A method for preparing paracetamol and p-aminophenol hydrochloride from lignin degradation monomers

Abstract

The invention discloses a method for preparing paracetamol and p-aminophenol hydrochloride from a lignin degradation monomer, and belongs to the technical field of high-value utilization of biomass. The method comprises the following steps: using a simple and easily available lignin degradation monomer 4-ethylphenol as a raw material, and directly obtaining paracetamol and p-aminophenol hydrochloride after sequentially protecting the phenolic hydroxyl group, benzyl oxidation, Beckmann rearrangement, and hydrolysis. The reaction system of the invention is simple, easy to operate, high in atom economy, easy to industrialize, and overcomes the disadvantage of high pollution caused by the use of petroleum-based raw materials in the traditional synthesis method, and has good environmental benefits and application prospects.

Description

Technical Field

[0001] The invention relates to a method for preparing paracetamol and p-aminophenol hydrochloride from lignin degradation monomers, belonging to the technical field of high-value utilization of biomass. Background Art

[0002] Lignin is a natural aromatic polymer composed of phenylpropane units connected by carbon-carbon bonds and carbon-oxygen bonds. It is abundant in reserves and is considered to be the most important raw material for producing aromatic compounds instead of fossil resources. However, lignin has long been used for papermaking and burned as a low-value fuel, lacking higher-value applications. The catalytic conversion of lignin to produce monomer chemicals is considered to be one of the most effective means of high-value utilization of lignin.

[0003] Paracetamol (acetaminophen) is commonly used to relieve fever and pain. It has good antipyretic and analgesic effects, low irritation, fast action and few side effects on the human body. It is a widely used analgesic. Para-aminophenol hydrochloride is an important organic synthesis intermediate with a wide range of uses. It can be used to synthesize medicines, dyes, rubber additives and other fine chemicals. As a pharmaceutical intermediate, it can be used to synthesize paracetamol, clofibrate, vitamin B1, propranolol, 6-hydroxyquinoline and other drugs.

[0004] Currently, the raw materials used in the production of paracetamol and p-aminophenol hydrochloride are mainly derived from petroleum-based bulk chemicals, which are processed from non-renewable fossil resources and have unsustainable development prospects. At the same time, petroleum-based bulk chemicals cause serious environmental pollution during the production process.

[0005] Therefore, it is very promising and of great significance to develop an efficient, green, simple and economical method to synthesize high-value aromatic molecules such as paracetamol and p-aminophenol hydrochloride using lignin degradation monomers as raw materials. Summary of the invention

[0006] The purpose of the present invention is to overcome some technical problems existing in the prior art. Aiming at the bottleneck of the lack of high-value application of lignin, the present invention provides a method for preparing paracetamol and p-aminophenol hydrochloride from lignin degradation monomers. The present invention realizes the high-value utilization of lignin biomass by catalytically degrading lignin and converting it into raw materials and pharmaceutical intermediates.

[0007] The present invention uses 4-ethylphenol, a simple and easily available lignin degradation monomer, as a raw material, and directly obtains paracetamol and p-aminophenol hydrochloride after sequentially protecting the phenolic hydroxyl group, oxidizing the benzyl position, Beckmann rearrangement, and hydrolyzing. The reaction formula for preparing paracetamol and p-aminophenol hydrochloride is as follows:

[0008]

[0009] In order to achieve the above technical purpose, the technical solution adopted by the present invention is as follows:

[0010] The present invention first provides a method for preparing paracetamol and p-aminophenol hydrochloride, the method comprising:

[0011] (1) Reduction catalytic degradation:

[0012] A monomer-rich lignin oil is prepared from biomass raw materials, wherein the structure of the monomer is shown in Formula I;

[0013] Wherein, the biomass raw material includes lignin raw material; preferably, the biomass raw material includes pine wood and beech wood;

[0014] The preparation method of the lignin oil comprises:

[0015] In a hydrogen atmosphere, biomass raw materials, catalysts and organic solvents are added to carry out reduction catalytic degradation of lignin. After a certain reaction time, the reactants are separated and purified to obtain monomer-rich lignin oil.

[0016] The catalyst is Pd / C, Cu 20 One of PMO, Ni / C, Raney Ni, and Ni / Al2O3; the organic solvent is methanol or isopropanol; the reaction temperature is 180-250°C, and the reaction time is 3-24h.

[0017] (2) Defunctionalization:

[0018] The monomer-rich lignin oil, catalyst and organic solvent are mixed and reacted at a certain temperature to obtain a product of formula II.

[0019] Wherein, the catalyst is Ni / SiO2-Al2O3, the organic solvent is any one of n-heptane, toluene, cyclohexane, cyclohexanol, and isopropanol, the reaction temperature is 220°C, and the reaction time is 18h;

[0020] The product of formula II, a catalyst and a solvent are mixed and reacted at a certain temperature to obtain the lignin degradation monomer 4-ethylphenol represented by the product of formula III;

[0021] Wherein, the catalyst is a porous nickel-based catalyst, the solvent is water, the reaction temperature is 200° C., and the reaction time is 6 hours.

[0022] (3) Phenolic hydroxyl protection:

[0023] Under nitrogen or argon atmosphere, the 4-ethylphenol obtained in step (2) is added to an organic solvent and stirred to dissolve, then a base is added to react sufficiently, and then an acylating agent is added to continue the reaction, and a saturated NaCl aqueous solution is added to quench the reaction, followed by extraction and distillation under reduced pressure to obtain a product of formula IV.

[0024] The base, the acylating agent and the 4-ethylphenol are used in a molar ratio of 1-3:1-3:1; after the 4-ethylphenol is added to the organic solvent and stirred and dissolved, the concentration of the 4-ethylphenol in the solution is 0.05-0.5M;

[0025] The reaction temperature after adding the base is -20-25°C, and the reaction time is 10-60min;

[0026] After adding the acylating agent, the reaction temperature is 0-40°C and the reaction time is 0.5-3h;

[0027] The organic solvent is any one of dichloromethane, acetonitrile, methanol, ethanol, ether, methyl tert-butyl ether, tetrahydrofuran, toluene, n-hexane, and ethyl acetate;

[0028] The base is any one of sodium hydride, potassium hydride, lithium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, lithium hexamethyldisilazide, alkyl lithium containing 1-10 carbon atoms, sodium alkyl alcohol containing 1-10 carbon atoms, potassium alkyl alcohol containing 1-10 carbon atoms, alkyl amide lithium containing 1-10 carbon atoms, and Grignard reagent containing 1-10 carbon atoms;

[0029] The acylating agent is any one of aliphatic acid chloride containing 1-20 carbon atoms, aliphatic acid anhydride containing 1-20 carbon atoms, aryl acid chloride containing 1-20 carbon atoms, aryl acid anhydride containing 1-20 carbon atoms, sulfonyl chloride containing 1-20 carbon atoms, sulfonic acid anhydride containing 1-20 carbon atoms, alkoxy acid chloride containing 1-20 carbon atoms, alkoxy acid anhydride containing 1-20 carbon atoms, alkylcarbamoyl chloride containing 1-20 carbon atoms, and alkylcarbamoyl anhydride containing 1-20 carbon atoms.

[0030] (4) Benzylic oxidation:

[0031] Under an oxygen atmosphere, the product of formula IV obtained in step (3), N-hydroxyphthalimide (NHPI) and a free radical initiator are dissolved in an organic solvent, stirred and mixed, and then sealed for reaction, and distilled under reduced pressure to obtain a product of formula V after purification.

[0032] Wherein, the N-hydroxyphthalimide, the peroxide initiator, and the product of formula IV are used in a molar ratio of 0.5-3:1-3:1; after the product of formula IV, N-hydroxyphthalimide, and the free radical initiator are dissolved in an organic solvent, the concentration of the product of formula IV in the solution is 0.05-0.5M;

[0033] The sealing reaction conditions are: heating to 60-160°C and reacting for 2-24h;

[0034] The free radical initiator is any one of benzoyl peroxide, lauroyl peroxide, cumene hydroperoxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, diisopropyl peroxide, tert-butyl perbenzoate, tert-butyl pervalerate, methyl ethyl ketone peroxide, cyclohexanone peroxide, diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, and tert-butyl nitrite;

[0035] The organic solvent is any one of dichloromethane, acetonitrile, methanol, ethanol, ether, methyl tert-butyl ether, tetrahydrofuran, toluene, n-hexane, and ethyl acetate.

[0036] (5) Beckmann rearrangement:

[0037] Under nitrogen or argon atmosphere, add the product of formula V obtained in step (4), hydroxylamine hydrochloride and an acid catalyst, then add an organic solvent and stir evenly. After heating the reaction solution to a certain temperature and reacting for a period of time, distill under reduced pressure and purify to obtain a product of formula VI.

[0038] The molar ratio of the hydroxylamine hydrochloride, the acid catalyst and the product of formula V is 1-4:1-4:1; after the product of formula V, hydroxylamine hydrochloride, the acid catalyst and the organic solvent are uniformly stirred, the concentration of the product of formula V in the solution is 0.05-0.5M;

[0039] The reaction conditions are: the temperature is 40-100° C. and the reaction time is 2-24 hours;

[0040] The acid catalyst is any one of sulfuric acid, hydrochloric acid, polyphosphoric acid, p-toluenesulfonic acid, trifluoroacetic acid, boron trifluoride ether complex, aluminum trichloride, titanium tetrachloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, methanesulfonyl chloride, and p-toluenesulfonyl chloride;

[0041] The organic solvent is any one of dichloromethane, acetonitrile, methanol, ethanol, ether, methyl tert-butyl ether, tetrahydrofuran, toluene, n-hexane, and ethyl acetate.

[0042] (6) Preparation of paracetamol or p-aminophenol hydrochloride by hydrolysis reaction:

[0043] Preparation of paracetamol by hydrolysis reaction: Under nitrogen or argon atmosphere, add the product of formula VI obtained in step (5) and an alkaline solution, then add an organic solvent and stir to dissolve. After a period of reaction, adjust the pH value to acidic, extract, and distill under reduced pressure to obtain the product paracetamol represented by formula VII.

[0044] The molar ratio of the alkaline solution to the product of formula VI is 2-20:1; the concentration of the product of formula VI in the reaction system of the stirring reaction is 0.05-0.5M;

[0045] The reaction conditions are: the reaction temperature is 10-80°C for 1-24h;

[0046] The pH value is adjusted to 1-6, preferably with 1M hydrochloric acid;

[0047] The alkaline solution is any one of sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, sodium bicarbonate solution, calcium hydroxide solution, and ammonia water;

[0048] The organic solvent is any one of acetonitrile, methanol, ethanol, tetrahydrofuran and dioxane.

[0049] Preparation of p-aminophenol hydrochloride by hydrolysis reaction:

[0050] Under nitrogen or argon atmosphere, add concentrated hydrochloric acid, the product of formula VI obtained in step (5) or the obtained paracetamol, then add an organic solvent and stir to dissolve, seal the obtained mixed solution and heat it to a certain temperature for reaction, distill under reduced pressure, and freeze-dry to obtain the product of formula VIII, p-aminophenol hydrochloride.

[0051] Wherein, the concentration of the product of formula VI or paracetamol in the mixed solution is 0.05-0.2M;

[0052] The reaction temperature is 80-140°C and the reaction time is 2-24h;

[0053] The organic solvent is any one of acetonitrile, methanol, ethanol, tetrahydrofuran and dioxane.

[0054] The structural formulas of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII and Formula VIII in steps (1) to (7) are:

[0055]

[0056] Wherein, R is a methoxy group or a hydrogen atom; R 1 It is any one of a fatty acyl group containing 1-20 carbon atoms, an aromatic acyl group containing 1-20 carbon atoms, a sulfonyl group containing 1-20 carbon atoms, an alkoxycarbonyl group containing 1-20 carbon atoms, and an alkylaminocarbonyl group containing 1-20 carbon atoms.

[0057] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0058] (1) The present invention uses lignocellulose as a raw material for the first time and completes the preparation of paracetamol and p-aminophenol hydrochloride through a multi-step reaction. The preparation method of the present invention is based on the existing catalytic degradation method of lignin and the method of converting 4-ethyl-2-methoxyphenol into 4-ethylphenol. It further innovatively uses lignin degradation monomer 4-ethylphenol as a raw material, and directly obtains paracetamol and p-aminophenol hydrochloride after phenolic hydroxyl protection, benzyl oxidation, Beckmann rearrangement, and hydrolysis.

[0059] (2) The present invention addresses the bottleneck of the lack of high-value applications of lignin and provides a method for preparing paracetamol and p-aminophenol hydrochloride from lignin degradation monomers. The high-value utilization of lignin biomass is achieved by catalytic degradation of lignin and conversion into pharmaceutical intermediates. At the same time, the yields of paracetamol and p-aminophenol hydrochloride are also high. Starting from 4-ethylphenol, the total yield of paracetamol is as high as 76%, and the total yield of p-aminophenol hydrochloride is as high as 75%.

[0060] (3) The present invention prepares high-value medicines from low-value wood waste, and the entire reaction system has high economic benefits, which is in line with the current pursuit of environmentally friendly, economical, green, and sustainable chemical concepts, and has very good market value. At the same time, the reaction system of the present invention has the advantages of simple steps, cheap and easy to obtain raw materials and reagents, simple post-processing, and high atomic economy, and is very easy to industrialize. DETAILED DESCRIPTION

[0061] In order to enable those skilled in the art to better understand the technical solution of the present invention, the preferred embodiments of the present invention are described in detail below, but the following embodiments do not limit the protection scope of the present invention.

[0062] In the embodiments of the present invention, conventional experimental methods are used for all the parts that are not explained in detail, and the processes involved in the embodiments are all understandable and easily implementable by those skilled in the art based on the product instructions or basic knowledge in the field.

[0063] In the following examples, various processes and methods not described in detail are conventional methods known in the art. The sources, trade names and components of the reagents used are indicated when they first appear, and the same reagents used thereafter are the same as those indicated for the first time unless otherwise specified; the reagents and materials involved are all obtained from commercial sources unless otherwise specified.

[0064] Example 1: Reductive catalytic degradation of lignocellulose

[0065] (1) Preparation of lignin oil rich in dihydropinone monomer using pine wood powder as raw material

[0066] Add 1g pine powder, 200mg Cu 20 -PMO catalyst, 10 mL methanol, hydrogen pressure 40 bar, 180 ° C for 18 hours. After the reaction is completed, it is cooled to room temperature, and the reactant is filtered to obtain a methanol solution rich in lignin monomers. The sample is quantitatively and qualitatively analyzed by GC-MS / FID, and then the solvent is removed by vacuum distillation to obtain lignin oil containing 25 mg of dihydroconiferyl alcohol. The structure of the dihydroconiferyl alcohol is

[0067] (2) Preparation of lignin oil rich in dihydromesic alcohol monomers using beech wood powder as raw material

[0068] Add 1g beech wood powder and 200mg Cu into a high temperature and high pressure reactor. 20 -PMO catalyst, 10mL methanol, hydrogen pressure 40bar, 180℃ reaction for 18h. After the reaction, cool to room temperature, filter the reactant to obtain a methanol solution rich in lignin monomers, use GC-MS / FID to perform quantitative and qualitative analysis on the sample, and then remove the solvent by vacuum distillation to obtain lignin oil containing 25mg dihydromesinol. The structure of dihydromesinol is

[0069] Embodiment 2:

[0070] 0.1 g of lignin oil rich in dihydroconiferyl alcohol or dihydrosinapine alcohol monomer, 0.1 g of Ni / SiO2-Al2O3 catalyst, 3 mL of organic solvent were added to a high temperature and high pressure reactor. The reaction temperature was 220 ° C and the reaction time was 18 h. After the reaction was completed, the catalyst was separated by centrifugation to obtain a mixed liquid sample of the product and the organic solvent. The sample was quantitatively and qualitatively analyzed by GC-MS / FID. The results are shown in Table 1. The conversion rates of the listed dihydroconiferyl alcohol and dihydrosinapine alcohol were the highest when the organic solvent was isopropanol, while the yields of 4-ethyl-2,5-dimethoxyphenol and 4-ethyl-2-methoxyphenol were the highest when the organic solvent was n-heptane. Then the solvent was removed by vacuum distillation, and 4-ethyl-2-methoxyphenol was obtained after column chromatography purification.

[0071] The structural formulas of the compounds before and after the reaction are as follows, namely dihydrosinapine alcohol (1S), dihydropinoyl alcohol (1G), 4-ethyl-2,5-dimethoxyphenol (3S) and 4-ethyl-2-methoxyphenol (3G):

[0072] Table 1. Monomer conversion under different solvent systems

[0073]

[0074] Example 3: Synthesis of 4-ethylphenol

[0075] (1) Synthesis of 4-ethylphenol using 4-ethyl-2-methoxyphenol as raw material

[0076] Under nitrogen atmosphere, 2mmol 4-ethyl-2-methoxyphenol, 15mL water and 200mg porous nickel-based catalyst were added to a high temperature and high pressure reactor, and the reaction was carried out at 200°C for 6h. After the reaction was completed, the catalyst was separated from the reactants to obtain a liquid sample, and the sample was quantitatively and qualitatively analyzed by GC-MS / FID. The conversion rate of 4-ethyl-2-methoxyphenol was 77.3%, and the selectivity of 4-ethylphenol was 85.5%. The liquid sample was then extracted, distilled under reduced pressure, and purified by column chromatography to obtain 4-ethyl-2-methoxyphenol.

[0077] The structural formulas of the compounds before and after the reaction are as follows: 4-ethyl-2-methoxyphenol (left) and 4-ethylphenol (right):

[0078]

[0079] (2) Synthesis of 4-ethylphenol using 4-ethyl-2,5-dimethoxyphenol as raw material

[0080] Under nitrogen atmosphere, 2mmol 4-ethyl-2,5-dimethoxyphenol, 15mL water and 200mg porous nickel-based catalyst were added to a high temperature and high pressure reactor, and the reaction was carried out at 200°C for 6h. After the reaction, the catalyst was separated from the reactants to obtain a liquid sample, which was quantitatively and qualitatively analyzed by GC-MS / FID. The conversion rate of 4-ethyl-2,5-dimethoxyphenol was 77.3%, and the selectivity of 4-ethylphenol was 85.5%. The liquid sample was then extracted, distilled under reduced pressure, and purified by column chromatography to obtain 4-ethyl-2-methoxyphenol.

[0081] The structural formulas of the compounds before and after the reaction are as follows: 4-ethyl-2,5-dimethoxyphenol (left) and 4-ethylphenol (right):

[0082]

[0083] Embodiment 4:

[0084] (1) Synthesis of 4-ethylphenyl acetate:

[0085] Under nitrogen protection, add 61.08 mg (0.50 mmol) of 4-ethylphenol and 2.5 mL of tetrahydrofuran to a dry reaction bottle, stir and dissolve, so that the concentration of 4-ethylphenol is 0.2 M. Then cool the reaction solution to 0 ° C, slowly add 40 mg (0.60 mmol, 60% in mineral oil) of sodium hydride, continue to stir and react for 30 minutes, then add 76.57 mg (1.50 mmol) of acetic anhydride, and stir the reaction mixture at 25 ° C for 1 hour. Add 2 mL of saturated NaCl aqueous solution to quench the reaction, and extract with ethyl acetate. Combine the organic layers, wash quickly with saturated NaHCO3, dry over anhydrous magnesium sulfate, filter, and distill under reduced pressure to obtain 4-ethylphenyl acetate. The yield is 99%, light yellow transparent liquid; the spectral data are: 1 H NMR (400MHz, CDCl3) δ7.23-7.17 (m, 2H), 7.02-6.96 (m, 2H), 2.64 (q, J=7.6Hz, 2H), 2.29 (s, 3H), 1.23 (t, J=7.6Hz, 3H). 13 C NMR (101MHz, CDCl3) δ169.36, 148.58, 141.51, 128.57, 121.17, 28.13, 20.83, 15.41.

[0086] The structural formulas of the compounds before and after the reaction are as follows: 4-ethylphenol (left) and 4-ethylphenyl acetate (right):

[0087]

[0088] (2) Synthesis of 4-acetoxyacetophenone:

[0089] In an oxygen atmosphere, add 82.10 mg (0.50 mmol) of 4-ethylphenyl acetate, 81.57 mg (0.50 mmol) of NHPI, and 146.23 mg (1.00 mmol) of di-tert-butyl peroxide to a dry thick-walled pressure bottle, then add 2.5 mL of acetonitrile and stir to dissolve, so that the concentration of the reaction solution is 0.2 M. Seal the thick-walled pressure bottle, react at 120°C for 16 hours, remove the solvent by vacuum distillation, and purify by column chromatography (SiO2, n-hexane / ethyl acetate = 10:1) to obtain 4-acetoxyacetophenone. The yield is 85%, light yellow solid; the spectral data are: 1 H NMR (400MHz, CDCl3) δ8.02–7.97(m, 2H), 7.22–7.17(m, 2H), 2.59(s, 3H), 2.32(s, 3H). 13C NMR (101MHz, CDCl3) δ196.94, 168.88, 154.42, 134.75, 130.88, 129.98, 121.81, 115.37, 26.61, 21.16.

[0090] The structural formulas of the compounds before and after the reaction are as follows: 4-ethylphenyl acetate (left) and 4-acetoxyacetophenone (right):

[0091]

[0092] (3) Synthesis of 4-acetoxyacetanilide:

[0093] Under nitrogen protection, add 89.09 mg (0.50 mmol) of 4-acetoxyacetophenone, 69.49 mg (1.00 mmol) of hydroxylamine hydrochloride, and 133.34 mg (1.00 mmol) of aluminum chloride to a dry Shrek tube, then add 5 mL of acetonitrile and stir evenly to make the concentration of the reaction solution 0.1 M. React at 70 ° C for 15 h, remove the solvent by vacuum distillation, and purify by column chromatography (SiO2, n-hexane / ethyl acetate = 1:1) to obtain 4-acetoxyacetanilide. The yield is 91%, white solid; the spectral data is: 1 H NMR (400MHz, CDCl3) δ7.54–7.44(m, 2H), 7.06–6.98(m, 2H), 2.29(s, 3H), 2.16(s, 3H). 13 C NMR (101MHz, CDCl3) δ169.96, 168.75, 146.82, 135.88, 121.95, 121.06, 24.42, 21.21.

[0094] The structural formulas of the compounds before and after the reaction are as follows: 4-acetoxyacetophenone (left) and 4-acetoxyacetanilide (right):

[0095]

[0096] (4) Synthesis of paracetamol:

[0097] Under nitrogen protection, add 38.64 mg (0.20 mmol) of 4-acetoxyacetanilide and 1 mL of 2M NaOH aqueous solution to a dry Shrek tube, then add 1 mL of anhydrous ethanol and stir to dissolve, so that the concentration of the reaction solution is 0.1 M. Stir the reaction at 25 ° C for 3 hours, dilute with water, add 1M hydrochloric acid to adjust the pH to about 3, extract with ethyl acetate, wash the organic phase with saturated sodium bicarbonate twice, dry with anhydrous magnesium sulfate, filter, and distill under reduced pressure to obtain paracetamol. The yield is 99%, white solid; the spectral data is: 1HNMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 9.14 (s, 1H), 7.36–7.29 (m, 2H), 6.70–6.63 (m, 2H), 1.97 (s, 3H). 13 C NMR (101MHz, DMSO-d6) δ167.60, 153.18, 131.05, 120.93, 115.05, 23.75.

[0098] The structural formulas of the compounds before and after the reaction are as follows: 4-acetoxyacetanilide (left) and paracetamol (right):

[0099]

[0100] (5) Synthesis of p-aminophenol hydrochloride:

[0101] Under nitrogen protection, add 75.58 mg (0.50 mmol) of acetaminophen and 2 mL of concentrated hydrochloric acid to a dry thick-walled pressure bottle, then add 1 mL of anhydrous ethanol and stir to dissolve, so that the concentration of the reaction solution is 0.167 M. Seal the thick-walled pressure tube, stir at 120°C for 16 hours, remove most of the water and ethanol by vacuum distillation, and freeze-dry to obtain p-aminophenol hydrochloride. The yield is 98%, light yellow solid; the spectral data are: 1 H NMR (400MHz, DMSO-d6) δ7.24–7.16(m, 2H), 6.89–6.82(m, 2H). 13 C NMR (101MHz, DMSO-d6) δ157.25, 124.42, 122.37, 116.14.

[0102] The structural formulas of the compounds before and after the reaction are as follows: paracetamol (left) and p-aminophenol hydrochloride (right)

[0103]

[0104] Embodiment 5:

[0105] (1) Synthesis of 4-ethylphenyl acetate:

[0106] Under nitrogen protection, add 61.08 mg (0.50 mmol) of 4-ethylphenol and 1 mL of acetonitrile to a dry reaction bottle, stir and dissolve, so that the concentration of the reaction solution is 0.5 M. Then cool the reaction solution to -20 ° C, slowly add 0.313 mL (0.50 mmol, 1.6 M in hexane) of n-butyl lithium, continue to stir the reaction for 60 min, then add 39.24 mg (0.50 mmol) of acetyl chloride, and stir the reaction mixture at 0 ° C for 3 h. Add 2 mL of saturated NaCl aqueous solution to quench the reaction, and extract with ethyl acetate. Combine the organic layers, quickly wash with saturated NaHCO3, dry over anhydrous magnesium sulfate, filter, and distill under reduced pressure to obtain 4-ethylphenyl acetate. The yield is 90%, light yellow transparent liquid; the spectral data are: 1 H NMR (400MHz, CDCl3) δ7.23-7.17 (m, 2H), 7.02-6.96 (m, 2H), 2.64 (q, J=7.6Hz, 2H), 2.29 (s, 3H), 1.23 (t, J=7.6Hz, 3H). 13 CNMR (101MHz, CDCl3) δ169.36, 148.58, 141.51, 128.57, 121.17, 28.13, 20.83, 15.41.

[0107] The structural formulas of the compounds before and after the reaction are as follows: 4-ethylphenol (left) and 4-ethylphenyl acetate (right)

[0108]

[0109] (2) Synthesis of 4-acetoxyacetophenone:

[0110] In an oxygen atmosphere, add 82.10 mg (0.50 mmol) of 4-ethylphenyl acetate, 40.79 mg (0.25 mmol) of NHPI, and 51.56 mg (0.50 mmol) of tert-butyl nitrite to a dry thick-walled pressure bottle, then add 10 mL of tetrahydrofuran and stir to dissolve, so that the concentration of the reaction solution is 0.05 M. Seal the thick-walled pressure bottle, react at 60°C for 24 hours, remove the solvent by vacuum distillation, and purify by column chromatography (SiO2, n-hexane / ethyl acetate = 10:1) to obtain 4-acetoxyacetophenone. The yield is 81%, light yellow solid; the spectral data are: 1 H NMR (400MHz, CDCl3) δ8.02–7.97(m, 2H), 7.22–7.17(m, 2H), 2.59(s, 3H), 2.32(s, 3H). 13C NMR (101MHz, CDCl3) δ196.94, 168.88, 154.42, 134.75, 130.88, 129.98, 121.81, 115.37, 26.61, 21.16.

[0111] The structural formulas of the compounds before and after the reaction are as follows: 4-ethylphenyl acetate (left), 4-acetoxyacetophenone (right)

[0112]

[0113] (3) Synthesis of 4-acetoxyacetanilide:

[0114] Under nitrogen protection, add 89.09 mg (0.50 mmol) of 4-acetoxyacetophenone, 34.74 mg (0.50 mmol) of hydroxylamine hydrochloride, and 70.97 mg (0.50 mmol) of boron trifluoride ether complex to a dry Shrek tube, then add 1 mL of methanol and stir evenly to make the concentration of the reaction solution 0.5 M. React at 40 ° C for 24 hours, remove the solvent by vacuum distillation, and purify by column chromatography (SiO2, n-hexane / ethyl acetate = 1:1) to obtain 4-acetoxyacetanilide. The yield is 81%, white solid; the spectral data is: 1 H NMR (400MHz, CDCl3) δ7.54–7.44(m, 2H), 7.06–6.98(m, 2H), 2.29(s, 3H), 2.16(s, 3H). 13 C NMR (101MHz, CDCl3) δ169.96, 168.75, 146.82, 135.88, 121.95, 121.06, 24.42, 21.21.

[0115] The structural formulas of the compounds before and after the reaction are as follows: 4-acetoxyacetophenone (left) and 4-acetoxyacetanilide (right)

[0116]

[0117] (4) Synthesis of paracetamol:

[0118] Under nitrogen protection, add 38.64 mg (0.20 mmol) of 4-acetoxyacetanilide and 0.2 mL of 2M NaOH aqueous solution to a dry Shrek tube, then add 0.2 mL of dioxane and stir to dissolve, so that the concentration of the reaction solution is 0.5 M. Stir the reaction at 10 ° C for 24 hours, dilute with water, add 1M hydrochloric acid to adjust the pH to about 6, extract with ethyl acetate, wash the organic phase with saturated sodium bicarbonate twice, dry with anhydrous magnesium sulfate, filter, and distill under reduced pressure to obtain paracetamol. The yield is 94%, white solid; the spectral data is: 1H NMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 9.14 (s, 1H), 7.36–7.29 (m, 2H), 6.70–6.63 (m, 2H), 1.97 (s, 3H). 13 C NMR (101MHz, DMSO-d6) δ167.60, 153.18, 131.05, 120.93, 115.05, 23.75.

[0119] The structural formulas of the compounds before and after the reaction are as follows: 4-acetoxyacetanilide (left) and paracetamol (right)

[0120]

[0121] (5) Synthesis of p-aminophenol hydrochloride:

[0122] Under nitrogen protection, add 75.58 mg (0.50 mmol) of acetaminophen and 2 mL of concentrated hydrochloric acid to a dry thick-walled pressure bottle, then add 0.5 mL of anhydrous methanol, stir and dissolve, so that the concentration of the reaction solution is 0.2 M. Seal the thick-walled pressure bottle, stir at 80°C for 24 hours, remove most of the water and methanol by vacuum distillation, and freeze-dry to obtain p-aminophenol hydrochloride. The yield is 96%, light yellow solid; the spectral data are: 1 H NMR (400MHz, DMSO-d6) δ7.24–7.16(m, 2H), 6.89–6.82(m, 2H). 13 C NMR (101MHz, DMSO-d6) δ157.25, 124.42, 122.37, 116.14.

[0123] The structural formulas of the compounds before and after the reaction are as follows: paracetamol (left) and p-aminophenol hydrochloride (right)

[0124]

[0125] Embodiment 6:

[0126] (1) Synthesis of 4-ethylphenyl acetate:

[0127] Under nitrogen protection, add 61.08 mg (0.50 mmol) of 4-ethylphenol and 10 mL of dichloromethane to a dry reaction bottle, stir and dissolve, so that the concentration of the reaction solution is 0.05 M. Then slowly add 60 mg (1.50 mmol) of sodium hydroxide, continue stirring and reacting at 25 ° C for 10 min, then add 76.57 mg (1.50 mmol) of acetic anhydride, and stir the reaction mixture at 40 ° C for 0.5 h. Add 2 mL of saturated NaCl aqueous solution to quench the reaction, and extract with ethyl acetate. Combine the organic layers, quickly wash with saturated NaHCO3, dry over anhydrous magnesium sulfate, filter, and distill under reduced pressure to obtain 4-ethylphenyl acetate. The yield is 86%, light yellow transparent liquid; the spectral data are: 1 H NMR (400MHz, CDCl3) δ7.23-7.17 (m, 2H), 7.02-6.96 (m, 2H), 2.64 (q, J=7.6Hz, 2H), 2.29 (s, 3H), 1.23 (t, J=7.6Hz, 3H). 13 C NMR (101MHz, CDCl3) δ169.36, 148.58, 141.51, 128.57, 121.17, 28.13, 20.83, 15.41.

[0128] The structural formulas of the compounds before and after the reaction are as follows: 4-ethylphenol (left) and 4-ethylphenyl acetate (right)

[0129]

[0130] (2) Synthesis of 4-acetoxyacetophenone:

[0131] In an oxygen atmosphere, add 82.10 mg (0.50 mmol) of 4-ethylphenyl acetate, 244.71 mg (1.50 mmol) of NHPI, and 291.34 mg (1.50 mmol) of tert-butyl peroxybenzoate to a dry thick-walled pressure bottle, then add 1 mL of n-hexane and stir to dissolve, so that the concentration of the reaction solution is 0.5 M. Seal the thick-walled pressure bottle, react at 160°C for 2 h, remove the solvent by reduced pressure distillation, and purify by column chromatography (SiO2, n-hexane / ethyl acetate = 10:1) to obtain 4-acetoxyacetophenone. The yield is 75%, light yellow solid; the spectral data are: 1 H NMR (400MHz, CDCl3) δ8.02–7.97(m, 2H), 7.22–7.17(m, 2H), 2.59(s, 3H), 2.32(s, 3H). 13C NMR (101MHz, CDCl3) δ196.94, 168.88, 154.42, 134.75, 130.88, 129.98, 121.81, 115.37, 26.61, 21.16.

[0132] The structural formulas of the compounds before and after the reaction are as follows: 4-ethylphenyl acetate (left), 4-acetoxyacetophenone (right)

[0133]

[0134] (3) Synthesis of 4-acetoxyacetanilide:

[0135] Under nitrogen protection, add 89.09 mg (0.50 mmol) of 4-acetoxyacetophenone, 138.98 mg (2.00 mmol) of hydroxylamine hydrochloride, and 228.05 mg (2.00 mmol) of trifluoroacetic acid to a dry Shrek tube, then add 10 mL of toluene and stir evenly to make the concentration of the reaction solution 0.05 M. React at 100 ° C for 2 h, remove the solvent by vacuum distillation, and purify by column chromatography (SiO2, n-hexane / ethyl acetate = 1:1) to obtain 4-acetoxyacetanilide. The yield is 81%, white solid; the spectral data is: 1 H NMR (400MHz, CDCl3) δ7.54–7.44(m, 2H), 7.06–6.98(m, 2H), 2.29(s, 3H), 2.16(s, 3H). 13 C NMR (101MHz, CDCl3) δ169.96, 168.75, 146.82, 135.88, 121.95, 121.06, 24.42, 21.21.

[0136] The structural formulas of the compounds before and after the reaction are as follows: 4-acetoxyacetophenone (left) and 4-acetoxyacetanilide (right)

[0137]

[0138] (4) Synthesis of paracetamol:

[0139] Under nitrogen protection, add 38.64 mg (0.20 mmol) of 4-acetoxyacetanilide and 2 mL of 2M NaOH aqueous solution to a dry Shrek tube, then add 2 mL of acetonitrile and stir to dissolve, so that the concentration of the reaction solution is 0.05 M. Stir the reaction at 80°C for 1 hour, dilute with water, add 1M hydrochloric acid to adjust the pH to about 1, extract with ethyl acetate, wash the organic phase with saturated sodium bicarbonate twice, dry with anhydrous magnesium sulfate, filter, and distill under reduced pressure to obtain paracetamol. The yield is 88%, white solid; the spectral data is: 1HNMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 9.14 (s, 1H), 7.36–7.29 (m, 2H), 6.70–6.63 (m, 2H), 1.97 (s, 3H). 13 C NMR (101MHz, DMSO-d6) δ167.60, 153.18, 131.05, 120.93, 115.05, 23.75.

[0140] The structural formulas of the compounds before and after the reaction are as follows: 4-acetoxyacetanilide (left) and paracetamol (right)

[0141]

[0142] (5) Synthesis of p-aminophenol hydrochloride:

[0143] Under nitrogen protection, add 75.58 mg (0.50 mmol) of acetaminophen and 2 mL of concentrated hydrochloric acid to a dry thick-walled pressure bottle, then add 8 mL of dioxane, stir and dissolve, so that the concentration of the reaction solution is 0.05 M. Seal the thick-walled pressure bottle, stir at 140°C for 2 h, remove most of the water and dioxane by vacuum distillation, and freeze-dry to obtain p-aminophenol hydrochloride. The yield is 88%, light yellow solid; the spectral data are: 1 H NMR (400MHz, DMSO-d6) δ7.24–7.16(m, 2H), 6.89–6.82(m, 2H). 13 C NMR (101MHz, DMSO-d6) δ157.25, 124.42, 122.37, 116.14.

[0144] The structural formulas of the compounds before and after the reaction are as follows: paracetamol (left) and p-aminophenol hydrochloride (right)

[0145]

[0146] Embodiment 7:

[0147] Synthesis of p-aminophenol hydrochloride:

[0148] Under nitrogen protection, add 96.60 mg (0.50 mmol) of 4-acetoxyacetanilide and 2 mL of concentrated hydrochloric acid to a dry thick-walled pressure bottle, then add 1 mL of anhydrous ethanol and stir to dissolve, so that the concentration of the reaction solution is 0.167 M. Seal the thick-walled pressure bottle, stir at 120°C for 16 h, remove most of the water and ethanol by vacuum distillation, and freeze-dry to obtain p-aminophenol hydrochloride. The yield is 98%, light yellow solid; the spectral data are: 1H NMR (400MHz, DMSO-d6) δ7.24–7.16(m, 2H), 6.89–6.82(m, 2H). 13 C NMR (101MHz, DMSO-d6) δ157.25, 124.42, 122.37, 116.14.

[0149] The structural formulas of the compounds before and after the reaction are as follows: 4-acetoxyacetanilide (left) and p-aminophenol hydrochloride (right)

[0150]

[0151] Embodiment 8:

[0152] Synthesis of p-aminophenol hydrochloride:

[0153] Under nitrogen protection, add 96.60 mg (0.50 mmol) of 4-acetoxyacetanilide and 2 mL of concentrated hydrochloric acid to a dry thick-walled pressure bottle, then add 8 mL of tetrahydrofuran, stir and dissolve, so that the concentration of the reaction solution is 0.05 M. Seal the thick-walled pressure bottle, stir at 80°C for 24 hours, remove most of the water and tetrahydrofuran by vacuum distillation, and freeze-dry to obtain p-aminophenol hydrochloride. The yield is 95%, light yellow solid; the spectral data are: 1 H NMR (400MHz, DMSO-d6) δ7.24–7.16(m, 2H), 6.89–6.82(m, 2H). 13 C NMR (101MHz, DMSO-d6) δ157.25, 124.42, 122.37, 116.14.

[0154] The structural formulas of the compounds before and after the reaction are as follows: 4-acetoxyacetanilide (left) and p-aminophenol hydrochloride (right)

[0155]

[0156] Embodiment 9:

[0157] Synthesis of p-aminophenol hydrochloride:

[0158] Under nitrogen protection, add 96.60 mg (0.50 mmol) of 4-acetoxyacetanilide and 2 mL of concentrated hydrochloric acid to a dry thick-walled pressure bottle, then add 0.5 mL of acetonitrile, stir and dissolve, so that the concentration of the reaction solution is 0.2 M. Seal the thick-walled pressure bottle, stir at 140 ° C for 2 h, remove most of the water and acetonitrile by vacuum distillation, and freeze-dry to obtain p-aminophenol hydrochloride. The yield is 85%, light yellow solid; the spectral data is: 1H NMR (400MHz, DMSO-d6) δ7.24–7.16(m, 2H), 6.89–6.82(m, 2H). 13 C NMR (101MHz, DMSO-d6) δ157.25, 124.42, 122.37, 116.14.

[0159] The structural formulas of the compounds before and after the reaction are as follows: 4-acetoxyacetanilide (left) and p-aminophenol hydrochloride (right)

[0160]

Claims

1. A method for preparing paracetamol and p-aminophenol hydrochloride by converting lignin degradation monomers, characterized in that: The method comprises: (1) Reduction catalytic degradation: A monomer-rich lignin oil is prepared from biomass raw materials, wherein the structure of the monomer is shown in Formula I; the reduction catalyst involved in the preparation of the lignin oil is Pd / C, Cu 20 One of PMO, Ni / C, Raney Ni, and Ni / Al2O3, wherein the biomass raw material is pine or beech; (2) Defunctionalization: Mixing monomer-rich lignin oil, a catalyst and an organic solvent to obtain a product of formula II; the catalyst is a Ni / SiO2-Al2O3 catalyst; The obtained product of formula II, a catalyst and a solvent are mixed and reacted to obtain the lignin degradation monomer 4-ethylphenol shown in formula III; the catalyst is a porous nickel-based catalyst; (3) Phenolic hydroxyl protection: under nitrogen or argon atmosphere, add the 4-ethylphenol obtained in step (2) into an organic solvent, stir and dissolve, add a base to react, then add an acylating agent to continue the reaction, add a saturated NaCl aqueous solution to quench the reaction, extract, and distill under reduced pressure to obtain a product of formula IV; (4) benzyl oxidation: under an oxygen atmosphere, dissolve the product of formula IV obtained in step (3), N-hydroxyphthalimide and a free radical initiator in an organic solvent, stir and mix, seal the reaction chamber, and perform vacuum distillation to obtain a product of formula V after purification; (5) Beckmann rearrangement: under nitrogen or argon atmosphere, add the product of formula V obtained in step (4), hydroxylamine hydrochloride, and an acid catalyst, then add an organic solvent and stir evenly, heat the reaction solution to a certain temperature and react for a period of time, then distill under reduced pressure and purify to obtain the product of formula VI; (6) Preparation of paracetamol or p-aminophenol hydrochloride by hydrolysis reaction: Preparation of paracetamol by hydrolysis reaction: Under nitrogen or argon atmosphere, add the product of formula VI obtained in step (5) and an alkaline solution, then add an organic solvent and stir to dissolve. After a period of reaction, adjust the pH value to acidic, extract, and distill under reduced pressure to obtain paracetamol represented by formula VII; Preparation of p-aminophenol hydrochloride by hydrolysis reaction: Under a nitrogen or argon atmosphere, add concentrated hydrochloric acid, the product of formula VI obtained in step (5) or the obtained paracetamol, then add an organic solvent and stir to dissolve, seal the obtained mixed solution, react for a period of time, distill under reduced pressure, and freeze-dry to obtain p-aminophenol hydrochloride represented by formula VIII; The structural formulas of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII and Formula VIII are as follows: , , , , , , , , wherein R is a methoxy group or a hydrogen atom; R 1 It is a fatty acyl group containing 1-20 carbon atoms.

2. The method according to claim 1, characterized in that The reaction temperature in step (2) is 220° C. and the reaction time is 18 h.

3. The method according to claim 1, characterized in that The reaction temperature in step (2) is 200° C. and the reaction time is 6 h.

4. The method according to claim 1, characterized in that In step (3), the base, the acylating agent, and the product of formula III are used in a molar ratio of 1-3:1-3:1; after the 4-ethylphenol and the organic solvent are mixed, the concentration of 4-ethylphenol in the mixed solution is 0.05-0.5 M; The reaction temperature after adding the base is -20-25°C, and the reaction time is 10-60 min; The reaction temperature after adding the acylating agent is 0-40°C, and the reaction time is 0.5-3h; The base is any one of sodium hydride, potassium hydride, lithium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, lithium hexamethyldisilazide, and alkyl lithium containing 1 to 10 carbon atoms; The acylating agent is any one of an aliphatic acid chloride containing 1 to 20 carbon atoms and an aliphatic acid anhydride containing 1 to 20 carbon atoms.

5. The method according to claim 1, characterized in that In step (4), the molar ratio of N-hydroxyphthalimide, free radical initiator and product of formula IV is 0.5-3:1-3:1; after the product of formula IV, N-hydroxyphthalimide and free radical initiator are dissolved in an organic solvent, the concentration of the product of formula IV in the solution is 0.05-0.5M; The sealing reaction conditions are: the reaction temperature is 60-160°C for 2-24 hours; The free radical initiator is any one of benzoyl peroxide, lauroyl peroxide, cumene hydroperoxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, diisopropyl peroxide, tert-butyl perbenzoate, tert-butyl pervalerate, methyl ethyl ketone peroxide, cyclohexanone peroxide, diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, and tert-butyl nitrite.

6. The method according to claim 1, characterized in that In step (5), the molar ratio of hydroxylamine hydrochloride, catalyst and product of formula V is 1-4:1-4:1; after the product of formula V, hydroxylamine hydrochloride, acid catalyst and organic solvent are uniformly stirred, the concentration of the product of formula V in the solution is 0.05-0.5 M; The reaction conditions are: the temperature is 40-100° C. and the reaction time is 2-24 h; The acid catalyst is any one of sulfuric acid, hydrochloric acid, polyphosphoric acid, p-toluenesulfonic acid, trifluoroacetic acid, boron trifluoride ether complex, aluminum trichloride, titanium tetrachloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, methanesulfonyl chloride, and p-toluenesulfonyl chloride.

7. The method according to claim 1, characterized in that In the process of preparing paracetamol by hydrolysis reaction in step (6), the molar ratio of the alkaline solution to the product of formula VI is 2-20:1; after the product of formula VI, the alkaline solution and the organic solvent are uniformly stirred, the concentration of the product of formula VI in the solution is 0.05-0.5 M; The stirring reaction conditions are: temperature of 10-80°C, time of 1-24 h; The pH value is adjusted to 1-6 with 1M hydrochloric acid; The alkaline solution is any one of sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, sodium bicarbonate solution, calcium hydroxide solution, and ammonia water.

8. The method according to claim 1, characterized in that In the process of preparing p-aminophenol hydrochloride by hydrolysis reaction in step (6), the concentration of the product of formula VI or paracetamol in the mixed solution is 0.05-0.2 M; The sealing reaction conditions are: temperature of 80-140° C. and time of 2-24 h.

9. The method according to claim 1, characterized in that: In the process of preparing the product of formula II in step (2), the organic solvent is any one of n-heptane, toluene, cyclohexane, cyclohexanol and isopropanol; in the process of preparing the lignin degradation monomer 4-ethylphenol shown in formula III, the solvent is water; in steps (3), (4) and (5), the organic solvent is any one of dichloromethane, acetonitrile, methanol, ethanol, ether, methyl tert-butyl ether, tetrahydrofuran, toluene, n-hexane and ethyl acetate; in the process of preparing paracetamol and p-aminophenol hydrochloride by hydrolysis reaction in step (6), the organic solvent is any one of acetonitrile, methanol, ethanol, tetrahydrofuran and dioxane.

Images