Preparation method of (R)-2-amino-3, 6-dihydro-4-dimethylamino-6-methyl-1, 3, 5-triazine hydrochloride

Abstract

The invention belongs to the technical field of pharmaceutical manufacturing, and discloses a preparation method of (R)-2-amino-3, 6-dihydro-4-dimethylamino-6-methyl-1, 3, 5-triazine hydrochloride, which comprises the following steps: mixing and dissolving paraldehyde and metformin hydrochloride in water, adding an acid catalyst, reacting, filtering and collecting solid; dissolving the solid in methanol, adding alkali, stirring, filtering, spin-drying the filtrate, and collecting the obtained solid; mixing the solid obtained in the previous step with a resolving agent for resolving, stirring overnight, filtering, and respectively collecting filtrate and solid; and recrystallizing the solid in the previous step, filtering, and replacing the resolving agent with hydrochloric acid to obtain the product. And after the acidic resolving agent is added, the filtered filtrate is subjected to spin-drying, neutralization, catalytic racemization of the basic catalyst and crystallization to obtain free raceme, and the free raceme can be used as a raw material to prepare a product according to the preparation method, so that the recovery and reuse of the filtrate are realized, the total yield of the reaction is increased, the cost is reduced, and the industrial green production is facilitated.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical manufacturing, and relates to a preparation method of imeglimin hydrochloride, specifically to a preparation method of (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride. Background Art

[0002] The scientific name of imeglimin hydrochloride is Imeglimin hydrochloride, also known as Imeglimin (EMD387008) Hydrochloride, and has several tautomers. One of its chemical names is (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride, which is an organic compound and is a white crystalline powder. Clinically, it is used to treat type II diabetes. It can normalize the blood glucose concentration of diabetic patients through multiple pathways such as improving mitochondrial function, increasing the sensitivity of peripheral tissues to insulin, and maintaining the normal function of β cells.

[0003] At present, there have been various reports on the preparation method of (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride, but these methods still have some deficiencies. For example, some methods use multiple-step reactions, which are cumbersome, resulting in high production costs and low yields; some methods use toxic or volatile organic solvents, causing great pollution to the environment; and some methods have problems such as harsh reaction conditions and complex operations, which are not conducive to industrial production.

[0004] The racemate of imeglimin hydrochloride was first synthesized in US7034021, using DMF as the reaction solvent, and the racemate of imeglimin hydrochloride was prepared by the reaction of metformin hydrochloride and acetaldehyde diethyl acetal, but the reaction yield was low.

[0005] In subsequent synthetic routes, the reaction solvents are all isopropanol, DMF, methanol, ethanol, and a mixed solvent of ethanol and water, such as patents CN 114763339 A, IN202221016969A, IN202221006058A, IN202121005219A, etc., all using a large amount of organic solvents, which does not conform to the concept of green chemistry.

[0006] In the treatment of the filtrate after resolution, only patent IN202121005219 mentions using sodium hydroxide as a catalyst, reflux treatment, preparing the racemate through a racemization reaction, and recycling it by circulation. And in this reaction, sodium hydroxide is input in an equivalent amount, not a catalytic amount. Therefore, further research is needed in terms of racemization. Summary of the Invention

[0007] Aiming at the above technical deficiencies, the present invention aims to provide a more efficient, economical and environmentally friendly preparation method of (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride. By optimizing the reaction route and reaction conditions, this method reduces the separation and purification steps of intermediates, thereby lowering the production cost. Meanwhile, it avoids the use of toxic or volatile organic solvents, reducing environmental pollution. In addition, this method also has the advantages of mild reaction conditions and simple operation, which is conducive to industrial production.

[0008] The present invention provides a preparation method of (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride, comprising the following steps:

[0009]

[0010] (1) Cyclization reaction: 0.5 - 1 equivalent of paraldehyde and 1 equivalent of metformin hydrochloride are mixed and dissolved in water, 0.3 - 1.5 equivalents of an acidic catalyst are added, the temperature is raised to 80 - 100 °C, and the reaction is carried out for 10 - 14 h. After the reaction is completed, the solvent water is removed by concentration, a poor solvent is added for pulping for 0.5 - 10 h, and the solid is collected by filtration;

[0011] (2) Preparation of free amine: The solid obtained in step (1) is dissolved in methanol or ethanol, a base is added, and after stirring for 0.5 - 10 h, it is filtered, the filtrate is rotary evaporated, and the obtained solid is collected;

[0012] (3) Resolution: The solid obtained in step (2) and a resolving agent are put into a mixed solvent, heated and dissolved, resolution is carried out, stirred overnight, and after filtration, the filtrate and the solid are collected separately;

[0013] (4) Recrystallization and preparation of hydrochloride: The solid in step (3) is heated and dissolved in a recrystallization solvent, 5 - 40 mL of the recrystallization solvent is used per gram of the solid, then placed at room temperature and stirred overnight, filtered, the filter cake is dried, and then the dried solid is put into a solvent, hydrochloric acid is used to replace the resolving agent, and the final product (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride is obtained;

[0014] (5) Treatment of the resolution filtrate: Take the filtrate in step (3), rotary evaporate it, suspend the obtained powder in the reaction solvent, add 1 - 1.5 equivalents of hydrochloric acid, stir overnight, filter, dry the filter cake, dissolve the obtained solid in methanol or ethanol, add potassium hydroxide or sodium hydroxide, stir for 0.5 - 10 h and then filter, rotary evaporate the filtrate, and collect the obtained solid;

[0015] (6) Racemization: Take the solid obtained in step (5), put it into the reaction solvent, use 0.5 - 40 mL of the reaction solvent per gram of the solid, add a basic catalyst, heat and react for 12 - 36 h. After the reaction is completed, concentrate the reaction solution, add a poor solvent and stir, filter, collect the solid to obtain the free 2 - amino - 3,6 - dihydro - 4 - dimethylamino - 6 - methyl - 1,3,5 - triazine racemate, which can be re - input into step (3) as a raw material;

[0016] Among them, the reaction temperature of step (1) is 80 - 100 °C.

[0017] Among them, in step (1), 3 - 8 mL of water is used per gram of metformin hydrochloride.

[0018] Among them, the acidic catalyst in step (1) is selected from one of formic acid, acetic acid, benzoic acid, oxalic acid, salicylic acid, citric acid, maleic acid, methanesulfonic acid, p - toluenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, glutamic acid, leucine, phosphoric acid, hydrochloric acid, sulfuric acid, nitric acid or oleic acid.

[0019] Among them, the poor solvent in step (1) and step (6) is selected from one of acetone, ether, isopropyl ether, tetrahydrofuran, 1,4 - dioxane, ethyl acetate, methyl acetate, isopropanol, cyclohexanol or acetonitrile.

[0020] Among them, the pulping temperature in step (1) is 0 - 10 °C.

[0021] Among them, the base in step (2) is selected from potassium hydroxide or sodium hydroxide.

[0022] Among them, the resolving agent in step (3) is selected from one of S-(+)-mandelic acid, N - acetyl - L - leucine, L - (-)-dibenzoyl tartaric acid, S-(+)-camphorsulfonic acid, D-(+)-di - p - methoxybenzoyl tartaric acid, D-(+)-di - p - methylbenzoyl tartaric acid, L-(+)-tartaric acid, D-(+)-di - p - nitrobenzoyl tartaric acid, D-(+)-di - p - chlorobenzoyl tartaric acid and D-(+)-di - p - bromobenzoyl tartaric acid.

[0023] Among them, the mixed solvent in step (3) is selected from methanol: water with a volume ratio of 3 - 4:1; or acetonitrile: water with a volume ratio of 2 - 4:1; or acetone: water with a volume ratio of 2 - 4:1; the amount of the mixed solvent used is 10 - 30 mL of the mixed solvent per gram of 2 - amino - 3,6 - dihydro - 4 - dimethylamino - 6 - methyl - 1,3,5 - triazine.

[0024] Among them, the molar ratio of the resolving agent to the free amine in step (3) is 0.4 - 1:1.1.

[0025] Among them, the recrystallization solvent in step (4) is selected from one of methanol, ethanol, isopropanol, dimethyl sulfoxide, N,N-dimethylformamide, water or any mixed solvent.

[0026] Among them, when the hydrochloride is replaced in step (4), the solvent is selected from one of water, acetone, ethanol, isopropanol, ethyl acetate, methyl acetate, acetonitrile, tetrahydrofuran or 1,4-dioxane and a mixed solution of the above solutions.

[0027] Among them, when the hydrochloride is replaced in step (4), the molar ratio of the amount of hydrochloric acid used to 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine is 1-3:1.

[0028] Among them, the reaction temperature in step (6) is 60-80 °C.

[0029] Among them, the basic catalyst in step (6) is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, DBU, TBD, sodium methoxide or sodium ethoxide.

[0030] Among them, the reaction solvent in step (6) is selected from methanol, ethanol, water, DMSO or DMF.

[0031] Among them, the amount of the basic catalyst used in step (6) is a catalytic amount, and the molar ratio of 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine to the basic catalyst is 1:0.1-0.2.

[0032] The beneficial effects of the present invention are as follows:

[0033] The preparation method of (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride provided by the present invention avoids the use of organic solvents during the reaction, selects water as the reaction solvent, can reduce the use of organic substances, and meets the requirements of green chemistry.

[0034] The preparation method of (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride provided by the present invention has been improved and optimized in terms of the racemization of non-target isomers, realizes the promotion of the racemization reaction by a catalytic amount of basic catalyst, realizes the recycling of the filtrate, increases the overall reaction yield, reduces the cost, and is conducive to industrial production.

[0035] The preparation method of (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride provided by the present invention has the advantages of high yield, simple operation and convenient post-treatment of the reaction, and is a green process suitable for industrialization. Detailed implementation manners

[0036] To make the objectives, technical solutions and advantages of this application clearer and more understandable, the embodiments of the present invention will be described in detail below. It should be noted that, without conflict, the embodiments in this application and the features in the embodiments can be combined arbitrarily with each other, and the steps in Embodiments 2 - 49 can be combined arbitrarily.

[0037] Embodiment 1

[0038] (1) Cyclization reaction: Weigh metformin hydrochloride (44 g) and place it in a pressure-resistant bottle. Add water (267 mL) to the pressure-resistant bottle. When stirring at room temperature, add concentrated hydrochloric acid (10.7 mL) with a concentration of 12 M. After stirring evenly, add paraldehyde (32 mL), heat up to 80 °C, and react for 12 h.

[0039] After the reaction is completed, concentrate the reaction solution. Subsequently, add acetone (110 mL) to the concentrated solution, stir at 70 °C for 30 mins until uniform, then cool to room temperature, transfer to an ice bath at 0 °C and stir to form a slurry for 2 h. Filter while at 0 °C, rinse three times with acetonitrile (20 mL), and dry at 100 °C for 2 h to obtain 47.8 g of a white powdery solid. The reaction yield is 94%.

[0040] (2) Preparation of free amine: Weigh imeglimin hydrochloride (47 g), dissolve it in anhydrous methanol (about 160 mL), stir until clear, transfer to a water bath at room temperature, and then add sodium hydroxide (9.8 g). Stir at room temperature for 4 h. Subsequently, filter, wash the filter cake three times with ethanol (20 mL), collect the filtrate, and spin-dry to obtain 38 g of a white solid. The reaction yield is 99%.

[0041] (3) Resolution: Take water (120 mL) and anhydrous methanol (400 mL), mix them evenly. Weigh L-(-)-tartaric acid (15 g) and add it to the mixed solvent. Heat up to 50 °C and stir to dissolve. Then add imeglimin free amine (31 g), stir to dissolve, and then stir at room temperature overnight. Subsequently, filter, rinse three times with ethanol (20 mL), and dry at 80 °C for 2 h to obtain 32.9 g of a white powdery solid. The yield based on a single configuration is 108%, and the ee value is 75%.

[0042] (4) Recrystallization: Weigh L-(-)-tartaric acid imeglimin (30 g), dissolve it in methanol (360 mL), stir and heat up to 60 °C to dissolve, then stir at room temperature overnight. Filter, rinse three times with ethanol (20 mL), and dry at 80 °C for 2 h to obtain 25.8 g of a white powdery solid. The yield is 86%, and the ee value is 93.1%. The white powdery solid obtained by recrystallization again is 22.3 g, the yield is 86%, and the ee value is 98.9%.

[0043] (5) Preparation of hydrochloride: Take L-(-)-Imeglimine tartrate (20 g), put it into ethanol (100 mL) to prepare a suspension, add 12M concentrated hydrochloric acid (3.4 mL), and stir at room temperature overnight. Concentrate to remove about 70 mL of ethanol, filter, wash, and dry to obtain 12.2 g of imeglimine hydrochloride with an ee value of 98.9%; take the filtrate and spin dry to obtain 9.7 g of white powder L-(-)-tartaric acid with an ee value of 99.9%.

[0044] (6) Treatment of the separation filtrate and racemization: The separation filtrate (520 mL) was taken and dried in a rotary oven to obtain 13.4 g of a white solid. The obtained solid was suspended in acetone (100 mL), and 12 M concentrated hydrochloric acid (9 mL) was added and stirred at room temperature overnight. The mixture was filtered and the filter cake was dried to obtain 19 g of a white solid.

[0045] Take the obtained imeglimine hydrochloride (19g), dissolve it in anhydrous methanol (about 80mL), stir until clear, transfer to a room temperature water bath, then add sodium hydroxide (4.89g), a large amount of white powder solid precipitates in the system, stir at room temperature for 4h. Then filter, wash the filter cake three times with ethanol (10mL), collect the filtrate, and spin dry to obtain 15.4g of white powder mixed with small block solids.

[0046] The obtained imeglimine free amine (15.4 g) was taken and put into methanol (75 mL), and then DBU (2.3 g) was added into the system, and the reaction was placed in a pressure bottle and stirred at 80°C for 24 hours. After the reaction was completed, the reaction system was concentrated, and then ethyl acetate (100 mL) was added, stirred at room temperature for 30 minutes, filtered, and the filter cake was dried at 60°C for 1 hour to obtain 14.2 g of imeglimine racemic free amine in the form of white powder, with a yield of 92% and an ee value of 1.7%.

[0047] The obtained free amine (14.2 g) was split in equal proportions according to step (3) to obtain 14.7 g of white powdery solid. The yield was 105% based on a single configuration and the ee value was 73%.

[0048] Example 2: Cyclization reaction

[0049] Weigh metformin hydrochloride (66 g) and place it in a pressure bottle. Add water (400 mL) to the pressure bottle. Add 12M concentrated hydrochloric acid (16 mL) while stirring at room temperature. Add paraldehyde (48 mL) after stirring evenly. Heat to 80°C and react for 12 h.

[0050] After the reaction was completed, the reaction solution was concentrated. Subsequently, acetone (160 mL) was added to the concentrated solution, and the mixture was stirred at 70 °C for 30 mins until homogeneous. Then, it was cooled to room temperature and transferred to an ice bath at 0 °C for stirring and pulping for 2 h. It was filtered at 0 °C, rinsed three times with acetonitrile (20 mL), and dried at 100 °C for 2 h to obtain 72 g of a white powdery solid. The reaction yield was 94.3%.

[0051] Example 3

[0052] In Example 2 above, the reaction temperature was adjusted to 100 °C to obtain 65 g of a white powdery solid. The reaction yield was 86%.

[0053] Example 4

[0054] In Example 2 above, hydrochloric acid was replaced with p-toluenesulfonic acid (55 g), and the pulping time was reduced to 1 h to obtain 68 g of a white powdery solid. The reaction yield was 90%.

[0055] Example 5

[0056] In Example 2 above, hydrochloric acid was replaced with oxalic acid (18 g) to obtain 66 g of a white powdery solid. The reaction yield was 86.7%.

[0057] Example 6

[0058] In Example 2 above, hydrochloric acid was replaced with leucine (105 g) to obtain 68 g of a white powdery solid. The reaction yield was 89%.

[0059] Example 7

[0060] In Example 2 above, hydrochloric acid was replaced with benzoic acid (48 g) to obtain 69 g of a white powdery solid. The reaction yield was 90.5%.

[0061] Example 8

[0062] In Example 2 above, hydrochloric acid was replaced with glutamic acid (58 g) to obtain 66 g of a white powdery solid. The reaction yield was 86.7%.

[0063] Example 9

[0064] In Example 2 above, hydrochloric acid was replaced with methanesulfonic acid (19 g) to obtain 75 g of a white powdery solid. The reaction yield was 98.2%.

[0065] Example 10

[0066] In Example 2 above, hydrochloric acid was replaced with formic acid (9 g) to obtain 69 g of a white powdery solid. The reaction yield was 90.4%.

[0067] Example 11

[0068] In Example 2 above, hydrochloric acid was replaced with camphorsulfonic acid (46 g), and 68 g of a white powdery solid was obtained, with a reaction yield of 89.0%.

[0069] Example 12

[0070] In Example 2 above, acetone was replaced with acetonitrile (180 mL), and 70 g of a white powdery solid was obtained, with a reaction yield of 91.7%.

[0071] Example 13

[0072] In Example 2 above, acetone was replaced with isopropyl ether (100 mL), and 71 g of a white powdery solid was obtained, with a reaction yield of 93.0%.

[0073] Example 14

[0074] In Example 2 above, acetone was replaced with 1,4-dioxane (120 mL), and 68 g of a white powdery solid was obtained, with a reaction yield of 89%.

[0075] Example 15

[0076] In Example 2 above, the reaction time was adjusted to 10 h, and 64 g of a white powdery solid was obtained, with a reaction yield of 84.1%.

[0077] Example 16

[0078] In Example 2 above, the pulping time was adjusted to 10 h, and 67 g of a white powdery solid was obtained, with a reaction yield of 88%.

[0079] Example 17: Preparation of free amine

[0080] Weigh irmeglimin hydrochloride (57.5 g) and dissolve it in anhydrous methanol (about 200 mL). Stir until clear, transfer it to a room temperature water bath, then add sodium hydroxide (12 g), and stir at room temperature for 4 h. Then filter, wash the filter cake three times with ethanol (20 mL), collect the filtrate, and spin-dry to obtain 46.5 g of a white solid, with a reaction yield of 98.8%

[0081] Example 18

[0082] In Example 17 above, the stirring at room temperature was adjusted to 1 h, and 45.7 g of a white powdery solid was obtained, with a reaction yield of 97.1%.

[0083] Example 19

[0084] In Example 17 above, sodium hydroxide was replaced with potassium hydroxide (16.8 g), and the stirring at room temperature was adjusted to 10 h, and 46.7 g of a white powdery solid was obtained, with a reaction yield of 99.2%.

[0085] Example 20: Resolution

[0086] Take water (120 mL) and anhydrous methanol (400 mL), mix them evenly. Weigh L-(-)-tartaric acid (15 g) and put it into the mixed solvent. Heat the temperature to 50 °C and stir to dissolve. Then add imeglimin free amine (31 g). After stirring to dissolve, place it at room temperature and stir overnight. Then filter, rinse three times with ethanol (20 mL), and dry at 80 °C for 2 h to obtain 30.2 g of white powdery solid. Based on the single configuration, the yield is 96% and the ee value is 76%.

[0087] Example 21

[0088] In Example 20 above, replace L-(-)-tartaric acid with N-acetyl-L-leucine (34.6 g) to obtain 32 g of white powdery solid. Based on the single configuration, the yield is 98% and the ee value is 74%.

[0089] Example 22

[0090] In Example 20 above, replace L-(-)-tartaric acid with D-(+)-di-p-toluoyl tartaric acid (31 g) to obtain 47 g of white powdery solid. Based on the single configuration, the yield is 86.9% and the ee value is 70%.

[0091] Example 23

[0092] In Example 20 above, replace L-(-)-tartaric acid with S-(+)-camphorsulfonic acid (51 g) to obtain 43 g of white powdery solid. Based on the single configuration, the yield is 111% and the ee value is 69%.

[0093] Example 24

[0094] In Example 20 above, replace L-(-)-tartaric acid with L-(-)-dibenzoyl tartaric acid (57 g) to obtain 70 g of white powdery solid. Based on the single configuration, the yield is 136% and the ee value is 58%.

[0095] Example 25

[0096] In Example 20 above, replace L-(-)-tartaric acid with D-(+)-di-p-methoxybenzoyl tartaric acid (66.9 g) to obtain 79 g of white powdery solid. Based on the single configuration, the yield is 138% and the ee value is 56%.

[0097] Example 26

[0098] In Example 20 above, replace anhydrous methanol with acetone (300 mL) to obtain 31 g of white powdery solid. Based on the single configuration, the yield is 102% and the ee value is 70%.

[0099] Example 27

[0100] In Example 20 above, anhydrous methanol was replaced with acetonitrile (240 mL) to obtain 31 g of a white powdery solid. The yield based on a single configuration was 102%, and the ee value was 73%.

[0101] Example 28: Recrystallization

[0102] Weigh L-(-)-tartaric acid imeglimin (30 g), dissolve it in methanol (360 mL), stir and heat to 60 °C for stirring and dissolution, then place it at room temperature and stir overnight. Filter, wash three times with ethanol (20 mL), and dry at 80 °C for 2 h to obtain 25.5 g of a white powdery solid. The yield was 85%, and the ee value was 93%. The white powdery solid obtained by recrystallization was 22 g, the yield was 86%, and the ee value was 99.1%.

[0103] Example 29

[0104] In Example 28 above, anhydrous methanol was replaced with DMF (200 mL) to obtain 24 g of a white powdery solid. The yield was 80%, and the ee value was 94.1%. The white powdery solid obtained by recrystallization was 20.4 g, the yield was 85%, and the ee value was 99.2%.

[0105] Example 30

[0106] In Example 28 above, anhydrous methanol was replaced with DMSO (230 mL) to obtain 21 g of a white powdery solid. The yield was 70%, and the ee value was 90.1%. The white powdery solid obtained by recrystallization was 15.5 g, the yield was 74%, and the ee value was 98.3%.

[0107] Example 31

[0108] In Example 28 above, anhydrous methanol was replaced with ethanol (1.2 L) to obtain 25 g of a white powdery solid. The yield was 83.3%, and the ee value was 89.1%. The white powdery solid obtained by recrystallization was 21.5 g, the yield was 86%, and the ee value was 97.3%.

[0109] Example 32

[0110] In Example 28 above, L-(-)-tartaric acid imeglimin was replaced with S-(+)-camphorsulfonic acid imeglimin (30 g), and the amount of methanol used was adjusted to (200 mL) to obtain 20 g of a white powdery solid. The yield was 67%, and the ee value was 90%. The white powdery solid obtained by recrystallization was 14 g, the yield was 70%, and the ee value was 98.3%.

[0111] Example 33

[0112] In Example 30 above, L-(-)-imiglimin tartrate was replaced with D-(+)-di-p-toluoyl tartaric acid imiglimin (30 g), and 22 g of a white powdery solid was obtained, with a yield of 73% and an ee value of 89.2%. 18 g of a white powdery solid was obtained by recrystallization, with a yield of 82% and an ee value of 95.9%.

[0113] Example 34

[0114] Weigh L-(-)-dibenzoyl tartaric acid imiglimin (30 g), dissolve it in methanol (360 mL), stir and heat to 60 °C for dissolution, then pour it into water (300 mL), and then stir at room temperature overnight. Filter, rinse three times with ethanol (20 mL), and dry at 80 °C for 2 h to obtain 26 g of a white powdery solid, with a yield of 87% and an ee value of 85%. 22.9 g of a white powdery solid was obtained by recrystallization, with a yield of 88% and an ee value of 97.7%.

[0115] Example 35: Preparation of Hydrochloride

[0116] Take L-(-)-dibenzoyl tartaric acid imiglimin (20 g) and put it into a mixed solvent of water (50 mL) and ethyl acetate (100 mL), add concentrated hydrochloric acid (9.7 mL) with a concentration of 12 M, and stir at room temperature overnight.

[0117] Subsequently, separate the aqueous phase and the organic phase, wash them three times with ethyl acetate (40 mL) and water (40 mL) respectively, and then rotary evaporate the organic phase. Concentrate the aqueous phase, then add about 100 mL of acetone to the aqueous phase and stir at room temperature for 1 h. Filter and wash both of them, and dry at 100 °C to obtain 7 g of imiglimin hydrochloride, with an ee value of 97.7%; 14.1 g of L-(-)-dibenzoyl tartaric acid, with an ee value of 99.9%.

[0118] Example 36

[0119] In Example 35 above, L-(-)-dibenzoyl tartaric acid imiglimin was replaced with D-(+)-di-p-nitrobenzoyl tartaric acid imiglimin (20 g), and the amount of hydrochloric acid was replaced with (9 mL) to obtain 6.86 g of a white powdery solid, with an ee value of 99.1%; 14.4 g of D-(+)-di-p-nitrobenzoyl tartaric acid, with an ee value of 99.9%.

[0120] Example 37

[0121] Take L-(-)-imiglimin tartrate (20 g) and put it into ethanol (100 mL) to prepare a suspension, add concentrated hydrochloric acid (3.4 mL) with a concentration of 12 M, and stir at room temperature overnight.

[0122] The mixture was concentrated to remove about 70 mL of ethanol, filtered, washed, and dried at 100° C. to obtain 12.3 g of imeglimine hydrochloride with an ee value of 99.2% and 9.7 g of L-(-)-tartaric acid with an ee value of 99.9%.

[0123] Embodiment 38

[0124] In the above Example 37, ethanol was replaced with acetone (200 mL), and the mixture was directly filtered without concentration to obtain 12.5 g of white powdery solid with an ee value of 99.1% and 9.7 g of L-(-)-tartaric acid with an ee value of 99.9%.

[0125] Embodiment 39

[0126] In the above Example 38, L-(-)-tartrate imeglimine was replaced by S-(+)-camphorsulfonic acid imeglimine (20 g), and the amount of hydrochloric acid was changed to (4.3 mL). 9.87 g of white powdery solid was obtained, with an ee value of 98.3%; 11.9 g of S-(+)-camphorsulfonic acid, with an ee value of 99.9%.

[0127] Example 40: Treatment of the resolved filtrate and racemization

[0128] Take the filtrate (520 mL) from Example 20 and spin dry to obtain 15.8 g of a white solid. Suspend the obtained solid in acetone (100 mL), add 12 M concentrated hydrochloric acid (9 mL), and stir at room temperature overnight. Filter and dry the filter cake to obtain 19 g of a white solid, with a yield of 98%.

[0129] Take the obtained imeglimine hydrochloride (19g), dissolve it in anhydrous methanol (about 80mL), stir until clear, transfer to a room temperature water bath, then add sodium hydroxide (4.89g), a large amount of white powder solid precipitates in the system, stir at room temperature for 4h. Then filter, wash the filter cake three times with ethanol (10mL), collect the filtrate, spin dry to obtain 15.3g of white powder mixed with small pieces of solid, the yield is 99%.

[0130] The obtained imeglitin free amine (15.3 g) was taken and put into methanol (75 mL), and then DBU (2.3 g) was added into the system, and the reaction was placed in a pressure bottle and stirred at 80°C for 24 hours. After the reaction was completed, the reaction system was concentrated, and then ethyl acetate (100 mL) was added, stirred at room temperature for 30 minutes, filtered, and the filter cake was dried at 60°C for 1 hour to obtain 14.3 g of white powdered imeglitin racemic free amine, with a yield of 93% and an ee value of 2%.

[0131] Embodiment 41

[0132] In Example 40 above, the reaction time was replaced with 14 h, and 14.8 g of a white powdery solid was obtained. The reaction yield was 97%, and the ee value was 12%.

[0133] Example 42

[0134] In Example 40 above, DBU was replaced with sodium hydroxide (0.6 g), and the reaction temperature was replaced with 70 °C. 6.4 g of a white powdery solid was obtained. The reaction yield was 42%, and the ee value was 5%.

[0135] Example 43

[0136] In Example 41 above, anhydrous methanol in the racemization step was replaced with water (20 mL), and 11.6 g of a white powdery solid was obtained. The reaction yield was 76%, and the ee value was 5%.

[0137] Example 44

[0138] In Example 40 above, anhydrous methanol in the racemization step was replaced with ethanol (600 mL), and 13.8 g of a white powdery solid was obtained. The reaction yield was 90%, and the ee value was 4%.

[0139] Example 45

[0140] In Example 40 above, DBU was replaced with TBD (2.77 g), and the reaction was carried out for 36 h. 11.3 g of a white powdery solid was obtained. The reaction yield was 74%, and the ee value was 6%.

[0141] Example 46

[0142] In Example 40 above, DBU was replaced with potassium tert-butoxide (1.7 g), and the reaction temperature was replaced with 60 °C. 14.2 g of a white powdery solid was obtained. The reaction yield was 93%, and the ee value was 3%.

[0143] Example 47

[0144] In Example 40 above, DBU was replaced with sodium methoxide (0.54 g), and anhydrous methanol in the racemization step was replaced with DMSO (10 mL). 13.8 g of a white powdery solid was obtained. The reaction yield was 90%, and the ee value was 4%.

[0145] Example 48

[0146] In Example 40 above, ethyl acetate was replaced with isopropanol (120 mL), and 12.8 g of a white powdery solid was obtained. The reaction yield was 84%, and the ee value was 2%.

[0147] Example 49

[0148] In Example 40 above, ethyl acetate was replaced with acetone (150 mL) to obtain 12.1 g of a white powdery solid. The reaction yield was 79%, and the ee value was 2%.

Claims

1. A method for preparing (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride, characterized in that: The following steps are involved: (1) Paraldehyde and metformin hydrochloride undergo cyclization reaction; (2) preparing free amine from the solid obtained in step (1); (3) the solid obtained in step (2) and the acidic resolving agent are put into a mixed solvent for resolving; (4) The solid obtained in step (3) is recrystallized and hydrochloride is prepared to obtain the final product (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride; (5) the filtrate obtained in step (3) is subjected to filtrate separation treatment; (6) The solid obtained in step (5) is added to a reaction solvent, with 0.5-40 mL of reaction solvent used per gram of solid, and an alkaline catalyst is added. The reaction is heated for 12-36 hours. After the reaction is completed, the reaction solution is concentrated, a poor solvent is added, stirred, filtered, and the solid is collected to obtain free 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine racemate, which can be used as a raw material to prepare (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride according to the above preparation method.

2. The method for preparing (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride according to claim 1, characterized in that: The following steps are involved: (1) Cyclization reaction: 0.5-1 equivalent of triacetaldehyde and 1 equivalent of metformin hydrochloride are mixed and dissolved in water, 0.3-1.5 equivalent of acidic catalyst is added, the temperature is raised to 80-100° C., and the reaction is carried out for 10-14 hours. After the reaction is completed, the solvent water is concentrated to remove the solvent, a poor solvent is added to slurry for 0.5-10 hours, and the solid is collected by filtration; (2) Preparation of free amine: dissolve the solid obtained in step (1) in methanol or ethanol, add alkali, stir for 0.5-10 hours, filter, spin dry the filtrate, and collect the obtained solid; (3) splitting: the solid obtained in step (2) and the splitting agent are placed in a mixed solvent, heated to dissolve, split, stirred overnight, filtered, and the filtrate and the solid are collected separately; (4) Recrystallization and preparation of hydrochloride: The solid obtained in step (3) is heated and dissolved in a recrystallization solvent, with 5-40 mL of the recrystallization solvent used per gram of solid, and then stirred at room temperature overnight, filtered, and the filter cake is dried. The dried solid is then put into a solvent, and hydrochloric acid is used to replace the resolving agent to obtain the final product (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride; (5) Treatment of the filtrate: Take the filtrate from step (3), spin dry, suspend the obtained powder in a reaction solvent, add 1-1.5 equivalent hydrochloric acid, stir overnight, filter, dry the filter cake, dissolve the obtained solid in methanol or ethanol, add potassium hydroxide or sodium hydroxide, stir for 0.5-10 hours, filter, spin dry the filtrate, and collect the obtained solid; (6) Racemization: The solid obtained in step (5) is added to a reaction solvent, with 0.5-40 mL of reaction solvent used per gram of solid, and an alkaline catalyst is added. The reaction is heated for 12-36 hours. After the reaction is completed, the reaction solution is concentrated, a poor solvent is added, stirred, filtered, and the solid is collected to obtain a free 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine racemate, which can be used as a raw material and then re-added to step (3).

3. The method for preparing (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride according to claim 2, characterized in that: The reaction temperature in step (1) is 80-100°C; 3-8 mL of water is used per gram of metformin hydrochloride; and the pulping temperature is 0-10°C.

4. The method for preparing (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride according to claim 2, characterized in that: In step (1), the acidic catalyst is selected from formic acid, acetic acid, benzoic acid, oxalic acid, salicylic acid, citric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, glutamic acid, leucine, phosphoric acid, hydrochloric acid, sulfuric acid, nitric acid or oleic acid.

5. The method for preparing (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride according to claim 2, characterized in that: In step (1) and step (6), the poor solvent is selected from acetone, ether, isopropyl ether, tetrahydrofuran, 1,4-dioxane, ethyl acetate, methyl acetate, isopropanol, cyclohexanol or acetonitrile.

6. The method for preparing (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride according to claim 2, characterized in that: In step (2), the base is selected from potassium hydroxide or sodium hydroxide.

7. The method for preparing (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride according to claim 2, characterized in that: In step (3), the resolving agent is selected from one of S-(+)-mandelic acid, N-acetyl-L-leucine, L-(-)-dibenzoyltartaric acid, S-(+)-camphorsulfonic acid, D-(+)-di-p-methoxybenzoyltartaric acid, D-(+)-di-p-methylbenzoyltartaric acid, L-(+)-tartaric acid, D-(+)-di-p-nitrobenzoyltartaric acid, D-(+)-di-p-chlorobenzoyltartaric acid and D-(+)-di-p-bromobenzoyltartaric acid; and the molar ratio of the resolving agent to the free amine is 0.4-1:1.

1.

8. The method for preparing (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride according to claim 2, characterized in that: In step (3), the mixed solvent is selected from methanol: water, with a volume ratio of 3-4:1; or acetonitrile: water, with a volume ratio of 2-4:1; or acetone: water, with a volume ratio of 2-4:1; and the amount of the mixed solvent is 10-30 mL per gram of 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine.

9. The method for preparing (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride according to claim 2, characterized in that: During the hydrochloride replacement in step (4), the ratio of the amount of hydrochloric acid used to the amount of 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine is 1-3:1; the solvent is selected from one of water, acetone, ethanol, isopropanol, ethyl acetate, methyl acetate, acetonitrile, tetrahydrofuran or 1,4-dioxane and a mixed solution of the above solutions; the recrystallization solvent is selected from one of methanol, ethanol, isopropanol, dimethyl sulfoxide, N,N-dimethylformamide, water or any mixed solvent.

10. The method for preparing (R)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride according to claim 2, characterized in that: In step (6), the alkaline catalyst is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, DBU, TBD, sodium methoxide or sodium ethoxide; the molar ratio of 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine to the alkaline catalyst is 1:0.1-0.2; the reaction solvent is selected from methanol, ethanol, water, DMSO or DMF; and the reaction temperature is 60-80°C.

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