Purification method of 4-methylaminoantipyrine

Abstract

The invention provides a purification method of 4-methylaminoantipyrine, and relates to the technical field of substance purification, and the purification method comprises the following steps: S1, 4-formylaminoantipyrine is methylated and hydrolyzed to obtain a 4-methylaminoantipyrine sulfate hydrolysate; s2, adding a sodium hydroxide solution into the 4-methylaminoantipyrine sulfate hydrolysate obtained in the step S1, adjusting the pH value to 0.5-1.5, adding a certain proportion of an extracting agent into the obtained turbid liquid to extract colloidal impurities, fully stirring, and standing for layering to obtain an impurity-removed 4-methylaminoantipyrine sulfate solution; and S3, adding a sodium hydroxide solution into the impurity-removed 4-methylaminoantipyrine sulfate solution obtained in the S2, and neutralizing until the pH value is 7.0-7.5, so as to obtain the 4-methylaminoantipyrine oil. According to the method, colloidal impurities are thoroughly removed, the operation is simple, the quality of the analgin intermediate 4-methylaminoantipyrine is greatly improved, and the influence of the impurities on the quality of the final product analgin is avoided.

Description

Technical Field

[0001] The invention relates to the technical field of substance purification, in particular to a method for purifying 4-methylaminoantipyrine. Background Art

[0002] Analgin is an antipyretic and analgesic drug, which is mostly used for fever, headache, rheumatic pain, neuralgia, dysmenorrhea, etc. The synthesis of Analgin uses pyrazolone as the starting material to obtain antipyrine, which is then nitrosated, reduced, and hydrolyzed to obtain 4-aminoantipyrine, which is then acylated to obtain 4-formylaminoantipyrine, which is then methylated, hydrolyzed, and neutralized to obtain 4-methylaminoantipyrine, which is then condensed to obtain the finished product Analgin.

[0003] The synthetic process of Analgin preparation is as follows:

[0004]

[0005]

[0006] 4-Methylaminoantipyrine is the main raw material for synthesizing analgin, and is prepared by condensing with sodium metabisulfite and formaldehyde. Due to the long production process of analgin, five steps of reaction are required from the starting material to the product, and each step of the reaction requires high temperature. Analgin is a non-condensed pyrazole ring compound, and the amino compound at the 4th position is a heat-sensitive substance. It is easily oxidized at high temperatures to form colloidal impurities. These polymer impurities are of many types and large in number, making them difficult to separate and remove. Unremoved colloidal impurities will accumulate in 4-methylaminoantipyrine. If they are not separated from the system, they will be directly brought to analgin, affecting the quality of the finished product. Therefore, appropriate methods must be taken to remove the colloidal impurities to avoid the impact of impurities on the production of analgin.

[0007] The traditional process is to add activated carbon to adsorb colloidal impurities, but the colloidal impurities have a large molecular weight and a complex structure, and the pore size requirements of the activated carbon are relatively strict. In addition, the impurities wrap around the activated carbon, which is not conducive to adsorption and also affects the carbon filtration speed, resulting in unsatisfactory impurity removal effect.

[0008] In patent CN101357903A, chloroform extraction is used to remove 4-aminoantipyrine colloid impurities. Chloroform is volatile and decomposes in the presence of light to produce highly toxic phosgene, which poses a safety hazard in production.

[0009] In patent CN105801487A, 4-methylaminoantipyrine is extracted with toluene. Toluene has low toxicity, and high-concentration gas is anesthetic and irritating. The World Health Organization's International Agency for Research on Cancer has classified it as a Class 3 carcinogen, and there are safety hazards in production.

[0010] In addition, toluene and chloroform are both Class II solvents, which are restricted for use by national regulations. They are highly irritating and pose certain hazards to the human body.

[0011] In order to overcome the drawbacks of the traditional impurity removal process, the present invention is proposed. Summary of the invention

[0012] The object of the present invention is to provide a method for purifying 4-methylaminoantipyrine. The method can completely remove colloidal impurities, is simple to operate, greatly improves the quality of the analgin intermediate 4-methylaminoantipyrine, and avoids the influence of impurities on the quality of the final product analgin.

[0013] In order to achieve the above object, the present invention adopts the following technical solutions:

[0014] The present invention provides a method for purifying 4-methylaminoantipyrine, comprising the following steps:

[0015] S1, 4-formylaminoantipyrine is methylated and hydrolyzed to obtain 4-methylaminoantipyrine sulfate hydrolyzate;

[0016] S2, add sodium hydroxide solution to the 4-methylaminoantipyrine sulfate hydrolyzate obtained in step S1, adjust the pH value to 0.5-1.5, then add a certain proportion of extraction agent to extract colloidal impurities in the obtained suspension, fully stir, and obtain the 4-methylaminoantipyrine sulfate solution of impurity removal after standing and stratification;

[0017] S3, add sodium hydroxide solution to the impurity-removed 4-methylaminoantipyrine sulfate solution obtained in S2 and neutralize to a pH value of 7.0-7.5 to obtain 4-methylaminoantipyrine oil.

[0018] Furthermore, the methylation step in step S1 is: methylating 4-formylaminoantipyrine with dimethyl sulfate in an alkaline environment at 15-25° C. and pH 8-14 to generate 4-formylmethylaminoantipyrine;

[0019] And / or, the hydrolysis step is: adding concentrated sulfuric acid to the methylation reaction solution of 4-formylmethylaminoantipyrine and heating the solution to 70° C. to 110° C. for hydrolysis to generate 4-methylaminoantipyrine sulfate hydrolyzate.

[0020] Furthermore, the mass concentration of the sodium hydroxide solution in step S2 is 25% to 32%.

[0021] Furthermore, the extractant in step S2 is one or more of diethyl ether, ethyl acetate, and n-heptane.

[0022] Furthermore, in step S2, the mass ratio of the 4-methylaminoantipyrine sulfate hydrolyzate to the extractant is 1:0.1-0.5.

[0023] Further, the extraction temperature in step S2 is 25-45°C;

[0024] And / or, the extraction time is 0.5-1h.

[0025] Furthermore, in step S3, the mass concentration of the sodium hydroxide solution is 25% to 32%.

[0026] Furthermore, in the step S3, the neutralization temperature is 65-85°C.

[0027] Furthermore, the purity of the 4-methylaminoantipyrine oil is 98.1-99.2%, and its thermal stability is good.

[0028] The present invention provides a method for purifying 4-methylaminoantipyrine, which has the beneficial effects of:

[0029] 1. The purification method of 4-methylaminoantipyrine of the present invention utilizes the extraction principle, wherein colloidal impurities are dissolved in an extractant, and the impurities are completely removed from the system by standing and stratifying, and the process operation is simple.

[0030] 2. The present invention is to neutralize the 4-methylaminoantipyrine hydrolyzate to pH 0.5-1.5 before adding the extractant. The pH ensures that the 4-methylaminoantipyrine exists in the form of sulfate and is soluble in water but insoluble in the extractant, which is beneficial to the adsorption and removal of colloidal impurities.

[0031] 3. The present invention purifies the last intermediate in the production of Analgin, thereby preventing impurities from being introduced into the Analgin product and ensuring product quality. DETAILED DESCRIPTION

[0032] In order to make the purpose, technical scheme and advantages of the present invention clearer, the technical scheme in the embodiment of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without making creative work are within the scope of protection of the present invention. The process parameters of the following embodiments that do not specify specific conditions are usually based on conventional conditions.

[0033] The endpoints and any values ​​of the ranges disclosed in the present 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 each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be regarded as specifically disclosed in the present invention.

[0034] The present invention provides a method for purifying 4-methylaminoantipyrine, comprising the following steps:

[0035] S1, 4-formylaminoantipyrine is methylated and hydrolyzed to obtain 4-methylaminoantipyrine sulfate hydrolyzate;

[0036] S2, add sodium hydroxide solution to the 4-methylaminoantipyrine sulfate hydrolyzate obtained in step S1, adjust the pH value to 0.5-1.5 (such as 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4), then add a certain proportion of extraction agent to extract colloidal impurities in the obtained suspension, fully stir, and obtain the 4-methylaminoantipyrine sulfate solution of removal of impurities after standing and stratification;

[0037] S3, add sodium hydroxide solution to the impurity-removed 4-methylaminoantipyrine sulfate solution obtained in S2 and neutralize to a pH value of 7.0-7.5 (e.g., 7.1, 7.2, 7.3, 7.4) to obtain 4-methylaminoantipyrine oil.

[0038] The purification method of the present invention is simple to operate, and only one-step extraction operation is required to separate the colloidal impurities in the 4-methylaminoantipyrine hydrolyzate. In step S2, sodium hydroxide is added to adjust the pH to 0.5-1.5, so that 4-methylaminoantipyrine can be present in the form of sulfate, which is soluble in water but insoluble in the extractant, and is conducive to the removal of colloidal impurities. If the pH is adjusted to a lower level in step S2, less colloidal impurities appear, and part of them are dissolved in the aqueous solution, and the removal is not thorough. If the pH is adjusted to a higher level, part of the 4-methylaminoantipyrine sulfate becomes 4-methylaminoantipyrine oil, which is also easily soluble in the organic phase, resulting in a low product yield.

[0039] 4-Methylaminoantipyrine is the last intermediate in the synthesis of analgin, that is, intermediate 4, and 4-aminoantipyrine is the second intermediate in the synthesis of analgin, that is, intermediate 2. From intermediate 2 to intermediate 4, acylation reaction, methylation reaction, hydrolysis reaction and neutralization reaction will be carried out, involving high temperature reaction. In this case, the colloidal impurities produced by intermediate 4 are more complex and have a larger molecular weight. The effect of decolorization with activated carbon is not ideal because the pore size of activated carbon is smaller than the molecular weight of impurities, which is not conducive to the adsorption of impurities. Therefore, it is more appropriate to use extraction to remove impurities from intermediate 4.

[0040] This is the last intermediate in the synthesis of Analgin. Removing impurities here is more thorough and more conducive to ensuring the quality of Analgin. Adding an extractant to the hydrolyzate of 4-aminoantipyrine can only remove some impurities, but new impurities can be generated after subsequent reactions, affecting the quality of Analgin. Therefore, it is necessary to remove impurities from 4-methylaminoantipyrine, the last intermediate in the synthesis of Analgin.

[0041] As an optional embodiment of the present invention, the methylation step in step S1 is: methylating 4-formylaminoantipyrine with dimethyl sulfate in an alkaline environment at 15-25° C. and pH 8-14 to generate 4-formylmethylaminoantipyrine;

[0042] And / or, the hydrolysis step is: adding concentrated sulfuric acid to the methylation reaction solution of 4-formylmethylaminoantipyrine and heating the solution to 70° C. to 110° C. for hydrolysis to generate 4-methylaminoantipyrine sulfate hydrolyzate.

[0043] As an optional implementation manner of the present invention, the mass concentration of the sodium hydroxide in step S2 is 25-32%.

[0044] As an optional embodiment of the present invention, the extractant in step S2 is one or more of diethyl ether, ethyl acetate, and n-heptane.

[0045] As an optional embodiment of the present invention, in step S2, the mass ratio of the 4-methylaminoantipyrine sulfate hydrolyzate to the extractant is 1:0.1-0.5 (such as 1:0.2, 1:0.3, 1:0.4).

[0046] As an optional embodiment of the present invention, the extraction temperature in step S2 is 25-45°C (e.g., 26°C, 28°C, 30°C, 32°C, 34°C, 36°C, 38°C, 40°C, 42°C, 44°C);

[0047] And / or, the extraction time is 0.5-1h (such as 0.6h, 0.7h, 0.8h, 0.9h).

[0048] As an optional implementation of the present invention, in step S3, the mass concentration of the sodium hydroxide solution is 25% to 32%.

[0049] As an optional embodiment of the present invention, in step S3, the neutralization temperature is 65-85°C.

[0050] The first addition of sodium hydroxide for neutralization in step S2 can be at a low temperature because the 4-methylaminoantipyrine sulfate solution is a salt with high water solubility. The second addition of sodium hydroxide for neutralization in step S3 must be at a high temperature. The melting point of 4-methylaminoantipyrine is 50-54° C., and the 4-methylaminoantipyrine oil can only be obtained if the temperature reaches above the melting point of the substance.

[0051] The 4-methylaminoantipyrine oil obtained by the purification method of the invention has a purity of 98.1-99.2% and good thermal stability.

[0052] The present invention will be further described in detail below with reference to specific embodiments and comparative examples.

[0053] The test methods in the following examples and comparative examples are conventional methods unless otherwise specified and can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions. The ether used in the examples is analytically pure; the ethyl acetate is analytically pure; the n-heptane is analytically pure; the activated carbon is pharmaceutical grade activated carbon, and its decolorization power is ≥12ml. The 4-methylaminoantipyrine sulfate hydrolyzate obtained in step S1 used in the following examples and comparative examples is prepared from the same batch.

[0054] Example 1

[0055] S1, 4-formylaminoantipyrine is methylated and hydrolyzed to obtain 4-methylaminoantipyrine sulfate hydrolyzate;

[0056] The methylation method comprises the following steps: methylating 4-formylaminoantipyrine with dimethyl sulfate in an alkaline environment at 25° C. and pH 10 to generate 4-formylmethylaminoantipyrine.

[0057] The hydrolysis method comprises the following steps: adding concentrated sulfuric acid to 4-formylmethylaminoantipyrine and heating the mixture to 90° C. to hydrolyze the mixture and generate a 4-methylaminoantipyrine sulfate hydrolyzate.

[0058] S2, the 4-methylaminoantipyrine sulfate hydrolyzate obtained in step S1 is cooled to 25 ℃, and a sodium hydroxide solution having a mass percent concentration of 32% is added to 500 ml of the hydrolyzate, and the pH value is adjusted to 1, and 200 ml of ether, an extractant, added to the above-mentioned suspension, is used to extract the colloidal impurities, and the 4-methylaminoantipyrine sulfate solution after the removal of impurities is obtained after standing and stratifying;

[0059] S3, the 4-methylaminoantipyrine sulfate solution after impurity removal obtained in S2 is heated to 70° C., and then a sodium hydroxide solution with a mass percentage concentration of 32% is added thereto, and the solution is neutralized to a pH value of 7.0 to obtain 4-methylaminoantipyrine oil.

[0060] Example 2

[0061] S1, 4-formylaminoantipyrine is methylated and hydrolyzed to obtain 4-methylaminoantipyrine sulfate hydrolyzate;

[0062] The methylation method comprises the following steps: methylating 4-formylaminoantipyrine with dimethyl sulfate in an alkaline environment at 25°C and pH 10 to generate 4-formylmethylaminoantipyrine.

[0063] The hydrolysis method comprises the following steps: adding concentrated sulfuric acid to 4-formylmethylaminoantipyrine and heating the mixture to 90° C. to hydrolyze the mixture and generate a 4-methylaminoantipyrine sulfate hydrolyzate.

[0064] S2, the 4-methylaminoantipyrine sulfate hydrolyzate obtained in step S1 is cooled to 25 ℃, and a sodium hydroxide solution with a mass percent concentration of 32% is added to 500 ml of the hydrolyzate, and the pH value is adjusted to 1, and 200 ml of ethyl acetate, an extractant, added to the above-mentioned suspension, is used to extract the colloidal impurities, and the 4-methylaminoantipyrine sulfate solution after standing and stratifying is obtained after impurity removal;

[0065] S3, the 4-methylaminoantipyrine sulfate solution after impurity removal obtained in S2 is heated to 70° C., and then a sodium hydroxide solution with a mass percentage concentration of 32% is added thereto, and the solution is neutralized to a pH value of 7.0 to obtain 4-methylaminoantipyrine oil.

[0066] Example 3

[0067] S1, 4-formylaminoantipyrine is methylated and hydrolyzed to obtain 4-methylaminoantipyrine sulfate hydrolyzate;

[0068] The methylation method comprises the following steps: methylating 4-formylaminoantipyrine with dimethyl sulfate in an alkaline environment at 25°C and pH 10 to generate 4-formylmethylaminoantipyrine.

[0069] The hydrolysis method comprises the following steps: adding concentrated sulfuric acid to 4-formylmethylaminoantipyrine and heating the mixture to 90° C. to hydrolyze the mixture and generate a 4-methylaminoantipyrine sulfate hydrolyzate.

[0070] S2, the 4-methylaminoantipyrine sulfate hydrolyzate obtained in step S1 is cooled to 25 ° C, a sodium hydroxide solution with a mass percentage concentration of 32% is added to 500 ml of the hydrolyzate, the pH value is adjusted to 1, and 200 ml of the extractant n-heptane added to the above suspension is used to extract the colloidal impurities, fully stirred, and the 4-methylaminoantipyrine sulfate solution after impurity removal is obtained after standing and stratification;

[0071] S3, the 4-methylaminoantipyrine sulfate solution obtained in S2 is heated to 70° C., and then a sodium hydroxide solution having a mass percentage concentration of 32% is added thereto, and the solution is neutralized to a pH value of 7.0 to obtain 4-methylaminoantipyrine oil.

[0072] Example 4

[0073] S1, 4-formylaminoantipyrine is methylated and hydrolyzed to obtain 4-methylaminoantipyrine sulfate hydrolyzate;

[0074] The methylation method comprises the following steps: methylating 4-formylaminoantipyrine with dimethyl sulfate in an alkaline environment at 25° C. and pH 10 to generate 4-formylmethylaminoantipyrine.

[0075] The hydrolysis method comprises the following steps: adding concentrated sulfuric acid to 4-formylmethylaminoantipyrine and heating the mixture to 90° C. to hydrolyze the mixture and generate a 4-methylaminoantipyrine sulfate hydrolyzate.

[0076] S2, the 4-methylaminoantipyrine sulfate hydrolyzate obtained in step S1 is cooled to 25 ℃, and a sodium hydroxide solution having a mass percent concentration of 32% is added to 500 ml of the hydrolyzate, and the pH value is adjusted to 1, and 50 ml of ether, an extractant, added to the above-mentioned suspension, is used to extract the colloidal impurities, and the 4-methylaminoantipyrine sulfate solution after the removal of impurities is obtained after standing and stratifying;

[0077] S3, the 4-methylaminoantipyrine sulfate solution after impurity removal obtained in S2 is heated to 70° C., and then a sodium hydroxide solution with a mass percentage concentration of 32% is added thereto, and the solution is neutralized to a pH value of 7.0 to obtain 4-methylaminoantipyrine oil.

[0078] Comparative Example 1

[0079] The difference between the comparative example and the embodiment is that the comparative example adopts a traditional activated carbon adsorption process to remove the colloidal impurities.

[0080] S1, 4-formylaminoantipyrine is methylated and hydrolyzed to obtain 4-methylaminoantipyrine sulfate hydrolyzate;

[0081] The methylation method comprises the following steps: methylating 4-formylaminoantipyrine with dimethyl sulfate in an alkaline environment at 25°C and pH 10 to generate 4-formylmethylaminoantipyrine.

[0082] The hydrolysis method comprises the following steps: adding concentrated sulfuric acid to 4-formylmethylaminoantipyrine and heating the mixture to 90° C. to hydrolyze the mixture and generate a 4-methylaminoantipyrine sulfate hydrolyzate.

[0083] S2, the 4-methylaminoantipyrine sulfate hydrolyzate obtained in step S1 was cooled to 25 ° C, 32% sodium hydroxide solution was added to 500 ml of the hydrolyzate, the pH value was adjusted to 1, 1 g of activated carbon was added to the above suspension, and the colloidal impurities were adsorbed at 90 ° C, fully stirred for 30 min, and filtered to obtain a 4-methylaminoantipyrine sulfate solution;

[0084] S3, the 4-methylaminoantipyrine sulfate solution obtained in S2 is cooled to 70° C., and then a sodium hydroxide solution having a mass percent concentration of 32% is added thereto, and the solution is neutralized to a pH value of 7.0 to obtain 4-methylaminoantipyrine oil.

[0085] Comparative Example 2

[0086] The only difference between this comparative example and Example 1 is that the pH value is adjusted to 2 in step S2.

[0087] S1, 4-formylaminoantipyrine is methylated and hydrolyzed to obtain 4-methylaminoantipyrine sulfate hydrolyzate;

[0088] The methylation method comprises the following steps: methylating 4-formylaminoantipyrine with dimethyl sulfate in an alkaline environment at 20°C and pH 10 to generate 4-formylmethylaminoantipyrine.

[0089] The hydrolysis method comprises the following steps: adding concentrated sulfuric acid to 4-formylmethylaminoantipyrine and heating the mixture to 90° C. to hydrolyze the mixture and generate a 4-methylaminoantipyrine sulfate hydrolyzate.

[0090] S2, the 4-methylaminoantipyrine sulfate hydrolyzate obtained in step S1 is cooled to 25 ° C, a sodium hydroxide solution with a mass percent concentration of 32% is added to 500 ml of the hydrolyzate, the pH value is adjusted to 2, and 200 ml of ether, an extractant, is added to the above-mentioned suspension to extract the colloidal impurities, fully stirred, and 4-methylaminoantipyrine sulfate solution is obtained after standing and stratification;

[0091] S3, the 4-methylaminoantipyrine sulfate solution obtained in S2 is heated to 70° C., and then a sodium hydroxide solution having a mass percentage concentration of 32% is added thereto, and the solution is neutralized to a pH value of 7.0 to obtain 4-methylaminoantipyrine oil.

[0092] Comparative Example 3

[0093] The only difference between this comparative example and Example 1 is that the pH value is adjusted to 0.3 in step S2.

[0094] S1, 4-formylaminoantipyrine is methylated and hydrolyzed to obtain 4-methylaminoantipyrine sulfate hydrolyzate;

[0095] The methylation method comprises the following steps: methylating 4-formylaminoantipyrine with dimethyl sulfate in an alkaline environment at 20°C and pH 10 to generate 4-formylmethylaminoantipyrine.

[0096] The hydrolysis method comprises the following steps: adding concentrated sulfuric acid to 4-formylmethylaminoantipyrine and heating the mixture to 90° C. to hydrolyze the mixture and generate a 4-methylaminoantipyrine sulfate hydrolyzate.

[0097] S2, the 4-methylaminoantipyrine hydrolyzate obtained in step S1 is cooled to 25 ℃, a sodium hydroxide solution with a mass percent concentration of 32% is added to 500 ml of the hydrolyzate, the pH value is adjusted to 0.3, 200 ml of ether, an extractant, is added to the above-mentioned suspension to extract the colloidal impurities, fully stirred, and the 4-methylaminoantipyrine sulfate solution after impurity removal is obtained after standing and stratification;

[0098] S3, heating the 4-methylaminoantipyrine sulfate solution obtained in S2 after the impurities are removed to 70° C., then adding a sodium hydroxide solution with a mass percentage concentration of 32%, neutralizing it to a pH value of 7.0, and obtaining 4-methylaminoantipyrine oil.

[0099] Comparative Example 4

[0100] The difference between this comparative example and Example 1 is that the extractant is chloroform.

[0101] S1, 4-formylaminoantipyrine is methylated and hydrolyzed to obtain 4-methylaminoantipyrine sulfate hydrolyzate;

[0102] The methylation method comprises the following steps: methylating 4-formylaminoantipyrine with dimethyl sulfate in an alkaline environment at 25° C. and pH 10 to generate 4-formylmethylaminoantipyrine.

[0103] The hydrolysis method comprises the following steps: adding concentrated sulfuric acid to 4-formylmethylaminoantipyrine and heating the mixture to 90° C. to hydrolyze the mixture and generate a 4-methylaminoantipyrine sulfate hydrolyzate.

[0104] S2, the 4-methylaminoantipyrine sulfate hydrolyzate obtained in step S1 is cooled to 25 ℃, and a sodium hydroxide solution having a mass percent concentration of 32% is added to 500 ml of the hydrolyzate, and the pH value is adjusted to 1, and 200 ml of chloroform, an extractant, added to the above-mentioned suspension, is used to extract the colloidal impurities, and the 4-methylaminoantipyrine sulfate solution after the removal of impurities is obtained after standing and stratifying;

[0105] S3, the 4-methylaminoantipyrine sulfate solution after impurity removal obtained in S2 is heated to 70° C., and then a sodium hydroxide solution with a mass percentage concentration of 32% is added thereto, and the solution is neutralized to a pH value of 7.0 to obtain 4-methylaminoantipyrine oil.

[0106] Effect test

[0107] The purity detection method in this application is the first supplement of the 2010 edition of the Chinese Pharmacopoeia, pages 361-362. The largest impurity and the second largest impurity in Table 1 are determined based on the peak area of ​​the impurity peak during liquid phase detection. The yield in Table 1 is calculated based on the initial amount of 4-formylamino antipyrine.

[0108] Performance data

[0109] Table 1 Detection results of 4-methylaminoantipyrine oil phase in Examples 1-4 and Comparative Examples 1-4.

[0110]

[0111] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for purifying 4-methylaminoantipyrine, characterized in that: The following steps are involved: S1, 4-formylaminoantipyrine is methylated and hydrolyzed to obtain 4-methylaminoantipyrine sulfate hydrolyzate; S2, add sodium hydroxide solution to the 4-methylaminoantipyrine sulfate hydrolyzate obtained in step S1, adjust the pH value to 0.5-1.5, then add a certain proportion of extraction agent to extract colloidal impurities in the obtained suspension, fully stir, and obtain the 4-methylaminoantipyrine sulfate solution of impurity removal after standing and stratification; S3, add sodium hydroxide solution to the impurity-removed 4-methylaminoantipyrine sulfate solution obtained in S2 and neutralize to a pH value of 7.0-7.5 to obtain 4-methylaminoantipyrine oil.

2. The purification method according to claim 1, characterized in that The methylation step in step S1 is: methylating 4-formylaminoantipyrine with dimethyl sulfate in an alkaline environment at 15-25° C. and pH 8-14 to generate 4-formylmethylaminoantipyrine; And / or, the hydrolysis step is: adding concentrated sulfuric acid to the methylation reaction solution of 4-formylmethylaminoantipyrine and heating the solution to 70° C. to 110° C. for hydrolysis to generate 4-methylaminoantipyrine sulfate hydrolyzate.

3. The purification method according to claim 1, characterized in that The mass concentration of the sodium hydroxide solution in step S2 is 25% to 32%.

4. The purification method according to claim 1, characterized in that The extractant in step S2 is one or more of diethyl ether, ethyl acetate, and n-heptane.

5. The purification method according to claim 1, characterized in that In step S2, the mass ratio of the 4-methylaminoantipyrine sulfate hydrolyzate to the extractant is 1:0.1-0.

5.

6. The purification method according to claim 1, characterized in that The extraction temperature in step S2 is 25-45°C; And / or, the extraction time is 0.5-1h.

7. The purification method according to claim 1, characterized in that In step S3, the mass concentration of the sodium hydroxide solution is 25% to 32%.

8. The purification method according to claim 1, characterized in that In the step S3, the neutralization temperature is 65-85°C.

9. A purification method according to claims 1-8, characterized in that The purity of the 4-methylaminoantipyrine oil is 98.1-99.2%, and the thermal stability is good.

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