Preparation method of ticagrelor intermediate 4, 6-dichloro-2-propylthio-5-aminopyrimidine

Abstract

The invention discloses a preparation method of 4, 6-dichloro-2-propylthio-5-aminopyrimidine serving as an intermediate of ticagrelor. The preparation method adopts an electrochemical reduction method and is carried out in an electrolytic bath comprising a cathode chamber and an anode chamber; the cathode electrolyte is a mixed solution comprising a compound II, supporting electrolyte and acid; the anolyte adopts an acid solution; in the electrochemical reduction process, active hydrogen H * generated by cathode electrolysis acts on nitryl of the compound II, and a reduction reaction is carried out to generate a compound I; the method is mild in reaction condition, simple in equipment and easy to operate; clean electrons are directly used as a reducing agent, so that the addition of an additional catalyst or reducing agent is effectively avoided, and the compound II can be well reduced into a target product compound I; the adopted electrolytic cell can react under the conditions of higher substrate concentration and higher current density, the reaction time is short, the yield is high, and the method is suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, and in particular to a method for preparing a ticagrelor intermediate 4,6-dichloro-2-propylthio-5-aminopyrimidine. Background Art

[0002] Antiplatelet therapy is one of the important treatment measures for acute coronary syndrome (ACS). Ticagrelor is a new type of cyclopentyltriazolopyrimidine (CPTP) oral antiplatelet drug. It is a selective adenosine diphosphate (ADP) receptor antagonist that acts on the P2Y12 ADP receptor to inhibit ADP-mediated platelet activation and aggregation. Its mechanism of action is similar to that of thienopyridine drugs (such as clopidogrel). However, the difference is that the interaction between ticagrelor and the platelet P2Y12 ADP receptor is reversible, without conformational changes and signal transmission, and the platelet function in the blood is quickly restored after drug withdrawal. Studies have shown that the efficacy of ticagrelor is significantly better than clopidogrel, and it is listed as a first-line recommended drug in multiple domestic and foreign guidelines. In the past two years, the European guidelines have listed the recommendation level of ticagrelor before clopidogrel, and clopidogrel can only be used in patients who cannot use ticagrelor.

[0003] Ticagrelor, chemical name is (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propylthiotriazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol, molecular formula is C 23 H 28 F2N6O4S, relative molecular mass is 522.574. The structural formula is as follows:

[0004]

[0005] Compound 4,6-dichloro-2-propylthio-5-aminopyrimidine (Compound I) is a key intermediate in the synthesis of ticagrelor. Currently, most of the existing technologies use compound 4,6-dichloro-2-propylthio-5-aminopyrimidine (Compound II) as a raw material, and reduce the nitro group at the 5-position of Compound II to an amino group to obtain the target intermediate Compound I:

[0006]

[0007] The method of reducing the 5-nitro group to form an amino group is currently a hot topic for researchers in this field. Most of them use the following methods: one is catalytic hydrogenation; the second is chemical reduction by adding a reducing agent; and the third is photocatalysis.

[0008] Patents CN1938284A, CN103923020A, and CN103992277A use catalytic hydrogenation methods, and report that commonly used metal catalysts include Pt / C, Pt / V / C, Pd / C, Raney Ni, etc. This method uses expensive and difficult-to-obtain precious metal catalysts, and the reaction is carried out under high pressure conditions, which has high process costs and high safety risks. In addition, there is the selectivity problem of group hydrogenation, that is, while -NO2 is hydrogenated, CS, -X (F / Cl / Br / I), etc. are also easily hydrogenated, which is not suitable for industrial production. Therefore, a method with low process costs is needed to replace it.

[0009] The chemical reduction method mainly uses iron powder, insurance powder (sodium dithionite), composite reducing agent (ferrous halide + sodium borohydride) and other reducing agents to carry out nitro reduction reaction. Patent WO2012138981A2 reports an improved process for preparing ticagrelor and its new intermediates. At room temperature, iron powder is added to a solution of compound II in methanol and acetic acid. The obtained reaction mixture is stirred at 50 °C for 3~5 hours. The purified compound I is obtained by filtration, vacuum distillation, extraction, alkali washing, and vacuum concentration. This method will produce a large amount of waste slag (iron mud), wastewater and other pollutants to the environment, increase the cost of post-processing, and is not in line with the current development concept of green chemistry. Patent CN103896857A reports that a mixture of sodium dithionite and NaHCO3 aqueous solution is added dropwise to a solvent containing compound II for reaction, and the reaction temperature is low, and the optimal reaction temperature is -5~0 °C. The post-reaction treatment adopts filtration, extraction, washing the organic phase with water, and vacuum concentration to obtain the purified compound I. This method requires the addition of a large amount of sodium dithionite as a reducing agent, and a large amount of Na2SO4 waste salt, waste water, etc. are produced after the reaction. In addition, the hydrosulfite has low stability and will react violently and burn when it comes into contact with water, which has poor safety in industrial production applications. Patent CN114213203A reports the use of a composite reducing agent (ferrous halide + sodium borohydride) to reduce compound 1. This method still produces a large amount of waste water and waste salt, increasing the cost of post-processing.

[0010] Patent CN116239539A reports a photocatalytic reduction reaction, in which compound II is mixed with an alcohol solvent and a photocatalyst to form a mixture, wherein nano titanium dioxide is used as a photocatalyst, and the mixture is reacted under light conditions to obtain a product, the product is centrifuged, the upper organic phase is taken, and the target compound I is obtained after being concentrated to dryness under reduced pressure. This method has mild reaction conditions, simple operation, and can be reacted at room temperature and pressure, but it also has certain disadvantages. This method needs to be carried out under specific light conditions, the light absorption range is limited, the utilization rate is low, the photocatalyst activity is low, and the solution transmittance will affect the photocatalytic effect, so industrial large-scale production is subject to greater limitations.

[0011] In summary, in the conventional catalytic hydrogenation reduction method, the precious metal catalyst is expensive and difficult to obtain, the reaction is carried out under high pressure conditions, the process cost is high, and there is a high safety risk. The conventional chemical reduction method of adding a reducing agent will produce a lot of waste such as iron mud, wastewater, and waste salt, which pollutes the environment and increases the cost of post-processing. The photocatalyst activity of the photocatalytic reduction reaction is low, and the light transmittance of the solution will affect the photocatalytic effect, and industrial production remains to be studied. Therefore, it is urgent to develop a method for preparing 4,6-dichloro-2-propylthio-5-aminopyrimidine that is economical, environmentally friendly, has mild reaction conditions, simple and easy equipment to operate, short reaction time, high yield, and is suitable for industrial production. Summary of the invention

[0012] The technical problem to be solved by the present invention is to provide an electrochemical reduction method for preparing 4,6-dichloro-2-propylthio-5-aminopyrimidine from compound II under acidic system conditions. The electrolytic reaction conditions are mild and the equipment is simple and easy to operate. The method directly uses clean electrons as a reducing agent, effectively avoiding the addition of additional catalysts or reducing agents. The generated active hydrogen H* is dissolved in the electrolyte and is not isolated from the reaction substrate, so compound II can be reduced to the target product compound I. The electrolytic cell used in the method can react under higher substrate concentration and larger current density, and has a short reaction time and high yield, and is suitable for industrial production.

[0013] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0014] The invention provides a method for preparing 4,6-dichloro-2-propylthio-5-aminopyrimidine. The preparation method adopts an electrochemical reduction method and is carried out in an electrolytic cell, wherein the electrolytic cell comprises a cathode chamber and an anode chamber, and the cathode chamber and the anode chamber are isolated by a cation exchange membrane; the cathode electrolyte is a mixed solution comprising a compound II, a supporting electrolyte and an acid; the anode electrolyte adopts an acid solution; during the electrochemical reduction process, active hydrogen H* generated by cathode electrolysis acts on a nitro group of the compound II to perform a reduction reaction, thereby generating 4,6-dichloro-2-propylthio-5-aminopyrimidine shown in formula I;

[0015]

[0016] In the cathode electrolyte of the present invention, compound II can be well dissolved therein to form a homogeneous solution.

[0017] Furthermore, the supporting electrolyte in the cathode electrolyte is selected from one or a combination of tetrabutylammonium perchlorate (TBAP), LiClO4, LiCl, NH4Cl, and NaBF4.

[0018] Furthermore, the acid in the cathode electrolyte is selected from one or a combination of HCl, H2SO4, and CH3COOH.

[0019] Furthermore, the solvent of the cathode electrolyte is one or a combination of CH3OH, EtOH, and CH3CN. Furthermore, the solvent of the cathode electrolyte is methanol.

[0020] Furthermore, in the cathode electrolyte, the mass ratio of compound II to cathode electrolyte is 1:120-1:25, the supporting electrolyte concentration is 0.1 M-0.3 M, and the acid concentration is 0.5-5 M. Furthermore, the acid in the cathode electrolyte is CH3COOH, and the concentration is 3-5 M.

[0021] Furthermore, the acid used in the anolyte is selected from one of H2SO4, CH3OOH, and H3PO4, and the solvent is H2O; the acid concentration in the anolyte is 1-2 M.

[0022] Furthermore, in the electrolytic cell, the cathode material is selected from one of copper sheet, copper mesh, foamed copper, and copper-nickel alloy; the anode material is selected from one of platinum sheet, platinum mesh, graphite plate, and DSA-coated titanium electrode.

[0023] Furthermore, in the electrochemical reduction process, an H-type electrolytic cell was used with a current density of 37.5 A / m 2 ~500 A / m 2 , the reaction temperature is 5 ℃~70 ℃, the reaction pressure is 0 MPa~0.5 MPa, the stirring speed is 200~1000 r / min, and the power-on time is 1~25 h. Furthermore, in the electrochemical reduction process, an H-type electrolytic cell is used with a current density of 75 A / m 2 ~375 A / m 2 , the reaction temperature is 10 ℃~25 ℃, the reaction pressure is normal pressure (i.e. 0.1MPa), the stirring speed is 600~1000 r / min, and the power-on time is 4~8 h. The present invention particularly preferably uses an H-type electrolytic cell in the electrochemical process, first at a current density of 125 A / m 2 , the reaction temperature is 10 ℃, the reaction pressure is normal pressure, and the stirring speed is 500~700 r / min. Keep warm and react for 2.5~3h; then at a current density of 75 A / m 2 , reaction temperature of 10 ° C, reaction pressure of normal pressure, stirring speed of 500-700 r / min, keep warm and power on for 4.5-5 hours to generate 4,6-dichloro-2-propylthio-5-aminopyrimidine shown in formula I.

[0024] Furthermore, in the electrochemical reduction process, a plate-and-frame electrolyzer was used, and the flow rates of the cathode electrolyte and the anolyte of the electrolyzer were 0.5-3.0 L / min, respectively, at a current density of 300-500 A / m 2 , under the condition of reaction temperature of 20-40 °C, keep the temperature and conduct electricity for 7-13 hours to generate 4,6-dichloro-2-propylthio-5-aminopyrimidine shown in formula I.

[0025] After the electrochemical reduction reaction, the cathode electrolyte obtained by the present invention is post-treated by steps including vacuum distillation, silica gel column chromatography, and vacuum concentration to dryness to purify compound I.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The present invention breaks the fixed mode of existing chemical reduction (catalytic hydrogenation or adding a reducing agent), adopts an electrochemical reduction method under acidic system conditions, uses clean electrons as a reducing agent to generate active hydrogen H* through cathode electrolysis to reduce compound II, does not need to add an additional reducing agent, and does not need a hydrogenation reaction device with higher process requirements and greater risk factors, greatly reduces the post-processing cost of waste, has mild reaction conditions, and is simple and easy to operate. It provides high-purity amino pyrimidine intermediates for the pharmaceutical industry, etc. At the same time, the electrolytic cell used in the method can react under higher substrate concentrations and larger current densities, and has a short reaction time and high yield, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The accompanying drawings are used to provide a further understanding of the embodiments of the present invention, constitute a part of this application, and do not constitute a limitation of the embodiments of the present invention. In the accompanying drawings:

[0029] Figure 1 This is a diagram of the liquid phase results of Compound II and Compound I before and after electrolysis in Example 1.

[0030] Figure 2 The catholyte of Example 6 was post-treated to obtain the purified compound I 1 HNMR data graph.

[0031] Figure 3 Schematic diagram of an H-type electrolytic cell device.

[0032] Figure 4 Schematic diagram of a plate and frame electrolyzer device. DETAILED DESCRIPTION

[0033] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with embodiments. The illustrative embodiments of the present invention and their description are only used to explain the present invention and are not intended to limit the present invention.

[0034] The reagents and raw materials used in the present invention are commercially available.

[0035] The electrochemical reduction of the embodiment of the present invention is Figure 3 , Figure 4 The electrolysis is carried out in the electrolytic cell shown, which includes a cathode chamber and an anode chamber, and the cathode chamber and the anode chamber are separated by a cation exchange membrane.

[0036] Example 1

[0037] 0.24 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 30 mL of 0.3 M tetrabutylammonium perchlorate and 3 M glacial acetic acid in methanol, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 3 In the H-type electrolytic cell shown, cathode electrolyte is added to the cathode chamber, and foam copper is used as the cathode material.

[0038] 30 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and platinum sheet was used as the anode material.

[0039] Start stirring and introduce N2 bubbling for 20 min to remove dissolved oxygen. Then turn on the power supply and conduct electricity at a current density of 125 A / m 2 , temperature 10 °C, stirring speed 600 r / min under normal pressure, keep warm and react for 2.9 h. At a current density of 75 A / m 2 , temperature 10 °C, stirring speed 600 r / min under normal pressure conditions, keep warm and react for 4.8 h.

[0040] Stop the power supply, take a sample of the cathode electrolyte, and analyze it using a high performance liquid chromatograph. The present invention uses a Waters 2695 high performance liquid chromatograph for analysis, the chromatographic column is Thermo Scientific Acclaim™ 120 C18, 5 µm (4.6×250 mm), the mobile phase is acetonitrile: water: glacial acetic acid = 70:30:0.1, the column temperature is 35°C, the UV detector wavelength is 254 nm, and the flow rate is 1.0 mL / min. The liquid phase results of compound II and compound I before and after electrolysis are as follows: Figure 1 As shown, the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was detected to be 95.36%.

[0041] Example 2

[0042] 0.24 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 30 mL of 0.3 M tetrabutylammonium perchlorate and 3 M glacial acetic acid in methanol, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 3 In the H-type electrolytic cell shown, cathode electrolyte is added to the cathode chamber, and foam copper is used as the cathode material.

[0043] 30 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and platinum sheet was used as the anode material.

[0044] Start stirring and introduce N2 bubbling for 20 min to remove dissolved oxygen. Then turn on the power supply and conduct electricity at a current density of 125 A / m 2 , temperature 15 °C, stirring speed 600 r / min under normal pressure, keep warm and react for 2.9 h. At a current density of 75 A / m 2 , temperature 15 °C, stirring speed 600 r / min under normal pressure conditions, keep warm and react for 4.8 h.

[0045] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 91.87%.

[0046] Example 3

[0047] 0.24 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 30 mL of a methanol solution of 0.3 M ammonium chloride and 3 M glacial acetic acid, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved, which was used as the cathode electrolyte. Figure 3 In the H-type electrolytic cell shown, cathode electrolyte is added to the cathode chamber, and foam copper is used as the cathode material.

[0048] 30 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and platinum sheet was used as the anode material.

[0049] Start stirring and introduce N2 bubbling for 20 min to remove dissolved oxygen. Then turn on the power supply and conduct electricity at a current density of 125 A / m 2 , temperature 25 °C, stirring speed 600 r / min under normal pressure, keep warm and react for 2.9 h. At a current density of 75 A / m 2 , temperature 25 °C, stirring speed 600 r / min under normal pressure conditions, keep warm and react for 4.3 h.

[0050] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 90.91%.

[0051] Example 4

[0052] 0.24 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 30 mL of 0.3 M tetrabutylammonium perchlorate and 3 M glacial acetic acid in ethanol, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 3 In the H-type electrolytic cell shown, cathode electrolyte is added to the cathode chamber, and foam copper is used as the cathode material.

[0053] 30 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and platinum sheet was used as the anode material.

[0054] Start stirring and introduce N2 bubbling for 20 min to remove dissolved oxygen. Then turn on the power supply and conduct electricity at a current density of 125 A / m 2 , temperature 10 °C, stirring speed 600 r / min under normal pressure, keep warm and react for 2.9 h. At a current density of 75 A / m 2 , temperature 10 °C, stirring speed 600 r / min under normal pressure conditions, keep warm and react for 4.8 h.

[0055] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 93.39%.

[0056] Example 5

[0057] 0.24 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 30 mL of 0.3 M lithium perchlorate and 3 M glacial acetic acid in methanol, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 3 In the H-type electrolytic cell shown, cathode electrolyte is added to the cathode chamber, and foam copper is used as the cathode material.

[0058] 30 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and platinum sheet was used as the anode material.

[0059] Start stirring and introduce N2 bubbling for 20 min to remove dissolved oxygen. Then turn on the power supply and conduct electricity at a current density of 125 A / m 2, temperature 10 °C, stirring speed 600 r / min under normal pressure, keep warm and react for 2.9 h. At a current density of 75 A / m 2 , temperature 10 °C, stirring speed 600 r / min under normal pressure conditions, keep warm and react for 4.8 h.

[0060] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 90.29%.

[0061] Example 6

[0062] 40.5 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 500 mL of a methanol solution containing 0.1 M ammonium chloride and 5 M glacial acetic acid, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 4 In the plate-and-frame electrolytic cell shown, cathode electrolyte is added to the cathode chamber, and foam copper is used as the cathode material.

[0063] 500 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and the anode material was a DSA-coated titanium electrode.

[0064] The circulating electrolyte was turned on, and the flow rates of the cathode electrolyte and the anode electrolyte were both 2.0 L / min. During the electrolytic reduction process, N2 was bubbled to remove dissolved oxygen. Then the power supply was turned on and the current density was 500 A / m 2 , temperature 20~40 °C, keep warm and keep the power on for 7.7 h.

[0065] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 89.43%.

[0066] The cathode electrolyte is post-treated, distilled under reduced pressure, chromatographed on a silica gel column, and concentrated to dryness under reduced pressure to obtain pure 4,6-dichloro-2-propylthio-5-aminopyrimidine. 1 HNMR data such as Figure 2 As shown, 1 H NMR (500 MHz, CDCl3) δ 4.22(s, 2H), 3.09 – 3.03 (t, 2H), 1.72 (h, J = 7.4 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H).

[0067] Example 7

[0068] 67.5 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 500 mL of a methanol solution of 0.1 M tetrabutylammonium perchlorate and 5 M glacial acetic acid, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 4 In the plate-and-frame electrolytic cell shown, cathode electrolyte is added to the cathode chamber, and foam copper is used as the cathode material.

[0069] 500 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and the anode material was a DSA-coated titanium electrode.

[0070] The circulating electrolyte was turned on, and the flow rates of the cathode electrolyte and the anode electrolyte were both 2.0 L / min. During the electrolytic reduction process, N2 was bubbled to remove dissolved oxygen. Then the power supply was turned on and the current density was 500 A / m 2 , temperature 20~40 °C, keep warm and react for 12.9 hours.

[0071] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 88.37%.

[0072] Comparative Example 1

[0073] 0.24 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 30 mL of 0.3 M tetrabutylammonium perchlorate and 3 M glacial acetic acid in methanol, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 3 In the H-type electrolytic cell shown, the cathode electrolyte is added to the cathode chamber, and the cathode material is a copper sheet.

[0074] 30 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and platinum sheet was used as the anode material.

[0075] Start stirring and introduce N2 bubbling for 20 min to remove dissolved oxygen. Then turn on the power supply and conduct electricity at a current density of 125 A / m 2 , temperature 5 °C, stirring speed 200 r / min under normal pressure conditions, keep warm and react for 4.6 h.

[0076] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 66.18%.

[0077] Comparative Example 2

[0078] 0.24 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 30 mL of 0.3 M tetrabutylammonium perchlorate and 3 M glacial acetic acid in methanol, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 3 In the H-type electrolytic cell shown, cathode electrolyte is added to the cathode chamber, and foam copper is used as the cathode material.

[0079] 30 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and platinum sheet was used as the anode material.

[0080] Stirring was started and N2 was bubbled in for 20 min to remove dissolved oxygen. Then the power supply was turned on and the current density was 250 A / m 2 , temperature 25 °C, stirring speed 1000 r / min under normal pressure conditions, keep warm and react for 2.3 h.

[0081] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 80.78%.

[0082] Comparative Example 3

[0083] 0.24 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 30 mL of 0.3 M tetrabutylammonium perchlorate and 3 M glacial acetic acid in methanol, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 3 In the H-type electrolytic cell shown, the cathode electrolyte is added to the cathode chamber, and the cathode material is a copper mesh.

[0084] 30 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and platinum mesh was used as the anode material.

[0085] Start stirring and introduce N2 bubbling for 20 min to remove dissolved oxygen. Then turn on the power supply and conduct electricity at a current density of 375 A / m 2 , temperature 15 °C, stirring speed 600 r / min under normal pressure conditions, keep warm and react for 1.5 h.

[0086] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 73.41%.

[0087] Comparative Example 4

[0088] 0.72 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 30 mL of a methanol solution of 0.3 M tetrabutylammonium perchlorate and 3 M glacial acetic acid, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 3 In the H-type electrolytic cell shown, the cathode electrolyte is added to the cathode chamber, and the cathode material is a copper mesh.

[0089] 30 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and platinum sheet was used as the anode material.

[0090] Stirring was started and N2 was bubbled in for 20 min to remove dissolved oxygen. Then the power supply was turned on and the current density was 250 A / m 2 , temperature 15 °C, stirring speed 200 r / min under normal pressure conditions, keep warm and react for 6.9 h.

[0091] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 76.90%.

[0092] Comparative Example 5

[0093] 0.72 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 30 mL of a methanol solution of 0.3 M tetrabutylammonium perchlorate and 3 M glacial acetic acid, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 3 In the H-type electrolytic cell shown, cathode electrolyte is added to the cathode chamber, and foam copper is used as the cathode material.

[0094] 30 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and platinum sheet was used as the anode material.

[0095] Start stirring and introduce N2 bubbling for 20 min to remove dissolved oxygen. Then turn on the power supply and conduct electricity at a current density of 125 A / m 2 , temperature 25 °C, stirring speed 600 r / min under normal pressure conditions, keep warm and react for 13.9 h.

[0096] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 83.83%.

[0097] Comparative Example 6

[0098] 1.21 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 30 mL of a methanol solution of 0.3 M tetrabutylammonium perchlorate and 3 M glacial acetic acid, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 3 In the H-type electrolytic cell shown, the cathode electrolyte is added to the cathode chamber, and the cathode material is a copper mesh.

[0099] 30 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and platinum mesh was used as the anode material.

[0100] Start stirring and introduce N2 bubbling for 20 min to remove dissolved oxygen. Then turn on the power supply and conduct electricity at a current density of 375 A / m 2 , temperature 25 °C, stirring speed 200 r / min under normal pressure conditions, keep warm and react for 7.7 h.

[0101] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 76.35%.

[0102] Comparative Example 7

[0103] 1.21 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 30 mL of a methanol solution of 0.3 M tetrabutylammonium perchlorate and 3 M glacial acetic acid, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 3 In the H-type electrolytic cell shown, cathode electrolyte is added to the cathode chamber, and the cathode material is copper-nickel alloy.

[0104] 30 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and platinum sheet was used as the anode material.

[0105] Start stirring and introduce N2 bubbling for 20 min to remove dissolved oxygen. Then turn on the power supply and conduct electricity at a current density of 125 A / m 2 , temperature 15 °C, stirring speed 1000 r / min under normal pressure conditions, keep warm and react for 23.2 h.

[0106] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 81.27%.

[0107] Comparative Example 8

[0108] 1.21 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 30 mL of a methanol solution of 0.3 M tetrabutylammonium perchlorate and 3 M glacial acetic acid, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 3 In the H-type electrolytic cell shown, cathode electrolyte is added to the cathode chamber, and the cathode material is copper-nickel alloy.

[0109] 30 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and platinum sheet was used as the anode material.

[0110] Stirring was started and N2 was bubbled in for 20 min to remove dissolved oxygen. Then the power supply was turned on and the current density was 250 A / m 2 , temperature 5 °C, stirring speed 600 r / min under normal pressure conditions, keep warm and react for 11.6 h.

[0111] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 69.91%.

[0112] Comparative Example 9

[0113] 0.72 g of 4,6-dichloro-2-propylthio-5-nitropyrimidine was added to 30 mL of a methanol solution of 0.3 M tetrabutylammonium perchlorate and 3 M glacial acetic acid, and stirred until 4,6-dichloro-2-propylthio-5-nitropyrimidine was completely dissolved. This was used as the cathode electrolyte. Figure 3 In the H-type electrolytic cell shown, cathode electrolyte is added to the cathode chamber, and the cathode material is copper-nickel alloy.

[0114] 30 mL of 2 M dilute sulfuric acid solution was added to the anode chamber, and platinum mesh was used as the anode material.

[0115] Start stirring and introduce N2 bubbling for 20 min to remove dissolved oxygen. Then turn on the power supply and conduct electricity at a current density of 375 A / m 2 , temperature 5 °C, stirring speed 1000 r / min under normal pressure conditions, keep warm and react for 4.6 h.

[0116] The power was turned off, and the cathode electrolyte was sampled and analyzed by high performance liquid chromatography. The detection method was the same as that in Example 1. The detection showed that the content of 4,6-dichloro-2-propylthio-5-aminopyrimidine was 67.46%.

Claims

1. A method for preparing 4,6-dichloro-2-propylthio-5-aminopyrimidine, characterized in that: The preparation method adopts an electrochemical reduction method and is carried out in an electrolytic cell, wherein the electrolytic cell comprises a cathode chamber and an anode chamber, and the cathode chamber and the anode chamber are separated by a cation exchange membrane; The cathode electrolyte is a mixed solution including compound II, a supporting electrolyte and an acid; the anode electrolyte is an acid solution; during the electrochemical reduction process, active hydrogen H* generated by cathode electrolysis acts on the nitro group of compound II to undergo a reduction reaction to generate 4,6-dichloro-2-propylthio-5-aminopyrimidine shown in formula I; 。 2. The preparation method according to claim 1, characterized in that: In the cathode electrolyte, the supporting electrolyte is selected from one or several combinations of tetrabutylammonium perchlorate, LiClO4, LiCl, NH4Cl, and NaBF4; the acid is selected from one or several combinations of HCl, H2SO4, and CH3COOH; and the solvent is one or several combinations of CH3OH, EtOH, and CH3CN.

3. The preparation method according to claim 1 or 2, characterized in that: In the cathode electrolyte, the mass ratio of compound II to cathode electrolyte is 1:120-1:25, the supporting electrolyte concentration is 0.1 M-0.3 M, and the acid concentration is 0.5-5 M.

4. The preparation method according to claim 3, characterized in that: The acid in the cathode electrolyte is CH3COOH with a concentration of 3-5 M.

5. The preparation method according to claim 1, characterized in that: The acid used in the anolyte is selected from one of H2SO4, CH3OOH, and H3PO4, and the solvent is H2O; the acid concentration in the anolyte is 1-2 M.

6. The preparation method according to claim 1, characterized in that: In the electrolytic cell, the cathode material is selected from one of copper sheet, copper mesh, foamed copper, and copper-nickel alloy; the anode material is selected from one of platinum sheet, platinum mesh, graphite plate, and DSA-coated titanium electrode.

7. The preparation method according to claim 1, characterized in that: During the electrochemical reduction process, an H-type electrolytic cell was used with a current density of 37.5 A / m 2 ~500 A / m 2 , the reaction temperature is 5 ℃~70 ℃, the reaction pressure is 0 MPa~0.5 MPa, the stirring speed is 200~1000 r / min, and the power-on time is 1~25 h.

8. The preparation method according to claim 1, characterized in that: During the electrochemical reduction process, an H-type electrolytic cell was used with a current density of 75 A / m 2 ~375 A / m 2 , the reaction temperature is 10 ℃ ~ 25 ℃, the reaction pressure is normal pressure, the stirring speed is 600 ~ 1000 r / min, and the power-on time is 4 ~ 8 h.

9. The preparation method according to claim 1, characterized in that: During the electrochemical reduction process, an H-type electrolytic cell was used to first 2 The reaction was carried out under the conditions of 10 °C reaction temperature, normal pressure reaction pressure, stirring speed of 500-700 r / min for 2.5-3 h; then the reaction was carried out under the conditions of 75 A / m 2 , the reaction temperature is 10 ° C, the reaction pressure is normal pressure, and the stirring speed is 500-700 r / min. The reaction is kept warm and powered on for 4.5-5 hours to generate 4,6-dichloro-2-propylthio-5-aminopyrimidine shown in formula I.

10. The preparation method according to claim 1, characterized in that: During the electrochemical reduction process, a plate-and-frame electrolytic cell was used, and the flow rates of the cathode electrolyte and the anode electrolyte of the electrolytic cell were 0.5-3.0 L / min, respectively. 2 , keep the reaction temperature at 20-40 °C and pass electricity for 7-13 hours to generate 4,6-dichloro-2-propylthio-5-aminopyrimidine shown in formula I.

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