A method for synthesizing an enoxamide intermediate, 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one

Abstract

The present application belongs to the field of chemical synthesis and pesticides, and particularly relates to a preparation method of an enoxacin intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-ketone. The present application comprises: using 3-ethylthiobutyraldehyde and methyl acetoacetate as raw materials, generating 2-acetyl-5-(ethylthio)hex-2-enate acid methyl ester through a Brain-Von Eggers reaction, then performing Michael addition and Claisen ester condensation with dimethyl malonate, and then performing hydrolysis through sodium hydroxide, and heating decarboxylation through hydrochloric acid to obtain 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-ketone. The preparation method is simple, convenient to operate, and easy to be scaled up in industry, and finally, the total yield of the similar one-pot reaction is as high as 77%.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of herbicide synthesis, in particular to a synthesis method of an intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one of clethodim. BACKGROUND

[0002] Farmers must need to weed, in agricultural production, manual weeding is a high intensity physical labor, in order to save labor, and avoid the loss caused by not timely weeding, therefore, chemical weeding is an inevitable trend. Chemical weeding is the process of using chemical herbicides to control weeds.

[0003] Cyclohexenone herbicide is a kind of high-efficiency and safe ACCase inhibitor with high selectivity, which is a better updated product compared with amide and sulfonylurea herbicides. Clethodim is a typical cyclohexenone herbicide with excellent selectivity and good effect on gramineous weeds. In recent years, clethodim has shown a rapid growth trend at home and abroad, replacing some herbicide varieties with large residues and heavy phytotoxicity. With the expansion of its use, the market of clethodim is also expanding. 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one is an important intermediate for synthesizing clethodim. However, in the actual production process, the traditional synthesis process of 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one has many steps and produces a large amount of waste, therefore, it is of great significance to find a more concise synthesis route and reduce the generation of waste in the production process for the industrial improvement and environmental protection of clethodim. SUMMARY

[0004] In view of the deficiencies in the prior art, the technical problem to be solved by the present application is to find a more concise and environmentally friendly synthesis route of 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one, and to improve the existing synthesis process which produces a large amount of waste.

[0005] In the existing process for synthesizing clethodim, a large amount of waste is generated in the reaction from the raw material to the final product. The original process of some reaction processes is as follows:

[0006] Since the present application does not involve the synthesis of compounds 1-6, the synthesis examples of compound 7 and target product 8 in the original process are introduced first. The synthesis route of target product 8 in the original process is as shown in Figure 1

[0007] Synthesis of compound 7:

[0008] ​In a 50 mL flask, add 0.010 mol of compound 6, 20 mL of toluene, slowly add 0.010 mol of compound 3 at 30℃, react for 2 hours at 35℃, after the reaction is completed, spin dry toluene, and purify by column chromatography to obtain compound 7 with a yield of 85%.

[0009] Synthesis of compound 8:

[0010] In a 50 mL flask, add 0.010 mol of compound 7, 20 mL of methanol, 0.011 mol of dimethyl malonate, and sodium salt formed by sodium methoxide, after the addition is completed, warm to reflux, react for 5 hours, after the reaction is completed, quench the reaction by adding a large amount of water, extract and remove the solvent with ethyl acetate, then add 10 mL of methanol, add 8 mL of 10% sodium hydroxide solution, stir at 60℃ for 1 h, cool to below 40℃, drop 10 mL of 10% sodium hydroxide solution, and then add 8 mL of 10% sodium hydroxide solution, stir at 60℃ for 1 h, after the reaction is completed, cool to room temperature, remove the methanol in the solution, extract the aqueous phase with ethyl acetate, and dry to obtain compound 8 with a total yield of 70%.

[0011] The technical scheme adopted by the present application to solve the technical problems is: the present application provides a synthesis method of the intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one of clethodim, which takes compound 3 and compound 9 as starting materials, takes the Wittig reaction as a key step, reacts to obtain compound 10, and gradually reacts to obtain compound 8, greatly simplifies the route, greatly reduces energy consumption and pollution, and the synthesis route of the target product 8 in the present process is as shown in the figure: Figure 2

[0012] Specifically, the following steps are followed:

[0013] Step (1), under the action of an ice bath and a catalyst, compound 3 and compound 9 and an appropriate amount of molecular sieves are reacted in an organic solvent for 4 hours, and after post-treatment, compound 10 is obtained;

[0014] Step (2), under reflux conditions, compound 10 and dimethyl malonate and sodium methoxide undergo Michael addition and Claisen ester condensation in an organic solvent, and under the action of alkaline hydrolysis and acid decarboxylation, the target compound 8 is obtained by reacting in a mixed solvent. That is, compound 10 undergoes three-step reactions of cyclization, hydrolysis and decarboxylation to obtain the target compound 8.

[0015] ​Preferably, the catalyst in step (1) is diethylamine, tetrahydropyrrole or piperidine, preferably the catalyst is tetrahydropyrrole; preferably, the organic solvent is one of N,N-dimethylformamide, anhydrous ethanol, anhydrous methanol, water, preferably the organic solvent is N,N-dimethylformamide; preferably, the molar ratio of compound 3 to compound 9 is 1:1.0-1.3, preferably the molar ratio is 1:1.0; preferably, R1 of compound 9 is methyl, ethyl or propyl, preferably R1 is methyl; preferably, the feeding sequence of compound 3 and compound 9 is that compound 9 is added dropwise into compound 3; preferably, the molecular sieve is 3A or 5A, preferably the molecular sieve is 3A; preferably, the post-treatment process is that a large amount of water and a small amount of ethyl acetate are added into the reaction solution for extraction and desolventization treatment.

[0016] Preferably, the organic solvent in step (2) is anhydrous methanol, anhydrous ethanol or toluene, preferably the organic solvent is anhydrous methanol; preferably, the molar ratio of compound 10, dimethyl malonate and sodium methoxide is 1:1.0-1.2:1.0-1.2, preferably the molar ratio is 1:1.1:1.1; preferably, the mixed solvent is methanol and water; preferably, the base is sodium hydroxide or potassium hydroxide, preferably the base is sodium hydroxide; preferably, the acid is hydrochloric acid or sulfuric acid, preferably the acid is hydrochloric acid; preferably, the molar ratio of compound 10 to the base is 1:1-4, preferably the molar ratio is 1:3.

[0017] The technical scheme of the present application has the following beneficial effects:

[0018] (1) The method for preparing compound 10 in the present application shortens the original synthesis route by two steps, and also shortens the continuous flow process by two steps, thereby reducing the reaction steps and the generation of three wastes, and being beneficial to reducing the production cost.

[0019] (2) The present application reduces the number of route steps, and the whole reaction is simple and easy to operate.

[0020] (3) The total yield of 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one obtained by the present application is high, and the total yield can reach 77%. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 is the synthesis route of target product 8 in the original process;

[0022] Figure 2 is the synthesis route of target product 8 in the present process;

[0023] Figure 3 is the gas chromatogram of compound 10;

[0024] Figure 4The high resolution spectrum of compound 10 is shown in Figure 1.

[0025] Figure 5 The nuclear magnetic spectrum of compound 10 is shown in Figure 2.

[0026] Figure 6 The liquid phase mass spectrum of compound 8 is shown in Figure 3.

[0027] Figure 7 The nuclear magnetic spectrum of compound 8 is shown in Figure 4.

[0028] Figure 8 The high resolution spectrum of compound 8 is shown in Figure 5. DETAILED DESCRIPTION

[0029] The present application will now be further described in conjunction with the following examples, which are intended to illustrate the present application but not to limit the scope of the present application.

[0030] I. Step (1), synthesis of compound 10:

[0031] Example 1

[0032] Into a 25 mL three-necked flask, 5 mmol of compound 3, 0.5 mmol of catalyst tetrahydro-pyrrole, appropriate amount of 3A molecular sieve and 10 mL of N,N-dimethylformamide were added, and 5 mmol of one of the acetoacetic acid methyl esters in the classification of compound 9 was slowly added dropwise in the ice bath condition, and the reaction was carried out for 4 hours in the ice bath condition. After water and ethyl acetate were added to extract the organic phase and spin dry, compound 10 was obtained after column chromatography purification, with a yield of 90%.

[0033] The structure characterization diagram of compound 10 is shown in Figure 1, Figures 3-5 Figure 3 The gas phase mass spectrum of compound 10 is shown in Figure 2, Figure 4 The high resolution spectrum of compound 10 is shown in Figure 1. Figure 5 The nuclear magnetic spectrum of compound 10 is shown in Figure 2.

[0034] Example 2

[0035] Compound 10 was obtained by replacing tetrahydro-pyrrole in Example 1 with diethylamine, with other conditions unchanged, with a yield of 75%.

[0036] Example 3

[0037] Compound 10 was obtained by replacing tetrahydro-pyrrole in Example 1 with piperidine, with other conditions unchanged, with a yield of 78%.

[0038] Example 4

[0039] Compound 10 was obtained by replacing the ice bath condition in Example 1 with normal temperature reaction, with other conditions unchanged, with a yield of 34%. ​

[0040] Example 5

[0041] The ice bath condition in Example 1 was replaced by 50 °C reaction, other conditions unchanged, the yield of compound 10 was 56%.

[0042] Example 6

[0043] The ice bath condition in Example 1 was replaced by 90 °C reaction, other conditions unchanged, the yield of compound 10 was 58%.

[0044] Example 7

[0045] The ice bath condition in Example 1 was replaced by 150 °C reaction, other conditions unchanged, the yield of compound 10 was 10%.

[0046] Example 8

[0047] The amount of catalyst in Example 1 was replaced by 1 mmol, that is, the amount of catalyst was 20%, other conditions unchanged, the yield of compound 10 was 75%.

[0048] Example 9

[0049] The amount of catalyst in Example 1 was replaced by 5 mmol, that is, the amount of catalyst was 100%, other conditions unchanged, the yield of compound 10 was 5%.

[0050] Example 10

[0051] The 3A molecular sieve catalyst in Example 1 was replaced by no molecular sieve, other conditions unchanged, the yield of compound 10 was 30%.

[0052] Example 11

[0053] The organic solvent N,N-dimethylformamide in Example 1 was replaced by ethanol, other conditions unchanged, the yield of compound 10 was 34%.

[0054] Example 12

[0055] The organic solvent N,N-dimethylformamide in Example 1 was replaced by methanol, other conditions unchanged, the yield of compound 10 was 32%.

[0056] Example 13

[0057] The organic solvent N,N-dimethylformamide in Example 1 was replaced by water, other conditions unchanged, the yield of compound 10 was 13%.

[0058] Example 14

[0059] By changing the order of adding compounds 3 and 9 in Example 1 to adding compound 3 to compound 9, while keeping other conditions unchanged, the yield of compound 10 was 50%.

[0060] Example 15

[0061] By changing the molar ratio of compound 3 to compound 9 in Example 1 to 1:1.2, while keeping other conditions unchanged, the yield of compound 10 was 76%.

[0062] Example 16

[0063] By changing the molar ratio of compound 3 to compound 9 in Example 1 to 1:1.3, while keeping other conditions unchanged, the yield of compound 10 was 77%.

[0064] Example 17

[0065] Replacing methyl acetoacetate with ethyl acetoacetate in Example 1, while keeping other conditions unchanged, yielded compound 10-1 in 79% yield.

[0066]

[0067] Example 18

[0068] Replacing methyl acetoacetate with propyl acetoacetate in Example 1, while keeping other conditions unchanged, yielded compound 10⁻² in 77% yield.

[0069]

[0070] II. Step (2), Synthesis of Compound 8:

[0071] Example 19

[0072] In a 50 mL three-necked flask, 5 mmol of compound 10, 15 mL of anhydrous methanol, 5.5 mmol of dimethyl malonate, and the sodium salt formed by sodium methoxide were added. After the addition was complete, the mixture was heated to 65 °C and refluxed for 1 hour. After the reaction was completed, a large amount of water was added to quench the reaction. The organic phase was extracted with ethyl acetate and evaporated to dryness. Water was added to dissolve the organic phase, followed by the addition of 15 mmol of 10% sodium hydroxide solution. The mixture was stirred at 60 °C for 0.5 hours, cooled to below 40 °C, and concentrated hydrochloric acid was added dropwise to bring the pH to 4.0. The mixture was then heated to 60 °C and stirred for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, and the methanol in the solution was removed. The aqueous phase was extracted with ethyl acetate and dried to obtain compound 8, with a yield of 85%.

[0073] The structural characterization diagram of compound 8 is shown below. Figures 6-8 As shown, Figure 6 This is the liquid phase mass spectrum of compound 8; Figure 7 The NMR spectrum of compound 8; Figure 8 This is the high-resolution spectrum of compound 8;

[0074] Example 20

[0075] The anhydrous methanol in Example 19 was replaced by anhydrous ethanol, and other conditions were unchanged, and the yield of compound 8 was 70%.

[0076] Example 21

[0077] The anhydrous methanol in Example 19 was replaced by toluene, and other conditions were unchanged, and the yield of compound 8 was 75%.

[0078] Example 21

[0079] The molar ratio of dimethyl malonate to sodium methoxide in Example 19 was replaced by 1:1.2, and other conditions were unchanged, and the yield of compound 8 was 73%.

[0080] Example 22

[0081] The dimethyl malonate in Example 19 was replaced by diethyl malonate, and other conditions were unchanged, and the yield of compound 8 was 72%.

[0082] Example 23

[0083] The dimethyl malonate in Example 19 was replaced by dipropyl malonate, and other conditions were unchanged, and the yield of compound 8 was 71%.

[0084] Example 24

[0085] The 10% sodium hydroxide solution in Example 19 was replaced by 30%, and other conditions were unchanged, and the yield of compound 8 was 77%.

[0086] Example 25

[0087] The 15mmol sodium hydroxide solution in Example 19 was replaced by 5mmol, and other conditions were unchanged, and the yield of compound 8 was 55%.

[0088] Example 26

[0089] The 15mmol sodium hydroxide solution in Example 19 was replaced by 10mmol, and other conditions were unchanged, and the yield of compound 8 was 69%.

[0090] Example 27

[0091] The decarboxylation reagent concentrated hydrochloric acid in Example 19 was replaced by concentrated sulfuric acid, and other conditions were unchanged, and the yield of compound 8 was 65%.

[0092] After comparison with the original process, the route of the application is greatly simplified, the energy consumption and pollution are greatly reduced, and the yield is also improved, which is suitable for industrial application.

[0093] Appendix: The names of the compounds involved in the present application are as follows:

[0094] Compound 1: but-2-enal;

[0095] Compound 2: ethanethiol;

[0096] Compound 3: 3-ethylthiobutyraldehyde;

[0097] Compound 4: methyl acetoacetate;

[0098] Compound 5: sodium acetoacetate;

[0099] Compound 6: acetoacetic acid;

[0100] Compound 7: 6-ethylthiohept-3-en-2-one;

[0101] Compound 8: 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one;

[0102] Compound 9: acetoacetate (including methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate)

[0103] Compound 10: 2-acetyl-5-(ethylthio)hex-2-enoate (including Compound 10-1: ethyl 2-acetyl-5-(ethylthio)hex-2-enoate; Compound 10-2: propyl 2-acetyl-5-(ethylthio)hex-2-enoate)

[0104] With the above ideal embodiments according to the present application as the inspiration, through the above description, relevant staff can make various changes and modifications without deviating from the scope of the technical idea of the present application. The technical scope of the present application is not limited to the content in the specification, and must be determined according to the scope of the claims.

Claims

1. A method for the synthesis of the allelochemical intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-l-one, characterized in that, The intermediate 8 of the enoxacin is prepared by using compound 3 and compound 9 as starting materials, using the brain text reaction as a key step, and ice bath reaction to obtain compound 10, and then gradually reacting, and the preparation is carried out according to the following steps: In step (1), compound 3 and compound 9 and appropriate molecular sieve are reacted in an organic solvent under the action of catalyst and ice bath for 4 hours, and after post-treatment, compound 10 is obtained; In step (2), compound 10 is reacted with dimethyl malonate and sodium methoxide in an organic solvent under reflux condition to occur Michael addition and Claisen ester condensation, and under the action of alkaline hydrolysis and acid decarboxylation, the target compound 8 is obtained by reaction in a mixed solvent under the condition of 60-70 DEG C reaction; The structural formula of the compound 3 is: The structural formula of the compound 9 is: The structural formula of the compound 10 is The structural formula of the compound 8 is: The R1 is methyl, ethyl or propyl; The catalyst in step (1) is diethylamine, tetrahydro pyrrole or piperidine; The organic solvent in step (1) is N, N-dimethylformamide; The molecular sieve is 3A molecular sieve.

2. The method for synthesizing the clethodim intermediate 5-[2-(ethio)propyl]-3-hydroxy-2-cyclohexen-1-one according to claim 1, characterized in that, The molar ratio of compound 3 to compound 9 in step (1) is 1:1.0-1.

3.

3. The method for synthesizing the clethodim intermediate 5-[2-(ethio)propyl]-3-hydroxy-2-cyclohexen-1-one according to claim 1, characterized in that, The mixed solvent in step (2) is methanol and water, the base is sodium hydroxide or potassium hydroxide, and the acid is hydrochloric acid or sulfuric acid.

4. The method for synthesizing the clethodim intermediate 5-[2-(ethio)propyl]-3-hydroxy-2-cyclohexen-1-one according to claim 1, characterized in that, The molar ratio of compound 10, dimethyl malonate and sodium methoxide in step (2) is 1:1.0-1.2:1.0-1.2, and the molar ratio of compound 10 to base is 1:1-4.

5. The method for synthesis of clethodim intermediate 5-[2-(ethylthio)propyl]-3- hydroxy-2-cyclohexen-l-one according to claim 1, characterized by, that the reaction mixture is heated to 60-65°C and the reaction is carried out at this temperature for 2-3 hours. The feeding sequence of compound 3 and compound 9 in step (1) is that compound 9 is added dropwise into compound 3.

6. The method of synthesis of clethodim intermediate 5-[2-(ethylthio)propyl]-3- hydroxy-2-cyclohexen-l-one according to claim 1, characterized by, that the reaction mixture is heated to 60-65°C and the reaction is carried out at this temperature for 2-3 hours. The post-treatment process in step (1) is that a large amount of water and a small amount of ethyl acetate are added into the reaction liquid for extraction and desolventization treatment.

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