A kind of preparation method of flurellana

Abstract

The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing flurana. The present invention uses seven-step reactions, including Friedel-Crafts reaction, substitution reaction, hydrolysis reaction, two-step condensation reaction, elimination reaction, and cyclization reaction, to synthesize flurana. Compared with the prior art, the present invention has the following advantages: 1. Using relatively cheap o-bromotoluene as the starting material reduces the material cost; 2. The process operation is simple and does not require a complicated post-treatment process; 3. The prior art mostly synthesizes the isoxazole ring first, mainly because the introduction of the side chain after the cyclization reduces the reaction steps, but the cyclization route is bound to increase too many by-products that are difficult to remove, and the yield is not high; the present synthetic route introduces the side chain first and finally generates the isoxazole ring, which is conducive to reducing the generation of by-products and ensuring the yield; 4. It does not involve high-pressure reaction, has low requirements on reaction equipment, and is safer to react, which is suitable for large-scale preparation of flurana.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing flurellana. Background Art

[0002] At present, there are many patents and literature reports on the synthesis of flurellana, such as routes 1 to 4.

[0003] Route 1:

[0004]

[0005] Patent WO2005085216 describes the synthesis of flurellan. The patent uses 2-methyl-4-formaldehyde oxime benzoic acid tert-butyl ester as the starting material, prepares the oxime chloro compound under the action of NCS, and then reacts with 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene to undergo a 1,3-dipolar ring second condensation reaction, and finally reacts with 2-amino-N-(2,2,2-trifluoroethyl)acetamide under alkaline conditions to produce flurellan. The disadvantage is that a large number of side reactions will occur during the 1,3-dipolar ring second condensation reaction, there are many impurities, and the yield is low through column chromatography separation.

[0006] Route 2:

[0007]

[0008] Patent CN109879826 describes another synthetic route for flurana. The patent condenses the 2-amino-N-(2,2,2-trifluoroethyl)acetamide group with benzoic acid in advance, and finally performs a 1,3-dipolar ring second condensation reaction with 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene to prepare flurana. This route has multiple active reaction sites in the 2-amino-N-(2,2,2-trifluoroethyl)acetamide group, so a large number of side reactions will occur during the NCS chlorination and the final 1,3-dipolar ring second condensation reaction, which will make it difficult to purify the final product in actual production, and the total yield is very low.

[0009] Route 3:

[0010]

[0011] Patent CN113512007A describes another synthetic route of flurana. This route uses 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethan-1-one and 4-acetyl-2-methylbenzonitrile as starting materials, and obtains the compound 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzonitrile under the action of a base. The latter uses Ac2O / 4-dimethylaminopyridine to remove a molecule of water to obtain an α, β-unsaturated ketone compound; the α, β-unsaturated ketone compound undergoes an isoxazole cyclization reaction under the action of hydroxylamine hydrochloride to obtain the corresponding carboxylic acid intermediate; the latter then undergoes a condensation reaction with 2-amino-N-(2,2,2-trifluoroethyl)acetamide to achieve the synthesis of flurana. The last step of the synthesis step of this route requires a high-pressure reaction, which is not suitable for large-scale production for safety reasons.

[0012] Route 4:

[0013]

[0014] The Hoveyda group in the United States developed a route for preparing chiral flurellana. The synthetic route first uses a boron reagent to prepare chiral (S)-2-(3,5-dichlorophenyl)-1,1,1-trifluoropent-4-ene-2-ol, and then uses ozone to oxidize the terminal double bond to obtain (S)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyraldehyde; the product of the reaction of the obtained aldehyde compound and (4-(methoxycarbonyl)-3-methylphenyl) magnesium chloride lithium chloride complex is directly oxidized by Dess-Martin to obtain (S)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyraldehyde. The first step is to prepare (S)-4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid methyl ester by cyclization under the action of hydroxylamine hydrochloride, PhI(OH)OTs and P(OMe)3; finally, (S)-4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid methyl ester and 2-amino-N-(2,2,2-trifluoroethyl)acetamide are condensed to achieve the preparation of S-configuration flurella. This route focuses on the synthesis of chiral molecules, with complex processes and is not suitable for industrial production.

[0015] Combining the current preparation methods of flurana, it is not difficult to find that the starting materials (tert-butyl 2-methyl-4-formaldehyde oxime benzoate, 2-amino-N-(2,2,2-trifluoroethyl)acetamide, 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethan-1-one and 2-(3,5-dichlorophenyl)-1,1,1-trifluoropent-4-ene-2-ol) in the existing process have complex structures, and the starting materials that can be purchased on the market are expensive, which also causes the material cost of flurana to be high. In addition, the existing methods all involve the step of ring closure to prepare 4,5-dihydroisoxazole intermediates, and the current ring closure precursors all contain multiple active groups, such as ester groups, acylamino groups, carboxyl groups, etc., and the ring closure reagents are all hydroxylamine hydrochloride. These active groups are very easy to react with hydroxylamine hydrochloride, thereby causing the entire preparation process to produce complex impurities, which brings bottlenecks to the subsequent product purification and industrial production. Summary of the invention

[0016] In order to solve the problems existing in the prior art, the present invention provides a method for preparing flurellana. The preparation method provided by the present invention does not involve high-pressure reaction, is easy to operate, and has a high yield.

[0017] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0018] The present invention provides a method for preparing flurellana, comprising the following steps:

[0019] After first dissolving o-bromotoluene and acetyl chloride, a Friedel-Crafts reaction is carried out under a catalyst condition to obtain 1-(4-bromo-3-methyl-phenyl)-ethanone;

[0020] The temperature of the Friedel-Crafts reaction is 25°C;

[0021] After dissolving 1-(4-bromo-3-methyl-phenyl)-ethanone and a cyaniding agent for a second time, a substitution reaction is carried out to obtain 2-methyl-4-acetylbenzonitrile;

[0022] The temperature of the substitution reaction is 110-120°C and the time is 6-10h;

[0023] After dissolving 2-methyl-4-acetylbenzonitrile for the third time, a hydrolysis reaction is performed to obtain 2-methyl-4-acetylbenzoic acid;

[0024] After dissolving 2-methyl-4-acetylbenzoic acid, a carboxyl activation reagent and N,N-dimethylformamide for the fourth time, the activation is performed, and the obtained product is sequentially mixed with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and triethylamine, and then subjected to a first condensation reaction to obtain an intermediate 1 having a structure shown in Formula 1;

[0025] The activation reaction is carried out at a temperature of 70 to 80°C for 1 to 2 hours; the first condensation reaction is carried out at a temperature of 0 to 5°C for 0.5 to 1.5 hours;

[0026] After the intermediate 1, 3',5'-dichloro-2,2,2-trifluoroacetophenone and triethylamine are dissolved for the fifth time, a second condensation reaction is performed to obtain an intermediate 2 having a structure shown in Formula 2;

[0027] The temperature of the second condensation reaction is 60-75°C and the time is 10h;

[0028] After the intermediate 2, the acylation catalyst, acetic anhydride and triethylamine are dissolved for the sixth time, an elimination reaction is performed to obtain an intermediate 3 having a structure shown in Formula 3;

[0029] The temperature of the elimination reaction is 65°C and the time is 8h;

[0030] After dissolving the intermediate 3, hydroxylamine hydrochloride and tetrabutylammonium bromide, a cyclization reaction is carried out to obtain fluralanol;

[0031]

[0032] Preferably, the molar ratio of o-bromotoluene to acetyl chloride is 0.9-3.0:1; and the Friedel-Crafts reaction time is 2-24 hours.

[0033] Preferably, the cyaniding agent includes one or more of sodium cyanide, potassium cyanide, cuprous cyanide and trimethylsilane cyanide;

[0034] The molar ratio of the 1-(4-bromo-3-methyl-phenyl)-ethanone to the cyaniding agent is 1:1-10.

[0035] Preferably, the hydrolysis reaction is carried out under acidic conditions or alkaline conditions, wherein the acidic conditions are provided by sulfuric acid, acetic acid, hydrochloric acid or phosphoric acid; and the alkaline conditions are provided by sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

[0036] Preferably, when the hydrolysis reaction is carried out under acidic conditions, the temperature of the hydrolysis reaction is 45 to 105° C., and the time of the hydrolysis reaction is 1 to 12 hours;

[0037] When the hydrolysis reaction is carried out under alkaline conditions, the temperature of the hydrolysis reaction is 30 to 40° C., and the time of the hydrolysis reaction is 1 to 12 hours.

[0038] Preferably, the carboxyl activation reagent includes one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride.

[0039] Preferably, the molar ratio of the 2-methyl-4-acetylbenzoic acid to 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride is 1:1 to 1.7.

[0040] Preferably, the molar ratio of the intermediate 1 to 3',5'-dichloro-2,2,2-trifluoroacetophenone is 1:1-2.

[0041] Preferably, the molar ratio of the intermediate 2 to acetic anhydride is 1:0.95-2.5.

[0042] Preferably, the molar ratio of the intermediate 3 to hydroxylamine hydrochloride is 1:0.95-3.0; the temperature of the cyclization reaction is -10-55°C; and the time of the cyclization reaction is 2-8h.

[0043] The invention provides a method for preparing flurellan, which comprises the following steps: first dissolving o-bromotoluene and acetyl chloride, and then performing Friedel-Crafts reaction under a catalyst condition to obtain 1-(4-bromo-3-methyl-phenyl)-ethanone; second dissolving 1-(4-bromo-3-methyl-phenyl)-ethanone and a cyaniding agent, and then performing a substitution reaction to obtain 2-methyl-4-acetylbenzonitrile; third dissolving 2-methyl-4-acetylbenzonitrile, and then performing a hydrolysis reaction to obtain 2-methyl-4-acetylbenzoic acid; fourth dissolving 2-methyl-4-acetylbenzoic acid and a carboxyl activation agent, and then performing activation to obtain a product. After sequentially mixing with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and triethylamine, a first condensation reaction is carried out to obtain an intermediate 1 having a structure shown in Formula 1; after the intermediate 1, 3',5'-dichloro-2,2,2-trifluoroacetophenone and triethylamine are dissolved for the fifth time, a second condensation reaction is carried out to obtain an intermediate 2 having a structure shown in Formula 2; after the intermediate 2, an acylation catalyst, acetic anhydride and triethylamine are dissolved for the sixth time, an elimination reaction is carried out to obtain an intermediate 3 having a structure shown in Formula 3; after the intermediate 3, hydroxylamine hydrochloride and tetrabutylammonium bromide are dissolved for the seventh time, a cyclization reaction is carried out to obtain flurellan. Compared with the prior art, the present invention has the following advantages: 1. It uses relatively cheap o-bromotoluene as the starting material, which reduces the material cost; 2. The process operation is simple and does not require a complicated post-processing process; 3. The prior art mostly synthesizes the isoxazole ring first, mainly because the introduction of the side chain after the ring formation will reduce the reaction steps, but the route of first ring formation is bound to increase too many by-products that are difficult to remove, and the yield is not high; this synthetic route introduces the side chain first and finally generates the isoxazole ring, which is conducive to reducing the generation of by-products and ensuring the yield; 4. It does not involve high-pressure reactions, does not require high reaction equipment, and the reaction is safer, which is suitable for large-scale preparation of flurana. 5. All reaction solvents of the present invention, such as ethyl acetate and n-hexane, can be recycled and reused, and the pollution to the environment is light. 6. The process has good stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 A synthetic route for flurellana;

[0045] Figure 2 is the liquid chromatogram of Flurellana obtained in Example 1;

[0046] Figure 3 This is the carbon NMR spectrum of flurellane obtained in Example 1;

[0047] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of flurellan obtained in Example 1;

[0048] Figure 5 This is the carbon NMR spectrum of flurellane obtained in Example 2;

[0049] Figure 6 This is the hydrogen nuclear magnetic resonance spectrum of flurellane obtained in Example 2. DETAILED DESCRIPTION

[0050] The present invention provides a method for preparing flurellana, comprising the following steps:

[0051] After first dissolving o-bromotoluene and acetyl chloride, a Friedel-Crafts reaction is carried out under a catalyst condition to obtain 1-(4-bromo-3-methyl-phenyl)-ethanone;

[0052] After dissolving 1-(4-bromo-3-methyl-phenyl)-ethanone and a cyaniding agent for a second time, a substitution reaction is carried out to obtain 2-methyl-4-acetylbenzonitrile;

[0053] After dissolving 2-methyl-4-acetylbenzonitrile for the third time, a hydrolysis reaction is performed to obtain 2-methyl-4-acetylbenzoic acid;

[0054] After dissolving 2-methyl-4-acetylbenzoic acid and a carboxyl activation reagent for the fourth time, the activated product is mixed with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and triethylamine in sequence, and then subjected to a first condensation reaction to obtain an intermediate 1 having a structure shown in Formula 1;

[0055] After the intermediate 1, 3',5'-dichloro-2,2,2-trifluoroacetophenone and triethylamine are dissolved for the fifth time, a second condensation reaction is performed to obtain an intermediate 2 having a structure shown in Formula 2;

[0056] After the intermediate 2, the acylation catalyst, acetic anhydride and triethylamine are dissolved for the sixth time, an elimination reaction is performed to obtain an intermediate 3 having a structure shown in Formula 3;

[0057] After dissolving the intermediate 3, hydroxylamine hydrochloride and tetrabutylammonium bromide, a cyclization reaction is carried out to obtain fluralanol;

[0058]

[0059] The invention first dissolves o-bromotoluene and acetyl chloride, and then performs Friedel-Crafts reaction under catalyst conditions to obtain 1-(4-bromo-3-methyl-phenyl)-ethanone.

[0060] In the present invention, the first solvent for the first dissolution preferably includes one or more of methanol, ethanol, acetone, dimethyl sulfoxide, dichloromethane, benzene, toluene and n-hexane, and more preferably dichloromethane. In the present invention, the catalyst preferably includes one or more of aluminum chloride, aluminum bromide, zinc chloride, ferric chloride, boron trifluoride, tin tetrachloride and titanium tetrachloride, and more preferably aluminum chloride.

[0061] In the present invention, the first dissolving step is preferably to mix o-bromotoluene and the first solvent, and then dropwise add acetyl chloride to the resulting mixed solution under ice-water bath conditions.

[0062] In the present invention, the molar ratio of o-bromotoluene to acetyl chloride is preferably 0.9-3.0:1, more preferably 1.1:1.

[0063] In the present invention, the temperature of the Friedel-Crafts reaction is 25° C., and the time of the Friedel-Crafts reaction is preferably 2 to 24 h, more preferably 10 h.

[0064] In the present invention, after the Friedel-Crafts reaction, the reaction solution is preferably extracted, and the obtained organic phase is washed with water, dried over anhydrous sodium sulfate, concentrated and distilled.

[0065] After obtaining 1-(4-bromo-3-methyl-phenyl)-ethanone, the present invention dissolves 1-(4-bromo-3-methyl-phenyl)-ethanone and a cyaniding agent for a second time, and then performs a substitution reaction to obtain 2-methyl-4-acetylbenzonitrile.

[0066] In the present invention, the cyaniding agent preferably includes one or more of sodium cyanide, potassium cyanide, cuprous cyanide and trimethylsilyl cyanide, and more preferably cuprous cyanide. In the present invention, the second solvent of the second solvent preferably includes one or more of acetonitrile, N,N dimethylformamide, toluene, xylene, dimethyl sulfoxide and methyl tert-butyl ether, and more preferably N,N dimethylformamide. In the present invention, the molar ratio of the 1-(4-bromo-3-methyl-phenyl)-ethanone to the cyaniding agent is preferably 1:1 to 10, and more preferably 1:2.

[0067] In the present invention, the temperature of the substitution reaction is 110-120° C., more preferably 115° C., and the time of the substitution reaction is 6-10 h, more preferably 10 h.

[0068] In the present invention, after the substitution reaction, the method preferably further comprises extracting the system obtained by the substitution reaction with dichloromethane, and washing the obtained organic phase with water and then concentrating it.

[0069] After obtaining 2-methyl-4-acetylbenzonitrile, the present invention dissolves 2-methyl-4-acetylbenzonitrile for the third time and then performs a hydrolysis reaction to obtain 2-methyl-4-acetylbenzoic acid.

[0070] In the present invention, the hydrolysis reaction is preferably carried out under acidic conditions or alkaline conditions. The acidic reagent providing the acidic conditions is preferably one or more of sulfuric acid, acetic acid, hydrochloric acid and phosphoric acid, and the pH value of the acidic conditions is preferably 1-2; in the present invention, the alkaline reagent providing the alkaline conditions is preferably one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, and the pH value of the alkaline conditions is preferably 10-11.

[0071] In the present invention, when the hydrolysis reaction is carried out under acidic conditions, the temperature of the hydrolysis reaction is preferably 45 to 105° C., more preferably 50 to 60° C., and the time of the hydrolysis reaction is 1 to 12 h, more preferably 2 to 10 h.

[0072] In the present invention, after the hydrolysis reaction under acidic conditions, the reaction system is preferably extracted with ethyl acetate, and the obtained organic phase is concentrated.

[0073] In the present invention, when the hydrolysis reaction is carried out under alkaline conditions, the temperature of the hydrolysis reaction is preferably 30-40° C., more preferably 40° C., and the time of the hydrolysis reaction is 1-12 h, more preferably 10 h.

[0074] In the present invention, after the hydrolysis reaction under alkaline conditions, it is preferred that the system obtained by the hydrolysis reaction is sequentially subjected to reduced pressure distillation, cold precipitation under acidic conditions and filtration. In the present invention, the cold precipitation is preferably carried out under ice-water bath and stirring conditions, the acidic conditions are preferably obtained by adjusting with dilute hydrochloric acid, and the pH value under the acidic conditions is preferably 1-2.

[0075] After obtaining 2-methyl-4-acetylbenzoic acid, the present invention dissolves 2-methyl-4-acetylbenzoic acid, a carboxyl activation reagent and N,N-dimethylformamide for the fourth time, and then activates the product. The obtained product is sequentially mixed with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and triethylamine, and then subjected to a first condensation reaction to obtain an intermediate 1 having a structure shown in Formula 1.

[0076] In the present invention, the fourth solvent of the fourth solvent is preferably one or more of dichloromethane, toluene, xylene, methyl tert-butyl ether, thionyl chloride and oxalyl chloride, more preferably toluene; the carboxyl activation reagent includes one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride, more preferably oxalyl chloride.

[0077] In the present invention, the specific step of the fourth dissolution is to dissolve 2-methyl-4-acetylbenzoic acid in the fourth solvent and then dropwise add a hydroxyl activation reagent.

[0078] In the present invention, the molar ratio of the 2-methyl-4-acetylbenzoic acid to the carboxyl activator is preferably 1:2; the amount of the N,N-dimethylformamide used is a catalytic amount. In the present invention, the N,N-dimethylformamide acts as a catalyst to promote the reaction of thionyl chloride with carboxyl to generate acyl chloride. The addition of N,N-dimethylformamide can reduce the reaction temperature of the activation reaction and shorten the time of the activation reaction.

[0079] In the present invention, the activation temperature is preferably 70-80° C., more preferably 80° C., and the activation time is preferably 1-2 h, more preferably 1.5 h.

[0080] In the present invention, the 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride is preferably used in the form of a tetrahydrofuran solution of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride. In the present invention, the molar ratio of the 2-methyl-4-acetylbenzoic acid and 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride is preferably 1:1 to 1.7, more preferably 1:1 to 1.2. In the present invention, the molar ratio of the 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and triethylamine is preferably 1:2. In the present invention, the triethylamine acts as an acid binding agent.

[0081] In the present invention, the temperature of the first condensation reaction is preferably 0-5°C, more preferably 2°C, and the time is preferably 0.5-1.5h, more preferably 1h.

[0082] In the present invention, after the first condensation reaction, it is preferred that the first condensation reaction system is sequentially extracted, and the organic phase obtained by extraction is evaporated to dryness. In the present invention, the extraction is preferably a mixture of the first condensation reaction system, water and ethyl acetate, followed by adjusting the pH to 1-2 with hydrochloric acid, separating the layers, evaporating the solvent from the organic phase, and recrystallizing the crude product.

[0083] In the present invention, the function of adjusting the pH value with hydrochloric acid is to remove excess triethylamine and break the emulsion.

[0084] After obtaining the intermediate 1, the present invention dissolves the intermediate 1, 3',5'-dichloro-2,2,2-trifluoroacetophenone and triethylamine for the fifth time, and then performs a second condensation reaction to obtain the intermediate 2 having the structure shown in Formula 2.

[0085] In the present invention, the fifth solvent of the fifth solvent is preferably one or more of toluene, xylene, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, dimethyltetrahydrofuran and dimethyl sulfoxide, more preferably toluene.

[0086] In the present invention, the molar ratio of the intermediate 1 to 3',5'-dichloro-2,2,2-trifluoroacetophenone is preferably 1:1-2, more preferably 1:1.5. In the present invention, the molar ratio of the intermediate 1 to triethylamine is preferably 1:2-3, more preferably 1:2. In the present invention, the role of the triethylamine is to adjust the acidity and alkalinity of the reaction system, catalyze the second condensation reaction, thereby reducing the condensation reaction temperature, shortening the condensation reaction time, increasing the yield of the product, and reducing the content of impurities in the product.

[0087] In the present invention, the temperature of the second condensation reaction is preferably 60 to 75° C., more preferably 60 to 65° C., and the time of the second condensation reaction is preferably 10 h.

[0088] In the present invention, after the second condensation reaction, the present invention preferably further comprises filtering the system obtained by the second condensation reaction, washing the obtained filter cake with toluene and then drying.

[0089] After obtaining intermediate 2, the present invention dissolves intermediate 2, acylation catalyst, acetic anhydride and triethylamine for the sixth time, and then performs an elimination reaction to obtain intermediate 3 having a structure shown in formula 3.

[0090] In the present invention, the sixth solvent of the fifth solvent is preferably one or more of toluene, xylene, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, dimethyltetrahydrofuran, dimethyl sulfoxide and methyl tert-butyl ether, more preferably toluene. In the present invention, the acylation catalyst preferably includes 4-dimethylaminopyridine.

[0091] In the present invention, the specific step of the sixth dissolution of the intermediate 2, the acylation catalyst, acetic anhydride and triethylamine is preferably: dissolving the intermediate 2 and the acylation catalyst in a sixth solvent, then heating to a temperature at which the elimination reaction occurs, and then dropping acetic anhydride and triethylamine in sequence.

[0092] In the present invention, the molar ratio of the intermediate 2 to acetic anhydride is preferably 1:0.95-2.5, more preferably 1:2.1-2.5. In the present invention, the molar ratio of the intermediate 2 to triethylamine is preferably 1:2-3, more preferably 1:2.1-2.2. In the present invention, the triethylamine acts as an acid binding agent.

[0093] In the present invention, the temperature of the elimination reaction is preferably 65°C; the time of the elimination reaction is preferably 8 hours. In the present invention, the elimination reaction is carried out at 65°C, and the impurity content of the obtained product is low, and the elimination reaction is carried out at 65°C, which is conducive to the actual heating operation of the production workshop.

[0094] In the present invention, after the elimination reaction, it is preferred that the system obtained by the elimination reaction is subjected to toluene extraction, and the pH value is adjusted to 1-2 with concentrated hydrochloric acid, and the obtained organic layer is washed with water, dried and concentrated.

[0095] In the present invention, the role of adjusting the pH to 1-2 with concentrated hydrochloric acid is to remove excess triethylamine and to achieve system emulsification.

[0096] In the present invention, the drying agent is preferably anhydrous sodium sulfate; and the concentration is preferably concentrated to obtain an oily substance.

[0097] After obtaining the intermediate 3, the present invention dissolves the intermediate 3, hydroxylamine hydrochloride and tetrabutylammonium bromide, and then performs a cyclization reaction to obtain flurellan.

[0098] In the present invention, the hydroxylamine hydrochloride is preferably used in the form of a sodium hydroxide aqueous solution of hydroxylamine hydrochloride. The sodium hydroxide aqueous solution of hydroxylamine hydrochloride comprises hydroxylamine hydrochloride, sodium hydroxide and water; the mass ratio of hydroxylamine hydrochloride, sodium hydroxide and water is preferably (3-4):(1.5-2):10, more preferably 3.2:1.84:10.

[0099] In the present invention, the seventh dissolution of the intermediate 3, hydroxylamine hydrochloride and tetrabutylammonium bromide is preferably to dissolve the intermediate 3 and tetrabutylammonium bromide in the seventh solvent, and then drip a sodium hydroxide aqueous solution of hydroxylamine hydrochloride into the resulting mixed solution. In the present invention, during the dripping, the temperature of the mixed solution is preferably controlled at 0 to 5°C.

[0100] In the present invention, the molar ratio of the intermediate 3 to hydroxylamine hydrochloride is preferably 1:0.95-3.0, more preferably 1:2; the molar ratio of the intermediate 3 to tetrabutylammonium bromide is preferably 1:4-5, more preferably 1:4.5; the temperature of the cyclization reaction is preferably -10-55°C, more preferably 25°C; the time of the cyclization reaction is preferably 2-8h, more preferably 4h.

[0101] In the present invention, after the cyclization reaction, it is preferred to further include adjusting the pH of the obtained cyclization reaction solution to 1-2, extracting the system obtained by the cyclization reaction with ethyl acetate, and washing the obtained organic layer with dilute hydrochloric acid, drying with a desiccant, and recrystallizing.

[0102] In the present invention, the desiccant is preferably anhydrous sodium sulfate; the recrystallization reagent is preferably obtained by mixing the oil obtained by drying with a mixture of n-hexane and ethyl acetate for recrystallization; the volume ratio of n-hexane to ethyl acetate is preferably 6:1.

[0103] As a specific embodiment of the present invention, the synthetic route of flurellana is as follows Figure 1 shown.

[0104] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0105] Example 1

[0106] Step 1: Synthesis of 1-(4-bromo-3-methyl-phenyl)-ethanone

[0107] In a 500mL reaction bottle equipped with a stirrer and a thermometer, add 200mL of dichloromethane, 136.8g (0.8mol) of 2-bromotoluene and 160g (1.2mol) of aluminum chloride, then add 69g (0.88mol) of acetyl chloride dropwise in an ice-water bath, remove the ice bath after the addition is complete, and naturally heat to 25°C to continue the reaction for 10h. After the reaction is completed, pour the reaction solution into ice water, stir while pouring, and separate the liquids. The aqueous phase is extracted with dichloromethane (2×150mL), and the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate, and concentrated to obtain 164.78g of liquid, which is distilled under reduced pressure to obtain 153.72g of colorless transparent liquid (i.e., 1-(4-bromo-3-methyl-phenyl)-ethanone), with a yield of 90.18%.

[0108] Step 2: Synthesis of 2-methyl-4-acetylbenzonitrile

[0109] In a 1L reaction bottle equipped with a stirrer and a thermometer, add 63.9g (0.3mol) 3-methyl-4-bromoacetophenone, 200mL N,N-dimethylformamide and 53.74g (0.6mol) cuprous cyanide, heat to 120°C, and react for 10h. After the reaction is completed, evaporate part of the solvent under reduced pressure, cool to below 30°C, add 400mL water and 200mL dichloromethane, stir and separate, extract the water layer with dichloromethane (2×80mL), combine the organic layers, wash the organic phase with water (4×60mL), and concentrate to obtain 40.3g yellow solid (i.e., 2-methyl-4-acetylbenzonitrile), with a yield of 84.33%.

[0110] Step 3: Synthesis of 2-methyl-4-acetylbenzoic acid

[0111] Alkaline hydrolysis: 320 mL of water, 320 mL of methanol, 16 g (0.4 mol) of sodium hydroxide and 31.8 g (0.2 mol) of 2-methyl-4-acetylbenzonitrile were added to a 1000 mL four-necked reaction bottle equipped with a stirrer and a thermometer, and the temperature was raised to 40°C for reaction for 10 h. Methanol was evaporated by reduced pressure distillation, and dilute hydrochloric acid was added under stirring in an ice bath to adjust the pH to 1-2. A white solid precipitated, which was filtered and dried to obtain 28.6 g of a white solid (i.e., 2-methyl-4-acetylbenzoic acid), with a yield of 80.3% and a melting point of 148°C-150°C.

[0112] Step 4: Synthesis of Intermediate 1

[0113] In a 250mL four-necked reaction flask equipped with a stirrer and a thermometer, add 12g (0.067mol) of 4-acetyl-2-methylbenzoic acid and 80mL of toluene, add two drops of N,N-dimethylformamide, heat to 60°C with stirring, add 15.9g (0.134mol) of thionyl chloride, react for 1.5h, and then concentrate the solvent to obtain a light yellow solid. Add 100ml of tetrahydrofuran to dissolve it to obtain an acyl chloride tetrahydrofuran solution.

[0114] Take another 500ml four-necked flask, add 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride 15.4g (0.08mol), tetrahydrofuran 40mL, triethylamine 13.56g (0.134mol), cool to 2°C, add the above prepared tetrahydrofuran solution of acyl chloride dropwise, keep warm for 1h after the addition is complete. Then add 100mL ethyl acetate and 100mL water, add hydrochloric acid to adjust the pH value to 1-2, separate the layers, evaporate the solvent from the obtained organic phase, and recrystallize the crude product to obtain 19.02g of white solid (i.e., intermediate 1), with a yield of 89.76%.

[0115] Step 5: Synthesis of Intermediate 2

[0116] In a 250mL four-necked reaction flask equipped with a stirrer and a thermometer, add 15.8g (0.05mol) of intermediate 1, 100mL of toluene, 10.1g (0.1mol) of triethylamine and 18.23g (0.075mol) of 3,5-dichloro-2,2,2-trifluoroacetophenone, raise the temperature to 75°C, and keep the temperature for 10h. When the temperature is lowered to below 35°C, a large amount of white turbidity appears, and the white solid is filtered out. The filter cake is washed with 60mL of toluene and dried to obtain 21.45g of white solid (i.e., intermediate 2), with a yield of 76.72%.

[0117] Step 6: Synthesis of Intermediate 3

[0118] Into a 250mL four-necked reaction flask equipped with a stirrer and a thermometer, add 19.57g (0.035mol) of intermediate 2, 0.916g (0.0075mol) of 4-dimethylaminopyridine and 60mL of toluene, raise the temperature to 65°C, add 7.86g (0.077mol) of acetic anhydride dropwise, and after the addition is complete, add 7.8g (0.077mol) of triethylamine dropwise, and maintain the reaction at 65°C for 8h.

[0119] After the reaction, the mixture was cooled to 35°C, 90 mL of toluene and 40 mL of water were added, and the pH was adjusted to 1-2 with concentrated HCl (to remove excess triethylamine in the system and emulsify the system in the same manner), the layers were separated, and the organic layer was washed with water (2×60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 15.02 g of an orange-yellow oil (i.e., intermediate 3) with a yield of 79.3%. The crude product was directly used in the next step.

[0120] Step 7: Synthesis of Flurellana

[0121] In a 500mL four-necked reaction flask equipped with a stirrer and a thermometer, 12.45g (0.023mol) of intermediate 3, 32.2g (0.10mol) of tetrabutylammonium bromide and 120mL of toluene were added. The temperature was controlled at 20-25°C, and 3.2g (0.046mol) of hydroxylamine hydrochloride and 10mL of an aqueous solution of sodium hydroxide (1.84g) were added dropwise. After the addition was completed, the mixture was kept warm at 25°C for 4h.

[0122] After the reaction, the pH was adjusted to 1-2, extracted once with 120 mL of ethyl acetate, the organic layer was washed with 120 mL of purified water, dried over anhydrous sodium sulfate and concentrated to obtain 11.5 g of a yellow oil, which was recrystallized by adding a mixed solvent (60 mL of n-hexane and 10 mL of ethyl acetate) to obtain 9.88 g of a white solid (i.e., flurellana) with a yield of 77.23%.

[0123] The liquid chromatogram of Flurellana obtained in Example 1 is as follows Figure 2 As shown, the carbon NMR spectrum is as follows Figure 3 As shown, the H NMR spectrum is as Figure 4 shown.

[0124] Example 2

[0125] Step 1: Synthesis of 1-(4-bromo-3-methyl-phenyl)-ethanone

[0126] In a 1000mL reaction bottle equipped with a stirrer and a thermometer, 350mL of dichloromethane, 171g (1.0mol) of 2-bromotoluene and 200g (1.5mol) of aluminum chloride were added, and then 86.35g (1.10mol) of acetyl chloride was added dropwise in an ice-water bath. After the addition was complete, the ice bath was removed, and the temperature was naturally raised to 25°C and the reaction was continued for 10h. After the reaction was completed, the reaction solution was poured into ice water, stirred while pouring, and the liquid was separated. The aqueous phase was extracted with dichloromethane (2×200mL), the organic phases were combined, washed with water, and dried over anhydrous sodium sulfate, and concentrated to obtain 164.78g of liquid, which was distilled under reduced pressure to obtain 187.2g of colorless transparent liquid (i.e., 1-(4-bromo-3-methyl-phenyl)-ethanone), with a yield of 87.88%.

[0127] Step 2: Synthesis of 2-methyl-4-acetylbenzonitrile

[0128] In a 2L reaction bottle equipped with a stirrer and a thermometer, add 127.8g (0.6mol) 3-methyl-4-bromoacetophenone, 400mL N,N-dimethylformamide and 107.48g (1.2mol) cuprous cyanide, heat to 110-120°C, and react for 10h. After the reaction is completed, evaporate part of the solvent under reduced pressure, cool to below 30°C, add 800mL water and 400mL dichloromethane, stir and separate, extract the water layer with dichloromethane (2×160mL), combine the organic layers, wash the organic phase with water (4×120mL), and concentrate to obtain 76.2g of yellow solid (i.e., 2-methyl-4-acetylbenzonitrile), with a yield of 79.87%.

[0129] Step 3: Synthesis of 2-methyl-4-acetylbenzoic acid

[0130] Acidic hydrolysis: Dissolve 63.6 g (0.4 mol) of 2-methyl-4-acetylbenzonitrile in 320 mL of glacial acetic acid and 320 mL of water, slowly add 320 mL of concentrated sulfuric acid, heat to 50-60 ° C and reflux for 5 h, cool to room temperature 25 ° C, pour the reaction solution into 200 mL of ice water, extract with ethyl acetate (2×480 mL), combine the organic phases and concentrate to obtain 39.48 g of solid, with a yield of 55.4%.

[0131] Step 4: Synthesis of Intermediate 1

[0132] In a 500mL four-necked reaction flask equipped with a stirrer and a thermometer, add 21.4g (0.12mol) of 4-acetyl-2-methylbenzoic acid and 160mL of toluene, add two drops of N,N-dimethylformamide, heat to 60°C and stir, add 28.56g (0.24mol) of dichlorothionyl, react for 1.5h, concentrate the solvent to obtain a light yellow solid, add 200ml of tetrahydrofuran to dissolve it, and obtain an acyl chloride tetrahydrofuran solution.

[0133] Take another 1L four-necked flask, add 27.73g (0.144mol) of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride, 80mL of tetrahydrofuran, and 24.3g (0.24mol) of triethylamine, cool to 2°C, then drop the prepared tetrahydrofuran solution of acyl chloride, and keep warm for 1h after the addition is complete. Then add 200mL of ethyl acetate and 200mL of water, add hydrochloric acid to adjust the pH value to 1-2, separate the layers, evaporate the solvent from the obtained organic phase, and recrystallize the crude product to obtain 32.41g of white solid (i.e., intermediate 1), with a yield of 85.41%.

[0134] Step 5: Synthesis of Intermediate 2

[0135] In a 500mL four-necked reaction flask equipped with a stirrer and a thermometer, add 28.47g (0.09mol) of intermediate 1, 200mL of toluene, 18.22g (0.18mol) of triethylamine and 32.8g (0.135mol) of 3,5-dichloro-2,2,2-trifluoroacetophenone, raise the temperature to 75°C, and keep the temperature for 10h. When the temperature is lowered to below 35°C, a large amount of white turbidity appears, and the white solid is filtered out. The filter cake is washed with 60mL of toluene and dried to obtain 37.54g of white solid (i.e., intermediate 2), with a yield of 74.59%.

[0136] Step 6: Synthesis of Intermediate 3

[0137] In a 500mL four-necked reaction flask equipped with a stirrer and a thermometer, add 28g (0.05mol) of intermediate 2, 1.22g (0.01mol) of 4-dimethylaminopyridine (catalyst) and 100mL of toluene, raise the temperature to 65°C, add 11.23g (0.11mol) of acetic anhydride dropwise, and then add 11.1g (0.11mol) of triethylamine (triethylamine produced by the neutralization system reaction, acid binding agent) dropwise after the addition is complete, and keep the reaction at 65°C for 8h.

[0138] After the reaction, the mixture was cooled to 35°C, 120 mL of toluene and 60 mL of water were added, the pH was adjusted to 1-2 with concentrated HCl, the layers were separated, the organic layer was washed with water (2×90 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 22.33 g of an orange-yellow oil (i.e., intermediate 3), with a yield of 82.5%. The crude product was directly used in the next step.

[0139] Step 7: Synthesis of Flurellana

[0140] In a 500mL four-necked reaction flask equipped with a stirrer and a thermometer, add 20g (0.037mol) of intermediate 3, 53.67g (0.167mol) of tetrabutylammonium bromide and 240mL of toluene. The temperature is controlled at 20-25°C. Add 5.14g (0.074mol) of hydroxylamine hydrochloride and 16mL of an aqueous solution of sodium hydroxide (3g) dropwise. After the addition is complete, keep warm at 25°C for 4h.

[0141] After the reaction, the pH was adjusted to 1-2, extracted once with 180 mL of ethyl acetate, the organic layer was washed with 150 mL of purified water, dried over anhydrous sodium sulfate and concentrated to obtain 19.89 g of a yellow oil, which was recrystallized by adding a mixed solvent (60 mL of n-hexane and 10 mL of ethyl acetate) to obtain 16.43 g of a white solid (i.e., flurellana) with a yield of 79.81%.

[0142] The carbon NMR spectrum of flurella obtained in Example 2 is as follows Figure 5 As shown, the H NMR spectrum is as Figure 6 shown.

[0143] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing fluororana, characterized in that: The following steps are involved: After first dissolving o-bromotoluene and acetyl chloride, a Friedel-Crafts reaction is carried out under a catalyst condition to obtain 1-(4-bromo-3-methyl-phenyl)-ethanone; The temperature of the Friedel-Crafts reaction is 25°C; After dissolving 1-(4-bromo-3-methyl-phenyl)-ethanone and a cyaniding agent for a second time, a substitution reaction is carried out to obtain 2-methyl-4-acetylbenzonitrile; The temperature of the substitution reaction is 110-120°C and the time is 6-10h; After dissolving 2-methyl-4-acetylbenzonitrile for the third time, a hydrolysis reaction is performed to obtain 2-methyl-4-acetylbenzoic acid; After dissolving 2-methyl-4-acetylbenzoic acid, a carboxyl activation reagent and N,N-dimethylformamide for the fourth time, the activation is performed, and the obtained product is sequentially mixed with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and triethylamine, and then subjected to a first condensation reaction to obtain an intermediate 1 having a structure shown in Formula 1; The activation reaction is carried out at a temperature of 70 to 80°C for 1 to 2 hours; the first condensation reaction is carried out at a temperature of 0 to 5°C for 0.5 to 1.5 hours; After the intermediate 1, 3',5'-dichloro-2,2,2-trifluoroacetophenone and triethylamine are dissolved for the fifth time, a second condensation reaction is performed to obtain an intermediate 2 having a structure shown in Formula 2; The temperature of the second condensation reaction is 60-75°C and the time is 10h; After the intermediate 2, the acylation catalyst, acetic anhydride and triethylamine are dissolved for the sixth time, an elimination reaction is performed to obtain an intermediate 3 having a structure shown in Formula 3; The temperature of the elimination reaction is 65°C and the time is 8h; After dissolving the intermediate 3, hydroxylamine hydrochloride and tetrabutylammonium bromide, a cyclization reaction is carried out to obtain fluralanol; 2. The preparation method according to claim 1, characterized in that The molar ratio of o-bromotoluene to acetyl chloride is 0.9-3.0:1; and the Friedel-Crafts reaction time is 2-24 hours.

3. The preparation method according to claim 1, characterized in that: The cyaniding agent includes one or more of sodium cyanide, potassium cyanide, cuprous cyanide and trimethylsilyl cyanide; The molar ratio of the 1-(4-bromo-3-methyl-phenyl)-ethanone to the cyaniding agent is 1:1-10.

4. The preparation method according to claim 1, characterized in that: The hydrolysis reaction is carried out under acidic conditions or alkaline conditions. The acidic conditions are provided by sulfuric acid, acetic acid, hydrochloric acid or phosphoric acid; the alkaline conditions are provided by sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

5. The preparation method according to claim 4, characterized in that: When the hydrolysis reaction is carried out under acidic conditions, the temperature of the hydrolysis reaction is 45 to 105° C., and the time of the hydrolysis reaction is 1 to 12 hours; When the hydrolysis reaction is carried out under alkaline conditions, the temperature of the hydrolysis reaction is 30 to 40° C., and the time of the hydrolysis reaction is 1 to 12 hours.

6. The preparation method according to claim 1, characterized in that: The carboxyl activation reagent includes one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride.

7. The preparation method according to claim 6, characterized in that: The molar ratio of the 2-methyl-4-acetylbenzoic acid to 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride is 1:1 to 1.

7.

8. The preparation method according to claim 1, characterized in that: The molar ratio of the intermediate 1 to 3',5'-dichloro-2,2,2-trifluoroacetophenone is 1:1-2.

9. The preparation method according to claim 1, characterized in that: The molar ratio of the intermediate 2 to acetic anhydride is 1:0.95-2.

5.

10. The preparation method according to claim 1, characterized in that: The molar ratio of the intermediate 3 to hydroxylamine hydrochloride is 1:0.95-3.0; the temperature of the cyclization reaction is -10-55°C; and the time of the cyclization reaction is 2-8h.

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