A method for purifying a pemafibrate intermediate

Abstract

The application provides a refining method of pemafibrate intermediate, in which, in the post-treatment process, silica gel stirring purification and extraction and suction filtration purification are added to replace twice silica gel column separation and purification, the post-treatment process is simple, the yield and purity of the product are higher, the yield and purity are not less than 97%, the whole preparation method is simple, the problem of a large amount of solid waste and waste liquid inevitably generated due to twice silica gel column separation and purification is solved, the production cost can be greatly reduced, and the method is suitable for industrial large-scale production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of drug synthesis, and particularly relates to a refining method of a pemafibrate intermediate, wherein the chemical name of the pemafibrate intermediate is (R)-2-(3-(benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxybutyl butylate. BACKGROUND

[0002] Pemafibrate is a new, highly selective PPAR alpha modulator developed by Kowa Company, and its structural formula is as follows. The drug binds to PPAR alpha and regulates the expression of genes involved in lipid metabolism, thereby reducing the triglyceride (TG) level in the blood and increasing the high-density lipoprotein cholesterol (HDL-C) level. Related studies have shown that pemafibrate has a significant effect on reducing fasting serum triglycerides, can enhance the effect of HDL-C, and this effect is persistent. Previously, this drug has been approved in Japan for the treatment of hyperlipidemia (including familial hyperlipidemia). In July 2017, pemafibrate ordinary tablets were granted global first marketing approval by the Japanese Ministry of Health, Labour and Welfare. On June 26, 2023, the new dosage form of pemafibrate sustained-release tablets was granted global first marketing approval by the PMDA in Japan for the treatment of hyperlipidemia (including familial hyperlipidemia). Compared with pemafibrate tablets, which need to be taken twice a day, the sustained-release tablets only need to be taken once a day. Pemafibrate is the first PPAR alpha modulator to be granted marketing approval worldwide, and can improve the problem of low serum triglyceride levels by regulating hepatic lipid metabolism. Its safety is superior to other betaine lipid-lowering drugs. According to the ClinicalTrials clinical trial registration website, in addition to hyperlipidemia, pemafibrate has three indications (non-alcoholic fatty liver, type 2 diabetes, and hypercholesterolemia) in the clinical research stage.

[0003]

[0004] At present, the preparation of pemafibrate generally adopts the preparation method disclosed in the original research patent, and its synthetic route is as follows:

[0005]

[0006] The preparation method of the intermediate 3 in the original research patent is relatively complex. Firstly, the side chain compound generated by the compound SMD and trifluoromethanesulfonic anhydride needs to be purified by column in the original research patent. Since the state of the side chain compound is oily, it is not easy to purify and has a great influence on the next step, so column purification is carried out in the original research patent. Secondly, the intermediate 3 generated by the reaction of the side chain compound and the intermediate 2 is also purified by column to obtain the intermediate 3 product with high purity, that is, (R)-2-(3-(benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxy butyl butyrate.

[0007] The step of preparing the intermediate 3 in the original research patent has obvious defects. When the compound SMD and trifluoromethanesulfonic anhydride are prepared into a side chain compound, it cannot be monitored by a point plate. In the original research patent, it is recorded that dichloromethane is used to flush the column, which needs a large amount of solvent and is very difficult to operate. There is basically no absorption, so the fractions can only be collected blindly, which is time-consuming and laborious. In addition, a large amount of silica gel is needed for silica gel column purification, and the silica gel cannot be reused, which will generate a large amount of solid waste. Moreover, the intermediate 3 generated by the reaction of the side chain compound and the intermediate 2 is purified by column with n-heptane and ethyl acetate as eluent in a volume ratio of 2:1. The column is a glass column, and the packing material is silica gel with a particle size of 200-300. The whole column purification time is about 3h, and it is found that the amount of eluent is about 1000 times. At present, the laboratory can only accept about 100g for column purification, which makes this step not suitable for large-scale production. In addition, column purification is rarely used in factories, which further limits its industrial application. SUMMARY

[0008] The purpose of the present application is to provide a method for purifying a pemafibrate intermediate based on the prior art. In the post-treatment process, silica gel stirring purification, extraction and filtration purification are used to replace the two silica gel column purifications for separation and purification. The post-treatment process is simple, the yield and purity of the product are high, the yield and purity are not less than 95%, the whole preparation method is simple, the problem of a large amount of solid waste and waste liquid caused by two silica gel column purifications for separation and purification cannot be avoided, the production cost can be greatly reduced, and it is suitable for large-scale industrial production. The chemical name of the pemafibrate intermediate is (R)-2-(3-(benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxy butyl butyrate, and its structural formula is as follows:

[0009]

[0010] The technical scheme of the present application is as follows:

[0011] A method for purifying a pemafibrate intermediate, comprising the following steps:

[0012] (1) Compound SMD is dissolved in dichloromethane, pyridine is added at -5-5℃, trifluoromethanesulfonic anhydride is added dropwise into the obtained mixture during stirring, after the dropwise addition is completed, the stirring reaction is continued, after the reaction is completed, silica gel is added into the obtained reaction solution, the stirring time is 10-60 min, suction filtration is performed, and rotary evaporation is performed to obtain compound SME, which is dissolved in acetonitrile to prepare an acetonitrile solution containing compound SME;

[0013] (2) Intermediate 2, potassium carbonate and acetonitrile are uniformly mixed, the acetonitrile solution containing compound SME prepared in step (1) is added into the obtained mixture, and the stirring reaction is performed at room temperature, after the reaction is completed, water is added into the obtained reaction solution to quench, extraction, washing, drying, suction filtration and concentration are performed to obtain intermediate 3; the specific synthesis route is as follows:

[0014] For the present application, in step (1), the side chain compound SME prepared from compound SMD and trifluoromethanesulfonic anhydride is purified by stirring with silica gel in the post-treatment process, which solves the problems in the prior art, for example, when the product compound SME is separated and purified by column chromatography, the product compound SME cannot be monitored by TLC and HPLC because it has no ultraviolet absorption, a large amount of eluent needs to be used for column washing, otherwise the yield of the product will be reduced; in addition, too much silica gel is filled in the adsorption column, which may cause adsorption decomposition, also leading to a reduction in the yield of the product. When column chromatography separation is performed in the post-treatment process, a large amount of silica gel needs to be filled in the adsorption column, the amount of silica gel used is high, and the silica gel cannot be reused, which will generate a large amount of solid waste in the expansion of production. In the process of experimental operation, silica gel is inhaled into the human body, and a large amount of silica gel used will affect human health. In addition, the amount of eluent used is also high, and a large amount of waste liquid will be generated in the expansion of production. At present, the laboratory can only accept about 100 g of crude product for column purification, and the column separation method is rarely used in factories, which further limits its industrial application.

[0015] In a preferred embodiment, the mesh number of the silica gel is 200-300.

[0016] For the present application, in step (1), in the post-treatment process, the stirring purification is performed by adding silica gel, and the mass ratio of compound SMD to silica gel is 1:5-15, which can be but is not limited to 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14 or 1:15, in a preferred embodiment, the mass ratio of compound SMD to silica gel is 1:8-12, and further preferably, the mass ratio of compound SMD to silica gel is 1:10.

[0017] In step (1), silica gel is added to the resulting reaction solution, and the stirring time is 30-60 min, which can be but is not limited to 30 min, 35 min, 40 min, 45 min, 50 min, 55 min or 60 min, and is preferably 30 min.

[0018] In a preferred embodiment, in step (1), pyridine is added at 0°C.

[0019] In a preferred embodiment, in step (1), the molar ratio of compound SMD to trifluoromethanesulfonic anhydride is 1:0.8-1.2, which can be but is not limited to 1:0.8, 1:0.9, 1:0.95, 1:1.0, 1:1.05, 1:1.1 or 1:1.2, and is preferably 1:1.0.

[0020] In a preferred embodiment, in step (1), the mass ratio of compound SMD to pyridine is 1:0.3-0.7, which can be but is not limited to 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.52, 1:0.54, 1:0.5, 1:0.6 or 1:0.7, and is preferably 1:0.52.

[0021] In a preferred embodiment, in step (2), the molar ratio of compound SMD to intermediate 2 is 1:0.5-0.9, which can be but is not limited to 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:8.5 or 1:0.9, and is preferably 1:0.7.

[0022] In a preferred embodiment, in step (2), the mass ratio of compound SMD to potassium carbonate is 1:0.6-1.2, which can be but is not limited to 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:0.95, 1:1.0, 1:1.1 or 1:1.2, and is preferably 1:0.9.

[0023] In a preferred embodiment, in step (2), the reaction time is 6-12 hours, and is preferably 8 hours.

[0024] In a preferred embodiment, in step (2), water is added to the resulting reaction solution to quench, extracted with dichloromethane, washed with brine, dried over sodium sulfate, concentrated by suction filtration, to obtain intermediate 3.

[0025] For the present application, in step (2), the post-treatment process is simple, extraction is carried out with dichloromethane, salt water washing, sodium sulfate drying, and concentration by suction filtration, so that the intermediate 3 is obtained, and the product intermediate 3 does not need to be separated and purified by silica gel column in the original patent, the post-treatment process is complicated, time-consuming, and when the production is expanded, a large amount of solid waste and waste liquid is inevitably produced, resulting in a substantial increase in production cost, which further limits its industrial application.

[0026] The technical scheme of the present application has the following advantages:

[0027] The present application provides a refining method for a pemafibrate intermediate, which replaces the separation and purification by silica gel column twice with the addition of silica gel stirring purification and extraction and suction filtration purification in the post-treatment process, the post-treatment process is simple, the yield and purity of the product are higher, the yield and purity are not less than 95%, the whole preparation method is simple, the problem of a large amount of solid waste and waste liquid being inevitably produced due to the separation and purification by silica gel column twice can be solved, the production cost can be substantially reduced, and the method is suitable for industrial large-scale production. DETAILED DESCRIPTION

[0028] The present application is further explained and described by specific examples and comparative examples, but this is not a limitation of the present application. Those skilled in the art can make any modification, equivalent replacement or improvement according to the basic idea of the present application, which shall be included in the scope of the present application.

[0029] Example 1

[0030] A refining method for a pemafibrate intermediate (i.e. intermediate 3), which comprises the following steps:

[0031] (1) 0.3 g of compound SMD (i.e. (S)-2-hydroxybutyl butyl ester) and 5 ml of dichloromethane are sequentially added to a 50 ml three-necked bottle, and after stirring to dissolve, the temperature is lowered to 0℃, 0.155 g of pyridine is added, and during the stirring process, 0.528 g of trifluoromethanesulfonic anhydride is added dropwise to the obtained mixture, after the dropwise addition is completed, the stirring reaction is continued for 30 min, after the reaction is completed, 3 g of 200-300 mesh silica gel is added to the obtained reaction solution, the stirring time is 30 min, suction filtration, and rotary drying, so that compound SME (i.e. butyl (S)-2-trifluoromethanesulfonyl hydroxybutyl ester) is obtained, which is dissolved in 10 ml of acetonitrile to prepare an acetonitrile solution containing compound SME;

[0032] (2) 0.53 g of intermediate 2 was added to 10 ml of acetonitrile, 0.272 g of potassium carbonate was added, and the mixture was stirred uniformly. Then, the acetonitrile solution containing compound SME prepared in step (1) was added to the mixture, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, water was added to quench the reaction, and dichloromethane was used for extraction. The obtained solution was washed with brine, dried over sodium sulfate, and concentrated by filtration to obtain a colorless oil, which was intermediate 3 ((R)-2-(3-(benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxybutyric acid butyl ester) with a yield of about 100% and a purity of 97.82%. The specific synthesis route is as follows:

[0033]

[0034] Example 2

[0035] A production process of a pemafibrate intermediate (i.e., intermediate 3) includes the following steps:

[0036] (1) 3.6 kg of compound SMD (i.e., (S)-2-hydroxybutyric acid n-butyl ester) and 15 L of dichloromethane were sequentially added to a 50 L reaction kettle, and the mixture was stirred until dissolved. Then, the temperature was lowered to 0°C, 2.9 kg of pyridine was added, and 7.64 kg of trifluoromethanesulfonic anhydride was added dropwise to the mixture during stirring. After the dropwise addition was completed, the stirring was continued for 30 min. After the reaction was completed, 36.0 kg of 200-300 mesh silica gel was added to the reaction solution, and the mixture was stirred for 30 min. Then, the mixture was filtered and dried to obtain compound SME (i.e., n-butyl (S)-2-trifluoromethanesulfonyloxybutyric acid ester), which was dissolved in 10 L of acetonitrile to prepare an acetonitrile solution containing compound SME;

[0037] (2) 5.3 kg of intermediate 2 was added to 20 L of acetonitrile, 4.75 kg of potassium carbonate was added, and the mixture was stirred uniformly. Then, the acetonitrile solution containing compound SME prepared in step (1) was added to the mixture, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, water was added to quench the reaction, and dichloromethane was used for extraction. The obtained solution was washed with brine, dried over sodium sulfate, centrifuged, and concentrated to obtain a colorless oil, which was intermediate 3 ((R)-2-(3-(benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxybutyric acid butyl ester) with a yield of about 100% and a purity of 97.75%.

[0038] Example 3

[0039] (1) Into a 50ml three-necked flask, compound SMD 0.3g (i.e. (S)-2-hydroxybutyric acid n-butyl ester) and dichloromethane 5ml were added in turn, after stirring to dissolution, the temperature was lowered to 0°C, pyridine 0.155g was added, during stirring, trifluoromethanesulfonic anhydride 0.528g was added dropwise to the resulting mixture, after dropwise addition was completed, stirring was continued for 30min, after the reaction was completed, 2.7g (SMD: silica gel = 1:9) 200-300 mesh silica gel was added to the resulting reaction solution, stirring was continued for 30min, suction filtration, rotary evaporation, to obtain compound SME (i.e. n-butyl (S)-2-trifluoromethanesulfonyl hydroxybutyrate), which was dissolved in 10ml acetonitrile to prepare an acetonitrile solution containing compound SME;

[0040] (2) 0.53g of intermediate 2 was added to 10ml acetonitrile, 0.272g of potassium carbonate was added, after stirring, the acetonitrile solution containing compound SME prepared in step (1) was added to the resulting mixture, stirring was carried out at room temperature for 8h, after the reaction was completed, water was added to quench the reaction, dichloromethane was used for extraction, salt water was used for washing, sodium sulfate was used for drying, suction filtration, concentration, to obtain colorless oil, which was intermediate 3 ((R)-2-(3-(benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxybutyric acid butyl ester), the yield was about 100%, and the purity was 97.05%.

[0041] Comparative Example 1 (original research)

[0042] (1) Into a 50ml three-necked flask, compound SMD 0.3g (i.e. (S)-2-hydroxybutyric acid n-butyl ester) and dichloromethane 5ml were added in turn, after stirring to dissolution, the temperature was lowered to 0°C, pyridine 0.155g was added, during stirring, trifluoromethanesulfonic anhydride 0.528g was added dropwise to the resulting mixture, after dropwise addition was completed, stirring was continued for 30min, after the reaction was completed, water was added for washing, the organic phase was collected, rotary evaporation, the resulting concentrate was subjected to column chromatography separation using an adsorption column filled with 30g 200-300 mesh silica gel, dichloromethane was used as the eluent, the amount was about 300ml, to obtain purified compound SME (i.e. n-butyl (S)-2-trifluoromethanesulfonyl hydroxybutyrate), which was dissolved in 10ml acetonitrile to prepare an acetonitrile solution containing compound SME;

[0043] (2) 0.53 g of intermediate 2 was added to 10 ml of acetonitrile, and 0.272 g of potassium carbonate was added, and the mixture was stirred to obtain a uniform mixture. Then, the acetonitrile solution containing compound SME prepared in step (1) was added to the mixture, and the reaction was stirred at room temperature for 14 hours. After the reaction was completed, water was added to quench the reaction, and dichloromethane was added for extraction. The organic layer was washed with brine, dried over sodium sulfate, and concentrated by filtration. The concentrated product was separated by column chromatography using a silica gel column filled with 30 g of silica gel with a particle size of 200-300 mesh. The column was eluted with 300 ml of n-heptane and ethyl acetate (2:1 by volume), and a colorless oil was obtained, which was intermediate 3 ((R)-2-(3-(benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxybutyric acid butyl ester), with a yield of about 95% and a purity of 93.64%.

[0044] For the present comparative example, the yield was 95%, which was relatively high, but the post-treatment process was too cumbersome and required two silica gel column separations for purification. In step (1), the product compound SME could not be monitored by TLC and HPLC because it did not have ultraviolet absorption, and a large amount of eluent was required for column washing, otherwise the yield of the product would be reduced. In addition, the silica gel column was filled with too much silica gel, which could cause adsorption decomposition and also reduce the yield of the product. Only 0.3 g of the reaction raw material compound SMD was used, and the silica gel column needed to be filled with 30 g of silica gel with a particle size of 200-300 mesh for column chromatography separation during the post-treatment process. The amount of silica gel used was 100 times that of the reaction raw material compound SMD, and the amount of silica gel used was high. Moreover, the silica gel could not be reused, and a large amount of solid waste would be generated during large-scale production. During the experimental operation, silica gel was inhaled into the human body, and the use of a large amount of silica gel would affect human health. In addition, 300 ml of dichloromethane was also required as the eluent, and a large amount of waste liquid would be generated during large-scale production. Currently, a laboratory can only accept about 50 g of crude product for column purification, and column purification separation methods are rarely used in factories, further limiting their industrial application.

[0045] In step (2), the product intermediate 3 also required silica gel column separation for purification, and the silica gel column needed to be filled with 30 g of silica gel with a particle size of 200-300 mesh for column chromatography separation, and 300 ml of n-heptane and ethyl acetate (2:1 by volume) was required as the eluent. During large-scale production, a large amount of solid waste and waste liquid was inevitably generated, the production cost was significantly increased, and the use of column purification separation methods further limited their industrial application.

[0046] Comparative Example 2

[0047] (1) Into a 50ml three-necked flask, compound SMD 0.3g (i.e. (S)-2-hydroxybutyric acid n-butyl ester) and dichloromethane 5ml were added in turn, after stirring to dissolution, the temperature was lowered to 0°C, pyridine 0.155g was added, and trifluoromethanesulfonic anhydride 0.528g was added dropwise into the resulting mixture during stirring, after dropwise addition was completed, the stirring reaction was continued for 30min, after the reaction was completed, water was added for quenching, the organic phase was collected, and rotary evaporation was performed to obtain compound SME (i.e. n-butyl (S)-2-trifluoromethanesulfonyloxybutyrate), which was dissolved in 10ml acetonitrile to prepare an acetonitrile solution containing compound SME;

[0048] (2) 0.53g of intermediate 2 was added into 10ml acetonitrile, and then 0.272g of potassium carbonate was added, after stirring was performed, the acetonitrile solution containing compound SME prepared in step (1) was added into the resulting mixture, and stirring reaction was performed at room temperature for 14h, after the reaction was completed, water was added into the resulting reaction solution for quenching, dichloromethane was used for extraction, and the organic phase was washed with brine, dried over sodium sulfate, and concentrated by filtration to obtain colorless oil, which was intermediate 3 ((R)-2-(3-(benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxybutyric acid butyl ester) with a yield of about 90% and a purity of less than 50%, i.e. the purity was too low.

[0049] For the present comparative example, in the preparation of compound SME and intermediate 3 in step (1), no silica gel column separation and purification was performed during the post-treatment, the post-treatment process was relatively simple, the yield of the obtained intermediate 3 was about 90%, but the purity was less than 50%, i.e. the purity was too low, and the impurity content was relatively high, which was not conducive to the smooth progress of the subsequent reaction.

[0050] The yield and purity of the product intermediate 3 in the examples and comparative examples were determined by using the HPLC detection method, and the results are shown in Table 1.

[0051] The chromatographic conditions of the HPLC detection method are as follows:

[0052]

[0053]

[0054] Table 1 Yield, purity and impurity content of the product intermediate 3 in the examples and comparative examples

[0055]

[0056] As shown in Table 1, compared with Comparative Examples 1 and 2, the yield and purity of the product intermediate 3 obtained in the present application Examples 1-3 are higher, the content of related substances is lower, in the post-treatment process, the addition of silica gel stirring purification and extraction and filtration purification are used instead of twice silica gel column separation and purification, the post-treatment process is simple, the yield and purity of the product are higher, the yield and purity are not less than 95%, the whole preparation method is simple, the problem of a large amount of solid waste and waste liquid inevitably generated due to twice silica gel column separation and purification is solved, the production cost can be greatly reduced, and it is suitable for industrial large-scale production.

[0057] The above examples are only used to illustrate the technical solutions of the present application, but not limit it; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that the technical solutions recorded in the foregoing examples can still be modified, or some technical features can be replaced by equivalents; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for purifying a pemafibrate intermediate, characterized by, It comprises the following steps: (1) dissolve compound SMD in dichloromethane, add pyridine under the condition of-5~5℃, drop trifluoromethanesulfonic anhydride into the obtained mixture during stirring, continue stirring after dropping, wait for the reaction to end, add silica gel into the obtained reaction solution, stirring time is 10-60min, suction filtration, spin dry, dissolve in acetonitrile to prepare acetonitrile solution containing compound SME; wherein, the mesh number of silica gel is 200-300; the mass ratio of compound SMD to silica gel is 1:8-12; (2) mix intermediate 2, potassium carbonate and acetonitrile uniformly, add the acetonitrile solution containing compound SME prepared in step (1) into the obtained mixture, carry out stirring reaction at room temperature, add water into the obtained reaction solution to quench, extract, wash, dry, suction filtration and concentrate, to obtain intermediate 3; the specific synthesis route is as follows: 。 2. The method of purifying a pemafibrate intermediate according to claim 1, wherein, In step (1), the mass ratio of compound SMD to silica gel is 1:

10.

3. The method of purifying a pemafibrate intermediate according to claim 1, wherein, In step (1), pyridine is added under the condition of 0℃; in step (1), silica gel is added into the obtained reaction solution, and the stirring time is 30-60min.

4. The method of purification of a pemafibrate intermediate according to claim 3, characterized in that, In step (1), silica gel is added into the obtained reaction solution, and the stirring time is 30min.

5. The method of purifying a pemafibrate intermediate according to claim 1, wherein, In step (1), the molar ratio of compound SMD to trifluoromethanesulfonic anhydride is 1:0.8-1.

2.

6. The method of purifying a pemafibrate intermediate according to claim 5, wherein, In step (1), the molar ratio of compound SMD to trifluoromethanesulfonic anhydride is 1:1.

0.

7. The method of purifying a pemafibrate intermediate according to claim 1, wherein, In step (1), the mass ratio of compound SMD to pyridine is 1:0.3-0.

7.

8. The method of purifying a pemafibrate intermediate according to claim 7, wherein, In step (1), the mass ratio of compound SMD to pyridine is 1:0.

52.

9. The method of purifying a pemafibrate intermediate according to claim 1, wherein, In step (2), the molar ratio of compound SMD to intermediate 2 is 1:0.5-0.

9.

10. The method of purification of a pemafibrate intermediate according to claim 9, characterized in that, In step (2), the molar ratio of compound SMD to intermediate 2 is 1:0.

7.

11. The method of purifying a pemafibrate intermediate according to claim 1, wherein, In step (2), the mass ratio of compound SMD to potassium carbonate is 1:0.6-1.

2.

12. The method of purification of a pemafibrate intermediate according to claim 11, characterized in that, In step (2), the mass ratio of compound SMD to potassium carbonate is 1:0.

9.

13. The method of purifying a pemafibrate intermediate according to claim 1, wherein, In step (2), the reaction time is 6-12 hours.

14. The method of purification of a pemafibrate intermediate according to claim 13, characterized in that, In step (2), the reaction time is 8 hours.

15. The method of purifying a pemafibrate intermediate according to claim 1, wherein, In step (2), add water into the obtained reaction solution to quench, extract with dichloromethane, wash with salt water, dry with sodium sulfate, suction filtration and concentrate, to obtain intermediate 3.

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