Preparation method of ethofuroxol
By reacting isobutyraldehyde and parabenzenequinone under amino acid catalysts and reacting with methanesulfonyl chloride and bromoethane under alkaline conditions, the complex and contaminated preparation of ethoxyfurosin in the prior art was successfully solved, and an efficient and environmentally friendly preparation method was achieved.
Patent Information
- Application Number
- CN202411582446.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-07
- Publication Date
- 2025-03-07
AI Technical Summary
The existing preparation methods for ethoxyfuros yellow have multiple reactions, low purity, difficult to handle impurities, expensive catalysts, and multiple washing operations, resulting in high production costs and environmental pollution.
The reaction of isobutyraldehyde and parabenzenequinone under amino acid catalysts was obtained to obtain intermediate Y-01, and then react with methanesulfonyl chloride and bromoethane under basic conditions to successfully produce ethoxyfurosin.
The high yield and high purity preparation of ethoxyfuroaceae yellow is achieved, the process flow is simplified, the environmental pollution and production costs are reduced, and it is also suitable for large-scale production.
Smart Images
Figure CN119569691A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the field of organic synthesis of pesticides, and in particular to a method for preparing ethoxyfuroxol. Background Art
[0002] Ethoxyfuroxan is a herbicide first developed by the German company AgrEvo for use in beet fields. It can destroy the photosynthesis of grass plants and inhibit their growth. It has the characteristics of low toxicity, broad spectrum and high selectivity. Sugar beets are highly resistant to it, which means that when a large amount of ethoxyfuroxan is used for weeding, sugar beet crops can still maintain normal growth and development without obvious damage. Moreover, ethoxyfuroxan not only has a significant weed control effect on grass plants in sugar beet fields, but also has a good weed control effect on many broad-leaved weeds. At the same time, ethoxyfuroxan can also be used as a component of a mixture, mixed with beet safe, beet Ning, etc. for weed control in sugar beet fields, which can not only reduce the use of other pesticides, but also improve the efficacy of the pesticides, achieve better weed control effects, and reduce pollution and damage to the environment.
[0003] However, the existing preparation methods of ethoxyfuroxol usually require multi-step reactions, have low purity, and contain a variety of difficult-to-handle impurities. At the same time, expensive catalysts are required in the preparation process. These problems not only increase production costs, but also impose a burden on the environment. In particular, in order to remove specific impurities in the post-processing of ethoxyfuroxol, multiple water washing operations are required, which will produce a large amount of washing wastewater.
[0004] Therefore, it is urgent to develop a more efficient, green, environmentally friendly, mild and easy-to-control method for preparing ethoxyfuroxol. Summary of the invention
[0005] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a method for preparing ethoxyfuroxanol
[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows:
[0007] In a first aspect, the present invention provides a method for preparing ethoxyfuroxol, comprising the following steps:
[0008] (1) Isobutyraldehyde and p-benzoquinone react under the catalysis of an amino acid catalyst to obtain an intermediate Y-01 as shown in formula (I):
[0009]
[0010] (2) The intermediate Y-01 reacts with methanesulfonyl chloride under alkaline conditions to obtain the intermediate Y-02 shown in formula (II):
[0011]
[0012] (3) The intermediate Y-02 reacts with ethyl bromide under alkaline conditions to obtain ethoxyfuroxanol as shown in (III):
[0013]
[0014] The ethoxyfuroxol prepared by the preparation method of the present invention has high yield and high purity, and can be used as a herbicide alone in the weeding process of beet crops; it can also be used as a component of a mixture, such as mixed with beet anhydride, beet chloranil, etc., for weeding in beet fields. It can not only reduce the use of other pesticides, but also improve the efficacy of the drug, achieve better weeding effect, and reduce pollution and damage to the environment.
[0015] The amino acid catalyst of the present invention is a series of catalysts with biomimetic catalytic performance derived from an amino acid skeleton. In the preparation method of the ethoxyfuroxol of the present invention, the amino acid catalyst is used to directly cause a cyclization reaction between p-benzoquinone and isobutyraldehyde to obtain a cyclized intermediate Y-01, the intermediate Y-01 undergoes a nucleophilic substitution reaction with methanesulfonyl chloride under alkaline conditions to obtain a difunctionalized intermediate Y-02, and the intermediate Y-02 reacts with ethyl bromide under alkaline conditions to obtain the target product ethoxyfuroxol. The preparation method of the present invention has easy-to-obtain raw materials, a feasible route, simple operation, mild reaction conditions, high yield and purity of the synthesized product, and does not require multiple impurity removal operations. It is a green, environmentally friendly, easy-to-control, and large-scale production synthetic route.
[0016] As a preferred embodiment of the method for preparing ethoxyfuroxol of the present invention, in step (1), the molar ratio of isobutyraldehyde, amino acid catalyst and p-benzoquinone is 1:(0.1-0.5):(1-1.5).
[0017] As a preferred embodiment of the method for preparing ethoxyfuroxol of the present invention, the amino acid catalyst is (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine.
[0018] The (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine of the present invention is a catalyst with biomimetic catalytic properties derived from a proline skeleton, which has unique reaction sites and spatial structures. In step (1) of the present invention, the secondary amine group in the catalyst can interact with p-benzoquinone to form an enamine intermediate, and then the enamine intermediate attacks the aldehyde group of isobutyraldehyde, and further undergoes a cyclization reaction to obtain the intermediate Y-01.
[0019] As a preferred embodiment of the method for preparing ethoxyfuroxol of the present invention, in step (1), a solvent is further added to the reaction; the solvent is at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, methanol, water, and dimethyl sulfoxide.
[0020] As a preferred embodiment of the method for preparing ethoxyfuroxol of the present invention, the mass ratio of the solvent to isobutyraldehyde is (3-15):1.
[0021] As a preferred embodiment of the method for preparing ethoxyfuroxol of the present invention, in step (2) and / or step (3), the alkaline condition is achieved by adding a base; the base is at least one of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, and pyridine.
[0022] Preferably, in step (2), the base is triethylamine; in step (2), the base is potassium carbonate.
[0023] As a preferred embodiment of the method for preparing ethoxyfuroxol of the present invention, in step (2), the molar ratio of the intermediate Y-01, the base and the methanesulfonyl chloride is 1:(1-2):(2-3.5).
[0024] As a preferred embodiment of the method for preparing ethoxyfuroxol of the present invention, in step (3), the molar ratio of the intermediate Y-02, the base and ethyl bromide is 1:(1-2):(1-1.5).
[0025] As a preferred embodiment of the method for preparing ethoxyfuroxol of the present invention, in step (2) and / or step (3), the reaction temperature is -5°C-50°C and the reaction time is 1-10h.
[0026] Compared with the prior art, the beneficial effects of the present invention are as follows: first, the preparation method of the present invention has easy-to-obtain raw materials, a feasible route, simple operation, mild reaction conditions, and no need for multiple impurity removal operations. It is a green, environmentally friendly, easy-to-control, and large-scale production synthetic route with potential industrial production value. Secondly, the preparation method of the present invention has a high yield and high purity. The efficacy of the ethoxyfuroxol can be improved when used alone or in combination with other pesticides, achieving a better weed control effect while reducing pollution and damage to the environment. BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Figure 1 is the structural formula of the ethopoxalate of the present invention;
[0028] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of the intermediate Y-02 in Example 1 of the present invention. DETAILED DESCRIPTION
[0029] To better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments. It should be understood by those skilled in the art that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.
[0030] The present invention provides a method for preparing ethoxyfuroxol, comprising the following synthesis steps:
[0031] (1) Preparation of intermediate Y-01:
[0032] Isobutyraldehyde, amino acid catalyst and solvent are added to a reaction vessel and stirred, and then p-benzoquinone is added and stirred to react to obtain intermediate Y-01. The specific reaction chemical formula is shown below:
[0033]
[0034] (2) Preparation of intermediate Y-02
[0035] After the intermediate Y-01 obtained in step (1) is mixed with a solvent, a base is added and stirred, and then methylsulfonyl chloride is added and stirred to react, thereby obtaining the intermediate Y-02. The specific reaction chemical formula is shown below:
[0036]
[0037] (3) Preparation of ethoxyfuroxil
[0038] After the intermediate Y-02 obtained in step (2) is mixed with a solvent, a base is added and stirred, and then ethyl bromide is added and stirred to react, thereby obtaining ethoxyfuroxol. The specific reaction chemical formula is shown below:
[0039]
[0040] In one embodiment, in step (1), the molar ratio of isobutyraldehyde, amino acid catalyst and p-benzoquinone is 1:(0.1-0.5):(1-1.5).
[0041] In one embodiment, in step (1), the molar ratio of isobutyraldehyde, amino acid catalyst and p-benzoquinone is 1:0.2:1.1.
[0042] In one embodiment, in step (1), the solvent is at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, methanol, water, and dimethyl sulfoxide.
[0043] In one embodiment, in step (1), the solvent is water.
[0044] In one embodiment, in step (1), the mass ratio of the solvent to the isobutyraldehyde is (3-15):1.
[0045] In one embodiment, in step (1), the mass ratio of the solvent to the isobutyraldehyde is 6:1.
[0046] In one embodiment, in step (1), the reaction temperature is 10°C-50°C.
[0047] In one embodiment, in step (1), the reaction temperature is 20°C-25°C.
[0048] In one embodiment, in step (1), the reaction time is 10 h-48 h.
[0049] In one embodiment, in step (1), the reaction time is 10 h-24 h.
[0050] In one embodiment, in step (2), the molar ratio of the intermediate Y-01, the base and the methanesulfonyl chloride is 1:(1-2):(2-3.5).
[0051] In one embodiment, in step (2), the molar ratio of the intermediate Y-01, the base and the methanesulfonyl chloride is 1:1.2:2.1.
[0052] In one embodiment, in step (2), the base is at least one of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, and pyridine.
[0053] In one embodiment, in step (2), the base is triethylamine.
[0054] In one embodiment, in step (2), the solvent is at least one of toluene, ethyl acetate, dichloromethane, dichloroethane, and diethyl ether.
[0055] In one embodiment, in step (2), the solvent is toluene.
[0056] In one embodiment, in step (2), the mass ratio of the solvent to the intermediate Y-01 is (3-20):1.
[0057] In one embodiment, in step (2), the mass ratio of the solvent to the intermediate Y-01 is 5:1.
[0058] In one embodiment, in step (2), the reaction temperature is -5°C to 50°C.
[0059] In one embodiment, in step (2), the reaction temperature is 0°C-5°C.
[0060] In one embodiment, in step (2), the reaction time is 1 h-10 h.
[0061] In one embodiment, in step (2), the reaction time is 1 h-2 h.
[0062] In one embodiment, in step (3), the molar ratio of the intermediate Y-02, the base and ethyl bromide is 1:(1-2):(1-1.5).
[0063] In one embodiment, in step (3), the molar ratio of the intermediate Y-02, the base and ethyl bromide is 1:1.2:1.1.
[0064] In one embodiment, in step (3), the base is at least one of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, and pyridine.
[0065] In one embodiment, in step (3), the base is potassium carbonate.
[0066] In one embodiment, in step (3), the solvent is at least one of toluene, ethyl acetate, dichloromethane, dichloroethane, and diethyl ether.
[0067] In one embodiment, in step (3), the solvent is toluene.
[0068] In one embodiment, in step (3), the mass ratio of the solvent to the intermediate Y-02 is (3-20):1.
[0069] In one embodiment, in step (3), the mass ratio of the solvent to the intermediate Y-02 is 6:1.
[0070] In one embodiment, in step (3), the reaction temperature is -5°C to 50°C.
[0071] In one embodiment, in step (3), the reaction temperature is 0°C-5°C.
[0072] In one embodiment, in step (3), the reaction time is 1 h-10 h.
[0073] In one embodiment, in step (3), the reaction time is 1 h-2 h.
[0074] The following is an elaboration in conjunction with specific embodiments to illustrate the practical effects of the solutions of the present invention.
[0075] Unless otherwise specified, the experimental methods used in the examples are all conventional methods; the materials, reagents, equipment, etc. used, unless otherwise specified, can be obtained from commercial sources.
[0076] The raw materials used in the following examples and comparative examples are described as follows, but are not limited to these materials:
[0077] (2S)-2-[Diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine, CAS No.: 848821-58-9, purchased from Anaiji Chemical, purity 95%, enantiomeric excess (ee): 99%;
[0078] (2S)-diphenylprolinol, CAS No.: 112068-01-6, purchased from Anaiji (A040234), purity 98%, enantiomeric excess (ee): 98%;
[0079] (S)-α,α-Bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl ether, CAS No.: 848821-61-4, purchased from Anaiji (D070452), purity 97%, enantiomeric excess (ee): 99%;
[0080] S-2-Pyrrolidine-1-methylpiperidine, CAS No.: 65921-41-7, purchased from Bidex Pharmaceuticals (BD265314), purity 95%, enantiomeric excess (ee): 98%.
[0081] Example 1: Preparation of ethoxyfuroxol
[0082] (1) Preparation of intermediate Y-01:
[0083] To the reaction bottle, 86 g of water, 14.4 g (0.20 mol) of isobutyraldehyde, and 13 g (0.04 mol) of catalyst (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine were added, and after stirring for 10 minutes, 23.78 g (0.22 mol) of p-benzoquinone was added, and stirring was continued for 24 hours. After the reaction was completed, ethyl acetate was added to extract twice, and the mixture was washed twice with saturated brine. The organic phase was collected and concentrated to obtain 28.0 g of the target compound intermediate Y-01 with a yield of 85%. The compound was directly put into the next step reaction.
[0084] (2) Preparation of intermediate Y-02:
[0085] Add 18.0g (0.10mol) of compound intermediate Y-01, 90g of toluene, and 23.3g (0.23mol) of triethylamine to the reaction flask, stir at 0°C for 15 minutes, then add 24.0g (0.21mol) of methylsulfonyl chloride dropwise for 1 hour, and continue to stir and react at the same temperature for 2 hours after the addition is completed. After the reaction is completed, warm to room temperature, add 100mL of water to wash once, add 50mL of 1M hydrochloric acid to wash once, add 50mL of saturated brine to wash once, and concentrate the organic phase to obtain 27.9g of intermediate Y-02, with a yield of 83%, and the compound is directly put into the next step of reaction.
[0086] (3) Preparation of ethoxyfuroxol:
[0087] 16.9g (0.05mol) of compound intermediate Y-02, 84.5g of toluene, and 8.3g (0.06mol) of potassium carbonate were added to the reaction bottle, and after stirring at 0°C for 15 minutes, 6.0g (0.06mol) of bromoethane solution was added dropwise, and the addition time was 2 hours. After the addition was completed, the reaction was continued to be stirred at this temperature for 1.5 hours. After the reaction was completed, it was warmed to room temperature, 100g of 10% sodium carbonate aqueous solution was added to wash once, 50g of 1M hydrochloric acid was added to wash once, 50g of saturated brine was added to wash once, and the organic phase was concentrated. The concentrate was purified and separated by column chromatography (n-hexane: dichloromethane = 1: 1) to obtain 10.9g of ethoxyfuroxanol, with a yield of 76%.
[0088] The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product ethoxyfuroxol are as follows:
[0089] 1H NMR (400MHz, CDCl3): δ7.03(d,J=7.2Hz,1H),6.80(d,J=6.4Hz,1H),7.02(s,1H),5.26(s,1H),3.95(qd,J= 6.0,5.6Hz,1H),3.65(qd,J=6.0,5.6Hz,1H),3.12(s,3H),1.32(s,3H),1.27(s,3H),1.25(t,J=5.6Hz,3H).
[0090] Example 2: Preparation of ethoxyfuroxol
[0091] The only difference between the preparation method of ethoxyfuroxol described in this example and that in Example 1 is that in step (1), the molar ratio of isobutyraldehyde, (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine and p-benzoquinone is 1:0.1:1, and 23.4 g of the target compound intermediate Y-01 is obtained with a yield of 71%.
[0092] Example 3: Preparation of ethoxyfuroxol
[0093] The only difference between the preparation method of ethoxyfuroxol described in this example and that in Example 1 is that in step (1), the molar ratio of isobutyraldehyde, (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine and p-benzoquinone is 1:0.5:1.5, and 29 g of the target compound intermediate Y-01 is obtained with a yield of 88%.
[0094] Example 4: Preparation of ethoxyfuroxol
[0095] The only difference between the preparation method of ethoxyfuroxol described in this example and that in Example 1 is that in step (1), the molar ratio of isobutyraldehyde, (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine and p-benzoquinone is 1:0.5:1.1, and 28 g of the target compound intermediate Y-01 is obtained with a yield of 85%.
[0096] Example 5: Preparation of ethoxyfuroxol
[0097] The only difference between the preparation method of ethoxyfuroxol described in this example and that in Example 1 is that in step (1), the molar ratio of isobutyraldehyde, (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine and p-benzoquinone is 1:0.1:1.1, and 22.4 g of the target compound intermediate Y-01 is obtained with a yield of 68%.
[0098] Example 6: Preparation of Ethofuroxol
[0099] The only difference between the preparation method of ethoxyfuroxol described in this example and that in Example 1 is that the solvent in step (1) is N,N-dimethylformamide, and 14.2 g of the target compound intermediate Y-01 is obtained with a yield of 43%.
[0100] Example 7: Preparation of Ethofuroxol
[0101] The only difference between the preparation method of ethoxyfuroxol described in this example and that in Example 1 is that the solvent in step (1) is dimethyl sulfoxide, and 8.6 g of the target compound intermediate Y-01 is obtained with a yield of 26%.
[0102] Example 8: Preparation of Ethofuroxol
[0103] The only difference between the preparation method of ethoxyfuroxol described in this example and that in Example 1 is that the mass ratio of water to isobutyraldehyde in step (1) is 3:1, and 25.4 g of the target compound intermediate Y-01 is obtained with a yield of 77%.
[0104] Example 9: Preparation of Ethofuroxol
[0105] The only difference between the preparation method of ethoxyfuroxol described in this example and that in Example 1 is that the mass ratio of water to isobutyraldehyde in step (1) is 15:1, and 26.4 g of the target compound intermediate Y-01 is obtained with a yield of 80%.
[0106] Comparative Example 1: Preparation of Ethofuroxol
[0107] The only difference between the preparation method of ethoxyfuroxol described in this comparative example and that in Example 1 is that the catalyst used in step (1) is 50.6 g (0.20 mol) of (2S)-diphenylprolinol, and 22.26 g of the target compound intermediate Y-01 is obtained, with a yield of 62%.
[0108] Comparative Example 2: Preparation of Ethofuroxol
[0109] The only difference between the preparation method of ethoxyfuroxol described in this comparative example and that in Example 1 is that the catalyst used in step (1) is 119.4 g (0.20 mol) of (S)-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl ether, and 4.4 g of the target compound intermediate Y-01 is obtained with a yield of 12%.
[0110] Comparative Example 3: Preparation of Ethofuroxol
[0111] The only difference between the preparation method of ethoxyfuroxol in this comparative example and that in Example 1 is that the catalyst used in step (1) is 36.4 g (0.20 mol) of S-2-pyrrolidine-1-methylpiperidine, and 25.8 g of the target compound intermediate Y-01 is obtained, with a yield of 72%.
[0112] Comparative Example 4: Preparation of Ethofuroxol
[0113] The only difference between the preparation method of ethoxyfuroxol described in this comparative example and that in Example 1 is that in step (1), the molar ratio of isobutyraldehyde to (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine is 1:0.05, and 18.2 g of the target compound intermediate Y-01 is obtained with a yield of 55%.
[0114] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.
Claims
1. A method for preparing ethoxyfuroxol, characterized in that: The following steps are involved: (1) Isobutyraldehyde and p-benzoquinone react under the catalysis of an amino acid catalyst to obtain an intermediate Y-01 as shown in formula (I): (2) The intermediate Y-01 reacts with methanesulfonyl chloride under alkaline conditions to obtain the intermediate Y-02 shown in formula (II): (3) The intermediate Y-02 reacts with ethyl bromide under alkaline conditions to obtain ethoxyfuroxanol as shown in formula (III):
2. The method for preparing ethoxyfuroxol according to claim 1, characterized in that: In step (1), the molar ratio of isobutyraldehyde, amino acid catalyst and p-benzoquinone is 1:(0.1-0.5):(1-1.5).
3. The method for preparing ethoxyfuroxol according to claim 1 or 2, characterized in that, The amino acid catalyst is (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine.
4. The method for preparing ethoxyfuroxol according to claim 1, characterized in that: In step (1), a solvent is further added to the reaction; the solvent is at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, methanol, water, and dimethyl sulfoxide.
5. The method for preparing ethoxyfuroxol according to claim 4, characterized in that: The mass ratio of the solvent to isobutyraldehyde is (3-15):
1.
6. The method for preparing ethoxyfuroxol according to claim 1, characterized in that: In step (2) and / or step (3), the alkaline condition is achieved by adding a base; the base is at least one of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, and pyridine.
7. The method for preparing ethoxyfuroxol according to claim 6, characterized in that: In step (2), the base is triethylamine; in step (3), the base is potassium carbonate.
8. The method for preparing ethoxyfuroxol according to claim 1, characterized in that: In step (2), the molar ratio of the intermediate Y-01, the base and the methanesulfonyl chloride is 1:(1-2):(2-3.5).
9. The method for preparing ethoxyfuroxol according to claim 1, characterized in that: In step (3), the molar ratio of the intermediate Y-02, the base and ethyl bromide is 1:(1-2):(1-1.5).
10. The method for preparing ethomofuram according to claim 1, characterized in that: In step (2) and / or step (3), the reaction temperature is -5°C to 50°C and the reaction time is 1 to 10 hours.