A process for the preparation of an ezetimibe intermediate

Abstract

This invention relates to a method for preparing an ezetimibe intermediate, belonging to the field of pharmaceutical synthesis technology. By limiting core conditions such as reaction temperature and rate, combined with real-time monitoring and stability range determination of p-hydroxybenzaldehyde residue, the method precisely solves the problem of difficulty in determining the endpoint caused by the reversibility of Schiff base reaction, achieving high purity and high yield of ezetimibe intermediate. Before the reaction, nitrogen is used to replace the air in the reactor to block the oxidation side reaction of raw materials from the source. At the same time, isopropanol is used as the single reaction solvent, without the introduction of additional auxiliaries, avoiding contamination by exogenous impurities. Combined with a dual-gradient cooling and low-speed crystallization process, the target product is slowly and orderly precipitated, reducing the problems of impurities trapped in crystals and impurities carried by the mother liquor. The method inhibits the formation of by-products in the entire process of reaction and post-processing, thereby improving the purity of the product.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology and relates to a method for preparing an ezetimibe intermediate. Background Technology

[0002] Ezetimibe is a first-line selective cholesterol absorption inhibitor widely used in the treatment of primary hypercholesterolemia, familial hypercholesterolemia, and other conditions. The industrial production efficiency and product quality of its active pharmaceutical ingredient (API) are highly dependent on the manufacturing process of its core synthetic intermediate. EZAB-5, as a key intermediate in the production of ezetimibe API, directly impacts the overall effectiveness of subsequent API synthesis due to its purity control, residual raw material management, and process industrial compatibility.

[0003] Chinese invention patent application CN106967106A discloses a method for producing ezetimibe intermediate. Stage 1: Using common commercial products p-hydroxybenzaldehyde and p-fluoroaniline as reactants and water as a reagent, a Schiff base is generated through heating and condensation, achieving a yield of up to 97.0%. Stage 2: This stage consists of two steps. First, the starting material 1 is reduced with chiral reducing reagent R-CBS and borane dimethyl sulfide to obtain an in-situ intermediate. This in-situ intermediate reacts directly with the Schiff base obtained in Stage 1 to obtain the final product, ezetimibe intermediate, with a yield exceeding 75.0%. In the first step of this stage, the organic phase is washed sequentially with sulfuric acid solution, 5% sodium sulfite solution, and 10% sodium chloride solution, and finally washed with water and dried with sodium sulfate, thoroughly removing various organic and inorganic impurities. Although the in-situ intermediate does not separate, its purity is high. The in-situ intermediate prepared in this way reacts with the Schiff base to obtain ezetimibe intermediate with high yield and high purity.

[0004] The existing EZAB-5 preparation process uses the Schiff base reaction of p-hydroxybenzaldehyde and p-fluoroaniline as the core reaction. However, this reaction is reversible, which can easily lead to large deviations in the detection results of p-hydroxybenzaldehyde residues. This poses significant challenges to the mid-control detection of raw material residues and the control of the process, making it difficult to accurately judge the reaction progress. At the same time, impurities are easily generated during the preparation process, resulting in low product purity and low yield. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing ezetimibe intermediates. By optimizing the process of precise feeding, gradient temperature-controlled crystallization, and vacuum drying, the purity and yield of ezetimibe intermediates are improved, and the impurity content is reduced.

[0006] The objective of this invention can be achieved through the following technical solutions: A method for preparing an ezetimibe intermediate includes the following steps: p-hydroxybenzaldehyde, p-fluoroaniline, and isopropanol were added to a reaction vessel under nitrogen protection and the reaction was maintained at this temperature for 3.5-4.5 hours. The residual p-hydroxybenzaldehyde content was then measured, the mixture was cooled, crystallized, centrifuged, and dried to obtain ezetimibe intermediate.

[0007] The reaction process is as follows: Furthermore, the mass ratio of p-hydroxybenzaldehyde, p-fluoroaniline, and isopropanol is 170-180:162-172:405-415.

[0008] Furthermore, the parameters for the heat preservation reaction are a temperature of 55-60℃ and a stirring rate of 70-90 r / min.

[0009] Furthermore, the residual content of p-hydroxybenzaldehyde is 5.1%-18.2%.

[0010] Furthermore, the cooling parameters are as follows: first, cool down to 35-40℃ at a cooling rate of 5℃ / h, and then continue to cool down to 0-5℃ at a cooling rate of 3℃ / h.

[0011] Furthermore, the crystallization time is 2-3 hours, and the stirring speed is 30-40 r / min.

[0012] Furthermore, the drying temperature is 45-50℃, and the vacuum degree is -0.08 to -0.09MPa.

[0013] Furthermore, the residual moisture content is 0.02-0.04%.

[0014] The beneficial effects of this invention are: This invention precisely solves the problem of difficulty in determining the endpoint caused by the reversibility of Schiff base reactions by limiting core conditions such as reaction temperature and rate, combined with real-time monitoring and stability range determination of p-hydroxybenzaldehyde residue. It achieves high purity and high yield of ezetimibe intermediate. Before the reaction, nitrogen is used to replace the air in the reactor to block the oxidation side reaction of raw materials from the source. At the same time, isopropanol is used as the single reaction solvent, without the introduction of additional additives, avoiding external impurity contamination. Combined with a dual-gradient cooling and low-speed crystallization process, the target product is slowly and orderly precipitated, reducing the problems of impurities trapped in crystals and impurities carried by the mother liquor. The generation of by-products is suppressed in the entire process of reaction and post-processing, thereby improving the purity of the product.

[0015] This invention precisely limits the ratio of p-hydroxybenzaldehyde, p-fluoroaniline, and isopropanol, ensuring that the two reactants react fully and completely in the optimal equivalence ratio, maximizing conversion efficiency. Through meticulous control of the entire process, including gradient crystallization, centrifugal washing, and vacuum drying, product loss is minimized, separation yield is improved, batch-to-batch yield differences are minimal, and the process is highly reproducible, making it fully suitable for the large-scale, standardized production needs of ezetimibe intermediates.

[0016] This invention addresses the problem of excessive moisture content in intermediates interfering with subsequent ezetimibe API synthesis. It employs a vacuum drying process at 45-50℃ and -0.08 to -0.09 MPa, which gently dehydrates the product without damaging its structure. The moisture content is strictly controlled at 0.02%-0.04%, far below the quality standard of ≤0.5%. This extremely low moisture content avoids side reactions in subsequent API synthesis, significantly improving the synthesis efficiency and quality stability of the final product, and achieving seamless integration between intermediate and API production.

[0017] This invention uses only isopropanol as a single solvent, without the need for additional reagents such as catalysts or acid-binding agents. The reaction and post-processing steps only include five steps: feeding, heat preservation reaction, gradient crystallization, centrifugation, and drying. The operation process is simplified, the amount of waste generated is extremely small, all process parameters are quantifiable and controllable, no complex equipment modifications are required, and it can be directly scaled up in existing pharmaceutical workshops, significantly reducing the industrial production cost of ezetimibe intermediates and possessing extremely strong industrial application value. Detailed Implementation

[0018] To further illustrate the technical means and effects of the present invention in achieving the intended purpose, the following detailed description of the specific implementation methods, features and effects of the present invention, in conjunction with preferred embodiments, is provided below.

[0019] Example 1: This example provides a method for preparing an ezetimibe intermediate, comprising the following steps: First, the air inside the reactor was replaced with nitrogen three times. Then, 175 kg of p-hydroxybenzaldehyde, 167 kg of p-fluoroaniline, and 410 kg of isopropanol were added to the reactor. The reaction was carried out at 57 °C and 80 r / min for 4 h. The residual p-hydroxybenzaldehyde content was found to be 5.1%. The temperature was lowered to 37 °C at a rate of 5 °C / h, and then further lowered to 2 °C at a rate of 3 °C / h. The mixture was kept at low temperature for 2.5 h to allow crystallization. The stirring speed was reduced to 35 r / min. After crystallization, the mixture was transferred to a centrifuge and centrifuged at 1100 r / min for 25 min. The filter cake was washed with a small amount of cold isopropanol and centrifuged for another 5 min. The mixture was then dried at 47 °C and -0.085 MPa until the moisture content was 0.04%, yielding ezetimibe intermediate (i.e., 4-[(4-fluorobenzylimino)methyl]phenol).

[0020] The purity of the ezetimibe intermediate prepared in Example 1 was accurately determined to be 99.9% by gas chromatography. Impurity 1 was 4-[(benzylimino)methyl]phenol, impurity 2 was 4-[(3-fluorobenzylimino)methyl]phenol, and impurity 3 was 4-[(4-chlorobenzylimino)methyl]phenol, with a total impurity content of 0.06% and a moisture content of 0.04%. The weight yield was calculated based on p-hydroxybenzaldehyde, with an expected weight yield of 145-165% and an actual weight yield of 164%.

[0021] Example 2: This example provides a method for preparing an ezetimibe intermediate, comprising the following steps: First, the air inside the reactor was replaced with nitrogen three times. Then, 170 kg of p-hydroxybenzaldehyde, 162 kg of p-fluoroaniline, and 405 kg of isopropanol were added to the reactor. The reaction was carried out at 55 °C and 70 r / min for 3.5 h. The residual p-hydroxybenzaldehyde content was found to be 13.4%. The temperature was lowered to 35 °C at a rate of 5 °C / h, and then further lowered to 0 °C at a rate of 3 °C / h. The mixture was kept at low temperature for 2 h to allow crystallization. The stirring speed was reduced to 30 r / min. After crystallization, the mixture was transferred to a centrifuge and centrifuged at 1000 r / min for 20 min. The filter cake was washed with a small amount of cold isopropanol and centrifuged for another 5 min. The mixture was then dried at 45 °C and -0.08 MPa until the moisture content was 0.04%, yielding ezetimibe intermediate (i.e., 4-[(4-fluorobenzylimino)methyl]phenol).

[0022] The purity of the ezetimibe intermediate prepared in Example 2 was accurately determined to be 99% by gas chromatography. Impurity 1 was 4-[(benzylimino)methyl]phenol, impurity 2 was 4-[(3-fluorobenzylimino)methyl]phenol, and impurity 3 was 4-[(4-chlorobenzylimino)methyl]phenol. The total impurity content was ≤0.05%, and the moisture content was 0.04%. The expected weight yield was 145-165%, and the actual weight yield was 153%.

[0023] Example 3: This example provides a method for preparing an ezetimibe intermediate, comprising the following steps: First, the air inside the reactor was replaced with nitrogen three times. Then, 180 kg of p-hydroxybenzaldehyde, 172 kg of p-fluoroaniline, and 415 kg of isopropanol were added to the reactor. The reaction was carried out at 60 °C and 90 r / min for 4.5 h. The residual p-hydroxybenzaldehyde content was found to be 18.2%. The temperature was lowered to 40 °C at a rate of 5 °C / h, and then further lowered to 5 °C at a rate of 3 °C / h. The mixture was kept at low temperature for 3 h to allow crystallization. The stirring speed was reduced to 40 r / min. After crystallization, the mixture was transferred to a centrifuge and centrifuged at 1200 r / min for 30 min. The filter cake was washed with a small amount of cold isopropanol and centrifuged for another 5 min. The mixture was then dried at 50 °C and -0.09 MPa until the moisture content was 0.02%, yielding ezetimibe intermediate (i.e., 4-[(4-fluorobenzylimino)methyl]phenol).

[0024] The purity of the ezetimibe intermediate prepared in Example 2 was accurately determined to be 99.2% by gas chromatography. Impurity 1 was 4-[(benzylimino)methyl]phenol, impurity 2 was 4-[(3-fluorobenzylimino)methyl]phenol, and impurity 3 was 4-[(4-chlorobenzylimino)methyl]phenol, with a total impurity content of 0.06% and a moisture content of 0.02%. The weight yield was calculated based on p-hydroxybenzaldehyde, with an expected weight yield of 145-165% and an actual weight yield of 154%.

[0025] Table 1. Summary of reactant input amounts, purity, and yields As shown in Table 1, the purity of the ezetimibe intermediates prepared in Examples 1-3 is ≥99%, and the weight yield is ≥153%. This may be because Examples 1-3 adopted precise raw material feeding ratios, appropriate condensation reaction temperatures and stirring rates, gradient cooling crystallization, and vacuum low-temperature drying, which allowed p-hydroxybenzaldehyde and p-fluoroaniline to fully undergo Schiff base condensation reaction in the isopropanol system, while effectively suppressing side reactions and impurity generation.

[0026] It should be noted that, in this document, terms such as “comprising,” “including,” or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus.

[0027] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention.

Claims

1. A process for the preparation of an ezetimibe intermediate, characterized by, Includes the following steps: p-hydroxybenzaldehyde, p-fluoroaniline and isopropanol were added to the reaction vessel under nitrogen protection and the reaction was maintained at the temperature for 3.5-4.5 h. The residual content of p-hydroxybenzaldehyde was detected, the temperature was lowered, crystals were precipitated, centrifuged, dried, and the residual moisture content was determined to obtain ezetimibe intermediate. The structural formula of the ezetimibe intermediate is shown in Formula 1: Formula 1.

2. The method for preparing an ezetimibe intermediate according to claim 1, characterized in that, The mass ratio of p-hydroxybenzaldehyde, p-fluoroaniline, and isopropanol is 170-180:162-172:405-415.

3. The method for preparing an ezetimibe intermediate according to claim 1, characterized in that, The parameters for the heat preservation reaction are a temperature of 55-60℃ and a stirring rate of 70-90 r / min.

4. The method for preparing an ezetimibe intermediate according to claim 1, characterized in that, The residual content of p-hydroxybenzaldehyde is 5.1%-18.2%.

5. The method for preparing an ezetimibe intermediate according to claim 1, characterized in that, The cooling parameters are as follows: first, the temperature is reduced to 35-40℃ at a cooling rate of 5℃ / h, and then further reduced to 0-5℃ at a cooling rate of 3℃ / h.

6. The method for preparing an ezetimibe intermediate according to claim 1, characterized in that, The crystallization time is 2-3 hours, and the stirring speed is 30-40 r / min.

7. The method for preparing an ezetimibe intermediate according to claim 1, characterized in that, The drying temperature is 45-50℃, and the vacuum degree is -0.08 to -0.09 MPa.

8. The method for preparing an ezetimibe intermediate according to claim 1, characterized in that, The residual moisture content is 0.02-0.04%.

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