CN111689847B - Preparation method of aryl propionic acid compound - Google Patents
Preparation method of aryl propionic acid compound Download PDFInfo
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Abstract
The invention provides a preparation method of an aryl propionic acid compound, which comprises the following steps: performing acetylation reaction on the substituted aryl benzene to obtain aryl acetophenone; carrying out hydrogenation reduction reaction on the alpha-substituted aryl ethanone to obtain alpha-substituted aryl ethanol; and in an acid solution, introducing carbon monoxide gas into the alpha-substituted aryl ethanol, and carrying out carbonylation reaction under the combined catalysis of a main catalyst and a cocatalyst to obtain the aryl propionic acid compound, wherein the cocatalyst has the following structural formula:
R1is one of hydrogen and substituted carboxylic acid group; r2Is hydrogen, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstitutedOne of substituted C3-C12 cycloalkyl, substituted carbonyl containing C6-C24 aryl or substituted aryl, substituted carbonyl containing C3-C12 heterocyclic group or substituted heterocyclic group, phenyl, substituted phenyl, naphthyl and substituted naphthyl.
Description
Technical Field
The invention relates to the field of synthesis of aryl propionic acid compounds, in particular to a preparation method of an aryl propionic acid compound.
Background
Compared with the traditional antipyretic analgesic aspirin and the like, the aryl propionic acid nonsteroidal anti-inflammatory analgesic has excellent antipyretic analgesic and anti-inflammatory effects, obvious curative effect and small side effect, and is rapidly developed and applied in recent years. Ibuprofen is used as an important variety and is widely applied to treating rheumatic arthritis, rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. Ibuprofen can be prepared by a three-step catalytic process, as shown in process (1) of the following formula:
the method has the characteristics of simple synthesis, no need of using a large amount of solvents, avoidance of generation of a large amount of three wastes and environmental friendliness. In the method, the key step is the synthesis of ibuprofen (English abbreviation: IBU) by carbonylation of 4-isobutylphenethyl alcohol (English abbreviation: IBPE). However, in this carbonylation reaction, 3- [4- (2-methylpropyl) phenyl ] as a linear isomer as an impurity may be formed as shown in the process (2)]Propionic acid (English abbreviation: 3-IPPA), the content of which is usually > 1%, is a problem in carbonylation selectivity. The impurity 3-IPPA is difficult to separate by the conventional method because of the similar property with ibuprofen. Therefore, how to reduce the content of the impurity linear chain isomer in the carbonylation reaction process and improve the reaction selectivity becomes difficult problems. On the other hand, the method uses expensive goldThe palladium is used as a carbonylation catalyst, and the conversion frequency TOF value is low, and is usually 300h-1-2000h-1The key to the successful industrialization of the carbonylation route is to improve the conversion efficiency and reduce the cost of the catalyst.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of an aryl propionic acid compound, which can improve the reaction selectivity and conversion efficiency of a target product.
The invention provides a preparation method of an aryl propionic acid compound, which comprises the following steps:
providing substituted aryl benzene, and performing acetylation reaction on the substituted aryl benzene to obtain aryl acetophenone; carrying out hydrogenation reduction reaction on the alpha-substituted aryl ethanone to obtain alpha-substituted aryl ethanol; and
introducing carbon monoxide gas into the alpha-substituted aryl ethanol in an acid solution, carrying out carbonylation reaction under the combined catalysis of a main catalyst and a cocatalyst to obtain an aryl propionic acid compound,
wherein the structural formula of the cocatalyst is as follows:
R1is one of hydrogen and substituted carboxylic acid group, and the substituted carboxylic acid group is one of acetoxy, propionyloxy, aryl propionyloxy and substituted aryl propionyloxy; r2Is one of hydrogen, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, substituted carbonyl containing C6-C24 aryl or substituted aryl, substituted carbonyl containing C3-C12 heterocyclic group or substituted heterocyclic group, phenyl, substituted phenyl, naphthyl and substituted naphthyl; ar is one of phenyl, substituted phenyl, naphthyl and substituted naphthyl,
wherein, when Ar is phenyl or substituted phenyl, R2Is at least one of ortho, meta and para substitution; when Ar is naphthyl or substituted naphthyl, R2Is C-5,6,7,8 positionAt least one of substitution.
The structural formula of the aryl propionic acid compound is as follows:
r is one of hydrogen, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, substituted carbonyl containing C6-C24 aryl or substituted aryl, substituted carbonyl containing C3-C12 heterocyclic group or substituted heterocyclic group, phenyl, substituted phenyl, naphthyl and substituted naphthyl. Ar is one of phenyl, substituted phenyl, naphthyl and substituted naphthyl. When Ar is phenyl or substituted phenyl, R is at least one of ortho-substitution, meta-substitution and para-substitution; when Ar is naphthyl or substituted naphthyl, R is at least one of C-5,6,7 and 8 position substitution.
In some embodiments, R is one of C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, substituted carbonyl containing C6-C12 aryl, substituted carbonyl containing C3-C6 heterocyclyl; h on the C1-C6 alkyl is not substituted or is substituted by more than 1 substituent A, and the substituent A is at least one of cyclopentanone and cyclohexanone; the heterocyclic group is at least one of furyl, pyrrolyl and thienyl.
In some embodiments, the arylpropionic acid compound comprises ibuprofen, naproxen, loxoprofen, ketoprofen, and suprofen, which have the following specific structural formulas:
in some embodiments, the cocatalyst has the following structural formula:
wherein R is3Is hydrogen, halogen, substituted orOne of unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, substituted carbonyl containing C6-C24 aryl or substituted aryl, substituted carbonyl containing C3-C12 heterocyclic group or substituted heterocyclic group, phenyl, substituted phenyl, naphthyl and substituted naphthyl. Ar is one of phenyl, substituted phenyl, naphthyl and substituted naphthyl. When Ar is phenyl or substituted phenyl, R3Is at least one of ortho, meta and para substitution; when Ar is naphthyl or substituted naphthyl, R3Is at least one of C-5,6,7,8 position substitution.
In some embodiments, R, R2And R3The same is true.
In some embodiments, the molar ratio of the co-catalyst to the procatalyst is from 1:10 to 1: 20.
In some embodiments, the procatalyst consists of palladium or a palladium compound that is at least one of palladium dichloride, palladium nitrate, palladium acetate, and palladium sulfate and a ligand that is a monodentate phosphine ligand.
In some embodiments, the monodentate phosphine ligand is triphenylphosphine, tri-p-tolylphosphine, diphenylbenzylphosphine, bis (diphenylphosphino) methane, 1, 2-bis (diphenylphosphino) ethane, diphenylcyclohexylphosphine, dicycloalkylarylphosphine, phenyldi (o-tolyl) phosphine, phenyldi (m-tolyl) phosphine, phenyldi (p-tolyl) phosphine, diphenyl (o-tolyl) phosphine, diphenyl (m-tolyl) phosphine, at least one of diphenyl (p-tolyl) phosphine, tri (o-tolyl) phosphine, tri (m-tolyl) phosphine, tri (p-tolyl) phosphine, phenyldibenzylphosphine, diphenylbenzylphosphine, tribenzylphosphine, phenyldinaphthylphosphine, diphenylnaphthylphosphine, trinaphthylphosphine, dicyclohexylbenzylphosphine, cyclohexyldibenzylphosphine, and a phosphite-based ligand.
In some embodiments, the molar ratio of Pd to the α -substituted arylethanol in the procatalyst is from 1:2000 to 1: 50000.
In some embodiments, the pressure of the carbon monoxide gas introduced into the carbonylation reaction is 1MPa to 30MPa, the reaction temperature is 20 ℃ to 150 ℃, and the conversion frequency is 2000h-1-15000h-1。
In some embodiments, the acidic solution contains hydrogen ions and halide ions, the molar ratio of the hydrogen ions to the α -substituted aryl alcohol is 0.1:1 to 2.5:1, and the molar ratio of the halide ions to the α -substituted aryl alcohol is 0.1:1 to 2.5: 1.
The preparation method of the aryl propionic acid compound has the following advantages:
in the carbonylation reaction, the added cocatalyst is due to its structural segment
And
similar to the structure of the reaction raw material alpha-substituted aryl ethanol, the solubility of the cocatalyst in the alpha-substituted aryl ethanol is far larger than that of the main catalyst (such as PdCl)2L2Wherein L is a ligand). Therefore, in the initial stage of the reaction, the cocatalyst is dissolved relatively quickly, and the active Pd (0) can be generated relatively quickly in the presence of the ligand L of the main catalyst, carbon monoxide, water and the like, so that the carbonylation reaction is promoted, and the reaction rate of the carbonylation reaction is greatly improved. Namely, the reaction selectivity of the product can be improved, and the content of the impurity linear chain isomer can be reduced. Meanwhile, the consumption of noble metal catalyst can be reduced, thereby realizing high-efficiency, high-quality and low-cost production.
The carbonylation reaction can also be applied to the following reactions:
drawings
FIG. 1 is a flow chart of the preparation method of the aryl propionic acid compound.
FIG. 2 is a gas chromatography detection spectrum of the carbonylation reaction solution of step S3 in example 1, wherein ibuprofen as the target product is retained at 15.90min and 3-IPPA as the impurity linear isomer is retained at 16.79 min.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Referring to fig. 1, embodiment 1 of the present invention provides a method for preparing an aryl propionic acid compound. The structural formula of the aryl propionic acid compound is as follows:
r is one of hydrogen, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, substituted carbonyl containing C6-C24 aryl or substituted aryl, substituted carbonyl containing C3-C12 heterocyclic group or substituted heterocyclic group, phenyl, substituted phenyl, naphthyl and substituted naphthyl; ar is one of phenyl, substituted phenyl, naphthyl and substituted naphthyl. When Ar is phenyl or substituted phenyl, R is at least one of ortho-substitution, meta-substitution and para-substitution; when Ar is naphthyl or substituted naphthyl, R is at least one of C-5,6,7 and 8 position substitution.
In some embodiments, the R is one of substituted or unsubstituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, unsubstituted C3-C6 cycloalkyl, substituted carbonyl containing C6-C12 aryl, substituted carbonyl containing C3-C6 heterocyclyl; the heterocyclic group is at least one of furyl, pyrrolyl and thienyl; when the R is a substituted C1-C6 alkyl, H on the C1-C6 alkyl is substituted by more than 1 substituent A, and the substituent A is at least one of cyclopentanone and cyclohexanone.
Specifically, the aryl propionic acid compound can comprise ibuprofen, naproxen, loxoprofen, ketoprofen and suprofen, and the specific structural formulas are as follows in sequence:
the preparation method of the aryl propionic acid compound comprises the following steps:
s1, providing substituted aryl benzene, and carrying out acetylation reaction on the substituted aryl benzene to obtain alpha-substituted aryl ethyl ketone;
s2, carrying out hydrogenation reduction reaction on the alpha-substituted aryl ethanone to obtain alpha-substituted aryl ethanol;
and S3, introducing carbon monoxide gas into the alpha-substituted aryl ethanol in an acidic solution, and carrying out carbonylation reaction under the combined catalytic action of a main catalyst and a cocatalyst to obtain the aryl propionic acid compound.
In step S1, the course of the acetylation reaction can be represented by the following reaction formula:
preferably, the compound is one of hydrogen, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, substituted carbonyl containing C6-C24 aryl or substituted aryl, substituted carbonyl containing C3-C12 heterocyclic group or substituted heterocyclic group, phenyl, substituted phenyl, naphthyl and substituted naphthyl; ar is one of phenyl, substituted phenyl, naphthyl and substituted naphthyl.
The first catalyst may be a catalyst used in the Friedel-Crafts reaction, such as a conventional Lewis acid, e.g., aluminum chloride, zinc chloride, boron trifluoride, bromine trifluoride, etc., or hydrogen fluoride, sulfuric acid, trifluoromethanesulfonic acid, etc., and may also be a solid super acid, a strongly acidic resin, a zeolite with acidic sites, or a molecular sieve.
The acetylating agent may be acetic acid, acetic anhydride, acetyl fluoride, acetyl chloride, acetyl bromide, methyl acetate, ketene, and the like.
The ratio of the molar amount of the acetylating agent to the molar amount of the substituted aryl benzene may be: 1:1 to 4:1, preferably 1.05:1 to 2.5: 1. The ratio of the molar amount of the first catalyst to the molar amount of the substituted aryl benzene may be: 1.2:1-1.5:1.
In the acetylation reaction, the reaction temperature is 70-30 ℃ below zero, and preferably 20-0 ℃ below zero. The reaction time is 0.5 to 10 hours, preferably 2 to 6 hours.
The selectivity of the aryl acetophenone in the acetylation reaction is 95-99%.
When acetyl chloride is used as the acylating agent and aluminum chloride is used as the first catalyst, the raw materials are generally prepared and reacted at a molar ratio of substituted arylbenzene, acetyl chloride and aluminum chloride of 1:1.05 to 1.2:1.2 to 1.5 at a temperature of from 70 ℃ to 30 ℃ below zero, preferably from 20 ℃ to 0 ℃ below zero. The reaction time is 0.5 to 10 hours, preferably 2 to 6 hours.
In step S2, the process of the hydrogenation reduction reaction can be represented by the following reaction formula:
the hydrogenation reduction reaction may be carried out by contacting hydrogen with a second catalyst; reduction may also be achieved by using a hydrogenation reagent containing available hydrogen. The second catalyst comprises a transition metal catalyst loaded by a carrier, wherein the transition metal can be nickel, palladium, platinum, rhodium, iridium, ruthenium and the like, and the carrier can be activated carbon, alumina, polymer resin, molecular sieve and the like, and can also be raney nickel. The loading ratio of the transition metal on the carrier (i.e., the mass ratio of the transition metal to the carrier) may be 1% to 50%, preferably 1% to 10%. The mass ratio of the second catalyst to the alpha-substituted arylethanone may be from 0.5% to 50%, preferably from 1% to 20%.
The hydrogenation reaction can use a solvent or not, and if the solvent is used, the solvent can be selected from methanol, ethanol, isopropanol, tert-butanol, aqueous methanol, aqueous ethanol, toluene, diethyl ether, tetrahydrofuran and the like. The mass ratio of the alpha-substituted arylethanone to the solvent can be 1:0.1-1:100, preferably 1:0.5-1: 5. In the hydrogenation reduction reaction, the partial pressure of the introduced hydrogen is 0.1MPa-10MPa, and preferably 0.5MPa-3.0 MPa.
The reaction temperature of the hydrogenation reduction reaction is 0-150 ℃, and preferably 20-80 ℃. The reaction time is 0.5 to 10 hours, preferably 1 to 6 hours.
In some embodiments, a base, such as sodium hydroxide solution, may also be added during the reaction of the hydrogenation reduction reaction to inhibit further hydrogenolysis of the product α -substituted aryl ethanol.
In step S3, the course of the carbonylation reaction can be represented by the following reaction formula:
the structural formula of the cocatalyst is as follows:
R1is one of hydrogen and substituted carboxylic acid group, and the substituted carboxylic acid group is one of acetoxy, propionyloxy, aryl propionyloxy and substituted aryl propionyloxy; r is2Is one of hydrogen, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, substituted carbonyl containing C6-C24 aryl or substituted aryl, substituted carbonyl containing C3-C12 heterocyclic group or substituted heterocyclic group, phenyl, substituted phenyl, naphthyl and substituted naphthyl; ar is one of phenyl, substituted phenyl, naphthyl and substituted naphthyl,
wherein, when Ar is phenyl or substituted phenyl, R1Is at least one of ortho, meta and para substitution; when Ar is naphthyl or substituted naphthyl, R1Is at least one of C-5,6,7,8 substituted.
Further, the structural formula of the cocatalyst is as follows:
wherein R is3Is one of hydrogen, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, substituted carbonyl containing C6-C24 aryl or substituted aryl, substituted carbonyl containing C3-C12 heterocyclic group or substituted heterocyclic group, phenyl, substituted phenyl, naphthyl and substituted naphthyl. Ar is one of phenyl, substituted phenyl, naphthyl and substituted naphthyl. When Ar is phenyl or substituted phenyl, R3Is at least one of ortho, meta and para substitution; when Ar is naphthyl or substituted naphthyl, R3Is at least one of C-5,6,7,8 position substitution.
In some embodiments, R, R2And R3The same is true.
The main catalyst consists of palladium or a palladium compound and a ligand L, wherein the palladium compound is at least one of palladium dichloride, palladium nitrate, palladium acetate and palladium sulfate, and the ligand L can be a monodentate phosphine ligand.
The monodentate phosphine ligand is triphenylphosphine, tri-p-tolylphosphine, diphenylbenzylphosphine, bis (diphenylphosphino) methane, 1, 2-bis (diphenylphosphino) ethane, diphenylcyclohexylphosphine, dicycloalkylarylphosphine, phenyldi (o-tolyl) phosphine, phenyldi (m-tolyl) phosphine, phenyldi (p-tolyl) phosphine, diphenyl (o-tolyl) phosphine, diphenyl (m-tolyl) phosphine, at least one of diphenyl (p-tolyl) phosphine, tri (o-tolyl) phosphine, tri (m-tolyl) phosphine, tri (p-tolyl) phosphine, phenyldibenzylphosphine, diphenylbenzylphosphine, tribenzylphosphine, phenyldinaphthylphosphine, diphenylnaphthylphosphine, trinaphthylphosphine, dicyclohexylbenzylphosphine, cyclohexyldibenzylphosphine, and a phosphite-based ligand. Preferably, the monodentate phosphine ligand is triphenylphosphine, phenylbis (o-tolyl) phosphine, phenylbis (m-tolyl) phosphine, phenylbis (p-tolyl) phosphine, diphenyl (o-tolyl) phosphine, diphenyl (m-tolyl) phosphine, diphenyl (p-tolyl) phosphine, tri (o-tolyl) phosphine, tri (m-tolyl) phosphine, tri (p-tolyl) phosphine, diphenylbenzylphosphine, diphenylcyclohexylphosphine.
Of course, the main catalyst may be in the form of a coordination compound, or may be palladium salt and phosphine ligand which are separately added to the reaction system. If the palladium salt and the phosphine ligand are separately added into the reaction system, the amount of the added phosphine ligand is ensured to be enough to coordinate with palladium, and when the molar ratio of the alpha-substituted aryl ethanol to Pd in the palladium salt is more than 7000, the molar ratio of P in the phosphine ligand to Pd in the palladium salt is more than 2; when the molar ratio of the alpha-substituted arylethanol to Pd in the palladium salt is less than 5000, the molar ratio of P in the phosphine ligand to Pd in the palladium salt should be greater than 1.
The cocatalyst is due to its structural fragment
Similar to the structure of the reaction raw material alpha-substituted aryl ethanol, the solubility of the cocatalyst in the alpha-substituted aryl ethanol is far higher than that of the main catalyst (such as PdCl)2L2Wherein L is a ligand). Therefore, in the initial stage of the reaction, the cocatalyst is dissolved relatively quickly, and the active Pd (0) can be generated relatively quickly in the presence of the ligand L of the main catalyst, carbon monoxide, water and the like, so that the carbonylation reaction is promoted, and the reaction rate of the carbonylation reaction is greatly improved. Specifically, the process can be represented by the following reaction formula.
The molar ratio of Pd in the main catalyst to the alpha-substituted aryl ethanol is 1:2000-1:50000, and the molar ratio of the cocatalyst to Pd in the main catalyst is 1:2-1:100, preferably 1:10-1: 20.
In the carbonylation reaction, the pressure of the introduced carbon monoxide gas is 1MPa-30MPa, preferably 10MPa-20 MPa; the reaction temperature is 20-150 ℃, preferably 125-135 ℃; the reaction time is from 1 hour to 5 hours, preferably from 1 hour to 2.5 hours. The conversion frequency (English abbreviation: TOF value) is 2000h-1-15000h-1Preferably up to 10000h-1-15000h-1。
The acidic solution contains hydrogen ions and halogen ions. The molar ratio of the hydrogen ions to the alpha-substituted aryl ethanol is 0.1:1-2.5:1, and the molar ratio of the halogen ions to the alpha-substituted aryl ethanol is 0.1:1-2.5: 1.
The hydrogen ions can be derived from aqueous solutions of inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and can also be organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and the like. The halogen ion can be derived from hydrochloric acid, and halogen salt such as sodium chloride, lithium chloride, potassium chloride, sodium bromide, potassium bromide, sodium iodide, potassium iodide, etc. The molar ratio of the hydrogen ions to the alpha-substituted arylethanol is 0.1:1 to 2.5:1, preferably 0.5:1 to 1:1. The molar ratio of the halogen ions to the alpha-substituted aryl ethanol is 0.1:1-2.5:1, preferably 0.5:1-1: 1. If hydrochloric acid is used as the hydrogen ion and halide ion source, the mass concentration of hydrochloric acid may be 1% to 37%, preferably 20% to 30%, and the molar ratio of hydrochloric acid to the α -substituted arylethanol is preferably 0.5:1 to 1.3: 1.
In step S3, an organic solvent may or may not be used. In some embodiments, the organic solvent may include ketone solvents such as 2-butanone, acetone, and 2-pentanone, aromatic solvents such as benzene, toluene, and xylene, and ether solvents such as tetrahydrofuran, and preferably butanone and acetone. The mass ratio of the organic solvent to the alpha-substituted aryl alcohol is 1:1-10:1, preferably 1:1-3: 1.
The selectivity of the target product can reach 90-97%, preferably 95-96%. The content of the impurity linear chain isomer is about 0.2-1.0%, and preferably only 0.2-0.5%.
The preparation method of the aryl propionic acid compound has the following advantages:
in the carbonylation reaction, the added cocatalyst contains substituted aryl group similar to the substituted aryl benzene as the reaction raw material in structure, and the solubility of the cocatalyst in alpha-substituted aryl ethanol is far higher than that of the main catalyst (such as PdCl)2L2Wherein L is a ligand). Due to the fact thatAnd at the initial stage of the reaction, the cocatalyst is rapidly dissolved, and can generate active Pd (0) relatively quickly in the presence of ligand L, carbon monoxide, water and the like of the main catalyst, so that the carbonylation reaction is started, the reaction rate of the carbonylation reaction is greatly improved, and the addition of the cocatalyst can greatly reduce the dosage of the catalyst. On the other hand, the formation of the linear isomer is mainly affected by the catalyst (e.g., PdCl)2) The higher the amount of catalyst used, the higher the linear isomer correspondingly. The addition of the cocatalyst can improve the reaction selectivity and reduce the content of impurity linear chain isomer while reducing the dosage of the catalyst. The invention reduces noble metal catalyst (such as PdCl) by introducing cocatalyst2) The dosage, thereby realizing high-efficiency, high-quality and low-cost production.
The preparation method of the aryl propionic acid compound of the present invention will be further described by examples.
The data and effects in the embodiments of the present invention do not limit the practical application range of the technology of the present invention.
The selectivity detection means is gas chromatography, namely GC method, and the selectivity is characterized by the area normalization method content of each substance in a GC spectrogram.
Example 1
This example provides a method for preparing ibuprofen, specifically including the following steps:
(S1) performing acetylation reaction on the isobutylbenzene to obtain 4-isobutylacetophenone, which comprises the following steps:
into a dry four-necked flask were charged 293.26g of anhydrous aluminum chloride and 536.80g of methylene chloride, and 164.85g of acetyl chloride was added dropwise with stirring while controlling the temperature at < -10 ℃. After the acetyl chloride is dripped, 268.40g of isobutylbenzene (isobutylbenzene: acetyl chloride: aluminum chloride: 1:1.05:1.1) is continuously dripped, the temperature is controlled to be less than-10 ℃ in the dripping process, the dripping is finished, after the constant temperature reaction is carried out for 1h, the reaction liquid is slowly dripped into an ice-water mixture for hydrolysis. And (3) standing and layering after hydrolysis is finished, separating out an organic phase, extracting a water phase for 1-2 times by using dichloromethane, combining the dichloromethane phase and a reaction organic phase, adjusting the pH value to 6.5 by using 3% sodium bicarbonate, finally washing by using deionized water, and performing solvent recovery and reduced pressure rectification on the obtained organic phase to obtain the 4-isobutylacetophenone, wherein the content is more than 99%, and the yield is 97%.
(S2) subjecting 4-isobutylacetophenone (abbreviated as IBAP in english) to a hydrogenation reduction reaction to obtain 1- (4-isobutyl-phenyl) -ethanol (abbreviated as IBPE in english) as follows:
adding IBAP (120g, 0.68 mol), 5% Pd/C catalyst (6g, 0.00283 mol) and methanol (120 g) into a 500mL autoclave, stirring and mixing, purging and replacing the reaction kettle with nitrogen for three times, purging and replacing with hydrogen for three times, finally filling hydrogen to 1.0MPa, starting stirring, controlling the temperature to be 30 ℃ and carrying out hydrogenation reaction. In the reaction process, the conversion rate is monitored by sampling GC analysis, the IBAP conversion rate is more than 99% after about 3 hours, the selectivity is 98%, the reaction is stopped, the feed liquid is discharged, the Pd/C catalyst is recovered from the feed liquid through filtration, the obtained filtrate is subjected to reduced pressure distillation to obtain IBPE, the content is 98.5%, and the yield is 95%.
(S3) the carbonylation of IBPE gave 2- (4-isobutylphenyl) propionic acid (ibuprofen, abbreviated as IBU)
To a 500mL autoclave were added IBPE (99.39g, 0.55 mol), butanone (90g, 1.25 mol), palladium dichloride (8.8mg, 0.05 mmol), triphenylphosphine (86.4mg, 0.33 mmol), cocatalyst Z1(2.6mg, 0.005 mmol), and 60g hydrochloric acid at 24% by mass, and the reactor was purged with nitrogen three times, then with carbon monoxide three times, and finally with carbon monoxide to 12 MPa. The materials are heated to 130 ℃ under stirring, the pressure in the kettle is increased to 16MPa, and the temperature and the pressure are maintained for reaction for 2 hours until the carbon monoxide gas absorption stops. Cooling the autoclave to room temperature, decompressing to discharge carbon monoxide, discharging reaction liquid, and reacting TOF value of 5000h-1. Sampling and GC detection: the IBPE conversion rate is 99.9 percent, the IBU selectivity is 94.9 percent, and the content of the impurity linear chain isomer 3-IPPA is 0.44 percent. And (3) separating an organic layer and a water layer, extracting the water layer by using 30g of butanone, combining the organic phases, washing with water, concentrating to obtain an IBU concentrate, dissolving the concentrate by using normal hexane, and cooling and crystallizing to obtain the IBU product.
Wherein the structure of the cocatalyst (code number Z1) is as follows:
further, the carbonylation reaction liquid of step S3 was subjected to gas chromatography, and the results are shown in fig. 2. As can be seen from FIG. 2, the target product IBU selectivity is 94.9%, the impurity linear chain isomer 3-IPPA content is 0.44%, and the reaction selectivity is excellent.
Example 2 to example 11
Examples 2 to 11 in order to change the kinds and amounts of the palladium compound and the phosphine ligand in the procatalyst of step (S3), the cocatalyst and other conditions in the same manner as in example 1 based on example 1, the following table shows. The final TOF values, conversion and selectivity results are also shown in table 1 below:
TABLE 1
As can be seen from Table 1, in examples 7 to 11, the TOF value, conversion and selectivity were all more excellent when the molar ratio of the palladium compound, phosphine ligand and 1- (4-isobutyl-phenyl) -ethanol, i.e., IBPE, in the procatalyst was in the range of 1:6:15000 to 1:10:20000, which also confirmed the preferable ranges as described earlier in this application.
Example 12-example 19
The reaction results of varying the kind and amount of the cocatalyst in the step (S3) based on example 1 are shown in the following table:
TABLE 2
As is clear from Table 2, in examples 12 to 14, TOF values decreased with decreasing amounts of the cocatalyst added, when the types of the cocatalysts were the same; in example 12 and examples 15 to 19, the reaction TOF values and selectivities of the different types of cocatalysts were slightly different.
Wherein the structure of the cocatalyst Z2-Z6 is as follows:
comparative examples 1 to 4
Comparative examples 1 to 4 correspond to example 1, example 2, example 7 and example 10, respectively, with the following differences: without the addition of cocatalyst, the other conditions were kept constant and the reaction results are given in table 3 below:
TABLE 3
As can be seen from Table 3, in comparative examples 1 to 4, in the case where no cocatalyst was added, the TOF value of the reaction was greatly reduced and the selectivity was remarkably deteriorated.
Example 20 to example 26
Examples 20 to 26 are the following table 4, in which the carbon monoxide pressure and the reaction temperature were changed and the other conditions were maintained, respectively, in the step (S3) in addition to example 1:
TABLE 4
As can be seen from Table 4, in examples 20 to 23, the TOF value of the reaction increased with the increase of the pressure under the same conditions, and the selectivity was also better, which exactly confirms that the selectivity is more excellent in the above-mentioned "the pressure of the carbon monoxide gas introduced into the carbonylation reaction is preferably in the range of 10 to 20 MPa" in the present application. In examples 24 to 26 and 1, the TOF value of the reaction increases with the increase of the temperature under the condition that other conditions are not changed, and the selectivity becomes slightly lower under the conditions that the temperature is lower than 125 ℃ (such as 120 ℃) and higher than 135 ℃ (such as 140 ℃), which also exactly verifies that the selectivity is more excellent under the condition that the reaction temperature of the carbonylation reaction is preferably in the range of 125 ℃ -135 ℃ in the application.
Example 27 to example 30
Examples 27 to 30 were carried out by changing the kind of the substituted aryl benzene as the starting material based on example 1, and the experimental results are shown in the following table 5, except that the conditions were changed:
TABLE 5
As can be seen from Table 5, in examples 27 to 30, satisfactory TOF values of the reaction and excellent selectivity were obtained by using different raw materials for the substituted arylbenzenes.
All possible combinations of the technical features of the above embodiments may not be described for the sake of brevity, but should be considered as within the scope of the present disclosure as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is specific and detailed, but not to be understood as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A preparation method of an aryl propionic acid compound comprises the following steps:
providing substituted aryl benzene, and performing acetylation reaction on the substituted aryl benzene to obtain alpha-substituted aryl ethanone;
carrying out hydrogenation reduction reaction on the alpha-substituted aryl ethanone to obtain alpha-substituted aryl ethanol; and
introducing carbon monoxide gas into the alpha-substituted aryl ethanol in an acid solution, carrying out carbonylation reaction under the combined catalysis of a main catalyst and a cocatalyst to obtain an aryl propionic acid compound,
wherein the structural formula of the cocatalyst is as follows:
R1is one of hydrogen and substituted carboxylic acid group, and the substituted carboxylic acid group is one of acetoxy, propionyloxy, aryl propionyloxy and substituted aryl propionyloxy; r2Is one of hydrogen, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, substituted carbonyl containing C6-C24 aryl or substituted aryl, substituted carbonyl containing C3-C12 heterocyclic group or substituted heterocyclic group, phenyl, substituted phenyl, naphthyl and substituted naphthyl; ar is one of phenyl, substituted phenyl, naphthyl and substituted naphthyl,
the main catalyst consists of palladium and a ligand or a palladium compound and a ligand; the palladium compound is at least one of palladium dichloride, palladium nitrate, palladium acetate and palladium sulfate, the ligand is a monodentate phosphine ligand,
the structural formula of the aryl propionic acid compound is as follows:
wherein, R is one of hydrogen, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, substituted carbonyl containing C6-C24 aryl or substituted aryl, substituted carbonyl containing C3-C12 heterocyclic group or substituted heterocyclic group, phenyl, substituted phenyl, naphthyl and substituted naphthyl; ar is one of phenyl, substituted phenyl, naphthyl and substituted naphthyl.
2. The process for preparing an arylpropionic acid compound of claim 1, wherein the cocatalyst has the formula:
wherein R is3Is one of hydrogen, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, substituted carbonyl containing C6-C24 aryl or substituted aryl, substituted carbonyl containing C3-C12 heterocyclic group or substituted heterocyclic group, phenyl, substituted phenyl, naphthyl and substituted naphthyl; ar is one of phenyl, substituted phenyl, naphthyl and substituted naphthyl.
3. The process for preparing an arylpropionic acid compound of claim 2, wherein R, R2And R3The same is true.
4. The method for preparing an arylpropionic acid compound according to claim 1, wherein R is one of a substituted or unsubstituted C1-C6 alkyl group, an unsubstituted C1-C6 alkoxy group, an unsubstituted C3-C6 cycloalkyl group, a substituted carbonyl group containing a C6-C12 aryl group, a substituted carbonyl group containing a C3-C6 heterocyclic group; the heterocyclic group is at least one of furyl, pyrrolyl and thienyl;
when the R is a substituted C1-C6 alkyl group, H on the C1-C6 alkyl group is substituted by more than 1 substituent A, wherein the substituent A is at least one of cyclopentanone and cyclohexanone.
5. The method for preparing an arylpropionic acid compound according to claim 4, wherein the arylpropionic acid compound comprises ibuprofen, naproxen, loxoprofen, ketoprofen, and suprofen, and the specific structural formulas are as follows in sequence:
6. the method of preparing an arylpropionic acid compound of claim 1, wherein the molar ratio of the co-catalyst to the main catalyst is 1:2 to 1: 100.
7. The method for producing an arylpropionic acid compound according to claim 1, wherein the monodentate phosphine ligand is triphenylphosphine, tri-p-tolylphosphine, diphenylbenzylphosphine, bis (diphenylphosphino) methane, 1, 2-bis (diphenylphosphino) ethane, diphenylcyclohexylphosphine, dicycloalkylarylphosphine, phenyldi (o-tolyl) phosphine, phenyldi (m-tolyl) phosphine, phenyldi (p-tolyl) phosphine, diphenyl (o-tolyl) phosphine, diphenyl (m-tolyl) phosphine, diphenyl (p-tolyl) phosphine, tri (o-tolyl) phosphine, tri (m-tolyl) phosphine, tri (p-tolyl) phosphine, phenyldibenzylphosphine, diphenylbenzylphosphine, tribenzylphosphine, phenyldinaphthylphosphine, diphenylnaphthylphosphine, trinaphthylphosphine, At least one of dicyclohexyl benzyl phosphine, cyclohexyl dibenzyl phosphine and phosphite ester ligand.
8. The method of claim 1, wherein the molar ratio of Pd to the α -substituted arylethanol in the procatalyst is from 1:2000 to 1: 50000.
9. The method of claim 1, wherein the pressure of the carbon monoxide gas introduced during the carbonylation reaction is 1MPa to 30MPa, the reaction temperature is 20 ℃ to 150 ℃, and the conversion frequency is 2000h-1-15000 h-1。
10. The method of producing an arylpropionic acid compound according to claim 1, wherein the acidic solution contains a hydrogen ion and a halogen ion, and the molar ratio of the hydrogen ion to the α -substituted arylethanol is 0.1:1 to 2.5:1, and the molar ratio of the halogen ion to the α -substituted arylethanol is 0.1:1 to 2.5: 1.
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