Process for the preparation of a pemafibrate intermediate

Abstract

The application provides a preparation method of a pemafibrate intermediate shown in the following formula, and the method comprises the following steps: dissolving an intermediate PB-II in anhydrous organic solvent, adding an acid binding agent and an intermediate PB-III, controlling the temperature to be greater than or equal to-5 DEG C to perform reaction, and obtaining an intermediate PB-IV (intermediate in formula II): by optimizing the reaction solvent, especially by adopting a specific anhydrous organic solvent and the proportion of the anhydrous organic solvent and reactants, and by optimizing the reaction condition in combination with a specific acid binding agent, it is surprisingly found that the content of isomer impurity I is greatly reduced, the generation of subsequent conductive impurity-pemafibrate isomer II is further reduced, and the reaction condition is mild and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, and specifically relates to a method for preparing a pemafibrate intermediate. Background Technology

[0002] Pemafibrate is a novel fibrate drug developed by Kowa Co., Ltd. of Japan. It was approved for marketing in Japan in June 2018 under the brand name Parmodia, and is primarily used to treat hyperlipidemia. The chemical name of pemafibrate is (R)-2-(3-((benzo[D]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxy)butyric acid, and its chemical structural formula is shown in Formula I below:

[0003]

[0004] According to research, there are multiple synthetic routes for pemafibrate, among which (R)-2-(3-(benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxybutyrate butyl ester is an important intermediate in the preparation of this drug, and its structure is shown in Formula II below.

[0005] Using this intermediate, the final product pemafibrate is obtained through a deesterification reaction, which is currently the mainstream synthetic route for pemafibrate.

[0006]

[0007] For example, the original patent EP1852426B1 discloses the preparation process of the Pemabet type II intermediate. Since the obtained type II compound is in an oily state, it needs to be purified by column chromatography to obtain the intermediate product. The reaction yield and purity are poor, and a large amount of product is lost in the post-processing. In addition, a large amount of solvent is used and the substrate concentration is low, which slows down the reaction rate and leads to a greater increase in isomer impurities. Among them, the presence of intermediate isomer impurities with the following structure (1) leads to the further transfer to Pemabet impurities (2), resulting in difficult post-processing and low yield after purification.

[0008]

[0009] CN118955421A improved the reaction conditions based on the original preparation method. In the post-processing, silica gel was added for stirring and purification, and extraction and filtration were used to replace the two silica gel column separation and purification. However, the chirality control of this reaction was poor and there were still many isomer impurities.

[0010] In summary, existing techniques for preparing pedamabetine II intermediates still suffer from a series of problems, including cumbersome procedures, low product yield and purity, high production costs, and long processing times. Therefore, it is necessary to develop a method for preparing pedamabetine II intermediates that is suitable for industrial production, has mild preparation conditions, is simple to operate, produces high product yield and chiral purity, and has low processing costs. Summary of the Invention

[0011] To address the aforementioned shortcomings in the existing technology, the main objective of this invention is to provide a method for preparing butyl (R)-2-(3-(benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxybutyrate, a pemabetate type II intermediate with a simple synthetic route, low cost, and high product yield and chiral purity.

[0012] The main technical solution of this invention is as follows:

[0013] A method for preparing a pemafibrate intermediate as shown in the following formula, the method comprising: dissolving intermediate PB-II in an anhydrous organic solvent, adding an acid-binding agent and intermediate PB-III, and reacting at a temperature controlled at ≥-5℃ to obtain intermediate PB-IV (intermediate of formula II):

[0014]

[0015] Preferably, in the above preparation method, the anhydrous organic solvent is selected from any one or a combination of anhydrous acetone and anhydrous tetrahydrofuran. The acid-binding agent is selected from any one or a combination of potassium carbonate, sodium carbonate, triethylamine, and potassium hydroxide. Preferably, the reaction solvent is anhydrous acetone, and the acid-binding agent is potassium carbonate.

[0016] In the preparation method, the temperature is controlled between -5 and 35°C, preferably between 10 and 30°C, and more preferably between 20 and 20°C.

[0017] In the preparation method, the reaction time is ≥1 hour, preferably ≥3 hours, and more preferably 3-5 hours.

[0018] Furthermore, in the above preparation method, the volume ratio of pemafid intermediate PB-II to anhydrous organic solvent is 1:(5-20); preferably 1:(5-20), more preferably 1:5.

[0019] Furthermore, the above preparation method also includes an extraction step, wherein the extraction solvent is selected from one or a combination of toluene, dichloromethane, toluene, and ethyl acetate, preferably toluene or dichloromethane. The number of extractions does not exceed three.

[0020] Furthermore, in the above preparation method, the potassium carbonate has a mesh size ≥ 100 mesh, preferably 100-400 mesh, and more preferably 200 mesh.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] (1) By optimizing the reaction solvent, especially by using a specific anhydrous organic solvent and its ratio with the reactants, and by combining it with a specific acid-binding agent, the present invention has surprisingly found that the content of isomer impurity (1) is greatly reduced, which further reduces the generation of subsequent conduction impurity Pemmerbet impurity (2). The removal of Pemmerbet impurity (2) is complicated and costly.

[0023] (2) The reaction conditions of this synthetic route are mild, which can simply and efficiently prepare the key intermediate formula II of pemabet, reduce the number of purification times of the finished product, improve the yield, and greatly reduce the production cost and cycle, making it very suitable for industrial production. Detailed Implementation

[0024] The present invention is further illustrated below by way of embodiments, but these embodiments are not intended to limit the invention to the scope of the embodiments described. All other embodiments obtained by those skilled in the art based on the embodiments of this application without inventive effort are within the scope of protection of this application.

[0025] Unless otherwise stated, all other reagents and raw materials used in this invention are commercially available.

[0026] The pemafid intermediate PB-IV (formula II intermediate) described in this invention can be prepared by the following reaction steps:

[0027]

[0028] Intermediate PB-II, reaction solvent, acid-binding agent, and intermediate PB-III are added to a reaction vessel to carry out a condensation reaction to obtain PB-IV (Pemabet type II intermediate).

[0029] In this invention, isomer impurities (1) were detected by HPLC, and the method is as follows: High performance liquid chromatograph: Dionex U3000, chromatographic column: DAICEL CHIRALCEL-OD-3R (150mm×4.6mm, 3μm), mobile phase A: 0.1% formic acid water; mobile phase B: 0.02% formic acid acetonitrile; diluent: acetonitrile. Sample concentration: 0.5mg / ml; detection wavelength: 250nm, column temperature: 35℃, flow rate: 0.5ml / min; injection volume: 10μl; injection plate temperature control: 8℃; elution gradient program:

[0030]

[0031]

[0032] Comparative Example 1

[0033] 10g of pemafibrate intermediate PB-II was added to the reaction flask, followed by 100mL of anhydrous tetrahydrofuran and potassium carbonate (40 mesh). The mixture was stirred for 1-2 hours, then intermediate PB-III was added. The temperature was controlled at 20±2℃, and the reaction was allowed to proceed for 6 hours until the reaction was essentially complete. Due to the high cost of the solvent, no post-treatment was performed, and isomers were not detected.

[0034] Comparative Example 2

[0035] Add 10g of PB-II intermediate, anhydrous toluene, and potassium carbonate (40 mesh) to the reaction flask. Stir for 1-2 hours, then add intermediate PB-III. Control the temperature to 20±2℃ and react for 6 hours. Take a sample for HPLC detection. A large amount of raw material remains, and there is basically no reaction.

[0036] Comparative Example 3

[0037] Add 10g of PB-II, anhydrous dichloromethane, and potassium carbonate (40 mesh) to a reaction flask. Stir for 1-2 hours, then add intermediate PB-III. Control the temperature to 20±2℃ and react for 6 hours. Take a sample for HPLC detection. A large amount of raw material remains, and there is basically no reaction.

[0038] Comparative Example 4

[0039] Add 10g of PB-II, anhydrous acetone, and potassium carbonate (200 mesh) to the reaction flask. Stir for 1-2 hours, then add intermediate PB-III. Control the temperature to 0±2℃ and react for 6 hours. A small amount of raw material is still not completely reacted.

[0040] Example 1

[0041] Add 10g of pemafibrate intermediate PB-II to the reaction flask, add 50mL of anhydrous acetone, add potassium carbonate (200 mesh), stir for 1-2h, add intermediate PB-III, control the temperature to 20±2℃, react for 4h, and the reaction is basically complete. Cool down to 0-10℃, quench with water, add toluene for extraction, separate the liquid, wash the organic phase with water, concentrate, and pemafibrate type II intermediate (PB-IV) is obtained, with a yield of 100.0% (amounts exceeding 100.0% are calculated as 100.0%, depending on the degree of concentration), and the isomer impurity (1) detection result is 0.56%.

[0042] Example 2

[0043] Add 10g of pemafibrate intermediate PB-II to the reaction flask, add 100mL of anhydrous acetone, add potassium carbonate (200 mesh), stir for 1-2h, add intermediate PB-III, control the temperature to 20±2℃, react for 4h, and the reaction is basically complete. Cool down to 0-10℃, quench with water, add toluene for extraction, separate the liquid, wash the organic phase with water, concentrate, and pemafibrate type II intermediate (PB-IV) is obtained, with a yield of 100.0% (amounts exceeding 100.0% are calculated as 100.0%, depending on the degree of concentration), and the isomer impurity (1) detection result is 0.94%.

[0044] Example 3

[0045] Add 10g of pemafibrate intermediate PB-II to the reaction flask, add 200mL of anhydrous acetone, add potassium carbonate (200 mesh), stir for 1-2h, add intermediate PB-III, control the temperature to 20±2℃, react for 6h, and the reaction is basically complete. Cool down to 0-10℃, quench with water, add toluene for extraction, separate the liquid, wash the organic phase with water, concentrate, and pemafibrate type II intermediate (PB-IV) is obtained, with a yield of 100.0% (amounts exceeding 100.0% are calculated as 100.0%, depending on the degree of concentration), and the isomer impurity (1) detection result is 2.48%.

[0046] Example 4

[0047] Add 10g of pemafibrate intermediate PB-II to the reaction flask, add 100mL of anhydrous acetone, add potassium carbonate (40 mesh), stir for 1-2h, add intermediate PB-III, control the temperature to 20±2℃, and react for 6h until the reaction is basically complete. Cool down to 0-10℃, quench with water, add toluene for extraction, separate the liquid, wash the organic phase with water, concentrate, and obtain pemafibrate type II intermediate (PB-IV) with a yield of 100.0% (amounts exceeding 100.0% are calculated as 100.0%, depending on the degree of concentration). The isomer impurity (1) test result is 2.37%.

[0048] Example 5

[0049] Add 10g of pemafibrate intermediate PB-II to the reaction flask, add 100mL of anhydrous acetone, add potassium carbonate (100 mesh), stir for 1-2h, add intermediate PB-III, control the temperature to 20±2℃, react for 4h, and the reaction is basically complete. Cool down to 0-10℃, quench with water, add toluene for extraction, separate the liquid, wash the organic phase with water, concentrate, and pemafibrate type II intermediate (PB-IV) is obtained, with a yield of 100.0% (amounts exceeding 100.0% are calculated as 100.0%, depending on the degree of concentration), and the isomer impurity (1) detection result is 0.94%.

[0050] Example 6

[0051] Add 10g of pemafid intermediate PB-II to the reaction flask, add 100mL of anhydrous acetone, add potassium carbonate (200 mesh), stir for 1-2h, add intermediate PB-III, control the temperature to 10±2℃, react for 6h, and the reaction is basically complete. Cool down to 0-10℃, quench with water, add toluene for extraction, separate the liquid, wash the organic phase with water, concentrate, and pemafid type II intermediate (PB-IV) is obtained, with a yield of 100.0% (amounts exceeding 100.0% are calculated as 100.0%, depending on the degree of concentration), and the isomer impurity (1) detection result is 1.52%.

[0052] Example 7

[0053] Add 10g of pemafibrate intermediate PB-II to a reaction flask, add 100mL of anhydrous acetone and potassium carbonate (200 mesh), stir for 1-2 hours, then add intermediate PB-III, control the temperature to 30±2℃, and react for 4 hours until the reaction is basically complete. Cool to 0-10℃, quench with water, extract with toluene, separate the liquid, wash the organic phase with water, and concentrate to obtain pemafibrate intermediate II (PB-IV), with a yield of 100.0% (yields exceeding 100.0% are considered 100.0%, depending on the degree of concentration), and the isomer detection result is 1.98%.

Claims

1. A method for preparing a pemafibrate intermediate as shown in the following formula, the method comprising: Intermediate PB-III was dissolved in an anhydrous organic solvent, and an acid-binding agent and intermediate PB-III were added. The reaction was carried out at a temperature controlled at ≥-5℃ to obtain intermediate PB-IV (intermediate of formula II).

2. The preparation method according to claim 1, characterized in that, The anhydrous organic solvent is selected from any one or a combination of anhydrous acetone, anhydrous tetrahydrofuran, and so on.

3. The preparation method according to claim 2, characterized in that, The acid-binding agent is selected from any one or a combination of potassium carbonate, sodium carbonate, triethylamine, and potassium hydroxide.

4. The preparation method according to claim 3, characterized in that, The temperature control temperature is -5 to 35°C, preferably 5 to 25°C, more preferably 20 ± 2°C; preferably, the reaction is carried out for ≥1 hour, more preferably ≥3 hours, and more preferably 3 to 5 hours.

5. The preparation method according to claim 4, characterized in that, The volume ratio of the pemafid intermediate PB-II to the anhydrous organic solvent is 1:(5-20); preferably 1:

5.

6. The preparation method according to claim 5, characterized in that, The preparation method further includes an extraction step, wherein the extraction solvent is selected from one or a combination of toluene, dichloromethane, toluene, and ethyl acetate.

7. The preparation method according to any one of claims 3-6, characterized in that, The potassium carbonate has a mesh size ≥ 100 mesh; preferably, it has a mesh size of 100-400 mesh.

8. A method for preparing a pemafibrate intermediate as shown in the following formula, the method comprising: Intermediate PB-III was dissolved in anhydrous acetone, and potassium carbonate (an acid-binding agent) and intermediate PB-III were added. The reaction was carried out at a controlled temperature of 5-25℃ to obtain intermediate PB-IV (intermediate of formula II). The volume ratio of pemafid intermediate PB-II to anhydrous organic solvent is 1:(5-20), and the potassium carbonate has a mesh size ≥100 mesh.

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