Efficient and green method for catalytically synthesizing N-(2-aminobenzoyl) glycine by lewis acid

Abstract

The invention relates to an efficient and green method for catalytically synthesizing N-(2-aminobenzoyl) glycine by using Lewis acid. According to the method, isatoic anhydride and glycine are used as raw materials, water is used as a solvent, a catalytic amount of Lewis acid is added to serve as a catalyst, a reaction mixture is synthesized through one-step reaction under the mild heating condition, and the target product N-(2-aminobenzoyl) glycine is obtained through aftertreatment. The method has the advantages that the water-dispersible lewis acid is used as a high-efficiency catalyst, amidation reaction of isatoic anhydride and glycine is directly catalyzed in a water phase under the condition that no traditional proton base is added, carbonyl of isatoic anhydride can be effectively activated by the lewis acid, ring opening of isatoic anhydride is promoted, nucleophilic attack of glycine is accepted, and the reaction efficiency is improved. The reaction is efficiently catalyzed at a relatively low temperature; the reaction steps are simple, green and environment-friendly, and industrial amplification is easy.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis technology, specifically to a highly efficient and green Lewis acid-catalyzed method for the synthesis of N-(2-aminobenzoyl)glycine, a key intermediate of cevelexatol sodium. Background Technology

[0002] N-(2-aminobenzoyl)glycine is an important intermediate in the synthesis of cevelex, a drug used to treat acute lung injury. Currently, the conventional synthetic method for this compound typically employs a two-step process: first, indomethacin anhydride and glycine methyl ester hydrochloride are reacted in an organic solvent (such as DMF or acetonitrile) to generate N-(2-aminobenzoyl)glycine methyl ester; then, a hydrolysis reaction is carried out under alkaline conditions (such as aqueous sodium hydroxide solution) to obtain the target product, N-(2-aminobenzoyl)glycine. This traditional method has the following obvious drawbacks: 1. Cumbersome steps: It requires two steps, esterification (or amidation) and hydrolysis, resulting in a long operation process and increased production cycle; 2. Low yield: Both steps involve losses, and the overall yield is usually low, leading to raw material waste and increased production costs; 3. Significant environmental impact: The use of organic solvents may generate saline organic wastewater, which is complex to treat and environmentally unfriendly; 4. High cost: Glycine methyl ester hydrochloride is more expensive than glycine, and the use of organic solvents increases raw material and production costs.

[0003] Therefore, developing a new method for synthesizing N-(2-aminobenzoyl)glycine that is simple in steps, has a high yield, is environmentally friendly, and has low cost is of great significance for the industrial production of cevelexta sodium. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a highly efficient and green method for the synthesis of N-(2-aminobenzoyl)glycine by Lewis acid catalysis, which can solve the problems of cumbersome synthesis steps, low yield, large environmental impact and high cost of N-(2-aminobenzoyl)glycine in the prior art.

[0005] To solve the above-mentioned technical problems, the technical solution of the present invention is as follows: using indomethacin anhydride and glycine as raw materials, water as solvent, and adding a catalytic amount of Lewis acid as a catalyst, the reaction mixture is synthesized in the next step under mild heating conditions, and then the target product N-(2-aminobenzoyl)glycine is obtained after post-treatment.

[0006] Furthermore, the Lewis acid is one or a combination of several of zinc chloride, zinc trifluoromethanesulfonate, stannous chloride, indium trichloride, and scandium trifluoromethanesulfonate.

[0007] Furthermore, the Lewis acid may also be one or a combination of several of copper trifluoromethanesulfonate, cerium ammonium nitrate, ferric chloride, and lithium bromide.

[0008] Furthermore, the Lewis acid is added in hydrate form or pre-dissolved in a portion of the reaction water before being added, and ultrasonic-assisted dispersion is used. After the catalyst is added, the reaction system is ultrasonically treated for 5-10 minutes to ensure that the indomethacin anhydride, glycine and catalyst are in full contact, and then the reaction is transferred to heating and stirring.

[0009] Furthermore, the reaction conditions for the next step under the mild heating conditions are: a reaction temperature of 70-85℃, a reaction time of 2-4 hours, and the reaction progress is monitored by thin-layer chromatography (TLC) or high-performance liquid chromatography (HPLC), with the endpoint being the near disappearance of the indigo anhydride starting material.

[0010] Furthermore, the molar ratio of indorubicin to glycine is 1:1.1~1.25, the volume of water used is 6-10 times the mass of indorubicin, and the molar amount of Lewis acid is 1.0~1.5% of the molar amount of indorubicin.

[0011] Furthermore, the post-processing steps are as follows: Cooling and crystallization: The reaction mixture was naturally cooled to room temperature, and then further cooled to 0-10°C in an ice-water bath, and aged at this temperature for 0.5-1 hour to allow the product to fully precipitate; Filtration and washing: After filtration, the resulting filter cake is thoroughly washed 2-3 times with ice water at 0-5℃; Decolorization and purification: If the product is dark in color, the crude product can be dissolved in a hot, dilute 1% sodium bicarbonate aqueous solution, and activated carbon can be added for decolorization for 10-15 minutes. Filter while hot, with the amount of activated carbon being 1-3% of the product weight. The filtrate is then slowly neutralized to pH 3-4 with 1 mol / L hydrochloric acid under stirring. At this point, the product will precipitate again with high purity. Drying: The final filter cake was placed in a vacuum drying oven at 50-60℃ and dried to constant weight to obtain high-purity N-(2-aminobenzoyl)glycine solid, which is off-white to grayish-white.

[0012] The advantages of this invention are: This invention utilizes water-dispersible Lewis acids as highly efficient catalysts to directly catalyze the amidation reaction of indigo anhydride and glycine in an aqueous phase without adding any traditional proton bases (such as triethylamine or sodium carbonate). Lewis acids (such as Zn...) 2 ⁺) It can effectively activate the carbonyl group of indomethacin anhydride, promote its ring opening, and accept the nucleophilic attack of glycine, thereby catalyzing the reaction efficiently at a lower temperature; This invention requires only a very small amount of Lewis acid catalyst to efficiently drive the reaction in an aqueous phase at around 80°C, avoiding the use of high-temperature strong bases or stoichiometric bases in traditional methods. It is highly efficient in catalysis and the conditions are mild. The reaction is a one-step direct amidation with a near 100% atom utilization rate. There are no derivatization or protection / deprotection steps, resulting in high atom economy and a simple reaction procedure. This invention uses water as the sole solvent, avoiding the use of organic solvents. The amount of catalyst used is small, and through optimized post-processing, catalyst metal residue can be effectively controlled, resulting in pharmaceutical intermediates that meet high-level standards. The products have high purity, controllable residues, and generate very little waste (especially saline wastewater), making them green, environmentally friendly, and easy to scale up industrially. The acid-base purification steps of this invention are flexible and can be adjusted according to the requirements of product color. By using inexpensive and readily available indigo anhydride, glycine, water, and Lewis acid catalysts, the raw material cost is much lower than that of the traditional route using glycine methyl ester hydrochloride and organic solvents / bases, resulting in a significant cost advantage. Detailed Implementation

[0013] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. The following embodiments will enable those skilled in the art to more fully understand this invention, but do not limit the invention to the scope of the described embodiments.

[0014] The specific implementation method adopts the following technical solution: using indomethacin anhydride and glycine as raw materials, water as solvent, adding a catalytic amount of Lewis acid as catalyst, and reacting in the next step under mild heating conditions to synthesize the reaction mixture, and then obtaining the target product N-(2-aminobenzoyl)glycine after post-treatment.

[0015] The Lewis acid is one or a combination of zinc chloride (ZnCl2), zinc trifluoromethanesulfonate (Zn(OTf)2), stannous chloride (SnCl2), indium trichloride (InCl3), and scandium trifluoromethanesulfonate (Sc(OTf)3). The Lewis acid can also be one or a combination of copper trifluoromethanesulfonate (Cu(OTf)2), cerium ammonium nitrate (CAN), ferric chloride (FeCl3), and lithium bromide (LiBr). Zinc chloride and zinc trifluoromethanesulfonate are particularly preferred because they have high catalytic activity, low price, and zinc ions are easy to control in aqueous phase through subsequent treatment.

[0016] Lewis acids are added in hydrate form or pre-dissolved in part of the reaction water before being added, and ultrasonic dispersion is used. After the catalyst is added, the reaction system is ultrasonically treated for 5-10 minutes to ensure that indomethacin anhydride, glycine and catalyst are in full contact, and then the reaction is heated and stirred.

[0017] The reaction conditions for the next step under mild heating conditions are: a reaction temperature of 70-85℃, within which the reaction rate is suitable and side reactions are controllable; a reaction time of 2-4 hours, with the reaction progress monitored by thin-layer chromatography (TLC) or high-performance liquid chromatography (HPLC), and the endpoint being the near disappearance of the indigo anhydride starting material.

[0018] The molar ratio of indorubicin anhydride to glycine is strictly controlled at 1:1.1~1.25. A slight excess of glycine is intended to drive the reaction to completion, while avoiding excessive amounts that would lead to difficulties in post-processing purification. The volume of water used is 6-10 times the mass of indorubicin anhydride to ensure a certain degree of suspension in the early stage of the reaction and sufficient dissolution and crystallization equilibrium in the later stage. The molar amount of Lewis acid is 1.0~1.5% of the molar amount of indorubicin anhydride.

[0019] After the reaction is complete, the target product is usually suspended in solid form or partially dissolved in the reaction solution. The post-processing steps are as follows: Cooling and crystallization: The reaction mixture is naturally cooled to room temperature, then further cooled to 0-10°C in an ice-water bath, and aged at this temperature for 0.5-1 hour to allow the product to fully precipitate; Filtration and washing: After filtration, the resulting filter cake is thoroughly washed 2-3 times with ice water at 0-5°C. This step is crucial to maximize the removal of trace amounts of Lewis acid catalyst, unreacted glycine, and their byproduct salts encapsulated in the solid product.

[0020] Decolorization and purification (optional): If the product is dark in color, the crude product can be dissolved in an appropriate amount of hot, dilute alkaline solution (1% sodium bicarbonate aqueous solution), and a small amount of activated carbon can be added for decolorization for 10-15 minutes. Filter while hot, using 1-3% of the product weight of activated carbon. The filtrate is then slowly neutralized to pH 3-4 (near the isoelectric point of the target product) with 1 mol / L hydrochloric acid under stirring. At this point, the product precipitates again with high purity. This step can significantly improve the appearance and chemical purity of the product. Drying: The final filter cake was placed in a vacuum drying oven at 50-60℃ and dried to constant weight to obtain high-purity N-(2-aminobenzoyl)glycine solid, which is off-white to grayish-white.

[0021] Lewis acids play a dual role in this reaction: carbonyl activator and Lewis acid metal ion (such as Zn). 2 ⁺) Coordination with the oxygen atom of the carbonyl group in indomethacin significantly enhances the electrophilicity of the carbonyl carbon, making it more susceptible to nucleophilic attack from the amino nitrogen atom of glycine, thereby greatly reducing the energy barrier for ring-opening amidation; Reaction medium regulator: Lewis acids (such as LiBr) can also indirectly promote the reaction by affecting the hydrogen bond network of water, changing the solubility of reactants and the reaction microenvironment.

[0022] Example 1a - Standard Process: In a 500 mL three-necked flask equipped with a stirrer, thermometer, and reflux condenser, deionized water (150 mL), indocyanine anhydride (25.0 g, 125.8 mmol), and zinc chloride hexahydrate (0.34 g, 1.26 mmol) were added. The mixture was ultrasonically dispersed at room temperature for 5 minutes, and then glycine (11.5 g, 153.2 mmol, 1.22 eq) was added. The mixture was heated to 80 ± 2 °C and stirred for 3 hours (HPLC monitoring showed that the remaining indocyanine anhydride was <1%). The reaction solution was allowed to cool naturally to room temperature, then cooled to below 5 °C in an ice-water bath and aged for 45 minutes. The mixture was filtered, and the filter cake was thoroughly washed with ice water (3 × 30 mL). The solid was dried under vacuum at 55 °C for 12 hours to obtain 30.2 g of off-white solid N-(2-aminobenzoyl)glycine, with a yield of 95.0% and an HPLC purity of 99.6%.

[0023] Example 1b - Including refining steps: Take 30.2 g of the crude product prepared above, add 300 mL of 1% sodium bicarbonate aqueous solution, heat to 70 °C and stir to dissolve, add 0.6 g of activated carbon, keep warm and stir for decolorization for 15 minutes; filter while hot, wash the filter cake with a small amount of hot water; combine the filtrate and washing liquid, slowly add 1 M hydrochloric acid dropwise under stirring to adjust the pH to 3.5, a large amount of solid precipitates out. Cool to 5 °C in an ice water bath, age for 1 hour, filter, wash with ice water, vacuum dry to obtain 29.5 g of white crystalline solid, recovery rate 98.3%, HPLC purity 99.8%, Zn residue (ICP-MS detection) < 5 ppm.

[0024] Through the above-described ice water washing and acid-base refining steps, residual metal ions (such as Zn) in the final product can be removed. 2 ⁺) The residue level is stably controlled below 10 ppm, which meets the stringent requirements for heavy metal residues in pharmaceutical intermediates.

[0025] Product quality indicators: The yield of the product obtained by this method is consistently between 92% and 96% (based on indomethacin).

[0026] Purity: As determined by HPLC, the purity is typically ≥99.5% (area normalization method).

[0027] Structural confirmation: its proton nuclear magnetic resonance spectrum (NMR spectrum) 1 H NMR, carbon spectrum 13 The C NMR and mass spectrometry (MS) data are completely consistent with the structure of the target compound.

[0028] [Comparative Experiment] To demonstrate the superiority of this invention, a comparative experiment using the traditional two-step method was conducted.

[0029] Comparative Example 1 - Traditional Two-Step Method: Step 1: Following the method described in the literature, indomethacin anhydride (2.5 kg) and glycine methyl ester hydrochloride (approximately 2.2 kg, 1.3 eq) were reacted in DMF to obtain N-(2-aminobenzoyl)glycine methyl ester, with a yield of approximately 90%.

[0030] Step 2: The ester obtained in the previous step is added to an aqueous sodium hydroxide solution for hydrolysis. After acid precipitation, filtration and drying, the final product N-(2-aminobenzoyl)glycine is obtained with a hydrolysis yield of about 85%.

[0031] Total yield = 90% × 85% = 76.5%.

[0032] By comparing Example 1 with Comparative Example 1, it can be seen that: compared with the traditional two-step method, the one-step method of the present invention has a significantly higher yield than the traditional method, and the steps are simpler, avoiding the use of organic solvents, requiring less catalyst, having high catalytic efficiency, mild conditions, being green and environmentally friendly, and easy to scale up industrially.

[0033] The foregoing has shown and described the basic principles and main features of the present invention, as well as its advantages. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A highly efficient and green method for the Lewis acid-catalyzed synthesis of N-(2-aminobenzoyl)glycine, characterized in that: Using indomethacin anhydride and glycine as raw materials, water as solvent, and a catalytic amount of Lewis acid as catalyst, a reaction mixture was synthesized in a step-by-step reaction under mild heating conditions, and then post-processed to obtain the target product N-(2-aminobenzoyl)glycine.

2. The method for the efficient and green Lewis acid-catalyzed synthesis of N-(2-aminobenzoyl)glycine according to claim 1, characterized in that: The Lewis acid is one or a combination of several of zinc chloride, zinc trifluoromethanesulfonate, stannous chloride, indium trichlorochloride, and scandium trifluoromethanesulfonate.

3. The method for the efficient and green Lewis acid-catalyzed synthesis of N-(2-aminobenzoyl)glycine according to claim 2, characterized in that: The Lewis acid may also be one or a combination of copper trifluoromethanesulfonate, cerium ammonium nitrate, ferric chloride, and lithium bromide.

4. The method for the efficient and green Lewis acid-catalyzed synthesis of N-(2-aminobenzoyl)glycine according to claim 1, characterized in that: The Lewis acid is added in hydrate form or pre-dissolved in part of the reaction water before being added, and ultrasonic dispersion is used. After the catalyst is added, the reaction system is ultrasonically treated for 5-10 minutes to ensure that the indomethacin anhydride, glycine and catalyst are in full contact, and then the reaction is heated and stirred.

5. The method for the efficient and green Lewis acid-catalyzed synthesis of N-(2-aminobenzoyl)glycine according to claim 1, characterized in that: The reaction conditions for the next step under the mild heating conditions are: a reaction temperature of 70-85℃, a reaction time of 2-4 hours, and monitoring of the reaction progress by thin-layer chromatography (TLC) or high-performance liquid chromatography (HPLC), with the endpoint being the near disappearance of the indigo anhydride starting material.

6. The method for the efficient and green Lewis acid-catalyzed synthesis of N-(2-aminobenzoyl)glycine according to claim 1, characterized in that: The molar ratio of indorubicin to glycine is 1:1.1~1.25, the volume of water used is 6-10 times the mass of indorubicin, and the molar amount of Lewis acid is 1.0~1.5% of the molar amount of indorubicin.

7. The method for the efficient and green Lewis acid-catalyzed synthesis of N-(2-aminobenzoyl)glycine according to claim 1, characterized in that: The post-processing steps are as follows: Cooling and crystallization: The reaction mixture was naturally cooled to room temperature, and then further cooled to 0-10°C in an ice-water bath, and aged at this temperature for 0.5-1 hour to allow the product to fully precipitate; Filtration and washing: After filtration, the resulting filter cake is thoroughly washed 2-3 times with ice water at 0-5℃; Decolorization and purification: If the product is dark in color, the crude product can be dissolved in a hot, dilute 1% sodium bicarbonate aqueous solution, and activated carbon can be added for decolorization for 10-15 minutes. Filter while hot, with the amount of activated carbon being 1-3% of the product weight. The filtrate is then slowly neutralized to pH 3-4 with 1 mol / L hydrochloric acid under stirring. At this point, the product will precipitate again with high purity. Drying: The final filter cake was placed in a vacuum drying oven at 50-60℃ and dried to constant weight to obtain high-purity N-(2-aminobenzoyl)glycine solid, which is off-white to grayish-white.