Chiral resolution method of fluralana

Abstract

The invention discloses a chiral resolution method of fluralana. The method provided by the invention comprises the following steps: (1) mixing a fluralana solution and a D-(+)-resolution reagent solution, carrying out heating reflux reaction, cooling to obtain a precipitate, and carrying out solid-liquid separation to obtain a solid I and a filtered mother solution; (2) sequentially adding an acid solution I and an alkali solution I into the solid I to separate out the solid, carrying out solid-liquid separation to obtain a solid II, and recrystallizing the solid II to obtain S-fluralan; (3) concentrating the filtered mother solution to obtain a solid-containing concentrated solution, sequentially adding an acid solution II and an alkali solution II into the solid-containing concentrated solution to separate out the solid, and carrying out solid-liquid separation to obtain a solid III; (4) dissolving the solid III in a solvent, adding an L-(+) resolution reagent, and carrying out heating reflux reaction, cooling and solid-liquid separation to obtain a solid IV; and (5) sequentially adding an acid solution III and an alkali solution III into the solid IV to separate out the solid, carrying out solid-liquid separation to obtain a solid V, and recrystallizing the solid V to obtain the R-fluralan. According to the fluralana chiral resolution method developed by the invention, fluralana is split into two chiral compounds R and S, the operation is simple, the yield is high, and the two chiral fluralana chiral compounds are obtained.

Description

Technical Field

[0001] The invention relates to the technical field of chiral separation, and in particular to a method for chiral separation of fluororana. Background Art

[0002] As the latest generation of veterinary drugs, fluralaner was successfully developed and synthesized by Nissan Chemical Industries, Ltd. of Japan in 2004 as a broad-spectrum anthelmintic of the isoxazoline class, and was authorized for an international patent in 2005. The compound has a pair of enantiomers, and the drug was marketed as a mixture of R and S. However, further research results later showed that the S configuration of fluralaner is its main insecticidal active component.

[0003] As a veterinary drug, Flurellana has been commercialized in Europe and the United States, and is mainly used for the prevention and treatment of external parasites of dogs and cats and mites of chickens. It has a fast effect, a long half-life and duration, is easily absorbed orally, is highly safe, and can kill a wide range of external parasites. In April 2019, Intervet International Co., Ltd. registered the import of Flurellana chewable tablets (trade name: Bravecto) in my country, which are used to treat flea and tick infections on the surface of dogs, and can also assist in the treatment of allergic dermatitis caused by fleas; in March 2023, Intervet International Co., Ltd. registered the import of Flurellana solution (trade name: EXZOLT) in my country, which is used to treat poultry red mites on chickens. In July 2023, Intervet International Co., Ltd. registered the import of Flurellana drops (trade name: BRAVECTO) in my country, which are used to treat fleas and ticks on cats and dogs. At present, the only literature and reviews on the synthesis process, analytical testing, biological effects and toxicology of flurellan API in China are available, and there are no related products. Therefore, flurellan has broad application prospects in the breeding and pet industries.

[0004] Patent CN202110824166.5 reports a method for preparing S-configuration-Florana; a method using a chiral compound with 1-[3,5-bis(trifluoromethyl)phenyl]-3-[(1R,2R)-(-)-2-(dimethylamino)cyclohexyl]thiourea as the starting material, and preparing S-configuration-Florana through five steps of nucleophilic substitution, hydroxyl protection, hydroxylamine oximation, Mitsunobu, and amide condensation, but the route of this method is too long, the loss is too great, and the price of the raw materials of the starting chiral compound is too high, which is not suitable for large-scale production.

[0005] Therefore, it is necessary to develop a better method for the chiral resolution of fluorouracil. Summary of the invention

[0006] The purpose of the present invention is to provide a method for the chiral separation of flurellana. The method for the chiral separation of flurellana developed by the present invention can separate flurellana into two chiral compounds, R and S, with simple operation and high yield, and two chiral flurellana chiral compounds can be obtained.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] The first aspect of the present invention is to provide a method for chiral separation of fluororana, comprising the following steps:

[0009] (1) mixing a solution of flurana and a solution of a D-(+)-resolving agent and heating them under reflux, cooling them to obtain a precipitate, and performing solid-liquid separation to obtain a solid and a filtered mother liquor;

[0010] (2) adding acid solution 1 and alkali solution 1 to the solid 1 in sequence to precipitate the solid, separate the solid and the liquid, and obtain solid 2, and recrystallize the solid 2 to obtain S-flurana;

[0011] (3) concentrating the filtered mother liquor to obtain a concentrated solution containing solids, and sequentially adding a second acid solution and a second alkali solution to the concentrated solution containing solids to precipitate solids, and performing solid-liquid separation to obtain a third solid;

[0012] (4) dissolving the solid (3) in a solvent, adding an L-(+) resolving agent, heating and refluxing, cooling, and solid-liquid separation to obtain a solid (4);

[0013] (5) adding acid solution 3 and alkali solution 3 to the solid 4 in sequence to precipitate the solid, separate the solid and the liquid, and obtain solid 5; and recrystallizing the solid 5 to obtain R-flurana.

[0014] As a preferred embodiment, step (1),

[0015] The solvent in the solution of flurana and the solvent in the solution of the D-(+)-resolution reagent are each independently selected from at least one of ethanol, methanol or DMF;

[0016] In the solution of flurana, the mass volume concentration of flurana is 0.02 g / ml to 0.1 g / ml;

[0017] In the solution of the D-(+)-resolution reagent, the mass volume concentration of the D-(+)-resolution reagent is 0.01 g / ml to 0.1 g / ml;

[0018] The molar ratio of the flurellana to the D-(+)-resolution reagent is 1:0.8 to 1:3;

[0019] The heating reflux reaction time is 18 to 36 hours;

[0020] The temperature of the heating reflux reaction is 80-150°C;

[0021] Allow to cool to room temperature.

[0022] As a preferred embodiment,

[0023] The D-(+)-resolving agent is selected from D-(+)-tartaric acid.

[0024] As a preferred embodiment, the acid solution 1, acid solution 2 and acid solution 3 in step (2), step (3) and step (5) are each independently selected from hydrochloric acid solution and sulfuric acid solution; preferably, the concentration of the acid solution 1, acid solution 2 and acid solution 3 is each independently 10wt% to 30wt%;

[0025] The alkali solution 1, alkali solution 2 and alkali solution 3 in step (2), step (3) and step (5) are each independently selected from concentrated aqueous ammonia; preferably, the concentration of the concentrated aqueous ammonia is 15wt% to 28wt%.

[0026] As a preferred embodiment, step (2),

[0027] The mass volume ratio of flurellane to acid solution 1 in step (1) is 1 g: 0.5-5 ml;

[0028] The mass volume ratio of flurellane to alkali solution 1 in step (1) is 1 g: 1-5 ml;

[0029] Using stirring to precipitate solids;

[0030] The recrystallization treatment uses an organic solvent for recrystallization; preferably, the organic solvent is selected from ethyl acetate, a mixed solvent of ethyl acetate and n-heptyl, a mixed solvent of ethyl acetate and toluene, methanol, ethanol, dichloromethane or acetonitrile.

[0031] As a preferred embodiment, step (3),

[0032] The mass volume ratio of the flurellane in step (1) to the second acid solution is 1 g: 0.5-2.5 ml;

[0033] The mass volume ratio of flurellane in step (1) to the alkali solution 2 is 1 g: 0.5-2.5 ml;

[0034] The mixture was stirred to allow solid to precipitate.

[0035] As a preferred embodiment, step (4),

[0036] The solvent is selected from at least one of ethanol, methanol or DMF;

[0037] The mass volume ratio of flurellane to solvent in step (1) is 1 g: 1-15 ml;

[0038] The molar ratio of flurellana in step (1) to the L-(+)-resolution reagent is 1:0.4 to 1:3;

[0039] The heating reflux reaction time is 18 to 36 hours;

[0040] The temperature of the heating reflux reaction is 80-150°C;

[0041] Allow to cool to room temperature.

[0042] As a preferred embodiment, step (4),

[0043] The L-(+)-resolving agent is selected from L-(+)-tartaric acid.

[0044] As a preferred embodiment, step (5),

[0045] The mass volume ratio of the flurellane in step (1) to the acid solution 3 is 1 g: 0.5-2.5 ml;

[0046] The mass volume ratio of flurellane in step (1) to alkali solution 3 is 1 g: 0.5-2.5 ml;

[0047] The mixture was stirred to allow solid to precipitate.

[0048] As a preferred embodiment, step (5),

[0049] The recrystallization treatment uses an organic solvent for recrystallization; preferably, the organic solvent is selected from ethyl acetate, a mixed solvent of ethyl acetate and n-heptyl, a mixed solvent of ethyl acetate and toluene, methanol, ethanol, dichloromethane or acetonitrile.

[0050] The present invention unexpectedly discovered that chiral tartaric acid reagent can split flurellana into R-flurellana and S-flurellana under certain conditions, while other chiral splitting reagents cannot achieve this.

[0051] The present invention adopts a chiral organic acid and flurellanine to form a salt for splitting, and then adopts an acid-base neutralization method to remove the organic acid to obtain chiral flurellanine. Specifically, the chiral splitting reagent selected in the present invention can perform chiral splitting on flurellanine according to the principle that:

[0052] The principle of chiral separation of the present invention is to utilize flurellana and chiral tartaric acid to react under certain conditions to produce R-flurellana organic acid salt and S-flurellana organic acid salt, and then separate the S-flurellana organic salt from the mother liquor by the difference in solubility of the two chiral organic salt compounds, and the R-flurellana organic salt is retained in the mother liquor. The S-flurellana organic salt is then dissociated from the chiral organic acid by the principle of strong acid to weak acid, and finally S-flurellana is obtained by acid-base neutralization with an organic weak base, and finally purified to obtain pure S-flurellana. The R-flurellana method is consistent with the above operation.

[0053] The beneficial effects brought by the technical solution of the present invention are:

[0054] 1. The present invention develops a method for the chiral separation of flurana, which can separate flurana into two chiral compounds, R and S. The method has simple operation and high yield, and two chiral flurana chiral compounds are obtained.

[0055] 2. Fluoranab has an enantiomer, which is divided into two configurations, R and S. However, literature reports that S-configured fluoranab has insecticidal activity. Therefore, the present invention directly splits fluoranab, reduces the usage of fluoranab, and enhances the activity of fluoranab. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 is the liquid phase chromatogram of R-Florellana of the present invention;

[0057] Figure 2 is the liquid chromatogram of S-Florellana of the present invention;

[0058] Figure 3 Schematic diagram of the chiral resolution process of fluororana. DETAILED DESCRIPTION

[0059] The present invention is further described in detail below through the accompanying drawings and specific embodiments. However, it should not be understood that the scope of the above subject matter is limited to the following embodiments. All technologies realized based on the content of the present invention belong to the scope.

[0060] The instruments, reagents, materials, etc. involved in this embodiment, unless otherwise specified, are all conventional instruments, reagents, materials, etc. already available in the prior art and can be obtained through regular commercial channels. The experimental methods, detection methods, etc. involved in the following embodiments, unless otherwise specified, are all conventional experimental methods, detection methods, etc. already available in the prior art.

[0061] Example 1

[0062] 10g (18mmol) of flurellane was added to 200ml of anhydrous ethanol and heated until the solid was completely dissolved. In another beaker, 4.15g (18mmol) of D-(+)-tartaric acid was added to 100ml of anhydrous ethanol and heated until it was completely dissolved. Then, this solution was added to the flurellane ethanol solution and heated under reflux for 24 hours. The temperature of the heating under reflux reaction was 80°C. The solution was cooled to room temperature to completely precipitate the D-(+)-tartrate and filtered. The salt was added to 20ml of 20% hydrochloric acid solution, and then 30ml of concentrated ammonia (25wt%) was added to the solution. Stirring was continued until all the solid was precipitated. The solution was filtered and recrystallized from ethyl acetate to obtain 4.0g of white solid, namely S-flurellane, with a yield of 80%, a purity of 99.8%, a specific rotation (°) of +61.89, and a melting point of 173.6-174.2°C.

[0063] The mother liquor of D-(+)-tartrate is concentrated to obtain a solid. All of the solid solution is added to 10 ml of 20% hydrochloric acid solution, and then 15 ml of concentrated ammonia (25 wt%) is added to the solution. Stirring is continued until all solids are precipitated, and the mixture is filtered. The solid is added to 100 ml of anhydrous ethanol, and then 2.1 g (9 mmol) of L-(+)-tartaric acid is added to the solution. The mixture is heated to reflux for 24 hours at a temperature of 80° C. The mixture is cooled to room temperature and filtered to obtain L-(+)-tartrate. The salt is added to 10 ml of 20% hydrochloric acid solution, and then 15 ml of concentrated ammonia (25 wt%) is added to the solution. Stirring is continued until all solids are precipitated, and the mixture is filtered and recrystallized from ethyl acetate to obtain 3.3 g of a white solid, i.e., R-Florana, with a yield of 66% and a purity of 99.7%. The specific rotation (°) is -59.03, and the melting point is 173.5-174.3°C.

[0064] The specific process of chiral separation of fluororana is as follows: Figure 3 As shown, the liquid chromatogram of R-Florellana prepared by the above method is as follows Figure 1 As shown, the liquid chromatogram of S-Florellana prepared by the above method is as follows Figure 2 shown.

[0065] Example 2

[0066] 4g (7.2mmol) of flurellane was added to 200ml of anhydrous ethanol and heated until the solid was completely dissolved. In another beaker, 1.66g (7.2mmol) of D-(+)-tartaric acid was added to 100ml of anhydrous ethanol and heated until it was completely dissolved. Then, this solution was added to the flurellane ethanol solution and heated under reflux for 20 hours. The temperature of the heating under reflux reaction was 80°C. The solution was cooled to room temperature to completely precipitate the D-(+)-tartrate and filtered. The salt was added to 8ml of 20% hydrochloric acid solution, and then 12ml of concentrated ammonia (25wt%) was added to the solution. Stirring was continued until the solid was completely precipitated. The solution was filtered and recrystallized from ethyl acetate to obtain S-flurellane with a yield of 70%, a purity of 99.7%, a specific rotation (°) of +61.83, and a melting point of 173.5-174.0°C.

[0067] The mother liquor of D-(+)-tartrate is concentrated to obtain solids. All of the solid solutions are added to 4 ml 20% hydrochloric acid solution, and then 6 ml of concentrated ammonia water is added to the solution, stirring is continued until all solids are precipitated, filtered, and the solid is added to 100 ml of anhydrous ethanol, and then 0.84 g (3.6 mmol) of L-(+)-tartaric acid is added to the solution, heated to reflux for 20 hours, and the temperature of the heating reflux reaction is 80°C; cooled to room temperature, filtered, and L-(+)-tartrate is obtained. All of the salt is added to 4 ml 20% hydrochloric acid solution, and then 6 ml of concentrated ammonia water is added to the solution, stirring is continued until all solids are precipitated, filtered, and recrystallized from ethyl acetate to obtain 1.23 grams of white solid, i.e., R-Florana, with a yield of 61.5% and a purity of 99.6%. The specific rotation (°) is -59.00, and the melting point is 173.6-174.2°C.

[0068] Example 3

[0069] 20g (36mmol) of flurellane was added to 200ml of anhydrous ethanol and heated until the solid was completely dissolved. In another beaker, 8.4g of D-(+)-tartaric acid was added to 100ml of anhydrous ethanol and heated until it was completely dissolved. Then, this solution was added to the flurellane ethanol solution and heated under reflux for 22 hours. The temperature of the heating under reflux reaction was 80°C. The solution was cooled to room temperature to completely precipitate the D-(+)-tartrate and filtered. The salt was added to 38ml of 20% hydrochloric acid solution, and then 58ml of concentrated ammonia (25wt%) was added to the solution. Stirring was continued until all the solid was precipitated. The solution was filtered and recrystallized from ethyl acetate to obtain S-flurellane with a yield of 78%, a purity of 99.8%, a specific rotation (°) of +61.31, and a melting point of 173.4-174.5°C.

[0070] The mother liquor of D-(+)-tartrate is concentrated to obtain solids. All of the solid solutions are added to 40 ml 20% hydrochloric acid solution, and then 60 ml concentrated ammonia water is added to the solution, stirring is continued until all solids are precipitated, filtered, and the solid is added to 100 ml anhydrous ethanol, and then 4.5 g L-(+)-tartaric acid is added to the solution, heated to reflux for 24 hours, and the temperature of the heating reflux reaction is 80°C; cooled to room temperature, filtered, and L-(+)-tartrate is obtained. All of the salt is added to 20 ml 20% hydrochloric acid solution, and then 30 ml concentrated ammonia water is added to the solution, stirring is continued until all solids are precipitated, filtered, and recrystallized from ethyl acetate to obtain 6.7 grams of white solid, i.e., R-Florana, with a yield of 67% and a purity of 99.4%. The specific rotation (°) is -58.4, and the melting point is 173.7-174.5°C.

[0071] Example 4

[0072] 10 g (18 mmol) of flurellane was added to 200 ml of anhydrous ethanol and heated until the solid was completely dissolved. In another beaker, 3.32 g (14.4 mmol) of D-(+)-tartaric acid was added to 100 ml of anhydrous ethanol and heated until it was completely dissolved. Then, this solution was added to the flurellane ethanol solution and heated under reflux for 24 hours. The temperature of the heating under reflux reaction was 80°C. The solution was cooled to room temperature to completely precipitate the D-(+)-tartrate and filtered. The salt was added to 20 ml of 20% hydrochloric acid solution, and then 30 ml of concentrated ammonia (25 wt%) was added to the solution. Stirring was continued until the solid was completely precipitated. The solution was filtered and recrystallized with methanol to obtain a white solid, namely S-flurellane, with a yield of 68%, a purity of 99.7%, a specific rotation (°) of +58.13, and a melting point of 173.4-174.3°C.

[0073] The mother liquor of D-(+)-tartrate is concentrated to obtain solids. All of the solid solutions are added to 10 ml 20% hydrochloric acid solution, and then 15 ml of concentrated ammonia water is added to the solution, stirring is continued until all solids are precipitated, filtered, and the solid is added to 100 ml of anhydrous ethanol, and then 1.68 g (7.2 mmol) of L-(+)-tartaric acid is added to the solution, heated to reflux for 24 hours, and the temperature of the heating reflux reaction is 80°C; cooled to room temperature, filtered, and L-(+)-tartrate is obtained. All of the salt is added to 10 ml 20% hydrochloric acid solution, and then 15 ml of concentrated ammonia water is added to the solution, stirring is continued until all solids are precipitated, filtered, and recrystallized from methanol to obtain a white solid, namely R-Florana, with a yield of 62% and a purity of 99.8%. The specific rotation (°) is -57.14, and the melting point is 173.4-174.2°C.

[0074] Example 5

[0075] 10g (18mmol) of flurellane was added to 200ml of anhydrous ethanol and heated until the solid was completely dissolved. In another beaker, 3.32g (14.4mmol) of D-(+)-tartaric acid was added to 100ml of anhydrous ethanol and heated until it was completely dissolved. Then, this solution was added to the flurellane ethanol solution and heated under reflux for 36 hours. The temperature of the heating under reflux reaction was 80°C. The solution was cooled to room temperature to completely precipitate the D-(+)-tartrate and filtered. The salt was added to 15ml of 20% hydrochloric acid solution, and then 25ml of concentrated ammonia (25wt%) was added to the solution. Stirring was continued until the solid was completely precipitated. The solution was filtered and recrystallized from ethyl acetate to obtain 3.3g of white solid, namely S-flurellane, with a yield of 66%, a purity of 99.7%, a specific rotation (°) of +60.15, and a melting point of 173.5-174.3°C.

[0076] The mother liquor of D-(+)-tartrate is concentrated to obtain solids. All of the solid solutions are added to 10 ml 20% hydrochloric acid solution, and then 15 ml of concentrated ammonia water is added to the solution, stirring is continued until all solids are precipitated, filtered, and the solid is added to 100 ml of anhydrous ethanol, and then 1.68 g (7.2 mmol) of L-(+)-tartaric acid is added to the solution, heated to reflux for 36 hours, and the temperature of the heating reflux reaction is 80°C; cooled to room temperature, filtered, and L-(+)-tartrate is obtained. All of the salt is added to 8 ml 20% hydrochloric acid solution, and then 12.5 ml of concentrated ammonia water is added to the solution, stirring is continued until all solids are precipitated, filtered, and recrystallized from ethyl acetate to obtain 3.5 grams of white solid, namely R-Florana, with a yield of 70% and a purity of 99.8%. The specific rotation (°) is -59.01, and the melting point is 173.4-174.5°C.

[0077] The above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A method for chiral separation of fluororana, characterized in that: The following steps are involved: (1) mixing a solution of flurana and a solution of a D-(+)-resolving agent and heating them under reflux, cooling them to obtain a precipitate, and performing solid-liquid separation to obtain a solid and a filtered mother liquor; (2) adding acid solution 1 and alkali solution 1 to the solid 1 in sequence to precipitate the solid, separate the solid and the liquid, and obtain solid 2, and recrystallize the solid 2 to obtain S-flurana; (3) concentrating the filtered mother liquor to obtain a concentrated solution containing solids, and sequentially adding a second acid solution and a second alkali solution to the concentrated solution containing solids to precipitate solids, and performing solid-liquid separation to obtain a third solid; (4) dissolving the solid (3) in a solvent, adding an L-(+) resolving agent, heating and refluxing, cooling, and solid-liquid separation to obtain a solid (4); (5) adding acid solution 3 and alkali solution 3 to the solid 4 in sequence to precipitate the solid, separate the solid and the liquid, and obtain solid 5; and recrystallizing the solid 5 to obtain R-flurana.

2. The method for chiral separation of fluororana according to claim 1, characterized in that: Step (1), The solvent in the solution of flurana and the solvent in the solution of the D-(+)-resolution reagent are each independently selected from at least one of ethanol, methanol or DMF; In the solution of flurana, the mass volume concentration of flurana is 0.02 g / ml to 0.1 g / ml; In the solution of the D-(+)-resolution reagent, the mass volume concentration of the D-(+)-resolution reagent is 0.01 g / ml to 0.1 g / ml; The molar ratio of the flurellana to the D-(+)-resolution reagent is 1:0.8 to 1:3; The heating reflux reaction time is 18 to 36 hours; The temperature of the heating reflux reaction is 80-150°C; Allow to cool to room temperature.

3. The method for chiral separation of fluororana according to claim 1, characterized in that: The D-(+)-resolving agent is selected from D-(+)-tartaric acid.

4. The method for chiral separation of fluororana according to claim 1, characterized in that: The acid solution 1, acid solution 2 and acid solution 3 in step (2), step (3) and step (5) are each independently selected from hydrochloric acid solution and sulfuric acid solution; preferably, the concentration of the acid solution 1, acid solution 2 and acid solution 3 is each independently 10wt% to 30wt%; The alkali solution 1, alkali solution 2 and alkali solution 3 in step (2), step (3) and step (5) are each independently selected from concentrated aqueous ammonia; preferably, the concentration of the concentrated aqueous ammonia is 15wt% to 28wt%.

5. The method for chiral separation of fluororana according to claim 1, characterized in that: Step (2), The mass volume ratio of flurellane to acid solution 1 in step (1) is 1 g: 0.5-5 ml; The mass volume ratio of flurellane to alkali solution 1 in step (1) is 1 g: 1-5 ml; Using stirring to precipitate solids; The recrystallization treatment uses an organic solvent for recrystallization; preferably, the organic solvent is selected from ethyl acetate, a mixed solvent of ethyl acetate and n-heptyl, a mixed solvent of ethyl acetate and toluene, methanol, ethanol, dichloromethane or acetonitrile.

6. The method for chiral separation of fluororana according to claim 1, characterized in that: Step (3), The mass volume ratio of the flurellane in step (1) to the second acid solution is 1 g: 0.5-2.5 ml; The mass volume ratio of flurellane in step (1) to the alkali solution 2 is 1 g: 0.5-2.5 ml; The mixture was stirred to allow solid to precipitate.

7. The method for chiral separation of fluororana according to claim 1, characterized in that: Step (4), The solvent is selected from at least one of ethanol, methanol or DMF; The mass volume ratio of flurellane to solvent in step (1) is 1 g: 1-15 ml; The molar ratio of flurellana in step (1) to the L-(+)-resolution reagent is 1:0.4 to 1:3; The heating reflux reaction time is 18 to 36 hours; The temperature of the heating reflux reaction is 80-150°C; Allow to cool to room temperature.

8. The method for chiral separation of fluororana according to claim 1, characterized in that: Step (4), The L-(+)-resolving agent is selected from L-(+)-tartaric acid.

9. The method for chiral separation of fluororana according to claim 1, characterized in that: Step (5), The mass volume ratio of the flurellane in step (1) to the acid solution 3 is 1 g: 0.5-2.5 ml; The mass volume ratio of flurellane in step (1) to alkali solution 3 is 1 g: 0.5-2.5 ml; The mixture was stirred to allow solid to precipitate.

10. The method for chiral separation of fluororana according to claim 1, characterized in that: Step (5), The recrystallization treatment uses an organic solvent for recrystallization; preferably, the organic solvent is selected from ethyl acetate, a mixed solvent of ethyl acetate and n-heptyl, a mixed solvent of ethyl acetate and toluene, methanol, ethanol, dichloromethane or acetonitrile.

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