A process for the synthesis of a pranlukast intermediate

Abstract

The application relates to the technical field of medicine preparation, and discloses a synthesis method of a pranlukast intermediate, which comprises the following steps: adding 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester, a solvent 1, a palladium-carbon catalyst and a copper catalyst into a reactor and uniformly mixing, introducing hydrogen after gas replacement, controlling a certain reaction temperature, keeping a certain pressure, filtering after reaction, recovering the catalyst in the filter cake, repeatedly using the filter cake for the following batch reaction, without adding the copper catalyst again, washing the filtrate with water, separating the liquid, adding a solvent 2 to the concentrated organic layer to perform crystallization, filtering and drying to obtain 8-amino-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester finished products. The method is simple in operation, low in requirement on equipment, high in yield, basically free of salt waste, friendly to the environment, high in purity of the obtained product, and can reach more than 99%, and the impurity is less than 0.5%.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically a method for synthesizing a prenstarc intermediate. Background Technology

[0002] Pranlukast is an oral selective cysteyl leukotriene receptor 1 (CysLT1) antagonist, belonging to the leukotriene receptor antagonist class of anti-asthmatic drugs. Developed by Ono Pharmaceutical Co., Ltd. of Japan, it was first marketed in Japan in 1995, becoming the world's first oral leukotriene receptor antagonist. This drug effectively inhibits airway inflammation and bronchoconstriction, primarily used for the prevention and long-term treatment of chronic bronchial asthma in adults and children. Clinical studies have shown that it improves lung function, reduces asthma symptoms, and is well-tolerated.

[0003] Ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate is an important intermediate for pranstar. There is a large market demand for ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate. Therefore, developing a new route suitable for industrialization based on existing literature has great social and economic benefits.

[0004] Currently, the main reported synthetic methods for ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate are: 1. Using ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate as a raw material, ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate was prepared in one step by reduction with stannous chloride under acidic conditions. (Chromenone Derivativesas Receptors for N-Benzoylamino Acids, Cesar Raposo et al, J. Chem. Soc., Perkin Trans. 1 (1994) 23 (15): 2113–2116.). This process uses a large amount of stannous chloride (6.5 mmol of stannous chloride was used for 1.5 mmol of raw material in the literature), and the production of 1 ton of product will generate 4-5 tons of tin salts, which will cause pollution in the wastewater.

[0005] 2. Using ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate as a raw material, ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate is prepared by palladium-catalyzed hydrogenation reduction in the presence of a strong base-weak acid salt or an organic base (Patent EP1479667A). This process involves the reduction of unsaturated bonds at other positions. While the addition of a strong base-weak acid salt or an organic base can suppress side reactions, 2-10% impurities are still generated, resulting in low selectivity. Furthermore, the added salt and organic base ultimately pollute the wastewater.

[0006] Each of the above methods has its own drawbacks, resulting in problems such as high production costs, large amounts of impurities, and pollution. Summary of the Invention

[0007] To address the aforementioned technical problems, the present invention aims to provide a method for synthesizing prenstar intermediates with good hydrogenation reduction selectivity, high yield, good product quality, and low pollution.

[0008] To achieve the above objectives, the present invention provides the following technical solution: The method includes the following steps: Ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate, solvent 1, palladium on carbon catalyst, and copper catalyst were added to the reactor and mixed evenly. After gas replacement, hydrogen gas was introduced. The reaction was carried out at a certain temperature and pressure. After the reaction was completed, the mixture was filtered. The filter cake was used as a recovered catalyst and could be reused in subsequent batches of reaction without the need to add copper catalyst again. The filtrate was washed with water and separated. The organic layer was concentrated and then crystallized by adding solvent 2. After filtration and drying, ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate was obtained.

[0009] Preferably, solvent 1 is one of ethanol, ethyl acetate, ethyl formate, benzene, toluene, or any combination thereof.

[0010] Preferably, the mass ratio of solvent 1 to ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate is 2-20:1.

[0011] Preferably, solvent 2 is one of n-hexane, n-heptane, cyclohexane, methylcyclohexane, petroleum ether, or any combination thereof.

[0012] Preferably, the reaction temperature is 20℃-100℃ and the reaction pressure is 0.1-5MPa.

[0013] Preferably, the palladium content in the palladium catalyst on carbon is 0.01-1%; the mass ratio of the palladium catalyst on carbon to ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate is 1:1-1000.

[0014] Preferably, the copper catalyst is a divalent copper salt; the molar ratio of the copper catalyst to the palladium in the palladium-carbon catalyst is 1:5-100.

[0015] Preferably, the copper catalyst is one of copper chloride, copper sulfate, copper nitrate, or any combination thereof.

[0016] Compared with the prior art, the beneficial effects of the present invention are: In this invention, ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate, solvent 1, palladium on carbon catalyst and copper catalyst are mixed evenly. After gas replacement, the mixture is heated to a certain temperature under a certain hydrogen pressure and the reaction is maintained. After the reaction is completed, the mixture is filtered, and the filter cake is reused in subsequent batches without the need to add copper catalyst again. The filtrate is washed with water and separated. After the organic layer is concentrated, solvent 2 is added to crystallize the mixture. The mixture is then filtered and dried to obtain ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate. In this invention, by adding a copper catalyst, copper ions adsorb onto palladium on carbon, causing partial poisoning of the palladium-carbon catalyst. Simultaneously, by controlling the reaction pressure and palladium content, the selectivity of the main reaction is greatly improved, and the occurrence of side reactions is reduced, thereby significantly increasing product yield and purity. The palladium-carbon catalyst, after one poisoning, can be reused in multiple batches without the need for repeated addition of copper catalyst. This method is simple to operate, requires minimal equipment, achieves high yield, and generates virtually no salt waste, making it environmentally friendly. The resulting product has high purity, reaching over 99%, with impurities <0.5%. Attached Figure Description

[0017] Figure 1 The reaction equation is for Example 1 of the present invention.

[0018] Figure 2 This is the LC-MS spectrum of the product in Embodiment 1 of the present invention.

[0019] Figure 3 The product of Embodiment 1 of the present invention 1 HNMR spectrum.

[0020] Figure 4 This is the HPLC chromatogram of the product from Example 1 of the present invention.

[0021] Figure 5 This is the HPLC spectrum of the product in Example 2 of the present invention.

[0022] Figure 6 This is the HPLC spectrum of the product from Example 3 of the present invention.

[0023] Figure 7 This is the HPLC chromatogram of the product in Example 4 of the present invention.

[0024] Figure 8 This is the HPLC spectrum of the product from Example 5 of the present invention.

[0025] Figure 9 This is the HPLC chromatogram of the product of Comparative Example 1 of the present invention. Detailed Implementation

[0026] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. 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 within the scope of protection of the present invention.

[0027] Example 1: Synthesis of ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate.

[0028] Add 131.6g of ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate and 500g of ethyl acetate to a 1L autoclave. Then add 5g of 0.5% palladium on carbon (purchased externally, model: Pd / C-0005400, manufacturer: Feima Catalyst, 50% water content) and 0.1g of 1% copper chloride aqueous solution. Combine the autoclaves, replace with N2 three times, replace with H2 three times, pressurize with H2 to 0.5MPa, heat to 55-60℃ and stir to maintain the temperature for reaction. During the reaction, pressurize with H2 to maintain the pressure at 0.5MPa. After 8 hours of reaction, take a sample. The reaction is considered complete when the remaining raw material is less than 0.5%. After the reaction was complete, the aeration was stopped, the reaction solution was vented, and then hot-filtered. The filtrate was washed with water and separated. The organic layer was desoluble under reduced pressure until a solid precipitated. 300 g of n-heptane was added, and the mixture was cooled to 0-5 °C to crystallize. The crystals were filtered, and the filter cake was washed with n-heptane and dried to obtain the product: 114.2 g, purity 99.3%, maximum single impurity 0.3%, yield 97.9%. LC-MS: m / z = 234.1, representing ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate [M+H]. + The peaks match the molecular weight, and the isotope peak ratios also conform; 1 HNMR: δ: 1.417-1.452 (t, 3H, -CH3), 4.382-4.486 (s+q, 4H, -NH2 and -CH2-), 7.046-7.078 (d+s, 2H, 6-position hydrogen of benzene ring and 4-position hydrogen of pyran ring), 7.192-7.232 (m, 1H, 5-position hydrogen of benzene ring), 7.494-7.513 (d, 1H, 4-position hydrogen of benzene ring). LC-MS, 1 HNMR and HPLC spectra of the product are shown below. Figures 2 to 4 .

[0029] Example 2: Synthesis of ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate.

[0030] Add 131.6g of ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate and 500g of ethyl acetate to a 1L autoclave. Then add 20g of 0.1% palladium on carbon (purchased externally, model: Pd / C-001400, manufacturer: Feima Catalyst, water content 56%) and 0.1g of 1% copper chloride aqueous solution. Combine the autoclaves, replace with N2 three times, and then replace with H2 three times. Pressurize with H2 to 0.3MPa, raise the temperature to 55-60℃, stir and maintain the temperature during the reaction. During the reaction, pressurize with H2 to maintain the pressure at 0.3MPa. After 12 hours of reaction, take a sample. The reaction is considered complete when the remaining raw material is less than 0.5%. After the reaction was complete, the aeration was stopped, the reaction solution was vented, and then hot-filtered. The filtrate was washed with water and separated. The organic layer was desoluble under reduced pressure until a solid precipitated. 300g of n-heptane was added, and the mixture was cooled to 0-5℃ to crystallize. The crystals were filtered, and the filter cake was washed with n-heptane and dried to obtain the product: 113.5g, purity 99.5%, maximum single impurity 0.2%, yield 97.3%. The HPLC chromatogram of the product is shown below. Figure 5 . Example 3: Synthesis of ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate.

[0031] Add 131.6g of ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate and 500g of ethyl acetate to a 1L autoclave. Then add 6g of 0.3% palladium on carbon (purchased externally, model: Pd / C-E003400, manufacturer: Feima Catalyst, water content 53%) and 0.1g of 1% copper sulfate aqueous solution. Combine the autoclaves, replace with N2 three times, replace with H2 three times, pressurize with H2 to 0.3MPa, heat to 55-60℃ and stir to maintain the temperature for reaction. During the reaction, pressurize with H2 to maintain the pressure at 0.3MPa. After 10 hours of reaction, take a sample. The reaction is considered complete when the remaining raw material is less than 0.5%. After the reaction was complete, the aeration was stopped, the reaction solution was vented, and then hot-filtered. The filtrate was washed with water and separated. The organic layer was desoluble under reduced pressure until a solid precipitated. 300g of n-heptane was added, and the mixture was cooled to 0-5℃ to crystallize. The crystals were filtered, and the filter cake was washed with n-heptane and dried to obtain the product: 114.1g, purity 99.3%, maximum single impurity 0.3%, yield 97.8%. The HPLC chromatogram of the product is shown below. Figure 6 .

[0032] Example 4: Synthesis of ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate.

[0033] In a 2L autoclave, 131.6g of ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate and 1000g of ethyl acetate were added, along with 5g of recovered catalyst (wet product, from Example 1). The autoclave was then closed, and the mixture was purged with N2 three times and H2 three times. The H2 pressure was increased to 0.1MPa, and the temperature was raised to 45-50℃. The mixture was stirred and kept at this temperature. During the reaction, the H2 pressure was maintained at 0.1MPa. After 15 hours of reaction, a sample was taken, and the reaction was considered complete when the remaining raw material was less than 0.5%. After the reaction was complete, the aeration was stopped, the reaction solution was vented, and the mixture was hot-filtered. The filtrate was washed with water and separated. The organic layer was desolventized under reduced pressure until a solid precipitated. 300g of n-heptane was added, and the mixture was cooled to 0-5℃ to crystallize. The crystals were filtered, and the filter cake was washed with n-heptane and dried to obtain 113.4g of the product with a purity of 99.4%, a maximum single impurity of 0.2%, and a yield of 97.2%. The HPLC chromatogram of the product is shown below. Figure 7 .

[0034] Example 5: Synthesis of ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate.

[0035] In a 1L autoclave, add 131.6g of ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate and 500g of ethyl acetate, then add 5g of recovered catalyst (wet product, from Example 4). Combine the autoclave, purge with N2 three times, then with H2 three times, pressurize with H2 to 1MPa, heat to 45-50℃ and stir to maintain the reaction temperature. During the reaction, maintain the H2 pressure at 1MPa. After 6 hours of reaction, take a sample. The reaction is considered complete when the remaining raw material is less than 0.5%. After the reaction is complete, stop the aeration, vent the reaction solution, pour it out and hot filter. Wash the filtrate with water and separate the layers. Desolventize the organic layer under reduced pressure until a solid precipitates. Add 300g of n-heptane, cool to 0-5℃ to crystallize, filter, wash the filter cake with n-heptane, and dry to obtain 114.6g of product with a purity of 99.3%, a maximum single impurity of 0.3%, and a yield of 98.3%. The HPLC chromatogram of the product is shown below. Figure 8 .

[0036] Comparative Example 1: Synthesis of ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate.

[0037] In a 1L autoclave, add 131.6g of ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate and 500g of ethyl acetate, then add 5g of 5% palladium on carbon (containing 50% water). Combine the autoclave, purge with N2 three times, then with H2 three times, pressurizing to 1MPa with H2, and heat to 55-60℃ with stirring and maintaining the temperature. During the reaction, maintain the pressure at 1MPa with H2. After 5 hours of reaction, take a sample; the reaction is considered complete when the remaining raw material is less than 0.5%. After the reaction is complete, stop the aeration, vent the reaction solution, pour it out, and hot filter. Wash the filtrate with water and separate the layers. Desolventize the organic layer under reduced pressure until a solid precipitates. Add 300g of n-heptane, cool to 0-5℃ to crystallize, filter, wash the filter cake with n-heptane, and dry to obtain 90.6g of product with a purity of 90.3%, a maximum single impurity of 6.5%, and a yield of 77.7%. The HPLC chromatogram of the product is shown below. Figure 9 .

[0038] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing a prensuline intermediate, characterized in that: The method includes the following steps: Ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate, solvent 1, palladium on carbon catalyst, and copper catalyst were added to the reactor and mixed evenly. After gas replacement, hydrogen gas was introduced. The reaction was carried out at a certain temperature and pressure. After the reaction was completed, the mixture was filtered. The filter cake was used as a recovered catalyst and could be reused in subsequent batches of reaction without the need to add copper catalyst again. The filtrate was washed with water and separated. The organic layer was concentrated and then crystallized by adding solvent 2. After filtration and drying, ethyl 8-amino-4-oxo-4H-1-benzopyran-2-carboxylate was obtained.

2. The method for synthesizing a prenlast intermediate according to claim 1, characterized in that: Solvent 1 is one of ethanol, ethyl acetate, ethyl formate, benzene, toluene, or any combination thereof.

3. The method for synthesizing a prensuline intermediate according to claim 1, characterized in that: The mass ratio of solvent 1 to ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate is 2-20:

1.

4. The method for synthesizing a prenlast intermediate according to claim 1, characterized in that: Solvent 2 is one of n-hexane, n-heptane, cyclohexane, methylcyclohexane, petroleum ether, or any combination thereof.

5. The method for synthesizing a prenlast intermediate according to claim 1, characterized in that: The reaction temperature is 20℃-100℃, and the reaction pressure is 0.1-5MPa.

6. The method for synthesizing a prenlast intermediate according to claim 1, characterized in that: The palladium content in the palladium-on-carbon catalyst is 0.01-1%; the mass ratio of the palladium-on-carbon catalyst to ethyl 8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate is 1:1-1000.

7. The method for synthesizing a prenlast intermediate according to claim 1, characterized in that: The copper catalyst is a divalent copper salt; the molar ratio of palladium in the copper catalyst to that in the palladium-carbon catalyst is 1:5-100.

8. The method for synthesizing a prenlast intermediate according to claim 7, characterized in that: The copper catalyst is one of copper chloride, copper sulfate, copper nitrate, or any combination thereof.

Images