Synthesis method of 4-bromo-3-(ethoxymethyl) benzoic acid

Abstract

The invention discloses a synthesis method of 4-bromo-3-(ethoxymethyl) benzoic acid, which comprises the following steps: (1) activating carboxyl of p-bromobenzoic acid serving as a raw material in the presence of an organic anhydride activator, and then performing chloromethylation reaction with paraformaldehyde in the presence of a chlorine-containing Lewis acid catalyst to obtain 4-bromo-3-(ethoxymethyl) benzoic acid; after the reaction is completed, carrying out post-treatment to obtain an intermediate 4-bromo-3-(chloromethyl) benzoic acid; and (2) carrying out nucleophilic substitution reaction on the intermediate obtained in the step (1) in ethanol under the action of inorganic alkali to prepare the target product 4-bromo-3-(ethoxymethyl) benzoic acid. According to the invention, through one-pot activation and chloromethylation of p-bromobenzoic acid, concise, efficient and highly economical synthesis from cheap raw materials to the sparsentan key intermediate is realized.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemical intermediates, in particular to a synthesis method of 4-bromo-3-(ethoxymethyl)benzoic acid. BACKGROUND

[0002] Sparsentan is an oral dual endothelin / angiotensin receptor antagonist developed by Travere Therapeutics INC company, which was accelerated approved by FDA in February 2023 for reducing proteinuria in adult patients with primary IgA nephropathy (Berger's disease) at risk of rapid progression.

[0003] Sparsentan blocks both endothelin type A (ETA) receptors and angiotensin II type 1 (AT1) receptors, inhibiting the kidney inflammation and fibrosis signaling pathways mediated by both, thereby slowing disease progression. As the first non-immunosuppressive targeted drug for IgA nephropathy, sparsentan breaks through the limitations of traditional supportive therapy (such as antihypertensive and antiproteinuric) and immunosuppressive therapy, and is granted the status of breakthrough therapy and orphan drug by FDA. Its accelerated approval is based on the significant reduction in proteinuria (a key risk indicator of disease progression) shown in the interim analysis of the phase III clinical trial, providing the first innovative therapy targeting the core mechanism of IgA nephropathy for patients with this disease.

[0004] In the production process of sparsentan, 4-bromo-3-(ethoxymethyl)benzoic acid is the most important synthetic intermediate. The main synthesis routes of 4-bromo-3-(ethoxymethyl)benzoic acid reported at present are as follows: In this synthesis route, expensive 4-bromo-3-methylbenzoic acid is used as the starting material, and the target product is prepared through esterification reaction, bromination reaction, and ethoxylation reaction. It can be seen that this synthesis route has the disadvantages of high production cost, difficulty in improving product purity, etc.

[0005] Patent CN105384620B reports that under the action of Lewis acid catalysts such as zinc chloride and iron chloride, benzoyl chloride and paraformaldehyde with high reactivity can be catalyzed to synthesize m-chloromethylbenzoic acid product. However, using benzoyl chloride with relatively poor reactivity cannot obtain the target product.

[0006] The above synthesis methods respectively have the disadvantages of serious environmental pollution, harsh reaction conditions, high equipment requirements, and high production cost. In view of the good application prospect and demand market of 4-bromo-3-(ethoxymethyl)benzoic acid, it is of very important industrial application value to develop an ideal production method of 4-bromo-3-(ethoxymethyl)benzoic acid. SUMMARY

[0007] To solve the above technical problems, the present application aims to provide a synthesis method of 4-bromo-3-(ethoxymethyl)benzoic acid. The present application realizes simple, efficient and high economic synthesis from cheap raw materials to sparsentan key intermediates through one-pot activation and chloromethylation of bromobenzoic acid.

[0008] To achieve the above technical purpose and achieve the above technical effect, the present application is realized by the following technical solutions: (1) Using p-bromobenzoic acid as raw material, the carboxyl group of p-bromobenzoic acid is activated in the presence of an organic acid anhydride activator, and then chloromethylated with polyformaldehyde in the presence of a chlorine-containing Lewis acid catalyst. After the reaction is completed, the intermediate 4-bromo-3-(chloromethyl)benzoic acid is obtained by post-treatment. (2) The intermediate obtained in step (1) is subjected to nucleophilic substitution reaction in ethanol in the presence of an inorganic base to prepare the target product 4-bromo-3-(ethoxymethyl)benzoic acid.

[0009] Further, in step (1), the temperature of the chloromethylation reaction is 80-150°C.

[0010] Further, in step (1), the organic acid anhydride activator is selected from at least one of acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, trifluoromethanesulfonic anhydride, and methanesulfonic anhydride.

[0011] Further, in step (1), the chlorine-containing Lewis acid catalyst is selected from at least one of zinc chloride, iron chloride, and aluminum trichloride.

[0012] Further, in step (1), the molar ratio of p-bromobenzoic acid, organic acid anhydride activator, chlorine-containing Lewis acid catalyst, and polyformaldehyde is 1:(8-10):(1-1.5):(1-1.6); wherein the molar amount of polyformaldehyde is calculated based on the molar amount of monomeric formaldehyde in polyformaldehyde.

[0013] Further, the post-treatment of step (1) includes: quenching, acidifying, crystallizing, and separating the reaction solution to obtain the intermediate 4-bromo-3-(chloromethyl)benzoic acid.

[0014] Further, in step (2), the temperature of the nucleophilic substitution reaction is 50-80°C.

[0015] Further, in step (2), the inorganic base is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0016] Further, in step (2), the molar ratio of the intermediate 4-bromo-3-(chloromethyl)benzoic acid to the inorganic base is 1: (2.1-2.5).

[0017] The beneficial effects of the present application are: The present application can efficiently construct the target molecule through two-step reaction, and the synthesis route is significantly simplified. In the first step reaction, the synergistic effect of the organic anhydride activator and the chlorine-containing Lewis acid catalyst is utilized to successfully realize the direct chloromethylation of the cheap p-bromobenzoic acid as the raw material, and the key intermediate is synthesized in one step with high selectivity. This design not only avoids the bottleneck of high price of the starting material 4-bromo-3-methylbenzoic acid in the traditional route, greatly reduces the raw material cost, but also breaks through the technical prejudice that the benzoic acid is generally considered to be insufficiently active in such reactions. On this basis, the second step reaction is carried out in an ethanol-inorganic base system, and the ethanol is used as a reactant and a solvent at the same time. Under the condition of a mild inorganic base, the chloromethyl group in the intermediate can efficiently undergo a nucleophilic substitution reaction with ethanol to smoothly introduce an ethoxymethyl group, and the target product is generated in one step.

[0018] The reaction conditions of the present application are relatively mild, the operation safety and controllability are higher, the whole process avoids the use of toxic and dangerous or expensive reagents, reduces the requirements for special equipment and production safety risks. The subsequent purification treatment of the present application method is simple, and high-purity final product can be obtained through extraction, acidification and recrystallization, which is very suitable for industrial production.

[0019] In summary, the method of the present application has multiple advantages such as simple route, economical cost, mild condition, safety and environmental protection, and high product purity, and can provide an innovative solution for the efficient and green industrial production of the key intermediate of sparsagrel. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 The nuclear magnetic resonance spectrum of 4-bromo-3-(ethoxymethyl)benzoic acid. DETAILED DESCRIPTION

[0021] The technical solutions in the present application will be described below in conjunction with specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0022] The present application provides a synthesis method of 4-bromo-3-(ethoxymethyl)benzoic acid, comprising the following steps: (1) using p-bromobenzoic acid as a raw material, activating the carboxyl group of p-bromobenzoic acid in the presence of an organic acid anhydride activator, then performing chloromethylation with paraformaldehyde in the presence of a chlorine-containing Lewis acid catalyst, and obtaining the intermediate 4-bromo-3-(chloromethyl)benzoic acid after post-treatment.

[0023] During the reaction of this step (1), the organic acid anhydride reacts with the carboxyl group to form a mixed anhydride intermediate (for example, p-bromobenzoic acid and acetic anhydride react to form p-bromobenzoic acid-acetic anhydride mixed anhydride). This mixed anhydride is weaker than the electron-withdrawing effect of the original carboxyl group, and may even temporarily enhance the electron density of the benzene ring through electronic effects, thereby making the benzene ring more susceptible to attack by electrophilic reagents (chloromethyl cations). In the presence of a Lewis acid catalyst (such as zinc chloride or aluminum chloride), paraformaldehyde decomposes to generate chloromethyl cations, which attack the meta position of the benzene ring to achieve chloromethylation. The activation effect of the organic acid anhydride overcomes the poor reactivity of benzoic acid, enabling the chloromethylation to proceed with high selectivity.

[0024] In this step (1), the temperature of the chloromethylation reaction is 80-150°C, and is further preferably 100-120°C; the organic acid anhydride activator is at least one selected from acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, trifluoromethanesulfonic anhydride, and methanesulfonic anhydride, and is further preferably at least one selected from acetic anhydride, trifluoromethanesulfonic anhydride, and methanesulfonic anhydride; the chlorine-containing Lewis acid catalyst is at least one selected from zinc chloride, iron chloride, and aluminum chloride, and is further preferably zinc chloride or aluminum chloride. In this step (1), the molar ratio of p-bromobenzoic acid, organic acid anhydride activator, chlorine-containing Lewis acid catalyst, and paraformaldehyde is 1:(8-10):(1-1.5):(1-1.6), wherein the molar amount of paraformaldehyde is based on the molar amount of monomeric formaldehyde in paraformaldehyde.

[0025] The post-treatment of this step (1) is acidification post-treatment, which specifically includes: quenching the reaction solution, adjusting to acidic conditions with an acid, precipitating a solid, and then performing solid-liquid separation, and further purification to obtain the intermediate. In the post-reaction treatment (such as pouring into dilute hydrochloric acid and crushed ice), the mixed anhydride intermediate is hydrolyzed to regenerate the carboxyl group.

[0026] (2) performing a nucleophilic substitution reaction on the intermediate obtained in step (1) in ethanol in the presence of an inorganic base to obtain the target product 4-bromo-3-(ethoxymethyl)benzoic acid.

[0027] The temperature of the nucleophilic substitution reaction is 50-80°C, and is further preferably 60-80°C; the inorganic base is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, and is further preferably at least one of potassium carbonate, sodium hydroxide, and potassium hydroxide. The molar ratio of the intermediate 4-bromo-3-(chloromethyl)benzoic acid to the inorganic base is 1: (2.1-2.5).

[0028] The synthetic route of the synthesis method is as follows: The application is further described below through specific examples.

[0029] Example 1 Example 1: Synthesis of 4-bromo-3-(chloromethyl)benzoic acid Under nitrogen protection, 10 g of p-bromobenzoic acid, 9.1 g of aluminum chloride, and 50 g of acetic anhydride were added to a reaction bottle, stirred for 30 minutes, 2.3 g of dry paraformaldehyde was added, heated to 100°C for reaction; liquid phase detection showed that the raw material p-bromobenzoic acid was completely reacted, the reaction liquid was cooled to room temperature, the reaction liquid was poured into crushed ice and a dilute hydrochloric acid solution, stirred for 2 hours, suction filtered, and washed with ice water; the solid was dissolved with ethyl acetate, the liquid was dried with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 11.9 g of solid, with a yield of 96%.

[0030] Example 2: Synthesis of 4-bromo-3-(chloromethyl)benzoic acid Under nitrogen protection, 10 g of p-bromobenzoic acid and 120 g of triflic anhydride were added to a reaction bottle, stirred to dissolve, 10.2 g of zinc chloride was added, heated to 80°C, and 2.3 g of dry paraformaldehyde was added in batches within 1 hour; after the addition was completed, the reaction was continued at 80°C; liquid phase detection showed that the raw material p-bromobenzoic acid was completely reacted, the reaction liquid was cooled to room temperature, the reaction liquid was poured into crushed ice and a dilute hydrochloric acid solution, stirred for 1 hour, suction filtered, and washed with ice water; the solid was dissolved with ethyl acetate, the liquid was dried with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 11.8 g of solid, with a yield of 95%.

[0031] Example 3: Synthesis of 4-bromo-3-(chloromethyl)benzoic acid Under nitrogen protection, 10 g of p-bromobenzoic acid, 12.2 g of iron chloride, and 87 g of methanesulfonic anhydride were added to a reaction bottle, stirred for 30 minutes, 2.3 g of dry paraformaldehyde was added, heated to 120°C for reaction; liquid phase detection showed that the raw material p-bromobenzoic acid was completely reacted, the reaction liquid was cooled to room temperature, the reaction liquid was poured into crushed ice and a dilute hydrochloric acid solution, stirred for 2 hours, suction filtered, and washed with ice water; the solid was dissolved with ethyl acetate, the liquid was dried with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 11.5 g of solid, with a yield of 92%.

[0032] Example 4: Synthesis of 4-bromo-3-(ethoxymethyl)benzoic acid Into a reaction flask, 25 g of 4-bromo-3-(chloromethyl)benzoic acid and 250 ml of ethanol were added, heated to 60°C, and 12.5 g of solid potassium hydroxide was added in portions within 1 hour; after the addition was completed, the reaction was continued at 60°C; the liquid phase was detected to determine that the reaction of the starting material 4-bromo-3-(chloromethyl)benzoic acid was complete, ethanol was removed by distillation under reduced pressure, the system was adjusted to pH 1-2 using 2N hydrochloric acid, and the product was crystallized by cooling, filtered, washed with ice water, and recrystallized from ethanol to obtain 23.3 g of product with a yield of 90%; as shown in Figure 1 1 H NMR (400 MHz, d6-DMSO): δ 1.23 (t, J = 7 Hz, 3H), 3.60 (q, J = 7 Hz, 2H), 4.55 (s, 2H), 7.80-7.75 (m, 2H), 8.04 (s, 1H), 13.20 (br s, 1H).

[0033] Example 5: Synthesis of 4-bromo-3-(ethoxymethyl)benzoic acid Into a reaction flask, 25 g of 4-bromo-3-(chloromethyl)benzoic acid and 350 ml of ethanol were added, and 30 g of potassium carbonate was added with stirring, and the reaction was carried out under reflux; the liquid phase was detected to determine that the reaction of the starting material 4-bromo-3-(chloromethyl)benzoic acid was complete, ethanol was removed by distillation under reduced pressure, the system was adjusted to pH 1-2 using 2N hydrochloric acid slowly, and the product was crystallized by cooling, filtered, washed with ice water, and recrystallized from ethanol to obtain 22.8 g of product with a yield of 88%.

[0034] It is obvious to a person skilled in the art that the present application is not limited to the details of the above-described exemplary embodiments, but can be implemented in other concrete forms without departing from the spirit or essential characteristics of the present application. Therefore, the embodiments should be considered in all respects as illustrative and not restrictive, the scope of the present application being defined by the appended claims rather than the above description, and it is intended to encompass all changes falling within the meaning and scope of the equivalent elements of the claims.

[0035] In addition, it should be understood that although the present specification is described in terms of embodiments, not every embodiment contains only one independent technical solution, and the present specification is described in this way only for the sake of clarity, and a person skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by a person skilled in the art.​

Claims

1. A method for synthesizing 4-bromo-3-(ethoxymethyl)benzoic acid, characterized in that, Includes the following steps: (1) Using p-bromobenzoic acid as raw material, the carboxyl group of p-bromobenzoic acid is activated in the presence of an organic acid anhydride activator, and then chloromethylated with paraformaldehyde in the presence of a chlorinated Lewis acid catalyst. After the reaction is completed, the intermediate 4-bromo-3-(chloromethyl)benzoic acid is obtained by post-treatment. (2) The intermediate obtained in step (1) was placed in ethanol and subjected to a nucleophilic substitution reaction under the action of an inorganic base to prepare the target product 4-bromo-3-(ethoxymethyl)benzoic acid.

2. The method for synthesizing 4-bromo-3-(ethoxymethyl)benzoic acid according to claim 1, characterized in that, In step (1), the temperature of the chloromethylation reaction is 80~150℃.

3. The method for synthesizing 4-bromo-3-(ethoxymethyl)benzoic acid according to claim 1, characterized in that, In step (1), the organic acid anhydride activator is selected from at least one of acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, trifluoromethanesulfonic anhydride, and methanesulfonic anhydride.

4. The method for synthesizing 4-bromo-3-(ethoxymethyl)benzoic acid according to claim 1, characterized in that, In step (1), the chlorinated Lewis acid catalyst is selected from at least one of zinc chloride, ferric chloride, and aluminum trichloride.

5. The method for synthesizing 4-bromo-3-(ethoxymethyl)benzoic acid according to claim 1, characterized in that, In step (1), the molar ratio of p-bromobenzoic acid, organic acid anhydride activator, chlorinated Lewis acid catalyst and paraformaldehyde is 1:(8~10):(1~1.5):(1~1.6).

6. The method for synthesizing 4-bromo-3-(ethoxymethyl)benzoic acid according to claim 1, characterized in that, The post-processing described in step (1) includes: quenching, acidifying, crystallizing, and separating the reaction solution to obtain the intermediate 4-bromo-3-(chloromethyl)benzoic acid.

7. The method for synthesizing 4-bromo-3-(ethoxymethyl)benzoic acid according to claim 1, characterized in that, Its features are, In step (2), the temperature of the nucleophilic substitution reaction is 50~80℃.

8. The method for synthesizing 4-bromo-3-(ethoxymethyl)benzoic acid according to claim 1, characterized in that, In step (2), the inorganic base is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.

9. The method for synthesizing 4-bromo-3-(ethoxymethyl)benzoic acid according to claim 1, characterized in that, In step (2), the molar ratio of the intermediate 4-bromo-3-(chloromethyl)benzoic acid to the inorganic base is 1:(2.1~2.5).

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