A preparation method of 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide

Abstract

The invention discloses a preparation method for synthesizing 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide, and belongs to the field of chemical synthesis. The invention provides a synthesis method of 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide, using 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid and 2-chloroethylamine as raw materials, adding a solvent, a base and a sulfonylating agent to react at low temperature to generate compound I; compound I reacts with tetrahydropyrrole under the action of a base to obtain 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide. The synthesis process of the invention has mild reaction conditions, simple operation, and the product is easy to purify, and the yield of the obtained product is 93.1% and the purity is 98.9%.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and in particular to a method for preparing 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide. Background Art

[0002] 2-Chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide, CAS No.: 1225208-44-5, molecular weight: 525.03572, molecular formula: C 29 H 33 C1N 2 O 5 , is a white solid. 2-Chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide is an important pharmaceutical intermediate and an important intermediate for the preparation of the new antibacterial drug cefiderocol.

[0003] Cefiderocol is a new type of iron-carrier cephalosporin that can penetrate the cell membrane of Gram-negative bacteria, enter the cell and bind to trivalent iron, inhibit the formation of bacterial cell wall by binding to receptors through iron transporter, thereby achieving antibacterial activity. It is used to treat complicated urinary tract infections caused by Gram-negative bacteria.

[0004] In the literature, EDC·HCl is used as a condensation agent, 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid and 1-(2-aminoethyl)pyrrolidine are used as raw materials to react in N,N-dimethylformamide. The process is simple to operate, but the product yield and purity are low.

[0005]

[0006] The literature describes the use of tetrahydrofuran as a reaction solvent, the addition of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid and dicyclohexylcarbodiimide, stirring the reaction, using HOBt as a catalyst, and then adding 1-(2-aminoethyl)pyrrolidine. This process uses HOBt as a catalyst to reduce the occurrence of side reactions, but the product is difficult to separate during post-treatment.

[0007]

[0008] The method in patent WO2016035847 uses tetrahydrofuran as a reaction solvent, 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid and 1-(2-aminoethyl)pyrrolidine as raw materials, drips triethylamine, stirs the reaction, and drips methanesulfonyl chloride at -10°C. This process can obtain a solid product without producing many impurities. The product yield is high, but the purity is average.

[0009]

[0010] In summary, the existing methods for synthesizing 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide all have shortcomings, and it is necessary to develop a more economical, more effective and safer synthesis technology. Summary of the invention

[0011] The present invention aims at the deficiencies of the prior art and provides a method for preparing 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide, and solves the problem of how to provide a new synthetic route that is simple to operate, green and environmentally friendly, and easy to synthesize the product with high yield and purity. To solve the above problems, the technical solution of the present invention is:

[0012]

[0013] (1) 2-Chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid is placed in a three-necked flask, a reaction solvent is added, and a base is added dropwise. The reaction system is moved to a low temperature environment, a sulfonylating agent is added dropwise, and after the addition is completed, the mixture is stirred. The low temperature environment is maintained, and a dichloromethane solution of 2-chloroethylamine is slowly added dropwise into the three-necked flask, and the mixture is stirred. After the reaction is completed, the mixture is poured into water, and the liquid is separated by extraction. The obtained organic phase is subjected to rotary evaporation and suction filtration to obtain compound I; (2) Compound I is placed in a three-necked flask, a reaction solvent and a base are added, and tetrahydropyrrole is added dropwise. After the addition is completed, the mixture is heated and stirred for 2 hours. After the reaction is completed, the pH is adjusted, the mixture is poured into water, and a solid is precipitated. The solid is filtered and dried to obtain 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide.

[0014] In the method for preparing 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide, the molar ratio of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid to 2-chloroethylamine used in step (1) is 1.0:1.1-1.8, preferably 1.0:1.5.

[0015] In the preparation method of 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide, the sulfonylating agent in step (1) is one of p-toluenesulfonyl chloride, methanesulfonyl chloride, pivaloyl chloride, ethanesulfonyl chloride and trifluoromethanesulfonyl chloride, and pivaloyl chloride is preferably used as the sulfonylating agent; the molar ratio of the used 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid to the sulfonylating agent is 1.0:1.3-1.6, and the preferred molar ratio is 1.0:1.3.

[0016] In the method for preparing 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide, the reaction temperature in step (1) is -5 to 0°C, preferably 0°C; the reaction temperature in step (2) is 30 to 80°C, preferably 50°C.

[0017] In the preparation method of 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide, the base described in step (1) is one of ammonia water, triethylamine, pyridine, and dimethylaminopyridine, preferably pyridine; and the base described in step (2) is one of sodium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate, preferably potassium carbonate.

[0018] In the preparation method of 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide, the reaction solvent in step (1) is one of dichloromethane, N,N-dimethylformamide and tetrahydrofuran, preferably dichloromethane; the reaction solvent in step (2) is one of N,N-dimethylformamide, dichloromethane and acetonitrile, preferably N,N-dimethylformamide.

[0019] In the method for preparing 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide, the pH in step (2) is adjusted to 8.0-10.0, preferably to 9.0.

[0020] The beneficial effects of the present invention are:

[0021] (1) The literature uses a condensation agent, which has a simple process operation and a short reaction route, but the post-treatment is complicated, DMF is difficult to remove, the energy consumption is high, and the economic efficiency is low; the process of the present invention belongs to a green process synthesis, with a simple operation process, low energy consumption, and high economic efficiency.

[0022] (2) The products of the traditional reaction method are difficult to separate during post-processing, which is not conducive to industrial production. The process of the present invention can simplify the operation of each step of the reaction, and the products are easy to separate and purify, which has a good prospect for industrial scale-up.

[0023] (3) The conventional reaction method uses methanesulfonyl chloride and p-toluenesulfonyl chloride for sulfonic anhydride reaction, and the obtained product has a high yield but a general purity. The process of the present invention uses pivaloyl chloride for sulfonic anhydride reaction, and the obtained product has a high yield and a high purity. DETAILED DESCRIPTION

[0024] 2-Chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid (content ≥97%), Shanghai Haiqu Chemical Co., Ltd.; pivaloyl chloride, Shanghai Shucan Industrial Co., Ltd.; pyridine, Sinopharm Chemical Reagent Co., Ltd.; dichloromethane (analytical grade), Tianjin Fuyu Fine Chemical Co., Ltd.; 2-chloroethylamine, Hubei Xinrunde Chemical Co., Ltd.; potassium carbonate, Sinopharm Chemical Reagent Co., Ltd.; tetrahydropyrrole (content ≥99%), Shandong Jinyueyuan New Materials Co., Ltd.; N,N-dimethylformamide (analytical grade), Tianjin Fuyu Fine Chemical Co., Ltd.

[0025] All compounds I in this specific embodiment have the chemical formula: 25 H 25 Cl 2 NO 5 ,

[0026] The specific structural formula is:

[0027]

[0028] The chemical formula of 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide is: 29 H 33 C1N 2 O 5 , the specific structural formula is:

[0029]

[0030] In order to further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0031] Example 1

[0032] Under nitrogen protection, 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid (5.0 g, 12.0 mmol) was added to a 100 ml three-necked flask, and then anhydrous dichloromethane (40.0 ml) was added and stirred to obtain a turbid liquid. Pyridine (1.5 ml, 19.0 mmol) was added dropwise, and the reaction liquid changed from turbid to clear. The reaction liquid was cooled to 0°C, and pivaloyl chloride (1.9 g, 15.6 mmol) was added dropwise, and white mist was generated. After the addition was completed, the reaction was carried out for 1 hour. The reaction temperature was controlled at 0°C, and a dichloromethane solution (10.0 ml) of chloroethylamine (1.4 g, 18.0 mmol) was slowly added dropwise. The reaction was stirred for 2 hours. After the reaction is completed, pour into water, extract and separate the liquids, and the obtained organic phase is subjected to rotary evaporation and suction filtration to obtain compound I; add compound I, potassium carbonate (2.5 g, 18.0 mmol) and N,N-dimethylformamide (30 ml) into a 100 ml three-necked flask, and add tetrahydropyrrole (2.2 g, 19.0 mmol) dropwise. After the addition is complete, heat to 50°C and stir for 2 hours. After TLC detection shows that the reaction is complete, adjust the pH to 9.0, add water (90 ml), precipitate a large amount of solid, cool to 10°C, stir and react for 30 minutes, reduce pressure and filter, collect the solid precipitate, and dry the solid to obtain a solid product with a product yield of 93.1% and a product purity of 98.9%.

[0033] Example 2

[0034] Under nitrogen protection, 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid (5.0 g, 12.0 mmol) was added to a 100 ml three-necked flask, and then anhydrous dichloromethane (40.0 ml) was added and stirred to obtain a turbid liquid. Pyridine (1.5 ml, 19.0 mmol) was added dropwise, and the reaction liquid changed from turbid to clear. The reaction liquid was cooled to -3 °C, and pivaloyl chloride (2.3 g, 19.0 mmol) was added dropwise, and white mist was generated. After the addition was completed, the reaction was carried out for 1 hour. The reaction temperature was controlled at -3 °C, and a dichloromethane solution (10.0 ml) of chloroethylamine (1.0 g, 13.0 mmol) was slowly added dropwise. The reaction was stirred for 2 hours. The reaction was continued for 1 hour. After completion, pour into water, extract and separate the liquids, and obtain the organic phase by rotary evaporation and suction filtration to obtain compound I; add compound I, potassium carbonate (2.5 g, 18.0 mmol) and N,N-dimethylformamide (30.0 ml) into a 100 ml three-necked flask, add tetrahydropyrrole (2.2 g, 19.0 mmol) dropwise, and after the addition is complete, heat to 50°C, stir for 2 hours, and detect the completion of the reaction by TLC. Adjust the pH to 8.0, add water (90.0 ml), precipitate a large amount of solid, cool to 10°C, stir and react for 30 minutes, reduce pressure and filter, collect the solid precipitate, dry the solid, and obtain a solid product with a product yield of 91.9% and a product purity of 98.4%.

[0035] Example 3

[0036] Under nitrogen protection, 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid (5.0 g, 12.0 mmol) was added to a 100 ml three-necked flask, and then anhydrous dichloromethane (40.0 ml) was added and stirred to obtain a turbid liquid. Pyridine (1.5 ml, 19.0 mmol) was added dropwise, and the reaction liquid changed from turbid to clear. The reaction liquid was cooled to -1 °C, and pivaloyl chloride (1.9 g, 15.6 mmol) was added dropwise, and white mist was generated. After the addition was completed, the reaction was allowed to react for 1 hour. The reaction temperature was controlled at -1 °C, and a dichloromethane solution (10.0 ml) of chloroethylamine (1.5 ml, 19.0 mmol) was slowly added dropwise, and the reaction was stirred for 2 hours. After the reaction was completed, , pour into water, extract and separate the liquid, and the obtained organic phase is rotary evaporated and filtered to obtain compound I; add compound I, potassium carbonate (2.5g, 18.0mmol) and N,N-dimethylformamide (30.0ml) into a 100ml three-necked flask, and add tetrahydropyrrole (2.2g, 19.0mmol) dropwise. After the addition is complete, heat to 80°C and stir for 2 hours. After TLC detection, the reaction is complete, adjust the pH to between 8.0 and 10.0, add water (90.0ml), precipitate a large amount of solid, cool to 10°C, stir and react for 30 minutes, reduce pressure and filter, collect the solid precipitate, dry the solid, and obtain a solid product with a product yield of 90.7% and a product purity of 97.9%.

[0037] Example 4

[0038] Under nitrogen protection, 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid (5.0 g, 12.0 mmol) was added to a 100 ml three-necked flask, and then anhydrous dichloromethane (40.0 ml) was added and stirred to obtain a turbid liquid. Pyridine (1.5 ml, 19.0 mmol) was added dropwise, and the reaction liquid changed from turbid to clear. The reaction liquid was cooled to -5 °C, and pivaloyl chloride (1.9 g, 15.6 mmol) was added dropwise, and white mist was generated. After the addition was completed, the reaction was carried out for 1 hour. The reaction temperature was controlled at -5 °C, and a dichloromethane solution (10.0 ml) of chloroethylamine (1.2 g, 16.0 mmol) was slowly added dropwise, and the reaction was stirred for 2 hours. The reaction was continued for 1 hour. After completion, pour into water, extract and separate the liquids, and obtain the organic phase by rotary evaporation and suction filtration to obtain compound I; add compound I, potassium carbonate (2.5 g, 18.0 mmol) and N,N-dimethylformamide (30.0 ml) into a 100 ml three-necked flask, add tetrahydropyrrole (2.2 g, 19.0 mmol) dropwise, and after the addition is complete, heat to 70°C, stir for 2 hours, and detect the completion of the reaction by TLC. Adjust the pH to 9.0, add water (90.0 ml), precipitate a large amount of solid, cool to 10°C, stir and react for 30 minutes, reduce pressure and filter, collect the solid precipitate, dry the solid, and obtain a solid product with a product yield of 89.6% and a product purity of 96.0%.

[0039] Example 5

[0040] Under nitrogen protection, 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid (5.0 g, 12.0 mmol) was added to a 100 ml three-necked flask, and then anhydrous dichloromethane (40.0 ml) was added and stirred to obtain a turbid liquid. Pyridine (1.5 ml, 19.0 mmol) was added dropwise, and the reaction liquid changed from turbid to clear. The reaction liquid was cooled to 0°C, and pivaloyl chloride (2.2 g, 18.0 mmol) was added dropwise, and white mist was generated. After the addition was completed, the reaction was carried out for 1 hour. The reaction temperature was controlled at -0°C, and a dichloromethane solution (10.0 ml) of chloroethylamine (1.0 g, 13.0 mmol) was slowly added dropwise, and the reaction was stirred for 2 hours. After the reaction was completed, After completion, pour into water, extract and separate the liquids, and obtain the organic phase by rotary evaporation and suction filtration to obtain compound I; add compound I, potassium carbonate (2.5 g, 18.0 mmol) and N,N-dimethylformamide (30.0 ml) into a 100 ml three-necked flask, add tetrahydropyrrole (2.2 g, 19.0 mmol) dropwise, and after the addition is complete, heat to 40°C, stir for 2 hours, and detect the completion of the reaction by TLC. Adjust the pH to 10.0, add water (90.0 ml), precipitate a large amount of solid, cool to 10°C, stir and react for 30 minutes, reduce pressure and filter, collect the solid precipitate, dry the solid, and obtain a solid product with a product yield of 87.9% and a product purity of 95.1%.

[0041] Example 6

[0042] Under nitrogen protection, 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid (5.0 g, 12.0 mmol) was added to a 100 ml three-necked flask, and then anhydrous dichloromethane (40.0 ml) was added and stirred to obtain a turbid liquid. Pyridine (1.5 ml, 19.0 mmol) was added dropwise, and the reaction liquid changed from turbid to clear. The reaction liquid was cooled to -5 °C, and pivaloyl chloride (2.2 g, 18.0 mmol) was added dropwise, and white mist was generated. After the addition was completed, the reaction was carried out for 1 hour. The reaction temperature was controlled at -5 °C, and a dichloromethane solution (10.0 ml) of chloroethylamine (1.6 g, 20.0 mmol) was slowly added dropwise, and the reaction was stirred for 2 hours. The reaction was continued for 1 hour. After completion, pour into water, extract and separate the liquids, and the obtained organic phase is rotary evaporated and filtered to obtain compound I; add compound I, potassium carbonate (2.5 g, 18.0 mmol) and N,N-dimethylformamide (30.0 ml) into a 100 ml three-necked flask, add tetrahydropyrrole (2.2 g, 19.0 mmol) dropwise, and after the addition is complete, heat to 30°C, stir for 2 hours, and detect the completion of the reaction by TLC. Adjust the pH to 10.0, add water (90.0 ml), precipitate a large amount of solid, cool to 10°C, stir and react for 30 minutes, reduce pressure and filter, collect the solid precipitate, dry the solid, and obtain a solid product with a product yield of 85.1% and a product purity of 93.9%.

[0043] Comparative Example 1

[0044] Under the protection of nitrogen, 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid (5.0 g, 12.0 mmol) and tetrahydrofuran (45.0 ml) were added to a 100 ml three-necked flask, and the mixture was stirred to obtain a turbid liquid. Triethylamine (2.7 ml, 19.0 mmol) was added dropwise, and the reaction solution was cooled to -4°C. Trifluoromethanesulfonyl chloride (15.6 mmol) was added dropwise at this temperature, and the mixture was stirred for 2 hours. After the reaction was completed, the mixture was poured into water, and the liquid was separated by extraction. The organic phase was evaporated and filtered to obtain compound I. Compound I and 5% aqueous sodium hydroxide solution (10 .0ml) and N,N-dimethylformamide (30.0ml), tetrahydropyrrole (2.2g, 19.0mmol) was added dropwise, and after the addition was complete, the temperature was raised to 20°C and stirred for 2 hours. The reaction was completed by TLC detection, and the pH was adjusted to 8.0. Anhydrous dichloromethane (45.0ml) was added for extraction. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. Petroleum ether (28.0ml) was added to the concentrate to precipitate a large amount of solid. The mixture was cooled to 5°C and stirred for reaction for 30 minutes. The solid precipitate was collected by filtration under reduced pressure and dried to obtain a solid product with a product yield of 36.2% and a product purity of 77.8%.

[0045] Comparative Example 2

[0046] Under nitrogen protection, 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid (5.0 g, 12.0 mmol) and N,N-dimethylformamide (40.0 ml) were added to a 100 ml three-necked flask, and a turbid solution was obtained by stirring. Triethylamine (2.7 ml, 19.0 mmol) was added dropwise, and the reaction solution changed from turbid to clear. The reaction solution was cooled to -3 °C, and pivaloyl chloride (21.6 mmol) was added dropwise at this temperature. The reaction was stirred for 2 hours, and compound I was obtained by rotary evaporation and filtration. Compound I and saturated sodium bicarbonate solution (10.0 ml) were added to a 100 ml three-necked flask. and N,N-dimethylformamide (30.0 ml), tetrahydropyrrole (2.2 g, 19.0 mmol) was added dropwise, after the addition was complete, the temperature was raised to 90°C, and the mixture was stirred for 2 hours. The reaction was completed by TLC detection, and the pH was adjusted to 10.0. Saturated sodium chloride (40.0 ml) was added for extraction. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Isopropyl ether (45.0 ml) was added to the concentrate to precipitate a large amount of solid. The mixture was cooled to 5°C and stirred for reaction for 30 minutes. The solid precipitate was collected by filtration under reduced pressure, and the solid product was obtained with a yield of 28.3% and a purity of 75.8%.

[0047] Although the above describes the specific implementation of the present invention in combination with the embodiments, it is not intended to limit the implementation of the present invention. For those skilled in the art, various modifications or variations that can be made by those skilled in the art on the basis of the technical solution of the present invention without creative work are still within the protection scope of the present invention.

Claims

1. A method for preparing 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide, characterized in that: The preparation method is: (1) 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid is placed in a reaction device, anhydrous dichloromethane is added and stirred, pyridine is added dropwise, the reaction system is moved to a -5 to 0°C environment, pivaloyl chloride is added dropwise, after the addition is completed, stirring is performed, and a dichloromethane solution of 2-chloroethylamine is slowly dropped into a three-necked flask while maintaining the -5 to 0°C environment, stirring, and after the reaction is completed, pouring into water, extracting and separating the liquids, and subjecting the obtained organic phase to rotary evaporation and suction filtration to obtain compound I; (2) Compound I is placed in a three-necked flask, N,N-dimethylformamide and potassium carbonate are added, tetrahydropyrrole is added dropwise, and after the addition is complete, the temperature is raised, the mixture is stirred, the pH is adjusted to 8-10, and the mixture is poured into water to precipitate a solid. The residue was filtered and dried to obtain 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide.

2. The method for preparing 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide according to claim 1, characterized in that: The molar ratio of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid to 2-chloroethylamine used in step (1) is 1.0:1.1-1.

8.

3. The method for preparing 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide according to claim 1, characterized in that: The molar ratio of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid to pivaloyl chloride in step (1) is 1.0:1.3-1.

6.

4. The method for preparing 2-chloro-3,4-di-p-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide according to claim 1, characterized in that: The reaction temperature of step (1) is -5 to 0°C; the reaction temperature of step (2) is 30 to 80°C.

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