Synthesis method of photo-degradation impurity C of key intermediate of atavtrombopag

Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a synthesis method of a photodegradation impurity C of an atavalopag key intermediate. The synthesis method comprises the following steps: adding 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine, a catalyst and alkali into a reaction solvent at room temperature, uniformly stirring, heating to 70-100 DEG C, and reacting for 3-4 hours; and carrying out reduced pressure distillation on the obtained reaction solution to remove the reaction solvent, adding the obtained solid into a recrystallization solvent, heating to 50-70 DEG C, dissolving, cooling, crystallizing, filtering, and drying the obtained solid to obtain the photodegradation impurity C which is 4, 4 '-bis (4-chlorothiophene-2-yl)-[5, 5'-bithiazole]-2, 2 '-diamine. Compared with a traditional light irradiation method, the synthesis method of the impurity C has the advantages that the reaction rate is greatly increased by selecting a cheap and easily available catalyst, the reaction conditions are mild, and separation and purification are easy.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and specifically relates to a method for synthesizing a photodegradable impurity C of a key intermediate of avatrombopag. Background Art

[0002] Avatrombopag is the world's first FDA-approved oral thrombopoietin receptor agonist (TPO-RA) for CLD-related thrombocytopenia. As the first domestic treatment for chronic liver disease (CLD)-related thrombocytopenia, it has introduced a world-leading "strong, long-lasting, safe and convenient" new diagnosis and treatment solution for Chinese chronic liver disease (CLD)-related thrombocytopenia patients. Impurity C is triggered by light and is also easily produced during the production and storage of intermediates. The research and control of impurity C directly affects the quality of the finished product of Avatrombopag.

[0003] The intermediate 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine is a common intermediate in multiple synthetic routes of avatrombopag. As shown in the following synthetic route, the original research route (CN1639157A) and other representative routes (CN112022825B) all use a common bromothiazolamine intermediate.

[0004]

[0005] The intermediate 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine is a white solid powder. Since there is a bromine atom substituent on its thiazole ring, the intermediate is prone to free radical reaction under light to form a photodegradable impurity C of debromination dimerization of the intermediate. The impurity C is dark brown in color. After being generated, it is not only easily transferred to the finished product, but also greatly affects the appearance of the finished product of avatrombopag. The reaction mechanism is as follows:

[0006] The preparation method of photodegradable impurity C usually uses strong light irradiation to accelerate the generation of photodegradable impurity C, and then separates and purifies it after enrichment. Direct irradiation of solid samples only works on the surface layer, and irradiation of the solution is affected by multiple factors such as transmittance and sample concentration, which greatly limits the production efficiency. Impurity C is easy to produce under light, but the color is very dark after production, which reduces the light transmittance of the solution and is not conducive to the further generation of impurity C. Therefore, the efficiency of preparing impurity C by irradiation is extremely low and cannot meet commercial needs. For example, when preparing impurity C by irradiation, the increase in impurity C after the intermediate is irradiated with strong light for 24 hours is only 0.75%, see Comparative Example 1 and Appendix of this application for details. Figure 3 And attached Figure 4 .

[0007] According to the guidelines for generic chemical drugs, the content of photodegradable impurity C in avatrombopag is required to be less than 0.15%. At the same time, impurity reference substances are also required as standard external standards during the factory inspection of drugs to accurately detect the impurity content in the drugs, providing a basis for drug manufacturers to control the impurity content during the production process.

[0008] Photodegradation impurity C is mainly used as an impurity reference substance for avatrombopag. It is used to identify and quantitatively analyze impurities in avatrombopag when developing and validating drug analysis methods to ensure the accuracy and reliability of the analysis methods; in addition, it is used to verify the purity and effectiveness of the drug in the quality control of avatrombopag production.

[0009] Compared with the irradiation method, the catalytic synthesis method is not affected by the color appearance, and the use of appropriate catalysts can achieve rapid and efficient mass production, which has obvious advantages in terms of time cost and economic cost. Therefore, exploring a new synthesis method for the photodegradation impurity C of the key intermediate of avatrombopag has become a technical problem that needs to be solved urgently. Summary of the invention

[0010] The technical problem to be solved by the present invention is to provide a method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag. The method uses a cheap and readily available catalyst to achieve rapid and efficient mass production of the photodegradable impurity C, thereby solving the problems of the conventional irradiation method, such as long cycle, difficulty in enrichment, and inability to meet commercial needs.

[0011] The method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag described in the present invention comprises the following steps: (1) Add avatrombopag intermediate 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine, catalyst and base to the reaction solvent in sequence at room temperature, stir evenly and then heat to 70-100°C for reaction for 3-4 hours; (2) The reaction solution obtained in step (1) is distilled under reduced pressure to remove the reaction solvent, the obtained solid is added to a recrystallization solvent and heated to 50-70° C. for dissolution, the temperature is lowered for crystallization and then filtered, and the obtained solid is dried to obtain a photodegradable impurity C, wherein the photodegradable impurity C is 4,4'-bis(4-chlorothiophene-2-yl)-[5,5'-bithiazole]-2,2'-diamine.

[0012] in: The reaction solvent in step (1) is one of acetonitrile, ethyl acetate or N,N-dimethylformamide; preferably, the reaction solvent is one of acetonitrile or ethyl acetate.

[0013] The catalyst in step (1) is one of cyclohexanol, cyclopentanol or n-hexanol; preferably, the catalyst is one of cyclopentanol or cyclohexanol.

[0014] In step (1), the base is one of triethylamine, N,N-diisopropylethylamine (DIPEA) or pyridine; preferably, the base is one of triethylamine or N,N-diisopropylethylamine (DIPEA).

[0015] The structural formula of 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine in step (1) is: .

[0016] The mass ratio of the volume of the reaction solvent in step (1) to 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine is 10, expressed in mL / g.

[0017] In step (1), the mass ratio of the catalyst to 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine is 0.05-0.2; preferably, the mass ratio is 0.1-0.15.

[0018] In step (1), the mass ratio of 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine to the base is 0.5-2; preferably, the mass ratio is 0.5-1.

[0019] The recrystallization solvent in step (2) is a mixture of one of n-hexane, n-heptane or cyclohexane and ethyl acetate, and the volume ratio of ethyl acetate to one of n-hexane, n-heptane or cyclohexane is 2:1.

[0020] The mass ratio of the volume of the recrystallization solvent added in step (2) to 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine is 3:1, expressed in mL / g.

[0021] The temperature for cooling and crystallizing in step (2) is -10~20°C, and the time for cooling and crystallizing is 1h.

[0022] In step (2), the drying temperature is 50°C-60°C and the drying time is 3h-5h.

[0023] The structural formula of the photodegradable impurity C in step (2) is: .

[0024] Compared with the prior art, the present invention has the following beneficial effects: The method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag described in the present invention greatly improves the reaction rate by selecting a cheap and readily available catalyst, has mild reaction conditions, is easy to separate and purify, and the production scale is not limited by special equipment such as photoreactors. The application of the present invention can meet the commercialization needs of impurity C quickly, efficiently and economically. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the H NMR spectrum of impurity C in Example 1; Figure 2 is the NMR carbon spectrum of impurity C in Example 1; Figure 3 This is the liquid chromatogram of the intermediate in Comparative Example 1 before irradiation (0 time); Figure 4 This is the liquid chromatogram of the intermediate of Comparative Example 1 after irradiation for 24 hours; Figure 5 The liquid chromatogram of the intermediate of Comparative Example 2 is shown below; Figure 6 The liquid chromatography spectrum of the intermediate of Comparative Example 3 is shown in FIG. DETAILED DESCRIPTION

[0026] The present invention is further described below with reference to the embodiments.

[0027] Example 1 The method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag described in Example 1 comprises the following steps: (1) Add 100 mL of acetonitrile to a three-necked flask at room temperature, start stirring, then add 10.0 g of avatrombopag intermediate 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine, 1.0 g of cyclohexanol and 10.0 g of triethylamine in sequence, stir evenly, then heat to 80 °C and stir for 3.5 h; (2) Stop the reaction, remove acetonitrile by vacuum distillation of the reaction solution, add 20 mL of ethyl acetate and 10 mL of n-hexane to the obtained solid, heat to 60°C and stir to dissolve, cool naturally to room temperature and then continue to cool to 0°C for crystallization for 1 hour, filter the obtained solid and dry it at 55°C for 4 hours to obtain the photodegradation impurity C, with a purity of 97.43% and a mass yield of 71.2%. The H NMR spectrum of the photodegradation impurity C is attached. Figure 1 The NMR carbon spectrum of the photodegradation impurity C is shown in the attached Figure 2 , by attaching Figure 1 and attached Figure 2 It can be concluded that the structure of the compound obtained by this method is consistent with the theoretical structure of the impurity C of the target compound, and no obvious impurities are found in the compound, indicating that this synthesis method can obtain impurity C with higher purity.

[0028] Example 2 The method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag described in Example 2 comprises the following steps: (1) Add 100 mL of ethyl acetate to a three-necked flask at room temperature, start stirring, then add 10.0 g of avatrombopag intermediate 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine, 0.5 g of cyclopentanol and 5.0 g of N,N-diisopropylethylamine in sequence, stir evenly, then heat to 70 °C and stir for 4 h; (2) Stop the reaction, remove ethyl acetate by distillation under reduced pressure, add 20 mL of ethyl acetate and 10 mL of n-heptane to the obtained solid, heat to 50 °C, stir and dissolve, cool naturally to room temperature, and then continue to cool to -10 °C for crystallization for 1 h. Filter the obtained solid and dry it at 60 °C for 3 h to obtain the photodegradation impurity C with a purity of 97.37% and a mass yield of 70.5%.

[0029] Example 3 The method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag described in Example 3 comprises the following steps: (1) Add 100 mL of N,N-dimethylformamide to a three-necked flask at room temperature, start stirring, then add 10.0 g of avatrombopag intermediate 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine, 2.0 g of n-hexanol and 20.0 g of pyridine in sequence, stir evenly, then heat to 100 °C and stir for 3 h; (2) Stop the reaction, add 50 mL of water to the reaction solution, stir to precipitate solid and filter, add 20 mL of ethyl acetate and 10 mL of cyclohexane to the obtained solid, heat to 70 °C and stir to dissolve, cool naturally to room temperature and continue to cool to 20 °C to keep warm for 1 hour to crystallize, filter the obtained solid and dry it at 50 °C for 5 hours to obtain photodegradation impurity C with a purity of 97.26% and a mass yield of 69.8%.

[0030] Comparative Example 1 The method for generating impurity C from the avatrombopag intermediate described in Comparative Example 1 by light irradiation comprises the following steps: Take 2.0g of the intermediate 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine and spread it in a petri dish with a diameter of 12cm. Take an appropriate amount of the intermediate (at 0) to test the liquid phase purity (see attached Figure 3 ), place the culture dish in an irradiation box with its lid open for light damage, the light reference setting is: UV intensity 90µw / cm 2 , visible light intensity 5000Lux. After leaving it under the above conditions for 24 hours, take out the sample. The surface of the sample changes from white to brown. Collect the sample into a ziplock bag and shake it thoroughly. Finally, take the mixed sample to test the liquid phase purity (see attached Figure 4 ).

[0031] Liquid phase spectrum at 0 time (attached Figure 3 ) shows that the intermediate does not contain impurity C before irradiation. After 24 hours of irradiation, the liquid phase spectrum (attached Figure 4 ), but the content of impurity C was low, accounting for only 0.75%, indicating that impurity C was easily produced under light, but its content was difficult to enrich.

[0032] Comparative Example 2 The method for influencing the synthesis of photodegradable impurities C without adding a catalyst described in Comparative Example 2 comprises the following steps: Add 100 mL of acetonitrile to a three-necked flask at room temperature, start stirring, then add 10.0 g of avatrombopag intermediate 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine and 10.0 g of triethylamine in sequence, stir evenly and heat to 80°C, keep stirring and react for 3 hours. After stopping the reaction, take the reaction solution for liquid chromatography inspection.

[0033] Liquid chromatography results (attached Figure 5 ) showed that the target peak of impurity C was not found in the above reaction solution, and only unreacted intermediates remained; indicating that in the absence of a catalyst, the intermediate could not generate impurity C in an alkaline environment.

[0034] Comparative Example 3 The method for influencing the synthesis of photodegradable impurity C without adding alkali described in this comparative example 3 comprises the following steps: Add 100 mL of acetonitrile to a three-necked flask at room temperature and start stirring. Then add 10.0 g of avatrombopag intermediate 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine and 1.0 g of cyclohexanol in sequence. After stirring evenly, heat to 80°C and stir to react for 3 hours. After stopping the reaction, take the reaction solution for liquid chromatography inspection.

[0035] Liquid chromatography results (attached Figure 6 ) shows that the target peak of impurity C is not found in the above reaction solution, and only unreacted intermediates remain; indicating that in the case of only catalyst without base, the intermediate cannot generate impurity C.

Claims

1. A method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag, characterized in that: The following steps are involved: (1) Add avatrombopag intermediate 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine, catalyst and base to the reaction solvent in sequence at room temperature, stir evenly and then heat to 70-100°C for reaction for 3-4 hours; (2) The reaction solution obtained in step (1) is distilled under reduced pressure to remove the reaction solvent, the obtained solid is added to a recrystallization solvent and heated to 50-70° C. for dissolution, the temperature is lowered for crystallization and then filtered, and the obtained solid is dried to obtain a photodegradable impurity C, wherein the photodegradable impurity C is 4,4'-bis(4-chlorothiophene-2-yl)-[5,5'-bithiazole]-2,2'-diamine.

2. The method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag according to claim 1, characterized in that: The reaction solvent in step (1) is one of acetonitrile, ethyl acetate or N,N-dimethylformamide.

3. The method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag according to claim 1, characterized in that: The catalyst in step (1) is one of cyclohexanol, cyclopentanol or n-hexanol.

4. The method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag according to claim 1, characterized in that: The base in step (1) is one of triethylamine, N,N-diisopropylethylamine (DIPEA) or pyridine.

5. The method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag according to claim 1, characterized in that: The structural formula of 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine in step (1) is: 。 6. The method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag according to claim 1, characterized in that: The mass ratio of the volume of the reaction solvent in step (1) to 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine is 10, expressed in mL / g; In step (1), the mass ratio of the catalyst to 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine is 0.05-0.2; In step (1), the mass ratio of 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine to the base is 0.5-2.

7. The method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag according to claim 1, characterized in that: The recrystallization solvent in step (2) is a mixture of one of n-hexane, n-heptane or cyclohexane and ethyl acetate, and the volume ratio of ethyl acetate to one of n-hexane, n-heptane or cyclohexane is 2:

1.

8. The method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag according to claim 1, characterized in that: The mass ratio of the volume of the recrystallization solvent added in step (2) to 5-bromo-4-(4-chloro-2-thienyl)-2-thiazolamine is 3:1, expressed in mL / g.

9. The method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag according to claim 1, characterized in that: The temperature for cooling and crystallizing in step (2) is -10-20°C, and the time for cooling and crystallizing is 1 hour; the drying temperature in step (2) is 50-60°C, and the drying time is 3-5 hours.

10. The method for synthesizing the photodegradable impurity C of the key intermediate of avatrombopag according to claim 1, characterized in that: The structural formula of the photodegradable impurity C in step (2) is: .

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