A process for the synthesis of urea 14 C]

Abstract

The application belongs to the technical field of synthesis, and particularly relates to a synthesis method of urea 14 C]. The synthesis method of urea 14 C] comprises the following steps: (1) reacting carbonate 14 C] with ammonia to obtain cyanamide salt 14 C]; (2) hydrolyzing the cyanamide salt 14 C] obtained in step (1) with concentrated sulfuric acid, and the hydrolysis temperature is 35-45 DEG C; (3) adjusting the pH of the hydrolysis product obtained in step (2) with ammonia water, and concentrating and purifying to obtain urea 14 C]. The synthesis method has the advantages of mild conditions, high reaction efficiency, high product yield (up to 95% or more), high purity (chemical purity is greater than or equal to 99%), and is suitable for large-scale preparation of key raw materials of a Helicobacter pylori diagnostic reagent.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a urea [ 14 The synthesis method of C]. Background Technology

[0002] Helicobacter pylori is the only bacterium currently known to survive in the human stomach. Studies have shown that Helicobacter pylori can cause gastritis, chronic gastroenteritis, gastric ulcers, duodenal ulcers, non-ulcer dyspepsia, and some types of gastric cancer. With more than 50% of the global population infected, Helicobacter pylori has received much attention from the medical community. The relationship between Helicobacter pylori infection and gastrointestinal diseases has been a hot topic and a challenge in global research on gastrointestinal infections for decades.

[0003] Currently, the main methods for detecting Helicobacter pylori infection include rapid urease test, Helicobacter pylori antibody test, and... 13 C or 14 Methods include C-breath test, pathological tissue section, and bacterial culture. 13 C or 14 The C-breath test has become the primary method for diagnosing Helicobacter pylori infection due to its ease of operation, specificity, and accuracy. Urea [ 14 C] is a key functional component in Helicobacter pylori infection detection kits. Currently, the production of urea... 14 The process of urea [C] is complex, involving many steps, which increases the probability of personnel exposure to radiation. Therefore, the existing technology still needs further improvement. (The text then abruptly shifts to a different topic: "Examining urea [...") 14 In the production process of C], yield and chemical purity are relatively more important factors, because a low yield will lead to the generation of more radioactive waste.

[0004] Existing technologies for synthesizing urea [ 14 C] Mainly as follows:

[0005] 1. Barium carbonate [ 14 C] is the initial material used to prepare potassium cyanide. 14 C], oxidized with potassium permanganate to obtain potassium cyanide. 14 C]; Potassium cyanide [ 14 C] Then, through reaction with ammonia, urea is obtained. 14 C). This method is used to extract barium carbonate [ 14 C] to the final urea [ 14 [C] involves three steps, resulting in a relatively long synthesis cycle, low overall yield, and the involvement of the highly toxic intermediate potassium cyanide in the intermediate process. 14 [C] poses a significant safety hazard.

[0006]

[0007] 2. Barium carbonate [ 14 [The initial material is reacted with lithium amino or sodium amino at 300℃~400℃ to obtain barium cyanamide.] 14 Urea is obtained after further purification via sulfuric acid hydrolysis. 14 C]. Due to the low melting points of lithium amino or sodium amino, it reacts with barium carbonate [ 14 After being mixed and heated to a certain temperature, the amino compound melts and reacts with barium carbonate. 14 The method allows for better contact, improving reaction efficiency. However, the post-processing is complex, the synthesis cycle is long, the contact time between operators and radioactive materials is increased, the molten amino metal compounds are highly corrosive to the container, and the final product cannot rule out the presence of inorganic salts.

[0008]

[0009] 3. Barium carbonate [ 14 Starting material, barium cyanamide was obtained by reacting it with dry, ultrapure ammonia gas in a closed reaction at 850°C. 14 Urea was obtained after purification by sulfuric acid hydrolysis. 14 C]. This method can produce urea with high biosafety and reliability without introducing an organic phase. 14 [C], and high-purity urea can be obtained without a recrystallization step. 14 [C]. This method involves two neutralization and purification processes after sulfuric acid hydrolysis: one method uses barium hydroxide + carbon dioxide / barium carbonate for neutralization (CN109896978A / CN117865852A), but this method requires sophisticated production equipment and involves numerous and complex subsequent steps, increasing the probability of operators being exposed to radiation. The other method uses ammonia for neutralization, but the yield and purity of the final product from the disclosed methods are both low (CN116920744A).

[0010]

[0011] Therefore, there is an urgent need in this field to develop a new type of urea that is easy to operate, safe and reliable, has a high yield, and ideal purity. 14 C] Synthesis process. Summary of the Invention

[0012] To address the aforementioned issues, this invention makes two key improvements to the existing process: first, it abandons the neutralization system based on barium hydroxide and carbon dioxide, and instead uses ammonia; second, it replaces dilute sulfuric acid with concentrated sulfuric acid as the hydrolysis reagent, and significantly increases the hydrolysis temperature. However, after determining that ammonia is used as the neutralizing agent and concentrated sulfuric acid as the hydrolysis reagent, the applicant found that increasing the hydrolysis temperature within the range of 10-30°C did not improve the product yield, which remained at around 85%. Unexpectedly, however, when the hydrolysis temperature was further increased to 40°C, the yield significantly increased to over 95% while maintaining a chemical purity of no less than 99%.

[0013] This invention provides a urea [ 14 The synthesis method of C] includes the following steps:

[0014] (1) To make carbonates [ 14 C] reacts with ammonia to obtain cyanamide salt. 14 C];

[0015] (2) Hydrolyze the cyanamide salt obtained in step (1) with concentrated sulfuric acid. 14 C], the hydrolysis temperature is 35℃~45℃;

[0016] (3) The hydrolysis product obtained in step (2) is adjusted to pH with ammonia, concentrated, and purified to obtain urea. 14 C).

[0017] In this invention, the "urea [ 14 C]”, its chemical structure is The CAS number is 594-05-8.

[0018] In this invention, the "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 a marker.

[0019] In this invention, the "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 a marker.

[0020] In this invention, the carbonate [ 14 [C], without particular limitation, may be 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 carbonate14 C] and lead carbonate 14 C).

[0021] In some specific embodiments of the present invention, the carbonate [ 14 C] is barium carbonate. 14 C).

[0022] In this invention, before step (1), the process includes: preheating at 200-300°C for 30-90 minutes, while simultaneously introducing ammonia gas to discharge air and moisture from the reactor.

[0023] In this invention, the reaction temperature in step (1) is 500~850℃.

[0024] In some specific embodiments of the present invention, the reaction temperature is 800°C.

[0025] In this invention, the reaction time of step (1) is not particularly limited and can be a time commonly used in the art, 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, and more preferably 3.5 hours.

[0026] In this invention, there are no particular restrictions on the use of solvents; commonly used solvents in the art can be used, but water for injection is preferred.

[0027] In some specific embodiments of the present invention, the hydrolysis temperature in step (2) is 40±2℃.

[0028] In this invention, in step (2), the carbonate [ 14 The molar ratio of C to concentrated sulfuric acid is 1:1~5.

[0029] In some specific embodiments of the present invention, the carbonate [ 14 The molar ratio of C to concentrated sulfuric acid is 1:4.

[0030] In this invention, there is no particular limitation on the hydrolysis time of step (2), which can be 20 to 50 hours, for example, any value between 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, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 49 hours or 50 hours.

[0031] In some specific embodiments of the present invention, the hydrolysis time in step (2) is 48 hours.

[0032] In this invention, in step (3), the pH is adjusted to 10~10.5 with ammonia.

[0033] In this invention, during step (3), the system temperature is controlled to not exceed 40°C during the pH adjustment process with ammonia.

[0034] In some specific embodiments of the present invention, after adjusting the pH with ammonia, the mixture is centrifuged, the supernatant is collected, concentrated, and the residue is extracted with anhydrous ethanol. The extract is then concentrated to obtain urea. 14 C] Pure product.

[0035] In some embodiments of the present invention, the centrifugation and collection of supernatant is repeated at least twice.

[0036] In some embodiments of the present invention, the anhydrous ethanol extraction is repeated at least three times.

[0037] The beneficial effects of this invention are:

[0038] This invention optimizes the synthesis conditions (hydrolysis temperature of 40℃), thereby improving process safety and ease of operation while also achieving high yield and high purity. The process route is simple, eliminating the need for low-temperature hydrolysis, and the post-neutralization treatment steps are straightforward (no need for CO2 introduction or prolonged precise pH control), significantly shortening the synthesis cycle and reducing operator exposure to radioactive materials. Furthermore, this method avoids the use of expensive barium hydroxide reagents, specialized gas treatment equipment, and cryogenic devices, resulting in lower raw material and equipment costs and easier industrial-scale production, thus facilitating urea […]. 14 [C] provides a brand-new solution for stable, safe, and economical production. Attached Figure Description

[0039] Figure 1 Urea [ 14 C] 1 H NMR spectrum;

[0040] Figure 2 Urea [ 14 The high-resolution mass spectrum of C]. Detailed Implementation

[0041] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. All features disclosed in this specification, or steps in all disclosed methods or processes, except for mutually exclusive features and / or steps, can be combined in any way.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0043] Example 1

[0044] Accurately weigh 1.33 ± 0.01 g (approximately 400 mCi) of barium carbonate using a 1 / 400 balance. 14 C] The solution was placed in a quartz boat and then placed in a tube furnace. The tube furnace heating program was set as follows: the first heating time was 30 minutes, the temperature was 230℃, and it was held for 1 hour; at the same time, the ammonia valve was opened to introduce high-purity ammonia into the tube furnace and control continuous bubbling; the second heating time was 1 hour, the temperature was 500~850℃ (specific temperatures are shown in Table 1), and it was held for another 3.5 hours. After the reaction was completed, it was naturally cooled to room temperature to obtain BaN. 14 The crude CN product is a white solid that requires no further processing and can be used directly in the next reaction step.

[0045] The above barium cyanide [ 14 C] The crude product was placed in a 50 mL round-bottom flask and dissolved and mixed with 10 mL of sterile water for injection. 2-5 eq (relative to barium carbonate) was weighed using a 1 / 400 balance. 14 [C], the specific equivalent of which is shown in Table 1) of concentrated sulfuric acid was slowly added dropwise to the system at room temperature, controlling the hydrolysis reaction temperature (specific temperatures are shown in Table 1). After the addition was complete, the system was placed at room temperature and the reaction was stirred for 15-48 hours (specific times are shown in Table 1). The pH of the system was adjusted to 10.0-10.5 with concentrated ammonia, and the system temperature was controlled not to exceed 40℃. The supernatant was collected by centrifugation, and the precipitate was mixed with sterile water for injection and centrifuged again (6000 r / min, 2 min). This process was repeated twice. The supernatants were combined and concentrated (controlling the water bath temperature at 50±5℃) to obtain ammonium sulfate and urea. 14 C] mixture, then add anhydrous ethanol (20~30mL, shake manually for about 30s) to the system, concentrate and desolvate twice, then extract the filtered product with anhydrous ethanol (20mL×3) (oil bath 80±5℃, stir for 15min), mix the extracts and filter and concentrate (water bath temperature controlled at 50±5℃) urea [ 14 C] is a white solid.

[0046] The urea obtained in this embodiment [ 14 The structure of the product was confirmed by spectral characterization: its proton nuclear magnetic resonance spectrum (NMR spectrum) Figure 1 ) and high-resolution mass spectrometry ( Figure 2 Both are related to urea. 14 The structure of [C] is consistent with the expected structure, confirming it as the target product.

[0047] Table 1. Specific experimental parameters, yield, and chemical purity data for Example 1.

[0048]

[0049] ND: No product detected / no product obtained

[0050] Comparative Example 1

[0051] Accurately weigh 1.33 ± 0.01 g (approximately 400 mCi) of barium carbonate using a 1 / 400 balance. 14 C] The solution was placed in a quartz boat and then placed in a tube furnace. The tube furnace heating program was set as follows: the initial heating time was 30 min, the temperature was 230℃, and it was held for 1 h; at the same time, the ammonia valve was opened to introduce high-purity ammonia into the tube furnace, and continuous bubbling was controlled; the temperature was then increased to 850℃ at 5℃ / min and held for 24 h. After the reaction was completed, the solution was allowed to cool naturally to room temperature to obtain BaN. 14 The crude CN product is a white solid that requires no further processing and can be used directly in the next reaction step.

[0052] The above barium cyanide [ 14 C] The crude product was placed in a 50 mL round-bottom flask and cooled using an ice-salt bath. 10 mL of 10% dilute sulfuric acid was added, maintaining the system temperature at 0°C. After the addition was complete, the system was kept at 0°C and stirred for 5 hours. The pH of the system was adjusted to 9.0 with concentrated ammonia, and the system temperature was maintained at 0°C. After concentration, ammonium sulfate and urea were obtained. 14 The mixture was further washed three times with anhydrous ethanol to obtain 308 mg (300.5 mCi) of urea. 14 C] is a white solid. The radioactivity yield is 75%, and the radiochemical purity is greater than 97.4%.

[0053] Comparative Example 2

[0054] Accurately weigh 1.33 ± 0.01 g (approximately 400 mCi) of barium carbonate using a 1 / 400 balance. 14 C] The solution was placed in a quartz boat and then placed in a tube furnace. The tube furnace heating program was set as follows: the first heating time was 30 minutes, the temperature was 230°C, and it was held for 1 hour; at the same time, the ammonia valve was opened to introduce high-purity ammonia into the tube furnace, and continuous bubbling was controlled; the second heating time was 1 hour, the temperature was 800°C, and it was held for 3.5 hours. After the reaction was completed, it was naturally cooled to room temperature to obtain BaN. 14 The crude CN product is a white solid that requires no further processing and can be used directly in the next reaction step.

[0055] The above barium cyanide [ 14C] The crude product was placed in a 50 mL round-bottom flask, and 10 mL of 10% dilute sulfuric acid was added at room temperature. After the addition was complete, the system was kept at room temperature and stirred for 48 h. The pH of the system was adjusted to 10.0-10.5 with concentrated ammonia, and the system temperature was controlled not to exceed 40℃. The supernatant was collected by centrifugation, and the precipitate was mixed with sterile water for injection and centrifuged again (6000 r / min, 2 min). This process was repeated twice. The supernatants were combined and concentrated (controlling the water bath temperature at 50±5℃) to obtain ammonium sulfate and urea. 14 C] mixture, then add anhydrous ethanol (20~30mL, shake manually for about 30s) to the system, concentrate and desolvate twice, then extract the filtered product with anhydrous ethanol (20mL×3) (oil bath 80±5℃, stir for 15min), mix the extracts and filter and concentrate (water bath temperature controlled at 50±5℃) to obtain 341mg (333mCi) urea [ 14 C] is a white solid. The radioactivity yield is 83%, and the radiochemical purity is greater than 96.9%.

[0056] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A type of urea [ 14 The synthesis method of C] is characterized by, Includes the following steps: (1) To make carbonates [ 14 C] reacts with ammonia to obtain cyanamide salt. 14 C], the cyanamide salt [ 14 C] No further processing is required; it can be used directly in the next reaction. (2) Hydrolyze the cyanamide salt obtained in step (1) with concentrated sulfuric acid. 14 C], the hydrolysis temperature is 35℃~45℃; (3) The hydrolysis product obtained in step (2) is adjusted to pH 10-10.5 with ammonia water, concentrated and purified to obtain urea. 14 C]; The carbonate [ 14 The molar ratio of C to concentrated sulfuric acid is 1:4; The carbonate [ 14 C] is selected from barium carbonate. 14 C], Strontium carbonate 14 C] and calcium carbonate 14 One or more of [C].

2. The synthesis method according to claim 1, characterized in that, The hydrolysis temperature is 40℃.

3. The synthesis method according to claim 1, characterized in that, The carbonate [ 14 C] is barium carbonate. 14 C).

4. The synthesis method according to claim 1, characterized in that, The reaction temperature in step (1) is 500~850℃.

5. The synthesis method according to claim 4, characterized in that, The reaction temperature is 800℃.

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