Preparation method of pinoxaden
By simplifying the preparation route of cyclohexane, intermediate 1 is generated by reacting hydrazine hydrate with compound (I), then intermediate 2 is generated by reacting hydrazine hydrate with compound (II), and finally intermediate 2 is generated by reacting hydrazine hydrate with 2,6-diethyl-4-methylbromobenzene and tervapotranilyl chloride. This solves the problems of complicated steps and safety hazards in the existing technology and achieves a high yield and low cost preparation effect.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIANGSU SEVENCONTINENT GREEN TECH RES INST CO LTD
- Filing Date
- 2024-11-11
- Publication Date
- 2026-05-12
AI Technical Summary
Existing methods for preparing clodinafop-propargyl are cumbersome, costly, and pose safety risks, especially when synthesizing key intermediates, which require protection/deprotection steps or the use of unstable and highly toxic compounds.
The reaction route simplifies the preparation of key intermediates by reacting hydrazine hydrate with compound (I) to generate intermediate 1, then reacting it with compound (II) to generate intermediate 2, and finally reacting it with 2,6-diethyl-4-methylbromobenzene and pivaloyl chloride.
A high-yield, low-cost, and safe preparation process for zoclofen has been achieved, reducing the number of steps and avoiding the use of highly toxic compounds.
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Figure CN122010976A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing zoclofen. Background Technology
[0002] Pinoxaden is the common name for clopyralid in English. Its chemical name is 8-(2,6-diethyl-4-methylphenyl)-1,2,4,5-tetrahydro-7-oxo-7H-pyrazolo[1,2-d][1,4,5]oxadiazaphen-9-yl 2,2-dimethylpropionate, and its structural formula is shown below.
[0003]
[0004] Phytochlor is a novel phenylpyrazole herbicide developed by Syngenta through experimental research. It possesses a unique chemical structure that inhibits the activity of acetyl-CoA carboxylase (ACCase), hindering fatty acid biosynthesis and interfering with cell membrane formation, leading to weed growth cessation and eventual death. It is effective in post-emergence control of annual grass weeds in wheat and barley fields, such as American privet, Japanese American privet, wild oats, ryegrass, sedge, foxtail, hard grass, purslane, and sedge, especially sedge, and also shows excellent control of stubborn grass weeds such as ryegrass.
[0005] Reported methods for synthesizing clopyralid include:
[0006] 1. Route 1
[0007]
[0008] 2. Route Two
[0009]
[0010] 3. Route Three
[0011]
[0012] The above-mentioned routes one and two, represented by Syngenta and patents CN108864144B and CN116514837A, both use hydrazine hydrate and acetic anhydride to synthesize N,N-diacetylhydrazine. Finally, deacetylation is required to obtain [1,4,5]oxadiaheptanane, which requires protection / deprotection steps. The process is complicated and the production cost is high.
[0013] The aforementioned Route 3, represented by patents CN110294768B and WO2022123541A1, avoids the protection / deprotection steps. However, the key intermediate 2,6-diethyl-4-methylphenylmalonate usually requires coupling malononitrile with 2,6-diethyl-4-methylbromobenzene. Malononitrile is a highly toxic and unstable compound, posing a safety hazard. Summary of the Invention
[0014] The purpose of this invention is to provide a method for preparing clodinafop-propargyl that has fewer steps, better safety, higher yield, and lower cost.
[0015] To achieve the above objectives, the technical solution adopted by the present invention is as follows:
[0016] A method for preparing clopyralid includes the following steps:
[0017] S1. Hydrazine hydrate undergoes a cyclization reaction with the compound shown in formula (I) to generate intermediate 1;
[0018] S2. React intermediate 1 with the compound shown in formula (II) in the presence of a base to generate intermediate 2;
[0019] S3. React intermediate 2 with 2,6-diethyl-4-methylbromobenzene under the action of a catalyst to generate intermediate 3;
[0020] S4. React the intermediate 3 with tervapotranil chloride in the presence of a base to obtain the zopyrrolizidine ester.
[0021] Wherein, the formula (I) is R1 and R2 are each independently selected from alkyl groups having 1 to 5 carbon atoms;
[0022] The structural formula of intermediate 1 is as follows:
[0023] Equation (II) is as follows X1 and X2 are independently selected from halogens and R3SO3-, respectively, where R3 is an alkyl group having 1 to 5 carbon atoms;
[0024] The structural formula of intermediate 2 is as follows:
[0025] The structural formula of the intermediate 3 is as follows:
[0026] The reaction route of the oxychloride ester of the present invention is as follows:
[0027]
[0028] Existing preparation methods inevitably require the synthesis of key intermediates: [1,4,5]oxadiazepane and / or 2,6-diethyl-4-methylphenylmalonate. However, the synthesis of [1,4,5]oxadiazepane requires protection / deprotection steps, which are cumbersome; the synthesis of 2,6-diethyl-4-methylphenylmalonate presents safety risks or low yields. This invention creatively avoids the preparation of the above-mentioned key intermediates. By reacting hydrazine hydrate with the compound shown in formula (I) to generate intermediate 1, and then reacting it with the compound shown in formula (II) to generate intermediate 2, and finally reacting it with 2,6-diethyl-4-methylbromobenzene and tervapotranilyl chloride, cyclophosphamide can be obtained. The entire reaction route has fewer steps, higher yield, lower cost, and better safety.
[0029] Preferably, R1 and R2 are each independently selected from alkyl groups having 1 to 3 carbon atoms, such as methyl, ethyl, and propyl.
[0030] In some embodiments, the compound represented by formula (I) is diethyl malonate.
[0031] Preferably, the molar ratio of the hydrazine hydrate to the compound shown in formula (I) is 1:(1-2), more preferably 1:(1.2-1.5), for example 1:1.2, 1:1.3, 1:1.4, 1:1.5.
[0032] Preferably, the reaction system in step S1 further includes a solvent, which is selected from one or more of methanol, ethanol, isopropanol, n-butanol, and water.
[0033] More preferably, the mass ratio of the solvent to the compound shown in formula (I) is (2-4):1, and more preferably (2.4-3.5):1.
[0034] Preferably, the reaction temperature in step S1 is 60–100°C, and more preferably 75–85°C.
[0035] Preferably, the reaction time of step S1 is 5 to 15 hours, and more preferably 8 to 12 hours.
[0036] Preferably, after the reaction in step S1 is completed, desolvation is performed under reduced pressure, and then the reaction in step S2 is carried out directly.
[0037] Preferably, the alkali in step S2 is selected from one or more of alkali metal or alkaline earth metal hydroxides, carbonates, and bicarbonates.
[0038] More preferably, the alkali in step S2 is potassium hydroxide and / or potassium carbonate.
[0039] In some preferred embodiments, the alkali in step S2 is potassium hydroxide and potassium carbonate, and the molar ratio of potassium hydroxide to potassium carbonate is (1.5-2.5):1, more preferably (2-2.5):1.
[0040] Preferably, the molar ratio of intermediate 1 to alkali in step S2 is 1:(1.5-3), more preferably 1:(1.5-2.5), and even more preferably 1:(2-2.5).
[0041] Preferably, the compound represented by formula (II) is selected from one or more of dichlorodiethyl ether, dibromodiethyl ether, diiododiethyl ether, and dimethyl sulfonate diethyl ether.
[0042] Preferably, the molar ratio of intermediate 1 to the compound shown in formula (II) is 1:(1-2), more preferably 1:(1-1.5), for example 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5.
[0043] Preferably, the reaction temperature in step S2 is 80–150°C, more preferably 80–120°C, for example 80°C, 90°C, 100°C, 110°C, or 120°C.
[0044] Preferably, the reaction system in step S2 further includes a solvent, which is selected from one or more of N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone.
[0045] More preferably, the mass ratio of intermediate 1 to solvent in step S2 is 1:(5-15), and more preferably 1:(8-12).
[0046] Preferably, step S2 further includes cooling and filtering the reaction system after the reaction is completed, concentrating the filtrate, and recrystallizing it using isopropanol.
[0047] Preferably, the catalyst is a palladium catalyst.
[0048] In some embodiments, the palladium catalyst is Pd(PPh3)2Cl2.
[0049] Preferably, the molar ratio of intermediate 2 to catalyst is 1:(0.0001-0.01), more preferably 1:(0.0005-0.005).
[0050] Preferably, the molar ratio of intermediate 2 to 2,6-diethyl-4-methylbromobenzene is 1:(0.9-1.5), and more preferably 1:(1-1.2).
[0051] Preferably, the reaction temperature in step S3 is 120–150°C, and more preferably 130–140°C.
[0052] Preferably, the reaction system in step S3 further includes a solvent, which is selected from one or more of toluene, xylene, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide.
[0053] Preferably, step S3 further includes removing the solvent from the reaction system after the reaction is completed, then adding water and diatomaceous earth, stirring and filtering, adding acid to the filtrate to adjust the pH of the system, and finally filtering to obtain the intermediate 3.
[0054] More preferably, the acid is concentrated sulfuric acid.
[0055] More preferably, the mixture is stirred at 70–90°C for 10–50 min.
[0056] Preferably, the molar ratio of intermediate 3 to tervaline chloride is 1:(1-1.5), more preferably 1:(1.1-1.3).
[0057] Preferably, the reaction system in step S4 further includes a solvent, which is selected from one or more of toluene, xylene, chlorobenzene, and dichloroethane.
[0058] Preferably, the base in step S4 is selected from one or more of triethylamine, N,N-dimethylethylamine, pyridine, and 4-dimethylaminopyridine.
[0059] More preferably, the molar ratio of intermediate 3 to alkali in step S4 is 1:(1~1.5).
[0060] Preferably, the reaction temperature in step S4 is -10 to 20°C, and more preferably -5 to 5°C.
[0061] Due to the application of the above-mentioned technical solution, the present invention has the following advantages compared with the prior art:
[0062] This invention produces cyclohexane by reacting hydrazine hydrate with the compound shown in formula (I) to generate intermediate 1, then reacting it with the compound shown in formula (II) to generate intermediate 2, and finally reacting it with 2,6-diethyl-4-methylbromobenzene and tervapotranilyl chloride. The entire reaction route has few steps, high yield, low cost, and good safety. Detailed Implementation
[0063] The present invention will be further described below with reference to embodiments. However, the present invention is not limited to the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to different requirements of specific applications, and the implementation conditions not specified are conventional conditions in the industry. The technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.
[0064] Unless otherwise specified, all raw materials mentioned below are commercially available products or can be prepared using existing methods.
[0065] Preparation of intermediate 1:
[0066] Example 1-1
[0067] Ethanol (120 g), diethyl malonate (48.05 g, 0.3 mol), and 80% hydrazine hydrate (12.52 g, 0.2 mol) were added sequentially to a four-necked flask, and the reaction was carried out at 80 °C for 9 h. After desolvation under reduced pressure, 90 g of water was added, and concentrated hydrochloric acid was added dropwise to adjust the pH to 2–3. The mixture was stirred in an ice bath for 0.5 h, filtered, washed with water, and dried to obtain 19.13 g of intermediate 1, with a molar yield of 95.57%.
[0068] Examples 1-2
[0069] Methanol (120 g), diethyl malonate (48.05 g, 0.3 mol), and 80% hydrazine hydrate (12.52 g, 0.2 mol) were added sequentially to a four-necked flask, and the reaction was carried out at 80 °C for 9 h. After desolvation under reduced pressure, 90 g of water was added, and concentrated hydrochloric acid was added dropwise to adjust the pH to 2–3. The mixture was stirred in an ice bath for 0.5 h, filtered, washed with water, and dried to obtain 18.28 g of intermediate 1, with a molar yield of 91.33%.
[0070] Examples 1-3
[0071] Ethanol (120 g), diethyl malonate (38.44 g, 0.24 mol), and 80% hydrazine hydrate (12.52 g, 0.2 mol) were added sequentially to a four-necked flask, and the reaction was carried out at 80 °C for 9 h. After desolvation under reduced pressure, 90 g of water was added, and concentrated hydrochloric acid was added dropwise to adjust the pH to 2-3. The mixture was stirred in an ice bath for 0.5 h, filtered, washed with water, and dried to obtain 17.62 g of intermediate 1, with a molar yield of 88.03%.
[0072] As can be seen from Examples 1-1 to 1-3, the type of solvent and the amount of raw materials fed have a certain impact on the yield of intermediate 1. For example, alcohol solvents such as ethanol and methanol can be used as reaction solvents for intermediate 1, and using ethanol as a reaction solvent can further improve the yield of intermediate 1 compared with using methanol. When the molar ratio of diethyl malonate to hydrazine hydrate increases, the yield of intermediate 1 tends to increase, but too much diethyl malonate will also lead to raw material waste. Therefore, the molar ratio of diethyl malonate to hydrazine hydrate should not be too large, preferably (1-2):1.
[0073] Preparation of intermediate 2:
[0074] Example 2-1
[0075] In a four-necked flask, intermediate 1 (20.01 g, 0.2 mol, synthesized according to the method in Example 1-1), dimethyl sulfoxide (200 g), and potassium hydroxide (26.40 g, 85%, 0.4 mol) were added sequentially. The mixture was heated to 80-85°C, and then dichlorodiethyl ether (37.18 g, 0.26 mol) was added dropwise over 2 hours. The mixture was kept at this temperature for 4 hours. After cooling to room temperature (25 ± 5°C), the mixture was filtered. The filtrate was concentrated, and 30 g of isopropanol was added for recrystallization to obtain 28.99 g of intermediate 2, with a molar yield of 85.2%.
[0076] Example 2-2
[0077] In a four-necked flask, intermediate 1 (20.01 g, 0.2 mol, synthesized according to the method in Example 1-1), dimethyl sulfoxide (200 g), potassium hydroxide (18.48 g, 85%, 0.28 mol), and potassium carbonate (16.59 g, 0.12 mol) were added sequentially. The mixture was heated to 80-85°C, and then dichlorodiethyl ether (37.18 g, 0.26 mol) was added dropwise over 2 hours. After the addition was complete, the mixture was kept at this temperature for 4 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. 30 g of isopropanol was added for recrystallization to obtain 30.08 g of intermediate 2, with a yield of 88.4%.
[0078] Example 2-3
[0079] In a four-necked flask, intermediate 1 (20.01 g, 0.2 mol, synthesized according to the method in Example 1-1), N,N-dimethylacetamide (200 g), and potassium carbonate (55.28 g, 0.4 mol) were added sequentially. The mixture was heated to 120 °C, and then dichlorodiethyl ether (37.18 g, 0.26 mol) was added dropwise over 2 hours. After the addition was complete, the mixture was kept at this temperature for 8 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. 30 g of isopropanol was added for recrystallization to obtain 28.45 g of intermediate 2, with a yield of 83.6%.
[0080] Examples 2-4
[0081] In a four-necked flask, intermediate 1 (20.01 g, 0.2 mol, synthesized by the method in Example 1-1), dimethyl sulfoxide (200 g), potassium hydroxide (18.48 g, 85%, 0.28 mol), and potassium carbonate (16.59 g, 0.12 mol) were added sequentially. The mixture was heated to 80-85°C, and then diethylene glycol dimethanesulfonate (68.20 g, 0.26 mol) was added dropwise over 2 hours. After the addition was complete, the mixture was kept at this temperature for 4 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. 30 g of isopropanol was added for recrystallization to obtain 28.28 g of intermediate 2, with a yield of 83.1%.
[0082] Comparative Example 1
[0083] Intermediate 1 (20.01 g, 0.2 mol, synthesized according to the method in Example 1-1), dimethyl sulfoxide (200 g), and triethylamine (40.48 g, 0.4 mol) were added sequentially to a four-necked flask. The mixture was heated to 80-85°C, and then dichlorodiethyl ether (37.18 g, 0.26 mol) was added dropwise over 2 hours. The mixture was then kept at this temperature for 4 hours. A sample was taken for monitoring; no intermediate 2 was formed.
[0084] Examples 2-5 (One-pot preparation)
[0085] Ethanol (120 g), diethyl malonate (48.05 g, 0.3 mol), and 80% hydrazine hydrate (12.52 g, 0.2 mol) were added sequentially to a four-necked flask, and the reaction was carried out at 80 °C for 9 h. After solvent removal under reduced pressure, dimethyl sulfoxide (200 g), potassium hydroxide (18.48 g, 85%, 0.28 mol), and potassium carbonate (16.59 g, 0.12 mol) were added sequentially to the flask. The mixture was heated to 80-85 °C, and then dichlorodiethyl ether (37.18 g, 0.26 mol) was added dropwise over 2 h. After the addition was completed, the mixture was kept at this temperature for 4 h. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. 30 g of isopropanol was added for recrystallization to give 29.16 g of intermediate 2, with a yield of 85.7%.
[0086] In the preparation of intermediate 2, the type of alkali and reactants can affect the yield of intermediate 2 to some extent. When using a combination of potassium hydroxide and potassium carbonate, the yield of intermediate 2 can be improved compared to using potassium hydroxide or potassium carbonate alone. Compared to diethylene glycol dimethanesulfonate, the yield of intermediate 2 is higher when using dichlorodiethyl ether. However, when triethylamine is used, intermediate 2 cannot be generated.
[0087] Preparation of intermediate 3:
[0088] Example 3-1
[0089] Intermediate 2 (34.03 g, 0.2 mol, synthesized according to the method in Example 2-2) and 150 g of dimethylformamide were added sequentially to a four-necked flask. The mixture was heated to 135 °C, and 2,6-diethyl-4-methylbromobenzene (49.97 g, 0.22 mol) and Pd(PPh3)2Cl2 solution (140.4 mg catalyst dissolved in 20 g of dimethylformamide) were added dropwise over 1 hour. The mixture was then kept at this temperature for 30 minutes. After removing the dimethylformamide by solvent removal, 100 g of water and 10 g of diatomaceous earth were added sequentially. The mixture was stirred at 80 °C for 30 minutes and then filtered. Concentrated sulfuric acid was added dropwise to the filtrate to adjust the pH to 2-3. The filtrate was then filtered to obtain 56.7 g of intermediate 3, with a yield of 89.6%.
[0090] Example 3-2
[0091] Intermediate 2 (34.03 g, 0.2 mol, synthesized according to the method in Example 2-2) and 150 g of dimethylformamide were added sequentially to a four-necked flask. The mixture was heated to 135 °C, and 2,6-diethyl-4-methylbromobenzene (49.97 g, 0.22 mol) and Pd(PPh3)2Cl2 solution (14 mg catalyst dissolved in 20 g of dimethylformamide) were added dropwise over 1 hour. The mixture was then kept at this temperature for 30 minutes. After removing the dimethylformamide by solvent removal, 100 g of water and 10 g of diatomaceous earth were added sequentially. The mixture was stirred at 80 °C for 30 minutes and then filtered. Concentrated sulfuric acid was added dropwise to the filtrate to adjust the pH to 2-3. The filtrate was then filtered to obtain 52.46 g of intermediate 3, with a yield of 82.9%.
[0092] Preparation of clopyralid:
[0093] Example 4
[0094] In a four-necked flask, intermediate 3 (31.64 g, 0.1 mol, synthesized according to the method in Example 3-1), triethylamine (12.14 g, 0.12 mol), and 90 g of chlorobenzene were added sequentially, followed by pentanoyl chloride (13.26 g, 0.11 mol). The mixture was stirred in an ice bath for 2 h. 100 g of water was added to wash the reaction system, and the aqueous phase was extracted with 50 g of chlorobenzene. The organic phases were combined, concentrated, and recrystallized in an ice bath with n-hexane. The resulting product was filtered and dried to obtain 33.04 g of cyclohexylpyridinium ether, with a yield of 80.5% and a purity of 97.6%.
[0095] The present invention has been described in detail above, with the aim of enabling those skilled in the art to understand and implement the invention. However, this description should not be construed as limiting the scope of protection of the invention. All equivalent changes or modifications made in accordance with the spirit and essence of the invention should be included within the scope of protection of the invention.
Claims
1. A method for preparing clodinafop-propargyl, characterized in that, The preparation method includes the following steps: S1. Hydrazine hydrate undergoes a cyclization reaction with the compound shown in formula (I) to generate intermediate 1; S2. React intermediate 1 with the compound shown in formula (II) in the presence of a base to generate intermediate 2; S3. React intermediate 2 with 2,6-diethyl-4-methylbromobenzene under the action of a catalyst to generate intermediate 3; S4. React the intermediate 3 with tervastatin chloride in the presence of a base to obtain the zopyrrolizidine ester. Wherein, the formula (I) is R1 and R2 are each independently selected from alkyl groups having 1 to 5 carbon atoms; The structural formula of intermediate 1 is as follows: Equation (II) is as follows X1 and X2 are independently selected from halogens and R3SO3-, respectively, where R3 is an alkyl group having 1 to 5 carbon atoms; The structural formula of intermediate 2 is as follows: The structural formula of the intermediate 3 is as follows:
2. The method for preparing clopyralid according to claim 1, characterized in that, The compound represented by formula (I) is diethyl malonate; and / or, The molar ratio of the hydrazine hydrate to the compound shown in formula (I) is 1:(1-2).
3. The method for preparing oxychlorpyrifos according to claim 1, characterized in that, The reaction system in step S1 further includes a solvent, which is selected from one or more of methanol, ethanol, isopropanol, n-butanol, and water; and / or, The reaction temperature in step S1 is 60–100°C.
4. The method for preparing oxychlorpyrifos according to claim 1, characterized in that, The alkali in step S2 is selected from one or more of alkali metal or alkaline earth metal hydroxides, carbonates, and bicarbonates.
5. The method for preparing oxychlorpyrifos according to claim 4, characterized in that, The alkali in step S2 is potassium hydroxide and / or potassium carbonate; and / or, In step S2, the molar ratio of intermediate 1 to alkali is 1:(1.5-3).
6. The method for preparing oxychlorpyrifos according to claim 1, characterized in that, The compound represented by formula (II) is selected from one or more of dichlorodiethyl ether, dibromodiethyl ether, diiododiethyl ether, and dimethyl sulfonate diethyl ether; and / or, The molar ratio of intermediate 1 to the compound shown in formula (II) is 1:(1-2).
7. The method for preparing oxychlorpyrifos according to claim 1, characterized in that, The reaction temperature in step S2 is 80–150°C; and / or, The reaction system in step S2 further includes a solvent, which is selected from one or more of N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone.
8. The method for preparing clopyralid according to claim 1, characterized in that, The catalyst is a palladium catalyst; and / or, The molar ratio of intermediate 2 to catalyst is 1:(0.0001~0.01).
9. The method for preparing clodinafop-propargyl according to claim 1, characterized in that, The molar ratio of intermediate 2 to 2,6-diethyl-4-methylbromobenzene is 1:(0.9–1.5); and / or, The reaction temperature in step S3 is 120–150°C; and / or, The reaction system in step S3 further includes a solvent, which is selected from one or more of toluene, xylene, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide.
10. The method for preparing clopyralid according to claim 1, characterized in that, The molar ratio of intermediate 3 to pivaloyl chloride is 1:(1-1.5); and / or, The reaction system in step S4 further includes a solvent, wherein the solvent is selected from one or more of toluene, xylene, chlorobenzene, and dichloroethane; and / or, The base in step S4 is selected from one or more of triethylamine, N,N-dimethylethylamine, pyridine, and 4-dimethylaminopyridine; and / or, In step S4, the molar ratio of intermediate 3 to alkali is 1:(1~1.5).