Preparation method for uracil-containing iminoaryl compound
By optimizing the synthetic route of compounds VII to X, the production problem of phenyluracil herbicides in the prior art has been solved, achieving high-purity products and low-cost industrial production, while avoiding the generation of highly toxic wastewater.
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- SHANDONG KINGAGROOT CROPSCIENCE CO LTD
- Filing Date
- 2025-11-04
- Publication Date
- 2026-05-15
AI Technical Summary
The production of existing phenyluracil herbicides suffers from problems such as high levels of waste, high toxicity, high production difficulty, low yield, and low product purity, making them unsuitable for large-scale industrial production.
Compound VII was reduced to obtain compound VIII. Compound VIII was reacted with hydroxylamine hydrochloride or hydroxylamine sulfate to obtain compound IX. Compound IX was reacted with IX-a to obtain uracil-containing iminoaryl compound X. The synthetic route included the selection of catalysts and solvents, the use of low-toxicity solvents and mild reaction conditions, and the optimization of synthetic steps.
The synthesis route yields a final product with a purity of over 99%, is simple in process, low in cost, easy to industrialize, avoids the generation of highly toxic wastewater, and reduces equipment requirements.
Smart Images
Figure CN2025132240_15052026_PF_FP_ABST
Abstract
Description
A method for preparing an iminoaryl compound containing uracil Technical Field
[0001] This invention belongs to the field of organic chemical synthesis, and specifically relates to a method for preparing iminoaryl compounds containing uracil. Background Technology
[0002] Various production processes exist for phenyluracil herbicides, but they generally suffer from high levels of waste, high toxicity, high production difficulty, and low yield and product purity. There is an urgent need to develop synthetic methods suitable for large-scale industrial production. For example, patent CN113880774 discloses a method for producing 2-chloro-4-fluoro-5-(3-methyl-2,6-dione-4-trifluoromethyl-2,3-dihydropyrimidinyl-1(6H)-yl)benzaldehyde from 2-fluoro-4-chloro-5-methylaniline as a raw material through acylation, cyclization, methylation, bromination, and hydrolysis. The key material used in this method, 2-fluoro-4-chloro-5-methylaniline, is not readily available in bulk and is difficult to obtain. Furthermore, the methylation process uses carbon tetrachloride as a solvent, which has high toxicity, resulting in low product purity, which is unfavorable for industrial production. Patent CN115124476 discloses a method for preparing 2-chloro-4-fluoro-5-(3-methyl-2,6-dione-4-trifluoromethyl-2,3-dihydropyrimidinyl-1(6H)-yl)benzaldehyde by using 2-fluoro-4-chloro-5-trifluoromethylaniline as raw material and sequentially performing acylation, cyclization, reduction, and hydrolysis. This method generates a large amount of fluorine-containing wastewater when converting trifluoromethyl to trichloromethyl, and uses diethyl phosphite when converting trichloromethyl to dichloromethyl, which generates a large amount of phosphorus-containing wastewater. The three wastes result in high costs and cumbersome operation, making it unsuitable for large-scale production. Patent CN 114656407 discloses a method for preparing 2-chloro-4-fluoro-5-(3-methyl-2,6-dione-4-trifluoromethyl-2,3-dihydropyrimidinyl-1(6H)-yl)benzaldehyde by using 2,4-dichlorotoluene as a raw material and sequentially performing nitration, fluorination, reduction, cyclization, bromination, and hydrolysis. This method has poor nitration selectivity, high bromination temperature, and the use of bromine under dichloroethane reflux conditions, which poses certain safety risks. In addition, it has high equipment requirements and is cumbersome to operate, making it unsuitable for large-scale production. Summary of the Invention
[0003] To address the aforementioned problems in the prior art, this invention provides a method for preparing iminoaryl compounds containing uracil.
[0004] The technical solution adopted in this invention is as follows:
[0005] A method for preparing an iminoaryl compound containing uracil, comprising the following steps:
[0006] (1) Compound VII was reduced to give compound VIII;
[0007] (2) Compound VIII reacts with hydroxylamine hydrochloride or hydroxylamine sulfate to give compound IX;
[0008] (3) Compound IX reacts with IX-a to give iminoaryl compound X containing uracil;
[0009] The synthesis route is as follows:
[0010] Where L represents halogen.
[0011] Preferably, step (1) is carried out in the presence of a catalyst and a solvent; more preferably, the solvent is selected from at least one of formic acid, acetic acid, propionic acid, ethanol, tetrahydrofuran, 1,4-dioxane, toluene or water; and / or the catalyst is Raney nickel or nickel-aluminum alloy.
[0012] Preferably, step (2) is carried out in the presence of a solvent; more preferably, the solvent is an alcohol (such as methanol, ethanol, isopropanol, tert-butanol, etc.).
[0013] Preferably, step (3) is carried out in the presence of an alkali and a polar solvent; more preferably, the alkali is selected from at least one of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, or potassium bicarbonate; and / or the polar solvent is selected from at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, or N-methylpyrrolidone; more preferably, the alkali is in the form of a powder.
[0014] In one specific embodiment, compound VII is obtained by cyclizing compound V and compound V-a1 to obtain VI, followed by methylation, or by cyclizing compound V with V-a2; the reaction formula is as follows:
[0015] Wherein, R1 is selected from alkyl or aryl, and R2 is selected from alkyl or aryl; the aforementioned "aryl" is optionally replaced by at least one group selected from hydroxyl, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, alkoxycarbonyl, alkylthio or alkylsulfonyl.
[0016] Preferably, R1 is selected from C1-C8 alkyl or aryl, and R2 is selected from C1-C8 alkyl or aryl; the aforementioned "aryl" is optionally substituted by at least one group selected from hydroxyl, halogen, cyano, nitro, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halo-C1-C8 alkyl, halo-C2-C8 alkenyl, halo-C2-C8 alkynyl, C1-C8 alkoxy, halo-C1-C8 alkoxy, C1-C8 alkoxy carbonyl, C1-C8 alkylthio or C1-C8 alkylsulfonyl.
[0017] More preferably, R1 is selected from C1-C4 alkyl or phenyl, and R2 is selected from methyl, ethyl, isopropyl or phenyl; the aforementioned "phenyl" is optionally substituted by at least one group selected from hydroxyl, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxy carbonyl, C1-C6 alkylthio or C1-C6 alkylsulfonyl.
[0018] Preferably, the cyclization reaction is carried out in the presence of a solvent and a base; more preferably, the solvent is selected from at least one of acetonitrile, tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, sulfolane, or N-methylpyrrolidone; the base is selected from at least one of inorganic bases (such as K2CO3, Na2CO3, Cs2CO3, NaHCO3, KF, CsF, K3PO4, NaOH, KOH, NaH, KH, etc.) or organic bases (such as AcOK, AcONa, t-BuONa, MeONa, EtONa, DMAP, pyrazole, triethylamine, DIEA, etc.); and / or the methylating agent is selected from at least one of iodomethane, chloromethane, bromomethane, dimethyl sulfate, or dimethyl carbonate.
[0019] In one specific embodiment, compound V is obtained by reacting compound IV with chloroformate compound IV-a, as shown in the following reaction formula:
[0020] Preferably, the reaction is carried out in the presence of a solvent; more preferably, a base is also present in the reaction; even more preferably, the solvent is selected from at least one of acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, 1,2-dichloroethane, toluene, xylene, chlorobenzene, or dichlorobenzene, and the base is selected from at least one of inorganic bases (such as K2CO3, Na2CO3, Cs2CO3, NaHCO3, NaOH, KOH, etc.) or organic bases (such as DMAP, triethylamine, DIEA, etc.).
[0021] In one specific embodiment, compound IV is obtained by reducing compound III with a hydride reagent, as shown in the following reaction formula:
[0022] Preferably, the reduction reaction is carried out in the presence of a hydrogenation solvent and a hydrogenation catalyst; more preferably, the hydrogenation solvent is selected from at least one of methanol, ethanol, isopropanol or water; and / or the hydrogenation catalyst is selected from at least one of sodium hydrosulfite, ferric chloride, iron powder, copper powder, Raney nickel, palladium on carbon or platinum on carbon.
[0023] In one specific embodiment, compound III is obtained by fluorination of compound II with a fluoride salt, as shown in the following reaction formula:
[0024] Preferably, the fluorination reaction is carried out in the presence of a fluorinating solvent; more preferably, the fluorinating solvent is selected from at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, sulfolane, or N-methylpyrrolidone, and / or the fluoride salt is selected from at least one of potassium fluoride, sodium fluoride, cesium fluoride, amine fluoride, or tetrabutylammonium fluoride.
[0025] In one specific embodiment, compound II is obtained by nitration of compound I with nitric acid, as shown in the following reaction formula:
[0026] Preferably, the nitration reaction is carried out in the presence of a nitration catalyst; more preferably, a nitration solvent is added during the reaction; even more preferably, the nitration solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, acetic acid, trifluoroacetic acid, or water, and / or the nitration catalyst is selected from at least one of concentrated sulfuric acid, acetic anhydride, or trifluoroacetic anhydride.
[0027] In another specific embodiment, the carbon atom attached to the L group in step (3) has an R configuration, and its reaction formula is as follows:
[0028] This application has the following advantages: compared with the prior art, the final product obtained by the synthetic route of this application has a purity of over 99%, and the process route does not generate highly toxic and difficult-to-treat wastewater. The raw materials used are cheap and readily available, the reaction process is simple, the conditions are mild, the equipment requirements are low, the process cost is low, and it is easy to carry out industrial production. Detailed Implementation
[0029] The following examples are for illustrative purposes only and should not be construed as limiting the invention in any way. The scope of protection of this invention is defined by the claims.
[0030] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.
[0031] Example 1
[0032] A method for preparing compound X includes the following steps:
[0033] 1) Preparation of compound II
[0034] Compound I, 2,4-dichlorobenzonitrile (172 g, 1.0 mol), was placed in a 1000 mL four-necked flask, and 300 mL of acetic anhydride was added. The mixture was stirred and dispersed at 20–30 °C for 30 min, followed by the dropwise addition of nitric acid (97.3 g, 1.05 mol). After the addition was complete, the mixture was kept at 20–30 °C for 2–3 h. After the reaction was complete, the reaction solution was slowly poured into ice, and a solid precipitated out. The solid was filtered, and the filter cake was dried under vacuum to obtain compound II (204.2 g, yield 94.1%).
[0035] 2) Preparation of Compound III
[0036] Compound II (200 g, 0.92 mol) was placed in a 500 mL four-necked flask, and 300 mL of DMSO was added. After stirring and dispersing, anhydrous potassium fluoride (64.3 g, 1.10 mol) was added, and the mixture was heated to 90–100 °C and reacted for 12 h. After the reaction was completed, the mixture was filtered and the DMSO was distilled off under reduced pressure. Water and toluene (500 mL) were added to the system, and after stirring, the mixture was allowed to stand and separated. The toluene phase was distilled under reduced pressure until no liquid flowed out, yielding crude compound III (180.3 g), which was directly used for the next step.
[0037] 3) Preparation of compound IV
[0038] 180.3 g of crude compound III and 500 ml of purified water were placed in a 1000 ml single-necked flask. Sodium hydrosulfite (245.0 g, 1.20 mol) was added in portions at room temperature. The temperature was then raised to 45–55 °C and maintained for 1.0 h. HPLC analysis confirmed the reaction was complete. 10% industrial hydrochloric acid was added dropwise within the 45–55 °C range to adjust the pH to approximately 2–3, and the reaction was continued for another 1.0 h. After the reaction was complete, the temperature was lowered, and the pH was adjusted to 7–8 with sodium hydroxide. The mixture was then extracted with 300 ml of dichloroethane. The resulting organic phase was concentrated under reduced pressure to obtain crude compound IV (163.5 g), which was directly used in the next step.
[0039] 4) Preparation of compound V-1 (2-fluoro-4-chloro-5-methylphenyl)carbamate
[0040] Compound IV (163.5 g, crude product) and DMAP (6.10 g, 0.05 mol) were dissolved in 500 mL of 1,2-dichloroethane. The mixture was heated to 80–85 °C, and phenyl IV-a-1 chloroformate was added dropwise to the system. After the addition was complete, the reaction was continued at this temperature for 4 h until the reaction was complete. Most of the dichloroethane was distilled off under normal pressure. After distillation, a large amount of solid precipitated after cooling to room temperature. The solid was filtered to obtain compound V-1 (213.1 g, 0.83 mol). The overall yield of the three steps (2), (3), and (4) was 90.2%.
[0041] 5) Synthesis of compound VII
[0042] Compound V-1 (200.0 g, 0.78 mol) was dissolved in 600 mL of DMF. Sodium tert-butoxide (82.4 g, 0.86 mol) and ethyl Va 3-amino-4,4,4-trifluorocrotonate (142.8 g, 0.78 mol) were added at room temperature, and the mixture was stirred for 2–3 h. After the reaction was complete, dimethyl sulfate (98.4 g, 0.78 mol) was added to the system, and the mixture was stirred at room temperature until the reaction was finished. Water and ethyl acetate were added to the system, and the mixture was extracted and separated. The organic phase was concentrated under reduced pressure to obtain crude compound VII (280.3 g), which was directly used in the next step.
[0043] 6) Synthesis of compound VIII
[0044] 280.3 g of compound VII was dissolved in 500 mL of formic acid, and the mixture was heated to 80–85 °C. Raney nickel (67.0 g) was added to the system in portions. After the reaction was complete, the formic acid was removed under reduced pressure. Then, 500 mL of water and 500 mL of dichloroethane were added to the system. The mixture was separated, and the organic phase was washed with alkali and concentrated under reduced pressure. After most of the dichloroethane evaporated, the mixture was cooled, and a solid precipitated. The solid was filtered to obtain compound VIII (217.4 g, 0.62 mol). The overall yield of steps 5) and 6) was 79.5%, and the HPLC purity was ≥99.0%.
[0045] 7) Synthesis of compound IX
[0046] Compound VIII (37.00 g) obtained in the previous step was added to a 500 mL reaction flask, along with 185 g of ethanol. The mixture was heated to 50 °C, and 8.09 g of hydroxylamine hydrochloride was added to the reaction flask in multiple batches. The mixture was kept warm and stirred for 2–3 h until the reaction was complete. The mixture was then cooled to room temperature, and 5% sodium hydroxide aqueous solution was added dropwise to adjust the system to neutral. After filtration and drying, 37.33 g of white solid IX was obtained, with a purity of 97.5% and a yield of 94.0%.
[0047] 8) Synthesis of compound X
[0048] Compound IX (37.33 g) was added to a 1000 mL reaction flask, along with 180 g of N,N-dimethylformamide, 6.91 g of anhydrous potassium carbonate powder, and 24.51 g of methyl s-2-chloropropionate. The mixture was stirred at 20-30 °C for 8 h. The reaction was considered complete when the starting material disappeared as detected by HPLC. The reaction solution was quenched in water, extracted with toluene, and the organic phase was washed with purified water and concentrated under reduced pressure to obtain 44.72 g of compound X, with a purity of 98.0% and a yield of 97%.
[0049] Example 2
[0050] The difference from Example 1 lies in the preparation of compound VII:
[0051] Intermediate VI (200.0 g, 0.78 mol) was dissolved in 600 mL of toluene. Sodium carbonate (127.2 g, 1.20 mol) and ethyl 3-amino-4,4,4-trifluorocrotonate (142.8 g, 0.78 mol) were added, and the mixture was heated to reflux and maintained at this temperature for 2–3 h. After the reaction was complete, the mixture was cooled to room temperature, and then dimethyl sulfate (98.4 g, 0.78 mol) was added to the system. The mixture was stirred at room temperature until the reaction was complete. 400 mL of water was added to the system, and after stirring, the mixture was allowed to stand and separated. The organic phase was concentrated under reduced pressure to obtain crude compound VII (291.0 g).
[0052] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.
Claims
1. A method for preparing an iminoaryl compound containing uracil, characterized in that, Includes the following steps: (1) Compound VII was reduced to give compound VIII; (2) Compound VIII reacts with hydroxylamine hydrochloride or ammonium bisulfate to give compound IX; (3) Compound IX reacts with IX-a to give iminoaryl compound X containing uracil; The synthesis route is as follows: Where L represents halogen.
2. The preparation method according to claim 1, characterized in that, The step (1) is carried out in the presence of a catalyst and a solvent; preferably, the solvent is selected from at least one of formic acid, acetic acid, propionic acid, ethanol, tetrahydrofuran, 1,4-dioxane, toluene or water; and / or the catalyst is Raney nickel or nickel-aluminum alloy. Step (2) is carried out in the presence of a solvent; preferably, the solvent is an alcohol; and / or Step (3) is carried out in the presence of an alkali and a polar solvent; preferably, the alkali is selected from at least one of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate or potassium bicarbonate; and / or the polar solvent is selected from at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane or N-methylpyrrolidone; more preferably, the alkali is in the form of a powder.
3. The preparation method according to claim 1 or 2, characterized in that, Compound VII is obtained by cyclizing compound V and compound Va to give VI, followed by methylation, as shown in the following reaction formula: Wherein, R1 is selected from alkyl or aryl, and R2 is selected from alkyl or aryl; the aforementioned "aryl" is optionally replaced by at least one group selected from hydroxyl, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, alkoxycarbonyl, alkylthio or alkylsulfonyl. Preferably, R1 is selected from C1-C8 alkyl or aryl, and R2 is selected from C1-C8 alkyl or aryl; the aforementioned "aryl" is optionally substituted by at least one group selected from hydroxyl, halogen, cyano, nitro, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halo-C1-C8 alkyl, halo-C2-C8 alkenyl, halo-C2-C8 alkynyl, C1-C8 alkoxy, halo-C1-C8 alkoxy, C1-C8 alkoxy carbonyl, C1-C8 alkylthio or C1-C8 alkylsulfonyl. More preferably, R1 is selected from C1-C4 alkyl or phenyl, and R2 is selected from methyl, ethyl, isopropyl or phenyl; the aforementioned "phenyl" is optionally substituted by at least one group selected from hydroxyl, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxy carbonyl, C1-C6 alkylthio or C1-C6 alkylsulfonyl. Preferably, the cyclization reaction is carried out in the presence of a solvent and a base; more preferably, the solvent is selected from at least one of acetonitrile, tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, sulfolane, or N-methylpyrrolidone; the base is selected from at least one of inorganic and organic bases; and / or the methylating agent is selected from at least one of iodomethane, chloromethane, bromomethane, dimethyl sulfate, or dimethyl carbonate.
4. The preparation method according to claim 3, characterized in that, Compound V is obtained by reacting compound IV with chloroformate compound IV-a, as shown in the following reaction formula: Preferably, the reaction is carried out in the presence of a solvent; more preferably, a base is also present in the reaction; even more preferably, the solvent is selected from at least one of acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, 1,2-dichloroethane, toluene, xylene, chlorobenzene or dichlorobenzene; and / or the base is selected from at least one of organic bases or inorganic bases.
5. The preparation method according to claim 4, characterized in that, Compound IV is obtained by the reduction reaction of compound III with a hydride reagent, as shown in the following reaction formula: Preferably, the reduction reaction is carried out in the presence of a hydrogenation solvent and a hydrogenation catalyst; more preferably, the hydrogenation solvent is selected from at least one of methanol, ethanol, isopropanol or water; and / or the hydrogenation catalyst is selected from at least one of sodium hydrosulfite, ferric chloride, iron powder, copper powder, Raney nickel, palladium on carbon or platinum on carbon.
6. The preparation method according to claim 5, characterized in that, Compound III is obtained by fluorination of compound II with a fluoride salt, as shown in the following reaction formula: Preferably, the fluorination reaction is carried out in the presence of a fluorinating solvent; more preferably, the fluorinating solvent is selected from at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, sulfolane, or N-methylpyrrolidone, and / or the fluoride salt is selected from at least one of potassium fluoride, sodium fluoride, cesium fluoride, amine fluoride, or tetrabutylammonium fluoride.
7. The preparation method according to any one of claims 6, characterized in that, Compound II is obtained by nitration of compound I with nitric acid, as shown in the following reaction formula: Preferably, the nitration reaction is carried out in the presence of a nitration catalyst; more preferably, a nitration solvent is added during the reaction; even more preferably, the nitration solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, acetic acid, trifluoroacetic acid, or water, and / or the nitration catalyst is selected from at least one of concentrated sulfuric acid, acetic anhydride, or trifluoroacetic anhydride.
8. The preparation method according to any one of claims 1-7, characterized in that, The carbon atom attached to the L group in step (3) has an R configuration, and its reaction formula is as follows: