Method, device and application of in-situ preparation and reaction integration of hydrogen isotope gas

Abstract

This application relates to a method, apparatus, and application for the in-situ preparation and reaction integration of hydrogen isotope gas. This solution involves loading a gas generating chamber of a dual-chamber reactor with borohydride / borodeuteride / bortritide, a solid acidic substance, and a solid reaction medium. Upon heating, the solid reaction medium melts, triggering a reaction and generating hydrogen isotope gas in situ and quantitatively. The generated gas diffuses into the gas reaction chamber via a top channel or a pipe with a condenser coil, where it participates in reactions such as catalytic hydrogenation, deprotection, and radioactive synthesis. This invention addresses the safety hazards of high-pressure hydrogen cylinders, the high cost of deuterium gas, and the limited availability of tritium gas. It enables the immediate production and use of hydrogen isotope gas, and can precisely control gas pressure (0.1-30 MPa) and metering (milliliter level). It is particularly suitable for the synthesis of carbon-14- and tritium-labeled compounds and deuterated pharmaceuticals in radioactive laboratories, significantly improving the safety, convenience, and cost-effectiveness of hydrogen isotope gas use.

Description

Technical Field

[0001] The present application relates to the field of organic chemical synthesis, and specifically to methods, devices, and applications for in-situ preparation and reaction integration of hydrogen isotope gases (including hydrogen, deuterium, and tritium, the same below), especially to realizing the integration of in-situ preparation and reaction of hydrogen isotope gases on a laboratory scale. Background Art

[0002] Hydrogen isotope gases (H2, D2, T2 / HT) have important applications in organic synthesis, especially in the preparation of isotope-labeled compounds, such as catalytic hydrogenation reduction, deprotection reactions, and radiolabeled synthesis. However, current technologies have the following key issues:

[0003] 1. Safety hazards of high-pressure gases: Hydrogen and deuterium stored in traditional high-pressure cylinders are flammable, explosive, and highly permeable. There is a risk of explosion due to leakage during long-term storage or transportation. In addition, organic chemistry laboratories (especially radiolabeled synthesis laboratories) have a significantly longer service life of cylinders due to low frequency of use or small single usage (<100 mmol / time), which increases the risk of leakage.

[0004] 2. Limitations of alternative methods: Methods such as metal-acid reactions (balloon collection), water electrolysis, and hydrogen storage materials are only suitable for low-pressure (≤0.5 MPa) and small-scale scenarios. They cannot meet the requirements of high pressure (0.1-30 MPa), precise measurement (milliliter-level gas), and preventing aerosolization and diffusion during radioactive operations.

[0005] 3. Special challenges in radioactive operation: Tritium gas (T2 / HT) has strong radioactivity and permeability. The minimum purchase amount (2.00×10 15 Bq tritiated uranium) far exceeds the equivalent daily operating volume of Class B laboratories (≤4×10 9 Bq), resulting in most laboratories being unqualified to purchase it; trace amounts of tritium gas must be pressurized before tritiation reaction can occur.

[0006] 4. Cost and efficiency issues: Deuterium gas cylinders are expensive, and the remaining gas is seriously wasted in small-volume scenarios. The special requirements of tritium gas operations for negative pressure environments and anti-leakage equipment further increase the technical threshold and cost.

[0007] In summary, the existing technology lacks a method and device that can safely prepare hydrogen isotope gas in situ and integrate it with the reaction, and is particularly unable to meet the needs of radioactive laboratories for trace, high-pressure, and high-safety hydrogen isotope gas. Summary of the Invention

[0008] The purpose of this application is to address the above-mentioned problems existing in the prior art and to provide a method, device and application of in-situ preparation and reaction integration of hydrogen isotope gas. The method triggers the reaction of borohydride or borodeuteride or borotritide by heating and melting the solid reaction medium, and quantitatively prepares hydrogen isotope gas (H2, D2, T2 / HT) in situ in a dual-chamber reactor and directly transports it to the reaction chamber to participate in the catalytic reaction, thereby realizing on-demand generation, precise measurement and safe integrated application of gas in a high-pressure environment, solving the problems of source, qualification restriction and safe operation of hydrogen isotope gas in radioactive laboratories.

[0009] To achieve the above-mentioned application objectives, the present application adopts the following technical solution: A method for in-situ preparation and reaction integration of hydrogen isotope gas comprises the following steps:

[0010] placing a borohydride, a borodeuteride, or a borotritide, a solid acidic substance, and a solid reaction medium in a gas generating chamber of a reactor, wherein the hydrogen isotope gas is hydrogen, deuterium, or tritium;

[0011] placing reactants, catalyst, and / or solvent in a gas reaction chamber of a reactor;

[0012] After sealing the reactor, evacuate to 0.60–0.70 kPa;

[0013] The solid reaction medium is melted by heating, thereby triggering a reaction in a system consisting of borohydride, borodeuteride, borotritide, acidic substance, and the solid reaction medium, thereby generating hydrogen isotope gas in situ;

[0014] The generated hydrogen isotope gas is directly introduced into the gas reaction chamber to participate in the catalytic reaction of the reactants.

[0015] Furthermore, when preparing hydrogen, the borohydride includes one or more of lithium borohydride, sodium borohydride, potassium borohydride, magnesium borohydride, calcium borohydride, tetramethylammonium borohydride, tetraethylammonium borohydride and tetrabutylammonium borohydride; the solid acidic substance includes one or more of phenols, aromatic acids, fatty acids, sulfonic acids and phosphoric acid; and the solid reaction medium includes one or more of ice, glacial acetic acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

[0016] Furthermore, when preparing deuterium gas, the borodeuteride includes one or more of lithium borodeuteride, sodium borodeuteride, potassium borodeuteride, magnesium borodeuteride, calcium deuterium borohydride, and tetramethylammonium borodeuteride; the solid acidic substance is one or more of (hydroxy-D)phenols and perdeuterated phosphoric acid; and the solid reaction medium is one or more of heavy water pre-ice cubes, perdeuterated phosphoric acid, and dimethyl sulfoxide.

[0017] Furthermore, when preparing tritium gas, the borotritiate is sodium borotritiate and / or potassium borotritiate, the solid acidic substance includes one or more of citric acid, methanesulfonic acid, and benzenesulfonic acid, and the solid reaction medium includes one or more of ice cubes prefabricated with tritium water, ice cubes, glacial acetic acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0018] The device for in-situ preparation and reaction integration of the above-mentioned hydrogen isotope gas comprises:

[0019] The reactor body is divided into a gas generation chamber and a gas reaction chamber which are interconnected at the top;

[0020] The gas generation chamber is filled with solid reactants for preparing hydrogen isotope gas, and the gas reaction chamber is filled with reaction substrates, catalysts and solvents for hydrogen isotope gas reaction;

[0021] The gas generation chamber and the gas reaction chamber are connected through a top channel or a pipe with a condensing coil, and the condensing coil is immersed in a low-temperature cooling bath;

[0022] The reactor body is equipped with a reactor cover so that the maximum tolerable pressure of the double-chamber reactor is greater than or equal to 5.0 MPa;

[0023] The reactor cover is provided with an inlet / exhaust valve for vacuuming and controlling the reaction pressure.

[0024] Furthermore, the device is an integrated dual-chamber reactor, in which the gas generation chamber is directly connected to the gas reaction chamber, and is suitable for trace to semi-trace reactions.

[0025] Furthermore, the device is a split double-chamber reactor, in which the gas generation chamber and the gas reaction chamber are connected by a condensing coil, and is suitable for reactions ranging from gram to hundred-gram levels.

[0026] Furthermore, the device is a miniature integrated dual-chamber reactor with a volume of ≤1 mL, which is specifically used for ultra-trace tritium gas labeling reactions.

[0027] Furthermore, the sealing method between the reactor body and the reactor cover is, when the volume of the reactor is less than or equal to 10 mL, threaded sealing is adopted; when the volume of the reactor is between 10 and 100 mL, snap-fit sealing is adopted; when the volume of the reactor is greater than 100 mL, bolt sealing is adopted.

[0028] An application of hydrogen isotope gas in an organic synthesis reaction, using the above method to prepare hydrogen isotope gas in situ and replace the hydrogen, deuterium and tritium supplied by high-pressure cylinders in the reaction, comprising:

[0029] Catalytic hydrogenation reduction, including debenzylation, nitro reduction, and cyano reduction;

[0030] Synthesis of deuterated or tritium-labeled compounds;

[0031] Reductive amination reaction.

[0032] Compared with the prior art, this application has the following effects:

[0033] 1. Significantly improve security:

[0034] Eliminate high-pressure hazards: Traditional methods rely on high-pressure hydrogen isotope gas cylinders, which pose safety risks such as leakage and explosion. This invention eliminates the risks of transporting, storing, and using high-pressure cylinders by preparing hydrogen isotope gas in situ.

[0035] Reduced radiation risk: In radiolabeled synthesis experiments (such as those involving long-half-life nuclides such as carbon-14 and tritium), the present invention adopts a closed system to effectively reduce the risk of ionizing radiation caused by leakage of unsealed radioactive materials, thereby ensuring the safety of experimenters, workplaces and the surrounding environment.

[0036] The process is safe and controllable: The hydrogen isotope raw materials used to prepare hydrogen isotope gas are stable and highly safe. In the gas generation chamber, the system materials do not react before the solid reaction medium melts. The reaction is triggered only when the solid reaction medium melts and comes into contact with other materials. Excessive reaction heat is consumed by the melting process of the solid materials in the system and will not cause a significant increase in the temperature of the gas generation chamber.

[0037] 2. Convenient operation and improved efficiency:

[0038] Raw materials are easy to purchase in the market: The hydrogen isotope raw materials used to prepare hydrogen isotope gas are easy to purchase in the market at a low price.

[0039] Integrated design: Integrating gas preparation and reaction into the same device simplifies the experimental process, reduces the number of operation steps, and improves experimental efficiency.

[0040] Precise control of gas volume and pressure: By adjusting the amount of reactants, the volume and pressure of generated gas can be precisely controlled to meet different experimental requirements and improve the repeatability and reliability of the experiment.

[0041] 3. Wide range of applications:

[0042] Wide pressure range: The generated gas pressure range is wide (0.1~30 MPa), suitable for various scenarios from ultra-trace, trace to constant reaction, meeting the needs of different experimental scales.

[0043] Adaptable to multiple isotopes: It can not only prepare hydrogen, but also deuterium and tritium, providing more possibilities for isotope labeling synthesis and expanding the application scope of the technology.

[0044] 4. Reduce costs and waste:

[0045] Save purchase costs: No need to purchase expensive high-pressure gas cylinders, especially small-volume cylinders that have a supply gap due to insufficient market demand.

[0046] Prepare on demand and reduce waste: Prepare gas immediately according to experimental needs, avoiding waste caused by gas surplus and long-term storage, while reducing safety hazards caused by gas expiration or leakage.

[0047] 5. Enhanced environmental protection:

[0048] Reduce chemical waste: Compared with traditional methods, the present invention reduces chemical waste and environmental pollution, which is in line with the development trend of green chemistry.

[0049] These beneficial effects give the present invention significant advantages in the preparation and application of hydrogen isotope gas, which not only improves the safety and efficiency of the experiment, but also reduces costs and waste, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 This is a schematic structural diagram of an integrated dual-chamber reactor according to an embodiment of the present application;

[0051] Figure 2 This is a schematic structural diagram of a split dual-chamber reactor according to an embodiment of the present application;

[0052] Figure 3 Schematic diagram of the micro-integrated dual-chamber reactor structure of an embodiment of the present application.

[0053] In the figure, 1. Reactor body; 2. Gas generating chamber; 3. Gas reaction chamber; 4. Reactor inner lining pipe; 5. Reactor cover; 6. Inlet valve; 7. Exhaust valve; 8. Pressure gauge; 9. Valve knob; 10. Condensation coil; 11. Low-temperature cooling bath; 12. Inlet / exhaust valve. DETAILED DESCRIPTION

[0054] The following will be combined with the accompanying drawings in the embodiments of this application to clearly and completely describe the technical solutions in the embodiments of this application. Obviously, the embodiments described are only part of the embodiments of this application, not all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field are within the scope of protection of this application.

[0055] Those skilled in the art should understand that, in the disclosure of this application, the terms "longitudinal", "transverse", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside", "outside", etc., indicating the orientation or position relationship, are based on the orientation or position relationship shown in the accompanying drawings. They are only for the convenience of describing this application and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation. Therefore, the above terms cannot be understood as limiting this application.

[0056] To address the unique needs of organic chemistry laboratories (especially radiolabeled synthesis laboratories) for hydrogen isotope gases, the present invention provides a technical integration method and experimental device for the in-situ preparation and reaction of hydrogen isotope gases in organic chemistry laboratories, demonstrating its application effect in organic synthesis, especially isotope-labeled synthesis.

[0057] The basic principle of the present invention is to utilize the phase change caused by the gradual melting of a solid reaction medium during a heating process to trigger the mutually isolated borohydride / borodeuteride / bortritide to react with solid materials that can release hydrogen cations, deuterium cations, and tritium cations, respectively. With the help of reaction heat, the reaction is accelerated to achieve in-situ quantitative production of hydrogen / deuterium / tritium.

[0058] Notes: ① Asterisks (*) in the chemical formulas in the examples indicate sites labeled with radioactive carbon-14 isotopes. ② The purpose of these examples is to demonstrate the practical application of the hydrogen / deuterium / tritium preparation methods and corresponding experimental apparatus described in this patent in organic synthesis (particularly radioisotope-labeled synthesis). This does not negate the experimental effectiveness of directly using cylinders of hydrogen / deuterium / tritium, but rather provides an alternative hydrogen isotope gas source. ③ The examples illustrate the effectiveness and practicality of the present invention through limited experimental results, but the present invention is not limited to the reactions listed.

[0059] Example 1

[0060] This embodiment provides a method for preparing hydrogen as follows:

[0061] In the gas reaction chamber, borohydride, solid acidic substance and solid reaction medium are separately added; the solid reaction medium gradually melts during the heating process, contacts the borohydride and solid acidic substance, and then triggers a reaction to produce hydrogen; as the reaction is triggered, the reaction heat accelerates the reaction, quickly producing a certain amount of hydrogen.

[0062] Among them, the borohydride includes lithium borohydride, sodium borohydride, potassium borohydride, magnesium borohydride, calcium borohydride, tetramethylammonium borohydride, tetraethylammonium borohydride and tetrabutylammonium borohydride, preferably sodium borohydride and potassium borohydride.

[0063] Among them, the solid acidic substance includes phenols (phenol, p-chlorophenol, etc.), aromatic acids (benzoic acid, salicylic acid, phenylacetic acid, etc.), fatty acids (chloroacetic acid, citric acid, glutaric acid, succinic acid, etc.), sulfonic acids (methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), phosphoric acid or a mixture of the above components, preferably citric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

[0064] Among them, the solid reaction medium includes ice, glacial acetic acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., preferably ice, methanesulfonic acid, benzenesulfonic acid and citric acid.

[0065] Example 2

[0066] This embodiment provides a method for preparing deuterium gas as follows:

[0067] In a gas reaction chamber, deuterated boride, a solid fully deuterated acidic substance, and a solid reaction medium are separately fed into the chamber. The solid reaction medium gradually melts during the heating process, contacts the deuterated boride and the solid fully deuterated acidic substance, and then triggers a reaction to produce deuterium gas. As the reaction is triggered, the reaction heat accelerates the reaction, rapidly producing a quantitative amount of deuterium gas.

[0068] Among them, the borodeuterides include lithium borodeuteride, sodium borodeuteride, potassium borodeuteride, magnesium borodeuteride, calcium borodeuteride, tetramethylammonium borodeuteride, etc., preferably sodium borodeuteride and potassium borodeuteride.

[0069] The solid perdeuterated acidic substances include (hydroxy-D)phenols (such as (hydroxy-D)phenol, (hydroxy-D)p-chlorophenol, etc.), perdeuterated phosphoric acid, etc., preferably perdeuterated phosphoric acid.

[0070] The solid reaction medium includes heavy water prefabricated ice cubes, deuterated phosphoric acid and dimethyl sulfoxide, preferably heavy water prefabricated ice cubes.

[0071] Example 3

[0072] This embodiment provides a method for preparing tritium gas as follows:

[0073] In the gas reaction chamber, borotritide, solid acidic substance and solid reaction medium are separately added; the solid reaction medium gradually melts during the heating process, contacts borotritide and solid acidic substance, and then triggers a reaction to produce tritium gas; as the reaction is triggered, the reaction heat accelerates the reaction, quickly producing a certain amount of tritium gas.

[0074] Among them, borotritiates include sodium borotritiate and potassium borotritiate.

[0075] Among them, the solid acidic substance includes phenols (phenol, p-chlorophenol, etc.), aromatic acids (benzoic acid, salicylic acid, phenylacetic acid, etc.), fatty acids (chloroacetic acid, citric acid, glutaric acid, succinic acid, etc.), sulfonic acids (methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), phosphoric acid or a mixture of the above components, preferably citric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

[0076] Among them, the solid reaction medium includes ice cubes prefabricated with tritium water, ice cubes, glacial acetic acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., preferably water and methanesulfonic acid.

[0077] Example 4

[0078] like Figure 1 As shown, this embodiment provides an experimental device and operating method for in-situ preparation and reaction of hydrogen isotope gas, which are specifically as follows:

[0079] One-piece dual-chamber reactor, such as Figure 1 As shown (this figure is only a structural diagram and does not represent the dimensions, connection method, and other information of the actual device in use; the same applies below). The device is made of seamless stainless steel and includes a stainless steel reactor body 1 and a stainless steel reactor cover 5. The stainless steel reactor body 1 is provided with a gas generation chamber 2 and a gas reaction chamber 3. The gas generation chamber 2 and the gas reaction chamber 3 are connected through a top channel. After sealing, the maximum pressure resistance of the reactor is 5.0 MPa. The inner wall of the gas reaction chamber 3 is provided with a reactor liner tube 4. The stainless steel reactor cover 5 is provided with a pressure gauge 8, an air inlet valve 6, and an exhaust valve 7. Both valves are provided with a valve knob 9.

[0080] Under anaerobic conditions, gas generation chamber 2 is loaded with materials for hydrogen / deuterium production: solid borohydride or borodeuteride, solid acidic material, and solid reaction medium (temperature below -20°C). Gas reaction chamber 3 is loaded with materials involved in the hydrogen / deuterium reaction, including reactants, catalysts, and solvents. Once all materials are loaded, the stainless steel reactor lid 5 is installed and secured with a snap fastener (when the reactor volume is less than 100 mL and the pressure is below 0.5 MPa) or bolts (when the reactor volume is greater than 100 mL and the pressure is above 0.5 MPa) to ensure a tight seal. Then, inlet valve 6 is closed, and the system is evacuated to a vacuum of 0.60-0.70 kPa through exhaust valve 7. Exhaust valve 7 is then closed. Finally, the reactor is kept warm until the solid reaction medium in gas generation chamber 2 melts upon absorption, triggering a reaction to produce hydrogen / deuterium. The generated hydrogen / deuterium diffuses through the top channel into gas reaction chamber 3 to participate in subsequent reactions. The device is mainly used for organic synthesis reactions involving trace or semi-trace amounts of hydrogen / deuterium.

[0081] Micro-reaction:

[0082] The amount of reactant is ≤1 mmol or less than 100 mg, the reactor volume is ≤50 mL, and the gas pressure is ≤0.5 MPa. It is suitable for radiolabeled synthesis (such as carbon-14 labeled substrate mass less than 100 mg) and trace deuteration reaction (such as <1 mmol substrate).

[0083] Semi-micro reaction:

[0084] The amount of reactant is 1~10 mmol or the mass is 100 mg~1 g, the reactor volume is 50~100 mL, and the gas pressure is 0.5~1.0 MPa. It is suitable for the synthesis of conventional deuterated reagents (such as 1~10 mmol substrates), synthesis of radioactive intermediates (such as carbon-14 labeling 1~10 mmol) and small-batch synthesis of conventional intermediates (such as 1~10 mmol).

[0085] Example 5

[0086] like Figure 2 Based on Example 4, this embodiment provides a split dual-chamber reactor. This device is made of seamless stainless steel and consists of a gas generation chamber 2, a stainless steel condenser coil 10, a gas reaction chamber 3, a stainless steel reactor cover 5, and other components. After sealing, the reactor has a maximum pressure tolerance of 5.0 MPa. The top side of the gas generation chamber 2 is connected to the top side of the gas reaction chamber 3 via a seamless stainless steel pipe. A stainless steel condenser coil 10, immersed in a cooling bath, is connected to the seamless stainless steel pipe to remove volatile substances such as water from the hydrogen / deuterium generated in the gas generation chamber 2. The refrigerant temperature in the low-temperature cooling bath 11 can be determined based on experimental needs. A dry ice-ethanol cooling system is preferred for large-scale hydrogen / deuterium production. This device is a scaled-up version of the device in Example 4 and is primarily used for gram- to 100-gram-scale reactions involving hydrogen / deuterium. Its operation is identical to that of Example 4. When loading the gas generation chamber 2, ensure that the materials are fully cooled to below -20°C, and each material is stacked separately at the bottom of the reaction chamber.

[0087] Example 6

[0088] like Figure 3 As shown, based on Example 4, this embodiment provides a miniature integrated dual-chamber reactor. This device is made of seamless stainless steel. The gas generation chamber 2 is connected to the gas reaction chamber 3 via a top channel. After sealing, the reactor has a maximum pressure tolerance of 5.0 MPa. Compared to the device in Example 4, this embodiment is a miniature device, with only a single inlet / exhaust valve 12 on the stainless steel reactor lid 5. This device is primarily used for the preparation of trace tritium markers (total activity greater than 3.70E+9 Bq, but the amount of substance is far less than 1 mmol). Its operation method is similar to that of the device in Example 4.

[0089] Example 7: Palladium-carbon catalyzed debenzylation

[0090] Reaction formula:

[0091]

[0092] In an argon-protected nuclear glove box, 4-(benzyloxy)-2-methyl-1-[phenyl-U- 14 C6]Benzofuran-6-carboxylic acid (1-1, 3.45E+8 Bq, 0.56 mmol), 10% palladium on carbon (352 mg), and methanol (10 mL) were added to the gas reaction chamber 3 of a stainless steel integrated dual-chamber reactor (Apparatus I in the accompanying figure, volume approximately 38 mL). Sodium borohydride (115 mg), prefabricated ice (approximately 4.1 g, temperature ≤ -20°C), and prefabricated block methanesulfonic acid (298 mg, temperature ≤ -20°C) were added to the gas generation chamber 2 of the stainless steel integrated dual-chamber reactor. The stainless steel reactor lid 5 was installed and secured with a snap fastener to ensure a seal. The dual-chamber reactor was evacuated, and when the vacuum reached 0.60-0.70 kPa, exhaust valve 7 was closed. The reactor was placed in a room temperature oil bath, and the reaction solution in the gas reaction chamber 3 was electromagnetically stirred. The system pressure reached a maximum (0.49 MPa) after approximately 8 minutes of stirring, then slowly decreased. After the pressure stabilized, stirring was continued for 1 hour. The mixed liquid in the gas reaction chamber 3 was filtered through a diatomaceous earth layer, and the solvent was removed under reduced pressure to obtain a white solid 4-hydroxy-2-methyl-1-[phenyl-U- 14 C6]Benzofuran-6-carboxylic acid (1-2, 3.14E+8Bq, radiochemical yield 91%):

[0093] 1 H-NMR (400 MHz, DMSO- d 6) δ: 12.90(s,1H),7.69(s,1H),7.51(d,J=7.2Hz,2H),7.44–7.38(m,3H),7.35(d,J=7.2Hz,1H),6.72(s,1H),5.29(s,2H),2.46(s,3H). ESI-MSm / z:193.2[M+H] + .

[0094] It can be seen that the total activity of the radiolabeled substances decreased from 3.45E+8 Bq to 3.14E+8 Bq, indicating that the conversion rate of the radioactive raw material 1-1 was high and the radiochemical yield of the target compound 1-2 was high; 1 H-NMR showed that the methylene peak of the benzyl group (5.29 ppm, -CH2Ph) disappeared and the hydroxyl peak (12.90 ppm, -OH) appeared, proving that the debenzylation was successful; ESI-MS mass-to-charge ratio was 193.2 [M+H] +, which is consistent with the molecular weight of the target compound.

[0095] Note: Hydrogen preparation and its application in radiosynthesis – debenzylation. The experimental process (room temperature, high pressure, micromilligram-scale reaction) involved on-site hydrogen preparation and application, resulting in a good radiochemical yield of the target compound. The experimental process avoided the use of bottled high-pressure hydrogen, eliminating the potential safety risks associated with its transportation and storage.

[0096] Reaction type: catalytic hydrodebenzylation reaction (belongs to the synthesis of radiolabeled compounds, the substrate contains carbon-14 label).

[0097] Core objective: To verify the feasibility of the present invention's "in-situ hydrogen preparation-reaction integration" method in radioactive synthesis and achieve safe and efficient debenzylation.

[0098] Through this embodiment, the advantages of the "in situ preparation-reaction integration" technology of the present invention in terms of safety, convenience and effectiveness in radiolabeled synthesis are intuitively demonstrated, providing a breakthrough solution for the synthesis of isotope-labeled compounds.

[0099] Example 8: Palladium-carbon catalyzed nitro reduction

[0100] Reaction formula:

[0101]

[0102] In an argon-protected nuclear glove box, 4-nitro[phenyl-U- 14 [C6] Ethyl phenylcarbamate (2-1, 2.3798E+9 Bq, 1.2 mmol), 10% palladium on carbon (30 mg), and ethanol (12 mL) were added to the gas reaction chamber 3 of a stainless steel integrated dual-chamber reactor (Apparatus I in the accompanying figure, volume approximately 38 mL). Sodium borohydride (158 mg), prefabricated ice (approximately 4.4 g, temperature ≤ -20°C), and prefabricated block methanesulfonic acid (406 mg, temperature ≤ -20°C) were added to the gas generation chamber 2 of the stainless steel integrated dual-chamber reactor. The stainless steel reactor lid 5 was installed and secured with a snap fastener to ensure a seal. The dual-chamber reactor was evacuated, and when the vacuum reached 0.60-0.70 kPa, exhaust valve 7 was closed. The reactor was placed in a room temperature oil bath, and the reaction solution in the gas reaction chamber 3 was electromagnetically stirred. The system pressure reached a maximum (0.86 MPa) after approximately 10 minutes of stirring, then slowly decreased. After the pressure stabilized, stirring was continued for 40 minutes. The mixed solution in the gas reaction chamber 3 was filtered through a diatomaceous earth layer, and the solvent was removed under reduced pressure to obtain a white solid 4-amino[phenyl-U- 14 C6] Ethylphenylcarbamate (2-2, 2.189E+9 Bq, radiochemical yield 92%):

[0103] 1 H-NMR (400MHz, CDCl3) δ: 7.12(d,J=8.1Hz,2H),6.62(d,J=8.5Hz,2H),6.44(s,1H),4.19(q,J=7.1Hz,2H),3.37(brs,2H),1.28(t,J=7.1Hz,3H). MS-ESI m / z:181.1[M+H] + The results of H-NMR spectrum analysis were consistent with the data of non-labeled compounds reported in the literature (Molecules. 2018, 23(12), 3163; DOI: 10.3390 / molecules23123163).

[0104] It can be seen that the radioactivity decreased from 2.3798E+9 Bq to 2.189E+9 Bq, indicating that the raw material 2-1 was fully converted and the yield of the target compound 2-2 was high; 1 H-NMR showed the appearance of a characteristic amino broad peak (3.37 ppm, brs), and the chemical shift of the benzene ring hydrogen shifted to the upfield (7.12 / 6.62 ppm), consistent with the structural change of the nitro group reduced to the amino group; ESI-MS mass-to-charge ratio 181.1 [M+H] + , which is consistent with the molecular weight of the target compound (180.2 g / mol), proving that the product structure is correct.

[0105] Note: Hydrogen preparation and its application in radioactive synthesis—reduction of nitro groups to amino groups. Hydrogen was prepared and used on-site during the experimental process (micromilligram-scale reaction), and the radiochemical yield was close to that of conventional non-radioactive syntheses reported in the literature, demonstrating satisfactory experimental results.

[0106] Reaction type: catalytic hydrogenation nitro reduction ( ), which is a typical reaction in the synthesis of radiolabeled compounds.

[0107] Core Value: To verify the feasibility of the "in-situ hydrogen preparation-reaction integration" technology of the present invention in the nitro reduction of trace radioactive substrates, and at the same time prove that the gas pressure controllability (0.86 MPa) is equivalent to that of traditional cylinder gas.

[0108] Through this embodiment, the advantages of the present invention in safety, efficiency and cost control in the synthesis of radiolabeled compounds are further highlighted, providing a technical solution that is both innovative and practical for organic synthesis, especially in the field of isotope labeling.

[0109] Example 9: Palladium-carbon catalyzed nitro reduction

[0110] Reaction formula:

[0111]

[0112] In an argon-protected nuclear glove box, 5-methyl-3-nitro-4,5,6,7-[2- 14 C]tetrahydropyrazolo[1,5- a Pyrazine (3-1, 6.172E+8 Bq, 0.38 mmol), 10% palladium on carbon (16 mg), and ethanol (8 mL) were added to the gas reaction chamber 3 of a stainless steel integrated dual-chamber reactor (Apparatus I in the accompanying figure, volume approximately 38 mL). Sodium borohydride (80 mg), prefabricated ice (approximately 4.2 g, temperature ≤ -20°C), and prefabricated block benzenesulfonic acid (353 mg, temperature ≤ -20°C) were added to the gas generation chamber 2 of the stainless steel integrated dual-chamber reactor. The stainless steel reactor lid 5 was installed and secured with a snap fastener to ensure a tight seal. The dual-chamber reactor was evacuated, and when the vacuum reached 0.60-0.70 kPa, exhaust valve 7 was closed. The reactor was placed in a room temperature oil bath, and the reaction solution in the gas reaction chamber 3 was electromagnetically stirred. The system pressure reached its maximum (0.47 MPa) after approximately 10 minutes of stirring. After 2 hours of stirring, the pressure stabilized and stirring was continued for 15 minutes. The mixed liquid in the gas reaction chamber 3 was filtered through a diatomaceous earth layer and desolvated under reduced pressure to obtain a dark green colloid 5-methyl-4,5,6,7-[2- 14 C]tetrahydropyrazolo[1,5- a ]Pyrazin-3-amine (3-2, 5.801E+8 Bq, radiochemical yield 94%):

[0113] 1 H-NMR(400MHz, CDCl3) δ: 7.16(s,1H),4.13(t,J=5.7Hz,2H),3.56(s,2H),3.48(s,2H),2.86(t,J=5.7Hz,2H),2.52(s,3H). ESI-MS: m / z=155[M+2+H] + . 1 The H-NMR analysis data were consistent with the non-labeled substance reported in the literature (WO2013164323A1, 2013-11-07).

[0114] The obtained product 3-2 1 The H-NMR spectrum showed a broad peak of amino group (3.48 ppm, brs), and the chemical shifts of pyrazole ring and methyl group (2.52 ppm, s, -CH3) were consistent with the literature, proving that the nitro group was successfully reduced to amino group; ESI-MS mass-to-charge ratio was 155 [M+2+H] + (The molecular weight of the non-labeled compound 3-2 is M = 153 g / mol; the target compound 3-2 can be regarded as 14 C replaces one site in the non-labeled compound 3-2 molecule 12 C, 2 is14 C atomic weight and 12 C), which is consistent with the theoretical molecular weight.

[0115] Note: Hydrogen preparation and its application in radioactive synthesis – reduction of nitro groups to amino groups. Hydrogen was prepared and used on-site during the experimental process (micromilligram-scale reaction). The radiochemical yield of the target compound was close to that of conventional non-radioactive syntheses reported in the literature, and the results were very satisfactory.

[0116] Reaction type: catalytic hydrogenation nitro reduction ( ), the substrate contains carbon-14 ( 14 C) Labeling, which is a key step in the synthesis of radioisotope-labeled compounds.

[0117] Core Value: Verify the feasibility of this invention in the nitro reduction of heterocyclic radioactive substrates and prove the applicability of the technology to complex molecular structures; demonstrate the advantages of precise pressure control (0.47 MPa) and radiochemical yield (94%) for in-situ hydrogen preparation, and highlight the balance between safety and efficiency.

[0118] This example further highlights the advantages of the present invention in terms of safety, reaction efficiency, and cost control in the synthesis of radiolabeled compounds. In particular, it provides an efficient and safe technical path for the isotope labeling of heterocyclic drugs, thereby promoting technological progress in the field of radioactive synthesis.

[0119] Example 10: Palladium-carbon-catalyzed reduction of cyano groups to methyl groups

[0120] Reaction formula:

[0121]

[0122] In an argon-protected nuclear glove box, 4-[5-(4-[cyano- 14[C]-[(trifluoromethyl)-1-[(4-1-nitrophenyl)-3-(trifluoromethyl)pyrazol-1-yl)benzene-1-sulfonamide (4-1, 4.4082E+8 Bq, 0.23 mmol), 10% palladium on carbon (16 mg), and methanol (8 mL) were added to the gas reaction chamber 3 of a stainless steel integrated dual-chamber reactor (Apparatus I in the accompanying figure, volume 38 mL). Sodium borohydride (41 mg), prefabricated ice (approximately 3.8 g, temperature ≤ -20°C), and pre-pressed monolithic benzenesulfonic acid (174 mg) were added to the gas generation chamber 2 of the stainless steel integrated dual-chamber reactor. The stainless steel reactor lid 5 was installed and secured with a snap fastener. The vacuum level of the dual-chamber reactor was evacuated to 0.60-0.70 kPa, and the exhaust valve 7 was closed. The reactor was placed in an oil bath at room temperature, and the reaction solution in the gas reaction chamber 3 was stirred electromagnetically. The system pressure reached its maximum (0.38 MPa) after stirring for about 10 minutes, and then slowly decreased. After stirring for 16 hours, the pressure stabilized and continued stirring for 30 minutes. The mixed solution in the gas reaction chamber 3 was filtered through a diatomaceous earth layer and desolvated under reduced pressure to obtain a light yellow solid 4-[5-(4-[methyl- 14 C]methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzene-1-sulfonamide (4-2, 2.5567E+8 Bq, radiochemical yield 58%):

[0123] 1 H-NMR (400 MHz, DMSO- d 6) δ: 2.32(s,3H),7.17(s,1H),7.18–7.23(m,4H),7.37(brs,2H),7.52(d,J=8.6Hz,2H),7.85(d,J=8.6Hz,2H). ESI-MS m / z:382.0[M+H] + ,384.1[M+2+H] + The H NMR spectrum analysis data were consistent with those reported in the literature (J Labelled Comp Radiopharm, 2017, 60(4): 213-220; DOI: 10.1002 / jlcr.3492).

[0124] The obtained product 4-2 1 The H-NMR spectrum clearly shows a characteristic singlet peak of methyl (2.32 ppm,s, -CH3). The chemical shifts of the benzene ring and pyrazole ring are consistent with the literature, proving that the cyano group was successfully reduced to methyl. ESI-MS: mass-to-charge ratio 382 [M+H] + (The corresponding molecular weight of the non-labeled compound 4-2 is 381 g / mol), 384 [M+2+H] + (+2 is 14 C atomic mass and 12C), which is consistent with the theoretical value.

[0125] Reaction type: catalytic hydrogenation reduction of cyano groups ( ), which is a key functional group transformation reaction in the synthesis of radioisotope-labeled compounds.

[0126] Core Value: Verify the feasibility of the present invention in the reduction of cyano groups to methyl groups, especially for heterocyclic radioactive substrates containing trifluoromethyl groups; demonstrate the low-pressure adaptability (0.38 MPa) of in-situ hydrogen preparation and precise control of radioactive labeling, highlighting the compatibility of the technology with complex functional groups.

[0127] Note: Application in radioactive synthesis - reduction of cyano groups to methyl groups. During the experimental process (micromilligram-scale reaction), hydrogen was generated on-site for the reaction. The radiochemical yield of the target compound was close to that reported in the literature, and the experimental results were satisfactory.

[0128] This example further highlights the advantages of the present invention in terms of safety, selectivity, and cost control in the synthesis of radiolabeled compounds with complex functional groups. It provides a feasible technical path for isotope labeling reactions of special groups such as fluorine-containing and sulfur-containing groups, and promotes the development of radioactive synthesis technology in a more precise and safer direction.

[0129] Example 11: Palladium-carbon-catalyzed perdeuteration reaction of cyano groups

[0130] Preparation of [Methyl-D3] Celecoxib

[0131] Reaction formula:

[0132]

[0133] In an argon-protected glove box, 4-[5-(4-cyanophenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzene-1-sulfonamide (5-1, 397 mg), 10% palladium on carbon (16 mg), and perdeuterated methanol (8 mL) were added to the gas reaction chamber 3 of a stainless steel integrated dual-chamber reactor (Apparatus I in the accompanying figure, volume approximately 38 mL). Sodium perdeuterated borohydride (64 mg), pre-made ice cubes of heavy water (approximately 4.0 g, temperature ≤ -20°C), and pre-pressed monolithic perdeuterated phosphoric acid (162 mg, temperature ≤ -20°C) were added to the gas generation chamber 2 of the stainless steel integrated dual-chamber reactor. The stainless steel reactor lid 5 was installed and secured with a snap fastener to ensure a seal. The reactor was evacuated, and when the vacuum reached 0.60–0.70 kPa, the exhaust valve 7 was closed. The reactor was placed in a room temperature oil bath, and the reaction solution in the gas reaction chamber 3 was electromagnetically stirred. After stirring for approximately 10 minutes, the system pressure reached a maximum (0.34 MPa), then slowly decreased. After stirring for 16 hours, the pressure stabilized and was stirred for an additional 30 minutes. The mixture in gas reaction chamber 3 was filtered through a diatomaceous earth layer. After vacuum desolventization and flash silica gel column chromatography, a white solid, 4-[5-(4-(methyl-D3)methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzene-1-sulfonamide (5-2, 328 mg, 85% yield), was obtained:

[0134] 1 H-NMR (DMSO- d 6) δ:7.17–7.26(m,5H),7.51(s,2H),7.54(d,J=8.7Hz,2H),7.87(d,J=8.7Hz,2H). ESI-MS m / z:385.1[M+H] + The analysis data were consistent with those reported in the literature (J Labelled CompRadiopharm, 2017, 60(4): 213-220; DOI: 10.1002 / jlcr.3492).

[0135] The obtained product 5-2 1 The H-NMR spectrum showed no methyl hydrogen (H) signals (because all were deuterated), and the hydrogen signals on the benzene and pyrazole rings were consistent with the literature, proving that the cyano group was successfully reduced to a fully deuterated methyl group; ESI-MS mass-to-charge ratio was 385.1 [M+H] + (The corresponding molecular weight is 384 g / mol. The deuterated methyl group contributes 3 deuterium atoms, and the molecular weight increases by 3 compared with the non-deuterated compound 5-1), which is consistent with the theoretical value.

[0136] Note: This method is used in the preparation of deuterium-substituted mass spectrometry internal standards (general organic synthesis) for the reduction of cyano groups to perdeuterated methyl groups. The experimental procedure (micromilligram-scale reaction) efficiently and conveniently utilizes readily available raw materials to prepare small amounts of deuterium gas for the reaction. The yield of the target compound is close to that reported in the literature, resulting in very satisfactory results. This method utilizes readily available raw materials, sodium borodeuteride and heavy water, making it economical and eliminating the need for expensive cylinders of high-pressure deuterium gas, the waste of excess cylinders, and the safety risks associated with its storage.

[0137] Reaction type: catalytic deuterium cyanide reduction ( ), which is a key reaction in the synthesis of deuterated drugs and isotope internal standards.

[0138] Core Value: Verify the feasibility of this invention in the integration of in-situ deuterium gas preparation and deuteration reaction, and achieve efficient synthesis of high-purity fully deuterated methyl; demonstrate the low-cost advantage of deuterium gas preparation raw materials (fully deuterated sodium borohydride, heavy water ice), and solve the industry pain point of "small usage and high cost" of traditional deuterium gas cylinders.

[0139] Through this embodiment, the advantages of the present invention in the cost, product purity and safety of the synthesis of deuterated compounds are further highlighted, especially providing an efficient and convenient technical path for the development of deuterated drugs and the preparation of isotope internal standards, and promoting the transformation of deuteration technology from "high-cost special" to "economical and universal".

[0140] Example 11: Palladium-carbon-catalyzed reduction of cyano groups to aminomethyl groups

[0141] Reaction formula:

[0142]

[0143] In an argon-protected glove box, 4-[(4-cyanophenyl)(methoxy)methyl]-1-tert-butoxycarbonylpiperidine (6-1, 6.006 g), acetic acid (11.50 mL), 10% palladium on carbon (1.856 g), and methanol (150 mL) were added to the gas reaction chamber (3) of a stainless steel split dual-chamber reactor (Apparatus II in the accompanying figure, volume approximately 536 mL). Sodium borohydride (1.744 g), prefabricated ice (approximately 63 g, temperature ≤ -20°C), and pre-pressed monolithic methanesulfonic acid (4.536 g, temperature ≤ -20°C) were added to the gas generation chamber (2) of the stainless steel split dual-chamber reactor. Stainless steel reactor caps (5) were added to each chamber and tightened with bolts to ensure a seal. The dual-chamber reactor was evacuated while cooling the condenser coil (10) in a dry ice-ethanol bath. When the reactor vacuum reached 0.60–0.70 kPa, the exhaust valve (7) was closed. The reaction solution in gas reaction chamber 3 was electromagnetically stirred. The system pressure reached its maximum (0.88 MPa) after approximately 11 minutes of stirring, then slowly decreased. After stirring for 7 hours, the pressure stabilized and was stirred for an additional 30 minutes. The mixed solution in gas reaction chamber 3 was filtered through a diatomaceous earth layer and desolvated under reduced pressure. The resulting residue was dispersed in dichloromethane (500 mL) and 15% aqueous sodium hydroxide solution (250 mL). After vigorous stirring for 1 hour, the layers were separated and the aqueous phase was extracted with dichloromethane (300 mL x 3). The organic phases were combined, dried, filtered, and desolvated under reduced pressure to obtain 4-[(4-aminomethylphenyl)(methoxy)methyl]-1-tert-butyloxycarbonylhexahydropyridine (6-2, 5.723 g, 94% yield) as a pale yellow oil:

[0144] 1 H-NMR (400MHz, CDCl3) δ: 7.30(d,J=7.7Hz,2H),7.20(d,J=7.7Hz,2H),4.26–3.94(m,2H),3.87(s,2H),3.78(d,J=7.7Hz,1H),3.18(s,3H),2.72–2.46( m,2H),2.03–1.94(m,1H),1.70(tdt,J=11.5,7.4,3.7Hz,1H),1.44(s,11H),1.26-1.15(m,2H),1.08(qd,J=12.6,4.7Hz,1H). ESI-MS m / z: 335.2[M+H] + The analytical data were consistent with those reported in the literature (Chem Sci, 2024, 15(36):14888~14898; DOI:10.1039 / d4sc03916e).

[0145] The obtained compound 6-2 1The H-NMR spectrum clearly shows the methylene peak of aminomethyl (3.87 ppm, s, -CH2NH2) and the methyl peak of tert-butyloxycarbonyl (1.44 ppm, s, -C(CH3)3), which is consistent with the literature data; the ESI-MS mass-to-charge ratio is 335.2 [M+H] + , corresponding to a molecular weight of 334.2 g / mol, proving that the target product has a correct structure.

[0146] Note: Application in general organic synthesis: reduction of a cyano group to an aminomethyl group. The experimental procedure (constant gram-scale reaction) utilizes readily available raw materials to efficiently generate hydrogen for the reaction, with yields close to those reported in the literature. The experimental setup demonstrates satisfactory results.

[0147] Reaction type: catalytic hydrocyanation reduction ( ), which is a typical reaction of reducing a cyano group to an amine compound, involves the construction of an aminomethyl group and is a key step in drug synthesis (such as anti-tumor drug intermediates).

[0148] Core Value: Verify the feasibility of the present invention in gram-scale (6.006 g) organic synthesis and prove the adaptability of the technology to normal-scale reactions; demonstrate the engineering advantages of the split dual-chamber reactor (Example 5) (such as condensation and impurity removal, bolt sealing), and solve the safety and efficiency problems of traditional methods in high-pressure, large-scale reactions.

[0149] Through this example, the advantages of the present invention in engineering design, reaction efficiency and safety of large-scale organic synthesis are further highlighted. In particular, it provides a technical path that is both innovative and practical for the synthesis of constant intermediates in drug research and development, and promotes the "in situ preparation-reaction integration" technology from the laboratory to industrial production.

[0150] Example 12: Palladium-on-carbon catalyzed reductive amination reaction

[0151] Reaction formula:

[0152]

[0153] In an argon-protected glove box, methylamine hydrochloride (7-1, 92.35 g), tetrahydro-4- H-pyran-4-one (136.77 g), triethylamine (4.20 g; pre-deoxygenated by argon bubbling), 10% palladium on carbon (4.9 g), and methanol (850 mL; pre-deoxygenated by argon bubbling) were added to the gas reaction chamber 3 of a stainless steel split dual-chamber reactor (Apparatus II in the accompanying figure, volume approximately 4.37 L). Sodium borohydride (53.32 g), pre-cast ice (approximately 992 g, temperature ≤ -20°C), and pre-pressed monolithic methanesulfonic acid (134.6 g, temperature ≤ -20°C) were added to the gas generation chamber 2 of the stainless steel split dual-chamber reactor. Stainless steel reactor caps 5 were attached to each reaction chamber and tightened with bolts to ensure a seal. A dry ice-ethanol bath was used to cool the condenser coil 10. Simultaneously, the vacuum level of the dual-chamber reactor was evacuated to 0.60-0.70 kPa, and the exhaust valve 7 was closed. The reaction solution in the gas reaction chamber 3 was electromagnetically stirred at room temperature. The system pressure reached its maximum (3.36 MPa) after stirring for about 14 minutes, and then the pressure slowly decreased. After stirring for 0.5 hours, the pressure stabilized. Finally, the gas reaction chamber 3 was immersed in a 60 ℃ ~ 70 ℃ oil bath and electromagnetic stirring was continued for 1.5 hours until the pressure stabilized. After the system temperature dropped to room temperature, the mixed solution in the gas reaction chamber 3 was filtered through a diatomaceous earth layer and washed with methanol. The filtrate and washing were desolvated under reduced pressure. The resulting residue was recrystallized with a mixed solvent of isopropyl alcohol / isopropyl ether and dried under reduced pressure to obtain colorless crystalline methyl (3,4,5,6-tetrahydro-2- H -pyran-4-yl)amine hydrochloride (7-2, 178.3 g, yield 86%):

[0154] 1 H-NMR (400 MHz, DMSO- d 6) δ:1.32–1.51(m,3H),1.71–1.92(m,2H),2.42(s,3H),2.51–2.62(m,1H),3.30–3.51(m,2H),3.80–4.01(m,2H).ESI-MS m / z:116.3[M+H] + The analytical data were consistent with those reported in the literature (Org Process Res Dev, 2002, 6(1):70~73; DOI:10.1021 / op010052o).

[0155] The obtained compound 7-2 1 The H-NMR spectrum clearly shows the methylene peak (1.32-1.92 ppm), methyl peak (2.42 ppm, s, -CH3) and adjacent hydrogen of the amino group (3.30-4.01 ppm) of the pyran ring, which is consistent with the literature data; the ESI-MS mass-to-charge ratio is 116.3 [M+H] + , corresponding to a molecular weight of 115.2 g / mol, proving that the target product has a correct structure.

[0156] Note: This is a reductive amination reaction used in common organic synthesis. During the experimental process (a small-scale 100-gram reaction), readily available raw materials were used to efficiently generate hydrogen for the reaction. The yield of the target compound was close to that reported in the literature, and the experimental setup performed satisfactorily.

[0157] Reaction type: reductive amination reaction (ketone + amine → imine → amine), a key reaction for building CN bonds in drug synthesis, the target product is methyl (3,4,5,6-tetrahydro-2 H -pyran-4-yl)amine hydrochloride is an important pharmaceutical intermediate (such as an antidepressant drug intermediate).

[0158] Core Value: Verify the feasibility and effectiveness of the present invention in 100-gram-scale (136.77 g) reactions (e.g., reductive amination), demonstrating the technology's engineering adaptability for large-scale organic synthesis; demonstrate the high-pressure tolerance (3.36 MPa) and efficient impurity removal design (condensing coil 10) of the split dual-chamber reactor (Example 5), addressing the safety hazards and impurity interference issues of traditional high-pressure cylinders in large-scale reactions.

[0159] Through this embodiment, the advantages of the present invention in the engineering feasibility, safety and efficiency of large-scale organic synthesis have reached a new level. In particular, it provides a technical path that is both innovative and practical for the industrial production of pharmaceutical intermediates, marking a key breakthrough in the "in situ preparation-reaction integration" technology from theory to engineering application.

[0160] Example 13: Tritiation reaction of aryl halides

[0161] Reaction formula:

[0162]

[0163] In the argon-protected nuclear industry glove box, N4-[4-(Benzyloxy)-3-iodophenyl]acetamide (8-1, 1.85 mg), palladium oxide (1.43 mg), and anhydrous triethylamine in anhydrous methanol (0.30 mL, 0.67 mmol / mL; pre-cooled to -20°C) were added to the gas reaction chamber 3 of a stainless steel micro-integrated dual-chamber reactor (Example 6, approximately 0.8 mL volume). Sodium borotritidate (3.70E+6 Bq), pre-cast ice (approximately 0.3 g, ≤ -20°C), and pre-pressed methanesulfonic acid pellets (18 mg) were added to the gas generation chamber 2 of the stainless steel integrated dual-chamber reactor. The stainless steel reactor lid 5 was screwed on and tightened to ensure a seal. The vacuum level of the dual-chamber reactor was evacuated to 0.60-0.70 kPa, and the exhaust valve 7 was closed. Electromagnetic stirring (using a strong magnetic triangular stirring magnet) was initiated at room temperature for 2 h in the reaction chamber 3. The microreactor was cooled to 0-5°C, the micro stainless steel reactor cover 5 was opened, the mixed liquid in the gas reaction chamber 3 was filtered, and the filter residue was washed with pre-cooled methanol (1 mL x 2). The filtrate and washing liquid were combined, desolvated under reduced pressure, and the obtained residue was purified by silica gel solid phase extraction column and high performance liquid chromatography to obtain N -[4-(Benzyloxy)[3-T]phenyl]acetamide (8-2, 1.813E+6 Bq, 1.85E+7 Bq / mmol; radiochemical yield 49%).

[0164] Note: Application in the synthesis of tritium-labeled compounds—tritiation reaction (radioactive reaction). The experimental process (ultra-trace reaction) utilizes the readily available raw material sodium borotritiate to efficiently prepare tritium gas (unavailable commercially) for the reaction. The radiochemical yield of the target compound is ideal, and the experimental setup performs satisfactorily.

[0165] Target product: Synthetic tritium ( 3 H or T) labeled compounds N -[4-(Benzyloxy)[3-T]phenyl]acetamide (8-2), used for radiotracer or nuclear medicine research.

[0166] Core reaction: A tritium atom is introduced into the position of the 3-iodophenyl group (either by replacing the iodine atom or by direct tritium substitution) through a palladium-catalyzed isotope exchange / coupling reaction of an aryl iodide with a tritium source.

[0167] Environmental control: Operate in an argon-protected nuclear industry glove box to ensure an oxygen-free and water-free environment (to prevent tritium gas leakage and reagent oxidation) and control radioactive safety.

[0168] This example uses a palladium-catalyzed tritium substitution reaction to introduce tritium atoms into aryl iodide substrates under strict oxygen-free, low-temperature, and radiation-protection conditions, achieving high-specific-activity radioactive tritium labeling. The key lies in the controlled generation of tritium gas, autonomous pressurization, activation of the aryl iodide by a palladium catalyst, and multi-step purification to ensure the radioactive and chemical purity of the product. Control of temperature, pressure, and agitation during operation is crucial for the success of the reaction, while nuclear-grade equipment ensures the safety of radioactive operations.

[0169] The parts not described in detail in this application are prior art, so this application does not describe them in detail.

[0170] It is to be understood that the term "one" should be understood as "at least one" or "one or more", that is, in one embodiment, the number of an element may be one, while in another embodiment, the number of the elements may be multiple, and the term "one" should not be understood as a limitation on the quantity.

[0171] Although this document uses a lot of professional terms, it does not exclude the possibility of using other terms. These terms are used only to more conveniently describe and explain the essence of this application; interpreting them as any additional restrictions is contrary to the spirit of this application.

[0172] This application is not limited to the above-mentioned optimal implementation method. Anyone can derive various other forms of products based on the inspiration of this application. However, no matter what changes are made in their shape or structure, any technical solution that is the same or similar to that of this application falls within the scope of protection of this application.

Claims

1. A method for in-situ preparation and reaction integration of hydrogen isotope gas, characterized in that: The following steps are involved: placing borohydride, borodeuteride, or borotritide, a solid acidic substance, and a solid reaction medium in a gas generating chamber of a reactor, wherein the hydrogen isotope gas is hydrogen, deuterium, or tritium; placing reactants, catalyst, and / or solvent in a gas reaction chamber of a reactor; After sealing the reactor, evacuate to 0.60–0.70 kPa; The solid reaction medium is melted by heating, thereby triggering a reaction in a system consisting of the borohydride, borodeuteride, borotritide, acidic substance, and the solid reaction medium, thereby generating hydrogen isotope gas in situ; The generated hydrogen isotope gas is directly introduced into the gas reaction chamber to participate in the catalytic reaction of the reactants.

2. The method for in-situ preparation and reaction integration of hydrogen isotope gas according to claim 1, characterized in that: When preparing hydrogen, the borohydride includes one or more of lithium borohydride, sodium borohydride, potassium borohydride, magnesium borohydride, calcium borohydride, tetramethylammonium borohydride, tetraethylammonium borohydride and tetrabutylammonium borohydride; the solid acidic substance includes one or more of phenols, aromatic acids, fatty acids, sulfonic acids and phosphoric acid; and the solid reaction medium includes one or more of ice, glacial acetic acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

3. The method for in-situ preparation and reaction integration of hydrogen isotope gas according to claim 1, characterized in that: When preparing deuterium gas, the borodeuteride includes one or more of lithium borodeuteride, sodium borodeuteride, potassium borodeuteride, magnesium borodeuteride, calcium deuterium borohydride, and tetramethylammonium borodeuteride; the solid acidic substance is one or more of (hydroxy-D)phenols and perdeuterated phosphoric acid; and the solid reaction medium is one or more of heavy water pre-made ice cubes, perdeuterated phosphoric acid, and dimethyl sulfoxide.

4. The method for in-situ preparation and reaction integration of hydrogen isotope gas according to claim 1, characterized in that: When preparing tritium gas, the borotritiate is sodium borotritiate and / or potassium borotritiate, the solid acidic substance includes one or more of citric acid, methanesulfonic acid, and benzenesulfonic acid, and the solid reaction medium includes one or more of ice cubes, glacial acetic acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and ice cubes prefabricated with tritium water.

5. The method for in-situ preparation and reaction integration of hydrogen isotope gas according to any one of claims 1 to 4, characterized in that: Also included is an apparatus for implementing the method, the apparatus comprising: The reactor body is divided into a gas generation chamber and a gas reaction chamber which are interconnected at the top; The gas generation chamber is filled with solid reactants for preparing hydrogen isotope gas, and the gas reaction chamber is filled with reaction substrates, catalysts and solvents for hydrogen isotope gas reaction; The gas generation chamber is connected to the gas reaction chamber through a top channel or a pipe with a condensing coil, and the condensing coil is immersed in a low-temperature cooling bath; The reactor body is equipped with a reactor cover so that the maximum tolerable pressure of the reactor body is greater than or equal to 5.0 MPa; The reactor cover is provided with an inlet / exhaust valve for vacuuming and controlling the reaction pressure.

6. The method for in-situ preparation and reaction integration of hydrogen isotope gas according to claim 5, characterized in that: The device is an integrated dual-chamber reactor, wherein the gas generation chamber is directly connected to the gas reaction chamber, and is suitable for micro to semi-micro reactions.

7. The method for in-situ preparation and reaction integration of hydrogen isotope gas according to claim 5, characterized in that: The device is a split double-chamber reactor, wherein the gas generating chamber and the gas reaction chamber are connected via a condensing coil, and is suitable for reactions ranging from gram to hundred-gram levels.

8. The method for in-situ preparation and reaction integration of hydrogen isotope gas according to claim 5, characterized in that: The device is a miniature integrated dual-chamber reactor with a volume of ≤1 mL, and is specifically used for ultra-trace tritium gas labeling reactions.

9. The method for in-situ preparation and reaction integration of hydrogen isotope gas according to claim 5, characterized in that: The sealing method between the reactor body and the reactor cover is, when the volume of the reactor is less than or equal to 10 mL, threaded sealing is adopted; when the volume of the reactor is between 10 and 100 mL, snap-fit sealing is adopted; when the volume of the reactor is greater than 100 mL, bolt sealing is adopted.

10. Application of hydrogen isotope gas in organic synthesis reaction, characterized in that: The hydrogen isotope gas prepared in situ by the method according to any one of claims 1 to 4 is used to replace the hydrogen, deuterium and tritium supplied by high-pressure cylinders to participate in the reaction, comprising: Catalytic hydrogenation reduction, including debenzylation, nitro reduction, and cyano reduction; Synthesis of deuterated or tritium-labeled compounds; Reductive amination reaction.

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