Synthesis method of butylphenylmorpholine

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthetic method of butylphenylmorpholine, which comprises the following steps of: reacting tert-butylbenzene with propionyl chloride to obtain tert-butylpropiophenone, reacting the product with cis-2, 6-dimethylmorpholine and paraformaldehyde to obtain 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2, 6-dimethylmorpholine-4-) propyl) benzene, and reacting the 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2, 6-dimethylmorpholine-4-) propyl) benzene with the product to obtain the butylphenylmorpholine. And reducing hydrogen under the action of a catalyst to obtain the butylphenylmorpholine. By optimizing a raw material route and process conditions, the defects of high cost, low purity and dependence on an acid-binding agent in the prior art are overcome, special equipment is not needed, and the method is suitable for industrial continuous production.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for synthesizing butylmorpholine. Background Technology

[0002] Butylmorpholine, also known as fipronil or propiconazole, is a colorless, aromatic, oily liquid with a boiling point above 300°C. It is a systemic morpholine fungicide and ergosterol reduction inhibitor with both preventative and curative effects. Developed and produced by BASF and Syngenta, it was launched in 1980 under the trade name Corbel and has shown good control effects against powdery mildew in cereals.

[0003] Chinese invention patent CN103275030A discloses a method for synthesizing butylmorpholine. This method uses lily alcohol as a raw material, undergoes an esterification reaction with methanesulfonyl chloride, and then reacts with 2,6-dimethylmorpholine in a substitution reaction to synthesize butylmorpholine. The main drawback of this method is the high cost of lily alcohol methanesulfonyl chloride and the requirement for an acid-binding agent in the reaction, resulting in high synthesis costs and making it unsuitable for large-scale industrial production. Some manufacturers replace methanesulfonyl chloride with thionyl chloride, first synthesizing chlorolily alcohol before reacting it with 2,6-dimethylmorpholine. While this reduces costs to some extent, thionyl chloride and its products are highly corrosive, and the product purity is low, limiting industrial production. Summary of the Invention

[0004] To address the problems existing in the prior art, this invention provides a simple, high-yield, and low-cost method for synthesizing butyromorpholine.

[0005] To solve the above-mentioned technical problems, the present invention provides a method for synthesizing butylmorpholine, comprising the following steps: S1. Add 50-60g of cis-2,6-dimethylmorpholine to 500mL of polar hydrophilic solvent, stir at room temperature for 10min, control the temperature at 20℃, and pass HCl gas to form salt for 2h to obtain a mixture containing cis-2,6-dimethylmorpholine hydrochloride. S2. Add 10-25g of paraformaldehyde and 90-105g of tert-butylacetone to the mixture, heat to 50℃, add protic acid catalyst, start stirring, reflux for 4h, after the reaction is completed, remove the polar hydrophilic solvent by rotary evaporation, add 300mL of acetone and stir for 15min, let stand, filter and dry to obtain 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propyl)benzene; S3. Add the catalyst, 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propyl)benzene, and 500 mL of polar hydrophilic solvent to a high-pressure reactor. The amount of catalyst is 3-8% of the mass of 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propyl)benzene. Purge with hydrogen to 3-10 MPa, raise the temperature to 60°C, and react until the pressure is constant. S4. After the reaction is complete, filter out the catalyst, add sodium hydroxide methanol solution to adjust the pH to ≥10.0, remove the polar hydrophilic solvent by vacuum distillation, add water to separate the phases, and then perform vacuum distillation on the separated organic phases to collect the fraction to obtain butylmorpholine.

[0006] Preferably, the tert-butylacetone comprises the following preparation steps: S21. Add Lewis acid catalyst and 400 mL aprotic solvent to the reaction vessel and stir at room temperature for 10 min to form a homogeneous catalytic system. S22. After stirring, add 90-100g of propionyl chloride and 130-145g of tert-butylbenzene to the catalytic system and stir to react; S23. After the reaction is complete, 150 mL of ice water is poured into the product and stirred for 30 min. The separated organic phase is washed with 30 mL of dilute hydrochloric acid and then washed with water until neutral. 5 g of anhydrous sodium sulfate is added for drying. The product is then distilled at atmospheric pressure to remove the aprotic solvent and obtain tert-butylacetone.

[0007] Preferably, the propionyl chloride comprises the following preparation steps: S221. Add 70-80g of propionic acid and 230-245g of thionyl chloride to the reaction vessel, and add 3-5mL of N,N-dimethylformamide dropwise. After the addition is complete, stir and reflux for 5h. S222. After the reaction is complete, distill at atmospheric pressure, collect the fraction, and obtain propionyl chloride.

[0008] Preferably, the polar hydrophilic solvent is one of methanol, ethanol, isopropanol, dimethylformamide, and dimethyl sulfoxide.

[0009] Preferably, the protic acid catalyst is one of hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, formic acid, and acetic acid.

[0010] Preferably, the catalyst is one of Raney nickel, palladium on carbon, or platinum on carbon.

[0011] Preferably, the aprotic solvent is one of dichloromethane, chloroform, carbon tetrachloride, toluene, and tetrahydrofuran.

[0012] Preferably, the Lewis acid catalyst is used in an amount of 100% to 300% of the molar amount of tert-butylbenzene.

[0013] Preferably, the Lewis acid catalyst is one of aluminum trichloride, aluminum chloride, zinc chloride, ferric chloride, and boron trifluoride diethyl ether.

[0014] After adopting the above technical solution, the beneficial effects of the present invention are: This invention overcomes the shortcomings of existing technologies, such as high cost, low purity, and dependence on acid-binding agents, by optimizing raw material routes and process conditions. It requires no special equipment and is suitable for continuous industrial production. Attached Figure Description

[0015] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0016] Figure 1 Here is the gas chromatogram of Example 1; Figure 2 Here is the gas chromatogram of Example 2; Figure 3 Here is the gas chromatogram of Example 3; Figure 4 This is the gas chromatogram of Example 4. Detailed Implementation

[0017] The features and exemplary embodiments of various aspects of the present invention will now be described in detail. To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are only configured to explain the present invention and are not configured to limit the present invention. For those skilled in the art, the present invention can be practiced without some of these specific details. The following description of the embodiments is merely to provide a better understanding of the present invention by illustrating examples of the invention.

[0018] Example 1 This embodiment provides a method for synthesizing butylmorpholine. The specific preparation steps and technical details are as follows.

[0019] I. Preparation of propionyl chloride Add 70g of propionic acid and 230g of thionyl chloride to a dry reaction vessel, and then add 3mL of N,N-dimethylformamide (DMF) as a catalyst. After the addition is complete, start stirring to ensure that the propionic acid, thionyl chloride, and catalyst are in full contact, avoiding uneven local concentrations that could lead to incomplete reaction.

[0020] After reflux for 5 hours, the product was distilled at atmospheric pressure, and the fraction at 80°C was collected to obtain a colorless and transparent liquid, which is propionyl chloride.

[0021] II. Preparation of tert-butylacetone Add 130g of aluminum trichloride and 400mL of dichloromethane to the reaction vessel and stir at room temperature for 10min to form a homogeneous catalytic system, thus avoiding slow or incomplete reaction start-up due to excessively low local catalyst concentration.

[0022] After stirring, 90 g of propionyl chloride and 130 g of tert-butylbenzene were added to the homogeneous catalytic system, and the reaction was stirred. The reaction endpoint was monitored by thin-layer chromatography, and the reaction was terminated when the tert-butylbenzene starting material spot disappeared.

[0023] After the reaction was complete, 150 mL of ice water was poured into the product for quenching, and the mixture was stirred for 30 min. The mixture was allowed to stand and separate into layers. The organic phase was washed 2–3 times with 30 mL of 5% hydrochloric acid, and then washed with water until neutral. 5 g of anhydrous sodium sulfate was added to the organic phase to adsorb any residual moisture and ensure the product remained dry.

[0024] The dried organic phase was distilled at atmospheric pressure to remove the solvent, and the fraction was collected to obtain a yellow transparent liquid, which is tert-butylacetone.

[0025] The amount of aluminum trichloride added should be 1 times the molar amount of tert-butylbenzene. It can be replaced by one of the Lewis acid catalysts, such as aluminum chloride, zinc chloride, ferric chloride, or boron trifluoride diethyl ether. Dichloromethane can be replaced by one of the aprotic solvents, such as chloroform, carbon tetrachloride, toluene, or tetrahydrofuran.

[0026] III. Preparation of 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propyl)benzene Add 50g of cis-2,6-dimethylmorpholine to 500mL of methanol, stir at room temperature for 10min, control the temperature at 20℃, introduce dry HCl gas, and react for 2h to obtain a mixture containing cis-2,6-dimethylmorpholine hydrochloride.

[0027] Add 10g of paraformaldehyde and 90g of tert-butylacetone to the mixture, heat to 50℃, add 0.5mL of concentrated hydrochloric acid, start stirring, and reflux for 4h.

[0028] After the reaction was completed, methanol was removed by rotary evaporation, 300 mL of acetone was added and stirred for 15 min, allowed to stand, filtered and dried to obtain white crystals, which were 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propyl)benzene.

[0029] Methanol can be replaced by one of the following polar hydrophilic solvents: ethanol, isopropanol, dimethylformamide, or dimethyl sulfoxide. Concentrated hydrochloric acid can be replaced by one of the following protic acids: sulfuric acid, hydrobromic acid, phosphoric acid, formic acid, or acetic acid.

[0030] IV. Synthesis of Butyromorpholine Platinum carbon (Pt / C) and all of the 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propylbenzene obtained in step 3 were added to 500 mL of methanol in a high-pressure reactor. The amount of platinum carbon used was 3% of the mass of 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propylbenzene. Hydrogen gas was introduced to 3 MPa, and the temperature was raised to 60 °C. The reaction was continued until the system pressure was constant (no more hydrogen gas was consumed), and the reaction was completed.

[0031] Platinum on carbon can be used as a catalyst, but it can be replaced by either Raney nickel or palladium on carbon (Pd / C).

[0032] After the reaction was completed, residual hydrogen was released, platinum carbon was filtered off, sodium hydroxide methanol solution was added to adjust the pH to ≥10.0, methanol was removed by vacuum distillation, 200 mL of water was added for phase separation, the separated organic phase was subjected to vacuum distillation, and the fraction was collected to obtain butylmorpholine.

[0033] The overall synthetic equation for butylmorpholine is as follows:

[0034] like Figure 1 As shown, the content of butylmorpholine is 98.377%.

[0035] Example 2 Unlike Example 1, step four does not involve hydrogenation reduction; specifically: 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propyl)benzene was added to 500 mL of methanol in a reaction vessel, and the pH was adjusted to 2.0 by adding glacial acetic acid dropwise. Zinc powder was added, with the amount of zinc powder being 1.2 times the molar amount of 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propyl)benzene. The temperature was raised to 40 °C, and the reaction was carried out for 3 h. After the reaction was completed, the zinc powder was filtered off, and the pH was adjusted to ≥10 by adding sodium hydroxide methanol solution. Methanol was removed by vacuum distillation, and 200 mL of water was added for phase separation. The separated organic phase was then subjected to vacuum distillation, and the fraction collected yielded butyl morpholine.

[0036] like Figure 2 As shown, the content of butylmorpholine is 98.347%.

[0037] Example 3 This embodiment provides a method for synthesizing butylmorpholine. The specific preparation steps and technical details are as follows.

[0038] 1) Add 74g of propionic acid and 236g of thionyl chloride to the reaction vessel, add 3.5mL of LDMF dropwise, start stirring after the addition is complete, reflux the reaction for 5h, and then distill the product under normal pressure, collect the fraction at 80℃ to obtain propionyl chloride; 2) Add aluminum trichloride and 400 mL of dichloromethane to the reaction vessel and stir at room temperature for 10 min to form a homogeneous catalytic system. The amount of aluminum trichloride added is 1.5 times the molar amount of tert-butylbenzene. 3) Add 95g propionyl chloride and 134g tert-butylbenzene to the homogeneous catalytic system, stir the reaction, monitor the reaction endpoint by thin-layer chromatography, and terminate the reaction when the tert-butylbenzene starting material spot disappears. 4) After the reaction is complete, pour 150 mL of ice water into the product to quench it, stir for 30 min, wash the separated organic phase 2-3 times with 30 mL of 5% hydrochloric acid, wash with water until neutral, add 5 g of anhydrous sodium sulfate to the organic phase, and distill the dried organic phase under normal pressure to remove the solvent, collect the distillate to obtain tert-butylphenylacetone. 5) Add 57g of cis-2,6-dimethylmorpholine to 500mL of methanol, stir at room temperature for 10min, control the temperature at 20℃, and pass dry HCl gas through to form salt for 2h to obtain a mixture containing cis-2,6-dimethylmorpholine hydrochloride. 6) Add 15g of paraformaldehyde and 95g of tert-butylacetone to the mixture, heat to 50℃, add 0.8mL of concentrated hydrochloric acid, start stirring, and reflux for 4h. 7) After the reaction was completed, methanol was removed by rotary evaporation, 300 mL of acetone was added and stirred for 15 min, allowed to stand, filtered and dried to obtain 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propyl)benzene.

[0039] 8) Add platinum carbon (Pt / C) and 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propylbenzene to 500 mL of methanol in a high-pressure reactor. The amount of platinum carbon is 5% of the mass of 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propylbenzene. Purge with hydrogen to 5 MPa, heat to 60 °C, and react until the system pressure is constant. The reaction is then complete. 9) After the reaction is complete, release the residual hydrogen gas, filter out the platinum carbon, add sodium hydroxide methanol solution to adjust the pH to ≥10.0, remove methanol by vacuum distillation, add 200mL of water for phase separation, and perform vacuum distillation on the separated organic phase to collect the fraction to obtain butylmorpholine.

[0040] like Figure 3 As shown, the content of butylmorpholine is 98.405%.

[0041] Example 4 This embodiment provides a method for synthesizing butylmorpholine. The specific preparation steps and technical details are as follows.

[0042] 1) Add 80g of propionic acid and 245g of thionyl chloride to the reaction vessel, add 5ml of LDMF dropwise, start stirring after the addition is complete, reflux for 5h, and then distill the product under normal pressure, collect the fraction at 80℃ to obtain propionyl chloride; 2) Add aluminum trichloride and 400 mL of dichloromethane to the reaction vessel and stir at room temperature for 10 min to form a homogeneous catalytic system. The amount of aluminum trichloride added is 3 times the molar amount of tert-butylbenzene. 3) Add 100g propionyl chloride and 145g tert-butylbenzene to the homogeneous catalytic system, stir the reaction, monitor the reaction endpoint by thin-layer chromatography, and terminate the reaction when the tert-butylbenzene starting material spot disappears. 4) After the reaction is complete, pour 150 mL of ice water into the product to quench it, stir for 30 min, wash the separated organic phase 2-3 times with 30 mL of 5% hydrochloric acid, wash with water until neutral, add 5 g of anhydrous sodium sulfate to the organic phase, and distill the dried organic phase under normal pressure to remove the solvent, collect the distillate to obtain tert-butylphenylacetone. 5) Add 60g of cis-2,6-dimethylmorpholine to 500mL of methanol, stir at room temperature for 10min, control the temperature at 20℃, and pass dry HCl gas through to form salt for 2h to obtain a mixture containing cis-2,6-dimethylmorpholine hydrochloride. 6) Add 25g paraformaldehyde and 105g tert-butylacetone to the mixture, heat to 50℃, add 1.0mL concentrated hydrochloric acid, start stirring, and reflux for 4h. 7) After the reaction was completed, methanol was removed by rotary evaporation, 300 mL of acetone was added and stirred for 15 min, allowed to stand, filtered and dried to obtain 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propyl)benzene.

[0043] 8) Add platinum carbon (Pt / C) and 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propylbenzene to 500 mL of methanol in a high-pressure reactor. The amount of platinum carbon is 8% of the mass of 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propylbenzene. Purge with hydrogen to 10 MPa, heat to 60 °C, and react until the system pressure is constant. The reaction is then complete. 9) After the reaction is complete, release the residual hydrogen gas, filter out the platinum carbon, add sodium hydroxide methanol solution to adjust the pH to ≥10.0, remove methanol by vacuum distillation, add 200mL of water for phase separation, and perform vacuum distillation on the separated organic phase to collect the fraction to obtain butylmorpholine.

[0044] like Figure 4 As shown, the content of butylmorpholine is 98.415%.

[0045] The embodiments described above are not exhaustive and do not limit the invention to specific implementations. Clearly, many modifications and variations can be made based on the above description. These embodiments are selected and specifically described in this specification to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to effectively utilize the invention and its modifications. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the invention should be included within the scope of protection of the invention.

Claims

1. A method for synthesizing butylmorpholine, characterized in that, Includes the following steps: S1. Add 50-60g of cis-2,6-dimethylmorpholine to 500mL of polar hydrophilic solvent, stir at room temperature for 10min, control the temperature at 20℃, and pass HCl gas to form salt for 2h to obtain a mixture containing cis-2,6-dimethylmorpholine hydrochloride. S2. Add 10-25g of paraformaldehyde and 90-105g of tert-butylacetone to the mixture, heat to 50℃, add protic acid catalyst, start stirring, reflux for 4h, after the reaction is completed, remove the polar hydrophilic solvent by rotary evaporation, add 300mL of acetone and stir for 15min, let stand, filter and dry to obtain 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propyl)benzene; S3. Add the catalyst, 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propyl)benzene, and 500 mL of polar hydrophilic solvent to a high-pressure reactor. The amount of catalyst is 3-8% of the mass of 4-tert-butyl-1-(2-methyl-1-oxy-3-(cis-2,6-dimethylmorpholino-4-)propyl)benzene. Purge with hydrogen to 3-10 MPa, raise the temperature to 60°C, and react until the pressure is constant. S4. After the reaction is complete, filter out the catalyst, add sodium hydroxide methanol solution to adjust the pH to ≥10.0, remove the polar hydrophilic solvent by vacuum distillation, add water to separate the phases, and then perform vacuum distillation on the separated organic phases to collect the fraction to obtain butylmorpholine.

2. The method for synthesizing butylmorpholine according to claim 1, characterized in that, The tert-butylacetone comprises the following preparation steps: S21. Add Lewis acid catalyst and 400 mL aprotic solvent to the reaction vessel and stir at room temperature for 10 min to form a homogeneous catalytic system. S22. After stirring, add 90-100g of propionyl chloride and 130-145g of tert-butylbenzene to the catalytic system and stir to react; S23. After the reaction is complete, 150 mL of ice water is poured into the product and stirred for 30 min. The separated organic phase is washed with 30 mL of dilute hydrochloric acid and then washed with water until neutral. 5 g of anhydrous sodium sulfate is added for drying. The product is then distilled at atmospheric pressure to remove the aprotic solvent and obtain tert-butylacetone.

3. The method for synthesizing butylmorpholine according to claim 2, characterized in that, The propionyl chloride comprises the following preparation steps: S221. Add 70-80g of propionic acid and 230-245g of thionyl chloride to the reaction vessel, and add 3-5mL of N,N-dimethylformamide dropwise. After the addition is complete, stir and reflux for 5h. S222. After the reaction is complete, distill at atmospheric pressure, collect the fraction, and obtain propionyl chloride.

4. The method for synthesizing butylmorpholine according to claim 1, characterized in that: The polar hydrophilic solvent is one of methanol, ethanol, isopropanol, dimethylformamide, and dimethyl sulfoxide.

5. The method for synthesizing butylmorpholine according to claim 1, characterized in that: The protic acid catalyst is one of hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, formic acid, and acetic acid.

6. The method for synthesizing butylmorpholine according to claim 1, characterized in that: The catalyst is one of Raney nickel, palladium on carbon, or platinum on carbon.

7. The method for synthesizing butylmorpholine according to claim 2, characterized in that: The aprotic solvent is one of dichloromethane, chloroform, carbon tetrachloride, toluene, and tetrahydrofuran.

8. The method for synthesizing butylmorpholine according to claim 2, characterized in that: The amount of Lewis acid catalyst used is 100% to 300% of the molar amount of tert-butylbenzene.

9. The method for synthesizing butylmorpholine according to claim 8, characterized in that: The Lewis acid catalyst is one of aluminum trichloride, aluminum chloride, zinc chloride, ferric chloride, and boron trifluoride diethyl ether.

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