A method for preparing pemafibrate

Abstract

The application discloses a preparation method of pemafibrate, which comprises the following steps: (1) reacting a compound SMA and a compound C to obtain an intermediate 1; (2) reacting the intermediate 1 with a compound D, and then performing sodium borohydride reduction to obtain an intermediate 2; (3) reacting the intermediate 2 with a compound E derivative to obtain an intermediate 3; and (4) performing hydrolysis reaction on the intermediate 3 to obtain the pemafibrate. According to the preparation method of the pemafibrate, the SMA and the compound C are used as starting materials, and the reaction temperature, the reaction time and the material ratio are strictly controlled, so that the yield and the purity of the product are high, the by-products are few, the post-treatment process is simple, column chromatography purification is not needed, and the preparation of subsequent high-quality products and impurity control are facilitated.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a synthesis method of Pemafibrate, wherein the chemical name of Pemafibrate is (2R)-2-[-3(-{1,3-benzoxazol-2-yl[3(-4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butyric acid. BACKGROUND

[0002] Pemafibrate is a new, highly selective PPAR alpha modulator developed by Kowa Company. This drug binds to PPAR alpha and regulates the expression of genes involved in lipid metabolism, thereby reducing the level of triglycerides (TG) in the blood and increasing the level of high-density lipoprotein cholesterol (HDL-C). 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. Pemafibrate ordinary tablets are used for the treatment of hyperlipidemia (including familial hyperlipidemia). Compared with Pemafibrate tablets, which need to be taken twice a day, sustained-release tablets only need to be taken once a day. Pemafibrate is the first PPAR alpha modulator to obtain market approval worldwide, and can improve the problem of low serum triglyceride levels by regulating hepatic lipid metabolism, and its safety is superior to other betaine lipid-lowering drugs.

[0003]

[0004] At present, patent CN100425594C reports several synthesis routes, in which several starting materials of the key fragments are derived from the structure of several decomposition fragments, as follows:

[0005]

[0006] Fragment decomposition:

[0007]

[0008] Among them, various synthesis routes have been protected.

[0009] In addition, the preparation method of EP1852426A1 (European patent) is A+B+C+D+E, and column chromatography purification is used in steps 1 and the following steps, and the synthesis route is as follows:

[0010]

[0011] The reaction of the intermediate 2 in step three and the compound C in the patent is extremely easy to form a double-substituted impurity X (more than 1%), and when the intermediate 3 in step four and the compound D react, the coupling side reaction of the hydroxyl and halogen groups is inevitable, causing the residual impurity Z which is difficult to remove, and is brought into the subsequent step, in the case that the intermediate 5 is an oil (not easy to refine and purify), which directly causes the low purity of the crude product and affects the quality, wherein the structural formula of the impurity X and the impurity Z is as follows. Therefore, the purification by column chromatography is needed in the whole preparation method except step 1, so as to improve the purity of the crude product, and the problem of a large amount of solid waste and waste liquid inevitably generated in the separation and purification by silica gel column chromatography for many times needs to be solved, the whole post-treatment process is complex and time-consuming, the production cost is high, and it is not suitable for industrial large-scale production.

[0012] SUMMARY

[0013] The purpose of the present application is to provide a new preparation method of pemafibrate on the basis of the prior art.

[0014] The purpose of the present application can be achieved by the following measures:

[0015] A preparation method of pemafibrate comprises the following steps:

[0016] (1) the reaction of the compound SMA and the compound C to obtain the intermediate 1;

[0017]

[0018] (2) the reaction of the intermediate 1 and the compound D, and then the reduction by potassium borohydride to obtain the intermediate 2;

[0019]

[0020] (3) the reaction of the intermediate 2 and the compound E derivative to obtain the intermediate 3;

[0021]

[0022] (4) the hydrolysis reaction of the intermediate 3 to obtain pemafibrate;

[0023]

[0024] The preparation method of the present application has the following synthesis route:

[0025]

[0026] In step (1), the molar ratio of SMA and compound C is 1:1.1-1:2, preferably 1:1.1-1.5, and more preferably 1:1.2.

[0027] In step (1), the reaction temperature is 20-80°C, and preferably 50-60°C.

[0028] In step (1), the reaction time is 20-40 hours, and preferably 30 hours.

[0029] In step (1), SMA can be directly purchased, which is cheap and can significantly shorten the reaction route. In addition, in step (1), direct coupling with compound C halide can avoid the by-products of the original research literature, and does not need to add a protection and deprotection process, which ensures the purity of the product and shortens the reaction route, and provides a good reference for industrial production.

[0030] In step (2), the reaction temperature of intermediate 1 and compound D is 10-30°C, preferably 15-25°C, and more preferably 20°C; and the reaction time is 20-40 hours, and preferably 30 hours.

[0031] In step (2), the molar ratio of intermediate 1 and compound D is 1:1.1-1:2, preferably 1:1.1-1.5, and more preferably 1:1.2.

[0032] In step (3), compound E derivative can be prepared by reacting compound E with trifluoromethanesulfonic anhydride;

[0033]

[0034] In step (3), the reaction conditions of compound E and trifluoromethanesulfonic anhydride are as follows: the reaction temperature is -5-5°C, and preferably 0°C; and the molar ratio of compound E and trifluoromethanesulfonic anhydride is 1:0.8-1.2, and preferably 1:1.0.

[0035] In step (3), the reaction temperature of intermediate 2 and compound E derivative is 10-30°C, preferably 15-25°C, and more preferably 20°C; and the reaction time is 10-20 hours, and preferably 14 hours.

[0036] Further, the molar ratio of intermediate 2 and compound E is 1:0.5-0.9, and preferably 1:0.7.

[0037] In step (4), the hydrolysis reaction conditions are as follows: the reaction temperature is 10-30℃, preferably 15-25℃, and more preferably 20℃; and the reaction time is 1-4 hours, and the base for hydrolysis is sodium hydroxide.

[0038] The technical solution of the present application has the following advantages:

[0039] The present application provides a new preparation method of pemafibrate, which uses SMA and compound C as starting materials, and strictly controls the reaction temperature, reaction time and material ratio. The product has high yield and purity, less by-products, simple post-treatment process, no need for column chromatography purification, and is beneficial to the preparation of subsequent high-quality products and impurity control. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 is the HPLC chart of intermediate 1 obtained in Example 1 in the present application;

[0041] Figure 2 is the HPLC chart of pemafibrate intermediate 1 obtained in Comparative Example 1 in the present application;

[0042] Figure 3 is the HPLC chart of intermediate 2 obtained in Example 1 in the present application;

[0043] Figure 4 is the HPLC chart of pemafibrate intermediate 2 obtained in Comparative Example 1 in the present application

[0044] Figure 5 is the HPLC chart of pemafibrate obtained in Example 1 in the present application;

[0045] Figure 6 is the HPLC chart of pemafibrate obtained in Comparative Example 1 in the present application;

[0046] Figure 7 is the MS confirmation chart of intermediate 1 N-(3-(4-methoxyphenoxy)propyl)benzo[d]oxazol-2-amine of Example 1 in the present application. DETAILED DESCRIPTION

[0047] The present application is further explained and described by specific examples and comparative examples, but this is not a limitation of the present application. Any modification, equivalent replacement or improvement according to the basic idea of the present application can be made by those skilled in the art, and should be included in the scope of the present application.

[0048] Example 1: Preparation method of pemafibrate, the synthesis route is as follows:

[0049]

[0050] a) Preparation of Pemafibrate intermediate 1 (N-(3-(4-methoxyphenoxy)propyl)benzo[d]oxazol-2-amine)

[0051] Into a 200ml three-necked flask was added 10.00g of SMA, DMF 40ml, and triethylamine 3.87g was added at 15-25°C, and the solid was completely dissolved. The temperature was raised to 50°C, and 2-chlorobenzoxazole (compound C) 10.1g was added dropwise to the resulting mixture, and the temperature was controlled at 50-60°C for 30 hours. The resulting reaction solution was cooled to room temperature, and water 40ml, ethyl acetate 100ml, and hydrochloric acid were added to adjust the pH to 3-4. The impurities were extracted, and the extraction was repeated once. Ethyl acetate 100ml was added to the resulting aqueous phase, and sodium hydroxide was added to adjust the pH to 8-10. The product was extracted, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a block, and recrystallized from isopropyl alcohol 50ml to obtain intermediate 1 solid 15.03g, purity 99%, yield 91.33%. The MS for confirming the structure thereof is shown in Figure 7 , the molecular weight of the compound is 298, the positive ion is 299, and the negative ion is 297, and it is confirmed to be intermediate 1. The related chromatogram is shown in Figure 1 .

[0052] b) Preparation of Pemafibrate intermediate 2

[0053] Into a 500ml three-necked flask was added 15.00g of intermediate 1 and methanol 50ml, and stirred and dissolved at 15-25°C. Compound D 7.37g was dissolved in 50ml of methanol, and added dropwise to the above mixture at 20°C for 10 minutes. During stirring, sodium borohydride aqueous solution (2.1g dissolved in 100ml of water) was added dropwise to the resulting reaction solution at 20°C for 20 minutes. After completion of the addition, it was stirred at 20°C for 12 hours. It was filtered, washed with water, and dried at 80°C under vacuum for 5 hours to obtain yellow crystals 19.1g, purity 99.52%, yield 93.43%. The related chromatogram is shown in Figure 3 .

[0054] c) Preparation of Pemafibrate intermediate 3

[0055] Preparation of n-butyl (S)-2-trifluoromethanesulfonyloxybutyrate (Compound E derivative): Into a 50 ml three-necked flask, n-butyl (S)-2-hydroxybutyrate (Compound E) 0.3 g, dichloromethane 5 ml were sequentially added, and the mixture was stirred to dissolve and cooled to 0°C. Then pyridine 0.155 g was added, and trifluoromethanesulfonic anhydride 0.528 g was added dropwise under the condition of 0°C. After the dropwise addition was completed, the mixture was stirred for 30 minutes. After the reaction was completed, the mixture was washed with water, and the organic phase was collected and dried by rotary evaporation. The obtained concentrate was subjected to chromatographic separation using an adsorption column packed with 30 g of silica gel having a particle size of 200-300 mesh, and eluted with dichloromethane in an amount of 300 ml. Thus, Compound E derivative (n-butyl (S)-2-trifluoromethanesulfonyloxybutyrate) was obtained, which was dissolved in 10 ml of acetonitrile.

[0056] Into a 50 ml three-necked flask, n-butyl (S)-2-hydroxybutyrate (Compound E) 0.3 g, dichloromethane 5 ml were sequentially added, and the mixture was stirred to dissolve and cooled to 0°C. Then pyridine 0.155 g was added, and trifluoromethanesulfonic anhydride 0.528 g was added dropwise under the condition of 0°C. After the dropwise addition was completed, the mixture was stirred for 30 minutes. After the reaction was completed, the mixture was washed with water, and the organic phase was collected and dried by rotary evaporation. The obtained concentrate was subjected to chromatographic separation using an adsorption column packed with 30 g of silica gel having a particle size of 200-300 mesh, and eluted with dichloromethane in an amount of 300 ml. Thus, Compound E derivative (n-butyl (S)-2-trifluoromethanesulfonyloxybutyrate) was obtained, which was dissolved in 10 ml of acetonitrile.

[0057] d) Preparation of pemafibrate:

[0058] Into a 50 ml three-necked flask, n-butyl (S)-2-hydroxybutyrate (Compound E) 0.3 g, dichloromethane 5 ml were sequentially added, and the mixture was stirred to dissolve and cooled to 0°C. Then pyridine 0.155 g was added, and trifluoromethanesulfonic anhydride 0.528 g was added dropwise under the condition of 0°C. After the dropwise addition was completed, the mixture was stirred for 30 minutes. After the reaction was completed, the mixture was washed with water, and the organic phase was collected and dried by rotary evaporation. The obtained concentrate was subjected to chromatographic separation using an adsorption column packed with 30 g of silica gel having a particle size of 200-300 mesh, and eluted with dichloromethane in an amount of 300 ml. Thus, Compound E derivative (n-butyl (S)-2-trifluoromethanesulfonyloxybutyrate) was obtained, which was dissolved in 10 ml of acetonitrile. Figure 5 .

[0059] Preparation of pemafibrate according to Comparative Example 1, which has the following synthetic route:

[0060]

[0061] (a) To a 500 ml three-necked flask, 10.00 g of SMA and 50 ml of methanol were added, and the mixture was stirred and dissolved at 15-25 °C. 6.7 g of SMB was dissolved in 50 ml of methanol, and the resulting solution was added dropwise to the above mixture at 20 °C over a period of 5 minutes. The reaction was carried out at 20 °C for 20 hours, and then 2.1 g of sodium borohydride dissolved in 100 ml of water was added dropwise to the resulting reaction solution at 20 °C over a period of 5 minutes. After the completion of the addition, the mixture was stirred at 20 °C for 12 hours. The resulting mixture was filtered, washed with water, and dried at 80 °C for 5 hours to obtain 13.9 g of yellow crystals of 3-[[3-(4-methoxyphenoxy)propyl]aminomethyl]phenol with a purity of 96% and a yield of 87.4.0%. The relevant chromatogram is shown in FIG. 1. Figure 2 .

[0062] (b) To a 20 ml three-necked flask, 1.0 g of 3-[[3-(4-methoxyphenoxy)propyl]aminomethyl]phenol, 4 ml of DMF, and 0.387 g of triethylamine were added, and the mixture was stirred until the solid was completely dissolved. The resulting mixture was warmed to 80 °C, and 0.534 g of compound SMC (2-chlorobenzoxazole) was added dropwise to the mixture. The reaction was carried out at 80 °C for 4 hours. After the completion of the reaction, the resulting reaction solution was cooled to 15-25 °C, and the solvent was removed by distillation. Ethyl acetate was added to the resulting product, and the mixture was washed with water and brine. The resulting mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain an oily substance. The resulting oily substance was packed in a column and purified by column chromatography using a mixture of n-heptane and ethyl acetate (volume ratio 3:1) as an eluent to obtain 1.3 g of a white solid with a purity of 97.86% and a yield of 92.3%. The relevant chromatogram is shown in FIG. 2. Figure 4 .

[0063] c) Preparation of the intermediate 3 of pemafibrate

[0064] Preparation of n-butyl (S)-2-trifluoromethanesulfonyloxybutyrate (compound E derivative): To a 50 ml three-necked flask, 0.3 g of n-butyl (S)-2-hydroxybutyrate (compound E), 5 ml of dichloromethane, and 0.155 g of pyridine were sequentially added, and the mixture was stirred and dissolved, and then cooled to 0 °C. Then, 0.528 g of trifluoromethanesulfonic anhydride was added dropwise to the mixture at 0 °C. After the completion of the addition, the mixture was stirred for 30 minutes. After the completion of the reaction, the mixture was washed with water, and the organic phase was collected and dried by evaporation. The resulting concentrate was packed in an adsorption column filled with 30 g of silica gel having a particle size of 200-300 mesh, and then subjected to chromatography. The eluent was dichloromethane, and the amount used was 300 ml. As a result, compound E derivative (n-butyl (S)-2-trifluoromethanesulfonyloxybutyrate) was obtained, which was dissolved in 10 ml of acetonitrile.

[0065] Into 10 ml of acetonitrile, 0.53 g of intermediate 2 was added, 0.272 g of potassium carbonate was added at 15-25 °C, stirred for 10 minutes, and the prepared n-butyl (S)-2-trifluoromethanesulfonyl hydroxy butyrate acetonitrile solution was added, and reacted at 15-25 °C for 14 hours, quenched with water, extracted with toluene, washed with brine, dried over sodium sulfate, concentrated by suction filtration, and 0.68 g of colorless oil was obtained, which was intermediate 3.

[0066] d) Preparation of pemafibrate:

[0067] Into a 50 ml three-necked reaction flask, 0.68 g of intermediate 3 oil was added, 20 ml of ethanol was added to stir and dissolve, 2 ml of 4N sodium hydroxide solution was added at 0 °C, and reacted at 15-25 °C for 3 hours, the ethanol was removed under reduced pressure, water was added, and the product was acidified by adding concentrated hydrochloric acid under ice bath cooling, extracted with ethyl acetate, washed with water, washed with brine, dried over anhydrous sodium sulfate, concentrated by filtration, and 0.50 g of white solid was obtained, with a purity of 96.1% and a yield of 82.6%. The relevant chromatogram is shown in Figure 6 .

[0068] The yield and purity of the product intermediate 2 in the examples and comparative examples were determined by HPLC detection method, as shown in Table 1 below:

[0069] Table 1 Comparative data of purity and impurity distribution of intermediate 2 in examples and comparative example 1

[0070]

[0071] From the above results, it can be seen that the intermediate 2 prepared in the present application has high yield, good purity and less impurities compared with comparative example 1. It is very helpful for the preparation of subsequent finished products, and it is easier to realize the industrialized production of target product.

[0072] Among them, the HPLC detection method is as follows:

[0073]

[0074]

[0075] The above examples are only used to illustrate the technical solutions of the present application, but not to 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 they can still modify the technical solutions recorded in the foregoing examples, or make equivalent replacement for part of the technical features; 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 process for the preparation of pemafibrate, characterized in that It comprises the following steps: (1) reacting compound SMA and compound C to obtain intermediate 1; (2) reacting intermediate 1 with compound D, and then reducing by sodium borohydride to obtain intermediate 2; (3) reacting intermediate 2 with compound E derivative to obtain intermediate 3; Compound E derivative intermediate 3 (4) obtaining pemetrexed by hydrolysis reaction of intermediate 3; 2. The production method according to claim 1, characterized by, In step (1), the molar ratio of compound SMA to compound C is 1:1.1-1:

2.

3. The preparation method according to claim 2, characterized in that In step (1), the molar ratio of compound SMA to compound C is 1:1.1-1.

5.

4. The production method according to claim 3, characterized by, In step (1), the molar ratio of compound SMA to compound C is 1:1.

2.

5. The preparation method according to claim 1, characterized in that In step (1), the reaction temperature is 20-80℃, and the reaction time is 20-40 hours.

6. The production method according to claim 5, wherein In step (1), the reaction temperature is 50-60℃; the reaction time is 30 hours.

7. The preparation method according to claim 1, characterized in that In step (2), the molar ratio of intermediate 1 to compound D is 1:1.1-1:

2.

8. The preparation method according to claim 7, characterized in that In step (2), the molar ratio of intermediate 1 to compound D is 1:1.1-1.

5.

9. The production method according to claim 8, characterized by, In step (2), the molar ratio of intermediate 1 to compound D is 1:1.

2.

10. The method of claim 1, wherein, In step (2), the reaction temperature is 10-30℃; the reaction time is 20-40 hours.

11. The method of claim 10, wherein, In step (2), the reaction temperature is 15-25℃; the reaction time is 30 hours.

12. The method of claim 11, wherein, In step (2), the reaction temperature is 20℃.

13. The method of claim 1, wherein, In step (3), the compound E derivative is prepared by reacting compound E with trifluoromethanesulfonic anhydride; 14. The method of claim 13, wherein, In step (3), the reaction conditions of compound E with trifluoromethanesulfonic anhydride are: the reaction temperature is -5-5℃; the molar ratio of compound E to trifluoromethanesulfonic anhydride is 1:0.8-1.

2.

15. The method of claim 14, wherein, In step (3), the reaction conditions of compound E with trifluoromethanesulfonic anhydride are: the reaction temperature is 0℃; the molar ratio of compound E to trifluoromethanesulfonic anhydride is 1:1.

0.

16. The method of claim 13, wherein, In step (3), the reaction temperature is 10-30℃; the reaction time is 10-20 hours.

17. The method of claim 16, wherein the method further comprises, In step (3), the reaction temperature is 15-25℃; the reaction time is 14 hours.

18. The method of claim 17, wherein, In step (3), the reaction temperature is 20℃.

19. The method of claim 13, wherein, In step (3), the molar ratio of intermediate 2 to compound E is 1:0.5-0.

9.

20. The method of claim 19, wherein, In step (3), the molar ratio of intermediate 2 to compound E is 1:0.

7.

21. The method of claim 1, wherein, In step (4), the hydrolysis reaction conditions are: the reaction temperature is 10-30℃; the reaction time is 1-4 hours, and the base used for hydrolysis is sodium hydroxide.

22. The method of claim 21, wherein, In step (4), the hydrolysis reaction conditions are: the reaction temperature is 15-25℃; the reaction time is 3 hours.

23. The method of claim 22, wherein, In step (4), the hydrolysis reaction conditions are: the reaction temperature is 20℃.

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