Preparation method of imeglumine hydrochloride

Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of imeglumine hydrochloride, which comprises the following steps: adding N, N-dimethyl-2, 4-diamino-1, 3, 5-triazine, formaldehyde, a catalyst and hydrochloric acid into a solvent, heating, and carrying out reflux reaction to obtain a dissolved clear solution; and distilling the clear solution, cooling, carrying out solid-liquid separation, leaching with a leacheate, drying, and refining to obtain a finished product of imegliflozin hydrochloride. The preparation method is simple and suitable for large-scale production. In the process of preparing the imeglumine hydrochloride, the composite catalyst, namely the mixture of p-toluenesulfonic acid and dodecylbenzene sulfonic acid, is adopted as the catalyst, so that the yield of an imeglumine hydrochloride sample can be remarkably improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a method for preparing imagleem hydrochloride. Background Technology

[0002] Imeglimum hydrochloride is a compound with the chemical name (6R)-(+)-4-dimethylamino-2-imino-6-methyl-1,2,5,6-tetrahydro-1,3,5-triazine hydrochloride and the molecular formula C6H2O. 14 ClN5, its compound structure is formula (I). Imeglitinide hydrochloride was initially discovered by Poxel and developed in collaboration with Sumitomo Pharmaceuticals Co., Ltd. of Japan. In Japan... The brand launched this product for the treatment of type 2 diabetes. Imeglitinide hydrochloride was first approved in Japan for the treatment of type 2 diabetes on June 23, 2021.

[0003] Indian invention patent publication number WO2023209729A1 discloses a method for preparing emegligamine and its salts, a method for preparing emegligamine hydrochloride compound of formula (I), the method comprising: a) reacting compound of formula (II) and compound of formula (III) in a solvent in the presence of p-toluenesulfonic acid monohydrate under appropriate conditions to obtain racemic compound of formula (IV); b) reacting racemic compound of formula (IV) with a suitable chiral amino acid or its derivative in the presence of a base and a solvent to obtain r-emegligamine l-amino acid salt compound of formula (V) r-emegligamine-l-amino acid salt (V); c) reacting compound of formula (V) with hydrochloric acid in the presence of a solvent to obtain emegligamine hydrochloride of formula (I); d) optionally purifying emegligamine hydrochloride of formula (I) obtained in step (c) using an alcohol solvent; wherein formula (I) is on page 1 of the specification, and formulas (II), (III), (IV), and (V) are on page 5 of the specification. Although the emeglemin synthesized by this method has high purity, the preparation method is complex and the yield is low. Summary of the Invention

[0004] In view of this, this application provides a method for preparing imaglimide hydrochloride to solve the technical problems of complex preparation methods and low yield in the prior art.

[0005] The technical solution of the present invention to solve the above-mentioned technical problems is as follows:

[0006] A method for preparing emegligamine hydrochloride includes the following steps:

[0007] S10. N,N-dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, catalyst, and hydrochloric acid are added to a solvent, heated to a predetermined temperature, and refluxed for a predetermined time to obtain a clear solution; wherein the catalyst is selected from at least one of p-toluenesulfonic acid and dodecylbenzenesulfonic acid;

[0008] S20. The solution is distilled, cooled, and then the solid and liquid are separated. The solution is then rinsed with an eluent and dried to obtain crude imaglimide hydrochloride. The eluent is isobutanol.

[0009] S30. Dissolve the crude emegglimepiride hydrochloride in a first ethanol, heat to 55°C to 60°C, stir, cool to room temperature, filter the solid, wash with a second ethanol, and dry the solid to obtain purified emegglimepiride hydrochloride. Both the first ethanol and the second ethanol are pure ethanol.

[0010] Preferably, in the above-mentioned method for preparing emegligamine hydrochloride, step S30, after "drying the solid", further includes the following step:

[0011] T31. The dried solid is added to a 90% methanol solution and mixed thoroughly. Then, L-(+) tartaric acid is added until the mixture gradually dissolves. Triethylamine is then slowly added dropwise at 10 to 15°C and stirred for 2 to 5 hours. The mixture is then filtered, the solid and liquid are separated, and the solid is washed. The separated solid is dried to obtain imagleem hydrochloride tartrate. The molar ratio of the dried solid, L-(+) tartaric acid, and triethylamine is (1 to 1.5):(1 to 1.3):1.

[0012] T32. Add the emegleemine hydrochloride tartrate to an ethanol solution and stir until homogeneous. Then add hydrochloric acid ethanol and heat to 70 to 90°C. Maintain the temperature under reflux for 20 to 50 minutes. Then slowly cool down to 10°C and maintain the temperature for 1 to 3 hours. Then filter, separate the solid and liquid, and dry the separated solid to obtain purified emegleemine hydrochloride with the chemical formula 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine. The molar ratio of emegleemine hydrochloride tartrate, ethanol solution, and hydrochloric acid ethanol is 1:(2 to 5):(5 to 10).

[0013] Preferably, in the above method for preparing emeglemin hydrochloride, in step S10, the catalyst is a mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid, and the molar ratio of p-toluenesulfonic acid to dodecylbenzenesulfonic acid is (1 to 3):3.

[0014] Preferably, in step S10, the molar ratio of p-toluenesulfonic acid and dodecylbenzenesulfonic acid in the above-mentioned method for preparing emeglemin hydrochloride is 2:3.

[0015] Preferably, in the above-mentioned method for preparing emegligamine hydrochloride, in step S10, the molar ratio of N,N-dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, catalyst and hydrochloric acid is 1:(1 to 1.5):(0.03 to 0.08):(1 to 1.15).

[0016] Preferably, in the above-mentioned method for preparing emeglemin hydrochloride, in step S10, the molar ratio of N,N-dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, catalyst and hydrochloric acid is 1:1.1:0.05:1.1.

[0017] Preferably, in the above-mentioned method for preparing emeglemin hydrochloride, in step S10, the weight ratio of the solvent to the N,N-dimethyl-2,4-diamino-1,3,5-triazine is (2 to 3):1.

[0018] Preferably, in the above method for preparing emegligamine hydrochloride, the solvent is isobutanol.

[0019] Preferably, in the above-mentioned method for preparing emeglemin hydrochloride, in step S10, the predetermined temperature is 96°C to 102°C, and the predetermined time is 10h to 12h.

[0020] The application of the above-mentioned method for preparing emegligamine hydrochloride in the preparation of emegligamine hydrochloride.

[0021] The present invention, by adopting the above technical solution, has at least the following beneficial effects:

[0022] This application discloses a method for preparing imagramine hydrochloride, comprising the following steps: adding N,N-dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, a catalyst, and hydrochloric acid to a solvent, heating, and refluxing to obtain a clear solution; distilling the solution, cooling, separating the solid and liquid phases, rinsing with an eluent, drying, and refining to obtain the finished imagramine hydrochloride. This preparation method is simple and suitable for large-scale production.

[0023] In the preparation of imagliflozin hydrochloride in this application, a composite catalyst, namely a mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid, is used as the catalyst, which significantly improves the yield of the imagliflozin hydrochloride sample. Experimental data show that the racemic imagliflozin hydrochloride prepared using the mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid as the catalyst has a yield increase of 19.79% (28.62%) compared to the racemic imagliflozin hydrochloride prepared using only p-toluenesulfonic acid as the catalyst, and a yield increase of 24.68% (38.41%) compared to the racemic imagliflozin hydrochloride prepared using only dodecylbenzenesulfonic acid as the catalyst. The final overall yield of imagliflozin hydrochloride is 12.74%, with a purity of 99.9%. Attached Figure Description

[0024] Figure 1 This is a schematic diagram illustrating the reaction principle of imagramine hydrochloride in this application.

[0025] Figure 2 This is a schematic diagram of the reaction principle in step T31 of the embodiment of this application.

[0026] Figure 3 This is a schematic diagram of the reaction principle in step T32 of the embodiment of this application.

[0027] Figure 4 This is the liquid chromatogram of the racemic isomer of emegligamine hydrochloride, sample 6, from Experimental Example 3 of this application.

[0028] Figure 5 This is a liquid chromatogram of L-(+) tartaric acid used in Experiment 3 of this application to separate the racemic isomer of emegligamine hydrochloride.

[0029] Figure 6 This is the liquid chromatogram of emegligamine hydrochloride in Experiment Example 3 of this application. Detailed Implementation

[0030] It should be noted that, unless otherwise specified, the embodiments and features described in the embodiments of the present invention can be combined with each other. The technical solutions of the present invention will be further described below with reference to the accompanying drawings of the embodiments of the present invention. The present invention is not limited to the following specific embodiments.

[0031] Please see Figures 1 to 2 In one specific embodiment of the present invention, a method for preparing imagleem hydrochloride includes the following steps:

[0032] S10. N,N-dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, catalyst and hydrochloric acid are added to a solvent, heated to a predetermined temperature, and refluxed for a predetermined time to obtain a clear solution; wherein, the catalyst is selected from at least one of p-toluenesulfonic acid and dodecylbenzenesulfonic acid;

[0033] In this scheme, N,N-dimethyl-2,4-diamino-1,3,5-triazine is impurity G in metformin hydrochloride. It is obtained by reacting dimethylamine hydrochloride with dicyandiamide to obtain crude metformin hydrochloride, followed by further reaction with DMF and purification. The molecular weight is 139. The catalyst is selected from at least one of p-toluenesulfonic acid and dodecylbenzenesulfonic acid. P-Toluenesulfonic acid has the chemical formula C7H8O3S, CAS number 104-15-4, and a molecular weight of 172.2. It is a non-oxidizing strong organic acid, one million times stronger than benzoic acid, and is a white needle-like or powdery crystal. It is hygroscopic and soluble in water, alcohol, and other polar solvents. Dodecylbenzenesulfonic acid has the chemical formula C7H8O3S. 18 H 30O3S, CAS No. 27176-87-0, molecular weight 326.49. Dodecylbenzenesulfonic acid, also known as linear alkylbenzene or dodecylbenzenesulfonic acid, is an anionic surfactant commonly used as a raw material for various detergents or to produce sodium, ammonium, and ethanolamine salts of linear alkylbenzenesulfonates. It can also be used as a curing catalyst for amino baking varnishes. In this application, a mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid is selected as the catalyst, which can significantly improve the yield and conversion rate of emeglimide hydrochloride. The molar ratio of p-toluenesulfonic acid to dodecylbenzenesulfonic acid is (1 to 3):3. The molar ratio of the two affects the yield and conversion rate of emeglimide hydrochloride. Preferably, the molar ratio of p-toluenesulfonic acid to dodecylbenzenesulfonic acid is 2:3.

[0034] In step S10, the solvent can be selected from methanol, ethanol, isopropanol, and isobutanol. Since isobutanol is widely used as a solvent in chemical reactions and is also a useful raw material in organic synthesis, isobutanol is preferred as the reaction solvent in this application. The molecular formula of isobutanol is C4H4H2O. 10 O, CAS number 78-83-1, molecular weight 74.12, is a colorless, flammable organic compound with a characteristic odor, mainly used as a solvent and in organic synthesis. Since catalysts primarily function to dissolve, dilute, and stabilize substances, the amount of solvent added should be sufficient to fully dissolve the solute. Therefore, as a preferred embodiment, in this scheme, the weight ratio of the solvent, isobutanol, to N,N-dimethyl-2,4-diamino-1,3,5-triazine is (2 to 3):1.

[0035] Preferably, the molar ratio of N,N-dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, catalyst, and hydrochloric acid is 1:(1 to 1.5):(0.03 to 0.08):(1 to 1.15), and more preferably, the molar ratio of N,N-dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, catalyst, and hydrochloric acid is 1:1.1:0.05:1.1.

[0036] Furthermore, the predetermined temperature is 96°C to 102°C, and the predetermined time is 10h to 12h.

[0037] S20. The solution is distilled, cooled, and then the solid and liquid are separated. The solution is then rinsed with an eluent and dried to obtain crude imaglimide hydrochloride. The eluent is isobutanol.

[0038] S30. Dissolve the crude emegglimepiride hydrochloride in an ethanol solution, heat to 55°C to 60°C, stir, cool to room temperature, filter the solid, wash with ethanol solution, and dry the solid to obtain purified emegglimepiride hydrochloride. Emegglimepiride hydrochloride is 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, with the molecular formula C6H12H2O.14 ClN5, CAS No. 775351-61-6, molecular weight 191.66.

[0039] In a preferred embodiment, step S30, after "drying the solid", further includes the following step:

[0040] T31. The dried solid, i.e., the racemic mixture of emegleemine hydrochloride, is added to a 90% methanol solution and mixed thoroughly. L-(+) tartaric acid is then added until the mixture gradually dissolves. Triethylamine is slowly added dropwise at 10-15°C, and the mixture is stirred for 2-5 hours. The mixture is then filtered, the solid and liquid are separated, and the solid is washed. The separated solid is dried to obtain emegleemine hydrochloride tartrate. The molar ratio of the racemic mixture of emegleemine hydrochloride, L-(+) tartaric acid, and triethylamine is (1-1.5):(1-1.3):1. The racemic mixture of emegleemine hydrochloride is 4-amino-3,6-dihydro-2-dimethylamino-6-methyl-1,3,5-triazine with a molecular weight of 155.2. The molecular weight of emegleemine hydrochloride tartrate is 305.3.

[0041] T32. The emegleemine hydrochloride tartrate is added to an ethanol solution and stirred until homogeneous. Then, ethanol hydrochloride is added, and the mixture is heated to 70-90°C and refluxed for 20-50 minutes. The temperature is then slowly lowered to 10°C and maintained at that temperature for 1-3 hours. The mixture is then filtered, and the solid and liquid are separated. The separated solid is dried to obtain purified emegleemine hydrochloride with the chemical formula 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine. The molar ratio of emegleemine hydrochloride tartrate, ethanol solution, and ethanol hydrochloride is 1:(2-5):(5-10). In this application, the ethanol hydrochloride contains 30.7% HCl, has a molecular weight of 36.5, and has an ethanol concentration of 100%.

[0042] For example, the preparation method of emegligamine hydrochloride includes the following steps:

[0043] N,N-Dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, catalyst, and hydrochloric acid were added to isobutanol in a molar ratio of 1:1.1:0.05:1.1. The mixture was heated to 96°C to 102°C and refluxed for 10 to 12 hours. The material gradually clarified from a suspension state, reaching a clear solution at the endpoint, indicating the end of the reaction. The catalyst was a mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid in a molar ratio of 2:3. The weight ratio of isobutanol to N,N-dimethyl-2,4-diamino-1,3,5-triazine was (2 to 3):1. The clear solution was then distilled to remove 0.5 times the amount of solvent. The solution was cooled to 10°C to 20°C for solid-liquid separation, followed by rinsing with 0.5 times the amount of isobutanol and drying to obtain crude emeglide hydrochloride. Finally, the crude emegglimepiride hydrochloride was dissolved in 5 to 7 times its weight in ethanol solution, heated to 55°C to 60°C, stirred, cooled to room temperature, the solid was filtered, washed with ethanol solution, and dried. The dried solid, i.e., the racemic mixture of emegglimepiride hydrochloride, was added to 90% methanol solution, stirred and mixed, and cooled to 10°C. Then L-(+)tartaric acid was added. After the mixture gradually dissolved, triethylamine was slowly added dropwise at 10 to 15°C, stirred for 2 to 5 hours, then filtered, the solid and liquid were separated, washed with methanol, and the separated solid was dried to obtain... The mixture of emegleemine hydrochloride tartrate, L-(+) tartaric acid, and triethylamine is prepared in a molar ratio of (1 to 1.5):(1 to 1.3):1. The emegleemine hydrochloride tartrate is added to an ethanol solution, stirred and mixed, and cooled to 10°C. Then, ethanol hydrochloride is added, and the mixture is heated to 70 to 90°C and refluxed for 20 to 50 minutes. The mixture is then slowly cooled to 10°C at a rate of 10°C / h and kept at that temperature for 1 to 3 hours. The mixture is then filtered, and the solid and liquid are separated. The separated solid is dried to obtain purified emegleemine hydrochloride.

[0044] In another specific embodiment of the present invention, the application of the above-described method for preparing emegligamine hydrochloride in the preparation of emegligamine hydrochloride is described.

[0045] It is worth noting that the process temperature and process time involved in the above embodiments are all temperatures or times used in the experiment. Any reasonable adjustments made by those skilled in the art based on the process temperature and process time provided by the present invention, within the error range, should be included within the protection scope of the present invention.

[0046] The following specific experimental examples further illustrate the technical solution and effects of the present invention.

[0047] It should be noted that in the embodiments of the present invention, N,N-dimethyl-2,4-diamino-1,3,5-triazine is from Ningxia Hengkang Technology Co., Ltd., with a purity of 99.4%; other reagents and solvents are commercially available and can be used without further purification.

[0048] The yield calculations for emegligamine hydrochloride samples were performed according to standard methods and formulas.

[0049] 1. Experimental Example 1

[0050] Weigh 13.90 g of N,N-dimethyl-2,4-diamino-1,3,5-triazine, 3.30 g of formaldehyde, p-toluenesulfonic acid (Table 1), and 4.01 g of hydrochloric acid, and place them in a beaker containing 34.75 g of isobutanol. Heat to 100℃±1℃ and reflux for 11 h. The material gradually becomes clear from a suspension, reaching a clear solution at the endpoint. The reaction is then complete, yielding a clear solution. Distill the solution to remove 0.5 times its weight of isobutanol. Cool to 15℃±1℃ for solid-liquid separation. Wash with 0.5 times its weight of isobutanol and dry to obtain crude emegglimepiride hydrochloride. Finally, dissolve the crude emegglimepiride hydrochloride in 6 times its weight of ethanol solution, heat to 57℃±1℃, stir, cool to room temperature, filter the solid, wash with ethanol, and dry the solid.

[0051] Table 1. Amounts of each raw material used in Experiment Example 1

[0052]

[0053]

[0054] The mass and yield of the dried solid (racemic mixture of emegligamine hydrochloride) were calculated, and the purity of the sample was determined by high performance liquid chromatography. The results are shown in the table below:

[0055] Table 2. Yields and purity of each sample in Experiment Example 1

[0056] sample Mass (g) Yield (%) purity(%) Sample 1 9.39 60.50 99.9 Sample 2 10.73 69.13 99.9 Sample 3 9.77 62.95 99.9

[0057] As can be seen from the table above, when p-toluenesulfonic acid is used as the catalyst, the quality and yield of the racemic mixture of emeglimide hydrochloride vary depending on the amount of catalyst used. The molar ratio of N,N-dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, catalyst, and hydrochloric acid used in Sample 1 was 1:1.1:0.03:1.1, with a mass of 9.39 g and a yield of 60.50%. The molar ratio of N,N-dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, catalyst, and hydrochloric acid used in Sample 2 was 1:1.1:0.05:1.1, with a mass of 10.73 g and a yield of 69.13%. The molar ratio of N,N-dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, catalyst, and hydrochloric acid used in Sample 3 was 1:1.1:0.08:1.1, with a mass of 9.77 g and a yield of 62.95%. It is evident that when the purity of the prepared sample is 99.9%, sample 2 has a slightly higher mass and yield compared to the other two groups of samples. In other words, the mass and yield of the racemic mixture of emegligamine hydrochloride prepared when the molar ratio of N,N-dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, catalyst, and hydrochloric acid is 1:1.1:0.05:1.1 are relatively high.

[0058] 10g of the dried solid of sample 2 (racemic mixture of emegleemine hydrochloride) and 22g of 90% methanol solution were added to a clean three-necked flask. The flask was placed in a low-temperature constant temperature bath, and the mixture was stirred and cooled to 10℃. After mixing evenly, 7.8g of L-(+) tartaric acid was added. After the mixture gradually dissolved, 4.75g of triethylamine was slowly added dropwise at 10 to 15℃. After the addition was completed, solid precipitated out. The mixture was stirred for 3 hours, then filtered, and the solid and liquid were separated. The solid was washed with 5g of methanol and dried to obtain 6g of emegleemine hydrochloride tartrate with a purity of 99.9% and a yield of 31%. To facilitate subsequent experiments, the preparation process of sample 2 and emegleemine hydrochloride tartrate was repeated to obtain 30g of emegleemine hydrochloride tartrate for later use.

[0059] Add 20g of emegligamine hydrochloride tartrate and 21g of ethanol (100% concentration) to a clean three-necked flask. Place the flask in a low-temperature constant temperature bath, turn on the stirrer, and cool to 10°C. After mixing evenly, add 8.06g of hydrochloric acid ethanol with an HCl content of 30.7%. Then place the flask in a water bath and heat to 80°C. Attach a reflux tube and keep it under reflux for 30 minutes. Then slowly cool to 10°C at a rate of 10°C / h and keep it at that temperature for 2 hours. Then filter, separate the solid and liquid, and dry the separated solid to obtain 5.8g of purified emegligamine hydrochloride with a purity of 99.9% and a yield of 46.2%.

[0060] Based on the above yields of 69.13% for the racemic mixture of imegglimepiride hydrochloride, 31% for imegglimepiride hydrochloride tartrate, and 46.2% for purified imegglimepiride hydrochloride, the total yield of imegglimepiride hydrochloride is calculated using the following method:

[0061] The total yield of imagrasmin hydrochloride = yield of racemic imagrasmin hydrochloride × yield of imagrasmin hydrochloride tartrate salt × yield of purified imagrasmin hydrochloride = 69.13% × 31% × 46.2%, yielding a total yield of imagrasmin hydrochloride of 9.9%.

[0062] 2. Experimental Example 2

[0063] Weigh out 13.90 g of N,N-dimethyl-2,4-diamino-1,3,5-triazine, 3.30 g of formaldehyde, catalyst (Table 3), and 4.01 g of hydrochloric acid, and place them in a beaker containing 34.75 g of isobutanol. Heat to 100℃±1℃ and reflux for 11 h. The material gradually becomes clear from a suspension, reaching a clear solution at the endpoint. The reaction is then complete, yielding a clear solution. Distill the solution to remove 0.5 times its weight of isobutanol. Cool to 15℃±1℃ for solid-liquid separation. Wash with 0.5 times its weight of isobutanol and dry to obtain crude emegglimepiride hydrochloride. Finally, dissolve the crude emegglimepiride hydrochloride in 6 times its weight of ethanol solution, heat to 57℃±1℃, stir, cool to room temperature, filter the solid, wash with ethanol solution, and dry the solid.

[0064] Table 3. Amounts of each raw material used in Experiment Example 2.

[0065]

[0066] The mass and yield of the dried solid (racemic mixture of emegligamine hydrochloride) were calculated, and the purity of the sample was determined by high performance liquid chromatography. The results are shown in the table below:

[0067] Table 4. Yields and purity of each sample in Experiment Example 2

[0068] sample Mass (g) Yield (%) purity(%) Sample 2 10.73 69.13 99.9 Sample 3 9.97 64.24 99.9 Sample 4 11.69 75.32 99.9

[0069] Please refer to Table 4. With other reactants remaining constant, the catalysts for Sample 2 were p-toluenesulfonic acid, Sample 3 was dodecylbenzenesulfonic acid, and Sample 4 was a 1:1 molar mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid. When the purity of the obtained samples was 99.9%, Sample 3 had the lowest mass and yield, at 9.97 g and 64.24%, respectively. The mass of Sample 4 was 11.69 g, an increase of 8.8% compared to Sample 2 and 17.3% compared to Sample 3; the yield of Sample 4 was 75.32%, an increase of 6.19% compared to Sample 2 and 11.08% compared to Sample 3. Therefore, using a composite catalyst, i.e., a mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid, can make the reaction of the reactants more complete and effectively improve the yield of the racemic emeglide hydrochloride.

[0070] 10g of the dried solid of sample 4 (racemic mixture of emegleemine hydrochloride) and 22g of 90% methanol solution were added to a clean three-necked beaker. The beaker was placed in a low-temperature constant temperature bath, stirred, and cooled to 10℃. After mixing evenly, 7.8g of L-(+) tartaric acid was added. After the mixture gradually dissolved, 4.75g of triethylamine was slowly added dropwise at 10-15℃. After the addition was completed, solid precipitated. The mixture was stirred for 3 hours, then filtered, the solid and liquid were separated, and washed with 5g of methanol. The separated solid was dried to obtain 6g of emegleemine hydrochloride tartrate with a purity of 99.9% and a yield of 31%. To facilitate subsequent experiments, the preparation process of sample 4 and emegleemine hydrochloride tartrate was repeated to obtain 30g of emegleemine hydrochloride tartrate for later use.

[0071] Add 20g of emegligamine hydrochloride tartrate and 21g of ethanol (100% concentration) to a clean three-necked flask. Place the flask in a low-temperature constant temperature bath, turn on the stirrer, and cool to 10°C. After mixing evenly, add 8.06g of hydrochloric acid ethanol with an HCl content of 30.7%. Then place the flask in a water bath and heat to 80°C. Attach a reflux tube and keep it under reflux for 30 minutes. Then slowly cool to 10°C at a rate of 10°C / h and keep it at that temperature for 2 hours. Then filter, separate the solid and liquid, and dry the separated solid to obtain 5.8g of purified emegligamine hydrochloride with a purity of 99.9% and a yield of 46.2%.

[0072] Based on the above yields of 75.32% for the racemic mixture of imegglimepiride hydrochloride, 31% for imegglimepiride hydrochloride tartrate, and 46.2% for purified imegglimepiride hydrochloride, the total yield of imegglimepiride hydrochloride is calculated using the following method:

[0073] The total yield of imagrasmin hydrochloride = yield of racemic imagrasmin hydrochloride × yield of imagrasmin hydrochloride tartrate salt × yield of purified imagrasmin hydrochloride = 75.32% × 31% × 46.2%, yielding a total yield of imagrasmin hydrochloride of 10.78%.

[0074] 3. Experimental Example 3

[0075] Weigh out 13.90 g of N,N-dimethyl-2,4-diamino-1,3,5-triazine, 3.3 g mol of formaldehyde, catalyst (Table 5), and 4.01 g of hydrochloric acid, and place them in a beaker containing 34.75 g of isobutanol. Heat to 100℃±1℃ and reflux for 11 h. The material gradually becomes clear from a suspension, reaching a clear solution at the endpoint. The reaction is then complete, yielding a clear solution. Distill the solution to remove 0.5 times its weight of isobutanol. Cool to 15℃±1℃ for solid-liquid separation. Wash with 0.5 times its weight of isobutanol and dry to obtain crude emegglimepiride hydrochloride. Finally, dissolve the crude emegglimepiride hydrochloride in 6 times its weight of ethanol solution, heat to 57℃±1℃, stir, cool to room temperature, filter the solid, wash with ethanol solution, and dry the solid.

[0076] Table 5. Amounts of each raw material used in Experiment Example 3

[0077]

[0078]

[0079] The mass and yield of the dried solid (racemic mixture of emegligamine hydrochloride) were calculated, and the purity of the sample was determined by high performance liquid chromatography. The results are shown in the table below:

[0080] Table 6. Yields and purity of each sample in Experiment Example 3

[0081] sample Mass (g) Yield (%) purity(%) Sample 4 11.69 75.32 99.9 Sample 5 11.50 74.10 99.9 Sample 6 13.8 88.92 99.9 Sample 7 12.08 77.84 99.9 Sample 8 11.31 72.87 99.9

[0082] As can be seen from Table 6, under the condition that other reaction raw materials remain unchanged, samples 4 to 8 are all racemic mixtures of emeglimide hydrochloride prepared using a mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid as catalyst. Sample 4, a catalyst composed of a 1:1 molar mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid, showed improved mass and yield compared to samples using a single catalyst. Sample 5, a catalyst composed of a 5:3 molar mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid, showed no significant difference in mass and yield compared to sample 4. Sample 6, a catalyst composed of a 2:3 molar mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid, showed a significant improvement in yield and conversion, with a mass of 13.8 g and a yield of 88.92%. Sample 7, a catalyst composed of a 1:3 molar mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid, showed improved mass and yield compared to samples 4 and 5, but the difference was not significant. Sample 8, a catalyst composed of a 1:4 molar mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid, had the lowest mass and yield of 11.31 g and 72.87%, respectively. In other words, when the purity of the obtained sample is 99.9%, sample 6 uses a composite catalyst, namely a mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid in a molar ratio of 2:3. The mass and yield of the racemic mixture of emegligamine hydrochloride are the highest, with a yield increase of 19.79% (28.62%) compared to sample 2 prepared using only p-toluenesulfonic acid as a catalyst, and a yield increase of 24.68% (38.41%) compared to sample 3 prepared using only dodecylbenzenesulfonic acid as a catalyst.

[0083] 10g of the dried solid of sample 6 (racemic mixture of emegleemine hydrochloride) and 22g of 90% methanol solution were added to a clean three-necked beaker. The beaker was placed in a low-temperature constant temperature bath, stirred, and cooled to 10℃. After mixing evenly, 7.8g of L-(+) tartaric acid was added. After the mixture gradually dissolved, 4.75g of triethylamine was slowly added dropwise at 10-15℃. After the addition was completed, solid precipitated. Stirring was continued for 3 hours. Then, the mixture was filtered, the solid and liquid were separated, and washed with 5g of methanol. The separated solid was dried to obtain 6g of emegleemine hydrochloride tartrate, with a purity of 99.9% and a yield of 31%. To facilitate subsequent experiments, the preparation process of sample 6 and emegleemine hydrochloride tartrate was repeated to obtain 30g of emegleemine hydrochloride tartrate for later use.

[0084] Add 20g of emegligamine hydrochloride tartrate and 21g of ethanol (100% concentration) to a clean three-necked flask. Place the flask in a low-temperature constant temperature bath, turn on the stirrer, and cool to 10°C. After mixing evenly, add 8.06g of hydrochloric acid ethanol with an HCl content of 30.7%. Then place the flask in a water bath and heat to 80°C. Attach a reflux tube and keep it under reflux for 30 minutes. Then slowly cool to 10°C at a rate of 10°C / h and keep it at that temperature for 2 hours. Then filter, separate the solid and liquid, and dry the separated solid to obtain 5.8g of purified emegligamine hydrochloride with a purity of 99.9% and a yield of 46.2%.

[0085] Based on the above yields of 88.92% for the racemic mixture of imegglimepiride hydrochloride, 31% for imegglimepiride hydrochloride tartrate, and 46.2% for purified imegglimepiride hydrochloride, the total yield of imegglimepiride hydrochloride is calculated using the following method:

[0086] The total yield of imagraglitin hydrochloride = yield of racemic imagraglitin hydrochloride × yield of imagraglitin hydrochloride tartrate salt × yield of purified imagraglitin hydrochloride = 88.92% × 31% × 46.2%, yielding a total yield of imagraglitin hydrochloride of 12.74%.

[0087] 4. Experimental Example 4

[0088] Weigh out 13.90 g of N,N-dimethyl-2,4-diamino-1,3,5-triazine, 3.3 g mol of formaldehyde, catalyst (0.34 g of p-toluenesulfonic acid and 0.98 g of dodecylbenzenesulfonic acid), 4.01 g of hydrochloric acid, and sodium borohydride (addition amounts are shown in the table below), and place them in a beaker containing 34.75 g of isobutanol. Heat to 100℃±1℃ and reflux for 11 h. The material gradually becomes clear from a suspension state, and the endpoint is a clear solution. The reaction ends, and a clear solution is obtained. Then, the clear solution is distilled to distill off 0.5 times the amount of isobutanol. Cool to 15℃±1℃ for solid-liquid separation, and then wash with 0.5 times the amount of isobutanol. Dry to obtain crude emegligamine hydrochloride. Finally, the crude emeglide hydrochloride was dissolved in an ethanol solution with a mass of 6 times its weight, heated to 57℃±1℃, stirred, cooled to room temperature, the solid was filtered, washed with ethanol solution, and dried.

[0089] Table 7. Amounts of each raw material used in Experiment Example 4

[0090]

[0091]

[0092] The mass and yield of the dried solid (racemic mixture of emegligamine hydrochloride) were calculated, and the purity of the sample was determined by high performance liquid chromatography. The results are shown in the table below:

[0093] Table 8. Yields and purity of each sample in Experiment Example 4

[0094] sample Mass (g) Yield (%) purity(%) Sample 9 14.24 91.77 99.9 Sample 10 14.3 92.14 99.9 Sample 11 14.64 94.36 99.9 Sample 12 14.46 93.21 99.9 Sample 13 14.52 93.58 99.9

[0095] As shown in Table 8, with the other reaction raw materials and conditions of Sample 6 unchanged, the addition of an appropriate amount of sodium borohydride to the reaction raw materials further improved the yield of the racemic mixture of emegligamine hydrochloride. When the molar ratio of N,N-dimethyl-2,4-diamino-1,3,5-triazine to sodium borohydride was 1:(0.1 to 0.5), the yield was greater than 91%, especially for Sample 11, where the yield reached as high as 94.36%. Sample 11 will be used for the next step of the experiment.

[0096] 10g of dried solid of sample 11 (racemic mixture of emegleemine hydrochloride) and 22g of 90% methanol solution were added to a clean three-necked beaker. The beaker was placed in a low-temperature constant temperature bath, stirred, and cooled to 10℃. After mixing evenly, 7.8g of L-(+) tartaric acid was added. After the mixture gradually dissolved, 4.75g of triethylamine was slowly added dropwise at 10 to 15℃. After the addition was completed, solid precipitated. Stirring was continued for 3 hours. Then, the mixture was filtered, the solid and liquid were separated, and washed with 5g of methanol. The separated solid was dried to obtain 6g of emegleemine hydrochloride tartrate, with a purity of 99.9% and a yield of 31%. To facilitate subsequent experiments, the preparation process of sample 11 and emegleemine hydrochloride tartrate was repeated to obtain 30g of emegleemine hydrochloride tartrate for later use.

[0097] Add 20g of emegligamine hydrochloride tartrate and 21g of ethanol (100% concentration) to a clean three-necked flask. Place the flask in a low-temperature constant temperature bath, turn on the stirrer, and cool to 10°C. After mixing evenly, add 8.06g of hydrochloric acid ethanol with an HCl content of 30.7%. Then place the flask in a water bath and heat to 80°C. Attach a reflux tube and keep it under reflux for 30 minutes. Then slowly cool to 10°C at a rate of 10°C / h and keep it at that temperature for 2 hours. Then filter, separate the solid and liquid, and dry the separated solid to obtain 5.8g of purified emegligamine hydrochloride with a purity of 99.9% and a yield of 46.2%.

[0098] Based on the above yields of 94.36% for the racemic mixture of imegglimepiride hydrochloride, 31% for imegglimepiride hydrochloride tartrate, and 46.2% for purified imegglimepiride hydrochloride, the total yield of imegglimepiride hydrochloride is calculated using the following method:

[0099] The total yield of imagrasmin hydrochloride = yield of racemic imagrasmin hydrochloride × yield of imagrasmin hydrochloride tartrate salt × yield of purified imagrasmin hydrochloride = 94.36% × 31% × 46.2%, yielding a total yield of imagrasmin hydrochloride of 13.51%.

[0100] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is neither necessary nor possible to exhaustively describe all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing emegligamine hydrochloride, characterized in that, Includes the following steps: S10. N,N-dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, catalyst and hydrochloric acid are added to a solvent, heated to a predetermined temperature, and refluxed for a predetermined time to obtain a clear solution; wherein, the catalyst is selected from at least one of p-toluenesulfonic acid and dodecylbenzenesulfonic acid; S20. The solution is distilled, cooled, and then the solid and liquid are separated. The solution is then rinsed with an eluent and dried to obtain crude imaglimide hydrochloride. The eluent is isobutanol. S30. The crude emegligamine hydrochloride is dissolved in a first ethanol, heated to 55°C to 60°C, stirred, cooled to room temperature, the solid is filtered, washed with a second ethanol, and the solid is dried to obtain purified emegligamine hydrochloride with the chemical formula 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine.

2. The method for preparing emegglimepiride hydrochloride according to claim 1, characterized in that, In step S30, after "drying the solid", the following steps are also included: T31. The dried solid is added to a 90% methanol solution, mixed evenly, and then L-(+) tartaric acid and triethylamine are added. The mixture is stirred for 2 to 5 hours, then filtered, separated from the solid, washed, and the separated solid is dried to obtain imagleem hydrochloride tartrate; wherein the molar ratio of the dried solid, L-(+) tartaric acid, and triethylamine is (1 to 1.5):(1 to 1.3):

1. T32. Add the emegligamine hydrochloride tartrate to an ethanol solution and stir until homogeneous. Then add hydrochloric acid ethanol, heat to 70 to 90°C, reflux for 20 to 50 minutes, then cool to 10°C and keep warm for 1 to 3 hours. Then filter, separate the solid and liquid, and dry the separated solid to obtain purified emegligamine hydrochloride with the chemical formula 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine. The molar ratio of emegligamine hydrochloride tartrate, ethanol solution, and hydrochloric acid ethanol is 1:(2 to 5):(5 to 10).

3. The method for preparing emegglimepiride hydrochloride according to claim 1, characterized in that, In step S10, the catalyst is a mixture of p-toluenesulfonic acid and dodecylbenzenesulfonic acid, and the molar ratio of p-toluenesulfonic acid to dodecylbenzenesulfonic acid is (1 to 3):

3.

4. The method for preparing emegligamine hydrochloride according to claim 3, characterized in that, In step S10, the molar ratio of p-toluenesulfonic acid and dodecylbenzenesulfonic acid is 2:

3.

5. The method for preparing emegglimepiride hydrochloride according to claim 1, characterized in that, In step S10, the molar ratio of N,N-dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, catalyst and hydrochloric acid is 1:(1 to 1.5):(0.03 to 0.08):(1 to 1.15).

6. The method for preparing emegglimepiride hydrochloride according to claim 1 or 5, characterized in that, In step S10, the molar ratio of N,N-dimethyl-2,4-diamino-1,3,5-triazine, formaldehyde, catalyst and hydrochloric acid is 1:1.1:0.05:1.

1.

7. The method for preparing emegglimepiride hydrochloride according to claim 1, characterized in that, In step S10, the weight ratio of the solvent to the N,N-dimethyl-2,4-diamino-1,3,5-triazine is (2 to 3):

1.

8. The method for preparing emegglimepiride hydrochloride according to claim 1, characterized in that, The solvent is isobutanol.

9. The method for preparing emegligamine hydrochloride according to claim 1, characterized in that, In step S10, the predetermined temperature is 96°C to 102°C, and the predetermined time is 10h to 12h.

10. The application of a method for preparing emegligamine hydrochloride as described in any one of claims 1 to 9 in the preparation of emegligamine hydrochloride.

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