WO2023035571A1 - Synthesis method for esaxerenone and intermediate thereof - Google Patents

Abstract

Provided is a new synthesis method for an intermediate of esaxerenone. The method comprises: (1) reacting 2-(trifluoromethyl)phenylacetic acid as a raw material with ethyl chloroformate or isobutyl chloroformate in an inert solvent in the presence of an alkali to produce a mixed anhydride, then reacting same with ammonia to obtain a corresponding amide compound of formula II; (2) subjecting the amide compound of formula II obtained in step (1) to a dehydration reaction in the presence of a dehydrating agent and an acid-binding agent to obtain an isocyanide compound of formula III; and (3) subjecting the isocyanide compound of formula III obtained in step (2) to a cyclization reaction with ethyl 2-butynonate in the presence of an alkali and a metal catalyst to form a pyrrole ring compound of formula IV; and the reaction equation is shown below: Compared to the prior art, the technical solution of the present invention has the advantages of a high yield, a simple post-treatment, low costs and easy industrialization, etc.

Description

The synthetic method of ethacillinone and its intermediate technical field

The present invention relates to the field of organic synthesis, in particular, to a synthetic method for an eschacillinone intermediate, and in addition to a synthetic method for eschacillinone.

Background technique

The chemical name of ethacillinone is (5P)-1-(2-hydroxyethyl)-N-[4-(methylsulfonyl)phenyl]-4-methyl-5-[2-(trifluoromethyl ) phenyl]-1H-pyrrole-3-carboxamide, the structural formula is as follows:

It is a selective mineralocorticoid receptor (MR) antagonist used in the treatment of hypertension.

At present, Chinese patents CN105164105A and CN105473552A report the synthesis route of ethacillinone of Daiichi Sankyo Co., Ltd., the original research company. It is not difficult to see from the above patent application that the construction of the key intermediate IV is one of the cores of the synthetic route of ethacillinone.

The preparation method of key intermediate IV is also reported, such as patent documents CN102186817A and WO2021078135A1. The preparation methods of key intermediate IV disclosed in the above patent documents are all prepared by Suzuki coupling reaction, and the palladium catalyst used in this reaction is expensive. The cost is high, and ligands need to be added, which is not conducive to purification and industrial production.

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

The cyclization step of this route uses hydrogen chloride gas as the reaction material, which is highly corrosive, and the palladium metal catalyst used in the chlorine group removal step is expensive and costly, which is not conducive to industrial scale-up production.

In addition, the development of preparation methods for pharmaceutically active compounds with high yield, high purity, simplicity and efficiency, low cost and easy industrial production is still full of challenges. Therefore, the present invention provides a synthetic method of an eschacillinone intermediate, which has the advantages of high yield, simple aftertreatment, low cost, and ease of industrialization, while making the product meet the purity required for registration of raw materials.

Contents of the invention

One of purpose of the present invention is to provide a kind of synthetic method of new eschacillinone intermediate, to solve the existing synthetic method of eschacillinone intermediate that preparation yield is low, cost is high, post-processing is complicated and inconvenient Conducive to the problem of industrialized production.

In order to achieve the above object, the first aspect of the present invention provides a kind of synthetic method of new oxacillinone intermediate compound formula IV, and this synthetic method comprises the following steps:

(1) The raw material 2-(trifluoromethyl)phenylacetic acid is reacted with ethyl chloroformate or isobutyl chloroformate in an inert solvent in the presence of a base to form a mixed anhydride, and then reacted with ammonia to obtain the corresponding amide Compound formula II;

(2) The amide compound formula II obtained in step (1) is prepared through a dehydration reaction in the presence of a dehydrating agent and an acid-binding agent to obtain an isonitrile compound formula III;

(3) The isonitrile compound formula III obtained in step (2) is cyclized with ethyl 2-butynoate to form the pyrrole ring compound formula IV in the presence of a base and a metal catalyst;

The process route is as follows:

Preferably, the inert solvent described in step (1) includes but not limited to one or more of the group consisting of halogenated hydrocarbons, benzene, toluene, ether, xylene, nitrobenzene, and acetonitrile; One or more of imidazole, pyridine, tetrabutylammonium fluoride, 2,6-lutidine, potassium carbonate, N,N-diisopropylethylamine, sodium carbonate, and triethylamine; 2 The molar ratio of -(trifluoromethyl)phenylacetic acid to 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; the reaction time is 12 hours to 36 hours.

Preferably, the dehydrating agent described in step (2) is one or more of P ₂ O ₅ , PCl ₃ , SOCl ₂ , COCl ₂ , ArSO ₂ Cl, POCl ₃ ; the acid-binding agent is an organic base Or inorganic base, described inorganic base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide etc.; Described organic base is triethylamine, diisopropylamine; Described solvent selects halogenated alkanes, two Chloromethane, dichloroethane.

Preferably, the base in step (3) is Pr ₃ N, pyridine, DBU, TEEDA; the metal catalyst is Cu ₂ O, CuCl, CuI, CuBr, Cu(OMe) ₂ , copper powder.

The second aspect of the present invention also provides the esacillinone intermediate compound formula IV, which is prepared by the above synthesis process.

反应制备得到化合物式Ⅴ；中间体化合物式Ⅴ的结构式如下所示： The third aspect of the present invention also provides a synthetic method of a new oxacillinone intermediate compound formula V, the synthetic method comprising the following steps: the above-mentioned pyrrole ring compound formula IV in a solvent, under the condition of the presence of a base, and

Reaction preparation obtains compound formula V; The structural formula of intermediate compound formula V is as follows:

The X is halogen, and the A is hydroxyl or halogen.

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 not limited to ethanol; the halogenated hydrocarbon solvent includes but not limited to dichloromethane or chloroform; the aromatic hydrocarbon solvents include but not limited to toluene, benzene, xylene or nitrobenzene; the ether solvents include but not limited to tetrahydrofuran, 1,4-dioxane Or the amide solvent includes but not limited to N,N-dimethylacetamide, N,N-dimethylformamide; the alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, tert-butanol Sodium, potassium tert-butoxide, cesium carbonate, sodium hydride, potassium carbonate, sodium carbonate, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine or pyridine; preferably sodium hydroxide, hydrogen Lithium oxide; the reaction temperature in 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.

The fourth aspect of the present invention also provides the esacillinone intermediate compound formula V, which is prepared by the aforementioned synthesis process.

The fifth aspect of the present invention also provides a kind of synthetic method of new ethacillinone, adopts following technical scheme:

The above-mentioned oxacillinone intermediate compound formula V and 4-methanesulfonyl aniline undergo condensation reaction under the action of a condensing agent to obtain compound formula VI, wherein the structural formula of compound formula VI is as follows:

Preferably, the condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT), and the solvent is dry N,N-dimethylformamide (DMF), in addition to adding a certain amount of alkali, commonly used alkali is N,N-diisopropylethylamine (DIPEA), triethylamine, pyridine, hexafluorophosphoric acid Benzotriazol-1-yl-oxytripyrrolidinyl (PyBop), preferably N,N-diisopropylethylamine (DIPEA).

The sixth aspect of the present invention also provides a second new preparation method of ethacillinone, which adopts the following technical scheme: the above-mentioned ethacillinone intermediate compound formula V is reacted with a suitable acylating reagent to obtain the acid chloride compound formula VII, The acid chloride compound formula VII is acylated with 4-methanesulfonylanilide to obtain compound VI, wherein the structural formula of the acid chloride compound formula VII is as follows:

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

The seventh aspect of the present invention also provides eschacillinone, which is prepared by any one of the aforementioned synthesis processes.

Applying the technical scheme of the present invention avoids the use of expensive palladium catalysts and reduces the cost; simultaneously avoids the use of ligands, and is simple in post-treatment and easy to purify; avoids the use of highly corrosive hydrogen chloride gas, which is beneficial to industrialized scale-up production; compared with existing According to the document CN101006052A, the yield of the eschacillinone intermediate compound formula IV is increased by 57.6 percentage points by applying the technical solution of the present invention.

Detailed ways

It should be noted that, in the case of no conflict, the embodiments in the present application and the features in the embodiments can be combined with each other. The present invention will be described in detail below in conjunction with examples.

As described in the background technology, the existing synthetic methods of oxacillinone intermediates have the problems of low preparation yield, high cost, complicated post-processing and unfavorable industrial production. In order to solve the above-mentioned technical problem, the application provides a kind of synthetic method of new eschacillinone intermediate compound formula IV, and this synthetic method comprises the following steps:

(1) The raw material 2-(trifluoromethyl)phenylacetic acid is reacted with ethyl chloroformate or isobutyl chloroformate in an inert solvent in the presence of a base to form a mixed anhydride, and then reacted with ammonia to obtain the corresponding amide Compound formula II;

(2) The amide compound formula II obtained in step (1) is prepared through a dehydration reaction in the presence of a dehydrating agent and an acid-binding agent to obtain an isonitrile compound formula III;

(3) The isonitrile compound formula III obtained in step (2) is cyclized with ethyl 2-butynoate to form pyrrole ring compound IV in the presence of a base and a metal catalyst;

The process route is as follows:

Preferably, the inert solvent described in step (1) includes but not limited to one or more of the group consisting of halogenated hydrocarbons, benzene, toluene, ether, xylene, nitrobenzene, and acetonitrile; One or more of imidazole, pyridine, tetrabutylammonium fluoride, 2,6-lutidine, potassium carbonate, N,N-diisopropylethylamine, sodium carbonate, and triethylamine; 2 The molar ratio of -(trifluoromethyl)phenylacetic acid to 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; the reaction time is 12 hours to 36 hours.

Preferably, the dehydrating agent described in step (2) is one or more of P ₂ O ₅ , PCl ₃ , SOCl ₂ , COCl ₂ , ArSO ₂ Cl, POCl ₃ ; the acid-binding agent is an organic base Or inorganic base, described inorganic base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide etc.; Described organic base is triethylamine, diisopropylamine; Described solvent selects halogenated alkanes, two Chloromethane, dichloroethane.

Preferably, the base in step (3) is Pr ₃ N, pyridine, DBU, TEEDA; the metal catalyst is Cu ₂ O, CuCl, CuI, CuBr, Cu(OMe) ₂ , copper powder.

The raw material 2-(trifluoromethyl)phenylacetic acid (compound formula I) can be purchased.

The second aspect of the present invention also provides the esacillinone intermediate compound formula IV, which is prepared by the above synthesis process.

The third aspect of the present invention also provides a kind of synthetic method of new oxacillinone intermediate compound formula V, and this synthetic method is as follows:

反应制备得到化合物式Ⅴ，其中所述X为卤素，所述A为羟基或卤素。 The specific synthetic method comprises the following steps: the pyrrole ring compound formula IV obtained by the above synthesis is mixed with

The compound formula V is prepared by reaction, wherein said X is halogen, and said A is hydroxyl or halogen.

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 not limited to ethanol; the halogenated hydrocarbon solvent includes but not limited to dichloromethane or chloroform; the aromatic hydrocarbon solvents include but not limited to toluene, benzene, xylene or nitrobenzene; the ether solvents include but not limited to tetrahydrofuran, 1,4-dioxane Or the amide solvent includes but not limited to N,N-dimethylacetamide, N,N-dimethylformamide; the alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, tert-butanol Sodium, potassium tert-butoxide, cesium carbonate, sodium hydride, potassium carbonate, sodium carbonate, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine or pyridine; preferably sodium hydroxide, hydrogen Lithium oxide; the reaction temperature in 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.

The fourth aspect of the present invention also provides the esacillinone intermediate compound formula V, which is prepared by the aforementioned synthesis process.

The fifth aspect of the present invention also provides a new synthetic method of ixacillinone, the preparation method is as follows:

The specific synthesis method includes the following steps: condensing the above-mentioned oxacillinone intermediate compound formula V and 4-methanesulfonylaniline under the action of a condensing agent to obtain oxacillinone (compound formula VI).

Preferably, the condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT), and the solvent is dry N,N-dimethylformamide (DMF), in addition to adding a certain amount of alkali, commonly used alkali is N,N-diisopropylethylamine (DIPEA), triethylamine, pyridine, hexafluorophosphoric acid Benzotriazol-1-yl-oxytripyrrolidinyl (PyBop), preferably N,N-diisopropylethylamine (DIPEA).

The sixth aspect of the present invention also provides the second new synthetic method of ixacillinone, the synthetic method is as follows:

The specific preparation method includes the following steps: react the above-mentioned ethacillinone intermediate compound V with a suitable acylating agent to obtain the acyl chloride compound VII, and then acylate the acyl chloride compound VII with 4-methylsulfonylanilide to obtain the compound VI.

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

The seventh aspect of the present invention also provides eschacillinone, which is prepared by any one of the aforementioned synthesis processes.

Applying the technical scheme of the present invention avoids the use of expensive palladium catalysts and reduces the cost; simultaneously avoids the use of ligands, and is simple in post-treatment and easy to purify; avoids the use of highly corrosive hydrogen chloride gas, which is beneficial to industrialized scale-up production; compared with existing According to the document CN101006052A, the yield of the eschacillinone intermediate compound formula IV is increased by 57.6 percentage points by applying the technical solution of the present invention.

The synthesis of embodiment 1 2-(trifluoromethyl) phenylacetamide (amide compound formula II)

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

The synthesis of embodiment 2 isocyanide compound formula III

Dissolve 10.2g of 2-(trifluoromethyl)phenylacetamide (0.05mol) in 100mL of dichloroethane, add 12.6g of triethylamine (0.125mol), lower the temperature of the reaction system to below -10°C, drop Add 0.05 mol of phosphorus oxychloride, and the dropwise addition is completed in about 20 minutes. Control the reaction temperature below 0°C and continue to stir for 1 hour, then raise the temperature to 25-30°C, and add 20% sodium carbonate solution dropwise to the reaction solution, and the dropwise addition is completed Then continue to stir for 5-10 minutes, let stand to separate layers, wash the organic phase twice with 5% sodium carbonate solution, dry with anhydrous magnesium sulfate, filter, and concentrate under reduced pressure below 20°C to obtain 9.0 g of isocyanide compound formula III, Yield 97.3%.

Example 3 Preparation of 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid ethyl ester (Exacillinone intermediate compound IV)

In an argon atmosphere, add cuprous oxide 0.36g (2.5mmol, 0.05eq) and DBU 7.65g (0.05mol, 1eq) to 500mL 1,4-dioxane solvent, ethyl 2-butynoate 6.73 g (0.06mol, 1.2eq) and 9.25g (0.05mol, 1eq) of the isonitrile compound formula III, stirred at 100°C for 2 hours, the reaction was detected to be complete, the reaction solution was cooled to room temperature, filtered, and acetic acid was added to the filtrate ethyl ester and saturated aqueous sodium chloride, extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified to obtain 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H- 12.3 g of ethyl pyrrole-3-carboxylate, yield 83%.

¹ H-NMR (400MHz, DMSO-d ₆ )δ8.43(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).

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

4-Methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid ethyl ester 15g (0.05mol, 1eq) was dissolved in 300ml of dichloroethane at room temperature, Add 10.1 g (0.05 mol, 1 eq) of tetraethylammonium bromide, add 20% NaOH aqueous solution (100 ml) dropwise to the reaction solution under stirring conditions, drop it for about 30 min, continue to react at room temperature for 1 h, and then react The solution was heated to 60°C and reacted for 2 hours, and the reaction was detected by spotting the plate. The reaction solution was cooled to room temperature, and the pH was adjusted to 5-6 with 2N hydrochloric acid, and the layers were allowed to stand. The aqueous phase was extracted twice with dichloromethane, and 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%.

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

3.77g (0.022mol, 1.1eq) of 4-methylsulfonylaniline, 6.26g (0.02mol, 1.0eq), 4.05g (0.03mol, 1.5eq), EDCI 5.75g (0.03mol, 1.5eq), DIPEA 5.16g (0.04mol, 2.0eq) was added to the reaction flask, 300mL DCM was added, the reaction was stirred at room temperature, and the reaction was tracked by TLC. After the reaction was complete, 100ml of saturated aqueous sodium chloride solution was added Extraction, the organic phase was washed 3 times with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated, and purified with a mixed solvent of ethyl acetate:petroleum ether volume ratio of 1:1 to obtain 8.4g, Yield 90%.

¹ H-NMR (400MHz, DMSO-d ₆ ) 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).

Comparative example 1

With reference to the preparation method of Example 16 in the existing document CN101006052A, the raw material methyl cyanoacetate is replaced with ethyl cyanoacetate to prepare 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H - Ethyl pyrrole-3-carboxylate, yield 21.5%.

Comparative example 2

Referring to the preparation method of Reference Example 3 in the existing document WO2010098286A1, 1-(2-hydroxyethyl)-N-[4-(methylsulfonyl)phenyl]-4-methyl-5-[2-( Trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide, the total yield was 7.6%.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims (10)

A kind of synthetic method of new ethacillinone intermediate compound formula IV, this synthetic method comprises the following steps: (1) The raw material 2-(trifluoromethyl)phenylacetic acid is reacted with ethyl chloroformate or isobutyl chloroformate in an inert solvent in the presence of a base to form a mixed anhydride, and then reacted with ammonia to obtain the corresponding amide Compound formula II; (2) The amide compound formula II obtained in step (1) is prepared through a dehydration reaction in the presence of a dehydrating agent and an acid-binding agent to obtain an isonitrile compound formula III; (3) The isonitrile compound formula III obtained in step (2) is cyclized with ethyl 2-butynoate to form the pyrrole ring compound formula IV in the presence of a base and a metal catalyst; The process route is as follows:

The synthetic method according to claim 1, wherein the inert solvent described in step (1) includes but is not limited to the group consisting of halogenated hydrocarbons, benzene, toluene, ether, xylene, nitrobenzene, and acetonitrile one or more; the base is imidazole, pyridine, tetrabutylammonium fluoride, 2,6-lutidine, potassium carbonate, N,N-diisopropylethylamine, sodium carbonate, three One or more of ethylamines; the molar ratio of 2-(trifluoromethyl)phenylacetic acid to base is 1:0.5~1; 2-(trifluoromethyl)phenylacetic acid and ethyl chloroformate or chloroformic acid The molar ratio of isobutyl ester is 1:1~1.5; the reaction temperature is 0°C~room temperature; the reaction time is 12 hours~36 hours. The synthesis method according to claim 1, characterized in that, preferably, the dehydrating agent described in step (2) is P ₂ O ₅ , PCl ₃ , SOCl ₂ , COCl ₂ , ArSO ₂ Cl, POCl ₃ One or more; the acid-binding agent is an organic base or an inorganic base, and the inorganic base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide, etc.; the organic base is triethyl Amine, diisopropylamine; Described solvent selects haloalkane, methylene dichloride, ethylene dichloride for use. The synthetic method according to claim 1, wherein the alkali described in step (3) is Pr ₃ N, pyridine pyridine, DBU, TEEDA; the metal catalyst is Cu ₂ O, CuCl, CuI, CuBr , Cu(OMe) ₂ , copper powder. A kind of synthetic method of new eschacillinone intermediate compound formula V, its synthetic method comprises the following steps: the pyrrole ring compound formula IV obtained by the synthetic method described in claims 1 to 4 is in a solvent, under the condition of alkali presence ,and

Reaction preparation obtains compound formula V; The structural formula of intermediate compound formula V is as follows:

The X is halogen, and the A is hydroxyl or halogen. The synthesis method according to claim 5, wherein 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 not limited to methylene chloride or chloroform; the aromatic hydrocarbon solvent includes but not limited to toluene, benzene, xylene or nitrobenzene; the ether solvent includes but not limited to Limited to tetrahydrofuran, 1,4-dioxane or the amide solvents include but not limited to N,N-dimethylacetamide, 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, tri Ethylamine or pyridine; preferably sodium hydroxide or lithium hydroxide; the reaction temperature in 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. A kind of synthetic method of new ethacillinone, it is characterized in that, the ethacillinone intermediate compound formula V obtained by the synthetic method described in claim 5～6 and 4-methanesulfonyl aniline are under the action of condensing agent Compound formula VI is obtained through condensation reaction, wherein the structural formula of compound formula VI is as follows:

The synthetic method according to claim 7, wherein the condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-hydroxybenzene And triazole (HOBT), the solvent is dry N,N-dimethylformamide (DMF), in addition to adding a certain amount of alkali, the commonly used alkali is N,N-diisopropylethylamine (DIPEA ), triethylamine, pyridine, benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyBop), preferably N,N-diisopropylethylamine (DIPEA). A kind of preparation method of new oxacillinone, it is characterized in that, the oxacillinone intermediate compound formula V obtained by the synthesis method described in claims 5 to 6 reacts with a suitable acylating reagent to obtain acid chloride compound VII, The acid chloride compound formula VII is acylated with 4-methanesulfonylanilide to obtain compound VI, wherein the structural formula of the acid chloride compound formula VII is as follows:

The synthetic method according to claim 9, wherein the acylating agent is oxalyl chloride, and the acylating reaction is preferably carried out in the presence of a base and a solvent, and the base is an organic base or an inorganic base. Alkalis, including but not limited to triethylamine, N,N-diisopropylethylamine; the solvent is a halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent or amide solvent; the halogenated Hydrocarbon solvents include but not limited to dichloromethane or chloroform; described aromatic hydrocarbon solvents include but not limited to toluene, benzene, xylene or nitrobenzene; described ether solvents include but not limited to tetrahydrofuran, 1,4 - dioxane or the amide solvents include but not limited to N,N-dimethylacetamide, N,N-dimethylformamide.