Preparation method of 1, 2-dimethyl-1, 4, 5, 6-tetrahydropyrimidine

Abstract

The invention is suitable for the technical field of organic synthesis, and provides a preparation method of 1, 2-dimethyl-1, 4, 5, 6-tetrahydropyrimidine, which comprises the following steps: (1) preparing a compound II; (2) preparing an intermediate III: adding a solvent into the compound II, stirring and mixing, dropwise adding an acylation reagent at controlled temperature, continuously reacting at controlled temperature after dropwise adding, adjusting the pH to 8-9 after reacting, separating liquid, extracting, merging organic layers, and carrying out reduced pressure distillation to remove the solvent, so as to obtain the intermediate III; (3) preparing an intermediate IV; and (4) preparing a compound 1, 2-dimethyl-1, 4, 5, 6-tetrahydropyrimidine: adding a cyclization catalyst into the compound IV, carrying out temperature control reaction, after the reaction is finished, filtering to remove the catalyst, and rectifying to obtain the compound 1, 2-dimethyl-1, 4, 5, 6-tetrahydropyrimidine. The raw materials used in the method are simple and easy to obtain, a large amount of waste water and waste liquid are not generated, major dangerous processes are not involved, the raw materials are sufficient in source, the solvent can be recycled and reused, and the process operation is simple, easy to implement, green and environmentally friendly.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine. Background Art

[0002] 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine has a chemical formula of C6H12N2. It is an important pharmaceutical intermediate that can be used to synthesize anthelmintic drugs such as pyrantel and methyl pyrantel. It is mainly used to treat ascariasis, enterobiasis, duodenal hookworm disease and whipworm disease. This series of drugs can be used not only by humans but also by livestock. Since it is rarely absorbed after oral administration and has low systemic toxicity, it is still one of the main anthelmintic drugs in Africa and remote areas with poor economic and sanitary conditions. 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine is a key fragment in the molecular structure of pyrantel drugs. Its chemical structure is shown in Formula I below:

[0003]

[0004] At present, there are many synthetic routes for 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine. Ye, Guozhong et al. reported in the journal [Tetrahedron Letters, 2009, vol. 50, #18, p. 2135-2139] a method for preparing acetonitrile by reacting with N-methylpropylenediamine under the catalysis of zinc chloride, but the yield of this process is only 45%. Chinese patent CN110156697 improves this process by using thioacetamide as a catalyst, which can increase the yield to 95%. However, thioacetamide is a Class 2B carcinogen published by the International Agency for Research on Cancer of the World Health Organization. This substance has a significant odor, and the odor is difficult to control during the production process. The process waste gas, wastewater and solid waste have a great impact on the environment and the health of operators, and are not suitable for large-scale industrial production. This process route is as follows Figure 1 shown.

[0005] Zhu, Bolin et al. reported in the journal [Chemical Communications, 2007, #21, p.2157-2159] a one-step reaction to prepare 1,2-dimethylhexahydropyrimidine using gold as a catalyst. The raw materials used in this process need to be customized and synthesized. The process uses oxygen under high pressure, which has a high process safety risk. At the same time, the catalyst is expensive, and the process has no production application value. This process route is as follows Figure 2 shown.

[0006] Chinese patent CN108822044 reported that N-methylpropylenediamine was used as raw material for preparation through two-step reaction. However, the second step of the cyclization reaction in this process requires the use of microwaves for catalytic reaction, which has a large application range and is difficult to implement industrially. Figure 3 shown.

[0007] Aoyagi, Naoto et al. reported in the journal [Tetrahedron Letters, 2018, vol. 59, #18, p. 1702-1704] that 1,1-dimethoxy-N,N-dimethylethylamine and N-methylpropylenediamine were used as raw materials for preparation. The process does not use solvents and has a yield of 95%, which has certain advantages. However, the raw material 1,1-dimethoxy-N,N-dimethylethylamine is expensive and needs to be customized, so the market competitiveness of the process is low. This process route is as follows Figure 4 shown.

[0008] Kraouti et al. reported in the journal [European Journal of Medicinal Chemistry, 1993, vol. 28, #12, p. 979-982] that ethyl acetimidate hydrochloride and N-methylpropylenediamine were used as raw materials for preparation. The reaction temperature of this process is relatively high at 125°C, and it is difficult to select a suitable solvent. The post-reaction treatment such as distillation is difficult, and it is not feasible for industrialization. Figure 5 shown.

[0009] In view of the limitations and shortcomings of the above-mentioned synthetic routes, it is necessary to develop a new 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine synthesis process, using cheap and readily available raw and auxiliary materials for production, avoiding the use of dangerous processes, and ensuring process yield, controlling process costs, and ensuring product quality to meet the commercialization needs of downstream pharmaceutical products. Summary of the invention

[0010] The object of the present invention is to provide a method for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine to solve the problems in the above-mentioned background technology.

[0011] To achieve the above object, the present invention provides the following technical scheme: a method for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine, wherein the 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine is condensed with acrylonitrile to obtain compound II, compound II is acylated to obtain compound III, compound III is reduced to obtain compound IV, and compound IV is cyclized to obtain the target product 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine.

[0012] Preferably, the method for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine comprises the following steps:

[0013] Step (1), preparation of compound II:

[0014] Add acrylonitrile and solvent to the reaction bottle, stir and mix, add methylamine solution dropwise, and after the addition is complete, control the temperature and continue the reaction. After the reaction is complete, remove the solvent by distillation under reduced pressure to obtain compound II;

[0015] Step (2), preparation of intermediate III:

[0016] Add a solvent to compound II, stir and mix, add an acylating agent dropwise under temperature control, and continue the reaction under temperature control. After the reaction is completed, adjust the pH to 8-9, separate the liquids, extract, combine the organic layers, and remove the solvent by distillation under reduced pressure to obtain intermediate III;

[0017] Step (3), preparation of intermediate IV:

[0018] Adding a solvent and a reducing agent to compound III, controlling the temperature to react, and after the reaction is completed, distilling to recover the solvent, adding drinking water and an extraction solvent, washing with an aqueous solution of ammonium chloride, separating the liquids, and distilling the organic layer under reduced pressure to remove the solvent to obtain an intermediate IV;

[0019] Step (4), preparing the compound 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine:

[0020] Add a cyclization catalyst to compound IV and react at a controlled temperature. After the reaction is completed, filter out the catalyst and perform distillation to obtain compound 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine.

[0021] Preferably, the solvent in step (1) is one of methanol and ethanol, and the methylamine is dissolved into a corresponding 30% methylamine methanol solution or a 30% methylamine ethanol solution.

[0022] Preferably, in step (2), the solvent is any one of dichloromethane, chloroform and toluene, and the acylating agent is one of acetyl chloride and acetic anhydride.

[0023] Preferably, in step (3), the solvent is one of tetrahydrofuran and methyltetrahydrofuran, and the reducing agent is lithium aluminum tetrahydride, borohydride (sodium borohydride, potassium borohydride, lithium borohydride) and Lewis acid, borohydride (sodium borohydride, potassium borohydride, lithium borohydride) and organic acid.

[0024] Preferably, the Lewis acid includes any one of ferric chloride, aluminum chloride, boron trifluoride and zinc chloride.

[0025] Preferably, the organic acid comprises trifluoroacetic acid, formic acid, or acetic acid.

[0026] Preferably, the catalyst in step (4) is any one of ferric chloride, aluminum chloride, boron trifluoride and zinc chloride.

[0027] Preferably, the extraction solvent is one of ethyl acetate or dichloromethane.

[0028] The present invention has at least the following beneficial effects:

[0029] (1) The raw materials used in the present invention are simple and easy to obtain, the market source is sufficient, and the process cost is low;

[0030] (2) The process used in the present invention does not involve high temperature, high pressure, or major hazardous processes, and the process safety is guaranteed;

[0031] (3) After the solvent is recovered from the intermediates in each step of the route of the present invention, the subsequent reaction can be directly carried out without purification and separation operations, and a large amount of waste water and waste liquid are not generated. The organic solvents in the process can be recovered and reused, and the process is green and environmentally friendly;

[0032] (4) The process of the present invention is simple to operate, has a high reaction conversion rate, a total yield of more than 70.0%, and an average yield of more than 90% per step, which has industrial advantages;

[0033] (5) The final product 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine obtained by the present invention can reach more than 98.0%. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The reaction route for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine in the journal [Tetrahedron Letters, 2009, vol.50, #18, p.2135-2139] and patent CN110156697 by Ye, Guozhong et al.;

[0035] Figure 2 The reaction route for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine by Zhu, Bolin et al. in the journal [Chemical Communications, 2007, #21, p.2157-2159];

[0036] Figure 3 This is the reaction route for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine in patent CN108822044;

[0037] Figure 4A reaction route for the preparation of 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine by Aoyagi, Naoto et al. in the journal [Tetrahedron Letters, 2018, vol.59, #18, p.1702-1704];

[0038] Figure 5 The reaction scheme for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine in the journal [European Journal of Medicinal Chemistry, 1993, vol. 28, #12, p. 979-982] by Kraouti et al.

[0039] Figure 6 A reaction scheme for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine according to the present invention;

[0040] Figure 7 This is the liquid phase detection spectrum of 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine produced in Example 1 of the present invention. DETAILED DESCRIPTION

[0041] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0042] The present invention provides a method for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine, wherein acrylonitrile is condensed to obtain compound II, compound II is acylated to obtain compound III, compound III is reduced to obtain compound IV, and compound IV is cyclized to obtain the target product 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine, and the specific steps are as follows:

[0043] Step (1), preparation of compound II:

[0044] Add acrylonitrile and solvent to the reaction bottle, stir and mix, add methylamine solution dropwise, and after the addition is complete, control the temperature and continue the reaction. After the reaction is complete, remove the solvent by distillation under reduced pressure to obtain compound II;

[0045] Step (2), preparation of intermediate III:

[0046] Add a solvent to compound II, stir and mix, add an acylating agent dropwise under temperature control, and continue the reaction under temperature control. After the reaction is completed, adjust the pH to 8-9, separate the liquids, extract, combine the organic layers, and remove the solvent by distillation under reduced pressure to obtain intermediate III;

[0047] Step (3), preparation of intermediate IV:

[0048] Adding a solvent and a reducing agent to compound III, controlling the temperature to react, and after the reaction is completed, distilling to recover the solvent, adding drinking water and an extraction solvent, washing with an aqueous solution of ammonium chloride, separating the liquids, and distilling the organic layer under reduced pressure to remove the solvent to obtain an intermediate IV;

[0049] Step (4), preparing the compound 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine:

[0050] Add a cyclization catalyst to compound IV and react at a controlled temperature. After the reaction is completed, filter out the catalyst and perform distillation to obtain compound 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine.

[0051] Furthermore, in step (1), the solvent is one of methanol and ethanol, and the methylamine is dissolved into a corresponding 30% methylamine methanol solution or a 30% methylamine ethanol solution.

[0052] Furthermore, in step (2), the solvent is any one of dichloromethane, chloroform and toluene, and the acylating agent is one of acetyl chloride and acetic anhydride.

[0053] Furthermore, in step (3), the solvent is one of tetrahydrofuran and methyltetrahydrofuran, and the reducing agent is lithium aluminum tetrahydride, borohydride (sodium borohydride, potassium borohydride, lithium borohydride) and Lewis acid, borohydride (sodium borohydride, potassium borohydride, lithium borohydride) and organic acid.

[0054] Furthermore, the Lewis acid includes any one of ferric chloride, aluminum chloride, boron trifluoride, and zinc chloride; the organic acid includes trifluoroacetic acid, formic acid, and acetic acid.

[0055] Furthermore, the catalyst in step (4) is any one of ferric chloride, aluminum chloride, boron trifluoride and zinc chloride.

[0056] Furthermore, the extraction solvent is one of ethyl acetate or dichloromethane.

[0057] Based on the above technical solution, the present invention provides the following partial embodiments:

[0058] Example 1

[0059] The specific synthesis method is as follows:

[0060] (1) Add 50 g (0.94 mol) of acrylonitrile and 200 mL of methanol to a 500 mL glass reaction bottle, start stirring, control the temperature to 0°C, and drop 108 g (1.04 mol, 1.1 eq) of 30% methylamine methanol solution into the reaction bottle. After the addition is complete, control the temperature to 0°C and keep the reaction for 2 hours. After the reaction is complete, heat the feed liquid to 70°C, and recover methanol at normal pressure to obtain compound I.

[0061] (2) Add 200 mL of dichloromethane to the above compound I, start stirring, control the temperature to 5°C, add 80 g (1.02 mol, 1.08 eq) of acetyl chloride to the reaction bottle, control the temperature to 30°C for 2 hours, and complete the reaction. Cool the reaction solution to 5°C, add sodium carbonate aqueous solution to the reaction solution, adjust the pH to 9, separate the liquids, add 100 mL of dichloromethane to the aqueous layer for extraction once, combine the organic layers, and recover dichloromethane at 40°C under normal pressure to obtain compound II.

[0062] (3) Add 200 mL of tetrahydrofuran to compound II, start stirring, control the temperature of the feed solution to 0°C, add 45 g of lithium aluminum tetrahydride (1.19 mol, 1.26 eq) to the reaction solution 20 times with an interval of 5 minutes each time, and continue the reaction at 0°C for 4 hours. After the reaction is completed, control the temperature to 50°C, recover the tetrahydrofuran under reduced pressure, and after recovery, cool to 0°C, add 100 mL of saturated ammonium chloride solution dropwise to the reaction bottle, and after the addition is complete, add 200 mL of ethyl acetate to the solution, stir for 5 minutes, separate the liquids, add 100 ml of ethyl acetate to the aqueous layer for extraction, combine the organic layers, control the temperature to 60°C, and recover the ethyl acetate under reduced pressure to obtain compound III.

[0063] (4) Add 10.5 g (0.08 mol, 0.08 eq) of zinc chloride to compound III, and keep the temperature at 80° C. for 16 hours. After the reaction is completed, cool the feed liquid to 30° C., filter to remove the catalyst, and start vacuum distillation of the liquid, controlling the pressure at 0.01 to 0.02 MPa. Collect the fraction at 120 to 130° C. to obtain 81.2 g of the finished product 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine, with a yield of 76.8% and a purity of 99.4%.

[0064] in, Figure 7 This is the liquid phase detection spectrum of the product 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine obtained in this example.

[0065] Example 2

[0066] (1) Add 10 g (0.19 mol) of acrylonitrile and 50 mL of ethanol to a 200 mL glass reaction bottle, start stirring, control the temperature to 5°C, and dropwise add 20.5 g (0.20 mol, 1.05 eq) of 30% methylamine ethanol solution to the reaction bottle. After the addition is complete, control the temperature to 5°C and keep the reaction for 3 hours. After the reaction is complete, heat the feed liquid to 80°C, and recover ethanol at normal pressure to obtain compound I.

[0067] (2) Add 40 mL of chloroform to the above compound I, start stirring, control the temperature to 5°C, and drop 16 g (0.20 mol, 1.08 eq) of acetyl chloride into the reaction bottle. After the addition is complete, control the temperature to 45°C and keep the reaction for 1 hour. The reaction is complete. The reaction solution is cooled to 10°C, and sodium bicarbonate aqueous solution is added to the reaction solution to adjust the pH to 8. After the adjustment is complete, separate the liquids, and recover the chloroform at 65°C and normal pressure in the organic layer to obtain compound II.

[0068] (3) Add 30 mL of 2-methyltetrahydrofuran to compound II, start stirring, control the temperature of the feed solution to -5°C, add 30.7 g (0.23 mol, 1.20 eq) of aluminum chloride, and add 8.7 g (0.23 mol, 1.20 eq) of sodium borohydride to the reaction solution in 5 times with an interval of 3 minutes each time. After the addition of materials is completed, keep the temperature at 0°C and continue the reaction for 3 hours. After the reaction is completed, control the temperature to 50°C, recover tetrahydrofuran under reduced pressure, and after recovery, cool to 0°C, add 25 mL of saturated ammonium chloride solution dropwise to the reaction bottle, and after the addition is completed, add 50 mL of dichloromethane to the solution, stir for 5 minutes, separate the organic layer, control the temperature to 40°C, and recover dichloromethane under normal pressure to obtain compound III.

[0069] (4) Add 5 g (0.03 mol, 0.16 eq) of boron trifluoride tetrahydrofuran to compound III, control the temperature at 70°C to react for 12 hours, and after the reaction is completed, cool the feed liquid to 40-50°C, and first remove the solvent by vacuum distillation. Then increase the temperature and perform vacuum distillation, control the pressure at 0.01-0.02 MPa, collect the fraction at 120-130°C, and obtain 15.9 g of the finished product 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine, with a yield of 75.2% and a purity of 98.9%.

[0070] Example 3

[0071] (1) Add 15 g (0.28 mol) of acrylonitrile and 100 mL of ethanol to a 200 mL glass reaction bottle, start stirring, control the temperature to -5°C, and dropwise add 33 g (0.32 mol, 1.13 eq) of 30% methylamine ethanol solution to the reaction bottle. After the addition is complete, control the temperature to -5°C and keep the reaction for 4 hours. After the reaction is complete, heat the feed liquid to 80°C, and recover ethanol at normal pressure to obtain compound I.

[0072] (2) Add 60 mL of toluene to the above compound I, start stirring, control the temperature to 5°C, and drop 35 g (0.30 mol, 1.21 eq) of acetic anhydride into the reaction bottle. After the dropwise addition is complete, control the temperature to 80°C and keep the reaction for 2 hours. The reaction is complete. The reaction solution is cooled to 10°C, and a 5% aqueous sodium hydroxide solution is added dropwise to the reaction solution to adjust the pH to 9. After the adjustment is complete, separate the liquids, and recover the toluene from the organic layer at 60°C under reduced pressure to obtain compound II.

[0073] (3) Add 80 mL of tetrahydrofuran to compound II, start stirring, control the temperature of the feed solution to 5°C, add 38.7 g (0.23 mol, 1.20 eq) of trifluoroacetic acid, add 7.0 g (0.32 mol, 1.14 eq) of lithium borohydride to the reaction solution in 8 times with an interval of 5 minutes each time, and continue the reaction at 5°C for 6 hours. After the reaction is completed, control the temperature to 50°C, recover tetrahydrofuran under reduced pressure, and after recovery, cool to 5°C, add 50 mL of saturated ammonium chloride solution dropwise to the reaction bottle, and after the addition is complete, add 50 mL of dichloromethane to the solution, stir for 5 minutes, separate the organic layer, control the temperature to 40°C, and recover dichloromethane under normal pressure to obtain compound III.

[0074] (4) Add 7 g (0.04 mol, 0.15 eq) of ferric chloride to compound III, control the temperature at 90°C to react for 20 hours, and after the reaction is completed, cool the feed liquid to 30°C, filter to remove the catalyst, and then heat the filtrate to vacuum distillation, control the pressure at 0.01-0.02 MPa, collect the 120-130°C fraction, and obtain 23.8 g of the finished product 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine, with a yield of 75.0% and a purity of 99.1%.

[0075] Embodiment 4:

[0076] (1) Add 50 g (0.94 mol) of acrylonitrile and 200 mL of recovered methanol (water content 0.2%) to a 500 mL glass reaction bottle, start stirring, control the temperature to 5°C, and dropwise add 110 g (1.06 mol, 1.13 eq) of 30% methylamine methanol solution to the reaction bottle. After the addition is complete, control the temperature to 5°C and keep the reaction for 2 hours. After the reaction is complete, heat the feed liquid to 70°C, and recover methanol at normal pressure to obtain compound I.

[0077] (2) Add 200 mL of recovered dichloromethane (water content 0.09%) to the above compound I, start stirring, control the temperature to 10°C, and drop 85 g (1.08 mol, 1.15 eq) of acetyl chloride into the reaction bottle. After the addition is complete, control the temperature to 40°C and keep the reaction for 2 hours. The reaction is complete. The reaction solution is cooled to 10°C, and sodium bicarbonate aqueous solution is added dropwise to the reaction solution to adjust the pH to 8. After the adjustment is complete, separate the liquids, add 100 mL of dichloromethane to the aqueous layer for extraction once, combine the organic layers, and recover dichloromethane at 40°C under normal pressure to obtain compound II.

[0078] (3) Add 200 mL of recovered tetrahydrofuran (the recovered tetrahydrofuran is dried with molecular sieves and then filtered, with a water content of 0.08%) to compound II, start stirring, control the temperature of the feed solution to 5°C, add 48 g of lithium aluminum hydroxide (1.26 mol, 1.34 eq) to the reaction solution in 18 portions at intervals of 5 minutes each time, and continue the reaction at 0°C for 3 hours. After the reaction is completed, control the temperature to 50°C, recover the tetrahydrofuran under reduced pressure, and after recovery, cool down to 5°C, add 120 mL of saturated ammonium chloride solution dropwise to the reaction bottle, and after the addition is complete, add 200 mL of ethyl acetate to the solution, stir for 5 minutes, and separate the liquids. Control the temperature of the organic layer to 60°C and recover the ethyl acetate under reduced pressure to obtain compound III.

[0079] (4) Add 10 g (0.075 mol, 0.08 eq) of aluminum chloride to compound III, and keep the temperature at 90° C. for 14 hours. After the reaction is completed, cool the feed liquid to 35° C., filter to remove the catalyst, and start vacuum distillation of the liquid, controlling the pressure at 0.01 to 0.02 MPa. Collect the fraction at 120 to 130° C. to obtain 78.2 g of the finished product 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine, with a yield of 74.0% and a purity of 99.2%.

[0080] In summary, the technical solution provided by the present invention does not use expensive reagents and raw and auxiliary materials, does not produce a large amount of wastewater and waste liquid in the synthesis process, does not involve major hazardous processes, has sufficient sources of raw materials, and the process solvents can be recycled and reused. The process operation is simple and easy, and the process is green and environmentally friendly.

[0081] The above shows and describes the basic principles, main features and advantages of the present invention. It is obvious to those skilled in the art that the present invention is not limited to the details of the above exemplary embodiments, and that the present invention can be implemented in other specific forms without departing from the spirit or basic features of the present invention. Therefore, no matter from which point of view, the embodiments should be regarded as exemplary and non-restrictive. The scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims are included in the present invention.

[0082] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine, characterized in that: The 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine is condensed with acrylonitrile to obtain compound II, compound II is acylated to obtain compound III, compound III is reduced to obtain compound IV, and compound IV is cyclized to obtain the target product 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine.

2. The method for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine according to claim 1, characterized in that: The preparation method of 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine comprises the following steps: Step (1), preparation of compound II: Add acrylonitrile and solvent to the reaction bottle, stir and mix, add methylamine solution dropwise, and after the addition is complete, control the temperature and continue the reaction. After the reaction is complete, remove the solvent by distillation under reduced pressure to obtain compound II; Step (2), preparation of intermediate III: Add a solvent to compound II, stir and mix, add an acylating agent dropwise under temperature control, and continue the reaction under temperature control. After the reaction is completed, adjust the pH to 8-9, separate the liquids, extract, combine the organic layers, and remove the solvent by distillation under reduced pressure to obtain intermediate III; Step (3), preparation of intermediate IV: Adding a solvent and a reducing agent to compound III, controlling the temperature to react, and after the reaction is completed, distilling to recover the solvent, adding drinking water and an extraction solvent, washing with an aqueous solution of ammonium chloride, separating the liquids, and distilling the organic layer under reduced pressure to remove the solvent to obtain an intermediate IV; Step (4), preparing the compound 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine: Add a cyclization catalyst to compound IV and react at a controlled temperature. After the reaction is completed, filter out the catalyst and perform distillation to obtain compound 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine.

3. The method for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine according to claim 2, characterized in that: In the step (1), the solvent is one of methanol and ethanol, and the methylamine is dissolved into a corresponding 30% methylamine methanol solution or a 30% methylamine ethanol solution.

4. The method for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine according to claim 2, characterized in that: In the step (2), the solvent is any one of dichloromethane, chloroform and toluene, and the acylating agent is one of acetyl chloride and acetic anhydride.

5. The method for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine according to claim 2, characterized in that: In the step (3), the solvent is one of tetrahydrofuran and methyltetrahydrofuran, and the reducing agent is lithium aluminum tetrahydride, borohydride and Lewis acid, borohydride and organic acid.

6. The method for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine according to claim 5, wherein the Lewis acid is any one of ferric chloride, aluminum chloride, boron trifluoride and zinc chloride.

7. The method for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine according to claim 5, wherein the organic acid comprises trifluoroacetic acid, formic acid, or acetic acid.

8. The method for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine according to claim 2, characterized in that: The catalyst in step (4) is any one of ferric chloride, aluminum chloride, boron trifluoride and zinc chloride.

9. The method for preparing 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine according to claim 2, wherein the extraction solvent is one of ethyl acetate or dichloromethane.

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