A method for the synthesis of a key intermediate of indobufen

Abstract

The application provides a preparation method of an indobufen key intermediate. The method uses 2-(4-nitrophenyl) butyric acid and phthalic anhydride as raw materials, and obtains the target compound (I) through a one-pot method. The method has the advantages of simple operation, mild conditions, high reaction yield, reduced cost through mother liquor recycling and reuse, significantly reduced "three wastes" and environmental protection, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for synthesizing a key intermediate of edoxaban. Background Technology

[0002] Indobufen is an antiplatelet aggregation drug primarily used to treat ischemic cardiovascular disease, ischemic cerebrovascular disease, and venous thrombosis caused by arteriosclerosis. It can also be used to prevent thrombosis during hemodialysis. It works by inhibiting cyclooxygenase-1 (COX-1) to reduce the production of thromboxane A2, thereby preventing platelet activation and aggregation. Indobufen exerts its antiplatelet aggregation effect by inhibiting the release of platelet factors such as ADP, serotonin, platelet factor 4, and β-thromboglobulin. This drug has no effect on various blood coagulation parameters, but it can moderately prolong bleeding time; abnormal platelet function returns to normal after discontinuation of the drug.

[0003] 2-[4-(1,3-dihydro-1,3-dicarbonyl-2H-isoindol-2-yl)phenyl]butyric acid (I) is a key intermediate in the synthesis of indobufen, and its quality and cost play a crucial role in the synthesis of indobufen.

[0004]

[0005] Chinese patent (CN106631974A) discloses a method for obtaining 2-[4-(1,3-dihydro-1,3-dicarbonyl-2H-isoindol-2-yl)phenyl]butyric acid from 2-(4-nitrophenyl)butyric acid as a starting material through a two-step reaction. The reaction process is shown below:

[0006]

[0007] In this process, the nitro reduction uses a carbon-supported noble metal catalyst, such as Pd / C or Pt / C, and the organic acid used is an acetic acid system. The reduced product, 2-(4-aminophenyl)butyric acid, then reacts with phthalic anhydride to obtain the target compound, 2-[4-(1,3-dihydro-1,3-dicarbonyl-2H-isoindol-2-yl)phenyl]butyric acid. The problem with this process is that 2-(4-aminophenyl)butyric acid is insoluble in the acetic acid system and will precipitate out. If a traditional heterogeneous catalyst is used, the product will be trapped with the catalyst, making catalyst recovery impossible. This significantly increases production costs and is detrimental to industrial production. Summary of the Invention

[0008] In view of the shortcomings of the existing technology, the purpose of this invention is to provide a method for synthesizing 2-[4-(1,3-dihydro-1,3-dicarbonyl-2H-isoindole-2-yl)phenyl]butyric acid, a key intermediate of indobufen. This method has the advantages of simple operation, mild conditions, high overall yield and significantly reduced cost, and is suitable for industrial production.

[0009] To achieve the above objectives, the present invention adopts the following technical solution;

[0010] A method for preparing 2-[4-(1,3-dihydro-1,3-dicarbonyl-2H-isoindol-2-yl)phenyl]butyric acid (I), the synthetic route of which is as follows:

[0011]

[0012] The preparation method includes the following steps:

[0013] S1: Add 2-(4-nitrophenyl)butyric acid, catalyst, glacial acetic acid, and phthalic anhydride to the hydrogenation reactor. Purge with hydrogen until the pressure inside the reactor reaches 0.5 MPa. After reacting at 80-100℃ for 4-6 hours, increase the pressure to 1.5 MPa and react for another 4 hours. After the reaction is complete, filter the liquid. Wash the filter cake with a small amount of glacial acetic acid. Recover the mother liquor and reuse it directly. Pulverize the solid with methanol at room temperature, filter, and dry to obtain 2-[4-(1,3-dihydro-1,3-dicarbonyl-2H-isoindol-2-yl)phenyl]butyric acid (I).

[0014] S2: Add 2-(4-nitrophenyl)butyric acid and phthalic anhydride to the mother liquor recovered from S1. Purge with hydrogen to a pressure of 0.5 MPa inside the reactor. Control the temperature at 80-100℃ and react for 4-6 hours. Then increase the pressure to 1.5 MPa and react for another 4 hours. After the reaction is complete, filter the liquid. Wash the filter cake with a small amount of glacial acetic acid. Recover the mother liquor and reuse it. Pulverize the solid with methanol at room temperature, filter, and dry to obtain 2-[4-(1,3-dihydro-1,3-dicarbonyl-2H-isoindol-2-yl)phenyl]butyric acid (I).

[0015] Furthermore, in S1, the catalyst is one of triphenylphosphine ruthenium chloride, pentamethylcyclopentadienyl bis(triphenylphosphine) ruthenium chloride, and tri(triphenylphosphine)carbonyl dihydroruthenium, preferably triphenylphosphine ruthenium chloride.

[0016] Furthermore, in S1, the molar ratio of 2-(4-nitrophenyl)butyric acid to the catalyst is 1:0.004 to 1:0.008, preferably 1:0.005.

[0017] Furthermore, in S1, the molar ratio of 2-(4-nitrophenyl)butyric acid to glacial acetic acid is 1:5 to 1:8.

[0018] Furthermore, in S1, the molar ratio of 2-(4-nitrophenyl)butyric acid to phthalic anhydride is 1:1.1 to 1:1.2, preferably 1:1.1.

[0019] Furthermore, in S2, the molar amounts of 2-(4-nitrophenyl)butyric acid and phthalic anhydride are the same as in S1.

[0020] Furthermore, the methanol is prepared at a room temperature of 10–30°C.

[0021] Compared with the prior art, the advantages of the present invention are as follows:

[0022] (1) A method for preparing a key intermediate of indobufen is provided. The reaction route is shortened by a one-pot synthesis method, and the reaction conditions are mild, the yield is higher, the product quality is better, and it is suitable for large-scale commercial production.

[0023] (2) The cost is lower by recycling and reusing solvents and catalysts, and the amount of "three wastes" is significantly reduced compared with traditional methods, which greatly reduces the environmental pressure in the production process. Detailed Implementation

[0024] To better understand the technical solution of the present invention, further explanation is provided in conjunction with specific embodiments of the present invention, so that those skilled in the art can better understand the present invention, but this is not intended to be a limitation.

[0025] Example 1

[0026] 400 g of 2-(4-nitrophenyl)butyric acid, 9.2 g of triphenylphosphine diruthenium chloride, 700 g of glacial acetic acid, and 313 g of phthalic anhydride were added to a hydrogenation reactor. Hydrogen gas was introduced until the pressure inside the reactor reached 0.5 MPa. After reacting at 80-100℃ for 4-6 hours, the pressure was increased to 1.5 MPa and the reaction was continued for another 4 hours. After the reaction was completed, the liquid was filtered. The filter cake was washed with a small amount of glacial acetic acid. The mother liquor was recovered and reused directly. The solid was slurried with 800 g of methanol at room temperature, filtered, and dried to obtain 540 g of 2-[4-(1,3-dihydro-1,3-dicarbonyl-2H-isoindol-2-yl)phenyl]butyric acid (I), yield 91.1%, mp: 216-218℃.

[0027] Example 2

[0028] The recovered mother liquor from Example 1 was added to a hydrogenation reactor along with 400 g of 2-(4-nitrophenyl)butyric acid and 313 g of phthalic anhydride. Hydrogen gas was introduced until the pressure inside the reactor reached 0.5 MPa. The reaction was carried out at 80-100°C for 4-6 hours, and then the pressure was increased by 1.5 MPa for another 4 hours. After the reaction was completed, the liquid was filtered, the filter cake was washed with a small amount of glacial acetic acid, the mother liquor was recovered and reused directly, and the solid was slurried with 800 g of methanol at room temperature, filtered, and dried to obtain 536 g of 2-[4-(1,3-dihydro-1,3-dicarbonyl-2H-isoindol-2-yl)phenyl]butyric acid (I), with a yield of 90.4% and mp: 216-218°C.

[0029] Example 3

[0030] 400 g of 2-(4-nitrophenyl)butyric acid, 7.7 g of pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium chloride, 700 g of glacial acetic acid, and 313 g of phthalic anhydride were added to a hydrogenation reactor. Hydrogen gas was introduced to bring the pressure inside the reactor to 0.5 MPa, and the reaction was carried out at 80-100℃ for 4-6 hours. Then, the pressure was increased to 1.5 MPa and the reaction was carried out for another 4 hours. After the reaction was completed, the liquid was filtered, the filter cake was washed with a small amount of glacial acetic acid, the mother liquor was recovered and reused directly, and the solid was slurried with 800 g of methanol at room temperature, filtered, and dried to obtain 532 g of 2-[4-(1,3-dihydro-1,3-dicarbonyl-2H-isoindol-2-yl)phenyl]butyric acid (I), with a yield of 89.7% and mp: 216-218℃.

[0031] Example 4

[0032] The recovered mother liquor from Example 3 was added to a hydrogenation reactor along with 400 g of 2-(4-nitrophenyl)butyric acid and 313 g of phthalic anhydride. Hydrogen gas was introduced until the pressure inside the reactor reached 0.5 MPa. The reaction was carried out at 80-100°C for 4-6 hours, and then the pressure was increased to 1.5 MPa for another 4 hours. After the reaction was completed, the liquid was filtered, the filter cake was washed with a small amount of glacial acetic acid, the mother liquor was recovered and reused directly, and the solid was slurried with 800 g of methanol at room temperature, filtered, and dried to obtain 530 g of 2-[4-(1,3-dihydro-1,3-dicarbonyl-2H-isoindol-2-yl)phenyl]butyric acid (I), with a yield of 89.4% and mp: 216-218°C.

[0033] Comparative Example 1

[0034] 85 kg of 2-(4-nitrophenyl)butyric acid, 2.2 kg of Pd / C catalyst, and 850 L of acetic acid were added to the hydrogenation reactor. Stirring was started, and hydrogen gas was introduced, with the hydrogen pressure controlled at 1.0 MPa and the reaction temperature controlled at 25 °C. The hydrogenation reaction was carried out while maintaining the hydrogen pressure at 1.0 MPa. When hydrogen was no longer consumed, the reaction was stopped, and the mixture was filtered to obtain 2-(4-aminophenyl)butyric acid filtrate.

[0035] Comparative Example 2

[0036] The filtrate of 2-(4-aminophenyl)butyric acid was added to a reaction vessel. When the temperature reached 40°C, 136 kg of phthalic anhydride was slowly added. The temperature was then raised to 80°C, and the reaction was stirred for 3 hours until the cyclization reaction was complete. The mixture was then cooled to 25°C, centrifuged, and dried to obtain 113.1 kg of 2-[4-(1,3-oxo-2-isoindololinyl]phenylbutyric acid, with a yield of 89.9%.

[0037] By comparing the processes of the examples and the comparative examples, it can be found that the "one-pot" process of the examples can realize the recycling and reuse of the mother liquor, which greatly reduces the process cost. Moreover, the product yield does not decrease significantly after recycling and reuse, making it suitable for large-scale industrial production. The recycling and reuse of the mother liquor significantly reduces the emission of "three wastes" and produces good environmental protection results.

[0038] Although the present invention has been described through embodiments thereof, other embodiments that can be conceived by those skilled in the art involving variations of the present invention are also included within the scope of the present invention and are interpreted and defined by the claims of the present invention.

Claims

1. A method for preparing a key intermediate of indobufen, characterized in that: Compound (I) was obtained from 2-(4-nitrophenyl)butyric acid and phthalic anhydride via a one-step reaction, with the mother liquor being recovered and reused. The synthetic route is as follows: Its features are: S1: 2-(4-nitrophenyl)butyric acid, catalyst, glacial acetic acid, and phthalic anhydride were added to a hydrogenation reactor. Hydrogen gas was introduced until the pressure inside the reactor reached 0.5 MPa. After reacting at 80-100℃ for 4-6 hours, the pressure was increased to 1.5 MPa and the reaction was continued for another 4 hours. After the reaction was completed, the liquid was filtered, the filter cake was washed with a small amount of glacial acetic acid, the mother liquor was recovered and reused directly, and the solid was slurried with methanol at room temperature, filtered, and dried to obtain compound (I). S2: Add 2-(4-nitrophenyl)butyric acid and phthalic anhydride to the mother liquor recovered from S1. Purge with hydrogen gas until the pressure inside the reactor reaches 0.5 MPa. After reacting at 80-100℃ for 4-6 hours, increase the pressure to 1.5 MPa and react for another 4 hours. After the reaction is complete, filter the liquid. Wash the filter cake with a small amount of glacial acetic acid. Recover the mother liquor and reuse it. Pulverize the solid with methanol at room temperature, filter, and dry to obtain compound (I).

2. The preparation method according to claim 1, characterized in that... One of the following: triphenylphosphine ruthenium chloride, pentamethylcyclopentadienyl bis(triphenylphosphine) ruthenium chloride, and tri(triphenylphosphine)carbonyl dihydroruthenium.

3. The preparation method according to claim 1, characterized in that... In step S1, the molar ratio of 2-(4-nitrophenyl)butyric acid to the catalyst is 1:0.004 to 1:0.

008.

4. The preparation method according to claim 1, characterized in that... In step S1, the molar ratio of 2-(4-nitrophenyl)butyric acid to glacial acetic acid is 1:5 to 1:

8.

5. The preparation method according to claim 1, characterized in that... In step S1, the molar ratio of 2-(4-nitrophenyl)butyric acid to phthalic anhydride is 1:1.1 to 1:1.

2.

6. The preparation method according to claim 1, characterized in that... In step S2, the molar amounts of 2-(4-nitrophenyl)butyric acid and phthalic anhydride are the same as in S1.

7. The preparation method according to claim 1, characterized in that... The methanol is pulped at room temperature at a temperature of 10–30°C.

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