A method for removing impurities from irbesartan

Abstract

The invention discloses a method for removing impurities from irbesartan, and belongs to the field of pharmaceutical chemical industry. The method comprises: (1) crushing a crude irbesartan product into a 60-120 mesh powder, adding the powder into an aqueous solution of a polymer polyvinyl pyrrolidone (PVP-K30), and stirring the solution at room temperature for 1-2 hours; (2) raising the temperature of the solution to 60-80°C, and keeping the temperature and stirring the solution for 1-2 hours; (3) after the insulation is completed, reducing the temperature to 15-45°C, keeping the temperature for 1-3 hours, and filtering the solution by suction. The filter cake is fully stirred and washed with double distilled water, and then filtered and vacuum dried to obtain high-purity irbesartan, wherein the potential genotoxic impurities are far below the limit, meet the irbesartan quality standard, and ensure the drug safety of irbesartan.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for removing impurities in irbesartan. Background Art

[0002] Irbesartan is a competitive angiotensin II (AT1) receptor antagonist originally developed by the French company Sanofi. It lowers blood pressure by blocking type I angiotensin II (AT-II) receptors. Irbesartan was first launched in the UK in 1997 and is clinically used to treat hypertension. It has the effect of protecting the liver and kidneys in the treatment of primary hypertension and is the most widely used variety in the sartan class.

[0003] The chemical name of irbesartan is: 2-butyl-3-[4-[2-(1H-tetrazol-5-yl)phenyl]benzyl]-1,3-diazaspiro-[4.4]non-1-en-4-one, with the following structure:

[0004]

[0005] Patent US5270317 discloses a method for preparing irbesartan. The method first uses cyclopentanone as a starting material, and reacts to synthesize 5-spirocyclohexydantoin pentane in the presence of KCN as a catalyst. Then, it is hydrolyzed in Ba(OH2) to obtain cycloleucine (1-aminocyclopentanoic acid), and the carboxylic acid is converted into an ester to obtain its hydrochloride form. The hydrochloride is removed in a 30% potassium carbonate solution, and then a ring-closing reaction is carried out with ethyl pentamethyleneimine in a xylene system to obtain an important intermediate fragment in the synthesis route of irbesartan - 2-n-butyl-4-spirocyclopentane-2-imidazoline-5-one. Under alkaline conditions, the intermediate undergoes a C-N coupling reaction with 2-cyano-4-bromomethylbiphenyl to obtain 1-[(2'-cyanobiphenyl-4-yl)methyl)-2-n-butyl-4-spirocyclopentane-2-imidazoline-5-one. The coupling reaction product is then treated with tributyl azide and trityl compound in a xylene system to obtain a compound with a -Ph3 protecting group. Finally, HCl is used to remove the protecting group on the tetrazole, and the final target compound irbesartan is obtained after separation and purification using a silica gel column.

[0006]

[0007] Patent WO 2005113518 A1 discloses a method for preparing irbesartan, which starts with cycloleucine (1-aminocyclopentanoic acid), reacts with n-valeryl chloride in a weakly alkaline system of triethylamine (TEA), and undergoes a substitution reaction on the amino group to obtain 1-pentanamidocyclopentane-1-carboxylic acid. Under the action of DCC, it undergoes a condensation reaction with 4'-(aminomethyl)-[1,1'-biphenyl]-2-carbonitrile to obtain N-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl-1-pentanamidocyclopentane-1-carboxamide. Next, it undergoes self-cyclization under the action of acid catalysis to obtain 4'-((2-butyl-4-oxo-1,3-diazaspiro[4,4]non-1-ene-3-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile. Finally, the tetrazole is constructed by sodium azide reaction to obtain the final target compound.

[0008]

[0009] In the above preparation method, since azide is used as a reactant, the preparation process of irbesartan will produce a variety of azide genotoxic impurities, which can cause cancer in various tissues and organs of the human body, and the safety of irbesartan cannot be guaranteed. Therefore, it is necessary to develop a new impurity purification control method.

[0010] A potential genotoxic impurity compound produced in the preparation process of irbesartan: 5-[4′-(azidomethyl)-[1,1′-biphenyl]-2-yl]-1H-tetrazolyl (CAS registration number: 152708-24-2), whose chemical structure is shown below and is referred to as impurity A below.

[0011]

[0012] Impurity A Summary of the invention

[0013] The technical problem to be solved by the present invention is to provide a method for removing impurity A in irbesartan in view of the current status of the prior art. The method has good effect and high yield, and at the same time is low in cost, has few impurities, and is green and environmentally friendly.

[0014] The technical solution adopted by the present invention to solve the above technical problems is:

[0015] A method for removing impurities in irbesartan comprises the following steps:

[0016] (1) Grind the crude irbesartan into 60-120 mesh powder, add it into an aqueous solution of polymer polyvinyl pyrrolidone PVP-K30, and stir at room temperature for 1-2 hours;

[0017] (2) Raise the solution temperature to 60-80°C and stir for 1-2 hours;

[0018] (3) After the insulation is completed, the temperature is lowered to 15-45°C and the temperature is maintained for 1-3 hours. The filter cake is filtered and washed with double distilled water, and then filtered and vacuum dried to obtain high-purity irbesartan.

[0019] As a preferred embodiment, the mass percentage concentration of the polymer PVP-K30 aqueous solution is 0.1-0.5%, and the weight of the polymer PVP-K30 aqueous solution is 4-12 times the weight of the crude irbesartan.

[0020] As a preferred embodiment, the heating temperature in step (2) is 70°C-80°C.

[0021] As a preferred embodiment, in step (3), the temperature is reduced to 20-40°C.

[0022] As a preferred embodiment, the amount of double distilled water used in step (3) is 2-3 times the weight of the filter cake.

[0023] The beneficial effects produced by the present invention are:

[0024] The present invention creatively proposes to control the impurity content of irbesartan through a purification method, thereby significantly reducing the impurity content in irbesartan, making the impurity content far below the limit, meeting the quality standard of irbesartan, and ensuring the drug safety of irbesartan; the method is simple and easy to operate, and can meet the requirements of industrial production.

[0025] (2) The product purified by the method of the present invention has a purity of up to 99.5% as determined by HPLC (high performance liquid chromatography), and a calculated yield of more than 99%. The product quality is stable and uniform. DETAILED DESCRIPTION

[0026] The following examples are used to further illustrate the present invention, but do not further limit the present invention. The experimental methods in the following examples are conventional methods unless otherwise specified. The PVP-K30 used in the following examples was purchased from Tianjin Guangfu Technology Development Co., Ltd., and other experimental materials were purchased from conventional biochemical reagent stores.

[0027] "h" represents the time unit "hour"; "℃" represents the temperature "degrees Celsius"; "mm" represents the length unit "millimeter"; "μm" represents the length unit "micrometer"; "ml / min" represents the "flow unit"; "g" represents the weight unit "gram"; "ppm" represents the "concentration unit".

[0028] The impurity detection method of crude irbesartan and purified products in the present invention: ACQUITY UPLC HSS T3 (100mm×2.1mm, 1.8μm) chromatographic column; 0.1% formic acid aqueous solution as mobile phase A, 0.1% formic acid methanol solution as mobile phase B, gradient elution; flow rate of 0.35ml / min, column temperature of 50°C; atmospheric pressure chemical ion source (APCI) positive / negative ion scanning, multiple reaction monitoring (MRM) mode for quantitative detection of impurity A. (Chinese Journal of New Drugs, 2023, 32 (7): 742-746, Determination of three azide genotoxic impurities in irbesartan and losartan potassium raw materials by ultra-high performance liquid chromatography-tandem mass spectrometry) Example 1

[0029] 50 g of crude irbesartan (purity 98.6%) was crushed and ground into 80 mesh powder in a reaction bottle (the content of impurity A was 81 ppm as determined by the above detection method), and 300 g of 0.5% aqueous solution of high polymer polyvinyl pyrrolidone PVP-K30 was added; stirred at room temperature for 1 hour, and the solution was heated to 80°C and stirred for 1 hour;

[0030] After the stirring was completed, the temperature was lowered to 25° C. and kept warm for 2 h. The precipitated solid was filtered out by suction. The obtained solid was fully washed with 150 g of double distilled water and then filtered out and vacuum dried to obtain irbesartan (yield 99.1%, purity 99.3%). The impurity A content after purification was 2 ppm. Example 2

[0031] 50 g of crude irbesartan (purity 99.0%) was crushed and ground into 100 mesh powder in a reaction bottle (the content of impurity A was 89 ppm as determined by the above detection method), and 400 g of 0.2% aqueous solution of polymer PVP-K30 was added; stirred at room temperature for 1 h, and the solution was heated to 80°C and stirred for 2 h;

[0032] After the stirring was completed, the temperature was lowered to 20° C. and kept warm for 2 h. The precipitated solid was filtered out by suction. The obtained solid was fully washed with 120 g of double distilled water and then filtered out and vacuum dried to obtain irbesartan (yield 99.3%, purity 99.5%). The impurity A content after purification was 4 ppm. Example 3

[0033] 100 g of crude irbesartan (purity 98.7%) was crushed and ground into 80 mesh powder in a reaction bottle (the content of impurity A was 67 ppm as determined by the above detection method), and 1000 g of 0.3% aqueous solution of polymer PVP-K30 was added; stirred at room temperature for 2 h, heated to 70 °C and stirred for 1.5 h;

[0034] After the stirring was completed, the temperature was lowered to 30° C. and kept warm for 1.5 h. The precipitated solid was filtered out by suction. The obtained solid was fully washed with 250 g of double distilled water and then filtered out and vacuum dried to obtain irbesartan (yield 99.4%, purity 99.5%). The impurity A content after purification was 4 ppm. Example 4

[0035] 100 g of crude irbesartan (purity 98.4%) was crushed and ground into 100 mesh powder in a reaction bottle (the content of impurity A was 78 ppm as determined by the above detection method), and 800 g of 0.5% aqueous solution of polymer PVP-K30 was added; stirred at room temperature for 1.5 h, heated to 75 °C and stirred for 2 h;

[0036] After the stirring was completed, the temperature was lowered to 35° C. and kept warm for 1.5 h. The precipitated solid was filtered out by suction. The obtained solid was fully washed with 250 g of double distilled water and then filtered out and vacuum dried to obtain irbesartan (yield 99.6%, purity 99.7%). The impurity A content after purification was 4 ppm. Example 5

[0037] 80 g of crude irbesartan (purity 98.6%) was crushed and ground into 60 mesh powder in a reaction bottle (the content of impurity A was 61 ppm as determined by the above detection method), and 400 g of 0.3% aqueous solution of polymer PVP-K30 was added; stirred at room temperature for 2 h, heated to 80 °C and stirred for 2 h;

[0038] After the stirring was completed, the temperature was lowered to 25° C. and kept warm for 3 h. The precipitated solid was filtered out by suction. The obtained solid was fully washed with 200 g of double distilled water and then filtered out and vacuum dried to obtain irbesartan (yield 99.7%, purity 99.6%). The impurity A content after purification was 2 ppm.

[0039] Comparative Example 1

[0040] The difference from Example 1 is that the polymer aqueous solution added to the crude irbesartan is a PVA 1788 (polyvinyl alcohol) aqueous solution, and the other conditions are the same as those in Example 1. Irbesartan (yield 87.4%, purity 99.1%) was obtained, and the impurity A content after purification was 65 ppm.

[0041] Compared with Comparative Example 1, the yield of the irbesartan product obtained in Example 1 of the present application is high, reaching more than 99%, and the content of impurity A after purification is lower, which meets the standards of the Chinese Pharmacopoeia.

[0042] Comparative Example 2

[0043] The difference from Example 1 is that the polymer aqueous solution added to the crude irbesartan is a PEO (polyethylene oxide, weight average molecular weight Mw 100,000) aqueous solution, and the other conditions are the same as those in Example 1. Irbesartan (yield 86.3%, purity 99.0%) was obtained, and the impurity A content after purification was 73 ppm.

[0044] Compared with Comparative Example 2, the yield of the irbesartan product obtained in Example 1 of the present application is high, reaching more than 99%, and the content of impurity A after purification is lower, which meets the standards of the Chinese Pharmacopoeia.

[0045] Comparative Example 3

[0046] The difference from Example 5 is that the polymer aqueous solution added to the crude irbesartan is a PAM (polyacrylamide, number average molecular weight Mn 150000) aqueous solution, and the other conditions are the same as those in Example 1. Irbesartan (yield 91.0%, purity 99.2%) was obtained, and the impurity A content after purification was 47 ppm.

[0047] Compared with Comparative Example 3, the yield of the irbesartan product obtained in Example 5 of the present application is high, reaching more than 99%, and the content of impurity A after purification is lower, which meets the standards of the Chinese Pharmacopoeia.

[0048] Comparative Example 4

[0049] The difference from Example 5 is that the polymer aqueous solution added to the crude irbesartan is a PEG 1000 (polyethylene glycol) aqueous solution, and the other conditions are the same as those in Example 1. Irbesartan (yield 88.6%, purity 99.1%) was obtained, and the impurity A content after purification was 54 ppm.

[0050] Comparative Example 5

[0051] The difference from Example 5 is that 298.5 g of water is added to the crude irbesartan to replace 300 g of 0.5% aqueous solution of polymer PVP-K30, and the other conditions are the same as those in Example 1. Irbesartan (yield 99.8%, purity 98.7%) is obtained, and the impurity A content after purification is 73 ppm.

[0052] Compared with Comparative Example 4, the yield of the irbesartan product obtained in Example 5 of the present application is high, reaching more than 99%, and the content of impurity A after purification is lower, which meets the standards of the Chinese Pharmacopoeia.

[0053] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for removing impurities from irbesartan, characterized in that: The method comprises the following steps: (1) Crush the crude irbesartan into 60-120 mesh powder, add it into an aqueous solution of polymer polyvinyl pyrrolidone PVP-K30, and stir it at room temperature for 1-2 hours; the mass percentage concentration of the aqueous solution of polymer PVP-K30 is 0.1-0.5%, and the weight of the aqueous solution of polymer PVP-K30 is 4-12 times the weight of the crude irbesartan; (2) Raise the solution temperature to 60-80°C and stir for 1-2 hours; (3) After the insulation is completed, the temperature is lowered to 15-45°C and the temperature is maintained for 1-3 hours. The filter cake is filtered and washed with double distilled water, and then filtered and vacuum dried to obtain irbesartan.

2. A method for removing impurities in irbesartan according to claim 1, characterized in that: The heating temperature in step (2) is 70-80°C.

3. A method for removing impurities in irbesartan according to claim 1, characterized in that: In step (3), the temperature is reduced to 20-40°C.

4. A method for removing impurities from irbesartan according to claim 1, characterized in that: The amount of double distilled water used in step (3) is 2-3 times the weight of the filter cake.

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