Preparation method of intermediate of GLP-1 RA

Abstract

The invention provides a preparation method of an intermediate of GLP-1 RA, and belongs to the technical field of pharmaceutical chemistry synthesis, and the preparation method comprises the following steps: S1, in the coexistence of a palladium catalyst, a phosphine ligand, a quaternary ammonium salt additive and a first organic base, carrying out a Heck coupling reaction on a compound 2 and acrylic acid in an amide solvent, and after the reaction is finished, carrying out a first post-treatment step to obtain a compound 3; and S2, in the presence of a catalyst, an activating agent and second organic alkali, feeding the compound 3 obtained in the step S1 and (R)-4-benzyl-2-oxazolidinone into a polar aprotic solvent to carry out one-pot amidation reaction, and after the reaction is finished, carrying out a second post-treatment step to obtain a compound 4. According to the preparation method, the low dosage of the palladium catalyst is realized, the production energy consumption, the catalyst cost and the production cost are remarkably reduced, the product purity is up to 98% or above, the reproducibility is good, the total yield can reach 70% or above, and a new path is provided for preparation of the compound 4.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis technology, and in particular to a method for preparing an intermediate of GLP-1 RA. Background Technology

[0002] GLP-1 receptor agonists (GLP-1 RAs), also known as incretin mimics, are insulin secretagogues. GLP-1 RAs are an important class of hypoglycemic drugs used to treat type 2 diabetes. They exert their hypoglycemic effect by activating glucagon-like peptide-1 receptors and have the characteristics of glucose-dependently promoting insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, suppressing appetite, reducing weight, and improving blood lipids. They can also reduce the risk of cardiovascular events.

[0003] International patent WO 2024137426 A1 discloses the synthetic route of the GLP-1 receptor agonist GLP-1 RA and its key intermediates. Compound 4 [(R,E)-5-(3-(4-benzyl-2-oxooxazolidine-3-yl)-3-oxoprop-1-en-1-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide] is the key intermediate in this synthesis. According to WO 2024137426A1, the synthesis of compound 4 involves two main steps: 1. Heck Coupling Reaction: Compound 2 [5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide] reacts with acrylic acid in the presence of a palladium catalyst and a phosphine ligand to generate compound 3 [(E)-3-[2-(methyl(phenyl)carbamoyl)-1H-indole-5-yl]acrylic acid].

[0004] 2. Amide reaction: Compound 3 is coupled with (R)-4-benzyl-2-oxazolidinone via CDI activation to generate compound 4. The specific synthetic reaction formula for compound 4 is as follows:

[0005] The existing technology has the following limitations: First, the amount of palladium catalyst used in the Heck coupling reaction is relatively high: in Preparation Example 2, the amount of palladium catalyst used is 0.25% of the molar amount of compound 2 (based on allyl palladium(II) chloride dimer), and the catalyst is expensive, resulting in high production costs.

[0006] Second, the amidation reaction is complicated to operate: the CDI two-step method (activation + coupling) is used for the amidation reaction. The reaction temperature and other parameters of the activation step and the coupling step are different, which can easily lead to increased difficulty in reaction control and increased reaction energy consumption. In addition, the intermediate reaction (such as compound 3-2 in the reaction formula) is filtered, washed, separated and solvent switched, which can easily lead to reduced production efficiency.

[0007] Therefore, developing a more economical and simpler synthetic method for GLP-1 RA intermediate compound 4 is an important task for those skilled in the art. Summary of the Invention

[0008] This invention provides a method for preparing an intermediate of GLP-1 RA, which solves the problems of high production cost caused by high palladium catalyst dosage in the Heck coupling reaction in the prior art, and increased reaction control difficulty, increased reaction energy consumption, and reduced production efficiency caused by the complicated operation of the two-step amidation reaction of CDI.

[0009] To achieve the above objectives, in a first aspect, the present invention provides a method for preparing an intermediate of GLP-1 RA, comprising: S1. Preparation of compound 3 by Heck coupling reaction: In the presence of palladium catalyst, phosphine ligand, quaternary ammonium salt additive and first organic base, compound 2 is subjected to Heck coupling reaction with acrylic acid in an amide solvent. After the reaction is completed, compound 3 is obtained by the first post-treatment step. S2. Preparation of compound 4 by one-pot amidation reaction: In the presence of a catalyst, an activator, and a second organic base, compound 3 obtained in S1 was reacted with (R)-4-benzyl-2-oxazolidinone in a polar aprotic solvent for a one-pot amidation reaction. After the reaction was completed, compound 4 was obtained by a second post-treatment step. Compound 2 is 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide; compound 4 is (R,E)-5-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide.

[0010] In this invention, the preparation of intermediate compound 4 of GLP-1 RA requires only two steps from compound 2 to compound 4, with mild reaction conditions, simple post-processing, high product purity (HPLC purity > 98%), good reproducibility, and an overall yield of over 70%, which is superior to or equivalent to existing technologies, providing a new route for the preparation of compound 4. Furthermore, by stabilizing the catalyst system with quaternary ammonium salt additives in the Heck coupling reaction, a low amount of palladium catalyst is achieved, and the one-pot method simplifies the amidation reaction steps, making the operation simpler. The energy consumption, catalyst cost, and production cost of the two-step preparation process are significantly reduced, making it more suitable for the large-scale production of compound 4, a key intermediate for GLP-1 receptor agonists, and possessing significant industrial application value.

[0011] According to the present invention, the molar ratio of compound 2 to acrylic acid is 1:(1.2-1.5), and the molar ratio of compound 3 to (R)-4-benzyl-2-oxazolidinone is 1:(1.2-1.5).

[0012] According to the present invention, the palladium catalyst is selected from at least one of palladium acetate (Pd(OAc)2), palladium chloride (PdCl2), and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4); the amount used is 0.01-0.1% of the molar amount of compound 2. Pd(OAc)2 is preferred as the palladium catalyst. The amount of palladium catalyst used is preferably 0.02-0.05% of the molar amount of compound 2. The improved Heck coupling reaction significantly reduces the amount of catalyst used, from 0.25% of the molar amount of compound 2 in the prior art to below 0.1%, a reduction of more than 80%, which can significantly reduce the catalyst and overall production costs.

[0013] According to the present invention, the phosphine ligand is selected from at least one of tris(o-tolyl)phosphine (P(o-tol)3) and triphenylphosphine (PPh3), and is used in an amount 2-4 times the molar amount of the palladium catalyst. P(o-tol)3 is preferred as the phosphine ligand. The addition of the phosphine ligand to the catalytic system is due to its unique electronic and steric properties, which regulate the activity, selectivity, and stability of the palladium catalyst, reducing the activation energy of the reaction system, improving reaction efficiency, and thus increasing yield and selectivity.

[0014] According to the present invention, the quaternary ammonium salt additive is selected from at least one of tetrabutylammonium bromide (Bu4NBr), tetrabutylammonium chloride (Bu4NCl), and tetraethylammonium bromide (Et4NBr), and is used in an amount of 0.1-1.0 equivalents of compound 2. The preferred quaternary ammonium salt additive is Bu4NBr. The preferred amount of the quaternary ammonium salt additive is 0.3-0.7 equivalents of compound 2. The quaternary ammonium salt additive, in conjunction with the phosphine ligand, makes the coupling reaction more complete, improves the catalytic efficiency, and enhances the mass transfer between the catalyst and the reaction solution. The palladium catalyst is highly dispersed, and the Pd atom utilization rate is improved, thus strengthening the reaction and reducing the catalyst consumption, thereby lowering the production cost of the reaction. Furthermore, the yield of compound 3 can be stably maintained above 80%.

[0015] According to the present invention, the first organic base is selected from at least one of N,N-diisopropylethylamine (DIPEA) and N,N-dicyclohexylmethylamine, and is used in an amount of 1.5-3 times the molar amount of compound 2. The first organic base is preferably N,N-dicyclohexylmethylamine.

[0016] According to the present invention, the amide solvent is selected from at least one of N,N-dimethylacetamide (DMAc) and N-methylpyrrolidone (NMP), and the mass-to-volume ratio of compound 2 to the amide solvent is 1 g:(9-12) mL. DMAc is preferred as the amide solvent. The amide solvent provides a more stable reaction environment, and when used in combination with phosphine ligands, the first organic base, and quaternary ammonium salt additives, the catalytic reaction proceeds rapidly and stably. While maintaining or increasing the reaction yield, the amount of catalyst used is greatly reduced, significantly lowering the reaction cost.

[0017] According to the present invention, the Heck coupling reaction is carried out at a temperature of 60-90°C for a reaction time of 3-6 hours, under nitrogen protection throughout the reaction, and the reaction ends when the content of compound 2 in the reaction system is <1.0%. The preferred reaction temperature is 70-80°C.

[0018] According to the present invention, the catalyst in S2 is 4-(N,N-dimethylamino)pyridine N-oxide (DMAPO), and the amount used is 1-5% of 3 moles of the compound. Preferably, the amount of catalyst used is 2% of 3 moles of the compound.

[0019] According to the present invention, the activator is di-tert-butyl dicarbonate (Boc2O), and the amount used is 1.2-1.8 equivalents of compound 3. Preferably, the amount of activator used is 1.3-1.5 equivalents of compound 3.

[0020] According to the present invention, the second organic base is triethylamine (Et3N), and the amount used is 1.5-3.0 equivalents of compound 3.

[0021] According to the present invention, the polar aprotic solvent is selected from at least one of acetonitrile (MeCN), tetrahydrofuran (THF), and N,N-dimethylformamide (DMF), and the mass-to-volume ratio of compound 3 to the polar aprotic solvent is 1 g:(10-15) mL. The preferred polar aprotic solvent is MeCN.

[0022] According to the present invention, the one-pot amidation reaction is carried out at a temperature of 0-40°C for a reaction time of 10-13 h, and the reaction ends when the content of compound 3 in the reaction system is <1.0%. The preferred reaction temperature is 20-25°C.

[0023] The amidation reaction abandons the two-step CDI method and instead adopts a one-pot DMAPO / Boc2O method, integrating the traditional multi-step reaction into a single operation. All steps are carried out in one reaction vessel without intermediate separation steps. This avoids the problems of increased reaction control difficulty, increased reaction energy consumption, and reduced production efficiency caused by the use of multiple reagents and purification of reaction intermediates in the traditional two-step CDI method. The operation is simpler, the synthesis time is shortened, the synthesis process is safe and reliable, the production efficiency is improved, the reaction energy consumption and product loss are reduced, the reaction yield is increased, and it is more suitable for large-scale production.

[0024] In a second aspect, the present invention provides a method for preparing an intermediate of GLP-1 RA and its use in the preparation of GLP-1 receptor agonists, specifically the method for preparing an intermediate of GLP-1 RA provided in the first aspect above.

[0025] Based on this, the present invention can also provide a catalytic system for the Heck coupling reaction as described above, comprising a palladium catalyst, a phosphine ligand, and a quaternary ammonium salt additive, wherein the Heck coupling reaction is carried out in a first organic base and an amide solvent; specifically, the molar amount of the palladium catalyst does not exceed 0.1% of the molar amount of the substrate; the quaternary ammonium salt additive is selected from at least one of tetrabutylammonium bromide (Bu4NBr), tetrabutylammonium chloride (Bu4NCl), and tetraethylammonium bromide (Et4NBr), and is used in an amount of 0.1-1.0 equivalents of the substrate; the first organic base is selected from at least one of N,N-diisopropylethylamine (DIPEA) and N,N-dicyclohexylmethylamine, and the amide solvent is selected from at least one of N,N-dimethylacetamide (DMAc) and N-methylpyrrolidone (NMP).

[0026] The present invention may also provide the use of a quaternary ammonium salt additive in reducing the amount of palladium catalyst used in the aforementioned Heck coupling reaction, which is carried out in an amide solvent containing a phosphine ligand and a first organic base.

[0027] The present invention provides a method for preparing compound 4, an intermediate of GLP-1 RA, requiring only two steps from compound 2 to compound 4. In the Heck coupling reaction, a quaternary ammonium salt additive stabilizes the catalyst system, which is then used in combination with a phosphine ligand, a first organic base, and an amide solvent. This significantly reduces the amount of palladium catalyst used while maintaining or improving the reaction yield. In the amidation reaction, the two-step CDI method is abandoned, and a one-pot DMAPO / Boc2O method is adopted, simplifying the reaction steps, improving production efficiency, reducing reaction energy consumption and product loss, and increasing the reaction yield. This two-step method for preparing compound 4 achieves low palladium catalyst usage, significantly reducing production energy consumption, catalyst cost, and production cost. The product has high purity (HPLC purity > 98%), good reproducibility, and an overall yield of over 70%. This provides a new route for the preparation of compound 4 and is more suitable for the large-scale production of compound 4, a key intermediate for GLP-1 receptor agonists. Detailed Implementation

[0028] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are also within the scope of protection of the present invention.

[0029] The following examples use conventional instruments and equipment in the art. Unless otherwise specified, the experimental materials and reagents used in the following examples are commercially available and conform to conventional specifications in the art. Any techniques or conditions not specifically described in the following examples can be performed according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0030] It should be noted that, in this invention and the following embodiments, unless otherwise specified, concentration, ratio, etc. are all weight concentration, weight ratio, etc., "%" all represent molar percentage, and "parts" all represent weight parts. These are common writing habits used by those skilled in the art, and therefore will not be repeated in this invention.

[0031] The method for preparing the intermediate of GLP-1 RA provided by this invention has the following synthetic reaction formula for the target product compound 4:

[0032] In a preferred embodiment, the first post-processing step includes: after the reaction is completed, adding acid to the cooled reaction system to adjust its pH to 3-4, cooling and crystallizing, and then filtering, washing, and drying to obtain compound 3. In order to prevent the solvent and other substances in the reaction system from affecting the next stage of the reaction, compound 3 is separated from the reaction system, which also facilitates the separation and recovery of catalysts and other substances from the reaction system.

[0033] In a preferred embodiment, the second post-processing step includes: after the reaction is completed, the volume of the reaction system is concentrated to 1 / 3-1 / 2 to recover part of the solvent, acid is added to adjust the pH to 3-5, and after cooling and crystallization, the mixture is filtered, washed, and dried to obtain compound 4.

[0034] In a preferred embodiment, when adjusting the pH of the system by adding acid in the first and second post-treatment steps, one of concentrated sulfuric acid, concentrated hydrochloric acid, p-toluenesulfonic acid, phosphoric acid, sulfonic acid, or boric acid is used. Concentrated sulfuric acid is preferred for post-treatment of the Heck coupling reaction. Concentrated hydrochloric acid is preferred for post-treatment of the one-pot amidation reaction. The concentration and amount of acid solution are not limited, and the final pH of the system shall prevail.

[0035] As a preferred embodiment, the preparation method of the aforementioned intermediate for GLP-1 RA includes the following specific steps: S1, Heck coupling reaction to prepare compound 3: Compound 2, an amide solvent, and a first organic base are added to a reaction vessel. After mixing, the mixture is heated to above 60°C, and nitrogen gas is then introduced into the reaction vessel for purging protection. Phosphine ligand, palladium catalyst, and quaternary ammonium salt additive are added sequentially to the reaction vessel. After thorough stirring, acrylic acid is added, and the temperature is raised to the reaction temperature. Stirring is then initiated, with the stirring rate maintained at a level that prevents the catalyst from settling to the bottom. The reaction time is 3-6 hours. The reaction is terminated when the content of compound 2 in the reaction system is <1.0%. The reaction system is cooled to below 50°C, and the pH is adjusted to 3-4 with acid. After further cooling to below 10°C, crystallization is carried out by stirring for 2-2.5 hours. The mixture is then filtered, and the filter cake is washed with water at least twice. It is then vacuum dried at 60-90°C for at least 12 hours. The resulting light yellow solid is compound 3.

[0036] S2, One-pot amidation reaction to prepare compound 4: Compound 3, a polar aprotic solvent, (R)-4-benzyl-2-oxazolidinone, and a second organic base were added to a reaction vessel. After mixing, the catalyst was added with stirring, followed by the slow dropwise addition of an activator at room temperature, ensuring the reaction system temperature did not exceed the reaction temperature during the dropwise addition. After the dropwise addition was complete, the reaction was maintained at 0-40℃ with stirring for 10-13 hours. The reaction was terminated when the content of compound 3 in the reaction system was <1.0%. Part of the solvent was recovered by concentrating the reaction system to 1 / 3-1 / 2 of its original volume. The pH was adjusted to 3-5 with acid, and the mixture was further cooled to below 5℃. Crystallization was then carried out with stirring for 2-2.5 hours. The mixture was then filtered, and the filter cake was washed with water at least twice and dried under vacuum at 50-70℃ for at least 12 hours. The resulting white solid was compound 4.

[0037] The present invention will be further described in detail below with reference to embodiments. However, it should be understood that the embodiments are for illustrative purposes only and are not intended to limit the scope of the present invention. Example 1

[0038] The preparation of compound 3 from compound 2, specifically the steps of the Heck coupling reaction to prepare compound 3, are as follows: Compound 2, amide solvent NMP, and the first organic base DIPEA were added to the reaction vessel. After mixing, the mixture was heated to above 60°C, and then nitrogen gas was introduced into the reaction vessel for purging protection. Phosphine ligand PPh3, palladium catalyst Pd(PPh3)4, and quaternary ammonium salt additive Bu4NBr were added sequentially to the reaction vessel. After stirring until homogeneous (approximately 10 min), acrylic acid was added. The temperature was raised to 70°C, and stirring was initiated at a rate sufficient to prevent catalyst settling. The reaction was considered complete when the content of compound 2 in the reaction system was <1.0% after 5 h. The reaction system was cooled to below 50°C, and concentrated sulfuric acid was added to adjust the pH to 4. After further cooling to below 10°C, the mixture was stirred to induce crystallization for 2.5 h. The crystals were then filtered, and the filter cake was washed with water at least twice and dried under vacuum at 80°C for 12 h. The resulting pale yellow solid was compound 3 (yield: 84.7%, HPLC purity: 98.5%).

[0039] In the above reaction, the molar ratio of compound 2 to acrylic acid is 1:1.4, the mass-volume ratio of compound 2 to solvent NMP is 1g:12mL, the amount of DIPEA is 2.5 times the molar amount of compound 2, the amount of PPh3 is 4 times the molar amount of palladium catalyst, the amount of palladium catalyst is 0.1% of the molar amount of compound 2, and the amount of Bu4NBr is 1.0 equivalent of compound 2. Example 2

[0040] The preparation of compound 3 from compound 2, specifically the steps of the Heck coupling reaction to prepare compound 3, are as follows: Compound 2 (32.8 g, 100 mmol), amide solvent DMAc (300 mL), and the first organic base N,N-dicyclohexylmethylamine (39.2 g, 200 mmol) were added to a 500 mL three-necked flask. After mixing, the mixture was heated to above 60 °C, and then nitrogen gas was introduced into the reaction vessel for purging protection. Phosphine ligand P(o-tol)3 (12.2 mg, 0.04 mmol), palladium catalyst Pd(OAc)2 (4.5 mg, 0.02 mmol, 0.02%), and quaternary ammonium salt additive Bu4NBr (16.1 g, 50 mmol, 0.5 equivalent) were added sequentially to the reaction vessel. After stirring until homogeneous (approximately 10 min), acrylic acid (8.6 g, 120 mmol) was added. The temperature was raised to 75 °C, and the reaction was stirred at a rate sufficient to prevent the catalyst from settling. The reaction was considered complete when the content of compound 2 in the reaction system was <1.0% after 3.5 h. The reaction system was cooled to below 50°C, and then concentrated sulfuric acid was added to adjust the pH to 3.5. After further cooling to below 10°C, the mixture was stirred to crystallize for 2 hours. The mixture was then filtered, and the filter cake was washed with water at least twice (200 mL × 2). The mixture was then vacuum dried at 60°C for 12 hours. The resulting light yellow solid was compound 3. Yield: 27.1 g, yield: 85.3%, HPLC purity: 98.8%. Example 3

[0041] The preparation of compound 3 from compound 2 was carried out using the same Heck coupling reaction as in Example 2, except that the quaternary ammonium salt additive used was Bu4NCl (50 mmol, 0.5 equivalent). The final yield of compound 3 was 26.3 g, with a yield of 82.4% and an HPLC purity of 98.3%. Example 4

[0042] The preparation of compound 3 from compound 2 was carried out using the same Heck coupling reaction as in Example 2, except that the quaternary ammonium salt additive used was Et4NBr (50 mmol, 0.5 equivalents). The final yield of compound 3 was 25.7 g, with a yield of 80.7% and an HPLC purity of 98.7%.

[0043] Comparative Example 1: The preparation of compound 3 from compound 2 involved the same steps as in Example 2 via the Heck coupling reaction, except that the quaternary ammonium salt additive Bu4NBr was not added to the reaction system, and the amount of palladium acetate was increased to 112 mg (0.5 mmol, 0.5%), and the amount of tris(o-tolyl)phosphine was increased to 304 mg (1.0 mmol, 1.0%). The final yield of compound 3 was 26.5 g, with a yield of 83.2% and an HPLC purity of 98.5%.

[0044] Comparing the production data of Examples 2-4 and Comparative Example 1, it can be found that although various quaternary ammonium salt additives have the effect of significantly reducing the amount of catalyst used, considering the yield, purity, and overall yield data of compound 3, Bu4NBr has the best effect. Furthermore, even with 25 times the amount of palladium used in Example 2, the yield was still lower than in Example 2 without the use of quaternary ammonium salt additives, fully demonstrating the significant synergistic effect of Bu4NBr in the catalyst system. Example 5

[0045] The preparation of compound 4 from compound 3, specifically, the one-pot amidation reaction steps for preparing compound 4 are as follows: Compound 3, the polar aprotic solvent THF, (R)-4-benzyl-2-oxazolidinone, and the second organic base Et3N were added to the reaction vessel. After mixing, the catalyst DMAPO was added with stirring, followed by the slow dropwise addition of the activator Boc2O at room temperature, while controlling the reaction system temperature to not exceed 40°C during the dropwise addition. After the dropwise addition was complete, the reaction was maintained at 40°C with stirring for 11.5 h. The reaction was terminated when the content of compound 3 in the reaction system was <1.0%. Part of the solvent was recovered by concentrating the reaction system to 1 / 2 volume to recover some of the solvent. The pH was adjusted to 5 with concentrated hydrochloric acid, and then further cooled to below 5°C. Crystallization was carried out with stirring for 2.5 h, followed by filtration. The filter cake was washed with water at least twice and dried under vacuum at 60°C for 12 h. The resulting white solid was compound 4 (yield, based on compound 3: 84.2%, HPLC purity: 98.2%).

[0046] In the above reaction, the molar ratio of compound 3 to (R)-4-benzyl-2-oxazolidinone was 1:1.4. The mass-to-volume ratio of compound 3 to THF was 1 g:13 mL. The amount of Et3N used was 3.0 equivalents of compound 3. The amount of DMAPO used was 3% of the molar amount of compound 3. The amount of Boc2O used was 1.7 equivalents of compound 3. Example 6

[0047] The preparation of compound 4 from compound 3, specifically, the one-pot amidation reaction steps for preparing compound 4 are as follows: Compound 3 (prepared in Example 2, 16.0 g, 50 mmol), the polar aprotic solvent MeCN (160 mL), (R)-4-benzyl-2-oxazolidinone (10.65 g, 60 mmol), and the second organic base Et3N (10.1 g, 100 mmol) were added to a reaction vessel (500 mL three-necked flask). After mixing, the catalyst DMAPO (152 mg, 1.0 mmol, 2%) was added with stirring. Then, the activator Boc2O (14.45 g, 65 mmol, 1.3 equivalents) was slowly added dropwise at room temperature, while controlling the temperature of the reaction system to not exceed the reaction temperature of 25 °C during the dropwise addition. The dropwise addition was completed within 2 h, and the reaction was stirred at 25 °C for 10 h. The reaction was terminated when the content of compound 3 in the reaction system was <1.0%. Part of the solvent was recovered by concentrating the reaction system to 1 / 3 of its original volume. The pH was then adjusted to 4 with concentrated hydrochloric acid, and the mixture was further cooled to below 5°C. After stirring, crystallization was carried out for 2 hours. The mixture was then filtered, and the filter cake was washed with water at least twice. It was then vacuum dried at 55°C for 12 hours. The resulting white solid was compound 4. Yield: 20.2 g, yield (based on compound 3): 84.8%, HPLC purity: 98.6%.

[0048] Comparative Example 2: The preparation of compound 3 to compound 4 specifically employs the conventional CDI amidation method, with the following steps: Referring to Preparation 3 of WO2024137426 A1: Compound 3 (prepared in Example 2, 16.0 g, 50 mmol) and ACN were added to the reactor, followed by the addition of CDI (60 mmol), and then washed with ACN. The reactants were stirred at 10°C for 2 h, filtered, and the resulting wet filter cake was washed with ACN. The wet filter cake, N,N-dimethylacetamide, (R)-4-benzyl-2-oxazolidinone (65 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were sequentially added to the reactor. The reactants were stirred at 25°C for 1 h, and then quenched with HCl to a pH of 4. The resulting suspension was stirred for 10 h and filtered. The wet filter cake was washed with water and dried under vacuum at 80 °C to constant weight to obtain compound 4. Yield: 18.5 g, yield (based on compound 3): 77.2%, HPLC purity: 98.0%.

[0049] Comparing the production data of Example 6 and Comparative Example 2, it can be found that the one-pot DMAPO / Boc2O method of the present invention has a higher yield, higher output, and improved purity. It also avoids the problems of increased reaction control difficulty, increased reaction energy consumption, and reduced production efficiency caused by the use of multiple reagents in multiple steps and the purification of intermediates in each step of the traditional two-step CDI method. Therefore, it is more suitable for large-scale production. Example 7

[0050] A method for preparing an intermediate of GLP-1 RA includes the following steps: S1: Compound 2 (65.6 g, 200 mmol), amide solvent DMAc (600 mL), and the first organic base N,N-dicyclohexylmethylamine (78.4 g, 400 mmol) were added to the reaction vessel. After mixing, the mixture was heated to above 60 °C, and then nitrogen gas was introduced into the reaction vessel for purging protection. Phosphine ligand P(o-tol)3 (24.4 mg, 0.08 mmol), palladium catalyst Pd(OAc)2 (9.0 mg, 0.04 mmol, 0.02%), and quaternary ammonium salt additive Bu4NBr (32.2 g, 100 mmol, 0.5 equivalent) were added sequentially to the reaction vessel. After stirring until homogeneous (approximately 10 min), acrylic acid (17.2 g, 240 mmol) was added. The temperature was raised to 75 °C, and stirring was started at a rate sufficient to prevent the catalyst from settling to the bottom. The reaction was terminated when the content of compound 2 in the reaction system was <1.0% after 3.5 h. The reaction system was cooled to below 50°C, and then concentrated sulfuric acid was added to adjust the pH to 3.5. After further cooling to below 10°C, the mixture was stirred to crystallize for 2 hours. The mixture was then filtered, and the filter cake was washed with water at least twice (200 mL × 2). The mixture was then vacuum dried at 60°C for 12 hours. The resulting light yellow solid was compound 3. Yield: 27.4 g, yield: 86.2%, HPLC purity: 98.7%.

[0051] S2: Add all of compound 3 obtained in S1 (27.4 g, 85.625 mmol), the polar aprotic solvent MeCN (275 mL), (R)-4-benzyl-2-oxazolidinone (18.28 g, 103 mmol), and the second organic base Et3N (17.37 g, 172 mmol) to the reaction vessel. After mixing, add the catalyst DMAPO (260.3 mg, 1.7125 mmol, 2%) with stirring. Then, slowly add the activator Boc2O (24.75 g, 111.3 mmol, 1.3 equivalents) dropwise at room temperature, controlling the temperature of the reaction system to not exceed the reaction temperature of 25 °C during the dropwise addition. The dropwise addition is completed within 2 h. The reaction is then maintained at 25 °C with stirring for 10 h. The reaction ends when the content of compound 3 in the reaction system is <1.0%. Part of the solvent was recovered by concentrating the reaction system to 1 / 3 of its original volume. The pH was then adjusted to 4 with concentrated hydrochloric acid, and the mixture was further cooled to below 5°C. After stirring, crystallization was carried out for 2 hours. The mixture was then filtered, and the filter cake was washed with water at least twice. It was then vacuum dried at 55°C for 12 hours. The resulting white solid was compound 4. Yield: 34.94 g, yield (based on compound 2): 73.6%, yield (based on compound 3): 85.4%, HPLC purity: 98.3%.

[0052] It should be noted that some detailed steps of the operation are not described in this invention, but are prior art known to those skilled in the art, and therefore will not be repeated here. Furthermore, in this invention, all features defined in the form of numerical ranges or percentage ranges, such as numerical values, quantities, contents, and concentrations, are for the sake of simplicity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual numerical values ​​(including integers and fractions) within those ranges.

[0053] It should be noted that the detailed structure of some devices is not described in this invention, but is prior art known to those skilled in the art, and therefore will not be elaborated here. In this invention, structures and devices not specifically limited can be purchased commercially, and those skilled in the art only need to install and operate them according to the accompanying instruction manual, without requiring any creative effort from those skilled in the art.

[0054] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. In this invention, not all possible combinations of the various technical features in each embodiment or implementation are described. As long as the combinations of these technical features do not contradict each other, the various technical features in each embodiment or implementation can be combined arbitrarily, and all possible combinations should be considered within the scope of this specification. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing an intermediate of GLP-1 RA, characterized in that, include: S1. Preparation of compound 3 by Heck coupling reaction: In the presence of palladium catalyst, phosphine ligand, quaternary ammonium salt additive and first organic base, compound 2 is subjected to Heck coupling reaction with acrylic acid in an amide solvent. After the reaction is completed, compound 3 is obtained by the first post-treatment step. S2. Preparation of compound 4 by one-pot amidation reaction: In the presence of a catalyst, an activator and a second organic base, compound 3 obtained in S1 and (R)-4-benzyl-2-oxazolidinone were fed into a polar aprotic solvent for one-pot amidation reaction. After the reaction was completed, compound 4 was obtained by a second post-processing step. Compound 2 is 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide; Compound 4 is (R,E)-5-(3-(4-benzyl-2-oxooxazolidine-3-yl)-3-oxoprop-1-en-1-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide.

2. The method for preparing the intermediate of GLP-1 RA according to claim 1, characterized in that, The molar ratio of compound 2 to acrylic acid is 1:(1.2-1.5), and the molar ratio of compound 3 to (R)-4-benzyl-2-oxazolidinone is 1:(1.2-1.5).

3. The method for preparing the intermediate of GLP-1 RA according to claim 1, characterized in that, The palladium catalyst is selected from at least one of palladium acetate, palladium chloride, and tetra(triphenylphosphine)palladium; the amount used is 0.01-0.1% of the molar amount of compound 2; the phosphine ligand is selected from at least one of tri(o-tolyl)phosphine and triphenylphosphine, and the amount used is 2-4 times the molar amount of the palladium catalyst.

4. The method for preparing the intermediate of GLP-1 RA according to claim 1, characterized in that, The quaternary ammonium salt additive is selected from at least one of tetrabutylammonium bromide, tetrabutylammonium chloride, and tetraethylammonium bromide, and is used in an amount of 0.1-1.0 equivalents of compound 2.

5. The method for preparing the intermediate of GLP-1 RA according to claim 1, characterized in that, The first organic base is selected from at least one of N,N-diisopropylethylamine and N,N-dicyclohexylmethylamine, and the amount used is 1.5-3 times the molar amount of compound 2; the amide solvent is selected from at least one of N,N-dimethylacetamide and N-methylpyrrolidone, and the mass-volume ratio of compound 2 to amide solvent is 1g:(9-12)mL.

6. The method for preparing the intermediate of GLP-1 RA according to claim 1, characterized in that, The Heck coupling reaction was carried out at a temperature of 60-90℃ for 3-6 hours, under nitrogen protection throughout the reaction, and ended when the content of compound 2 in the reaction system was less than 1.0%.

7. The method for preparing the intermediate of GLP-1 RA according to claim 1, characterized in that, The catalyst in S2 is 4-(N,N-dimethylamino)pyridine N-oxide, and the amount used is 1-5% of the molar amount of compound 3; the activator is di-tert-butyl dicarbonate, and the amount used is 1.2-1.8 equivalents of compound 3.

8. The method for preparing the intermediate of GLP-1 RA according to claim 1, characterized in that, The second organic base is triethylamine, and the amount used is 1.5-3.0 equivalents of compound 3; the polar aprotic solvent is selected from at least one of acetonitrile, tetrahydrofuran, and N,N-dimethylformamide, and the mass-volume ratio of compound 3 to polar aprotic solvent is 1 g:(10-15) mL.

9. The method for preparing the intermediate of GLP-1 RA according to claim 1, characterized in that, The one-pot amidation reaction is carried out at a temperature of 0-40℃ for 10-13 hours, and the reaction ends when the content of compound 3 in the reaction system is less than 1.0%.

10. The method for preparing intermediates of GLP-1 RA and its use in the preparation of GLP-1 receptor agonists, characterized in that, The preparation method is the preparation method of the intermediate of GLP-1 RA according to any one of claims 1-9.

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