A multi-element synergistic preparation method for mechanical chemical activation of boron sodium deuteride

Abstract

This invention discloses a multi-element synergistic preparation method for sodium borodeuteride through mechanochemical activation, which relates to the field of labeling reagent preparation technology. This multi-element synergistic preparation method for sodium borodeuteride through mechanochemical activation employs a technical route of "in-situ high-purity sodium borodeuteride preparation + mechanochemical activation solid-state metathesis + combined non-destructive purification + resource recycling": First, metallic sodium is dispersed and reacted in liquid paraffin to obtain sodium borodeuteride with a deuteration rate ≥99.5%. Then, using sodium borodeuteride as a deuterium source, it undergoes an anion metathesis reaction with boron source and magnesium powder under ambient temperature and pressure through high-energy ball milling. The crude product is purified by low-temperature extraction with liquid ammonia and recrystallization with organic amines, ultimately obtaining a high-purity sodium borodeuteride product with a purity ≥99% and a deuteration rate ≥99 atom%D. The energy consumption of this invention is only 1 / 5 to 1 / 8 of that of traditional methods, the total production cycle is shortened to less than 8 hours, the deuterium atom utilization rate is ≥95%, the production safety is high, and the emissions of waste are low, making it suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of labeling reagent preparation technology, specifically to a multi-element synergistic preparation method for sodium borodeuteride through mechanochemical activation. Background Technology

[0002] Sodium borodeuteride (NaBD4) is an important stable isotope labeling reagent widely used in organic synthesis, drug metabolism research, analytical chemistry, and new energy materials. In recent years, with the rapid development of the deuterated drug industry, the market demand for sodium borodeuteride with high deuteration rate (≥99 atom%D) and high purity (≥98%) has been increasing.

[0003] Currently known methods for preparing sodium borodeuteride mainly include: high-temperature solid-phase reduction (modified Bayer method), sodium borohydride deuteration derivatization method, metal deuteride metathesis method, and mechanochemical method. Among them, the high-temperature solid-phase reduction method (modified Bayer method) is the earliest method used in industry. Literature reports that this method can obtain sodium borodeuteride with a purity of over 99% and an abundance greater than 99.9 atom%D. This method uses anhydrous borax, quartz sand, metallic sodium, and deuterium gas as raw materials, reacting at a high temperature of 450℃. The typical reaction equation is: Na2B4O7+2SiO2+16Na+8D2→4NaBD4+4Na2SiO3; Although the high-temperature solid-state reduction method has been applied in industry, analysis has revealed the following significant drawbacks in this existing technology: 1. Deuteration rate is limited: At high temperatures, it is difficult to completely avoid hydrogen contamination (raw material crystal water, sodium metal surface hydrides, reactor wall adsorbed water, etc.), and the use of non-deuterated purification solvents will further dilute the deuterium isotope abundance, which limits the further improvement of the deuteration rate.

[0004] 2. High reaction temperature and high energy consumption: The reaction needs to be heated to 450℃ and maintained for several hours. The heating and heat preservation process consumes a lot of energy, and the total production cycle is long (usually >24 hours), which does not conform to the development concept of green chemistry.

[0005] 3. High equipment requirements and poor safety: High-temperature and high-pressure reactors require large investments, metallic sodium is extremely prone to oxidation and combustion at 450℃, and deuterium pressurization operation poses a risk of leakage, resulting in numerous safety hazards.

[0006] 4. The purification process is complicated: the high-temperature sintered product is in block form and needs to be mechanically crushed before extraction. Metal impurities are easily introduced during the crushing process, and two purifications are required to achieve high purity, making the operation complicated.

[0007] 5. Low deuterium utilization rate: In high-temperature reactions, the utilization rate of deuterium gas in a single pass is only 50%-70%, and the unreacted deuterium gas is difficult to fully recover, resulting in a waste of expensive deuterium resources.

[0008] In addition, although the metathesis reactions reported in the literature can be carried out under ball milling conditions at room temperature, most of them use expensive metal deuterides (such as lithium deuteride) as deuterium sources, resulting in high production costs and making them unsuitable for industrial scale-up. Summary of the Invention

[0009] To solve the above-mentioned technical problems, the present invention is implemented through the following technical solution: A multi-element synergistic preparation method for the mechanochemical activation of sodium borodeide includes the following steps: Step 1: Preparation of sodium deuteride: Under inert gas protection, metallic sodium is added to liquid paraffin, heated to melt, and then dispersed by high-speed stirring into liquid sodium droplets with a particle size of 10-100 μm. High-purity deuterium gas with a purity of ≥99.8% is introduced, and the reaction is carried out at 200-350℃ for 4-8 hours. After the reaction is completed, anhydrous organic solvent is added for washing, the liquid paraffin is removed by filtration, and the solid sodium deuteride with a deuteration rate of ≥99.5% is obtained by vacuum drying.

[0010] Step 2, Mechanochemical metathesis reaction: The sodium deuteride obtained in Step 1, the boron source, and the reducing agent magnesium powder are mixed in stoichiometric ratio and added to a high-energy ball mill. The ball milling reaction is carried out at room temperature and pressure under an inert protective atmosphere. The ball milling speed is 200-500 rpm, the ball-to-material ratio is (10-50):1, and the ball milling time is 1-4 hours to obtain crude sodium borodeuteride.

[0011] Step 3, Low-temperature extraction with liquid ammonia: At -33℃ to -40℃, add 5-10 times the mass of anhydrous liquid ammonia to the crude sodium borodeuteride, stir and extract for 30-60 minutes, filter to remove insoluble impurities, slowly heat the filtrate to room temperature, the ammonia gas evaporates and crystals are precipitated, and the first purified product is obtained.

[0012] Step 4: Recrystallization and purification of organic amines: Dissolve the purified product in anhydrous organic amines, heat to 40-60℃ to completely dissolve, filter while hot to remove trace amounts of insoluble matter, slowly cool the filtrate to 0-5℃ for recrystallization, filter and collect the crystals, and vacuum dry at 80-120℃ for 3-6 hours to obtain high-purity sodium borodeuteride product.

[0013] Step 5: Solvent and deuterium gas recovery and recycling: The unreacted deuterium gas from step one is condensed, dried, purified, and then returned to the sodium deuteride preparation system for recycling. The ammonia gas volatilized in step three is condensed and recovered as liquid ammonia for recycling. The mother liquor obtained from filtration in step four is distilled to recover organic amines for recycling.

[0014] Preferably, the anhydrous organic solvent in step one is selected from one or more of n-hexane, cyclohexane, or toluene.

[0015] Preferably, the boron source in step 2 is selected from one or both of anhydrous borax or anhydrous sodium metaborate.

[0016] Preferably, in step 2, the mixed raw materials also contain quartz sand as an additive, and the molar ratio of quartz sand to boron source is (1-2):1.

[0017] Preferably, in step 2, the inert protective atmosphere is argon or deuterium with a gas purity ≥ 99.99%; the grinding jar is made of stainless steel or zirconium oxide, and the grinding balls have a diameter of 5-15 mm.

[0018] Preferably, the magnesium powder in step 2 has a purity of ≥99.5% and a particle size of 200-400 mesh; The specific molar ratio of sodium deuteride, boron source, and magnesium powder is as follows: When borax is used as the boron source, the ratio is (16-18):1:(8-10); When sodium metaborate is used as the boron source, (3-4):1:(1-1.2).

[0019] Preferably, the anhydrous organic amine in step 4 is selected from one or more of isopropylamine, ethylenediamine, or n-propylamine.

[0020] This invention provides a multi-factor synergistic preparation method for sodium borodeuteride through mechanochemical activation. It possesses the following beneficial effects: (i) The mechanochemical activation multi-element synergistic preparation method of sodium borodeuteride uses self-produced sodium deuteride with high deuteration rate as the deuterium source and uses anhydrous inert solvent throughout the process to minimize hydrogen pollution; at the same time, the mechanochemical method avoids high temperature environment, effectively suppresses hydrogen-deuterium exchange side reaction, and the deuteration rate of the product is stable.

[0021] (II) The mechanochemical activation multi-element synergistic preparation method of sodium borodeuteride is carried out by the reaction at room temperature and pressure, without the need for high temperature and high pressure equipment at 450℃, and the energy consumption is only 1 / 5-1 / 8 of the traditional high temperature solid phase method; the total production cycle is shortened to less than 8 hours, and the production efficiency is greatly improved.

[0022] (III) The mechanochemical activation multi-element synergistic preparation method of sodium borodeuteride uses inexpensive and readily available metallic sodium and deuterium gas to produce sodium deuteride, replacing expensive lithium deuteride, with a deuterium atom utilization rate of ≥95%; at the same time, the solvent and deuterium gas can be recycled, further reducing production costs.

[0023] (iv) The mechanochemical activation multi-element synergistic preparation method of sodium borodeuteride, the high-energy collision generated by mechanochemical activation continuously generates fresh reaction interfaces, overcomes the diffusion limitation of traditional solid reaction, and the reaction time is only 1-4 hours; by optimizing the shear stress conditions, the product yield is ≥85%, and can reach up to 94%.

[0024] (V) The mechanochemical activation multi-element synergistic preparation method of sodium borodeuteride adopts the combined purification process of "liquid ammonia low-temperature extraction + organic amine recrystallization". It utilizes the characteristics of high solubility of NaBD4 in liquid ammonia and good recrystallization effect in organic amine, and the synergistic effect ensures that the product purity is ≥99% and the crystal structure is intact, which meets the strict requirements of high-end fields such as deuterated drugs. Detailed Implementation

[0025] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0026] Example 1: This example provides a multi-factor synergistic preparation method for the mechanochemical activation of sodium borodeuteride, including the following steps: Step 1: Preparation of Sodium Deuteride: Under argon protection, 100g of metallic sodium was added to 500mL of liquid paraffin. The mixture was heated to 250℃ to melt the sodium, and dispersed into droplets with a particle size of approximately 20-50μm by high-speed stirring. High-purity deuterium gas (≥99.8%) was continuously introduced while stirring, and the reaction was allowed to proceed for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, washed three times with anhydrous n-hexane, filtered to remove the liquid paraffin, and vacuum dried at 80℃ for 4 hours to obtain approximately 95g of grayish-white powdered sodium deuteride. The purity of the sodium deuteride was determined to be 99.8%, and the deuteration rate was 99.6%.

[0027] Step 2, Mechanochemical Ball Milling Reaction: Take 80g of sodium deuteride prepared in Step 1, 30g of anhydrous borax, 15g of quartz sand, and 25g of 300-mesh magnesium powder with a purity of 99.8%, mix them evenly, and then add them to a planetary ball mill. The ball mill jar is filled with 99.99% pure deuterium gas for protection. The ball milling speed is 400 rpm, the ball-to-material ratio is 30:1, the ball diameter is 10mm, and the ball milling time is 2.5 hours. After ball milling, take out approximately 120g of crude product in an inert atmosphere.

[0028] Step 3: Low-temperature extraction with liquid ammonia: Transfer the crude product to a pressure-resistant extraction vessel, cool to -35°C, add 800 mL of anhydrous liquid ammonia, and stir for 40 minutes. Filter to remove insoluble impurities such as MgO and Na2O, and slowly heat the filtrate to room temperature. Ammonia gas evaporates and white crystals precipitate, yielding approximately 85 g of the first-stage purified product.

[0029] Step 4: Recrystallization and purification of organic amines: Dissolve the purified product in 500 mL of anhydrous isopropylamine, heat to 50°C until completely dissolved, and filter while hot to remove trace amounts of insoluble matter. Slowly cool the filtrate to 0°C and allow it to crystallize for 2 hours. Collect the crystals by filtration, wash twice with a small amount of cold isopropylamine, and dry under vacuum at 100°C for 4 hours to obtain approximately 78 g of white crystalline powder as the final product.

[0030] The final product was tested and found to have a purity of 99.2% and a deuteration rate of 99.3% (atom%D). The XRD pattern showed that the crystal structure was intact and there were no obvious impurity peaks.

[0031] Example 2: This example provides a multi-factor synergistic preparation method for the mechanochemical activation of sodium borodeonide. The difference from Example 1 is that sodium metaborate is used as the boron source. The specific steps are as follows: Preparation of sodium deuteride: Same as in Example 1; Mechanochemical ball milling reaction: Take 90g of sodium deuteride prepared in step 1, 40g of anhydrous sodium metaborate, and 20g of 300-mesh magnesium powder with a purity of 99.8%, mix them evenly, and then add them to a planetary ball mill. The ball mill jar is filled with argon gas of 99.99% purity for protection. The ball milling speed is 450 rpm, the ball-to-material ratio is 25:1, the ball diameter is 10mm, and the ball milling time is 2 hours. After ball milling, approximately 115g of crude product is taken out in an inert atmosphere.

[0032] Low-temperature extraction with liquid ammonia: The crude product was cooled to -35°C, and 600 mL of anhydrous liquid ammonia was added. The mixture was stirred and extracted for 40 minutes. Insoluble impurities were removed by filtration, and the filtrate was heated to volatilize the ammonia gas, yielding approximately 76 g of the first-stage purified product.

[0033] Organic amine recrystallization purification: The purified product was dissolved in 450 mL of anhydrous isopropylamine, heated to 50 °C to dissolve, and filtered while hot. The filtrate was cooled to 0 °C to crystallize, the crystals were collected by filtration, and dried under vacuum to obtain approximately 70 g of the final product.

[0034] The final product was tested and found to have a purity of 98.8% and a deuteration rate of 99.2% (atom%D).

[0035] Example 3: This example provides a multi-factor synergistic preparation method for the mechanochemical activation of sodium borodeuteride. The difference from Example 1 lies in the ball milling parameters. The specific steps are as follows: Step 1, Preparation of sodium deuteride: Same as in Example 1; Step 2, Mechanochemical Ball Milling Reaction: Take 80g of sodium deuteride, 30g of anhydrous borax, 15g of quartz sand, and 25g of magnesium powder prepared in Step 1, mix them evenly, and then add them to a planetary ball mill. The ball mill jar is filled with deuterium gas for protection, the ball milling speed is 500 rpm, the ball-to-material ratio is 50:1, and the ball milling time is 1.5 hours.

[0036] Step 3: Low-temperature extraction with liquid ammonia: Same as in Example 1, yielding approximately 87g of purified product.

[0037] Step 4: Recrystallization and purification of organic amines: Same as in Example 1, yielding approximately 80g of final product.

[0038] The final product was tested and found to have a purity of 99.0%, a deuteration rate of 99.4% (atom%D), and a yield of 87%.

[0039] Comparative example, high-temperature solid-phase reduction method; Anhydrous borax, quartz sand, and metallic sodium are mixed in stoichiometric ratio and placed in a high-pressure reactor. The reactor is evacuated to below 10 Pa, deuterium gas is introduced to 0.5 MPa, and the temperature is raised to 450°C for 10 hours.

[0040] After the reaction was completed, the product was cooled to room temperature, the block-shaped product was removed, mechanically pulverized, extracted with isopropylamine, filtered, and dried to obtain sodium borodeuteride product.

[0041] The product purity was 94.2% (requiring two recrystallizations to reach over 99%), the deuteration rate was 99.1 atom%D, the total production cycle was 26 hours, the energy consumption was approximately 6.5 times that of Example 1, and the deuterium utilization rate was 62%.

[0042] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0043] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A multi-element synergistic preparation method for the mechanochemical activation of sodium borodeuteride, characterized in that, Includes the following steps: Step 1: In-situ preparation of sodium deuteride: Under the protection of an inert gas, metallic sodium is dispersed in liquid paraffin, melted and stirred at high speed into droplets, and high-purity deuterium gas is introduced to react and generate sodium deuteride. After washing and vacuum drying, solid sodium deuteride is obtained. Step 2, Mechanochemical Activation Metathesis: The sodium deuteride, boron source, and reducing agent magnesium powder are mixed in stoichiometric ratio and ball-milled at room temperature and pressure in a high-energy ball mill under an inert protective atmosphere. Solid anionic metathesis is achieved through mechanical activation to generate crude sodium borodeuteride. Step 3: Low-temperature selective extraction with liquid ammonia: The crude sodium borodeuteride is extracted with anhydrous liquid ammonia at -33℃ to -40℃. After separating the insoluble byproducts, the ammonia gas is volatilized to obtain the first purified product. Step 4: Recrystallization and purification of organic amines: Dissolve the purified product in anhydrous organic amines, heat to dissolve, filter while hot, cool to crystallize, and vacuum dry to obtain high-purity sodium borodeuteride.

2. The method for the synergistic preparation of sodium borodeuteride by mechanochemical activation according to claim 1, characterized in that: In step one, the particle size of the liquid sodium droplets is controlled to be 10-100 μm, the reaction temperature is 200-350℃, and the reaction time is 4-8 hours; the washing process uses at least one of anhydrous n-hexane, cyclohexane, or toluene.

3. The method for the synergistic preparation of sodium borodeuteride by mechanochemical activation according to claim 2, characterized in that: The high-purity deuterium gas in step one has a purity of ≥99.8%, a vacuum drying temperature of 60-100℃, and a drying time of 3-5 hours.

4. The method for the synergistic preparation of sodium borodeuteride by mechanochemical activation according to claim 1, characterized in that: The boron source in step two is selected from one or both of anhydrous borax or anhydrous sodium metaborate. When the boron source is anhydrous borax, quartz sand is also added as an additive, and the molar ratio of quartz sand to anhydrous borax is (1-2):

1.

5. The method for the synergistic preparation of sodium borodeuteride by mechanochemical activation according to claim 1, characterized in that: The process parameters for the ball milling reaction in step two are as follows: The ball mill speed is 200-500 rpm, the ball-to-material ratio is (10-50):1, and the ball milling time is 1-4 hours.

6. The method for the synergistic preparation of sodium borodeuteride by mechanochemical activation according to claim 5, characterized in that: In step two, the inert protective atmosphere is argon or deuterium. The grinding jar is made of stainless steel or zirconium oxide, and the grinding balls have a diameter of 5-15mm.

7. The method for the synergistic preparation of sodium borodeuteride by mechanochemical activation according to claim 1, characterized in that: The magnesium powder in step two has a purity of ≥99.5% and a particle size of 200-400 mesh; The raw material molar ratio is: When anhydrous borax is used as the boron source, the ratio of sodium deuteride:borax:magnesium powder is (16-18):1:(8-10). When anhydrous sodium metaborate is used as the boron source, the ratio of sodium deuteride:sodium metaborate:magnesium powder is (3-4):1:(1-1.2).

8. The method for the synergistic preparation of sodium borodeuteride by mechanochemical activation according to claim 1, characterized in that: In step three, the amount of anhydrous liquid ammonia used is 5-10 times the amount of crude sodium borodeuteride, and the extraction stirring time is 30-60 minutes.

9. The method for the synergistic preparation of sodium borodeuteride by mechanochemical activation according to claim 1, characterized in that: In step four, the anhydrous organic amine is selected from at least one of isopropylamine, ethylenediamine, or n-propylamine. The heating and melting temperature is 40-60℃, and the cooling and crystallization temperature is 0-5℃; the vacuum drying temperature is 80-120℃, and the drying time is 3-6 hours.