A process for the synthesis of cloquintocet

Abstract

The application discloses a method for synthesizing benoxacor, and belongs to the technical field of chemical organic synthesis. The method comprises the following steps: taking DMF as a solvent, fully reacting ortho-nitrophenol with monochloroacetone and alkali at a certain temperature, centrifuging after the reaction is completed, obtaining a first filter cake and a DMF solution of 2-nitro-2-phenoxypropanone, removing part of the DMF through vacuum distillation, detecting the content of chloroacetone in the gas chromatograph, and adjusting the mass concentration of the 2-nitro-2-phenoxypropanone DMF solution to 10-20% after the content of chloroacetone is detected to be lower than 0.02% by using the area normalization method; then, adding Raney nickel into the 2-nitro-2-phenoxypropanone DMF solution, and performing hydrogenation reaction by passing hydrogen; after the reaction is completed, the upper clear liquid is extracted, and 3,4-dihydro-3-methyl-2H-1,4-benzoxazine DMF solution is obtained through filtration; then, an acid-binding agent alkali is added, and acylation reaction is performed by dropwise adding dichloroacetyl chloride, so as to synthesize benoxacor. The method can greatly simplify the operation process of frequently changing solvents in the process of synthesizing benoxacor, and can avoid the generation of a large amount of waste brine.

Description

Technical Field

[0001] This invention relates to the field of chemical organic synthesis technology, and more specifically, to a method for synthesizing cyclohexanone. Background Technology

[0002] Metolachlor, also known as methoxychloride, is an antidote for dichloroacetamide herbicides. It can reduce the phytotoxicity of metolachlor to corn and can also serve as an effective component in the safener for chloroacetamide herbicides. Currently, the preparation process of metolachlor uses o-nitrophenol and monochloroacetone as starting materials, toluene as solvent, and an acid-binding agent and catalyst. After passing the reaction, it is washed with water (to dissolve the sodium chloride salt generated in the reaction), toluene is removed, and a hydrogenation reaction is carried out in an alcohol solvent. After hydrogenation, the solvent is removed. The acylation reaction is again carried out using toluene as a solvent and an acid-binding agent, with dichloroacetyl chloride added dropwise. After the reaction is complete, it is washed with water, toluene is removed, and recrystallization is performed in an alcohol solvent. The product is then obtained by centrifugation and drying. This three-step reaction involves frequent solvent changes and solvent removal, making the operation cumbersome and resulting in significant solvent loss.

[0003] For example, Ciba-Geigy's patents US4601745 and EP0149974 disclose a method for synthesizing amide compounds. This patent uses sodium carbonate as an acidifying agent and benzene as a solvent. After the reaction of 2,3-dihydro-3-methyl-1,4-benzoxazine with dichloroacetyl chloride is completed, water is added for post-treatment. Benzene is a strong carcinogen.

[0004] German company Cetor GmbH discloses a method for preparing acylamide compounds in patents CN101781267 and EP2206706. This patent uses liquid alkali as an acid-coating agent and adds water for post-treatment after the reaction is completed.

[0005] Lü Chengcheng from Harbin University of Science and Technology published a synthesis process for cyclohexanone, which uses toluene as a solvent and triethylamine as an acid-coating agent to synthesize cyclohexanone. After the reaction is completed, water is added for post-treatment to generate the salt.

[0006] Shandong United Pesticide Industry Co., Ltd.'s patents CN201910462199.2 and CN110054595A employ a high-temperature reflux method to add dichloroacetyl chloride dropwise, while simultaneously absorbing hydrogen chloride gas from the tail gas. The absorbed hydrogen chloride gas is dissolved in water to prepare hydrochloric acid as a byproduct, thus avoiding the generation of large amounts of waste brine.

[0007] A paper published in the journal DE GRUYTER by YE FEI et al. from the Department of Applied Chemistry, Northeast Agricultural University, China, describes a simple and efficient synthesis of a novel N-dichloroacetyl-3,4-dihydro-2H-1,4-benzoxazine. Using o-aminophenol and 1,2-dibromoethane as raw materials and DMSO as solvent, 3,4-dihydro-H-1,4-benzoxazine was synthesized. Then, using benzene as solvent and NaCO3 as an acidifier, it was reacted with dichloroacetyl chloride to prepare f-N-dichloroacetyl-3,4-dihydro-2H-1,4-benzoxazine. This process suffers from poor selectivity in the first step, resulting in numerous impurities and a yield of only 62%. It also utilizes a variety of solvents, including DMSO, benzene, esters, and petroleum-based solvents.

[0008] The above-mentioned synthesis process of cyclohexane is not simple enough, and it will generate a large amount of waste brine or require frequent solvent replacement during the reaction (the solvent loss during the desolvation process is large, the energy consumption is high, and the operation cycle is long).

[0009] To address the aforementioned technical problems, this invention aims to provide a novel method for synthesizing cyclohexane. Summary of the Invention

[0010] 1. Technical problems to be solved

[0011] In view of the problems existing in the prior art, the purpose of this invention is to provide a method for synthesizing methylparaben, which can greatly simplify the operation process of frequently changing solvents during the synthesis of methylparaben, and at the same time, avoid the generation of a large amount of waste brine.

[0012] 2. Technical Solution

[0013] To solve the above problems, the present invention adopts the following technical solution.

[0014] A method for synthesizing cyclohexane includes the following steps:

[0015] S1. Etherification reaction

[0016]

[0017] o-Nitrophenol, monochloroacetone, DMF, and alkali are added to a reaction vessel. The o-nitrophenol and monochloroacetone react completely at 50-70℃. After the reaction is complete, the reaction solution is centrifuged to obtain a first filter cake and a DMF solution of 2-nitro-2-phenoxypropanone. Some DMF is removed by vacuum distillation, and the solution is detected by gas chromatography. After the content of chloroacetone is found to be less than 0.02% by the area normalization method, the appropriate amount of DMF is added to the DMF solution of 2-nitro-2-phenoxypropanone to make the mass concentration of the DMF solution of 2-nitro-2-phenoxypropanone 10-20%.

[0018] S2. Hydrogenation reaction

[0019]

[0020] Raney nickel catalyst was added to a DMF solution of 2-nitro-2-phenoxypropanone. Hydrogenation reaction was carried out by passing hydrogen through the catalyst at a reaction temperature of 60-70℃, a reaction pressure of 2.0-3.5 MPa, and a certain stirring speed. After the reaction was completed, stirring was stopped, the mixture was allowed to stand, the supernatant was removed, and the solution was filtered to obtain a DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine.

[0021] S3. Acylation reaction

[0022]

[0023] Add an acid-binding base to a DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine, and add dichloroacetyl chloride dropwise at 30-40°C. Continue the reaction at 40-50°C. After the reaction is complete, filter to obtain a second filter cake and filtrate. Decolorize the filtrate, add a certain amount of water, cool, crystallize, precipitate, and centrifuge. Dry the obtained solid to obtain the herbicides product.

[0024] In step S3, the molar ratio of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine to dichloroacetyl chloride is 1:1.02-1.2.

[0025] In step S3, water is added to reduce the solubility of the herbicides in DMF.

[0026] The acid-binding base is used to neutralize the hydrogen chloride generated by the reaction of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine with dichloroacetyl chloride.

[0027] In step S1, when the DMF in the 2-nitro-2-phenoxypropionone solution is removed under reduced pressure, a portion of unreacted monohydroacetone is also removed during this process. This is detected by gas chromatography, and the content of chloroacetone is found to be below 0.02% using the area normalization method. This reduces the toxic effect of monochloroacetone on the hydrogenation reaction in step S2.

[0028] Furthermore, in step S1, the molar ratio of o-nitrophenol, monochloroacetone, DMF and base is 1:(1.1-1.5):(10-16):(1.1-1.6).

[0029] Furthermore, in step S1, the molar ratio of o-nitrophenol, monochloroacetone, DMF, and base is 1:1 to 1:14:1.4.

[0030] Furthermore, in step S2, the molar ratio of 2-nitro-2-phenoxypropanone to Raney nickel is 1:2-5.0.

[0031] Furthermore, in step S2, the molar ratio of 2-phenoxyacetone to Raney nickel is 1:4.0.

[0032] Furthermore, in step S3, the molar ratio of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine to the acid-binding agent is 1:1.1-2.0.

[0033] Furthermore, in step S3, the molar ratio of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine to the acid-binding base is 1:1.3.

[0034] Furthermore, the reaction temperature in step S1 is 50-70℃, and the reaction time is 5-15 hours.

[0035] Furthermore, in step S1, the alkali is one or both of sodium carbonate and sodium bicarbonate.

[0036] Furthermore, after the first filter cake in step S1 is centrifuged, it is rinsed with DMF. After rinsing, the rinsing solution is added to a DMF solution of 2-nitro-2-phenoxypropanone for vacuum distillation to remove DMF. The rinsing solution is added to the DMF solution of 2-nitro-2-phenoxypropanone to reduce the loss of the product 2-nitro-2-phenoxypropanone.

[0037] The DMF removed by vacuum distillation can be used as a DMF solvent in the reaction of o-nitrophenol and monochloroacetone in step S1.

[0038] The first filter cake consists of unreacted alkali and sodium chloride.

[0039] Furthermore, in step S3, the acid-binding agent is one or both of sodium carbonate and sodium bicarbonate.

[0040] Furthermore, in step S3, the filtrate is decolorized using activated carbon.

[0041] Furthermore, in step S3, the cooling crystallization temperature is -15 to 0°C.

[0042] Furthermore, in step S3, the second filter cake is rinsed with DMF. After rinsing, the rinsing solution is added to the filtrate for decolorization, in order to reduce the loss of acetaminophen.

[0043] Furthermore, in step S3, the second filter cake consists of unreacted acid-binding alkali and sodium chloride salt.

[0044] Furthermore, in step S2, the reaction temperature is 60-70℃, the reaction pressure is 2.0-3.5 MPa, and the reaction time is 5-10 hours.

[0045] 3. Beneficial effects

[0046] Compared with the prior art, the advantages of this invention are:

[0047] (1) This invention uses the same solvent in both the reaction and rinsing processes, which avoids frequent solvent changes, greatly simplifies the operation process, reduces production costs, and facilitates the industrial production of acetaminophen.

[0048] (2) The method for synthesizing cyclohexane provided by the present invention not only does not produce a large amount of waste brine, but also allows the solvent in the reaction process to be repeatedly recycled. Detailed Implementation

[0049] The present invention will be further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

[0050] Example 1: A method for synthesizing cyclohexane, comprising the following steps:

[0051] S1. Etherification reaction

[0052] 14 mol DMF, 1.4 mol sodium carbonate, 1 mol o-nitrophenol, and 1.1 mol monochloroacetone were added to a reaction vessel and reacted thoroughly at 50°C. After the reaction was completed, the reaction solution was taken out for testing. After passing the test, the reaction solution was centrifuged to obtain a first filter cake and a first filtrate. The first filtrate was a DMF solution of 2-nitro-2-phenoxyacetone. The first filter cake was washed with DMF. The washing solution and the first filtrate were combined and subjected to vacuum to remove part of the solvent DMF. The solution was detected by gas chromatography. After the content of chloroacetone was found to be less than 0.02% by the area normalization method, an equal amount of recovered DMF without monochloroacetone was added to obtain a 0.95 mol DMF solution of 2-nitro-2-phenoxyacetone.

[0053] S2. Hydrogenation reaction

[0054] The DMF solution of 2-nitro-2-phenoxypropionone obtained in step S1 was added to a hydrogenation reactor, and 3.8 mol of Raney nickel catalyst was added. Hydrogen was then continuously introduced to carry out the hydrogenation reaction while stirring. The reaction temperature was 63°C and the reaction pressure was 3.0 MPa. After the reaction was completed, stirring was stopped and the mixture was allowed to stand for a period of time. After standing, the supernatant was extracted, filtered, and a DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine was obtained. The content of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine in the DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine was 0.93 mol.

[0055] S3 acylation reaction

[0056] The DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine obtained in step 2 was added to the acylation reactor, sodium carbonate was added as an acid-binding agent, and 1.2 mol of dichloroacetyl chloride was added dropwise at 30-40℃. After the addition was completed, the mixture was kept at 40-50℃ and samples were taken. After the reaction was completed, the mixture was filtered to obtain a second filter cake and a second filtrate. The second filter cake was washed with DMF. After the washing was completed, the washing solution was added to the second filtrate. Activated carbon was added to the second filtrate for decolorization, and a certain amount of water was added. The mixture was cooled, and the product precipitated. After centrifugation and washing, the solid was dried to obtain the cyclohexanone product with a yield of 84.5%.

[0057] Example 2: A method for synthesizing cyclohexane, comprising the following steps:

[0058] S1. Etherification reaction

[0059] 28 mol DMF, 2.8 mol sodium carbonate, 2 mol o-nitrophenol, and 2.1 mol monochloroacetone were added to a reaction vessel and reacted thoroughly at 55°C. After the reaction was completed, the reaction solution was taken out for testing. After passing the test, the reaction solution was centrifuged to obtain a first filter cake and a first filtrate. The first filtrate was a DMF solution of 2-nitro-2-phenoxyacetone. The first filter cake was washed with DMF. The first filtrate and the washing solution were combined and subjected to vacuum to remove part of the solvent DMF. The solution was detected by gas chromatography. After the content of chloroacetone was found to be less than 0.02% by the area normalization method, an equal amount of recovered DMF that had been removed by vacuum was added to obtain a 1.92 mol DMF solution of 2-nitro-2-phenoxyacetone.

[0060] S2. Hydrogenation reaction

[0061] The DMF solution of 2-nitro-2-phenoxypropionone obtained in step S1 was added to a hydrogenation reactor, and 7.68 mol of Raney nickel catalyst was added. Hydrogen was then continuously introduced to carry out the hydrogenation reaction while stirring. The reaction temperature was 63°C and the reaction pressure was 3.0 MPa. After the reaction was completed, stirring was stopped and the mixture was allowed to stand for a period of time. After standing, the supernatant was extracted, filtered, and a DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine was obtained. The content of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine in the DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine was 1.86 mol.

[0062] S3 acylation reaction

[0063] The DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine obtained in step 2 was added to an acylation reactor, sodium carbonate was added as an acid-binding agent, and 1.92 mol of dichloroacetyl chloride was added dropwise at 30-40℃. After the addition was completed, the mixture was kept at 40-50℃ and samples were taken. After the reaction was completed, the mixture was filtered to obtain a second filter cake and a second filtrate. The second filter cake was washed with DMF. After the washing was completed, the washing solution was added to the second filtrate. Activated carbon was added to the second filtrate for decolorization, and a certain amount of water was added. The mixture was cooled, and the product precipitated. After centrifugation and washing, the solid was dried to obtain the cyclohexanone product with a yield of 85.6%.

[0064] Example 3: A method for synthesizing cyclohexane, comprising the following steps:

[0065] S1. Etherification reaction

[0066] 14 mol DMF, 1.4 mol sodium carbonate, 1 mol o-nitrophenol, and 1.1 mol monochloroacetone were added to a reaction vessel and reacted thoroughly at 66°C. After the reaction was completed, the reaction solution was taken out for testing. After passing the test, the reaction solution was centrifuged to obtain a first filter cake and a first filtrate. The first filtrate was a DMF solution of 2-nitro-2-phenoxyacetone. The first filter cake was washed with DMF. The filtrate and the washing liquid were combined and subjected to vacuum treatment to remove part of the solvent DMF. The solution was detected by gas chromatography. After the content of chloroacetone was found to be less than 0.02% by the area normalization method, an equal amount of recovered DMF with monochloroacetone removed was added to obtain a 0.955 mol DMF solution of 2-nitro-2-phenoxyacetone.

[0067] S2. Hydrogenation reaction

[0068] The DMF solution of 2-nitro-2-phenoxypropionone obtained in step S1 was added to a hydrogenation reactor, along with 3.82 mol of Raney nickel catalyst. Hydrogen was then continuously introduced to carry out the hydrogenation reaction, while stirring was performed. The reaction temperature was 65°C and the reaction pressure was 3.0 MPa. After the reaction was completed, stirring was stopped, and the mixture was allowed to stand for a period of time. After standing, the supernatant was extracted, filtered, and a DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine was obtained. The content of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine in the DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine was 0.931 mol.

[0069] S3 acylation reaction

[0070] The DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine obtained in step 2 was added to an acylation reactor, sodium carbonate was added as an acid-binding agent, and 1.10 mol of dichloroacetyl chloride was added dropwise at 30-40℃. After the addition was completed, the mixture was kept at 40-50℃ and samples were taken. After the reaction was completed, the mixture was filtered to obtain a second filter cake and a second filtrate. The second filter cake was washed with DMF. After the washing was completed, the washing solution was added to the second filtrate. Activated carbon was added to the second filtrate for decolorization, and a certain amount of water was added. The mixture was cooled, and the product precipitated. After centrifugation and washing, the solid was dried to obtain the cyclohexanone product with a yield of 84.7%.

[0071] Example 4: A method for synthesizing cyclohexane, comprising the following steps:

[0072] S1. Etherification reaction

[0073] 14 mol DMF, 1.4 mol sodium carbonate, 1 mol o-nitrophenol, and 1.1 mol monochloroacetone were added to a reaction vessel and reacted thoroughly at 70°C. After the reaction was completed, the reaction solution was taken out for testing. After passing the test, the reaction solution was centrifuged to obtain a first filter cake and a first filtrate. The first filtrate was a DMF solution of 2-nitro-2-phenoxypropanone. The first filter cake was washed with DMF, and the washing solution and the first filtrate were combined and subjected to vacuum to remove part of the solvent DMF. The solution was detected by gas chromatography. After the content of chloroacetone was found to be less than 0.02% by the area normalization method, DMF that did not contain monochloroacetone was added. The amount added was equal to the amount removed under vacuum to obtain a DMF solution of 2-nitro-2-phenoxypropanone. The content of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine in the DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine was 0.96 mol.

[0074] S2. Hydrogenation reaction

[0075] The DMF solution of 2-nitro-2-phenoxypropionone obtained in step S1 was added to a hydrogenation reactor, Raney nickel catalyst was added, and hydrogen was continuously introduced to carry out the hydrogenation reaction while stirring. The reaction temperature was 60℃ and the reaction pressure was 3.5 MPa. After the reaction was completed, stirring was stopped and the mixture was allowed to stand for a period of time. After standing, the supernatant was extracted, filtered, and 0.925 mol of DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine was obtained.

[0076] S3 acylation reaction

[0077] The DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine obtained in step 2 was added to an acylation reactor, sodium carbonate was added as an acid-binding agent, and 1.10 mol of dichloroacetyl chloride was added dropwise at 30-40℃. After the addition was completed, the mixture was kept at 40-50℃ and samples were taken. After the reaction was completed, the mixture was filtered to obtain a second filter cake and a second filtrate. The second filter cake was washed with DMF. After the washing was completed, the washing solution was added to the second filtrate. Activated carbon was added to the second filtrate for decolorization, and a certain amount of water was added. The mixture was cooled, and the product precipitated. After centrifugation and washing, the solid was dried to obtain the cyclohexanone product with a yield of 85.2%.

Claims

1. A method for synthesizing cyclohexanone, characterized in that: Includes the following steps: S1. Etherification reaction o-Nitrophenol, monochloroacetone, DMF, and alkali were added to a reaction vessel. The o-nitrophenol and monochloroacetone reacted completely at a certain temperature. After the reaction was complete, the reaction solution was centrifuged to obtain a first filter cake and a DMF solution of 2-nitro-2-phenoxypropanone. Part of the DMF was removed by vacuum distillation. The solution was then analyzed using gas chromatography. After determining that the chloroacetone content was below 0.02% using the area normalization method, the appropriate amount of DMF was added to the 2-nitro-2-phenoxypropanone DMF solution to achieve a DMF concentration of 10-20%. S2. Hydrogenation reaction Raney nickel catalyst was added to a DMF solution of 2-nitro-2-phenoxypropanone. Hydrogenation reaction was carried out by passing hydrogen through the catalyst at a reaction temperature of 60-70℃, a reaction pressure of 2.0-3.5 MPa, and a certain stirring speed. After the reaction was completed, stirring was stopped, the mixture was allowed to stand, the supernatant was removed, and the solution was filtered to obtain a DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine. S3. Acylation reaction An acid-binding base was added to a DMF solution of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine, and dichloroacetyl chloride was added dropwise at 30-40°C. The molar ratio of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine to dichloroacetyl chloride was 1:1.02-1.

2. The reaction was carried out at 40-50°C. After the reaction was completed, the mixture was filtered to obtain a second filter cake and a filtrate. The filtrate was decolorized, and then a certain amount of water was added. The mixture was cooled, crystallized, precipitated, and centrifuged. The obtained solid was dried to obtain the herbicides product. In step S2, the molar ratio of 2-nitro-2-phenoxypropanone to Raney nickel is 1:2-5.0; In step S3, the molar ratio of 3,4-dihydro-3-methyl-2H-1,4-benzoxazine to the acid-binding agent is 1:1.1-2.

0. The molar ratio of o-nitrophenol, monochloroacetone, DMF and base in step S1 is 1:(1.1-1.5):(10-16):(1.1-1.6).

2. The method for synthesizing cyclohexanone according to claim 1, characterized in that: The alkali in step S1 and the acid-binding alkali in step S3 are both selected from one or two of sodium carbonate and sodium bicarbonate.

3. The method for synthesizing cyclohexanone according to claim 1, characterized in that: In step S3, the filtrate is decolorized using activated carbon.

4. The method for synthesizing cyclohexanone according to claim 1, characterized in that: In step S3, the cooling crystallization temperature is -15 to 0℃.

5. The method for synthesizing cyclohexane according to claim 1, characterized in that: After the first filter cake in step S1 is centrifuged, it is rinsed with DMF. After rinsing, the rinsing solution is added to a DMF solution of 2-nitro-2-phenoxypropanone for vacuum distillation to remove DMF.

6. The method for synthesizing cyclohexane according to claim 1, characterized in that: In step S3, the second filter cake is rinsed with DMF. After rinsing, the rinsing solution is added to the filtrate for decolorization.

7. The method for synthesizing cyclohexanone according to claim 1, characterized in that: The reaction temperature in step S1 is 50-70℃, and the reaction time is 5-15 hours.

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