A preparation method of quinpiramine and its intermediates

Abstract

The invention discloses a preparation method of quinpiramine and an intermediate thereof, and belongs to the technical field of organic synthesis. The present invention synthesizes a quinpiramine intermediate using N-(4-methoxy-2-methylquinoline-6-yl)acetamide, iodomethane and pyrimidine iodide as raw materials, and quinpiramine can be synthesized based on the intermediate. The raw materials used in the preparation method of the present invention can be prepared by the acetylation reaction of common quinoline derivatives to obtain a quinpiramine intermediate, compared to the prior art requiring a specific quinolinone imine structure, the preparation method of the present invention has a shorter synthesis path, easier raw materials to obtain, lower production cost, and combined with the optimized preparation process, the target product obtained has the characteristics of high purity and high yield.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, in particular to a preparation method of quinpiramine and an intermediate thereof. Background Art

[0002] Quinapyramine, also known as methylthioquinamine and anchovy, has a molecular formula of C 17 H 22 N6+, with a molecular weight of 310.4, was developed in the 1950s by the British Boots Pure Drug Company (now a subsidiary of Sanofi) to combat trypanosomiasis (such as Trypanosoma evansi infection in cattle and horses). It has since been widely used in livestock farming in Africa, Asia, and Latin America, significantly reducing trypanosomiasis-related mortality in livestock.

[0003] Pharmaceutical intermediates play a key role in the chemical synthesis of drugs. They are intermediate compounds from raw materials to final drugs and are intermediate products in the chemical synthesis process. After a series of chemical reactions, the target drug is finally formed. Currently, there are few reports on the synthesis methods of quinpiramine intermediates. The published synthesis methods include: 6-amino-1,2-dimethyl-1H-quinolin-4-one imine monohydrochloride and 2-amino-4-chloro-1,6-dimethylpyrimidine iodide are reacted with sodium iodide to obtain quinpiramine intermediates. The synthesis route is as follows: Figure 1 Alternatively, quinopilamine intermediate is obtained by reacting 6-amino-1,2-dimethyl-1H-quinolin-4-one imine monohydrochloride with 2-amino-1,6-dimethyl-4-methylthiopyrimidine iodide with potassium iodide. The synthetic route is as follows: Figure 2 shown.

[0004] Although the above method can synthesize the target product, the raw materials used are not easy to obtain, and how to control key technical indicators such as product quality and yield is not disclosed. Therefore, it is not convenient for the industrial production of quinpiramine and its intermediates.

[0005] In view of this, the present invention is proposed. Summary of the Invention

[0006] The object of the present invention is to provide a preparation method of quinpiramine and its intermediates, the preparation method has a shorter synthesis path and lower raw material cost, and the preparation method of the present invention can achieve high-purity and high-yield preparation of the target product.

[0007] The present invention is achieved in that:

[0008] In one aspect, the present invention provides a method for preparing a quinpiramine intermediate, comprising:

[0009] N-(4-methoxy-2-methylquinolin-6-yl)acetamide is reacted with a methyl halide to synthesize product A; product A is then reacted with pyrimidine iodide to synthesize product B; product B is then subjected to an amination reaction to obtain 6-(2-amino-1,6-dimethyl-pyrimidin-4-ylamino)-4-amino-1,2-dimethyl-quinoline diiodide;

[0010] Among them, the pyrimidine iodide includes 2-amino-4-chloro-1,6-dimethylpyrimidine iodide and 2-amino-1,6-dimethyl-4-methylthiopyrimidine iodide.

[0011] On the other hand, the present invention provides a method for preparing quinpiramine, which includes the method for preparing the above-mentioned quinpiramine intermediate.

[0012] The present invention has the following beneficial effects:

[0013] The present invention synthesizes a quinpiramine intermediate using N-(4-methoxy-2-methylquinolin-6-yl)acetamide, iodomethane, and pyrimidine iodide as raw materials. Quinpiramine can be synthesized based on the intermediate. The raw materials used in the preparation method of the present invention can be prepared by acetylation of common quinoline derivatives to obtain the quinpiramine intermediate. Compared with the prior art method that requires a specific quinolinone imine structure, the preparation method of the present invention has a shorter synthesis path, more readily available raw materials, and lower production costs. Combined with an optimized preparation process, the obtained target product has the characteristics of high purity and high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.

[0015] Figure 1 This is a synthetic route for synthesizing quinpiramine intermediates using 6-amino-1,2-dimethyl-1H-quinolin-4-one imine monohydrochloride, 2-amino-4-chloro-1,6-dimethylpyrimidine iodide, and sodium iodide as raw materials;

[0016] Figure 2 A synthetic route for synthesizing quinpiramine intermediates using 6-amino-1,2-dimethyl-1H-quinolin-4-one imine monohydrochloride, 2-amino-1,6-dimethyl-4-methylthiopyrimidine iodide, and potassium iodide as raw materials;

[0017] Figure 3 This is the synthetic route of the quinpiramine intermediate of the present invention;

[0018] Figure 4 The chromatographic test results of the product obtained in Example 1 are as follows;

[0019] Figure 5 This is the synthetic route of product B in Example 2. DETAILED DESCRIPTION

[0020] To make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are used. Where the manufacturer of the reagents or instruments is not specified, all are conventional products that can be purchased commercially.

[0021] The synthetic route of quinpiramine intermediate of the present invention is as follows Figure 3 As shown, it includes: reacting N-(4-methoxy-2-methylquinolin-6-yl)acetamide with methyl halide to synthesize product A; then reacting product A with pyrimidine iodide to synthesize product B; and then performing an amination reaction on product B to obtain 6-(2-amino-1,6-dimethyl-pyrimidin-4-ylamino)-4-amino-1,2-dimethyl-quinoline diiodide.

[0022] Wherein, the preparation method of product A is as follows:

[0023] N-(4-methoxy-2-methylquinolin-6-yl)acetamide is dissolved in an ethylene glycol ether solution to obtain an N-(4-methoxy-2-methylquinolin-6-yl)acetamide solution, to which iodomethane is added, mixed, and reacted; then, a first cooling crystallization is performed, the precipitate is collected, and the precipitate is dissolved in an ethylene glycol ether aqueous solution; then, a second cooling crystallization is performed, the precipitate is collected, and dried to obtain product A.

[0024] In the above preparation process, ethylene glycol ethyl ether solution is used as the solvent of the raw material because its ether bond (lipophilicity) and hydroxyl group (hydrophilicity) enable it to fully dissolve the hydrophobic substrate (N-substituted acetamide) and can also be used as a gradient crystallization purification solvent.

[0025] In some embodiments, the molar ratio of iodomethane to N-(4-methoxy-2-methylquinolin-6-yl)acetamide is (1-1.4):1. More preferably, the molar ratio of iodomethane to N-(4-methoxy-2-methylquinolin-6-yl)acetamide is (1.1-1.2):1. At these ratios, better reaction efficiency can be achieved.

[0026] In some embodiments, the reaction conditions of iodomethane and N-(4-methoxy-2-methylquinolin-6-yl)acetamide are: temperature 85° C. to 90° C., and reaction time 12 to 15 h.

[0027] In some embodiments, the conditions for the first cooling crystallization and the second cooling crystallization are: cooling to 10° C. to 15° C. and crystallizing for 2 to 5 hours.

[0028] In some embodiments, the concentration of the ethylene glycol ethyl ether aqueous solution used to dissolve the precipitate is 30% to 70%. More preferably, the concentration of the ethylene glycol ethyl ether aqueous solution is 50% to 60%.

[0029] The present invention uses ethylene glycol ether aqueous solution as solvent because the polarity difference of this mixed solvent can selectively separate out target product and avoid impurity cocrystallization. The lower the ethylene glycol ether concentration is, the faster the recrystallization rate is. The solvent cost reduces but causes product purity to decline because of insufficient solubility. High concentration can improve dissolving power, improve product purity, but solvent cost is slightly high and can lose product. Higher purity and yield can be obtained simultaneously within the concentration range of the present invention.

[0030] In some embodiments, the temperature during dissolution of the precipitate is 60°C to 80°C.

[0031] The preparation method of product B is as follows:

[0032] Product A is dissolved in a sodium carbonate solution, and 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide is added thereto, mixed and then heated under reflux for reaction; after the reaction is completed, a first cooling, a first filtration and a first rinsing are performed in sequence, and then the obtained filter cake is dissolved in water, and an alkali metal halide is added thereto, and after dissolution, a second cooling, a second filtration, a second rinsing and drying are performed in sequence.

[0033] In some embodiments, the molar ratio of 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide to product A is (1-1.3):1. More preferably, the molar ratio of 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide to product A is (1.05-1.1):1. At these ratios, better reaction efficiency can be achieved.

[0034] In some embodiments, the heating reflux reaction conditions are: temperature of 95° C. to 100° C., and time of 2 to 5 h.

[0035] In some embodiments, the first cooling and the second cooling are to reduce the temperature to 20°C-25°C.

[0036] In some embodiments, the rinsing agent for the first rinse is dilute hydrochloric acid and water to neutralize the residual alkali (sodium carbonate) and remove unreacted raw materials; the rinsing agent for the second rinse is water.

[0037] In some embodiments, the alkali metal halide includes sodium iodide and potassium iodide.

[0038] In the actual research process, it was found that 2-amino-1,6-dimethyl-4-methylthiopyrimidine iodide can also be used as a raw material to prepare product B. The specific method is as follows:

[0039] Product A is dissolved in a sodium hydroxide solution, and 2-amino-1,6-dimethyl-4-methylthiopyrimidine iodide is added thereto, and the mixture is mixed and then heated under reflux for reaction under a nitrogen environment; after the reaction is completed, a first cooling, a first filtration and a first rinsing are performed in sequence, and then the obtained filter cake is dissolved in water, and an alkali metal halide is added thereto, and after dissolution, a second cooling, a second filtration, a second rinsing and drying are performed in sequence.

[0040] In some embodiments, the molar ratio of 2-amino-1,6-dimethyl-4-methylsulfanylpyrimidine iodide to product A is (1.1-1):1.

[0041] In some embodiments, the heating reflux reaction conditions are: temperature of 110° C. to 120° C., and time of 4 to 8 h.

[0042] Other reaction conditions are the same as those for preparing product B using 2-amino-4-chloro-1,6-dimethylpyrimidine iodide as the raw material, including: lowering the temperature to 20°C~25°C for the first and second cooling steps; the rinsing agents for the first rinse are dilute hydrochloric acid and water; the rinsing agent for the second rinse is water; and the alkali metal halide includes sodium iodide and potassium iodide.

[0043] The preparation method of synthesizing quinpiramine intermediate, 6-(2-amino-1,6-dimethyl-pyrimidin-4-ylamino)-4-amino-1,2-dimethyl-quinoline diiodide, using product B is as follows:

[0044] The product B, ammonium chloride, and ethanolammonia solution are mixed, sealed, and heated to perform an amination reaction. After the reaction is completed, the temperature is lowered for a third time and concentrated. Then, water and dilute hydrochloric acid are added to the concentrate to dissolve it and adjust the pH to weak acidity. Then, an alkali metal halide is added, mixed, and then cooled for a fourth time, filtered for a third time, rinsed for a third time, and dried.

[0045] In some embodiments, the molar ratio of ammonium chloride to product B in the amination reaction system is (10-12):1. This ratio achieves good reaction efficiency. Furthermore, ethanolamine serves as both a solvent and ammonia in the reaction system.

[0046] In some embodiments, the temperature of the amination reaction is 130° C. to 150° C., and the time is 4 to 8 h.

[0047] In some embodiments, the third cooling step and the fourth cooling step are steps of lowering the temperature to 20°C to 25°C.

[0048] In some embodiments, the molar ratio of alkali metal halide to product B is 2:1.

[0049] In some embodiments, the alkali metal halide includes sodium iodide and potassium iodide.

[0050] The present invention optimizes the reaction conditions of each step based on the above synthetic route, and determines the optimal preparation method to achieve the preparation of the target product with high purity and high yield. It has been verified that the purity of the obtained target product is over 99.9%, while the single-step yield can reach up to over 80%, and the total yield is over 70%.

[0051] The quinpiramine intermediate obtained by the preparation method of the quinpiramine intermediate provided by the present invention can be treated with hydrochloric acid-ethanol to directly replace iodide ions, and can be used as a terminal product of quinpiramine dichloride after crystallization and purification.

[0052] The features and performance of the present invention are further described in detail below with reference to the embodiments.

[0053] Example 1

[0054] This embodiment provides a method for preparing a quinpiramine intermediate, and its synthetic route is as follows: Figure 3 The specific steps are as follows:

[0055] 1. Preparation of Product A

[0056] S1. Dissolve 115 g of N-(4-methoxy-2-methylquinolin-6-yl)acetamide in 700 g of ethylene glycol ether solution and stir at 25°C. Add 78 g of iodomethane (the molar ratio of iodomethane to N-(4-methoxy-2-methylquinolin-6-yl)acetamide is 1.1:1) and stir for 10 minutes. Heat to 85°C and maintain the reaction for 14 hours to complete the reaction.

[0057] S2. Cool to 10°C and allow to crystallize for 3 h. Filter and dissolve the filter cake in 200 ml of 50% ethylene glycol ether aqueous solution. Heat to 70°C and dissolve.

[0058] S3. Cool the mixture to 10°C for 3 h, filter it, and dry it to obtain 160.6 g of product A (6-acetylamino-4-methoxy-1,2-dimethylquinoline iodide) in a yield of 86.3%.

[0059] 2. Preparation of Product B

[0060] S1. Add 1200 g of water and 33.92 g of sodium carbonate to a 3000 ml flask and stir until dissolved. Then add 160.6 g of product A and 130 g of 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide (i.e., the molar ratio of 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide to product A is 1.05:1) and stir until uniform.

[0061] S2. Raise the temperature to 95°C and reflux for 4 h to complete the intermediate control reaction.

[0062] S3. The reaction solution was cooled to 20 ° C, filtered, and the filter cake was rinsed with 100 ml of dilute hydrochloric acid and 100 ml of water;

[0063] S4 obtained filter cake was added to 2000 ml of water, heated to 90 ℃, stirred to dissolve, added 128.9 g of solid sodium iodide, stirred to dissolve;

[0064] S5. Cool to 20°C, filter, rinse the filter cake with 200 ml of water, and dry to obtain 219.1 g of product B 6-(2-amino-1,6-dimethyl-pyrimidin-4-ylamino)-4-methoxy-1,2-dimethyl-quinoline diiodide in a yield of 87.8%.

[0065] 3. Preparation of intermediates

[0066] S1. Add 219.1 g of product B, 202 g of ammonium chloride (molar ratio of ammonium chloride to product B is 10:1), and 1010 ml of 7% ethanolammonia solution to an ammoniation tank. Seal the tank and heat to 140°C for ammoniation. Keep the temperature for 6 hours to complete the reaction.

[0067] S2 cooled to 20 ℃, the reaction solution was concentrated to dryness, 3500 ml of water was added, pH = 6-7 was adjusted with dilute hydrochloric acid, the temperature was raised to 80 ℃ to dissolve, 113 g of sodium iodide was added, and the solution was stirred;

[0068] S3. Cool to 20°C, filter, rinse the filter cake with 300 ml of water, and dry to obtain 198.5 g of the final target product 6-(2-amino-1,6-dimethyl-pyrimidin-4-ylamino)-4-amino-1,2-dimethyl-quinoline diiodide with a purity of 99.94% and a total yield of 70.5%.

[0069] The final target product obtained was analyzed by high performance liquid chromatography. Figure 4 shown.

[0070] Example 2

[0071] This example provides another preparation method of quinpiramine intermediate. The difference between this preparation method and Example 1 is that the synthesis route of product B is different. Figure 5 The specific steps are as follows:

[0072] 1. Preparation of Product A

[0073] S1. Dissolve 73.5 g of N-(4-methoxy-2-methylquinolin-6-yl)acetamide in 450 g of ethylene glycol ether solution and stir at 25°C. Add 50 g of iodomethane and stir for 10 min. Heat to 85°C and keep incubating for 14 h to complete the reaction.

[0074] S2. Cool to 10°C for 3 h, filter, and dissolve the filter cake in 130 ml of 50% ethylene glycol ether solution. Heat to 70°C and dissolve.

[0075] S3. Cool the mixture to 10°C for 3 h, filter it, and dry it to obtain 100.6 g of product A (6-acetylamino-4-methoxy-1,2-dimethylquinoline iodide) with a yield of 84.7%.

[0076] 2. Preparation of Product B

[0077] S1.750 g water and 37.5 g sodium hydroxide were added to a 3000 ml flask, stirred to dissolve, and then 100.6 g product A and 84 g 2-amino-1,6-dimethyl-4-methylthiopyrimidine iodide were added and stirred evenly;

[0078] S2. Raise the temperature to 110°C, pass nitrogen protection, and reflux for 6 hours to complete the intermediate control reaction;

[0079] S3. The reaction solution was cooled to 20 ° C, filtered, and the filter cake was rinsed with 60 ml of dilute hydrochloric acid and 60 ml of water;

[0080] S4 obtained filter cake was added to 1200 ml of water, heated to 90 ℃, stirred to dissolve, added 128.9 g of solid sodium iodide, stirred to dissolve;

[0081] S5. Cool to 20°C, filter, rinse the filter cake with 200 ml of water, and dry to obtain 118.2 g of product B 6-(2-amino-1,6-dimethyl-pyrimidin-4-ylamino)-4-methoxy-1,2-dimethyl-quinoline diiodide in a yield of 75.6%.

[0082] 3. Preparation of intermediates

[0083] S1. Add 118.2 g of product B, 109 g of ammonium chloride, and 545 ml of 7% ethanolammonia solution to an ammoniation tank, seal the tank, and heat to 140°C for ammoniation. Keep the temperature for 6 h, and the reaction is complete.

[0084] S2. Cool to 20 ° C, concentrate the reaction solution to dryness, add 1900 ml of water, adjust pH = 6-7 with dilute hydrochloric acid, heat to 80 ° C to dissolve, add 61 g of sodium iodide, stir and dissolve;

[0085] S3. Cool to 20°C, filter, rinse the filter cake with 160 ml of water, and dry to obtain 102 g of the final target product, 6-(2-amino-1,6-dimethyl-pyrimidin-4-ylamino)-4-amino-1,2-dimethyl-quinoline diiodide, with a purity of 99.87% and a total yield of 56.7%.

[0086] Example 3

[0087] The difference from Example 1 is that the amount of iodomethane used is different, and the molar ratio of iodomethane to N-(4-methoxy-2-methylquinolin-6-yl)acetamide is 1.2:1.

[0088] Example 4

[0089] The difference from Example 1 is that the amount of iodomethane used is different, and the molar ratio of iodomethane to N-(4-methoxy-2-methylquinolin-6-yl)acetamide is 1.3:1.

[0090] Example 5

[0091] The difference from Example 1 is that the amount of iodomethane used is different, and the molar ratio of iodomethane to N-(4-methoxy-2-methylquinolin-6-yl)acetamide is 1.4:1.

[0092] Example 6

[0093] The difference from Example 1 is that the concentration of the ethylene glycol ethyl ether aqueous solvent used for recrystallization during the preparation of Product A is different, and its concentration is 60%.

[0094] Example 7

[0095] The difference from Example 1 is that the amount of 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide used in the process of preparing product B is different, and the molar ratio of 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide to product A is 1.1:1.

[0096] Example 8

[0097] The difference from Example 1 is that the amount of 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide used in the process of preparing product B is different, and the molar ratio of 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide to product A is 1.2:1.

[0098] Example 9

[0099] The difference from Example 1 is that the amount of 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide used in the process of preparing product B is different, and the molar ratio of 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide to product A is 1.3:1.

[0100] Example 10

[0101] The difference from Example 1 is that the amount of ammonium chloride used is different, and the molar ratio of ammonium chloride to product B is 11:1.

[0102] Example 11

[0103] The difference from Example 1 is that the amount of ammonium chloride used is different, and the molar ratio of ammonium chloride to product B is 12:1.

[0104] Comparative Example 1

[0105] The difference from Example 1 is that the amount of iodomethane used is different, and the molar ratio of iodomethane to N-(4-methoxy-2-methylquinolin-6-yl)acetamide is 1:1.

[0106] Comparative Example 2

[0107] The difference from Example 1 is that the amount of iodomethane used is different, and the molar ratio of iodomethane to N-(4-methoxy-2-methylquinolin-6-yl)acetamide is 1.05:1.

[0108] Comparative Example 3

[0109] The difference from Example 1 is that the concentration of the ethylene glycol ethyl ether aqueous solvent used for recrystallization during the preparation of Product A is different, and its concentration is 30%.

[0110] Comparative Example 4

[0111] The difference from Example 1 is that the concentration of the ethylene glycol ethyl ether aqueous solvent used for recrystallization during the preparation of Product A is different, and its concentration is 40%.

[0112] Comparative Example 5

[0113] The difference from Example 1 is that the concentration of the ethylene glycol ethyl ether aqueous solvent used for recrystallization during the preparation of Product A is different, and its concentration is 70%.

[0114] Comparative Example 6

[0115] The difference from Example 1 is that the amount of 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide used in the process of preparing product B is different, and the molar ratio of 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide to product A is 1:1.

[0116] Comparative Example 7

[0117] The difference from Example 1 is that the amount of ammonium chloride used is different, and the molar ratio of ammonium chloride to product B is 5:1.

[0118] Comparative Example 8

[0119] The difference from Example 1 is that the amount of ammonium chloride used is different, and the molar ratio of ammonium chloride to product B is 7.5:1.

[0120] Experimental Example 1

[0121] The products obtained by the preparation methods of Example 1, Examples 3-5 and Comparative Examples 1-2 were compared, and the results are shown in Table 1:

[0122] Table 1 Comparison of reaction effects with different iodomethane dosages

[0123]

[0124] According to the results in Table 1, it can be seen that when the amount of iodomethane used is more than 1.2 mol of raw material, the remaining amount of raw material detected by the central control is less than 1% after 14 hours of reaction, and there is no obvious change when it continues to increase. Considering the comprehensive cost, the amount of iodomethane used is more appropriate, among which 1.1-1.2 mol times is the best, which can achieve better reaction efficiency.

[0125] Experimental Example 2

[0126] The products obtained by the preparation methods of Example 1, Example 6 and Comparative Examples 3-5 were compared, and the results are shown in Table 2:

[0127] Table 2 Comparison of reaction effects at different ethylene glycol ether aqueous solvent concentrations

[0128]

[0129] According to the results in Table 2, it can be seen that the optimal ratio is 50%-60% of ethylene glycol ethyl ether concentration, the product purity is ≥99.5%, and the yield can be maintained above 80%.

[0130] Experimental Example 3

[0131] The products obtained by the preparation methods of Example 1, Examples 7-9 and Comparative Example 6 were compared, and the results are shown in Table 3:

[0132] Table 3 Comparison of reaction effects with different dosages of 2-amino-4-chloro-1,6-dimethylpyrimidine iodide

[0133]

[0134] According to the results in Table 2, it can be seen that when the amount of 2-amino-4-chloro-1,6-dimethylpyrimidine iodide is 1.05 mol times or more of the raw material, the remaining raw material can be less than 1% after 4 hours of reaction. At the same time, to prevent excessive pyrimidine iodide from causing side reactions, the amount can be kept at 1.0.5-1.1 mol times.

[0135] Experimental Example 4

[0136] The products obtained by the preparation methods of Example 1, Examples 10-11 and Comparative Examples 7-8 were compared, and the results are shown in Table 4:

[0137] Table 4 Comparison of reaction effects with different ammonium chloride dosages

[0138]

[0139] According to the results in Table 2, it can be seen that when the amount of ammonium chloride reaches 10 mol times, the raw material can eventually react to less than 1%. Considering the reaction efficiency and cost, the amount can be kept at 10-12 mol times.

[0140] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A method for preparing a quinpiramine intermediate, characterized in that: include: N-(4-methoxy-2-methylquinolin-6-yl)acetamide is reacted with a methyl halide to synthesize product A; Then, product A is reacted with pyrimidine iodide to synthesize product B; product B is then subjected to an amination reaction to obtain 6-(2-amino-1,6-dimethyl-pyrimidin-4-ylamino)-4-amino-1,2-dimethyl-quinoline diiodide; Among them, pyrimidine iodides include 2-amino-4-chloro-1,6-dimethylpyrimidine iodide and 2-amino-1,6-dimethyl-4-methylthiopyrimidine iodide; The steps of preparing the product A include: Dissolving N-(4-methoxy-2-methylquinolin-6-yl)acetamide in ethylene glycol ethyl ether solution to obtain an N-(4-methoxy-2-methylquinolin-6-yl)acetamide solution, adding iodomethane thereto, mixing well, and reacting; After the reaction is completed, the first cooling crystallization is carried out, the precipitate is collected, and the precipitate is dissolved with an ethylene glycol ether aqueous solution; the second cooling crystallization is carried out, the precipitate is collected, and dried to obtain product A; the chemical structure of the product A is as follows: The steps of preparing the product B include: Dissolve product A in sodium carbonate solution, add 2-amino-4-chloro-1,6-dimethylpyrimidinium iodide, mix well, and heat under reflux for reaction; After the reaction is completed, the first cooling, the first filtration and the first rinsing are carried out in sequence, and then the obtained filter cake is dissolved in water, and an alkali metal halide is added, and after dissolution, the second cooling, the second filtration, the second rinsing and the drying are carried out in sequence; or The steps of preparing the product B include: Dissolve product A in sodium hydroxide solution, add 2-amino-1,6-dimethyl-4-methylthiopyrimidinium iodide, mix well, and heat under reflux for reaction under nitrogen atmosphere; After the reaction is completed, the first cooling, the first filtration and the first rinsing are carried out in sequence, and then the obtained filter cake is dissolved in water, and an alkali metal halide is added, and after dissolution, the second cooling, the second filtration, the second rinsing and the drying are carried out in sequence; The chemical structural formula of the product B is as follows: The steps of synthesizing 6-(2-amino-1,6-dimethyl-pyrimidin-4-ylamino)-4-amino-1,2-dimethyl-quinoline diiodide using product B include: The product B, ammonium chloride, and ethanolammonia solution are mixed, sealed, and heated to perform an amination reaction. After the reaction is completed, the temperature is lowered for a third time and concentrated. Then, water and dilute hydrochloric acid are added to the concentrate to dissolve it and adjust the pH to weak acidity. Then, an alkali metal halide is added, mixed, and then cooled for a fourth time, filtered for a third time, rinsed for a third time, and dried.

2. The preparation method according to claim 1, characterized in that The molar ratio of the iodomethane to N-(4-methoxy-2-methylquinolin-6-yl)acetamide is (1-1.4):

1.

3. The preparation method according to claim 1, characterized in that The concentration of the ethylene glycol ethyl ether aqueous solution used to dissolve the precipitate is 50% to 60%; the temperature when dissolving the precipitate is 60°C to 80°C.

4. The preparation method according to claim 1, characterized in that The molar ratio of the 2-amino-4-chloro-1,6-dimethylpyrimidine iodide to the product A is (1-1.3):

1.

5. The preparation method according to claim 1, characterized in that In the amination reaction system, the molar ratio of ammonium chloride to product B is (10~12):

1.

6. A method for preparing quinpiramine, characterized in that: The invention relates to a method for preparing the quinpiramine intermediate according to any one of claims 1 to 5.

Images