CN112979439A - Preparation method of benzophenone derivative - Google Patents
Preparation method of benzophenone derivative Download PDFInfo
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- CN112979439A CN112979439A CN201911285821.3A CN201911285821A CN112979439A CN 112979439 A CN112979439 A CN 112979439A CN 201911285821 A CN201911285821 A CN 201911285821A CN 112979439 A CN112979439 A CN 112979439A
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- C07—ORGANIC CHEMISTRY
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
Abstract
The invention provides a preparation method of a benzophenone derivative, which comprises the following steps: benzoic acid compound shown as formula I, trichlorotoluene compound shown as formula II and benzene compound shown as formula III in Fe2O3To obtain the benzophenone derivative. The preparation method provided by the invention is used for preparing the metal oxide Fe with higher stability and safety2O3As a catalyst, the corrosion of materials to equipment is avoided, and the catalyst is more green and environment-friendly; the preparation method obtains the target product through one-step reaction, and has mild reaction conditions and simple process; and the benzoic acid compound which is the main byproduct generated in the reaction can be washed, extracted and removed in the post-treatmentThe solvent is recovered by the method and then used as a reaction raw material for preparing the benzophenone derivative again, thereby reducing the wastewater treatment cost and fully utilizing resources.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a benzophenone derivative.
Background
The benzophenone compound is an important organic fine chemical product, and has a plurality of varieties and wide application because of different types, positions and numbers of substituent groups on aromatic rings at two ends of carbonyl. For example, benzophenone hydrogen transfer photoinitiators mainly based on 4-methylbenzophenone and 2,4, 6-trimethylbenzophenone have high quantum efficiency, high curing speed, absorption spectrum range matched with an irradiation light source, no dark reaction, and environmental friendliness, and are widely used in the fields of coatings, adhesives, electronic devices, optical fiber materials and the like. The benzophenone compound can absorb 290-400 nm ultraviolet light, can also absorb a part of visible light, and has good compatibility with other materials, so that the benzophenone compound can be used as an important ultraviolet absorbent to be applied to the fields of plastics, printing ink and cosmetics, wherein the 2, 4-dihydroxy benzophenone and the derivatives thereof have good application prospects. In addition, the benzophenone compound is also an intermediate of a plurality of medicines, such as 4-chlorobenzophenone for producing an antiallergic drug, 2-amino-5-chlorobenzophenone is an intermediate of a tranquilizer, and ketoprofen which is a high-efficiency anti-inflammatory analgesic is prepared by brominating, cyaniding, hydrolyzing and methylating m-phenylbenzophenone.
The benzophenone derivative has wide application field and great demand in chemical and pharmaceutical production, so the innovation and optimization of the preparation process are important research subjects in the field of organic synthesis. CN103342634A discloses a method for synthesizing 4,4 '-dihydroxybenzophenone, which comprises the steps of taking p-hydroxybenzoic acid and phenol as raw materials, and synthesizing 4,4' -dihydroxybenzophenone by a one-step method in an organic solvent by using an acid catalyst and a dehydrating agent, wherein the catalyst is one or a mixture of methanesulfonic acid and polyphosphoric acid; the method has mild conditions, the yield reaches more than 80 percent, but the used acidic catalyst has strong corrosivity on metal and strong stimulation on skin mucous membrane of human body, the usage amount is 2 molar equivalents of p-hydroxybenzoic acid or more, a large amount of acidic waste liquid which is difficult to treat is generated, and the industrial production is difficult to continuously develop. CN106045828B discloses a preparation method of 4,4' -difluorobenzophenone, which comprises the following steps: firstly, performing acylation reaction on p-fluorotrichlorotoluene and fluorobenzene under the catalytic action of aluminum trichloride to generate 4,4' -difluorophenyl dichloromethane, and performing hydrolysis reaction on the 4,4' -difluorophenyl dichloromethane to obtain 4,4' -difluorobenzophenone; the preparation method needs two steps of reactions, wherein aluminum trichloride which is more than 1 molar equivalent relative to p-fluorotrichlorotoluene is used as a catalyst in the first step of reaction, and waste liquid containing high-concentration aluminum trichloride is generated in the second step of hydrolysis process, so that the harmless treatment difficulty is high, and the preparation method is difficult to meet the requirements of cleanness, environmental protection and high efficiency in industrial production. CN107129432A discloses a synthesis method of ultraviolet absorbent 4,4' -dihexyl benzophenone, which comprises the following steps: taking p-hydroxybenzoic acid as an initial raw material, protecting hydroxyl by acetylation, and then carrying out Friedel-crafts acylation reaction with phenol under the catalysis of zinc chloride and phosphorus oxychloride to obtain an intermediate p-hydroxybenzoic acid phenyl ester; preparing an intermediate 4,4' -dihydroxy benzophenone by deacetylation protective group and Fries rearrangement; finally salifying with potassium carbonate, and reacting with 1-bromohexane under the catalysis of tetrabutylammonium bromide through Williamson reaction to obtain a 4,4' -bis (hexyloxy) benzophenone product; the method needs to obtain a target product through multi-step reactions, the preparation route is complex, and a large amount of zinc chloride and phosphorus oxychloride are used as catalysts in the second Friedel-crafts acylation reaction, so that a large amount of strong-acid wastewater containing chlorine, phosphorus and zinc can be generated, the post-treatment of the wastewater reaches harmless discharge standards, and the process is difficult to industrially apply.
In general, the conventional synthetic routes for benzophenone derivatives include phosgene method, benzoyl chloride method, carbon dioxide method, carbon monoxide method, benzoic acid (or benzoic anhydride) method, carbon tetrachloride method, catalytic oxidation method, decarboxylation method, and the like. Wherein, the phosgene method needs to use raw material phosgene with strong toxic and side effects, which causes great threat or harm to human body and environment; the benzoyl chloride method, the benzoic acid method, the trichlorotoluene method and the like have the problems of more byproducts, low yield and high cost, and the three wastes generated in the production are more, are not environment-friendly and are difficult to apply or continue in industrial production; in addition, in the reaction, the iron chloride, the aluminum chloride and the zinc chloride are used, so that the Lewis acid catalyst is easy to absorb moisture and hydrolyze, and releases highly toxic hydrogen chloride gas, so that the production requirement of matched storage equipment is high, the investment is large, meanwhile, the safety and health of operators who take the catalyst on site for a long time are greatly threatened or damaged, and long-term negative effects are brought to the environment.
Therefore, it is still desirable in the art to develop a method for preparing benzophenone derivatives that is more friendly to the producer and the environment, has low requirement of the catalyst for storage equipment, simple production process, high yield and low cost.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a preparation method of a benzophenone derivative, which takes a benzoic acid compound, a trichlorotoluene compound and a benzene compound as starting materials and adopts Fe2O3The target product benzophenone derivative is obtained through one-step reaction under the catalysis of the method, the process route is simple, the byproducts are few, the recovery and the reutilization are easy, the yield is high, and the raw materials and the catalyst have the characteristics of safety and environmental protection, so that the method is a green and friendly preparation process.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of a benzophenone derivative, which comprises the following steps: benzoic acid compound shown as formula I, trichlorotoluene compound shown as formula II and benzene compound shown as formula III in Fe2O3To obtain the benzophenone derivative, wherein the reaction formula is as follows:
wherein R is1、R2Each independently selected from halogen, hydroxyl, nitro, amino, substituted or unsubstituted C1-C10 (e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10) straight chain or branched chain alkyl, substituted or unsubstituted C1-C10 (e.g. C1, C2, C3, C4, C5, C6, C7,C8, C9, or C10) alkoxy, or a substituted or unsubstituted C6 to C30 (e.g., C6, C8, C10, C12, C15, C18, C20, C22, C25, C27, or C29) aromatic hydrocarbon group.
n and m are each independently an integer of 0 to 5, for example 0, 1, 2, 3, 4 or 5, and n + m.gtoreq.1, i.e. n and m are not both 0at the same time.
In the benzoic acid compound shown in the formula I and the trichlorotoluene compound shown in the formula II, when n is more than 1, R1The same or different; in the benzene compound shown in the formula III, when m is more than 1, R2The same or different.
The preparation method provided by the invention takes the benzoic acid compound as one of the initial raw materials and takes Fe2O3As a catalyst, the method solves the problems of more byproducts, serious corrosion to equipment and adverse influence on operators and environment in the traditional preparation of benzophenone compounds by a benzoyl chloride method. Compared with the prior art, the preparation method has the following characteristics: firstly, the main side reaction of the benzophenone derivative in the preparation is hydrolysis reaction between benzoyl chloride compound and water, and benzoic acid by-product is generated; the invention takes the benzoic acid compound as one of the reaction raw materials, effectively inhibits the hydrolysis reaction of the benzoyl chloride compound, greatly reduces the generation of byproducts, and improves the conversion rate of the raw materials and the yield of the benzophenone derivative. Secondly, a small amount of by-product benzoic acid compounds generated in the reaction can be separated from the benzophenone derivatives through a post-treatment washing process (acid washing, water washing or alkali washing), and the recovered high-purity benzoic acid compounds can be obtained after benzene extraction and debenzolization after separation and can be used as reaction raw materials for preparation of the benzophenone derivatives again, so that the wastewater treatment cost is reduced, and the full utilization of resources is realized. Thirdly, the traditional friedel-crafts acylation reaction adopts Lewis acid such as ferric chloride, aluminum chloride, zinc chloride and the like as a catalyst, metal chloride is easy to absorb moisture and hydrolyze and releases highly toxic hydrogen chloride gas, so that the traditional friedel-crafts acylation reaction has a corrosion effect on production matched storage equipment, and threatens or damages the safety and health of operators who take the catalyst on site for a long timeHarm, negative impact on the environment; the invention adopts metal oxide Fe2O3As the catalyst, the corrosion of production materials to equipment is reduced, the investment cost of the equipment is reduced, no negative influence is brought to field operators and the environment, and the catalyst is more green and environment-friendly. Fourthly, the synthetic route designed by the invention has high atom utilization rate, the reaction product comprises target products of benzophenone derivatives and HCl, HCl gas is discharged out of the reaction device in the reaction and then is absorbed by water, the obtained hydrochloric acid can be used as a chemical raw material for utilization, and the production of industrial three wastes in the preparation process is less. Therefore, the preparation method provided by the invention has the characteristics of simple process route, environmental friendliness and low cost, is more friendly to operators, realizes the maximum utilization of raw materials, and generates less industrial three wastes.
Preferably, the Fe2O3The molar ratio of the benzoic acid compound to the benzoic acid compound is (0.08 to 0.2):1, for example, 0.09:1, 0.1:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, 0.17:1, 0.18:1, or 0.19:1, and more preferably (0.1 to 0.15): 1.
In the invention, a specific metal oxide Fe2O3The benzophenone derivative serving as a catalyst has the characteristics of small using amount, high catalytic efficiency, high utilization rate, good storage stability and the like, can efficiently promote the conversion of raw materials to target products, and finally obtains the benzophenone derivative with high yield.
The molar ratio of the benzoic acid compound to the trichlorotoluene compound is preferably 1 (1 to 2), for example, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, or 1:1.9, and more preferably 1 (1.1 to 1.7).
The molar ratio of the benzoic acid compound to the benzene compound is preferably 1 (5 to 10), for example, 1:5.2, 1:5.4, 1:5.6, 1:5.8, 1:6, 1:6.2, 1:6.5, 1:6.8, 1:7, 1:7.1, 1:7.2, 1:7.3, 1:7.4, 1:7.5, 1:7.6, 1:7.7, 1:7.8, 1:7.9, 1:8, 1:8.2, 1:8.5, 1:8.7, 1:9, 1:9.3, 1:9.5, 1:9.7, or 1:9.9, and more preferably 1 (7 to 8).
In the present invention, the benzene compound is not only a reaction raw material but also a solvent in the reaction, and therefore, a large excess amount thereof is required.
Preferably, the reaction temperature is 120-165 ℃, such as 122 ℃, 125 ℃, 127 ℃, 130 ℃, 133 ℃, 135 ℃, 138 ℃, 140 ℃, 142 ℃, 145 ℃, 148 ℃, 150 ℃, 152 ℃, 155 ℃, 158 ℃, 160 ℃, 162 ℃ or 164 ℃.
Preferably, the reaction time is 4-8 h, such as 4.2h, 4.5h, 4.7h, 5h, 5.2h, 5.5h, 5.7h, 6h, 6.3h, 6.5h, 6.8h, 7h, 7.3h, 7.5h, 7.7h or 7.9h, etc.
Preferably, the pressure of the reaction is 0.18 to 0.80MPa, such as 0.2MPa, 0.22MPa, 0.25MPa, 0.28MPa, 0.3MPa, 0.33MPa, 0.35MPa, 0.38MPa, 0.4MPa, 0.43MPa, 0.45MPa, 0.48MPa, 0.5MPa, 0.52MPa, 0.55MPa, 0.58MPa, 0.6MPa, 0.62MPa, 0.65MPa, 0.68MPa, 0.7MPa, 0.72MPa, 0.75MPa, 0.77MPa, or 0.79MPa, and the like.
Preferably, the halogen comprises fluorine, chlorine, bromine or iodine.
Preferably, the substituent in the substituted alkyl, substituted alkoxy, substituted aryl is selected from at least one of halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, nitro or amino.
Preferably, said R is1、R2Each independently selected from any one of halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, C1-C5 (such as C1, C2, C3, C4 or C5) straight chain or branched chain alkyl, C1-C5 (such as C1, C2, C3, C4 or C5) alkoxy.
Preferably, n and m are each independently an integer of 0 to 3, such as 0, 1, 2 or 3; and n + m is more than or equal to 1.
Preferably, the HCl generated in the reaction is discharged from the reaction device through a condensation circulation device during the reaction process.
Preferably, the HCl is discharged from the reaction device and absorbed by water, and the obtained hydrochloric acid is used as a chemical raw material for continuous use.
Preferably, the method for judging the end point of the reaction is as follows: no HCl gas was vented from the reactor.
Preferably, the preparation method further comprises a post-treatment step.
Preferably, the post-treatment step comprises washing and removal of the solvent.
Preferably, the washing is selected from any one of acid washing, water washing or alkali washing or a combination of at least two of them.
Preferably, the pickling method comprises the following steps: and stirring and mixing the reaction product with acid liquor, standing and layering, and keeping an organic phase.
Preferably, the temperature of the mixing is 50 to 80 ℃, such as 52 ℃, 55 ℃, 58 ℃, 60 ℃, 62 ℃, 65 ℃, 67 ℃, 70 ℃, 72 ℃, 75 ℃, 77 ℃ or 79 ℃.
Preferably, the acid solution has a concentration of 3 to 10%, for example, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, or 9.5%. Illustratively, the acid solution is hydrochloric acid.
Preferably, the alkali washing method comprises the following steps: and stirring and mixing the reaction product with alkali liquor, and then standing for layering to keep an organic phase.
Preferably, the concentration of the alkali liquor is 1-5%, such as 1.2%, 1.5%, 1.7%, 2%, 2.3%, 2.5%, 2.8%, 3%, 3.2%, 3.5%, 3.8%, 4%, 4.2%, 4.5%, 4.7%, or 4.9%. Illustratively, the alkali solution is an aqueous solution of sodium hydroxide.
In the present invention, since the aqueous phase obtained in the washing step contains the benzoic acid compound as a reaction by-product, the aqueous phases obtained in the washing step are combined, extracted with benzene (for example, extracted 1 time, 2 times, or 3 times), and then the organic phase is subjected to atmospheric distillation and/or vacuum distillation to recover benzene, and the obtained solid residue is the benzoic acid compound as a reaction by-product, which is used as a reaction raw material for the further production of the benzophenone derivative.
Preferably, the temperature of the mixing is 75-85 ℃, such as 76 ℃, 77 ℃, 78 ℃, 79 ℃, 80 ℃, 81 ℃, 82 ℃, 83 ℃ or 84 ℃.
Preferably, the method for removing the solvent comprises normal pressure desolventizing and/or reduced pressure desolventizing.
Preferably, the temperature of the desolventizing agent is 85-100 ℃, such as 86 ℃, 88 ℃, 90 ℃, 92 ℃, 94 ℃, 96 ℃, 98 ℃ or 99 ℃ and the like.
Preferably, the pressure for decompression and desolventization is 1000-1500 Pa, such as 1050Pa, 1100Pa, 1150Pa, 1200Pa, 1250Pa, 1300Pa, 1350Pa, 1400Pa or 1450 Pa.
Preferably, the preparation method further comprises rectification of the crude product.
Preferably, the conditions for receiving the fraction during rectification are 140-150 ℃ (such as 141 ℃, 142 ℃, 143 ℃, 144 ℃, 145 ℃, 146 ℃, 147 ℃, 148 ℃ or 149 ℃ and the like), and the pressure is lower than 500 Pa.
Preferably, the preparation method specifically comprises the following steps: benzoic acid compound shown as formula I, trichlorotoluene compound shown as formula II and benzene compound shown as formula III in Fe2O3Reacting for 4-8 hours at 120-165 ℃ and 0.18-0.80 MPa to generate benzophenone derivatives and HCl, wherein the HCl is discharged out of the reaction device through a condensation circulating device and absorbed by water in the reaction process, and the reaction end point is reached when no HCl gas is discharged from the reaction device; washing, removing the solvent and rectifying the obtained reaction product to obtain the benzophenone derivative.
Wherein, the Fe2O3The molar ratio of the benzoic acid compound to the benzoic acid compound is (0.08-0.2): 1, the molar ratio of the benzoic acid compound to the trichlorotoluene compound is 1 (1-2), and the molar ratio of the benzoic acid compound to the benzene compound is 1 (5-10).
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention provides a preparation method of benzophenone derivatives by using metal oxide Fe2O3As catalyst, Fe2O3The water-air separator is stable to water and air, can not decompose corrosive toxic gas, is convenient to store and use, effectively avoids corrosion of production materials to equipment, remarkably reduces negative effects on field operators and the environment, and is more environment-friendly.
(2) The invention isThe preparation method takes benzoic acid compounds, trichlorotoluene compounds and benzene compounds as raw materials, and uses Fe2O3The target product can be obtained through one-step reaction under the catalysis of the (C), the reaction condition is mild, the preparation process is simple, and the equipment investment, energy consumption, labor cost and the like required by production are reduced.
(3) The main byproduct benzoic acid compound generated in the preparation method provided by the invention can be recovered by washing, extracting and desolventizing in the post-treatment process, and then is used as a reaction raw material for preparing the benzophenone derivative again, so that the wastewater treatment cost is reduced, and the resource is fully utilized.
(4) According to the preparation method, through the design and optimization of the initial raw materials, the catalyst and the process route, the conversion rate of the raw materials is improved, the byproducts are reduced, the yield of the benzophenone derivative can reach 94-97%, and the purity can reach more than 98.5%. In the preparation method provided by the invention, the raw materials and the catalyst have low cost and high utilization rate; the catalyst has high stability, can not cause corrosion of storage equipment, can not bring negative effects to operators and environment, has high yield and purity of products and less industrial three wastes, is a green and environment-friendly preparation method with low cost, and is suitable for large-scale industrial production.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
In the following examples of the present invention, starting materials p-fluorobenzoic acid, p-methoxybenzoic acid, p-chlorobenzoic acid, benzoic acid, p-fluorotrichlorotoluene, p-methoxytrichlorotoluene, p-chlorotrichlorotoluene, trichlorotoluene, fluorobenzene, anisole, chlorobenzene, benzene, and 1,3, 5-trimethylbenzene were obtained from the market.
The method for calculating the yield of the benzophenone derivative comprises the following steps: the yield is equal to the product benzophenone derivative molar amount/(the raw material benzoic acid compound molar amount + the raw material trichlorotoluene compound molar amount-the recovered benzoic acid compound molar amount) × 100%; the purity of the product was determined by high performance liquid chromatography (HPLC, LC-20AT, Shimadzu, Japan) external standard method.
Example 1
This example provides a method for preparing 4,4' -difluorobenzophenone, which comprises the following reaction formula:
the method comprises the following specific steps:
fluorobenzene (10.316mol), p-fluorobenzoic acid (1.338mol) and Fe were mixed under stirring2O3(0.138mol) and p-fluorotrichlorotoluene (1.582mol) are sequentially added into a reaction kettle, jacket steam is used for heating, after the p-fluorotrichlorotoluene is added, the mixture is stirred and reacted for 6 hours at 150 ℃ and 0.4MPa until no hydrogen chloride gas is discharged, and the reaction end point is reached; in the reaction process, the discharged gas is recovered by a water circulation condensing system, wherein the organic components are pressed back to the reaction kettle again, and the discharged hydrogen chloride gas is absorbed by water to prepare 30 percent industrial hydrochloric acid. Obtaining brown reaction mixed liquid after the reaction is finished, carrying out filter pressing and washing on the brown reaction mixed liquid, desolventizing the obtained organic layer at 90 ℃ under normal pressure and reduced pressure (the pressure is 1200Pa) to recover fluorobenzene, and obtaining a crude product of 4,4' -difluorobenzophenone; and (3) placing the crude product of the 4,4 '-difluorobenzophenone in a rectifying still, heating and carrying out vacuum rectification, and collecting fractions at the temperature of 140-150 ℃ when the pressure is less than 500Pa to obtain 554.2g of purified 4,4' -difluorobenzophenone, wherein the purity is 98.9% and the yield is 95.4%.
And (3) recovering a byproduct p-fluorobenzoic acid: combining the water phases obtained by washing, extracting and layering by using benzene (150mL multiplied by 2 times), collecting the combined organic phases, and distilling and recovering the benzene under normal pressure and reduced pressure to obtain 8.9g of solid residue, namely 8.9g of recovered p-fluorobenzoic acid, wherein the content of the p-fluorobenzoic acid is 98.2% by HPLC (high performance liquid chromatography) quantitative determination; the recovered p-fluorobenzoic acid is used as a starting material for preparing 4,4' -difluorobenzophenone.
Example 2
This example provides a method for preparing 4,4' -dimethoxy benzophenone, which comprises the following reaction formula:
the method comprises the following specific steps:
anisole (10.316mol), p-methoxybenzoic acid (1.338mol), Fe were mixed under stirring2O3(0.138mol) and p-methoxytrichlorotoluene (1.582mol) are sequentially added into a reaction kettle, jacket steam is used for heating, after the p-methoxytrichlorotoluene is added, the reaction is stirred for 6 hours at 155 ℃ and 0.5MPa until no hydrogen chloride gas is discharged, and the reaction end point is reached; in the reaction process, the discharged gas is recovered by a water circulation condensing system, wherein the organic components are pressed back to the reaction kettle again, and the discharged hydrogen chloride gas is absorbed by water to prepare 30 percent industrial hydrochloric acid. Obtaining brown reaction mixed liquid after the reaction is finished, carrying out filter pressing and washing on the brown reaction mixed liquid, desolventizing the obtained organic layer at the temperature of 95 ℃ under normal pressure and reduced pressure (the pressure is 1300Pa) to recover anisole, and obtaining a crude product of 4,4' -dimethoxy benzophenone; and (3) placing the crude product of the 4,4 '-dimethoxy benzophenone in a rectifying still, heating and carrying out vacuum rectification, and collecting fractions at the temperature of 140-150 ℃ when the pressure is less than 500Pa to obtain 625.5g of purified 4,4' -dimethoxy benzophenone, wherein the purity is 99.11% and the yield is 96.6%.
And (3) recovering a byproduct p-methoxybenzoic acid: combining the water phases obtained in the washing, extracting and layering the water phases by using benzene (150mL multiplied by 2 times), collecting the combined organic phases, and distilling and recovering the benzene under normal pressure and reduced pressure to obtain 10.2g of solid residue, namely the mass of the recovered p-anisic acid is 10.2g, and the content of the p-anisic acid is 98.2% by HPLC quantitative determination; the recovered p-methoxybenzoic acid is used as a starting material for preparing 4,4' -dimethoxy benzophenone.
Example 3
This example provides a method for preparing 4,4' -dichlorobenzophenone, which comprises the following reaction formula:
the method comprises the following specific steps:
chlorobenzene (10.316mol), p-chlorobenzoic acid (1.338mol), Fe were mixed under stirring2O3(0.138mol) and p-chlorotrifluoromethane (1.582mol) are sequentially added into a reaction kettle, are heated by jacket steam, and are stirred and react for 7 hours at 145 ℃ and 0.6MPa after the p-chlorotrifluoromethane is added until no hydrogen chloride gas is discharged to reach the reaction end point; in the reaction process, the discharged gas is recovered by a water circulation condensing system, wherein the organic components are pressed back to the reaction kettle again, and the discharged hydrogen chloride gas is absorbed by water to prepare 30 percent industrial hydrochloric acid. Obtaining brown reaction mixed liquid after the reaction is finished, carrying out filter pressing and washing on the brown reaction mixed liquid, desolventizing the obtained organic layer at 85 ℃ under normal pressure and reduced pressure (the pressure is 1000Pa) to recover chlorobenzene, and obtaining a crude product of 4,4' -dichlorobenzophenone; and (3) placing the crude product of 4,4 '-dichlorobenzophenone in a rectifying still, heating and carrying out vacuum rectification, and collecting fractions at the temperature of 140-150 ℃ when the pressure is less than 500Pa to obtain 642.8g of purified 4,4' -dichlorobenzophenone, wherein the purity is 98.42% and the yield is 95.7%.
And (3) recovering a byproduct p-chlorobenzoic acid: combining the water phases obtained by washing, extracting and layering by using benzene (150mL multiplied by 2 times), collecting the combined organic phases, and recovering the benzene by normal-pressure and reduced-pressure distillation to obtain 9.5g of solid residue, namely 9.5g of recovered p-chlorobenzoic acid, wherein the content of the p-chlorobenzoic acid is 97.9% by HPLC quantitative determination; the recovered p-chlorobenzoic acid is used as a starting material for preparing 4,4' -dichlorobenzophenone.
Example 4
This example provides a method for preparing 4-methoxybenzophenone, which has the following reaction formula:
the method comprises the following specific steps:
benzene (10.316mol), p-methoxybenzoic acid (1.338mol), Fe were mixed under stirring2O3(0.138mol) and p-methoxytrichlorotoluene (1.582mol) are added into a reaction kettle in sequence, the mixture is heated by jacket steam, and the p-methoxytrichlorotoluene is added at the temperature of 160 ℃ and the temperature of 0.2MPa, stirring and reacting for 4.5 hours until no hydrogen chloride gas is discharged, and reaching the end point of the reaction; in the reaction process, the discharged gas is recovered by a water circulation condensing system, wherein the organic components are pressed back to the reaction kettle again, and the discharged hydrogen chloride gas is absorbed by water to prepare 30 percent industrial hydrochloric acid. Obtaining brown reaction mixed liquid after the reaction is finished, carrying out filter pressing and washing on the brown reaction mixed liquid, desolventizing the obtained organic layer at 100 ℃ under normal pressure and reduced pressure (the pressure is 1000Pa) to recover benzene, and obtaining a crude product of the 4-methoxybenzophenone; and (3) placing the crude product of the 4-methoxybenzophenone into a rectifying still, heating and carrying out vacuum rectification, and collecting fractions at the temperature of 140-150 ℃ when the pressure is less than 500Pa to obtain 548.5g of purified 4-methoxybenzophenone, wherein the purity is 99.22% and the yield is 96.7%.
And (3) recovering a byproduct p-methoxybenzoic acid: combining the water phases generated by washing, extracting and layering by using benzene (150mL multiplied by 2 times), collecting the combined organic phases, and distilling and recovering the benzene under normal pressure and reduced pressure to obtain 10.1g of solid residue, namely the mass of recovered p-anisic acid is 10.1g, and the content of the p-anisic acid is 98.2% by HPLC quantitative determination; the recovered p-methoxybenzoic acid is used as a starting material for preparing 4-methoxybenzophenone.
Example 5
This example provides a method for preparing 2,4, 6-trimethylbenzophenone, which has the following reaction formula:
the method comprises the following specific steps:
1,3, 5-trimethylbenzene (10.316mol), benzoic acid (1.338mol) and Fe were mixed under stirring2O3(0.138mol) and trichlorotoluene (1.582mol) are sequentially added into a reaction kettle, jacket steam is used for heating, after the trichlorotoluene is added, the reaction is stirred for 8 hours at 125 ℃ and 0.18MPa until no hydrogen chloride gas is discharged, and the reaction end point is reached; in the reaction process, the discharged gas is recovered by a water circulation condensing system, wherein the organic components are pressed back to the reaction kettle again, and the discharged hydrogen chloride gas is absorbed by water to prepare 30 percent industrial hydrochloric acid. After the reaction is finished, brown reaction mixture is obtainedMixing the solution, performing filter pressing and washing on the brown reaction mixed solution, desolventizing the obtained organic layer at 85 ℃ under normal pressure and reduced pressure (the pressure is 1000Pa) to recover 1,3, 5-trimethylbenzene to obtain a crude product of 2,4, 6-trimethylbenzophenone; and (3) placing the crude product 2,4, 6-trimethylbenzophenone in a rectifying still, heating and carrying out vacuum rectification, and collecting fractions at the temperature of 140-150 ℃ when the pressure is less than 500Pa to obtain 568.8g of purified 2,4, 6-trimethylbenzophenone, wherein the purity is 98.53 percent, and the yield is 94.9 percent.
Recovery of by-product benzoic acid: mixing the water phases obtained by washing, extracting and layering by using benzene (150mL multiplied by 2 times), collecting the combined organic phases, and distilling and recovering the benzene under normal pressure and reduced pressure to obtain 9.7g of solid residue, namely 9.7g of recovered p-anisic acid, wherein the content of the benzoic acid is 98.5% by HPLC quantitative determination; the recovered benzoic acid is used as a starting material for the preparation of 2,4, 6-trimethylbenzophenone.
Example 6
This example provides a method for preparing 4-chlorobenzophenone, which has the following reaction formula:
the method comprises the following specific steps:
benzene (13.3mol), p-chlorobenzoic acid (1.338mol), Fe were mixed under stirring2O3(0.12mol) and p-chlorotrifluoromethane (1.472mol) are sequentially added into a reaction kettle, are heated by jacket steam, are stirred and react for 8 hours at 120 ℃ and 0.2MPa after being added until no hydrogen chloride gas is discharged, and reach the reaction end point; in the reaction process, the discharged gas is recovered by a water circulation condensing system, wherein the organic components are pressed back to the reaction kettle again, and the discharged hydrogen chloride gas is absorbed by water to prepare 30 percent industrial hydrochloric acid. Obtaining brown reaction mixed liquid after the reaction is finished, carrying out filter pressing and washing on the brown reaction mixed liquid, desolventizing the obtained organic layer at 85 ℃ under normal pressure and reduced pressure (the pressure is 1000Pa) to recover chlorobenzene, and obtaining a crude product of 4-chlorobenzophenone; placing the crude product of 4-chlorobenzophenone in a rectifying still, heating and carrying out vacuum rectification, and collecting the mixture at the temperature of 140-150 ℃ when the pressure is less than 500PaAs a result, 544.6g of purified 4-chlorobenzophenone was obtained in 98.42% purity and 94.1% yield.
And (3) recovering a byproduct p-chlorobenzoic acid: combining the water phases generated by washing, extracting and layering by using benzene (150mL multiplied by 2 times), collecting the combined organic phases, and recovering the benzene by normal-pressure and reduced-pressure distillation to obtain 10.7g of solid residue, namely the mass of the recovered p-chlorobenzoic acid is 10.7g, and the content of the p-chlorobenzoic acid is 98.3% by HPLC quantitative determination; the recovered p-chlorobenzoic acid is used as a starting material for the preparation of 4-chlorobenzophenone.
Example 7
This example provides a method for preparing 2-fluorobenzophenone, which has the following reaction formula:
the method comprises the following specific steps:
benzene (6.7mol), o-fluorobenzoic acid (1.338mol) and Fe were added under stirring2O3(0.26mol) and o-fluorotrichlorotoluene (2.65mol) are sequentially added into a reaction kettle, are heated by jacket steam, are stirred and react for 4 hours at 165 ℃ and 0.8MPa after the o-fluorotrichlorotoluene is added until no hydrogen chloride gas is discharged, and reach the reaction end point; in the reaction process, the discharged gas is recovered by a water circulation condensing system, wherein the organic components are pressed back to the reaction kettle again, and the discharged hydrogen chloride gas is absorbed by water to prepare 30 percent industrial hydrochloric acid. Obtaining brown reaction mixed liquid after the reaction is finished, carrying out filter pressing and washing on the brown reaction mixed liquid, desolventizing the obtained organic layer at the temperature of 95 ℃ under normal pressure and reduced pressure (the pressure is 1500Pa) to recover chlorobenzene, and obtaining a crude product of 2-fluorobenzophenone; and (3) placing the crude product of the 2-fluorobenzophenone into a rectifying still, heating and carrying out vacuum rectification, and collecting fractions at the temperature of 140-150 ℃ when the pressure is less than 500Pa to obtain 508.4g of the purified 2-fluorobenzophenone, wherein the purity is 98.77%, and the yield is 95.2%.
And (3) recovering a by-product o-fluorobenzoic acid: combining the water phases obtained by washing, extracting and layering by using benzene (150mL multiplied by 2 times), collecting the combined organic phases, and distilling and recovering the benzene under normal pressure and reduced pressure to obtain 10.4g of solid residue, namely the mass of the recovered o-fluorobenzoic acid is 10.4g, and the content of the o-fluorobenzoic acid is 97.7% by HPLC (high performance liquid chromatography) quantitative determination; the recovered o-fluorobenzoic acid is used as a starting material for preparing 2-fluorobenzophenone.
The applicant states that the present invention is illustrated by the above examples to provide a preparation method of benzophenone derivatives, but the present invention is not limited to the above examples, i.e. it does not mean that the present invention must be implemented by the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. A preparation method of a benzophenone derivative is characterized by comprising the following steps: benzoic acid compound shown as formula I, trichlorotoluene compound shown as formula II and benzene compound shown as formula III in Fe2O3To obtain the benzophenone derivative, wherein the reaction formula is as follows:
wherein R is1、R2Each independently selected from any one of halogen, hydroxyl, nitro, amino, substituted or unsubstituted C1-C10 straight chain or branched chain alkyl, substituted or unsubstituted C1-C10 alkoxy, and substituted or unsubstituted C6-C30 aromatic hydrocarbon;
n and m are each independently an integer of 0-5, and n + m is not less than 1.
2. The method of claim 1, wherein the Fe is2O3The molar ratio of the benzoic acid compound to the benzoic acid compound is (0.08-0.2): 1, and preferably (0.1-0.15): 1.
3. The production method according to claim 1 or 2, wherein the molar ratio of the benzoic acid-based compound to the trichlorotoluene-based compound is 1 (1 to 2), preferably 1 (1.1 to 1.7);
preferably, the molar ratio of the benzoic acid compound to the benzene compound is 1 (5-10), and more preferably 1 (7-8).
4. The method according to any one of claims 1 to 3, wherein the reaction temperature is 120 to 165 ℃;
preferably, the reaction time is 4-8 h;
preferably, the pressure of the reaction is 0.18-0.80 MPa.
5. The method according to any one of claims 1 to 4, wherein the halogen comprises fluorine, chlorine, bromine or iodine;
preferably, the substituent of the substituted alkyl, the substituted alkoxy and the substituted aromatic hydrocarbon group is selected from at least one of halogen, hydroxyl, nitro or amino;
preferably, said R is1、R2Each independently selected from any one of halogen, hydroxyl, C1-C5 straight chain or branched chain alkyl and C1-C5 alkoxy;
preferably, n and m are each independently an integer of 0-3, and n + m is not less than 1.
6. The preparation method according to any one of claims 1 to 5, wherein HCl generated in the reaction is discharged out of the reaction device through a condensation circulating device during the reaction;
preferably, the HCl is discharged from the reaction device and then absorbed by water;
preferably, the method for judging the end point of the reaction is as follows: no HCl gas was vented from the reactor.
7. The production method according to any one of claims 1 to 6, characterized by further comprising a post-treatment step;
preferably, the post-treatment step comprises washing and removal of the solvent.
8. The production method according to claim 7, wherein the washing is selected from any one of acid washing, water washing, or alkali washing or a combination of at least two of them;
preferably, the pickling method comprises the following steps: stirring and mixing the reaction product with acid liquor, then standing and layering, and retaining an organic phase;
preferably, the mixing temperature is 50-80 ℃;
preferably, the concentration of the acid liquor is 3-10%;
preferably, the alkali washing method comprises the following steps: stirring and mixing the reaction product with alkali liquor, standing and layering, and keeping an organic phase;
preferably, the concentration of the alkali liquor is 1-5%;
preferably, the mixing temperature is 75-85 ℃;
preferably, the method for removing the solvent comprises normal pressure desolventizing and/or reduced pressure desolventizing;
preferably, the temperature of the solvent removal is 85-100 ℃;
preferably, the pressure for decompression desolventizing is 1000-1500 Pa.
9. The production method according to any one of claims 1 to 7, characterized by further comprising rectification of the crude product;
preferably, the condition of receiving the fraction during rectification is 140-150 ℃ and the pressure is lower than 500 Pa.
10. The preparation method according to any one of claims 1 to 9, which is specifically characterized by: benzoic acid compound shown as formula I, trichlorotoluene compound shown as formula II and benzene compound shown as formula III in Fe2O3Reacting for 4-8 h at 120-165 ℃ and 0.18-0.80 MPa to generate benzophenone derivatives and HCl, wherein the HCl is discharged out of the reaction device through a condensation circulating device and absorbed by water in the reaction process, and the HCl is discharged when no HCl gas is discharged from the reaction deviceReaching the reaction end point; washing, removing the solvent and rectifying the obtained reaction product to obtain the benzophenone derivative;
wherein, the Fe2O3The molar ratio of the benzoic acid compound to the benzoic acid compound is (0.08-0.2): 1, the molar ratio of the benzoic acid compound to the trichlorotoluene compound is 1 (1-2), and the molar ratio of the benzoic acid compound to the benzene compound is 1 (5-10).
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| CN115925525A (en) * | 2022-11-28 | 2023-04-07 | 湖北省宏源药业科技股份有限公司 | Synthetic method of 4,4' -difluorobenzophenone |
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| JP2009001506A (en) * | 2007-06-19 | 2009-01-08 | Sankyo Kasei Kk | Production method of trihydroxybenzophenone |
| CN104610036A (en) * | 2015-01-30 | 2015-05-13 | 江苏省海洋资源开发研究院(连云港) | Method for preparing p-chlorodiphenyl ketone |
| CN105272839A (en) * | 2015-10-23 | 2016-01-27 | 上虞佳英化工有限公司 | Synthesis method of diphenyl ketone |
| CN107501087A (en) * | 2017-09-27 | 2017-12-22 | 南通利奥化工科技有限公司 | A kind of production method of dichlorobenzoyl chloride coproduction chlorobenzoyl chloride and trichloro-benzenes |
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| JP2009001506A (en) * | 2007-06-19 | 2009-01-08 | Sankyo Kasei Kk | Production method of trihydroxybenzophenone |
| CN104610036A (en) * | 2015-01-30 | 2015-05-13 | 江苏省海洋资源开发研究院(连云港) | Method for preparing p-chlorodiphenyl ketone |
| CN105272839A (en) * | 2015-10-23 | 2016-01-27 | 上虞佳英化工有限公司 | Synthesis method of diphenyl ketone |
| CN107501087A (en) * | 2017-09-27 | 2017-12-22 | 南通利奥化工科技有限公司 | A kind of production method of dichlorobenzoyl chloride coproduction chlorobenzoyl chloride and trichloro-benzenes |
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| CN115925525A (en) * | 2022-11-28 | 2023-04-07 | 湖北省宏源药业科技股份有限公司 | Synthetic method of 4,4' -difluorobenzophenone |
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