Preparation method of torasemide cyclization impurity

Abstract

The invention provides a preparation method of a torasemide cyclization compound as shown in a formula I in a torasemide injection, which comprises the following step of: carrying out cyclization reaction on torasemide sulfamide as shown in a formula II and a compound as shown in a formula III in an organic solvent in the presence of strong base to obtain a target product. The preparation method provided by the invention is simple to operate, the used reagent is low in toxicity, the reaction yield is high, and a product with relatively high purity can be obtained through simple post-treatment. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for preparing a torasemide cyclized impurity which is an impurity in torasemide injection. Background Art

[0002] Torasemide, also known as Torasemide in English, is suitable for patients with congestive heart failure, ascites caused by liver cirrhosis, and edema caused by kidney disease who need rapid diuresis or cannot take oral diuretics. Its structural formula is as follows:

[0003]

[0004] The original research instructions of torasemide injection clearly list its prescription including torasemide, polyethylene glycol 400, tromethamine, sodium hydroxide and water for injection. During the storage process, torasemide injection will generate a cyclized impurity, the structural formula of which is shown in Formula I:

[0005]

[0006] The generation mechanism of torasemide cyclization impurities is shown in the figure below:

[0007]

[0008] First, the sulfonylurea group in the torsemide molecule is relatively unstable. Under the preparation conditions of aqueous solution, it will undergo hydrolysis to remove a molecule of carbon dioxide and isopropylamine to produce torsemide sulfonamide. In addition, the excipient polyethylene glycol 400 in the torsemide injection may undergo oxidative degradation to produce trace formaldehyde, which can undergo addition and dehydration with torsemide sulfonamide to form a Schiff base, and finally undergo intramolecular cyclization to form torsemide sulfonamide cyclization impurities. During the formulation development and testing process, we found that because the torsemide in the formulation will hydrolyze to produce sulfonamide impurities, and the polyethylene glycol 400 used will inevitably degrade to produce formaldehyde, the torsemide sulfonamide impurities will undergo dehydration cyclization with formaldehyde to produce torsemide cyclization impurities, and they can be detected in each batch of samples.

[0009] With reference to the relevant provisions of ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use), impurities exceeding the identification limit can be treated as known impurities and their content can be controlled within the quality control limit. The maximum daily dose of torasemide injection is 100 mg, the impurity identification limit of the product is 0.2%, and the quality control limit is 0.5%. According to the report of the document "HPLC Determination of Impurities in Torsemide Tablets and Injections" (Song Dongmei, Chinese Journal of Pharmaceutical Industry, 2006, 37 (3), P187-189), the contents of the cyclized impurity shown in Formula I detected in three batches of torasemide injection were 0.079%, 0.5%, and 0.29%, respectively. Since this impurity is commonly present in torasemide injection, it is very necessary to control the content of this impurity in daily life. At present, this impurity is also commonly present in the enterprise quality standards as a known impurity.

[0010] CN114736217A discloses for the first time a method for synthesizing a torsemide cyclized impurity of formula I, which comprises reacting torsemide with paraformaldehyde in an organic solvent under acidic conditions at a temperature of 60 to 120°C to obtain the torsemide cyclized impurity. This method has the disadvantages of low yield and high reagent toxicity. Summary of the invention

[0011] The object of the present invention is to provide a method for preparing an improved torasemide cyclized impurity of formula I, wherein the synthetic route is as follows:

[0012]

[0013] The method comprises the following steps:

[0014] (1) reacting the torsemide sulfonamide of formula II with the compound of formula III in an organic solvent in the presence of a strong base to obtain a compound of formula I;

[0015] (2) isolating and obtaining the compound represented by formula I;

[0016] In the compound of formula III, X and Y are independently selected from bromine or iodine.

[0017] According to a specific embodiment of the present invention, the strong base in step (1) is selected from one or more inorganic bases or organic bases; wherein the inorganic base is preferably an alkali metal hydroxide, more preferably sodium hydroxide and potassium hydroxide; the organic base is preferably an alkali metal alkoxide, more preferably potassium tert-butoxide or sodium tert-butoxide.

[0018] According to a specific embodiment of the present invention, the molar ratio of the compound represented by formula III in step (1) to torsemide sulfonamide is 1:1 to 10:1, more preferably 1.1:1 to 5:1, and more preferably 1.1:1 to 2:1.

[0019] According to a specific embodiment of the present invention, the molar ratio of the strong base to torsemide sulfonamide in step (1) is 1.5:1 to 10:1, more preferably 1.5:1 to 5:1, and more preferably 2:1 to 3:1.

[0020] According to a specific embodiment of the present invention, the organic solvent in step (1) is selected from ethers or polar aprotic solvents, and the ethers are preferably tetrahydrofuran or 1,4-dioxane; the polar aprotic solvent is preferably N-methylpyrrolidone, N,N'-dimethylformamide, dimethyl sulfoxide; the organic solvent is further preferably tetrahydrofuran or 1,4-dioxane.

[0021] According to a specific embodiment of the present invention, the volume usage of the organic solvent per gram of torsemide sulfonamide is 8 to 15 mL, and more preferably 8 to 10 mL.

[0022] According to a specific embodiment of the present invention, the reaction temperature in step (1) is 20-50°C, more preferably 20-40°C, and more preferably 30-40°C.

[0023] According to a specific embodiment of the present invention, the reaction time in step (1) is preferably 5 to 24 hours, more preferably 10 to 15 hours.

[0024] According to a specific embodiment of the present invention, the separation process of step (2) comprises the following steps:

[0025] a) after the reaction is completed, adding a non-aqueous organic solvent to the reaction system;

[0026] b) adjusting the pH to acidic, preferably to pH 2 to 6, more preferably to pH 2 to 4, with hydrochloric acid;

[0027] c) extracting and separating to obtain an organic layer;

[0028] d) removing the solvent in the organic layer by distillation; optionally, further comprising recrystallizing the distillation substrate with a mixed solvent of alcohol and water.

[0029] The water-insoluble organic solvent in step a) is preferably dichloromethane.

[0030] The recrystallization alcohol in step d) is preferably methanol or ethanol; the solvent volume ratio of the alcohol to water is preferably 1:2 to 2:1.

[0031] The preparation method provided by the invention is simple to operate, the reagents used are low in toxicity, the reaction yield is high, and a product with high purity can be obtained through simple post-treatment.

[0032] The torsemide cyclized impurity represented by formula I prepared according to the present invention can be further used as a reference substance for quality control of torsemide injection. DETAILED DESCRIPTION

[0033] In order to more fully understand the present invention, the following specific examples are given, but the present invention is not limited to the following examples.

[0034] Herein, % is weight / weight (w / w) percentage unless otherwise stated.

[0035] Unless otherwise indicated, any numerical value should be understood to be modified by the term "about" in all cases, indicating that such value may vary within a certain range. When no range is stated (such as a range of error or the standard deviation of the mean value given in a graph or data table), the term "about" should be understood to mean a larger range including the stated value, as well as a range including plus or minus 10% of the stated value, taking into account significant figures.

[0036] Example 1

[0037] 50 g of torsemide sulfonamide was added to 500 mL of tetrahydrofuran, followed by the addition of 32 g of finely powdered potassium hydroxide, and after stirring for 15-30 minutes, 49.5 g of dibromomethane was slowly added dropwise, and the reaction was continued at 35-40° C. with stirring for 10 hours; after the reaction was completed, 300 mL of dichloromethane was added, and the pH value was adjusted to 3.0 with 1 mol / L hydrochloric acid solution under stirring, and the stirring was continued at room temperature for 10 minutes. After standing for stratification, the organic layer was separated, and then the water layer was extracted with 200 mL of dichloromethane, the organic layers were combined, and the dichloromethane and tetrahydrofuran were evaporated on a rotary evaporator. The residual solid was recrystallized with methanol: water = (1:1, v / v), filtered and dried to finally obtain 44.3 g of the torsemide cyclized impurity shown in formula I, with an HPLC purity of 99.7% and a yield of 85%.

[0038] Example 2

[0039] 50 g of torsemide sulfonamide was added to 500 mL of tetrahydrofuran, followed by the addition of 42.6 g of potassium tert-butoxide, and after stirring for 15-30 minutes, 49.5 g of dibromomethane was slowly added dropwise, and the reaction was continued at 30-35° C. with stirring for 13 hours; after the reaction was completed, 300 mL of dichloromethane was added, and the pH value was adjusted to 3.0 with 1 mol / L hydrochloric acid solution under stirring, and the stirring was continued at room temperature for 10 minutes. After standing for stratification, the organic layer was separated, and then the water layer was extracted with 200 mL of dichloromethane, the organic layers were combined, and the dichloromethane and tetrahydrofuran were evaporated on a rotary evaporator. The residual solid was recrystallized with methanol: water = (1:1, v / v), filtered and dried to finally obtain 45.5 g of the torsemide cyclized impurity shown in formula I, with an HPLC purity of 99.4% and a yield of 87%.

[0040] Example 3

[0041] 50 g of torsemide sulfonamide was added to 400 mL of 1,4-dioxane, followed by the addition of 32 g of finely powdered potassium hydroxide, and after stirring for 15-30 minutes, 52.8 g of dibromomethane was slowly added dropwise, and the reaction was continued at 35-40° C. with stirring for 15 hours; after the reaction was completed, 250 mL of dichloromethane was added, and the pH value was adjusted to 3.0 with 1 mol / L hydrochloric acid solution under stirring, and the stirring was continued at room temperature for 10 minutes. After standing and stratification, the organic layer was separated, and then the water layer was extracted with 300 mL of dichloromethane, the organic layers were combined, and the dichloromethane and 1,4-dioxane were evaporated on a rotary evaporator. The residual solid was recrystallized with methanol: water = (1:1, v / v), filtered and dried to finally obtain 46.0 g of the torsemide cyclized impurity shown in Formula I, with an HPLC purity of 99.7% and a yield of 88%.

[0042] Example 4

[0043] 50 g of torsemide sulfonamide was added to 400 mL of 1,4-dioxane, followed by the addition of 24.3 g of fine powdered sodium hydroxide, and after stirring for 15-30 minutes, 57.8 g of diiodomethane was slowly added dropwise, and the reaction was continued at 35-40° C. with stirring for 10 hours; after the reaction was completed, 300 mL of dichloromethane was added, and the pH value was adjusted to 3.0 with 1 mol / L hydrochloric acid solution under stirring, and the stirring was continued at room temperature for 10 minutes. After standing for stratification, the organic layer was separated, and then the water layer was extracted with 200 mL of dichloromethane, the organic layers were combined, and the dichloromethane and 1,4-dioxane were evaporated on a rotary evaporator. The residual solid was recrystallized with methanol: water = (1:1, v / v), filtered and dried to finally obtain 45.0 g of the torsemide cyclized impurity shown in formula I, with an HPLC purity of 99.2% and a yield of 86%.

[0044] Example 5

[0045] 50 g of torsemide sulfonamide was added to 500 mL of tetrahydrofuran, followed by the addition of 32 g of finely powdered potassium hydroxide. After stirring for 15-30 minutes, 50.5 g of bromoiodomethane was slowly added dropwise, and the reaction was continued at 35-40° C. with stirring for 10 hours. After the reaction was completed, 200 mL of dichloromethane was added, and the pH value was adjusted to 3.0 with 1 mol / L hydrochloric acid solution under stirring, and the stirring was continued at room temperature for 10 minutes. After standing for stratification, the organic layer was separated, and then the water layer was extracted with 200 mL of dichloromethane. The organic layers were combined and placed on a rotary evaporator to evaporate dichloromethane and tetrahydrofuran. The obtained residual solid was recrystallized with methanol: water = (1:1, v / v), filtered and dried to finally obtain 45.5 g of the torsemide cyclized impurity shown in formula I, with an HPLC purity of 99.1% and a yield of 87%.

[0046] Example 6

[0047] 50 g of torsemide sulfonamide was added to 400 mL of tetrahydrofuran, followed by the addition of 32 g of finely powdered potassium hydroxide. After stirring for 15-30 minutes, 62.0 g of diiodomethane was slowly added dropwise, and the reaction was continued at 35-40° C. with stirring for 10 hours. After the reaction was completed, 300 mL of dichloromethane was added, and the pH value was adjusted to 3.0 with 1 mol / L hydrochloric acid solution under stirring, and the stirring was continued at room temperature for 10 minutes. After standing for stratification, the organic layer was separated, and then the water layer was extracted with 200 mL of dichloromethane. The organic layers were combined and placed on a rotary evaporator to evaporate dichloromethane and tetrahydrofuran. The residual solid was recrystallized with methanol: water = (1:1, v / v), filtered and dried to finally obtain 47.0 g of the torsemide cyclized impurity shown in Formula I, with an HPLC purity of 99.5% and a yield of 90%.

[0048] Example 7

[0049] The method for detecting the quality of torasemide using the torasemide cyclized impurity prepared by the method of the embodiment of the present invention as a reference substance is as follows:

[0050] Test solution: Accurately measure 10 mL of torsemide injection, place in a 50 mL volumetric flask, add mobile phase A [buffer: methanol = 90:10 (%, v / v)], dissolve and dilute to the scale, shake well, and it can be used as the test solution.

[0051] Torsemide cyclized impurity reference substance stock solution 1: Accurately weigh 10.0 mg of the torsemide cyclized impurity prepared in the example of the present invention as a reference substance, transfer it to a 10 mL volumetric flask, and dissolve it with mobile phase A [buffer:methanol=90:10 (%, v / v)] and dilute to the scale to obtain a stock solution 1 with a concentration of 1.0 mg / mL.

[0052] Torsemide cyclized impurity reference substance stock solution 2: Accurately measure 1.0 mL of stock solution 1, transfer it to a 10 mL volumetric flask, and dissolve it with mobile phase A [buffer: methanol = 90:10 (%, v / v)] and dilute to the scale to obtain a stock solution 2 with a concentration of 100 μg / mL.

[0053] Torsemide cyclized impurity reference solution: According to the requirements of the linear range, use a pipette or micropipette to accurately aspirate 0.5, 1, 2, 5 and 10 mL of stock solution 2, transfer to a 100 mL volumetric flask, and then use mobile phase A [buffer: methanol = 90:10 (%, v / v)] to make up to the scale and dilute to a series of working solutions with different concentrations, with final concentrations of 0.5, 1, 2, 5 and 10 μg / mL, respectively.

[0054] Chromatographic conditions:

[0055] Instrument: Waters high performance liquid chromatograph

[0056] Chromatographic column: Xterra MS C18, 150×4.6mm, 3μm

[0057] Buffer: 20 mM ammonium acetate in water, pH adjusted to 3.5 with acetic acid

[0058] Mobile phase A: buffer: methanol = 90:10 (%, v / v)

[0059] Mobile phase B: methanol

[0060] Detection wavelength: 288nm

[0061] Column temperature: 30°C

[0062] Flow rate: 0.8 mL / min

[0063] Injection volume: 50 μL

[0064] gradient:

[0065]

[0066] Example 8

[0067] Two batches of original research samples of torsem injection (trade name Torem) and one batch of self-developed samples were placed under accelerated conditions (40±2°C, 75±5% RH) for 6 months, and samples were taken on the 0th day, the 1st month, the 3rd month, and the 6th month, respectively. The content of torsemide cyclized impurities therein was detected by referring to the method of Example 7, and the results were as follows:

[0068]

Claims

1. A method for preparing the torasemide cyclized impurity shown in formula I, wherein the synthetic route is as follows: The method comprises the following steps: (1) reacting the torsemide sulfonamide of formula II with the compound of formula III in an organic solvent in the presence of a strong base to obtain a compound of formula I; (2) isolating and obtaining the compound represented by formula I; In the compound of formula III, X and Y are independently selected from bromine or iodine.

2. The method according to claim 1, wherein the strong base in step (1) is selected from one or more of an inorganic base or an organic base; wherein the inorganic base is preferably an alkali metal hydroxide, more preferably sodium hydroxide and potassium hydroxide; and the organic base is preferably an alkali metal alkoxide, more preferably potassium tert-butoxide or sodium tert-butoxide.

3. The method according to claim 1, wherein the molar ratio of the compound represented by formula III in step (1) to torsemide sulfonamide is 1:1 to 10:1, more preferably 1.1:1 to 5:1, and more preferably 1.1:1 to 2:

1.

4. The method according to claim 1, wherein in step (1), the molar ratio of the strong base to torsemide sulfonamide is 1.5:1 to 10:1, more preferably 1.5:1 to 5:1, and more preferably 2:1 to 3:

1.

5. The method according to claim 1, wherein the organic solvent in step (1) is selected from ethers or polar aprotic solvents, the ethers are preferably tetrahydrofuran or 1,4-dioxane; the polar aprotic solvent is preferably N-methylpyrrolidone, N,N'-dimethylformamide, dimethyl sulfoxide; the organic solvent is further preferably tetrahydrofuran or 1,4-dioxane.

6. The method according to claim 1, wherein the reaction temperature in step (1) is 20 to 50°C, more preferably 20 to 40°C, and more preferably 30 to 40°C.

7. The method according to claim 1, wherein the reaction time in step (1) is preferably 5 to 24 hours, more preferably 10 to 15 hours.

8. The method according to claim 1, wherein the separation process of step (2) comprises the following steps: a) after the reaction is completed, adding a non-aqueous organic solvent to the reaction system; b) adjusting the pH to acidic with hydrochloric acid; c) extracting and separating to obtain an organic layer; d) removing the solvent in the organic layer by distillation; optionally, further comprising recrystallizing the distillation substrate with a mixed solvent of alcohol and water.

9. The method according to claim 8, wherein the water-insoluble organic solvent in step a) is preferably dichloromethane; in step b) the pH is preferably adjusted to 2 to 6 with hydrochloric acid, more preferably to 2 to 4; in step d) the preferred alcohol for recrystallization is methanol or ethanol; further, the solvent volume ratio of the alcohol to water is 1:2 to 2:

1.

10. The method according to any one of claims 1 to 9, characterized in that The prepared torsemide cyclized impurity was used as a reference substance for quality control of torsemide injection.

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