Preparation method of benzopyrone

Abstract

The present invention provides a preparation method of benzopyrone. The preparation method includes: step S1, using trifluoronitrobenzene as the first raw material, performing ortho-substitution reaction with nitromethane to obtain 1,2-difluoro-4-nitro-3-nitromethylenebenzene, and performing para-substitution reaction with alkoxide to obtain a first intermediate; step S2, subjecting the first intermediate to a Nef reaction, converting the nitromethyl group to a carboxyl group to obtain a second intermediate; step S3, subjecting the second intermediate to a reduction reaction, an oxidation reaction, and a denitrogenation rearrangement reaction to convert the nitro group to an aldehyde hydrazine to obtain an aldehyde hydrazine intermediate; step S4, under the action of a catalyst, subjecting the aldehyde hydrazine intermediate to a nucleophilic addition reaction with the second raw material to generate a secondary alcohol intermediate, and subjecting the secondary alcohol intermediate to a ring-closing reaction to obtain a target product. The above-mentioned method for preparing benzopyrone has a wide range of raw material sources, relatively mild reaction conditions, and a high overall reaction yield.

Description

Technical Field

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

[0002] Liquid crystal compounds having a benzopyrone skeleton and negative dielectric anisotropy can be widely used in the manufacture of liquid crystal materials because they meet the requirements of high stability to heat and light, high maximum temperature of the nematic phase, low minimum temperature of the liquid crystal phase, low viscosity, suitable optical anisotropy, large negative dielectric anisotropy, suitable elastic constants and good compatibility with other liquid crystal compounds.

[0003] At present, benzopyrone compounds are mainly prepared by the following technical routes:

[0004] Route 1

[0005]

[0006] Route 2

[0007]

[0008]

[0009] Among them, route one uses 2-fluoro-4-bromophenol as a raw material and undergoes etherification, LDA to form aldehyde, aldehyde oxidation, carboxyl protection, coupling cyclization and other steps to prepare only alkyl-substituted benzopyrone derivatives, and the total yield of alkyl-substituted benzopyrone in the original text is about 16%, which is a low yield; route two uses 3-fluoro-4-ethoxyphenylacetaldehyde as a raw material, which needs to be prepared separately, and lithium reagents are needed in the process. The reaction conditions are harsh, and the yield in the process is mostly 30-40%.

[0010] In summary, the synthesis of benzopyrone compounds is relatively difficult and the conditions are relatively harsh, and a more easily achievable method for synthesizing benzopyrone is urgently needed. Summary of the invention

[0011] The main purpose of the present invention is to provide a method for preparing benzopyrone to solve the problems of great difficulty and low yield in the prior art in preparing benzopyrone.

[0012] In order to achieve the above object, according to one aspect of the present invention, a method for preparing benzopyrone is provided, the preparation comprising:

[0013] Step S1, using trifluoronitrobenzene as the first raw material, undergoing an ortho-substitution reaction with nitromethane to obtain 1,2-difluoro-4-nitro-3-nitromethanebenzene, and 1,2-difluoro-4-nitro-3-nitromethanebenzene undergoing a para-substitution reaction with an alcohol salt to obtain a first intermediate, the structure of the first intermediate is shown in Formula I, wherein R 1 is selected from an alkyl group having 1 to 4 carbon atoms;

[0014]

[0015] Step S2, subjecting the first intermediate to a Nef reaction to convert the nitromethyl group into a carboxyl group to obtain a second intermediate;

[0016] Step S3, converting the nitro group of the second intermediate into aldehyde hydrazine through reduction reaction, oxidation reaction and denitrogenation rearrangement reaction to obtain an aldehyde hydrazine intermediate;

[0017] Step S4, in the presence of a catalyst, subjecting the aldehyde hydrazine intermediate to a nucleophilic addition reaction with a second raw material having a structure as shown in formula ⅠⅠ to generate a secondary alcohol intermediate, and subjecting the secondary alcohol intermediate to a ring-closure reaction to obtain a target product having a structure as shown in formula ⅢⅠ.

[0018]

[0019]

[0020] In Formula ⅠⅠ and Formula ⅢⅠⅠ, R 2 is selected from substituted or unsubstituted cyclohexyl, phenyl or bicyclohexylalkyl, the substituents are each independently C 1 ~C 5 Any one of the alkyl groups; in Formula ⅢⅠⅠ, R 1 It is selected from alkyl groups having 1 to 4 carbon atoms.

[0021] Further, the amount of nitromethane used is 5 to 20 times the molar amount of the first raw material trifluoronitrobenzene;

[0022] Preferably, an organic base is added to the ortho-substitution reaction of step S1; preferably, the organic base includes any one or more of triethylamine, triethylenediamine, tetramethylguanidine, N-methylmorpholine and quaternary ammonium base; preferably, the amount of the organic base is 1-3 times the molar amount of the first raw material trifluoronitrobenzene.

[0023] Further, in step S1, the temperature of the ortho-substitution reaction is -10 to -30°C, and preferably, the ortho-substitution reaction is carried out in an inert gas atmosphere;

[0024] Preferably, the ortho-substitution reaction comprises: adding nitromethane and an organic base into a reaction container, cooling to a reaction temperature of the substitution reaction in an inert gas atmosphere, adding a first raw material, trifluoronitrobenzene, to carry out the substitution reaction; preferably, the first raw material, trifluoronitrobenzene, is added dropwise;

[0025] Preferably, after the ortho-substitution reaction is completed, the reaction system is washed with water, and concentrated under reduced pressure to recover nitromethane to obtain 1,2-difluoro-4-nitro-3-nitromethanebenzene.

[0026] Further, in step S1, the para-substitution reaction includes: mixing 1,2-difluoro-4-nitro-3-nitromethylbenzene with a first solvent and an alcohol salt, heating under reflux, reacting for 5-10 hours, adding a first acidic aqueous solution to the system to adjust the pH value, concentrating, beating and washing with water to obtain a first intermediate;

[0027] Preferably, the alkoxide includes any one or more of sodium alkoxide and potassium alkoxide; preferably, the amount of the alkoxide used is 1 to 2 times the molar amount of 1,2-difluoro-4-nitro-3-nitromethylbenzene;

[0028] Preferably, the first solvent includes any one or more of ethanol, methanol, propanol and isopropanol;

[0029] Preferably, the pH value is adjusted to neutral;

[0030] Preferably, the first acidic aqueous solution includes any one or more of hydrochloric acid solution, sulfuric acid solution, acetic acid solution, ammonium chloride aqueous solution and ammonium sulfate aqueous solution.

[0031] Further, in step S2, a first catalyst is added to the Neff reaction, and the first catalyst includes any one or more of tetrabutylammonium iodide, zinc acetate, and zinc iodide;

[0032] Preferably, the first catalyst comprises tetrabutylammonium iodide and zinc acetate, more preferably, the amount of tetrabutylammonium iodide is 2-10% of the molar amount of the first intermediate, and the amount of zinc acetate is 5-20% of the molar amount of the first intermediate;

[0033] Preferably, the Nef reaction is carried out in a second solvent, and the second solvent is water; preferably, the amount of the second solvent is 1 to 5 times the volume of the first intermediate;

[0034] Preferably, step S2 comprises: mixing the first intermediate with the second solvent and the first catalyst, performing a Nef reaction, and after the reaction is completed, performing acidification and a first purification to obtain a second intermediate;

[0035] Preferably, the temperature of the Neff reaction is 80-100°C and the reaction time is 10-30 hours;

[0036] Preferably, the first purification comprises dissolving and extracting the acidified product with methyl tert-butyl ether, washing with water, and concentrating the product, and washing the solid product obtained by concentration with petroleum ether to obtain a second intermediate.

[0037] Further, in step S3, the reduction reaction is a reaction with hydrogen under the action of a second catalyst, and the second catalyst includes any one or more of Raney nickel, palladium carbon and platinum carbon;

[0038] Preferably, the pressure of hydrogen is 0.2-1 MPa;

[0039] Preferably, the reduction reaction is carried out in a third solvent, and the third solvent includes any one or more of ethanol, methanol and water;

[0040] Preferably, the reduction reaction temperature is 30 to 50° C., and the reaction time is 5 to 10 hours;

[0041] Preferably, the reduction reaction process includes: mixing the second intermediate with the second catalyst and the third solvent, charging hydrogen into the reaction device for reaction, and after the reaction is completed, filtering, concentrating and crystallizing to obtain the reduction product.

[0042] Further, in step S3, the oxidation reaction includes mixing the product of the reduction reaction with trioxymethylene and a fourth solvent, reacting for a first time, adding an oxidant, continuing the reaction for a second time, and after the reaction is completed, performing a second purification to obtain a product of the oxidation reaction, wherein the fourth solvent is an organic solvent;

[0043] Preferably, the oxidant is selected from any one or more of aqueous hydrogen peroxide and tert-butyl hydroperoxide;

[0044] Preferably, the molar amount of the formaldehyde monomer in trioxymethylene is 1 to 3 times the molar amount of the product of the reduction reaction;

[0045] Preferably, the fourth solvent comprises acetonitrile;

[0046] Preferably, the reaction temperature is 75-85°C, and more preferably, the oxidant is added at 60-70°C;

[0047] Preferably, the first time is 8-10 hours, and the second time is 5-8 hours;

[0048] Preferably, the second purification comprises separating the fourth solvent by distillation or reduced pressure distillation, filtering, washing with water to remove hydrogen peroxide, and drying to obtain the oxidation reaction product.

[0049] Further, in step S3, the treatment process of the denitrogenation rearrangement reaction includes: dissolving the product of the oxidation reaction with a fifth solvent, mixing with hydrazine hydrate monohydrate, reacting under reflux, and performing a third purification to obtain an aldehyde hydrazine intermediate;

[0050] Preferably, the fifth solvent comprises ethanol;

[0051] Preferably, the third purification comprises: concentration under reduced pressure, extraction with methyl cyclopentyl ether, and washing with water.

[0052] Further, in step S4, the nucleophilic addition reaction is carried out under the action of a second base reagent and a catalyst;

[0053] Preferably, the second alkaline reagent includes any one or more of potassium carbonate, potassium phosphate and potassium tert-butoxide; more preferably, the amount of the second alkaline reagent is 2 to 10% of the molar amount of the aldehyde hydrazine intermediate;

[0054] Preferably, the catalyst comprises Fe(dmpe) 2 Cl 2 ;

[0055] Optionally, an additive is added to the nucleophilic reaction, and the additive is selected from any one or more of sodium fluoride, potassium fluoride and cesium fluoride. Preferably, the amount of the additive is 2 to 10% of the molar amount of the aldehyde hydrazine intermediate;

[0056] Preferably, the nucleophilic addition reaction is carried out in an inert gas atmosphere.

[0057] Furthermore, the ring-closing reaction is a Mitsunobu reaction; preferably, the treatment process of the ring-closing reaction includes: mixing the secondary alcohol intermediate with triphenylphosphine and a sixth solvent, dropping diethyl azodicarboxylate to react, after the reaction is completed, adding water to quench the reaction, and performing a fourth purification to obtain the target product;

[0058] Preferably, the temperature of the ring-closure reaction is 0-10°C;

[0059] Preferably, the sixth solvent includes any one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and methyl cyclopentyl ether;

[0060] Preferably, the fourth purification comprises concentration under reduced pressure, ethanol freezing washing, filtration and drying.

[0061] Furthermore, R 1 is selected from an alkyl group having 2 to 4 carbon atoms, R 2 is selected from substituted or unsubstituted cyclohexyl, phenyl or bicyclohexylalkyl, the substituents are each independently C 1 ~C 5 Any of the alkyl groups;

[0062] Preferably, R 1 is selected from ethyl or n-butyl, R 2 is selected from substituted or unsubstituted cyclohexyl, phenyl or dicyclohexylalkyl, preferably, the substituent is located at the para position, and the substituent is C1 ~C 4 Any of the alkyl groups.

[0063] The technical scheme of the present invention is applied, trifluoronitrobenzene is used as the starting material, firstly ortho-substituted with nitromethane, then para-substituted with alkoxide, the obtained nitro substituted product is subjected to Nef reaction, then reduced, oxidative denitrogenation rearrangement to convert the nitro group into aldehyde hydrazine, then nucleophilic addition with aldehyde of specific structure is carried out under the catalysis of iron catalyst to generate secondary alcohol intermediate, and finally the target product is obtained by ring closure. The above method for preparing benzopyrone has a wide range of raw materials, relatively mild reaction conditions, high overall reaction yield, and the prepared product is easy to separate and purify, which can effectively reduce the process cost of benzopyrone compounds. DETAILED DESCRIPTION

[0064] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application can be combined with each other. The present invention will be described in detail below in conjunction with the embodiments.

[0065] As analyzed in the background technology of this application, the prior art has the problem of great difficulty in preparing benzopyrone and low yield. In order to solve this problem, this application provides a method for preparing benzopyrone. The preparation method comprises: step S1, using trifluoronitrobenzene as the first raw material, and performing an ortho-substitution reaction with nitromethane to obtain 1,2-difluoro-4-nitro-3-nitromethane, and 1,2-difluoro-4-nitro-3-nitromethane undergoes a para-substitution reaction with an alcohol salt to obtain a first intermediate, the structure of the first intermediate is shown in formula I, wherein R 1 is selected from an alkyl group having 1 to 4 carbon atoms;

[0066]

[0067] Step S2, subjecting the first intermediate to a Nef reaction to convert the nitromethyl group to a carboxyl group to obtain a second intermediate; Step S3, subjecting the second intermediate to a reduction reaction, an oxidation reaction and a denitrogenation rearrangement reaction to convert the nitro group to an aldehyde hydrazine to obtain an aldehyde hydrazine intermediate; Step S4, subjecting the aldehyde hydrazine intermediate to a nucleophilic addition reaction with a second raw material having a structure as shown in Formula ⅠⅠ under the action of a catalyst to generate a secondary alcohol intermediate, and subjecting the secondary alcohol intermediate to a ring-closing reaction to obtain a target product having a structure as shown in Formula ⅠⅠⅠ,

[0068]

[0069] In Formula ⅠⅠ and Formula ⅢⅠⅠ, R 2 is selected from substituted or unsubstituted cyclohexyl, phenyl or dicyclohexylalkyl. If it is substituted cyclohexyl, phenyl or dicyclohexylalkyl, the substituents are each independently C 1 ~C 5Any one of the alkyl groups; in Formula ⅢⅠⅠ, R 1 It is selected from alkyl groups having 1 to 4 carbon atoms.

[0070] The present invention uses trifluoronitrobenzene as a starting material, first performs ortho-substitution with nitromethane, then performs para-substitution with an alkoxide, the obtained nitro substitution product undergoes a Nef reaction, and then undergoes reduction, oxidative denitrogenation rearrangement to convert the nitro group into aldehyde hydrazine, and then undergoes nucleophilic addition with an aldehyde of a specific structure under the catalysis of an iron catalyst to generate a secondary alcohol intermediate, and finally obtains the target product by ring closure. The above method for preparing benzopyrone has a relatively wide source of raw materials, relatively mild reaction conditions, a high overall reaction yield, and the prepared product is easy to separate and purify, which can effectively reduce the process cost of benzopyrone compounds.

[0071] In some embodiments of the present application, R 1 is selected from an alkyl group having 2 to 4 carbon atoms, such as ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, R 2 is selected from substituted or unsubstituted cyclohexyl, phenyl or bicyclohexylalkyl, the substituents are each independently C 1 ~C 5 Any one of the alkyl groups; preferably, R 1 is selected from ethyl or n-butyl, R 2 is selected from substituted or unsubstituted cyclohexyl, phenyl or bicyclohexylalkyl. When the cyclohexyl, phenyl or bicyclohexylalkyl has a substituent, the substituent is preferably located at the para position of the aldehyde group, and the substituent is C 1 ~C 4 Considering the application of the target product in anisotropic liquid crystal monomers, it is preferred that the second raw material is an aldehyde having a trans structure.

[0072] In some embodiments of the present application, taking the target product 7-ethoxy-8-fluoro-3,4-dihydro-3-(trans-4-propylcyclohexyl)-1H-2-benzopyran-1-one as an example, the reaction equation of the benzopyrone synthesis route of the present application is as follows:

[0073]

[0074] In the above step S1, the fluorine at the ortho-position of the nitro group can be replaced with a nitromethyl group by a substitution reaction with nitromethane. During the reaction, nitromethane can be used as both a reaction reagent and a solvent for the substitution reaction, which is more convenient for subsequent product separation and raw material recovery and reuse; of course, the reaction can also be carried out under the condition of adding other solvents. In some preferred embodiments of the present application, the amount of nitromethane used is 5 to 20 times the molar amount of the raw material trifluoronitrobenzene.

[0075] In some typical embodiments of the present application, in order to further improve the yield and reaction rate of the target product, an organic base is added to the ortho-substitution reaction of step S1; for example, the organic base can be any one or more of triethylamine, triethylenediamine, tetramethylguanidine (TMG), N-methylmorpholine and quaternary ammonium base; preferably, the amount of the above-mentioned organic base is 1-3 times the molar amount of the first raw material trifluoronitrobenzene, and the effect is particularly obvious.

[0076] In some embodiments of the present application, in step S1, the temperature of the ortho-substitution reaction is -10 to -30°C, and the yield of the target product is high. In order to further improve the yield of the target product, the above-mentioned ortho-substitution reaction is carried out in an inert gas atmosphere. In some typical embodiments of the present application, the above-mentioned ortho-substitution reaction includes: adding nitromethane and an organic base to a reaction vessel, cooling to the reaction temperature of the substitution reaction in an inert gas atmosphere, adding the first raw material trifluoronitrobenzene, and carrying out the substitution reaction; preferably, the first raw material trifluoronitrobenzene is added in a dropwise manner to prevent one-time addition and the generation of other by-products. Those skilled in the art can separate and purify the reaction solution of the above-mentioned ortho-substitution reaction according to the prior art to obtain the target product. In some embodiments of the present application, after the above-mentioned ortho-substitution reaction is completed, the reaction system is washed with water, concentrated under reduced pressure to recover nitromethane, and the residue is subjected to subsequent reactions.

[0077] The product of the above ortho-substitution reaction, 1,2-difluoro-4-nitro-3-nitromethylbenzene, is used as a reaction raw material for para-substitution to obtain a compound in which the nitro group is para-substituted with an alkoxy group. The specific reaction conditions can refer to the prior art. In some embodiments of the present application, the above para-substitution reaction includes: mixing 1,2-difluoro-4-nitro-3-nitromethylbenzene with a first solvent and an alcohol salt, heating to reflux, reacting for 5-10 hours, adding a first acidic aqueous solution to the system to adjust the pH value, concentrating, beating and washing with water, and the obtained solid product, i.e., the above first intermediate, can be directly used in the next preparation process without further purification; preferably, the alcohol salt includes any one or more of sodium alcoholate and potassium alcoholate; preferably, the amount of alcohol salt is 1 to 2 times the molar amount of 1,2-difluoro-4-nitro-3-nitromethylbenzene, which is conducive to further improving the yield of the target product. The above first solvent is any one or more of organic solvents ethanol, methanol, propanol and isopropanol. After the reaction is completed, an acid is added to react the remaining sodium alcoholate. In some embodiments of the present application, the first acidic aqueous solution includes any one or more of hydrochloric acid solution, sulfuric acid solution, acetic acid, ammonium chloride aqueous solution and ammonium sulfate aqueous solution. Preferably, the first acidic aqueous solution is added to adjust the pH value of the reaction solution to neutral.

[0078] In the above step S2, the nitromethyl group in the product compound of step S1 is subjected to a Neff reaction to prepare the corresponding acid. The process conditions and operation methods of the Neff reaction can refer to the prior art, and the present application does not limit it. In some embodiments of the present application, a first catalyst is added to the above Neff reaction, and the first catalyst includes any one or more of tetrabutylammonium iodide, zinc acetate, and zinc iodide. In some preferred embodiments of the present application, in order to further improve the conversion rate of the target product, the above first catalyst includes tetrabutylammonium iodide and zinc acetate; preferably, the amount of tetrabutylammonium iodide is 2-10% of the molar amount of the first intermediate, and the amount of zinc acetate is 5-20% of the molar amount of the first intermediate, which has a particularly obvious promoting effect on the target reaction. In some embodiments of the present application, the above Neff reaction is carried out in a second solvent, and the second solvent is water, which has a promoting effect on the conversion of the target compound; preferably, the amount of the above second solvent is 1-5 times the volume of the above first intermediate, which has a particularly obvious promoting effect on the reaction.

[0079] In some typical embodiments of the present application, the above step S2 includes: mixing the above first intermediate with the second solvent and the first catalyst, performing a Neff reaction, acidifying and first purifying after the reaction is completed to obtain the above second intermediate; preferably, the temperature of the Neff reaction is 80-100°C, the reaction time is 10-30 hours, and the yield of the target product is high; in some embodiments of the present application, the first catalyst includes zinc iodide, and the reaction temperature of the Neff reaction is 95-100°C. The above acidification can be added with an acid in the prior art, such as hydrochloric acid, and the above first purification can refer to the prior art. In some embodiments of the present application, the first purification includes dissolving and extracting the acidified product with methyl tert-butyl ether, washing with water, and concentrating. The solid product obtained by concentration is washed with petroleum ether to obtain a solid product, i.e., the above second intermediate.

[0080] In the above step S3, the above second intermediate is reduced to convert the nitro group on the benzene ring into an amino group, that is, the intermediate 5 in the reaction equation. The reduction reaction can refer to the method and process of reducing the nitro group to the amino group in the prior art. In some embodiments of the present application, in order to further improve the conversion rate of the target product, the above reduction reaction is to react with hydrogen under the action of a second catalyst, and the second catalyst includes any one or more of Raney nickel, palladium carbon, and platinum carbon; preferably, the pressure of hydrogen is 0.2-1MPa, and the conversion rate of the target reduction product is high. In some embodiments of the present application, the above reduction reaction is carried out in a third solvent, and the third solvent includes any one or more of ethanol, methanol, and water, which is conducive to further improving the yield and selectivity of the reaction. In some preferred embodiments, the reaction temperature of the above reduction reaction is 30-50°C, and the reaction time is 5-10 hours. In some typical embodiments of the present application, the treatment process of the above reduction reaction includes: mixing the second intermediate with the second catalyst and the third solvent, filling hydrogen into the reaction device for reaction, and after the reaction is completed, filtering, concentrating, and crystallizing to obtain the reduction product.

[0081] In the above step S3, the product prepared by the reduction reaction is further oxidized to convert the amino group into a -CHNOH group. In some embodiments of the present application, the treatment process of the above oxidation reaction includes mixing the product of the reduction reaction with trioxymethylene and a fourth solvent, reacting for a first time, adding an oxidant, continuing the reaction for a second time, and after the reaction is completed, a second purification is performed to obtain the product of the oxidation reaction, wherein the fourth solvent is an organic solvent. In some embodiments of the present application, the above oxidant is selected from any one or more of aqueous hydrogen peroxide and tert-butyl hydroperoxide. Preferably, the molar amount of formaldehyde monomer in trioxymethylene is 1 to 3 times the molar amount of the product of the reduction reaction, which is more conducive to the above reaction and improves the conversion rate; preferably, the above fourth solvent includes any one or more of acetonitrile, ethylene glycol, and propylene glycol. When the temperature of the above reaction is 75-85°C, the yield of the target product is higher. More preferably, the oxidant is added at 60-70°C to prevent the reaction from being too intense, resulting in the formation of by-products, thereby affecting the yield of the target product. In some preferred embodiments, the first time is 8-10 hours and the second time is 5-8 hours, which is conducive to obtaining a higher yield of the target product. In some embodiments of the present application, the second purification includes separating the fourth solvent by distillation or reduced pressure distillation, filtering, washing with water to remove hydrogen peroxide, and drying to obtain the product of the oxidation reaction.

[0082] In the above step S3, the -CHNOH group on the benzene ring of the intermediate compound is further converted into a hydrazide group by denitrogenation rearrangement. In some typical embodiments of the present application, the treatment process of the above denitrogenation rearrangement reaction includes: dissolving the product of the oxidation reaction with a fifth solvent, mixing with hydrazine hydrate monohydrate, reacting under reflux, and obtaining an aldehyde hydrazine intermediate through a third purification. The above fifth solvent can be selected from the prior art, such as ethanol; in some preferred embodiments of the present application, the above third purification includes: concentration under reduced pressure, extraction with methyl cyclopentyl ether, and washing with water, and the obtained solution is used for the next reaction.

[0083] In the above step S4, the above hydrazide intermediate undergoes a nucleophilic addition reaction with a second raw material having an aldehyde group of a specific configuration to generate a secondary alcohol intermediate, which is further ring-closed to obtain the target product. In some embodiments of the present application, the above nucleophilic addition reaction is carried out under the action of a second base reagent and a catalyst; in some embodiments of the present application, the above second base reagent includes any one or more of potassium carbonate, potassium phosphate and potassium tert-butoxide; when the amount of the second base reagent is 2 to 10% of the molar amount of the aldehyde hydrazide intermediate, the promoting effect on the reaction is more obvious; the above catalyst is Fe(dmpe) 2 Cl 2 . In some embodiments of the present application, an additive is also added to the above nucleophilic reaction, and the additive is selected from any one or more of sodium fluoride, potassium fluoride and cesium fluoride. Preferably, the amount of the additive is 2-10% of the molar amount of the aldehyde hydrazine intermediate. In some embodiments of the present application, the above nucleophilic addition reaction is carried out in an inert gas atmosphere, and the yield of the target product is higher. In some embodiments of the present application, the processing process of the above nucleophilic addition reaction is: under the protection of an inert gas, the catalyst, the second alkaline reagent and the additive are added to a three-necked flask in sequence, and then the methyl cyclopentyl ether solution of the hydrazide intermediate prepared in the step is added dropwise, and after the addition is complete, the second raw material is added to the system, and the reaction is continued at room temperature for 10 hours. The salt insoluble matter is filtered out, and the resulting solution is washed with water and concentrated to obtain a secondary alcohol intermediate of an oily substance, that is, intermediate 9 in the above reaction equation.

[0084] In some typical embodiments of the present application, the above ring-closing reaction is a Mitsunobu reaction. The specific operation method of the specific reaction can refer to the prior art. In some embodiments of the present application, the processing process of the above ring-closing reaction includes: mixing the secondary alcohol intermediate with triphenylphosphine and the sixth solvent, dropping diethyl azodicarboxylate to react, adding water to quench the reaction after the reaction, and obtaining the target product through the fourth purification. The above sixth solvent can be selected from organic solvents, such as any one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and methyl cyclopentyl ether; preferably, the temperature of the above ring-closing reaction is 0-10°C, which is conducive to the further yield of the product. In some preferred embodiments of the present application, the above fourth purification includes reduced pressure concentration, ethanol freeze washing, filtration, and drying to obtain a high-purity target product.

[0085] The beneficial effects that can be achieved by the present application will be further illustrated below in combination with embodiments and comparative examples.

[0086] Example 1

[0087] Synthesis of 2-nitro-5-ethoxy-6-fluoronitrobenzene, the reaction equation is as follows:

[0088]

[0089] Add 610g of nitromethane and 176g of tetraethylammonium hydroxide to a 2L three-necked flask. Under the protection of inert gas, cool the system to -10 to -15°C, then drop 177g of 2,3,4-trifluoronitrobenzene. After the addition is complete, the system is kept warm and stirred to react until the central control is qualified. Wash with water, concentrate under reduced pressure to recover nitromethane, add 1L of ethanol and 82g of sodium ethoxide to the residue, and reflux for 5 hours. Add dilute hydrochloric acid to the system to adjust the pH value to neutral, concentrate, and wash the residue with water. The obtained yellow solid product 3 is about 196g, which can be directly used in the next preparation process without further purification. The total yield of the two steps is 80% based on trifluoronitrobenzene.

[0090] Example 2

[0091] Synthesis of 2-nitro-5-ethoxy-6-fluorobenzoic acid, the reaction equation is shown below:

[0092]

[0093] The obtained solid product 3, 800 ml of water, 6 g of tetrabutylammonium iodide and 15 g of zinc acetate were placed in a 2L three-necked flask, the temperature was controlled at 80-85°C for reaction for 20 hours, the temperature was lowered, hydrochloric acid was added to adjust the pH to 1-2, methyl tert-butyl ether was used for dissolution and extraction, the mixture was washed with water and concentrated, and the solid product was washed with 500 ml of petroleum ether to obtain 169 g of solid product, i.e., intermediate 4 shown in the reaction equation, with a process yield of 90%.

[0094] Example 3

[0095] Synthesis of 2-amino-5-ethoxy-6-fluorobenzoic acid, the reaction equation is as follows:

[0096]

[0097] Add 160g of intermediate 4, 600ml of anhydrous ethanol, and 5g of Raney nickel to a 2L autoclave, maintain a hydrogen pressure of 0.5MPa, and control the temperature at 30-35°C for hydrogenation reaction for 5 hours. Filter and concentrate, add 300ml of toluene petroleum ether (1:2) to the residue for crystallization, and finally obtain 128g of the target product, that is, intermediate 5 shown in the reaction equation, with a process yield of 92%.

[0098] Example 4

[0099] Synthesis of 2-carboxy-3-fluoro-4-ethoxybenzaldehyde hydrazine, the reaction equation is as follows:

[0100]

[0101] The intermediate 5 prepared in Example 3 was put into a 1L three-necked flask, 300ml of acetonitrile and 30g of paraformaldehyde were added, and the temperature was controlled to reflux for 8 hours, and the temperature was lowered to 65°C, and then 250ml of 35% hydrogen peroxide was added, and the reaction was continued to reflux and stir for 6 hours. The acetonitrile was distilled off under reduced pressure, the temperature was lowered, and suction was filtered. The solid product was rinsed with water until it was non-oxidizing (the rinsed water phase was tested for non-oxidizing with starch potassium iodide test paper), and 116g of intermediate 6 was dried, and the process yield was about 80%. The dried product was put into a 2L three-necked flask, 115g of hydrazine hydrate monohydrate and 800ml of anhydrous ethanol were added, and the reaction was refluxed for 2h, ethanol was recovered under reduced pressure, the temperature was lowered, 600ml of methyl cyclopentyl ether was added for extraction, and the methyl cyclopentyl ether solution of intermediate 7 was obtained, containing about 124g of intermediate 7, and the yield was about 95%.

[0102] Example 5

[0103] To synthesize secondary alcohol intermediates, the reaction equation is as follows:

[0104]

[0105] Under nitrogen protection, 12g of catalyst Fe(dmpe) 2 Cl 2 , 58g potassium phosphate and 42g cesium fluoride were added to a three-necked flask in sequence, and then all the methyl cyclopentyl ether solution containing intermediate 7 prepared in Example 4 was added dropwise. After the addition was completed, 84g aldehyde 8 (as shown in the equation) was added to the system and the reaction was continued at room temperature for 10h. The salt insolubles were filtered off, and the resulting solution was washed with water and concentrated to obtain 180g of oily intermediate 9 with a yield of 85%.

[0106] Example 6

[0107] Synthesis of 7-ethoxy-8-fluoro-3,4-dihydro-3-(trans-4-alkylcyclohexyl)-1H-2-benzopyran-1-one, the reaction equation is as follows:

[0108]

[0109] 180g of the above concentrate, 134g of triphenylphosphine and 500ml of tetrahydrofuran were placed in a 2L three-necked flask, cooled to 5-10°C under nitrogen protection, 93g of diethyl azodicarboxylate was added dropwise, and after the addition was completed, the system was kept warm and stirred for 30 minutes. 10ml of water was added to the system, and the system was concentrated under reduced pressure. The system was freeze-washed with ethanol several times, filtered and dried to obtain 140g of the target product with a yield of 90%, a GC purity of 99.9%, and an mp of 102-104°C.

[0110] Example 7

[0111] The difference from Example 1 is that the amount of nitromethane added is 305 g.

[0112] The obtained yellow solid product 3 is about 171 g, and the total yield of two steps based on trifluoronitrobenzene is 70%.

[0113] Example 8

[0114] The difference from Example 1 is that the amount of nitromethane added is 183 g.

[0115] The obtained yellow solid product 3 is about 122 g, and the total yield of two steps based on trifluoronitrobenzene is 50%.

[0116] Example 9

[0117] The difference from Example 4 is that the temperature is not lowered, and hydrogen peroxide is added at the reflux temperature.

[0118] A methyl cyclopentyl ether solution of intermediate 7 was obtained, containing about 111 g of intermediate 7, with a yield of about 85%.

[0119] Example 10

[0120] The difference from Example 5 is that cesium fluoride was not added.

[0121] The same treatment process as in Example 5 was used to obtain 42 g of intermediate 9 as an oily substance.

[0122] Embodiment 11

[0123] The difference from Example 5 is that the structural formula of aldehyde 8 is The amount added was 76 g, and 160 g of secondary alcohol intermediate was obtained. Then, the 160 g of secondary alcohol intermediate was subjected to a ring-closure reaction under the same conditions as in Example 6 to obtain 122 g of the target product with a yield of 85%, a GC purity of 99.8%, and an mp of 92-93°C.

[0124] Example 12

[0125] The difference from Example 5 is that the structural formula of aldehyde 8 is The amount added was 92 g, and 188 g of secondary alcohol intermediate was obtained. Then, the 188 g of secondary alcohol intermediate was subjected to a ring-closure reaction under the same conditions as in Example 6 to obtain 147 g of the target product with a yield of 92%, a GC purity of 99.9%, and an mp of 108-109°C.

[0126] Embodiment 13

[0127] The difference from Example 1 is that 116 g of sodium n-butoxide is used instead of 82 g of sodium ethoxide. The reaction equation is as follows:

[0128]

[0129] The total yield of the two steps based on trifluoronitrobenzene was 72%.

[0130] Then, the target product of the following structure was synthesized in the same manner as in Examples 2 to 6, with a total yield of 54.4%, a GC purity of 99.9%, and an mp of 88-90°C.

[0131]

[0132] Embodiment 14

[0133] The difference from Example 5 is that the structural formula of aldehyde 8 is The amount added was 58 g, and 160 g of secondary alcohol intermediate was obtained. Then, the 160 g of secondary alcohol intermediate was subjected to a ring-closing reaction under the same conditions as in Example 6 to obtain 130 g of the corresponding target product with a yield of 92%, a GC purity of 99.9%, and an mp of 109-111°C.

[0134] Embodiment 15

[0135] The difference from Example 5 is that the structural formula of aldehyde 8 is The amount added was 129 g, and 229 g of secondary alcohol intermediate was obtained. Then, the 229 g of secondary alcohol intermediate was subjected to a ring-closing reaction under the same conditions as in Example 6 to obtain 188 g of the corresponding target product with a yield of 95%, a GC purity of 99.9%, and an mp of 132-133°C.

[0136] From the above description, it can be seen that the above-mentioned embodiments of the present invention achieve the following technical effects: trifluoronitrobenzene is used as the starting material, first ortho-substituted with nitromethane, then para-substituted with alkoxide, the obtained nitro substitution product is subjected to the Nef reaction, and then the nitro group is converted into aldehyde hydrazine by reduction, oxidative denitrogenation rearrangement, and then the aldehyde of a specific structure is subjected to nucleophilic addition under the catalysis of an iron catalyst to generate a secondary alcohol intermediate, and finally the target product is obtained by ring closure. The above-mentioned method for preparing benzopyrone has a wide range of raw materials, relatively mild reaction conditions, a high overall reaction yield, and the prepared product is easy to separate and purify, which can effectively reduce the process cost of benzopyrone compounds. The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention. For those skilled in the art, the present invention may have various changes and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing benzopyrone, characterized in that: include: Step S1, using trifluoronitrobenzene as the first raw material, and carrying out an ortho-substitution reaction with nitromethane, the temperature of the ortho-substitution reaction is -10 to -30°C, to obtain 1,2-difluoro-4-nitro-3-nitromethylbenzene, mixing 1,2-difluoro-4-nitro-3-nitromethylbenzene with a first solvent and an alcohol salt, heating to reflux, reacting for 5-10 hours, adding a first acidic aqueous solution to the system to adjust the pH value, concentrating, beating and washing with water to obtain a first intermediate, the structure of the first intermediate is shown in Formula I, Formula I Wherein, R1 is selected from an alkyl group having 1 to 4 carbon atoms; Step S2, subjecting the first intermediate to a Nef reaction to convert the nitromethyl group into a carboxyl group to obtain a second intermediate, wherein a first catalyst is added to the Nef reaction, and the first catalyst includes any one or more of tetrabutylammonium iodide, zinc acetate, and zinc iodide; Step S3, converting the nitro group of the second intermediate into aldehyde hydrazine through reduction reaction, oxidation reaction and denitrogenation rearrangement reaction to obtain an aldehyde hydrazine intermediate; the reduction reaction is a reaction with hydrogen under the action of a second catalyst; the oxidation reaction includes mixing the product of the reduction reaction with trioxymethylene and a fourth solvent, reacting for a first time, adding an oxidant, continuing the reaction for a second time, and after the reaction is completed, performing a second purification to obtain a product of the oxidation reaction; the treatment process of the denitrogenation rearrangement reaction includes: dissolving the product of the oxidation reaction with a fifth solvent, mixing with hydrazine hydrate monohydrate, reacting under reflux, and performing a third purification to obtain the aldehyde hydrazine intermediate; Step S4, in the presence of a catalyst, subjecting the aldehyde hydrazine intermediate to a nucleophilic addition reaction with a second raw material having a structure as shown in formula ⅠⅠ to generate a secondary alcohol intermediate, subjecting the secondary alcohol intermediate to a ring-closing reaction to obtain a target product having a structure as shown in formula ⅢⅠ, wherein the nucleophilic addition reaction is carried out in the presence of a second base reagent and a catalyst, wherein the catalyst comprises Fe(dmpe)2Cl2; and the ring-closing reaction is a Mitsunobu reaction; Formula Ⅰ Formula ⅠⅠⅠ In Formula ⅠⅠ and Formula ⅢⅠ, R2 is selected from substituted or unsubstituted cyclohexyl, phenyl or bicyclohexylalkyl, and the substituents are each independently any one of C1~C5 alkyl; in Formula ⅢⅠ, R1 is selected from alkyl having 1 to 4 carbon atoms.

2. The preparation method according to claim 1, characterized in that: The amount of nitromethane used is 5 to 20 times the molar amount of the first raw material trifluoronitrobenzene.

3. The preparation method according to claim 2, characterized in that: An organic base is added to the ortho-substitution reaction in step S1.

4. The preparation method according to claim 3, characterized in that: The organic base includes any one or more of triethylamine, triethylenediamine, tetramethylguanidine, N-methylmorpholine and quaternary ammonium base.

5. The preparation method according to claim 3, characterized in that: The amount of the organic base used is 1-3 times the molar amount of the first raw material trifluoronitrobenzene.

6. The preparation method according to claim 3, characterized in that: In the step S1, the ortho-substitution reaction is carried out in an inert gas atmosphere.

7. The preparation method according to claim 6, characterized in that: The ortho-substitution reaction comprises: adding nitromethane and the organic base into a reaction container, cooling the reaction container to a reaction temperature of the substitution reaction in the inert gas atmosphere, adding the first raw material trifluoronitrobenzene, and performing the substitution reaction.

8. The preparation method according to claim 6, characterized in that: The first raw material trifluoronitrobenzene is added dropwise.

9. The preparation method according to claim 6, characterized in that: After the ortho-substitution reaction is completed, the reaction system is washed with water, concentrated under reduced pressure to recover nitromethane, and 1,2-difluoro-4-nitro-3-nitromethane is obtained.

10. The preparation method according to claim 1, characterized in that: In the step S1, the alkoxide includes any one or more of sodium alkoxide and potassium alkoxide.

11. The preparation method according to claim 1, characterized in that: In the step S1, the amount of the alkoxide used is 1 to 2 times the molar amount of 1,2-difluoro-4-nitro-3-nitromethylbenzene.

12. The preparation method according to claim 1, characterized in that: In the step S1, the first solvent includes any one or more of ethanol, methanol, propanol and isopropanol.

13. The preparation method according to claim 1, characterized in that: In the step S1, the pH value is adjusted to neutral.

14. The preparation method according to claim 1, characterized in that: In the step S1, the first acidic aqueous solution includes any one or more of a hydrochloric acid solution, a sulfuric acid solution, an acetic acid solution, an ammonium chloride aqueous solution, and an ammonium sulfate aqueous solution.

15. The preparation method according to claim 1, characterized in that: In the step S2, the first catalyst includes tetrabutylammonium iodide and zinc acetate.

16. The preparation method according to claim 15, characterized in that: The amount of tetrabutylammonium iodide used is 2-10% of the molar amount of the first intermediate, and the amount of zinc acetate used is 5-20% of the molar amount of the first intermediate.

17. The preparation method according to claim 1, characterized in that: The Nef reaction is carried out in a second solvent, and the second solvent is water.

18. The preparation method according to claim 17, characterized in that: The amount of the second solvent used is 1 to 5 times the volume of the first intermediate.

19. The preparation method according to claim 17, characterized in that: The step S2 comprises: mixing the first intermediate with the second solvent and the first catalyst to perform a Nef reaction, and after the reaction is completed, performing acidification and a first purification to obtain a second intermediate.

20. The preparation method according to claim 19, characterized in that: The temperature of the Nef reaction is 80-100° C., and the reaction time is 10-30 hours.

21. The preparation method according to claim 19, characterized in that: The first purification includes dissolving and extracting the acidified product with methyl tert-butyl ether, washing with water, and concentrating the product; and washing the solid product obtained by concentration with petroleum ether to obtain a second intermediate.

22. The preparation method according to claim 1, characterized in that: In step S3, the second catalyst includes any one or more of Raney nickel, palladium carbon and platinum carbon.

23. The preparation method according to claim 1, characterized in that: The pressure of the hydrogen is 0.2-1 MPa.

24. The preparation method according to claim 1, characterized in that: The reduction reaction is carried out in a third solvent, and the third solvent includes any one or more of ethanol, methanol and water.

25. The preparation method according to claim 1, characterized in that: The reduction reaction temperature is 30-50° C., and the reaction time is 5-10 hours.

26. The preparation method according to claim 1, characterized in that: The treatment process of the reduction reaction includes: mixing the second intermediate with the second catalyst and the third solvent, filling hydrogen into the reaction device for reaction, and after the reaction is completed, filtering, concentrating and crystallizing to obtain the reduction product.

27. The preparation method according to claim 1, characterized in that: In the step S3, the fourth solvent is an organic solvent.

28. The preparation method according to claim 1, characterized in that: In step S3, the oxidant is selected from any one or more of aqueous hydrogen peroxide solution and tert-butyl hydroperoxide.

29. The preparation method according to claim 1, characterized in that: In the step S3, the molar amount of the formaldehyde monomer in the trioxymethylene is 1 to 3 times the molar amount of the product of the reduction reaction.

30. The preparation method according to claim 1, characterized in that: In the step S3, the fourth solvent includes acetonitrile.

31. The preparation method according to claim 1, characterized in that: In step S3, the temperature of the oxidation reaction is 75-85°C.

32. The preparation method according to claim 31, characterized in that: In the step S3, the oxidant is added at 60-70°C.

33. The preparation method according to claim 1, characterized in that: In step S3, the first time is 8-10 hours, and the second time is 5-8 hours.

34. The preparation method according to claim 1, characterized in that: In the step S3, the second purification includes separating the fourth solvent by distillation or reduced pressure distillation, filtering, washing with water to remove hydrogen peroxide, and drying to obtain the product of the oxidation reaction.

35. The preparation method according to claim 27, characterized in that: In the step S3, the fifth solvent includes ethanol.

36. The preparation method according to claim 27, characterized in that: In the step S3, the third purification includes: concentration under reduced pressure, extraction with methyl cyclopentyl ether, and washing with water.

37. The preparation method according to claim 1, characterized in that In step S4, the second alkaline reagent includes any one or more of potassium carbonate, potassium phosphate and potassium tert-butoxide.

38. The preparation method according to claim 37, characterized in that: The amount of the second alkaline reagent used is 2-10% of the molar amount of the aldehyde hydrazine intermediate.

39. The preparation method according to claim 1, characterized in that: An additive is also added into the nucleophilic addition reaction, and the additive is selected from any one or more of sodium fluoride, potassium fluoride and cesium fluoride.

40. The preparation method according to claim 39, characterized in that: The dosage of the additive is 2-10% of the molar amount of the aldehyde hydrazine intermediate.

41. The preparation method according to claim 1, characterized in that The nucleophilic addition reaction is carried out in an inert gas atmosphere.

42. The preparation method according to claim 1, characterized in that The treatment process of the ring-closing reaction includes: mixing the secondary alcohol intermediate with triphenylphosphine and a sixth solvent, dropping diethyl azodicarboxylate into the mixture for reaction, adding water to quench the reaction after the reaction is completed, and performing a fourth purification to obtain the target product.

43. The preparation method according to claim 42, characterized in that: The temperature of the ring-closure reaction is 0-10°C.

44. The preparation method according to claim 42, characterized in that: The sixth solvent includes any one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and methyl cyclopentyl ether.

45. The preparation method according to claim 42, characterized in that: The fourth purification includes reduced pressure concentration, ethanol freezing washing, filtration and drying.

46. ​​The preparation method according to claim 1, characterized in that The R1 is selected from an alkyl group having 2 to 4 carbon atoms, the R2 is selected from a substituted or unsubstituted cyclohexyl group, a phenyl group or a bicyclohexyl alkyl group, and the substituents are each independently any one of a C1 to C5 alkyl group.

47. The preparation method according to claim 1, characterized in that The R1 is selected from ethyl or n-butyl, and the R2 is selected from substituted or unsubstituted cyclohexyl, phenyl or bicyclohexylalkyl.

48. The preparation method according to claim 47, characterized in that The substituent is located at the para position, and the substituent is any one of C1~C4 alkyl.

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