A process for the synthesis of an ezetimibe intermediate

Abstract

This invention discloses a synthetic process for etimibe intermediates, belonging to the field of pharmaceutical preparation technology. Addressing the problems of easy hydrolysis of the imine bond, difficulty in suppressing the N-benzylation side reaction, and easy hydrolysis and deactivation of benzyl bromo in the O-benzylation reaction of (Z)-4-[(4-fluorophenylimino)methyl]phenol, this invention first uses isopropanol as a solvent to add p-fluoroaniline dropwise at 45-55℃ to condense and obtain EZE-19, which is then dried to a moisture content ≤0.5%. Then, in a dichloromethane-water biphase system, using potassium carbonate as a base and tetrabutylammonium bromide as a phase transfer catalyst, and controlling the amount of aqueous phase used in the reaction stage, an O-benzylation reaction is carried out with benzyl bromo under mild reflux conditions at 40-45℃. The reaction solution is washed with potassium hydroxide, washed with water until neutral, concentrated, replaced with isopropanol solvent, and slowly cooled and crystallized with methanol to obtain high-purity (Z)-N-(4-benzyloxyphenylmethylene)-4-fluoroaniline, suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a synthetic process for an etimibe intermediate. Background Technology

[0002] Ezetimibe, chemically named 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-phenol)-2-acetidinone, has a relatively long synthetic route involving several key intermediates. Patent application CN102285932A discloses a method for preparing an etimibe intermediate. This method uses 4-(4-fluorobenzoyl)butyric acid as a starting material, which undergoes a cyclization reaction with chlorinating agents such as thionyl chloride or oxalyl chloride in an organic solvent such as dichloromethane to obtain 6-(4-fluorophenyl)-3,4-dihydropyran-2-one. This 6-one is then condensed with (S)-4-phenyloxazolidinone in the presence of an organic base to obtain (4S)-3-[5-(4-fluorophenyl)-1,5-oxopentyl]-4-phenyl-2-oxazolidinone. This method uses corrosive chlorination reagents such as thionyl chloride, which requires sophisticated equipment, puts a lot of pressure on waste treatment, and involves intermediates that are different from those in this invention.

[0003] Patent application CN102978253A discloses a method for synthesizing an etimibe intermediate. This method involves the asymmetric reduction of (4S)-3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone under the catalysis of a chiral carbonyl reductase to obtain (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxy-1-oxopentyl]-4-phenyl-2-oxazolidinone. This method requires expensive chiral catalysts or enzymes, and the reaction conditions must be strictly controlled (pH 5.5–8.5, temperature 20–50°C), resulting in high production costs. It also does not relate to the intermediates of this invention.

[0004] (Z)-N-(4-benzyloxybenzylmethyl)-4-fluoroaniline (hereinafter referred to as EZE-20) is an important intermediate in the synthesis route of etimibe. It is usually prepared by first condensing p-hydroxybenzaldehyde and p-fluoroaniline to generate (Z)-4-[(4-fluorophenylimino)methyl]phenol (hereinafter referred to as EZE-19), and then by O-benzylation of the phenolic hydroxyl group. In this route, the EZE-19 molecule contains both a phenolic hydroxyl group and an imine bond (C=N). The following technical challenges arise during O-benzylation: First, the imine bond is easily hydrolyzed and broken under strong acid or alkaline conditions, generating p-hydroxybenzaldehyde and p-fluoroaniline, leading to decreased yield and increased impurities. Second, the nitrogen atom on the imine bond has a certain nucleophilicity and may undergo N-benzylation with benzyl bromo, generating quaternary ammonium salt impurities and affecting product purity. Third, benzylation reactions typically require strong bases (such as sodium hydride or sodium hydroxide) and high reaction temperatures, which contradicts the stability of the imine bond. Fourth, excessive water in the reaction system leads to the hydrolytic deactivation of benzyl bromo, while insufficient water affects the solubility of inorganic bases and interfacial mass transfer. Therefore, a synthesis process for EZE-20 with mild reaction conditions, high selectivity, good product purity, and suitability for industrial production needs to be developed. Summary of the Invention

[0005] To address the problems in existing technologies regarding the O-benzylation reaction of (Z)-4-[(4-fluorophenylimino)methyl]phenol, such as easy hydrolysis and breakage of the imine bond, difficulty in suppressing N-benzylation side reactions, easy hydrolysis and deactivation of benzyl bromide, and low product purity, this invention provides a synthetic process for etimibe intermediates. This process involves a mild O-benzylation reaction in a dichloromethane-water biphase system using potassium carbonate as a base and tetrabutylammonium bromide as a phase transfer catalyst. The amount of aqueous phase used in the reaction stage is controlled to balance base dissolution and phase transfer efficiency. Combined with potassium hydroxide alkali washing and isopropanol-methanol gradient solvent replacement purification, this process achieves highly selective and high-purity preparation of (Z)-N-(4-benzyloxybenzylmethyl)-4-fluoroaniline.

[0006] The objective of this invention can be achieved through the following technical solutions: A synthetic process for an etimibe intermediate includes the following steps: (1) Preparation of EZE-19: p-hydroxybenzaldehyde was added to isopropanol, stirred and heated until dissolved, and p-fluoroaniline was added dropwise at 45-55℃. After the addition was complete, the reaction was kept at 45-55℃ and the reaction endpoint was monitored by high performance liquid chromatography. After the reaction was completed, the temperature was lowered to 15-25℃, centrifuged, the filter cake was washed with isopropanol and dried at 50-60℃ until the moisture content was ≤0.5% to obtain (Z)-4-[(4-fluorophenylimino)methyl]phenol (EZE-19); (2) O-benzylation reaction: The (Z)-4-[(4-fluorophenylimino)methyl]phenol obtained in step (1) was mixed with dichloromethane, stirred and dispersed, and then potassium carbonate, water and tetrabutylammonium bromide were added. The mixture was stirred to form a biphase system, and then benzyl bromide was added. The mixture was heated to 40-45℃ and refluxed. Thin-layer chromatography was used to monitor the reaction until the (Z)-4-[(4-fluorophenylimino)methyl]phenol spots disappeared. (3) Post-treatment purification: After the reaction is completed, potassium hydroxide aqueous solution is added to the reaction system for alkaline washing, and after stirring, the system is allowed to stand for phase separation. The aqueous phase is discarded. The organic phase is washed with water until neutral, the organic phase is separated and concentrated to recover dichloromethane. Isopropanol is added to the concentrated residue for solvent replacement treatment, and then methanol is added. After heating to dissolve, the mixture is slowly cooled to crystallize. After centrifugation, the crystallized product is dried at 50-60℃ until the water content is ≤0.5% to obtain (Z)-N-(4-benzyloxybenzylmethyl)-4-fluoroaniline (EZE-20).

[0007] In step (1), isopropanol was chosen as the solvent for the condensation reaction because it has good solubility for p-hydroxybenzaldehyde. Heating the reaction system makes it homogeneous, which is beneficial for the stable progress of the condensation reaction. After the reaction, cooling the product EZE-19 significantly reduces its solubility in isopropanol and crystallizes out, which can be directly separated by centrifugation without additional concentration or extraction, simplifying the operation. The addition of p-fluoroaniline by dropping avoids side reactions caused by excessively high local concentrations, making the reaction stable and controllable. The holding temperature of 45-55℃ balances the reaction rate and the stability of the imine bond: if the temperature is too low, the reaction rate is slow and the production cycle is long; if the temperature is too high, the imine bond that has been generated may be hydrolyzed or other side reactions may occur. The reaction endpoint was monitored by HPLC to ensure that the p-hydroxybenzaldehyde residue was ≤5.0% and the purity of EZE-19 was ≥80.0%, so as to avoid the influence of raw material residue on the subsequent benzylation reaction. Drying to a moisture content of ≤0.5% is a key control indicator: residual moisture in EZE-19 will react with benzyl bromide in step (2) to generate benzyl alcohol, which consumes the benzylating reagent and introduces impurities. Therefore, strictly controlling the moisture content of the intermediate is an important prerequisite for ensuring the complete O-benzylation reaction.

[0008] In step (2), dichloromethane serves as the organic phase to dissolve EZE-19 and benzyl bromide, while potassium carbonate is dissolved in the aqueous phase. The reaction proceeds at the two-phase interface under the action of a phase-transfer catalyst. Dichloromethane has a boiling point of approximately 40°C and a reflux temperature of 40–45°C. This temperature range is mild, providing the activation energy required for the O-benzylation reaction while remaining far below the temperature at which imine bonds undergo significant hydrolysis, thus protecting the imine bonds. Potassium carbonate is chosen as the base instead of strong bases such as sodium hydroxide or sodium hydride because it has a mild alkalinity (the pH of a saturated solution is approximately 11.6), allowing for the gradual release of OH- in the two-phase system. -It deprotonates the phenolic hydroxyl groups to generate phenolic anions, while preventing the imine bonds from being hydrolyzed and broken due to excessive alkalinity; potassium carbonate has limited solubility in water (about 111 g / L at 20℃), which can maintain the pH of the aqueous phase within a relatively stable range and avoid excessively high local alkalinity concentration.

[0009] TBAB quaternary ammonium salt cation (Bu4N) + TBAB is lipophilic and can form ion pairs with phenoxy anions in the aqueous phase, extracting them from the aqueous phase to the organic phase. This allows the phenoxy anions to undergo a nucleophilic substitution reaction with benzyl bromo in the organic phase. After the reaction, the TBAB cation returns to the aqueous phase to complete the catalytic cycle. The use of TBAB significantly increases the rate of O-benzylation in the biphase system, enabling complete conversion under mild conditions of 40–45°C, avoiding the hydrolysis of imine bonds caused by prolonged heating.

[0010] The amount of water used in the reaction stage needs to be strictly controlled: too little water will result in poor dissolution of potassium carbonate, ineffective participation of the solid-phase base in the reaction, and insufficient interfacial area leading to reduced phase transfer catalytic efficiency; too much water will cause excessive dilution of phenolic anions in the aqueous phase, increasing the TBAB extraction load and actually reducing the concentration of phenolic anions in the organic phase, thus decreasing the reaction rate. This invention controls the amount of water used in the reaction stage to be 1.5 to 2.0 times the weight of EZE-19. Within this range, potassium carbonate can be fully dissolved to form a saturated solution, and the volume ratio of the organic phase to the aqueous phase is appropriate, resulting in the highest phase transfer catalytic efficiency.

[0011] In step (3), after the reaction is complete, potassium hydroxide aqueous solution is added for alkaline washing. At this time, the O-benzylation reaction is completed, and the phenolic hydroxyl group of product EZE-20 is protected by benzyl, so the molecule no longer has acidic phenolic hydroxyl groups, and its stability to alkali is significantly improved. However, the unreacted EZE-19 still contains phenolic hydroxyl groups, which form potassium phenoxy salt in KOH solution and dissolve in the aqueous phase. The N-benzylation quaternary ammonium salt byproduct hydrolyzes into water-soluble components under alkaline conditions, and the residual benzyl bromohydrolyzes into benzyl alcohol under alkaline conditions. These impurities can be effectively removed by alkaline washing. After alkaline washing, water is used to wash until neutral to remove residual KOH and the generated inorganic salts. After concentrating and recovering dichloromethane, isopropanol is added for solvent replacement: isopropanol is miscible with residual dichloromethane and carries it away during the concentration process. At the same time, isopropanol has good solubility for some moderately polar impurities and can remove some impurities during stirring. Finally, methanol is added, and the product is heated to dissolve. During the slow cooling process, the product crystallizes out in the methanol, while a small amount of impurities remain in the methanol mother liquor, thus obtaining a high-purity product. The product is dried to a moisture content of ≤0.5% to ensure product stability and meet subsequent usage requirements.

[0012] Furthermore, in step (1), the weight ratio of p-hydroxybenzaldehyde to p-fluoroaniline is 1:(0.91~1.00). A slight excess of p-fluoroaniline can ensure that the relatively expensive p-hydroxybenzaldehyde reacts completely. The amount of isopropanol used is 2.0~2.8 times the weight of p-hydroxybenzaldehyde. At this ratio, p-hydroxybenzaldehyde can be completely dissolved after heating, and the product crystallization yield is high after cooling.

[0013] Furthermore, in step (1), high-performance liquid chromatography (HPLC) is used to monitor the reaction endpoint. The reaction ends when the residual amount of p-hydroxybenzaldehyde in the reaction solution is ≤5.0% and the purity of (Z)-4-[(4-fluorophenylimino)methyl]phenol is ≥80.0%. HPLC endpoint control ensures complete condensation reaction and avoids excessive residual p-hydroxybenzaldehyde, which would consume benzyl bromo to generate impurities such as 4-benzyloxybenzaldehyde in the subsequent benzylation step.

[0014] Furthermore, in step (2), the amount of dichloromethane used is 10 to 15 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol. At this amount, EZE-19 and benzyl bromo can be completely dissolved, the two-phase system is well mixed by stirring, and the reaction rate and equipment utilization will not be reduced due to excessive solvent volume.

[0015] Furthermore, in step (2), the amount of potassium carbonate used is 1.5 to 2.5 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol; the amount of tetrabutylammonium bromide used is 0.2 to 0.5 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol. Within this range of amounts, the phase transfer catalytic effect is sufficient, and the post-processing burden and cost will not be increased due to excessive amounts.

[0016] Furthermore, in step (2), the weight ratio of benzyl bromo to (Z)-4-[(4-fluorophenylimino)methyl]phenol is 0.80 to 0.95:1. Slight excess of benzyl bromo ensures complete conversion of EZE-19, but excessive excess will increase the removal burden of residual benzyl bromo and the risk of N-benzylation side reaction. The amount of water added simultaneously with potassium carbonate is 1.5 to 2.0 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol, as mentioned above, to balance alkali dissolution and phase transfer efficiency.

[0017] Furthermore, in step (3), the mass concentration of the potassium hydroxide aqueous solution is 8% to 12%. At this concentration, the alkaline washing ability is sufficient to effectively remove phenolic impurities and hydrolysis byproducts, while the imine bonds of the product will not be damaged during long-term washing due to excessive concentration. The amount of potassium hydroxide used is 0.08 to 0.15 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol, which is sufficient to neutralize and extract residual acidic and phenolic impurities.

[0018] Furthermore, in step (3), the amount of isopropanol used in the solvent replacement treatment is 0.4 to 1.5 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol, which can effectively replace residual dichloromethane and dissolve moderately polar impurities; Furthermore, in step (3), the amount of methanol used for crystallization is 1.5 to 2.5 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol. Under this ratio, the product can be completely dissolved upon heating, and the crystallization yield and purity are both good after cooling.

[0019] Furthermore, the dichloromethane mentioned in step (2) comprises recovered dichloromethane; and / or the (Z)-4-[(4-fluorophenylimino)methyl]phenol used in step (2) comprises (Z)-4-[(4-fluorophenylimino)methyl]phenol recovered from the condensation reaction mother liquor. The process of this invention exhibits good tolerance to the recovery of dichloromethane and the recovery of EZE-19 mother liquor. The recovered solvent can be reused after simple distillation, and the recovered mother liquor can be dried and mixed into fresh EZE-19 in a certain proportion without affecting product quality, significantly reducing production costs and waste emissions.

[0020] The beneficial effects of this invention are as follows: (1) In the condensation reaction step, isopropanol was used as the reaction solvent. Taking advantage of the good solubility of p-hydroxybenzaldehyde in isopropanol, the substrate was completely dissolved by stirring and heating to form a homogeneous reaction system, which provided good mass transfer conditions for the condensation reaction. Fluoroaniline was added dropwise and the reaction temperature was controlled at 45-55℃. After the addition was completed, the reaction was kept at 45-55℃ to avoid side reactions caused by excessively high local concentrations of fluoroaniline. At the same time, this temperature range ensured the rate of the condensation reaction and prevented imine bond hydrolysis or other thermal side reactions caused by excessively high temperature. The reaction endpoint was monitored in real time by high performance liquid chromatography, with the residual p-hydroxybenzaldehyde content ≤5%. The reaction is qualified by using 0.0% and EZE-19 purity ≥80.0% to ensure full conversion of raw materials and avoid over-reaction that introduces impurities. After the reaction, the temperature is lowered to 15-25℃, and EZE-19 crystallizes out by taking advantage of its significantly reduced solubility in isopropanol at low temperatures. The solid-liquid separation is achieved by centrifugation, and the filter cake is washed with isopropanol to remove adsorbed residual p-fluoroaniline and p-hydroxybenzaldehyde. Finally, it is dried at 50-60℃ until the moisture content is ≤0.5%. Strict control of the moisture content of the intermediate avoids the problem of moisture being introduced into the subsequent benzylation step, which would lead to the hydrolysis and deactivation of benzyl bromo, thus providing quality assurance for the complete O-benzylation reaction.

[0021] (2) In the O-benzylation reaction step, dried EZE-19 is mixed with dichloromethane and stirred to disperse the substrate uniformly in the organic phase; potassium carbonate is added as a base, a controlled amount of water, and tetrabutylammonium bromide as a phase transfer catalyst, and stirred to form a dichloromethane-water biphase system. Potassium carbonate has a mild base and gradually releases hydroxide ions in the aqueous phase to selectively deprotonate the phenolic hydroxyl groups of EZE-19 to generate phenoxy anions. At the same time, it does not cause the imine bond to break due to excessive base. The amount of aqueous phase is controlled at 1.5 to 2.0 times the weight of EZE-19 to ensure that potassium carbonate is fully dissolved and that mass transfer is achieved at the phase interface, while avoiding excessive dilution of phenoxy anions by the aqueous phase. Low phase transfer catalytic efficiency; the quaternary ammonium salt cation of tetrabutylammonium bromide forms a lipophilic ion pair with the phenoxy anion in the aqueous phase, which is then extracted to the organic phase to react with benzyl bromide in the Williamson ether synthesis reaction. After the reaction, the quaternary ammonium salt cation returns to the aqueous phase to complete the catalytic cycle, allowing O-benzylation to proceed rapidly under mild conditions; after adding benzyl bromide, the temperature is raised to 40-45℃ for reflux reaction. The low boiling point of dichloromethane at about 40℃ naturally controls the reaction temperature within a mild range, avoiding thermal degradation of imine bonds without precise temperature control. At the same time, thin-layer chromatography is used to monitor until the EZE-19 spot disappears, ensuring complete benzylation of the phenolic hydroxyl group and avoiding residual EZE-19 from affecting product purity.

[0022] (3) In the post-treatment purification step, after the reaction is completed, potassium hydroxide aqueous solution is added for alkaline washing. At this time, the phenolic hydroxyl group of product EZE-20 has been protected by benzyl group, and its stability to alkali is significantly improved. However, the unreacted EZE-19 still contains phenolic hydroxyl group and generates potassium phenoxy salt under alkaline conditions, which dissolves in the aqueous phase. The N-benzylated quaternary ammonium salt byproduct is hydrolyzed into water-soluble components under alkaline conditions. The residual benzyl bromo is also hydrolyzed into benzyl alcohol. After stirring, the phase is separated and the aqueous phase is discarded, which can effectively remove the above impurities. The organic phase is then washed with water until neutral to remove the residual potassium hydroxide and the generated inorganic salt. The organic phase is separated and concentrated. Dichloromethane is recovered, enabling solvent recycling. Isopropanol is added to the concentrated residue for solvent replacement. Isopropanol is miscible with the residual dichloromethane and carries it away during concentration. It also has good solubility for moderately polar impurities, which are removed during stirring. Methanol is then added, and the product is heated to completely dissolve before slow cooling and crystallization. The difference in solubility between the product and impurities in methanol is used for further purification, with a small amount of impurities remaining in the methanol mother liquor. After centrifugation, the crystallized product is dried at 50–60°C until the moisture content is ≤0.5%, ensuring product stability and meeting subsequent usage requirements.

[0023] (4) The technical features of each step are progressive and synergistic: In the condensation step, the selection of isopropanol solvent, the dropping process, temperature control, HPLC endpoint monitoring, and moisture control provide a high-quality intermediate for O-benzylation; in the benzylation step, the combination of potassium carbonate mild alkali, tetrabutylammonium bromide phase transfer catalysis, the control of the amount of aqueous phase in the two-phase system, and low-temperature reflux at 40-45℃ achieves highly selective O-benzylation of phenolic hydroxyl groups and protects the imine bond; in the post-treatment step, KOH alkali washing, water washing to neutral, isopropanol solvent replacement, and slow cooling crystallization with methanol form a gradient purification system, which together ensures the purity of the product from both reaction control and post-treatment levels. The EZE-20 obtained by the process of this invention has low impurity content and high purity, and the process is stable and reliable. The recovery of dichloromethane and the recovery of EZE-19 mother liquor can be reused without affecting product quality, making it suitable for large-scale industrial production. Detailed Implementation

[0024] The specific embodiments of the present invention will be described in detail below, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments.

[0025] The raw materials used in this invention are as follows: p-hydroxybenzaldehyde (purity ≥99%), p-fluoroaniline (purity ≥99%), benzyl bromide (purity ≥99%), potassium carbonate (industrial grade), tetrabutylammonium bromide (industrial grade), potassium hydroxide (industrial grade), isopropanol (industrial grade), dichloromethane (industrial grade), and methanol (industrial grade), all of which are commercially available.

[0026] In this invention, the HPLC detection conditions are general detection conditions; the TLC developing solvent is ethyl acetate:cyclohexane = 1:1 (volume ratio); and the moisture content is determined using a Karl Fischer moisture analyzer.

[0027] Example 1 (1) Preparation of EZE-19 Add 410 kg of isopropanol and 175 kg of p-hydroxybenzaldehyde to the reaction vessel, stir and heat until dissolved. Control the temperature at 45–55 °C, and slowly add 167 kg of p-fluoroaniline dropwise to the reaction vessel. After the addition is complete, maintain the temperature at 47.0–53.1 °C and stir to react.

[0028] During the incubation reaction, 10 mL of the reaction solution was taken and the residual amount of p-hydroxybenzaldehyde and the purity of EZE-19 were detected by HPLC. The reaction reached its endpoint when the residual amount of p-hydroxybenzaldehyde was 1.9% and the purity of EZE-19 was 92.1%.

[0029] The reaction solution was cooled to 15–25°C and centrifuged. The filter cake was washed with 60 kg of isopropanol. The filter cake was dried at 50–59.3°C, with samples taken every 3–4 hours to check the moisture content. Drying was stopped when the moisture content was ≤0.5%. The product was cooled and discharged, yielding 284.0 kg of EZE-19 product, with a yield of 162.3% (w / w, based on the amount of p-hydroxybenzaldehyde fed). The product was a light yellow powder with an HPLC purity of ≥96.0%.

[0030] (2) Preparation of EZE-20 Add 90 kg of EZE-19 and 1197 kg of dichloromethane to the reactor and stir to disperse and dissolve EZE-19. Add 173.7 kg of potassium carbonate, 153 kg of drinking water, and 28 kg of tetrabutylammonium bromide and stir to form a two-phase system.

[0031] Add 75.6 kg of benzyl bromide to the reactor and reflux at 40–45 °C. Take samples periodically for TLC analysis (developing solvent: ethyl acetate: cyclohexane = 1:1). The endpoint is reached when the EZE-19 spot disappears or becomes very faint (reflux temperature 40.0–45.0 °C).

[0032] After the reaction was complete, a pre-prepared potassium hydroxide aqueous solution (9.9 kg KOH dissolved in 90 kg drinking water, with a mass concentration of approximately 9.9%, and the amount of KOH used was 0.11 times the weight of EZE-19) was added. After stirring and washing, the mixture was allowed to stand and separate phases, and the aqueous phase was discarded. The organic phase was washed with 260 kg of drinking water, allowed to stand and separate phases, and the washing was repeated until the pH of the aqueous phase was neutral.

[0033] The organic phase was separated, and dichloromethane was recovered by vacuum concentration. 60 kg of isopropanol was added to the concentrated residue for solvent displacement treatment, followed by 180 kg of methanol. The mixture was heated to reflux to dissolve the solvent, and then slowly cooled to crystallize. The mixture was centrifuged, and the filter cake was washed with a small amount of methanol. The filter cake was vacuum dried at 50–60 °C, with samples taken every 3–4 hours to check the moisture content. Drying was stopped when the moisture content was ≤0.5% (measured at 0.10%), yielding 118.2 kg of EZE-20 product, with a yield of 131.3% (w / w, based on the amount of EZE-19 fed).

[0034] The obtained EZE-20 was a yellowish-white powder with lumps. Testing showed: identification conformed to the analytical test procedure; HPLC purity was 99.6%, content was 100%; EBB6 impurity was 0.09%, other single maximum impurities were 0.18%, and total impurities were 0.36%.

[0035] Example 2 (1) Preparation of EZE-19: It is basically the same as in Example 1, except that the heat preservation temperature is 47.0-53.6℃, ​​the endpoint is reached when the residual amount of p-hydroxybenzaldehyde is 2.5% and the purity of EZE-19 is 90.4% by HPLC detection, the drying temperature is 50.0-59.5℃, the moisture content is 0.10%, and 284.1 kg of EZE-19 product is obtained, with a yield of 162.3%.

[0036] (2) Preparation of EZE-20: It is basically the same as in Example 1. Using 90 kg of this batch of EZE-19, the reflux temperature is 40.0~45.0℃, the TLC is qualified, the moisture content is 0.12%, and 117.0 kg of EZE-20 product is obtained, with a yield of 130.0%.

[0037] The obtained EZE-20 was a pale yellow powder with lumps. Analysis showed: HPLC purity 99.8%, content 99%; EBB6 impurity 0.09%, other single largest impurities 0.08%, total impurities 0.25%.

[0038] Example 3 (1) Preparation of EZE-19: It is basically the same as in Example 1. The heat preservation temperature is 47.0~53.8℃. The endpoint is reached when the residual amount of p-hydroxybenzaldehyde is 2.2% and the purity of EZE-19 is 90.6% by HPLC detection. The drying temperature is 51.0~59.6℃ and the moisture content is 0.10%. 285.5 kg of EZE-19 product is obtained, with a yield of 163.1%.

[0039] (2) Preparation of EZE-20: It is basically the same as in Example 1. 90 kg of EZE-19 in this batch was used. 257 kg of fresh dichloromethane and 940 kg of recycled dichloromethane were mixed and used (total 1197 kg). The reflux temperature was 40.0-45.0℃. The TLC was qualified. The moisture content was 0.09%. 118.8 kg of EZE-20 product was obtained, with a yield of 132.0%.

[0040] The obtained EZE-20 was a yellowish-white powder with lumps. Analysis showed: HPLC purity 99.9%, content 99%; EBB6 impurity 0.08%, other single maximum impurities ≤0.05%, total impurities 0.08%.

[0041] Example 4 Preparation of EZE-20: The preparation was essentially the same as in Example 1, except that 70 kg of EZE-19 was added, along with 20 kg of S-EZE-19 recovered from the condensation reaction mother liquor (total 90 kg); 217 kg of fresh dichloromethane and 980 kg of recovered dichloromethane were mixed and used (total 1197 kg). The reflux temperature was 40.0–44.8 °C, TLC was satisfactory, and the moisture content was 0.08%. This yielded 115.5 kg of EZE-20, with a yield of 128.0%.

[0042] The obtained EZE-20 was a pale yellow powder with lumps. Analysis showed: HPLC purity 99.9%, content 100%; EBB6 impurity 0.09%, other single largest impurities 0.06%, total impurities 0.15%.

[0043] Example 5 Preparation of EZE-20: The preparation method was basically the same as in Example 1, except that 70 kg of EZE-19 was added, along with 20 kg of recovered S-EZE-19; 317 kg of fresh dichloromethane and 880 kg of recovered dichloromethane were mixed (totaling 1197 kg). The reflux temperature was 40.0–44.5 °C, TLC was satisfactory, and the moisture content was 0.09%. This yielded 117.1 kg of EZE-20, with a yield of 130.1%.

[0044] The obtained EZE-20 was a pale yellow powder with lumps. Analysis showed: HPLC purity 99.8%, content 100%; EBB6 impurity 0.09%, other single maximum impurities 0.07%, total impurities 0.16%.

[0045] Example 6 Preparation of EZE-20: The preparation method was basically the same as in Example 1, except that 70 kg of EZE-19 was added, along with 20 kg of recovered S-EZE-19; 59 kg of fresh dichloromethane and 1138 kg of recovered dichloromethane were mixed (totaling 1197 kg, with recovered dichloromethane accounting for 95.1%). The reflux temperature was 40.0–44.7°C, TLC was satisfactory, and the moisture content was 0.08% after drying, yielding 118.8 kg of EZE-20 product, with a yield of 132.0%.

[0046] The obtained EZE-20 was a yellow-green powder with lumps. Analysis showed: HPLC purity 99.8%, content 100%; EBB6 impurity 0.09%, other single maximum impurities 0.11%, total impurities 0.20%.

[0047] Example 7 (1) Preparation of EZE-19: 350 kg of isopropanol and 175 kg of p-hydroxybenzaldehyde were added to a reaction vessel and stirred and heated to dissolve. 159 kg of p-fluoroaniline was added dropwise at 45-55℃ and the reaction was maintained at this temperature. The endpoint was reached when the residual p-hydroxybenzaldehyde content was 4.2% and the purity of EZE-19 was 88.7% by HPLC monitoring. The mixture was cooled to 15-25℃, centrifuged, washed with isopropanol, and dried at 50-60℃ until the moisture content was 0.12%, yielding 278.5 kg of EZE-19 product, with a yield of 159.1%.

[0048] (2) Preparation of EZE-20: Take 90 kg of the above EZE-19, add 900 kg of dichloromethane, 135 kg of potassium carbonate, 135 kg of drinking water and 18 kg of tetrabutylammonium bromide, and stir to form a two-phase system. Add 72 kg of benzyl bromide, reflux at 40-45℃, and monitor by TLC until the EZE-19 spots disappear. After the reaction is complete, wash with KOH aqueous solution (7.2 kg of KOH dissolved in 82.8 kg of water, concentration 8.0%, KOH 0.08 times) as alkali, wash with water until neutral, and concentrate. Add 36 kg of isopropanol for displacement treatment, add 135 kg of methanol, heat to dissolve, and slowly cool to crystallize. Centrifuge, dry at 50-60℃ to 0.15% moisture content, and obtain 112.8 kg of EZE-20 product, with a yield of 125.3%.

[0049] The obtained EZE-20 was a yellowish-white powder. Analysis showed: HPLC purity 99.7%, content 99%; EBB6 impurity 0.10%, other single maximum impurities 0.15%, total impurities 0.32%.

[0050] Example 8 (1) Preparation of EZE-19: 490 kg of isopropanol and 175 kg of p-hydroxybenzaldehyde were added to a reaction vessel and stirred and heated to dissolve. 175 kg of p-fluoroaniline was added dropwise at 45-55℃ and the reaction was maintained at this temperature. The endpoint was reached when the residual p-hydroxybenzaldehyde was 1.5% and the purity of EZE-19 was 93.2% as monitored by HPLC. After cooling and centrifugation, the product was washed with isopropanol and dried at 50-60℃ until the moisture content was 0.09%, yielding 286.2 kg of EZE-19 product, with a yield of 163.5%.

[0051] (2) Preparation of EZE-20: Take 90 kg of the above EZE-19, add 1350 kg of dichloromethane, 225 kg of potassium carbonate, 180 kg of drinking water and 45 kg of tetrabutylammonium bromide, and stir to form a two-phase system. Add 85.5 kg of benzyl bromide, reflux at 40-45℃, and monitor by TLC until the EZE-19 spots disappear. After the reaction is complete, wash with KOH aqueous solution (13.5 kg of KOH dissolved in 99 kg of water, concentration 12.0%, KOH 0.15 times) as alkali, wash with water until neutral, and concentrate. Add 135 kg of isopropanol for displacement treatment, add 225 kg of methanol, heat to dissolve, slowly cool to crystallize, centrifuge, dry at 50-60℃ to 0.08% moisture content, and obtain 119.5 kg of EZE-20 product, with a yield of 132.8%.

[0052] The obtained EZE-20 was a pale yellow powder. Analysis showed: HPLC purity 99.8%, content 100%; EBB6 impurity 0.08%, other single maximum impurities 0.10%, total impurities 0.18%.

[0053] Example 9 Preparation of EZE-20: The preparation was essentially the same as in Example 1, except that the amounts of dichloromethane (900 kg), potassium carbonate (153 kg), tetrabutylammonium bromide (22.5 kg), benzyl bromide (73.8 kg), and water (144 kg) were used in the reaction stage; the KOH aqueous solution concentration was 8.5% (8.1 kg KOH dissolved in 87 kg water); isopropanol was 54 kg, and methanol was 162 kg. The reflux temperature was 40–45 °C, TLC was satisfactory, and the moisture content was 0.11%. This yielded 116.2 kg of EZE-20, with a yield of 129.1%.

[0054] The obtained EZE-20 was a yellowish-white powder. Analysis showed: HPLC purity 99.7%, content 99%; EBB6 impurity 0.09%, other single maximum impurities 0.13%, total impurities 0.28%.

[0055] Example 10 Preparation of EZE-20: The preparation method was basically the same as in Example 1, except that all dichloromethane used was recycled dichloromethane (1197 kg, 0% fresh dichloromethane), and 70 kg of EZE-19 was added along with 20 kg of recycled S-EZE-19; 198 kg of potassium carbonate, 36 kg of tetrabutylammonium bromide, and 81 kg of benzyl bromide; a KOH aqueous solution concentration of 10.5% (10.8 kg of KOH dissolved in 92.5 kg of water); 108 kg of isopropanol; and 207 kg of methanol. The mixture was refluxed at 40–45°C, passed TLC, and dried to a moisture content of 0.09%, yielding 117.8 kg of EZE-20 product, with a yield of 130.9%.

[0056] The obtained EZE-20 was a pale yellow powder. Analysis showed: HPLC purity 99.8%, content 100%; EBB6 impurity 0.09%, other single maximum impurities 0.09%, total impurities 0.22%.

[0057] Comparative Example 1 The only difference from Example 1 is that tetrabutylammonium bromide was not added; the amounts of other raw materials and operating conditions remained the same. After reflux for 8 hours, TLC showed that the EZE-19 spot was still quite obvious, and it did not completely disappear even after reflux for another 12 hours. After stopping the reaction, the product was post-processed according to the method in Example 1 to obtain the EZE-20 product. Analysis showed: HPLC purity 96.8%, content 95.2%; EBB6 impurity 0.32%, other single largest impurity 0.68%, total impurities 2.35%.

[0058] The results showed that without a phase transfer catalyst, the phenoxy anions in the biphase system had difficulty entering the organic phase to react with benzyl bromide, resulting in a slow reaction rate, incomplete conversion, and partial hydrolysis of imine bonds due to prolonged heating, leading to a significant increase in impurities.

[0059] Comparative Example 2 The only difference from Example 1 was that sodium hydroxide (50.3 kg) was used instead of potassium carbonate; the amounts of other raw materials and operating conditions remained the same. After reflux for 2 hours, TLC showed that the EZE-19 spot disappeared, but the color of the reaction solution darkened significantly. Following the method of Example 1, EZE-20 was obtained as the final product. Analysis revealed: HPLC purity 94.5%, content 93.8%; EBB6 impurity 0.45%, other single largest impurity 0.92%, total impurities 3.18%.

[0060] The results showed that although the reaction rate was accelerated when using strong alkaline sodium hydroxide, the imine bond underwent significant hydrolysis in the strong alkaline aqueous solution, generating degradation impurities such as p-hydroxybenzaldehyde and p-fluoroaniline. In addition, the N-benzylation side reaction increased, and the purity and yield of the product decreased significantly.

[0061] Comparative Example 3 The only difference from Example 1 is that after the reaction, washing with potassium hydroxide aqueous solution was not performed; instead, the mixture was washed directly with water until neutral, then concentrated, treated with isopropanol, and crystallized from methanol. EZE-20 was obtained as the final product. Testing revealed: HPLC purity 97.2%, content 96.5%; EBB6 impurity 0.28%, other single largest impurities 0.55%, total impurities 1.86%.

[0062] The results showed that without potassium hydroxide alkaline washing, the residual unreacted EZE-19 and N-benzylation byproducts could not be effectively removed, leading to an increase in the content of EBB6 and other impurities and a decrease in product purity.

[0063] Comparative Example 4 The only difference from Example 1 was that toluene was used instead of dichloromethane as the solvent, and the reaction temperature was refluxed at 80–85°C. The amounts of other raw materials and operating conditions remained the same. After reflux for 3 hours, TLC showed that the EZE-19 spot disappeared, but many polar impurity spots appeared in the reaction solution. Following the method of Example 1, EZE-20 was obtained. Analysis showed: HPLC purity 95.6%, content 94.1%; EBB6 impurity 0.38%, other single largest impurities 0.75%, total impurities 2.62%.

[0064] The results showed that when the reaction temperature was too high, the thermal stability of the imine bond decreased, and the hydrolysis and N-benzylation side reactions were aggravated. Even after the same post-treatment purification, the purity of the product still could not meet the standard.

[0065] Comparative Example 5 The only difference from Example 1 was the amount of potassium carbonate used: 90 kg; all other conditions remained the same. After reflux for 10 hours, TLC showed that the EZE-19 spots had not disappeared, and faint spots remained even after another 2 hours of reaction. Following the method of Example 1, EZE-20 was obtained as the final product. Analysis revealed: HPLC purity of 97.5%, content of 96.8%; EBB6 impurity 0.22%, other single largest impurities 0.48%, and total impurities 1.65%.

[0066] The results showed that when the amount of potassium carbonate was insufficient, the deprotonation of the phenolic hydroxyl group was incomplete, the concentration of phenolic anions was low, the reaction rate was slow and the conversion was incomplete, and extending the reaction time led to an increase in side reactions.

[0067] Comparative Example 6 The only difference from Example 1 was that the amount of benzyl bromide used was 63 kg, while all other conditions remained the same. The reaction was stopped when TLC showed that the EZE-19 spot no longer decreased. Post-processing was performed according to the method in Example 1 to obtain the EZE-20 product. Analysis showed: HPLC purity 97.8%, content 97.0%; EBB6 impurity 0.15%, other single largest impurity 0.62%, total impurities 1.42%.

[0068] The results showed that EZE-19 could not be completely converted when the amount of benzyl bromide was insufficient. Although most of the residual EZE-19 could be removed by washing with KOH, some residue remained and affected the purity and yield of the product.

[0069] Comparative Example 7 The only difference from Example 1 is that after concentrating the organic phase and treating it with isopropanol, methanol was not added for crystallization, and the product was directly concentrated to dryness. Testing revealed: HPLC purity 98.2%, content 97.8%; EBB6 impurity 0.18%, other single largest impurities 0.42%, total impurities 1.15%.

[0070] The results showed that omitting the methanol recrystallization step meant that isopropanol treatment could only remove some impurities, lacking the purification effect of methanol hot dissolution and cold crystallization, and the residual impurities in the product increased significantly.

[0071] Results Analysis The quality test results of EZE-20 for each embodiment and comparative example are shown in Table 1.

[0072] Table 1. Quality Inspection Results of EZE-20 Finished Products

[0073] As can be seen from the data in Table 1: (1) Examples 1 to 6 are industrial-scale verification batches. Using the process of this invention, the EBB6 impurity of the obtained EZE-20 is ≤0.09%, the other single maximum impurity is ≤0.18%, the total impurity is ≤0.36%, the chromatographic purity is 99.6% to 99.9%, and the content is 99% to 100%, all of which meet the quality standards. Example 3 uses recovered dichloromethane, and Examples 4 to 6 use recovered S-EZE-19 and different proportions of recovered dichloromethane. The product quality is comparable to that of Examples 1 to 2 using fresh raw materials, indicating that the process of this invention has good tolerance to recovered solvent and recovered mother liquor and strong process stability. The products obtained in Examples 7 to 10 all meet the quality standards. In Example 7, the reaction time was slightly prolonged when potassium carbonate, TBAB, and benzyl bromide were all at the lower limit, but the product was still qualified; in Example 8, the reaction rate was fast and the purity was high under the upper limit conditions.

[0074] In Comparative Example 1, without the use of TBAB phase transfer catalyst, the O-benzylation reaction rate in the two-phase system was significantly reduced, and incomplete conversion was still not achieved after 12 hours of reaction. Prolonged reflux led to imine bond hydrolysis, resulting in a total impurity level of 2.35% and a chromatographic purity decrease to 96.8%. This demonstrates that TBAB plays a crucial role in phase transfer catalysis in the two-phase system. In Comparative Example 2, using NaOH instead of potassium carbonate, significant imine bond hydrolysis occurred under strongly alkaline conditions, increasing the N-benzylation side reaction, resulting in a total impurity level of 3.18% and a chromatographic purity of only 94.5%. This demonstrates that the mild alkalinity of potassium carbonate is a key factor in protecting imine bonds and inhibiting side reactions. In Comparative Example 3, omitting the KOH alkaline washing step, the EBB6 impurity increased from 0.09% to 0.28%, other single largest impurities increased from 0.18% to 0.55%, and total impurities increased from 0.36% to 1.86%. This demonstrates that KOH alkaline washing can effectively remove unreacted EZE-19 and N-benzylation byproducts, and is an important post-treatment step for controlling product impurity content. Comparative Example 4, reacting at a high temperature of 80–85°C, showed severe thermal degradation of the imine bonds, resulting in a total impurity of 2.62%. This demonstrates that a mild reflux temperature of 40–45°C is crucial for maintaining imine bond stability and suppressing side reactions. Comparative Example 5, with its low potassium carbonate content and insufficient alkali, resulted in incomplete deprotonation, a slow and incomplete reaction, and a total impurity of 1.65%. This demonstrates that a potassium carbonate content of 1.5–2.5 times the original amount is reasonable. Comparative Example 6, with its low bromobenzyl weight ratio and insufficient benzylating reagent, resulted in EZE-19 residue and a total impurity of 1.42%. This demonstrates that a bromobenzyl weight ratio of 0.80–0.95:1 is necessary. Comparative Example 7, omitting the methanol crystallization step, could not achieve sufficient purification with isopropanol treatment alone, resulting in a total impurity of 1.15%. This demonstrates that a gradient purification combination of isopropanol solvent displacement and methanol crystallization is an important feature for ensuring product purity.

[0075] The material balance data for each embodiment are shown in Table 2.

[0076] Table 2 Material Balance Data from Examples

[0077] As shown in Table 2, the yields of EZE-20 in Examples 1–10 ranged from 125.3% to 132.8% (w / w), with small batch-to-batch variations and good process reproducibility. Example 7 had a slightly lower yield because all parameters were taken at their lower limits; Example 8 had a slightly higher yield because parameters were taken at their upper limits and a larger excess of p-fluoroaniline, both within reasonable ranges. The three industrial batch yields of the EZE-19 preparation step were 162.3%, 162.3%, and 163.1% (w / w), respectively, demonstrating similar stability and reliability.

[0078] The above-disclosed embodiments are merely a few specific examples of the present invention. However, the embodiments of the present invention are not limited thereto, and any variations that can be conceived by those skilled in the art should fall within the protection scope of the present invention.

Claims

1. A synthetic process for an etimibe intermediate, characterized in that, Includes the following steps: (1) Add p-hydroxybenzaldehyde to isopropanol, stir and heat until dissolved, add p-fluoroaniline dropwise at 45-55℃, and keep the reaction at 45-55℃ after the addition is complete. Monitor the reaction endpoint with high performance liquid chromatography. After the reaction is completed, cool down to 15-25℃, centrifuge, wash the filter cake with isopropanol, and dry at 50-60℃ until the moisture content is ≤0.5% to obtain (Z)-4-[(4-fluorophenylimino)methyl]phenol; (2) The (Z)-4-[(4-fluorophenylimino)methyl]phenol obtained in step (1) is mixed with dichloromethane, stirred and dispersed, and then potassium carbonate, water and tetrabutylammonium bromide are added. The mixture is stirred to form a biphase system, and then benzyl bromide is added. The mixture is heated to 40-45℃ and refluxed. Thin-layer chromatography is used to monitor the reaction until the (Z)-4-[(4-fluorophenylimino)methyl]phenol spots disappear. (3) After the reaction is completed, potassium hydroxide aqueous solution is added to the reaction system for alkaline washing. After stirring, the system is allowed to stand for phase separation and the aqueous phase is discarded. The organic phase is washed with water until neutral, the organic phase is separated and concentrated to recover dichloromethane. Isopropanol is added to the concentrated residue for solvent replacement treatment, followed by methanol. After heating to dissolve, the mixture is slowly cooled to crystallize. The product is centrifuged and dried at 50-60℃ until the water content is ≤0.5% to obtain (Z)-N-(4-benzyloxybenzylmethyl)-4-fluoroaniline.

2. The synthesis process of the etimibe intermediate according to claim 1, characterized in that, In step (1), the weight ratio of p-hydroxybenzaldehyde to p-fluoroaniline is 1:(0.91 to 1.00); the amount of isopropanol used is 2.0 to 2.8 times the weight of p-hydroxybenzaldehyde.

3. The synthesis process of the etimibe intermediate according to claim 1, characterized in that, In step (1), the reaction endpoint is monitored by high performance liquid chromatography. The reaction ends when the residual amount of p-hydroxybenzaldehyde in the reaction solution is ≤5.0% and the purity of (Z)-4-[(4-fluorophenylimino)methyl]phenol is ≥80.0%.

4. The synthesis process of the etimibe intermediate according to claim 1, characterized in that, In step (2), the amount of dichloromethane used is 10 to 15 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol.

5. The synthesis process of the etimibe intermediate according to claim 1, characterized in that, In step (2), the amount of potassium carbonate used is 1.5 to 2.5 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol; the amount of tetrabutylammonium bromide used is 0.2 to 0.5 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol.

6. The synthesis process of the etimibe intermediate according to claim 1, characterized in that, In step (2), the weight ratio of benzyl bromo to (Z)-4-[(4-fluorophenylimino)methyl]phenol is 0.80 to 0.95:1; the amount of water added simultaneously with potassium carbonate is 1.5 to 2.0 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol.

7. The synthetic process for the etimibe intermediate according to claim 1, characterized in that, In step (3), the mass concentration of the potassium hydroxide aqueous solution is 8% to 12%, and the amount of potassium hydroxide used is 0.08 to 0.15 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol.

8. The synthesis process of the etimibe intermediate according to claim 1, characterized in that, In step (3), the amount of isopropanol used in the solvent replacement treatment is 0.4 to 1.5 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol.

9. The synthetic process for the etimibe intermediate according to claim 1, characterized in that, In step (3), the amount of methanol used for crystallization is 1.5 to 2.5 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol.

10. The synthesis process of the etimibe intermediate according to claim 1, characterized in that, The dichloromethane mentioned in step (2) comprises recovered dichloromethane; and / or the (Z)-4-[(4-fluorophenylimino)methyl]phenol used in step (2) comprises (Z)-4-[(4-fluorophenylimino)methyl]phenol recovered from the condensation reaction mother liquor.

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