Process for the preparation of metamizole of controlled content of the impurity 4-n-methylsulfonylmetamizole sodium

Abstract

The application belongs to the technical field of compound synthesis, and particularly relates to a preparation method of dipyrone with controlled content of 4-N methylene sulfonic acid sodium dipyrone impurity, which comprises the following steps: dissolving 4-formylaminoantipyrine in water, and then adding dimethyl sulfate and lye to react to obtain a methylation liquor; the obtained methylation liquor is hydrolyzed and neutralized, and then is left to stand and separate into layers, the upper 4-methylaminoantipyrine oil is cooled and crystallized to obtain 4-methylaminoantipyrine solid; the obtained 4-methylaminoantipyrine solid, ethanol, sodium pyrosulfite, activated carbon and formaldehyde are mixed to react to obtain dipyrone; the mass percentage of 4-aminoantipyrine in the 4-formylaminoantipyrine is not more than 1.5%. The content of 4-N methylene sulfonic acid sodium dipyrone (unknown impurity) in the prepared dipyrone is less than or equal to 0.05%, which meets the requirements of the European Pharmacopoeia.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis technology, and specifically relates to a method for preparing aminopyrine by controlling the content of the aminopyrine impurity 4-N-methylenesulfonate sodium aminopyrine. Background Technology

[0002] Metamizole is mainly used to reduce fever, and is also used to treat acute arthritis, headache, rheumatic pain, toothache, and muscle pain. The synthesis process of metamizole generally involves using pyrazolone as a base material, followed by methylation to obtain antipyrine (AT); then nitrosation and reduction to 4-aminoantipyrine (AA), followed by formylation to obtain 4-formylaminoantipyrine (FAA), then methylation to obtain 4-methylaminoantipyrine (MAA); finally, a condensation reaction yields metamizole.

[0003] With the continuous development of the metamizole market, the product has gradually entered the European market. However, the quality standards for metamizole required by the EU COS standard differ somewhat from those required by my country's national standard. The EU COS standard is stricter in terms of content and impurities. This requires us to change our existing production methods to produce metamizole raw materials with higher purity (i.e., a dry product content of 99.0%–101.0%) and fewer impurities (i.e., any other detected unknown impurities ≤ 0.05%) to meet the COS standard. According to the EP Pharmacopoeia, when metamizole is detected using high-performance liquid chromatography, an unknown impurity peak (adjacent to the solvent methanol peak, with very high polarity) is frequently detected, affecting the quality of metamizole. The inventors of this application discovered through research that the unknown impurity is sodium 4-N methylenesulfonate aminopyrine. According to the EP Pharmacopoeia, the content of the unknown impurity needs to be ≤0.05%. The content of sodium 4-N methylenesulfonate aminopyrine in the aminopyrine prepared using the existing technology is greater than 0.05%, which does not meet the requirements of the EP Pharmacopoeia. Therefore, it is necessary to further optimize the preparation process of aminopyrine to reduce the content of this impurity. Summary of the Invention

[0004] To address the aforementioned shortcomings in the existing technology, the present invention aims to provide a method for preparing aminopyrine with controlled content of sodium 4-N-methylenesulfonate (an unknown impurity). This invention limits the mass percentage of 4-aminoantipyrine in 4-formylaminoantipyrine to no more than 1.5%. By dissolving 4-formylaminoantipyrine in water and simultaneously adding dimethyl sulfate and alkali solution for reaction, the prepared aminopyrine can contain ≤0.05% sodium 4-N-methylenesulfonate (an unknown impurity), complying with the requirements of the European Pharmacopoeia.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] This invention provides a method for preparing metamizole with controlled content of the metamizole impurity 4-N-methylenesulfonate sodium metamizole, the preparation method comprising the following steps:

[0007] Preparation of methylation solution: Dissolve 4-formylaminoantipyrine in water, and then add dimethyl sulfate and alkaline solution to react and obtain methylation solution;

[0008] Preparation of 4-methylaminoantipyrine solid: The obtained methylated solution was hydrolyzed, neutralized and then allowed to stand to separate into layers. The upper layer of 4-methylaminoantipyrine oil was taken and cooled to crystallize, thus obtaining 4-methylaminoantipyrine solid.

[0009] Preparation of aminopyrine: The obtained 4-methylaminoantipyrine solid, ethanol, sodium metabisulfite, activated carbon, and formaldehyde were mixed and reacted to obtain aminopyrine;

[0010] The mass percentage of 4-aminoantipyrine in the 4-formylaminoantipyrine shall not exceed 1.5%.

[0011] This invention limits the mass percentage of 4-aminoantipyrine in 4-formamidaminoantipyrine to no more than 1.5%. After dissolving 4-formamidaminoantipyrine in water, dimethyl sulfate and alkaline solution are added simultaneously for reaction. This allows the content of sodium 4-N-methylenesulfonate aminopyrine (unknown impurity) in the prepared aminopyrine to be ≤0.05%, which complies with the requirements of the European Pharmacopoeia.

[0012] Furthermore, in the step of preparing the methylated solution, 4-formylaminoantipyrine is dissolved in water and stirred; when the temperature of the solution after stirring is 5-15°C, dimethyl sulfate and alkaline solution are added simultaneously, and the reaction temperature does not exceed 25°C.

[0013] And / or, in the step of preparing the methylation solution, the alkaline solution includes at least one of an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of sodium carbonate; the reaction time is 30-60 min, and the pH value of the solution after the dimethyl sulfate and the alkaline solution are added is 9-11;

[0014] And / or, in the step of preparing the methylated solution, the mass ratio of the 4-formylaminoantipyrine, water, dimethyl sulfate and the alkali in the alkaline solution is: 1:(1.5-2):(0.55-1):(0.35-0.63);

[0015] And / or, in the step of preparing the methylation solution, the alkali solution contains 30%-40% alkali by mass.

[0016] Furthermore, in the step of preparing 4-methylaminoantipyrine solid, the hydrolysis step includes: stirring the methylated solution and then adding concentrated sulfuric acid for hydrolysis;

[0017] And / or, the concentrated sulfuric acid has a mass fraction of 93-98%, and the mass ratio of 4-formylaminoantipyrine to concentrated sulfuric acid is 1:(0.5-1);

[0018] And / or, in the step of preparing 4-methylaminoantipyrine solid, the hydrolysis temperature is 80-106°C and the hydrolysis time is 3-5 hours;

[0019] And / or, in the step of preparing 4-methylaminoantipyrine solid, the neutralization includes primary neutralization and secondary neutralization; the primary neutralization step includes: adding the hydrolyzed solution to a primary neutralization tank and heating it, then adding alkali solution to neutralize to a pH value of 2-2.5, adding water to adjust the specific gravity of the solution to 1.18-1.22, and then adding activated carbon for decolorization.

[0020] Furthermore, in the first neutralization step, the decolorization temperature is 80-90℃, and the decolorization time is 0.5-1 hour;

[0021] And / or, in the first neutralization step, the amount of activated carbon added is 0.5-1% of the mass of 4-formylaminoantipyrine; the temperature is raised to 60-100°C; the alkaline solution includes at least one of liquid ammonia, ammonia water, sodium hydroxide aqueous solution, or sodium carbonate aqueous solution;

[0022] And / or, the secondary neutralization step includes: filtering the liquid after primary neutralization, passing alkaline solution through it at 60-100℃ until the pH of the liquid is 7.2-7.5, to obtain the liquid after secondary neutralization, and adding water to adjust the specific gravity of the liquid to 1.23-1.27.

[0023] Furthermore, in the secondary neutralization step, the alkaline solution includes at least one of liquid ammonia, an aqueous solution of sodium hydroxide, or an aqueous solution of sodium carbonate.

[0024] Furthermore, in the preparation of aminopyrine, the reaction temperature is 78-82°C; during the reaction, an alkali is added to adjust the pH of the reaction solution to 7.0-7.5, wherein the alkali includes at least one of sodium carbonate and sodium hydroxide;

[0025] And / or, in the preparation step of aminopyrine, the reaction time is 50-60 min.

[0026] Furthermore, in the preparation step of aminopyrine, the mass ratio of the 4-methylaminoantipyrine solid, ethanol, sodium metabisulfite, activated carbon, and formaldehyde is 1:(1-5):(0.4372-0.6559):(0.005-0.01):(0.138-0.207); the ethanol is aqueous ethanol, and the volume fraction of ethanol in the aqueous ethanol is 90%-93%.

[0027] Furthermore, in the preparation step of aminopyrine, the formaldehyde is added in the form of an aqueous formaldehyde solution, wherein the mass fraction of formaldehyde in the aqueous formaldehyde solution is 30%-40%.

[0028] Furthermore, in the preparation of aminopyrine, after the reaction is completed, the liquid is filtered and pressed into a crystallization tank, and then crystallized, centrifuged and dried to obtain the finished aminopyrine product.

[0029] Furthermore, the content of sodium 4-N-methylenesulfonate aminopyrine in the aminopyrine is ≤0.05%.

[0030] Compared with the prior art, the present invention has at least the following beneficial effects:

[0031] This invention limits the mass percentage of 4-aminoantipyrine in 4-formamidaminoantipyrine to no more than 1.5%. After dissolving 4-formamidaminoantipyrine in water, dimethyl sulfate and alkaline solution are added simultaneously for reaction. This allows the content of sodium 4-N-methylenesulfonate aminopyrine (unknown impurity) in the prepared aminopyrine to be ≤0.05%, which complies with the requirements of the European Pharmacopoeia. Attached Figure Description

[0032] Figure 1 The high-performance liquid chromatogram of aminopyrine prepared in Example 1 and its corresponding peak table are shown.

[0033] Figure 2 The high-performance liquid chromatogram and corresponding peak table of sodium 4-N methylenesulfonate aminopyrine prepared in this invention. Detailed Implementation

[0034] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions in the embodiments of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Those skilled in the art should understand that the embodiments described are merely illustrative of the invention and should not be considered as specific limitations thereof. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0035] The embodiments of the present invention are implemented under the premise of the technical solution of the present invention, and detailed implementation methods and processes are given. However, the protection scope of the present invention is not limited to the following embodiments. The process parameters in the following embodiments that do not specify specific conditions are generally in accordance with conventional conditions.

[0036] The endpoints and any values ​​of the ranges disclosed in this invention are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this invention.

[0037] This invention provides a method for preparing metamizole with controlled content of the metamizole impurity 4-N-methylenesulfonate sodium metamizole, comprising the following steps:

[0038] Preparation of methylation solution: Dissolve 4-formylaminoantipyrine in water, and then add dimethyl sulfate and alkaline solution to react and obtain methylation solution;

[0039] Preparation of 4-methylaminoantipyrine solid: The obtained methylated solution was hydrolyzed, neutralized and then allowed to stand to separate into layers. The upper layer of 4-methylaminoantipyrine oil was taken and cooled to crystallize, thus obtaining 4-methylaminoantipyrine solid.

[0040] Preparation of aminopyrine: The obtained 4-methylaminoantipyrine solid, ethanol, sodium metabisulfite, activated carbon, and formaldehyde were mixed and reacted to obtain aminopyrine;

[0041] The mass percentage of 4-aminoantipyrine in the 4-formylaminoantipyrine shall not exceed 1.5%.

[0042] The inventors of this application have discovered that if 4-methylaminoantipyrine (MAA) contains a small amount of 4-aminoantipyrine (AA), 4-aminoantipyrine (AA) reacts with formaldehyde and sodium metabisulfite to first form 4-N-desmethylaminopyrine (EP impurity E), and EP impurity E further condenses to form 4-N-methylenesulfonate sodium aminopyrine impurity. Therefore, FAA should be methylated as completely as possible to avoid unreacted FAA from generating AA in the subsequent hydrolysis stage.

[0043] The equation for the reaction of the unknown impurity (sodium 4-N-methylenesulfonate, metamizole) is as follows:

[0044]

[0045] The inventors of this invention discovered that by simultaneously adding dimethyl sulfate and alkali solution to the methylation tank, the hydrolysis of dimethyl sulfate in the alkaline aqueous solution can be prevented, ensuring complete methylation of FAA. If the alkali solution is added first and then the dimethyl sulfate, the dimethyl sulfate will undergo minor hydrolysis in the excess alkali solution. Adding dimethyl sulfate and alkali solution separately, since dimethyl sulfate is unstable and easily generates sulfuric acid and methanol, allows for simultaneous addition, minimizing losses and the production of impurities.

[0046] In this invention, after the methylation of FAA (4-formylaminoantipyrine), the mixture is hydrolyzed and neutralized, and then allowed to stand and separate into layers. The upper layer of MAA (4-methylaminoantipyrine) oil is directly cooled and crystallized to obtain MAA crystals, eliminating the need for the dehydration step. This saves steam and allows AA to be directly removed from the centrifugal mother liquor.

[0047] This invention limits the mass percentage of 4-aminoantipyrine in 4-formamidaminoantipyrine to no more than 1.5%. After dissolving 4-formamidaminoantipyrine in water, dimethyl sulfate and alkaline solution are added simultaneously for reaction. This allows the content of sodium 4-N-methylenesulfonate aminopyrine (unknown impurity) in the prepared aminopyrine to be ≤0.05%, which complies with the requirements of the European Pharmacopoeia.

[0048] This invention reduces the dehydration step in the preparation of 4-methylaminoantipyrine solids by allowing the neutralized liquid to stand and separate into layers, thereby directly cooling and crystallizing the obtained MAA oil. In the preparation of metamizole, the ethanol solubility is reduced to 90-93%, which can make the content of 4-N-methylenesulfonate sodium metamizole in the prepared metamizole ≤0.05%, which meets the requirements of the European Pharmacopoeia.

[0049] In an optional embodiment of the present invention, in the step of preparing the methylated solution, 4-formylaminoantipyrine is dissolved in water and stirred; when the temperature of the solution after stirring is 5-15°C, dimethyl sulfate and alkali solution are added simultaneously, and the reaction temperature does not exceed 25°C. The inventors have found that if the solution temperature is too high, the decomposition rate of dimethyl sulfate is too fast, which reduces the yield and purity of aminopyrine.

[0050] In an optional embodiment of the present invention, in the step of preparing the methylation solution, the alkaline solution includes at least one of an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of sodium carbonate; the reaction time is 30-60 min (e.g., 30 min, 40 min, 50 min, or 60 min); and the pH value of the solution after the dimethyl sulfate and the alkaline solution are added is 9-11. If the pH value is too low, the acidity is stronger, the reaction proceeds in the reverse direction, the reaction is incomplete, and the yield decreases. If the pH value is too high, it accelerates the decomposition of dimethyl sulfate.

[0051] As an optional embodiment of the present invention, in the step of preparing the methylated solution, the mass ratio of 4-formylaminoantipyrine, water, dimethyl sulfate and alkali in the alkaline solution is 1:(1.5-2):(0.55-1):(0.35-0.63).

[0052] As an optional embodiment of the present invention, in the step of preparing the methylation solution, the mass percentage of alkali in the alkali solution is 30%-40% (for example, it can be 30%, 35% or 40%).

[0053] In an optional embodiment of the present invention, the hydrolysis step in the preparation of 4-methylaminoantipyrine solid includes: stirring the methylated solution and then adding concentrated sulfuric acid for hydrolysis. Replacing the concentrated sulfuric acid with dilute sulfuric acid will reduce the hydrolysis rate.

[0054] As an optional embodiment of the present invention, the concentrated sulfuric acid has a mass fraction of 93-98%, and the mass ratio of 4-formylaminoantipyrine to concentrated sulfuric acid is 1:(0.5-1).

[0055] As an optional embodiment of the present invention, in the step of preparing 4-methylaminoantipyrine solid, the hydrolysis temperature is 80-106°C (for example, it can be 80°C, 90°C or 106°C), and the hydrolysis time is 3-5 hours.

[0056] As an optional embodiment of the present invention, in the step of preparing 4-methylaminoantipyrine solid, the neutralization includes primary neutralization and secondary neutralization; the primary neutralization step includes: adding the hydrolyzed solution to a primary neutralization tank and heating it, then adding alkali solution to neutralize to a pH value of 2-2.5, adding water to adjust the specific gravity of the solution to 1.18-1.22, and then adding activated carbon for decolorization.

[0057] In this invention, water is added to adjust the specific gravity of the feed solution in preparation for oil separation after secondary neutralization. If the specific gravity is too low, even after secondary neutralization, the specific gravity will still be low, and the oil phase will have a similar specific gravity to the water phase, resulting in poor separation. More MAA oil will dissolve in the aqueous phase, leading to a low yield. If the specific gravity is too high, the salt in the aqueous phase may reach a supersaturated state, making it easy to precipitate and become trapped in the MAA oil.

[0058] As an optional embodiment of the present invention, in the first neutralization step, the decolorization temperature is 80-90℃ (for example, it can be 80℃, 85℃ or 90℃), and the decolorization time is 0.5-1 hour.

[0059] As an optional embodiment of the present invention, in the first neutralization step, the amount of activated carbon added is 0.5-1% of the mass of 4-formylaminoantipyrine; the temperature is raised to 60-100°C (e.g., 60°C, 80°C, or 100°C); the alkaline solution includes at least one of liquid ammonia, ammonia water, sodium hydroxide aqueous solution, or sodium carbonate aqueous solution.

[0060] As an optional embodiment of the present invention, the secondary neutralization step includes: filtering the liquid after primary neutralization, passing alkaline solution through it at 60-100°C until the pH of the liquid is 7.2-7.5, to obtain the liquid after secondary neutralization, and adding water to adjust the specific gravity of the liquid to 1.23-1.27.

[0061] During the research, the inventors discovered that adjusting the amount of water added could make the specific gravity difference between 4-methylaminoantipyrine oil and aqueous solution larger, which would be more conducive to the separation of oil and water. If the amount of water added was too small, the MAA oil would encapsulate the salt; if the amount of water added was too large, the separation of MAA and water would be indistinct, affecting the yield.

[0062] As an optional embodiment of the present invention, in the secondary neutralization step, the alkaline solution includes at least one of liquid ammonia, an aqueous solution of sodium hydroxide, or an aqueous solution of sodium carbonate.

[0063] As an optional embodiment of the present invention, in the preparation step of aminopyrine, the reaction temperature is 78-82°C; during the reaction, an alkali is added to adjust the pH of the reaction solution to 7.0-7.5, wherein the alkali includes at least one of sodium carbonate and sodium hydroxide.

[0064] As an optional embodiment of the present invention, the reaction time in the preparation step of aminopyrine is 50-60 min.

[0065] In an optional embodiment of the present invention, in the preparation step of aminopyrine, the mass ratio of the 4-methylaminoantipyrine solid, ethanol, sodium metabisulfite, activated carbon, and formaldehyde is 1:(1-5):(0.4372-0.6559):(0.005-0.01):(0.138-0.207); the ethanol is aqueous ethanol, and the volume fraction of ethanol in the aqueous ethanol is 90%-93%.

[0066] As an optional embodiment of the present invention, in the preparation step of aminopyrine, the formaldehyde is added in the form of an aqueous formaldehyde solution, wherein the mass fraction of formaldehyde in the aqueous formaldehyde solution is 30%-40%.

[0067] As an optional embodiment of the present invention, in the preparation of aminopyrine, after the reaction is completed, the liquid is filtered and pressed into a crystallization tank, and then crystallized, centrifuged and dried to obtain the finished aminopyrine product.

[0068] As an optional embodiment of the present invention, the content of sodium 4-N-methylenesulfonate aminopyrine (unknown impurity) in the aminopyrine is ≤0.05%.

[0069] The content of sodium 4-N-methylenesulfonate (unknown impurity) in the metamizole was obtained according to the calculation method for the content of unknown impurities in finished metamizole products as specified in the European Pharmacopoeia (EP10.0).

[0070] In a preferred embodiment of the present invention, the content of sodium 4-N-methylenesulfonate aminopyrine (unknown impurity) in the aminopyrine is ≤0.02%.

[0071] The present invention will now be described in further detail with reference to specific embodiments and comparative examples.

[0072] In the following embodiments and comparative examples:

[0073] The preparation method of sodium 1,4-N-methylenesulfonate aminopyrine is as follows:

[0074] AA and sodium metabisulfite were added to ethanol and stirred until homogeneous. Formaldehyde aqueous solution (the mass percentage of formaldehyde in the formaldehyde aqueous solution was 30%) was added dropwise at room temperature. After the addition was complete, the temperature was raised to reflux and reacted for 3 hours. The temperature was then lowered to 15°C to crystallize and obtain sodium 4-N-methylenesulfonate aminopyrine. The molar ratio of AA, formaldehyde and sodium metabisulfite was 1:4:4.

[0075] The prepared sodium 4-N-methylenesulfonate aminopyrine was analyzed by high-performance liquid chromatography (HPLC) according to the method specified in EP10.0 (the detection method is the same as the HPLC method for aminopyrine in the examples). The obtained HPLC chromatogram and its corresponding peak table are shown below. Figure 2 As shown. By Figure 1 and Figure 2 It can be seen that the retention time of the unknown impurity in Example 1 is 0.590 min, and the retention time of sodium 4-N methylenesulfonate aminopyrine is also 0.590 min. This indicates that sodium 4-N methylenesulfonate aminopyrine is the unknown impurity in Example 1, that is, the unknown impurity in the aminopyrine product prepared in Example 1 is sodium 4-N methylenesulfonate aminopyrine.

[0076] 2. The specific gravity was measured using a hydrometer.

[0077] Example 1

[0078] This embodiment provides a method for preparing aminopyrine with controlled content of sodium 4-N methylene sulfonate, an impurity in aminopyrine, comprising the following steps:

[0079] S1. Preparation of methylation solution (FAA methylation): Add 800g of water to the reaction vessel (methylation tank), add 500g of 4-formylaminoantipyrine (FAA, the mass percentage of AA in FAA is 0.7%), start stirring, and continuously cool down. When the temperature inside the tank reaches 10℃, start adding 350g of dimethyl sulfate and 740g of 30wt% sodium hydroxide aqueous solution dropwise. The addition is completed within 30min. Control the temperature of the entire process (from the addition of dimethyl sulfate and sodium hydroxide aqueous solution to the completion of the reaction) not to exceed 25℃. After the addition is completed, the pH value of the solution (reaction solution) is 10. Then carry out the reaction for 50min. The methylation is qualified, and the methylation solution is obtained.

[0080] S2. Preparation of 4-methylaminoantipyrine solid:

[0081] Hydrolysis: The methylated solution from step S1 is pumped into a hydrolysis tank, stirring is started, 500g of concentrated sulfuric acid (93% by mass) is added, the temperature is controlled at 100℃, and hydrolysis is carried out for 4 hours.

[0082] First neutralization: Start stirring, add the hydrolyzed liquid to the first neutralization tank, then add 500g of purified water and heat to 80℃. Then, introduce liquid ammonia for neutralization. Stop introducing ammonia when the pH value is 2.5. Adjust the specific gravity to 1.2 with water, add 3g of activated carbon, maintain the temperature at 80℃, and keep warm for 1 hour for decolorization.

[0083] Secondary neutralization: After decolorization, the liquid is filtered and pressed into a secondary neutralization tank. Liquid ammonia is introduced to adjust the acidity. The temperature is maintained at 90℃. Neutralization is stopped when the pH reaches 7.2, and the liquid after secondary neutralization is obtained. The specific gravity of the liquid is adjusted to 1.25 with water. The liquid is allowed to stand and separate into layers. The upper oily layer is taken to obtain MAA (4-methylaminoantipyrine) oil.

[0084] Cooling and crystallization: Place the MAA oil into a crystallization tank, cool it to 20°C, crystallize, and centrifuge to obtain 387g of solid MAA. AA (4-aminoantipyrine) and inorganic salts are discharged from the system with the mother liquor.

[0085] S3. Preparation of Analgin (condensation reaction): First, add 800g of 93% ethanol (ethanol to water volume ratio of 93:7) to the condensation reaction vessel, start stirring, then add 387g of MAA, 174g of sodium metabisulfite, and 3g of activated carbon. Add 185g of 30wt% formaldehyde aqueous solution at room temperature, completing the addition within half an hour. Heat to 80℃ and reflux for 50 minutes at boiling point. During reflux, adjust the pH of the reaction solution to 7.2 with sodium carbonate to maintain the pH value of the reaction solution at 7.2. After the reaction is completed, press the solution through a filter into a crystallization tank, cool to 20℃, crystallize, centrifuge, and dry to obtain 649.6g of finished Analgin product.

[0086] Yield calculation formula:

[0087] The yield of aminopyrine obtained using the preparation method of this embodiment is 90%.

[0088] High-performance liquid chromatography (HPLC) detection: The aminopyrine product prepared in this embodiment was detected according to EP10.0. The detection results are shown in Table 1. The HPLC chromatogram and its corresponding peak table are shown below. Figure 1 As shown.

[0089] Table 1. Analgin (EP10.0) Test Record (HPLC)

[0090]

[0091]

[0092] Example 2

[0093] This embodiment provides a method for preparing aminopyrine with controlled content of sodium 4-N methylene sulfonate, an impurity in aminopyrine, comprising the following steps:

[0094] The difference between this embodiment and Embodiment 1 is that in step S3, the condensation reaction time is 60 min, while the remaining steps are the same as in Embodiment 1.

[0095] The yield of aminopyrine obtained using the preparation method of this embodiment is 90.5%.

[0096] High-performance liquid chromatography (HPLC) detection: The aminopyrine product prepared in this example was detected according to EP10.0, and the detection results are shown in Table 2:

[0097] Table 2. Analgin (EP10.0) Test Record (HPLC)

[0098]

[0099] Example 3

[0100] This embodiment provides a method for preparing aminopyrine with controlled content of sodium 4-N methylene sulfonate, an impurity in aminopyrine, comprising the following steps:

[0101] The difference between this embodiment and Embodiment 1 is that in step S3, the ethanol concentration is 91%, while the remaining steps are the same as in Embodiment 1.

[0102] The yield of aminopyrine obtained using the preparation method of this embodiment is 90.2%.

[0103] High-performance liquid chromatography (HPLC) detection: The aminopyrine product prepared in this example was detected according to EP10.0, and the detection results are shown in Table 3.

[0104] Table 3. Analgin (EP10.0) Test Record (HPLC)

[0105]

[0106] Example 4

[0107] This embodiment provides a method for preparing aminopyrine with controlled content of sodium 4-N methylene sulfonate, an impurity in aminopyrine, comprising the following steps:

[0108] The difference between this embodiment and Embodiment 1 is that in step S2, the hydrolysis temperature is 80°C and the hydrolysis time is 5 hours, while the remaining steps are the same as in Embodiment 1.

[0109] The yield of aminopyrine obtained using the preparation method of this embodiment is 90.0%.

[0110] High-performance liquid chromatography (HPLC) detection: The aminopyrine product prepared in this example was detected according to EP10.0, and the detection results are shown in Table 4.

[0111] Table 4. Analgin (EP10.0) Test Record (HPLC)

[0112]

[0113]

[0114] Comparative Example 1

[0115] This comparative example provides a method for preparing aminopyrine with controlled content of sodium 4-N methylene sulfonate, which includes the following steps:

[0116] The difference between this comparative example and Example 1 is that the mass percentage of 4-aminoantipyrine in 4-formylaminoantipyrine is 2%, while the other steps are the same as in Example 1.

[0117] The yield of aminopyrine obtained using the preparation method of this comparative example was 87.5%.

[0118] High performance liquid chromatography (HPLC) detection: The aminopyrine product prepared in this comparative example was detected according to EP10.0. The detection results are shown in Table 5.

[0119] Table 5. Analgin (EP10.0) Test Record (HPLC)

[0120]

[0121] Comparative Example 2

[0122] This comparative example provides a method for preparing aminopyrine with controlled content of sodium 4-N methylene sulfonate, which includes the following steps:

[0123] The difference between this comparative example and Example 1 is that dimethyl sulfate is added first, followed by an aqueous solution of sodium hydroxide; the remaining steps are the same as in Example 1.

[0124] The yield of aminopyrine obtained using the preparation method of this comparative example was 87.8%.

[0125] High-performance liquid chromatography (HPLC) analysis: The aminopyrine product prepared in this comparative example was analyzed according to EP10.0. The test results are shown in Table 6.

[0126] Table 6. Analgin (EP10.0) Test Record (HPLC)

[0127]

[0128] Comparative Example 3

[0129] This comparative example provides a method for preparing aminopyrine with controlled content of sodium 4-N methylene sulfonate, which includes the following steps:

[0130] The difference between this comparative example and Example 1 is that the obtained MAA oil was dehydrated by vacuum distillation and then directly subjected to condensation reaction without cooling and crystallization. All other steps were the same as in Example 1.

[0131] The yield of aminopyrine obtained using the preparation method of this comparative example was 90.0%.

[0132] High performance liquid chromatography (HPLC) detection: The aminopyrine product prepared in this comparative example was tested according to EP10.0, and the test results are shown in Table 7:

[0133] Table 7. Analgin (EP10.0) Test Record (HPLC)

[0134]

[0135]

[0136] Comparative Example 4

[0137] This comparative example provides a method for preparing aminopyrine with controlled content of sodium 4-N methylene sulfonate, which includes the following steps:

[0138] The difference between this comparative example and Example 1 is that in step S1, after adding 4-formylaminoantipyrine, no cooling operation is performed, and dimethyl sulfate and sodium hydroxide aqueous solution are added dropwise simultaneously. It is not necessary to control the temperature of the entire process. The remaining steps are the same as in Example 1.

[0139] The yield of aminopyrine obtained using the preparation method of this comparative example was 68.5%.

[0140] High performance liquid chromatography (HPLC) detection: The aminopyrine product prepared in this comparative example was detected according to EP10.0. The detection results are shown in Table 8.

[0141] Table 8. Analgin (EP10.0) Test Record (HPLC)

[0142]

[0143] Comparative Example 5

[0144] This comparative example provides a method for preparing aminopyrine with controlled content of sodium 4-N methylene sulfonate, which includes the following steps:

[0145] The difference between this comparative example and Example 1 is that in step S2, only one neutralization is performed. The one-time neutralization step includes: adding the hydrolyzed solution to the one-time neutralization tank, then adding 500g of purified water and heating to 80°C, then introducing liquid ammonia for neutralization, stopping the introduction of liquid ammonia when the pH value reaches 7.2, adding 3g of activated carbon, maintaining the temperature at 80°C, and keeping it at this temperature for 1 hour for decolorization; after decolorization, filtering the solution through a filter to obtain the solution after one-time neutralization, then adding purified water to adjust the specific gravity of the solution to 1.25, allowing it to stand and separate into layers, and taking the upper oily layer to obtain MAA (4-methylaminoantipyrine) oil. The remaining steps are the same as in Example 1.

[0146] The yield of aminopyrine obtained using the preparation method of this comparative example was 80%.

[0147] High performance liquid chromatography (HPLC) detection: The aminopyrine product prepared in this comparative example was detected according to EP10.0. The detection results are shown in Table 9.

[0148] Table 9. Analgin (EP10.0) Test Record (HPLC)

[0149]

[0150] Compared to Example 1, the yield of aminopyrine prepared in this comparative example was lower, and the content of 4-N-methylenesulfonate sodium aminopyrine was higher, exceeding the requirements of the European Pharmacopoeia. The inventors speculate that the reason may be as follows: In Example 1, the pH was low after the first neutralization. At this time, 4-methylaminoantipyrine (MAA) was dissolved in the aqueous solution in the form of a salt with sulfuric acid, while the impurities may be in colloidal form, i.e., organic form. By adding activated carbon, the small molecules of MAA sulfate aqueous solution were released from the activated carbon, while the organic impurities remained in the activated carbon and were removed from the system with the waste carbon, thus achieving the separation of impurities from the product. In this comparative example, the pH value after neutralization was higher, and MAA sulfate was converted into MAA organic matter. Due to the high temperature, the melting point of MAA was reached, and MAA existed in a molten state, i.e., MAA oil existed, resulting in the desired product. At this time, the product and impurities were not easily separated by adding activated carbon, and the product was not easily separated from the activated carbon. Therefore, the yield of aminopyrine prepared in this comparative example was lower, and the content of 4-N-methylenesulfonate sodium aminopyrine was higher.

[0151] Comparative Example 6

[0152] This comparative example provides a method for preparing aminopyrine with controlled content of sodium 4-N methylene sulfonate, which includes the following steps:

[0153] The difference between this comparative example and Example 1 is that in the secondary neutralization step S2, water is used to adjust the specific gravity of the liquid to 1.21, while the remaining steps are the same as in Example 1.

[0154] The yield of aminopyrine obtained using the preparation method of this comparative example was 70.4%.

[0155] High performance liquid chromatography (HPLC) detection: The aminopyrine product prepared in this comparative example was detected according to EP10.0, and the detection results are shown in Table 10:

[0156] Table 10. Analgin (EP10.0) Test Record (HPLC)

[0157]

[0158] Comparative Example 7

[0159] This comparative example provides a method for preparing aminopyrine with controlled content of sodium 4-N methylene sulfonate, which includes the following steps:

[0160] The difference between this comparative example and Example 1 is that in step S3, the ethanol is 95% ethanol, while the remaining steps are the same as in Example 1.

[0161] The yield of aminopyrine obtained using the preparation method of this comparative example was 90.8%.

[0162] High performance liquid chromatography (HPLC) detection: The aminopyrine product prepared in this comparative example was detected according to EP10.0, and the detection results are shown in Table 11:

[0163] Table 11. Test Record of Analgin (EP10.0) (HPLC)

[0164]

[0165] Compared with Example 1, the content of sodium 4-N-methylenesulfonate aminopyrine in the finished aminopyrine product increased, exceeding the requirements of the European Pharmacopoeia. The inventors speculate that the reason may be that since the unknown impurity (sodium 4-N-methylenesulfonate aminopyrine) is a highly polar sodium salt that is easily soluble in water, appropriately reducing the ethanol solubility is beneficial to the removal of the unknown impurity.

[0166] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention shall be within the scope of protection of the pending claims of the present invention.

Claims

1. A method for preparing aminopyrine with controlled content of sodium 4-N-methylenesulfonate, an impurity in aminopyrine, characterized in that, The preparation method includes the following steps: Preparation of methylation solution: Dissolve 4-formylaminoantipyrine in water, and then add dimethyl sulfate and alkaline solution to react and obtain methylation solution; Preparation of 4-methylaminoantipyrine solid: The obtained methylated solution was hydrolyzed, neutralized and then allowed to stand to separate into layers. The upper layer of 4-methylaminoantipyrine oil was taken and cooled to crystallize, thus obtaining 4-methylaminoantipyrine solid. Preparation of aminopyrine: The obtained 4-methylaminoantipyrine solid, ethanol, sodium metabisulfite, activated carbon, and formaldehyde were mixed and reacted to obtain aminopyrine; The 4-aminoantipyrine content in the 4-formylaminoantipyrine does not exceed 1.5% by mass; In the step of preparing the methylated solution, 4-formylaminoantipyrine is dissolved in water and stirred; when the temperature of the solution after stirring is 5-15°C, the dimethyl sulfate and the alkaline solution are added simultaneously, and the reaction temperature does not exceed 25°C. In the step of preparing the methylation solution, the alkaline solution is an aqueous sodium hydroxide solution; after the dimethyl sulfate and the alkaline solution are added, the pH value of the solution is 9-11. In the preparation of 4-methylaminoantipyrine solid, the neutralization includes primary neutralization and secondary neutralization; the primary neutralization step includes: adding the hydrolyzed solution to a primary neutralization tank and heating it, then adding alkali solution to neutralize to a pH value of 2-2.5, adding water to adjust the specific gravity of the solution to 1.18-1.22, and then adding activated carbon for decolorization; In the first neutralization step, the alkaline solution is liquid ammonia; The secondary neutralization step includes: filtering the liquid after primary neutralization, passing alkaline solution through it at 60-100℃ until the pH of the liquid is 7.2-7.5, to obtain the liquid after secondary neutralization, and adding water to adjust the specific gravity of the liquid to 1.23-1.

27. In the secondary neutralization step, the alkaline solution is liquid ammonia; In the preparation of aminopyrine, the ethanol is aqueous ethanol, and the volume fraction of ethanol in the aqueous ethanol is 90%-93%. The content of sodium 4-N-methylenesulfonate aminopyrine in the aminopyrine is ≤0.05%; The structural formula of the aminopyrine impurity 4-N-methylenesulfonate sodium aminopyrine is shown below: 。 2. The preparation method according to claim 1, characterized in that, In the step of preparing the methylated solution, the reaction time is 30-60 min; And / or, in the step of preparing the methylated solution, the mass ratio of the 4-formylaminoantipyrine, water, dimethyl sulfate, and alkali in the alkaline solution is: 1:(1.5-2):(0.55-1):(0.35-0.63). And / or, in the step of preparing the methylation solution, the alkali solution contains 30%-40% alkali by mass.

3. The preparation method according to claim 1, characterized in that, In the step of preparing 4-methylaminoantipyrine solid, the hydrolysis step includes: stirring the methylated solution and then adding concentrated sulfuric acid for hydrolysis; And / or, the concentrated sulfuric acid has a mass fraction of 93-98%, and the mass ratio of 4-formylaminoantipyrine to concentrated sulfuric acid is 1:(0.5-1). And / or, in the step of preparing 4-methylaminoantipyrine solid, the hydrolysis temperature is 80-106°C and the hydrolysis time is 3-5 hours.

4. The preparation method according to claim 3, characterized in that, In the first neutralization step, the decolorization temperature is 80-90℃, and the decolorization time is 0.5-1 hour; And / or, in the first neutralization step, the amount of activated carbon added is 0.5-1% of the mass of 4-formylaminoantipyrine; the temperature is raised to 60-100°C.

5. The preparation method according to claim 1, characterized in that, In the preparation of aminopyrine, the reaction temperature is 78-82℃; during the reaction, an alkali is added to adjust the pH of the reaction solution to 7.0-7.5, wherein the alkali is sodium carbonate; And / or, in the preparation step of aminopyrine, the reaction time is 50-60 min.

6. The preparation method according to claim 1, characterized in that, In the preparation of aminopyrine, the mass ratio of the 4-methylaminoantipyrine solid, ethanol, sodium metabisulfite, activated carbon, and formaldehyde is 1:(1-5):(0.4372-0.6559):(0.005-0.01):(0.138-0.207).

7. The preparation method according to claim 1, characterized in that, In the preparation of aminopyrine, formaldehyde is added in the form of an aqueous formaldehyde solution, wherein the mass fraction of formaldehyde in the aqueous formaldehyde solution is 30%-40%.

8. The preparation method according to claim 1, characterized in that, In the preparation of aminopyrine, after the reaction is completed, the liquid is filtered and pressed into a crystallization tank, and then crystallized, centrifuged and dried to obtain the finished aminopyrine product.

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