CN110615734A - Industrialized synthesis method of o-aldehyde phenyl fatty acid - Google Patents
Industrialized synthesis method of o-aldehyde phenyl fatty acid Download PDFInfo
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Abstract
The invention provides an industrialized synthesis method of o-aldehyde phenyl fatty acid, which comprises the following steps: aromatic lactone or o-methylphenyl fatty acid is used as a raw material, and the o-formyl phenyl fatty acid is obtained through halogenation reaction and hydrolysis. Halogen is used in the production process, and if halogen acid or halogen salt formed by hydrolysis is directly discharged to the environment, the halogen source cost accounts for the most part of the whole process cost and serious environmental pollution is caused; the invention can obtain activated halogen source in real time by adding specific oxidant in the reaction process, realizes the closed circulation of halogen elements by matching with the subsequent hydrolysis process, saves a large amount of raw material cost on the whole, reduces the environmental pollution, has high product yield and is beneficial to large-scale production.
Description
Technical Field
The invention relates to the field of drug intermediates, in particular to an industrial synthesis method of o-aldehyde phenyl fatty acid.
Background
The o-formyl phenyl fatty acid is an important drug intermediate, for example, o-carboxybenzaldehyde is an important intermediate for synthesizing medicaments such as talniflumate, phthalein ampicillin and the like, and has wide market demand. In the prior art, the main synthetic method of o-aldehyde phenyl fatty acid comprises the following steps: (1) the product is prepared by taking aromatic lactone as a raw material and halogenating NBS (N-bromosuccinimide) or phosphorus tribromide, and the final product yield is high (about 60-70%), but the defects are that NBS needs to be prepared and the economic benefit is poor. The reason for this is that NBS or phosphorus tribromide is used in large amounts, but a bromine source closed cycle cannot be formed, and the loss is large. (2) Aromatic lactone is used as a raw material, and bromine is halogenated to prepare a product; but the method has the problems of low product yield (about 30 percent), incapability of forming bromine source closed cycle, large bromine consumption and serious environmental pollution caused by waste water discharge. Either high cost, environmental pressure, or low yield from conventional processes inevitably become a significant problem limiting the continuous large-scale production of ortho-aldehyde phenyl fatty acids.
Therefore, how to obtain the o-aldehyde phenyl fatty acid with low cost, high yield, high quality and environmental protection is still worth exploring.
Disclosure of Invention
In order to solve the above problems, the present inventors have conducted intensive studies and, as a result, have found that: taking aromatic lactone or o-methylphenyl fatty acid as a raw material, and performing halogenation reaction and hydrolysis to obtain o-aldehyde phenyl fatty acid; in one mode, the halogen element in the halogenation reaction is derived from a halogen salt such as NaBr or a hydrogen halide solution such as HBr, the halogen salt or the hydrogen halide is activated by an oxide to generate a halogen simple substance and then participates in the halogenation reaction, the halogen simple substance can be continuously generated and participates in the reaction due to the existence of an oxidant, the halogen element is separated from an intermediate after hydrolysis, the halogen salt or the hydrogen halide is formed again, and the closed cycle of the halogen can be realized; in another mode, the halogen element in the halogenation reaction is a halogen simple substance, the halogen simple substance which is equivalent to or slightly excessive from the reaction raw material is adopted for reaction, the halogen simple substance in the reaction later stage system reacts (almost completely), the halogen ion exists in the solvent, the oxidant is added, the halogen ion is oxidized to generate the halogen simple substance and then participates in the halogenation reaction, on the premise of realizing the complete reaction of the raw material, the dosage of the halogen simple substance is reduced, and the closed cycle of the halogen can be realized. The invention fundamentally solves the problem of closed circulation of halogen, saves a large amount of raw material cost, reduces environmental pollution, and has higher yield (at the top level of the industry), thereby completing the invention.
The object of the present invention is to provide the following:
(1) a method for synthesizing o-aldehyde phenyl fatty acid comprises the following steps: taking aromatic lactone or o-methylphenyl fatty acid as a raw material, and performing halogenation reaction and hydrolysis to obtain o-aldehyde phenyl fatty acid;
the structure of the aromatic lactone is as follows:
wherein, X is selected from hydrogen element or halogen, the halogen is selected from F, Cl or Br, preferably F or Cl, and more preferably Cl; n takes a value of 0-2;
the structure of the o-methylphenyl fatty acid is as follows:wherein m is 0-2.
The industrialized synthesis method of o-aldehyde phenyl fatty acid provided by the invention has the following beneficial effects:
(1) the invention greatly expands the selection range of the traditional halogen source in the process, and discards expensive NBS or PBr reported in the literature3Or halogen simple substance which is not easy to operate, which directly reduces the cost of raw materials and the difficulty of industrialized operation.
(2) The method adds a set oxidant in the halogenation process, and adopts Br by oxidizing/activating halogen ions in a reaction system into a halogen simple substance2Or I2When halogen sources except the simple substance are reacted, the halogenation reaction rate is improved;
meanwhile, the addition of the oxidant is beneficial to the improvement of the conversion rate of reaction raw materials (aromatic lactone and o-methylphenyl fatty acid), so that the use amount of halogen sources can be greatly reduced in the industrial synthesis process, and the method is beneficial to cost control, environmental protection and operation of halogen sources such as bromine, hydrogen bromide and the like.
(3) The oxidant is added into the reaction system dropwise or in multiple times, so that the problem of overlarge local concentration of the halogen simple substance does not exist, and the problem of increased side reaction caused by the substitution of hydrogen on the benzene ring is effectively reduced.
(4) In the hydrolysis reaction stage, the hydrolysis is carried out in a reflux mode, so that the efficiency of the hydrolysis reaction can be greatly improved, and the whole hydrolysis reaction can be completed by using less hydrolysis solvent.
(5) In the invention, the hydrolyzed mother liquor can regenerate corresponding halogen salt or hydrogen halide solution, and the halogen salt or hydrogen halide solution is applied to the halogenation reaction stage again, thereby solving the difficult problem of halogen source closed circulation in the industrial synthesis process, greatly reducing the environmental protection pressure and the cost pressure caused by halogen loss.
(6) In the purification stage, the traditional heating, heating and stirring or heating ultrasonic mode is replaced by the reflux purification mode, and compared with the traditional heating or heating and stirring purification mode, the reflux purification mode realizes the full mixing of solid and liquid, improves the purification effectiveness, and is more convenient to implement in industrialization compared with the heating ultrasonic mode, so that the reflux purification mode is more reasonable.
Drawings
FIG. 1 is a diagram showing the o-carboxybenzaldehyde obtained in the first preparation in example 11H-NMR spectrum;
FIG. 2 is a liquid chromatography-mass spectrum diagram of o-carboxybenzaldehyde obtained in the first preparation in example 1 under positive ion mode;
FIG. 3 is a liquid chromatography-mass spectrum diagram of o-carboxybenzaldehyde obtained in the first preparation in example 1 under an anion mode.
Detailed Description
The features and advantages of the present invention will become more apparent and appreciated from the following detailed description of the invention.
The word "exemplary" is used exclusively herein to mean "serving as an example, embodiment, or illustration. Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments. While the various aspects of the embodiments are presented in drawings, the drawings are not necessarily drawn to scale unless specifically indicated.
The invention aims to provide a method for synthesizing o-aldehyde phenyl fatty acid, which comprises the following steps: aromatic lactone or o-methylphenyl fatty acid is used as a raw material, and the o-formyl phenyl fatty acid is obtained through halogenation reaction and hydrolysis.
In the invention, the structure of the aromatic lactone is as follows:
wherein, X is selected from hydrogen element or halogen, the halogen is selected from F, Cl or Br, preferably F or Cl, and more preferably Cl;
and n is 0-2.
The structure of the o-methylphenyl fatty acid is as follows:wherein m is 0-2.
In the present invention, the halogenation process is: adding reaction raw materials, a halogen source and a solvent into a reaction kettle, carrying out reflux reaction, keeping the reaction temperature at 60-100 ℃, the reaction time at 3-12 h, preferably 80-90 ℃, and the reaction time at 4-7 h, and reacting to obtain an intermediate.
In the present invention, the solvent may be any non-aromatic hydrocarbon solvent which dissolves the reaction raw materials, and is preferably selected from any one or more of dichloromethane, trichloromethane or tetrachloromethane.
In the invention, the halogen source for carrying out the halogenation reaction is selected from one or more of elementary halogen, halogen salt or hydrogen halide solution;
wherein the halogen is selected from liquid bromine (Br)2) Or elemental iodine (I)2)；
The halide salt is a salt containing halide ions selected from NaBr, KBr, CaBr2NaI, KI or CaI2One or more of; preferably one or more of NaBr or NaI, more preferably NaBr.
The hydrogen halide solution is an acid containing halogen ions, i.e., an aqueous hydrogen halide solution, selected from HBr or HI.
In the present invention, when the reaction is carried out using an aromatic lactone as a reaction raw material, if X is H, F or Cl, the halogen source for the halogenation reaction is selected from one or more of the above halogen simple substance, halogen salt or hydrogen halide solution;
if X is Br, the halogen source for the halogenation is selected from I2Halogen salts obtained by reaction of aqueous HI or hydroiodic acid with alkali metal hydroxides, e.g. NaI, KI or CaI2One or more of (a).
As can be seen from the selection of the halogen source, the invention greatly expands the selection range of the traditional halogen source in the process, and discards the expensive NBS or PBr reported in the literature3It is clear that this directly reduces the cost of the raw material.
Theoretically, by Br2Or I2The aromatic lactone or the ortho-lactone obtained by halogenating the simple substanceAnd (3) hydrolyzing the methyl phenyl fatty acid to obtain the o-formyl phenyl fatty acid product. The inventor of the invention finds that simple halogenation-hydrolysis reaction of only aromatic lactone or o-methylphenyl fatty acid and halogen source has slower halogenation reaction rate, and more importantly, the yield of the final product cannot be obviously improved.
On the other hand, when Br is used2Or I2When halogen sources other than the simple substance are used for reaction, the halogenation reaction rate is slower, which is quite unfavorable for the industrial application of the halogen sources.
Through a great deal of research, the problem of slow reaction rate can be solved by adding the set oxidant in the halogenation reaction process, which is mainly based on the activation effect of the set oxidant on halogen ions existing in the reaction system, namely, the halogen ions are oxidized into simple halogen substances. The inventor also surprisingly finds that the addition of the oxidant is beneficial to the improvement of the conversion rate of reaction raw materials (aromatic lactone and o-methylphenyl fatty acid) because the oxidant promotes the participation of halogen sources in the reaction, so that the dosage of the halogen sources can be greatly reduced in the industrial synthesis process, and the method is beneficial to cost control, environmental protection and operation of halogen sources such as bromine, hydrogen bromide and the like.
In the invention, when the halogen source is a halogen simple substance, or the halogen source is a halogen salt or a hydrogen halide solution, the time for adding the oxidant into the reaction system in the halogenation reaction process is different, specifically:
(i) when the halogen source is a halogen simple substance, adding an oxidant when the consumption of the halogen simple substance is between 50 and 100 percent;
(ii) when the halogen source is a halogen salt or a hydrogen halide solution, the halogen source and the oxidant are added to the reaction system simultaneously or sequentially to provide an activated halogen source.
Preferably, (i') when the halogen source is a halogen simple substance, the halogen simple substance is added into the reaction system in a dropwise manner or in multiple times, and the oxidant is added into the reaction system in a dropwise manner or in multiple times;
(ii') when the halogen source is a halogen salt or a hydrogen halide solution, the halogen source is added to the reaction system at one time, and the oxidizing agent is added to the reaction system dropwise or in multiple portions.
When the halogen source is a simple halogen, the oxidant is not added simultaneously with the simple halogen, because: when the halogenation reaction starts, the reaction system has sufficient halogen simple substances capable of carrying out rapid reaction, and an oxidant is not required to be added to reactivate halogen ions generated after the halogen simple substances replace reaction raw materials, namely aromatic lactone or o-methylphenyl fatty acid, into the halogen simple substances, because the halogen simple substances generated by reactivation at the moment can not obviously promote the halogenation reaction; when the halogen simple substance is consumed by 50-100%, a large amount of halogen ions generated after the reaction raw material aromatic lactone or o-methylphenyl fatty acid is replaced exist in a reaction system, the halogen simple substance is obviously reduced to cause the reaction speed to be slow, at the moment, the oxidant is added, a large amount of halogen ions are activated (oxidized) into the halogen simple substance to participate in the halogenation reaction again, the improvement on the speed is more favorable and obvious, and the effective utilization rate of the oxidant is higher.
Meanwhile, the aromatic lactone or the o-methylphenyl fatty acid which is used as the reaction raw material has a benzene ring structure, the possibility of substituting H element on the benzene ring by halogen exists, and when the halogen source, particularly halogen simple substance, has higher content (more than 2 equivalents of the aromatic lactone or the o-methylphenyl fatty acid which is used as the reaction raw material), the probability of benzene ring substitution side reaction is obviously increased. The oxidant is added when the halogen simple substance is consumed by 50-100%, and the side reaction is reduced on the premise that the level of the halogen simple substance is controlled to meet the requirement of the reaction rate.
When the halogen source is halogen salt or hydrogen halide solution, the halogen source and the oxidant are added into the reaction system simultaneously or sequentially, and the oxidant can activate (oxidize) halogen ions into halogen simple substances, so that the halogen salt or the hydrogen halide solution participates in the halogenation reaction in the form of the halogen simple substances with higher activity, and the reaction rate is favorably improved.
In the invention, (i) when the halogen source is a halogen simple substance, the molar ratio of the dosage of the halogen simple substance to the dosage of the reaction raw material (aromatic lactone or o-methylphenyl fatty acid) is (0.55-1.0): 1; preferably (0.65-0.80): 1.
for the halogen simple substance, 1/2 equivalents are theoretically enough for carrying out halogenation reaction and generating 1 equivalent of hydrogen halide, in the actual production, 0.55-1.0 equivalent of the halogen simple substance is added, after the consumption is 50% -100%, the oxidant is added to replace the halogen in the hydrogen halide, and the reaction is continuously completed, so that the purposes of reducing the halogen consumption and saving the cost are achieved.
(ii) When the halogen source is a halogen salt or a hydrogen halide solution, the molar ratio of the amount of the halogen source to the amount of the reaction raw material (aromatic lactone or o-methylphenyl fatty acid) is (1.2-2.0): 1; preferably (1.5-1.8): 1.
in the invention, the purpose of the oxidant is to activate halogen ions generated in the halogen source reaction process or owned by the oxidant into a halogen simple substance, so the oxidability of the oxidant is inevitably stronger than that of the halogen; the oxidant is selected from chlorine (Cl)2) Hydrogen peroxide (active ingredient H)2O2) One or more of the above compounds are preferably hydrogen peroxide due to the non-toxic and side reaction-free characteristics of hydrogen peroxide.
In a preferred embodiment, the hydrogen peroxide content of the hydrogen peroxide solution is 10 to 28% by weight. The concentration of hydrogen peroxide has an important influence on the halogenation reaction rate and the yield of the final product. The concentration of hydrogen peroxide is higher than 28 percent (weight), and after the hydrogen peroxide is added into a reaction system, the hydrogen peroxide and halogen ions quickly react to locally generate a high-concentration halogen simple substance, so that although the reaction rate is promoted to be improved, the probability of generating a benzene ring substitution side reaction is increased; if the concentration of the hydrogen peroxide is lower than 10 wt%, the rate of activating halogen ions into halogen simple substances is reduced, and the overall rate of halogenation reaction is further influenced. The present inventors have found that when the hydrogen peroxide content in hydrogen peroxide is 11 to 18% by weight, preferably 13 to 15% by weight, both the reaction rate and the product yield can be effectively balanced.
In a preferred embodiment, the oxidizing agent is hydrogen peroxide, and if the halogen source is a halogen simple substance, the molar ratio of the amount of hydrogen peroxide to the amount of the halogen simple substance in the oxidizing agent is (0.7-1.2): 1, preferably (0.8-1.1): 1. when a halogen simple substance is used as a halogen source, 1mol of the halogen simple substance reacts with a raw material to generate 1mol of halogen ions, and (0.7-1.2) mol of hydrogen peroxide is used for effectively activating the halogen ions.
In another preferred embodiment, the oxidizing agent is hydrogen peroxide, and if the halogen source is a halogen salt or a hydrogen halide solution, the molar ratio of the amount of hydrogen peroxide in the oxidizing agent to the amount of halogen ions in the halogen source is (1.0-1.8): 1. when a halogen salt or a hydrogen halide solution is used as a halogen source, 1mol of halogen ions completely generate a halogen simple substance, and 0.5mol of hydrogen peroxide needs to be consumed, but the hydrogen peroxide is not added at one time generally, and in consideration of ineffective decomposition of the hydrogen peroxide, (1.0 to 1.8) mol equivalent, preferably (1.2 to 1.5) mol equivalent of hydrogen peroxide is used.
When other oxidants are adopted, the dosage requirement of converting halogen ions into simple halogen substances is also met.
In the invention, the hydrolysis process is as follows: and (3) refluxing, cooling, crystallizing and filtering the intermediate obtained by the halogenation reaction under the acidic, neutral or alkaline condition to obtain the o-aldehyde phenyl fatty acid target product.
The halogenation reaction can obtain an intermediate which is 3-substituted bromide or 3-substituted iodide, and can form an o-aldehyde phenyl fatty acid product through hydrolysis.
In the present invention, the hydrolysis is carried out under acidic conditions, and the acid used is one or more of inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or organic acids such as formic acid, glacial acetic acid, etc.
The hydrolysis is carried out under alkaline conditions, the base used being an inorganic base such as NaOH, KOH, Ca (OH)2Or an organic base such as one or more of sodium methoxide, sodium ethoxide, etc.
The hydrolysis is carried out under neutral condition, and the hydrolysis can be realized by adopting production water.
The reason why the hydrolysis is performed by refluxing instead of the conventional heating or heating-stirring hydrolysis method in the present invention is that the inventors found that the efficiency of the hydrolysis reaction can be greatly improved by refluxing hydrolysis method compared to the conventional hydrolysis method, and the whole hydrolysis reaction can be completed by using less hydrolysis solvent. Since the filtered mother liquor contains a large amount of halogen ions after the reflux reaction is cooled, crystallized and filtered, and exists in the form of halogen salt or hydrogen halide solution (depending on the acid-base property of the hydrolysis solvent), we know that the halogen salt or the hydrogen halide solution can be used for the halogenation reaction, so that the filtered mother liquor needs to be recycled and reused in the halogenation reaction, and the hydrolysis solvent is added more in the hydrolysis process, so that the content of the halogen ions in the mother liquor is too low, the direct reuse of the mother liquor is not facilitated, and the filtered mother liquor can be directly used for the next halogenation reaction after being concentrated or supplemented with more halogen ions.
Meanwhile, the selection of the halogen salt or the hydrogen halide solution has the advantages of expanding a bromine source in the process and improving the operability of the bromine source (the bromine or iodine simple substance is stored and used relatively to the halogen salt or the hydrogen halide solution, and is relatively inconvenient), and the more obvious advantage is that the mother solution after hydrolysis generates the corresponding halogen salt or the hydrogen halide solution again, so that the problem of closed circulation of the halogen source in the industrial synthesis process is solved, the environmental protection pressure is greatly reduced, and the cost pressure caused by halogen loss is reduced.
In a preferred embodiment, the mass ratio of the volume of the hydrolysis solvent to the intermediate in the hydrolysis process is 1: (0.7 to 1.0), preferably 1: (0.85-1.0); the refluxing time is 1-3 h, preferably 1.5-2.5 h.
In a preferred embodiment, the temperature is reduced to 0-5 ℃ after the reflux reaction, and the filtration is carried out after the constant temperature crystallization for 6-8 h.
In the invention, the industrial synthesis method of o-aldehyde phenyl fatty acid also comprises a purification process of the product, wherein the purification process comprises the following steps: adding a product to be purified, activated carbon and a purification solvent into a purification container, heating and refluxing, carrying out hot filtration, stirring and cooling for crystallization, filtering, and washing with cold water to obtain a purified product.
In a preferred embodiment, the weight ratio of the activated carbon to the product to be purified is between 0.5% and 0.7%.
In a preferred embodiment, the purification solvent may be an alcoholic solvent or water, preferably water.
In a preferred embodiment, the reflux time is 0.5 to 1 hour.
In the invention, the product is prevented from being adsorbed on the activated carbon in a solid form after purification at low temperature by adopting a thermal filtration mode, so that the product yield is reduced.
In the invention, the traditional heating, heating and stirring or heating ultrasonic mode is replaced by the reflux purification mode, and the reason is that the reflux purification mode realizes the full mixing of solid and liquid compared with the traditional heating or heating and stirring purification mode, improves the purification effectiveness, and is more convenient to implement industrially compared with the heating ultrasonic mode, thereby being more reasonable.
In the present invention, the reflux purification mode is preferably performed 1 to 2 times, i.e., high purification of the product can be achieved.
Examples
The present invention will be further described below by way of specific examples, taking the synthesis of o-carboxybenzaldehyde as an example. However, these examples are only illustrative and do not set any limit to the scope of the present invention.
Example 1
250mL four-mouth bottle equipped with electromagnetic stirring, thermometer, feed tube and condenser tube, into which CCl was added4100.0mL of o-methylbenzoic acid and 20.1g (0.15mol) of o-methylbenzoic acid, heating to 80 ℃ under stirring and illumination to react, adding 15.7g (0.10mol) of bromine into a four-mouth bottle in a dropwise manner, and refluxing for 4 hours; then 30.3g of 14% hydrogen peroxide is dripped, bromination is continued, and after 2 hours, the intermediate (3-bromophenylphthalide) is obtained by decompression and desolventization at 75 ℃.
A100 mL four-necked flask was equipped with an electromagnetic stirrer, a Y-type tube, a thermometer, and a condenser tube. 33.4g of the intermediate obtained in the above step and 35mL of water were added. Heating and refluxing for 2 hours, cooling to 0 ℃, filtering after 8 hours, reserving the mother liquor for later use, and leaching the filter cake with ice water to obtain 22.4g of crude product.
Adding 75mL of water and 0.2g of activated carbon, refluxing for 45min, performing hot filtration, stirring, cooling, crystallizing, filtering, washing with cold water to obtain 18.8g, performing secondary recrystallization with 45mL of water to obtain 17.0g (wet), and drying to obtain 14.8g of o-carboxybenzaldehyde, wherein the purity is 99.7% and the yield is 66.6%. Process for producing the o-carboxybenzaldehyde1The H-NMR spectrum is shown in FIG. 1, the liquid chromatogram-mass spectrum in positive ion mode is shown in FIG. 2, and the liquid chromatogram-mass spectrum in negative ion mode is shown in FIG. 3. The structural formula of o-carboxybenzaldehyde is shown below:
product structure warp1H-NMR analysis confirms that the characteristic peaks: after the carboxyl and the aldehyde group form a ring, H formants (8.16-8.18, d,1H) on the hydroxyl group, H formants (6.67-6.68, d,1H) on the carbon adjacent to the hydroxyl group, 4H of the disubstituted benzene ring have two groups of formants in the benzene ring region, H formants (7.78-7.85, m,2H) on the c position and the d position, and H formants (7.64-7.69, m,2H) on the e position and the f position.1The H-NMR spectrum was in agreement with that described in the reference (chem. Eur. J.2016,22,3009-3018, supporting information).
In the mass spectrum under the positive ion mode, a fragment ion peak with m/z of 133.0 exists, and the peak is formed after hydroxyl groups are broken off by o-carboxybenzaldehyde (Mr of 150).
In the mass spectrogram under the negative ion mode, a molecular ion peak with m/z being 149.6 exists, and the peak is consistent with the molecular ion peak formed under the o-carboxybenzaldehyde negative ion mode.
Recycling mother liquor for next round of reaction: a250 mL four-necked flask was equipped with an electromagnetic stirrer, a thermometer, a feed tube and a condenser tube. Adding CCl4100.0mL of the hydrolysis mother liquor is added, 1.6g (0.01mol) of bromine and 20.1g (0.15mol) of o-methylbenzoic acid are supplemented, and the steps are repeated to finally obtain 14.5g of a target product with the purity of 99.8% and the yield of 65.3%.
Example 2
250mL four-mouth bottle equipped with electromagnetic stirring, thermometer, feed tube and condenser tube, into which CCl was added4100.0mL of phthalide and 20.1g (0.15mol) of phthalide, heating to 80 ℃ under stirring and illumination to react, adding 15.7g (0.10mol) of bromine into a four-mouth bottle in a dropwise manner, and refluxing for 4 hours; then dropwise adding 15.15g of 28% hydrogen peroxide, continuing bromination, and after 2 hours, carrying out decompression and desolventizing at 75 ℃ to obtain 32.0g of an intermediate (3-bromophenylphthalide).
A100 mL four-necked flask was equipped with an electromagnetic stirrer, a Y-type tube, a thermometer, and a condenser tube. 32.0g of the intermediate obtained in the above step and 35mL of water were added. Heating and refluxing for 2 hours, cooling to 5 ℃, filtering after 8 hours, reserving the mother liquor for later use, and leaching the filter cake with ice water to obtain 21.4g of crude product.
Adding 75mL of water and 0.2g of activated carbon, refluxing for 45min, performing hot filtration, stirring, cooling, crystallizing, filtering, washing with cold water to obtain 18.6g, performing secondary recrystallization by using 45mL of water to obtain 17.0g (wet), and drying to obtain 14.3g of o-carboxybenzaldehyde, wherein the purity is 99.9% and the yield is 63.5%.
Recycling mother liquor for next round of reaction: a250 mL four-necked flask was equipped with an electromagnetic stirrer, a thermometer, and a condenser tube. Adding CCl4100.0mL, add the above hydrolyzed mother liquor, supplement bromine 1.6g (0.01mol), phthalide 20.1g (0.15mol), repeat the above steps, finally obtain the target product 14.0g, the purity is 99.7%, the yield is 62.2%.
Example 3
250mL four-mouth bottle equipped with electromagnetic stirring, thermometer, feed tube and condenser tube, into which CCl was added4100.0mL of NaBr aqueous solution (23.2g of NaBr dissolved in 100mL of water, 0.225mol) and 20.1g (0.15mol) of o-carboxytoluene, heating to 80 ℃ under stirring and illumination for reaction, refluxing for 6 hours, and dropwise adding 71g of 14% hydrogen peroxide in the refluxing process; after bromination was complete, intermediate 32.8g was obtained by desolventizing under reduced pressure at 75 ℃.
A100 mL four-necked flask was equipped with an electromagnetic stirrer, a Y-type tube, a thermometer, and a condenser tube. 32.8g of the intermediate obtained in the above step and 35mL of water were added. Heating and refluxing for 2 hours, cooling to 0 ℃, filtering after 8 hours, reserving the mother liquor for later use, and leaching the filter cake with ice water to obtain 22.8g of crude product.
Adding 75mL of water and 0.2g of activated carbon, refluxing for 45min, performing hot filtration, stirring, cooling, crystallizing, filtering, washing with cold water to obtain 18.0g, performing secondary recrystallization with 45mL of water to obtain 16.5g (wet), and drying to obtain 14.3g of o-carboxybenzaldehyde, wherein the purity is 99.9% and the yield is 64.4%.
Recycling mother liquor for next round of reaction: a250 mL four-necked flask was equipped with an electromagnetic stirrer, a thermometer, a feed tube and a condenser tube. Adding CCl4100.0mL of the hydrolysis mother liquor was added, 2.06g (0.02mol) of NaBr and 20.1g (0.15mol) of o-carboxytoluene were added, and the above steps were repeated to obtain 14.2g of the target product with a purity of 99.8% and a yield of 63.9%.
Example 4
250mL four-mouth bottle equipped with electromagnetic stirring, thermometer, feed tube and condenser tube, into which CCl was added4100.0mL of NaBr aqueous solution (23.2g of NaBr dissolved in 100mL of water, 0.225mol) and 25.4g (0.15mol) of 3-chlorophthalin, heating to 80 ℃ under stirring and illumination for reaction, refluxing for 6 hours, and dropwise adding 71g of 14% hydrogen peroxide in the refluxing process; after bromination, 32.6g of intermediate (3-bromophenylphthalide) was obtained by desolvation under reduced pressure at 75 ℃.
A100 mL single-neck flask was charged with electromagnetic stirring, a Y-tube, a thermometer, and a condenser. 32.6g of the intermediate obtained in the above step and 35mL of water were added. Heating and refluxing for 2 hours, cooling to 0 ℃, filtering after 8 hours, reserving the mother liquor for later use, and leaching the filter cake with ice water to obtain 23.8g of crude product.
Adding 75mL of water and 0.2g of activated carbon, refluxing for 45min, performing hot filtration, stirring, cooling, crystallizing, filtering, washing with cold water to obtain 19.2g, performing secondary recrystallization by using 45mL of water to obtain 17.5g (wet), and drying to obtain 15.3g of o-carboxybenzaldehyde, wherein the purity is 99.8% and the yield is 67.9%.
Recycling mother liquor for next round of reaction: a250 mL four-necked flask was equipped with an electromagnetic stirrer, a thermometer, a feed tube and a condenser tube. Adding CCl4100.0mL, add the above hydrolyzed mother liquor, supplement NaBr 2.06g (0.02mol), 3-chlorophthalin 25.4g (0.15mol), repeat the above steps, finally obtain the target product 15.6g, the purity is 99.8%, the yield is 69.3%.
Example 5
The reaction conditions were the same as in example 1, except that: in the first reaction process, the consumption of bromine is 0.12 mol.
Example 6
The reaction conditions were the same as in example 1, except that: in the first reaction process, bromine is added into a reaction vessel at one time.
Example 7
The reaction conditions were the same as in example 3, except that: in the first reaction process, the dosage of NaBr is 0.18 mol.
Example 8
The reaction conditions were the same as in example 3, except that: in the first reaction process, the dosage of NaBr is 0.30 mol.
Example 9
The reaction conditions were the same as in example 3, except that: in the first reaction process, 35.5g of 28% hydrogen peroxide is adopted.
Example 10
The reaction conditions were the same as in example 3, except that: in the first reaction process, 24.8g of 40% hydrogen peroxide is adopted.
Example 11
The reaction conditions were the same as in example 3, except that: in the first reaction process, 124g of 8% hydrogen peroxide is adopted.
Comparative example
Comparative example 1
The reaction conditions were the same as in example 1, except that: in the first reaction process, the consumption of bromine is 0.25 mol.
Comparative example 2
The reaction conditions were the same as in example 3, except that: in the first reaction process, a heating and stirring mode is adopted to replace a reflux purification mode in the purification process.
The results of the reactions of examples 1-11 and comparative examples 1-2 are summarized in Table 1:
TABLE 1
The invention has been described in detail with reference to specific embodiments and illustrative examples, but the description is not intended to be construed in a limiting sense. Those skilled in the art will appreciate that various equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its embodiments without departing from the spirit and scope of the present invention, which fall within the scope of the present invention. The scope of the invention is defined by the appended claims.
Claims (10)
1. A method for synthesizing o-aldehyde phenyl fatty acid comprises the following steps: aromatic lactone or o-methylphenyl fatty acid is used as a raw material, and the o-formyl phenyl fatty acid is obtained through halogenation reaction and hydrolysis.
2. The method of claim 1,
the structure of the aromatic lactone is as follows:
wherein, X is selected from hydrogen element or halogen, the halogen is selected from F, Cl or Br, preferably F or Cl, and more preferably Cl; n takes a value of 0-2;
the structure of the o-methylphenyl fatty acid is as follows:wherein m is 0-2.
3. The process according to claim 1, characterized in that the halogenation reaction is carried out by: adding reaction raw materials, a halogen source and a solvent into a reaction kettle, carrying out reflux reaction, keeping the reaction temperature at 60-100 ℃, reacting for 3-12 h,
preferably, the reaction temperature is 80-90 ℃, the reaction time is 4-7 h, and an intermediate is obtained through reaction.
4. The method of claim 3, wherein the halogen source for performing the halogenation reaction is selected from one or more of a simple halogen, a halogen salt or a hydrogen halide solution;
wherein the halogen is selected from liquid bromine (Br)2) Or elemental iodine (I)2)；
The halide salt is a salt containing halide ions selected from NaBr, KBr, CaBr2NaI, KI or CaI2One or more of; preferably one or more of NaBr or NaI, more preferably NaBr;
the hydrogen halide solution is an acid containing halogen ions, i.e., an aqueous hydrogen halide solution, selected from HBr or HI.
5. The method as claimed in claim 4, wherein the set oxidant is added during the halogenation reaction, and the time for adding the set oxidant into the reaction system is different according to different time of the halogen source:
when the halogen source is a halogen simple substance, adding an oxidant when the consumption of the halogen simple substance is between 50 and 100 percent; and/or
When the halogen source is halogen salt or hydrogen halide solution, the halogen source and the oxidant are added into the reaction system simultaneously or sequentially to provide activated halogen source;
preferably, when the halogen source is a halogen simple substance, the halogen simple substance is added into the reaction system in a dropwise manner or in multiple times, and the oxidant is added into the reaction system in a dropwise manner or in multiple times; and/or
Preferably, when the halogen source is a halogen salt or a hydrogen halide solution, the halogen source is added to the reaction system at one time, and the oxidizing agent is added to the reaction system dropwise or in multiple portions.
6. The method according to one of claims 1 to 5,
when the halogen source is a halogen simple substance, the molar ratio of the amount of the halogen simple substance to the amount of the aromatic lactone or the o-methylphenyl fatty acid which is a reaction raw material is (0.55-1.0): 1; preferably (0.65-0.80): 1; and/or
When the halogen source is a halogen salt or a hydrogen halide solution, the molar ratio of the amount of the halogen source to the amount of the aromatic lactone or the o-methylphenyl fatty acid as the reaction raw material is (1.2-2.0): 1; preferably (1.5-1.8): 1.
7. the method according to any one of claims 1 to 5, wherein the oxidant is selected from one or more of chlorine gas and hydrogen peroxide, preferably hydrogen peroxide.
8. The method of claim 1, wherein the hydrolysis is carried out by: and (3) refluxing the intermediate obtained by the halogenation reaction under the acidic, neutral or alkaline condition, cooling, crystallizing and filtering to obtain the o-aldehyde phenyl fatty acid target product.
9. The method of claim 8, wherein the mass ratio of the volume of the hydrolysis solvent to the intermediate during hydrolysis is 1: (0.7 to 1.0), preferably 1: (0.85-1.0);
the refluxing time is 1-3 h, preferably 1.5-2.5 h.
10. The method according to claim 1, wherein the method is preferably an industrial synthesis method of o-aldehyde phenyl fatty acid, more preferably the method further comprises a purification process of the product, the purification process is: adding a product to be purified, activated carbon and a purification solvent into a purification container, heating and refluxing, carrying out hot filtration, stirring and cooling for crystallization, filtering, and washing with cold water to obtain a purified product.
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| CN115385787A (en) * | 2022-10-28 | 2022-11-25 | 寿光祥铭化工有限公司 | Preparation method of 2-carboxyl benzaldehyde |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3914286A (en) * | 1969-01-31 | 1975-10-21 | Orchimed Sa | Lower alkyl esters of p-benzoylphenoxy isobutyric acid |
| CN103613071A (en) * | 2013-11-07 | 2014-03-05 | 浙江双益环保科技发展有限公司 | Method for recycling bromine from bromine-containing wastewater of brominated butyl rubber |
| CN104447303A (en) * | 2014-11-26 | 2015-03-25 | 太仓运通生物化工有限公司 | Preparation technology of carboxybenzaldehyde |
| CN104496949A (en) * | 2014-11-27 | 2015-04-08 | 太仓运通生物化工有限公司 | Preparation method of 3-bromophthalide |
| CN107043321A (en) * | 2017-04-25 | 2017-08-15 | 连云港市工业投资集团有限公司 | A kind of method of the dichlorobenzaldehyde of high selectivity 2,3 |
-
2018
- 2018-07-13 CN CN201810771781.2A patent/CN110615734B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3914286A (en) * | 1969-01-31 | 1975-10-21 | Orchimed Sa | Lower alkyl esters of p-benzoylphenoxy isobutyric acid |
| CN103613071A (en) * | 2013-11-07 | 2014-03-05 | 浙江双益环保科技发展有限公司 | Method for recycling bromine from bromine-containing wastewater of brominated butyl rubber |
| CN104447303A (en) * | 2014-11-26 | 2015-03-25 | 太仓运通生物化工有限公司 | Preparation technology of carboxybenzaldehyde |
| CN104496949A (en) * | 2014-11-27 | 2015-04-08 | 太仓运通生物化工有限公司 | Preparation method of 3-bromophthalide |
| CN107043321A (en) * | 2017-04-25 | 2017-08-15 | 连云港市工业投资集团有限公司 | A kind of method of the dichlorobenzaldehyde of high selectivity 2,3 |
Non-Patent Citations (4)
| Title |
|---|
| TROYANSKY，EMMANUIL I: "Aluminum", 《E-EROS ENCYCLOPEDIA OF REAGENTS FOR ORGANIC SYNTHESIS》 * |
| 化学工业部人事教育司化学工业部教育培训中心组织编写: "《有机化学反应 1》", 31 August 1997, 化学工业出版社 * |
| 国农业百科全书总编辑委员会农药卷编辑委员会: "《中国农业百科全书 农药卷》", 31 October 1993, 农业出版社 * |
| 梁足培等: "芳胺类化合物的原位氧化溴化工艺研究", 《潍坊学院学报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115385787A (en) * | 2022-10-28 | 2022-11-25 | 寿光祥铭化工有限公司 | Preparation method of 2-carboxyl benzaldehyde |
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