CN1434026A

CN1434026A - Process for prepraring p-acetpamidophenol

Info

Publication number: CN1434026A
Application number: CN 03112820
Authority: CN
Inventors: 戴杰; 罗拥军; 吕建国
Original assignee: NANJING CHEMICAL PLANT CHINA PETROCHEMICAL CORP
Current assignee: NANJING CHEMICAL PLANT CHINA PETROCHEMICAL CORP
Priority date: 2003-02-11
Filing date: 2003-02-11
Publication date: 2003-08-06
Anticipated expiration: 2023-02-11
Also published as: CN1193982C

Abstract

The method for preparing acetaminophen relates to a technological process for making hydrogenation reduction of p-nitrophenol and acetylation reaction of p-aminophenol in same process and adopting acetic acid and acid anhydride to make combined acidation. Said invention is characterized by that in medium acetic acid/acetic acid aqueous solution, under the action of catalyst the p-nitrophenol can be reduced into p-aminophenol by means of catalytic hydrogenation, then the catalyst is filtered from reduction product, said product can be acidated by using acetic acid in the medium at 100-150 deg.C, the conversion rate of p-aminophenol is 30-80%, then the excess acetic anhydride can be added at 50-100 deg.c to make p-aminophenol completely acidate, then the above-mentioned is separated and refined so as to obtain the acetaminophen finished product.

Description

Preparation method of Acetaminophen

A field of technology

The present invention relates to a process for preparing phenol acetaminophen method, especially relates to a preparation of ethyl p-nitrophenol Amido-phenol method.

Second, Background

Acetaminophen (English name p-acetaminophenol or n-acetyl-p-aminophenol, hereinafter referred to as APAP), due to its anti-inflammatory effect is good, fast-acting, side effects on the human body, is gradually replacing the previous Antipyretic analgesics and widely used. APAP can be used for the manufacture of dyes, photographic medicines. Acetaminophen synthesis in many ways, usually by right-aminophenol (hereinafter referred to as PAP) and acetic acid or vinegar Anhydride acetylation reaction in the system, while the PAP may be a source of nitro chloro benzene obtained via the following route:

APAP production of one-step and two-step of the points. Two-step method generally refers to the PAP and APAP were prepared independently. PAP in the production, transportation, storage process easier oxidation discoloration, therefore, PAP manufacturer of vacuum drying should be carried out, While outsourcing production APAP PAP required before using active carbon and recrystallization methods refined to meet the drugs used in the synthesis Codex standards APAP original drug. This leads to complex process, the total reduction in yield, energy consumption, the production cost is high and waste Large, poor economic returns. For this reason, many domestic and foreign scientific research departments and manufacturers have done a lot of improvement research, Invented the one-step synthesis of APAP, will PAP synthesis and subsequent acylation preparation APAP arranged in the same two-step reaction A process, the newly generated PAP then acylated to APAP, to avoid the transportation problem of oxidation during storage and Vacuum drying and re-refining and other processes. ...

APAP production of one-step and two-step of the points. Two-step method generally refers to the PAP and APAP were prepared independently. PAP in the production, transportation, storage process easier oxidation discoloration, therefore, PAP manufacturer of vacuum drying should be carried out, While outsourcing production APAP PAP required before using active carbon and recrystallization methods refined to meet the drugs used in the synthesis Codex standards APAP original drug. This leads to complex process, the total reduction in yield, energy consumption, the production cost is high and waste Large, poor economic returns. For this reason, many domestic and foreign scientific research departments and manufacturers have done a lot of improvement research, Invented the one-step synthesis of APAP, will PAP synthesis and subsequent acylation preparation APAP arranged in the same two-step reaction A process, the newly generated PAP then acylated to APAP, to avoid the transportation problem of oxidation during storage and Vacuum drying and re-refining and other processes. ...₂O as a catalyst in acetic medium in the catalytic hydrogenation of PNP PAP, while The resulting PAP anhydride acylation, does not require complex purification process to obtain high-quality medicine directly APAP. The process Adding acetic anhydride in two steps, the first PNP added amount representing 0.8 to 1.2 parts by weight of acetic anhydride, at a hydrogen pressure of 0.3 ~ 0.4MPa, 80 ~ 90 ℃ conditions, the reaction was carried out to the suction of the theoretical amount of hydrogen; account and an additional amount of 0.25 parts by weight of PNP Acetic anhydride, heated to 70 ~ 100 ℃ maintained, which aims to make the acylation reaction. Subsequently adding water and sodium bisulfite, will The reaction mixture was filtered while hot and the filtrate cooled and crystallized can be obtained APAP. US4264525 way instead of adding the acetic anhydride Batch join. In this method, acetic anhydride as the acylating agent, because the reaction of acetic anhydride with the water formed during the hydrolysis reaction, leading to Acetic anhydride consumption is relatively high, about 1.4 times the theoretical amount, corresponding to a large number of by-produced acetic acid recovered energy consumption is relatively high, from Process, said hydrolyzed to acetic acid produced in theory pay is unreasonable, and from cost considerations, acetic anhydride prices Acetate, about twice as high prices, so there is worth one-step improvement. ...

O as a catalyst in acetic medium in the catalytic hydrogenation of PNP PAP, while The resulting PAP anhydride acylation, does not require complex purification process to obtain high-quality medicine directly APAP. The process Adding acetic anhydride in two steps, the first PNP added amount representing 0.8 to 1.2 parts by weight of acetic anhydride, at a hydrogen pressure of 0.3 ~ 0.4MPa, 80 ~ 90 ℃ conditions, the reaction was carried out to the suction of the theoretical amount of hydrogen; account and an additional amount of 0.25 parts by weight of PNP Acetic anhydride, heated to 70 ~ 100 ℃ maintained, which aims to make the acylation reaction. Subsequently adding water and sodium bisulfite, will The reaction mixture was filtered while hot and the filtrate cooled and crystallized can be obtained APAP. US4264525 way instead of adding the acetic anhydride Batch join. In this method, acetic anhydride as the acylating agent, because the reaction of acetic anhydride with the water formed during the hydrolysis reaction, leading to Acetic anhydride consumption is relatively high, about 1.4 times the theoretical amount, corresponding to a large number of by-produced acetic acid recovered energy consumption is relatively high, from Process, said hydrolyzed to acetic acid produced in theory pay is unreasonable, and from cost considerations, acetic anhydride prices Acetate, about twice as high prices, so there is worth one-step improvement. ...

III SUMMARY OF THE INVENTION A technical problem

The object of the present invention is to provide a simple process, material consumption, low energy consumption, low cost of production of NOx by the features Phenol preparation Acetaminophen ways to deal with the art of acetic anhydride consumed in large, multi-produced acetic acid, or vinegar Concentrated acids need to consume a lot of energy, raw materials difficult to recycle acetic problem. Two technical solutions

In order to solve the above problems and achieve the object described below, the present invention adopts the combination of acetic acid and acetic anhydride acylation techniques party Case, i.e., a phenol acetaminophen preparation method comprises the following steps:

a) an aqueous solution of acetic acid or acetic acid as a medium, the presence of a hydrogenation catalyst, at 0.3 ~ 0.5MPa, 60 ~ 100 ℃ conditions, will nitrophenol hydrogenation, to the complete conversion of p-nitrophenol p-aminophenol;

b) from step a) reducing the resulting product is filtered off the catalyst, the temperature was raised to 100 ~ 150 ℃ and for 1 to 4 Hours, acylation of the amino group to a phenol conversion rate of 30 to 80%;

c) cooling to 50 ~ 100 ℃, the step b) the material obtained by adding excess acetic anhydride to completely turn-aminophenol As Acetaminophen.

According to the above aspect, the present invention is the hydrogenation of PAP in two steps, step b) (acylated-I), and step Step c) (acylated-II) is acylated, were used in the hydrogenation reaction medium of acetic acid and acetic anhydride as the acylating new agent. Hydrogenation of acetic acid used in the reaction medium, the reduction and acylation reaction in the formation of water, acetic acid concentration will gradually drop Low, acylating-I aim to maximize the use of acetic acid medium, in order to reduce the amount of acetic anhydride followed. In the present invention, conditions, Acylation of PAP-II to ensure complete conversion, the conversion rate of acylation-I (the acylation rate) up to a certain range. Therefore, in the hydrogenation step a), the lower concentration of acetic acid can be used, such as the mass% concentration of 30 to 90% aqueous acetic acid Solution of p-nitrophenol / acetic acid molar ratio of 1.5 to 6.0, the reaction temperature is 100 ~ 150 ℃, acylation rate of 30 ~ 80% Range. The preferred solution is to use a concentration of 45 mass% to 65% acetic acid solution at 115 ~ 140 ℃ -I under acylation reaction. To more effectively prevent the oxidation of PAP, acylating-I can be a hydrogen or an inert gas protection Manner. ...

Using lower concentrations of acetic acid is also advantageous, first, the target compound APAP reduce the solubility in acetic acid. Indeed, APAP solubility increases with increasing concentration of acetic acid in the prior art, the use of high concentrations of acetic anhydride or Acetic acid acylation, required before the separation of deionized water were added to a 50% aqueous acetic acid, or, that for this purpose. Although Acylation perspective, enabling high concentration of acetic acid, but in the subsequent separation operations increase the crystallization yield, select a lower The acetic acid concentration is reasonable. Taken together, the acetic acid concentration is preferably 45 to 65% solution. Two is to facilitate the return of acetic acid Close utilization, using 45 to 65% aqueous acetic acid solution as a medium, after the separation of the APAP simple distillation under atmospheric pressure, 35 to 55% recycled dilute acetic acid, and acetic acid by-produced little, and then slightly raise concentrated by distillation to 45 to 65% can be used in the hydrotreating step Step a). ...

In the acylation-II added acetic anhydride used in continuous mode will bring better results. Experiments show that, in order to obtain a high acid The rate of one-time feeding, excess acetic anhydride need about 40%, while continuously feeding slowly, just about 10% excess. Because To, acetic anhydride acylating accompanies the hydrolysis reaction, the hydrolysis reaction rate constant in Table 1 below:

Table 1 acetic anhydride hydrolysis rate constant

T/℃	20	40
T/℃	20	40	k/min ^-1	0.107	0.248

Obviously, this is a first order reaction, the half-life

t_{\frac{1}{2}} = \frac{\ln 2}{k}

Only with the reaction rate constant k or the reaction temperature, and the Acetic anhydride concentration. The higher the concentration of acetic anhydride same time, a greater amount of hydrolysis. Therefore, continuous and even join acetic anhydride Is an ideal way, the reaction medium can be maintained relatively low concentration of acetic anhydride, helps to reduce the hydrolysis of acetic anhydride.

In summary, with the above two methods acylation with acetic anhydride acylating agents used alone, compared to significantly reduce the acetic anhydride Dosage; and the use of a continuous feeding mode, only a small amount of acetic anhydride to acetic acid hydrolysis occurs, in the process arrangement The more reasonable. Also, because the acetic anhydride used in the acylation-II as acylating agent, without acylating agent such as acetic acid is used, for the Acylated conducted as completely as possible, the need for a concentrated acetic acid, significantly reducing energy consumption;-produced acetic acid and concentrated by mentioning back after Closing economically viable use.

Technical solution of the present invention, the catalyst used in the hydrogenation reaction can be selected Pd / C, Pt / C, Pt₂O, or modified Skeleton such as Ni, for example, 0.5 to 5% Pd / C catalyst at a reaction pressure of 0.3 ~ 0.5MPa, reaction temperature is 60 ~ 100 ℃, preferably in the range 75 ~ 95 ℃ temperature. Since skeletal Ni cause PNP benzene hydrogenation, therefore required to carry them OK passivation.

The present invention is obtained APAP, can be isolated and purified by conventional methods. Acylating solution was cooled to room temperature, filtered, washed To obtain a crystalline crude APAP; crystallization mother liquor by distillation at atmospheric pressure after the cooling most dilute acetic acid, crystallization, filtration, Another portion of the crude product can be obtained. Crude water and adding activated carbon, Na₂S ₂O ₅Recrystallization to give the line with China Pharmacopoeia standards APAP product, total yield 85%.

3 technical effect

The preparation method of Acetaminophen with process simple, material consumption, low energy consumption, low production costs Special Points, solve the prior art acetic anhydride consumed in large, multi-produced acetic acid, or acetic acid concentrates need to consume a lot of energy, raw vinegar Acid difficult to recycle issue.

Fourth, the specific embodiments

The following examples of the invention will be described in detail technical solutions. Unless otherwise specified, the following percentages are Mass percentage.

Example 1

In 500mL of industrial autoclave 100g nitrophenol (content 94.17%), 200mL55% dilute vinegar Acids and 0.4g5% Pd / C catalyst, respectively, with nitrogen, hydrogen substitution, the heating temperature at 80 ℃, 0.4MPa hydrogen pressure No reaction to hydrogen so far. Stop stirring, settling more than 15 minutes, with the band of the filter will be restored under the discharge pipe to the hydraulic Acylation reactor.

Under the protection of nitrogen, the acylation reaction kettle was heated to further liquid 130 ~ 135 ℃, for 1.5 to 2.0 hours, cooled To 80 ℃, 90 min with a metering pump into 33 g of acetic anhydride, and then for 0.5 hours, the solution sampled and analyzed PAP acylation Less than 0.1% in the margin of the material, cooling and crystallization, filtration, a crude product. Crystallization mother liquor by simple distillation, cooling and crystallization, Filtration, the crude product was recovered

Refined products: crude product by adding 500mL of distilled water, 1 g of activated carbon, 0.4 g of Na₂S ₂O ₅Was heated under reflux for 10 minutes Clock, hot filtration, cooling and crystallization, filtration and washed twice with distilled water, 100 ℃ drying 0.5 to 2 hours to give pure white Finished 87.0 g, total yield of 85.1% (in PNP meter), in line with the Chinese Pharmacopoeia standards.

Examples 2 to 5

According to the procedure of Example 1, changing the concentration of acetic acid solution and an acylation reaction temperature-I, and in accordance with the acylation -I,-II acylation acylation rate adjustment amount of acetic anhydride is added, the specific implementation of the results are shown in Table 2.

Table 2

No.	Catalytic hydrogenation		Acylated-I		Acylated-II
	Catalytic hydrogenation		Acylated-I		Acylated-II			Concentration of acetic acid	Conversion rate	The reaction temperature	Acylation rate	Acetic anhydride		PAP I Amount
	Dosage	Excess ratio										Acetic anhydride
	Dosage	Excess ratio	Example 2	45％	＞99.9％	140℃	64％					30g	1.2		0.04％
Example 3	65％	135℃	Example 2	45％		140℃	64％	77％	17.5g	1.1	0.06％	30g	1.2		0.04％
Example 3	65％	135℃	Example 4	85％		120℃	68％	77％	17.5g	1.1	0.06％	25.4g	1.15	0.08％
Example 4...	100％	110℃	Example 4	85％		120℃	68％	45％	41.8g	1.1	0.07％	25.4g	1.15	0.08％

Claims

Example 4...

a) an aqueous solution of acetic acid or acetic acid as a medium, the presence of a hydrogenation catalyst, at 0.3 ~ 0.5MPa, 60 ~ 100 ℃, will nitrophenol hydrogenation, to complete conversion of p-nitrophenol p-aminophenol;

b) From a) reducing the resulting product is filtered off the catalyst, the temperature was raised to 100 ~ 150 ℃ and maintained for 1-4 hours, acyl Based on the amino phenol conversion to reach 30 to 80 percent;

c) cooling to 50 ~ 100 ℃, to b) the resulting material was added to an excess of acetic anhydride, to complete conversion of p-aminophenol For acetaminophen.
(2) as claimed in claim 1, wherein the preparation method of acetaminophen, wherein step a) Mass% concentration of said medium is 30 to 90% aqueous acetic acid solution; nitrophenol / acetic acid molar ratio of 1.5 to 6.0.
3 according to claim 2, wherein the preparation method of acetaminophen, wherein said acetic acid Mass% concentration of the aqueous solution of 45 to 65%.
As claimed in claim 1, wherein the preparation method of acetaminophen, wherein step c), Number of moles of acetic anhydride added, is not less than the non-converted to the desired aminophenol complete acylation of 1.1 times the number of moles of acetic anhydride.
5 according to claim 1, wherein the preparation method of acetaminophen, wherein step b) The reaction temperature is 115 ~ 140 ℃.
As claimed in claim 1 for the preparation of acetaminophen method, wherein step c) The reaction temperature is 75 ~ 95 ℃.
As claimed in claim 1 for the preparation of acetaminophen method, wherein step a) Said hydrogenation catalyst is Pd / C, Pt / C, Pt₂O or modified Raney nickel.
As claimed in claim 7, wherein the preparation method of acetaminophen, wherein the catalytic hydrogenation of Agent is 0.5 to 5% Pd / C catalyst, catalytic hydrogenation temperature is 75 ~ 95 ℃.
As claimed in claim 1 for the preparation of acetyl-p-aminophenol, characterized in that step b) in the Hydrogen or inert gas protection.
A process according to claims 1 to 9, in any one of the preceding claims for the preparation of acetyl-p-aminophenol, characterized In that the resulting separation of acetaminophen, the water and the activated carbon was added, Na₂S ₂O ₅Recrystallization, to further enhance Pure.