A method for synthesizing cyclohexenone derivatives from alkoxypropylene

Abstract

The present invention provides a simple method for synthesizing cyclohexenone derivatives from alkoxypropylene, specifically as follows: Using alkoxypropylene and α,β-unsaturated aldehyde as raw materials, first a Diels-Alder reaction occurs to obtain a dihydropyran intermediate, which subsequently undergoes hydrolysis ring-opening and Aldol condensation ring-closing to finally obtain a series of cyclohexenone derivatives. The present invention uses inexpensive and readily available alkoxypropylene and α,β-unsaturated aldehyde as starting materials. By optimizing conditions such as the catalyst and feeding ratio, the yield of the Diels-Alder reaction between the two is greatly improved, significantly superior to that reported in known literature, laying a foundation for the scale-up application of this method. Secondly, the catalyst of the present invention is novel and is in-situ prepared from phosphate ester and alkylaluminum hydride, with high catalytic efficiency and good selectivity. Finally, the conversion of the dihydropyran intermediate to cyclohexenone is achieved through a water-oil two-phase process, simplifying the process and the post-treatment process, and realizing the recycling of the acid catalyst.

Description

Technical Field

[0001] The present invention belongs to the field of fine chemicals, and particularly relates to a method for synthesizing cyclohexenone derivatives by using alkoxypropylene as a raw material through Diels-Alder addition and intramolecular Aldol condensation reactions. Background Art

[0002] m-Cresol, whose chemical name is 3-methylphenol, is one of the most common alkylphenols. m-Cresol is a colorless or light yellow liquid with a phenol odor and exists naturally in organisms. As an important synthetic intermediate, m-Cresol has extremely wide applications, mainly in the fields of pesticides, pharmaceuticals, perfume and flavor, organic dyes, etc., such as products like fomesafen, fenitrothion, fenthion, thymol powder, menthol, dye DPA, etc. p-Cresol, also known as 4-methylphenol, is a colorless to pink crystal with a smoky and herbal odor and exists naturally in products such as strawberries, cheese, coffee, and cocoa. Similar to m-Cresol, p-Cresol is also a very important synthetic intermediate and can be used to produce products such as the fungicide tolclofos-methyl, the insecticides flucythrinate and ethofenprox, the rubber antioxidant 264, the spice anisole and anisaldehyde, etc.

[0003] Due to the wide applications and large consumption of m-Cresol and p-Cresol, a variety of production methods for m-Cresol and p-Cresol have been developed industrially, including both natural cresol extraction methods and chemical synthesis methods. The so-called natural cresol extraction method mainly extracts m-Cresol and p-Cresol from coal tar and refining by-products. As early as in the 1940s and 1950s, reports on the application of relevant production methods appeared. However, since coal tar contains a mixture of various phenols, including phenol, m-Cresol, p-Cresol, xylenol, trimethylphenol, and higher alkyl-substituted phenol derivatives, selectively separating m-Cresol and p-Cresol from such a large number of mixed phenols has a complex process, high cost, and limited production capacity. After the 1980s, this method was gradually phased out, and currently only a few manufacturers in China and the United States are still using it.

[0004] The chemical synthesis methods of m-cresol and p-cresol include the toluenesulfonic acid alkali fusion method, the chlorotoluene hydrolysis method, the cymene peroxide pyrolysis method, etc. The toluenesulfonic acid alkali fusion method is to react toluenesulfonic acid with sodium hydroxide under high-temperature melting conditions to obtain cresol; the main product is p-cresol, and only a small amount of m-cresol (S.W. Eglund, R.S. Aries, D.F. Othmer, Ind. Eng. Chem. 1953, 45, 189.). The first step of the chlorotoluene hydrolysis method is to chlorinate toluene to obtain a mixture of o-chlorotoluene and p-chlorotoluene. This mixture is hydrolyzed in an aqueous sodium hydroxide solution under high temperature and high pressure to obtain a mixture of o-, m-, and p-cresols, with a ratio greater than 1:2:1, mainly m-cresol (R.N. Shreve, C.J. Marsel, Ind. Eng. Chem. 1946, 38, 254.). The cymene peroxide pyrolysis method is to react toluene with propylene to obtain a cymene mixture, which is then peroxidized, pyrolyzed and other reactions to obtain a cresol mixture. The product of this method is also a mixture of three cresols, mainly m-cresol and p-cresol. Due to the instability of the peroxy intermediate, the raw material conversion rate and the concentration of peroxides need to be strictly controlled in the peroxidation reaction, and a large amount of cymene needs to be recycled. Therefore, the process flow of this method is very cumbersome (H. Kaminata, Kagakushi Kenkyu 1998, 25, 126).

[0005] The above methods all obtain a cresol mixture. o-Cresol is relatively easy to separate, but the boiling points of m-cresol and p-cresol only differ by 0.4 °C, and the separation of the two is very cumbersome. Generally, multiple crystallization purification or the method of alkylation - rectification - dealkylation is used to separate the two. There is currently another method for synthesizing cresol, namely the cyclohexenone dehydrogenation method. The corresponding 3-methylcyclohexenone or 4-methylcyclohexenone can respectively undergo dehydrogenation reactions to selectively obtain m-cresol or p-cresol. 3-Methylcyclohexenone and 4-methylcyclohexenone can be prepared separately, without the above-mentioned problem of separating m-cresol and p-cresol; however, at present, this method has not been widely used. The main problem is still that the preparation methods of 3-methylcyclohexenone or 4-methylcyclohexenone are few and the cost is high, so it is not actually applied for the time being. Patent CN106883111B uses 2-alkoxypropene and acrolein as raw materials to synthesize 2-methyl-2-alkoxy-3,4-dihydropyran, and then hydrolyzes and opens the ring to obtain 2-cyclohexen-1-one; it is reported that the aldehyde substrate is limited to acrolein, the total reaction yield is low (20 - 36%), and in the second step of the reaction, an excessive amount of acid is used as a catalyst, and alkali is directly added to neutralize the acid after the reaction, generating more three wastes.

[0006]

[0007] In summary, m-cresol and p-cresol are both very important synthetic intermediates and have very wide applications in the fields of medicine, pesticides, fragrances and flavors, materials, etc. At present, the synthesis methods of cresols such as the toluenesulfonic acid alkali fusion method, the hydrolysis method of chlorotoluene, and the cleavage method of cymene peroxide have relatively complex process flows, and the obtained product is a mixture of three cresols, making separation and purification difficult (separation of m-cresol and p-cresol). The cyclohexenone dehydrogenation method has no related separation problems, but there are few preparation methods for 3-methylcyclohexenone or 4-methylcyclohexenone, which limits the wide application of this method. Therefore, there is an urgent need to develop new and efficient preparation methods for cyclohexenone to achieve the cheap production of m-cresol and p-cresol. Summary of the Invention

[0008] The purpose of the present invention is to provide a simple method for synthesizing cyclohexenone derivatives from alkoxypropylene. This method uses phosphate ester and alkylaluminum hydride as catalysts, has mild reaction conditions, a wider substrate scope, and can obtain a series of dihydropyran intermediates in high yields; in the hydrolysis ring-opening and Aldol condensation ring-closing reactions of the dihydropyran intermediates, the recovery and reuse of the acid catalyst are realized, reducing the three wastes and the cost; compared with the previously reported methods, the overall yield of the route is significantly improved.

[0009] To achieve the above purpose and technical effects, the present invention adopts the following technical solutions:

[0010] A preparation method of cyclohexenone derivatives: using alkoxypropylene and α,β-unsaturated aldehyde as raw materials, first undergoing a Diels-Alder reaction to obtain a dihydropyran intermediate, and then the intermediate undergoes hydrolysis ring-opening and Aldol condensation ring-closing to finally obtain a series of cyclohexenone derivatives.

[0011] The structural formula of the alkoxypropylene is as follows:

[0012] Among them, R1 is methyl, ethyl, propyl, isopropyl or a C4-C10 alkyl substituent;

[0013] The structural formula of the α,β-unsaturated aldehyde is as follows:

[0014] , where R2 and R3 independently selected from methyl, ethyl, propyl or a C4-C10 alkyl substituent or substituents such as hydrogen, fluorine, chlorine, bromine, trifluoromethyl, phenyl, alkoxycarbonyl, nitro, etc.

[0015] In the present invention, the reaction route of the cyclohexenone derivative is shown as follows:

[0016]

[0017] Among them, the reaction mechanism of hydrolysis ring-opening and Aldol condensation ring-closing is as follows:

[0018]

[0019] In the present invention, the catalyst for the Diels - Alder reaction is obtained by in - situ mixing of a phosphate ester and an alkylaluminum hydride;

[0020] Preferably, the phosphate ester is selected from one or more of dimethyl phosphate, diethyl phosphate, dipropyl phosphate, diisopropyl phosphate, dibutyl phosphate, diphenyl phosphate, diisooctyl phosphate, bis(4 - nitrophenyl) phosphate, di - tert - butyl phosphate, bis(2 - methacryloyloxyethyl) hydrogen phosphate; preferably, the dosage of the phosphate ester is 0.5 - 4.0 mol% of the molar amount of the α,β - unsaturated aldehyde.

[0021] Preferably, the alkylaluminum hydride is selected from one or more of diethylaluminum hydride, dipropylaluminum hydride, dibutylaluminum hydride, diisobutylaluminum hydride, dicyclohexylaluminum hydride, diphenylaluminum hydride, phenylethylaluminum hydride, phenylisopropylaluminum hydride; preferably, the dosage of the alkylaluminum hydride is 0.5 - 4.0 mol% of the molar amount of the α,β - unsaturated aldehyde.

[0022] In the present invention, the feed molar ratio of the α,β - unsaturated aldehyde to the alkoxypropene is 1:5 to 1:12, and the two raw materials are fed in one - pot; the temperature of the Aldol condensation ring - closing reaction is 100 - 160 °C, preferably 110 - 130 °C, and the reaction time is 2 - 8 hours, preferably 4 - 6 hours.

[0023] In the present invention, the Diels - Alder reaction is preferably carried out under solvent - free conditions; if a solvent is added, aprotic solvents such as toluene, tetrahydrofuran, 2 - methyltetrahydrofuran, dichloroethane, ethyl acetate, etc. are preferred.

[0024] In the present invention, the conversion of the dihydropyran intermediate to cyclohexenone, that is, the hydrolysis ring - opening and Aldol condensation ring - closing reactions are carried out in one pot, and the hydrolysis ring - opening and Aldol condensation ring - closing reactions are catalyzed by an acid catalyst, preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, perchloric acid, etc.; the dosage of the acid catalyst is 5.0 - 20.0 mol% of the molar amount of the dihydropyran intermediate, and the concentration of the acid catalyst is 0.5 - 3.0 M.

[0025] In the present invention, a small amount of tertiary amine can be added to promote the reaction of the conversion of dihydropyran to cyclohexenone, and the tertiary amine is selected from one or more of tripropylamine, tributylamine, trioctylamine; the dosage is 0.5 - 1.0 mol% of the molar amount of the dihydropyran intermediate.

[0026] In the present invention, the hydrolysis ring-opening and Aldol condensation ring-closing reactions are carried out in a water-oil two-phase system, where the aqueous phase is an aqueous solution of an acid catalyst, and the oil phase is a dihydropyran raw material and a solvent; the solvent is selected from solvents immiscible with water, preferably one or more of petroleum ether, n-hexane, cyclohexane, n-heptane, toluene, dichloromethane, and dichloroethane.

[0027] In the present invention, the reaction pressure of the hydrolysis ring-opening and Aldol condensation ring-closing reactions is atmospheric pressure; and /

[0028] Or, the reaction temperature is 40 - 80 °C; and / or, the reaction time is 3 - 6 hours.

[0029] In the present invention, after the reaction of converting dihydropyran to cyclohexenone is completed, it further includes a step of refining and phase separation. The organic phase is the product and the solvent, and the aqueous phase is the catalyst acid solution; after the oil-water phase separation, the oil phase is separated by distillation to obtain the product, and the aqueous phase can be recycled and applied to the next batch of reactions.

[0030] The present invention adopts the above technical solutions and has the following positive effects:

[0031] 1. The raw materials such as alkoxypropylene, α,β-unsaturated aldehyde, and catalyst used in this method are easily available in large quantities and low in price. The synthetic route is novel and the yield is high, having a cost advantage;

[0032] 2. Using phosphate ester and alkylaluminum hydride as catalysts to promote the Diels-Alder reaction between alkoxypropylene and α,β-unsaturated aldehyde, the catalyst is novel. Combined with the optimization of conditions such as temperature and feeding ratio, the reaction time is significantly shortened and the reaction yield is improved, which is significantly better than the known literature reports, laying a foundation for the scale-up application of this method;

[0033] 3. The conversion of the dihydropyran intermediate to cyclohexenone is realized through a water-oil two-phase process, simplifying the process and the post-treatment process, realizing the recycling of the acid catalyst, with simple operation and easy scale-up, having a good application prospect; adding a small amount of tertiary amine in the reaction can, after combining with the acid catalyst, play a phase transfer catalytic role and accelerate the reaction yield. Specific Embodiments

[0034] The present invention will be described in detail below through examples, but the present invention is not limited to the following examples.

[0035] The main raw material information is as follows:

[0036] Crotonaldehyde, acrolein, methacrolein, Wanhua Chemical, 99%; 2-methoxypropylene, 2-pentenal, 3-chloro-2-butenal, 2-ethoxypropylene, 2-isopropoxypropylene, homemade, purity 99%; diphenyl phosphate, dimethyl phosphate, McLean Biochemical, 99%; diisobutylaluminum hydride toluene solution (1M, 2M), Xilong reagent; di(methacryloyloxyethyl) hydrogen phosphate, San Chemical, 99%; diethylaluminum hydride toluene solution (1M), dipropylaluminum hydride hexane solution (1M), Anage reagent, 95%; tripropylamine, tributylamine, trioctylamine, AR, Aladdin reagent.

[0037] Toluene, n-hexane, o-xylene, Xilong reagent, chromatographic grade. Cyclohexane, dichloroethane, n-heptane, Aladdin, AR. Hydrochloric acid (1.0M, 0.5M, 2.0M), sulfuric acid (1.2M), phosphoric acid (3.0M), hydrobromic acid (1.5M), Sinopharm reagent, AR, purchase concentrated acid and dilute it yourself before use. Sodium bicarbonate, sodium sulfate, Sinopharm reagent, AR.

[0038] The gas chromatography test conditions of the present invention are as follows:

[0039] Instrument model: Shimadzu GC-2010-plus; Chromatographic column: DB-3 (60m×0.25mm×0.25μm); Column temperature: Initial temperature 60℃, increase to 100℃ at 4℃ / min, then increase to 170℃ at 10℃ / min, and finally increase to 230℃ at 15℃ / min, and maintain for 8min; Inlet temperature: 280℃; FID detector temperature: 320℃; Split injection, split ratio 80:1; Injection volume: 0.2μL; Hydrogen flow rate: 40mL / min; Air flow rate: 400mL / min, tail gas flow rate 30mL / min. Carrier gas nitrogen, purity not less than 99.99%; fuel gas hydrogen, purity not less than 99.99%; Auxiliary gas (septum purge and tail): nitrogen with the same properties as the carrier gas.

[0040] Embodiment 1:

[0041] Diels-Alder Addition of Crotonaldehyde and 2-Methoxypropylene Catalyzed by Aluminum Phosphate

[0042] In the glove box, a toluene solution of diisobutylaluminum hydride (1 M, 10.0 mL) was added to a 100 mL single-necked flask equipped with a magnetic stir bar. The single-necked flask was placed on a magnetic stirrer and stirring was started (600 rpm). A toluene solution (10 mL) of diphenyl phosphate (2.5 g, 10.0 mmol) was slowly added to this solution. A small amount of bubbles were generated during the addition. After stirring and reacting for 20 minutes, a clear and homogeneous phosphoric acid-aluminum catalyst solution was obtained. The single-necked flask was sealed and taken out of the glove box, and was protected by a nitrogen balloon with strict nitrogen protection for standby. At room temperature, a 1 L autoclave was sealed. After checking for leaks with nitrogen (1.0 MPa) without problems, the autoclave was purged with nitrogen 3 times, and finally 0.1 MPa of nitrogen was retained. Crotonaldehyde (70.1 g, 1.0 mol) and 2-methoxypropene (576.9 g, 8.0 mol) were successively added to the autoclave with a peristaltic pump. Stirring was started (600 rpm). After the two were mixed evenly, the phosphoric acid-aluminum catalyst solution prepared previously was pumped into the autoclave with a peristaltic pump, and the pipeline was rinsed with a small amount of toluene to ensure that there was no catalyst residue in the feeding pipeline. After all the materials were added, heating was started. When the internal temperature of the reaction kettle reached 120 °C, timing was started. After heat preservation and stirring reaction for 4 hours, a sample was taken through the bottom tube of the reaction kettle, and the reaction solution was analyzed by GC. The aldehyde raw material was basically completely converted, and the selectivity of the product 2-methoxy-2,4-dimethyl-3,4-dihydropyran was 98.0%.

[0043] Example 2:

[0044] Phosphoric acid-aluminum catalyzed Diels-Alder addition of crotonaldehyde and 2-methoxypropene

[0045] In the glove box, a toluene solution of diisobutylaluminum hydride (1 M, 4.7 mL) was added to a 100 mL single-necked flask equipped with a magnetic stir bar. The single-necked flask was placed on a magnetic stirrer and stirring was started (600 rpm). A toluene solution (10 mL) of diphenyl phosphate (1.16 g, 4.7 mmol) was slowly added to this solution. A small amount of bubbles were generated during the addition. After stirring and reacting for 20 minutes, a clear and homogeneous phosphoric acid-aluminum catalyst solution was obtained. The single-necked flask was sealed and taken out of the glove box, and was strictly protected with nitrogen by a nitrogen balloon and reserved for use. At room temperature, a 1 L autoclave was sealed. After checking for leaks with nitrogen (1.0 MPa) without problems, the autoclave was purged with nitrogen 3 times, and finally 0.1 MPa of nitrogen was retained. Crotonaldehyde (65.2 g, 0.93 mol) and 2-methoxypropene (335.3 g, 4.65 mol) were successively added to the autoclave with a peristaltic pump. Stirring was started (600 rpm). After the two were mixed evenly, the phosphoric acid-aluminum catalyst solution prepared previously was pumped into the autoclave with a peristaltic pump, and the pipeline was rinsed with a small amount of toluene to ensure that there was no catalyst residue in the feeding pipeline. After all the materials were added, heating was started. When the internal temperature of the reaction kettle reached 160 °C, timing was started. After heat-insulating and stirring and reacting for 8 hours, a sample was taken through the bottom pipe of the reaction kettle, and the reaction solution was analyzed by GC. The aldehyde raw material was basically completely converted, and the selectivity of the product 2-methoxy-2,4-dimethyl-3,4-dihydropyran was 92.9%.

[0046] Example 3:

[0047] Diels-Alder addition of crotonaldehyde and 2-methoxypropene catalyzed by phosphoric acid-aluminum

[0048] In the glove box, a toluene solution of diisobutylaluminum hydride (2 M, 15.4 mL) was added to a 100 mL single-necked flask equipped with a magnetic stir bar. The single-necked flask was placed on a magnetic stirrer and stirring was started (600 rpm). A toluene solution (30 mL) of diphenyl phosphate (7.71 g, 30.8 mmol) was slowly added to this solution. A small amount of bubbles were generated during the addition. After stirring and reacting for 20 minutes, a clear and homogeneous phosphoric acid-aluminum catalyst solution was obtained. The single-necked flask was sealed and taken out of the glove box, and was strictly protected by a nitrogen balloon with nitrogen for standby. At room temperature, a 1 L autoclave was sealed. After checking for leaks with nitrogen (1.0 MPa) without problems, the autoclave was purged with nitrogen 3 times, and finally 0.1 MPa of nitrogen was retained. Crotonaldehyde (54.0 g, 0.77 mol) and 2-methoxypropene (666.3 g, 9.24 mol) were successively added to the autoclave with a peristaltic pump. Stirring was started (600 rpm). After the two were mixed evenly, the phosphoric acid-aluminum catalyst solution prepared previously was pumped into the autoclave with a peristaltic pump, and the pipeline was rinsed with a small amount of toluene to ensure that there was no catalyst residue in the feeding pipeline. After all the materials were added, heat tracing was started. When the internal temperature of the reaction kettle reached 100 °C, timing was started. After heat-preserving and stirring for 2 hours, a sample was taken through the bottom tube of the reaction kettle, and the reaction solution was analyzed by GC. The aldehyde raw material was basically completely converted, and the selectivity of the product 2-methoxy-2,4-dimethyl-3,4-dihydropyran was 99.3%.

[0049] Example 4:

[0050] Diels-Alder addition of crotonaldehyde and 2-methoxypropene catalyzed by phosphoric acid-aluminum

[0051] In the glove box, a toluene solution of diethylaluminum hydride (1 M, 6.9 mL) was added to a 100 mL single-necked flask equipped with a magnetic stir bar. The single-necked flask was placed on a magnetic stirrer and stirring was started (600 rpm). A toluene solution (10 mL) of bis(2-methacryloyloxyethyl) hydrogen phosphate (2.22 g, 6.9 mmol) was slowly added to this solution. A small amount of bubbles were generated during the addition. After stirring and reacting for 20 minutes, a clear and homogeneous phosphoric acid-aluminum catalyst solution was obtained. The single-necked flask was sealed and taken out of the glove box, and was strictly protected by a nitrogen balloon with nitrogen for standby. At room temperature, a 1 L autoclave was sealed. After checking for leaks with nitrogen (1.0 MPa) without problems, the autoclave was purged with nitrogen 3 times, and finally 0.1 MPa of nitrogen was retained. Crotonaldehyde (80.6 g, 1.15 mol) and 2-methoxypropene (497.5 g, 6.9 mol) were successively added to the autoclave with a peristaltic pump. Stirring was started (600 rpm). After the two were mixed evenly, the phosphoric acid-aluminum catalyst solution prepared previously was pumped into the autoclave with a peristaltic pump, and the pipeline was rinsed with a small amount of toluene to ensure that there was no catalyst residue in the feeding pipeline. After all the materials were added, heating was started. When the internal temperature of the reaction kettle reached 120 °C, timing was started. After heat-preserving and stirring the reaction for 4 hours, a sample was taken through the bottom pipe of the reaction kettle, and the reaction solution was analyzed by GC. The aldehyde raw material was basically completely converted, and the selectivity of the product 2-methoxy-2,4-dimethyl-3,4-dihydropyran was 98.6%.

[0052] Example 5:

[0053] Phosphoric acid-aluminum catalyzed Diels-Alder addition of 3-chloro-2-butenal and 2-ethoxypropene

[0054] In the glove box, a n-hexane solution of diisopropylaluminum hydride (1 M, 9.5 mL) was added to a 100 mL single-necked flask equipped with a magnetic stir bar. The single-necked flask was placed on a magnetic stirrer and stirring was started (600 rpm). A n-hexane solution (10 mL) of dimethyl phosphate (1.2 g, 9.5 mmol) was slowly added to this solution. A small amount of bubbles were generated during the addition. After stirring and reacting for 20 minutes, a clear and homogeneous phosphoric acid-aluminum catalyst solution was obtained. The single-necked flask was sealed and taken out of the glove box, and was strictly protected with nitrogen by a nitrogen balloon and reserved for use. At room temperature, a 1 L autoclave was sealed. After checking for leaks with nitrogen (1.0 MPa) without problems, the autoclave was purged with nitrogen 3 times, and finally 0.1 MPa of nitrogen was retained. 3-Chloro-2-butenal (99.3 g, 0.6 mol) and 2-ethoxypropene (491.0 g, 5.7 mol) were successively added to the autoclave with a peristaltic pump. Stirring was started (600 rpm). After the two were mixed evenly, the phosphoric acid-aluminum catalyst solution prepared previously was pumped into the autoclave with a peristaltic pump, and the pipeline was rinsed with a small amount of toluene to ensure that there was no catalyst residue in the feeding pipeline. After all the materials were added, heating was started. When the internal temperature of the reaction kettle reached 120 °C, timing was started. After heat-preserving and stirring for 4 hours, a sample was taken through the bottom tube of the reaction kettle, and the reaction solution was analyzed by GC. The aldehyde raw material was basically completely converted, and the selectivity of the product 4-chloro-2-ethoxy-2,4-dimethyl-3,4-dihydropyran was 97.7%.

[0055] Example 6:

[0056] Phosphoric acid-aluminum catalyzed Diels-Alder addition of acrolein and 2-isopropoxypropene

[0057] In the glove box, a toluene solution of diisobutylaluminum hydride (1 M, 4.2 mL) was added to a 100 mL single-necked flask equipped with a magnetic stir bar. The single-necked flask was placed on a magnetic stirrer and stirring was started (600 rpm). A toluene solution (10 mL) of bis(2-methacryloyloxyethyl) phosphate (1.34 g, 4.2 mmol) was slowly added to this solution. A small amount of bubbles were generated during the addition. After stirring and reacting for 20 minutes, a clear and homogeneous phosphoric acid-aluminum catalyst solution was obtained. The single-necked flask was sealed and taken out of the glove box, and was strictly protected with nitrogen using a nitrogen balloon and reserved for use. At room temperature, a 1 L autoclave was sealed. After checking for leaks with nitrogen (1.0 MPa) without problems, the autoclave was purged with nitrogen 3 times, and finally 0.1 MPa of nitrogen was retained. Acrolein (46.5 g, 0.83 mol) and 2-isopropoxypropene (581.9 g, 5.81 mol) were successively added to the autoclave using a peristaltic pump. Stirring was started (600 rpm). After the two were mixed evenly, the phosphoric acid-aluminum catalyst solution prepared previously was pumped into the autoclave using a peristaltic pump, and the pipeline was rinsed with a small amount of toluene to ensure that there was no catalyst residue in the feeding pipeline. After all the materials were added, heat tracing was started. When the internal temperature of the reaction kettle reached 100 °C, timing was started. After maintaining the temperature and stirring and reacting for 3 hours, a sample was taken through the bottom pipe of the reaction kettle, and the reaction solution was analyzed by GC. The aldehyde raw material was basically completely converted, and the selectivity of the product 2-isopropoxy-2-dimethyl-3,4-dihydropyran was 99.2%.

[0058] Example 7:

[0059] Phosphoric acid-aluminum catalyzed Diels-Alder addition of methacrolein and 2-methoxypropene

[0060] In the glove box, a toluene solution of diisobutylaluminum hydride (1 M, 11.6 mL) was added to a 100 mL single-necked flask equipped with a magnetic stir bar. The single-necked flask was placed on a magnetic stirrer and stirring was started (600 rpm). A toluene solution (15 mL) of bis(2-methacryloyloxyethyl) hydrogen phosphate (3.72 g, 11.6 mmol) was slowly added to this solution. A small amount of bubbles were generated during the addition. After stirring and reacting for 20 minutes, a clear and homogeneous phosphoric acid-aluminum catalyst solution was obtained. The single-necked flask was sealed and taken out of the glove box, and was strictly protected by a nitrogen balloon with nitrogen for standby. At room temperature, a 1 L autoclave was sealed. After checking for leaks with nitrogen (1.0 MPa) without problems, the autoclave was purged with nitrogen 3 times, and finally 0.1 MPa of nitrogen was retained. Methacrolein (54.0 g, 0.77 mol) and 2-methoxypropene (444.2 g, 6.16 mol) were successively added to the autoclave with a peristaltic pump. Stirring was started (600 rpm). After the two were mixed evenly, the phosphoric acid-aluminum catalyst solution prepared above was pumped into the autoclave with a peristaltic pump, and the pipeline was rinsed with a small amount of toluene to ensure that there was no catalyst residue in the feeding pipeline. After all the materials were added, heating was started. When the internal temperature of the reaction kettle reached 130 °C, timing was started. After heat-preserving and stirring for 6 hours, a sample was taken through the bottom tube of the reaction kettle, and the reaction solution was analyzed by GC. The aldehyde raw material was basically completely converted, and the selectivity of the product 2-methoxy-2,5-dimethyl-3,4-dihydropyran was 96.8%.

[0061] Example 8:

[0062] Phosphoric acid-aluminum catalyzed Diels-Alder addition of 2-pentenal and 2-methoxypropene

[0063] In the glove box, a toluene solution of diisobutylaluminum hydride (2 M, 4.9 mL) was added to a 100 mL single-necked flask equipped with a magnetic stir bar. The single-necked flask was placed on a magnetic stirrer and stirring was started (600 rpm). A toluene solution (15 mL) of bis(2-methacryloyloxyethyl) phosphate (3.14 g, 9.8 mmol) was slowly added to this solution. A small amount of bubbles were generated during the addition. After stirring and reacting for 20 minutes, a clear and homogeneous phosphoric acid-aluminum catalyst solution was obtained. The single-necked flask was sealed and taken out of the glove box, and was strictly protected by a nitrogen balloon with nitrogen for standby. At room temperature, a 1 L autoclave was sealed. After checking for leaks with nitrogen (1.0 MPa) without problems, the autoclave was purged with nitrogen 3 times, and finally 0.1 MPa of nitrogen was retained. 2-Pentenal (54.7 g, 0.65 mol) and 2-methoxypropene (375.0 g, 5.2 mol) were successively added to the autoclave with a peristaltic pump. Stirring was started (600 rpm). After they were mixed evenly, the previously prepared phosphoric acid-aluminum catalyst solution was pumped into the autoclave with a peristaltic pump, and the pipeline was rinsed with a small amount of toluene to ensure that there was no catalyst residue in the feeding pipeline. After all the materials were added, heating was started. When the internal temperature of the reaction kettle reached 130 °C, timing was started. After heat-preserving and stirring for 5 hours, samples were taken through the bottom tube of the reaction kettle, and the reaction solution was analyzed by GC. The aldehyde raw material was basically completely converted, and the selectivity of the product 2-methoxy-2-methyl-4-ethyl-3,4-dihydropyran was 99.1%.

[0064] Example 9:

[0065] Synthesis of 5-methyl-2-cyclohexenone from 2-methoxy-2,4-dimethyl-3,4-dihydropyran

[0066] In a nitrogen atmosphere, at room temperature, a 1 L three-necked flask equipped with a magnetic stir bar was placed in an oil bath. Then, solvent toluene (90 mL), tributylamine (0.24 g, 1.3 mmol), and hydrochloric acid (26.0 mL, concentration 1 M) were successively added, and stirring (800 rpm) and heating (55 °C) were started. A constant-pressure dropping funnel was connected above the three-necked flask, and 2-methoxy-2,4-dimethyl-3,4-dihydropyran (37.0 g, 0.26 mol) was loaded into the constant-pressure dropping funnel. When the temperature of the reaction solution in the three-necked flask reached 55 °C, the dihydropyran intermediate was slowly added dropwise to the reaction solution, and the addition was completed in 1 hour. After the addition was completed, the reaction was continued for 5 hours under constant temperature and rapid stirring. The oil phase was taken for analysis. After adding the internal standard o-xylene, GC chromatography analysis was carried out. The conversion rate of the dihydropyran intermediate > 99%, and the selectivity of 5-methyl-2-cyclohexenone was 87%. For post-treatment, the reaction solution was cooled to room temperature and then poured into a separatory funnel. After the oil and water were separated, the oil phase was washed twice with 10 wt% sodium bicarbonate, dried over anhydrous sodium sulfate, and then the solvent toluene and the product 5-methyl-2-cyclohexenone were separated by distillation.

[0067] Example 10:

[0068] Synthesis of 5-methyl-2-cyclohexenone from 2-methoxy-2,4-dimethyl-3,4-dihydropyran

[0069] In a nitrogen atmosphere, at room temperature, a 1 L three-necked flask equipped with a magnetic stirrer was placed in an oil bath. Then, successively, the solvent toluene (100 mL), tributylamine (0.50 g, 2.7 mmol), and hydrochloric acid (27.0 mL, concentration 0.5 M) were added. Stirring (800 rpm) and heating (85 °C) were started. A constant-pressure dropping funnel was connected above the three-necked flask, and 2-methoxy-2,4-dimethyl-3,4-dihydropyran (38.4 g, 0.27 mol) was loaded into the constant-pressure dropping funnel. When the temperature of the reaction solution in the three-necked flask reached 80 °C, the dihydropyran intermediate was slowly added dropwise to the reaction solution, and the addition was completed in 1 hour. After the addition was completed, the reaction was continued for 6 hours under constant temperature and rapid stirring. The oil phase was taken for analysis, and after adding the internal standard o-xylene, GC chromatography analysis was carried out. The conversion rate of the dihydropyran intermediate > 99%, and the selectivity of 5-methyl-2-cyclohexenone was 95%. For post-treatment, the reaction solution was cooled to room temperature and then poured into a separatory funnel. After phase separation of the oil and water, the oil phase was washed twice with 10 wt% sodium bicarbonate, dried over anhydrous sodium sulfate, and then the solvent toluene and the product 5-methyl-2-cyclohexenone were separated by distillation.

[0070] Example 11:

[0071] Synthesis of 5-methyl-2-cyclohexenone from 2-methoxy-2,4-dimethyl-3,4-dihydropyran

[0072] In a nitrogen atmosphere, at room temperature, a 1 L three-necked flask equipped with a magnetic stirrer was placed in an oil bath. Then, successively, the solvent toluene (100 mL), tributylamine (0.29 g, 1.6 mmol), and hydrochloric acid (31 mL, concentration 2 M) were added. Stirring (800 rpm) and heating (55 °C) were started. A constant-pressure dropping funnel was connected above the three-necked flask, and 2-methoxy-2,4-dimethyl-3,4-dihydropyran (44.1 g, 0.31 mol) was loaded into the constant-pressure dropping funnel. When the temperature of the reaction solution in the three-necked flask reached 50 °C, the dihydropyran intermediate was slowly added dropwise to the reaction solution, and the addition was completed in 1 hour. After the addition was completed, the reaction was continued for 3 hours under constant temperature and rapid stirring. The oil phase was taken for analysis, and after adding the internal standard o-xylene, GC chromatography analysis was carried out. The conversion rate of the dihydropyran intermediate > 99%, and the selectivity of 5-methyl-2-cyclohexenone was 98%. For post-treatment, the reaction solution was cooled to room temperature and then poured into a separatory funnel. After phase separation of the oil and water, the oil phase was washed twice with 10 wt% sodium bicarbonate, dried over anhydrous sodium sulfate, and then the solvent toluene and the product 5-methyl-2-cyclohexenone were separated by distillation.

[0073] Example 12:

[0074] Synthesis of 2 - cyclohexenone from 2 - isopropoxy - 2 - methyl - 3,4 - dihydropyran

[0075] Under a nitrogen atmosphere, at room temperature, a 1 L three - necked flask equipped with a magnetic stirrer was placed in an oil bath. Then, successively added were the solvent cyclohexane (80 mL), tripropylamine (0.19 g, 1.3 mmol), and sulfuric acid (21.7 mL, concentration 1.2 M). Stirring (800 rpm) and heating (55 °C) were started. A constant - pressure dropping funnel was connected above the three - necked flask, and 2 - isopropoxy - 2 - methyl - 3,4 - dihydropyran (40.6 g, 0.26 mol) was charged into the constant - pressure dropping funnel. When the temperature of the reaction solution in the three - necked flask reached 50 °C, the dihydropyran intermediate was slowly added dropwise to the reaction solution, and the addition was completed in 1 hour. After the addition was completed, the reaction was continued for 3 hours under constant temperature and rapid stirring. The oil phase was taken for analysis, and after adding the internal standard o - xylene, GC chromatography analysis was carried out. The conversion rate of the dihydropyran intermediate > 99%, and the selectivity of 2 - cyclohexenone was 96%. For post - treatment, the reaction solution was cooled to room temperature and then poured into a separatory funnel. After phase separation of the oil and water, the oil phase was washed twice with 10 wt% sodium bicarbonate, dried over anhydrous sodium sulfate, and then the solvent cyclohexane and the product 2 - cyclohexenone were separated by distillation.

[0076] Example 13:

[0077] Synthesis of 4 - methyl - 2 - cyclohexenone from 2 - methoxy - 2,5 - dimethyl - 3,4 - dihydropyran

[0078] Under a nitrogen atmosphere, at room temperature, a 1 L three - necked flask equipped with a magnetic stirrer was placed in an oil bath. Then, successively added were the solvent dichloroethane (120 mL), trioctylamine (0.58 g, 1.7 mmol), and phosphoric acid (22 mL, concentration 3 M). Stirring (800 rpm) and heating (55 °C) were started. A constant - pressure dropping funnel was connected above the three - necked flask, and 2 - methoxy - 2,5 - dimethyl - 3,4 - dihydropyran (46.9 g, 0.33 mol) was charged into the constant - pressure dropping funnel. When the temperature of the reaction solution in the three - necked flask reached 50 °C, the dihydropyran intermediate was slowly added dropwise to the reaction solution, and the addition was completed in 1 hour. After the addition was completed, the reaction was continued for 3 hours under constant temperature and rapid stirring. The oil phase was taken for analysis, and after adding the internal standard o - xylene, GC chromatography analysis was carried out. The conversion rate of the dihydropyran intermediate > 99%, and the selectivity of 4 - methyl - 2 - cyclohexenone was 98%. For post - treatment, the reaction solution was cooled to room temperature and then poured into a separatory funnel. After phase separation of the oil and water, the oil phase was washed twice with 10 wt% sodium bicarbonate, dried over anhydrous sodium sulfate, and then the solvent dichloroethane and the product 4 - methyl - 2 - cyclohexenone were separated by distillation.

[0079] Example 14:

[0080] Synthesis of 5-ethyl-2-cyclohexenone from 2-methoxy-2-methyl-4-ethyl-3,4-dihydropyran

[0081] In a nitrogen atmosphere, at room temperature, a 1 L three-necked flask equipped with a magnetic stirrer was placed in an oil bath. Then, successively added were the solvent n-heptane (120 mL), tributylamine (0.26 g, 1.4 mmol), and hydrobromic acid (37.3 mL, concentration 1.5 M). Stirring (800 rpm) and heating (65 °C) were started. A constant pressure dropping funnel was connected above the three-necked flask, and 2-methoxy-2-methyl-4-ethyl-3,4-dihydropyran (43.7 g, 0.28 mol) was charged into the constant pressure dropping funnel. After the temperature of the reaction solution in the three-necked flask reached 60 °C, the dihydropyran intermediate was slowly added dropwise to the reaction solution, and the addition was completed in 1 hour. After the addition was completed, the reaction was continued for 4 hours while maintaining constant temperature and rapid stirring. The oil phase was taken for analysis, and after adding the internal standard o-xylene, GC chromatography analysis was carried out. The conversion rate of the dihydropyran intermediate > 99%, and the selectivity of 5-ethyl-2-cyclohexenone was 97%. For post-treatment, the reaction solution was cooled to room temperature and then poured into a separatory funnel. After the oil and water were separated, the oil phase was washed twice with 10 wt% sodium bicarbonate, dried over anhydrous sodium sulfate, and then the solvent n-heptane and the product 5-ethyl-2-cyclohexenone were separated by distillation.

[0082] Example 15:

[0083] Synthesis of 5-ethyl-2-cyclohexenone from 2-methoxy-2-methyl-4-ethyl-3,4-dihydropyran

[0084] In a nitrogen atmosphere, at room temperature, a 1 L three-necked flask equipped with a magnetic stirrer was placed in an oil bath. Then, successively added were the solvent n-heptane (120 mL) and the aqueous phase recovered in Example 14 (37.0 mL). Stirring (800 rpm) and heating (65 °C) were started. A constant pressure dropping funnel was connected above the three-necked flask, and 2-methoxy-2-methyl-4-ethyl-3,4-dihydropyran (43.7 g, 0.28 mol) was charged into the constant pressure dropping funnel. After the temperature of the reaction solution in the three-necked flask reached 60 °C, the dihydropyran intermediate was slowly added dropwise to the reaction solution, and the addition was completed in 1 hour. After the addition was completed, the reaction was continued for 4 hours while maintaining constant temperature and rapid stirring. The oil phase was taken for analysis, and after adding the internal standard o-xylene, GC chromatography analysis was carried out. The conversion rate of the dihydropyran intermediate > 99%, and the selectivity of 5-ethyl-2-cyclohexenone was 96%. For post-treatment, the reaction solution was cooled to room temperature and then poured into a separatory funnel. After the oil and water were separated, the oil phase was washed twice with 10 wt% sodium bicarbonate, dried over anhydrous sodium sulfate, and then the solvent n-heptane and the product 5-ethyl-2-cyclohexenone were separated by distillation.

[0085] Comparative Example 1

[0086] Diels-Alder addition of crotonaldehyde and 2-methoxypropene catalyzed by phosphoric acid

[0087] In a nitrogen atmosphere, diphenyl phosphate (2.5 g, 10.0 mmol) was dissolved in toluene (20 mL) to obtain a clear and homogeneous solution. After sealing the single-necked flask, it was protected with a nitrogen balloon and set aside. At room temperature, a 1 L autoclave was sealed. After checking for leaks with nitrogen (1.0 MPa), the autoclave was purged with nitrogen three times, and finally 0.1 MPa of nitrogen was retained. Using a peristaltic pump, crotonaldehyde (70.1 g, 1.0 mol) and 2-methoxypropene (576.9 g, 8.0 mol) were successively added to the autoclave. Stirring was started (600 rpm). After the two were mixed evenly, the previously prepared phosphate solution was pumped into the autoclave using a peristaltic pump, and the pipeline was rinsed with a small amount of toluene to ensure that there was no catalyst residue in the feeding pipeline. After all the materials were added, heating was started. When the internal temperature of the reaction kettle reached 120 °C, timing began. After maintaining the temperature and stirring for 4 hours, a sample was taken through the bottom tube of the reaction kettle, and the reaction solution was analyzed by GC. The aldehyde conversion rate was 58.0%, and the selectivity of the product 2-methoxy-2,4-dimethyl-3,4-dihydropyran was 73.0%.

[0088] Comparative Example 2:

[0089] Diels-Alder addition of crotonaldehyde and 2-methoxypropene catalyzed by alkylaluminum hydride

[0090] In a glove box, a toluene solution of diisobutylaluminum hydride (1 M, 10.0 mL) was added to a single-necked flask. The single-necked flask was sealed and taken out of the glove box, and was strictly protected with a nitrogen balloon and set aside. At room temperature, a 1 L autoclave was sealed. After checking for leaks with nitrogen (1.0 MPa) without problems, the autoclave was purged with nitrogen three times, and finally 0.1 MPa of nitrogen was retained. Using a peristaltic pump, crotonaldehyde (70.1 g, 1.0 mol) and 2-methoxypropene (576.9 g, 8.0 mol) were successively added to the autoclave. Stirring was started (600 rpm). After the two were mixed evenly, the aluminum catalyst solution in the single-necked flask was pumped into the autoclave using a peristaltic pump, and the pipeline was rinsed with a small amount of toluene to ensure that there was no catalyst residue in the feeding pipeline. After all the materials were added, heating was started. When the internal temperature of the reaction kettle reached 120 °C, timing began. After maintaining the temperature and stirring for 4 hours, a sample was taken through the bottom tube of the reaction kettle, and the reaction solution was analyzed by GC. The aldehyde conversion rate was 31.0%, and the selectivity of the product 2-methoxy-2,4-dimethyl-3,4-dihydropyran was 48.6%. Comparative Example 3:

[0091] Synthesis of 5-methyl-2-cyclohexenone from 2-methoxy-2,4-dimethyl-3,4-dihydropyran

[0092] In a nitrogen atmosphere, a 1 L three-necked flask equipped with a magnetic stir bar was placed in an oil bath at room temperature. Then, solvent methanol (90 mL) and hydrochloric acid (26.0 mL, concentration 5 M) were added successively. The mixture was homogeneous. Stirring (800 rpm) and heating (55 °C) were started. A constant pressure dropping funnel was connected above the three-necked flask, and 2-methoxy-2,4-dimethyl-3,4-dihydropyran (37.0 g, 0.26 mol) was loaded into the constant pressure dropping funnel. When the temperature of the reaction solution in the three-necked flask reached 55 °C, the dihydropyran intermediate was slowly added dropwise to the reaction solution, and the addition was completed in 1 hour. After the addition was completed, the reaction was continued for 5 hours under constant temperature and rapid stirring. The oil phase was taken for analysis. After adding the internal standard o-xylene, GC chromatographic analysis was carried out. The conversion rate of the dihydropyran intermediate > 99%, and the selectivity of 5-methyl-2-cyclohexenone was 63%. For the post-treatment, after the reaction solution was cooled to room temperature, saturated sodium carbonate aqueous solution (60 mL) was added to neutralize the hydrochloric acid. Then it was poured into a separating funnel. After the oil and water were separated, the organic phase was dried over anhydrous sodium sulfate, and the product 5-methyl-2-cyclohexenone was obtained by fractional distillation.

Claims

1. A method for preparing a cyclohexenone derivative, the method comprising the following steps: using alkoxypropylene and α,β-unsaturated aldehyde as raw materials, first undergoing a Diels-Alder reaction to obtain a dihydropyran intermediate This intermediate then undergoes hydrolysis ring-opening and Aldol condensation ring-closing to finally obtain a series of cyclohexenone derivatives The catalyst for the Diels-Alder reaction is obtained by in-situ mixing of a phosphate ester and an alkylaluminum hydride; the phosphate ester is selected from one or more of dimethyl phosphate, diethyl phosphate, dipropyl phosphate, diisopropyl phosphate, dibutyl phosphate, diphenyl phosphate, diisooctyl phosphate, bis(2-methacryloyloxyethyl) hydrogen phosphate; the alkylaluminum hydride is selected from diethylaluminum hydride, dipropylaluminum hydride, dibutylaluminum hydride, diisobutylaluminum hydride; The structural formula of the α,β-unsaturated aldehyde is as follows: Among them, R2 and R3 are independently selected from methyl, ethyl, propyl or C4-C10 alkyl substituents, or hydrogen, fluorine, chlorine, bromine, trifluoromethyl, phenyl, alkoxycarbonyl, nitro substituents; The structural formula of the alkoxypropylene is as follows: Among them, R1 is a methyl, ethyl, propyl or C4-C10 alkyl substituent.

2. The preparation method according to claim 1, characterized in that, The dosage of the phosphate ester is 0.5-4.0 mol% of the molar amount of the α,β-unsaturated aldehyde.

3. The preparation method according to claim 1, characterized in that The dosage of the alkylaluminum hydride is 0.5-4.0 mol% of the molar amount of the α,β-unsaturated aldehyde.

4. The preparation method according to any one of claims 1-3, characterized in that, The feed molar ratio of the α,β-unsaturated aldehyde and the alkoxypropylene is 1:5 to 1:12, and the two raw materials are fed in one-pot.

5. The preparation method according to any one of claims 1 to 3, characterized in that, The Diels-Alder reaction is carried out under solvent-free conditions.

6. The preparation method according to any one of claims 1-3, characterized in that, The solvent for the Diels-Alder reaction is selected from aprotic solvents such as toluene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloroethane, ethyl acetate.

7. The preparation method according to any one of claims 1-3, characterized in that The conversion of the dihydropyran intermediate to the cyclohexenone derivative, namely the hydrolysis ring-opening and Aldol condensation ring-closing reactions, are carried out in one pot; the hydrolysis ring-opening and Aldol condensation ring-closing reactions are catalyzed by an acid catalyst, and the acid catalyst is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, perchloric acid; the dosage of the acid catalyst is 5.0-20.0 mol% of the molar amount of the dihydropyran intermediate, and the concentration of the acid catalyst is 0.5-3.0 M.

8. The preparation method according to claim 7, characterized in that A small amount of tertiary amine is also added to promote the reaction in the conversion of the dihydropyran intermediate to the cyclohexenone derivative, and the tertiary amine is selected from one or more of tripropylamine, tributylamine, trioctylamine; the dosage of the tertiary amine is 0.5-1.0 mol% of the molar amount of the dihydropyran intermediate.

9. The preparation method according to any one of claims 1 to 3, characterized in that, The hydrolysis ring-opening and Aldol condensation ring-closing reactions are carried out in a water-oil two-phase system, where the aqueous phase is an aqueous solution of the acid catalyst, and the oil phase is the dihydropyran raw material and the solvent; the solvent is selected from solvents immiscible with water.

10. The preparation method according to claim 9, characterized in that, The solvent is one or more of petroleum ether, n-hexane, cyclohexane, n-heptane, toluene, dichloromethane, dichloroethane.

11. The preparation method according to any one of claims 1 to 3, characterized in that, The reaction pressure of the hydrolysis ring-opening and Aldol condensation ring-closing reactions is atmospheric pressure; and / or, the reaction temperature is 40-80 °C; and / or, the reaction time is 3-6 hours; and / or, after the conversion of the dihydropyran intermediate to the cyclohexenone derivative reaction is completed, it also includes a step of refining and phase separation. The organic phase is the product and the solvent, and the aqueous phase is the catalyst acid solution; after the oil-water phase separation, the oil phase is separated by distillation to obtain the product, and the aqueous phase is recycled and applied to the next batch of reactions.

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