Method for preparing 1, 3-thiazolidine-2-ketone by microwave reactor

Abstract

The invention discloses a method for preparing 1, 3-thiazolidine-2-ketone by a microwave reactor, which comprises the following steps: grinding raw materials cysteamine hydrochloride and urea, fully mixing, adding into a reaction container, putting into the microwave reactor, and heating to react while stirring; cooling the reaction liquid, dissolving with an extracting agent, extracting, and filtering to obtain a solid which is a byproduct ammonium chloride; and evaporating the filtered liquid to recover the extracting agent, cooling the solid material, recrystallizing, and drying to obtain the finished product 1, 3-thiazolidine-2-ketone. The invention systematically studies the application of microwave heating in the preparation process of 1, 3-thiazolidine-2-ketone, a complete synthesis and purification process is formed, the prepared product has good appearance and high purity, the quality indexes of different batches of products have small difference, and the application prospect is good.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemical product production, and particularly relates to a method for preparing 1,3-tetrahydrothiazol-2-one using a microwave reactor. Background Art

[0002] 1,3-Tetrahydrothiazol-2-one, also known as 2-thiazolidinone, is composed of a thiazole ring and a keto group. There are sulfur atoms and nitrogen atoms in the thiazole ring. It has strong electrophilicity and alkalinity. It is a representative starting material for nitrogen-sulfur heterocyclic thiazole compounds. At the same time, it itself has good fungicidal activity and is directly used as a bactericide, insecticide, and plant growth regulator.

[0003] After consulting the literature, the synthesis methods of 1,3-tetrahydrothiazol-2-one can be divided into the following types according to the starting materials: (1) cysteamine (cysteamine hydrochloride) method; (2) 2-thiazolethione method; (3) ethanolamine method; (4) 2-aminoethylthiol method; (5) oxazolethione; (6) 2-iminothiazolidine method; (7) 2-aminoethylsulfuric acid method. Considering the cost, raw material source, production process cleanliness, environmental protection and industrialization, the cysteamine hydrochloride and urea condensation method, which can achieve industrial-scale production, was selected for research. The existing research results on the preparation of 1,3-tetrahydrothiazol-2-one by condensation of cysteamine hydrochloride and urea mainly include: Zhang Ruisheng conducted a detailed study on the synthesis of 2-thiazolidinone by cysteamine-urea method in his master's thesis "Synthesis Research and Process Design of 2-thiazolidinone, a Key Intermediate of Novel Nematicide Thiazophos" (2009) at Shandong University, and conducted experiments on 2-thiazolidinone from the perspectives of raw material ratio, feeding method, solvent screening, etc., screened out the optimized process conditions for the synthesis of 2-thiazolidinone and determined the appropriate process parameters: the molar ratio of cysteamine hydrochloride to urea is 1.0:1.5, the heating time is 2.5h; the reaction temperature is 160±5℃; toluene is used as the extraction solvent, and the yield can reach 90-91% based on cysteamine hydrochloride. The shortcomings of this process route are: (1) the raw material urea is too much in excess (the molar ratio of cysteamine hydrochloride to urea is 1.0:1.5); (2) the reaction temperature is relatively high (reaction temperature 160±5℃). Under this reaction condition, urea will inevitably undergo side reactions to produce triuret or even tetrauret, cyanuric acid, triamine, etc., which are difficult to remove after the reaction is completed, resulting in low product purity and high impurity content, which cannot be used in pharmaceutical synthesis; (3) the synthesis production cycle is long, with the heating time alone reaching 2.5h. Combined with the raw material heating and reaction completion cooling, the unit operation cycle is estimated to be no less than 5h; (4) there is no quantifiable method to determine whether the reaction is completed; (5) The low purity and high impurity content of the product have led to many limitations in application fields with strict requirements.

[0004] The Chinese patent (CN 110563666 A) proposes a process for synthesizing cysteamine hydrochloride and urea by hot melt method. The process includes the following main operations: (1) hot melting cysteamine hydrochloride and urea in a reactor and then performing a cyclization reaction; (2) adding toluene to the hot melt synthesis product obtained in the reactor for hot extraction; (3) filtering the extract and distilling the filtrate under reduced pressure to remove toluene; (4) transferring the liquid phase after toluene removal into a crystallization kettle for cooling, crystallization, and drying. The main shortcomings of this process are: (1) high reaction temperature and long reaction time (only the heat preservation reaction requires 2.5h-3.5h); (2) the toluene extract is directly cooled, centrifuged, and air-dried to obtain the finished product, and the product purity is low because the toluene extract contains by-product ammonium chloride (NH 4 Cl), it will inevitably remain in the finished product. If no secondary treatment (such as recrystallization) is carried out, the product content is difficult to exceed 98%; (3) The toluene loss is relatively large. After vacuum distillation, the toluene recovery rate is only 75%. The remaining 25% is retained in the centrifugal mother liquor (which can be considered for recovery), and part of it is present in the washing liquid obtained after washing the ammonium chloride by-product with 95% industrial ethanol. Chemical industry technicians know that it is difficult to separate the liquid containing water, toluene and ethanol to obtain ethanol or toluene with low water content, which increases the difficulty of continuing to use toluene and ethanol.

[0005] The Chinese patent (application number 202210815682.6) uses cysteamine hydrochloride and urea to synthesize by stepwise heating. The main operating steps are: (1) cysteamine hydrochloride and urea condensation reaction; (2) toluene extraction and filtration to obtain solid ammonium chloride; the filtrate is de-roughed and toluene is evaporated; (3) the liquid phase after toluene is evaporated enters the distillation kettle, and the crude product 1,3-tetrahydrothiazol-2-one is directly evaporated; (4) the crude product is dissolved in toluene, toluene is evaporated, cooled and crystallized to obtain the final product. Although this process route has some innovations in crude product purification, it still has the following disadvantages: (1) The energy consumption of the crude product post-treatment step is too large during the operation. The toluene liquid containing the crude product is first evaporated toluene, and then distilled to obtain the crude product. The crude product is dissolved in toluene for a second time, and then toluene is evaporated, cooled and crystallized to obtain the final product. The melting point of 1,3-tetrahydrothiazol-2-one is 49°C, and the boiling point is 160°C / 20mmHg column. During the distillation operation, the gaseous 1,3-tetrahydrothiazol-2-one can easily clog the condenser (generally, the 1,3-tetrahydrothiazol-2-one flows through the condenser tube side and the cooling medium flows through the condenser shell side in the conventional operation); the operation needs to be carried out under a relatively high vacuum degree; (2) although the distillation is carried out under vacuum conditions, since the gas phase temperature is relatively high when the 1,3-tetrahydrothiazol-2-one is evaporated, it is undoubtedly that the liquid phase temperature will be even higher. When the liquid phase temperature is high, 1,3-tetrahydrothiazol-2-one will inevitably undergo decomposition, polymerization or other complex reactions to generate multiple complex colored compounds, which will result in the finished product having a poor appearance, color and low yield.

[0006] The existing method of synthesizing 1,3-tetrahydrothiazol-2-one using cysteamine hydrochloride and urea as raw materials adopts an oil bath heating method, which has high reaction temperature, long reaction time, many side reactions and low yield; the post-treatment of the condensation liquid after the reaction and the purification of the finished product consume a lot of energy, the operation is cumbersome, and the product purity is low. Therefore, finding and forming a whole set of new production processes has important practical significance and economic value.

[0007] Microwaves are widely used in various fields of chemistry as an effective heat source. Microwave-assisted synthesis technology is a new combinatorial chemistry technology for preparing compounds developed in recent years and has been widely used in organic synthesis reaction research. The device used for microwave synthesis is simple, easy to operate, and suitable for most organic synthesis reactions. It can not only overcome the shortcomings of traditional solid-phase synthesis technology and liquid-phase combinatorial synthesis technology that cannot improve product yields, but also has the characteristics of fast reaction speed, short reaction time, high yield, few by-products, easy product purification, low environmental pollution, and selective promotion of the main reaction, and no mechanical stirring is required. This shows the superiority of this method in synthesis.

[0008] Currently, there is no public technology for applying microwave technology to the synthesis of 1,3-tetrahydrothiazol-2-one. Summary of the invention

[0009] In order to solve the deficiencies of the prior art, the present invention proposes a method for preparing 1,3-tetrahydrothiazol-2-one using a microwave reactor. The technical solution of the present invention is as follows:

[0010] A method for preparing 1,3-thiazol-2-one by using a microwave reactor comprises: grinding raw materials cysteamine hydrochloride and urea, mixing them fully, adding them into a reaction container, placing them in a microwave reactor, and heating and reacting them under stirring with a magnetic stirrer; after the reaction is completed, cooling the reaction liquid, dissolving, extracting and filtering with an extractant, and the solid matter is the by-product ammonium chloride; filtering the liquid, evaporating and recovering the extractant, and cooling the solid material, recrystallizing and drying it to obtain the finished product 1,3-thiazol-2-one.

[0011] The specific steps include:

[0012] S1. Raw material pretreatment

[0013] The raw materials cysteamine hydrochloride and urea are weighed and ground, mixed thoroughly, and the materials are ground to a particle size of 30-100 mesh, preferably 50 mesh;

[0014] S2. Condensation reaction

[0015] Put the ground material into a reaction container, and place the reaction container in a microwave reactor; connect the outlet of the reaction container to a three-way pipe, a condenser, an ammonia receiving bottle, a vacuum receiving bottle, and a water ring vacuum pump in sequence; insert a thermometer into the reaction container through an outlet of the three-way pipe, and heat for a period of time under the condition of a microwave power of 200W±50W until all the solid materials are melted into liquid, and the temperature is 70-80℃; start the temperature reaction, and the reaction temperature is adjusted in two steps:

[0016] The first step is to adjust the microwave power and control the reaction temperature to 120-130°C for 10-15 minutes;

[0017] The second step is to adjust the microwave power and control the reaction temperature to 135-140°C for 5-10 minutes.

[0018] The method for determining the reaction endpoint is: observe that there is no visual gas discharge from the interface between the three-way pipe and the condenser and the inner tube of the condenser; at the same time, check that the pH value of the solution in the ammonia absorption bottle has no obvious change within 2 minutes. Turn off the power of the microwave reactor when the reaction is completed.

[0019] S3, extraction, evaporation, the extraction solvent is 95% ethanol.

[0020] The reaction solution was cooled to below 50°C, 95% ethanol was added, and a liquid iron removal agent sodium fumarate was added, and the mixture was stirred with a magnetic stirrer for 20-40 minutes, and then filtered. The obtained solid was washed with ethanol to obtain ammonium chloride as a byproduct;

[0021] Heat and evaporate the filtrate obtained by filtration, collect the condensate with a gas phase temperature of 76-78℃, and continue to reuse the ethanol; when the gas phase temperature exceeds 78℃, turn off the heating, change the normal pressure evaporation to reduced pressure evaporation, and adjust the vacuum degree during reduced pressure evaporation to 0.05MPa-0.07MPa. When it is observed that the gas phase temperature begins to drop, turn on the heating and continue to evaporate at the set vacuum degree. When the gas phase temperature reaches 40℃, cool the material to below 40℃ with cooling water under vacuum state, and turn off the vacuum pump.

[0022] S4, recrystallization, drying

[0023] Add 95% ethanol to the cooled reaction vessel, heat it up, control the internal temperature to 55-60°C, and keep it under reflux for 40-60 minutes. Cool it with frozen brine, filter it by suction, and reuse the filtrate; dry the obtained crystals at no higher than 40°C to obtain the finished product.

[0024] In the embodiment of the present invention, the molar ratio of cysteamine hydrochloride to urea is 1:1.05-1.15.

[0025] The mass ratio of 95% industrial ethanol to cysteamine hydrochloride is 1:3.05-3.21 (twice).

[0026] The reaction principle of the present invention is described as follows:

[0027] When using microwave heating for organic synthesis reactions, the effect of microwaves on the molecules of the substance may be weak or strong depending on the structure of the substance. As an efficient heating method, its main principle is that molecules are heated by converting mechanical energy into thermal energy by moving under a high-frequency electric field. The molecular vibration mode of the reactants is stimulated in a high-energy state, the collision frequency and energy of the reactant molecules are increased, and the desired chemical target substances are produced by breaking and reorganizing chemical bonds. The microwave radiation energy is used to quickly heat the reaction medium, accelerate the reaction process, and promote the reaction, thereby greatly improving the reaction efficiency and reducing the reaction time. Because microwave heating has very good selectivity, it can avoid the generation of impurities and unnecessary side reactions in chemical reactions under certain conditions. It is a fast, efficient, and energy-saving chemical method.

[0028] Microwave heating is different from traditional heating. Traditional heating is based on a high-temperature heat source and heats from the outside to the inside through convection and conduction. That is, the surface of the object is heated first, and then gradually heated from the inside to the inside through conduction and convection. The energy utilization rate is low. In order to avoid excessive temperature gradients, the heating speed is often not too fast, and the components of the mixed material in the same reaction device cannot be selectively heated. In this way, the heating speed is very slow and the temperature distribution is uneven. Microwave heating is a heating method that converts the absorbed electromagnetic energy into thermal energy through dielectric molecules. Compared with traditional heating, microwave heating has the following significant advantages: (1) Rapid heating, uniform heating, and high heating efficiency. Microwave energy propagates in an object at the speed of light, and can instantly convert microwave energy into thermal energy of the material, and penetrate the thermal energy into the heated material, heating the inside and outside at the same time without the need for heat conduction process, so there is no heat loss in the surrounding air and heating box; (3) Selective heating and strong heating penetration. The heat penetration depth is at the same order of magnitude as the wavelength, which can reach several centimeters to more than ten centimeters, while traditional heating is surface heating, and the penetration depth is only in the micrometer order of magnitude; (4) It can greatly accelerate the reaction rate when used in organic synthesis reactions, which can be increased by several times, dozens of times or even thousands of times; (5) Since microwaves are strong electromagnetic waves, the microwave plasma produced often contains high-energy atoms, molecules and ions that cannot be obtained by thermodynamic methods, thus enabling some reactions that are impossible to occur in thermodynamics to occur; (6) It is safe and harmless. Since microwave energy is controlled to work in a heating chamber and waveguide made of metal, there is very little microwave leakage, no radiation hazard or harmful gas emission, no waste heat and dust pollution, and no pollution to the environment.

[0029] In the present invention, the water content in the raw materials cysteamine hydrochloride and urea has an influence on the reaction: theoretically, when the materials are heated by a microwave reactor, the presence of a small amount of water helps to improve the safety of the operation. For this reaction, although the chemical properties of urea itself are inactive, under the set reaction conditions, urea will still react with water to generate compounds of various structures, which will affect the reaction ratio of urea and cysteamine hydrochloride. The ammonia generated by the hydrolysis of urea enters the solution in the ammonia absorption bottle, which also affects the judgment of the reaction end point. Therefore, the water content in the raw materials must be controlled to be ≤0.3%, and the cysteamine hydrochloride used requires no crystal water in the molecule.

[0030] In the present invention, the influence of the molar ratio of cysteamine hydrochloride to urea: taking cysteamine hydrochloride as the ingredient basis, changing the amount of urea. In the existing conventional heating operation, the molar ratio of cysteamine hydrochloride to urea is as high as 1:1.5-1:2. Too much urea will cause side reactions, and unreacted urea will remain in the reaction solution, which will bring difficulties to the subsequent product purification and affect the purity of the final product; too much urea will also affect the product production cost and economic benefits. The present invention solves the disadvantages caused by excessive urea by adopting a microwave reactor.

[0031] In the present invention, the effect of microwave power (reaction temperature) on the condensation reaction: Since the melting point difference between cysteamine hydrochloride and urea is too large, both are solid at room temperature. If only one is heated with microwave power, it is possible that the two materials are not completely melted, and part of the materials have begun to react, and the reaction is incomplete. The microwave power was adjusted many times in the experiment. First, the microwave power was reduced to ensure that cysteamine hydrochloride and urea were completely dissolved at low temperature to form a uniform liquid phase. Secondly, the microwave power was increased to prompt most of the materials to complete the reaction at a relatively low temperature; then the microwave power was increased (while increasing the reaction temperature) to increase the collision probability between the reactant molecules, speed up the reaction speed, and the remaining small amount of unreacted materials were completely reacted.

[0032] During the experiment, it was found that when the power is too high, the reaction materials tend to adhere to the wall of the round-bottom flask. A small amount of sample sticking to the wall of the flask will reduce the reaction effect on the one hand, and on the other hand, it will absorb microwaves locally to generate heat, causing local damage to the reaction flask due to heating, and also affect the full and uniform contact of the reactants, resulting in incomplete reaction, increased side reactions, carbonization of materials, difficulty in post-processing, a significant reduction in yield, and poor product appearance; if the microwave power is too low, due to insufficient reaction energy, the two materials basically do not undergo condensation reaction, and even if the radiation time is extended, they cannot fully react, affecting the yield and even failing to obtain the target compound. Therefore, this study used three microwave power adjustments, namely, first using an appropriate low power to promote the melting of the two materials, then increasing the power to induce the reaction; then increasing the power to heat at a higher temperature for a short time to ensure that the materials react fully and improve the conversion rate of the raw materials. Such a temperature gradient can both induce the reaction and avoid overreaction, significantly improving the yield.

[0033] In the present invention, the influence of reaction time: under the set reaction temperature and material ratio conditions, the reaction time has a great influence on the condensation reaction process, product quality and yield. The experimental results show that after the induction reaction of cysteamine hydrochloride and urea at a low temperature begins, appropriately extending the reaction time helps to improve the conversion rate of cysteamine hydrochloride; the formation of 1,3-tetrahydrothiazol-2-one is a fast reaction, and it is also detected in the experiment that the product is generated after only irradiation for 20 seconds. The yield increases with time. When the yield is increased to a certain extent, increasing the irradiation time will not increase it. Because the activation energy of the reaction is different at different temperatures, there is a maximum conversion rate under a certain temperature condition, and continuing to extend the reaction time basically has no effect on improving the conversion rate. When the reaction temperature is raised to 140°C again, the by-products increase significantly as the reaction time is prolonged. When the reaction time is extended for more than 3 minutes at a temperature higher than 140°C, multiple side reactions may occur, and the reaction system may absorb excessive microwave energy and decompose, generating a variety of by-products with complex structures. In addition to causing a decrease in yield, the product crystal form after recrystallization is disordered and irregular; the product appearance is slightly yellow or yellow-brown. If the reaction time is insufficient, cysteamine hydrochloride and urea are difficult to react completely or the reaction stops at generating intermediate transition products that are not the target product, which also leads to poor product quality, low yield, and unqualified products.

[0034] In the present invention, the selection of the extractant and its influence on the product quality and yield are as follows: the ideal extractant satisfies the following conditions: (1) it has sufficient solubility in the finished product and is almost insoluble in ammonium chloride; (2) it is inexpensive and safe to use; (3) the boiling point should not be too high for easy recovery. A number of solvents have been proposed in the literature, such as short-chain fatty alcohol toluene, ethylene dichloride, chloroform, straight-chain fatty acid esters, etc., with different performances. Since the reaction conditions in this study are different from the current conventional synthesis conditions, experimental screening has shown that toluene has a higher boiling point. Compared with other low-boiling alcohols, it consumes more energy in evaporation and recovery operations. The drying conditions for the finished product containing toluene are relatively strict, so ethanol is selected for extraction and used for subsequent recrystallization.

[0035] In the present invention, the influence of the recrystallization operation on the product quality and yield: the impurities contained in the solid material obtained after evaporating the extractant mainly include: unreacted urea, biuret, triuret, cyanuric acid, etc. generated by the self-reaction of urea. During the recrystallization operation, factors such as the amount of solvent added, the number of times the solvent is applied, the temperature raised by heating the solvent, the temperature reached by cooling with a freezing medium, the cooling rate, the stirring speed of the crystallizer, whether to add seed crystals, etc. have a great influence on the appearance, crystal form, purity, and yield of the obtained finished product. Once the operation is improper, secondary crystallization may be performed to prepare qualified products.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] 1. The present invention adopts a microwave heating synthesis preparation method. Microwave radiation is called an internal heating method because its special dielectric heating mechanism can make the material molecules absorb energy uniformly and effectively inside and outside the radiation field to generate thermal effects. It does not rely on the promotion of temperature gradients and has the characteristics of fast heating speed and uniform temperature of the heated system. Under low-temperature conditions, the reactant molecules can obtain the energy required for reaction and accelerated diffusion, thereby increasing the reaction speed, so that the reaction of cysteamine hydrochloride and urea can be achieved with a high yield. The synthesis process is simple, the reaction conditions are mild, and it is easy to realize the automatic control of the entire production process, which meets the development requirements of chemical automation production.

[0038] 2. Microwave heating has a high energy utilization efficiency. Under the set conditions, the temperature of the reaction materials cysteamine hydrochloride and urea rises very quickly and the temperature distribution is uniform. There is no hysteresis effect in heating. When the microwave source is turned off, no microwave energy is transmitted to the material, and the reaction can be terminated as soon as possible;

[0039] 3. Using cysteamine hydrochloride and urea as raw materials, 1,3-tetrahydrothiazol-2-one was synthesized under solvent-free and catalyst-free conditions. Compared with the conventional oil bath heating method, microwave heating was used, the temperature was reduced by 20-30°C, the reaction time was only 1 / 4 to 1 / 5 of that of oil bath heating, and the molar ratio of cysteamine hydrochloride to urea was reduced from 1:(1.5-2) to 1:(1.05-1.15), the side reactions occurred less, and the amount of by-products generated was reduced;

[0040] 4. When conducting the condensation reaction, use three different microwave powers to increase the temperature in stages. First, set a relatively small microwave power to heat at a low temperature to completely dissolve the cysteamine hydrochloride and urea to form a uniform liquid phase. Secondly, increase the microwave power to induce a reaction at the selected temperature and prompt most of the materials to complete the condensation reaction. Then continue to increase the microwave power (and increase the reaction temperature at the same time) to increase the collision probability between the reactant molecules, so that a small amount of unreacted products continue to react in depth, accelerate the reaction rate, and improve the raw material conversion rate. A reasonable temperature gradient avoids or reduces the adhesion of the reaction materials to the wall of the round-bottom flask (a small amount of sample sticking to the wall of the flask will make the reaction effect poor on the one hand), reduces the damage caused by local heating of the reaction bottle, and avoids insufficient and uneven contact of the reactants, and eliminates the carbonization of the materials, which will lead to a series of subsequent problems such as incomplete reaction, increased side reactions, difficulty in post-processing, significant reduction in yield, and poor product appearance.

[0041] 5. Use ethanol to replace toluene in the existing process to extract and recrystallize the condensation reaction liquid. Due to the lower reaction temperature, shorter reaction time, fewer side reactions, and less by-products, the amount of ethanol used in the extraction operation is reduced by 10%, and the amount of ethanol used in the recrystallization operation is reduced by 20%; the mother liquor produced by recrystallization is directly used for the extraction operation. In this way, the consumption of ethanol is significantly reduced. After the mother liquor produced by recrystallization is recycled ten times, it is distilled and the obtained ethanol can be used continuously. The distillation residue is treated together with the residue obtained by the extraction operation.

[0042] 6. The product single-pass yield is over 81%, exceeding the existing production process;

[0043] 7. The purity of the product exceeds 99.3%. The mother liquor obtained by recrystallization is recycled for extraction operation. After ten times of use, the purity of the obtained product still reaches 99.04%;

[0044] 8. Compared with the existing synthesis process, this study improves the stability of product quality, reduces energy consumption, reduces production costs, and has significant economic benefits;

[0045] 9. For the first time, the product index test "iron ion (Fe 3+ This indicator has laid a foundation for the use of products in the special cable industry and rubber products and provided reliable data.

[0046] 10. A detection method for judging whether the condensation reaction has ended is proposed. The method has strong applicability, is easy to operate, and can be easily remotely controlled. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0048] Figure 1 The present invention provides a flow chart of a method for preparing 1,3-tetrahydrothiazol-2-one using a microwave reactor.

[0049] Figure 2 The liquid chromatography analysis chromatogram of the product in Example 5 is shown.

[0050] Figure 3 The liquid chromatography analysis chromatogram of the product in Example 11 is shown. DETAILED DESCRIPTION

[0051] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0052] The technical problems to be solved by the present invention are:

[0053] 1. Lower the reaction temperature and determine the appropriate reaction temperature under microwave heating conditions

[0054] 2. Determine the appropriate response time;

[0055] 3. Reasonably determine the ratio of cysteamine hydrochloride and urea;

[0056] 4. Improve product storage stability

[0057] 5. Reduce the iron ions (Fe 3+ (a) content;

[0058] 6. Research and determine the appropriate extractant to extract the liquid obtained from the condensation reaction, determine the product crystallization process, and improve the purity of 1,3-tetrahydrothiazol-2-one;

[0059] 7. Improve the yield of 1,3-tetrahydrothiazol-2-one and thus improve the economic benefits of the product.

[0060] Based on the existing process of synthesizing 1,3-tetrahydrothiazol-2-one using cysteamine hydrochloride and urea as raw materials, this study applied the basic theory of organic synthesis, combined with an in-depth exploration and interpretation of the reaction mechanism of 1,3-tetrahydrothiazol-2-one, and drew on the successful experience of microwave heating in organic synthesis. The preparation process of 1,3-tetrahydrothiazol-2-one was systematically studied, and a complete synthesis and purification process was formed. The prepared products have good appearance, high purity, and the quality indicators of different batches of products are very close, which has good application prospects.

[0061] The present invention solves the above-mentioned problems in the following ways:

[0062] A method for preparing 1,3-tetrahydrothiazol-2-one by microwave reactor, the process flow is as follows Figure 1 shown.

[0063] Unless otherwise specified, % in this application document refers to wt%.

[0064] (I) Main quality requirements of raw materials

[0065] Solid cysteamine hydrochloride, content ≥99%, moisture ≤0.3%;

[0066] Urea complies with GB 2440-2001, moisture content ≤ 0.3%;

[0067] 95% industrial ethanol, free of benzene derivatives

[0068] (II) Material Proportion

[0069] The molar ratio of cysteamine hydrochloride (100%) to urea (100%) is 1: (1.05-1.15)

[0070] The mass ratio of 95% industrial ethanol to cysteamine hydrochloride is 1:(3.05-3.21).

[0071] The moisture content of the raw materials is ≤0.3%, and the cysteamine hydrochloride used is required to have no crystal water in the molecule.

[0072] The concentration of added 50% potassium thiram liquid is 1.5%-2.5% of the urea mass.

[0073] (III) Operation

[0074] Example 1

[0075] 1. Weigh 34.5 g of cysteamine hydrochloride and 19.6 g of urea, grind them to a particle size of 50 mesh with a mortar, mix them, put the ground materials into a three-necked round-bottom flask with a magnetic stirrer, and place the round-bottom flask in a microwave reactor. Assemble the round-bottom flask, three-way pipe, condenser pipe, ammonia receiving bottle (quantitative water has been added to the bottle), vacuum buffer bottle, and water ring vacuum pump. The outlet of the reaction vessel is connected to the three-way pipe, condenser, ammonia receiving bottle, vacuum receiving bottle, and water ring vacuum pump in sequence. A thermometer is placed at the empty port of the three-way pipe, and the pH value in the ammonia receiving bottle is detected by pH test paper or pH meter (acid-base meter).

[0076] 2. Carefully check the instrument connection status, and after confirming that it is correct, turn on the power of the microwave reactor, set the microwave power to 200W and heat for a period of time until all the solid materials are melted into liquid, and the temperature displayed on the thermometer of the three-necked round-bottom flask is 70-80℃.

[0077] 3. When it is observed that all the materials in the round-bottom flask have turned into liquid, start the temperature reaction, turn on the water ring vacuum pump, adjust the vacuum degree to 0.02MPa, and adjust the reaction temperature in two steps.

[0078] In the first step, the microwave power was set to 400 W and the temperature was maintained at 120 °C for 14 min;

[0079] Step 2: Set the microwave power to 500W and wait for the temperature to reach 140℃ for 5 minutes. During the operation, pay attention to the gas discharge from the interface between the three-way pipe and the condenser and the inner tube of the condenser. If no gas is discharged, check the pH value of the solution in the ammonia absorption bottle for no obvious change within 2 minutes, and continue the reaction for 1 minute. The reaction is over. Turn off the power of the microwave reactor.

[0080] Heating in stages avoids local overheating of the reaction materials. When microwaves are used for heating, the heat is distributed over the entire reaction material, which is fast and uniform. The energy is dispersed inside the melted liquid, but the heating range does not include the vessel wall, so most of the liquid temperature is higher than the temperature of the inner surface of the reactor. In traditional heating methods, some substances that are more sensitive to temperature may decompose in the hotter reaction, or local high temperatures may trigger other reactions. It can be seen that compared with the conversion rate of traditional heating methods, microwave heating has a higher reaction rate and a smoother reaction.

[0081] 4. Cool the reaction solution to below 50°C, add 106 g of 95% ethanol and 0.4 g of 50% potassium thiram liquid, stir magnetically for 30 minutes, filter, wash the obtained solid with ethanol, and obtain ammonium chloride as a by-product;

[0082] Put the filtrate obtained by suction filtration into a three-necked flask, slowly heat and evaporate, collect the condensate with a gas phase temperature of 76-78℃ as ethanol for further reuse; when the gas phase temperature exceeds 78.0℃, turn off the heating, change the normal pressure evaporation to reduced pressure evaporation, and adjust the vacuum degree to 0.05MPa during reduced pressure evaporation. Turn on the heating when the gas phase temperature begins to drop, and continue evaporation at the set vacuum degree. When the gas phase temperature reaches 40℃, cool the material in the three-necked flask to below 40℃ under vacuum, and turn off the vacuum pump.

[0083] 5. Add 110 g of 95% ethanol to the cooled three-necked flask, start stirring, heat and raise the temperature, control the temperature in the three-necked flask to 50°C, and keep it under reflux for 50 minutes. The material in the three-necked flask is cooled to 10°C with frozen brine, filtered, and the filtrate is reused; the obtained crystals are dried at no more than 40°C to obtain 25.38 g of the finished product. The melting point of the prepared sample is 49.6°C, the purity is 99.37%, and the calculated yield is 81.33%.

[0084] Example 2

[0085] 1. Weigh 34.5 g of cysteamine hydrochloride and 20 g of urea, grind them to a particle size of 30 mesh in a mortar, mix them, put the ground materials into a three-necked round-bottom flask with a magnetic stirrer, and place the round-bottom flask in a microwave reactor. Assemble the round-bottom flask, three-way pipe, condenser tube, ammonia receiving bottle (a certain amount of water has been added to the bottle), vacuum buffer bottle, and water ring vacuum pump;

[0086] 2. Carefully check the instrument connection status, and after confirming that it is correct, turn on the power of the microwave reactor, set the microwave power to 200W and heat for a period of time until all the solid materials are melted into liquid, and the temperature displayed on the thermometer of the three-necked round-bottom flask is 70-80℃.

[0087] 3. When it is observed that all the materials in the round-bottom flask have turned into liquid, start the temperature reaction, turn on the water ring vacuum pump, adjust the vacuum degree to 0.02-0.03MPa, and adjust the reaction temperature in two steps.

[0088] In the first step, the microwave power was set to 400 W and the temperature was maintained at 122 °C for 14 min.

[0089] Step 2: Set the microwave power to 500W and wait for the temperature to reach 138°C for 7 minutes. During the operation, pay attention to the gas discharge from the interface between the three-way pipe and the condenser and the inner tube of the condenser. If no gas is discharged, check the pH value of the solution in the ammonia absorption bottle for no obvious change within 2 minutes, and continue the reaction for 1 minute. The reaction is over. Turn off the power of the microwave reactor.

[0090] 4. The reaction solution was cooled to below 50°C, ethanol obtained by filtration of the crystallization in Example 1 was added, 95% ethanol was added to 108 g, 0.4 g of 50% potassium thiram liquid was added, magnetic stirring was performed for 35 minutes, filtration was performed, and the obtained solid was washed with ethanol to obtain ammonium chloride as a by-product;

[0091] Put the filtrate obtained by suction filtration into a three-necked flask, slowly heat and evaporate, collect the condensate with a gas phase temperature of 76-78℃ as ethanol for further reuse; when the gas phase temperature exceeds 78.0℃, turn off the heating, change the normal pressure evaporation to reduced pressure evaporation, and adjust the vacuum degree to 0.06MPa during reduced pressure evaporation. Turn on the heating when the gas phase temperature begins to drop, and continue evaporation at the set vacuum degree. When the gas phase temperature reaches 40℃, cool the material in the three-necked flask to below 40℃ under vacuum, and turn off the vacuum pump.

[0092] 5. Add the ethanol recovered by evaporation in Example 1 to the cooled three-necked flask, add 95% ethanol to 110 g, start stirring, heat and raise the temperature, control the temperature in the three-necked flask to 60°C, and keep it under reflux for 45 minutes. Cool the material in the three-necked flask to 12°C with frozen brine, filter it with suction, and reuse the filtrate; dry the obtained crystals at no more than 40°C to obtain 29.1 g of finished product. The melting point of the prepared sample is 50.3°C, the purity is 99.41%, and the calculated yield is 93.29%.

[0093] Example 3

[0094] 1. Weigh 34.5 g of cysteamine hydrochloride and 20.3 g of urea, grind them to a particle size of 100 mesh in a mortar, mix them, put the ground materials into a three-necked round-bottom flask with a magnetic stirrer, and place the round-bottom flask in a microwave reactor. Assemble the round-bottom flask, three-way pipe, condenser tube, ammonia receiving bottle (a certain amount of water has been added to the bottle), vacuum buffer bottle, and water ring vacuum pump;

[0095] 2. Carefully check the instrument connection status, and after confirming that it is correct, turn on the power of the microwave reactor, set the microwave power to 200W and heat for a period of time until all the solid materials are melted into liquid, and the temperature displayed on the thermometer of the three-necked round-bottom flask is 70-80℃.

[0096] 3. When it is observed that all the materials in the round-bottom flask have turned into liquid, start the temperature reaction, turn on the water ring vacuum pump, adjust the vacuum degree to 0.02-0.03MPa, and adjust the reaction temperature in two steps.

[0097] The first step was to set the microwave power to 400 W and wait until the temperature reached 125 °C and maintain it for 12 min;

[0098] Step 2: Set the microwave power to 500W and wait for the temperature to reach 136°C for 9 minutes. During the operation, pay attention to the gas discharge from the interface between the three-way pipe and the condenser and the inner tube of the condenser. If no gas is discharged, check the pH value of the solution in the ammonia absorption bottle for no obvious change within 2 minutes, and continue the reaction for 1.5 minutes. The reaction is over. Turn off the power of the microwave reactor.

[0099] 4. The reaction solution was cooled to below 50°C, ethanol obtained by filtration of the crystallization in Example 2 was added, 95% ethanol was added to 111 g, 0.5 g of 50% potassium thiram liquid was added, magnetic stirring was performed for 20 minutes, filtration was performed, and the obtained solid was washed with ethanol to obtain ammonium chloride as a by-product;

[0100] Put the filtrate obtained by suction filtration into a three-necked flask, slowly heat and evaporate, collect the condensate with a gas phase temperature of 76-78℃ as ethanol for further reuse; when the gas phase temperature exceeds 78.0℃, turn off the heating, change the normal pressure evaporation to reduced pressure evaporation, and adjust the vacuum degree to 0.06MPa during reduced pressure evaporation. Turn on the heating when the gas phase temperature begins to drop, and continue evaporation at the set vacuum degree. When the gas phase temperature reaches 40℃, cool the material in the three-necked flask to below 40℃ under vacuum, and turn off the vacuum pump.

[0101] 5. Add the ethanol recovered by evaporation in Example 2 to the cooled three-necked flask, add 95% ethanol to 106 g, start stirring, heat and raise the temperature, control the temperature in the three-necked flask to 55°C, and keep it under reflux for 55 minutes. The material in the three-necked flask is cooled by 12°C with frozen brine, filtered by suction, and the filtrate is reused; the obtained crystals are dried at no more than 40°C to obtain 29.4 g of the finished product. The melting point of the prepared sample is 50.0°C, the purity is 99.36%, and the calculated yield is 94.21%.

[0102] Example 4

[0103] 1. Weigh 34.5 g of cysteamine hydrochloride and 20.7 g of urea, grind them to a particle size of 50 mesh in a mortar, mix them, put the ground materials into a three-necked round-bottom flask with a magnetic stirrer, and place the round-bottom flask in a microwave reactor. Assemble the round-bottom flask, three-way pipe, condenser tube, ammonia receiving bottle (quantitative water has been added to the bottle), vacuum buffer bottle, and water ring vacuum pump;

[0104] 2. Carefully check the instrument connection status, and after confirming that it is correct, turn on the power of the microwave reactor, set the microwave power to 200W and heat for a period of time until all the solid materials are melted into liquid, and the temperature displayed on the thermometer of the three-necked round-bottom flask is 70-80℃.

[0105] 3. When it is observed that all the materials in the round-bottom flask have turned into liquid, start the temperature reaction, turn on the water ring vacuum pump, adjust the vacuum degree to 0.02-0.03MPa, and adjust the reaction temperature in two steps.

[0106] The first step was to set the microwave power to 400 W and wait until the temperature reached 130 °C and maintain it for 10 min;

[0107] Step 2: Set the microwave power to 500W and wait for the temperature to reach 135°C for 6 minutes. During the operation, pay attention to the gas discharge from the interface between the three-way pipe and the condenser and the inner tube of the condenser. If no gas is discharged, check the pH value of the solution in the ammonia absorption bottle for 2 minutes without obvious changes, and continue the reaction for 2 minutes. The reaction is over. Turn off the power of the microwave reactor.

[0108] 4. The reaction solution was cooled to below 50°C, ethanol obtained by filtration of the crystallization in Example 3 was added, 95% ethanol was added to 116 g, 0.5 g of 50% potassium thiram liquid was added, magnetic stirring was performed for 40 minutes, and filtration was performed. The obtained solid was washed with ethanol to obtain ammonium chloride as a by-product;

[0109] Put the filtrate obtained by suction filtration into a three-necked flask, slowly heat and evaporate, collect the condensate with a gas phase temperature of 76-78℃ as ethanol for further reuse; when the gas phase temperature exceeds 78.0℃, turn off the heating, change the normal pressure evaporation to reduced pressure evaporation, and adjust the vacuum degree to 0.07MPa during reduced pressure evaporation. Turn on the heating when the gas phase temperature begins to drop, and continue evaporation at the set vacuum degree. When the gas phase temperature reaches 40℃, cool the material in the three-necked flask to below 40℃ under vacuum, and turn off the vacuum pump.

[0110] 5. Add the ethanol recovered by evaporation in Example 3 to the cooled three-necked flask, add 95% ethanol to 115 g, start stirring, heat and raise the temperature, control the temperature in the three-necked flask to 60°C, and keep it under reflux for 60 minutes. Cool the material in the three-necked flask to 14°C with frozen brine, filter it with suction, and reuse the filtrate; dry the obtained crystals at no more than 40°C to obtain 28.20 g of finished product. The melting point of the prepared sample is 49.5°C, the purity is 99.33%, and the calculated yield is 90.35%.

[0111] Example 5

[0112] 1. Weigh 34.5 g of cysteamine hydrochloride and 21.3 g of urea, grind them to a particle size of 50 mesh in a mortar, mix them, put the ground materials into a three-necked round-bottom flask with a magnetic stirrer, and place the round-bottom flask in a microwave reactor. Assemble the round-bottom flask, three-way pipe, condenser tube, ammonia receiving bottle (quantitative water has been added to the bottle), vacuum buffer bottle, and water ring vacuum pump.

[0113] 2. Carefully check the instrument connection status, and after confirming that it is correct, turn on the power of the microwave reactor, set the microwave power to 200W and heat for a period of time until all the solid materials are melted into liquid, and the temperature displayed on the thermometer of the three-necked round-bottom flask is 70-80℃.

[0114] 3. When it is observed that all the materials in the round-bottom flask have turned into liquid, start the temperature reaction, turn on the water ring vacuum pump, adjust the vacuum degree to 0.02-0.03MPa, and adjust the reaction temperature in two steps.

[0115] In the first step, the microwave power was set to 400 W and the temperature was maintained at 128 °C for 10 min.

[0116] Step 2: Set the microwave power to 500W and wait for the temperature to reach 149°C for 6 minutes. During the operation, pay attention to the gas discharge from the interface between the three-way pipe and the condenser and the inner tube of the condenser. If no gas is discharged, check the pH value of the solution in the ammonia absorption bottle for no obvious change within 2 minutes, and continue the reaction for 3 minutes. The reaction is over. Turn off the power of the microwave reactor.

[0117] Step 4, cooling the reaction solution to below 50°C, adding ethanol obtained by filtration of the crystallization in Example 4, adding 95% ethanol to 117 g, adding 0.5 g of 50% potassium thiram liquid, stirring magnetically for 35 minutes, filtering, washing the obtained solid with ethanol, and obtaining ammonium chloride as a by-product;

[0118] Put the filtrate obtained by suction filtration into a three-necked flask, slowly heat and evaporate, collect the condensate with a gas phase temperature of 76-78℃ as ethanol for further reuse; when the gas phase temperature exceeds 78.0℃, turn off the heating, change the normal pressure evaporation to reduced pressure evaporation, and adjust the vacuum degree to 0.05MPa during reduced pressure evaporation. Turn on the heating when the gas phase temperature begins to drop, and continue evaporation at the set vacuum degree. When the gas phase temperature reaches 40℃, cool the material in the three-necked flask to below 40℃ under vacuum, and turn off the vacuum pump.

[0119] 5. Add the ethanol recovered by evaporation in Example 4 to the cooled three-necked flask, add 95% ethanol to 120 g, start stirring, heat and raise the temperature, control the temperature in the three-necked flask to 50°C, and keep it under reflux for 60 minutes. The material in the three-necked flask is cooled to 15°C with frozen brine, filtered, and the filtrate is reused; the obtained crystals are dried at no more than 40°C to obtain 26.51 g of finished product. The melting point of the prepared sample is 51.1°C, the purity is 99.32%, and the calculated yield is 86.07%.

[0120] The product of Example 5 was subjected to liquid chromatography analysis. Figure 2 shown.

[0121] The main chromatographic conditions for liquid phase detection are: chromatographic column: Agilent ZORBAX SB-C18 (4.6mm×250mm, 5μm); detection wavelength: 220nm; column temperature: 30℃; mobile phase: methanol+water=35:65 (volume ratio); flow rate: 1.0mL / min; injection volume: 20μL.

[0122] All indicators of the product in Example 5 were analyzed, and the results are shown in Table 1:

[0123] Table 1 Product quality indicators prepared in Example 5

[0124] project index Analyze the results Appearance White crystals White crystal Content (HPLC external standard), % ≧ 99.0 99.32 Moisture,%≤ 0.3 0.19 Ash content, %≤ 0.3 0.13 Melting point, °C 49-52 51.1 Water Solubility Completely soluble, transparent clear solution pH value (5% aqueous solution) 9.0-11.0 9.8 <![CDATA[Iron ions (calculated as Fe 3+ ), 10 -6 > — 14

[0125] The ethanol used in Examples 2 to 5 is the ethanol recovered by evaporation and filtration in the previous example. The purity and yield of the obtained finished product are relatively high after one or two applications. However, it is not difficult to see from the melting point data that the melting points of Examples 2 to 5 show an upward trend, which is consistent with the decrease in the product purity value. The ethanol obtained by filtration is a saturated 1,3-thiazol-2-one solution. When it is used for the next time, part of the 1,3-thiazol-2-one will precipitate, so the product yields obtained in Examples 2 to 5 are all higher than those in Example 1.

[0126] Example 6

[0127] The material ratio, process parameters and operation are the same as those in Example 5, except that the ethanol obtained by evaporation recovery and suction filtration in Steps 4 and 5 is used as follows:

[0128] Step 4, cooling the reaction solution to below 50°C, adding ethanol obtained by filtration of the crystallization in Example 5, adding 95% ethanol to 117 g, adding 0.5 g of 50% potassium thiram liquid, stirring magnetically for 35 minutes, filtering, washing the obtained solid with ethanol, and obtaining ammonium chloride as a by-product;

[0129] Step 5: Add the ethanol recovered by evaporation in Example 5 and add 95% ethanol to 120 g into the cooled three-necked flask, and perform the remaining operations in the same manner.

[0130] The obtained product is 25.85 g. The melting point of the prepared sample is 51.2°C, the purity is 99.22%, and the calculated yield is 82.73%.

[0131] Example 7

[0132] The material ratio, process parameters and operation are the same as those in Example 5, except that the ethanol obtained by evaporation recovery and suction filtration in Steps 4 and 5 is as follows:

[0133] Step 4, cooling the reaction solution to below 50°C, adding ethanol obtained by filtration of the crystallization in Example 6, adding 95% ethanol to 117 g, adding 0.4 g of 50% potassium thiram liquid, stirring magnetically for 35 minutes, filtering, washing the obtained solid with ethanol, and obtaining ammonium chloride as a by-product;

[0134] Step 5: Add the ethanol recovered by evaporation in Example 6 into the cooled three-necked flask and add 95% ethanol to 120 g, and perform the remaining operations in the same manner.

[0135] The obtained product is 27.06 g. The melting point of the prepared sample is 51.4°C, the purity is 99.16%, and the calculated yield is 86.54%.

[0136] Example 8

[0137] The material ratio, process parameters and operation are the same as those in Example 5, except that the ethanol obtained by evaporation recovery and suction filtration in Steps 4 and 5 is as follows:

[0138] Step 4, cooling the reaction solution to below 50°C, adding ethanol obtained by filtration of the crystallization in Example 7, adding 95% ethanol to 117 g, adding 0.5 g of 50% potassium thiram liquid, stirring magnetically for 35 minutes, filtering, washing the obtained solid with ethanol, and obtaining ammonium chloride as a by-product;

[0139] Step 5: Add the ethanol recovered by evaporation in Example 7 into the cooled three-necked flask and add 95% ethanol to 120 g, and perform the remaining operations in the same manner.

[0140] The obtained product is 25.80 g. The melting point of the prepared sample is 51.4°C, the purity is 99.11%, and the calculated yield is 82.47%.

[0141] Example 9

[0142] The material ratio, process parameters and operation are the same as those in Example 5, except that the ethanol obtained by evaporation recovery and suction filtration in Steps 4 and 5 is as follows:

[0143] Step 4, the reaction solution was cooled to below 50°C, ethanol obtained by filtration of the crystallization in Example 8 was added, 95% ethanol was added to 117 g, 0.5 g of 50% potassium thiram liquid was added, magnetic stirring was performed for 35 minutes, filtration was performed, and the obtained solid was washed with ethanol to obtain ammonium chloride as a by-product;

[0144] Step 5: Add the ethanol recovered by evaporation in Example 8 and add 95% ethanol to 120 g into the cooled three-necked flask, and perform the remaining operations in the same manner.

[0145] The obtained product is 25.70 g. The melting point of the prepared sample is 51.6°C, the purity is 99.05%, and the calculated yield is 82.11%.

[0146] Example 10

[0147] The material ratio, process parameters and operation are the same as those in Example 5, except that the ethanol obtained by evaporation recovery and suction filtration in Steps 4 and 5 is as follows:

[0148] Step 4, cooling the reaction solution to below 50°C, adding ethanol obtained by filtration of crystallization in Example 9, adding 95% ethanol to 117 g, adding 0.5 g of 50% potassium thiram liquid, stirring magnetically for 35 minutes, filtering, washing the obtained solid with ethanol, and obtaining ammonium chloride as a by-product;

[0149] Step 5: Add the ethanol recovered by evaporation in Example 9 into the cooled three-necked flask and add 95% ethanol to 120 g, and perform the remaining operations in the same manner.

[0150] The obtained product is 26.32 g. The melting point of the prepared sample is 51.6°C, the purity is 99.03%, and the calculated yield is 84.07%.

[0151] Embodiment 11

[0152] The material ratio, process parameters and operation are the same as those in Example 5, except that the ethanol recovered and filtered in Steps 4 and 5 is used as follows:

[0153] Step 4, cooling the reaction solution to below 50°C, adding ethanol obtained by filtration of the crystallization in Example 10, adding 95% ethanol to 117 g, adding 0.5 g of 50% potassium thiram liquid, stirring magnetically for 35 minutes, filtering, washing the obtained solid with ethanol, and obtaining ammonium chloride as a by-product;

[0154] Step 5: Add the ethanol recovered by evaporation in Example 10 into the cooled three-necked flask and add 95% ethanol to 120 g, and perform the remaining operations in the same manner.

[0155] The obtained product is 25.94 g. The melting point of the prepared sample is 52.1°C, the purity is 98.55%, and the calculated yield is 82.49%.

[0156] The product of Example 11 was subjected to liquid chromatography analysis. Figure 3 .

[0157] The main chromatographic conditions for liquid phase detection are the same as those in Example 5.

[0158] All indicators of the product in Example 11 were analyzed, and the results are shown in Table 2.

[0159] Table 2 Product quality indicators prepared in Example 11

[0160]

[0161]

[0162] From the analysis results of Example 11, it can be seen that after the extractant ethanol was used 10 times, the prepared product was unqualified, especially the content was reduced, the ash content was increased, and the iron ion content was increased. This is mainly because after the extractant was used multiple times, the impurities dissolved by the original extractant were gradually accumulated in the finished product.

[0163] Analyzing Examples 6 to 11, after multiple applications of ethanol, the purity and yield of the prepared finished products are on a downward trend, especially after ten applications (Example 11), the purity of the product is lower than 99.0%. In the evaporation stage of the reaction solution, some impurities remain in the material obtained by evaporation; impurities also remain in the mother liquor obtained by filtration during the recrystallization stage. The more times of application, the more impurities dissolved and gradually accumulated in ethanol. Under the same operating conditions, they must precipitate with the finished product, reducing the product content. Despite this, the ethanol obtained by suction filtration is a saturated 1,3-tetrahydrothiazol-2-one solution. When used for the next time, part of the 1,3-tetrahydrothiazol-2-one will precipitate, so the product yields obtained in Examples 6 to 11 are all higher than those in Example 1, but the purity is reduced.

[0164] Comparative Example 1,

[0165] The raw materials cysteamine hydrochloride and urea were weighed and used directly in the synthesis reaction without any treatment. The material ratio, process parameters and operation were exactly the same as those in Example 1.

[0166] The method was used to obtain 25.13 g of the finished product. The melting point of the prepared sample was 51.1°C, the purity was 99.05%, and the calculated yield was 80.27%.

[0167] Comparative Example 2,

[0168] The raw material cysteamine hydrochloride and urea were directly used for the synthesis reaction without any treatment, and the material ratio, process parameters and operation were basically the same as those in Example 1. The difference was that the reaction time of the first and second steps in operation step 3 was extended, and the other operations remained unchanged.

[0169] Step 3: When it is observed that all the materials in the round-bottom flask have turned into liquid, the temperature reaction is started, the water ring vacuum pump is turned on, the vacuum degree is adjusted to 0.02 MPa, and the reaction temperature is adjusted in two steps.

[0170] The first step was to set the microwave power to 400 W and wait until the temperature reached 120 °C for 15 min;

[0171] In the second step, the microwave power was set to 500 W and the temperature was maintained at 140°C for 8 min.

[0172] The method was used to obtain 25.20 g of the finished product. The melting point of the prepared sample was 49.9°C, the purity was 99.07%, and the calculated yield was 80.52%.

[0173] The data of Example 1, Comparative Example 1 and Comparative Example 2 are analyzed. The raw materials cysteamine hydrochloride and urea in Comparative Example 1 are directly reacted without grinding treatment, and the yield and purity of the obtained finished product are decreased; Comparative Example 2 shows that the raw materials are not pretreated, and the reaction time is extended without improving the yield and purity of the finished product. However, the raw materials are ground, and the particle size of the materials becomes finer. Under the same conditions, the melting of the small particles of the materials is relatively faster than that of the large particles. Grinding also substantially increases the mixing degree of the two materials, which is conducive to increasing the collision probability after melting and accelerating the reaction. Therefore, it is beneficial to pretreat the materials.

[0174] Comparative Example 3: Synthesis of 1,3-tetrahydrothiazol-2-one by conventional heating

[0175] According to the process route proposed in the Chinese patent (CN 110563666 A), the difference from the present invention is that: (1) cysteamine hydrochloride and urea are added at a molar ratio of 1:1.5; (2) 95% ethanol is used instead of toluene, and other process parameters and operation procedures are exactly the same as those in CN 110563666 A. 34.5 g of cysteamine hydrochloride and 27.36 g of urea are added, and the extraction and subsequent operations are exactly the same as those proposed in CN 110563666 A.

[0176] The method was used to obtain 22.17 grams of the finished product. The melting point of the prepared sample was 52.4°C, the purity was 98.27%, and the calculated yield was 70.26%.

[0177] Comparative Example 3 is compared and analyzed with Example 1. The addition amount of cysteamine hydrochloride is the same but the addition amount of urea is very different. The purity and yield of the obtained products are very different and the melting point of the product is relatively high, which highlights the technical advantages of the present invention.

[0178] The existing production process for preparing 1,3-thiazol-2-one using cysteamine hydrochloride and urea as raw materials, an intermittent synthesis reactor, and a condensation reaction has the following main problems: (1) even if the two materials in the same synthesis reactor are completely melted under the reaction conditions, the mixing is uneven. In the actual reaction process, the composition of the materials at the bottom, middle, and top of the synthesis reactor is quite different, and the radial distribution of the material composition on the same interface is quite different; (2) the reaction temperature is too high. If the temperature is too high, side reactions are likely to occur, and local overheating of the materials in the reactor is likely to occur, which has the direct impact of: (3) too much excess urea, under the reaction conditions, urea will inevitably undergo side reactions such as condensation and polycondensation, generating a variety of by-products with complex structures, which brings certain difficulties to the subsequent purification of the finished product; (4) the product purity is low, generally maintained at 96% to 98%; (5) the product yield is low, and the product yield obtained by the existing technology generally does not exceed 80%; (6) the energy consumption is high and the production cost is high. In view of the above problems, the present invention adopts microwave heating instead of conventional heating (which requires a sufficiently long reaction time to control the reaction rate and heat transfer rate) to synthesize 1,3-tetrahydrothiazol-2-one from cysteamine hydrochloride and urea under solvent-free and catalyst-free conditions, and conducts in-depth research on product purification to form a complete production process. The microwave heating synthesis method has attracted more and more attention due to its advantages of being fast, convenient, environmentally friendly, and energy-saving, and is also in line with the modern scientific development concept of green chemistry. The research results show that this method is suitable for the synthesis of 1,3-tetrahydrothiazol-2-one.

[0179] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing 1,3-tetrahydrothiazol-2-one using a microwave reactor, characterized in that: include: The raw materials cysteamine hydrochloride and urea are ground and fully mixed, added into a reaction container, placed in a microwave reactor, and heated to react under stirring; after the reaction is completed, the reaction liquid is cooled, dissolved, extracted, and filtered with an extractant, and the solid material is cooled, recrystallized, and dried to obtain the finished product 1,3-tetrahydrothiazol-2-one.

2. The method for preparing 1,3-tetrahydrothiazol-2-one using a microwave reactor according to claim 1, characterized in that: The specific steps include: S1. Raw material pretreatment, The raw materials cysteamine hydrochloride and urea are weighed and ground, mixed thoroughly, and ground into a particle size of 30-100 mesh; S2, condensation reaction, Put the ground material into a reaction container, and place the reaction container in a microwave reactor; connect the outlet of the reaction container to a three-way pipe, a condenser, an ammonia receiving bottle, a vacuum receiving bottle, and a water ring vacuum pump in sequence; heat under microwave for a period of time until all the solid materials are melted into liquid at a temperature of 70-80°C; start heating reaction, and adjust the reaction temperature in two steps; S3, extraction and evaporation; S4, recrystallization and drying.

3. The method for preparing 1,3-tetrahydrothiazol-2-one using a microwave reactor according to claim 2, characterized in that: In step S1, the molar ratio of cysteamine hydrochloride to urea is 1:1.05-1.

15.

4. The method for preparing 1,3-tetrahydrothiazol-2-one using a microwave reactor according to claim 2, characterized in that: The two-step adjustment process of the reaction temperature in step S2 includes: The first step is to adjust the microwave power and control the reaction temperature to 120-130°C for 10-15 minutes; The second step is to adjust the microwave power and control the reaction temperature to 135-140°C for 5-10 minutes.

5. The method for preparing 1,3-tetrahydrothiazol-2-one using a microwave reactor according to claim 2, characterized in that: The method for determining the reaction endpoint of step S2 is as follows: observe the interface between the three-way pipe and the condenser and the inner tube of the condenser to see if there is any visual gas discharge; and at the same time, detect that the pH value of the solution in the ammonia absorption bottle has no obvious change within 2 minutes.

6. The method for preparing 1,3-tetrahydrothiazol-2-one using a microwave reactor according to claim 2, characterized in that: In step S3, the extractant is 95% ethanol; The mass ratio of 95% ethanol to cysteamine hydrochloride is 1:3.05-3.

21.

7. The method for preparing 1,3-tetrahydrothiazol-2-one using a microwave reactor according to claim 2, characterized in that: In step S3, the reaction solution is cooled to below 50°C, 95% ethanol is added, and iron removal agent liquid sodium fumei is added, magnetic stirring is performed for 20-40 minutes, and suction filtration is performed.

8. The method for preparing 1,3-tetrahydrothiazol-2-one using a microwave reactor according to claim 2, characterized in that: In step S3, the filtrate obtained by filtration is heated and evaporated, and the condensate with a gas phase temperature of 76-78° C. is collected, and the ethanol is continuously reused; when the gas phase temperature exceeds 78° C., the heating is turned off, and the normal pressure evaporation is changed to reduced pressure evaporation, and the vacuum degree during the reduced pressure evaporation is adjusted to 0.05 MPa-0.07 MPa; when it is observed that the gas phase temperature begins to drop, the heating is turned on, and the evaporation is continued at the set vacuum degree; when the gas phase temperature reaches 40° C., the material is cooled to below 40° C. with cooling water under vacuum, and the vacuum pump is turned off.

9. The method for preparing 1,3-tetrahydrothiazol-2-one using a microwave reactor according to claim 2, characterized in that: In step S4, 95% ethanol is added to the cooled reaction container, and the temperature is raised to control the temperature in the reaction container to 55-60° C., and maintained under reflux for 40-60 minutes.

10. The method for preparing 1,3-tetrahydrothiazol-2-one using a microwave reactor according to claim 2, characterized in that: The product is cooled and filtered with frozen brine, and the filtrate is recycled; the obtained crystals are dried at a temperature not higher than 40°C to obtain the finished product.

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