0.5 hours. After cooling to room temperature, filter, rinse with anhydrous ethanol, and dry under reduced pressure. The material is collected to obtain 16.04g of 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid, with a yield of 74.82% and a HPLC purity of 99.23%.

[0030] In order to more intuitively demonstrate the effect of the molar ratio of 2-(4-aminophenyl)butyric acid to o-phthalaldehyde on the process of the present invention, a comparison is made by an equivalent replacement method;

[0031] Comparative Example 1:

[0032] The preparation method is the same as that of Example 1, except that in the preparation process of this comparative example, the molar ratio of 2-(4-aminophenyl)butyric acid to o-phthalaldehyde is 1:0.9;

[0033] Comparative Example 2:

[0034] The preparation method is the same as that of Example 1, except that in the preparation process of this comparative example, the molar ratio of 2-(4-aminophenyl)butyric acid to o-phthalaldehyde is 1:1.0;

[0035] Comparative Example 3:

[0036] The preparation method is the same as that of Example 1, except that in the preparation process of this comparative example, the molar ratio of 2-(4-aminophenyl)butyric acid to o-phthalaldehyde is 1:1.3;

[0037] Comparative Example 4:

[0038] The preparation method is the same as that of Example 1, except that in the preparation process of this comparative example, the molar ratio of 2-(4-aminophenyl)butyric acid to o-phthalaldehyde is 1:1.5;

[0039] Table 1: Effect of the molar ratio of 2-(4-aminophenyl)butyric acid to o-phthalaldehyde on yield and purity

[0040]

[0041] From the data analysis in Table 1, we can see that:

[0042] (1) Comparative Examples 1-2 and the present invention are compared:

[0043] The molar ratio of 2-(4-aminophenyl)butyric acid to o-phthalaldehyde is too low, and the product yield is too low. The reason may be that 2-(4-aminophenyl)butyric acid cannot react completely, but the excess 2-(4-aminophenyl)butyric acid can be removed in the post-treatment process;

[0044] (2) Comparative Examples 3-4 and the present invention are compared:

[0045] The molar ratio of 2-(4-aminophenyl)butyric acid to o-phthalaldehyde is too high, and the product quality is poor. The reason may be that after the 2-(4-aminophenyl)butyric acid is completely reacted, o-phthalaldehyde cannot be removed during the post-treatment process, resulting in a purity far lower than that of the present invention.

[0046] (3) The present invention preferably uses a molar ratio of 2-(4-aminophenyl)butyric acid to o-phthalaldehyde of 1:1.09 to 1.3. Under heating conditions, no catalyst is required to directly react to obtain 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid, and the yield and purity are higher than those in the comparative example.

[0047] In order to more intuitively demonstrate the effect of the reaction temperature of 2-(4-aminophenyl)butyric acid and o-phthalaldehyde on the process of the present invention, a comparison is made by an equivalent replacement method;

[0048] Comparative Example 4:

[0049] The preparation method is the same as that of Example 1, except that: in the preparation process of this comparative example, the reaction temperature is 25°C;

[0050] Comparative Example 5:

[0051] The preparation method is the same as that of Example 1, except that: in the preparation process of this comparative example, the reaction temperature is 35°C;

[0052] Comparative Example 6:

[0053] The preparation method is the same as that of Example 1, except that: in the preparation process of this comparative example, the reaction temperature is 45°C;

[0054] Comparative Example 7:

[0055] The preparation method is the same as that of Example 1, except that: in the preparation process of this comparative example, the reaction temperature is 85°C;

[0056] Table 2: Effect of reaction temperature of 2-(4-aminophenyl)butyric acid and o-phthalaldehyde on process

[0057]

[0058] From the data analysis in Table 2, we can see that:

[0059] (1) Comparative Examples 4-7 are compared with the present invention:

[0060] The temperature is too low, the product yield is low, and the quality is poor. The reason may be that the temperature is too low, and the reaction between 2-(4-aminophenyl)butyric acid and o-phthalaldehyde is incomplete, thus affecting the yield and quality of the product;

[0061] The temperature was too high and the experiment could not proceed normally. The boiling point of tetrahydrofuran is 66°C. The temperature was too high and the solvent boiled violently and could not be condensed and refluxed well. Therefore, the experiment could not proceed normally.

[0062] (2) The present invention preferably adopts a reaction temperature of 55 to 75° C. Under heating conditions, no catalyst needs to be added, and 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid is directly obtained by reaction, and the yield and purity are higher than those of the comparative example;

[0063] In order to more intuitively demonstrate the effects of the present invention on the reaction of the reaction solvent, the raw materials at different positions of the amino group of the benzene ring and o-phthalaldehyde, a comparative experiment was conducted.

[0064] Comparative Example 8:

[0065] The preparation method is the same as that of Example 3, except that: in the preparation process of this comparative example, the reactants are 2-(3-aminophenyl)butyric acid and o-phthalaldehyde;

[0066] Comparative Example 9:

[0067] The preparation method is the same as that of Example 3, except that: in the preparation process of this comparative example, the reactants are 2-(2-aminophenyl)butyric acid and o-phthalaldehyde;

[0068] Comparative Example 10:

[0069] The preparation method is the same as that of Example 3, except that in the preparation process of this comparative example, the reaction solvent is methanol;

[0070] Comparative Example 11:

[0071] The preparation method is the same as that of Example 3, except that in the preparation process of this comparative example, the reaction solvent is ethanol;

[0072] Table 3: Effects of reaction solvent, raw materials at different positions of the amino group of the benzene ring and o-phthalaldehyde on the reaction;

[0073]

[0074] From the data analysis in Table 3, we can see that:

[0075] (1) By comparing and analyzing the above table: 2-(3-aminophenyl)butyric acid and 2-(2-aminophenyl)butyric acid cannot react with o-phthalaldehyde due to steric hindrance. Therefore, the present invention is only applicable to the reaction of 2-(4-aminophenyl)butyric acid with o-phthalaldehyde; it can be seen that not all groups with amino groups, even groups with amino groups containing benzene rings, can react with o-phthalaldehyde to form a closed ring structure to obtain a similar structure as 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid of the present invention.

[0076] (2) Methanol and ethanol are protic solvents used as reaction solvents. It is theoretically speculated that methanol and ethanol are protic solvents used as reaction solvents and will react with the raw material o-phthalaldehyde to undergo aldol condensation under the catalysis of carboxylic acid. However, compared with tetrahydrofuran, methanol and ethanol are protic solvents used as reaction solvents and have the following disadvantages: more by-products and lower purity of the obtained product.

[0077] Embodiment 4:

[0078] Add 54mL N,N-dimethylformamide and o-phthalaldehyde (10.71g, 79.85mmol, 1.10eq) to a 250ml three-necked flask, stir, heat to an internal temperature of 55°C, and start dripping a solution of 2-(4-aminophenyl)butyric acid (13.01g, 72.59mmol, 1.0eq) and 130mL N,N-dimethylformamide. After dripping, control the reaction temperature to 65°C for 4h. TLC is used to detect the reaction progress. After the reaction is completed, stop heating, remove the solvent under reduced pressure to obtain a dark red solid. When no liquid drops, add 95% ethanol, control the temperature to 75-80°C, and reflux for 0.5 hours. After cooling to room temperature, filter, rinse with anhydrous ethanol, and dry under reduced pressure. The material is obtained as 13.46g of 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid, with a yield of 62.78% and a HPLC purity of 99.15%.

[0079] As another embodiment of the present invention, the same as Example 1-3, except that tetrahydrofuran is used as the reaction solvent instead of N,N-dimethylformamide, and the purity as in Example 1-3 can be obtained, but the yield is poorer than that in Example 1-3, which is 62.78%; it is also possible to directly react to obtain 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid by controlling the molar ratio of 2-(4-aminophenyl)butyric acid to o-phthalaldehyde under heating conditions without adding a catalyst, and N,N-dimethylformamide is used as the reaction solvent of the present invention for protection.

[0080] In summary, 2-(2-aminophenyl)butyric acid is directly reacted with o-phthalaldehyde to prepare 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid. By controlling the molar ratio of 2-(4-aminophenyl)butyric acid to o-phthalaldehyde, under heating conditions, no catalyst is needed to be added, and 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid is directly obtained by reaction.

Claims

1. A method for preparing 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid, characterized in that The following steps are involved: (1) In an organic solvent, 2-(4-aminophenyl)butyric acid and o-phthalaldehyde are directly reacted by heating; (2) The product was concentrated under reduced pressure and slurried under reflux with ethanol-water to obtain 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid.

2. The method for preparing 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid according to claim 1, characterized in that The molar ratio of the 2-(4-aminophenyl)butyric acid to o-phthalaldehyde is 1:1.09-1.

3.

3. The method for preparing 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid according to claim 1, characterized in that The reaction temperature is 55-75°C.

4. The method for preparing 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid according to any one of claims 1 to 3, characterized in that The solvent for the reaction is tetrahydrofuran.

5. The method for preparing 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid according to any one of claims 1 to 3, characterized in that The solvent of the reaction is N,N-dimethylformamide.

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