A preparation method of indobufen and its application in pharmaceutical composition

Abstract

A preparation method of indobufen and its application in a pharmaceutical composition. The present invention belongs to the field of pharmaceutical synthesis, and specifically discloses a preparation method of indobufen. The present invention uses 2-(4-aminophenyl)butyric acid as a starting material, performs a substitution reaction with 2-bromomethylbenzoic acid, then performs a cyclization reaction, and finally refines and purifies to obtain indobufen. Compared with other synthetic routes, the present invention has simple and easy-to-obtain starting materials, controllable intermediate quality, mild reaction conditions, suitable for large-scale industrial production, and high purity of the prepared indobufen. The indobufen bulk drug prepared by the present invention is combined with pharmaceutically acceptable excipients to obtain indobufen tablets.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical synthesis, and specifically relates to a method for preparing indobufen. Background Art

[0002] Indobufen is a very effective platelet cyclooxygenase inhibitor, and its biochemical, efficacy and clinical effects are comparable to those of standard dose aspirin. Its main indications are ischemic cardiovascular disease, ischemic cerebrovascular disease and venous thrombosis caused by arteriosclerosis. It can also be used to prevent thrombosis during hemodialysis.

[0003] Indobufen is as effective as apixaban and dabigatran in terms of the number of clinical net benefit events (stroke, systemic embolism, bleeding events and all-cause mortality), and is effective in preventing non-valvular atrial fibrillation with a better price. Indobufen's inhibitory effect on prostaglandins is significantly weaker than that of aspirin. Indobufen is more selective and tolerable than aspirin in treatment. A multi-center clinical trial in Italy conducted a monitoring study on indobufen after its marketing and found that indobufen is highly safe and has a low risk of bleeding.

[0004] Indobufen was originally developed and produced by Pfizer Italia Srl, with the trade name Ibustrin. It was first approved in 1984 and produced in Italy. Its chemical structure is: .

[0005] Some synthesis methods of indobufen have been reported in domestic and foreign literature, such as:

[0006] Prior art 1: Gao Xuemin et al., in "Synthesis of the anticoagulant indobufen" (China Pharmaceutical Industry Journal, 1989, 20 (11)), the route is:

[0007] .

[0008] This route uses 2-(4-nitrophenyl)butyric acid to react with phthalic anhydride to obtain 2-[4-(1,3-dioxo-2-isoindolinyl)phenyl]butyric acid, and then zinc powder is used to reduce 2-[4-(1,3-dioxo-2-isoindolinyl)phenyl]butyric acid. The first step reaction yield is 85.1%, and the yield is 68.5%. The overall yield is low. In addition, the zinc powder acidification system produces "three wastes".

[0009] Prior art 2: Zheng Gengxiu et al., "Preparation process of indobufen" (China Pharmaceutical Industry Journal, 1991, 22 (7)) The route is:

[0010] .

[0011] The document reports that benzyl cyanide is used as the starting material, and a three-step reaction is performed to obtain the intermediate 2-(4-nitrophenyl)butyric acid, which is then reduced to 2-(4-aminophenyl)butyric acid with iron powder, and then reacted with phthalic anhydride to obtain 2-[4-(1,3-dioxo-2-isoindolinyl)phenyl]butyric acid. 2-[4-(1,3-dioxo-2-isoindolinyl)phenyl]butyric acid is reduced with zinc powder to obtain the indole part. This route is relatively long, the yield is not high, and more "three wastes" are produced, which is not suitable for large-scale production.

[0012] Prior art 3: Hangzhou Sino-US Huadong Pharmaceutical Co., Ltd. invention patent CN106631974A route is:

[0013] .

[0014] This route uses hydrogen and palladium carbon to reduce the nitro group, uses phthalic anhydride for cyclization, and finally uses zinc powder and acid system to reduce the carbonyl group to obtain indobufen. The first step of the reaction uses precious metals for catalysis, which is relatively expensive, and using zinc powder to reduce the carbonyl group is prone to produce "three wastes".

[0015] The above-mentioned existing technical routes all have certain defects, and therefore a preparation method of indobufen with simple process, high yield and suitable for large-scale industrial production is needed. Summary of the invention

[0016] The purpose of the present invention is to provide a method suitable for large-scale industrial production with simple process, high yield, high product purity and less "three wastes" to overcome the shortcomings of the existing preparation technology of indobufen.

[0017] The present invention discloses a method for preparing indobufen, comprising the following steps:

[0018] A. Substitution reaction

[0019]

[0020] B. Cyclization reaction

[0021]

[0022] C. Refining and purification.

[0023] In the substitution reaction described in step A, the base is any one of potassium carbonate, sodium carbonate, lithium hydroxide, potassium hydroxide, and sodium hydroxide, preferably potassium carbonate; the solvent is any one of N,N-dimethylformamide, acetonitrile, and tetrahydrofuran, preferably tetrahydrofuran; and the reaction temperature is controlled at 55 to 80°C.

[0024] The substitution reaction described herein is carried out at a ratio of 2-(4-aminophenyl)butyric acid to potassium carbonate of 1:1.5 to 3 by mass, preferably 1:2;

[0025] In the cyclization reaction described in step B, the organic acid is selected from any one of formic acid, acetic acid, propionic acid, and butyric acid, preferably acetic acid; the reaction temperature is controlled at 100-140°C;

[0026] In the cyclization reaction, the mass volume ratio of 2-((4-(1-carboxypropyl)phenylamino)methyl)benzoic acid:acetic acid is 1:5-15, preferably 1:8;

[0027] The refining and purification described in step C is carried out using conventional processes.

[0028] In order to ensure the purity of the crude indobufen product, the quality of the intermediate needs to be controlled. The present application has carried out quality control on the 2-((4-(1-carboxypropyl)phenylamino)methyl)benzoic acid obtained by the substitution reaction, such as total impurities less than 3.0%, and other single impurities less than 1.5%. At the same time, in order to ensure the purity of the final product of indobufen, the crude product obtained by the cyclization reaction has also been quality controlled, with total impurities less than 2.5% and other single impurities less than 1.0%. Only by controlling the impurities of the crude product can the effect of refining and purification be guaranteed, and in industrial production, it can be ensured that the final indobufen product reaches the quality standard of less than 0.7% total impurities and less than 0.1% other single impurities.

[0029] The preparation method of indobufen disclosed by the invention has high yield (95% to 98%) of substitution reaction and simple post-treatment; high yield (92% to 95%) of cyclization reaction and simple post-treatment; high total yield (87% to 93%) of two-step reaction, low reagent and solvent cost, less impurities, short process time, and is suitable for large-scale industrial production.

[0030] The method for preparing indobufen disclosed by the invention uses 2-(4-aminophenyl)butyric acid as a starting material, and after two-step reaction and refining and purification, the total yield of indobufen is high, reaching 78% to 83%, and the impurity content is low, which can achieve a total impurity content of less than 0.5%, and other single impurities are less than 0.1%.

[0031] The method for preparing indobufen disclosed in the present invention has a relatively new route, a simple process and is environmentally friendly, and the obtained final product has high purity and meets the pharmaceutical quality requirements. Specific embodiments

[0032] Example 1 Substitution reaction and cyclization reaction

[0033] 500L of tetrahydrofuran was added to the reactor, and then 50Kg of 2-(4-aminophenyl)butyric acid, 100Kg of potassium carbonate, and 60Kg of 2-bromomethylbenzoic acid were added. Stirring was started, and the reaction temperature was controlled to 66°C for reflux reaction. The reaction was carried out for 12h. After the reaction was completed, the reaction was stopped and cooled to room temperature. The potassium carbonate solid was filtered out, and the mother liquor was evaporated under reduced pressure to obtain 85.6Kg of compound 2-((4-(1-carboxypropyl)phenylamino)methyl)benzoic acid, with a yield of 98% and a HPLC purity of 97.5%.

[0034] 856 kg of acetic acid was added to the reactor, followed by 85.6 kg of 2-((4-(1-carboxypropyl)phenylamino)methyl)benzoic acid. The stirring was started and the temperature was raised to 118°C for reflux reaction. After 18 hours of reaction, the cyclization reaction was completed and the solvent was recovered under reduced pressure. 750 kg of purified water was added to the residue, cooled to 25°C and stirred for 2 hours. The mixture was filtered and dried to obtain 75.6 kg of 2-[4-(1-oxo-2-isoindolyl)phenyl]butyric acid with a yield of 94% and a HPLC purity of 98.1%.

[0035] Example 2-5 Comparative test of substitution reaction and cyclization reaction

[0036] In the following Examples 2-5, 50 kg of 2-(4-aminophenyl)butyric acid was used as the starting reaction raw material. Unless otherwise specified, other materials and processes were the same as those in Example 1:

[0037] .

[0038] It can be seen from the above table that when the materials and process conditions are selected outside the protection scope of this application, the yield of the intermediate is lower, the purity is lower, and more impurities are generated.

[0039] Example 6 Refining and Purification

[0040] 1800 kg of methanol was added to the crystallization kettle, and then 100 kg of crude indobufen was added, stirring was started, and the mixture was heated to reflux and dissolved. After stirring for 30 min, heating was turned off, and the mixture was naturally cooled to room temperature and stirred for 2 h. Filtering was performed to obtain 91 kg of finished indobufen, with a refined yield of 91%, a HPLC purity of 99.8%, and other individual impurities less than 0.1%.

[0041] The crude 2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid obtained by the method of the above Examples 2-4 was refined and purified according to Example 6 to obtain the finished indobufen, and the yield and purity were equivalent to those in this Example.

[0042] The finished indobufen product prepared by the method of the present invention is applied to the corresponding preparation prescription research, and the specific prescription research examples are shown in Examples 7-8.

[0043] Example 7 Preparation of Indobufen Pharmaceutical Composition

[0044] Indobufen 200g

[0045] Lactose (anhydrous lactose) 30g

[0046] Microcrystalline cellulose 40g

[0047] Cross-linked carboxymethyl cellulose sodium 4g

[0048] Polyvinylpyrrolidone 7g

[0049] Talc 1g

[0050] Magnesium stearate 6g;

[0051] Preparation process of 200 mg indobufen tablets: indobufen, lactose and microcrystalline cellulose cross-linked sodium carboxymethyl cellulose are mixed evenly, polyvinyl pyrrolidone aqueous solution is added to prepare a soft material, and wet granules are obtained by passing through a 20-mesh sieve, drying at about 50°C, granulating through a 20-mesh sieve, adding talc and magnesium stearate, mixing evenly, and tableting to obtain 1000 indobufen tablets.

[0052] Example 8 Preparation of Indobufen Pharmaceutical Composition

[0053] Indobufen 200g

[0054] Lactose (anhydrous lactose) 40g

[0055] Microcrystalline cellulose 20g

[0056] Hydroxypropyl methylcellulose 4g

[0057] Sodium carboxymethyl starch 13g

[0058] Micro powder silica gel 3g

[0059] Zinc stearate 2g;

[0060] Preparation process of 200 mg indobufen tablets: indobufen and lactose, microcrystalline cellulose, and sodium carboxymethyl starch are mixed evenly, hydroxypropyl methylcellulose aqueous solution is added to prepare a soft material, and wet granules are obtained by passing through a 20-mesh sieve, which are dried at about 50°C, sieved through a 20-mesh sieve, and micro-powdered silica gel and zinc stearate are added. After mixing evenly, the granules are pressed into tablets to obtain 1000 indobufen tablets.

Claims

1. A method for preparing indobufen, comprising the following steps: A. Substitution reaction ； B. Cyclization reaction ； C. Refining and purification; The base used in the substitution reaction is potassium carbonate; the organic acid used in the cyclization reaction is formic acid, acetic acid or propionic acid, and the reaction temperature is controlled at 100-140°C.

2. The preparation method according to claim 1, characterized in that The solvent used in the substitution reaction is any one of N,N-dimethylformamide, acetonitrile and tetrahydrofuran.

3. The preparation method according to claim 1, characterized in that The solvent used in the substitution reaction is tetrahydrofuran, and the reaction temperature is controlled at 55-80°C.

4. The preparation method according to claim 1, characterized in that In the substitution reaction, by mass, 2-(4-aminophenyl)butyric acid:potassium carbonate=1:1.5-3.

5. The preparation method according to claim 1, characterized in that In the substitution reaction, by mass, 2-(4-aminophenyl)butyric acid:potassium carbonate=1:

2.

6. The preparation method according to claim 1, characterized in that In the cyclization reaction, the organic acid used is acetic acid.

7. The preparation method according to claim 1, characterized in that In the cyclization reaction, the mass volume ratio of 2-((4-(1-carboxypropyl)phenylamino)methyl)benzoic acid:acetic acid is 1:5-15.

8. The preparation method according to claim 1, characterized in that In the cyclization reaction, the mass volume ratio of 2-((4-(1-carboxypropyl)phenylamino)methyl)benzoic acid:acetic acid is 1:8.

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