One-pot multi-component preparation method of chiral Dufulin compound
The single-configuration chiral fluorophos compound was prepared by a one-pot, multi-component reaction, which solved the problem of the activity difference between fluorophos isomers and realized a high-efficiency, low-cost, green pesticide synthesis suitable for industrial application.
Patent Information
- Application Number
- CN202511253291.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-03
- Publication Date
- 2025-11-11
AI Technical Summary
In existing technologies, phosmet is produced in racemic form, which leads to differences in antiviral activity and environmental behavior between the two isomers, making it difficult to achieve efficient, low-risk, and green chiral pesticide synthesis.
A single-pot, multi-component reaction method was adopted, utilizing a chiral amino catalyst, to prepare a single-configuration chiral toxic fluoride phosphate compound through a mixed reflux reaction of quinine, substituted benzyl bromide, solvent, 2-amino-4-methylbenzothiazole, 2-fluorobenzaldehyde, diethyl phosphite, and alkaline reagent, combined with extraction and water washing steps.
A low-cost, clean synthesis of chiral fluorophos was achieved under mild reaction conditions and with high product yield, making it suitable for industrial production. Furthermore, the single-configuration fluorophos compound exhibited superior antiviral activity against plant viruses compared to the racemic form.
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Figure CN120923549A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pesticide synthesis technology, and in particular to a one-pot, multi-component preparation method for chiral toxic fluoride compounds. Background Technology
[0002] Plant viral diseases, often referred to as "plant cancer," are difficult to control and easily spread. They primarily affect cash crops such as tobacco, vegetables, and fruit trees, as well as food crops like rice and corn, severely impacting crop quality and yield, and sometimes leading to total crop failure and affecting farmers' income. Toluene-2-methylphosphonic acid, chemically named N-[2-(4-methylbenzothiazolyl)]-2-amino-2-fluorophenyl-O,O-diethylphosphonic acid ester, is an antiviral compound with independent intellectual property rights in my country. It is a new generation of highly effective, broad-spectrum, and low-toxicity antiviral drug independently developed by the National Key Laboratory of Green Pesticides at Guizhou University. It is a pioneering new pesticide variety in my country and can be used to control various plant viral and bacterial diseases frequently occurring in Guangxi, Guizhou, and Yunnan provinces, such as Southern Rice Black-streaked Dwarf Disease and Citrus Canker. Toluene-2-methylphosphonic acid is characterized by its outstanding efficacy in controlling viral diseases and its low cost, which can significantly promote increased production and income for farmers.
[0003] The molecular structure of phosphonium thiocyanate contains a chiral center substituted with an aminophosphate ester, resulting in two chiral isomers. Currently, phosphonium thiocyanate is produced and applied in its racemic form. New pest control technologies have been developed, including phosphonium thiocyanate immune activation for disease prevention, phosphonium thiocyanate and pymetrozine seed treatment, key seedling protection, and synergistic effects during the tillering stage. These technologies have solved the major disease control challenges of various food and economic crops, such as rice viral diseases and citrus bacterial diseases.
[0004] However, previous structural studies have shown that the two isomers of cyhalofop-P-ethyl exhibit differences in antiviral activity and certain differences in environmental behavior. Therefore, this invention, based on the phosphate ester active center in the cyhalofop-P-ethyl molecule, developed a novel chiral clean production process. Utilizing an asymmetric one-pot multi-component reaction method with a chiral amino catalyst as the core technology, a single-configuration chiral cyhalofop-P-ethyl molecule was efficiently synthesized. The pesticide antiviral activity of cyhalofop-P-ethyl molecules with different chiral structures was investigated. This technology provides a highly efficient synthetic technique for the creation of efficient, low-risk, and green chiral pesticides. Summary of the Invention
[0005] To address the aforementioned problems, this invention provides a one-pot, multi-component preparation method for chiral toxic fluoride phosphorus compounds. This method features a simple preparation process, low cost, high reaction yield, and suitability for industrial production.
[0006] To achieve the above objectives, the present invention provides the following technical solution:
[0007] This invention provides a one-pot, multi-component method for preparing chiral toxic fluoride phosphorus compounds, comprising the following steps:
[0008] 1) Quinine and substituted benzyl bromide were mixed with a solvent and refluxed to obtain a reaction solution;
[0009] 2) Mix 2-amino-4-methylbenzothiazole and 2-fluorobenzaldehyde, solvent, and catalyst, and reflux to obtain the reaction system;
[0010] 3) The reaction system described in step 2) is mixed with diethyl phosphite, the reaction solution described in step 1), and alkaline reagent, and then stirred to obtain a stirred reaction mixture;
[0011] 4) The stirred reaction material described in step 3) is extracted with an extractant, and after separation, an organic phase is obtained. The organic phase is washed with water and the solvent is removed to obtain a chiral fluorophosphorus compound.
[0012] Preferably, the volume ratio of quinine, substituted benzyl bromide, and solvent in step 1) is 0.3–200.36 mmol: 0.31–202.55 mmol: 10–500 mL;
[0013] The solvent includes tetrahydrofuran and / or toluene.
[0014] Preferably, the reflux conditions in step 1) include: a temperature of 65–110°C and a time of 8 hours.
[0015] Preferably, in step 2), the mass of 2-amino-4-methylbenzothiazole, the mass of 2-fluorobenzaldehyde, the volume of the solvent, and the mass of the catalyst are 5–3000 g: 3.89–2300 g: 40–15000 mL: 198–119000 mg.
[0016] Preferably, the solvent in step 2) includes one or more of benzene, toluene, and xylene;
[0017] The catalyst includes cesium carbonate and / or potassium phosphate.
[0018] Preferably, the reflux conditions in step 2) include: a temperature of 115–100°C and a time of 8–14 hours.
[0019] Preferably, the volume of the reaction system in step 2) and the mass of diethyl phosphite, the volume of the reaction solution in step 1) and the mass of the alkaline reagent are 40mL-15L: 4.2g~2550g: 10mL-500mL: 65mg~77g.
[0020] Preferably, the alkaline reagent includes potassium phosphate and / or potassium carbonate.
[0021] Preferably, the extraction solution in step 4) comprises a hydrogen chloride solution and / or a sodium hydroxide solution;
[0022] The concentration of the hydrogen chloride solution is 1 mol / L;
[0023] The concentration of the sodium hydroxide solution is 1 mol / L.
[0024] Preferably, when the extractant is a hydrogen chloride solution, the stirred reaction mixture is mixed with the hydrogen chloride solution and stirred for 5 minutes;
[0025] When the extractant is a hydrogen chloride solution and a sodium hydroxide solution, the stirred reaction mixture is mixed with the hydrogen chloride solution and stirred for 5 minutes, and then mixed with the sodium hydroxide solution and stirred for 5 minutes.
[0026] The beneficial effects of this invention are:
[0027] This invention achieves low-cost and clean synthesis of chiral toxic fluoride phosphorus; the preparation method of this invention is rationally designed, with mild reaction conditions, readily available raw materials, convenient operation, high product yield, and is suitable for large-scale production, with good industrial reproducibility. Attached Figure Description
[0028] Figure 1 This is a reaction process diagram of the present invention; Detailed Implementation
[0029] This invention provides a one-pot, multi-component method for preparing chiral toxic fluoride phosphorus compounds, comprising the following steps:
[0030] 1) Quinine and substituted benzyl bromide were mixed with a solvent and refluxed to obtain a reaction solution;
[0031] 2) Mix 2-amino-4-methylbenzothiazole and 2-fluorobenzaldehyde, solvent, and catalyst, and reflux to obtain the reaction system;
[0032] 3) The reaction system described in step 2) is mixed with diethyl phosphite, the reaction solution described in step 1), and alkaline reagent, and then stirred to obtain a stirred reaction mixture;
[0033] 4) The stirred reaction material described in step 3) is extracted with an extractant, and after separation, an organic phase is obtained. The organic phase is washed with water and the solvent is removed to obtain a chiral fluorophosphorus compound.
[0034] This invention involves mixing quinine and substituted benzyl bromide with a solvent and then refluxing the mixture to obtain a reaction solution. In this invention, the preferred volume ratio of quinine, substituted benzyl bromide, and solvent is 0.3–200.36 mmol: 0.31–202.55 mmol: 10–500 mL. In this invention, the solvent preferably includes tetrahydrofuran and / or toluene. In this invention, the preferred refluxing conditions are a temperature of 65–110 °C and a time of 8 h.
[0035] This invention involves mixing 2-amino-4-methylbenzothiazole and 2-fluorobenzaldehyde, a solvent, and a catalyst, followed by reflux to obtain a reaction system. In this invention, the preferred mass ratios of 2-amino-4-methylbenzothiazole, 2-fluorobenzaldehyde, solvent, and catalyst are 5–3000 g: 3.89–2300 g: 40–15000 mL: 198–119000 mg. In this invention, the solvent includes one or more of benzene, toluene, and xylene. In this invention, the catalyst preferably includes cesium carbonate and / or potassium phosphate. In this invention, the preferred reflux conditions include a temperature of 115–100°C and a time of 8–14 h.
[0036] In this invention, the reaction system is mixed with diethyl phosphite, the reaction solution from step 1), and an alkaline reagent, and then stirred to obtain a stirred reaction mixture. In this invention, the preferred ratio of the volume of the reaction system to the mass of diethyl phosphite, the volume of the reaction solution from step 1), and the mass of the alkaline reagent is 40 mL-15 L: 4.2–2550 g: 10 mL-500 mL: 65 mg–77 g. In this invention, the alkaline reagent preferably includes potassium phosphate and / or potassium carbonate.
[0037] This invention involves extracting the stirred reaction mixture with an extractant, separating the liquids to obtain an organic phase, washing the organic phase with water to remove the solvent, and then obtaining a chiral fluorophosphorus compound. In this invention, the extractant preferably comprises a hydrogen chloride solution and / or a sodium hydroxide solution; the concentration of the hydrogen chloride solution is preferably 1 mol / L; the concentration of the sodium hydroxide solution is preferably 1 mol / L. In this invention, when the extractant is preferably a hydrogen chloride solution, the stirred reaction mixture is mixed with the hydrogen chloride solution and stirred for 5 minutes. In this invention, when the extractant is preferably a hydrogen chloride solution and a sodium hydroxide solution, the stirred reaction mixture is mixed with the hydrogen chloride solution and stirred for 5 minutes, then mixed with the sodium hydroxide solution and stirred for 5 minutes.
[0038] To further illustrate the present invention, the following detailed description is provided in conjunction with embodiments, but these should not be construed as limiting the scope of protection of the present invention.
[0039] Example 1
[0040] (1) Quinine (0.30 mmol) and 3,5-dibromobenzyl bromide (0.31 mmol) were added to a 25 mL round-bottom flask, and tetrahydrofuran (10 mL) was added as a solvent. The mixture was heated to 70 °C and refluxed for 8 h. After the reaction system cooled naturally to room temperature, no further treatment was required, and the reaction solution could be used directly as a chiral catalyst.
[0041] (2) Add 2-amino-4-methylbenzothiazole (5.0 g, 30.5 mmol) and 2-fluorobenzaldehyde (3.8 g, 30.5 mmol) to a 100 mL round-bottom flask, add toluene (40 mL) as solvent, and then add cesium carbonate (198 mg, 0.6 mmol) to the reaction system. Heat to 115 °C and reflux for 8 h.
[0042] (3) Cool the reaction system (2) to room temperature naturally, add diethyl phosphite (4.2 g, 30.5 mmol) and the catalyst reaction solution prepared in step (1), and then add potassium phosphate (65 mg, 0.3 mmol) to the reaction system and stir at room temperature for 10 h.
[0043] (4) After the reaction was completed, dilute hydrochloric acid (1 mol / L, 40 mL) was added to the reaction system, and the mixture was stirred vigorously for 5 min. The organic phase was washed with water (40 mL × 3 times) and the solvent was removed by evaporation to obtain the (S)-configuration toxic phosphonium product with a yield of 85.8%, a purity of 92.7%, and an er value of 95.5:4.5.
[0044] Example 2
[0045] (1) Add quinine (0.30 mmol) and 3-fluorobenzyl bromide (0.31 mmol) to a 25 mL round-bottom flask, add toluene (10 mL) as solvent, and heat to 110 °C under reflux for 8 h. After the reaction system cools naturally to room temperature, no further treatment is required, and the reaction solution can be used directly as a chiral catalyst.
[0046] (2) Add 2-amino-4-methylbenzothiazole (5.0 g, 30.5 mmol) and 2-fluorobenzaldehyde (3.8 g, 30.5 mmol) to a 100 mL round-bottom flask, add toluene (40 mL) as solvent, and then add cesium carbonate (198 mg, 0.6 mmol) to the reaction system. Heat to 115 °C and reflux for 8 h.
[0047] (3) Cool the reaction system (2) to room temperature naturally, add diethyl phosphite (4.2 g, 30.5 mmol) and the catalyst reaction solution prepared in step (1), and then add potassium phosphate (65 mg, 0.3 mmol) to the reaction system and stir at room temperature for 10 h.
[0048] (4) After the reaction was completed, dilute hydrochloric acid (1 mol / L, 40 mL) was added to the reaction system, and the mixture was stirred vigorously for 5 min. The organic phase was washed with water (40 mL × 3 times) and the solvent was removed by evaporation to obtain the (R)-configuration fluorophos product with a yield of 85.8%, a purity of 92.7%, and an er value of 95.5:4.5.
[0049] Example 3
[0050] (1) Quinine (0.61 mmol) and 2,4-dichlorobenzyl chloride (0.62 mmol) were added to a 25 mL round-bottom flask, and tetrahydrofuran (15 mL) was added as a solvent. The mixture was heated to 65 °C and refluxed for 8 h. After the reaction system cooled naturally to room temperature, no further treatment was required, and the reaction solution could be used directly as a chiral catalyst.
[0051] (2) Add 2-amino-4-methylbenzothiazole (10.0 g, 60.9 mmol) and 2-fluorobenzaldehyde (7.7 g, 61.0 mmol) to a 250 mL round-bottom flask, add benzene (70 mL) as solvent, and then add cesium carbonate (397 mg, 1.2 mmol) to the reaction system. Heat to 117 °C and reflux for 8 h.
[0052] (3) Cool the reaction system (2) to room temperature naturally, add diethyl phosphite (8.5g, 61.4mmol) and the catalyst reaction solution prepared in step (1), and then add potassium phosphate (258mg, 1.2mmol) to the reaction system and stir at room temperature for 10h.
[0053] (4) After the reaction was completed, dilute hydrochloric acid (1 mol / L, 60 mL) was added to the reaction system, and the mixture was stirred vigorously for 5 min. The organic phase was washed with water (60 mL × 3 times) and the solvent was removed by evaporation to obtain the (S)-configuration toxic phosphonium product with a yield of 84.9%, a purity of 91.3%, and an er value of 95:5.
[0054] Example 4
[0055] (1) Quinine (1.23 mmol) and 3-chlorobenzyl bromide (1.25 mmol) were added to a 50 mL round-bottom flask, and tetrahydrofuran (25 mL) was added as a solvent. The mixture was heated to 70 °C and refluxed for 8 h. After the reaction system cooled naturally to room temperature, no further treatment was required, and the reaction solution could be used directly as a chiral catalyst.
[0056] (2) Add 2-amino-4-methylbenzothiazole (20.0 g, 121.8 mmol) and 2-fluorobenzaldehyde (15.26 g, 123.0 mmol) to a 500 mL round-bottom flask, add xylene (140 mL) as solvent, and then add potassium phosphate (517 mg, 2.4 mmol) to the reaction system. Heat to 115 °C and reflux for 8 h.
[0057] (3) Cool the reaction system (2) to room temperature naturally, add diethyl phosphite (17g, 123.0mmol) and the catalyst reaction solution prepared in step (1), and then add potassium phosphate (517mg, 2.4mmol) to the reaction system and stir at room temperature for 12h.
[0058] (4) After the reaction was completed, dilute hydrochloric acid (1 mol / L, 100 mL) was added to the reaction system, and the mixture was stirred vigorously for 5 min. The mixture was then separated. Dilute sodium hydroxide solution (1 mol / L, 100 mL) was added to the organic phase system, and the mixture was stirred vigorously for 5 min. The mixture was then separated. The organic phase was washed with water (100 mL × 3 times), and the solvent was removed by evaporation to obtain the (S)-configuration fluorophos product. The yield was 85.1%, the purity was 94.1%, and the er value was 94.5:5.5. The main purpose of the dilute hydrochloric acid extraction was to remove insoluble substances in the reaction system, and the main purpose of the sodium hydroxide solution extraction was to remove the hydrochloric acid that was not completely removed in the previous step.
[0059] Example 5
[0060] (1) Quinine (3.08 mmol) and 4-nitrobenzyl chloride (3.11 mmol) were added to a 100 mL round-bottom flask, and tetrahydrofuran (50 mL) was added as a solvent. The mixture was heated to 75 °C and refluxed for 8 h. After the reaction system cooled naturally to room temperature, no further treatment was required, and the reaction solution could be used directly as a chiral catalyst.
[0061] (2) Add 2-amino-4-methylbenzothiazole (50.0 g, 304.5 mmol) and 2-fluorobenzaldehyde (38.2 g, 307.5 mmol) to a 1000 mL round-bottom flask, add 300 mL of trimethylbenzene as a solvent, and then add cesium carbonate (1.98 g, 6.1 mmol) to the reaction system. Heat to 120 °C and reflux for 12 h.
[0062] (3) Cool the reaction system (2) to room temperature naturally, add diethyl phosphite (42.5g, 307.5mmol) and the catalyst reaction solution prepared in step (1), and then add potassium phosphate (1.29g, 6.1mmol) to the reaction system and stir at room temperature for 14h.
[0063] (4) After the reaction was completed, dilute hydrochloric acid (1 mol / L, 300 mL) was added to the reaction system, and the mixture was stirred vigorously for 5 min. The mixture was then separated. Dilute sodium hydroxide solution (1 mol / L, 300 mL) was added to the organic phase system, and the mixture was stirred vigorously for 5 min. The mixture was then separated. The organic phase was washed with water (300 mL × 3 times) and the solvent was removed by evaporation to obtain the (S)-configuration toxic phosphonium product. The yield was 85.1%, the purity was 92.8%, and the er value was 94:6.
[0064] Example 6
[0065] (1) Quinine (6.16 mmol) and 3-cyanobenzyl chloride (6.22 mmol) were added to a 250 mL round-bottom flask, and tetrahydrofuran (100 mL) was added as a solvent. The mixture was heated to 70 °C and refluxed for 8 h. After the reaction system cooled naturally to room temperature, no further treatment was required, and the reaction solution could be used directly as a chiral catalyst.
[0066] (2) Add 2-amino-4-methylbenzothiazole (100.0 g, 609 mmol) and 2-fluorobenzaldehyde (76.3 g, 615 mmol) to a 1000 mL round-bottom flask, add toluene (500 mL) as solvent, and then add cesium carbonate (3.97 g, 12.1 mmol) to the reaction system. Heat to 120 °C and reflux for 12 h.
[0067] (3) Cool the reaction system (2) to room temperature naturally, add diethyl phosphite (85.0 g, 615 mmol) and the catalyst reaction solution prepared in step (1), and then add potassium carbonate (1.69 g, 12.1 mmol) to the reaction system and stir at room temperature for 16 h.
[0068] (4) After the reaction was completed, dilute hydrochloric acid (1 mol / L, 400 mL) was added to the reaction system, and the mixture was stirred vigorously for 5 min. The organic phase was washed with water (400 mL × 3 times) and the solvent was removed by evaporation to obtain the (S)-configuration toxic fluoride product with a yield of 81.7%, a purity of 91.3%, and an er value of 94:6.
[0069] Example 7
[0070] (1) Quinine (200.36 mmol) and 3,5-bis(trifluoromethyl)benzyl bromide (202.35 mmol) were added to a 1000 mL round-bottom flask, and tetrahydrofuran (500 mL) was added as a solvent. The mixture was heated to 80 °C and refluxed for 8 h. After the reaction system cooled naturally to room temperature, no further treatment was required, and the reaction solution could be used directly as a chiral catalyst.
[0071] (2) Add 2-amino-4-methylbenzothiazole (3.0 kg, 18.3 mol) and 2-fluorobenzaldehyde (2.3 kg, 18.4 mol) to a 30 L reactor, add toluene (15 L) as solvent, and then add cesium carbonate (119 g, 365 mmol) to the reaction system. Heat to 115 °C and reflux for 14 h.
[0072] (3) Cool the reaction system (2) to room temperature naturally, add diethyl phosphite (2.55 kg, 18.4 mol) and the catalyst reaction solution prepared in step (1), and then add potassium phosphate (77 g, 365 mmol) to the reaction system and stir at room temperature for 14 h.
[0073] (4) After the reaction is complete, dilute hydrochloric acid (1 mol / L, 10 L) is added to the reaction system, and the mixture is stirred vigorously for 5 min. The organic phase is washed with water (10 L × 3 times) and the solvent is removed by evaporation to obtain the (S)-configuration toxic fluoride product with a yield of 80.2%, a purity of 85.1%, and an er value of 92:8.
[0074] Application Example 1
[0075] This invention also provides the application of the single-configuration toxicphos obtained from the above-mentioned technical solution against plant viruses. The therapeutic activity of chiral toxicphos compounds against plant viruses: Select suitable tobacco plants, sprinkle corundum on the leaves of the entire tobacco plant and inoculate with the corresponding plant virus. After 1-1.5 hours of treatment, wash the corundum off the tobacco leaves with clean water and dry them. The prepared chiral toxicphos solution is applied to the right side of the entire tobacco leaf, while the blank control solvent is applied to the left side. After incubation in an artificial climate chamber for 4 to 5 days, count the number of local lesions appearing on both sides of the tobacco leaves, with three parallel samples for each compound.
[0076] Protective activity of chiral fluorophos compounds against plant viruses: Suitable tobacco plants were selected, and a chiral fluorophos solution was prepared and applied to the right side of the entire tobacco leaf, while a blank control solution was applied to the left side. After 24 hours, emery was sprinkled on the tobacco leaves, followed by inoculation with the corresponding plant virus. After 1-1.5 hours of treatment, the emery was washed off the tobacco leaves with clean water, and the leaves were dried. After incubation in an artificial climate chamber for 4-5 days, the number of localized lesions appearing on both sides of the tobacco leaves was counted, with three replicates for each compound.
[0077] Inactivation activity of chiral flufenoxuron compounds against plant viruses: Equal volumes of the corresponding plant virus solution and chiral flufenoxuron solution were uniformly mixed (solution A) and allowed to act for 30 minutes to inhibit the virus. An equal volume of plant virus solution was mixed with a blank solution of DMSO (solution B) as a control. Suitable tobacco plants were selected and sprinkled with carborundum. Solution A was applied to the right side of the entire tobacco leaf, and solution B was applied to the left side. After 1-1.5 hours of action, the carborundum on the tobacco leaves was washed off with water and the leaves were dried. After incubation in an artificial climate chamber for 4-5 days, the number of localized lesions on the tobacco leaves was counted, with three replicates for each compound.
[0078] The antiviral activity of the compound was calculated using the following formula:
[0079]
[0080] For example, using resistance to Potato Virus Y (PVY) as the research object, the antiviral bioactivity of hand-type flufenoxuron was tested using the half-leaf necrotic spot method at a drug concentration of 500 μg / mL. The anti-PVY therapeutic activity, protective activity, and inactivation activity of (S)-flufenoxuron against PVY were 50.1%, 49.4%, and 52.2%, respectively, which were superior to the anti-PVY activity of racemic flufenoxuron (therapeutic activity 46.6%, protective activity 48.2%, and inactivation activity 47.1%) and the anti-PVY activity of (R)-flufenoxuron (therapeutic activity 45.7%, protective activity 46.5%, and inactivation activity 48.3%).
[0081] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.
Claims
1. A one-pot, multi-component method for preparing a chiral toxic fluoride phosphorus compound, characterized in that, Includes the following steps: 1) Quinine and substituted benzyl bromide (chlorine) were mixed with a solvent and refluxed to obtain a reaction solution; 2) Mix 2-amino-4-methylbenzothiazole and 2-fluorobenzaldehyde, solvent, and catalyst, and reflux to obtain the reaction system; 3) The reaction system described in step 2) is mixed with diethyl phosphite, the reaction solution described in step 1), and alkaline reagent, and then stirred to obtain a stirred reaction mixture; 4) The stirred reaction material described in step 3) is extracted with an extractant, and after separation, an organic phase is obtained. The organic phase is washed with water and the solvent is removed to obtain a chiral fluorophosphorus compound.
2. The one-pot multi-component preparation method according to claim 1, characterized in that, In step 1), the volume ratio of quinine, substituted benzyl bromide, and solvent is 0.3–200.36 mmol: 0.31–202.55 mmol: 10–500 mL. The solvent includes tetrahydrofuran and / or toluene.
3. The one-pot multi-component preparation method according to claim 1, characterized in that, The reflux conditions in step 1) include: a temperature of 65–110°C and a time of 8 hours.
4. The one-pot multi-component preparation method according to claim 1, characterized in that, Step 2) The mass of 2-amino-4-methylbenzothiazole, the mass of 2-fluorobenzaldehyde, the volume of solvent, and the mass of catalyst are 5-3000g: 3.89-2300g: 40-15000mL: 198-119000mg.
5. The one-pot multi-component preparation method according to claim 1 or 4, characterized in that, Step 2) The solvent includes one or more of benzene, toluene, and xylene; The catalyst includes cesium carbonate and / or potassium phosphate.
6. The one-pot multi-component preparation method according to claim 1, characterized in that, The reflux conditions in step 2) include: a temperature of 115–100°C and a time of 8–14 hours.
7. The one-pot multi-component preparation method according to claim 1, characterized in that, The volume of the reaction system in step 3) and the mass of diethyl phosphite, the volume of the reaction solution in step 1), and the mass of the alkaline reagent are 40mL-15L: 4.2g~2550g: 10mL-500mL: 65mg~77g.
8. The one-pot multi-component preparation method according to claim 1 or 7, characterized in that, The alkaline reagent includes potassium phosphate and / or potassium carbonate.
9. The one-pot multi-component preparation method according to claim 1, characterized in that, Step 4) The extraction solution includes a hydrogen chloride solution and / or a sodium hydroxide solution; The concentration of the hydrogen chloride solution is 1 mol / L; The concentration of the sodium hydroxide solution is 1 mol / L.
10. The one-pot multi-component preparation method according to claim 9, characterized in that, When the extract is a hydrogen chloride solution, the stirred reaction mixture is mixed with the hydrogen chloride solution and stirred for 5 minutes. When the extractant is a hydrogen chloride solution and a sodium hydroxide solution, the stirred reaction mixture is mixed with the hydrogen chloride solution and stirred for 5 minutes, and then mixed with the sodium hydroxide solution and stirred for 5 minutes.