Preparation method of N-(5-pyrimidinylmethyl)-2-pyridineamine

Abstract

This invention relates to a method for preparing a heterocyclic compound, specifically to a method for preparing N-(5-pyrimidinylmethyl)-2-pyridineamine, comprising the following steps: (1) reacting 4,6-dihydroxypyrimidine with N,N-dimethylformamide and phosphorus oxychloride at 20-30°C for 0.5-1 hour, and then heating to 110-115°C for 3-4 hours to obtain 4,6-dichloropyrimidin-5-carboxaldehyde; (2) reacting 4,6-dichloropyrimidin-5-carboxaldehyde with palladium on carbon catalyst and metal salt co-catalyst in a hydrogen atmosphere at 40-50°C for 5-6 hours to obtain 5-hydroxymethylpyrimidine; (3) reacting 5-hydroxymethylpyrimidine with methanesulfonyl chloride at -5-5°C to obtain methyl pyrimidin-5-methanesulfonate; (4) reacting methyl pyrimidin-5-methanesulfonate with 2-aminopyridine at 50-60°C for 4 hours to obtain N-(5-pyrimidinylmethyl)-2-pyridineamine.

Description

Technical Field

[0001] This invention relates to a method for preparing a heterocyclic compound, specifically a method for preparing N-(5-pyrimidinylmethyl)-2-pyridineamine. This compound, as an important pharmaceutical intermediate, is widely used in the field of drug molecule synthesis. Background Technology

[0002] N-(5-pyrimidinylmethyl)-2-pyridineamine is an important class of nitrogen-containing heterocyclic intermediates widely used in pesticides and pharmaceuticals. With its expanding applications, developing efficient, economical, and environmentally friendly synthetic methods is of great significance.

[0003] Currently, there are several main methods for preparing N-(5-pyrimidinylmethyl)-2-pyridineamine. Chinese patent application CN118239891A discloses two synthetic routes. Route one involves constructing a pyrimidine ring using methyl methoxyacrylate and orthoformate, followed by ethylene glycol protection, hydrogenation dechlorination, reaction with 2-aminopyridine, and reduction to obtain the target product. Route two involves directly reacting 4-chloro-5-carboxypyrimidine with 2-aminopyridine, followed by reduction to obtain the target product. Chinese patent application CN118251388A employs a completely different synthetic strategy, using a three-step method: reacting 3-chloropropionyl chloride with N,N-dialkylformamide and oxalyl chloride, then reacting with pyridine-2-amine, and finally reacting with formamidinium salt to obtain the target product.

[0004] However, the above methods still have some limitations: Route 1 of CN118239891A involves more reaction steps, including protection and deprotection, increasing process complexity; Route 2, while reducing the number of steps, requires the prior preparation of 4-chloro-5-formylpyrimidine, which has a high cost. Although CN118251388A avoids the complexity of pyrimidine ring construction, the yield and purity of the final product need improvement. Furthermore, these methods generally suffer from low catalyst utilization and harsh reaction conditions, which are not conducive to industrial production.

[0005] It is particularly noteworthy that in the above synthetic route, if the intermediate pyrimidine-5-carboxaldehyde is used, due to its unstable structure, it is prone to side reactions such as oxidation and polymerization, resulting in low product yield and poor purity, which brings many inconveniences to the production.

[0006] Therefore, there is an urgent need to develop an efficient, economical, and environmentally friendly method for preparing N-(5-pyrimidinylmethyl)-2-pyridineamine to meet the needs of industrial production. Summary of the Invention

[0007] The purpose of this invention is to provide an efficient, economical, and environmentally friendly method for preparing N-(5-pyrimidinylmethyl)-2-pyridineamine. This method avoids the unstable intermediate pyrimidin-5-carboxaldehyde, improves product yield and purity, reduces waste emissions, and is suitable for industrial production.

[0008] To achieve the above objectives, the present invention provides the following technical solution:

[0009] The preparation method of N-(5-pyrimidinylmethyl)-2-pyridineamine includes the following steps:

[0010] (1) 4,6-Dihydroxypyrimidine is reacted with N,N-dimethylformamide and phosphorus oxychloride at 20~30℃ for 0.5~1 hours, and then the temperature is raised to 110~115℃ and reacted for 3~4 hours to obtain 4,6-dichloropyrimidine-5-carboxaldehyde;

[0011] (2) The 4,6-dichloropyrimidine-5-carboxaldehyde obtained in step (1) is reacted with palladium on carbon catalyst and metal salt co-catalyst in a hydrogen atmosphere at 40~50℃ for 5~6 hours to obtain 5-hydroxymethylpyrimidine;

[0012] (3) The 5-hydroxymethylpyrimidine obtained in step (2) is reacted with methanesulfonyl chloride at -5~5℃ to obtain methyl pyrimidine-5-methanesulfonate;

[0013] (4) The methyl pyrimidine-5-methanesulfonate obtained in step (3) is reacted with 2-aminopyridine at 50~60℃ for 4 hours to obtain N-(5-pyrimidinemethyl)-2-pyridineamine.

[0014] Preferably, in step (1), the mass ratio of N,N-dimethylformamide to 4,6-dihydroxypyrimidine is 6~7:1, and the mass ratio of phosphorus oxychloride to 4,6-dihydroxypyrimidine is 6~7:1.

[0015] Preferably, the reaction in step (1) is carried out under nitrogen protection. After the reaction is completed, part of the phosphorus oxychloride is recovered by depressurization, dissolved in dichloroethane, and then the reaction mixture is added to water. After separation, the aqueous phase is extracted with dichloroethane, the organic phases are combined, the organic phases are washed with saturated brine, and concentrated under reduced pressure to obtain the 4,6-dichloropyrimidine-5-carboxaldehyde.

[0016] Preferably, the palladium-on-carbon catalyst in step (2) is 5% palladium on carbon, and the metal salt co-catalyst is selected from one or more of ferric chloride, zinc chloride, copper chloride, and manganese chloride.

[0017] Preferably, the mass ratio of the palladium-on-carbon catalyst to the metal salt co-catalyst in step (2) is 10:1 to 2:1, more preferably 5:1 to 3:1.

[0018] Preferably, the reaction in step (2) is carried out in isopropyl acetate solvent, the reaction is carried out under a hydrogen pressure of 1.5~2.5 MPa, and the reaction further includes the addition of triethylamine.

[0019] Preferably, the reaction in step (3) is carried out in dichloromethane solvent, and the reaction further includes the addition of triethylamine as a base. The reaction is carried out at -5°C for 30 minutes, and then the reaction is continued at 20~25°C for 2 hours.

[0020] Preferably, the molar ratio of methanesulfonyl chloride to 5-hydroxymethylpyrimidine in step (3) is 1.2:1 to 1.5:1.

[0021] Preferably, the reaction in step (4) is carried out in N,N-dimethylformamide solvent, the molar ratio of 2-aminopyridine to methyl pyrimidine-5-methanesulfonate is 1:1 to 1.2:1, and the reaction further includes the addition of triethylamine as a base.

[0022] Preferably, after the reaction in step (4) is completed, most of the solvent is removed by vacuum distillation, water is added to the residue, and the residue is extracted with dichloromethane. The organic phases are combined and concentrated under reduced pressure to obtain N-(5-pyrimidinylmethyl)-2-pyridineamine, wherein the purity of N-(5-pyrimidinylmethyl)-2-pyridineamine is not less than 95%.

[0023] The beneficial effects of this invention are:

[0024] 1. Innovative Process Route: This invention uses 4,6-dihydroxypyrimidine as the starting material and achieves formylation and chlorination in one step via the Vilsmeier-Haack reaction. This is followed by palladium on carbon / metal salt co-catalyzed hydrogenation reduction, methanesulfonation, and nucleophilic substitution steps to efficiently synthesize the target product. This route avoids the unstable intermediate pyrimidine-5-carboxaldehyde, significantly improving process stability.

[0025] 2. Introduction of a Co-catalytic System: This invention introduces a metal salt as a co-catalyst for palladium on carbon in the hydrogenation reduction step, forming a bifunctional catalytic system. In this system, palladium on carbon is mainly responsible for the hydrogenation reduction reaction, while the metal salt, as a Lewis acid, co-activates the formaldehyde group, enhancing its affinity for hydrogen, improving reduction efficiency, shortening reaction time, reducing side reactions, and improving product quality.

[0026] 3. High reaction efficiency: The entire synthetic route is compact, with mild and controllable reaction conditions, resulting in high product yield and good purity. In particular, the application of a synergistic catalytic system reduces the reaction time of the hydrogenation reduction step from the traditional 6-7 hours to 5-6 hours, while reducing the amount of palladium on carbon by 10%-15%, significantly lowering production costs.

[0027] 4. Environmentally friendly: By rationally designing the process route and reaction conditions, the generation of waste is reduced. In particular, the partial recovery and utilization of phosphorus oxychloride in step (1) reduces the discharge of waste gas, wastewater, and solid waste, which is in line with the concept of green chemistry.

[0028] 5. Strong industrial applicability: The raw materials used in this invention are readily available, the operation is simple, the process parameters are clear, and the equipment requirements are not high, making it suitable for industrial production. The scale-up effect of each step is small, which is conducive to industrial implementation. Attached Figure Description

[0029] Figure 1 This is the gas chromatogram of Example 5. Detailed Implementation

[0030] The following is combined with Figure 1 The present invention will be further described with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0031] The core of the method for preparing N-(5-pyrimidinylmethyl)-2-pyridineamine of the present invention lies in using 4,6-dihydroxypyrimidine as a starting material, achieving formylation and chlorination in one step via the Vilsmeier-Haack reaction, followed by steps such as palladium on carbon / metal salt synergistic catalytic hydrogenation reduction, methanesulfonation and nucleophilic substitution, to efficiently synthesize the target product.

[0032] In step (1), the formylation and chlorination of 4,6-dihydroxypyrimidine are achieved in one step using the Vilsmeier-Haack reaction in the presence of N,N-dimethylformamide and phosphorus oxychloride. The reaction mechanism is as follows: first, N,N-dimethylformamide reacts with phosphorus oxychloride to generate the Vilsmeier reagent; then, an electrophilic substitution reaction occurs at the 5-position of 4,6-dihydroxypyrimidine to introduce a formyl group; simultaneously, the hydroxyl groups at the 4,6-position are substituted with chlorine in the presence of phosphorus oxychloride, yielding 4,6-dichloropyrimidine-5-carboxaldehyde in one step. This step is characterized by mild reaction conditions, simple operation, and high atom economy.

[0033] Step (2) is one of the innovations of this invention, introducing a palladium-on-carbon / metal salt synergistic catalytic system. In this system, palladium on carbon is mainly responsible for the hydrogenation reduction reaction, while the metal salt (such as ferric chloride, zinc chloride, etc.) acts as a Lewis acid to synergistically activate the formaldehyde group, enhancing its affinity for hydrogen. This bifunctional catalytic system significantly improves the reduction selectivity of the formaldehyde group while suppressing side reactions such as excessive reduction of aromatic rings. In addition, the synergistic effect accelerates the reaction rate, shortening the reaction time from the traditional 6-7 hours to 5-6 hours, while reducing the amount of palladium on carbon by 10%-15%, significantly reducing production costs.

[0034] Step (3) involves activating the hydroxyl group with methanesulfonyl chloride to convert 5-hydroxymethylpyrimidine into methyl pyrimidine-5-methanesulfonate. Methanesulfonate esters are excellent leaving groups, laying the foundation for subsequent nucleophilic substitution reactions. This step is carried out at low temperatures to control the exothermic and selective nature of the reaction.

[0035] Step (4) is a nucleophilic substitution reaction of 2-aminopyridine to methyl pyrimidine-5-methanesulfonate, which is carried out efficiently under appropriate temperature and base conditions, directly yielding the target product N-(5-pyrimidinemethyl)-2-pyridineamine.

[0036] The present invention will be described in detail below through specific embodiments: Example 1

[0037] The preparation method of N-(5-pyrimidinylmethyl)-2-pyridineamine includes the following steps:

[0038] Step (1): Preparation of 4,6-dichloropyrimidine-5-carboxaldehyde:

[0039] Under nitrogen protection, 684.0 g of phosphorus oxychloride was added to a 1.0 L reaction flask, followed by the addition of 98.0 g of N,N-dimethylformamide with stirring. After the addition was complete, the mixture was kept at 20 °C for 0.5 h. Next, 100.0 g of 4,6-dihydroxypyrimidine was added to the reaction system in portions, and the temperature was raised to 110 °C and maintained for 3 h.

[0040] After the reaction was complete, the temperature was lowered to 50°C, and 250.0 g of phosphorus oxychloride was recovered under reduced pressure (this solution can be reused directly). Then, 800.0 g of dichloroethane was added and stirred to dissolve. Next, at a temperature not exceeding 30°C, the reaction system was slowly added to 800 g of water, and stirring continued for 0.5 h after the addition was complete. The mixture separated into layers; the aqueous phase was extracted again with 300 g of dichloroethane, and the organic phases were combined. The organic phase was then washed once more with saturated brine and concentrated under reduced pressure to obtain 4,6-dichloropyrimidin-5-carboxaldehyde with a purity of 97% and a yield of 98%.

[0041] Step (2): Preparation of 5-hydroxymethylpyrimidine:

[0042] The 4,6-dichloropyrimidine-5-carboxaldehyde obtained in the previous step was added to a 2.0L autoclave along with 800g of isopropyl acetate, 150g of triethylamine, 5g of 5% palladium on carbon catalyst, and 1g of ferric chloride (III) (the mass ratio of palladium on carbon to ferric chloride was 5:1). The autoclave was purged with nitrogen three times and hydrogen twice. Hydrogen was then introduced, and the pressure was controlled at 2.0 MPa. The temperature was raised to 45℃ and maintained for 5.5 hours until the system no longer absorbed hydrogen, at which point the reaction was complete. The autoclave was then cooled and filtered. The filter cake was then soaked in 300g of isopropyl acetate. The filtrates were combined and concentrated under reduced pressure to dryness, yielding an oily substance, 5-hydroxymethylpyrimidine, with a purity of 98% and a yield of 92%.

[0043] Step (3): Preparation of methyl pyrimidine-5-methanesulfonate:

[0044] Add 66g of the 5-hydroxymethylpyrimidine obtained in the previous step, 600g of dichloromethane, and 91g of triethylamine to a 1.0L reaction flask. Under nitrogen protection, stir and cool to -5°C. Then, slowly add 82g of methanesulfonyl chloride to the system, keeping the temperature below 5°C. After the addition is complete, stir the reaction at 0°C for 30 min, then raise the temperature to 25°C and continue the reaction for 2 h.

[0045] After the reaction was complete, the temperature was lowered to 5°C, and 300 mL of water was slowly added while stirring for 30 min. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted once more with 200 g of dichloromethane, and the organic phases were combined. The organic phase was washed once with 200 g of saturated sodium chloride solution. The solution was concentrated under reduced pressure to obtain a yellow oily substance, methyl pyrimidine-5-methanesulfonate, with a purity of 96.5% and a yield of 87%.

[0046] Step (4): Preparation of N-(5-pyrimidinylmethyl)-2-pyridineamine:

[0047] To a 1.0 L reaction flask, add 600 g of N,N-dimethylformamide, 80 g of methyl pyrimidine-5-methanesulfonate, and 47 g of triethylamine sequentially. Under nitrogen protection, add 48 g of 2-aminopyridine. First, stir the reaction at room temperature for 1 h, then raise the temperature to 55 °C and stir for 4 h. The reaction is then checked for completeness.

[0048] The N,N-dimethylformamide was heated and distilled under reduced pressure. After cooling, 500g of water was added to the residue, followed by three extractions with 300g of dichloromethane each, resulting in separate layers. The organic phases were combined and concentrated under reduced pressure to obtain a reddish-brown oily substance, which was N-(5-pyrimidinylmethyl)-2-pyridinamine with a purity of 95.6% and a yield of 90.2%. Example 2

[0049] The preparation method of (5-pyrimidinylmethyl)-2-pyridineamine includes the following steps:

[0050] It is basically the same as Example 1, except that:

[0051] In step (2), 0.8 g of zinc chloride was used instead of ferric chloride as a co-catalyst (the mass ratio of palladium on carbon to zinc chloride was 6.25:1), the reaction temperature was 40 °C, and the reaction time was 6 h. 5-Hydroxymethylpyrimidine was obtained with a purity of 97.5% and a yield of 91%.

[0052] The remaining steps were the same as in Example 1, and N-(5-pyrimidinylmethyl)-2-pyridinamine was finally obtained with a purity of 95.8% and a yield of 89.5%. Example 3

[0053] The preparation method of (5-pyrimidinylmethyl)-2-pyridineamine includes the following steps:

[0054] It is basically the same as Example 1, except that:

[0055] In step (1), the reaction temperature is 30℃ and kept at that temperature for 1 hour, and then the temperature is raised to 115℃ and kept at that temperature for 4 hours.

[0056] In step (2), 1.5 g of copper chloride was used as a co-catalyst (the mass ratio of palladium on carbon to copper chloride was 3.33:1), the reaction pressure was 1.5 MPa, the reaction temperature was 50 °C, and the reaction time was 5 h. 5-Hydroxymethylpyrimidine was obtained with a purity of 98.5% and a yield of 93%.

[0057] In step (3), the amount of methanesulfonyl chloride used is 90g.

[0058] In step (4), the reaction temperature is 60℃ and the reaction time is 3.5h.

[0059] N-(5-pyrimidinylmethyl)-2-pyridineamine was finally obtained with a purity of 96.0% and a yield of 91.5%. Example 4

[0060] The preparation method of (5-pyrimidinylmethyl)-2-pyridineamine includes the following steps:

[0061] It is basically the same as Example 1, except that:

[0062] In step (2), a mixed catalyst of palladium on carbon and manganese chloride was used, wherein 5 g of palladium on carbon and 1.25 g of manganese chloride (the mass ratio of palladium on carbon to manganese chloride was 4:1), the reaction pressure was 2.5 MPa, the reaction temperature was 48 °C, and the reaction time was 5.5 h. 5-hydroxymethylpyrimidine was obtained with a purity of 99% and a yield of 94%.

[0063] In step (3), the reaction is carried out at -5℃ for 40 min, and then the temperature is raised to 20℃ to continue the reaction for 2 h.

[0064] In step (4), the amount of 2-aminopyridine used is 50g.

[0065] N-(5-pyrimidinylmethyl)-2-pyridineamine was finally obtained with a purity of 96.5% and a yield of 92.0%. Example 5

[0066] The preparation method of (5-pyrimidinylmethyl)-2-pyridineamine includes the following steps:

[0067] It is basically the same as Example 1, except that:

[0068] In step (1), the amount of phosphorus oxychloride is 700g and the amount of N,N-dimethylformamide is 100g.

[0069] In step (2), a mixed metal salt synergistic catalyst was used, namely 0.5 g of ferric chloride and 0.5 g of zinc chloride (the mass ratio of palladium on carbon to the mixed metal salt was 5:1), the reaction pressure was 1.8 MPa, and the reaction temperature was 42℃. Please refer to... Figure 1 5-Hydroxymethylpyrimidine was obtained with a purity of 98.69% and a yield of 92.5%.

[0070] In step (4), the amount of N,N-dimethylformamide used is 650g and the amount of triethylamine used is 50g.

[0071] N-(5-pyrimidinylmethyl)-2-pyridineamine was finally obtained with a purity of 96.2% and a yield of 91.0%.

[0072] Comparative Example 1

[0073] Preparation of N-(5-pyrimidinylmethyl)-2-pyridineamine (without co-catalyst)

[0074] It is basically the same as Example 1, except that:

[0075] In step (2), only 5g of 5% palladium on carbon catalyst was used, without the addition of metal salt co-catalysts. The reaction temperature was 45℃, and the reaction time was extended to 7h. 5-hydroxymethylpyrimidine was obtained with a purity of 96% and a yield of 85%.

[0076] N-(5-pyrimidinylmethyl)-2-pyridineamine was finally obtained with a purity of 94.5% and a yield of 82.0%.

[0077] Comparative Example 2

[0078] Preparation of N-(5-pyrimidinylmethyl)-2-pyridineamine (co-catalyst dosage too low)

[0079] It is basically the same as Example 1, except that:

[0080] In step (2), 5g of 5% palladium on carbon catalyst and 0.2g of ferric chloride (mass ratio of palladium on carbon to ferric chloride is 25:1) were used, the reaction temperature was 45℃, and the reaction time was 6.5h. 5-hydroxymethylpyrimidine was obtained with a purity of 96.5% and a yield of 87%.

[0081] N-(5-pyrimidinylmethyl)-2-pyridineamine was finally obtained with a purity of 95.0% and a yield of 85.5%.

[0082] Comparative Example 3

[0083] Preparation of N-(5-pyrimidinylmethyl)-2-pyridineamine (excessive amount of co-catalyst)

[0084] It is basically the same as Example 1, except that:

[0085] In step (2), 5g of 5% palladium on carbon catalyst and 2.5g of ferric chloride (mass ratio of palladium on carbon to ferric chloride is 2:1) were used. The reaction temperature was 45℃ and the reaction time was 5h. 5-hydroxymethylpyrimidine was obtained with a purity of 95% and a yield of 84%. The product contained a small amount of metal impurities.

[0086] N-(5-pyrimidinylmethyl)-2-pyridineamine was finally obtained with a purity of 94.0% and a yield of 83.0%.

[0087] Experimental testing and results analysis

[0088] To verify the superiority of the method of the present invention, key indicators of the above embodiments and comparative examples were tested and compared, mainly including parameters such as reaction time, catalyst dosage, product yield, and purity. The test results are shown in the table below:

[0089] Table 1. Comparison of experimental results from different embodiments and comparative examples.

[0090]

[0091] As can be seen from the table above, the method of the present invention has significant advantages over traditional methods:

[0092] 1. Shorter reaction time: In Examples 1-5 using the synergistic catalytic system, the hydrogenation reaction time was generally shortened to 5-6 hours, while in Comparative Example 1 without the synergistic catalyst, it took 7 hours to complete the reaction.

[0093] 2. Increased yield: The yields of 5-hydroxymethylpyrimidine in Examples 1-5 were 91%–94%, and the yields of the final products were 89.5%–92.0%, which were significantly higher than the 85% and 82.0% of Comparative Example 1.

[0094] 3. Improved product purity: The purity of 5-hydroxymethylpyrimidine in Examples 1-5 was 97.5% to 99.0%, and the purity of the final product was 95.6% to 96.5%, which was higher than that of Comparative Example 1 (96.0% and 94.5%).

[0095] 4. Importance of catalyst ratio: Too low a synergistic catalyst (Comparative Example 2) or too high a synergistic catalyst (Comparative Example 3) will lead to a decrease in yield and purity. The optimal ratio of palladium on carbon to metal salt is between 3:1 and 6:1.

[0096] 5. Effects of different metal salts: Ferric chloride, zinc chloride, copper chloride and manganese chloride all showed good synergistic catalytic effects, among which copper chloride (Example 3) and manganese chloride (Example 4) were slightly better, which may be related to their Lewis acidity and redox properties.

[0097] Further analysis of the synergistic catalytic system revealed that the metal salt, acting as a Lewis acid, can coordinate with the formaldehyde group, activating the C=O bond and enhancing its affinity for hydrogen. Simultaneously, palladium on carbon activates hydrogen gas. This synergistic effect significantly improves the efficiency and selectivity of the reduction reaction. Furthermore, the metal salt can stabilize the palladium catalyst, reducing its loss and aggregation, extending catalyst lifetime, and improving its utilization rate.

[0098] In summary, by introducing a palladium-on-carbon / metal salt synergistic catalytic system, this invention successfully solves the problems of long reaction time, low yield, and poor purity in traditional methods, providing a new, efficient, economical, and environmentally friendly method for the industrial production of N-(5-pyrimidinylmethyl)-2-pyridineamine.

[0099] Based on the above experimental results, the optimal implementation scheme of the present invention is as follows:

[0100] 1. The starting material is 4,6-dihydroxypyrimidine, which is formylated and chlorinated in one step via the Vilsmeier-Haack reaction to obtain 4,6-dichloropyrimidine-5-carboxaldehyde.

[0101] 2. The hydrogenation reduction step uses a synergistic catalytic system composed of palladium on carbon and manganese chloride (mass ratio 4:1), and reacts for 5-6 hours at a hydrogen pressure of 1.5-2.5 MPa and a temperature of 45-50℃ to obtain high-purity 5-hydroxymethylpyrimidine.

[0102] 3. The mesylation step is carried out at low temperature, followed by a slow increase in temperature to ensure the selectivity and completeness of the reaction.

[0103] 4. The final nucleophilic substitution reaction is carried out under appropriate temperature and base conditions to directly obtain high-purity N-(5-pyrimidinylmethyl)-2-pyridineamine.

[0104] This approach not only avoids the unstable intermediate pyrimidine-5-carboxaldehyde, but also significantly improves reaction efficiency and product quality and reduces waste emissions through the application of a synergistic catalytic system, making it suitable for industrial production.

[0105] This invention provides a novel method for preparing N-(5-pyrimidinylmethyl)-2-pyridinamine. This method uses 4,6-dihydroxypyrimidine as a starting material and efficiently synthesizes the target product through steps including Vilsmeier-Haack reaction, synergistic catalytic hydrogenation reduction, methanesulfonation, and nucleophilic substitution. In particular, the palladium-on-carbon / metal salt synergistic catalytic system introduced in the hydrogenation reduction step significantly improves reaction efficiency and product quality, providing a new technical solution for the industrial production of N-(5-pyrimidinylmethyl)-2-pyridinamine.

[0106] The above embodiments are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any simple modifications or equivalent substitutions made by those skilled in the art to the technical solutions of the present invention without departing from the spirit and scope of the present invention shall fall within the protection scope of the present invention.

Claims

1. Process for the preparation of N-(5-pyrimidinylmethyl)-2-pyridinamine, characterized in that, The method comprises the following steps: (1) reacting 4,6-dihydroxypyrimidine with N,N-dimethylformamide and phosphorus oxychloride at 20-30℃ for 0.5-1 hour, then raising the temperature to 110-115℃ and reacting for 3-4 hours to obtain 4,6-dichloropyrimidine-5-carboxaldehyde; (2) reacting the 4,6-dichloropyrimidine-5-carboxaldehyde obtained in step (1) with a palladium-carbon catalyst and a metal salt synergistic catalyst in a hydrogen atmosphere at 40-50℃ for 5-6 hours to obtain 5-hydroxymethylpyrimidine; (3) reacting the 5-hydroxymethylpyrimidine obtained in step (2) with methanesulfonyl chloride at-5-5℃ to obtain pyrimidine-5-methanesulfonic acid methyl ester; (4) reacting the pyrimidine-5-methanesulfonic acid methyl ester obtained in step (3) with 2-aminopyridine at 50-60℃ for 4 hours to obtain N-(5-pyrimidylmethyl)-2-pyridinamine; The palladium-carbon catalyst in step (2) is 5% palladium-carbon, and the metal salt synergistic catalyst is selected from one or more of iron chloride, zinc chloride, copper chloride and manganese chloride; The mass ratio of the palladium-carbon catalyst to the metal salt synergistic catalyst in step (2) is 5:1-3:1; The reaction in step (2) is carried out in an isopropyl acetate solvent, the reaction is carried out under a hydrogen pressure of 1.5-2.5 MPa, and the reaction further comprises adding triethylamine.

2. The production method according to claim 1, characterized by, The mass ratio of the N,N-dimethylformamide to the 4,6-dihydroxypyrimidine in step (1) is 6-7:1, and the mass ratio of the phosphorus oxychloride to the 4,6-dihydroxypyrimidine is 6-7:

1.

3. The preparation method according to claim 1, characterized in that, The reaction in step (1) is carried out under nitrogen protection, after the reaction is completed, part of the phosphorus oxychloride is recovered by reduced pressure, is dissolved in dichloroethane, then the reaction mixture is added to water, after the layers are separated, the aqueous phase is extracted with dichloroethane, the combined organic phase is washed with saturated brine, and the organic phase is concentrated under reduced pressure to obtain the 4,6-dichloropyrimidine-5-carboxaldehyde.

4. The method of claim 1, wherein, The reaction in step (3) is carried out in a dichloromethane solvent, the reaction further comprises adding triethylamine as a base, and the reaction is carried out at-5℃ for 30 minutes, and then at 20-25℃ for 2 hours.

5. The preparation method according to claim 1, characterized in that, The molar ratio of the methanesulfonyl chloride to the 5-hydroxymethylpyrimidine in step (3) is 1.2:1-1.5:

1.

6. The method of claim 1, wherein, The reaction in step (4) is carried out in an N,N-dimethylformamide solvent, the molar ratio of the 2-aminopyridine to the pyrimidine-5-methanesulfonic acid methyl ester is 1:1-1.2:1, and the reaction further comprises adding triethylamine as a base.

7. The preparation method according to claim 1, characterized in that, After the reaction in step (4) is completed, most of the solvent is removed by distillation under reduced pressure, water is added to the residual liquid, extracted with dichloromethane, the combined organic phase is concentrated under reduced pressure to obtain N-(5-pyrimidylmethyl)-2-pyridinamine, and the purity of the N-(5-pyrimidylmethyl)-2-pyridinamine is not less than 95%.

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