Refining method of Pinefibrate intermediate PM02

Abstract

The invention discloses a refining method of a Pinefibrate intermediate PM02. The method comprises the following steps: 1, carrying out a heating reflux reaction on a reaction solvent, PM01, triethylamine and PM-SM03; 2, adding tetrahydrofuran and saturated saline solution into the reaction product system, and separating liquid to obtain a saline solution phase and a tetrahydrofuran phase; 3, adding tetrahydrofuran into the salt water phase, extracting to obtain tetrahydrofuran phases, combining the tetrahydrofuran phases, washing, drying, carrying out suction filtration, and concentrating to obtain PM02 oily matter; and 4, adding methyl tert-butyl ether into the PM02 oily substance, heating for dissolving, cooling for crystallization, then carrying out suction filtration, leaching a filter cake by using the methyl tert-butyl ether, then carrying out suction drying, and drying to obtain PM02. According to the method, the tetrahydrofuran and the saturated saline solution are adopted for extraction separation, methyl tert-butyl ether is adopted for crystallization, high-yield and high-purity PM02 is obtained, and the problems of equipment corrosion and acid-containing wastewater treatment caused by a large amount of waste liquid generated by column purification and strong acid crystallization are solved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a refining method of a pemafibrate intermediate PM02. BACKGROUND

[0002] Pemafibrate, with the English name Pemafibrate, is developed by Japan's Sankyo Group, and was approved in Japan on July 3, 2017 for the treatment of hyperlipidemia. Pemafibrate is the first PPAR alpha modulator approved for marketing in the world, which can improve the problem of low serum triglyceride level by regulating hepatic lipid metabolism, and its safety is superior to other betaine lipid-lowering drugs.

[0003] The synthetic route disclosed in patent EP1852426A1 is column chromatography purification except step 1, and the synthetic route is as follows:

[0004] The synthetic route disclosed in the non-patent document (Yukiyoshi Yamazaki, et al, Synthesis, 2008(7), 1017-1022) is also column chromatography purification, and the synthetic route is as follows:

[0005] The current mainstream synthetic route of pemafibrate is still the original research route, and PM02 (chemical name 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol) is a key intermediate in the route, which affects the quality of the finished product. In the existing published literature, in addition to column chromatography purification, there are also refining methods as shown in Table 1: Table 1

[0006] The existing purification method, column chromatography purification, will produce a large amount of waste liquid, the production cost is high, and it is difficult to realize commercial large-scale production. Patent IN202321024436A uses ethyl acetate as the reaction solvent, and uses ethyl acetate-n-heptane crystallization to prepare PM02. The disadvantages of this method are heterogeneous reaction, poor repeatability, long reaction time, high energy consumption of mixed solvent recovery, and increased production cost. Patent CN116462638A first extracts, then adds acid or acid solution in the organic phase to crystallize PM02 salt. The disadvantages of this method are that strong acid may corrode equipment, and acid-containing wastewater needs to be neutralized and treated, increasing production cost; in addition, PM02 salt needs to be further isolated when preparing pemafibrate, increasing the operation steps and further increasing the production cost. SUMMARY

[0007] The technical problem solved by the present application is to provide a refining method of pemafibrate intermediate PM02 to overcome the shortcomings of the prior art.

[0008] To solve the above technical problems, the technical scheme adopted by the present application is as follows: a refining method of pemafibrate intermediate PM02, characterized in that the method comprises the following steps: Step one, heating and refluxing reaction of reaction solvent, PM01, triethylamine and PM-SM03; Step two, after the heating and refluxing reaction in step one is completed, the reaction product system is cooled to room temperature, tetrahydrofuran and saturated brine are added, and after stirring and separating, brine phase and tetrahydrofuran phase are obtained; Step three, tetrahydrofuran is added to the brine phase obtained in step two for extraction, and after stirring and separating, tetrahydrofuran phase is obtained, then the tetrahydrofuran phases obtained in steps two and three are combined, washed with saturated brine and dried with sodium sulfate, filtered and concentrated to obtain PM02 oil; Step four, methyl tert-butyl ether is added to the PM02 oil obtained in step three, and the mixture is heated and stirred to dissolve, then the mixture is cooled and crystallized, filtered, and the filter cake is washed with methyl tert-butyl ether, dried, and then the wet product is obtained, and the wet product is dried to obtain PM02.

[0009] The refining method of pemafibrate intermediate PM02, characterized in that the molar equivalent ratio of PM01, PM-SM03 and triethylamine in step one is 1.0:1.0~1.2:1.0~1.2.

[0010] The refining method of pemafibrate intermediate PM02, characterized in that the volume of the reaction solvent to the mass of PM01 in step one is 3~6:1, the unit of mass is g, and the unit of volume is mL.

[0011] The refining method of pemafibrate intermediate PM02, characterized in that the reaction solvent in step one is tetrahydrofuran, dioxane or acetonitrile.

[0012] The refining method of the pemafibrate intermediate PM02 has the characteristics that the ratio of the volume of the tetrahydrofuran added in step two to the mass of PM01 in step one is 3:1, the unit of mass is g, and the unit of volume is mL.

[0013] The refining method of the pemafibrate intermediate PM02 has the characteristics that the ratio of the volume of the saturated brine added in step two to the mass of PM01 in step one is 4:1, the unit of mass is g, and the unit of volume is mL.

[0014] The refining method of the pemafibrate intermediate PM02 has the characteristics that the ratio of the volume of the tetrahydrofuran added in step three to the mass of PM01 in step one is 2:1, the unit of mass is g, and the unit of volume is mL.

[0015] The refining method of the pemafibrate intermediate PM02 has the characteristics that the ratio of the volume of the saturated brine added in step three to the mass of PM01 in step one is 2:1, the unit of mass is g, and the unit of volume is mL.

[0016] The refining method of the pemafibrate intermediate PM02 has the characteristics that the ratio of the volume of the methyl tert-butyl ether added to the PM02 oil in step four to the mass of PM01 in step one is 3-5:1, the unit of mass is g, and the unit of volume is mL. Preferably, the ratio is 4:1.

[0017] PM01 in the application is the abbreviation of 3-[[3-(4-methoxyphenoxy)propyl]aminomethyl]phenol, PM02 is the abbreviation of 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol, and PM-SM03 is the abbreviation of 2-chlorobenzoxazole.

[0018] Compared with the prior art, the application has the following advantages: 1. In the application, tetrahydrofuran and saturated brine are added to the reaction solvent, PM01, triethylamine, and PM-SM03 to separate and extract the reaction product system, so that PM02 exists in the tetrahydrofuran phase. PM02 is obtained by crystallization with methyl tert-butyl ether, which avoids the problem of a large amount of waste liquid generated by column purification, the solvent can be recycled and reused, the production cost is reduced, and the application is suitable for industrial production.

[0019] 2、The present application uses tetrahydrofuran, dioxane or acetonitrile as a reaction solvent, tetrahydrofuran and saturated brine for extraction separation, and combines methyl tert-butyl ether crystallization to play a synergistic effect: a lower boiling point polar solvent is beneficial to faster reaction, and the risk of residual to the crystallization system is smaller, which does not affect the subsequent crystallization, and then the mutually insoluble tetrahydrofuran and saturated brine are used for post-treatment, wherein the saturated brine can fully elute the triethylamine hydrochloride in the reaction product system, and the tetrahydrofuran is easier to distill clean, avoiding the increase of the polarity of the crystallization system and affecting the crystallization effect, avoiding the complicated process of multiple water washing and extraction in the conventional operation, and the PM02 oil obtained under the conditions of the first two steps can be successfully solidified and crystallized in methyl tert-butyl ether to obtain PM02 with high purity and high yield.

[0020] 3、The PM02 refining method of the present application is simple to operate, and does not need to strictly control the addition speed of reagents and solvents, and the production process is easy to control.

[0021] 4、The PM02 refining method of the present application does not involve strong acid, has low loss rate of production equipment, does not produce acid-containing wastewater, and is environmentally friendly.

[0022] 5、The PM02 refining method of the present application obtains PM02 solid with high yield and purity.

[0023] The technical solutions of the present application are further described in detail below through examples. DETAILED DESCRIPTION

[0024] Example 1 This example includes the following steps: Step one, 100mL tetrahydrofuran, 20.0g PM01, 7.03g triethylamine and 11.72g PM-SM03 are added to a 500mL three-necked flask, and then heated to 65~70℃ for reflux reaction for 7h; Step two, after the reflux reaction in step one is completed, the reaction product system in the reaction bottle is cooled to room temperature, 60mL tetrahydrofuran and 80mL saturated brine are added, stirred and separated to obtain a brine phase and a tetrahydrofuran phase; Step three, 40mL tetrahydrofuran is added to the brine phase obtained in step two for extraction, and after stirring and separation, a tetrahydrofuran phase is obtained, then the tetrahydrofuran phases obtained in steps two and three are combined, washed with 40mL saturated brine and dried with sodium sulfate, and then filtered and concentrated to obtain PM02 oil; Step four, 60 mL of methyl tert-butyl ether was added to the PM02 oil obtained in step three and stirred to dissolve at 40°C, and then cooled to 0°C and kept for 15 h. After cooling, the filter cake was obtained by suction filtration, and then washed with 10 mL of methyl tert-butyl ether. After drying, the wet product was obtained, and then dried at 55°C to obtain 26.5 g of PM02.

[0025] The yield of PM02 prepared in this example was calculated to be 94.1% (yield = mass of PM02 x molecular weight of PM01 / (mass of PM01 x molecular weight of PM02) x 100%), and the mass purity detected by HPLC was 97.5%.

[0026] Comparative Example 1 This comparative example includes the following steps: Step one, 100 mL of N,N-dimethylacetamide, 20.0 g of PM01, 7.03 g of triethylamine and 11.72 g of PM-SM03 were added to a 500 mL three-necked flask, and then heated to 65-70°C for reflux reaction for 7 h. Step two, after the reflux reaction in step one was completed, the reaction product system in the reaction bottle was cooled to room temperature, 60 mL of tetrahydrofuran and 80 mL of saturated brine were added, and then stirred and separated to obtain the brine phase and the tetrahydrofuran phase. Step three, 40 mL of tetrahydrofuran was added to the brine phase obtained in step two for extraction, and then stirred and separated to obtain the tetrahydrofuran phase. Then, the tetrahydrofuran phases obtained in steps two and three were combined, washed with 40 mL of saturated brine and dried with sodium sulfate. After suction filtration and concentration, PM02 oil was obtained. Step four, 60 mL of methyl tert-butyl ether was added to the PM02 oil obtained in step three and stirred to dissolve at 40°C, and then cooled to 0°C and kept for 15 h. After cooling, the filter cake was obtained by suction filtration, and then washed with 10 mL of methyl tert-butyl ether. After drying, the wet product was obtained, and then dried at 55°C to obtain 26.5 g of PM02.

[0027] Comparative Example 2 This comparative example includes the following steps: Step one, 100 mL of N,N-dimethylacetamide, 20.0 g of PM01, 7.03 g of triethylamine and 11.72 g of PM-SM03 were added to a 500 mL three-necked flask, and then heated to 65-70°C for reflux reaction for 7 h. Step two, after the reflux reaction in step one was completed, the reaction product system in the reaction bottle was cooled to room temperature, 60 mL of tetrahydrofuran and 80 mL of saturated brine were added, and then stirred and separated to obtain the brine phase and the tetrahydrofuran phase. Step three, 40 mL of tetrahydrofuran was added to the salt water phase obtained in step two for extraction, and the tetrahydrofuran phase was obtained after stirring and separation, then the tetrahydrofuran phases obtained in steps two and three were combined, and were washed with 40 mL of saturated brine and dried with sodium sulfate, and were filtered and concentrated to obtain PM02 oil; Step four, 80 mL of methyl tert-butyl ether was added to the PM02 oil obtained in step three and was stirred and dissolved at 40℃, and was cooled to 0℃ and was kept for 15 h for crystallization, and the oil was precipitated, and the crystallization failed, and PM02 was not obtained.

[0028] Comparing the present example 1 with the comparative examples 1-2, in the comparative example 1, N,N-dimethylacetamide was used instead of tetrahydrofuran as the reaction solvent, although the reaction was fast, but the target product could not be crystallized; in the comparative example 2, tetrahydrofuran-n-heptane was used instead of methyl tert-butyl ether, and the crystallization was not successful; it is shown that by using tetrahydrofuran, dioxane or acetonitrile as the reaction solvent, and using tetrahydrofuran and saturated brine for extraction and separation, and using methyl tert-butyl ether for crystallization, the crystallization process is ensured to be smooth, and the yield and purity of the product PM02 are improved.

[0029] Example 2 The present example includes the following steps: Step one, 100 mL of acetonitrile, 20.0 g of PM01, 7.03 g of triethylamine and 11.72 g of PM-SM03 were added to a 500 mL three-necked flask, and then the temperature was raised to 65-70℃ for heating and reflux reaction for 7 h; Step two, after the heating and reflux reaction in step one was completed, the temperature was lowered to room temperature, 60 mL of tetrahydrofuran and 80 mL of saturated brine were added to the reaction product system in the reaction flask, and the salt water phase and the tetrahydrofuran phase were obtained after stirring and separation; Step three, 40 mL of tetrahydrofuran was added to the salt water phase obtained in step two for extraction, and the tetrahydrofuran phase was obtained after stirring and separation, then the tetrahydrofuran phases obtained in steps two and three were combined, and were washed with 40 mL of saturated brine and dried with sodium sulfate, and were filtered and concentrated to obtain PM02 oil; Step four, 80 mL of methyl tert-butyl ether was added to the PM02 oil obtained in step three and was stirred and dissolved at 40℃, and was cooled to 0℃ and was kept for 15 h for crystallization, and the oil was precipitated, and the crystallization failed, and PM02 was not obtained.

[0030] It is calculated that the yield of PM02 prepared in the present example is 93.7%, and the mass purity detected by HPLC is 93.3%.

[0031] Example 3 The embodiment comprises the following steps: Step one, 80 mL of dioxane, 20.0 g of PM01, 7.03 g of triethylamine and 11.72 g of PM-SM03 are added into a 500 mL three-necked flask, and then the reaction is heated to reflux at 65-70°C for 7 h; Step two, after the reaction in step one is completed, the reaction product system in the reaction flask is cooled to room temperature, 60 mL of tetrahydrofuran and 80 mL of saturated brine are added, and after stirring and separation, the brine phase and the tetrahydrofuran phase are obtained; Step three, 40 mL of tetrahydrofuran is added to the brine phase obtained in step two for extraction, and after stirring and separation, the tetrahydrofuran phase is obtained, then the tetrahydrofuran phases obtained in steps two and three are combined, and 40 mL of saturated brine is used for washing and sodium sulfate drying, and then the mixture is filtered and concentrated to obtain PM02 oil; Step four, 80 mL of methyl tert-butyl ether is added to the PM02 oil obtained in step three, and the mixture is stirred and dissolved at 40°C, then the mixture is cooled to 0°C and kept for 15 h, the filter cake is obtained after filtration, and then the filter cake is washed with 10 mL of methyl tert-butyl ether, and the mixture is dried to obtain wet product, and then the wet product is dried at 55°C to obtain 26.7 g of PM02.

[0032] It is calculated that the yield of PM02 prepared in the embodiment is 94.8%, and the mass purity detected by HPLC is 93.9%.

[0033] Example 4 The embodiment comprises the following steps: Step one, 100 mL of tetrahydrofuran, 20.0 g of PM01, 7.03 g of triethylamine and 11.72 g of PM-SM03 are added into a 500 mL three-necked flask, and then the reaction is heated to reflux at 65-70°C for 7 h; Step two, after the reaction in step one is completed, the reaction product system in the reaction flask is cooled to room temperature, 60 mL of tetrahydrofuran and 80 mL of saturated brine are added, and after stirring and separation, the brine phase and the tetrahydrofuran phase are obtained; Step three, 40 mL of tetrahydrofuran is added to the brine phase obtained in step two for extraction, and after stirring and separation, the tetrahydrofuran phase is obtained, then the tetrahydrofuran phases obtained in steps two and three are combined, and 40 mL of saturated brine is used for washing and sodium sulfate drying, and then the mixture is filtered and concentrated to obtain PM02 oil; Step four, 100 mL methyl tert-butyl ether was added to the PM02 oil obtained in step three, and the mixture was stirred and dissolved at 40°C. After cooling to 0°C, the mixture was incubated for 15 h. The filter cake obtained after suction filtration was washed with 10 mL methyl tert-butyl ether, and the wet product was obtained after suction drying. The wet product was dried at 55°C to obtain 25.8 g of PM02.

[0034] The yield of PM02 prepared in this example was calculated to be 91.8%, and the mass purity detected by HPLC was 98.5%.

[0035] Example 5 This example includes the following steps: Step one, 1000 mL tetrahydrofuran, 200.0 g PM01, 70.3 g triethylamine and 117.2 g PM-SM03 were added to a 3000 mL three-necked flask, and then the mixture was heated to 65-70°C for reflux reaction for 7 h. Step two, after the reflux reaction in step one was completed, the reaction product system in the reaction bottle was cooled to room temperature, 600 mL tetrahydrofuran and 800 mL saturated brine were added, and the mixture was stirred and separated to obtain a brine phase and a tetrahydrofuran phase. Step three, 400 mL tetrahydrofuran was added to the brine phase obtained in step two for extraction, and the mixture was stirred and separated to obtain a tetrahydrofuran phase. Then the tetrahydrofuran phases obtained in steps two and three were combined, washed with 400 mL saturated brine, and dried with sodium sulfate. After suction filtration and concentration, PM02 oil was obtained. Step four, 800 mL methyl tert-butyl ether was added to the PM02 oil obtained in step three, and the mixture was stirred and dissolved at 40°C. After cooling to 0°C, the mixture was incubated for 15 h. The filter cake obtained after suction filtration was washed with 100 mL methyl tert-butyl ether, and the wet product was obtained after suction drying. The wet product was dried at 55°C to obtain 261.0 g of PM02.

[0036] The yield of PM02 prepared in this example was calculated to be 92.7%, and the mass purity detected by HPLC was 98.4%.

[0037] The above is only a preferred embodiment of the present application, and does not limit the present application in any way. Any simple modification, change and equivalent change made to the above embodiment according to the technical essence of the present application are still within the protection scope of the technical solution of the present application.

Claims

1. A method for purifying a pemafibrate intermediate PM02, characterized by, The method comprises the following steps: Step one, heating reflux reaction of reaction solvent, PM01, triethylamine and PM-SM03; Step two, after the heating reflux reaction in step one is completed, the reaction product system is added with tetrahydrofuran and saturated brine, and after stirring and liquid separation, brine phase and tetrahydrofuran phase are obtained; Step three, tetrahydrofuran is added to the brine phase obtained in step two for extraction, and after stirring and liquid separation, tetrahydrofuran phase is obtained, then the tetrahydrofuran phases obtained in steps two and three are combined, and saturated brine is used for washing and sodium sulfate is used for drying, and after suction filtration and concentration, PM02 oil is obtained; Step four, methyl tert-butyl ether is added to the PM02 oil obtained in step three, and the mixture is stirred and dissolved after being heated, and then the filter cake is obtained after suction filtration, and then the filter cake is washed with methyl tert-butyl ether, and the wet product is obtained after suction drying, and then the wet product is dried to obtain PM02.

2. The method of purifying a pemafibrate intermediate PM02 according to claim 1, wherein, The molar equivalent ratio of PM01, PM-SM03 and triethylamine in step one is 1.0:1.0-1.2:1.0-1.

2.

3. The method of purifying a pemafibrate intermediate PM02 according to claim 1, wherein, The volume to mass ratio of the reaction solvent to PM01 in step one is 3-6:1, the unit of mass is g, and the unit of volume is mL.

4. The method of purifying a pemafibrate intermediate PM02 according to claim 1, wherein The reaction solvent in step one is tetrahydrofuran, dioxane or acetonitrile.

5. The method of purifying a pemafibrate intermediate PM02 according to claim 1, wherein The volume to mass ratio of tetrahydrofuran to PM01 in step two is 3:1, the unit of mass is g, and the unit of volume is mL.

6. The method of purifying a pemafibrate intermediate PM02 according to claim 1, wherein The volume to mass ratio of saturated brine to PM01 in step two is 4:1, the unit of mass is g, and the unit of volume is mL.

7. The method of purifying a pemafibrate intermediate PM02 according to claim 1, wherein The volume to mass ratio of tetrahydrofuran to PM01 in step three is 2:1, the unit of mass is g, and the unit of volume is mL.

8. The method of purifying a pemafibrate intermediate PM02 according to claim 1, wherein The volume to mass ratio of saturated brine to PM01 in step three is 2:1, the unit of mass is g, and the unit of volume is mL.

9. The method of purifying a pemafibrate intermediate PM02 according to claim 1, wherein, The volume to mass ratio of methyl tert-butyl ether to PM01 in step four is 3-5:1, the unit of mass is g, and the unit of volume is mL.

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