A method for preparing high-purity and high-yield benzylpyridine compounds

Abstract

The present invention relates to the field of medical technology, and discloses a method for preparing a high-purity and high-yield benzyloxypyridine compound. 2-fluoropyridine and p-phenylenediol are used as starting materials, potassium tert-butoxide is added to a solvent to catalyze a reaction, and a crude intermediate is prepared; a high-purity intermediate is obtained by a purification process of dissolving the crude intermediate under acidic conditions and neutralizing and crystallizing the intermediate with an alkali; and finally, the high-purity intermediate is obtained by reacting with a chlorination reagent, and high-purity 2-(4-(chloromethyl)benzyloxy)pyridine is obtained through low-boiling point solvent replacement and post-processing. The product purity obtained by this preparation method is higher than 99.5%, and no risk impurities and unreacted starting materials are detected, thereby ensuring the safety of the product, while increasing the total yield to more than 75%, significantly reducing production costs.

Description

Technical Field

[0001] The present 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 highly lethal fungal infection, with both morbidity and mortality rates increasing significantly in recent years. The core components of the fungal cell wall include glucan, chitin, and mannoproteins. Glycosylphosphatidylinositol-anchored proteins (GPI-APs) mediate the covalent linkage between mannoproteins and glucan by anchoring to the cell membrane and cell wall, and are crucial for maintaining cell wall structure, host adhesion, and morphological regulation. Gwt1, 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, preventing fungal surface mannoproteins from anchoring to the cell wall. This disrupts cell wall integrity and weakens the fungus's ability to adhere to host tissues, ultimately exerting an antifungal effect.

[0003] Formula (1)

[0004] The compound represented by formula (1) is a novel aminopyridine anti-IFD drug that exhibits significant antibacterial activity against Candida, Cryptococcus, and Aspergillus. It can effectively improve the survival rate of candidemia model mice and demonstrates outstanding therapeutic potential in the candidal vaginal infection model.

[0005] The benzyloxypyridine compound (2) is an important component of formula (1) and a key starting material, and its structural formula is as follows:

[0006] Formula (2)

[0007] 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: cumbersome operation, low purity, large impurities, low yield, high cost, high three wastes, and are not suitable for industrial production.

[0008] Existing methods for preparing formula (2) include the following:

[0009] Method 1: EP2065377A1 discloses a method for preparing formula (2).

[0010]

[0011] Methyl p-hydroxybenzoate and 2-(hydroxymethyl)pyridine are used as raw materials to undergo Mitsunobu reaction in the presence of triphenylphosphine and DEAD to obtain key intermediate 1. Then, key intermediate 1 is reacted with lithium aluminum hydride or sodium hydride to obtain key intermediate 2. Key intermediate 2 undergoes chlorination reaction in the presence of triphenylphosphine and carbon tetrachloride, and finally post-processed by column chromatography to obtain formula (2).

[0012] This method has the following main disadvantages: the method route is long, 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, the purification using column chromatography, the high production cost, the high pollution of the three wastes, and is not suitable for industrial production.

[0013] Method 2: US2007105904A1 discloses a method for preparing formula (2).

[0014]

[0015] Using 2-fluoropyridine and 4-phenylenedimethanol as raw materials, a substitution reaction is carried out under the action of sodium hydrogen to obtain an intermediate, which undergoes a chlorination reaction under the action of triphenylphosphine and carbon tetrachloride, and is finally post-treated and purified by column chromatography to obtain formula (2).

[0016] 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 steps. The production cost is high, the three wastes are highly polluting, and it is not suitable for industrial production.

[0017] Method 3: Example 1 of WO2023241507A1 discloses a method for preparing formula (2), and the method route is consistent with that of US2007105904A1.

[0018] 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, the purity is low, and it is difficult to meet the GMP large-scale production requirements; especially the related substances in formula (2) such as tert-butyl alcohol and impurity A and impurity B The residue is large, and the SM2 residue in formula (2) further undergoes chlorination reaction with hydrochloric acid in the subsequent steps 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.

[0019] 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 residue 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 in response to frequent influenza. Summary of the Invention

[0020] 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 benzyloxypyridine compound with high purity and high yield.

[0021] A method for preparing high-purity and high-yield benzyloxypyridine compounds.

[0022] Formula (2)

[0023] The benzyloxypyridine compound is 2-(4-(chloromethyl)benzyloxy)pyridine shown in formula (2), and the preparation steps include:

[0024] Preparation of the intermediate: Using 2-fluoropyridine and p-phenylenediol as starting materials, potassium tert-butoxide is added to solvent 1 to catalyze the reaction, followed by quenching, extraction, and pretreatment to obtain a crude intermediate;

[0025] Intermediate purification: dissolve the crude intermediate in solvent 2, adjust the pH to acidic with acid to dissolve it, then neutralize with alkali to crystallize, filter and dry to obtain a high-purity intermediate;

[0026] Preparation of target product: The high-purity intermediate reacts with a chlorination reagent, and high-purity 2-(4-(chloromethyl)benzyloxy)pyridine is obtained by low-boiling point solvent replacement and post-treatment.

[0027] Furthermore, the specific steps of preparing the intermediate include:

[0028] Synthesis: Under nitrogen protection, dissolve tert-butyl alcohol in solvent 1, add potassium tert-butoxide in batches under temperature control, add 2-fluoropyridine after complete dispersion, and react under stirring;

[0029] 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;

[0030] 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.

[0031] Furthermore, the solvent is selected from any one or more of tetrahydrofuran, toluene, acetonitrile, acetone, and butanone.

[0032] The extractant is selected from any one or more of toluene, methyl tert-butyl ether, isopropyl acetate, and isopropyl ether.

[0033] The amount of terephthalic acid methanol used is 1.5 to 2.5 times the molar amount of 2-fluoropyridine.

[0034] The desiccant is anhydrous sodium sulfate.

[0035] Furthermore, the temperature of adding potassium tert-butoxide in batches is 0±5°C.

[0036] The dispersion time of potassium tert-butoxide is 0.5 hours.

[0037] The reaction temperature under stirring conditions is 25±5°C and the reaction time is 3 to 8 hours.

[0038] The quenching temperature is <10℃,

[0039] The beating temperature of pretreatment is 5±5℃;

[0040] The concentration of sodium chloride solution is 10%.

[0041] Furthermore, the specific steps of intermediate refining include:

[0042] Dissolution: Disperse the crude intermediate in solvent 2, add acid dropwise to adjust the pH under controlled temperature, and stir until completely dissolved;

[0043] 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.

[0044] 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.

[0045] 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.

[0046] The base is selected from any one or more of potassium phosphate, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, and triethylamine.

[0047] Furthermore, in the dissolving step, the dissolving temperature after adding acid is 0-30°C and the pH is controlled to 1-3;

[0048] The pH is adjusted to 6-9 during the crystallization step.

[0049] Furthermore, the specific steps of preparing the target product include:

[0050] Chlorination reaction: dissolve the high-purity intermediate in dichloromethane, add the chlorination reagent dropwise under controlled temperature, and after the addition, heat and stir until the reaction is complete;

[0051] 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 redispersed 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.

[0052] Furthermore, the chlorination agent is selected from any one or more of phosphorus trichloride, phosphorus oxychloride, N-chlorosuccinimide, and trimethylsilyl chloride.

[0053] The low boiling point solvent is selected from any one or more of n-hexane, methyl tert-butyl ether, isopropyl ether, and isopropyl acetate.

[0054] The desiccant is anhydrous sodium sulfate.

[0055] Furthermore, the temperature of adding the chlorination agent dropwise is <10°C,

[0056] The chlorination reaction temperature is 20±5℃ or 35±5℃,

[0057] The beating temperature is 5±5℃;

[0058] The pH adjustment range during the low-boiling point solvent exchange and workup steps was 7-8.

[0059] The above one or more technical solutions in the embodiments of the present invention have at least one of the following technical effects:

[0060] The present invention solves the problem of expensive reagents required in methods 1 and 2 mentioned in the background art, avoids complex operations such as column chromatography purification in post-processing, and also avoids the use of flammable and explosive reagents such as LAH and NaH, thereby reducing environmental pollution, lowering production costs, and improving production safety.

[0061] Parameter optimization significantly improved yield. Furthermore, the chemical purification of INT-1 effectively removed SM2 residues at the source, avoiding the production of potential mutagenic impurities (Impurities A and B) predicted by the software as Class 2 in Method 3. This laid a solid foundation for the efficient synthesis of subsequent APIs.

[0062] Compared with the formula (2) prepared in the comparative example, which has a purity of 97.6%, impurity A detected at 0.9%, impurity B detected at 0.5%, and SM2 detected at 0.8%, the formula (2) prepared in this scheme has a purity of ≥99.5%, and impurities A, impurity B, and SM2 are not detected, thereby improving the safety of the product and making it more suitable for application in drug research and development.

[0063] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. 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 any creative work.

[0065] Figure 1 This is a HPLC test chart of formula (2) prepared in one embodiment of the present invention;

[0066] Figure 2 This is the NMR test image of formula (2) prepared in one embodiment of the present invention;

[0067] Figure 3 This is a mass spectrum test chart of formula (2) prepared in one embodiment of the present invention. DETAILED DESCRIPTION

[0068] To make the purpose, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with the accompanying drawings of the present invention. Obviously, the embodiments described are part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. The following embodiments are used to illustrate the present invention, but are not used to limit the scope of the present invention.

[0069] In order to facilitate understanding of the contents of the specific embodiments, the abbreviations used in the specific embodiments are listed below:

[0070] 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;

[0071] Formula (2): 2-(4-(chloromethyl)benzyloxy)pyridine;

[0072] SM1 (starting material 1): 2-fluoropyridine;

[0073] SM2 (starting material 2): p-phenylenediol;

[0074] Impurity A: p-dichlorobenzyl;

[0075] Impurity B: p-chloromethylbenzyl alcohol;

[0076] INT-1 (intermediate): (4-(pyridin-2-yloxy)methyl)benzyl alcohol.

[0077] 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 a dual optimization effect in improving the purity and yield of the final product through process optimization and reagent selection.

[0078] Before improving the preparation method, the causes of the generation of impurities A and B were first analyzed and studied. The synthesis mechanism is as follows:

[0079]

[0080] As shown above, impurity A and impurity B are mainly caused 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). In the subsequent step of synthesizing the API (active pharmaceutical ingredient), it can further undergo a corresponding chlorination reaction with the hydrochloric acid reagent, further producing impurity A (p-dichlorobenzyl) and impurity B (p-chloromethylbenzyl alcohol), which seriously increases the quality risk of the finished product.

[0081] Since SM2 is soluble in both aqueous 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 production of impurities A and B cannot be avoided, affecting the safety of the product.

[0082] Therefore, the initial goal of the design is to remove SM2 (p-phenylenediol) from the source.

[0083] A method for preparing high-purity and high-yield benzyloxypyridine compounds.

[0084]

[0085] The benzyloxypyridine compound is 2-(4-(chloromethyl)benzyloxy)pyridine shown in formula (2),

[0086] Preparation of intermediates: Under nitrogen protection, SM1 (2-fluoropyridine) and SM2 (p-phenylenediol) are used as starting materials, and potassium tert-butoxide (t-BuOK) is added to solvent one to catalyze the reaction. After the reaction, the crude intermediate is obtained by quenching, extraction, and pretreatment.

[0087] The specific steps are as follows:

[0088] Synthesis: Under nitrogen protection, dissolve SM2 (p-phenylenediol, the amount is calculated based on the molar ratio of SM1) in organic solvent 1, add potassium tert-butoxide (t-BuOK) in batches at a temperature of 0±5°C, stir for 0.5 hours, add SM1 (2-fluoropyridine), raise the temperature to 25±5°C, stir, and react for 3-8 hours.

[0089] Quenching and extraction: After the reaction is completed, the reaction solution is added dropwise to purified water at a temperature of <10°C to quench the reaction solution. The solution is extracted with an extractant and separated to obtain the organic phase.

[0090] 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.

[0091] The organic solvent is selected from any one or more of tetrahydrofuran, toluene, acetonitrile, acetone, and butanone, preferably tetrahydrofuran.

[0092] 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.

[0093] The amount of SM2 used is 1.5 to 2.5 times the molar amount of SM1.

[0094] Purification 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 a base to crystallize, filtered, and dried to obtain a high-purity intermediate.

[0095] This step ensures that SM2 (p-phenylenediol) residues are effectively removed.

[0096] The specific steps are as follows:

[0097] Dissolution: Disperse the crude intermediate in solvent 2, control the temperature at 0-30°C, add acid dropwise to adjust the pH to 1-3, and stir until completely dissolved and the solution becomes clear and transparent.

[0098] Crystallization: add alkaline solution to the solution to adjust the pH to 6-9, precipitate a white solid, filter and dry to obtain a high-purity intermediate.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] Preparation of target product: Under nitrogen protection, the high-purity intermediate reacts with a chlorination reagent, and high-purity formula (2) is obtained by low-boiling point solvent replacement and post-treatment.

[0103] The specific steps are as follows:

[0104] Chlorination reaction: Dissolve the high-purity intermediate in dichloromethane (DCM), add the chlorination reagent dropwise at a temperature <10°C, and then heat and stir until the reaction is complete.

[0105] Low-boiling-point solvent replacement and post-treatment: Concentrate under reduced pressure, replace with a low-boiling-point solvent, stir for 12 hours, and filter. The filter cake is redispersed in a low-boiling-point solvent and the pH is adjusted to 7-8 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, cooled to 5±5°C, and slurried for 1 hour. It is then filtered and dried to obtain the product (2).

[0106] The chlorination agent is selected from any one or more of phosphorus trichloride, phosphorus oxychloride, N-chlorosuccinimide, and trimethylsilyl chloride.

[0107] The low boiling point solvent is selected from any one or more of n-hexane, methyl tert-butyl ether, isopropyl ether, and isopropyl acetate.

[0108] The desiccant is anhydrous sodium sulfate.

[0109] The chlorination reaction temperature is 20±5℃ or 35±5℃.

[0110] The synthesis and post-treatment method is simple to operate, has low production cost, and has little environmental pollution. The product purity is ≥99.5%, impurities A, impurity B, and SM2 are not detected, and the comprehensive yield is higher than 75%, which is suitable for industrial production.

[0111] A number of more detailed embodiments will be given below to enable those skilled in the art to more clearly understand the technical solutions of the present invention.

[0112] Example 1:

[0113] Under nitrogen protection, 4.45 kg of tetrahydrofuran (THF) was added to a 20 L glass reactor and stirring was started. Then 1.42 kg of SM2 (p-phenylenediol, the amount added was 2.0 times the molar number of SM1) was added. 1155.7 g of potassium tert-butoxide was added in batches at 0±5°C, and then the temperature was raised to 25±5°C and stirred for half an hour. 500.0 g of SM1 (2-fluoropyridine, molecular formula C5H4FN, molecular weight 97.09) was added to the system, and the temperature was maintained at 25±5°C and stirred for 5 hours. Then, the reaction solution was added dropwise to 10 L of purified water with the temperature controlled below 10.0°C to quench.

[0114] After quenching, filter the mixture, and extract the filtrate with 1 L of methyl tert-butyl ether (4 times). Wash the organic phase with 5 L of 10% sodium chloride aqueous solution (2 times). Add anhydrous sodium sulfate, dry, and filter the organic phase. Concentrate the filtrate under reduced pressure to a residual volume of 1 L. Cool to 5 ± 5°C, stir for 1 hour, filter, and dry to obtain a white solid.

[0115] The white solid was dispersed in 2.5 L of purified water. 750 ml of 1 M HCl was added dropwise at a temperature of 20 ± 5 ° C to adjust the pH of the system to 1.5 and stirred until dissolved. After dissolution, 1 M NaOH was added dropwise at a temperature of 20 ± 5 ° C to adjust the pH of the system to 7.8. A large amount of white solid precipitated from the system. After filtration and drying, 942.2 g of white product INT-1 was obtained with a purity of 99.5%, no SM2 was detected, and a yield of 85%.

[0116] Under nitrogen, add 900.0g of INT-1 to 11.97kg of dichloromethane (DCM) and stir to dissolve. After addition, evacuate the reactor and replace the atmosphere with nitrogen three times. Maintain the temperature below 10.0°C and add 961.7g of phosphorus oxychloride dropwise. After addition, raise the temperature to 35±5°C and stir until the reaction is complete. Concentrate under reduced pressure to obtain a white solid.

[0117] The white solid was dispersed in 9 L of methyl tert-butyl ether, stirred at 25 ± 5 ° C for 1 to 2 hours, cooled to 20 ± 5 ° C and filtered. The obtained white filter cake was dispersed again in 9 L of methyl tert-butyl ether, and saturated sodium bicarbonate aqueous solution was added under stirring to adjust the pH to 7.4. The organic phase was separated and washed with 9 L of 10% sodium chloride aqueous solution. After separation, the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to 1 L under reduced pressure, cooled to 5 ± 5 ° C and stirred for 1 hour. After drying, 879.4 g of white solid product (2) was obtained with a purity of 99.7%, impurity A was not detected, impurity B was not detected, and SM2 was not detected. The yield was 90%.

[0118] 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.

[0119] Table 1:

[0120]

[0121] The nuclear magnetic test results of the product are ¹H-NMR (400MHz,CDCl3),

[0122] 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),

[0123] 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),

[0124] 5.42(s,2H),4.62(s,2H).

[0125] The mass spectrometry (ES+) detection results of the product are: m / z [M+H] + : 426.14; Calculated value: m / z: 425.38.

[0126] From the above test results, it can be seen that the preparation scheme of the present invention can produce high-purity product (2) with high yield.

[0127] Example 2:

[0128] Under nitrogen, 1.98 kg of acetonitrile (ACN) was added to a 10-L glass reactor with stirring. 0.64 kg of SM2 (1.80 equivalents) was then added. 520.1 g of potassium tert-butoxide was added portionwise at 0 ± 5°C. The mixture was then heated to 25 ± 5°C with stirring for half an hour. 250.0 g of SM1 was added, and the temperature was raised to 25 ± 5°C with stirring for 8 hours. The reaction mixture was then quenched by adding it dropwise to 5 L of purified water, controlled below 10.0°C. After quenching, the reaction mixture was filtered, and the filtrate was extracted with 0.5 L of toluene four times. The organic phase was washed with 2.5 L of 10% sodium chloride aqueous solution twice, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a remaining 500 mL, cooled to 5 ± 5°C with stirring for 1 hour, filtered, and dried to yield a white solid.

[0129] The white solid was dispersed in 1.3 L of methanol, and 278.1 g of oxalic acid was added thereto at a temperature of 5±5°C to adjust the pH of the system to 2.1 and stirred until dissolved. After dissolution, 1 M sodium carbonate solution was added dropwise to the system at a temperature of 5±5°C to adjust the pH of the system to 6.5. A large amount of white solid was precipitated in the system. After filtration and drying, 460.0 g of white product INT-1 was obtained with a purity of 99.4%, no SM2 was detected, and a yield of 83%.

[0130] Under nitrogen, add 450.0g of INT-1 to 6.0kg of dichloromethane (DCM) and stir to dissolve. After addition, evacuate the reactor and replace the atmosphere with nitrogen three times. Maintain the temperature below 10.0°C and add 418.7g of N-chlorosuccinimide. After addition, raise the temperature to 25±5°C and stir until the reaction is complete. Concentrate under reduced pressure to yield a white solid.

[0131] The white solid was dispersed in 4.5 L of isopropyl ether, stirred at 25 ± 5 ° C for 1 to 2 hours, and then 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. The organic phase was separated and washed with 4.5 L of 10% sodium chloride aqueous solution. After separation, the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and dried to obtain 444.6 g of white solid product (Formula (2)) with a purity of 99.6%. Impurities A, B and SM2 were not detected. The yield was 91%.

[0132] Example 3:

[0133] Under nitrogen, add 1.98 kg of acetone to a 10 L glass reactor and start stirring. Then, add 0.89 kg of SM2 (2.5 equivalents). Add 722.4 g of potassium tert-butoxide in portions at 0 ± 5 °C. Then, raise the temperature to 25 ± 5 °C and stir for half an hour. Add 250.0 g of SM1, raise the temperature to 25 ± 5 °C and stir for 3 hours. Then, control the temperature below 10.0 °C and quench the reaction by adding the mixture dropwise into 5 L of purified water. After quenching, filter the mixture, and extract the filtrate with 0.5 L of ethyl acetate four times. The organic phase is washed with 2.5 L of 10% aqueous sodium chloride solution twice, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to a remaining 500 mL, cooled to 5 ± 5 °C, stirred for 1 hour, filtered, and dried to obtain a white solid.

[0134] The white solid was dispersed in 1.3 L of ethanol, and acetic acid was added thereto at a temperature of 20±5°C to adjust the pH of the system to 3.0 and stirred until dissolved. After dissolution, 1 M sodium bicarbonate solution was added dropwise to the system at a temperature of 20±5°C to adjust the pH of the system to 6.9. A large amount of white solid was precipitated in the system. After filtration and drying, 454.5 g of white product INT-1 was obtained with a purity of 99.3%, no SM2 was detected, and a yield of 82%.

[0135] Under nitrogen, add 450.0g of INT-1 to 6.0kg of dichloromethane (DCM) and stir to dissolve. After addition, evacuate the reactor and replace the atmosphere with nitrogen three times. Maintain the temperature below 10.0°C and add 574.2g of phosphorus trichloride dropwise. After addition, raise the temperature to 35±5°C and stir until the reaction is complete. Concentrate under reduced pressure to obtain a white solid.

[0136] The white solid was dispersed in 4.5 L of n-hexane, stirred at 25 ± 5 °C for 1 to 2 hours, and then 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. The organic phase was separated and washed with 4.5 L of 10% sodium chloride aqueous solution. After separation, the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and dried to obtain 455.0 g of white solid product (Formula (2)) with a purity of 99.7%. Impurities A, B, and SM2 were not detected. The yield was 93%.

[0137] Example 4:

[0138] Under nitrogen, add 2.03 kg of butanone to a 10 L glass reactor with stirring. Then, add 0.89 kg of SM2 (2.5 equivalents). Add 722.4 g of potassium tert-butoxide in portions at 0 ± 5 °C. Then, raise the temperature to 25 ± 5 °C with stirring for half an hour. Add 250.0 g of SM1, raise the temperature to 25 ± 5 °C with stirring for 3 hours, and then control the temperature below 10.0 °C. Quench the reaction solution by adding it dropwise to 5 L of purified water. After quenching, filter the reaction mixture, and extract the filtrate with 0.5 L of isopropyl acetate (4 times). The organic phase is washed with 2.5 L of 10% aqueous sodium chloride solution (2 times), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to a remaining 500 mL, cooled to 5 ± 5 °C, stirred for 1 hour, filtered, and dried to yield a white solid.

[0139] The white solid was dispersed in 1.3 L of acetone, and formic acid was added thereto at a temperature of 20±5°C to adjust the pH of the system to 1.2 and stirred until dissolved. After dissolution, triethylamine was added dropwise to the system at a temperature of 25±5°C to adjust the pH of the system to 8.5. At this time, a large amount of white solid precipitated from the system. After filtration and drying, 465.6 g of white product INT-1 was obtained with a purity of 99.5%, no SM2 was detected, and a yield of 84%.

[0140] Under nitrogen, add 450.0g of INT-1 to 5.32kg of dichloromethane (DCM) and stir to dissolve. After addition, evacuate the reactor and replace the atmosphere with nitrogen three times. Maintain the temperature below 10.0°C and dropwise add 302.8g of trimethylsilyl chloride. After addition, raise the temperature to 35±5°C and stir until the reaction is complete. Concentrate under reduced pressure to obtain a white solid.

[0141] The white solid was dispersed in 4.0 L of methyl tert-butyl ether, stirred at 25 ± 5 ° C for 1 to 2 hours, and then 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. The organic phase was separated and washed with 4.0 L of 10% sodium chloride aqueous solution. After separation, the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and dried to obtain 443.1 g of white solid product (Formula (2)) with a purity of 99.5%. Impurities A, B and SM2 were not detected. The yield was 91%.

[0142] Example 5:

[0143] Under nitrogen, 2.16 kg of toluene was added to a 10 L glass reactor with stirring. Then, 0.71 kg of SM2 (2.0 equivalents) was added. 577.9 g of potassium tert-butoxide was added portionwise at 0 ± 5°C. The temperature was then raised to 25 ± 5°C with stirring for half an hour. 250.0 g of SM1 was added to the system, and the temperature was raised to 25 ± 5°C with stirring for 3 hours. The reaction mixture was then quenched by adding it dropwise to 5 L of purified water, controlled below 10.0°C. After quenching, the reaction mixture was filtered, and the filtrate was extracted with 0.5 L of toluene three times. The organic phase was washed with 2.5 L of 10% aqueous sodium chloride solution twice, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a remaining 500 mL, cooled to 5 ± 5°C with stirring for 1 hour, filtered, and dried to yield a white solid.

[0144] The white solid was dispersed in 1.3 L of water, and p-toluenesulfonic acid was added thereto to adjust the pH of the system to 2.5 at a temperature of 20±5°C and stirred until dissolved. After dissolution, potassium phosphate solution was added dropwise to the system at a temperature of 20±5°C to adjust the pH of the system to 8.2. At this time, a large amount of white solid precipitated from the system. After filtration and drying, 471.1 g of white product INT-1 was obtained with a purity of 99.5%, no SM2 was detected, and a yield of 85%.

[0145] Under nitrogen, add 450.0g of INT-1 to 6.0kg of dichloromethane (DCM) and stir to dissolve. After addition, evacuate the reactor and replace the atmosphere with nitrogen three times. Maintain the temperature below 10.0°C and add 574.2g of phosphorus trichloride dropwise. After addition, raise the temperature to 35±5°C and stir until the reaction is complete. Concentrate under reduced pressure to obtain a white solid.

[0146] The white solid was dispersed in 4.5 L of isopropyl acetate, stirred at 25 ± 5 ° C for 1 to 2 hours, and then cooled to 20 ± 5 ° C and filtered. The obtained white filter cake was dispersed again in 4.5 L of isopropyl acetate, and a saturated sodium bicarbonate aqueous solution was added under stirring to adjust the pH to 7.3. The organic phase was separated and washed with 4.5 L of 10% sodium chloride aqueous solution. After separation, the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and dried to obtain 439.7 g of white solid product (Formula (2)) with a purity of 99.4%. Impurities A, B and SM2 were not detected. The yield was 90%.

[0147] Comparative Example:

[0148] Under nitrogen, 200.0 g of SM1 and 426.0 g of SM2 were added to 2 L of N,N-dimethylformamide (DMF). Stirring was initiated and the temperature was lowered to 0°C. 346.0 g of potassium tert-butoxide was added portionwise. After the addition was complete, the reaction system was stirred at 20-35°C for 1 hour. HPLC indicated the reaction was complete. The reaction solution was added to 4 L of ice water and washed with 2 L of n-heptane. The aqueous phase was extracted with 2 L of isopropyl acetate. The organic phase was washed with 2 L of 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield 177.4 g of compound INT-1 with a purity of 93.3%. SM2 was detected at 6.3% (yield 40%).

[0149] 150.0 g of compound INT-1 was added to 1.5 L of dichloromethane. The solution was cooled to 0°C and 76 ml of thionyl chloride was slowly added dropwise. After the addition was complete, 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 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 (2) with a purity of 97.6%, impurity A 0.9%, impurity B 0.5%, SM2 0.8%, and a yield of 72%.

[0150] The comparison of product yield and purity of the examples and comparative examples is shown in Table 2.

[0151] Table 2:

[0152]

[0153] As can be seen from the above table, 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.

[0154] No SM2 residues, impurities A and impurities B were detected in Examples 1-5.

[0155] By optimizing and adjusting the amount of solvent and SM2 used in the preparation of intermediates and the order of addition based on patent WO2023241507A1, the yield of the intermediates was improved; the final total yield was >75%, effectively reducing production costs.

[0156] HPLC detection method:

[0157] Use octadecylsilane bonded silica gel as the filler (Waters Xbridge C18, 4.6mm×150mm, 3.5μm or a chromatographic column with equivalent performance); use 10mM ammonium formate buffer (dissolve 0.63g of ammonium formate in 1000ml of water and adjust the pH to 10.0 with aqueous ammonia) as mobile phase A, and acetonitrile as mobile phase B; perform gradient elution according to the table below; flow rate: 0.8ml / min; detection wavelength: 215nm; column temperature: 30°C; injection volume: 3μl.

[0158] The elution procedure is shown in Table 3.

[0159] Table 3:

[0160]

[0161] 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 various embodiments of the present invention.

Claims

1. A method for preparing a benzylpyridine 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 the intermediate: Using 2-fluoropyridine and p-phenylenediol as starting materials, potassium tert-butoxide is added to solvent 1 to catalyze the reaction, followed by quenching, extraction, and pretreatment to obtain a crude intermediate; Intermediate refining: Disperse the crude intermediate in solvent 2, add acid dropwise at controlled temperature to adjust the pH to acidic, and stir until completely dissolved; Solvent 2 is selected from any one or more of methanol, ethanol, water, and acetone; Adding alkaline solution dropwise to the solution to adjust the pH to 6-9, precipitating solid, and then 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 low-boiling point solvent replacement and post-treatment.

2. The method for preparing a benzylpyridine compound according to claim 1, wherein The specific steps for preparing the intermediate include: Synthesis: Under nitrogen protection, dissolve tert-butyl alcohol in solvent 1, add potassium tert-butoxide 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 a benzylpyridine compound according to claim 2, wherein 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 methanol 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 a benzylpyridine compound according to claim 3, wherein The temperature of adding potassium tert-butoxide in batches 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℃, The pre-treatment beating temperature is 5±5℃, The concentration of sodium chloride solution is 10%.

5. The method for preparing a benzylpyridine compound according to claim 1, wherein The 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.

6. The method for preparing a benzylpyridine compound according to claim 5, wherein: After adding acid in the dissolution step, the dissolution temperature is 0~30℃ and the pH is controlled to 1~3. The pH is adjusted to 6-9 during the crystallization step.

7. The method for preparing a benzylpyridine compound according to claim 1, wherein: The specific steps for preparing the target product include: Chlorination reaction: dissolve the high-purity intermediate in dichloromethane, add the chlorination reagent dropwise under 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 redispersed 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.

8. The method for preparing a benzylpyridine compound according to claim 1, wherein 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.

9. The method for preparing a benzylpyridine compound according to claim 7, wherein: 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 exchange and workup steps was 7-8.

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