A method for preparing a thienopyrimidine mercaptoacetic acid compound and a salt thereof
By optimizing the preparation method, using organic bases as acid-binding agents and alcohol solvents for pulping and refining, the problems of low purity and low yield of thiophene-pyrimidine mercaptoacetic acid compounds in the prior art have been solved. This has resulted in an efficient and simple preparation process, improved product solubility, and facilitated drug development.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
- Filing Date
- 2026-02-09
- Publication Date
- 2026-05-29
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic compound synthesis and pharmaceutical technology. Specifically, this invention relates to a method for preparing thienenopyrimidine thioglycolic acid compounds and their salts. Background Technology
[0002] Hyperuricemia is a metabolic disease caused by purine metabolism disorder. Under normal dietary conditions, a fasting serum uric acid level >0.42 mmol / L on two separate days is sufficient for a diagnosis of hyperuricemia. Gout is a crystal-related disease caused by the deposition of monosodium urate (MSU), and is the most common chronic disease of inflammatory arthritis. Hyperuricemia is a direct trigger for gout. With changes in lifestyle and rising dietary standards, the incidence of hyperuricemia and gout is increasing. Hyperuricemia has become the "fourth high" after hyperglycemia, hypertension, and hyperlipidemia, and in recent years it has shown a trend of affecting younger people. The prevalence of hyperuricemia in China is 14%, with 24.5% in men and 3.6% in women. The global gout market reached $4.1 billion in 2021 and is projected to grow to $11 billion by 2030. Many currently available drugs for treating hyperuricemia are ineffective in lowering blood uric acid levels and have serious toxic side effects; for example, benzbromarone is hepatotoxic, and rasinard is nephrotoxic. Therefore, developing novel anti-hyperuricemia drugs with better activity and higher safety is of great value.
[0003] Patent CN116102573A (publication date May 12, 2023) discloses a class of thienopyrimidine compounds containing a thienomethylene structure for the treatment of gout and hyperuricemia. These compounds have a novel structure and significantly superior activity compared to retinal. Given their novel skeletal structure, they do not produce nephrotoxic metabolites similar to retinal, and thus hold promise for overcoming the nephrotoxicity defects of retinal, bringing significant clinical application value. Their structural formula is shown in Formula II.
[0004]
[0005] Patent CN116102573A discloses a method for preparing this type of compound, the specific route of which is as follows:
[0006] Reaction conditions: (i) Phosgene, dichloromethane, triethylamine, 0~30℃; (ii) a: thiophene methylamine, tetrahydrofuran, triethylamine, room temperature; b: methanol, potassium hydroxide, room temperature; (iii) N,N-dimethylformamide, potassium carbonate, 2-bromocarboxylic acid, room temperature.
[0007] This route consists of three steps. In the preparation of compound II from M2, N,N-dimethylformamide is used as the solvent and potassium carbonate as the acid-binding agent. This reaction system is heterogeneous, which is not conducive to complete reaction, resulting in a large amount of residual M2 and low product purity, requiring cumbersome column chromatography purification. Furthermore, using N,N-dimethylformamide as the solvent requires post-processing with water followed by extraction with a large amount of organic solvent, which is cumbersome and inefficient. In particular, this method exhibits a significant scale-up effect; the amount of residual M2 increases with larger batches. Therefore, this method suffers from drawbacks such as small batch size, cumbersome post-processing, the need for column chromatography purification, low product purity, and low yield, making it unsuitable for large-scale production. Compound II has poor solubility, which is detrimental to drug formulation. Forming it into a salt with a base can greatly improve its solubility, which is beneficial for later formulation development and clinical application. Summary of the Invention
[0008] To address the shortcomings of existing technologies, this invention provides a method for preparing thiophene-pyrimidine thioglycolic acid compounds and their salts.
[0009] The technical solution of the present invention is as follows: (1) Using an organic base as an acid-binding agent, the compound of formula III reacts with 2-bromoacetic acid in tetrahydrofuran. After the reaction is complete, the solvent is evaporated, water is added, the pH is adjusted to about 5 with acid, filtered, and dried to obtain the crude product of compound II. (2) The crude product of compound II is refluxed and pulped in an alcohol solvent, cooled to room temperature, filtered, and dried to obtain the refined product of compound II; (3) The purified product of compound II reacts with sodium hydroxide aqueous solution in an alcohol solvent to form a salt. After the reaction is complete, the solvent is evaporated, acetone is added and slurry is stirred, filtered, and dried to obtain compound I.
[0010] As a preferred embodiment, the organic base mentioned in step (1) of the method of the present invention is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, and 4-dimethylaminopyridine; Preferably, the molar ratio of the organic base to the compound of formula III in step (1) of the method of the present invention is 1:1 to 10:1.
[0011] Furthermore, the molar ratio of 2-bromoacetic acid to compound III in step (1) of the method of the present invention is 1:1 to 10:1.
[0012] As a preferred embodiment, the acid mentioned in step (1) of the method of the present invention is one or more of hydrochloric acid, sulfuric acid, and phosphoric acid.
[0013] Preferably, the alcohol solvent mentioned in step (2) of the method of the present invention is selected from one or more of methanol, ethanol, and isopropanol.
[0014] Furthermore, the alcohol solvent mentioned in step (3) of the method of the present invention is selected from one or more of methanol, ethanol, and isopropanol.
[0015] Preferably, the weight ratio of acetone to the purified compound of formula II in step (3) of the method of the present invention is 1:1 to 30:1.
[0016] This invention uses an organic base as an acid-binding agent. Compound III is reacted with 2-bromoacetic acid in tetrahydrofuran to prepare crude compound II. By optimizing the reaction parameters, compound III can be reacted almost completely, and the crude compound II obtained has an HPLC purity of over 98%. The crude compound II is then purified by pulping with an alcohol solvent, further increasing its purity to over 99%, significantly reducing the safety risks posed by impurities. This method is simple to operate, avoiding the cumbersome extraction and column chromatography purification procedures described in patent CN116102573A. The solvent used is recyclable, avoiding the generation of large amounts of nitrogenous wastewater when using N,N-dimethylformamide. The product yield and purity are significantly improved compared to existing technologies.
[0017] This invention provides a method for preparing the salt form of thiophene-pyrimidine mercaptoacetic acid compounds. The compound of formula II reacts with an alkali in an alcohol solvent to form a salt. After the reaction is completed, the solvent is evaporated. At this time, the product properties are not good. By screening various solvents such as acetone, toluene, tetrahydrofuran, and acetonitrile, acetone was selected for pulping. The resulting salt form of the compound of formula I has good properties and the product purity can reach 99.5%. Detailed Implementation
[0018] Example 1 Preparation of crude compound of formula II Compound III (60.0 g, 203.8 mmol), tetrahydrofuran (600 ml), and triethylamine (41.2 g, 407.6 mmol) were added to a reaction flask, stirred, and cooled to 10–15 °C. 2-Bromoacetic acid (31.1 g, 224.2 mmol) was added in portions while maintaining the temperature at 10–15 °C. After the addition was complete, the temperature was slowly raised to room temperature. The reaction was carried out at room temperature for 3 h. TLC analysis (using dichloromethane as the developing solvent) indicated the reaction was complete. Tetrahydrofuran was recovered under reduced pressure. Water (900 ml) was added, and dilute hydrochloric acid was added dropwise with stirring to adjust the pH to approximately 5. Stirring was continued for 1 h. The mixture was filtered, and the filter cake was washed with water until neutral. It was dried at 50–60 °C to obtain 70.4 g of a white solid, which was the crude compound II, with a yield of 98.0% and an HPLC purity of 98.0%.
[0019] Example 2 Preparation of crude compound of formula II Compound III (60.0 g, 203.8 mmol), tetrahydrofuran (600 ml), and triethylamine (51.5 g, 509.5 mmol) were added to a reaction flask, stirred, and cooled to 10–15 °C. 2-Bromoacetic acid (34.0 g, 244.6 mmol) was added in portions while maintaining the temperature at 10–15 °C. After the addition was complete, the temperature was slowly raised to room temperature. The reaction was carried out at room temperature for 3 h. TLC analysis (using dichloromethane as the developing solvent) indicated the reaction was complete, and tetrahydrofuran was recovered under reduced pressure. Water (500 ml) was added, and dilute hydrochloric acid was added dropwise with stirring to adjust the pH to approximately 5. Stirring was continued for 1 h. The mixture was filtered, and the filter cake was washed with water until neutral. It was dried at 50–60 °C to obtain 70.7 g of a white solid, which was the crude product of compound II, with a yield of 98.5% and an HPLC purity of 98.8%.
[0020] Example 3 Purification of crude compounds of formula II The crude product of Formula II obtained in Example 1 (20.0 g) and ethanol (100 ml) were added to a reaction flask, heated to reflux with stirring, and kept under reflux for 20 min. Then the mixture was cooled to room temperature, filtered, and dried at 50-60 °C to obtain 18.9 g of white solid, which is the purified product of Formula II, with a yield of 94.5% and an HPLC purity of 99.2%.
[0021] Example 4 Purification of crude compounds of formula II The crude product of Formula II obtained in Example 1 (20 g) and ethanol (160 ml) were added to a reaction flask, heated to reflux with stirring, and kept under reflux for 20 min. Then the mixture was cooled to room temperature, filtered, and dried at 50-60 °C to obtain 18.3 g of white solid, which is the purified product of Formula II, with a yield of 91.5% and an HPLC purity of 99.4%.
[0022] Example 5 Purification of crude compounds of formula II The crude product of Formula II obtained in Example 1 (10.0 g) and methanol (50 ml) were added to a reaction flask, heated to reflux with stirring, and kept under reflux for 20 min. Then the mixture was cooled to room temperature, filtered, and dried at 50-60 °C to obtain 8.6 g of white solid, which is the purified product of Formula II, with a yield of 86.0% and an HPLC purity of 99.0%.
[0023] Example 6 Purification of crude compounds of formula II The crude product of Formula II obtained in Example 1 (10.0 g) and isopropanol (50 ml) were added to a reaction flask, heated to reflux with stirring, and kept under reflux for 20 min. Then the mixture was cooled to room temperature, filtered, and dried at 50-60 °C to obtain 8.8 g of white solid, which is the purified product of Formula II, with a yield of 88.0% and an HPLC purity of 99.1%.
[0024] Example 7 Preparation of Formula I compounds The purified product of Formula II (30.0 g, 85.1 mmol) and methanol (300 ml) were added to a reaction flask. An aqueous solution of sodium hydroxide (3.4 g, 85.1 mmol) (120 ml) was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 h, and the solid gradually dissolved. The mixture was filtered to remove a small amount of insoluble matter, and the filtrate was evaporated under reduced pressure to obtain a viscous solid. Acetone (450 ml) was added and the mixture was refluxed and stirred for 2 h. The mixture was then cooled to room temperature, filtered, and dried at 50-60 °C to obtain 31.5 g of a white solid, which is the compound of Formula I. The obtained solid was loose and uniform in appearance. The yield was 99.1%, and the HPLC purity was 99.5%.
[0025] Example 8 Preparation of Formula I compounds The purified product of Formula II (5.0 g, 14.2 mmol) and methanol (50 ml) were added to a reaction flask. An aqueous solution of sodium hydroxide (0.57 g, 14.2 mmol) (20 ml) was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 h, and the solid gradually dissolved. The mixture was filtered to remove a small amount of insoluble matter, and the filtrate was evaporated under reduced pressure to obtain a viscous solid. Acetone (75 ml) was added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered, and dried at 50-60 °C to obtain 4.9 g of white solid, which is the compound of Formula I. The obtained solid contained some lumpy particles. The yield was 98.0%, and the HPLC purity was 99.5%.
[0026] Comparative Example 1 Preparation of Formula I compounds The purified product of Formula II (5.0 g, 14.2 mmol) and methanol (50 ml) were added to a reaction flask. An aqueous solution of sodium hydroxide (0.57 g, 14.2 mmol) (20 ml) was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 h, and the solid gradually dissolved. The mixture was filtered to remove a small amount of insoluble matter, and the filtrate was evaporated under reduced pressure to obtain a viscous solid. Acetonitrile (75 ml) was added and the mixture was stirred at about 60 °C for 2 h. The mixture was cooled to room temperature, filtered, and dried at 50-60 °C to obtain 3.5 g of white solid, which is the compound of Formula I, with a yield of 70.0% and an HPLC purity of 99.4%.
[0027] Comparative Example 2 Preparation of Formula I compounds The purified product of Formula II (5.0 g, 14.2 mmol) and methanol (50 ml) were added to a reaction flask. An aqueous solution of sodium hydroxide (0.57 g, 14.2 mmol) (20 ml) was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 h, and the solid gradually dissolved. The mixture was filtered to remove a small amount of insoluble matter, and the filtrate was evaporated under reduced pressure to obtain a viscous solid. Toluene (75 ml) was added and the mixture was stirred at about 60 °C for 2 h. The mixture was then cooled to room temperature, filtered, and dried at 50-60 °C to obtain 4.3 g of white lumpy solid, which is the compound of Formula I, with a yield of 86.0% and an HPLC purity of 99.4%.
[0028] Comparative Example 3 Preparation of Compounds of Formula II Compound III (20.0 g, 67.9 mmol), N,N-dimethylformamide (120 ml), and ground potassium carbonate (28.1 g, 203.7 mmol) were added to a reaction flask. 2-Bromoacetic acid (10.4 g, 74.7 mmol) was slowly added in portions with stirring. The reaction was carried out at room temperature for 10 h. TLC analysis (using dichloromethane as the developing solvent) showed that compound III remained. 500 ml of water was added to the system, and the pH was adjusted to weakly acidic by adding dilute hydrochloric acid. A solid precipitated, which was filtered, washed with water, and dried to obtain 21.8 g of a white solid, the crude compound II, with an HPLC purity of 88.2%. The crude compound II was purified by column chromatography (MeOH:DCM = 1:30) and then refined with ethyl acetate to obtain 16.3 g of a white solid, the purified compound II, with a yield of 68.2% and an HPLC purity of 96.5%.
[0029] For any points not covered above, existing technologies shall apply.
[0030] Although specific embodiments of the present invention have been described in detail by way of examples, those skilled in the art should understand that the above examples are for illustrative purposes only and are not intended to limit the scope of the invention. Those skilled in the art can make various modifications or additions to the described specific embodiments or use similar methods to replace them, without departing from the direction of the invention or exceeding the scope defined by the appended claims. Those skilled in the art should understand that any modifications, equivalent substitutions, improvements, etc., made to the above embodiments based on the technical essence of the present invention should be included within the protection scope of the present invention.
Claims
1. A method for preparing a thiophene-pyrimidine thioglycolic acid compound and its salt, characterized in that: Includes the following steps: (1) Using an organic base as an acid-binding agent, the compound of formula III reacts with 2-bromoacetic acid in tetrahydrofuran. After the reaction is complete, the solvent is evaporated, water is added, the pH is adjusted to about 5 with acid, filtered, and dried to obtain the crude product of compound II. (2) The crude product of compound II is refluxed and pulped in an alcohol solvent, cooled to room temperature, filtered, and dried to obtain the refined product of compound II; (3) The purified product of compound II reacts with sodium hydroxide aqueous solution in an alcohol solvent to form a salt. After the reaction is complete, the solvent is evaporated, acetone is added and slurry is stirred, filtered, and dried to obtain compound I. The compounds of Formula I, Formula II and Formula III are shown below: 。 2. The method according to claim 1, characterized in that: The organic base mentioned in step (1) is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, and 4-dimethylaminopyridine.
3. The method according to claim 1, characterized in that: The molar ratio of the organic base to the compound of formula III in step (1) is 1:1 to 10:
1.
4. The method according to claim 1, characterized in that: The molar ratio of 2-bromoacetic acid to compound III in step (1) is 1:1 to 10:
1.
5. The method according to claim 1, characterized in that: The acid mentioned in step (1) is one or more of hydrochloric acid, sulfuric acid, and phosphoric acid.
6. The method according to claim 1, characterized in that: The alcohol solvent mentioned in step (2) is selected from one or more of methanol, ethanol, and isopropanol.
7. The method according to claim 1, characterized in that: The alcohol solvent mentioned in step (3) is selected from one or more of methanol, ethanol, and isopropanol.
8. The method according to claim 1, characterized in that: The weight ratio of acetone to the purified compound of formula II in step (3) is 1:1 to 30:1.