One-pot rapid synthesis method of 1,3-diaminothiourea

Abstract

The present invention relates to a method for rapidly synthesizing 1,3-diaminothiourea by a one-pot method. A thermometer, a dropping funnel and a piston with a conduit are equipped on a four-necked flask. A certain amount of ammonia water with a mass fraction of 10%, hydrogen peroxide solution with a mass fraction of 5% and mercaptoethanol are added to the four-necked flask. Carbon disulfide is added to the dropping funnel. The four-necked flask is placed in an ultrasonic reactor, and the ultrasonic frequency is set to 60-65 kHz, the power is 400 W, and the heating temperature is 40 °C. When the temperature of the materials in the flask reaches 40 °C, carbon disulfide is started to be dropped, and at the same time, ultrasonic-assisted reaction is started. After the reaction is completed, it is naturally cooled to room temperature, and the product is filtered to obtain the crude product of 1,3-diaminothiourea. The finished product of 1,3-diaminothiourea is obtained after purification and drying. The present invention uses ultrasonic radiation-assisted reaction and can rapidly and efficiently synthesize 1,3-diaminothiourea by a one-pot method, solving the defects of long synthesis time, high reaction temperature, harsh conditions and low yield in the prior art.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of organic compounds, and in particular to a method for synthesizing 1,3-diaminothiourea, in particular to a method for rapidly synthesizing 1,3-diaminothiourea in a one-pot process. Background Art

[0002] 1,3-Diaminothiourea is a white crystalline solid. The industrial product is slightly gray. It is insoluble in ether, difficult to dissolve in ethanol, easily soluble in olefinic acid and dilute alkali, soluble in hot water, and slightly soluble in ice water. Its molecular formula is CH6N4S, molecular weight is 106.15, and density is 1.273g / cm 3 , boiling point 230.1±23.0℃, vapor pressure 0.067mmHg at 25℃, flash point 93℃, can be used as an intermediate for organic synthesis reagents, drugs and dyes.

[0003] Thiosemicarbazide and its derivatives have been widely used in many fields such as pesticides, medical treatment, and chemical industry. The main ones are as follows:

[0004] (1) In the field of pesticides, semicarbazide and its derivatives have been continuously discovered and applied in the fields of pest control. For example, semicarbazide is also called rodenticide and is widely used in insecticides and rodenticides. Phenylthiourea has a relatively obvious inhibitory effect on the tyrosinase, i.e., phenoloxidase, of the insect housefly. Benzaldehyde thiosemicarbazide, 4-methoxybenzaldehyde thiosemicarbazide, 4-cyanobenzaldehyde thiosemicarbazide and 4-chlorobenzaldehyde thiosemicarbazide can produce a significant inhibitory effect on the crude enzyme solution of phenoloxidase of Pieris rapae.

[0005] (2) In the chemical industry, thiosemicarbazide and its derivatives have good optical properties, such as fluorescence, second-order nonlinear optics, etc. For example, thiosemicarbazide reagents have been continuously developed and applied in photometric analysis such as fluorescence spectrophotometry and atomic absorption spectrometry. In addition, ethylene thiourea can be used as an accelerator for chloroprene rubber, chlorosulfonated polyethylene rubber, chloroethanol rubber, and polyacrylate rubber, and can also be used as a copper plating brightener.

[0006] (3) In the medical field, semicarbazide Schiff base compounds have obvious biological activities such as antibacterial, treatment of Alzheimer's disease, and anti-tumor. For example, keto-semicarbazide has obvious inhibitory effects on many bacteria; semicarbazide-substituted pyrazole compounds and semicarbazide compounds can be used to treat Alzheimer's disease; and the complexes of benzil semicarbazide have inhibitory effects on ovarian cancer cells.

[0007] At present, there are few reports on the synthesis methods of 1,3-diaminothiourea. The common synthesis methods are as follows:

[0008] (1) It is obtained by the reaction of ammonia and sodium sulfide under hydrothermal conditions. In the experiment, ammonia water and sodium sulfide (in approximately equal parts) are first mixed and dissolved in water. Secondly, borax solution is added and stirred evenly. The temperature is stabilized between 100 - 120 °C. After a certain period of time (usually stirring for 4 - 5 hours), 1,3 - diaminothiourea is produced. At the end of the reaction, a small amount of coolant is added externally, and the 1,3 - diaminothiourea crystals can be separated by crystallization and precipitation at room temperature. Although this method can obtain the target product with only one reaction, this preparation method not only has a relatively high temperature during the reaction, is relatively demanding on the reactant ratio, but also the yield of the finally synthesized target product is relatively low (less than 70%).

[0009] (2) It is obtained by the reaction of hydrazine hydrate and 2 - chloroethanol. First, hydrazine hydrate and 2 - chloroethanol are mixed under an ice bath, and then carbon disulfide is added dropwise with stirring, which is added dropwise in about 1 h. Then, it is stirred at room temperature for 30 min, and yellow crystals of hydrazine dithiocarbazate precipitate out. Then, solid sodium hydroxide is added, and the reaction temperature is controlled at 75 - 85 °C by heating and the reaction is carried out for 10 h. A large amount of yellow precipitate precipitates out after the reaction is completed. Then, the precipitate is filtered and washed with water to obtain white granular 1,3 - diaminothiourea. Although the yield of this method is relatively high (about 80%), the reaction time is long, and the heating decomposition temperature of the intermediate hydrazine dithiocarbazate needs to be strictly controlled in the second step. Otherwise, it is very easy to have excessive boiling, causing the material to fill or rush out of the reactor, which will not only affect the yield of 1,3 - diaminothiourea, but also pose a safety hazard.

[0010] Therefore, it is necessary to research and design a rapid and safe synthesis method of 1,3 - diaminothiourea, so that it can complete the preparation of 1,3 - diaminothiourea quickly, conveniently, efficiently and at low cost, which is necessary for reducing the production cost of 1,3 - diaminothiourea and expanding its application range. Summary of the Invention

[0011] The purpose of the present invention is to provide a method for rapidly synthesizing 1,3 - diaminothiourea by a one - pot method. Using ammonia water, hydrogen peroxide and carbon disulfide as raw materials and mercaptoethanol as a catalyst, 1,3 - diaminothiourea is rapidly and efficiently synthesized by a one - pot method with ultrasonic radiation - assisted reaction, solving the defects of the existing synthesis methods such as long synthesis time, high reaction temperature, harsh conditions and low yield.

[0012] The present invention is specifically realized through the following technical solutions. A method for rapidly synthesizing 1,3 - diaminothiourea by a one - pot method according to the present invention includes the following steps:

[0013] (1) Take a four - necked flask, equip it with a thermometer, a dropping funnel and a piston with a conduit. The dropping funnel switch is closed, and the outlet of the conduit is led into dilute sodium hydroxide solution for standby;

[0014] (2) Add a certain amount of ammonia water with a mass fraction of 10%, a certain amount of hydrogen peroxide solution with a mass fraction of 5%, and a certain amount of mercaptoethanol into the four-necked flask in step (1). After adding, seal the feeding port with a piston, add a certain amount of carbon disulfide into the dropping funnel, and set aside.

[0015] (3) Place the four-necked flask in step (2) in an ultrasonic reactor, set the ultrasonic frequency to 60 - 65 kHz, the power to 400 W, and the heating temperature to 40 °C.

[0016] (4) When the thermometer shows that the temperature of the material in the flask is 40 °C, open the switch of the dropping funnel and start to slowly drop carbon disulfide into the flask, and at the same time start the ultrasonic-assisted reaction; after the reaction ends, naturally cool to room temperature, and a large amount of yellow precipitate will precipitate.

[0017] (5) Filter the reaction product obtained in step (4), and the obtained filter residue is the crude product of 1,3-diaminothiourea.

[0018] (6) Wash the crude product of 1,3-diaminothiourea obtained in step (5) with water and filter it 3 - 5 times to purify the product, then put it into an oven and dry it at about 37 °C under normal pressure in the oven to obtain the finished product of 1,3-diaminothiourea.

[0019] In the method for the one-pot rapid synthesis of 1,3-diaminothiourea described above, in step (2), the molar ratio of ammonia water to hydrogen peroxide is 2:(1 - 1.2). The molar ratio of the taken mercaptoethanol to ammonia water is 1:(14 - 20).

[0020] In the method for the one-pot rapid synthesis of 1,3-diaminothiourea described above, in step (2), the molar ratio of carbon disulfide to ammonia water is (1 - 1.2):4.

[0021] In the method for the one-pot rapid synthesis of 1,3-diaminothiourea described above, in step (4), the dropping time of carbon disulfide is 1 h, the ultrasonic-assisted reaction time is 2 - 3 h, and the ultrasonic-assisted reaction is carried out while dropping carbon disulfide.

[0022] In the method for the one-pot rapid synthesis of 1,3-diaminothiourea described above, the molar yield of the finally obtained high-purity 1,3-diaminothiourea compared to carbon disulfide is 89.3 - 92%.

[0023] Compared with the prior art, the present invention has obvious advantages and beneficial effects. By means of the above technical solutions, the present invention can achieve considerable technological progressiveness and practicality, and has a wide range of utilization values. It has at least the following advantages:

[0024] (1). The one-pot rapid synthesis method of 1,3-diaminothiourea of the present invention has simple process steps and convenient operation. Compared with the traditional process for synthesizing 1,3-diaminothiourea, the present invention uses ammonia water, hydrogen peroxide and carbon disulfide as reaction raw materials, which are easy to obtain, safe to use, friendly to operate and low in cost. At the same time, with 2-mercaptoethanol as the telogen, the generated 1,3-diaminothiourea is not easily decomposed, and the degree of polymerization of the intermediate product is effectively controlled, thus greatly reducing the generation of by-products, reducing the loss of raw materials and avoiding waste.

[0025] (2). The present invention adopts the ultrasonic radiation-assisted reaction mode in the synthesis process. At a specific ultrasonic frequency and ultrasonic power, through ultrasonic oscillation, the contact between raw material molecules is more sufficient, and the basic reaction and bonding between raw materials are faster, more sufficient and more thorough, and the conversion rate of the target product is higher. It is measured that the molar yield of the target compound 1,3-diaminothiourea in the process method of the present invention can reach more than 85%, greatly saving the reaction time, improving the reaction efficiency, the purity and quality of the finished compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is the single crystal XRD pattern of the finished product 1,3-diaminothiourea prepared in Example 1 of the present invention;

[0027] Figure 2 is the diffraction peak pattern of the finished product 1,3-diaminothiourea prepared in Example 1 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0028] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the scope of protection of the present invention.

[0029] A one-pot rapid synthesis method of 1,3-diaminothiourea provided by the present invention uses ammonia water, hydrogen peroxide and carbon disulfide as raw materials, and mercaptoethanol as a catalyst, and adopts the ultrasonic radiation-assisted reaction mode to realize the rapid and efficient preparation of 1,3-diaminothiourea. The key points of the process method lie in the material ratio between reaction raw materials, the setting of ultrasonic radiation frequency parameters, etc. The specific process steps are as follows:

[0030] (1). Take a four-necked flask, equip it with a thermometer, a dropping funnel (the dropping funnel switch is closed) and a piston with a conduit, and lead the outlet of the conduit into dilute sodium hydroxide solution for standby.

[0031] (2) Add a certain amount of ammonia water with a mass fraction of 10%, a certain amount of hydrogen peroxide solution with a mass fraction of 5%, and a certain amount of mercaptoethanol into the four-necked flask in step (1). After adding, seal the feeding port with a piston; and add a certain amount of carbon disulfide into the dropping funnel for standby.

[0032] (3) Place the four-necked flask in step (2) into an ultrasonic reactor, set the frequency of the ultrasonic reactor to 60 - 65 kHz, the power to 400 W, and the heating temperature to 40 °C.

[0033] (4) When the thermometer shows that the temperature of the material in the flask is 40 °C, open the switch of the dropping funnel and start to slowly drip carbon disulfide into the four-necked flask, and at the same time start the ultrasonic-assisted reaction; after the reaction is completed, cool it naturally to room temperature, and a large amount of yellow precipitate will precipitate.

[0034] In this step, control the dropping time of carbon disulfide to be 1 h, the ultrasonic-assisted reaction time to be 2 - 3 h, and carry out the ultrasonic-assisted reaction while dripping carbon disulfide.

[0035] The reaction equation for this step is:

[0036]

[0037] The generated hydrogen sulfide gas enters the dilute sodium hydroxide solution through the conduit for absorption treatment. The structural formula of the target product 1,3-diaminothiourea is:

[0038]

[0039] (5) Filter the reaction product obtained in step (4), and the obtained filter residue is the crude product of 1,3-diaminothiourea.

[0040] (6) Purify the crude product of 1,3-diaminothiourea obtained in step (5) by washing with water and filtering 3 - 5 times, and then put it into an oven and dry it at about 37 °C under normal pressure in the oven to obtain the finished product of 1,3-diaminothiourea.

[0041] In an application example, the prepared high-purity 1,3-diaminothiourea can be further processed for the preparation of pharmaceutical intermediates, such as reacting with aldehydes and ketones to prepare Schiff base compounds.

[0042] Preferably, in step (2), the molar ratio of NH₃ in ammonia water to hydrogen peroxide is controlled to be 2:(1 - 1.2), the molar ratio of the taken mercaptoethanol to NH₃ in ammonia water is controlled to be 1:(14 - 20), and the molar ratio of carbon disulfide to NH₃ in ammonia water is controlled to be (1 - 1.2):4.

[0043] Furthermore, during the reaction process, the four-necked flask should be kept sealed as much as possible to avoid the escape of the generated hydrogen sulfide gas.

[0044] The following are specific examples to illustrate the present invention in detail. In the following examples, the experimental methods and detection methods, unless otherwise specified, are all conventional methods in the art; the experimental processes, if not specified otherwise, are carried out under normal temperature and pressure conditions; the reagents and materials, unless otherwise specified, can be purchased on the market. The calculation formula for the yield (molar yield) of the high-purity 1,3-diaminothiourea relative to carbon disulfide in the examples is:

[0045]

[0046] Example 1

[0047] (1) Take a four-necked flask, equip it with a thermometer, a dropping funnel (the dropping funnel switch is closed), and a piston with a conduit, and lead the outlet of the conduit into dilute sodium hydroxide solution for standby.

[0048] (2) Add 7.12 ml (the amount of ammonia in the ammonia water is 0.400 mol) of 10% ammonia water, 8.16 ml (the amount of hydrogen peroxide is 0.240 mol) of 5% hydrogen peroxide solution, and 1.89 ml (0.027 mol) of mercaptoethanol into the four-necked flask in step (1). After adding, seal the feeding port with the piston, and add 6.04 ml (0.100 mol) of carbon disulfide into the dropping funnel for standby.

[0049] (3) Place the four-necked flask in step (2) in an ultrasonic reactor, set the ultrasonic frequency to 60 kHz, the power to 400 W, and the heating temperature to 40 °C;

[0050] (4) When the thermometer shows that the temperature of the materials in the flask is 40 °C, open the dropping funnel switch and start slowly dropping carbon disulfide into the flask, and at the same time start ultrasonic-assisted reaction; the dropping time of carbon disulfide is 1 h, and the ultrasonic-assisted reaction time is 2.5 h. The ultrasonic-assisted reaction is carried out while dropping carbon disulfide. After the reaction is completed, cool it naturally to room temperature, and a large amount of yellow precipitate will precipitate.

[0051] (5) Filter the reaction product obtained in step (4), and the obtained filter residue is the crude product of 1,3-diaminothiourea.

[0052] (6) Wash the crude 1,3-diaminothiourea obtained in step (5) and filter it 4 times for purification, then put it into an oven and dry it under normal pressure at about 37 °C in the oven to obtain the finished product of 1,3-diaminothiourea. After drying, weigh it to obtain 9.715 g of 1,3-diaminothiourea, and the molar yield of 1,3-diaminothiourea calculated based on carbon disulfide is 91.7%.

[0053] Perform elemental analysis on the prepared 1,3-diaminothiourea using a Perkin-Elmer 1400C elemental analyzer. The obtained data are as follows: C: 11.16% (theoretical value is 11.31%), H: 5.78% (theoretical value is 5.70%), N: 52.98% (theoretical value is 52.78%), S: 30.28% (theoretical value is 30.21%). It can be seen that the analytical values of the product are basically consistent with the theoretical values.

[0054] Perform single crystal X-ray diffraction analysis and detection on the high-purity 1,3-diaminothiourea prepared in this example. The obtained single crystal XRD pattern is analyzed using Mercury software, and the single crystal XRD pattern and diffraction peak pattern of the sample are respectively as Figure 1 and Figure 2 shown.

[0055] Example 2

[0056] (1) Take a four-necked flask, equip it with a thermometer, a dropping funnel (the dropping funnel switch is closed) and a piston with a conduit, and lead the outlet of the conduit into dilute sodium hydroxide solution for standby.

[0057] (2) Add 7.12 ml (the amount of ammonia in ammonia water is 0.400 mol) of 10% ammonia water solution, 6.80 ml (the amount of hydrogen peroxide is 0.200 mol) of 5% hydrogen peroxide solution and 1.40 ml (0.020 mol) of mercaptoethanol into the four-necked flask in step (1). After adding, seal the feeding port with a piston, and add 6.04 ml (0.100 mol) of carbon disulfide into the dropping funnel for standby.

[0058] (3) Place the four-necked flask in step (2) in an ultrasonic reactor, set the ultrasonic frequency to 62 kHz, the power to 400 W, and the heating temperature to 40 °C;

[0059] (4) When the thermometer shows that the temperature of the materials in the flask is 40 °C, open the dropping funnel switch and start to slowly drop carbon disulfide into the flask, and at the same time start ultrasonic-assisted reaction; the dropping time of carbon disulfide is 1 h, and the ultrasonic-assisted reaction time is 3 h. Perform ultrasonic-assisted reaction while dropping carbon disulfide. After the reaction is completed, cool it naturally to room temperature, and a large amount of yellow precipitate will precipitate.

[0060] (5) Filter the reaction product obtained in step (4), and the obtained filter residue is crude 1,3-diaminothiourea.

[0061] (6) Wash the crude 1,3-diaminothiourea obtained in step (5) with water and filter it three times for purification, then put it into an oven and dry it at about 37 °C under normal pressure in the oven to obtain the finished product of 1,3-diaminothiourea. After drying, weigh it and obtain 9.466 g of 1,3-diaminothiourea. Calculate the molar yield of 1,3-diaminothiourea based on carbon disulfide to be 89.3%.

[0062] Example 3

[0063] (1) Take a four-necked flask, equip it with a thermometer, a dropping funnel (the dropping funnel switch is closed), and a piston with a conduit, and lead the outlet of the conduit into dilute sodium hydroxide solution for standby.

[0064] (2) Add 7.12 ml (the amount of ammonia in ammonia water is 0.400 mol) of 10% ammonia water solution, 6.80 ml (the amount of hydrogen peroxide is 0.200 mol) of 5% hydrogen peroxide solution and 1.75 ml (0.025 mol) of mercaptoethanol to the four-necked flask in step (1). After adding, seal the feeding port with a piston, and add 7.25 ml (0.120 mol) of carbon disulfide to the dropping funnel for standby.

[0065] (3) Place the four-necked flask in step (2) in an ultrasonic reactor, set the ultrasonic frequency to 65 kHz, the power to 400 W, and the heating temperature to 40 °C;

[0066] (4) When the thermometer shows that the temperature of the material in the flask is 40 °C, open the dropping funnel switch and start slowly dropping carbon disulfide into the flask, and at the same time start ultrasonic-assisted reaction; the dropping time of carbon disulfide is 1 h, the ultrasonic-assisted reaction time is 2 h, and ultrasonic-assisted reaction is carried out while dropping carbon disulfide. After the reaction is completed, naturally cool to room temperature, and a large amount of yellow precipitate will precipitate;

[0067] (5) Filter the reaction product obtained in step (4), and the obtained filter residue is crude 1,3-diaminothiourea.

[0068] (6) Wash the crude 1,3-diaminothiourea obtained in step (5) with water and filter it five times for purification, then put it into an oven and dry it at about 37 °C under normal pressure in the oven to obtain the finished product of 1,3-diaminothiourea. After drying, weigh it and obtain 11.473 g of 1,3-diaminothiourea. Calculate the molar yield of 1,3-diaminothiourea based on carbon disulfide to be 90.1%.

[0069] In the above examples, the liquid can be taken by a pipette gun.

[0070] The method for rapidly synthesizing 1,3-diaminothiourea by one-pot method provided by the present invention uses ammonia water, hydrogen peroxide and carbon disulfide as raw materials, mercaptoethanol as a catalyst, and realizes the rapid and efficient preparation of 1,3-diaminothiourea by means of ultrasonic wave radiation assistance reaction. It has the advantages of simple reaction equipment, mild reaction conditions, high yield, fast speed, easy operation, low cost, easy separation and purification, etc. Compared with the traditional synthesis method, the ultrasonic technology has the advantages of simple operation, short reaction time, high efficiency and low energy consumption. The method of the present invention is simple and feasible, easy to operate, and rapidly synthesizes 1,3-diaminothiourea by one-pot method, and has good industrial application prospects.

[0071] The above are only embodiments of the present invention, and do not impose any form of limitation on the present invention. The present invention can also have other forms of embodiments according to the above structure and function, which will not be listed one by one. Therefore, any person skilled in the art, without departing from the scope of the technical solution of the present invention, any simple modification, equivalent change and modification made to the above embodiments based on the technical essence of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing 1,3-diaminothiourea by a one-pot method, characterized in that It includes the following steps: (1) Take a four-necked flask, equip it with a thermometer, a dropping funnel and a piston with a conduit. Close the switch of the dropping funnel, and let the outlet of the conduit lead into dilute sodium hydroxide solution for standby; (2) Add 10% ammonia water solution, 5% hydrogen peroxide solution and mercaptoethanol into the four-necked flask in step (1). After adding, seal the charging port with the piston; Add carbon disulfide into the dropping funnel for standby; (3) Place the four-necked flask in step (2) into an ultrasonic reactor, set the ultrasonic frequency to 60 - 65 kHz, the power to 400 W, and the heating temperature to 40 °C; (4) When the thermometer shows that the temperature of the materials in the flask is 40 °C, open the switch of the dropping funnel and start to slowly add carbon disulfide into the flask, and at the same time start the ultrasonic-assisted reaction; After the reaction ends, cool it naturally to room temperature, and a large amount of yellow precipitate will precipitate out; (5) Filter the reaction product obtained in step (4), and the obtained filter residue is crude 1,3-diaminothiourea; (6) Wash and filter the crude 1,3-diaminothiourea obtained in step (5) 3 - 5 times to purify the product, and then put it into an oven and dry it at 37 °C under normal pressure in the oven to obtain the finished product of 1,3-diaminothiourea.

2. The method for synthesizing 1,3-diaminothiourea by a one-pot method according to claim 1, characterized in that In step (2), the molar ratio of ammonia water to hydrogen peroxide is 2:(1 - 1.2).

3. The method for synthesizing 1,3-diaminothiourea by a one-pot method according to claim 1, characterized in that In step (2), the molar ratio of the taken mercaptoethanol to ammonia water is 1:(14 - 20).

4. The method for synthesizing 1,3-diaminothiourea by a one-pot method according to claim 1, characterized in that In step (2), the molar ratio of carbon disulfide to ammonia water is (1 - 1.2):

4.

5. The method for synthesizing 1,3-diaminothiourea by a one-pot method according to claim 1, characterized in that In step (4), the dropping time of carbon disulfide is 1 h, the ultrasonic-assisted reaction time is 2 - 3 h, and the ultrasonic-assisted reaction is carried out while adding carbon disulfide.

6. The method for synthesizing 1,3-diaminothiourea by a one-pot method according to claim 1, characterized in that The molar yield of the finally obtained 1,3-diaminothiourea in step (6) compared to carbon disulfide is 89.3 - 92%.

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