阅读说明：本技术 一步法加氢合成扑热息痛的方法 (Method for synthesizing paracetamol by one-step hydrogenation ) 是由 黄军 张方荣 竺少铭 于 2021-07-30 设计创作，主要内容包括：本发明涉及一种一步法加氢对硝基苯酚制备扑热息痛的方法,用加氢金属催化剂,在高压釜中加入对硝基苯酚和乙酸酯,充入氢气,在特定的反应温度下催化加氢酰胺化,反应得到产物扑热息痛。该催化反应工艺简单高效,并且产品易于分离,催化剂易于回收再用。扑热息痛收率可达90％以上,溶剂蒸馏分离可以直接得到扑热息痛粗品,产品可以经过一次重结晶得到高纯度产品。该一步法制备扑热息痛工艺,具有很好的工业应用前景。(The invention relates to a method for preparing paracetamol by one-step hydrogenation of p-nitrophenol. The catalytic reaction process is simple and efficient, the product is easy to separate, and the catalyst is easy to recycle. The yield of the paracetamol can reach more than 90 percent, the solvent can be distilled and separated to directly obtain a crude paracetamol product, and the product can be recrystallized once to obtain a high-purity product. The one-step method for preparing paracetamol has good industrial application prospect.)

1. The one-step process of synthesizing paracetamol through hydrogenation features that metal catalyst is added into high pressure reactor, p-nitrophenol and acetate are filled into the high pressure reactor, hydrogen is filled into the high pressure reactor, and catalytic hydroamidation is carried out at specific reaction temperature to obtain paracetamol product.

2. The process of claim 1 wherein the hydrogenation metal catalyst is Ni/C, Pd/C, Pt/C, Ir/C, Raney Ni or PtNi/C; wherein the metal loading mass in the Ni/C, Pd/C, Pt/C, Ir/C or PtNi/C catalyst is 5-55% of the carrier mass.

3. The process of claim 1, wherein the acetate is ethyl acetate, methyl acetate, propyl acetate, butyl acetate, isopropyl acetate, or tert-butyl acetate.

4. The method of claim 1, wherein the amount of the hydrogenation metal catalyst is 1.0-35.0% of the mass of the p-nitrophenol; the mass of the p-nitrophenol is 1 to 50 percent of the mass of the acetic ester.

5. The method according to claim 1, wherein the hydrogen gas is charged in an amount of 5 to 20 atmospheres; the reaction temperature is 120-180 ℃, and the reaction time is 2-10 h.

Technical Field

The invention relates to synthetic paracetamol, in particular to a method for synthesizing paracetamol through one-step hydrogenation.

Background

Paracetamol (acetaminophen, APAP) is a commonly used antipyretic analgesic. Currently, the widely used production process is to prepare p-aminophenol (PAP) by hydrogenation of p-nitrophenol, followed by further acetylation to obtain APAP. In the process, acetyl chloride or acetic anhydride is used for acylating the p-aminophenol, hydrochloric acid or acetic acid needs to be released, amino and phenolic hydroxyl groups are acylated at the same time, and acetyl on the phenolic hydroxyl group needs to be removed. Moreover, the process requires more separation steps, resulting in a poor overall yield. In 2017, Li Hong Juan et Al take Pt/alpha-Al₂O₃Adding nitrobenzene as a raw material into a mixed solution of acetic acid and zinc acetate to obtain APAP (ammonium paratungstate) by a one-pot method for serving as a hydrogenation catalystChemical reaction engineering and process, 2017,33(3):249-254,283), which realizes the one-pot synthesis of APAP but has lower yield of APAP. Meanwhile, the addition of acetic acid has high requirements on a reaction vessel, and the stability of the catalyst is also influenced. The one-step process also has a problem of multiple product separation steps. The traditional two-step method for producing paracetamol comprises the following steps:

in recent years, selective amidation reactions have been studied more extensively. Zyrui et al directly amidate amines with unactivated esters without solvents and transition metals by using sodium t-butoxide as a base (Green chem.,2021,23, 3972-3982). However, high purity PAP is difficult to obtain, so that APAP is abundant in impurities and difficult to purify. Chenxing spring et al in 2005 catalyzed acetylation of phenol and acetic anhydride with HF to obtain 4-hydroxyacetophenone, oximation with hydroxylamine sulfate to obtain p-hydroxyacetophenone oxime, and finally in SOCl₂The APAP is obtained by rearrangement in ethyl acetate solvent under catalysis (applied chemical industry, 2005,34(11): 719-720). The synthesis process of the APAP has the advantages of high yield and high purity, and has the defects of large amount of acid and alkali used in the synthesis process, certain potential safety hazard and complex process steps. And nitrobenzene or nitrophenol is used as a raw material, and the problems of insufficient PAP purity and complicated operation can be avoided by combining reduction and amidation in the same reactor.

Chi Wai Cheung et al used nickel (II) chloride dimethyl ether complex Ni (glyme) Cl as catalyst, 1, 10-phenanthroline as ligand, Zn as reducing agent, trimethylchlorosilane as additive to directly amidate nitroarenes with unactivated esters in 2017 to give the corresponding amide product in 94% yield (Nat Commun 8,14878 (2017)). But the silyl ether, zinc chloride and silicon oxide are produced as by-products, and the production cost is high. The subsequent tertiary amide transamidation (J.Am.chem.Soc.2018,140,22, 6789-6792) using manganese metal as a reducing agent and a promoter and using nitroarene as a nitrogen source, and the direct amidation (org.chem.Front.2019, 6,756-761) of ester and nitroarene avoid using additional catalysts or ligands, but the organic solvent used in the synthesis process is not environment-friendly. Michael Fairley et al used lithium amide as a metal precursor to obtain various related synthetic carboxamides (chem.Sci.,2020,11,6500-6509) by ester amidation or amide transamidation with good yields. However, the lithium reagent is dissolved in the reaction system and is not easy to recover.

Therefore, the catalyst which is easy to recycle is used, and a process method which is one-step synthesized, safe and environment-friendly is developed, so that the method has good industrial prospect. The paracetamol is synthesized by using acetate (such as ethyl acetate) as an acetylating agent in a one-step method, better acetylation yield can be obtained under specific conditions, and only ethanol is released in an acylation reaction to be beneficial to being removed together with the ethyl acetate. Meanwhile, ethyl acetate can be directly used as a solvent, is relatively convenient to remove and is beneficial to product purification. Since the amide group is relatively stable, acylation of the phenol can be substituted in situ to give the amide. Generally, from the stability point of view, the acetamide group > ethyl acetate > acetyl phenol, so that the one-step method for synthesizing paracetamol can obtain higher selectivity.

Disclosure of Invention

The invention provides a process method for synthesizing paracetamol by one-step hydrogenation, aiming at improving the defects of the prior art. The paracetamol is prepared by catalyzing p-nitrophenol by controlling reaction conditions. The method has the advantages of directly carrying out amidation reaction without PAP separation, realizing one-step synthesis of APAP, having good catalytic effect, being easy to recover and reuse, being capable of completely reacting to generate the product paracetamol in the reaction process, and having good industrial application prospect.

The technical scheme of the invention is as follows: the one-step process of synthesizing paracetamol through hydrogenation features that metal catalyst is added into high pressure reactor, p-nitrophenol and acetate are filled into the high pressure reactor, hydrogen is filled into the high pressure reactor, and catalytic hydroamidation is carried out at specific reaction temperature to obtain paracetamol product. Stopping heating, cooling to room temperature, and detecting the conversion rate of p-nitrophenol and the selectivity of APAP. The basic reaction of the invention is:

preferably, the hydrogenation metal catalyst is Ni/C, Pd/C, Pt/C, Ir/C, Raney Ni or PtNi/C and the like; Pd/C, Pt/C, Ir/C, Raney Ni and the like are commercially available metal catalysts; wherein the metal loading in the Ni/C, Pd/C, Pt/C, Ir/C or PtNi/C catalyst is 5-55% of the carrier mass; the Ni/C and PtNi/C catalysts can also be prepared on the basis of the literature (ACS Catal.2021,11,8197-8210), and the specific preparation method is as follows:

the Ni/C catalyst containing 50% Ni is prepared by dissolving 24.8g nickel acetate in 500ml ethylene glycol solution, adding 5.8g activated carbon, heating to 165 deg.C, slowly adding 800ml water solution containing 21.3g sodium carbonate dropwise under vigorous stirring, maintaining 165 deg.C for aging for 1h, filtering, washing, and drying.

The PtNi/C catalyst containing 5% of Pt and 50% of Ni is prepared by dissolving 1.04g of chloroplatinic acid and 16.5g of nickel acetate in ethylene glycol solution, adding 3.5g of activated carbon, heating to 165 ℃, slowly dropwise adding 500ml of aqueous solution containing 14.1 g of sodium carbonate under vigorous stirring, maintaining the temperature at 165 ℃ for aging for 1h after dropwise adding, filtering, washing and drying.

Preferably, the acetate is ethyl acetate, methyl acetate, propyl acetate, butyl acetate, isopropyl acetate or tert-butyl acetate.

Preferably, the dosage of the hydrogenation metal catalyst is 1.0-35.0% of the mass of the p-nitrophenol; the mass of the p-nitrophenol is 1 to 50 percent of the mass of the acetic ester.

Preferably, the hydrogen is charged in an amount of 5 to 20 atmospheres; the reaction temperature is 120-180 ℃, and the reaction time is 2-10 h.

Has the advantages that:

the preparation method of the catalyst provided by the invention is simple, and the paracetamol is prepared by catalyzing p-nitrophenol by controlling the reaction conditions. APAP is synthesized by one-step hydrogenation and amidation of p-nitrophenol, and the process is simple and efficient. The catalyst has high activity for catalyzing p-nitrophenol and has selectivity of more than 99% for paracetamol, is easy to recycle, and is very suitable for industrial production. The product paracetamol is easy to separate and purify. The solvent is distilled to obtain a crude product of paracetamol, and a high-purity product can be obtained through one-step recrystallization.

Detailed Description

Example 1:

the Ni/C catalyst containing 50% Ni is prepared by dissolving 24.8g nickel acetate in 500ml ethylene glycol solution, adding 5.8g activated carbon, heating to 165 deg.C, slowly adding 800ml water solution containing 21.3g sodium carbonate dropwise under vigorous stirring, maintaining 165 deg.C for aging for 1h, filtering, washing, and drying, and is hereinafter referred to as Ni/C-0.5.

In the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated to dryness under reduced pressure to give a crude product (crude product yield 97%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (93%). The filtered catalyst was washed with acetonitrile, dried 5 times and reused, and the catalyst recovery is shown in table 1.

Example 2:

in the autoclave, 13.9g of p-nitrophenol, 0.39g of a commercial Pt/C catalyst containing 5% Pt and 34.7g of methyl acetate were charged. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated to dryness under reduced pressure to give a crude product (yield 85%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (79%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.

Example 3:

in the autoclave, 13.9g of p-nitrophenol, 0.38g of a commercially available Ir/C catalyst containing Ir 5% and 46.3g of propyl acetate were charged. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (yield of crude product 84%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (75%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.

Example 4:

in the autoclave were charged 13.9g of p-nitrophenol, 0.213g of a commercial Pd/C catalyst containing 5% Pd and 69.5g of butyl acetate. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (yield of crude product 86%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (80%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.

Example 5:

in the autoclave, 13.9g of p-nitrophenol, 1.173g of Raney Ni catalyst and 139 g of isopropyl acetate were charged. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (crude yield 88%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (83%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.

Example 6:

the PtNi/C catalyst containing 5% of Pt and 50% of Ni is prepared by dissolving 1.04g of chloroplatinic acid and 16.5g of nickel acetate in ethylene glycol solution, adding 3.5g of activated carbon, heating to 165 ℃, slowly dropwise adding 500ml of aqueous solution containing 14.1 g of sodium carbonate under vigorous stirring, maintaining the temperature at 165 ℃ for aging for 1h after dropwise adding, filtering, washing and drying.

In an autoclave, 13.9g of p-nitrophenol, 0.39g of PtNi/C catalyst and 1390g of tert-butyl acetate were charged. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (yield of crude product 92%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (86%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.

Example 7:

in the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 120 ℃ for reaction for 5 hours, taking the autoclave out after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 93%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (crude product yield 76%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (71%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.

Example 8:

in the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 150 ℃ for reaction for 5 hours, taking the autoclave out after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (yield of crude product 87%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (83%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.

Example 9:

in the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 180 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated to dryness under reduced pressure to give a crude product (crude product yield 96%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (91%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.

Example 10:

in the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 5 atmospheres, putting the autoclave into a heating kettle sleeve with the temperature of 160 ℃ for reaction for 5 hours, taking the autoclave out after the reaction is finished, cooling the autoclave to the room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 96%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (yield of crude product 81%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (74%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.

Example 11:

in the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling 20 atmospheres of hydrogen, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking the autoclave out after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated to dryness under reduced pressure to give a crude product (yield of crude product 94%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (91%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.

Example 12:

in the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve with the temperature of 160 ℃ for reaction for 2 hours, taking the autoclave out after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 91%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated to dryness under reduced pressure to give a crude product (crude product yield 75%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (70%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.

Example 13:

in the autoclave, 13.9g of p-nitrophenol, 2.35gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve with the temperature of 160 ℃ for reaction for 10 hours, taking the autoclave out after the reaction is finished, cooling the autoclave to the room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated to dryness under reduced pressure to give a crude product (crude product yield 97%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (90%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.

Example 14:

in the autoclave, 13.9g of p-nitrophenol, 4.70gNi/C-0.5 catalyst and 270g of ethyl acetate were added. Screwing the autoclave, filling hydrogen with 10 atmospheres, putting the autoclave into a heating kettle sleeve at 160 ℃ for reaction for 5 hours, taking out the autoclave after the reaction is finished, cooling the autoclave to room temperature, sampling, and detecting the conversion rate (the conversion rate of p-nitrophenol is 100%) by liquid chromatography. The catalyst in the reaction solution was filtered off, and the solvent was evaporated under reduced pressure to obtain a crude product (crude product yield 93%). The crude product was dissolved in water with heating, crystallized by cooling at room temperature, filtered and dried to give the product and its yield was calculated (89%). The filtered catalyst is washed by acetonitrile, dried for 5 times and reused, and the recovery and use conditions of the catalyst are kept stable.

The catalyst of example 1 was filtered and washed with acetonitrile, dried and reused. The process flow is identical to that of example 1, and the catalyst recovery and use conditions are as follows:

TABLE 1