Preparation method of high-purity and high-yield benzyloxypyridine compound

Abstract

The invention relates to the technical field of medicines, and discloses a preparation method of a high-purity and high-yield benzyloxypyridine compound, which comprises the following steps: by taking 2-fluoropyridine and terephthalyl alcohol as initial raw materials, adding potassium tert-butoxide into a solvent I for catalytic reaction to prepare an intermediate crude product; obtaining a high-purity intermediate through a purification process of dissolving the intermediate crude product under an acidic condition and carrying out alkali neutralization crystallization; and finally, reacting with a chlorination reagent, and carrying out low-boiling-point solvent replacement and post-treatment to obtain the high-purity 2-(4-(chloromethyl) benzyloxy) pyridine. The purity of the product obtained by the preparation method is higher than 99.5%, risky impurities and unreacted initiators are not detected, the safety of the product is ensured, meanwhile, the total yield is increased to more than 75%, and the production cost is remarkably reduced.

Description

Technical Field

[0001] The invention relates to the field of medical technology, and in particular to a method for preparing a high-purity and high-yield benzyloxypyridine compound. Background Art

[0002] Invasive fungal disease (IFD) is a type of fungal infectious disease with a very high mortality rate. Its morbidity and mortality have increased significantly in recent years. The core components of the fungal cell wall include glucan, chitin and mannoprotein. Among them, glycosylphosphatidylinositol anchored protein (GPI-AP) mediates the covalent connection between mannoprotein and glucan by anchoring to the cell membrane and cell wall, which is crucial for maintaining cell wall structure, host adhesion and morphological regulation. Gwt1, as a key acetylase in the GPI biosynthesis pathway, is directly involved in the generation of GPI precursors. When its activity is inhibited, GPI-AP synthesis is blocked, resulting in the inability of fungal surface mannoprotein to anchor to the cell wall, thereby destroying the integrity of the cell wall and weakening the fungus's ability to adhere to host tissues, ultimately exerting an antifungal effect.

[0003] Formula (1) The compound represented by formula (1) is a novel aminopyridine anti-IFD drug, which exhibits significant antibacterial activity against Candida, Cryptococcus and Aspergillus, can effectively improve the survival rate of candidemia model mice, and shows outstanding therapeutic potential in the candidal vaginal infection model. The benzyloxypyridine compound (2) is an important component of formula (1) and a key starting material, and has the following structural formula: Formula (2) Currently, there are few synthetic methods for this compound reported in existing literature, and it has not been fully commercialized. In addition, the existing synthetic methods have certain disadvantages: complicated operation, low purity, large impurities, low yield, high cost, high three wastes, and are not suitable for industrial production.

[0004] Existing methods for preparing formula (2) include the following: Method 1: EP2065377A1 discloses a method for preparing formula (2). Using methyl p-hydroxybenzoate and 2-(hydroxymethyl)pyridine as raw materials, a Mitsunobu reaction is carried out under the action of triphenylphosphine and DEAD to obtain key intermediate 1, and then key intermediate 1 is reacted with lithium aluminum hydride or sodium hydride to obtain key intermediate 2. Key intermediate 2 is chlorinated under the action of triphenylphosphine and carbon tetrachloride, and finally post-processed by column chromatography to obtain formula (2).

[0005] This method has the following main disadvantages: the method has a long route, the reagents used are expensive, the use of lithium aluminum hydride or sodium hydrogen reagents is prone to flammability and explosion risks, the use of the highly toxic reagent carbon tetrachloride, purification using column chromatography, high production costs, high pollution of the three wastes, and is not suitable for industrial production.

[0006] Method 2: US2007105904A1 discloses a method for preparing formula (2). Using 2-fluoropyridine and p-phenylenedimethanol as raw materials, a substitution reaction is carried out under the action of sodium hydrogen to obtain an intermediate, which is then subjected to a chlorination reaction under the action of triphenylphosphine and carbon tetrachloride, and finally post-treated by column chromatography to obtain formula (2).

[0007] This method has the following main disadvantages: the use of sodium hydrogen reagents in this route is prone to flammable and explosive risks, the use of carbon tetrachloride, a highly toxic reagent, and the use of column chromatography for purification in both post-treatment steps, which has high production costs and high pollution from the three wastes, making it unsuitable for industrial production.

[0008] Method 3: Example 1 of WO2023241507A1 discloses a method for preparing compound (2), and the method route is consistent with that of US2007105904A1.

[0009] The method has the following main disadvantages: although potassium tert-butoxide is used instead of sodium hydride or lithium aluminum hydride, and dichloromethane is used instead of carbon tetrachloride / triphenylphosphine, the compounds INT-1 and formula (2) in the patent are both concentrated and dried products, which are not suitable for industrial production. In addition, the solid phase of the product is sticky, the batch stability is poor, the yield is low, and the purity is low, which makes it difficult to meet the GMP large-scale production requirements; in particular, the related substances of formula (2) contain tert-butyl alcohol and impurity A. and impurity B The residue is relatively large. The SM2 residue in formula (2) further undergoes chlorination reaction with hydrochloric acid in the subsequent step to produce impurities A and B, which additionally increases the cumulative risk. The QSAR software predicts that impurities A / B are both Class 2 potential mutagenic impurities. According to the ICHM7 guidelines, they need to be strictly controlled.

[0010] In order to improve drug safety, lay a good quality foundation for the efficient synthesis of subsequent APIs, reduce production costs, and solve the problem of SM2 residues from the source, the market urgently needs a method for preparing a high-purity and high-yield benzyloxypyridine compound of formula (2) to meet the needs of prevention and treatment of frequent influenza. Summary of the invention

[0011] The present invention aims to solve at least one of the technical problems existing in the related art. To this end, the present invention provides a method for preparing a high-purity and high-yield benzyloxypyridine compound.

[0012] A method for preparing high-purity and high-yield benzyloxypyridine compounds. Formula (2) The benzyloxypyridine compound is 2-(4-(chloromethyl)benzyloxy)pyridine shown in formula (2), and the preparation steps include: Preparation of intermediates: using 2-fluoropyridine and tert-butyl alcohol as starting materials, adding potassium tert-butylate to solvent one for catalytic reaction, and performing quenching, extraction and pretreatment after the reaction to obtain a crude intermediate; Refining of intermediates: dissolving the crude intermediate in solvent 2, adjusting the pH to acidic with acid to dissolve it, neutralizing with alkali to crystallize, filtering and drying to obtain a high-purity intermediate; Preparation of target product: The high-purity intermediate reacts with a chlorination reagent, and high-purity 2-(4-(chloromethyl)benzyloxy)pyridine is obtained by replacement with a low-boiling point solvent and post-treatment.

[0013] Furthermore, the specific steps of preparing the intermediate include: Synthesis: Under nitrogen protection, dissolve tert-butyl alcohol in solvent 1, add potassium tert-butylate in batches under temperature control, add 2-fluoropyridine after complete dispersion, and react under stirring; Quenching and extraction: After the reaction is completed, the reaction solution is added dropwise to purified water for quenching, extracted with an extractant, and the organic phase is separated; Pretreatment: The organic phase is washed with sodium chloride solution, dried with a desiccant and then filtered. The filtrate is concentrated and then cooled and pulped. The crude intermediate is obtained by filtration and drying.

[0014] Furthermore, the solvent is selected from any one or more of tetrahydrofuran, toluene, acetonitrile, acetone and butanone. The extractant is selected from any one or more of toluene, methyl tert-butyl ether, isopropyl acetate, and isopropyl ether. The amount of terephthalic acid alcohol used is 1.5 to 2.5 times the molar amount of 2-fluoropyridine. The desiccant is anhydrous sodium sulfate.

[0015] Furthermore, the batch addition temperature of potassium tert-butoxide is 0±5°C. The dispersion time of potassium tert-butoxide is 0.5 hours. The reaction temperature under stirring conditions is 25±5°C and the reaction time is 3 to 8 hours. The quenching temperature is <10°C, The pre-treatment pulping temperature is 5±5℃; The concentration of sodium chloride solution is 10%.

[0016] Furthermore, the specific steps of intermediate refining include: Dissolution: Disperse the crude intermediate in solvent 2, add acid dropwise to adjust pH under temperature control, and stir until completely dissolved; Crystallization: Add alkaline solution to the solution to adjust the pH to 6-9, precipitate the solid, and then filter and dry to obtain a high-purity intermediate.

[0017] Furthermore, the second solvent is selected from any one or more of methanol, ethanol, ethyl acetate, methyl tert-butyl ether, water, toluene, isopropyl acetate, and acetone. The organic acid or inorganic acid is selected from any one or more of acetic acid, formic acid, hydrochloric acid, oxalic acid, benzenesulfonic acid, p-toluenesulfonic acid, and fumaric acid. The base is selected from any one or more of potassium phosphate, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, and triethylamine.

[0018] Furthermore, in the dissolving step, after adding acid, the dissolving temperature is 0-30°C, and the pH is controlled to 1-3; The pH is adjusted to 6-9 during the crystallization step.

[0019] Furthermore, the specific steps of preparing the target product include: Chlorination reaction: dissolve the high-purity intermediate in dichloromethane, add the chlorination reagent dropwise at a controlled temperature, and after the addition, heat and stir until the reaction is complete; Low boiling point solvent replacement and post-treatment: The solution after the chlorination reaction is concentrated under reduced pressure, replaced with a low boiling point solvent and then filtered. The filter cake is dispersed in a low boiling point solvent and the pH is adjusted to neutral with a saturated sodium bicarbonate solution. The organic phase is separated and washed with a 10% sodium chloride solution. The organic phase is dried, concentrated, pulped, filtered and dried to obtain the product 2-(4-(chloromethyl)benzyloxy)pyridine.

[0020] Further, the chlorination agent is selected from any one or more of phosphorus trichloride, phosphorus oxychloride, N-chlorosuccinimide, and trimethylsilyl chloride. The low boiling point solvent is selected from any one or more of n-hexane, methyl tert-butyl ether, isopropyl ether, and isopropyl acetate. The desiccant is anhydrous sodium sulfate.

[0021] Furthermore, the temperature of adding the chlorination reagent dropwise is <10°C, The chlorination reaction temperature is 20±5℃ or 35±5℃, The beating temperature is 5±5℃; The pH adjustment range during the low boiling point solvent replacement and work-up steps was 7-8.

[0022] The above one or more technical solutions in the embodiments of the present invention have at least one of the following technical effects: The present invention solves the problem of using expensive reagents in methods 1 and 2 mentioned in the background technology, avoids complex operations such as column chromatography purification in post-treatment, and also avoids using LAH and NaH flammable and explosive reagents, thereby reducing environmental pollution, reducing production costs, and improving production safety; The yield was greatly improved through parameter optimization. At the same time, the chemical purification method of INT-1 effectively removed SM2 residues from the source, avoiding the generation of potential mutagenic impurities predicted by the software as Class 2 in Method 3, namely, impurity A and impurity B, laying a good quality foundation for the efficient synthesis of subsequent APIs. Compared with the purity of formula (2) prepared in the comparative example of 97.6%, impurity A was detected at 0.9%, impurity B was detected at 0.5%, and SM2 was detected at 0.8%. The purity of formula (2) prepared in this scheme was ≥99.5%, and impurities A, impurity B and SM2 were not detected, which improved the safety of the product and made it more suitable for application in drug research and development.

[0023] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0025] Figure 1 This is a HPLC test chart of the compound of formula (2) prepared in one embodiment of the present invention; Figure 2 This is a nuclear magnetic resonance test image of the compound of formula (2) prepared in one embodiment of the present invention; Figure 3 This is a mass spectrum test chart of formula (2) prepared in one embodiment of the present invention. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical scheme and advantages of the present invention clearer, the technical scheme of the present invention will be clearly and completely described below in conjunction with the drawings in the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. The following embodiments are used to illustrate the present invention, but cannot be used to limit the scope of the present invention.

[0027] In order to facilitate understanding of the contents of the specific implementation mode, the abbreviations used in the specific implementation mode are listed as follows: Formula (1): (2-amino-5-(3-(4-((pyridin-2-yloxy)methyl)phenyl)prop-1-yn-1-yl)pyridin-1-ium-1-yl)methyl hydrogen phosphate; Formula (2): 2-(4-(chloromethyl)benzyloxy)pyridine; SM1 (starting material 1): 2-fluoropyridine; SM2 (starting material 2): ​​p-tert-butyl alcohol; Impurity A: p-dichlorobenzyl; Impurity B: p-Chloromethylbenzyl alcohol; INT-1 (intermediate): (4-(pyridin-2-yloxy)methyl)benzyl alcohol.

[0028] The purpose of the present invention is to provide a method for preparing a compound of formula (2) with high purity and yield, and to achieve an effective balance or even double optimization effect in improving the purity and yield of the final product through process optimization and reagent selection.

[0029] Before improving the preparation method, the causes of the generation of impurities A and B were first analyzed and studied, and their synthesis mechanisms are as follows: As shown above, impurity A and impurity B are mainly produced by SM2 (p-phenylenediol) that remains unreacted during the synthesis of INT-1 (intermediate 1), which undergoes a corresponding chlorination reaction during the chlorination step of the preparation formula (2), and can further undergo a corresponding chlorination reaction with the hydrochloric acid reagent in the subsequent API (active pharmaceutical ingredient) synthesis step, further producing impurity A (p-dichlorobenzyl) and impurity B (p-chloromethylbenzyl alcohol), which seriously increases the quality risk of the finished product.

[0030] Since SM2 is soluble in both aqueous solvents and organic solvents, and INT-1 is a low-melting-point solid, it is difficult to effectively remove unreacted SM2 through extraction and washing methods, and the generation of impurities A and B cannot be avoided, thus affecting the safety of the product.

[0031] Therefore, the initial goal of the design is to remove SM2 (paraphenylenediol) from the source.

[0032] A method for preparing high-purity and high-yield benzyloxypyridine compounds. The benzyloxypyridine compound is 2-(4-(chloromethyl)benzyloxy)pyridine represented by formula (2), Preparation of intermediates: Under nitrogen protection, SM1 (2-fluoropyridine) and SM2 (p-phenylenediol) are used as starting materials, potassium tert-butoxide (t-BuOK) is added to solvent one to catalyze the reaction, and after the reaction, the crude intermediate is obtained by quenching, extraction, and pretreatment.

[0033] The specific steps are as follows: Synthesis: Under nitrogen protection, SM2 (p-phenylenedimethanol, the input amount is calculated based on the molar ratio of SM1) is dissolved in organic solvent 1, potassium tert-butoxide (t-BuOK) is added in batches at a temperature of 0±5℃, and after stirring for 0.5 hour, SM1 (2-fluoropyridine) is added, the temperature is raised to 25±5℃, stirred, and the reaction is carried out for 3 to 8 hours.

[0034] Quenching and extraction: After the reaction is completed, the reaction solution is added dropwise into purified water to quench the reaction solution while maintaining the temperature at <10°C. The solution is extracted with an extractant and separated to obtain the organic phase.

[0035] Pretreatment: The organic phase was washed with 10% sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, cooled to 5±5°C and slurried for 1 hour, filtered and dried to obtain the crude intermediate.

[0036] The organic solvent is selected from any one or more of tetrahydrofuran, toluene, acetonitrile, acetone and butanone, preferably tetrahydrofuran.

[0037] The extractant is selected from any one or more of toluene, methyl tert-butyl ether, isopropyl acetate, and isopropyl ether, preferably methyl tert-butyl ether.

[0038] The amount of SM2 used is 1.5 to 2.5 times the molar amount of SM1.

[0039] Refining of intermediates: Under nitrogen protection, the crude intermediate is dissolved in solvent 2, and the pH is adjusted to acidic with an organic acid or an inorganic acid to dissolve it, and then neutralized with an alkali to crystallize, filtered, and dried to obtain a high-purity intermediate.

[0040] This step ensures that SM2 (p-phenylenediol) residues are effectively removed.

[0041] The specific steps are as follows: Dissolution: Disperse the crude intermediate in solvent 2, control the temperature at 0-30°C, add acid to adjust the pH to 1-3, stir until completely dissolved and the solution is clear and transparent.

[0042] Crystallization: add alkaline solution to the solution to adjust the pH to 6-9, precipitate white solid, filter and dry to obtain high-purity intermediate.

[0043] The second solvent is selected from any one or more of methanol, ethanol, ethyl acetate, methyl tert-butyl ether, water, toluene, isopropyl acetate, and acetone, preferably water.

[0044] The organic acid or inorganic acid is selected from any one or more of acetic acid, formic acid, hydrochloric acid, oxalic acid, benzenesulfonic acid, p-toluenesulfonic acid, and fumaric acid, preferably hydrochloric acid or oxalic acid.

[0045] The base is selected from any one or more of potassium phosphate, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, and triethylamine, preferably NaOH or sodium carbonate.

[0046] Preparation of target product: Under nitrogen protection, the high-purity intermediate reacts with a chlorination reagent, and is replaced with a low-boiling point solvent and post-treated to obtain a high-purity compound (2).

[0047] The specific steps are as follows: Chlorination reaction: Dissolve the high-purity intermediate in dichloromethane (DCM), add the chlorination reagent dropwise at a temperature of <10°C, and after the addition, heat and stir until the reaction is complete.

[0048] Low boiling point solvent replacement and post-treatment: Concentrate under reduced pressure, replace with low boiling point solvent, stir for 12 hours and filter. The filter cake is dispersed in a low boiling point solvent and the pH is adjusted to 7-8 with saturated sodium bicarbonate solution. The organic phase is separated and washed with 10% sodium chloride solution. The organic phase is dried, concentrated, cooled to 5±5°C and slurried for 1 hour, then filtered and dried to obtain the product (2).

[0049] The chlorination agent is selected from any one or more of phosphorus trichloride, phosphorus oxychloride, N-chlorosuccinimide, and trimethylchlorosilane.

[0050] The low boiling point solvent is selected from any one or more of n-hexane, methyl tert-butyl ether, isopropyl ether and isopropyl acetate.

[0051] The desiccant is anhydrous sodium sulfate.

[0052] The chlorination reaction temperature is 20±5℃ or 35±5℃.

[0053] The synthesis and post-treatment method is easy to operate, has low production cost, little environmental pollution, a product purity of ≥99.5%, impurities A, impurity B and SM2 are not detected, and a comprehensive yield is higher than 75%, which is suitable for industrial production.

[0054] A number of more detailed embodiments are given below to enable those skilled in the art to more clearly understand the technical solutions of the present invention.

[0055] Embodiment 1: Under nitrogen protection, 4.45 kg of tetrahydrofuran (THF) was added to a 20 L glass reactor, stirring was started, and then 1.42 kg of SM2 (p-phenylenediol, the amount added was 2.0 times the molar number of SM1) was added, and 1155.7 g of potassium tert-butoxide was added in batches at 0±5°C, and then stirred for half an hour at 25±5°C, and 500.0 g of SM1 (2-fluoropyridine, molecular formula C5H4FN molecular weight 97.09) was added to the system, and stirring was maintained at 25±5°C for 5 hours, and then the temperature was controlled below 10.0°C and the reaction solution was added dropwise into 10 L of purified water to quench.

[0056] After quenching, filter, and extract the filtrate with methyl tert-butyl ether 1L×4. Wash the organic phase after extraction with 10% sodium chloride aqueous solution 5L×2, add anhydrous sodium sulfate to dry and filter the organic phase, and concentrate the filtrate under reduced pressure to a remaining 1L, cool to 5±5℃, stir for 1 hour, filter, and dry to obtain a white solid.

[0057] The white solid was dispersed in 2.5L purified water, and 750ml of 1M HCl was added dropwise at a temperature of 20±5℃ to adjust the pH of the system to 1.5 and stirred until dissolved. After dissolved, 1M NaOH was added dropwise at a temperature of 20±5℃ to adjust the pH of the system to 7.8. A large amount of white solid was precipitated from the system. After filtration and drying, 942.2g of white product INT-1 was obtained with a purity of 99.5%, no SM2 was detected, and a yield of 85%.

[0058] Under nitrogen protection, add 900.0g INT-1 to 11.97kg dichloromethane (DCM) and stir to dissolve. After the addition, evacuate the reactor and replace with nitrogen three times. Control the temperature below 10.0℃, add 961.7g phosphorus oxychloride to the system, raise the temperature to 35±5℃ and stir until the reaction is completed, and then reduce the pressure and concentrate the system to obtain a white solid.

[0059] The white solid was dispersed in 9L methyl tert-butyl ether, stirred at 25±5°C for 1-2 hours, cooled to 20±5°C and filtered. The obtained white filter cake was dispersed again in 9L methyl tert-butyl ether, and a saturated sodium bicarbonate aqueous solution was added under stirring to adjust the pH to 7.4, and the organic phase was separated. The organic phase was washed with 9L 10% sodium chloride aqueous solution, and the organic phase was separated and dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated to 1L under reduced pressure, cooled to 5±5°C and stirred for 1 hour, and dried to obtain 879.4g of white solid product (2), purity: 99.7%, impurity A was not detected, impurity B was not detected, SM2 was not detected, and yield: 90%.

[0060] The product of Example 1 was subjected to HPLC test. The test chart is shown in Figure 1 , the test results are shown in Table 1.

[0061] Table 1:

[0062] The nuclear magnetic test results of the product are ¹H-NMR (400MHz,CDCl3), δ8.20(dd,J=1.3,5.0Hz,1H),7.61(ddd,J=1.9,6.9,8.5Hz,1H),7.51-7.47(m,2H), 7.42(d,J=8.3Hz,2H),6.91(ddd,J=0.8,5.1,7.0Hz,1H),6.84(d,J=8.3Hz,1H), 5.42(s,2H),4.62(s,2H).

[0063] The mass spectrometry (ES+) test results of the product are: m / z [M+H] + :426.14; theoretical value: m / z: 425.38.

[0064] From the above test results, it can be seen that the preparation scheme of the present invention can prepare a high-purity product (2) with high yield.

[0065] Embodiment 2: Under nitrogen protection, add 1.98kg acetonitrile (ACN) to a 10L glass reactor, start stirring, then add 0.64kg SM2 (1.80 equivalents), control 0±5℃ to add 520.1g potassium tert-butoxide in batches, then stir at 25±5℃ for half an hour, add 250.0g SM1 to the system, stir at 25±5℃ for 8 hours, then control the temperature below 10.0℃ to add the reaction solution dropwise to 5L purified water to quench. After quenching, filter, and extract the filtrate with 0.5L×4 of toluene. The organic phase is washed with 2.5L×2 of 10% sodium chloride aqueous solution, added with anhydrous sodium sulfate to dry and filter, the filtrate is concentrated under reduced pressure to leave 500ml, cooled to 5±5℃, stirred for 1 hour, filtered, and dried to obtain a white solid.

[0066] The white solid was dispersed in 1.3L methanol, and 278.1g of oxalic acid was added thereto at a temperature of 5±5℃ to adjust the pH value of the system to 2.1 and stirred until dissolved. After dissolution, 1M sodium carbonate solution was added dropwise at a temperature of 5±5℃ to adjust the pH value of the system to 6.5. A large amount of white solid was precipitated in the system. After filtration and drying, 460.0g of white product INT-1 was obtained with a purity of 99.4%, no SM2 was detected, and a yield of 83%.

[0067] Under nitrogen protection, add 450.0g INT-1 to 6.0kg dichloromethane (DCM) and stir to dissolve. After the addition, evacuate the reactor and replace with nitrogen three times. Control the temperature below 10.0℃, add 418.7g N-chlorosuccinimide to the system, raise the temperature to 25±5℃ and stir until the reaction is completed, and then reduce the pressure and concentrate the system to obtain a white solid.

[0068] The white solid was dispersed in 4.5 L of isopropyl ether, stirred at 25±5°C for 1-2 hours, cooled to 20±5°C and filtered. The obtained white filter cake was dispersed again in 4.5 L of isopropyl ether, and a saturated sodium bicarbonate aqueous solution was added under stirring to adjust the pH to 7.4, and the organic phase was separated. The organic phase was washed with 4.5 L of 10% sodium chloride aqueous solution, and the organic phase was separated and dried with anhydrous sodium sulfate. The filtrate was concentrated and dried under reduced pressure to obtain 444.6 g of white solid product (2), purity: 99.6%, impurity A, impurity B and SM2 were not detected, and the yield was 91%.

[0069] Embodiment 3: Under nitrogen protection, add 1.98 kg acetone to a 10L glass reactor, start stirring, then add 0.89 kg SM2 (2.5 equivalents), control 0±5℃ to add 722.4 g potassium tert-butoxide in batches, then stir at 25±5℃ for half an hour, add 250.0 g SM1 to the system, stir at 25±5℃ for 3 hours, then control the temperature below 10.0℃ to add the reaction solution dropwise to 5L purified water to quench. After quenching, filter, and extract the filtrate with ethyl acetate 0.5L×4. The organic phase is washed with 10% sodium chloride aqueous solution 2.5L×2, added anhydrous sodium sulfate to dry and filter, the filtrate is concentrated under reduced pressure to leave 500 ml, cooled to 5±5℃, stirred for 1 hour, filtered, and dried to obtain a white solid.

[0070] The white solid was dispersed in 1.3L ethanol, and acetic acid was added thereto at a temperature of 20±5℃ to adjust the pH value of the system to 3.0 and stirred until dissolved. After dissolved, 1M sodium bicarbonate solution was added dropwise to the system at a temperature of 20±5℃ to adjust the pH value of the system to 6.9. A large amount of white solid was precipitated from the system. After filtration and drying, 454.5g of white product INT-1 was obtained with a purity of 99.3%, no SM2 was detected, and a yield of 82%.

[0071] Under nitrogen protection, add 450.0g INT-1 to 6.0kg dichloromethane (DCM) and stir to dissolve. After the addition, evacuate the reactor and replace with nitrogen three times. Control the temperature below 10.0℃, add 574.2g phosphorus trichloride to the system dropwise, raise the temperature to 35±5℃ and stir until the reaction is completed, then concentrate the system under reduced pressure to obtain a white solid.

[0072] The white solid was dispersed in 4.5 L of n-hexane, stirred at 25±5°C for 1-2 hours, cooled to 20±5°C and filtered. The obtained white filter cake was dispersed again in 4.5 L of n-hexane, and a saturated sodium bicarbonate aqueous solution was added under stirring to adjust the pH to 7.1, and the organic phase was separated. The organic phase was washed with 4.5 L of 10% sodium chloride aqueous solution, and the organic phase was separated and dried with anhydrous sodium sulfate. The filtrate was concentrated and dried under reduced pressure to obtain 455.0 g of white solid product (2), purity: 99.7%, impurity A, impurity B and SM2 were not detected, and the yield was 93%.

[0073] Embodiment 4: Under nitrogen protection, add 2.03kg butanone to a 10L glass reactor, start stirring, then add 0.89kg SM2 (2.5 equivalents), control 0±5℃ to add 722.4g potassium tert-butoxide in batches, then stir at 25±5℃ for half an hour, add 250.0g SM1 to the system, stir at 25±5℃ for 3 hours, then control the temperature below 10.0℃ to add the reaction solution dropwise to 5L purified water to quench. After quenching, filter, and extract the filtrate with 0.5L×4 isopropyl acetate. The organic phase is washed with 2.5L×2 of 10% sodium chloride aqueous solution, added with anhydrous sodium sulfate to dry and filter, the filtrate is concentrated under reduced pressure to leave 500ml, cooled to 5±5℃, stirred for 1 hour, filtered, and dried to obtain a white solid.

[0074] The white solid was dispersed in 1.3L acetone, and formic acid was added thereto at a temperature of 20±5℃ to adjust the pH value of the system to 1.2 and stirred until dissolved. After dissolved, the temperature was controlled at 25±5℃, and triethylamine was added dropwise to the system to adjust the pH value of the system to 8.5. At this time, a large amount of white solid was precipitated in the system. After filtration and drying, 465.6g of white product INT-1 was obtained with a purity of 99.5%, SM2 was not detected, and the yield was 84%.

[0075] Under nitrogen protection, add 450.0g INT-1 to 5.32kg dichloromethane (DCM) and stir to dissolve. After the addition, evacuate the reactor and replace with nitrogen three times. Control the temperature below 10.0℃, add 302.8g trimethylsilyl chloride dropwise to the system, raise the temperature to 35±5℃ and stir until the reaction is completed, and then reduce the pressure and concentrate the system to obtain a white solid.

[0076] The white solid was dispersed in 4.0 L of methyl tert-butyl ether, stirred at 25±5°C for 1-2 hours, cooled to 20±5°C and filtered. The obtained white filter cake was dispersed again in 4.0 L of methyl tert-butyl ether, and a saturated sodium bicarbonate aqueous solution was added under stirring to adjust the pH to 7.6, and the organic phase was separated. The organic phase was washed with 4.0 L of 10% sodium chloride aqueous solution, and the organic phase was separated and dried with anhydrous sodium sulfate. The filtrate was concentrated and dried under reduced pressure to obtain 443.1 g of white solid product (2), purity: 99.5%, impurity A, impurity B and SM2 were not detected, and the yield was 91%.

[0077] Embodiment 5: Under nitrogen protection, add 2.16 kg of toluene to a 10L glass reactor, start stirring, then add 0.71 kg of SM2 (2.0 equivalents), control 0±5℃ to add 577.9 g of potassium tert-butoxide in batches, then stir at 25±5℃ for half an hour, add 250.0 g of SM1 to the system, stir at 25±5℃ for 3 hours, then control the temperature below 10.0℃ to drop the reaction solution into 5L purified water to quench. After quenching, filter, and extract the filtrate with 0.5L×3 of toluene. The organic phase is washed with 2.5L×2 of 10% sodium chloride aqueous solution, added with anhydrous sodium sulfate to dry and filter, the filtrate is concentrated under reduced pressure to leave 500 ml, cooled to 5±5℃, stirred for 1 hour, filtered, and dried to obtain a white solid.

[0078] The white solid was dispersed in 1.3L of water, and p-toluenesulfonic acid was added thereto at a temperature of 20±5℃ to adjust the pH value of the system to 2.5 and stirred until dissolved. After dissolution, potassium phosphate solution was added dropwise to the system at a temperature of 20±5℃ to adjust the pH value of the system to 8.2. A large amount of white solid was precipitated from the system. After filtration and drying, 471.1g of white product INT-1 was obtained with a purity of 99.5%, no SM2 was detected, and a yield of 85%.

[0079] Under nitrogen protection, add 450.0g INT-1 to 6.0kg dichloromethane (DCM) and stir to dissolve. After the addition, evacuate the reactor and replace with nitrogen three times. Control the temperature below 10.0℃, add 574.2g phosphorus trichloride to the system dropwise, raise the temperature to 35±5℃ and stir until the reaction is completed, then concentrate the system under reduced pressure to obtain a white solid.

[0080] The white solid was dispersed in 4.5 L isopropyl acetate, stirred at 25±5°C for 1-2 hours, cooled to 20±5°C and filtered. The obtained white filter cake was dispersed again in 4.5 L isopropyl acetate, and a saturated sodium bicarbonate aqueous solution was added under stirring to adjust the pH to 7.3, and the organic phase was separated, and the organic phase was washed with 4.5 L 10% sodium chloride aqueous solution. After the organic phase was separated, it was dried and filtered with anhydrous sodium sulfate, and the filtrate was concentrated and dried under reduced pressure to obtain 439.7 g of white solid product (2), purity: 99.4%, impurity A, impurity B and SM2 were not detected, and the yield was 90%.

[0081] Comparative Example: Under nitrogen protection, 200.0g SM1 and 426.0g SM2 were added to 2L N,N-dimethylformamide (DMF), stirring was started, the temperature of the system was lowered to 0°C, 346.0g potassium tert-butoxide was added in batches, and after the addition was completed, the reaction system was stirred at 20-35°C for 1 hour. HPLC showed that the reaction was complete. The reaction solution was added to 4L ice water, washed with 2L of n-heptane × 2, the aqueous phase was extracted with 2L of isopropyl acetate × 2, the organic phase was washed with 2L of 10% sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 177.4g of compound INT-1, with a purity of 93.3%, SM2 detected 6.3%, and a yield of 40%). 150.0 g of compound INT-1 was added to 1.5 L of dichloromethane, the solution was cooled to 0°C, 76 ml of thionyl chloride was slowly added dropwise, and the reaction system was stirred at 15°C for 1 hour. HPLC showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to form a solid, slurried with 1.2 L of n-heptane, filtered, and the filter cake was added to 1.5 L of ethyl acetate, the pH was adjusted to 7 with saturated sodium bicarbonate, the organic phase was separated and washed with 1.5 L of 10% sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 117.3 g of compound formula (2), with a purity of 97.6%, impurity A 0.9%, impurity B 0.5%, SM2 0.8%, and a yield of 72%.

[0082] The comparison of product yield and purity of the examples and comparative examples is shown in Table 2.

[0083] Table 2:

[0084] It can be seen from the above table that the preparation method provided by the present invention can effectively remove the SM2 remaining in the reaction, thereby avoiding the generation of impurities A and B at the same time, and ultimately effectively ensuring the safety of the product.

[0085] No SM2 residues, impurities A and impurities B were detected in Examples 1-5.

[0086] The yield of the intermediate was improved by optimizing the amount of solvent and SM2 used in the preparation of the intermediate and the order of addition based on the WO2023241507A1 patent; the final total yield was >75%, effectively reducing the production cost.

[0087] HPLC detection method: Use octadecylsilane bonded silica gel as filler (Waters Xbridge C18, 4.6mm×150mm, 3.5μm or chromatographic column with equivalent performance); use 10mM ammonium formate buffer (take 0.63g of ammonium formate and add 1000ml of water to dissolve it, and adjust the pH value to 10.0 with ammonia water) as mobile phase A, and acetonitrile as mobile phase B; perform gradient elution according to the table below; the flow rate is 0.8ml per minute; the detection wavelength is 215nm; the column temperature is 30℃; the injection volume is 3μl.

[0088] The elution procedure is shown in Table 3. Table 3:

[0089] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a high-purity and high-yield benzyloxypyridine compound, characterized in that: Formula (2) The benzyloxypyridine compound is 2-(4-(chloromethyl)benzyloxy)pyridine shown in formula (2), and the preparation steps include: Preparation of intermediates: using 2-fluoropyridine and tert-butyl alcohol as starting materials, adding potassium tert-butylate to solvent one for catalytic reaction, and performing quenching, extraction and pretreatment after the reaction to obtain a crude intermediate; Refining of intermediates: dissolving the crude intermediate in solvent 2, adjusting the pH to acidic with acid to dissolve it, neutralizing with alkali to crystallize, filtering and drying to obtain a high-purity intermediate; Preparation of target product: The high-purity intermediate reacts with a chlorination reagent, and high-purity 2-(4-(chloromethyl)benzyloxy)pyridine is obtained by replacement with a low-boiling point solvent and post-treatment.

2. The method for preparing high-purity and high-yield benzyloxypyridine compounds according to claim 1, characterized in that: The specific steps of preparing the intermediate include: Synthesis: Under nitrogen protection, dissolve tert-butyl alcohol in solvent 1, add potassium tert-butylate in batches under temperature control, add 2-fluoropyridine after complete dispersion, and react under stirring; Quenching and extraction: After the reaction is completed, the reaction solution is added dropwise to purified water for quenching, extracted with an extractant, and the organic phase is separated; Pretreatment: The organic phase is washed with sodium chloride solution, dried with a desiccant and then filtered. The filtrate is concentrated and then cooled and pulped. The crude intermediate is obtained by filtration and drying.

3. The method for preparing high-purity and high-yield benzyloxypyridine compounds according to claim 2, characterized in that: Solvent 1 is selected from any one or more of tetrahydrofuran, toluene, acetonitrile, acetone, and butanone, The extractant is selected from any one or more of toluene, methyl tert-butyl ether, isopropyl acetate, and isopropyl ether. The amount of terephthalic acid alcohol used is 1.5 to 2.5 times the molar amount of 2-fluoropyridine. The desiccant is anhydrous sodium sulfate.

4. The method for preparing high-purity and high-yield benzyloxypyridine compounds according to claim 3, characterized in that: The batch addition temperature of potassium tert-butoxide is 0±5℃, The dispersion time of potassium tert-butoxide is 0.5 hours. The reaction temperature under stirring conditions is 25±5°C and the reaction time is 3 to 8 hours. The quenching temperature is <10°C, The pre-treatment pulping temperature is 5±5℃. The concentration of sodium chloride solution is 10%.

5. The method for preparing high-purity and high-yield benzyloxypyridine compounds according to claim 1, characterized in that: The specific steps of intermediate refining include: Dissolution: Disperse the crude intermediate in solvent 2, add acid dropwise to adjust pH under temperature control, and stir until completely dissolved; Crystallization: Add alkaline solution to the solution to adjust the pH to 6-9, precipitate the solid, and then filter and dry to obtain a high-purity intermediate.

6. The method for preparing high-purity and high-yield benzyloxypyridine compounds according to claim 5, characterized in that: Solvent 2 is selected from any one or more of methanol, ethanol, ethyl acetate, methyl tert-butyl ether, water, toluene, isopropyl acetate, and acetone. The organic acid or inorganic acid is selected from any one or more of acetic acid, formic acid, hydrochloric acid, oxalic acid, benzenesulfonic acid, p-toluenesulfonic acid, and fumaric acid. The base is selected from any one or more of potassium phosphate, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, and triethylamine.

7. The method for preparing high-purity and high-yield benzyloxypyridine compounds according to claim 6, characterized in that: After adding acid in the dissolution step, the dissolution temperature is 0-30°C and the pH is controlled to 1-3. The pH is adjusted to 6-9 during the crystallization step.

8. The method for preparing high-purity and high-yield benzyloxypyridine compounds according to claim 1, characterized in that: The specific steps for preparing the target product include: Chlorination reaction: dissolve the high-purity intermediate in dichloromethane, add the chlorination reagent dropwise at a controlled temperature, and after the addition, heat and stir until the reaction is complete; Low boiling point solvent replacement and post-treatment: The solution after the chlorination reaction is concentrated under reduced pressure, replaced with a low boiling point solvent and then filtered. The filter cake is dispersed in a low boiling point solvent and the pH is adjusted to neutral with a saturated sodium bicarbonate solution. The organic phase is separated and washed with a 10% sodium chloride solution. The organic phase is dried, concentrated, pulped, filtered and dried to obtain the product 2-(4-(chloromethyl)benzyloxy)pyridine.

9. The method for preparing high-purity and high-yield benzyloxypyridine compounds according to claim 1, characterized in that: The chlorination agent is selected from any one or more of phosphorus trichloride, phosphorus oxychloride, N-chlorosuccinimide, and trimethylchlorosilane. The low boiling point solvent is selected from any one or more of n-hexane, methyl tert-butyl ether, isopropyl ether, and isopropyl acetate. The desiccant is anhydrous sodium sulfate.

10. The method for preparing high-purity and high-yield benzyloxypyridine compounds according to claim 1, characterized in that: The temperature of adding chlorination reagent is <10℃. The chlorination reaction temperature is 20±5℃ or 35±5℃, The beating temperature is 5±5℃; The pH adjustment range during the low boiling point solvent replacement and work-up steps was 7-8.

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