A process for the preparation of an ezetimibe intermediate

Abstract

The application discloses a preparation method of an ezetimibe intermediate and belongs to the technical field of medicine preparation. In view of the problem that the N-benzylation side reaction of the imine nitrogen atom and bromobenzene occurs in the O-benzylation process of (Z)-4-[(4-fluorophenylimino)methyl]phenol, and the impurities such as EBB6 are difficult to control, zinc bromide is introduced into a dichloromethane-water two-phase system, the zinc bromide forms a Zn←N coordination bond with the imine nitrogen in the organic phase to reduce the nucleophilicity of the nitrogen atom, and tetrabutylammonium bromide transfers the phenolic oxygen anion to the organic phase to perform O-benzylation, and the two constitute a coordination protection-phase transfer bifunctional catalytic system; after the reaction, the zinc is removed through temperature control alkaline washing, two-stage quantitative concentration, isopropyl alcohol replacement and methanol programmed cooling crystallization, and (Z)-N-(4-benzyloxybenzylidene)-4-fluoroaniline is obtained. The product has high chromatographic purity, uniform crystal particle size and good fluidity, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and specifically relates to a method for preparing etimibe intermediate. Background Technology

[0002] Ezetimibe is a cholesterol absorption inhibitor jointly developed by Merck and Schering-Plough. Approved by the FDA in 2002, it reduces intestinal cholesterol absorption by selectively inhibiting the Niemann-Pick C1-like 1 protein (NPC1L1) at the brush border of the small intestinal mucosa. Clinically, it is used to treat primary hypercholesterolemia and homozygous familial hypercholesterolemia. (Z)-N-(4-benzyloxybenzylmethyl)-4-fluoroaniline is a key precursor in the synthesis of the β-lactam ring in the etimibe synthetic route. Its industrial preparation typically involves the condensation of p-hydroxybenzaldehyde with p-fluoroaniline to generate (Z)-4-[(4-fluorophenylimino)methyl]phenol, followed by O-benzylation of the phenolic hydroxyl group.

[0003] Patent application CN102978253A discloses a method for synthesizing etimibe intermediates. This method uses (4S)-3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone as a substrate, with NADP as a coenzyme and isopropanol as a co-substrate, and utilizes a chiral carbonyl reductase-catalyzed asymmetric reduction to obtain (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxy-1-oxopentyl]-4-phenyl-2-oxazolidinone. This method requires the use of chiral enzyme preparations, and the reaction process must be strictly controlled at pH 5.5–8.5 and temperature 20–50°C. Furthermore, the coenzyme regeneration system increases the complexity of the process and production costs. The intermediate structure involved in this method differs from that of this invention.

[0004] In the O-benzylation reaction of (Z)-4-[(4-fluorophenylimino)methyl]phenol, the substrate molecule contains both a phenolic hydroxyl group and an imine bond (C=N), possessing two nucleophilic sites. The phenolic hydroxyl group deprotonates under basic conditions to form a phenoxy anion, which reacts with benzyl bromide in a Williamson ether synthesis to generate the target product. However, the nitrogen atom on the imine bond also possesses a lone pair of electrons, which can attack the methylene carbon of benzyl bromide to undergo N-benzylation, generating quaternary ammonium salt byproducts (the main source of EBB6 impurities). These byproducts have structures similar to the target product and small polarity differences, making them difficult to completely remove by recrystallization, directly affecting the purity of the final product. Furthermore, the imine bond is easily hydrolyzed and cleaved under strong acid or strong base conditions to generate p-hydroxybenzaldehyde and p-fluoroaniline, and benzyl bromide is easily hydrolyzed to benzyl alcohol in aqueous systems, thus becoming inactive. Existing processes employ a dichloromethane-water biphase system, potassium carbonate as the base, and tetrabutylammonium bromide as the phase transfer catalyst, which to some extent balances reactivity and imine bond stability. However, effective methods for suppressing the N-benzylation side reaction are still lacking, the EBB6 impurity content fluctuates between batches, and fine crystals and agglomeration are prone to occur when the crystallization process is poorly controlled. Therefore, it is necessary to develop a preparation method that can selectively suppress the N-benzylation side reaction during the reaction process while ensuring the quality of product crystallization. Summary of the Invention

[0005] In view of the problems in the prior art, such as the easy N-benzylation side reaction of imine nitrogen atom during O-benzylation of (Z)-4-[(4-fluorophenylimino)methyl]phenol, the difficulty in effectively controlling impurities such as EBB6, and the unstable crystal quality of the product, the present invention provides a method for preparing etimibe intermediate.

[0006] The objective of this invention can be achieved through the following technical solutions: In a first aspect, the present invention provides a method for preparing an etimibe intermediate, comprising the following steps: (1) p-hydroxybenzaldehyde and p-fluoroaniline were condensed in isopropanol solvent. After the reaction was completed, the mixture was crystallized under controlled temperature, separated, washed and dried to obtain (Z)-4-[(4-fluorophenylimino)methyl]phenol (EZE-19). (2) Disperse (Z)-4-[(4-fluorophenylimino)methyl]phenol obtained in step (1) in dichloromethane, first add zinc bromide and stir to complete imine nitrogen coordination, then add potassium carbonate, water and tetrabutylammonium bromide to form a biphase reaction system, and add benzyl bromide to carry out reflux O-benzylation reaction; (3) After the reaction was completed, the zinc ions and impurities were removed by temperature-controlled alkaline washing with potassium hydroxide aqueous solution. After two-stage vacuum concentration and isopropanol solvent replacement, the organic phase was dissolved in methanol and crystallized by programmed cooling. After separation and drying, (Z)-N-(4-benzyloxybenzylmethyl)-4-fluoroaniline (EZE-20) was obtained.

[0007] The key to this invention lies in the coordination protection-phase transfer bifunctional catalytic system formed by zinc bromide and tetrabutylammonium bromide in step (2). In the molecular structure of the substrate (Z)-4-[(4-fluorophenylimino)methyl]phenol, both the phenolic hydroxyl oxygen atom and the imine nitrogen atom are nucleophilic. Under the action of potassium carbonate, the phenolic hydroxyl group is deprotonated to form a phenoxy anion, which is then converted to a quaternary ammonium cation Bu4N by tetrabutylammonium bromide. + After extraction into the dichloromethane phase, it reacts with benzyl bromo to form an O-benzylated product. However, the imine nitrogen atom retains a lone pair of electrons in its sp² hybridized orbital, which can also attack the benzylic carbon atom of benzyl bromo, generating an N-benzylated quaternary ammonium salt byproduct. This side reaction competes with the target O-benzylation reaction for the same molecule of benzyl bromo, and once the N-benzylated product is formed, it is difficult to remove in post-processing.

[0008] To suppress N-benzylation, zinc bromide is added to the organic phase before the addition of the alkali solution. Zinc bromide has a certain solubility in dichloromethane, and in the presence of tetrabutylammonium bromide, excess Br... - It coordinates with ZnBr2 to form [ZnBr3]. - Coordinate anions and react with Bu4N + The zinc ions associate into lipophilic [Bu4N][ZnBr3] ion pairs, thus stabilizing zinc in the organic phase. + Zn² is a boundary acid, and the imine nitrogen is a boundary base; the two have a strong coordination affinity. + The empty 4s / 4p orbital of the nitrogen atom accepts the lone pair of electrons from the sp² orbital of the imine nitrogen atom, forming a Zn←N coordinate bond. The formation of this coordinate bond causes the electron cloud of the nitrogen atom to shift towards the Zn² orbital. + The shift in nitrogen atom reduces its nucleophilicity, weakens its nucleophilic attack on the benzylic carbon of bromobenzyl, and thus inhibits the N-benzylation side reaction.

[0009] On the phenol-oxygen anion side, it exists in the aqueous phase as ArO. - Form exists, with Bu4N + After forming an ion pair, it is extracted into the organic phase. The phenoxy anion is a hard base and reacts with Bu4N. + They combine to form ion pairs through electrostatic interactions; while Zn² + As a boundary acid, its affinity for the hard base phenoloxide anion is weaker than its affinity for the boundary base imine nitrogen, and the phenoloxide anion has already been absorbed by Bu4N. + The positive charge shielding of Zn² + The addition of [Bu4N][ZnBr3] does not significantly affect the O-benzylation reaction. Therefore, the [Bu4N][ZnBr3] ion pair simultaneously performs two functions: its [ZnBr3]... - Partially through Zn² + N-protection is achieved through coordination with imine nitrogen, and its Bu4N+ Phase transfer carrying phenoxy anions facilitates O-alkylation. Coordination protection and phase transfer catalysis do not function independently, but are coupled through the same complex ion pair. If only tetrabutylammonium bromide is present without zinc bromide, the imine nitrogen lacks protection, and N-benzylation occurs as usual; if only zinc bromide is present without a phase transfer catalyst, the phenoxy anion struggles to enter the organic phase, and the O-benzylation reaction rate decreases significantly. Both are indispensable, jointly achieving the enhancement of O-selectivity.

[0010] The timing of zinc bromide addition is equally important. In this invention, zinc bromide is added to the dichloromethane organic phase and stirred before the potassium carbonate aqueous solution, allowing it to first coordinate with the substrate imine nitrogen. If the potassium carbonate aqueous solution is added first, followed by zinc bromide, then Zn²⁺… + It immediately reacts with CO3² upon entering the aqueous phase. - The formation of zinc carbonate precipitate (ZnCO3 has a very small solubility product) prevents it from entering the organic phase and coordinating with imine nitrogen, thus losing its coordination protection effect.

[0011] After the reaction is complete, the potassium hydroxide alkaline washing in step (3) simultaneously performs the functions of impurity removal and zinc removal. In the alkaline aqueous phase, Zn²⁺ + With OH - Zinc hydroxide precipitate is formed, which is further converted into soluble zincate in the aqueous phase and removed in the presence of excess alkali; the Zn←N coordination bond is due to Zn² + The bonds are released when the product is extracted into the aqueous phase, and the imine bonds are restored to a free state.

[0012] Further, the specific process of step (1) is as follows: p-hydroxybenzaldehyde is added to isopropanol, stirred and heated until dissolved, p-fluoroaniline is added dropwise at 45-55℃, and the reaction is kept at 45-55℃ after the addition is completed. The reaction endpoint is monitored by high performance liquid chromatography. The reaction ends when the residual p-hydroxybenzaldehyde in the reaction solution is ≤5.0% and the purity of (Z)-4-[(4-fluorophenylimino)methyl]phenol is ≥80.0%. After the reaction is completed, the temperature is first lowered to 30-35℃ at a rate of 8-10℃ / h and kept at 1-2h, and then lowered to 15-25℃ at a rate of 5-8℃ / h. After centrifugation, the filter cake is washed with isopropanol and dried under vacuum at 50-60℃ until the moisture content is ≤0.5%. In terms of crystallization control, the temperature is first rapidly reduced to the metastable region to induce the formation of stable crystal nuclei, and then the temperature is slowly reduced to allow the crystals to grow steadily, avoiding explosive nucleation and fine needle-like crystals caused by rapid cooling. The resulting columnar crystals have uniform particle size, low moisture content in the centrifuged filter cake, and stable moisture content ≤0.5% after drying, reducing the moisture introduced into the benzylation step from the source and reducing the risk of benzyl bromide hydrolysis.

[0013] Furthermore, the weight ratio of p-hydroxybenzaldehyde to p-fluoroaniline is 1:(0.91-1.00), the amount of isopropanol used is 2.0-2.8 times the weight of p-hydroxybenzaldehyde, and the amount of isopropanol used for washing is 0.2-0.7 times the weight of p-hydroxybenzaldehyde.

[0014] Further, in step (2), the amount of zinc bromide used is 0.03 to 0.08 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol; zinc bromide is pre-dissolved in a portion of dichloromethane before being added, or added directly to the organic phase in solid form; after adding zinc bromide, the mixture is stirred for 10 to 20 minutes to complete the coordination; after adding benzyl bromide, the temperature is raised to 40 to 45°C and refluxed for reaction, and the reaction endpoint is reached by monitoring the disappearance of the (Z)-4-[(4-fluorophenylimino)methyl]phenol spots using thin-layer chromatography. Zinc bromide is catalytically significant, and a range of 0.03 to 0.08 times is sufficient to provide coordination protection for most of the substrate imine nitrogen; if the amount is too low, the protection is incomplete, and if the amount is too high, there will be excess Zn². + It will weakly coordinate with phenoxy anions, slowing down the O-benzylation reaction rate and increasing the zinc removal burden in the post-treatment. Adding zinc bromide to the organic phase before the alkaline solution and stirring for coordination can avoid Zn²⁺ ions. + The process of adding the solid to the aqueous phase and reacting with carbonate ions to form zinc carbonate precipitate, thus rendering the solid ineffective, is the core operational sequence for ensuring coordination protection. Both direct addition of the solid and addition of the solid pre-dissolved in dichloromethane can achieve effective coordination.

[0015] Further, in step (2), the amount of dichloromethane used is 10 to 15 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol; 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; the weight ratio of benzyl bromide to (Z)-4-[(4-fluorophenylimino)methyl]phenol is (0.80 to 0.95):1; and 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. Tetrabutylammonium bromide, as a phase transfer catalyst, can extract phenolic anions from the aqueous phase into the organic phase in the form of ion pairs; at the same time, it can form a [Bu4N][ZnBr3] complex ion pair with zinc bromide, so that zinc can exist stably in the organic phase.

[0016] Further, in step (3), the mass concentration of the potassium hydroxide aqueous solution is 8%–12%, and the amount of potassium hydroxide used is 0.08–0.15 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol; the alkaline washing temperature is 30–35°C, and the washing time is 20–30 min. Under temperature-controlled washing at 30–35°C, the phenolic hydroxyl groups of the unreacted substrate form salts that dissolve in the aqueous phase, the N-benzylated quaternary ammonium salt hydrolyzes into water-soluble components, the residual benzyl bromohydrolyzes into benzyl alcohol, and Zn² + The product is converted into zinc hydroxide / zincate and enters the aqueous phase. Various impurities and zinc ions can be removed simultaneously in one step. At the same time, the phenolic hydroxyl group of the product has been blocked by benzyl group, and imine hydrolysis will not occur after short-term contact with dilute alkali.

[0017] Furthermore, in step (3), the temperature of the first stage of vacuum concentration is ≤35℃ and the vacuum degree is ≤-0.08MPa, and the concentration is carried out until the weight of the residue is 1.5 to 2.0 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol. The temperature of the second stage of vacuum concentration is ≤40℃ and the vacuum degree is ≤-0.08MPa, and the concentration is carried out until the weight of the residue is 1.2 to 1.5 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol. The amount of isopropanol used for solvent replacement is 0.5 to 1.0 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol. The first stage of low-temperature concentration recovers most of the dichloromethane. After adding isopropanol, the second stage of concentration is carried out. Taking advantage of the miscibility between isopropanol and dichloromethane, the residual dichloromethane is completely removed in the form of mixed vapor, avoiding the dichloromethane residue from changing the solvent polarity of the methanol crystallization system, which would lead to incomplete crystallization or abnormal crystal shape.

[0018] Further, in step (3), the amount of methanol used is 1.8 to 2.2 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol; after the material is decolorized by activated carbon, it is first cooled to 38 to 42°C at a rate of 8 to 12°C / h and held at that temperature for 1 to 2 hours, then cooled to 10 to 15°C at a rate of 3 to 5°C / h and held at that temperature for 2 to 3 hours; the crystalline product is vacuum dried at 50 to 60°C until the moisture content is ≤0.5%. The activated carbon content is 0.5%–2% of the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol. After stirring at 55–65℃ for 15–30 min, the mixture is filtered while hot. During the heat treatment stage at 38–42℃, (Z)-N-(4-benzyloxybenzylmethyl)-4-fluoroaniline seed crystals are added, with the seed crystal content being 0.5%–2% of the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol. The temperature is first lowered to the metastable region for heat treatment and seed crystals are added to guide directional nucleation and reduce particle size distribution. Then, the temperature is slowly lowered to allow for stable crystal growth, avoiding explosive nucleation that produces a large number of fine crystals. Finally, a granular product with uniform particle size, good flowability, and a low angle of repose is obtained, exhibiting excellent anti-caking properties.

[0019] Furthermore, the dichloromethane mentioned in step (2) includes recycled dichloromethane, which, after distillation, must meet the following requirements: dichloromethane content ≥ 98.5%, moisture ≤ 0.2%, benzyl bromide residue ≤ 0.1%, benzyl alcohol content ≤ 0.5%; the proportion of recycled dichloromethane to the total amount of dichloromethane used does not exceed 95%.

[0020] Furthermore, the (Z)-4-[(4-fluorophenylimino)methyl]phenol used in step (2) includes the product recovered from the condensation reaction mother liquor in step (1). The recovered product is dried to a moisture content of ≤0.5% and then incorporated into the fresh product. The amount incorporated accounts for 15% to 25% of the total feed. The recovery and reuse of the product dissolved in the mother liquor improves the overall yield of the condensation step. Controlling the incorporation ratio and moisture content avoids adverse effects on the benzylation reaction.

[0021] The beneficial effects of this invention are: (1) In this invention, zinc bromide is introduced into the dichloromethane organic phase. Zinc bromide and tetrabutylammonium bromide form a [Bu4N][ZnBr3] complex ion pair, constituting a coordination protection-phase transfer bifunctional catalytic system. Zn² + By reducing the electron cloud density and nucleophilicity of the imine nitrogen atom through the Zn←N coordination bond, the N-benzylation side reaction is selectively suppressed during the reaction; Bu4N + Phenoxy anions are transferred to the organic phase for O-benzylation. Coordination protection and phase transfer are coupled through the same complex ion pair; both are indispensable, resulting in a significant reduction in EBB6 impurities and total impurities. Zinc bromide is added to the organic phase before the addition of alkali solution to complete coordination, avoiding the addition of Zn²⁺. + In aqueous phase, zinc carbonate precipitate forms, rendering the reaction ineffective; a catalytic amount (0.03–0.08 times) of zinc bromide ensures coordination protection without affecting the O-benzylation reaction rate. After the reaction, alkali washing with potassium hydroxide removes Zn²⁺. + Zinc hydroxide / zincate is generated and enters the aqueous phase. The Zn←N coordination is released, the imine bond in the product is restored, and no zinc residue remains.

[0022] (2) In this invention, isopropanol is used as a solvent to condense p-hydroxybenzaldehyde and p-fluoroaniline at 45-55°C. The reaction extent is accurately controlled by monitoring the endpoint (p-hydroxybenzaldehyde residue ≤5.0%, product purity ≥80.0%) using HPLC. After the reaction, a two-stage controlled cooling process is adopted, cooling from 8-10°C / h to 30-35°C and then cooling from 5-8°C / h to 15-25°C. After the formation of a stable crystal nucleus group in the metastable region, the crystals grow slowly. The resulting intermediate is a columnar crystal with uniform particle size. The centrifuged filter cake has low moisture content. After washing with isopropanol, it is vacuum dried at 50-60°C until the moisture content is ≤0.5%. This reduces the moisture introduced into the benzylation step from the source and lowers the risk of benzyl bromide hydrolysis.

[0023] (3) This invention uses potassium carbonate as the base, whose saturated solution has a pH of approximately 11.6, which is mildly alkaline. This alkalinity can deprotonate phenolic hydroxyl groups to generate phenoxy anions without causing hydrolysis of imine bonds. The dichloromethane-water two-phase system separates the organic substrate and the inorganic base into two phases, and the imine bonds in the organic phase are less affected by the alkaline solution in the aqueous phase. The reflux temperature of 40-45°C is mild and matches the boiling point of dichloromethane, eliminating the need for additional pressurization equipment. TLC monitoring continues until the substrate spots disappear, avoiding over-reaction. The dosage of each material (10-15 times dichloromethane, 1.5-2.5 times potassium carbonate, 0.2-0.5 times tetrabutylammonium bromide, 0.80-0.95 times benzyl bromide, and 1.5-2.0 times water) controls costs and side reactions while ensuring complete reaction.

[0024] (4) In this invention, the substrate is washed with an 8%–12% potassium hydroxide aqueous solution at 30–35°C for 20–30 min under controlled temperature. At this temperature, the unreacted substrate phenolic hydroxyl groups form salts, N-benzylated quaternary ammonium salts are hydrolyzed, and residual benzyl bromohydrolyzes to benzyl alcohol and Zn²⁺. + It is converted into zinc hydroxide / zincate, and various impurities and zinc ions are removed simultaneously in a one-step alkaline wash; then it is washed with water until neutral to remove residual alkali and water-soluble salts, providing a pure organic phase for subsequent concentration and crystallization.

[0025] (5) This invention employs a two-stage quantitative concentration process: concentration at ≤35℃ under reduced pressure to 1.5–2.0 times, followed by further concentration at ≤40℃ to 1.2–1.5 times after the addition of isopropanol. The first stage recovers most of the dichloromethane, while the second stage utilizes the miscibility of isopropanol and dichloromethane to remove the residual dichloromethane. The weight of the residue is used as the concentration endpoint criterion, which is intuitive and reliable; low-temperature reduced pressure avoids thermal degradation of the product; and isopropanol replacement eliminates the interference of residual dichloromethane on methanol crystallization.

[0026] (6) The process of this invention has good adaptability to the recovery of solvents and mother liquor. Dichloromethane recovered can be reused at a ratio not exceeding 95% after distillation and meeting the content, moisture, benzyl bromide residue and benzyl alcohol content indicators. The condensation mother liquor recovery product is dried to a moisture content of ≤0.5% and then mixed with fresh substrate at 15% to 25%. The product quality is comparable to that of fresh raw materials, which reduces solvent consumption and raw material loss and is suitable for large-scale industrial production. Detailed Implementation

[0027] 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.

[0028] 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, content ≥99%), tetrabutylammonium bromide (industrial grade, content ≥99%), zinc bromide (industrial grade, content ≥98%), potassium hydroxide (industrial grade, content ≥90%), isopropanol (industrial grade, content ≥99.5%), dichloromethane (industrial grade, content ≥99.5%), methanol (industrial grade, content ≥99.5%), and activated carbon (type 767 needle-grade activated carbon), all of which are commercially available.

[0029] Example 1 (1) Preparation of (Z)-4-[(4-fluorophenylimino)methyl]phenol 410 kg of isopropanol and 175 kg of p-hydroxybenzaldehyde were added to a reaction vessel and stirred until dissolved. 167 kg of p-fluoroaniline was added dropwise at 45–55 °C, and the reaction was maintained at 47.0–53.1 °C after the addition was complete. The endpoint was reached when HPLC analysis showed a p-hydroxybenzaldehyde residue of 1.9% and a product purity of 92.1%. The temperature was lowered to 32 °C at a rate of 9 °C / h and maintained for 1.5 h, then lowered to 20 °C at a rate of 6 °C / h. After centrifugation, the filter cake was washed twice with 90 kg of isopropanol. The product was then vacuum dried at 50–59.3 °C until the moisture content reached 0.08%, yielding 284.0 kg of the final product, with a yield of 162.3% (w / w). The product appeared as light yellow columnar crystals with an HPLC purity of 96.8%.

[0030] (2) Preparation of (Z)-N-(4-benzyloxybenzylmethyl)-4-fluoroaniline Add 90 kg of the above product and 1197 kg of dichloromethane to the reactor and stir to disperse. Add 4.5 kg of zinc bromide (0.05 times the amount of the product) and stir for 15 min. 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. Add 75.6 kg of benzyl bromide and reflux at 40–45 °C. Monitor by TLC until the substrate spots disappear (reflux temperature 40.0–45.0 °C).

[0031] After the reaction is complete, add a KOH aqueous solution preheated to 32℃ (9.9 kg KOH dissolved in 90 kg water, concentration 9.9%), stir and wash at 30-35℃ for 25 min, let stand to separate phases and discard the aqueous phase. Wash the organic phase with 260 kg of drinking water at 30-35℃ until neutral.

[0032] The organic phase was concentrated under reduced pressure at 30–35°C and -0.085 MPa until a residue of approximately 153 kg (1.7 times) was obtained. 60 kg of isopropanol was added, and the concentration was further carried out at 35–40°C and -0.085 MPa until a residue of approximately 122 kg (1.36 times) was obtained.

[0033] Add 180 kg of methanol and heat to 62 °C to dissolve. Add 0.9 kg of activated carbon, stir at 60 °C for 20 min to decolorize, and filter while hot. Cool the filtrate to 40 °C at a rate of 10 °C / h and maintain the temperature for 1.5 h (add 0.9 kg of seed crystals after 30 min of maintenance), then cool to 12 °C at a rate of 4 °C / h and maintain the temperature for 2.5 h. Centrifuge, wash with cold methanol, and vacuum dry at 50–60 °C to a moisture content of 0.10%, yielding 119.8 kg of the final product, with a yield of 133.1%.

[0034] The product was a white, granular crystal without clumping. HPLC purity was 99.9%, content was 100%; EBB6 impurity was 0.04%, other single maximum impurities were 0.06%, and total impurities were 0.12%; D50 was 275 μm, and the angle of repose was 33°; zinc residue was not detected.

[0035] Example 2 The difference between this embodiment and Example 1 is that the amount of zinc bromide used is 2.7 kg (0.03 times), while the other raw materials and preparation process are the same as in Example 1.

[0036] Example 3 The difference between this embodiment and Example 1 is that the amount of zinc bromide used is 7.2 kg (0.08 times), while the other raw materials and preparation process are the same as in Example 1.

[0037] Example 4 The difference between this embodiment and Example 1 is that 257 kg of fresh dichloromethane and 940 kg of recycled dichloromethane were mixed and used together (totaling 1197 kg, with a recycling rate of 78.5%; the recycled dichloromethane was tested and found to have a content of 99.1%, moisture of 0.12%, benzyl bromodetectable, and benzyl alcohol of 0.2%, which is qualified).

[0038] Example 5 The difference between this embodiment and Example 1 is that 70 kg of (Z)-4-[(4-fluorophenylimino)methyl]phenol was added, along with 20 kg of recovered mother liquor (totaling 90 kg, with a recovered material ratio of 22.2% and a moisture content of 0.3%); 217 kg of fresh dichloromethane and 980 kg of recovered dichloromethane were used (with a recovery ratio of 81.9%, which is qualified).

[0039] Example 6 The difference between this embodiment and Example 1 is that 70 kg of (Z)-4-[(4-fluorophenylimino)methyl]phenol was added along with 20 kg of recovered mother liquor; 60 kg of fresh dichloromethane and 1137 kg of recovered dichloromethane were used (recovery rate 95.0%, test results: content 98.6%, moisture 0.18%, benzyl bromo 0.08%, benzyl alcohol 0.4%, qualified).

[0040] Example 7 The difference between this embodiment and Example 1 is that the condensation step uses 350 kg of isopropanol and 160 kg of p-fluoroaniline; the benzylation step uses 900 kg of dichloromethane, 135 kg of potassium carbonate, 135 kg of drinking water, 18 kg of tetrabutylammonium bromide, 72 kg of benzyl bromide, and 3.6 kg of zinc bromide (0.04 times); the KOH aqueous solution concentration is 8.0% (7.2 kg of KOH / 82.8 kg of water); and the components include 45 kg of isopropanol, 162 kg of methanol, and 0.45 kg of activated carbon.

[0041] Example 8 The difference between this embodiment and Example 1 is that the condensation step uses 490 kg of isopropanol and 175 kg of p-fluoroaniline; the benzylation step uses 1350 kg of dichloromethane, 225 kg of potassium carbonate, 180 kg of drinking water, 45 kg of tetrabutylammonium bromide, 85.5 kg of benzyl bromide, and 5.4 kg of zinc bromide (0.06 times); the KOH aqueous solution concentration is 12.0% (13.5 kg of KOH / 99 kg of water); and the ingredients include 90 kg of isopropanol, 198 kg of methanol, and 1.8 kg of activated carbon.

[0042] Comparative Example 1 The difference between this comparative example and Example 1 is that zinc bromide was not added; the remaining raw materials and preparation process were the same as in Example 1. 118.2 kg of the finished product was obtained, with a yield of 131.3%.

[0043] Comparative Example 2 The difference between this comparative example and Example 1 is that zinc chloride was used instead of zinc bromide (equimolar amount, 2.7 kg), while the other raw materials and preparation process were the same as in Example 1. 117.8 kg of the finished product was obtained, with a yield of 130.9%.

[0044] Comparative Example 3 The difference between this comparative example and Example 1 is that zinc bromide was added after the potassium carbonate aqueous solution (i.e., alkaline water was added first to form a biphase system, and then zinc bromide was added). The remaining raw materials and preparation process were the same as in Example 1. 116.5 kg of the finished product was obtained, with a yield of 129.4%.

[0045] Comparative Example 4 The difference between this comparative example and Example 1 is that, during methanol crystallization, programmed cooling was not used. After heating and dissolving, cooling water was directly circulated to rapidly cool the temperature to 10°C (approximately 30°C / h), without holding at 38–42°C and 10–15°C. All other conditions remained the same. The final product was obtained.

[0046] Comparative Example 5 The difference between this comparative example and Example 1 is that it does not employ two-stage concentration. After washing the organic phase with water, it is directly concentrated to dryness under reduced pressure (without isopropanol replacement), and then methanol is added to cool and crystallize according to the procedure in Example 1. The finished product is obtained.

[0047] Comparative Example 6 The difference between this comparative example and Example 1 is that the KOH aqueous solution was not preheated, and the alkali washing was performed for 30 min at room temperature (20-25°C), while all other conditions remained the same. The final product was obtained. HPLC chromatographic purity was 99.7%, EBB6 impurity 0.08%, other single maximum impurities 0.12%, total impurities 0.24%, D50 255 μm, and angle of repose 34°. The final product was obtained.

[0048] Comparative Example 7 The difference between this comparative example and Example 1 is that the amount of zinc bromide used was 13.5 kg (0.15 times), while all other conditions were the same. 112.3 kg of the final product was obtained, with a yield of 124.8%.

[0049] Performance testing All examples and comparative examples of (Z)-N-(4-benzyloxybenzylmethyl)-4-fluoroaniline were subjected to the following performance tests: 1. HPLC chromatographic purity and related substances: C18 column, acetonitrile-water gradient elution, detection wavelength 230 nm, area normalization method calculation.

[0050] 2. Moisture content: determined by Karl Fischer method.

[0051] 3. Crystal particle size D50: determined by laser particle size analyzer and dry dispersion method.

[0052] 4. Angle of repose: Fixed funnel method, the funnel outlet is 5cm above the horizontal plate surface, the sample falls freely to form a cone, and the base angle of the cone is measured.

[0053] 5. Zinc residue: Atomic absorption spectrophotometry, detection limit 1 ppm.

[0054] 6. Agglomeration: Take 50g of sample, seal it in a PE bag, apply 2kg static pressure and leave it for 7 days, then observe the degree of agglomeration.

[0055] The results are shown in Tables 1 and 2: Table 1 Finished Product Quality Inspection Results

[0056] Table 2 Material Balance Data from Examples

[0057] As shown in Table 1, the products from Examples 1 to 8, using the process of this invention, had an HPLC purity of 99.8%–99.9%, EBB6 impurity of 0.03%–0.06%, other single maximum impurities ≤0.10%, total impurities of 0.08%–0.20%, and a content of 99%–100%. Zinc residue was not detected (<1 ppm), and all met the quality standards. Compared with Comparative Example 1 (EBB6 0.09%, total impurities 0.36%) without zinc bromide, the EBB6 impurity in Example 1 was reduced by approximately 56%, and the total impurities were reduced by approximately 67%, indicating that without zinc bromide, imine nitrogen lacked coordination protection, and the N-benzylation side reaction was not inhibited.

[0058] Both Example 2 and Example 3 products were qualified. Example 3 had the lowest EBB6 impurity due to more adequate coordination protection. Comparative Example 7 used 0.15 times zinc bromide and excess Zn²⁺. + With weak coordination with phenoxy anions, the reaction time was extended from approximately 6 hours to 12 hours, and the total impurities increased to 0.45%, with zinc residue at 8 ppm. This indicates that 0.03–0.08 times is a reasonable range that balances coordination protection and reaction rate. Examples 4–6 used recycled dichloromethane and recycled mother liquor. Under conditions of quality control of the recycled solvent and proportional blending of recycled materials, the product quality was comparable to that of Examples 1–3 using fresh raw materials, with EBB6 impurities of 0.03%–0.05% and total impurities of 0.08%–0.16%. This demonstrates that the process of this invention has good tolerance to recycled solvents and recycled mother liquor, and good process stability.

[0059] Comparative Example 2, using zinc chloride instead of zinc bromide, showed 0.07% EBB6 impurities and 0.25% total impurities, a weaker effect than the zinc bromide system. This indicates that while zinc chloride has a certain coordination effect, the solubility and stability of [Bu4N][ZnCl3] in dichloromethane are lower than those of [Bu4N][ZnBr3], resulting in insufficient formation of complex ion pairs and a weaker coordination protection effect compared to zinc bromide, with slightly higher zinc residue. Comparative Example 3 added zinc bromide after the alkaline solution, partially removing Zn²⁺. + In the aqueous phase with CO3² -Zinc carbonate precipitate was formed, which could not enter the organic phase to coordinate with imine nitrogen, and the coordination protection effect was basically lost, proving that adding zinc bromide before the alkali solution was a necessary operational sequence. Comparative Example 4 did not use programmed cooling crystallization. Rapid cooling led to explosive nucleation, resulting in fine crystals with a wide particle size distribution and poor flowability and anti-caking properties. However, the EBB6 impurity of 0.05% was still lower than that of Comparative Example 1 without zinc bromide, indicating that the bifunctional catalytic system and crystallization control play roles at the levels of reaction selectivity and physical morphology, respectively, and cannot replace each other. Comparative Example 5 did not use two-stage concentration. Dichloromethane residue was 0.08%, and total impurities were 0.32%, indicating that when concentrated to dryness in a single stage, the residual dichloromethane was encapsulated in an oily substance. The addition of methanol released it and changed the solvent polarity, leading to increased impurity precipitation and poor crystal morphology during crystallization. Comparative Example 6 was alkali washed at room temperature. EBB6 of 0.08% was higher than that of Example 1 of 0.04%, indicating that the hydrolysis rate of quaternary ammonium salt and the extraction rate of phenolic impurities were slow at room temperature, and the alkali washing was insufficient.

[0060] As shown in Table 2, the yields of Examples 1–8 ranged from 126.9% to 134.2% (w / w). Compared to Comparative Example 1 (131.3%), the yield of Example 1 increased to 133.1%, attributed to the reduction in N-benzylation side reactions resulting in greater conversion of the substrate to the target product. Example 7 had a slightly lower yield due to using the lower limits of the parameters, while Example 8 had the highest yield due to using the upper limits of the parameters and sufficient coordination protection; both yields were within a reasonable range.

[0061] 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 method for preparing an etimibe intermediate, characterized in that, Includes the following steps: (1) p-hydroxybenzaldehyde and p-fluoroaniline were condensed in isopropanol solvent. After the reaction was completed, the mixture was crystallized under controlled temperature, separated, washed and dried to obtain (Z)-4-[(4-fluorophenylimino)methyl]phenol; (2) Disperse (Z)-4-[(4-fluorophenylimino)methyl]phenol obtained in step (1) in dichloromethane, first add zinc bromide and stir to complete imine nitrogen coordination, then add potassium carbonate, water and tetrabutylammonium bromide to form a biphase reaction system, and add benzyl bromide to carry out reflux O-benzylation reaction; (3) After the reaction was completed, the zinc ions and impurities were removed by temperature-controlled alkaline washing with potassium hydroxide aqueous solution. After two-stage vacuum concentration and isopropanol solvent replacement, the organic phase was dissolved in methanol and crystallized by programmed cooling. After separation and drying, (Z)-N-(4-benzyloxybenzylmethyl)-4-fluoroaniline was obtained.

2. The method for preparing the etimibe intermediate according to claim 1, characterized in that, The specific process of step (1) is as follows: p-hydroxybenzaldehyde is added to isopropanol, stirred and heated until dissolved, p-fluoroaniline is added dropwise at 45-55℃, and the reaction is kept at 45-55℃ after the addition is completed. The reaction endpoint is monitored by high performance liquid chromatography. The reaction ends when the residual p-hydroxybenzaldehyde in the reaction solution is ≤5.0% and the purity of (Z)-4-[(4-fluorophenylimino)methyl]phenol is ≥80.0%. After the reaction is completed, the temperature is first lowered to 30-35℃ at a rate of 8-10℃ / h and kept at 1-2h, and then lowered to 15-25℃ at a rate of 5-8℃ / h. After centrifugation, the filter cake is washed with isopropanol and dried under vacuum at 50-60℃ until the moisture content is ≤0.5%.

3. The method for preparing the etimibe intermediate according to claim 2, characterized in that, The weight ratio of p-hydroxybenzaldehyde to p-fluoroaniline is 1:(0.91-1.00), the amount of isopropanol used is 2.0-2.8 times the weight of p-hydroxybenzaldehyde, and the amount of isopropanol used for washing is 0.2-0.7 times the weight of p-hydroxybenzaldehyde.

4. The method for preparing the etimibe intermediate according to claim 1, characterized in that, In step (2), the amount of zinc bromide used is 0.03 to 0.08 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol; zinc bromide is pre-dissolved in a portion of dichloromethane before being added, or added directly to the organic phase in solid form; after adding zinc bromide, the mixture is stirred for 10 to 20 minutes to complete the coordination; after adding benzyl bromide, the temperature is raised to 40 to 45°C and refluxed for reaction, and the reaction endpoint is reached by monitoring the disappearance of the (Z)-4-[(4-fluorophenylimino)methyl]phenol spots using thin-layer chromatography.

5. The method for preparing 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; 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; the weight ratio of benzyl bromide to (Z)-4-[(4-fluorophenylimino)methyl]phenol is (0.80 to 0.95):1; and 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.

6. The method for preparing 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; the alkaline washing temperature is 30 to 35°C, and the washing time is 20 to 30 minutes.

7. The method for preparing the etimibe intermediate according to claim 1, characterized in that, In step (3), the temperature of the first stage of vacuum concentration is ≤35℃ and the vacuum degree is ≤-0.08MPa, and the concentration is carried out until the weight of the residue is 1.5 to 2.0 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol. The temperature of the second stage of vacuum concentration is ≤40℃ and the vacuum degree is ≤-0.08MPa, and the concentration is carried out until the weight of the residue is 1.2 to 1.5 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol. The amount of isopropanol used for solvent replacement is 0.5 to 1.0 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol.

8. The method for preparing the etimibe intermediate according to claim 1, characterized in that, In step (3), the amount of methanol used is 1.8 to 2.2 times the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol; after the material is decolorized by activated carbon, it is first cooled to 38 to 42°C at a rate of 8 to 12°C / h and kept at that temperature for 1 to 2 hours, and then cooled to 10 to 15°C at a rate of 3 to 5°C / h and kept at that temperature for 2 to 3 hours. The crystalline product was vacuum dried at 50–60 °C until the moisture content was ≤0.5%; the amount of activated carbon used was 0.5%–2% of the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol, and the product was stirred at 55–65 °C for 15–30 min and then filtered while hot; during the heat preservation stage at 38–42 °C, (Z)-N-(4-benzyloxybenzylmethyl)-4-fluoroaniline seed crystals were added, and the amount of seed crystals added was 0.5%–2% of the weight of (Z)-4-[(4-fluorophenylimino)methyl]phenol.

9. The method for preparing the etimibe intermediate according to claim 1, characterized in that, The dichloromethane mentioned in step (2) includes recycled dichloromethane, which, after distillation, must meet the following requirements: dichloromethane content ≥ 98.5%, moisture ≤ 0.2%, benzyl bromide residue ≤ 0.1%, benzyl alcohol content ≤ 0.5%; the proportion of recycled dichloromethane to the total amount of dichloromethane used shall not exceed 95%.

10. The method for preparing the etimibe intermediate according to claim 1, characterized in that, The (Z)-4-[(4-fluorophenylimino)methyl]phenol used in step (2) contains the product recovered from the condensation reaction mother liquor in step (1). The recovered product is dried to a moisture content of ≤0.5% and then incorporated into the fresh product. The amount incorporated accounts for 15% to 25% of the total feed amount.

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