Used in the preparation of urea- 14 C's method

Abstract

The present disclosure provides a method for preparing urea- 14 C, comprising the following successive steps: (a) reacting a carbonate- 14 C with a gas containing ammonia gas to obtain a cyanamide salt- 14 C; (b) hydrolyzing the cyanamide salt- 14 C obtained in the step (a) to obtain a hydrolysis product, and then sequentially subjecting the hydrolysis product to neutralization, solid-liquid separation and solvent removal treatments to obtain a crude urea- 14 C; and (c) purifying the crude urea- 14 C obtained in the step (b) to obtain urea- 14 C.

Description

Technical Field

[0001] This disclosure relates to methods for preparing urea- 14 C's method. Background Technology

[0002] Urea - 14 C is used for production. 14 Urea is one of the main raw materials for the C-breath test reagent. In existing technology, urea- 14 The common method for synthesizing C is to use barium carbonate... 14 C reacts with ammonia at high temperature to form barium cyanamide. 14 C, then barium cyanamide- 14 C is hydrolyzed under acidic conditions to give urea-14C, and then purified to obtain pure urea-14C. 14 C. Although the basic reaction principle is clear, in practical applications, different processing methods still have a significant impact on the yield and purity of the final product. Specifically, for urea- 14 C, the product yield and purity are crucial. The yield directly affects the collection and disposal of radioactive waste; a higher yield results in less radioactive waste, while a lower yield results in more, increasing environmental pressure, waste disposal costs, and radiation protection requirements. Furthermore, due to pharmaceutical safety concerns, the purity and toxic impurity content of the product are subject to very strict requirements. In addition, because this synthesis involves… 14 C represents a radioactive nuclide, and radiation protection must be considered during the process. During synthesis, contact with the reaction substrate or reaction solution should be minimized, and the risk of contamination should be reduced during transfer. When handling the reaction, the amount of solvents used, such as water and ethanol, should be kept to a minimum to reduce the amount of waste products.

[0003] However, existing methods report the use of barium hydroxide or ammonia for neutralization of sulfuric acid during post-treatment. Since barium hydroxide is water-soluble, accurate neutralization is impossible; only excess barium hydroxide can be added. This excess barium hydroxide requires further neutralization with carbon dioxide, increasing the amount of material used in the reaction. Furthermore, excess carbon dioxide also forms barium bicarbonate, which dissolves in water. After filtration or centrifugation, some barium bicarbonate remains mixed with urea. 14 C remains in the filtrate, requiring further purification, which adds pressure to subsequent purification processes. The same issue arises when using ammonia. Furthermore, regarding urea... 14 There are also issues with the batch size of the C active pharmaceutical ingredient synthesis. Current production processes mainly take place in horizontal quartz tubes or U-shaped tubes because thorough mixing with ammonia is crucial at high temperatures. If the batch size is too large, solid barium carbonate...14 The carbon powder will accumulate, preventing gas from smoothly penetrating to the bottom layer of barium carbonate. 14 When C powder comes into contact with it, the reaction cannot proceed completely, thus preventing the production volume of a single batch from being increased, i.e., preventing large-scale production.

[0004] Therefore, existing methods for preparing urea- 14 C's method still needs improvement. Summary of the Invention

[0005] This disclosure is made in view of the above-mentioned problems, and its purpose is to provide a new method for preparing urea- 14 Method C effectively solves problems such as high yield, high purity, simplified operation steps, and increased reaction scale per batch.

[0006] To achieve the above objectives, this disclosure provides a novel method for preparing urea- 14 Method C improves the yield and purity of the final product by optimizing the neutralization step, the solid-liquid separation step of the neutralization product, the purification step, and specific process parameters. On the other hand, it improves the efficiency of the pyrolysis reaction by improving the reaction device, which can simultaneously carry out trace or large-scale synthesis and greatly reduces the transfer of radioactive materials, thus minimizing radioactive contamination and the generation of radioactive waste.

[0007] This disclosure provides a method for preparing urea- 14 The method of C includes the following sequential steps:

[0008] (a) to make carbonate- 14 C reacts with an ammonia-containing gas to obtain cyanamide salt. 14 C;

[0009] (b) Hydrolysis of the cyanamide salt obtained in step (a) 14 C, to obtain hydrolysis products, and then the hydrolysis products are subjected to neutralization, solid-liquid separation and solvent removal treatment in sequence to obtain urea- 14 C coarse product; and

[0010] (c) Purify the urea obtained in step (b) 14 Crude product C, to obtain urea- 14 C;

[0011] Optionally, the carbonate- 14 C is selected from one or more of the following groups: barium carbonate - 14 C. Strontium carbonate 14 C. Calcium carbonate 14 C and lead carbonate - 14C, preferably barium carbonate- 14 C.

[0012] In any implementation, in the method:

[0013] Step (a) is performed at 400-950°C, preferably by a gradient increase from 400°C to 950°C, optionally at a rate of 5-50°C / min, preferably 10°C / min; and / or

[0014] The reaction in step (a) is carried out for 2-6 hours, preferably 3 hours; and / or

[0015] The ammonia-containing gas is ammonia or a mixture of ammonia and an inert gas, wherein the ammonia content in the mixture of ammonia and an inert gas is not less than 25% by volume, preferably 50% by volume. Optionally, the inert gas is selected from one or more of the following group: nitrogen, argon, helium, and neon, preferably argon; and / or

[0016] The flow rate of the ammonia-containing gas is 1-40 mL / min / g carbonate. 14 C, preferably 15-20 mL / min / g carbonate- 14 C. The 1-40 mL / min / g carbonate- 14 C refers to the percentage of carbonate per gram - 14 C, the flow rate of the ammonia-containing gas is 1-40 mL / min, thus, relative to 2g of carbonate - 14 C, the flow rate of ammonia-containing gas is 2-80 mL / min, and so on.

[0017] In any implementation, in the method:

[0018] The hydrolysis in step (b) includes the following sequential steps:

[0019] (b1) The cyanamide salt obtained in step (a) is... 14 C is dissolved in an aqueous solvent, preferably pure water, to obtain cyanamide salt. 14 Solution C; optionally, relative to the amount of carbonate used in step (a) - 14 C, the amount of the aqueous solvent added is 10-100 mL, 20-90 mL, 40-80 mL, or 60 mL; and

[0020] (b2) The cyanamide salt obtained in step (b1) 14 Add acid, preferably a strong acid, to solution C for hydrolysis, preferably for 12-36 hours, to obtain hydrolysis products;

[0021] Optionally, the acid is selected from one or more of the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and nitric acid, preferably sulfuric acid;

[0022] Optionally, the added acid is related to the carbonate used in step (a). 14 The molar ratio of C is (2.5-10):1 or (4-6):1 or 5:1;

[0023] Optionally, steps (b1) and / or (b2) are performed at 30-60°C and / or under an inert gas atmosphere, wherein the inert gas is selected from one or more of the group consisting of nitrogen, argon, helium, and neon, preferably argon; or

[0024] The hydrolysis in step (b) includes the following steps: optionally, at 30-60°C and / or under inert gas protection, the cyanamide salt obtained in step (a) is hydrolyzed... 14 C is dissolved in a dilute acid solution and hydrolyzed, preferably for 12-36 hours, to obtain the hydrolysis product;

[0025] Optional, wherein:

[0026] Relative to the amount of carbonate used in step (a) - 14 C, the volume of the dilute acid solution is 10-100 mL, 20-90 mL, 40-80 mL, or 60 mL; and / or

[0027] The dilute acid solution is a mixture of acid and solvent; and / or

[0028] The acid is preferably selected from one or more of the following: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and nitric acid, more preferably sulfuric acid; and / or

[0029] The solvent is preferably an aqueous solvent, more preferably pure water; and / or

[0030] The volume ratio of the acid to the solvent is preferably 1:(5-40) or 1:(10-30).

[0031] In any implementation, in the method:

[0032] The neutralization in step (b) is carried out by adding a neutralizing medium, and preferably includes the following sequential steps:

[0033] (b1') Add a neutralizing medium to the hydrolysis product of step (b); and

[0034] (b2') Neutralize at 30-60°C, preferably 40°C, and / or under inert gas protection and / or with stirring for 0.5-5 hours, preferably 1-2 hours;

[0035] Preferably, the solubility of the neutralizing medium in the solvent of the hydrolysis product at 20°C is no more than 0.01 g / 100 g solvent, more preferably no more than 0.001 g / 100 g solvent, and even more preferably no more than 0.0001 g / 100 g solvent;

[0036] Optionally, the neutralizing medium is a carbonate and / or a sulfite and / or a water-insoluble hydroxide and / or other basic salt and / or other oxide, wherein the carbonate is preferably selected from one or more of the following: barium carbonate, strontium carbonate, calcium carbonate, lead carbonate, magnesium carbonate and zinc carbonate, more preferably barium carbonate; the sulfite is preferably selected from barium sulfite and / or calcium sulfite; the water-insoluble hydroxide is preferably selected from one or more of the following: lead hydroxide, strontium hydroxide, calcium hydroxide and magnesium hydroxide; the other basic salt is preferably basic lead carbonate; and the other oxide is preferably selected from one or more of the following: lead oxide, silver oxide, lead tetroxide, magnesium oxide, zinc oxide and copper oxide.

[0037] Optionally, the molar ratio of the added neutralizing medium to the acid used in the hydrolysis process of step (b) is (1-3):1;

[0038] Optionally, the inert gas is selected from one or more of the group consisting of nitrogen, argon, helium and neon, preferably argon;

[0039] Preferably, the step of detecting the pH value of the system is not included after the neutralization step in step (b).

[0040] In any implementation, in the method:

[0041] The solid-liquid separation in step (b) is performed by filtration, preferably including the following sequential steps:

[0042] (b1”) The product obtained by neutralization in step (b) is initially filtered using a first filter material to obtain a first filtrate;

[0043] (b2”) The first filtrate is further filtered using a second filter material to obtain a second filtrate;

[0044] in:

[0045] The pore size of the first filter material is larger than that of the second filter material. Preferably, the pore size of the first filter material is ≤10 micrometers, and the pore size of the second filter material is ≤0.45 micrometers; and / or

[0046] The first filter material comprises quartz wool, preferably quartz wool with a pore size ≤ 10 micrometers; and / or

[0047] The second filter material comprises a microporous filter membrane, preferably a microporous filter membrane with a pore size ≤ 0.45 micrometers;

[0048] Preferably, the preliminary filtering includes the following sequential steps:

[0049] The product obtained from neutralization in step (b) is filtered using a first filter material, and water is added sequentially from the top layer for washing multiple times, preferably three times. The filtrates are then combined to obtain a first filtrate.

[0050] In any implementation, in the method:

[0051] The solvent removal in step (b) is performed by vacuum distillation, preferably at low temperature.

[0052] In any implementation, in the method:

[0053] Step (c) is carried out using a low-boiling-point organic solvent that is non-toxic to humans. Preferably, step (c) includes the following sequential steps:

[0054] (c1) Use a low-boiling-point organic solvent that is non-toxic to the human body to treat the urea obtained in step (b). 14 C. The crude product is dissolved and then filtered to obtain the filtrate.

[0055] (c2) The filtrate obtained in step (c1) is subjected to solvent removal treatment to obtain urea- 14 C;

[0056] Preferably, the low-boiling-point organic solvent that is non-toxic to the human body is pharmaceutical-grade anhydrous ethanol;

[0057] Preferably, the solvent removal is performed under vacuum drying.

[0058] In any implementation, in the method:

[0059] The urea in step (c) 14 C does not contain biuret and / or triuret and / or cyanuric acid.

[0060] In any embodiment, the method is carried out using a reaction system comprising: a first container configured to contain a first reactant; a second container configured to contain a second reactant and communicatively connected to the first container such that the second reactant can enter the first container; and a third container configured to receive products obtained from the reaction in the first container from the first container, wherein the first container is non-horizontally arranged such that a first end of two opposing ends of the first container is vertically higher than a second end, wherein a filter is disposed at at least one of the first and second ends, wherein the first container is provided with an inlet sub-port and an outlet sub-port at the first end, and the third container is provided with another inlet sub-port and an outlet sub-port, wherein the second and third containers are communicatively connected to the first container at the second ends, and wherein the reaction system further comprises a heating unit configured to heat the first container.

[0061] According to an embodiment of this disclosure, a filtration device is arranged in the connecting pipe between the first container and the third container.

[0062] According to embodiments of this disclosure, the filtration device includes a microporous filtration membrane.

[0063] According to an embodiment of this disclosure, the heating unit includes a surrounding high-temperature furnace and a heating jacket, which respectively surround the first container and have different heating temperature ranges.

[0064] According to an embodiment of this disclosure, the first container is a quartz tube.

[0065] According to embodiments of this disclosure, the first container has the same or different diameters along its length.

[0066] According to an embodiment of this disclosure, the diameter of the section of the first container near the first end is greater than the diameter of the section near the second end, that is, the diameter of the section vertically upward is greater than the diameter of the section vertically downward.

[0067] According to an embodiment of this disclosure, the first container is arranged vertically.

[0068] According to an embodiment of this disclosure, the first container branches off along a vertically upward segment.

[0069] According to an embodiment of the present disclosure, the reaction system further includes a fourth container configured to contain an inert gas, wherein the fourth container is in communication with the first container at a second end such that the inert gas can enter the first container.

[0070] According to an embodiment of this disclosure, a one-way regulating valve is provided in the connecting pipeline between the first container and the second, third, and fourth containers respectively.

[0071] According to embodiments of this disclosure, an inlet sub-port and an outlet sub-port, and another inlet sub-port and an outlet sub-port, are each equipped with a regulating valve.

[0072] According to embodiments of this disclosure, the filter is made of a material with good stability, especially a material that is resistant to high temperature, acid, and alkali, such as quartz wool, asbestos, or ceramic fiber.

[0073] The reaction system proposed in this disclosure can minimize operational complexity while ensuring the yield and purity of the final product. Furthermore, the reaction system can be made more flexible by matching a suitable first container according to the desired amount of product. Attached Figure Description

[0074] To better understand the purpose, features, advantages, and functions of this disclosure, reference can be made to the preferred embodiments shown in the accompanying drawings. The same reference numerals in the drawings refer to the same components. Those skilled in the art should understand that the drawings are intended to schematically illustrate preferred embodiments of this disclosure and are not intended to limit the scope of this disclosure; the components in the drawings are not drawn to scale.

[0075] The present disclosure is illustrated below with reference to the accompanying drawings.

[0076] Figure 1 An embodiment of the reaction system according to this disclosure is schematically shown;

[0077] Figure 2 Another embodiment of the reaction system according to this disclosure is illustrated schematically; and

[0078] Figures 3 to 5 Each of the following feasible embodiments of a first container for a reaction system according to the present disclosure is illustrated schematically. Detailed Implementation

[0079] The following describes in detail the method for preparing urea according to this disclosure. 14 The implementation of method C is described below. However, unnecessary detailed descriptions may be omitted. For example, detailed descriptions of well-known matters and repetitive descriptions of practically identical structures may be omitted. This is to avoid making the following description unnecessarily lengthy and to facilitate understanding by those skilled in the art. Furthermore, the accompanying drawings and the following description are provided to enable those skilled in the art to fully understand this disclosure and are not intended to limit the subject matter of the claims.

[0080] In this disclosure, "range" is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be combined arbitrarily; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60-120 and 80-110 are listed for a specific parameter, it is expected that ranges of 60-110 and 80-120 are also expected. Furthermore, if minimum range values ​​1 and 2 are listed, and if maximum range values ​​3, 4, and 5 are listed, then the following ranges are all expected: 1-3, 1-4, 1-5, 2-3, 2-4, and 2-5. In this disclosure, unless otherwise stated, the numerical range "ab" is a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" have been listed herein; "0-5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is described as an integer greater than or equal to 2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0081] The terms "first," "second," etc., used in this disclosure are used merely for clarity of description to distinguish between objects and do not limit the size, quantity, or other order of the objects they describe. Directional terms indicate orientations or positional relationships based on the orientations or positional relationships shown in the accompanying drawings, and are used solely for the purpose of describing this disclosure, not to indicate or imply that the objects referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as limiting this disclosure.

[0082] Unless otherwise specified, all embodiments and optional embodiments of this disclosure can be combined to form new technical solutions.

[0083] Unless otherwise specified, all steps in this disclosure may be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), indicating that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, the mention that the method may also include step (c) indicates that step (c) may be added to the method in any order; for example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc.

[0084] Unless otherwise specified, the terms “comprising,” “including,” “having,” “containing,” or any other variations thereof used in this disclosure are intended to cover non-exclusive inclusion.

[0085] Unless otherwise specified, the indefinite articles “a” and “an” preceding an element or component in this disclosure do not impose any limitation on the quantity requirement (i.e., the number of times) of the element or component. Therefore, “an” or “a” should be interpreted as including one or at least one, and the singular form of an element or component also includes the plural form, unless the quantity is clearly intended to define the singular form.

[0086] Furthermore, numerous expressions will be mentioned in the following description, which are defined to have the following meanings.

[0087] The term "urea" 14 C" is also known as " 14 "C-Urea" has the following chemical structural formula: The CAS number is 594-05-8.

[0088] The term "carbonate" 14 "C" refers to a radioactive nuclide. 14 C replaces the stable isotope carbon in carbonates. 12 C, and with 14 Radiolabeled compounds with C as the label.

[0089] The term "cyanamide salt" 14 "C" refers to a radioactive nuclide. 14 C-substituted stable isotopic carbon in cyanamide salts 12 C, and with 14 Radiolabeled compounds with C as the label.

[0090] The term "neutralizing medium" refers to a substance that acts as a neutralizing agent.

[0091] The term "vacuum distillation," also known as "reduced pressure distillation," refers to the separation of substances that are difficult to separate when heated to boiling point at atmospheric pressure under reduced pressure.

[0092] As mentioned above, the existing technology for preparing urea- 14 Method C still has problems that cannot avoid the use of harmful solvents, simplify the operation steps, improve the yield and purity of the final product, improve the efficiency of the pyrolysis reaction, and can simultaneously carry out trace or large-scale synthesis while greatly reducing the transfer of radioactive materials. These problems urgently need to be solved.

[0093] New method for preparing urea - 14 C's method

[0094] To at least partially address one or more of the aforementioned problems and other potential problems, this disclosure provides a novel method for preparing urea-14C, comprising the following sequential steps:

[0095] (a) to make carbonate- 14 C reacts with an ammonia-containing gas to obtain cyanamide salt.14 C;

[0096] (b) Hydrolysis of the cyanamide salt obtained in step (a) 14 C, to obtain hydrolysis products, and then the hydrolysis products are subjected to neutralization, solid-liquid separation and solvent removal treatment in sequence to obtain urea- 14 C coarse product; and

[0097] (c) Purify the urea obtained in step (b) 14 Crude product C, to obtain urea- 14 C.

[0098] Step (a)

[0099] About carbonates - 14 C, without particular limitation, may be any of those commonly used in the art, such as one or more selected from the following group: barium carbonate - 14 C. Strontium carbonate 14 C. Calcium carbonate 14 C and lead carbonate - 14 C, preferably barium carbonate- 14 C.

[0100] There are no particular limitations on the reaction temperature in step (a), and those commonly used in the art can be used, but it is preferred to be carried out at 400-950°C, for example, 400°C, 410°C, 420°C, 430°C, 440°C, 450°C, 460°C, 470°C, 480°C, 490°C, 500°C, 510°C, 520°C, 530°C, 540°C, 550°C, 560°C, 570°C, 580°C, 590°C, 600°C, 610°C, 620°C, 630°C, etc. 0℃, 640℃, 650℃, 660℃, 670℃, 680℃, 690℃, 700℃, 710℃, 720℃, 730℃, 740℃, 750℃, 760℃, 770℃, 780℃, 790℃, 800℃, 810℃, 820℃, 830℃, 840℃, 850℃, 860℃, 870℃, 880℃, 890℃, 900℃, 910℃, 920℃, 930℃, 940℃, 950℃, or any value between these values. More preferably, step (a) is performed by gradually increasing the temperature from 400℃ to 950℃. By using a gradient temperature increase, it is beneficial to control the reaction rate and prevent the reaction from being too vigorous, resulting in a large negative pressure and excessive water vapor in the system, which would affect efficiency.

[0101] There are no particular limitations on the rate of gradient heating; those commonly used in the art can be used, but preferably 5-50℃ / min. For example, rates such as 5℃ / min, 6℃ / min, 7℃ / min, 8℃ / min, 9℃ / min, 10℃ / min, 11℃ / min, 12℃ / min, 13℃ / min, 14℃ / min, 15℃ / min, 16℃ / min, 17℃ / min, 18℃ / min, 19℃ / min, 20℃ / min, 21℃ / min, 22℃ / min, 23℃ / min, 24℃ / min, 25℃ / min, and 26℃ / min can be used. The speeds are 27℃ / min, 28℃ / min, 29℃ / min, 30℃ / min, 31℃ / min, 32℃ / min, 33℃ / min, 34℃ / min, 35℃ / min, 36℃ / min, 37℃ / min, 38℃ / min, 39℃ / min, 40℃ / min, 41℃ / min, 42℃ / min, 43℃ / min, 44℃ / min, 45℃ / min, 46℃ / min, 47℃ / min, 48℃ / min, 49℃ / min, 50℃ / min, or any value between these values, preferably 10℃ / min.

[0102] There are no particular limitations on the reaction time for step (a), and those commonly used in the art can be used, but it is preferred to be 2-6 hours, such as 2 hours, 3 hours, 4 hours, 5 hours, 6 hours or any value between these values, more preferably 3 hours.

[0103] There are no particular limitations on the ammonia-containing gas used in step (a). Any gas commonly used in the art can be used, such as ammonia or a mixture of ammonia and an inert gas, preferably a mixture of ammonia and an inert gas. Using a mixture of ammonia and an inert gas makes the reaction more stable and facilitates the removal of water vapor, thereby improving reaction efficiency.

[0104] There are no particular limitations on the ammonia content in the mixture of ammonia and inert gas; those commonly used in the art can be used, but preferably not less than 25% by volume, for example, not less than 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, and 58% by volume. 59% by volume, 60% by volume, 61% by volume, 62% by volume, 63% by volume, 64% by volume, 65% by volume, 66% by volume, 67% by volume, 68% by volume, 69% by volume, 70% by volume, 71% by volume, 72% by volume, 73% by volume, 74% by volume, 75% by volume, 76% by volume, 77% by volume, 78% by volume, 79% by volume, 80% by volume, 81% by volume, 82% by volume, 83% by volume, 84% by volume, 85% by volume, 86% by volume, 87% by volume, 88% by volume, 89% by volume, 90% by volume, 91% by volume, 92% by volume, 93% by volume, 94% by volume, 95% by volume, 96% by volume, 97% by volume, 98% by volume, 99% by volume, or any value between these values, preferably 50% by volume.

[0105] There are no particular limitations on the inert gas used; those commonly used in the art can be used, such as one or more selected from the group consisting of nitrogen, argon, helium, and neon, with argon being preferred.

[0106] There are no particular limitations on the flow rate of the ammonia-containing gas; those commonly used in the art can be used, but 1-40 mL / min / g carbonate is preferred. 14 C, for example, can be 1 mL / min / g carbonate - 14 C, 2 mL / min / g carbonate - 14 C, 3 mL / min / g carbonate - 14 C, 4 mL / min / g carbonate - 14 C, 5 mL / min / g carbonate - 14 C, 6 mL / min / g carbonate - 14 C, 7 mL / min / g carbonate - 14 C, 8 mL / min / g carbonate - 14 C, 9 mL / min / g carbonate - 14 C, 10 mL / min / g carbonate - 14C, 11 mL / min / g carbonate - 14 C, 12 mL / min / g carbonate - 14 C, 13 mL / min / g carbonate - 14 C, 14 mL / min / g carbonate - 14 C, 15 mL / min / g carbonate - 14 C, 16 mL / min / g carbonate - 14 C, 17 mL / min / g carbonate - 14 C, 18 mL / min / g carbonate-14C, 19 mL / min / g carbonate-14C, 20 mL / min / g carbonate- 14 C, 21 mL / min / g carbonate - 14 C, 22 mL / min / g carbonate - 14 C, 23 mL / min / g carbonate - 14 C, 24 mL / min / g carbonate - 14 C, 25 mL / min / g carbonate - 14 C, 26 mL / min / g carbonate - 14 C, 27 mL / min / g carbonate - 14 C, 28 mL / min / g carbonate - 14 C, 29 mL / min / g carbonate - 14 C, 30 mL / min / g carbonate - 14 C, 31 mL / min / g carbonate - 14 C, 32 mL / min / g carbonate - 14 C, 33 mL / min / g carbonate - 14 C, 34 mL / min / g carbonate - 14 C, 35 mL / min / g carbonate - 14 C, 36 mL / min / g carbonate - 14 C, 37 mL / min / g carbonate - 14 C, 38 mL / min / g carbonate - 14 C, 39 mL / min / g carbonate - 14 C, 40 mL / min / g carbonate - 14 C or any value between these values, preferably 15-20 mL / min / g carbonate. 14 C.

[0107] Step (b) - Hydrolysis

[0108] There are no particular limitations on the hydrolysis in step (b), and those methods commonly used in the art can be employed.

[0109] Preferably, in the first embodiment, the hydrolysis in step (b) comprises the following sequential steps:

[0110] (b1) The cyanamide salt obtained in step (a) is... 14 C dissolves in an aqueous solvent to obtain cyanamide salt- 14 Solution C; and

[0111] (b2) The cyanamide salt obtained in step (b1) 14 Acid is added to solution C to hydrolyze the solution and obtain the hydrolysis product.

[0112] There are no particular restrictions on the aqueous solvent; those commonly used in the field can be used, but pure water is preferred.

[0113] There are no particular limitations on the amount of aqueous solvent added; those commonly used in the art can be used. However, preferably, the amount should be relative to the amount of carbonate used in step (a). 14 C, the amount of water added is 10-100mL or 20-90mL or 40-80mL, for example, it can be 10mL, 20mL, 30mL, 40mL, 50mL, 60mL, 70mL, 80mL, 90mL, 100mL or any value between these values, preferably 60mL.

[0114] There are no particular limitations on the acid used; those commonly used in the art can be employed, but strong acids are preferred. Typically, the acid is selected from one or more of the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and nitric acid, with sulfuric acid being preferred.

[0115] Regarding the acid and the carbonate used in step (a) - 14 The molar ratio of C is not particularly limited and can be those commonly used in the art, but is preferably (2.5-10):1 or (4-6):1. For example, it can be 2.5:1, 3:1, 4:1, 5:1, 6:1 or any value between these values, preferably 5:1.

[0116] There are no particular limitations on the hydrolysis time in step (b2), and those commonly used in the art can be used, but it is preferred to be 12-36 hours, for example, it can be 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours or any value between these values.

[0117] There are no particular limitations on the implementation temperature of steps (b1) and / or (b2), and those commonly used in the art can be used, but preferably 30-60°C, for example, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C or any value between these values.

[0118] Regarding steps (b1) and / or (b2), they are preferably carried out under the protection of an inert gas, which is optionally selected from one or more of the group consisting of nitrogen, argon, helium and neon, with argon being preferred.

[0119] Preferably, in the second embodiment, the hydrolysis of step (b) includes the following steps: causing the cyanamide salt obtained in step (a) to... 14 C is dissolved in a dilute acid solution and hydrolyzed to obtain the hydrolysis product.

[0120] Regarding the amount of dilute acid solution in step (b) of the second embodiment, it is relative to the amount of carbonate used in step (a) per gram. 14 C is 10-100mL, 20-90mL, or 40-80mL, for example, it can be 10mL, 20mL, 30mL, 40mL, 50mL, 60mL, 70mL, 80mL, 90mL, 100mL or any value between these values, preferably 60mL.

[0121] There are no particular limitations on the implementation temperature of step (b) in the second embodiment. Temperatures commonly used in the art can be used, but 30-60°C is preferred. For example, it can be 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, or any value between these values.

[0122] Regarding step (b) in the second embodiment, it is preferably carried out under the protection of an inert gas, wherein the inert gas is optionally selected from one or more of the following group: nitrogen, argon, helium and neon, preferably argon.

[0123] There are no particular limitations on the hydrolysis time of step (b) in the second embodiment. Those commonly used in the art can be used, but it is preferred to be 12-36 hours, for example, it can be 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours or any value between these values.

[0124] There are no particular limitations on the dilute acid solution used; those commonly used in the art can be employed, such as a mixture of acid and solvent.

[0125] There are no particular limitations on the acid used, and those commonly used in the art can be used. However, preferably, the acid is selected from one or more of the following group: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and nitric acid, and more preferably sulfuric acid.

[0126] There are no particular limitations on the solvent used; those commonly used in the art can be used, such as aqueous solvents, and more preferably pure water.

[0127] There are no particular limitations on the volume ratio of the acid to the solvent, and those commonly used in the art can be used. However, preferably, the volume ratio of the acid to the solvent is 1:(5-40) or 1:(10-30), for example, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20. 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49, 1:50.

[0128] The inventors unexpectedly discovered that the second embodiment described above is slightly superior to the first embodiment. This is because the direct addition of dilute acid inhibits the condensation of barium cyanamide, reduces impurity content, and thus helps to improve the yield and productivity of the final product.

[0129] Step (b) - Neutralization

[0130] There are no particular restrictions on the neutralization in step (b), and it can be done in the manner commonly used in the art, such as by adding a neutralizing medium.

[0131] Preferably, the neutralization in step (b) comprises the following consecutive steps:

[0132] (b1') Add a neutralizing medium to the hydrolysis product of step (b); and

[0133] (b2') Neutralize for 0.5-5 hours at 30-60°C and / or under inert gas protection and / or with stirring;

[0134] There are no particular limitations on the neutralizing medium; those commonly used in the art can be used. However, preferably, the solubility of the neutralizing medium in the solvent of the hydrolysis product at 20°C is no greater than 0.01 g / 100 g solvent, more preferably no greater than 0.001 g / 100 g solvent, and even more preferably no greater than 0.0001 g / 100 g solvent. Optionally, the neutralizing medium is a carbonate and / or a sulfite and / or a water-insoluble hydroxide and / or other basic salt and / or other oxide. The carbonate is preferably selected from one or more of the following: barium carbonate, strontium carbonate, calcium carbonate, lead carbonate, magnesium carbonate, and zinc carbonate, more preferably barium carbonate. The sulfite is preferably selected from barium sulfite and / or calcium sulfite. The water-insoluble hydroxide is preferably selected from one or more of the following: lead hydroxide, strontium hydroxide, calcium hydroxide, and magnesium hydroxide. The other basic salt is preferably basic lead carbonate. The other oxide is preferably selected from one or more of the following: lead oxide, silver oxide, lead tetroxide, magnesium oxide, zinc oxide, and copper oxide. Neutralizing sulfuric acid hydrolysate with a neutralizing medium with extremely low solubility not only achieves the neutralization purpose but also, because it is insoluble in water, will not dissolve in water even if added in excess. This eliminates the need for pH control or other endpoint measures, making the neutralization process very simple and easy to perform, and readily repeatable. It is also highly effective for neutralizing radioactive nuclides. More preferably, when hydrochloric acid and / or hydrobromic acid and / or hydroiodic acid are used for hydrolysis, the neutralizing medium should preferably be one or more of silver carbonate, silver hydroxide (or silver oxide), lead carbonate, lead hydroxide, basic lead carbonate, lead tetroxide, and lead oxide.

[0135] There are no particular limitations on the molar ratio of the neutralizing medium to the acid used in the hydrolysis process of step (b), and those commonly used in the art can be used, but preferably (1-3):1, for example, 1:1, 1:2 or 3:1.

[0136] There are no particular limitations on the inert gas used; those commonly used in the art can be used, such as one or more selected from the group consisting of nitrogen, argon, helium, and neon, with argon being preferred.

[0137] In a preferred embodiment, the step of detecting the pH value of the system is not included after the neutralization step in step (b).

[0138] The implementation temperature of step (b2') can be, for example, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, or any value between these values, preferably 40°C.

[0139] Regarding the implementation time of step (b2'), it can be, for example, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours or any value between these, preferably 1-2 hours.

[0140] Step (b) - Solid-Liquid Separation

[0141] There are no particular limitations on the solid-liquid separation in step (b), and methods commonly used in the art, such as filtration, can be employed.

[0142] Preferably, the solid-liquid separation in step (b) comprises the following sequential steps:

[0143] (b1”) The product obtained by neutralization in step (b) is initially filtered using a first filter material to obtain a first filtrate;

[0144] (b2”) The first filtrate is further filtered using a second filter material to obtain a second filtrate;

[0145] in:

[0146] The pore size of the first filter material is larger than that of the second filter material. Preferably, the pore size of the first filter material is ≤10 micrometers, and the pore size of the second filter material is ≤0.45 micrometers; and / or

[0147] The first filter material comprises silica wool; and / or

[0148] The second filter material comprises a microporous filter membrane;

[0149] There are no particular limitations on the preliminary filtering, and methods commonly used in the art can be employed. However, preferably, the preliminary filtering includes the following sequential steps:

[0150] The product obtained by neutralization in step (b) is filtered using the first filter material. Water is added from the upper layer to wash the product multiple times, preferably three times, and the filtrates are combined to obtain the first filtrate.

[0151] There are no particular restrictions on the pore size of the quartz wool. Those commonly used in the art can be used, such as quartz wool with a pore size ≤ 10 micrometers, such as 1 micrometer, 2 micrometers, 3 micrometers, 4 micrometers, 5 micrometers, 6 micrometers, 7 micrometers, 8 micrometers, 9 micrometers, 10 micrometers or any value between these values.

[0152] There are no particular limitations on the pore size of the microporous filter membrane. Those commonly used in the art can be used, such as microporous filter membranes with a pore size ≤ 0.45 micrometers, such as 0.1 micrometer, 0.2 micrometer, 0.3 micrometer, 0.4 micrometer, 0.45 micrometer or any value between these values.

[0153] By using two filtration processes with different pore sizes, both impurity removal and filtration efficiency can be achieved, which helps to improve the purity and yield of the final product while simplifying the preparation process.

[0154] Step (b) - Solvent Removal

[0155] There are no particular limitations on the solvent removal in step (b), and methods commonly used in the art can be employed, such as vacuum distillation; preferably, the vacuum distillation is carried out at low temperature.

[0156] Step (c)

[0157] There are no particular limitations on step (c), and it can be carried out in the manner commonly used in the art. For example, step (c) can be carried out using a low-boiling-point organic solvent that is non-toxic to the human body. Preferably, step (c) includes the following sequential steps:

[0158] (c1) Use a low-boiling-point organic solvent that is non-toxic to the human body to treat the urea obtained in step (b). 14 C. The crude product is dissolved and then filtered to obtain the filtrate.

[0159] (c2) The filtrate obtained in step (c1) is subjected to solvent removal treatment to obtain urea- 14 C.

[0160] There are no particular limitations regarding the use of low-boiling-point organic solvents that are non-toxic to humans; those commonly used in the field can be used, but pharmaceutical-grade anhydrous ethanol is preferred. Using pharmaceutical-grade ethanol as the extraction solvent can significantly reduce urea levels. 14 Inorganic salt impurities in C, along with pharmaceutical ethanol and subsequent urea- 14 The solvent used in formulation C is consistent, avoiding the use of other harmful solvents and reducing costs. It is both safe and reliable, and effectively removes inorganic salts for purification. This facilitates the synthesis of pharmaceutical-grade urea. 14 C, because it involves drug safety issues, pharmaceutical-grade urea -14 Product C has strict requirements regarding purity and the presence of toxic impurities.

[0161] In a preferred embodiment, the solvent removal is performed under vacuum drying.

[0162] In a preferred embodiment, the urea in step (c) - 14 C does not contain biuret and / or triuret and / or cyanuric acid.

[0163] Reaction System

[0164] To at least partially solve one or more of the above-mentioned problems and other potential problems, this disclosure provides methods for implementing the above-described method for preparing urea. 14 The reaction system 1 of method C includes a first container 10, a second container 20 connected to the first container 10 via a pipe 50B, and a third container 30 connected to the first container 10 via a pipe 50E.

[0165] The first container 10 is configured to contain a first reactant. The second container 20 is configured to contain a second reactant. The third container 30 is configured to receive the product obtained from the reaction in the first container 10. Here, the corresponding reactants may be gaseous, liquid, solid, or other states, depending on the article to be prepared by the reaction system 1. Preferably, the solid may be in particulate or powder form.

[0166] In addition, other substances that promote the reaction can be delivered to the first container 10, which will be further explained below.

[0167] The reactants involved in the reaction can react in the first container 10, so the reactants contained in the second container can be transferred to the first container. The product obtained from the reaction in the first container 10 can be transferred to the third container 30 for further processing.

[0168] The first container 10 has an open first end 11A and a second end 11B positioned opposite each other in the longitudinal direction. Preferably, in the reaction system 1, the first container 10 is arranged non-horizontally, such that the first end 11A of the first container 10 is vertically higher than the second end 11B. Exemplarily, Figure 1 The first container 10 is shown to be arranged vertically, that is, the first container 10 is arranged to be perpendicular to the horizontal plane.

[0169] The first container 10 may be constructed as a cylindrical body. For example, the first container 10 is a quartz tube.

[0170] The first end 11A and the second end 11B of the first container 10 may be provided with end caps 12A and 12B respectively. The end caps may be provided with ports 14A and 14B respectively. The ports may have a corresponding number of inlet sub-ports and / or outlet sub-ports as needed.

[0171] exist Figure 1 In the reaction system 1, port 14A located at the first end 11A has an inlet sub-port and an outlet sub-port, which are connected to pipes 50A and 50D respectively; similarly, port 14A located at the second end 11B may also have an inlet sub-port and an outlet sub-port, which are connected to pipes 50B and 50E connected to the second container 20 and the third container 30 respectively. Therefore, the second container 20 and the third container 30 are connected to the first container 10 at the second end 11B.

[0172] The third container 30 can also be configured with an inlet sub-port and an outlet sub-port, which are connected to pipelines 50F and 50G respectively.

[0173] When the reactants contained in the first container 30 are in granular or powder form, a filter 70 may be arranged at at least one of the first end 11A and the second end 11B to prevent the reactants from undesirably entering the pipeline through the first end 11A and the second end 11B and causing blockage. The filter 70 may be made of a material with good stability, especially a material that is resistant to high temperatures, acids, and alkalis. For example, the filter may be made of quartz wool, asbestos, ceramic fibers, etc. Of course, other suitable filters may be provided according to the actual reaction requirements.

[0174] The reaction system 1 also includes a heating unit 60 configured to heat the first container 10.

[0175] For example, the heating unit may be configured as an adjustable heating unit so that the first container 10 can be heated at different temperatures.

[0176] For example, the heating unit 60 may include a surrounding high-temperature furnace and a heating jacket, which respectively surround the first container and have different heating temperature ranges, i.e., the surrounding high-temperature furnace may have a higher heating temperature than the heating jacket, wherein the surrounding high-temperature furnace and the heating jacket may be interchangeable to meet the heating requirements under the corresponding reaction conditions.

[0177] For example, if technically feasible, the heating unit 60 may also be configured to have a first heating unit and a second heating unit respectively surrounding the first container 10, having different heating temperature ranges, and the first heating unit and the second heating unit may be selectively activated as needed without replacement, so that the first container can operate in different temperature ranges.

[0178] To further improve the filtration effect, a filter device 54 can be arranged in the connecting pipe between the first container 10 and the third container 30, which can filter smaller particles than the filter 70. For example, the filter device 54 may include a microporous filter membrane.

[0179] Preferably, in order to control the flow of the reaction-promoting substances and the products generated in the reaction within the reaction system, valves, such as regulating valves, one-way regulating valves, or other suitable valves, may be provided as needed in the pipelines 50A, 50B, 50D, 50E, 50F, and 50G that supply the first container 10, the second container 20, and the third container 30. Regulating valves or one-way regulating valves can also be used to regulate flow rates. For example, regulating valve 52A in pipeline 50A can be configured to introduce fluid into the first container 10; regulating valve 52D in pipeline 50D can be configured to discharge fluid from the first container 10; one-way regulating valve 52B in pipeline 50B can be configured to allow reactants to be transported only from the second container to the first container; one-way regulating valve 52E in pipeline 52E can be configured to allow products to be transported only from the first container to the third container; regulating valve 52F in pipeline 50F can be configured to introduce fluid into the third container; and one-way regulating valve 52G in pipeline 50G can be configured to discharge fluid from the third container. It should be noted that the fluids mentioned here are merely exemplary, and where technically feasible, other forms of the object to be transported can also be transported through pipelines.

[0180] exist Figure 2 Another embodiment of the reaction system according to this disclosure is shown, which is related to... Figure 1 The reaction systems have partially identical structures. To avoid redundancy, regarding... Figure 2 The reaction system and Figure 1 For the same part of the reaction system, please refer to the reference for... Figure 1 The explanation provided is for reference only, while the following text only describes the relationship with... Figure 1 Different parts of the reaction system.

[0181] Figure 2 The reaction system and Figure 1 The difference in the reaction system lies in the number of sub-ports of port 14B assigned to the second end 11B. Specifically, port 14B at the second end 11B of the first container 10 also has additional sub-ports, which are assigned to... Figure 2The reaction system has a fourth container 40. Here, the other sub-port can be connected to the fourth container 40 via a conduit 50C to transfer the contents contained in the fourth container 40 to the first container 10. Preferably, a one-way regulating valve 52C is also arranged in the conduit 50C. Exemplarily, the one-way regulating valve 52C can be configured to allow flow only from the fourth container 40 to the first container 10. The fourth container 40 can be configured to contain reactants, inert gases, or other suitable substances.

[0182] To accommodate the desired amount of product, the first container 10 of the above-described reaction system 1 may have different constructions.

[0183] As in Figure 1 and Figure 2 As shown, the first container 10 is tubular and has different diameters along its entire length; that is, the first container 10 may have a first segment 10A and a second segment 10B, with the diameter of the first segment 10A being larger than the diameter of the second segment 10B. The lengths of the first segment 10A and the second segment 10B can be set as needed. Exemplarily, in use, when liquid and gas are present or generated simultaneously in the first container 10, the first segment 10A with the larger diameter is positioned above the second segment 10B to prevent or minimize the escape of gas, carrying liquid, from the first container 10 through port 14A.

[0184] exist Figures 3 to 5 Other possible implementations of the first container 10 are schematically shown in the figure.

[0185] Figure 3 The first container 10 shown is in the form of a hollow cylinder with the same diameter in the length direction.

[0186] Figure 4 The first container shown branches off in its vertically upward section, forming a forked portion 10C. The free end of the forked portion is open and equipped with a plug (not shown) that can be removed if needed. The body of the first container has the same diameter in the longitudinal direction.

[0187] Figure 5 The first container shown also branches off in its vertically upward section, forming a branch 10C. However, the first container may also have a section 10A that is larger in diameter than the other sections in the longitudinal direction.

[0188] Although Figures 3 to 5 The filter 70 is schematically shown at the second end 10B of the first container, but the filter 70 may also be arranged at the first end and / or the fork of the first container.

[0189] In embodiments not shown, a plurality of second containers may also be arranged, configured to contain a variety of different reactants participating in the reaction, and capable of communicating with the first container so that reactants can enter the first container when needed.

[0190] The following describes embodiments of this disclosure. The embodiments described below are exemplary and are only used to explain this disclosure, and should not be construed as limiting this disclosure. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all conventional products that can be obtained commercially.

[0191] Example 1

[0192] Preparation of urea- 14 The specific steps of method C are as follows:

[0193] (a) Synthesis of cyanamide salts - 14 C

[0194] Weigh 1g Ba 14 CO3 was introduced into the reaction tube, and then the air in the reaction tube was purged with argon. A mixture of ammonia and argon (volume ratio 1:1) was then introduced into the reaction tube at a flow rate of 15 mL / min. Simultaneously, the temperature of the reaction tube was raised from room temperature to 400°C using a high-temperature furnace (approximately 20-60 minutes). The temperature was then gradually increased from 400°C to 950°C using a gradient heating method (heating rate of 10°C / min). The reaction was allowed to proceed for approximately 3 hours. The high-temperature furnace was then removed, and the temperature was lowered while maintaining a gas flow rate of 15 mL / min until the temperature dropped below 600°C. Then, pure argon was introduced until no ammonia flowed out of the gas outlet, yielding white BaN. 14 CN;

[0195] (b) Hydrolysis of BaN 14 CN, neutralization, solid-liquid separation and solvent removal treatment

[0196] Attach a heating mantle to the reaction tube, controlling the temperature of the mantle at 30-60℃, and simultaneously introduce argon gas at a flow rate of 15 mL / min. Then, introduce the above-mentioned white BaN... 14 Add 60 mL of dilute sulfuric acid solution (a mixture of sulfuric acid and water in a volume ratio of 1:29) to CN and keep it warm for 24 hours for hydrolysis;

[0197] Then, add barium carbonate solid (molar equivalent of twice the amount of sulfuric acid added) to the above hydrolysis product, and continue to keep warm, aerate and stir for 2 hours to complete the neutralization (no pH value needs to be sampled and tested during the whole process).

[0198] After neutralization, the neutralization product in the reaction tube is filtered through a quartz wool-filled layer (8 micrometers pore size) to remove the solids. Water is added from the top layer and the mixture is washed three times. The filtrates are combined and then filtered through a microporous membrane (0.22 micrometers pore size). The resulting filtrate is then vacuum distilled at low temperature to remove water, yielding urea. 14 Crude product;

[0199] (c) Purification of urea - 14 C coarse product

[0200] The urea obtained in step (b) above - 14 Crude urea was dissolved in pharmaceutical-grade anhydrous ethanol, filtered, and then the anhydrous ethanol was removed under vacuum drying to obtain pure urea. 14 C.

[0201] Example 2

[0202] It is basically the same as Example 1, except that in step (a), instead of using a mixture of ammonia and argon, pure ammonia is used.

[0203] Example 3

[0204] The process is basically the same as in Example 1, except that in step (a), instead of using a gradient heating, the temperature is directly raised to 850°C and reacted for 3 hours.

[0205] Example 4

[0206] The process is basically the same as in Example 1, except that in step (b), instead of directly using dilute sulfuric acid solution for hydrolysis, water is added first, followed by concentrated sulfuric acid. The specific steps are as follows:

[0207] Attach a heating mantle to the reaction tube and control the temperature of the heating mantle to 50℃. Simultaneously, introduce argon gas at a flow rate of 15mL / min. Then, add 58mL of pure water through the liquid addition port and keep it warm for about 20-100 minutes. Next, add 2mL of concentrated sulfuric acid through the liquid addition port and keep it warm for 24 hours for hydrolysis.

[0208] Example 5

[0209] The process is basically the same as in Example 1, except that in step (b), barium hydroxide is used instead of carbonate for neutralization. The specific steps are as follows:

[0210] Then, add an appropriate amount of barium hydroxide to the above hydrolysis products to neutralize the excess sulfuric acid, and then pass CO2 gas into the solution to neutralize the excess barium hydroxide. Take a sample to detect the pH value until the solution pH value reaches 7 and then stop passing CO2 gas.

[0211] Example 6

[0212] The process is basically the same as in Example 1, except that in step (b), instead of filtration for solid-liquid separation, centrifugation is used. The specific steps are as follows:

[0213] After neutralization, the neutralization product in the reaction tube is centrifuged, and the supernatant is collected. The supernatant is then vacuum distilled at low temperature to remove water, yielding urea. 14 Crude product.

[0214] Example 7

[0215] The process is basically the same as in Example 1, except that in step (c), anhydrous n-propanol is used instead of pharmaceutical-grade anhydrous ethanol for purification. The specific steps are as follows:

[0216] The urea obtained in step (b) above - 14 Crude urea was dissolved in anhydrous n-propanol, filtered, and then the anhydrous n-propanol was removed under vacuum drying to obtain pure urea. 14 C.

[0217] Example 8

[0218] The above reaction system 1 was used to prepare urea. 14 C, specifically as follows:

[0219] The first container 10 of the reaction system 1 is configured to contain powdered barium carbonate. 14 C.

[0220] At this point, the quartz wool is first placed into the vertically downward section of the first container 10, and then the aforementioned powdered barium carbonate is placed inside. 14 C. In the powdered barium carbonate- 14 After C is loaded into the first container 10, quartz wool is loaded into the vertical section of the first container 10.

[0221] The second container 20 is configured to contain ammonia. In order to deliver ammonia to the first container 10 through the pipeline 50B, the one-way regulating valve 52B is opened, and the flow rate of ammonia is set through the one-way regulating valve 52B.

[0222] The fourth container 40 is configured to contain argon gas. In order to deliver argon gas to the first container 10 through the pipeline 50C, the one-way regulating valve 52C is opened and the flow rate of argon gas is set through the one-way regulating valve 52C.

[0223] Argon is used as a purging gas. Specifically, in powdered barium carbonate... 14After C is filled into the first container and the relevant pipeline is connected, open the one-way regulating valve 52C and open the regulating valve 52D of the pipeline 50D, which is located at the first end of the first container and serves as a discharge pipeline, so that argon gas can be introduced into the first container to discharge the air in the first container and avoid possible undesirable reactions.

[0224] In addition, argon gas is used to dilute ammonia gas (i.e., a mixture of the two is used) to control the reaction between ammonia gas and powdered barium carbonate during pyrolysis. 14 The reaction rate of C is reduced, and the water produced during the reaction is carried away.

[0225] A mixture of ammonia and argon is introduced into the first container 10 at its vertically downward end, i.e., its second end, wherein the ammonia content in the mixture is 50% by volume, and wherein, for each gram of carbonate... 14 C sets the flow rate of the ammonia-containing gas to 15 mL / min.

[0226] The heating unit 60 (i.e., the surrounding high-temperature furnace) surrounds the first container 10 circumferentially. At this time, the surrounding high-temperature furnace is set to raise the reaction temperature from 400°C to 950°C using a gradient heating method (heating rate of 10°C / min), and then react for about 3 hours.

[0227] Cyanamine salt was obtained via a pyrolysis reaction in the first container. 14 C. After the pyrolysis reaction is complete, cool the high-temperature furnace while maintaining a gas flow rate of 15 mL / min until the temperature is below 600°C. At this point, close the one-way regulating valve 52B to stop the supply of ammonia to the first container 10, and keep valve 52C open so that only argon gas is introduced into the first container until no ammonia gas flows out of the first container.

[0228] Next, we will discuss cyanamide salts. 14 C undergoes further processing, namely hydrolysis, neutralization, separation, and solvent removal, to obtain urea. 14 Crude product.

[0229] During hydrolysis, the temperature inside the first container is maintained at 50°C. To achieve this, the temperature of the heating unit is adjusted. The surrounding high-temperature furnace of the heating unit 60 is replaced with a heating jacket. During hydrolysis, a dilute acid solution (a mixture of sulfuric acid and water at a volume ratio of 1:29) is introduced into the first container 10 through a pipe 50A arranged on the upper side of the first container 10.

[0230] The hydrolysis reaction described above was carried out for 24 hours under insulated and argon atmosphere conditions. During this time, the one-way regulating valve 52C remained open, and the flow rate of the inert gas was adjusted by regulating the one-way regulating valve so that the inert gas flowed from bottom to top through the first container in the direction of arrow R.

[0231] To neutralize the excess acid added during hydrolysis, barium carbonate solid (molar equivalent of twice the amount of sulfuric acid added) was added to the first container by removing the end cap installed at the first end or bifurcation 10C of the first container, and then the container was kept warm, ventilated and stirred for 2 hours to complete the neutralization.

[0232] After neutralization, close valve 52C associated with the argon container and open the valve located at the junction for receiving urea from the first container. 14 The valve 52E is located on the pipe 50E of the third container 30 for solution C. The third container 30 is a vacuum container or has been pre-vacuumed, ensuring that the urea obtained in the first container... 14 Solution C is more easily transferred to the third container for purification. A vacuum pump (not shown) is connected to line 50G, which supplies the third container, and a one-way regulating valve 52G is arranged in line 50G.

[0233] During the transfer process, the filter 70 (i.e., quartz wool with a pore size of 8 micrometers) arranged in the first container and the filter device 54 arranged in the pipeline 50E filter the solution. The filter device 54 is a microporous filter membrane with a pore size of 0.22 micrometers.

[0234] During the transfer, the product in the first container is washed three times, and the washed water is transferred to the third container to transfer as much urea-14C as possible from the first container to the third container, reducing urea-14C concentration. 14 C remains in the first container.

[0235] In the urea- 14 After C is transferred to the third container, valve 52E in pipeline 50E can be closed, and the third container can be evacuated. At this time, the urea-containing material transferred to the third container is then subjected to low-temperature treatment. 14 The solution of C is subjected to vacuum distillation to remove water, thereby obtaining urea. 14 C crude product, in which water vapor is discharged from the third container through one-way regulating valve 50G.

[0236] A non-toxic, low-boiling-point organic solvent (pharmaceutical-grade anhydrous ethanol) is introduced into the third container via another conduit (50F) to obtain urea. After filtration, the urea is dried under vacuum to obtain urea. 14 Pure C.

[0237] The reaction system described above for preparing urea-14C enables the relevant high-temperature, hydrolysis, and neutralization operations to be carried out in a closed system, minimizing the involvement of radioactive nuclides. 14The transfer of liquid radioactive materials in C should be minimized to avoid contamination as much as possible. At the same time, the amount of materials and solvents involved in the reaction process should be minimized, as well as the pH monitoring of reactants or reaction solutions during the processing, in order to avoid generating excessive radioactive waste.

[0238] test

[0239] The test results of Examples 1-8 above are shown in Table 1 below.

[0240] Table 1

[0241]

[0242] As can be clearly seen from Table 1, the method disclosed herein for preparing urea- 14 The improved method of C avoids the use of harmful solvents, simplifies the operation steps, improves the yield and purity of the final product, improves the efficiency of the pyrolysis reaction, allows for simultaneous micro- or large-scale synthesis, and greatly reduces the transfer of radioactive materials, thus minimizing radioactive contamination and the generation of radioactive waste, thereby achieving beneficial technical effects.

[0243] It should be noted that this disclosure is not limited to the above-described embodiments. The above embodiments are merely examples, and any embodiments with the same essential structure and achieving the same effect as the technical concept within the scope of this disclosure are included in the technical scope of this disclosure. Furthermore, various modifications that can be conceived by those skilled in the art to the embodiments, and other ways of constructing by combining some of the constituent elements of the embodiments, are also included in the scope of this disclosure without departing from the spirit of this disclosure.

Claims

1. A process for the preparation of urea- 14 C comprising the following successive steps:​ (a) reacting a carbonate salt 14 C with a gas containing ammonia to obtain a cyanamide salt 14 C; (b) hydrolyzing the cyanamide salt obtained in step (a)- 14 C, to obtain a hydrolysis product, and then sequentially subjecting the hydrolysis product to neutralization, solid-liquid separation, and solvent removal treatments to obtain urea- 14 C, crude product; and (c) purifying the urea obtained in step (b) 14 C crude, to obtain urea 14 C; Optionally, the carbonate- 14 C is selected from one or more of the following groups: barium carbonate - 14 C. Strontium carbonate 14 C and calcium carbonate - 14 C; The neutralization in step (b) is carried out by adding a neutralizing medium, which includes the following sequential steps: (b1 ') adding a neutralization medium to the hydrolysate of step (b); and (b2') Neutralize for 0.5-5 hours under 30-60°C and / or inert gas protection and / or with stirring; The neutralizing medium has a solubility of no more than 0.01 g / 100 g solvent in the solvent of the hydrolysis product at 20 °C. The neutralizing medium is a carbonate, which is selected from one or more of the following groups: barium carbonate, strontium carbonate, and calcium carbonate; The hydrolysis of step (b) comprises the step of dissolving the cyanamide salt obtained in step (a) in a dilute acid solution at 30-60 °C and / or under inert gas protection 14 C is hydrolyzed in a dilute acid solution to obtain a hydrolysis product; The solid-liquid separation in step (b) is performed by filtration; The solid-liquid separation in step (b) includes the following sequential steps: (b1”) The product obtained by neutralization in step (b) is initially filtered using a first filter material to obtain a first filtrate; (b2”) The first filtrate is further filtered using a second filter material to obtain a second filtrate; The pore size of the first filter material is larger than that of the second filter material; The pore size of the first filter material is ≤10 micrometers, and the pore size of the second filter material is ≤0.45 micrometers.

2. The method of claim 1, wherein: The carbonate salt 14 C is barium carbonate 14 C.

3. The method according to claim 1, wherein: Step (a) is performed at 400-950°C; and / or The reaction in step (a) is carried out for 2-6 hours; and / or The ammonia-containing gas is ammonia or a mixture of ammonia and an inert gas, wherein the ammonia content in the mixture of ammonia and an inert gas is not less than 25% by volume. Optionally, the inert gas is selected from one or more of the following group: nitrogen, argon, helium, and neon; and / or The flow rate of the ammonia-containing gas is 1-40 mL / min / g carbonate 14 C.

4. The method according to claim 3, wherein: Step (a) is performed by gradually increasing the temperature from 400°C to 950°C, optionally at a rate of 5-50°C / min; and / or The reaction in step (a) is carried out for 3 hours; and / or The ammonia-containing gas is ammonia or a mixture of ammonia and an inert gas, wherein the ammonia content in the mixture of ammonia and an inert gas is not less than 50% by volume; and / or The flow rate of the ammonia-containing gas is 15-20 mL / min / g carbonate 14 C.

5. The method of claim 4, wherein: The gradient heating rate is 10 °C / min; and / or The inert gas is argon.

6. The method according to claim 1, wherein: The amount of the dilute acid solution is 10-100 mL per gram of the carbonate used in the step (a). 14 C, the amount of the dilute acid solution is 10-100 mL; and / or The dilute acid solution is a mixture of acid and solvent.

7. The method according to claim 6, wherein: The amount of the dilute acid solution is 20-90 mL relative to each gram of the carbonate used in the step (a). 14 C, the amount of the dilute acid solution is 20-90 mL.

8. The method according to claim 6, wherein: The amount of the dilute acid solution is 40-80 mL relative to each gram of the carbonate salt used in the step (a). 14 C, the amount of the dilute acid solution is 40-80 mL.

9. The method according to claim 6, wherein: Relative to the amount of carbonate used in step (a) - 14 C, the volume of the dilute acid solution is 60 mL.

10. The method of claim 6, wherein: Step (b) lasts 12-36 hours; and / or The acid is selected from one or more of the following group: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and nitric acid; and / or The solvent is an aqueous solvent; and / or The ratio of acid to solvent is 1:(5-40).

11. The method of claim 10, wherein: The acid is sulfuric acid; and / or The aqueous solvent is pure water; and / or The ratio of acid to solvent is 1:(10-30).

12. The method according to any one of claims 1-11, wherein: The step (b2') is performed at 40°C; and / or Step (b2') lasts for 1-2 hours; Optionally, the molar ratio of the added neutralizing medium to the acid used in the hydrolysis process of step (b) is (1-3):1; Optionally, the inert gas is selected from one or more of the group consisting of nitrogen, argon, helium, and neon.

13. The method according to claim 12, wherein: The inert gas is argon.

14. The method according to any one of claims 1-11, wherein: The carbonate is barium carbonate.

15. The method according to any one of claims 1-11, wherein: The step of neutralization in step (b) does not include the step of detecting the pH value of the system.

16. The method according to any one of claims 1-11, wherein: The first filter material comprises silica wool; and / or The second filter material comprises a microporous filter membrane.

17. The method of claim 16, wherein: The first filter material comprises quartz wool with a pore size ≤ 10 micrometers; and / or The second filter material comprises a microporous filter membrane with a pore size ≤ 0.45 micrometers.

18. The method according to any one of claims 1-11, wherein: The initial filtering includes the following sequential steps: The product obtained by neutralization in step (b) is filtered using the first filter material. Water is added from the upper layer to wash the product multiple times and the filtrates are combined to obtain the first filtrate.

19. The method of claim 18, wherein: Wash the top layer with water three times and combine the filtrates.

20. The method according to any one of claims 1-11, wherein: The solvent removal in step (b) is performed by vacuum distillation.

21. The method of claim 20, wherein: The vacuum distillation is carried out at low temperature.

22. The method according to any one of claims 1-11, wherein: Step (c) is performed using a low-boiling-point organic solvent that is non-toxic to humans.

23. The method according to claim 22, wherein: Step (c) includes the following consecutive steps: (c1) dissolving the urea obtained in step (b) in a low-boiling organic solvent which is not toxic to the human body 14 C The crude product was dissolved and then filtered to obtain a filtrate; (c2) subjecting the filtrate obtained in step (cl) to a solvent removal treatment to obtain urea 14 C.

24. The method according to claim 23, wherein: The low-boiling-point organic solvent that is non-toxic to the human body is pharmaceutical-grade anhydrous ethanol.

25. The method according to claim 23, wherein: The solvent removal in step (c2) is carried out under vacuum drying.

26. The method according to any one of claims 1-11, wherein: The urea of step (c)- 14 C does not contain biuret and / or triuret and / or cyanuric acid.

27. The method according to any one of claims 1-11, wherein it is carried out using a reaction system (1), said reaction system (1) comprising: A first container (10) is configured to contain a first reactant; The second container (20) is configured to contain the second reactant and is in communication with the first container (10) so that the second reactant can enter the first container (10); A third container (30) is configured to receive from the first container (10) the product obtained from the reaction in the first container (10). in, The first container (10) is arranged non-horizontally, such that the first end (11A) of the two opposite ends of the first container (10) is higher in the vertical direction than the second end (11B). A filter (70) is arranged at at least one of the first end (11A) and the second end (11B). The first container (10) is provided with an inlet sub-port and an outlet sub-port at the first end (11A), and the third container (30) is provided with another inlet sub-port and an outlet sub-port. The second container (20) and the third container (30) are connected to the first container (10) at the second end (11B). The reaction system (1) further includes a heating unit (60) configured to heat the first container (10).

28. The method according to claim 27, wherein a filter device (54) is arranged in the connecting pipe between the first container (10) and the third container (30) in the reaction system (1).

29. The method according to claim 28, wherein in the reaction system (1), the filtration device (54) comprises a microporous filtration membrane.

30. The method according to claim 27, wherein in the reaction system (1), the heating unit (60) includes a surrounding high-temperature furnace and a heating jacket, the surrounding high-temperature furnace and the heating jacket respectively surround the first container and have different heating temperature ranges.

31. The method according to claim 27, wherein in the reaction system (1), the first container (10) is a quartz tube.

32. The method according to claim 27, wherein in the reaction system (1), the first container (10) has the same or different diameters along its length.

33. The method according to claim 32, in the reaction system (1), the diameter of the section of the first container (10) near the first end (11A) is greater than the diameter of the section near the second end (11B).

34. The method according to claim 27, wherein in the reaction system (1), the first container (10) is arranged vertically.

35. The method according to claim 27, wherein in the reaction system (1), the first container (10) branches off in a vertically upward section.

36. The method according to claim 27, wherein the reaction system (1) further comprises a fourth container (40) configured to contain an inert gas, wherein, The fourth container (40) is connected to the first container (10) at the second end (11B) so that the inert gas can enter the first container (10).

37. The method according to claim 36, wherein in the reaction system (1), a one-way regulating valve is provided in the connecting pipeline between the first container (10) and the second container (20), the third container (30) and the fourth container (40).

38. The method according to claim 36, wherein in the reaction system (1), the inlet sub-port and the outlet sub-port and the other inlet sub-port and the outlet sub-port are respectively assigned regulating valves.

39. The method according to claim 27, wherein in the reaction system (1), the filter (70) is made of quartz wool, asbestos or ceramic fiber.

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