Synthesis method of 1-tert-butyl-3-ethyl carbodiimide

Abstract

The invention provides a synthesis method of 1-tert-butyl-3-ethyl carbodiimide, which comprises the following steps of: synthesizing 1-tert-butyl-3-ethyl carbodiimide; the method is mild in reaction condition, simple in step and environment-friendly, and high-yield and high-purity synthesis of a target product can be realized. The synthesis method comprises the following steps: (1) carrying out an addition reaction on ethyl isothiocyanate and tert-butylamine in an organic solvent I at 30-60 DEG C to obtain ethyl tert-butyl thiourea; the organic solvent I is selected from one or more of petroleum ether, normal hexane and normal heptane; (2) carrying out oxidative desulfurization reaction on the ethyl tert-butyl thiourea and a sodium hypochlorite aqueous solution with the concentration of 10-15wt% in an organic solvent II at the temperature of 0-10 DEG C; removing sulfur generated in the reaction, and then purifying the feed liquid to obtain 1-tert-butyl-3-ethylcarbodiimide; and the organic solvent II is selected from halogenated hydrocarbon.

Description

Technical Field

[0001] This invention relates to the field of preparation technology of 1-tert-butyl-3-ethylcarbodiimide, and specifically to a method for synthesizing 1-tert-butyl-3-ethylcarbodiimide. Background Technology

[0002] 1-Tert-Butyl-3-ethylcarbodimide (TBEC) is a very useful dehydration condensation agent. Its most notable feature is that the urea byproduct generated in the reaction has extremely low solubility in diethyl ether and ethyl acetate, and can be removed from the reaction system by simple filtration. This property gives it a unique purification advantage in liquid-phase synthesis, making it particularly suitable for synthetic processes where the simplicity of purification procedures is crucial.

[0003] CN109369459A discloses a method for producing N,N'-di-tert-butylcarbodiimide using the thiourea process. This method first synthesizes N,N'-di-tert-butylthiourea from tert-butylamine and carbon disulfide in an aqueous medium. The N,N'-di-tert-butylthiourea is then filtered, dried, and subjected to a first oxidation process. A caustic soda, solvent, and catalyst are added sequentially to a reaction vessel, and the temperature is raised to 60-65°C. An oxidant is added, and the reaction is carried out at 60-65°C for 2 hours, followed by a 20-25 minute settling period. The lower aqueous phase is discarded. A second oxidation reaction is then performed, with a measured amount of oxidant and catalyst added dropwise. The reaction is carried out at 65°C for 1 hour. After neutralization with alkali and washing with water, the aqueous layer is separated, the solvent is distilled off, and the N,N'-di-tert-butylcarbodiimide is obtained by vacuum distillation. This method requires the use of hydrogen peroxide, two oxidation steps, and the combined use of a catalyst, making it cumbersome and costly. CN112250600A and CN103382168B both use the thiourea method, employing hydrogen peroxide and sodium hydrosulfide as secondary oxidizing agents, which involves complex operation and high technical requirements.

[0004] CN104193654B1 discloses a method for preparing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, the steps of which are as follows: (1) N,N'-dimethylpropanediamine and carbon disulfide are used as raw materials and reacted in an organic solvent at 10~15℃ to generate intermediate 1; (2) intermediate 1 is reacted with ethyl chloroformate in an organic solvent at 10~15℃, and triethylamine is used as an acid-binding agent to obtain intermediate 2; (3) intermediate 2 is reacted with ethylamine in an organic solvent at 10~15℃ to obtain intermediate 3; (4) EDTA or TEBA catalyst is added to intermediate 3 and oxidized once with an oxidant at 20~30℃ to obtain crude 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, which is then extracted and separated to obtain intermediate 4; (5) intermediate 4 is reacted with hydrochloride to obtain the product 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The purpose of this process is to improve the yield of EDC hydrochloride, and a phase transfer catalyst needs to be added in step (4) of this process. JP1996198836A discloses a method for preparing 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, which mentions that potassium hydroxide needs to be added to the reaction system to improve the yield, and a phase transfer catalyst needs to be added to make the desulfurization reaction proceed appropriately. Its oxidation reaction is a three-phase system, and the reaction process has drawbacks such as violent exothermic reaction and uncontrollable reaction.

[0005] In the existing technology, it is necessary to develop a new synthetic process for 1-tert-butyl-3-ethylcarbodiimide to achieve both high yield and high purity, and to have the advantages of mild reaction conditions, simple steps, and good reaction safety. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides a method for synthesizing 1-tert-butyl-3-ethylcarbodiimide. The method of this invention features mild reaction conditions, simple steps, and environmental friendliness, and can achieve high yield and high purity synthesis of the target product.

[0007] To achieve its objective, the present invention provides the following technical solution: This invention provides a method for synthesizing 1-tert-butyl-3-ethylcarbodiimide, comprising the following steps: (1) Ethyl isothiocyanate and tert-butylamine are added in organic solvent I at 30-60°C to obtain ethyl tert-butylthiourea; wherein organic solvent I is selected from one or more of petroleum ether, n-hexane, n-heptane, n-pentane, isopentane, n-octane, and isooctane; (2) The ethyl tert-butylthiourea is reacted with a sodium hypochlorite aqueous solution of 10-15 wt% in organic solvent II at 0-10 °C to undergo an oxidative desulfurization reaction; the sulfur produced by the reaction is removed, and then the solution is purified to obtain 1-tert-butyl-3-ethylcarbodiimide; the organic solvent II is selected from halogenated hydrocarbons.

[0008] Preferably, step (1) specifically includes the following operations: mixing ethyl isothiocyanate and the organic solvent I, heating to 30~35°C; then adding tert-butylamine, and then maintaining the temperature at 40~60°C for reaction; Preferably, the tert-butylamine is added by dripping, and the temperature is preferably controlled to be ≤40°C during the dripping process.

[0009] Preferably, in step (1), after the reaction is complete, the reaction solution is cooled to 10~15℃, then the solid and liquid are separated, and the obtained solid phase is dried to obtain ethyl tert-butylthiourea; Preferably, the liquid phase obtained from the solid-liquid separation can be reused as the organic solvent I in step (1).

[0010] Preferably, step (2) specifically includes the following operations: mixing ethyl tert-butylthiourea and the organic solvent II, and cooling to 0~5℃, then adding the sodium hypochlorite aqueous solution dropwise. Preferably, the temperature is controlled at 0~10℃ when adding the sodium hypochlorite aqueous solution dropwise. After the dropwise addition is completed, the reaction solution is kept warm, and the starch potassium iodide test paper turns blue, indicating that the reaction has reached its endpoint.

[0011] Preferably, in step (1), the organic solvent I is one or more of petroleum ether, n-hexane, and n-heptane, more preferably petroleum ether; And / or, the organic solvent II mentioned in step (2) is one or more of dichloromethane, trichloromethane, dichloroethane, and carbon tetrachloride.

[0012] Optionally, in step (2), the concentration of the sodium hypochlorite aqueous solution is 10~12wt% or 12~15wt%, more preferably 12wt%.

[0013] Preferably, in step (2), after the reaction is complete, the reaction solution is filtered to remove the sulfur produced by the reaction. Then the filtrate is allowed to stand and separate into layers to obtain an organic layer I and an aqueous layer I. The aqueous layer I is extracted with the organic solvent II. The extracted organic layer II is combined with the organic layer I and then concentrated under reduced pressure to obtain crude 1-tert-butyl-3-ethylcarbodiimide. The crude product is then distilled to obtain the 1-tert-butyl-3-ethylcarbodiimide product.

[0014] Preferably, in step (1), the molar ratio of ethyl isothiocyanate to tert-butylamine is 1:1 to 2, preferably 1:1; In step (2), the mass ratio of the ethyl tert-butylthiourea to the sodium hypochlorite aqueous solution is 1:7~9.

[0015] Furthermore, in step (2), no catalyst or inorganic base is added when the oxidative desulfurization reaction is carried out.

[0016] Preferably, in step (1), the ethyl isothiocyanate is prepared by a method comprising the following steps: (a) Add an aqueous solution of ethylamine with a concentration of 68-72 wt% and carbon disulfide dropwise to a mixture of alkali and water at a temperature of 10-15°C, and then stir the reaction solution at 10-30°C. (b) Add sodium carbonate and cyanuric chloride to the reaction solution obtained in step (a), and stir the reaction solution at 20~40°C; monitor the reaction until it is complete, let it stand and separate into layers, and the upper layer is ethyl isothiocyanate.

[0017] Preferably, in step (a), the alkaline solution is a sodium hydroxide aqueous solution with a concentration of 48-52 wt%. And / or, in step (a), the mass ratio of the alkaline solution to the water is 1:4~5, the mass ratio of the ethylamine aqueous solution to the alkaline solution is 1:1~2, and the molar ratio of the carbon disulfide to the ethylamine is 1:0.5~1.1; And / or, the molar ratio of the cyanuric chloride used in step (b) to the ethylamine used in step (a) is 1:1 to 3.5; And / or, in step (b), the molar ratio of the cyanuric chloride to the sodium carbonate is 1:1~2.

[0018] The technical solution provided by this invention has the following beneficial effects: The method for synthesizing 1-tert-butyl-3-ethylcarbodiimide provided by this invention has a reasonable process route design, uses readily available raw materials, has mild reaction conditions and simple steps, and can obtain the target product with high yield and high purity, and can achieve large-scale production.

[0019] In the oxidative desulfurization step of the present invention, sodium hypochlorite is used as the oxidant. Compared with hydrogen peroxide, triphosgene, sulfonyl chloride and other reagents, the reaction is safer and the reagent cost is low and environmentally friendly. Moreover, in step (2) of the present invention, the substrate can be fully oxidized without the addition of a phase transfer catalyst. Sodium hypochlorite decomposes quickly, and excess sodium hypochlorite immediately decomposes into sodium chloride and oxygen. In the reaction system of step (2) of the present invention, the sulfur produced by the reaction will not be over-oxidized.

[0020] The oxidation reaction in step (2) of this invention is a two-phase system, which makes the temperature constant, reaction initiation and reaction rate more controllable; in the preferred embodiment, the main solvent system is a low-boiling-point solvent (such as petroleum ether, chloroform), which is easy to separate and recover, has low energy consumption, is conducive to improving the reaction rate, and is easy to control and switch. Attached Figure Description

[0021] Figure 1 TBEC prepared in Example 3 1 H-NMR spectrum. Detailed Implementation

[0022] To facilitate understanding of the present invention, the following description, in conjunction with embodiments, will further illustrate the invention. It should be understood that the following embodiments are merely for a better understanding of the invention and do not imply that the invention is limited to these embodiments.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The term "and / or" may be used herein to include any and all combinations of one or more of the associated listed items.

[0024] This invention provides a method for synthesizing 1-tert-butyl-3-ethylcarbodiimide, comprising the following steps: (1) Ethyl isothiocyanate and tert-butylamine are subjected to an addition reaction in organic solvent I at 30~60℃ (e.g. 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, etc.) to obtain ethyl tert-butylthiourea; wherein the organic solvent I is selected from one or more of petroleum ether, n-hexane, n-heptane, n-pentane, isopentane, n-octane, and isooctane, preferably one or more of low polarity petroleum ether, n-hexane, and n-heptane, and more preferably petroleum ether; (2) The ethyl tert-butylthiourea is reacted with an aqueous solution of sodium hypochlorite at a concentration of 10-15 wt% (e.g., 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, etc.) in organic solvent II at 0-10°C (e.g., 0°C, 3°C, 5°C, 7°C, 10°C, etc.) to remove the sulfur produced by the reaction. The solution is then purified to obtain 1-tert-butyl-3-ethylcarbodiimide. The organic solvent II is selected from halogenated hydrocarbons, preferably one or more of dichloromethane, trichloromethane, dichloroethane, and carbon tetrachloride.

[0025] The method for synthesizing 1-tert-butyl-3-ethylcarbodiimide provided by this invention uses simple and readily available raw materials, requires mild reaction conditions, has simple steps, and yields high-purity target products, enabling large-scale production processes.

[0026] In the oxidative desulfurization reaction of step (2) of the present invention, a sodium hypochlorite aqueous solution of a specific concentration and a specific organic solvent II are used. No catalyst (e.g., phase transfer catalyst) or other reagents (e.g., inorganic bases such as potassium hydroxide) are required. The process is simple and the reaction is safe. Elemental sulfur is obtained in this process and can be refined and sold as a by-product sulfur, generating additional economic benefits.

[0027] The inventors have discovered that in the process of preparing 1-tert-butyl-3-ethylcarbodiimide according to the process of the present invention, when the desulfurization oxidation reaction is carried out in step (2), halogenated hydrocarbons such as chloroform are used as organic solvents, and sodium hypochlorite aqueous solution with a concentration of 10~15wt% is used as oxidant. The desulfurization oxidation reaction of ethyltert-butylthiourea is a two-phase system with a relatively constant reaction temperature, and the reaction initiation and reaction rate are more controllable. Moreover, in this reaction system, it is not necessary to add strong bases such as potassium hydroxide, nor is it necessary to add phase transfer catalysts (such as EDTA or TEBA). This can effectively avoid over-oxidation, reduce side reactions, improve yield, and prevent elemental sulfur from being over-oxidized to produce sodium sulfate / potassium sulfate, which is more conducive to the recovery of by-product sulfur and the purification of target product. This invention uses a 10-15 wt% sodium hypochlorite aqueous solution as an oxidant and carries out a desulfurization oxidation reaction in the presence of the aforementioned organic solvent. The removed hydrogen sulfide is a strong reducing agent and is immediately oxidized to elemental sulfur by the oxidant. If a phase transfer catalyst or a strong base such as potassium hydroxide is added to the system, potassium sulfide will be generated and further oxidized to potassium sulfate. The reaction system of this invention can reduce the occurrence of such side reactions, improve the yield of the target product, and achieve a high sulfur recovery rate (up to 95% or more).

[0028] In the process of the present invention, the substrate can be fully oxidized in step (2) without the addition of a phase transfer catalyst, and the sodium hypochlorite decomposes quickly. Excess sodium hypochlorite can be immediately decomposed into sodium chloride and oxygen, and the sulfur element dispersed in the organic phase of the system will not be over-oxidized.

[0029] In step (2) of this invention, organic solvent II is a halogenated hydrocarbon with a low boiling point and relatively high polarity. Compared with other solvents, the oxidation reaction is easier to carry out, which helps to reduce the reaction risk. At the same time, it facilitates post-processing extraction, layering and distillation purification.

[0030] The reaction pathway of the 1-tert-butyl-3-ethylcarbodiimide of this invention is shown below:

[0031] In this invention, the concentration of the sodium hypochlorite aqueous solution used in step (2) is 10-15 wt%, optionally 10-12 wt% or 12-15 wt%, more preferably 12 wt%. If the concentration is too low, too much wastewater will be generated, which is uneconomical and environmentally unfriendly. If the concentration is too high, the decomposition during the reaction is too violent, and the reagent itself is not easy to store. The inventors have found that using a sodium hypochlorite aqueous solution of the preferred concentration in the process of this invention can take into account both a high yield and purity of the target product and a high sulfur recovery rate.

[0032] Preferably, step (1) specifically includes the following operations: mixing ethyl isothiocyanate and organic solvent I, heating to 30~35℃; then adding tert-butylamine, and then maintaining the reaction at 40~60℃. The reaction endpoint can be monitored using conventional monitoring methods in the art, such as HPLC monitoring, until the conversion rate of ethyl isothiocyanate is ≥99.5%. In some examples, the reaction time is 12~15h. Tert-butylamine can be added all at once, in multiple portions, or by dropping, without particular limitation; in some preferred embodiments, the tert-butylamine is added by dropping, preferably with the temperature controlled ≤40℃ during the dropping process.

[0033] Preferably, in step (1), after the reaction is complete, the reaction liquid is cooled to 10~15℃, and then solid-liquid separation is performed (e.g., centrifugation, filtration, etc.). The obtained solid phase is dried (e.g., vacuum drying, etc.) to obtain ethyl tert-butylthiourea. Preferably, in step (1), the liquid phase obtained from the solid-liquid separation can be reused directly as the organic solvent I without further processing.

[0034] In step (1) of this invention, petroleum ether, n-hexane, and n-heptane are preferably used as solvents. These solvents are low-polarity organic solvents. Reacting in such solvents can increase the reaction rate and reduce side reactions. Furthermore, ethyl tert-butylthiourea has extremely low solubility in these solvents, facilitating solid-liquid separation. The separated liquid phase can be reused in step (1). Using the preferred solvents, compared to using other solvents, under essentially the same conditions, can achieve both higher yields and purity of the target product. For example, compared to using toluene, the preferred solvents of this invention are not only less toxic but also facilitate achieving both higher yields and purity of the target product. More preferably, the organic solvent I is petroleum ether.

[0035] Preferably, step (2) specifically includes the following operations: mixing ethyl tert-butylthiourea and the organic solvent II, and cooling to 0~5°C, then adding the sodium hypochlorite aqueous solution dropwise; preferably, the temperature is controlled at 0~10°C when adding the sodium hypochlorite aqueous solution dropwise; after the dropwise addition is completed, the reaction solution is kept warm, and the reaction endpoint is reached when potassium iodide test paper turns blue during the reaction process, and the warming reaction time is, for example, 2 hours. The dropping rate of the sodium hypochlorite aqueous solution can vary within a wide range, and those skilled in the art can make conventional adjustments according to the actual situation such as the reaction scale and equipment conditions. The usual dropping time can be, for example, 1~24 hours, preferably 2~8 hours; when adding the sodium hypochlorite aqueous solution dropwise, it can be added as slowly as possible to avoid exothermic effects.

[0036] Preferably, in step (2), after the reaction is complete, the reaction solution is filtered to remove the sulfur produced by the reaction. Then, the filtrate is allowed to stand and separate into layers to obtain an organic layer I and an aqueous layer I. The aqueous layer I is extracted with the organic solvent II. The volume ratio of the aqueous layer I to the organic solvent II can be, for example, 4~7:1 (specifically, 5:1, etc.). The extracted organic layer II is combined with the organic layer I and then concentrated under reduced pressure. For example, the solvent is removed by concentrated under reduced pressure at a water bath temperature of 25~30℃ and a reduced vacuum degree of -0.08~-0.09 MPa to obtain crude 1-tert-butyl-3-ethylcarbodiimide. The crude product is then distilled to obtain the 1-tert-butyl-3-ethylcarbodiimide product. The distillation specifically includes: a vacuum degree of -0.095 MPa~-0.098 MPa, a water bath temperature of 50~60℃, and an internal temperature controlled within 35~40℃.

[0037] Preferably, in step (1), the molar ratio of ethyl isothiocyanate to tert-butylamine is 1:1 to 2, more preferably 1:1; in step (2), the mass ratio of ethyl tert-butylthiourea to the sodium hypochlorite aqueous solution is 1:7 to 9.

[0038] Preferably, in step (1), the mass ratio of ethyl isothiocyanate to organic solvent I is 1:2~4; in step (2), the mass ratio of ethyl tert-butylthiourea to organic solvent II is 1:3~5.

[0039] In this invention, in step (2), no catalyst or inorganic base (e.g., alkali metal hydroxide) is added when the oxidative desulfurization reaction is carried out.

[0040] In the process of this invention, the main solvent system is a low-boiling-point solvent (such as petroleum ether, chloroform, etc.), which is easy to separate and recover, has low energy consumption, helps to improve the reaction rate, and is easy to control and switch (in continuous production, low-boiling-point solvents can achieve rapid solvent switching and system cleaning, reduce cross-contamination between batches, and improve production flexibility).

[0041] Preferably, in step (1), the ethyl isothiocyanate is prepared by a method comprising the following steps: (a) In a mixture of alkali and water at a temperature of 10-15°C, an aqueous solution of ethylamine with a concentration of 68-72 wt% is added dropwise, followed by the addition of carbon disulfide, and then the reaction mixture is stirred at 10-30°C; in some examples, the reaction time for this step is, for example, 2 h. (b) Add sodium carbonate and cyanuric chloride to the reaction solution obtained in step (a), and stir the reaction solution at 20-40°C; monitor the completion of the reaction, allow it to stand and separate into layers, and the upper layer obtained is ethyl isothiocyanate. In some examples, the reaction time in step (b) is, for example, 6-8 hours.

[0042] In the preferred embodiment, ethyl isothiocyanate is prepared using steps (a) and (b) above. The reaction is carried out under specific reaction conditions and in a specific reaction system. In step (a), no strongly polar organic solvent is required. In step (b), the product ethyl isothiocyanate reacts with cyanuric chloride in the presence of sodium carbonate, and no additional organic solvent is required. The presence of sodium carbonate in step (b) ensures that the product ethyl isothiocyanate does not decompose in water for a long time, resulting in excellent stability of the target product. Compared with using strong bases such as sodium hydroxide, this method can improve the yield. Moreover, the preparation of ethyl isothiocyanate using the above process does not require subsequent pH adjustment with the addition of sodium hydroxide or concentration operations. Only simple post-processing operations are needed to obtain the target product.

[0043] For reference, the synthetic reaction pathway of the above-mentioned ethyl isothiocyanate is as follows:

[0044] Preferably, in step (a), the alkaline solution is a sodium hydroxide aqueous solution with a concentration of 48-52 wt%. The inventors have found that using this specific concentration of sodium hydroxide aqueous solution in step (a) results in a significantly better reaction effect compared to using other alkaline solutions (such as potassium salts), effectively improving the conversion rate of carbon disulfide, shortening the reaction time, and obtaining a high-purity product.

[0045] And / or, in step (a), the mass ratio of the alkaline solution to the water is 1:4~5, the mass ratio of the ethylamine aqueous solution to the alkaline solution is 1:1~2, and the molar ratio of the carbon disulfide to the ethylamine is 1:0.5~1.1; And / or, the molar ratio of the cyanuric chloride used in step (b) to the ethylamine used in step (a) is 1:1 to 3.5; And / or, in step (b), the molar ratio of the cyanuric chloride to the sodium carbonate is 1:1~2.

[0046] Specifically, in this invention, each reaction step proceeds until the reaction reaches its endpoint, and the reaction progress can be monitored using conventional monitoring methods in the art. For example, in step (2), potassium iodide test paper is used; if it turns blue, the reaction endpoint has been reached. In other steps, unless otherwise specified, the reaction progress can be monitored by HPLC, which will not be elaborated further.

[0047] The present invention will be further illustrated by the following embodiments, but it should not be construed as the present invention being limited to these embodiments.

[0048] Where specific experimental steps or conditions are not specified in the examples, the corresponding conventional experimental steps or conditions in this technical field can be followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0049] In the following embodiments: 1 ¹H NMR was obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0050] High-performance liquid chromatography (HPLC) chromatograms were determined using a Quattro Micro™ API triple quadrupole mass spectrometer with ESI ionization mode.

[0051] Example 1: Synthesis of ethyl isothiocyanate (a) Add 54.8 g of 50 wt% sodium hydroxide aqueous solution and 250 g of water to the reaction flask and cool to 10-15 °C. Add 45 g of 70 wt% ethylamine aqueous solution dropwise, followed by 50 g of carbon disulfide. After the addition is complete, stir at 20 °C for 2 h.

[0052] (b) Add 36g of sodium carbonate and 41g of cyanuric chloride in batches, stir and react at 30°C for 7 hours, then keep warm and let stand for 1 hour to separate the layers. Remove the lower water layer and the upper oil layer is ethyl isothiocyanate. The upper oil layer does not require any other purification operations and can be used directly as a raw material for subsequent reactions.

[0053] Results: The yield of ethyl isothiocyanate was 95%.

[0054] Example 2: Preparation of ethyl tert-butylthiourea Add 40g of ethyl isothiocyanate and 150g of petroleum ether to a dry reaction flask, start stirring, heat the hot water to 30~35℃, add 33.6g of tert-butylamine dropwise, control the temperature to ≤40℃, and keep warm at 50℃ for 12h after the addition is complete.

[0055] After the reaction was completed, the temperature was lowered to 10-15℃, filtered, and wet ethyl tert-butylthiourea was obtained. After vacuum drying, 73g of dry ethyl tert-butylthiourea was obtained with a purity ≥99% and a yield of 99%.

[0056] Example 3: Preparation of TBEC Add 50g of ethyl tert-butylthiourea and 160ml of chloroform to a 1000ml reaction flask, start stirring, and freeze to 0~5℃.

[0057] Add 360g of a 12wt% sodium hypochlorite aqueous solution dropwise, controlling the temperature at 0~10℃, and complete the addition in 4 hours. After the addition is complete, keep the solution warm for 2 hours. The reaction endpoint is reached when the starch-potassium iodide test paper turns blue.

[0058] After the reaction is complete, the mixture is filtered to remove the sulfur produced, with a sulfur recovery rate of over 95%. The filtrate is allowed to stand and separate into two layers: organic layer I and aqueous layer I. Aqueous layer I is extracted with 160 ml of chloroform, and after separation, organic layer II is obtained. Organic layers I and II are combined to obtain the organic layer solution, while aqueous layer I is discarded.

[0059] The organic layer solution was concentrated under reduced pressure at a water bath temperature of 25~30℃ and a vacuum degree of -0.08~-0.09Mpa to recover chloroform, yielding crude TBEC solution.

[0060] The above crude TBEC feed solution was subjected to distillation under the following conditions: vacuum degree -0.095 MPa to -0.098 MPa, water bath temperature 50-60℃, internal temperature controlled within 35-40℃, and reflux ratio adjusted to 10:1. The low-boiling-point impurity chloroform was first removed by distillation. Once the column top temperature reached a constant 40℃, the chloroform was collected. The reflux ratio was adjusted to 5:1, and the finished TBEC product was collected with a purity ≥98.5%. The yield of TBEC product was 35.5 g, with a yield of 90.2%. 1 See the H-NMR spectrum. Figure 1 .

[0061] Example 4: Scale-up of the preparation process for ethyl tert-butylthiourea Add 400 kg of ethyl isothiocyanate and 990 kg of petroleum ether to a 3000 L condensation vessel, start stirring, heat the hot water to 30-35 °C, add 336 kg of tert-butylamine dropwise, control the temperature at 40 °C, and keep at 50 °C for 15 h after the addition is complete.

[0062] After the reaction was completed, the temperature was lowered to 10-15℃, and the product was centrifuged to obtain wet ethyl tert-butyl. The product was then placed in a double-cone rotary vacuum dryer, and the hot water temperature was controlled at 35-40℃, the vacuum degree was -0.90-0.95 MPa, and the product was vacuum dried for 6 hours. The weight loss on drying was measured to be ≤1%, and 720 kg of dry ethyl tert-butylthiourea was obtained with a purity >99% and a yield of 97.8%.

[0063] Example 5: Scale-up of TBEC preparation process and material feeding Add 250 kg of ethyl tert-butyl thiourea and 800 L of chloroform to a 5000 L desulfurization reactor, start stirring, and turn on the chilled brine to cool to 0-5 °C.

[0064] Add 2000 kg of 12 wt% sodium hypochlorite aqueous solution dropwise, controlling the temperature at 0~10℃, and complete the addition in 8 hours. After the addition is complete, keep the solution warm for 2 hours. The reaction endpoint is reached when starch-potassium iodide test paper turns blue.

[0065] After the reaction is completed, the desulfurization reaction liquid is obtained. It is then filtered to remove the sulfur produced in the reaction, with a sulfur recovery rate of over 95%.

[0066] The filtrate was allowed to stand and separate into two layers, yielding organic layer I and aqueous layer I. Aqueous layer I was extracted with 800L of chloroform, and after separation, organic layer II was obtained. Organic layer I and organic layer II were combined to obtain the organic layer solution, while aqueous layer I was discarded.

[0067] The organic layer solution was concentrated under reduced pressure at a water bath temperature of 25~30℃ and a vacuum degree of -0.08~-0.09Mpa to recover chloroform, yielding crude TBEC solution.

[0068] The above crude TBEC feed solution was subjected to distillation under the following conditions: vacuum degree -0.095 MPa to -0.098 MPa, water bath temperature 50-60℃, internal temperature controlled within 35-40℃, and reflux ratio adjusted to 10:1. The low-boiling-point impurity chloroform was first removed by distillation. Once the column top temperature reached a constant 40℃ and the chloroform was completely collected, the reflux ratio was adjusted to 5:1, and the finished TBEC product was collected with a purity ≥98.5%. The yield of TBEC product was 180.9 kg, with a yield of 91.9%.

[0069] Comparative Example 1 The procedure was carried out in accordance with Example 3, except that the concentration of the sodium hypochlorite aqueous solution was 10 wt%.

[0070] Results: The final TBEC product had a purity of 98% and a yield of 88%. The sulfur recovery rate was 95%.

[0071] Comparative Example 2 The procedure was carried out in accordance with Example 3, except that the concentration of the sodium hypochlorite aqueous solution was 15 wt%.

[0072] Results: The final TBEC product had a purity of 96% and a yield of 85%. The sulfur recovery rate was 86%.

[0073] Comparative Example 3 The procedure is carried out in accordance with Example 3, except that: Before adding the sodium hypochlorite aqueous solution, 0.5g of phase transfer catalyst EDTA was also added to the reaction flask.

[0074] After the reaction is complete: During the post-processing purification of the product, the liquid obtained after the reaction is filtered to obtain the filtrate, and then allowed to stand to separate into organic layer I and aqueous layer I. Organic layer I needs to be washed 4 times with 1 mol / L dilute hydrochloric acid, and the aqueous layer is discarded after each wash. By adding dilute hydrochloric acid to wash, EDTA is protonated to ensure that EDTA is extracted into the aqueous phase, thereby achieving separation from the organic product. The washing wastewater needs to be properly treated.

[0075] Results: The final TBEC product had a purity of 98% and a yield of 73%. The sulfur recovery rate was 30%.

[0076] Comparative Example 4 The procedure is carried out in accordance with Example 3, except that: Before adding the sodium hypochlorite aqueous solution, 25g of potassium hydroxide was also added to the reaction flask.

[0077] After the reaction is complete: the yellow sulfur element basically disappears, and a large amount of sulfate crystals are produced in the reaction solution, which are difficult to remove by filtration after the reaction is complete.

[0078] Results: The final TBEC product had a purity of 97% and a yield of 69%. The sulfur recovery rate was 5%.

[0079] Comparative Example 5 The procedure is the same as in Example 1, except that: In step (a), sodium hydroxide is replaced with potassium hydroxide.

[0080] Results: The yield of ethyl isothiocyanate was 91%.

[0081] Comparative Example 6 The procedure is the same as in Example 1, except that: In step (b), sodium carbonate is replaced with sodium hydroxide.

[0082] Results: The yield of ethyl isothiocyanate was 85%.

[0083] It is readily understood that the above embodiments are merely illustrative examples for clear explanation and do not imply that the invention is limited thereto. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for synthesizing 1-tert-butyl-3-ethylcarbodiimide, characterized in that, Includes the following steps: (1) Ethyl isothiocyanate and tert-butylamine are added in organic solvent I at 30-60°C to obtain ethyl tert-butylthiourea; wherein organic solvent I is selected from one or more of petroleum ether, n-hexane, n-heptane, n-pentane, isopentane, n-octane, and isooctane; (2) The ethyl tert-butylthiourea is reacted with a sodium hypochlorite aqueous solution of 10-15 wt% in organic solvent II at 0-10 °C to undergo an oxidative desulfurization reaction; the sulfur produced by the reaction is removed, and then the solution is purified to obtain 1-tert-butyl-3-ethylcarbodiimide; the organic solvent II is selected from halogenated hydrocarbons.

2. The synthesis method according to claim 1, characterized in that, Step (1) specifically includes the following operations: Ethyl isothiocyanate and organic solvent I are mixed and heated to 30~35℃; then tert-butylamine is added, and then the reaction is maintained at 40~60℃. Preferably, the tert-butylamine is added by dripping, and the temperature is preferably controlled to be ≤40°C during the dripping process.

3. The synthesis method according to claim 1 or 2, characterized in that, In step (1), after the reaction is complete, the reaction liquid is cooled to 10~15℃, then the solid and liquid are separated, and the obtained solid phase is dried to obtain ethyl tert-butylthiourea; Preferably, the liquid phase obtained from the solid-liquid separation can be reused as the organic solvent I in step (1).

4. The synthesis method according to any one of claims 1-3, characterized in that, Step (2) specifically includes the following operations: mix ethyl tert-butylthiourea and the organic solvent II, and cool to 0~5℃, then add the sodium hypochlorite aqueous solution dropwise. Preferably, the temperature is controlled at 0~10℃ when adding the sodium hypochlorite aqueous solution dropwise. After the dropwise addition is completed, keep the reaction solution warm. The starch potassium iodide test paper turns blue, indicating that the reaction has reached the endpoint.

5. The synthesis method according to any one of claims 1-4, characterized in that, In step (1), the organic solvent I is one or more of petroleum ether, n-hexane, and n-heptane, more preferably petroleum ether; And / or, the organic solvent II mentioned in step (2) is one or more of dichloromethane, trichloromethane, dichloroethane, and carbon tetrachloride.

6. The synthesis method according to any one of claims 1-5, characterized in that, In step (2), the concentration of the sodium hypochlorite aqueous solution is 10~12wt% or 12~15wt%, more preferably 12wt%.

7. The synthesis method according to any one of claims 1-6, characterized in that, In step (2), after the reaction is complete, the reaction solution is filtered to remove the sulfur produced by the reaction. Then the filtrate is allowed to stand and separate into layers to obtain organic layer I and water layer I. Water layer I is extracted with the organic solvent II. Organic layer II obtained by extraction is combined with organic layer I and then concentrated under reduced pressure to obtain crude 1-tert-butyl-3-ethylcarbodiimide. The crude product is then distilled to obtain 1-tert-butyl-3-ethylcarbodiimide product.

8. The synthesis method according to any one of claims 1-7, characterized in that, In step (1), the molar ratio of ethyl isothiocyanate to tert-butylamine is 1:1 to 2, preferably 1:1; In step (2), the mass ratio of the ethyl tert-butylthiourea to the sodium hypochlorite aqueous solution is 1:7~9.

9. The synthesis method according to any one of claims 1-8, characterized in that, In step (2), no catalyst or inorganic base is added when the oxidative desulfurization reaction is carried out.

10. The synthesis method according to any one of claims 1-9, characterized in that, In step (1), the ethyl isothiocyanate is prepared by a method comprising the following steps: (a) Add an aqueous solution of ethylamine with a concentration of 68-72 wt% and carbon disulfide dropwise to a mixture of alkali and water at a temperature of 10-15°C, and then stir the reaction solution at 10-30°C. (b) Add sodium carbonate and cyanuric chloride to the reaction solution obtained in step (a), and stir the reaction solution at 20~40°C; monitor the reaction until it is complete, let it stand and separate into layers, and the upper layer is ethyl isothiocyanate.

11. The synthesis method according to claim 10, characterized in that, In step (a), the alkaline solution is a sodium hydroxide aqueous solution with a concentration of 48~52wt%; And / or, in step (a), the mass ratio of the alkaline solution to the water is 1:4~5, the mass ratio of the ethylamine aqueous solution to the alkaline solution is 1:1~2, and the molar ratio of the carbon disulfide to the ethylamine is 1:0.5~1.1; And / or, the molar ratio of the cyanuric chloride used in step (b) to the ethylamine used in step (a) is 1:1 to 3.5; And / or, in step (b), the molar ratio of the cyanuric chloride to the sodium carbonate is 1:1~2.

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