Synthesis method of clethodim intermediate 5-[2-(ethylthio) propyl]-3-hydroxy-2-cyclohexene-1-ketone

Abstract

The invention belongs to the field of chemical synthesis and pesticides, and particularly relates to a preparation method of a clethodim intermediate 5-[2-(ethylthio) propyl]-3-hydroxy-2-cyclohexene-1-ketone. The preparation method comprises the following steps: by taking 3-ethylthio butyraldehyde and methyl acetoacetate as raw materials, carrying out a Knoevenagel reaction to generate 2-acetyl-5-(ethylthio) hex-2-methyl olefine acid, then carrying out Michael addition and Claisen ester condensation on the 2-acetyl-5-(ethylthio) hex-2-methyl olefine acid and dimethyl malonate, and then hydrolyzing by sodium hydroxide to obtain the 2-acetyl-5-(ethylthio) hex-2-methyl olefine acid. And heating hydrochloric acid for decarboxylation to obtain the 5-[2-(ethylthio) propyl]-3-hydroxy-2-cyclohexene-1-ketone. The preparation method disclosed by the invention is simple, convenient to operate and easy to industrially amplify, and the total yield is up to 77% finally through similar one-pot reaction.

Description

Technical Field

[0001] The invention relates to the technical field of herbicide synthesis, and in particular to a method for synthesizing clethodim intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexene-1-one. Background Art

[0002] Farmers must weed when they farm. In agricultural production, manual weeding is a high-intensity physical labor. In order to save labor and avoid losses caused by untimely weeding, chemical weeding is an inevitable trend. The so-called chemical weeding is the process of using chemical herbicides to control weeds.

[0003] Cyclohexenone herbicides are a class of highly efficient, safe and highly selective ACCase inhibitors, and are better replacement products compared to amide and sulfonylurea herbicides. Clethodim is a typical cyclohexenone herbicide with excellent selectivity and good control effect on grass weeds. In recent years, Clethodim has shown a rapid growth trend both at home and abroad, replacing some herbicide varieties with large residues and heavy phytotoxicity, and with the expansion of its uses, the Clethodim market is also expanding. 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexene-1-one is an important intermediate for the synthesis of Clethodim. However, in the actual production process, the traditional 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexene-1-one synthesis process has many steps and will produce a large amount of three wastes. Therefore, it is important to explore a more streamlined synthesis route and reduce the generation of three wastes in the production process for the industrial improvement and environmental protection of Clethodim. Summary of the invention

[0004] In view of the deficiencies in the prior art, the technical problem to be solved by the present invention is to explore a more streamlined and environmentally friendly synthesis route of 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexene-1-one and to improve the problem that a large amount of three wastes will be generated in the existing synthesis process.

[0005] In the technology of synthesizing clethodim using the existing process, it takes many steps from the synthesis of raw materials to the final product, which will produce a large amount of three wastes. The reaction process of the original process is as follows:

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

[0007] Synthesis of compound 7:

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

[0009] Synthesis of compound 8:

[0010] In a 50mL three-necked flask, add 0.010mol of compound 7, 20mL of methanol, 0.011mol of sodium salt formed by dimethyl malonate and sodium methoxide. After the addition is completed, heat to reflux and react for 5 hours. After the reaction is completed, add a large amount of water to quench the reaction. After ethyl acetate extraction and desolventization, add 10mL of methanol and 8mL of 10% sodium hydroxide solution, stir at 60℃ for 1h, cool to below 40℃, add concentrated hydrochloric acid dropwise to pH=4.0, heat to 60℃ and stir for 1h. After the reaction is completed, cool to room temperature, remove methanol from the solution, extract the aqueous phase with ethyl acetate, and obtain compound 8 after drying with a total yield of 70%.

[0011] The technical solution adopted by the present invention to solve the technical deficiencies is: the present invention provides a method for synthesizing clethodim intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexene-1-one, using compound 3 and compound 9 as starting materials, taking the Novoweng reaction as the key step, reacting to obtain compound 10, and then gradually reacting to obtain compound 8, the route is greatly simplified, and energy consumption and pollution are greatly reduced. The synthetic route of the target product 8 in this process is as follows Figure 2 As shown:

[0012] Follow these steps:

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

[0014] Step (2), under reflux conditions, compound 10 reacts with dimethyl malonate and sodium methoxide in an organic solvent to undergo Michael addition and Claisen ester condensation, reacts at 60-70° C. and under the action of alkaline hydrolysis and acid decarboxylation, and then reacts in a mixed solvent to obtain the target compound 8. That is, compound 10 undergoes three steps of cyclization, hydrolysis and decarboxylation to obtain the target compound 8.

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

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

[0017] The technical solution of the present invention has the following beneficial effects:

[0018] (1) The method for preparing compound 10 according to the present invention in a kettle form shortens the original synthesis route by two steps, and is also two steps shorter than the original process applied to continuous flow, thereby reducing the number of reaction steps and the generation of three wastes, which is beneficial to reducing production costs.

[0019] (2) The present invention reduces the number of steps in the route, making the entire reaction simple and easy to operate.

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

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

[0022] Figure 2 This is the synthetic route of the target product 8 in this process;

[0023] Figure 3 is the gas phase mass spectrum of compound 10;

[0024] Figure 4is the high-resolution spectrum of compound 10;

[0025] Figure 5 is the NMR spectrum of compound 10;

[0026] Figure 6 is the liquid phase mass spectrum of compound 8;

[0027] Figure 7 is the NMR spectrum of compound 8;

[0028] Figure 8 This is the high-resolution spectrum of compound 8. DETAILED DESCRIPTION

[0029] The present invention will now be further described in detail with reference to examples. The following examples are used to illustrate the present invention but are not intended to limit the scope of the present invention.

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

[0031] Example 1

[0032] In a 25mL three-necked flask, 5mmoL of compound 3, 0.5mmoL of catalyst tetrahydropyrrole, an appropriate amount of 3A molecular sieves and 10mL of N,N-dimethylformamide were added, and 5mmoL of methyl acetoacetate from the compound 9 dissolved in an appropriate amount of solvent N,N-dimethylformamide was slowly added dropwise under ice bath conditions. The reaction was carried out for 4 hours under ice bath conditions. Water and ethyl acetate were added to extract the organic phase and the phase was spin-dried. Compound 10 was obtained after purification by column chromatography with a yield of 90%.

[0033] The structural representation diagrams of compound 10 are shown in Figure 3-Figure 5 As shown, Figure 3 is the gas phase mass spectrum of compound 10, Figure 4 is the high-resolution spectrum of compound 10; Figure 5 is the NMR spectrum of compound 10.

[0034] Example 2

[0035] The tetrahydropyrrole in Example 1 was replaced with diethylamine, and other conditions remained unchanged. The yield of compound 10 was 75%.

[0036] Example 3

[0037] The tetrahydropyrrole in Example 1 was replaced by piperidine, and other conditions remained unchanged. The yield of compound 10 was 78%.

[0038] Actual Case Example 4

[0039] The ice bath condition in Example 1 was replaced with a room temperature reaction, while other conditions remained unchanged, and the yield of compound 10 was 34%.

[0040] Example 5

[0041] The ice bath condition in Example 1 was replaced with a reaction temperature of 50° C., while other conditions remained unchanged. The yield of compound 10 was 56%.

[0042] Example 6

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

[0044] Example 7

[0045] The ice bath condition in Example 1 was replaced with a reaction at 150°C, while other conditions remained unchanged. The yield of compound 10 was 10%.

[0046] Example 8

[0047] The amount of catalyst in Example 1 was changed from 0.5 mmoL to 1 mmoL, that is, 20% of the amount of catalyst, and other conditions remained unchanged. The yield of compound 10 was 75%.

[0048] Example 9

[0049] The amount of catalyst in Example 1 was changed from 0.5 mmoL to 5 mmoL, that is, 100% of the amount of catalyst, and other conditions remained unchanged. The yield of compound 10 was 5%.

[0050] Example 10

[0051] The 3A molecular sieve catalyst in Example 1 was replaced by one without adding molecular sieve, and other conditions remained unchanged. The yield of compound 10 was 30%.

[0052] Embodiment 11

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

[0054] Example 12

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

[0056] Embodiment 13

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

[0058] Embodiment 14

[0059] The order of adding compound 3 and compound 9 in Example 1 was changed to adding compound 3 dropwise into compound 9, and other conditions remained unchanged. The yield of compound 10 was 50%.

[0060] Embodiment 15

[0061] The molar ratio of compound 3 to compound 9 in Example 1 was changed to 1:1.2, and other conditions remained unchanged. The yield of compound 10 was 76%.

[0062] Example 16

[0063] The molar ratio of compound 3 to compound 9 in Example 1 was changed to 1:1.3, and other conditions remained unchanged. The yield of compound 10 was 77%.

[0064] Embodiment 17

[0065] The methyl acetoacetate in Example 1 was replaced with ethyl acetoacetate, and other conditions remained unchanged to obtain compound 10-1 with a yield of 79%.

[0066]

[0067] Embodiment 18

[0068] The methyl acetoacetate in Example 1 was replaced with propyl acetoacetate, and other conditions remained unchanged to obtain compound 10-2 with a yield of 77%.

[0069]

[0070] 2. Step (2), synthesis of compound 8:

[0071] Embodiment 19

[0072] In a 50mL three-necked flask, 5mmol of compound 10, 15mL of anhydrous methanol, 5.5mmol of dimethyl malonate and sodium salt formed by sodium methoxide were added. After the addition was completed, the temperature was raised to 65℃ and refluxed, and the reaction was carried out 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 dried, and then water was added to dissolve it. Then, 15mmol of 10% sodium hydroxide solution was added, and the mixture was stirred at 60℃ for 0.5 hour, cooled to below 40℃, and concentrated hydrochloric acid was added dropwise to pH=4.0. The mixture was heated to 60℃ and stirred for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, the methanol in the solution was removed, and the aqueous phase was extracted with ethyl acetate. After drying, compound 8 was obtained with a yield of 85%.

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

[0074] Embodiment 20

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

[0076] Embodiment 21

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

[0078] Embodiment 21

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

[0080] Embodiment 22

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

[0082] Embodiment 23

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

[0084] Embodiment 24

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

[0086] Embodiment 25

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

[0088] Embodiment 26

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

[0090] Embodiment 27

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

[0092] Compared with the original process, the route of the present invention is greatly simplified, the energy consumption and pollution are greatly reduced, the yield is also improved, and it is suitable for industrial application.

[0093] Appendix: The names of the compounds involved in the present invention 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 Compound 10-1: 2-acetyl-5-(ethylthio)hex-2-enoate ethyl ester; Compound 10-2: 2-acetyl-5-(ethylthio)hex-2-enoate propyl ester)

[0104] Based on the above ideal embodiments of the present invention, the relevant staff can make various changes and modifications without departing from the technical concept of the present invention through the above description. The technical scope of the present invention is not limited to the content of the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A method for synthesizing clethodim intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexene-1-one, characterized in that: Compound 3 and compound 9 are used as starting materials, and the Novoweng reaction is used as the key step. Compound 10 is obtained by ice bath reaction, and the clethodim intermediate 8 is finally obtained by stepwise reaction. Specifically, the steps are as follows: Step (1), in an ice bath and under the action of a catalyst, compound 3 reacts with compound 9 and an appropriate amount of molecular sieves in an organic solvent for 4 hours, and after post-treatment, compound 10 is obtained; Step (2), under reflux conditions, compound 10 reacts with dimethyl malonate and sodium methoxide in an organic solvent to undergo Michael addition and Claisen ester condensation, reacts at 60-70° C. and under the action of alkaline hydrolysis and acid decarboxylation, and reacts in a mixed solvent to obtain the target compound 8; 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.

2. The method for synthesizing the clethodim intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexene-1-one according to claim 1, characterized in that: The catalyst described in step (1) is diethylamine, tetrahydropyrrole or piperidine.

3. The method for synthesizing the clethodim intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexene-1-one according to claim 1, characterized in that: The organic solvent described in step (1) is N,N-dimethylformamide, ethanol, methanol or water.

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

3.

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

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

7. The method for synthesizing the clethodim intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexene-1-one according to claim 1, characterized in that: The order of adding compound 3 and compound 9 in step (1) is to drop compound 9 into compound 3; the molecular sieve is 3A or 5A, preferably 3A molecular sieve.

8. The method for synthesizing the clethodim intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexene-1-one according to claim 1, characterized in that: The post-treatment process in step (1) is to add a large amount of water and a small amount of ethyl acetate into the reaction solution for extraction and then desolventization.

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