CN115894271A - A kind of preparation method of the paracetamol that controls paracetamol impurity H content - Google Patents

Abstract

The invention belongs to the technical field of paracetamol impurity removal, and in particular relates to a preparation method of paracetamol for controlling the H content of the paracetamol impurity. The preparation method of the present invention comprises the following steps: carry out acylation reaction after mixing p-aminophenol, glacial acetic acid, antioxidant and dilute acid, carry out acid mining after the reaction, cool down and crystallize, and centrifuge to obtain solid matter and acylation mother liquor, solid After the substance is washed, the crude product of paracetamol is obtained; the crude product of paracetamol is decolorized, filtered, recrystallized, centrifuged, and dried in sequence to obtain the fine product of paracetamol; the mass fraction of acetic acid in dilute acid is 40‑45%. The invention reduces the esterification reaction between acetaminophen and glacial acetic acid by reducing the concentration of acetic acid in the acylation mother liquor, thereby reducing the content of impurity H in the acetaminophen. In addition, this process adjustment did not have a significant adverse effect on the removal of other impurities and the yield of the final product.

Description

A kind of preparation method of the paracetamol that controls paracetamol impurity H content

technical field

The invention belongs to the technical field of acetaminophen impurity removal, and in particular relates to a preparation method of acetaminophen for controlling the content of acetaminophen impurity H, that is, to provide a method for reducing acetaminophen impurity H in acetaminophen method.

Background technique

Acetaminophen is produced by the acylation reaction of p-aminophenol and glacial acetic acid, also known as paracetamol. It is white crystal or crystalline powder; odorless, slightly bitter taste. It is a commonly used antipyretic and analgesic drug. Its antipyretic effect is slow and long-lasting, and it has the advantages of little irritation and few allergic reactions. At present, acetaminophen has become one of the most widely used drugs in the world. It is the number one antipyretic and analgesic drug in the international pharmaceutical market, and it is also one of the varieties with the largest output of raw materials in my country.

Acetaminophen is produced by the acylation reaction of p-aminophenol and glacial acetic acid. During the production process, there are often finished products that should meet the quality requirements of the European Pharmacopoeia EP when they enter the EU market. 4-Acetoxyacetyl The impurity aniline has been included in the European Pharmacopoeia, and it is defined as acetaminophen impurity H, and its content in acetaminophen is regulated to be ≤0.05%.

Therefore, in order to obtain qualified or better quality acetaminophen products and improve the qualification rate of different batches of products in the large-scale production process, it is necessary to continuously study how to reduce acetaminophen impurities in the process of preparing or purifying acetaminophen H content, it is particularly important to provide a method for preparing acetaminophen with ultra-low impurity H content.

Contents of the invention

The present invention provides a kind of preparation method of the paracetamol that controls paracetamol impurity H content, and its purpose is in order to solve the situation in the prior art, produces paracetamol impurity H in the process of synthesizing paracetamol, thereby Improve the quality of acetaminophen finished products and improve the qualified rate of different batches of products.

For above-mentioned technical defect, one of purpose of the present invention is to provide the preparation method of the paracetamol of controlling paracetamol impurity H content.

First aspect, the present invention provides a kind of preparation method of the paracetamol that controls paracetamol impurity H content, comprises the following steps:

Preparation of crude paracetamol: p-aminophenol, glacial acetic acid, antioxidant and dilute acid are mixed for acylation reaction, after the reaction, acid mining, cooling crystallization, and centrifugation are carried out to obtain solid matter and acylation mother liquor, the solid matter Obtain paracetamol crude product after washing;

Preparing the refined paracetamol: decolorizing, filtering, recrystallizing, centrifuging, and drying the crude paracetamol in sequence to obtain the refined paracetamol;

Wherein, the dilute acid is an aqueous solution of glacial acetic acid or the previously recovered acylation mother liquor, and the mass fraction of acetic acid in the dilute acid is 40-45% (for example: 41%, 43%, 44%).

In the above preparation method, as a preferred embodiment, the molar ratio of p-aminophenol and glacial acetic acid is 1: (1-1.2);

And/or, the mass ratio of the p-aminophenol and the antioxidant is 1:(0.005-0.03), preferably 1:(0.015-0.03);

And/or, the mass ratio of p-aminophenol and dilute acid is 1:(1-3), preferably 1:(1.4-1.6).

In the above preparation method, as a preferred embodiment, the content of p-aminophenol is ≥99.7% (HPLC), and the content of 4,4'-diaminodiphenyl ether in p-aminophenol is ≤0.1% (HPLC).

In the above preparation method, as a preferred embodiment, the time of the acylation reaction is 3-6h (for example: 4h, 5h);

The temperature of the acylation reaction is 95-120°C (for example: 100°C, 105°C, 110°C, 115°C); preferably 95°C-98°C.

In the above preparation method, as a preferred embodiment, the temperature of the acid extraction is 100-150°C (for example: 120°C, 130°C, 140°C);

The time for the acid extraction is 2-3h (for example 2.5h);

When the mass ratio of p-aminophenol and extracted acetic acid is 1: (0.16-0.30), stop acid extraction.

In the above preparation method, as a preferred embodiment, the temperature-lowering crystallization refers to cooling to 25-30° C. for crystallization.

In the above preparation method, as a preferred embodiment, in the decolorization treatment, pure water, a decolorant and an antioxidant are added to the crude acetaminophen to perform decolorization treatment;

Further preferably, the mass ratio of the paracetamol crude product, pure water, decolorizer and antioxidant is 1:(1.5-2.0):(0.02-0.07):(0.01-0.05);

And/or, the decolorizing agent is activated carbon;

And/or, the antioxidant is sodium metabisulfite;

And/or, the temperature of the decolorization treatment is 95-110°C, that is, boiling;

And/or, the time for the decolorization treatment is 20-40 minutes, preferably 30 minutes.

In the above preparation method, as a preferred embodiment, the recrystallization treatment is to crystallize the filtrate after the filtration treatment by lowering the temperature, preferably lowering the temperature to 25-30°C.

In the second aspect, the present invention also provides acetaminophen obtained by the above preparation method;

In the above acetaminophen, as a preferred embodiment, the acetaminophen impurity H content in the acetaminophen is less than 0.005%.

The inventor unexpectedly found that reducing the concentration of the dilute acid added in the crude product preparation process can reduce the content of acetaminophen impurity H in acetaminophen, and at the same time have no obvious adverse effects on the removal of other impurities, and the yield of the final product has not changed. reduce.

Compared with the prior art, the present invention has the following beneficial effects:

1. The method of the present invention can control the content of impurity H in the paracetamol below 0.005%, the content of impurity H in the paracetamol produced in multiple batches is controlled stably, and the qualified rate of the product is high.

2. The present invention reduces the esterification reaction of acetaminophen and glacial acetic acid by reducing the concentration of acetic acid in the acylation mother liquor (dilute acid), thereby reducing the content of impurity H in the acylation mother liquor, and due to the reduction of the concentration of acetic acid in the acylation mother liquor , reducing the unit consumption of acetic acid and saving production costs. In addition, this process adjustment did not have a significant adverse effect on the removal of other impurities and the yield of the final product.

3. For the preferred technical solution of the present invention, the content of the paracetamol impurity N in the finished product can be further reduced to below 0.005%.

Detailed ways

The following will clearly and completely describe the technical solutions in the embodiments of the present invention, so that those skilled in the art can practice and reproduce them. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments of the present invention belong to the protection scope of the present invention.

A method for preparing acetaminophen that controls the content of acetaminophen impurity H of the present invention will be further described in detail below through examples. The given examples are only to illustrate the present invention, rather than to limit the scope of the present invention. The examples provided below can be used as the basis for further improvement or application by those skilled in the art, and do not constitute a specific limitation to the present invention in any way.

The percentages not specified in the following examples are percentages by mass.

Example 1

Preparation of paracetamol crude product: 100g of p-aminophenol (the content of p-aminophenol is 99.76% (HPLC), wherein 4,4'-diaminodiphenyl ether≤0.1%), 65g of glacial acetic acid, 0.8g of sodium metabisulfite and 150g of acylation mother liquor (the mass fraction of acetic acid is 40%) was added into a 1000ml four-neck bottle for acylation reaction, and after 3 hours of reaction at 110°C, acid mining was carried out. After 2 hours of acid extraction, when the amount of acid extraction was 30 g, the acid extraction was stopped, the temperature was lowered to 25° C., and 139 g of crude acetaminophen was obtained by centrifugation.

Preparation of paracetamol recrystallization: add 139g of crude paracetamol, 210g of purified water, 6.95g of sodium metabisulfite and 2.78g of activated carbon into a 1000ml four-neck flask for recrystallization reaction, decolorize at 100°C for 30min, filter carbon, and filtrate Slowly cool down to 25°C, centrifuge, and dry to obtain 128g of refined acetaminophen finished product, with a yield of 92.4%.

According to the EP10 standard, the content of each impurity in the refined acetaminophen product is detected, and the specific content of each impurity is shown in Table 1. The minimum reporting limits of the detection methods for impurities H and N recorded in the EP10 standard are both 0.03%.

Table 1

name EP10 standard Acetaminophen Impurity J ≤10ppm not detected Impurity K ≤50ppm 1ppm Other single unknown impurity ≤0.05% 0.050% sum of all impurities ≤0.2 0.060% Impurity H ≤0.05% not detected Impurity N ≤0.05% 0.050%

Among them, "other single unknown impurity" refers to the single impurity with the largest content among impurities except impurity J and K.

Using the method of this example to produce multiple batches of paracetamol, impurity H was not detected.

Example 2

Preparation of paracetamol crude product: 100g of p-aminophenol (the content of p-aminophenol is 99.76% (HPLC), wherein 4,4'-diaminodiphenyl ether≤0.1%), 66g of glacial acetic acid, 0.6g of sodium metabisulfite And 150g of acylation mother liquor (the mass fraction of acetic acid is 42%) was added into a 1000ml four-necked bottle for acylation reaction, and after 3 hours of reaction at 113°C, acid mining was carried out, at 110°C for 1 hour, and then the temperature was slowly raised to 135°C. After 2 hours of acid extraction, when the amount of acid extraction was 30 g, the acid extraction was stopped, the temperature was lowered to 25° C., and 135 g of crude acetaminophen was obtained by centrifugation.

Preparation of paracetamol recrystallization: add 135g of crude paracetamol, 210g of purified water, 7.0g of sodium metabisulfite and 2.9g of activated carbon into a 1000ml four-necked bottle for recrystallization reaction, decolorize at 100°C for 30min, filter the charcoal, and filtrate Slowly lower the temperature to 25° C., centrifuge, and dry to obtain 129 g of refined paracetamol finished product, with a yield of 93.1%.

According to the EP10 standard, the content of each impurity in the refined acetaminophen product is detected, and the specific content of each impurity is shown in Table 2.

Table 2

name EP10 standard Acetaminophen Impurity J ≤10ppm not detected Impurity K ≤50ppm 1ppm Other single unknown impurity ≤0.05% 0.057% sum of all impurities ≤0.2 0.069% Impurity H ≤0.05% not detected Impurity N ≤0.05% 0.057%

Among them, "other single unknown impurity" refers to the single impurity with the largest content among impurities except impurity J and K.

Example 3

Preparation of paracetamol crude product: 100g of p-aminophenol (the content of p-aminophenol is 99.79% (HPLC), wherein 4,4'-diaminodiphenyl ether≤0.1%), 66g of glacial acetic acid, 1.0g of sodium metabisulfite And 150g of acylation mother liquor (the mass fraction of acetic acid is 45%) was added into a 1000ml four-necked bottle for acylation reaction, after 3 hours of reaction at 105°C, acid mining was carried out, at 110°C for 1 hour, and then the temperature was slowly raised to 135°C. After 2 hours of acid extraction, when the amount of acid extraction was 30 g, the acid extraction was stopped, the temperature was lowered to 25° C., and 142 g of crude acetaminophen was obtained by centrifugation.

Preparation of paracetamol recrystallization: Add 142g of crude paracetamol, 210g of purified water, 7.0g of sodium metabisulfite and 3.0g of activated carbon into a 1000ml four-neck flask for recrystallization reaction, decolorize at 100°C for 30min, filter the charcoal, and filtrate Slowly lower the temperature to 25° C., centrifuge, and dry to obtain 128 g of refined acetaminophen finished product, with a yield of 92.4%.

According to the EP10 standard, the content of each impurity in the refined paracetamol product is detected, and the specific content of each impurity is shown in Table 3.

table 3

name EP10 standard Acetaminophen Impurity J ≤10ppm not detected Impurity K ≤50ppm 1ppm Other single unknown impurity ≤0.05% 0.033% sum of all impurities ≤0.2 0.045% Impurity H ≤0.05% not detected Impurity N ≤0.05% 0.033%

Among them, "other single unknown impurity" refers to the single impurity with the largest content among impurities except impurity J and K.

Comparative example 1

Preparation of paracetamol crude product: 100g of p-aminophenol (the content of p-aminophenol is 99.76% (HPLC), wherein 4,4'-diaminodiphenyl ether≤0.1%), 65g of glacial acetic acid, 0.8g of sodium metabisulfite and 150g of acylation mother liquor (the mass fraction of acetic acid is 54%) was added into a 1000ml four-necked bottle for acylation reaction, and after 3 hours of reaction at 110°C, acid mining was carried out. After aciding for 2 hours, when the amount of acid collected was 30g, the acid collection was stopped, the temperature was lowered to 25°C, and 139g of crude paracetamol was obtained by centrifugation.

Preparation of acetaminophen recrystallization: add 139g of acetaminophen, 210g of purified water, 6.95g of sodium metabisulfite and 2.78g of activated carbon into a 1000ml four-necked bottle for recrystallization reaction, decolorize at 100°C for 30min, filter carbon, and the filtrate slowly Cool down to 25°C, centrifuge, and dry to obtain 128 g of refined acetaminophen finished product, with a yield of 92.4%.

According to the EP10 standard, the content of each impurity in the refined paracetamol product is detected, and the specific content of each impurity is shown in Table 4.

Table 4

name EP10 standard Acetaminophen Impurity J ≤10ppm not detected Impurity K ≤50ppm 1ppm Other single unknown impurity ≤0.05% 0.05% sum of all impurities ≤0.2 0.11% Impurity H ≤0.05% 0.05% Impurity N ≤0.05% 0.05%

Among them, "other single unknown impurity" refers to the single impurity with the largest content among impurities except impurity J and K.

Example 4

The difference between the process of this example and Example 1 is only that the acylation reaction temperature in the preparation of the crude paracetamol is 95° C., and other process conditions are the same as those of Example 1. The yield of the refined paracetamol finished product of this embodiment 4 is 92.5%.

According to the EP10 standard, the content of various impurities in the refined paracetamol product is detected, and the specific content of each impurity is shown in Table 5 below.

table 5

name EP10 standard Acetaminophen Impurity J ≤10ppm not detected Impurity K ≤50ppm 1ppm Other single unknown impurity ≤0.05% 0.041% sum of all impurities ≤0.2 0.054% Impurity H ≤0.05% not detected Impurity N ≤0.05% 0.041%

Among them, "other single unknown impurity" refers to the single impurity with the largest content among impurities except impurity J and K.

Example 5

The difference between this embodiment and the process of Example 1 is only that the amount of sodium metabisulfite used in the preparation of the crude paracetamol is 1.5 g, and other process conditions are the same as in Example 1. The yield of the refined paracetamol finished product of this embodiment 5 is 92.4%.

According to the EP10 standard, the content of each impurity in the refined acetaminophen product is detected, and the specific content of each impurity is shown in Table 6 below.

Table 6

name EP10 standard Acetaminophen Impurity J ≤10ppm not detected Impurity K ≤50ppm 1ppm Other single unknown impurity ≤0.05% 0.010% sum of all impurities ≤0.2 0.018% Impurity H ≤0.05% not detected Impurity N ≤0.05% 0.010%

Among them, "other single unknown impurity" refers to the single impurity with the largest content among impurities except impurity J and K.

Example 6

The difference between the process of this example and Example 1 is that the amount of sodium metabisulfite used in the preparation of the crude paracetamol is 1.5 g, the temperature of the acylation reaction in the preparation of the crude paracetamol is 95° C., and other process conditions are the same as in Example 1. same. The yield of the refined paracetamol finished product of this embodiment 6 is 92.7%.

According to the EP10 standard, the content of each impurity in the refined acetaminophen product is detected, and the specific content of each impurity is shown in Table 7 below.

Table 7

name EP10 standard Acetaminophen Impurity J ≤10ppm not detected Impurity K ≤50ppm 1ppm Other single unknown impurity ≤0.05% 0.012% sum of all impurities ≤0.2 0.012% Impurity H ≤0.05% not detected Impurity N ≤0.05% not detected

Among them, "other single unknown impurity" refers to the single impurity with the largest content among impurities except impurity J and K.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention are within the scope of the pending rights of the present invention. within the scope of protection.

Claims (10)

1. a preparation method for controlling the paracetamol impurity H content of paracetamol, is characterized in that, comprises the following steps: Preparation of crude paracetamol: p-aminophenol, glacial acetic acid, antioxidant and dilute acid are mixed for acylation reaction, after the reaction, acid mining, cooling crystallization, and centrifugation are carried out to obtain solid matter and acylation mother liquor, the solid matter Obtain paracetamol crude product after washing; Preparing the refined paracetamol: decolorizing, filtering, recrystallizing, centrifuging, and drying the crude paracetamol in sequence to obtain the refined paracetamol; Wherein, the dilute acid is an aqueous solution of glacial acetic acid or the previously recovered acylation mother liquor, and the mass fraction of acetic acid in the dilute acid is 40-45%. 2. the preparation method of the paracetamol of controlling paracetamol impurity H content according to claim 1, is characterized in that, the mol ratio of described para-aminophenol and glacial acetic acid is 1: (1-1.2); And/or, the mass ratio of the p-aminophenol and the antioxidant is 1:(0.005-0.03), preferably 1:(0.015-0.03); And/or, the mass ratio of p-aminophenol and dilute acid is 1:(1-3), preferably 1:(1.4-1.6). 3. the preparation method of the paracetamol of controlling paracetamol impurity H content according to claim 1, is characterized in that, described p-aminophenol content ≥ 99.7%, 4,4'- in p-aminophenol Diaminodiphenyl ether content ≤ 0.1%. 4. the preparation method of the paracetamol of controlling paracetamol impurity H content according to claim 1, is characterized in that, the time of described acylation reaction is 3-6h; The temperature of the acylation reaction is 95-120°C, preferably 95°C-98°C. 5. the preparation method of the paracetamol of controlling paracetamol impurity H content according to claim 1, is characterized in that, the temperature of described acid extraction is 100-150 ℃; The time for the acid extraction is 2-3h; When the mass ratio of p-aminophenol and extracted acetic acid is 1: (0.16-0.30), stop acid extraction. 6 . The method for preparing paracetamol according to claim 1 , wherein the paracetamol impurity H content is controlled, wherein the cooling crystallization refers to cooling down to 25-30° C. for crystallization. 7. the preparation method of the paracetamol of controlling paracetamol impurity H content according to claim 1, is characterized in that, in described decolorization treatment, in described paracetamol crude product, add pure water, Decolorizing agent and antioxidant for decolorization treatment; Further preferably, the mass ratio of the paracetamol crude product, pure water, decolorizer and antioxidant is 1:(1.5-2.0):(0.02-0.07):(0.01-0.05); And/or, the decolorizing agent is activated carbon; And/or, the antioxidant is sodium metabisulfite; And/or, the temperature of the decolorization treatment is 95-110°C, that is, boiling; And/or, the time for the decolorization treatment is 20-40 minutes, preferably 30 minutes. 8. the preparation method of the paracetamol of controlling paracetamol impurity H content according to claim 1, it is characterized in that, described recrystallization treatment is the filtrate cooling crystallization after filtration treatment, preferably, cooling to 25-30°C. 9. The acetaminophen obtained by the preparation method described in any one of claims 1-8. 10. The acetaminophen according to claim 9, characterized in that, the acetaminophen impurity H content in the acetaminophen is lower than 0.005%.