Preparation method of deuterated 4-pyridine-d4 borate

Abstract

The invention discloses a preparation method of deuterated 4-pyridine-d4 borate, which comprises the following steps: S10, performing bromination reaction on deuterated 4-aminopyridine, sodium nitrite and liquid bromine under the action of hydrobromic acid, quenching and neutralizing the reaction liquid after the reaction is finished, then adding an ether solvent for extraction, washing with water, and drying to obtain a deuterated 4-bromopyridine-d4 organic phase, then carrying out salifying to obtain a deuterated 4-bromopyridine hydrochloride d4; and S20, carrying out neutralization dissociation and dehydration pretreatment on the deuterated 4-bromopyridine hydrochloride-d4 obtained in the step S10, adding a borate reagent into the organic phase in an inert atmosphere, adding an alkyl lithium reagent, carrying out lithium-bromine exchange and boric acidification reaction, and after the reaction is finished, carrying out quenching and purification post-treatment to obtain the target product deuterated 4-pyridine borate. According to the preparation method, efficient extraction, salification and transfer of an unstable intermediate product are effectively realized, and the reaction yield and the product purity of the whole route are improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of deuterated reagent preparation, and particularly relates to a preparation method of deuterated 4-pyridine-boronic acid-d4. BACKGROUND

[0002] Deuterated organic molecules, especially deuterated drug molecules and their key intermediates, have shown increasing value in the fields of pharmaceutical research and development, metabolism research, and material science. Due to the higher kinetic isotope effect of carbon-deuterium bond (C-D) compared to carbon-hydrogen bond (C-H), the introduction of deuterium atoms into drug molecules can change their pharmacokinetic properties, such as slowing down metabolism, prolonging half-life, and reducing side effects. Therefore, deuterium substitution technology has become one of the important strategies for new drug research and development.

[0003] Pyridine-4-boronic acid is an extremely important pharmaceutical and chemical intermediate, which is widely used in Suzuki-Miyaura coupling reactions to construct biaryl structural units. This structure is the core skeleton of many active pharmaceutical ingredients (APIs). Its deuterated analogue, deuterated 4-pyridine-boronic acid-d4, plays an irreplaceable role as an isotopic tracer or in the preparation of highly deuterated drug molecules.

[0004] Toshimichi Ohmura et al. disclosed a preparation method of deuterated 4-pyridine-boronic acid-d4 key intermediate deuterated 4-bromopyridine hydrochloride-d4 (“Mechanism of 2,6-Dichloro-4,4'-bipyridine-Catalyzed Diboration of Pyrazines Involving a Bipyridine-Stabilized Boryl Radical”, Bull. Chem. Soc. Jpn. 2021, 94, 1894-1902). After the bromination reaction of deuterated 4-aminopyridine is completed, ether is used for extraction, and then HCl in ether is added to prepare the hydrochloride intermediate. However, the above post-treatment process has the following problems: on the one hand, due to the hydrophilicity of ether, water is easily introduced into the organic phase during extraction and subsequent salting operations, causing partial hydrolysis or caking of deuterated 4-bromopyridine hydrochloride-d4, affecting product purity and process stability; on the other hand, the crystallinity of deuterated 4-bromopyridine-d4 is poor when it is salted out in ether, making the salting step difficult to separate and resulting in process loss; finally, from the perspective of production safety, ether, as a low-boiling, highly volatile ether solvent, can form an explosive mixture with air, posing a serious risk of combustion and explosion, introducing additional safety hazards and making it unsuitable for industrial production.

[0005] In summary, there is an urgent need in the art to develop a completely new synthesis and purification method of deuterated 4-boronic acid pyridine-d4 which can maintain high yield and high purity throughout the entire process. This method fundamentally solves the efficient salting and transfer of unstable deuterated 4-bromopyridine-d4, realizes the free state of the key intermediate deuterated 4-boronic acid pyridine hydrochloride-d4 in a hydrophilic environment, and successfully performs the subsequent lithium-bromine exchange and boration reaction. SUMMARY

[0006] The present application provides a preparation method of deuterated 4-boronic acid pyridine-d4, which effectively realizes efficient extraction, salting and transfer of unstable deuterated 4-bromopyridine-d4, and improves the reaction yield and product purity of the entire route.

[0007] To solve the above problems, the technical scheme adopted by the present application is as follows:

[0008] A preparation method of deuterated 4-boronic acid pyridine-d4, comprising the following steps:

[0009] S10: Preparation of deuterated 4-bromopyridine hydrochloride-d4

[0010] Under the action of hydrobromic acid, deuterated 4-aminopyridine, sodium nitrite and liquid bromine are subjected to a bromination reaction. After the reaction is completed, the reaction solution is quenched and neutralized, then an ether solvent is added for extraction, washed with water, dried to obtain deuterated 4-bromopyridine-d4 organic phase, and then salted to obtain deuterated 4-bromopyridine hydrochloride-d4;

[0011] The structure of the ether solvent is R 1 OR 2 , wherein R 1 and R 2 are independently selected from C1-C6 alkyl, and at least one of R 1 and R 2 is a branched alkyl group;

[0012] S20: Preparation of deuterated 4-boronic acid pyridine

[0013] The deuterated 4-bromopyridine hydrochloride-d4 obtained in step S10 is subjected to neutralization and free state and dehydration pretreatment, then a boronic acid ester reagent is added to the above organic phase under an inert atmosphere, and a lithium-bromine exchange and boration reaction is performed by adding an alkyl lithium reagent. After the reaction is completed, the target product deuterated 4-boronic acid pyridine is obtained after quenching and purification post-treatment.

[0014] The dehydration pretreatment is performed using a spherical alkali metal hydroxide.

[0015] The application uses aprotic ether solvent with branched structure instead of diethyl ether in the extraction process in the preparation process of deuterated 4-bromopyridine hydrochloride-d4, which significantly enhances the hydrophobicity, effectively reduces the introduction of water into the organic phase in the extraction and subsequent salting operation process, thereby fundamentally inhibiting the possible hydrolysis side reaction and caking phenomenon of hydrochloride in the salting stage, ensuring the high purity and excellent physical form of the product, and improving the process stability; at the same time, after neutralizing the free, spherical alkali metal hydroxide is used for dehydration pretreatment, which provides a more suitable environment for the subsequent lithium-bromine exchange, and increases the yield of the whole route.

[0016] The specific process of step S10 is as follows:

[0017] Put hydrobromic acid into the reactor, add deuterated 4-aminopyridine in batches under stirring, and control the temperature to be 10-15℃ during the addition; after the deuterated 4-aminopyridine-d4 is completely dissolved, slowly drop liquid bromine, and control the temperature to be-5-5℃ during the drop; then drop sodium nitrite solution, and control the temperature to be-5-0℃ during the drop; then drop sodium sulfite solution to quench liquid bromine, drop sodium hydroxide aqueous solution to neutralize hydrobromic acid, and control the temperature to be 10-15℃ during the drop; then extract with organic solvent, wash with water, and dry to obtain deuterated 4-bromopyridine-d4 organic phase; finally, drop hydrogen chloride methanol solution into the organic phase to form salt, and after filtration and drying, deuterated 4-bromopyridine hydrochloride-d4 is obtained.

[0018] In step S10, the mass percentage of the hydrobromic acid solution is 40%-60%;

[0019] In step S10, the mass-volume ratio of the deuterated 4-aminopyridine-d4 to the hydrobromic acid solution is 1:(5-10) g / mL;

[0020] In step S10, the molar ratio of the liquid bromine to the deuterated 4-aminopyridine-d4 is (2-4):1;

[0021] In step S10, the molar ratio of the sodium nitrite to the deuterated 4-aminopyridine-d4 is (1.5-3):1;

[0022] In step S10, the molar ratio of the sodium sulfite used for quenching to the liquid bromine is (1.2-1.5):1;

[0023] In step S10, the molar ratio of the sodium hydroxide used for neutralization to the hydrobromic acid is (1-1.2):1;

[0024] In step S10, the organic solvent used for extraction is selected from one of methyl tert-butyl ether, ethyl tert-butyl ether, tert-amyl methyl ether, and diisopropyl ether;

[0025] In step S10, the volume ratio of the extracted organic solvent to the reaction solution is (1-3):1;

[0026] In step S10, the molar ratio of the hydrogen chloride methanol solution to deuterated 4-aminopyridine-d4 is (1.0~1.2):1;

[0027] In step S10, the concentration of the hydrogen chloride methanol solution is 1.0–3.0 mol / L;

[0028] The specific process of step S20 is as follows:

[0029] The obtained deuterated 4-bromopyridine hydrochloride-d4 was dissolved in tetrahydrofuran and neutralized by adding sodium hydroxide aqueous solution, with the addition temperature controlled at -5 to 0℃. Then, the phases were separated, and spherical alkali metal hydroxide was added to the organic phase for dehydration pretreatment. Under an inert atmosphere, borate ester reagent was added to the above organic phase, followed by slow addition of alkyl lithium reagent to carry out lithium-bromine exchange and borate reaction. After the reaction was completed, the crude reaction solution was quenched with hydrochloric acid to obtain a crude reaction solution. The crude reaction solution was purified and treated to obtain the target product, deuterated 4-boronic acid pyridine.

[0030] In step S20, the mass-to-volume ratio of the hydrochloric acid salt to the tetrahydrofuran solution is 1:(2-4) g / mL;

[0031] In step S20, the concentration of the sodium hydroxide aqueous solution used for free hydrochloride is 10% to 30%;

[0032] In step S20, the molar ratio of sodium hydroxide used for free hydrochloride to deuterated 4-bromopyridine hydrochloride-d4 is (1.2~1.5):1;

[0033] In step S20, the volume-to-mass ratio of the organic phase to the spherical alkali metal hydroxide is 1:(0.05-0.3), preferably 1:(0.1-0.2).

[0034] In step S20, the spherical alkali metal hydroxide used for dehydration pretreatment is selected from spherical sodium hydroxide, spherical potassium hydroxide, or mixtures thereof;

[0035] In step S20, the particle size distribution D90 of the spherical hydroxide is 3–8 mm, and the bulk density is 0.8–1.2 g / cm³. 3 ;

[0036] In step S20, the borate ester is selected from triisopropyl borate, triethyl borate, tripropyl borate, and tributyl borate.

[0037] In step S20, the alkyl lithium is selected from n-butyllithium, sec-butyllithium, and tert-butyllithium;

[0038] In step S20, the molar ratio of the theoretical value of 4-bromopyridine-d4 to the borate ester and alkyl lithium is 1:(1.2~1.5):(1.2~1.5).

[0039] In step S20, the purification and treatment process of the crude reaction solution includes dissolving in water, separating phases, extracting the aqueous phase with dichloromethane, adding an alkali metal hydroxide solution to adjust the pH to 6.8-7.2 to precipitate the product, filtering, and successively slurrying with water, methanol or ethanol, and drying the filter cake to obtain deuterated 4-borate pyridine-d4.

[0040] In step S20, the alkali metal hydroxide used in the purification and post-treatment of the crude reaction solution is selected from sodium hydroxide, potassium hydroxide, or a mixture thereof, and the concentration of the alkali metal hydroxide is 40-50%.

[0041] The salt formation, lithium-bromine exchange, and borate formation processes are as follows:

[0042]

[0043] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0044] (1) In the preparation of the key intermediate deuterated 4-bromopyridine hydrochloride-d4, this invention, on the one hand, creatively selects aprotic ether solvents with branched structures, such as methyl tert-butyl ether, through systematic solvent screening. Their significantly enhanced hydrophobicity effectively reduces the introduction of water into the organic phase during extraction and subsequent salting operations, thereby fundamentally inhibiting the hydrolysis side reactions and agglomeration that may occur in the salting stage of hydrochloride, ensuring the high purity and excellent physical morphology of the product, and improving process stability. Secondly, these branched ether solvents have higher boiling points and flash points, and their physical properties significantly reduce the volatility and flammability of the solvent, thereby fundamentally improving the inherent safety level of the process and meeting the stringent safety requirements of industrial production. On the other hand, in the salting step, a methanol solution of hydrochloric acid is innovatively used instead of an ether solution of hydrochloric acid. Methanol, as a proton solvent, can effectively induce and optimize the crystallization process of the product, promoting the formation of deuterated 4-bromopyridine hydrochloride-d4 into crystals with regular crystal structure, uniform particle size, and easy filtration and washing. Ultimately, it achieves synergistic optimization and simultaneous improvement in product purity, process yield, and operating efficiency.

[0045] (2) A unique treatment strategy was adopted in the key freeing step of preparing the target product from deuterated 4-bromopyridine hydrochloride-d4: firstly, it was dissolved in tetrahydrofuran organic solvent, then neutralized and freed at low temperature using sodium hydroxide aqueous solution. After phase separation, the organic phase was pretreated with spherical hydroxide for dehydration. This design is based on the subsequent participation of alkyl lithium in the reaction. A high-concentration tetrahydrofuran solution was prepared first to further control the water content of the reaction system. In addition, due to the instability of the substrate, sodium hydroxide solution was added dropwise at low temperature for neutralization and freeing to avoid substrate damage. Furthermore, the pretreatment with spherical hydroxide after phase separation has a dual advantage: on the one hand, it can effectively neutralize the trace amounts of hydrogen chloride that may remain and enter the organic phase due to freeing; on the other hand, it creates an important anhydrous environment for the subsequent lithium-halogen exchange reaction, which is extremely sensitive to moisture. The use of spherical hydroxide achieves efficient dehydration and facilitates separation operation, avoiding the problems of introducing impurities or cumbersome operation of traditional desiccants, and is easy to industrialize. Attached Figure Description

[0046] Figure 1 The image shows the proton NMR spectrum of the product obtained in Example 1. Detailed Implementation

[0047] Example 1:

[0048] Step S10: Preparation of deuterated 4-bromopyridine hydrochloride-d4

[0049] Under nitrogen protection, 2.8 L of 48% hydrobromic acid solution was placed in a reactor. 400 g of deuterated 4-aminopyridine-d4 was added in batches with stirring, maintaining a temperature of 15°C during the addition process. After the deuterated 4-aminopyridine-d4 was completely dissolved, 1958 g of liquid bromine was slowly added dropwise, maintaining a temperature of 0°C during the dropwise addition. Stirring continued for 30 min after the dropwise addition was completed. Then, 2.5 L of 30 wt% sodium nitrite solution was added dropwise, maintaining a temperature of 0°C during the dropwise addition. Stirring continued for 30 min after the dropwise addition was completed. Then, 12.5 L of 16 wt% sodium sulfite solution was added dropwise to quench the liquid bromine, followed by 6.4 L of 25 wt% sodium hydroxide aqueous solution to neutralize the hydrobromic acid, maintaining a temperature of 15°C during the dropwise addition. The reaction solution was stirred for 30 min after the dropwise addition was completed to obtain a reaction solution containing deuterated 4-bromopyridine-d4.

[0050] The above reaction solution was extracted three times with 3V methyl tert-butyl ether, the organic phases were combined, washed with water and dried to obtain an organic phase containing deuterated 4-bromopyridine;

[0051] The above-mentioned organic phase containing deuterated 4-bromopyridine-d4 was cooled to 10°C, and then 1900g of methanol solution of hydrogen chloride was added dropwise for salt formation. After filtration and drying, 712.03g of deuterated 4-bromopyridine hydrochloride-d4 was obtained with a purity >99%, a deuteration degree of 98.33%, and a yield of 87.1%.

[0052] Step S20: Preparation of deuterated pyridine-d4 borate

[0053] 4-Bromopyridine hydrochloride-d4 free: Add 2.0 L THF to a 10 L reaction flask, then add 600 g of 4-bromopyridine hydrochloride-d4 while stirring. Add 720 mL of 25 wt% sodium hydroxide solution dropwise while maintaining an internal temperature of -5 °C. After the addition is complete, stir for 30 min to separate the phases. Cool the organic phase to -5 °C, and then add 490 g of spherical sodium hydroxide solid (specifications: D90 6 mm, bulk density 1.0 g / cm³) to the 4-bromopyridine-d4 reaction solution while stirring. 3 Dry for 1 hour, filter, and wash the filter cake with anhydrous THF to obtain a pale yellow liquid 4-bromopyridine-d4 solution. Take a sample for testing, the water content is 253 ppm, HPLC 100%, and the free separation is ended.

[0054] Preparation of boric acid by butyllithium reaction: The above 4-bromopyridine-d4 solution was added to a 10L reaction flask, followed by 2.5L of anhydrous THF. After cooling to -40℃ with ethanol and dry ice, 850g of triisopropyl borate was added. After cooling to -70℃, 1500ml (1.2eq) of n-BuLi was slowly added dropwise, keeping the temperature below -65℃. After the addition was completed, the mixture was stirred for 30min. HPLC detection showed no residual raw materials, indicating the reaction was complete.

[0055] Post-processing: 1.2 L of 6M hydrochloric acid was added dropwise at -10℃, pH=1, and stirred for 30 min. Then, 1.2 L of water was added to dissolve the mixture. The phases were separated, and the aqueous phase was extracted three times with a 3V DCM. The aqueous phase was then cooled to -5℃, and 50 wt% potassium hydroxide solution was added dropwise to adjust the pH to 7. A white solid precipitated out of the system. The mixture was stirred for 30 min, filtered, and the filter cake was successively slurried with water and ethanol, filtered, and dried in a 40℃ forced-air drying oven for 48 hours to obtain 340.67 g of pyridine-d4 deuterated 4-borate (purity >99%, molar yield 89.7%). 1 1H NMR analysis showed that the degree of deuteration of pyridine-d4-deuterated 4-borate was 98.42%, and the 1H NMR spectrum is shown below. Figure 1 As shown, the 1H NMR data are 1 HNMR (400MHz, D2O) 7.23 (s, 1.69H), 8.03 (s, 1.47H).

[0056] Example 2:

[0057] This embodiment is basically the same as Embodiment 1, except that in this embodiment, step S10 uses methyl tert-butyl ether to extract three times.

[0058] Example 3:

[0059] This embodiment is basically the same as Embodiment 1, except that in this embodiment, step S10 uses 3V diisopropyl ether for extraction three times.

[0060] Example 4:

[0061] This embodiment is basically the same as Embodiment 1, except that: in step S20 of this embodiment, the spherical sodium hydroxide solid (specification: D90 is 8mm, bulk density is 1.2g / cm³) 3 ).

[0062] Example 5:

[0063] This embodiment is basically the same as Embodiment 1, except that in step S20, the spherical sodium hydroxide solid is replaced with spherical potassium hydroxide solid (specifications: D90 is 6mm, bulk density is 1.1g / cm³). 3 )

[0064] Example 6:

[0065] This embodiment is basically the same as Embodiment 1, except that in step S20 of this embodiment, the aqueous phase is cooled to -5°C and 30wt% potassium hydroxide solution is added dropwise to adjust the pH to 7.

[0066] Comparative Example 1:

[0067] This comparative example is basically the same as Example 1, except that in step S10 of this comparative example, sodium nitrite is added first, followed by liquid bromine, and the order of addition is changed.

[0068] Comparative Example 2:

[0069] This comparative example is basically the same as Example 1, except that in step S10 of this comparative example, 3V tetrahydrofuran is used for extraction three times.

[0070] Comparative Example 3:

[0071] This comparative example is basically the same as Example 1, except that in step S10 of this comparative example, a diethyl ether solution of hydrogen chloride is used for salt formation.

[0072] Comparative Example 4:

[0073] This comparative example is basically the same as Example 1, except that in step S20 of this comparative example, the spherical sodium hydroxide solid (specification: D90 is 2mm, bulk density is 0.8g / cm³) 3 ).

[0074] Comparative Example 5:

[0075] This comparative example is basically the same as Example 1, except that: in this comparative example, the dehydration pretreatment in step S20 uses flake sodium hydroxide.

[0076] Comparative Example 6:

[0077] This comparative example is basically the same as Example 1, except that in step S20 of this comparative example, the aqueous phase is cooled to -5°C and 20wt% sodium hydroxide solution is added dropwise.

[0078] Comparative Example 7:

[0079] This comparative example is basically the same as Example 1, except that in step S20 of this comparative example, the pH of the post-treatment aqueous phase is adjusted to 6.

[0080] Table 1. Reaction data from Examples 2 to Comparative Examples 7

[0081]

[0082] According to Table 1, in Comparative Example 1, sodium nitrite was added first, followed by liquid bromine in step S10. The order of addition was changed, and a highly active diazonium salt intermediate was formed in the system first. Due to the lack of a sufficient concentration of bromine source in the system, the diazonium salt intermediate was decomposed and impurities were formed, resulting in a decrease in the yield and purity of the deuterated 4-bromopyridine intermediate.

[0083] In Comparative Example 2, tetrahydrofuran was used instead of methyl tert-butyl ether as the extraction solvent in step S10. Although there was no significant difference in deuteration degree and purity, the solubility of deuterated 4-bromopyridine in tetrahydrofuran was greater than that in methyl tert-butyl ether. As a result, the target product remained in the mother liquor and was difficult to precipitate in the subsequent salt formation step, leading to a loss in the yield of deuterated 4-bromopyridine hydrochloride-d4.

[0084] In Comparative Example 3, step S10 uses a diethyl ether solution of hydrogen chloride for salt formation. Since diethyl ether is an aprotic solvent, its molecular polarity and coordination ability are relatively weak. During the salt formation and crystallization process, the generated deuterated 4-bromopyridine hydrochloride crystals have problems such as irregular crystal form, wide particle size distribution, and easy formation of fine powder or aggregates, which leads to a decrease in the yield and purity of the deuterated 4-bromopyridine intermediate.

[0085] In Comparative Example 4, step S20 uses a D90 of 2 mm and a bulk density of 0.8 g / cm³. 3 The reduced particle size and bulk density of spherical sodium hydroxide make it difficult to separate the organic phase. Some 4-bromopyridine-d4 is adsorbed and remains between the spherical sodium hydroxide particles, resulting in the loss of the organic phase and a decrease in the yield of intermediates.

[0086] In Comparative Example 5, the dehydration pretreatment in step S20 uses flake sodium hydroxide. Due to its irregular planar structure, the intermediate is severely trapped and adsorbed, which also leads to the loss of intermediate during the separation and transfer process and a decrease in yield.

[0087] In Comparative Example 6, during the post-treatment process in step S20, the aqueous phase was cooled to -5°C and a 20wt% sodium hydroxide solution was added dropwise. The low concentration of sodium hydroxide solution introduced more water during the pH adjustment process, which led to an increase in the amount of product dissolved in the aqueous phase. The product yield decreased due to the loss of dissolution.

[0088] In Comparative Example 7, during step S20, the pH of the post-treatment aqueous phase was adjusted to 6. Due to the increased solubility of pyridine-d4-deuterated 4-borate in the slightly acidic aqueous phase, it failed to precipitate completely near its optimal isoelectric point. As a result, some product was lost in the mother liquor due to dissolution, leading to a decrease in product yield.

Claims

1. A method for preparing deuterated 4-borate pyridine-d4, characterized in that, Includes the following steps: S10: Preparation of deuterated 4-bromopyridine hydrochloride-d4 Under the action of hydrobromic acid, deuterated 4-aminopyridine, sodium nitrite and liquid bromine undergo bromination reaction. After the reaction is completed, the reaction solution is quenched and neutralized, and then an ether solvent is added for extraction, water washing and drying to obtain deuterated 4-bromopyridine-d4 organic phase, which is then salted to obtain deuterated 4-bromopyridine hydrochloride-d4. The structure of the ether solvent is R 1 OR 2 , where R 1 and R 2 Independently selected from C1-C6 alkyl groups, and R 1 and R 2 At least one of them is a branched alkyl group; S20: Preparation of pyridine deuterated 4-boronic acid The deuterated 4-bromopyridine hydrochloride-d4 obtained in step S10 was subjected to neutralization, dehydration and pretreatment. Then, under an inert atmosphere, a borate ester reagent was added to the above organic phase, followed by the addition of an alkyl lithium reagent to carry out lithium-bromine exchange and borate reaction. After the reaction was completed, the product deuterated 4-boronic acid pyridine was obtained after quenching and purification. The dehydration pretreatment is carried out using spherical alkali metal hydroxides.

2. The method for preparing deuterated 4-borate pyridine-d4 according to claim 1, characterized in that, The specific process of step S10 is as follows: Hydrobromic acid was placed in a reactor, and deuterated 4-aminopyridine was added in batches with stirring, with the addition temperature controlled at 10–15 °C. After the deuterated 4-aminopyridine-d4 was completely dissolved, liquid bromine was slowly added dropwise, with the addition temperature controlled at -5–5 °C. Then, sodium nitrite solution was added dropwise, with the addition temperature controlled at -5–0 °C. Subsequently, sodium sulfite solution was added dropwise to quench the liquid bromine, and sodium hydroxide aqueous solution was added dropwise to neutralize the hydrobromic acid, with the addition temperature controlled at 10–15 °C. Then, the mixture was extracted with an organic solvent, washed with water, and dried to obtain the organic phase of deuterated 4-bromopyridine-d4. Finally, an alcoholic solution of hydrogen chloride was added dropwise to the organic phase to form a salt, and after filtration and drying, deuterated 4-bromopyridine hydrochloride-d4 was obtained.

3. The method for preparing deuterated 4-borate pyridine-d4 according to claim 1 or 2, characterized in that, In step S10, the hydrobromic acid solution has a mass percentage of 40% to 60%. In step S10, the mass-to-volume ratio of the deuterated 4-aminopyridine-d4 to the hydrobromic acid solution is 1:(5-10) g / mL; In step S10, the molar ratio of liquid bromine to deuterated 4-aminopyridine-d4 is (2-4):1; In step S10, the molar ratio of sodium nitrite to deuterated 4-aminopyridine-d4 is (1.5-3):1; In step S10, the molar ratio of sodium sulfite used for quenching to liquid bromine is (1.2~1.5):1; In step S10, the molar ratio of sodium hydroxide to hydrobromic acid used for neutralization is (1-1.2):

1.

4. The method for preparing deuterated 4-borate pyridine-d4 according to claim 1 or 2, characterized in that, In step S10, the ether solvent is selected from one of methyl tert-butyl ether, ethyl tert-butyl ether, tert-amyl methyl ether, and diisopropyl ether; In step S10, the volume ratio of the extracted organic solvent to the reaction solution is (1-3):

1.

5. The method for preparing deuterated 4-borate pyridine-d4 according to claim 1 or 2, characterized in that, In step S10, the hydrogen chloride alcohol solution is a hydrogen chloride methanol solution; The molar ratio of the hydrogen chloride methanol solution to deuterated 4-aminopyridine-d4 is (1.0-1.2):1; In step S10, the concentration of the hydrogen chloride methanol solution is 1.0–3.0 mol / L.

6. The method for preparing deuterated 4-borate pyridine-d4 according to claim 1, characterized in that, The specific process of step S20 is as follows: The obtained deuterated 4-bromopyridine hydrochloride-d4 was dissolved in tetrahydrofuran and neutralized by adding sodium hydroxide aqueous solution, with the addition temperature controlled at -5 to 0℃. Then, the phases were separated, and spherical alkali metal hydroxide was added to the organic phase for dehydration pretreatment. Under an inert atmosphere, borate ester reagent was added to the above organic phase, followed by slow addition of alkyl lithium reagent to carry out lithium-bromine exchange and borate reaction. After the reaction was completed, the crude reaction solution was quenched with hydrochloric acid to obtain a crude reaction solution. The crude reaction solution was purified and treated to obtain the target product, deuterated 4-boronic acid pyridine.

7. The method for preparing deuterated 4-borate pyridine-d4 according to claim 1 or 6, characterized in that, In step S20, the mass-to-volume ratio of the deuterated 4-bromopyridine hydrochloride to the tetrahydrofuran solution is 1:(2-4) g / mL; In step S20, the concentration of the sodium hydroxide aqueous solution used for free hydrochloride is 10% to 30%; In step S20, the molar ratio of sodium hydroxide used for free hydrochloride to deuterated 4-bromopyridine hydrochloride-d4 is (1.2~1.5):1; The volume-to-mass ratio of the organic phase to the spherical alkali metal hydroxide is 1:(0.05~0.3)mL / g.

8. The method for preparing deuterated 4-borate pyridine-d4 according to claim 1 or 6, characterized in that, In step S20, the spherical alkali metal hydroxide is selected from spherical sodium hydroxide, spherical potassium hydroxide, or mixtures thereof; The spherical hydroxide has a particle size distribution D90 of 3–8 mm and a bulk density of 0.8–1.2 g / cm³. 3 .

9. The method for preparing deuterated 4-borate pyridine-d4 according to claim 1 or 6, characterized in that, In step S20, the borate ester is selected from triisopropyl borate, triethyl borate, tripropyl borate, and tributyl borate. In step S20, the alkyl lithium is selected from n-butyllithium, sec-butyllithium, and tert-butyllithium; In step S20, the molar ratio of the theoretical value of 4-bromopyridine-d4 to the borate ester and alkyl lithium is 1:(1.2~1.5):(1.2~1.5).

10. The method for preparing deuterated 4-borate pyridine-d4 according to claim 6, characterized in that, In step S20, the purification and treatment process of the crude reaction solution includes dissolving in water, separating phases, extracting the aqueous phase with dichloromethane, adding an alkali metal hydroxide solution to adjust the pH to 6.8-7.2 to precipitate the product, filtering, and successively slurrying with water, methanol or ethanol, and drying the filter cake to obtain deuterated 4-borate pyridine-d4. The alkali metal hydroxide used in the purification and post-treatment of the crude reaction solution is selected from sodium hydroxide, potassium hydroxide, or a mixture thereof, and the concentration of the alkali metal hydroxide is 40-50%.

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