A method for synthesizing a pharmaceutical intermediate 4H-pyrido[1,2-a]pyrimidin-4-one derivative and a catalytic system

Abstract

The application discloses a synthesis method and a catalytic system of a pharmaceutical intermediate 4H-pyrido[1,2-a]pyrimidin-4-one derivative. The catalytic system is composed of an acidic eutectic solvent as a catalyst and toluene as a reaction solvent, wherein the acidic eutectic solvent is obtained by mixing and heating choline chloride and zinc chloride. The method is to synthesize 4H-pyrido[1,2-a]pyrimidin-4-one derivative by taking 2-aminopyridine compound and ethyl acetoacetate as reaction raw materials and under the catalysis of the catalytic system composed of the acidic eutectic solvent and toluene. The method provided by the application can significantly improve the utilization rate of raw materials, shorten the reaction time, and the product purification process is simple, convenient, economical, efficient and environment-friendly. In addition, the catalytic system composed of the catalyst and the reaction solvent can be recycled for multiple times and regenerated after simple treatment.

Description

Technical Field

[0001] This invention relates to the field of catalytic synthesis technology of pharmaceutical intermediates, and particularly to a method and catalytic system for synthesizing a pharmaceutical intermediate 4H-pyrido[1,2-a]pyrimidine-4-one derivative. Background Technology

[0002] Nitrogen-containing heterocycles are important skeletal structures in natural products and drug molecules, possessing diverse pharmacological activities and making them a key research focus in drug development. Furthermore, nitrogen-containing heterocyclic compounds exhibit various biological activities, such as significant antibacterial, antiviral, and antidepressant effects, with some compounds already successfully applied clinically. 4H-pyrido[1,2-a]pyrimidine-4-one derivatives have attracted considerable attention due to their excellent biological and pharmacological activities. They possess a wide range of biological activities, including antidepressant, antimalarial, anti-inflammatory, anticancer, and anti-allergic effects, and can also act as aldose reductase inhibitors and 5-HT6 antagonists, exhibiting excellent pharmacokinetic properties and low toxicity. As an important pharmaceutical intermediate, many pharmaceutical companies have developed numerous drugs using 4H-pyrido[1,2-a]pyrimidine-4-one derivatives as their parent structure, such as liximab for treating spinal muscular atrophy in patients aged 2 months and older, and risperidone for treating schizophrenia. Therefore, the synthesis of 4H-pyrido[1,2-a]pyrimidine-4-one derivatives has become a hot topic of research.

[0003] In recent years, eutectic solvents, as a type of eutectic mixture produced by the combined reaction of hydrogen bond acceptors (such as quaternary ammonium salts) and hydrogen bond donors (such as amides, carboxylic acids, and polyols) in a certain stoichiometric ratio at a specific temperature, have been widely used in many fields, such as extraction, separation, and catalysis, due to their green, inexpensive, and easy-to-prepare characteristics. As an important type of eutectic solvent, acidic eutectic solvents composed of hydrogen bond acceptors and hydrogen bond donors such as organic or inorganic acids can be used as acid catalysts in organic synthesis reactions.

[0004] Existing catalytic systems have drawbacks such as being non-recyclable and non-renewable, requiring column chromatography for product purification, and resulting in long reaction times, low raw material utilization, and severe environmental pollution due to poor catalyst activity. Summary of the Invention

[0005] The purpose of this invention is to provide a method and catalytic system for synthesizing the pharmaceutical intermediate 4H-pyrido[1,2-a]pyrimidin-4-one derivative. The method provided by this invention significantly improves the utilization rate of raw materials, shortens the reaction time, and the product purification process is simple, convenient, economical, efficient, and environmentally friendly. Furthermore, the catalytic system composed of the catalyst and reaction solvent can be recycled multiple times and regenerated after simple treatment, thus solving the problems mentioned in the background art, such as the inability to recycle and regenerate the catalytic system, the need for column chromatography for product purification, and the long reaction time, low raw material utilization, and severe environmental pollution caused by poor catalyst activity.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] A catalytic system for the synthesis of a pharmaceutical intermediate, 4H-pyrido[1,2-a]pyrimidin-4-one derivative, comprising an acidic eutectic solvent as a catalyst and toluene as a reaction solvent, wherein the acidic eutectic solvent is obtained by mixing and heating choline chloride and zinc chloride in a molar ratio of 1:4.

[0008] Furthermore, the catalytic system is applied, and the preparation process of the catalytic system is as follows:

[0009] Add an appropriate volume of toluene to a three-necked flask equipped with a magnetic stirrer and a spherical condenser. Add an appropriate amount of acidic eutectic solvent while stirring vigorously at room temperature. Mix thoroughly to form a heterogeneous catalytic system.

[0010] A method for synthesizing a pharmaceutical intermediate, 4H-pyrido[1,2-a]pyrimidin-4-one derivative, is disclosed. This method uses 2-aminopyridine compounds and ethyl acetoacetate as reactants, and synthesizes the 4H-pyrido[1,2-a]pyrimidin-4-one derivative under the catalysis of an acidic eutectic solvent and toluene. The chemical reaction formula is as follows:

[0011]

[0012] The specific steps of the synthesis method are as follows:

[0013] (1) Weighing of raw materials: Weigh the 2-aminopyridine compound and ethyl acetoacetate of the reaction raw materials accurately according to a molar ratio of 1:1.

[0014] (2) Catalytic reaction: The weighed reaction raw materials are added to the catalytic system and mixed evenly. Then, under vigorous stirring, the mixture is slowly heated in a methyl silicone oil bath to the required reaction temperature. The reaction temperature is maintained until the raw material spot disappears. When the reaction is over, the stirring and heating are immediately turned off and the three-necked flask is removed from the oil bath. The mixture is allowed to cool naturally to room temperature. The liquid is separated, and the upper liquid is evaporated to remove toluene and collected to obtain the solid crude product.

[0015] (3) Purification of the product: The obtained crude solid product was recrystallized from ethanol to finally obtain the 4H-pyrido[1,2-a]pyrimidin-4-one derivative.

[0016] (4) Recycling of the catalytic system: The lower layer of liquid obtained from the separation in (2) is mixed with the collected toluene without any treatment, and the reactants are added directly under magnetic stirring. The catalyst is recycled according to the steps in (2) and (3). When the liquid chromatography purity of the product 4H-pyrido[1,2-a]pyrimidin-4-one derivative is lower than 98.5% or its yield decreases by more than 5% compared with the first use of the catalytic system, the catalytic system is stopped from recycling and enters (5) for regeneration.

[0017] (5) Regeneration of the catalytic system: Add an appropriate volume of ethyl acetate detergent to the lower layer liquid generated in (2) during the last cycle of the catalytic system, stir magnetically for 20 minutes, and then separate the liquid. Then add the same volume of ethyl acetate to the lower layer liquid, stir magnetically for 20 minutes, and then separate the liquid again. Repeat this process 3 times. Finally, dry the lower layer liquid obtained in the third cycle under vacuum at 85°C to constant weight to obtain the regenerated catalyst.

[0018] Next, add it to a new solvent consisting of the toluene collected in (2) and the toluene that needs to be added to make up the required volume, stir well, and you can get a regenerated catalytic system.

[0019] Furthermore, the reaction temperature in step two is 97–108°C.

[0020] Furthermore, the reaction pressure is one atmosphere, and the reaction time is 41–84 min.

[0021] Furthermore, the volume of the reaction solvent toluene, in milliliters, is 6 to 8 times the amount of the 2-aminopyridine compound, in millimoles, and the amount of the acidic eutectic solvent catalyst used is 5 to 8 times the amount of the 2-aminopyridine compound.

[0022] Furthermore, in step five, ethyl acetate wash is used at a volume of 2 to 5 times that of the reaction solvent toluene.

[0023] Furthermore, the chemical reaction formula for the 4H-pyrido[1,2-a]pyrimidin-4-one derivative synthesized by the synthetic method is as follows:

[0024] .

[0025] Furthermore, the 2-aminopyridine compound is selected from... ... , , , , , , , , , , and Any one of them.

[0026] Compared with the prior art, the beneficial effects of the present invention are:

[0027] 1. This invention relates to the synthesis of 4H-pyrido[1,2-a]pyrimidin-4-one derivatives using 2-aminopyridine compounds and ethyl acetoacetate as reactants in a catalytic system composed of an acidic eutectic solvent and toluene. By using the catalytic system of this invention to synthesize 4H-pyrido[1,2-a]pyrimidin-4-one derivatives and optimizing the reaction process parameters, the utilization rate of reactants and the yield of products can be significantly improved, and the product purification process can be simplified, resulting in good atom economy.

[0028] 2. The catalytic system of this invention has advantages such as high catalytic activity, recyclability, and regeneration. Furthermore, the amount of catalyst used during the catalytic process and the amount lost during recycling are both low, allowing for a high number of recycling cycles. More importantly, the catalytic system requires no pretreatment or regeneration before recycling, making it simple, economical, efficient, and offering significant environmental and social benefits, thus facilitating large-scale industrial production.

[0029] 3. The reaction pressure of this invention is one atmosphere, the reaction time is short, the reaction conditions are relatively mild, and it is easy to operate in practice. In addition, the reactants do not need to be added in batches, which makes it highly operable, and the purification process of the product is simple, thus facilitating industrial-scale production. Attached Figure Description

[0030] Figure 1 The 1H NMR spectrum of the product 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one in Example 1;

[0031] Figure 2The carbon NMR spectrum of the product 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one in Example 1;

[0032] Figure 3 The 1H NMR spectrum of the product 9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one in Example 7;

[0033] Figure 4 The image shows the carbon NMR spectrum of the product 9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one from Example 7. Detailed Implementation

[0034] 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.

[0035] The synthesis method of the acidic eutectic solvent catalyst used in this invention is based on the relevant material (Preparation of novel, moisture-stable, Lewis-acidic ionic liquids containing quaternary ammonium salts with functional side chains [J], Chemical Communications, 2001, 19: 2010-2011).

[0036] The essential features and significant effects of the present invention can be seen from the following embodiments, but they do not limit the present invention in any way. Any non-essential improvements and adjustments made by those skilled in the art based on the content of the present invention are within the protection scope of the present invention.

[0037] The present invention will be further described below through specific embodiments, wherein the reaction products in the embodiments were tested and characterized using an AVANCE NEO 300MHz nuclear magnetic resonance spectrometer from Bruker GmbH, Germany; and the melting point was determined using a capillary melting point apparatus from Shanghai Jiahang Instruments Co., Ltd.

[0038] Example 1

[0039] 6 ml of toluene was added to a three-necked flask equipped with a magnetic stirrer and a spherical condenser. 0.05 mmol of an acidic eutectic solvent was then added while stirring at room temperature, and the mixture was thoroughly mixed to form a heterogeneous catalytic system. Next, 1 mmol of 2-aminopyridine and 1 mmol of ethyl acetoacetate were added while stirring, and the mixture was thoroughly mixed to form a reaction system. The mixture was then heated uniformly to 97 °C in a methyl silicone oil bath and maintained at this temperature for 41 min. Once the starting material spot disappeared as detected by TLC (thin-plate chromatography), heating was immediately stopped, magnetic stirring was resumed, and the three-necked flask was removed from the oil bath. The mixture was allowed to cool naturally to room temperature, and the reaction solution was transferred to a separatory funnel for separation. The toluene was then evaporated from the supernatant and collected, yielding a white solid crude product. Finally, the crude product was recrystallized from ethanol and dried under vacuum at 75 °C to constant weight to obtain white crystals, with a mass of 0.16 g. The purity was determined to be 99.4% by high performance liquid chromatography, and the yield was calculated to be 97%. The white crystals were identified as 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one by melting point determination and nuclear magnetic resonance hydrogen and carbon spectrum detection.

[0040] The properties and structural parameters of the product 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one obtained in this embodiment are as follows:

[0041]

[0042] mp 118~120℃; 1 H NMR (300MHz, CDCl3): δ = 2.48 (s, 3H), 6.36 (s, 1H), 7.14 (t, J = 7.2Hz, 1H), 7.64 (d, J = 7.6Hz, 1H), 7.74 (t, J = 8.1Hz, 1H), 9.06 (d, J = 7.2Hz, 1H);

[0043] 13 C NMR (75.47MHz, CDCl3): δ = 165.2, 157.8, 150.6, 136.4, 127.2, 125.5, 115.2, 103.3, 24.4.

[0044] Example 2

[0045] 7 ml of toluene was added to a three-necked flask equipped with a magnetic stirrer and a spherical condenser. 0.07 mmol of an acidic eutectic solvent was added under stirring at room temperature, and the mixture was homogeneous to form a heterogeneous catalytic system. Then, 1 mmol of 2-amino-3-methylpyridine and 1 mmol of ethyl acetoacetate were added under stirring, and the mixture was homogeneous to form a reaction system. The mixture was then heated uniformly to 101 °C in a methyl silicone oil bath and maintained at this temperature for 59 min. When the starting material spot disappeared as detected by TLC (thin-plate chromatography), heating was immediately stopped, magnetic stirring was resumed, and the three-necked flask was removed from the oil bath. The mixture was allowed to cool naturally to room temperature, and the reaction solution was transferred to a separatory funnel for separation. The toluene was then evaporated from the upper layer and collected, yielding a white solid crude product. Finally, the crude product was recrystallized from ethanol and dried under vacuum at 75 °C to constant weight to obtain white crystals, with a mass of 0.16 g. The purity was determined to be 99.2% by high performance liquid chromatography, and the yield was calculated to be 90%. The white crystals were identified as 2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one by melting point determination and nuclear magnetic resonance hydrogen and carbon spectrum detection.

[0046] The properties and structural parameters of the product 2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one obtained in this embodiment are as follows:

[0047]

[0048] mp 122~124℃; 1 H NMR (300MHz, CDCl3): δ = 2.38 (s, 3H), 2.43 (s, 3H), 6.19 (s, 1H), 6.90 (d, J = 7.5Hz, 1H), 7.31 (s, 1H), 8.85 (d, J = 7.2Hz, 1H);

[0049] 13 C NMR (75.47MHz, CDCl3): δ = 164.5, 158.4, 150.2, 134.7, 134.4, 125.2, 114.3, 103.0, 24.8, 18.2.

[0050] Example 3

[0051] 7 ml of toluene was added to a three-necked flask equipped with a magnetic stirrer and a spherical condenser. 0.07 mmol of an acidic eutectic solvent was then added under stirring at room temperature, and the mixture was thoroughly mixed to form a heterogeneous catalytic system. Next, 1 mmol of 2-amino-4-methylpyridine and 1 mmol of ethyl acetoacetate were added under stirring, and the mixture was thoroughly mixed to form a reaction system. The mixture was then heated uniformly in a methyl silicone oil bath to 103 °C and maintained at this temperature for 63 min. When the starting material spot disappeared as detected by TLC (thin-plate chromatography), heating was immediately stopped, magnetic stirring was resumed, and the three-necked flask was removed from the oil bath. The mixture was allowed to cool naturally to room temperature, and the reaction solution was transferred to a separatory funnel for separation. The toluene was then evaporated from the supernatant and collected, yielding a white solid crude product. Finally, the crude product was recrystallized from ethanol and dried under vacuum at 75 °C to constant weight to obtain white crystals, with a mass of 0.15 g. The purity was determined to be 99.3% by high performance liquid chromatography, and the yield was calculated to be 88%. The white crystals were identified as 2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one by melting point determination and nuclear magnetic resonance hydrogen and carbon spectrum detection.

[0052] The properties and structural parameters of the product 2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one obtained in this embodiment are as follows:

[0053]

[0054] mp 97~99℃; 1 H NMR (300MHz, CDCl3): δ = 2.28 (s, 3H), 2.33 (s, 3H), 6.18 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.46 (d, J = 8.8Hz, 1H), 8.69 (s, 1H);

[0055] 13 C NMR (75.47MHz, CDCl3): δ = 164.3, 157.5, 149.2, 138.4, 124.7, 124.1, 102.6, 24.5, 18.0.

[0056] Example 4

[0057] 7 ml of toluene was added to a three-necked flask equipped with a magnetic stirrer and a spherical condenser. 0.07 mmol of an acidic eutectic solvent was added under stirring at room temperature, and the mixture was homogeneous to form a heterogeneous catalytic system. Then, 1 mmol of 2-amino-5-methylpyridine and 1 mmol of ethyl acetoacetate were added under stirring, and the mixture was homogeneous to form a reaction system. The mixture was then heated uniformly to 99 °C in a methyl silicone oil bath and maintained at this temperature for 47 min. When the starting material spot disappeared as detected by TLC (thin-plate chromatography), heating was immediately stopped, magnetic stirring was resumed, and the three-necked flask was removed from the oil bath. The mixture was allowed to cool naturally to room temperature, and the reaction solution was transferred to a separatory funnel for separation. The toluene was then evaporated from the supernatant and collected, yielding a brown solid crude product. Finally, the crude product was recrystallized from ethanol and dried under vacuum at 75 °C to constant weight to obtain brown crystals, with a mass of 0.17 g. The purity was determined to be 99.5% by high performance liquid chromatography, and the yield was calculated to be 95%. The brown crystal was identified as 2,8-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one by melting point determination and nuclear magnetic resonance hydrogen and carbon spectrum detection.

[0058] The properties and structural parameters of the product 2,8-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one obtained in this embodiment are as follows:

[0059]

[0060] mp 133~135℃; 1 H NMR (300MHz, CDCl3): δ = 2.41 (s, 3H), 2.46 (s, 3H), 6.24 (s, 1H), 6.93 (d, J = 7.5Hz, 1H), 7.35 (s, 1H), 8.87 (d, J = 7.2Hz, 1H);

[0061] 13 C NMR (75.47MHz, CDCl3): δ = 165.2, 157.8, 150.4, 148.2, 126.5, 123.8, 117.8, 107.3, 24.7, 21.4.

[0062] Example 5

[0063] 7 ml of toluene was added to a three-necked flask equipped with a magnetic stirrer and a spherical condenser. 0.07 mmol of an acidic eutectic solvent was added under stirring at room temperature, and the mixture was thoroughly mixed to form a heterogeneous catalytic system. Then, 1 mmol of 2-amino-6-methylpyridine and 1 mmol of ethyl acetoacetate were added under stirring, and the mixture was thoroughly mixed to form a reaction system. The mixture was then heated uniformly to 97 °C in a methyl silicone oil bath and maintained at this temperature for 45 min. When the starting material spot disappeared as detected by TLC (thin-plate chromatography), heating was immediately stopped, magnetic stirring was resumed, and the three-necked flask was removed from the oil bath. The mixture was allowed to cool naturally to room temperature, and the reaction solution was transferred to a separatory funnel for separation. The toluene was then evaporated from the upper layer and collected, yielding a yellow solid crude product. Finally, the crude product was recrystallized from ethanol and dried under vacuum at 75 °C to constant weight to obtain yellow crystals, with a mass of 0.17 g. The purity was determined to be 99.3% by high performance liquid chromatography, and the yield was calculated to be 96%. The yellow crystals were identified as 2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one by melting point determination and nuclear magnetic resonance hydrogen and carbon spectrum detection.

[0064] The properties and structural parameters of the product 2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one obtained in this embodiment are as follows:

[0065]

[0066] mp 85~87℃; 1 H NMR (300MHz, CDCl3): δ = 2.37 (s, 3H), 2.41 (s, 3H), 6.20 (s, 1H), 6.89 (d, J = 7.5Hz, 1H), 7.28 (s, 1H), 8.84 (d, J = 7.2Hz, 1H);

[0067] 13 C NMR (75.47MHz, CDCl3): δ = 165.5, 157.9, 150.9, 148.5, 126.6, 124.0, 117.7, 102.1, 24.8.

[0068] Example 6

[0069] 7 ml of toluene was added to a three-necked flask equipped with a magnetic stirrer and a spherical condenser. 0.06 mmol of an acidic eutectic solvent was then added under stirring at room temperature, and the mixture was thoroughly mixed to form a heterogeneous catalytic system. Next, 1 mmol of 2-amino-5-fluoropyridine and 1 mmol of ethyl acetoacetate were added under stirring, and the mixture was thoroughly mixed to form a reaction system. The mixture was then heated uniformly in a methyl silicone oil bath to 104 °C and maintained at this temperature for 62 min. When the starting material spot disappeared as detected by TLC (thin-plate chromatography), heating was immediately stopped, magnetic stirring was resumed, and the three-necked flask was removed from the oil bath. The mixture was allowed to cool naturally to room temperature, and the reaction solution was transferred to a separatory funnel for separation. The toluene was then evaporated from the supernatant and collected, yielding a yellow solid crude product. Finally, the crude product was recrystallized from ethanol and dried under vacuum at 75 °C to constant weight to obtain yellow crystals, with a mass of 0.16 g. The purity was determined to be 99.4% by high performance liquid chromatography, and the yield was calculated to be 88%. The yellow crystals were identified as 7-fluoro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one by melting point determination and nuclear magnetic resonance hydrogen and carbon spectrum detection.

[0070] The properties and structural parameters of the product 7-fluoro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one obtained in this example are as follows:

[0071]

[0072] mp 152~154℃; 1 H NMR (300MHz, CDCl3): δ = 2.48 (s, 3H), 6.39 (s, 1H), 7.61~7.67 (m, 2H), 8.95~8.98 (m, 1H);

[0073] 13 C NMR (75.47MHz, CDCl3): δ = 164.9, 157.6, 148.9, 136.7, 129.1, 127.4, 127.1, 103.3, 24.8.

[0074] Example 7

[0075] 7 ml of toluene was added to a three-necked flask equipped with a magnetic stirrer and a spherical condenser. 0.06 mmol of an acidic eutectic solvent was added under stirring at room temperature, and the mixture was homogeneous to form a heterogeneous catalytic system. Then, 1 mmol of 2-amino-3-hydroxypyridine and 1 mmol of ethyl acetoacetate were added under stirring, and the mixture was homogeneous to form a reaction system. The mixture was then heated uniformly to 105 °C in a methyl silicone oil bath and maintained at this temperature for 67 min. When the starting material spot disappeared as detected by TLC (thin-plate chromatography), heating was immediately stopped, magnetic stirring was resumed, and the three-necked flask was removed from the oil bath. The mixture was allowed to cool naturally to room temperature, and the reaction solution was transferred to a separatory funnel for separation. The toluene was then evaporated from the supernatant and collected, yielding a pale yellow crude solid. Finally, the crude product was recrystallized from ethanol and dried under vacuum at 75 °C to constant weight to obtain pale yellow crystals, weighing 0.16 g. The purity was determined to be 99.1% by high performance liquid chromatography, and the yield was calculated to be 89%. The light yellow crystals were identified as 9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one by melting point determination and nuclear magnetic resonance hydrogen and carbon spectrum detection.

[0076] The properties and structural parameters of the product 9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one obtained in this example are as follows:

[0077]

[0078] mp 132~134℃; 1 H NMR (300MHz, CDCl3): δ = 2.46 (s, 3H), 4.86 (br, 1H), 6.32 (s, 1H), 7.03 (t, J = 7.5Hz, 1H), 7.14 (app d, J = 7.5Hz, 1H), 8.49 (app d, J = 7.2Hz, 1H);

[0079] 13 C NMR (75.47MHz, CDCl3): δ = 163.1, 157.8, 148.3, 144.1, 117.8, 115.1, 113.0, 103.6, 24.1.

[0080] Example 8

[0081] 7 ml of toluene was added to a three-necked flask equipped with a magnetic stirrer and a spherical condenser. 0.08 mmol of an acidic eutectic solvent was added under stirring at room temperature, and the mixture was thoroughly mixed to form a heterogeneous catalytic system. Then, 1 mmol of 2-amino-5-nitropyridine and 1 mmol of ethyl acetoacetate were added under stirring, and the mixture was thoroughly mixed to form a reaction system. The mixture was then heated uniformly to 108 °C in a methyl silicone oil bath and maintained at this temperature for 84 min. When the starting material spot disappeared as detected by TLC (thin-plate chromatography), heating was immediately stopped, magnetic stirring was resumed, and the three-necked flask was removed from the oil bath. The mixture was allowed to cool naturally to room temperature, and the reaction solution was transferred to a separatory funnel for separation. The toluene was then evaporated from the supernatant and collected, yielding a yellow solid crude product. Finally, the crude product was recrystallized from ethanol and dried under vacuum at 75 °C to constant weight to obtain yellow crystals, with a mass of 0.16 g. The purity was determined to be 99.5% by high performance liquid chromatography, and the yield was calculated to be 77%. The yellow crystals were identified as 2-methyl-7-nitro-4H-pyrido[1,2-a]pyrimidin-4-one by melting point determination and nuclear magnetic resonance hydrogen and carbon spectrum detection.

[0082] The properties and structural parameters of the product 2-methyl-7-nitro-4H-pyrido[1,2-a]pyrimidin-4-one obtained in this example are as follows:

[0083]

[0084] mp 106~108℃; 1 H NMR (300MHz, CDCl3): δ = 2.51 (s, 3H), 6.45 (s, 1H), 7.62 (d, J = 9.6Hz, 1H), 8.34 (d, J = 9.6Hz, 1H), 9.98 (d, J = 2.1Hz, 1H);

[0085] 13 C NMR (75.47MHz, CDCl3): δ = 166.6, 157.0, 150.2, 146.6, 128.9, 127.7, 126.9, 104.9, 24.8.

[0086] Example 9

[0087] 8 ml of toluene was added to a three-necked flask equipped with a magnetic stirrer and a spherical condenser. 0.08 mmol of an acidic eutectic solvent was added under stirring at room temperature, and the mixture was homogeneous to form a heterogeneous catalytic system. Then, 1 mmol of ethyl 2-aminonicotinic acid and 1 mmol of ethyl acetoacetate were added under stirring, and the mixture was homogeneous to form a reaction system. The mixture was then heated uniformly in a methyl silicone oil bath to 106 °C and maintained at this temperature for 74 min. When the starting material spot disappeared as detected by TLC (thin-plate chromatography), heating was immediately stopped, magnetic stirring was resumed, and the three-necked flask was removed from the oil bath. The mixture was allowed to cool naturally to room temperature, and the reaction solution was transferred to a separatory funnel for separation. The toluene was then evaporated from the supernatant and collected, yielding a yellow solid crude product. Finally, the crude product was recrystallized from ethanol and dried under vacuum at 75 °C to constant weight to obtain yellow crystals, with a mass of 0.19 g. The purity was determined to be 99.2% by high performance liquid chromatography, and the yield was calculated to be 83%. The yellow crystals were identified as ethyl 2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-4-one by melting point determination and nuclear magnetic resonance hydrogen and carbon spectrum detection.

[0088] The properties and structural parameters of the product ethyl 2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-4-one obtained in this example are as follows:

[0089]

[0090] mp 120~122℃; 1 H NMR (300MHz, CDCl3): δ = 1.42 (t, J = 7.2Hz, 1H), 2.46 (s, 3H), 4.47 (q, J = 7.2Hz, 2H), 6.36 (s, 1H), 7.08 (t, J = 7.1Hz, 1H), 7.96 (d, J = 6.9Hz, 1H), 9.09 (d, J = 7.2Hz, 1H);

[0091] 13 C NMR (75.47MHz, CDCl3): δ = 165.7, 164.9, 157.5, 147.8, 136.6, 129.5, 113.4, 104.0, 98.1, 62.2, 24.9.

[0092] Examples 10-15

[0093] Using the reaction described in Example 1 as a probe reaction, a repeatability test was conducted on the catalytic system consisting of an acidic eutectic solvent catalyst and a toluene reaction solvent. The lower layer of liquid after separation in Example 1 was added directly to the collected toluene without any treatment, and the mixture was stirred and mixed evenly. Then, 1 mmol of 2-aminopyridine and 1 mmol of ethyl acetoacetate were added. The catalytic system was used repeatedly according to the reaction conditions and operating steps of Example 1. The catalytic system was used a total of 7 times. The purity and yield of the product 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one were shown in Table 1 for each use.

[0094] Table 1. Results of repeatability tests of the catalytic system in the synthesis of 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0095]

[0096] Given the requirement for high purity as a pharmaceutical intermediate, the purity of the product in this invention is set at 98.5%. Considering economic factors, the yield reduction is set at 5%. Specifically, the catalytic system is discontinued when the liquid chromatography purity of 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one falls below 98.5% or its yield decreases by more than 5% compared to the first use of the catalytic system. As can be seen from the data in Table 1, the optimal number of uses for the catalytic system in Example 1 is 5.

[0097] Example 16

[0098] Using the reaction described in Example 1 as a probe reaction, a regeneration test was conducted on the catalytic system composed of an acidic eutectic solvent catalyst and a toluene reaction solvent: 15 ml of ethyl acetate was added to the lower layer of the liquid obtained after separation in Example 15, and the mixture was magnetically stirred for 20 minutes before separation. Then, another 15 ml of ethyl acetate was added to the lower layer, and the mixture was magnetically stirred for 20 minutes before separation again. This process was repeated three times. Finally, the lower layer obtained in the third step was vacuum dried at 85°C to constant weight to obtain the regenerated acidic eutectic solvent catalyst. This was then added to a new solvent consisting of 5.1 ml of toluene collected in Example 15 and 0.9 ml of toluene added to make up the total 6 ml. After thorough mixing, the regenerated catalytic system was obtained.

[0099] Examples 17-21

[0100] Using the reaction involved in Example 1 as a probe reaction, a reusability test was conducted on the catalytic system after regeneration, consisting of an acidic eutectic solvent catalyst and a toluene reaction solvent: 1 mmol of 2-aminopyridine and 1 mmol of ethyl acetoacetate were added to the regenerated catalytic system obtained in Example 16, and the regenerated catalytic system was reused repeatedly according to the reaction conditions and operating steps of Example 1. The catalytic system was used a total of 5 times, and the changes in purity and yield of the product 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one each time are shown in Table 2.

[0101] Table 2. Results of repeated use of the regenerated catalyst system in the synthesis of 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.

[0102]

[0103] As can be seen from the data in Table 2, the regenerated catalytic system can be reused and can be used up to 4 times without further treatment, realizing the catalytic system's recyclability, regeneration, and the simplification, greening, and large-scale continuous industrial production of the product purification process.

[0104] Figures 1-4 The proton and carbon NMR spectra data confirm that the corresponding 4H-pyrido[1,2-a]pyrimidin-4-one derivatives can be obtained by the method of the present invention.

[0105] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A catalytic system for the synthesis of a pharmaceutical intermediate, 4H-pyrido[1,2-a]pyrimidin-4-one derivative, characterized in that, The catalytic system consists of an acidic eutectic solvent as a catalyst and toluene as a reaction solvent. The acidic eutectic solvent is obtained by mixing and heating choline chloride and zinc chloride.

2. The catalytic system for synthesizing the pharmaceutical intermediate 4H-pyrido[1,2-a]pyrimidin-4-one derivative according to claim 1, characterized in that, The molar ratio of choline chloride to zinc chloride is 1:

4.

3. The catalytic system for synthesizing the pharmaceutical intermediate 4H-pyrido[1,2-a]pyrimidin-4-one derivative according to claim 1, characterized in that, The preparation process of the catalytic system is as follows: Add an appropriate volume of toluene to a three-necked flask equipped with a magnetic stirrer and a spherical condenser. Add an appropriate amount of acidic eutectic solvent while stirring vigorously at room temperature. Mix thoroughly to form a heterogeneous catalytic system.

4. A method for synthesizing a pharmaceutical intermediate 4H-pyrido[1,2-a]pyrimidin-4-one derivative, using the catalytic system for synthesizing the pharmaceutical intermediate 4H-pyrido[1,2-a]pyrimidin-4-one derivative as described in claim 2, characterized in that, The synthesis method includes the following steps: Step 1: Accurately weigh the reaction raw materials, 2-aminopyridine compound and ethyl acetoacetate, at a molar ratio of 1:1; Step 2: Add the weighed reaction raw materials to the catalytic system and mix them evenly. Under vigorous stirring, slowly heat the mixture in a methyl silicone oil bath to the required reaction temperature. Maintain this reaction temperature until the raw material spot disappears. Once the reaction is complete, turn off the stirring and heating, remove the three-necked flask from the oil bath, and allow it to cool naturally to room temperature. Separate the liquids, evaporate the toluene from the upper layer of liquid and collect it to obtain the solid crude product. Step 3: The obtained crude solid product was recrystallized from ethanol to finally obtain a 4H-pyrido[1,2-a]pyrimidin-4-one derivative; Step 4: Mix the lower layer liquid obtained from the separation in Step 2 with the collected toluene, and add the reaction raw materials directly under magnetic stirring. The catalyst is recycled according to the steps in Steps 2 and 3. When the liquid chromatography purity of the product 4H-pyrido[1,2-a]pyrimidin-4-one derivative is lower than 98.5% or its yield decreases by more than 5% compared to the first use of the catalyst system, the catalyst system is stopped from recycling and regenerated in Step 5. Step 5: Add an appropriate volume of ethyl acetate detergent to the lower layer liquid obtained in Step 2, stir magnetically for 20 minutes, and then separate the liquid. Add the same volume of ethyl acetate to the lower layer liquid, stir magnetically for 20 minutes, and then separate the liquid again. Repeat this process 3 times. Finally, vacuum dry the lower layer liquid obtained in the third step at 85°C to constant weight to obtain the regenerated catalyst. Step 6: Add the regenerated catalyst to the new solvent composed of the toluene collected in Step 2 and the toluene that needs to be added to make up the required volume, stir well, and the regenerated catalyst system can be obtained.

5. The method for synthesizing a pharmaceutical intermediate 4H-pyrido[1,2-a]pyrimidin-4-one derivative according to claim 4, characterized in that, The reaction temperature in step two is 97–108 °C.

6. The method for synthesizing a pharmaceutical intermediate 4H-pyrido[1,2-a]pyrimidin-4-one derivative according to claim 4, characterized in that, The reaction pressure is one atmosphere, and the reaction time is 41–84 min.

7. The method for synthesizing a pharmaceutical intermediate 4H-pyrido[1,2-a]pyrimidin-4-one derivative according to claim 4, characterized in that, The volume of the reaction solvent toluene, in milliliters, is 6 to 8 times the amount of the 2-aminopyridine compound, in millimoles, and the amount of the acidic eutectic solvent catalyst used is 5 to 8 times the amount of the 2-aminopyridine compound.

8. The method for synthesizing a pharmaceutical intermediate 4H-pyrido[1,2-a]pyrimidin-4-one derivative according to claim 4, characterized in that, In step five, use ethyl acetate as a washing agent, which is 2 to 5 times the volume of the reaction solvent toluene.

9. The method for synthesizing a pharmaceutical intermediate 4H-pyrido[1,2-a]pyrimidin-4-one derivative according to claim 4, characterized in that, The chemical reaction formula for the 4H-pyrido[1,2-a]pyrimidin-4-one derivative synthesized by the synthetic method is as follows: 。 10. The method for synthesizing a pharmaceutical intermediate 4H-pyrido[1,2-a]pyrimidin-4-one derivative according to claim 4, characterized in that, 2-Aminopyridine compounds are selected from , , , , , , , , , , , and Any one of them.

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