Process for the synthesis of esacillinone and intermediates thereof

Abstract

The application provides a new synthesis method of esacioxin intermediate. The method comprises the following steps: (1) reacting raw material 2-(trifluoromethyl) phenylacetic acid with ethyl chloroformate or isobutyl chloroformate in an inert solvent in the presence of a base to generate a mixed anhydride, and then reacting with ammonia to obtain a corresponding amide compound formula II; (2) preparing an isonitrile compound formula III through a dehydration reaction of the amide compound formula II obtained in the step (1) in the presence of a dehydrating agent and an acid binding agent; (3) cyclizing the isonitrile compound formula III obtained in the step (2) with 2-butynoic acid ethyl ester in the presence of a base and a metal catalyst to form a pyrrole ring compound formula IV; and the reaction formula is shown in the following formula: compared with the prior art, the technical scheme of the application has the advantages of high yield, simple post-treatment, low cost and easy industrialization.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more specifically, to a method for synthesizing an ethacillinone intermediate, and further to a method for synthesizing ethacillinone. Background Technology

[0002] The chemical name of esaxillinone is (5P)-1-(2-hydroxyethyl)-N-[4-(methanesulfonyl)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide, and its structural formula is as follows:

[0003]

[0004] It is a selective mineralocorticoid receptor (MR) antagonist used to treat hypertension.

[0005] Currently, Chinese patents CN105164105A and CN105473552A report the synthetic route of edaxillinone from the original manufacturer, Daiichi Sankyo Co., Ltd. It is clear from these patent applications that the construction of key intermediate IV is one of the core components of the edaxillinone synthetic route.

[0006]

[0007] There are also reports on the preparation methods of key intermediate IV, such as patent documents CN102186817A and WO2021078135A1. The preparation methods of key intermediate IV disclosed in the above patent documents are all obtained by Suzuki coupling reaction. The palladium catalyst used in this reaction is expensive and costly. In addition, ligands need to be added, which is not conducive to purification and industrial production.

[0008] Chinese patents CN105164105A and CN105473552A report a synthetic route for obtaining key intermediate IV via cyclization. This route uses 2-bromo-1-[2-(trifluoromethyl)phenyl]propane-1-one as the starting material, reacting it with ethyl cyanoacetate to obtain intermediate 2. Then, through cyclization and removal of the chlorine group, the key intermediate IV is obtained. The reaction formula is as follows:

[0009] .

[0010] The cyclization step of this route uses hydrogen chloride gas as a reactant, which is highly corrosive, and the palladium metal catalyst used in the step of removing chlorine groups is expensive, resulting in high costs and making it unsuitable for industrial-scale production.

[0011] Furthermore, developing methods for preparing pharmaceutically active compounds with high yield, high purity, simplicity, high efficiency, low cost, and ease of industrial production remains challenging. Therefore, this invention provides a method for synthesizing an ethacillinone intermediate that offers advantages such as high yield, simple post-processing, low cost, and ease of industrialization, while simultaneously ensuring the product meets the purity requirements for active pharmaceutical ingredient registration. Summary of the Invention

[0012] One of the objectives of this invention is to provide a new method for synthesizing ethacillinone intermediates, in order to solve the problems of low yield, high cost, complex post-processing, and unfavorable conditions for industrial production in existing methods for synthesizing ethacillinone intermediates.

[0013] To achieve the above objectives, the first aspect of the present invention provides a novel method for synthesizing an ethacillinone intermediate compound of formula IV, the method comprising the following steps:

[0014] (1) The raw material 2-(trifluoromethyl)phenylacetic acid is reacted with ethyl chloroformate or isobutyl chloroformate in an inert solvent under the presence of alkali to generate a mixed acid anhydride, which is then reacted with ammonia to obtain the corresponding amide compound of formula II.

[0015] (2) The amide compound II obtained in step (1) was dehydrated in the presence of a dehydrating agent and an acid-binding agent to prepare isonitrile compound III;

[0016] (3) The isonitrile compound III obtained in step (2) cyclizes with ethyl 2-butynedoate in the presence of a base and a metal catalyst to form pyrrole compound IV;

[0017] The process route is as follows:

[0018] .

[0019] Preferably, the inert solvent in step (1) includes, but is not limited to, one or more of the group consisting of halogenated hydrocarbons, benzene, toluene, diethyl ether, xylene, nitrobenzene, and acetonitrile; the base is one or more of the group consisting of imidazole, pyridine, tetrabutylammonium fluoride, 2,6-dimethylpyridine, potassium carbonate, N,N-diisopropylethylamine, sodium carbonate, and triethylamine; the molar ratio of 2-(trifluoromethyl)phenylacetic acid to the base is 1:0.5~1; the molar ratio of 2-(trifluoromethyl)phenylacetic acid to ethyl chloroformate or isobutyl chloroformate is 1:1~1.5; the reaction temperature is 0℃~room temperature; and the reaction time is 12 hours~36 hours.

[0020] Preferably, the dehydrating agent in step (2) is one or more of P2O5, PCl3, SOCl2, COCl2, ArSO2Cl, and POCl3; the acid-binding agent is an organic or inorganic base, wherein the inorganic base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide, etc.; the organic base is triethylamine or diisopropylamine; and the solvent is a haloalkane, dichloromethane, or dichloroethane.

[0021] Preferably, the base mentioned in step (3) is Pr3N, pyridine, DBU, or TEEDA; and the metal catalyst is Cu2O, CuCl, CuI, CuBr, Cu(OMe)2, or copper powder.

[0022] A second aspect of the invention also provides an ethacillinone intermediate compound of formula IV, which is prepared by the above-described synthetic process.

[0023] A third aspect of the present invention also provides a novel method for synthesizing an ethacillinone intermediate compound of formula V, the method comprising the following steps: reacting the above-mentioned pyrrole ring compound of formula IV in a solvent, under the presence of a base, with... The reaction yielded compound V; the structural formula of intermediate compound V is shown below:

[0024]

[0025] X is a halogen, and A is a hydroxyl group or a halogen.

[0026] Preferably, the solvent is an alcohol solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an ether solvent, or an amide solvent; the alcohol solvent includes, but is not limited to, ethanol; the halogenated hydrocarbon solvent includes, but is not limited to, dichloromethane or chloroform; the aromatic hydrocarbon solvent includes, but is not limited to, toluene, benzene, xylene, or nitrobenzene; the ether solvent includes, but is not limited to, tetrahydrofuran, 1,4-dioxane; or the amide solvent includes, but is not limited to, N,N-dimethylacetamide or N,N-dimethylformamide; the base is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, sodium hydride, potassium carbonate, sodium carbonate, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, or pyridine; preferably sodium hydroxide or lithium hydroxide; the reaction temperature of this step is room temperature to 80°C, preferably room temperature to 60°C, and the reaction time is 1 to 20 hours, preferably 2 to 3 hours.

[0027] A fourth aspect of the invention also provides an ethacillinone intermediate compound of formula V, which is prepared by the aforementioned synthetic process.

[0028] The fifth aspect of the present invention also provides a novel method for synthesizing ethacillinone, employing the following technical solution:

[0029] The aforementioned ethacillinone intermediate compound V reacts with 4-methanesulfonyl aniline via a condensation reaction to yield compound VI, the structural formula of which is shown below:

[0030] .

[0031] Preferably, the condensing agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT), the solvent is dry N,N-dimethylformamide (DMF), and a certain amount of base is added. Commonly used bases are N,N-diisopropylethylamine (DIPEA), triethylamine, pyridine, benzotriazole-1-yl-oxytripyrrolidine hexafluorophosphate (PyBop), with N,N-diisopropylethylamine (DIPEA) being preferred.

[0032] The sixth aspect of the present invention also provides a second novel method for preparing ethacillinone, employing the following technical solution: the above-mentioned ethacillinone intermediate compound of formula V reacts with a suitable acylation reagent to obtain an acyl chloride compound of formula VII, and the acyl chloride compound of formula VII then undergoes an acylation reaction with 4-methanesulfonylaniline to obtain compound VI, wherein the structural formula of the acyl chloride compound of formula VII is shown below:

[0033] .

[0034] Preferably, the acylation reagent is oxalyl chloride, and the acylation reaction is preferably carried out in the presence of a base and a solvent. The base is an organic or inorganic base, including but not limited to triethylamine and N,N-diisopropylethylamine; the solvent is a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an ether solvent, or an amide solvent; the halogenated hydrocarbon solvent includes but is not limited to dichloromethane or chloroform; the aromatic hydrocarbon solvent includes but is not limited to toluene, benzene, xylene, or nitrobenzene; the ether solvent includes but is not limited to tetrahydrofuran and 1,4-dioxane; or the amide solvent includes but is not limited to N,N-dimethylacetamide and N,N-dimethylformamide.

[0035] A seventh aspect of the invention also provides ethacillinone, which is prepared by any of the foregoing synthetic processes.

[0036] By applying the technical solution of this invention, the use of expensive palladium catalysts is avoided, thus reducing costs; at the same time, the use of ligands is avoided, making post-processing simple and easy to purify; the use of highly corrosive hydrogen chloride gas is avoided, which is conducive to industrial-scale production; compared with the existing literature CN101006052A, the yield of the intermediate compound of formula IV of ethacillinone prepared by applying the technical solution of this invention is increased by 57.6 percentage points. Detailed Implementation

[0037] It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined with each other. The present invention will now be described in detail with reference to the embodiments.

[0038] As described in the background section, existing methods for synthesizing ethacillinone intermediates suffer from low yields, high costs, complex post-processing, and are unsuitable for industrial production. To address these technical problems, this application provides a novel method for synthesizing ethacillinone intermediate compound IV, which includes the following steps:

[0039] (1) The raw material 2-(trifluoromethyl)phenylacetic acid is reacted with ethyl chloroformate or isobutyl chloroformate in an inert solvent under the presence of alkali to generate a mixed acid anhydride, which is then reacted with ammonia to obtain the corresponding amide compound of formula II.

[0040] (2) The amide compound II obtained in step (1) was dehydrated in the presence of a dehydrating agent and an acid-binding agent to prepare isonitrile compound III;

[0041] (3) The isonitrile compound III obtained in step (2) cyclizes with ethyl 2-butynedoate in the presence of a base and a metal catalyst to form pyrrole ring compound IV;

[0042] The process route is as follows:

[0043] .

[0044] Preferably, the inert solvent in step (1) includes, but is not limited to, one or more of the group consisting of halogenated hydrocarbons, benzene, toluene, diethyl ether, xylene, nitrobenzene, and acetonitrile; the base is one or more of the group consisting of imidazole, pyridine, tetrabutylammonium fluoride, 2,6-dimethylpyridine, potassium carbonate, N,N-diisopropylethylamine, sodium carbonate, and triethylamine; the molar ratio of 2-(trifluoromethyl)phenylacetic acid to the base is 1:0.5~1; the molar ratio of 2-(trifluoromethyl)phenylacetic acid to ethyl chloroformate or isobutyl chloroformate is 1:1~1.5; the reaction temperature is 0℃~room temperature; and the reaction time is 12 hours~36 hours.

[0045] Preferably, the dehydrating agent in step (2) is one or more of P2O5, PCl3, SOCl2, COCl2, ArSO2Cl, and POCl3; the acid-binding agent is an organic or inorganic base, wherein the inorganic base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide, etc.; the organic base is triethylamine or diisopropylamine; and the solvent is a haloalkane, dichloromethane, or dichloroethane.

[0046] Preferably, the base mentioned in step (3) is Pr3N, pyridine, DBU, or TEEDA; and the metal catalyst is Cu2O, CuCl, CuI, CuBr, Cu(OMe)2, or copper powder.

[0047] The raw material 2-(trifluoromethyl)phenylacetic acid (compound formula I) can be obtained by purchase.

[0048] A second aspect of the invention also provides an ethacillinone intermediate compound of formula IV, which is prepared by the above-described synthetic process.

[0049] A third aspect of the present invention also provides a novel method for synthesizing an ethacillinone intermediate compound of formula V, the method being as follows:

[0050] .

[0051] The specific synthetic method includes the following steps: The pyrrole ring compound IV obtained above is reacted with... The reaction prepares a compound of formula V, wherein X is a halogen and A is a hydroxyl group or a halogen.

[0052] Preferably, the solvent is an alcohol solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an ether solvent, or an amide solvent; the alcohol solvent includes, but is not limited to, ethanol; the halogenated hydrocarbon solvent includes, but is not limited to, dichloromethane or chloroform; the aromatic hydrocarbon solvent includes, but is not limited to, toluene, benzene, xylene, or nitrobenzene; the ether solvent includes, but is not limited to, tetrahydrofuran, 1,4-dioxane; or the amide solvent includes, but is not limited to, N,N-dimethylacetamide or N,N-dimethylformamide; the base is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, sodium hydride, potassium carbonate, sodium carbonate, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, or pyridine; preferably sodium hydroxide or lithium hydroxide; the reaction temperature of this step is room temperature to 80°C, preferably room temperature to 60°C, and the reaction time is 1 to 20 hours, preferably 2 to 3 hours.

[0053] A fourth aspect of the invention also provides an ethacillinone intermediate compound of formula V, which is prepared by the aforementioned synthetic process.

[0054] A fifth aspect of the present invention also provides a novel method for synthesizing ethacillinone, the preparation method being as follows:

[0055] .

[0056] The specific synthetic method includes the following steps: the above-mentioned ethacillinone intermediate compound V and 4-methanesulfonyl aniline are condensed in the presence of a condensing agent to obtain ethacillinone (compound formula VI).

[0057] Preferably, the condensing agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT), the solvent is dry N,N-dimethylformamide (DMF), and a certain amount of base is added. Commonly used bases are N,N-diisopropylethylamine (DIPEA), triethylamine, pyridine, benzotriazole-1-yl-oxytripyrrolidine hexafluorophosphate (PyBop), with N,N-diisopropylethylamine (DIPEA) being preferred.

[0058] The sixth aspect of the present invention also provides a second novel method for synthesizing ethacillinone, the method being as follows:

[0059] .

[0060] The specific preparation method includes the following steps: reacting the above-mentioned ethacillinone intermediate compound V with a suitable acylation reagent to obtain acyl chloride compound VII, and then reacting acyl chloride compound VII with 4-methanesulfonyl aniline to obtain compound VI.

[0061] Preferably, the acylation reagent is oxalyl chloride, and the acylation reaction is preferably carried out in the presence of a base and a solvent. The base is an organic or inorganic base, including but not limited to triethylamine and N,N-diisopropylethylamine; the solvent is a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an ether solvent, or an amide solvent; the halogenated hydrocarbon solvent includes but is not limited to dichloromethane or chloroform; the aromatic hydrocarbon solvent includes but is not limited to toluene, benzene, xylene, or nitrobenzene; the ether solvent includes but is not limited to tetrahydrofuran and 1,4-dioxane; or the amide solvent includes but is not limited to N,N-dimethylacetamide and N,N-dimethylformamide.

[0062] A seventh aspect of the invention also provides ethacillinone, which is prepared by any of the foregoing synthetic processes.

[0063] By applying the technical solution of this invention, the use of expensive palladium catalysts is avoided, thus reducing costs; at the same time, the use of ligands is avoided, making post-processing simple and easy to purify; the use of highly corrosive hydrogen chloride gas is avoided, which is conducive to industrial-scale production; compared with the existing literature CN101006052A, the yield of the intermediate compound of formula IV of ethacillinone prepared by applying the technical solution of this invention is increased by 57.6 percentage points.

[0064] Example 1 Synthesis of 2-(trifluoromethyl)phenylacetamide (amide compound formula II)

[0065]

[0066] 20.4 g (0.1 mol, 1 eq) of 2-(trifluoromethyl)phenylacetic acid, 13.0 g (0.12 mol, 1.2 eq) of ethyl chloroformate, 4.7 g (0.06 mol, 0.6 eq) of pyridine, and 11.9 g (0.15 mol, 1.5 eq) of ammonium bicarbonate were added to 500 mL of 1,4-dioxane solvent. The mixture was stirred at room temperature for 12 hours. After the reaction was confirmed to be complete, ethyl acetate and brine were added for extraction. The organic phase was dried, concentrated, and the crude product was obtained. The crude product was then crystallized from ethyl acetate and petroleum ether to obtain 19.9 g of amide compound II, with a yield of 98.0%.

[0067] Example 2 Synthesis of isonitrile compound of formula III

[0068]

[0069] 10.2 g of 2-(trifluoromethyl)phenylacetamide (0.05 mol) was dissolved in 100 mL of dichloroethane, and 12.6 g of triethylamine (0.125 mol) was added. The temperature of the reaction system was lowered to below -10 °C, and 0.05 mol of phosphorus oxychloride was added dropwise over approximately 20 minutes. The reaction temperature was maintained below 0 °C, and stirring was continued for 1 hour. Then, the temperature was raised to 25-30 °C, and 20% sodium carbonate solution was added dropwise to the reaction solution. After the addition was complete, stirring was continued for 5-10 minutes. The mixture was allowed to stand and separate into layers. The organic phase was washed twice with 5% sodium carbonate solution, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure below 20 °C to obtain 9.0 g of isonitrile compound III, with a yield of 97.3%.

[0070] Example 3 Preparation of ethyl 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (exacillinone intermediate compound IV)

[0071]

[0072] In an argon atmosphere, 0.36 g (2.5 mmol, 0.05 eq) of cuprous oxide, 7.65 g (0.05 mol, 1 eq) of DBU, 6.73 g (0.06 mol, 1.2 eq) of ethyl 2-butynedoate, and 9.25 g (0.05 mol, 1 eq) of isonitrile compound III were added to 500 mL of 1,4-dioxane solvent. The mixture was stirred at 100 °C for 2 hours. After the reaction was confirmed to be complete, the reaction solution was cooled to room temperature, filtered, and ethyl acetate and saturated sodium chloride aqueous solution were added to the filtrate for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified to give 12.3 g of ethyl 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid, with a yield of 83%.

[0073] 1 H-NMR (400MHz, DMSO-d6) δ 8.43(s, 1H), 7.79(m, 1H), 7.63-7.39(m, 4H), 4.33-4.29(m, 2H), 2.19(s, 3H), 1.37-1.34(m, 3H).

[0074] Example 4 Preparation of 1-(2-hydroxyethyl)4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid

[0075]

[0076] 15 g (0.05 mol, 1 eq) of ethyl 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid was dissolved in 300 mL of dichloroethane at room temperature. 10.1 g (0.05 mol, 1 eq) of tetraethylammonium bromide was added. 20% NaOH aqueous solution (100 mL) was added dropwise to the reaction solution under stirring, completing the addition over approximately 30 min. The reaction was continued at room temperature for 1 h, then heated to 60 °C and reacted for 2 h. The reaction was checked for completeness by TLC. The reaction solution was cooled to room temperature, and the pH was adjusted to 5-6 with 2N hydrochloric acid. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried, and concentrated to obtain 14.7 g of 1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid, with a yield of 94%.

[0077] Example 6 Preparation of 1-(2-hydroxyethyl)-N-[4-(methanesulfonyl)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide

[0078]

[0079] 3.77 g (0.022 mol, 1.1 eq) of 4-methanesulfonylaniline, 6.26 g (0.02 mol, 1.0 eq) of the ethacillinone intermediate compound V, 4.05 g (0.03 mol, 1.5 eq) of HOBT, 5.75 g (0.03 mol, 1.5 eq) of EDCI, and 5.16 g (0.04 mol, 2.0 eq) of DIPEA were added to a reaction flask, followed by 300 mL of DCM. The reaction was stirred at room temperature and monitored by TLC. After the reaction was complete, 100 mL of saturated sodium chloride aqueous solution was added for extraction. The organic phase was washed three times with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The organic phase was purified with a 1:1 mixture of ethyl acetate and petroleum ether to obtain 8.4 g of the product, with a yield of 90%.

[0080] 1 H-NMR (400MHz, DMSO-d6) δ: 7.94-7.90 (m, 2H), 7.86-7.78 (m, 3H), 7.69-7.65 (m, 2H), 7.64-7.62 (m, 1H), 7.36-7.33 (m, 1H), 7.29 (s, 1H) 4.39-4.35 (m, 2H), 3.29-3.10 (m, 5H), 2.18 (s, 3H).

[0081] Comparative Example 1

[0082] Referring to the preparation method in Example 16 of the existing literature CN101006052A, the raw material methyl cyanoacetate was replaced with ethyl cyanoacetate to prepare ethyl 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid, with a yield of 21.5%.

[0083] Comparative Example 2

[0084] Following the preparation method of Reference Example 3 in existing literature WO2010098286A1, 1-(2-hydroxyethyl)-N-[4-(methanesulfonyl)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide was prepared with an overall yield of 7.6%.

[0085] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A novel synthesis method of esacioxin intermediate compound of formula IV, which comprises the following steps: (1) reacting the starting material 2-(trifluoromethyl) phenylacetic acid with ethyl chloroformate or isobutyl chloroformate in the presence of a base in an inert solvent to form a mixed anhydride, and then reacting with ammonia to obtain the corresponding amide compound of formula II; (2) preparing the isonitrile compound of formula III by dehydration reaction of the amide compound of formula II obtained in step (1) in the presence of a dehydrating agent and an acid binding agent; wherein (3) cyclizing the isonitrile compound of formula III obtained in step (2) with ethyl 2-butynoate in the presence of a base and a metal catalyst to form the pyrrole ring compound of formula IV; the base in step (3) is DBU; and the metal catalyst is Cu2O; 。 2. The method of synthesis of claim 1, wherein, the process route is shown as follows:

3. The method of synthesis of claim 1, wherein, the inert solvent in step (1) is selected from one or more of halogenated hydrocarbons, benzene, toluene, diethyl ether, xylene, nitrobenzene, acetonitrile; the base is one or more of imidazole, pyridine, tetrabutylammonium fluoride, 2,6-lutidine, potassium carbonate, N,N-diisopropyl ethylamine, sodium carbonate, triethylamine; the molar ratio of 2-(trifluoromethyl) phenylacetic acid to the base is 1:0.5-1; the molar ratio of 2-(trifluoromethyl) phenylacetic acid to ethyl chloroformate or isobutyl chloroformate is 1:1-1.5; the reaction temperature is 0°C to room temperature; and the reaction time is 12 hours to 36 hours.

4. A novel method for synthesizing an ethacillinone intermediate compound of formula V, the method comprising the following steps: the steps of the method for synthesizing a pyrrole ring compound of formula IV according to any one of claims 1 to 3, further comprising reacting the pyrrole ring compound of formula IV with a solvent in the presence of a base. The reaction yielded compound V; the structural formula of intermediate compound V is shown below: ， the dehydrating agent in step (2) is one or more of P2O5, PCl3, SOCl2, COCl2, POCl3; the acid binding agent is an organic base or an inorganic base, the inorganic base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide; the organic base is triethylamine, diisopropylamine; and the solvent is selected from dichloromethane and dichloroethane.

5. The method of synthesis of claim 4, wherein, X is halogen, and A is hydroxyl.

6. A novel process for the synthesis of esacsinone characterized in that, the solvent is an alcohol solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an ether solvent or an amide solvent; the alcohol solvent is selected from ethanol; the halogenated hydrocarbon solvent is selected from dichloromethane or chloroform; the aromatic hydrocarbon solvent is selected from toluene, benzene, xylene or nitrobenzene; the ether solvent is selected from tetrahydrofuran and 1,4-dioxane; the amide solvent is selected from N,N-dimethylacetamide and N,N-dimethylformamide; the base is sodium hydroxide or lithium hydroxide; the reaction temperature is room temperature to 80°C; and the reaction time is 1-20 hours. 。 7. The method of synthesis of claim 6, wherein, comprising the following steps: the synthesis method of the compound of formula V in any one of claims 4-5, further comprising a condensation reaction of the esacioxin intermediate compound of formula V with 4-methanesulfonylaniline in the presence of a condensing agent to obtain the compound of formula VI, wherein the structural formula of the compound of formula VI is shown as follows: the condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT), the solvent is dry N,N-dimethylformamide (DMF), and a certain amount of base is further added, and the base is N,N-diisopropyl ethylamine (DIPEA).

8. A novel process for the preparation of esacixefin characterized in that, The method comprises the following steps: the synthesis method of the compound of formula V in any one of claims 4-5, further comprising the reaction of the intermediate compound of formula V in esacillin ketone with a suitable acylating agent to obtain an acyl chloride compound VII, and the acyl chloride compound VII is further acylated with 4-methylsulfonylaniline to obtain compound VI, wherein the structural formula of the acyl chloride compound VII and the compound VI are as follows: ， 。 9. The method of synthesis of claim 8, wherein, The acylating agent is oxalyl chloride, the acylating reaction is carried out in the presence of a base and a solvent, the base is triethylamine or N,N-diisopropylethylamine, the solvent is a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an ether solvent or an amide solvent, the halogenated hydrocarbon solvent is selected from dichloromethane or chloroform, the aromatic hydrocarbon solvent is selected from toluene, benzene, xylene or nitrobenzene, the ether solvent is selected from tetrahydrofuran or 1,4-dioxane, and the amide solvent is selected from N,N-dimethylacetamide or N,N-dimethylformamide.

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