Method for preparing Pinefibrate by one-pot method

Abstract

The invention discloses a method for preparing Pinefibrate by a one-pot method. The method comprises the following steps: 1, stirring PM02, a reaction solvent and inorganic alkali under the protection of nitrogen; 2, dissolving PM03 and acetonitrile, dropwise adding into a stirring system, and reacting at room temperature; 3, adding potassium trimethylsilanolate, continuously reacting at room temperature, filtering, adjusting the filtrate to be neutral, removing the solvent, adjusting the pH value to be 12-13, extracting to remove impurities, adjusting the pH value to be 3-4 by adopting hydrochloric acid, extracting, washing, drying and performing suction filtration to obtain an ethyl acetate solution of palmatate; and 4, adding n-heptane, heating, decolorizing and filtering by adopting activated carbon, adding n-heptane again, preserving heat, cooling and crystallizing to obtain the Pinefibrate. According to the method, PM04 generated by reaction of PM02 and PM03 at room temperature is directly subjected to next-step feeding reaction, so that separation and purification of an oily intermediate PM04 are avoided, the reaction time is shortened, and the method is simple to operate, low in cost, good in finished product quality, high in yield and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a one-pot method for preparing pemafibrate. BACKGROUND

[0002] Pemafibrate, with the English name Pemafibrate, is developed by Japan's Sankyo Group and approved in Japan on July 3, 2017 for the treatment of hyperlipidemia. Pemafibrate is the first PPAR alpha modulator approved for marketing worldwide, which 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] At present, the preparation of pemafibrate generally adopts the preparation method disclosed in the original research patent. The synthetic route disclosed in the patent EP1852426A1 is as follows:

[0004] In the preparation method disclosed in the original research, 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol is reacted with (S)-2-(((trifluoromethyl)sulfonyl)oxy)butyric acid butyl ester to generate intermediate 5, and high-purity intermediate 5, i.e. (R)-2-(3-((benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxy)butyric acid butyl ester, is obtained by column purification. The intermediate 5 is an oil (not easy to refine and purify), which will directly cause the low purity of the crude product and affect the quality of the finished pemafibrate product. In the original research patent, n-heptane and ethyl acetate in a volume ratio of 2:1 are used as eluents for column purification of intermediate 5, 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 waste solid and waste liquid. The whole post-treatment process is complex and tedious, time-consuming, and has a high production cost, which is not suitable for commercial mass production.

[0005] The patent CN118955420A discloses a preparation method of pemafibrate, wherein the post-treatment of the preparation of intermediate 5 is as follows: after the reaction is completed, water is added for quenching, toluene is extracted, salt water is washed, sodium sulfate is dried, and the concentrated product is purified to obtain an oily intermediate 5. The whole post-treatment process is relatively complicated.

[0006] Based on the above problems existing in the prior art, there is an urgent need for a preparation method of pemafibrate which is more simple to operate, shorter in production cycle, more environmentally friendly, lower in cost, and higher in yield. SUMMARY

[0007] The technical problem to be solved by the present application is to provide a one-pot method for preparing pemafibrate in view of the deficiencies of the prior art. The preparation method directly uses PM02 and PM03 to generate PM04 through room temperature reaction, and then generates the product through SN2 nucleophilic substitution reaction. The impurities generated in the reaction can be removed through hydrolysis reaction. The product can be directly used for hydrolysis reaction with potassium trimethylsilanol without separation and purification. The separation and purification of oily intermediate PM04 is avoided, the reaction time is shortened, the operation is simple, the cost is low, the product quality is good, the yield is high, and the method is suitable for industrial production. The problems of complicated post-processing, complex operation, long cycle and high cost in the prior art are solved. To solve the above technical problems, the technical scheme adopted by the present application is as follows: a one-pot method for preparing pemafibrate, characterized in that the method comprises the following steps: Step one: stirring PM02, a reaction solvent and an inorganic base under nitrogen protection; Step two: stirring and dissolving PM03 and acetonitrile to prepare a PM03-acetonitrile mixture, and then dropping the mixture into the stirred system in step one for room temperature reaction; Step three: adding potassium trimethylsilanol to the system after the room temperature reaction in step two is completed, and continuing the room temperature reaction. After the reaction is completed, the obtained filtrate is adjusted to neutral PH=6-7 with 3mol / L dilute hydrochloric acid, the solvent is removed by rotary evaporation, then the PH is adjusted to 12-13 with 1mol / L sodium hydroxide solution, and impurities are removed by extraction with methyl tert-butyl ether, followed by adjustment of the PH to 3-4 with hydrochloric acid and extraction with ethyl acetate, followed by water washing twice, saturated brine washing once, drying with anhydrous sodium sulfate and suction filtration to obtain an ethyl acetate solution of pemafibrate; Step four: adding n-heptane to the ethyl acetate solution of pemafibrate in step three and heating, decolorizing with activated carbon, and then filtering while hot. Adding n-heptane to the obtained filtrate and keeping warm, and then cooling and crystallizing to obtain pemafibrate.

[0008] The present application adopts a one-pot method to prepare pemafibrate. PM02 and PM03 are used as raw materials to complete SN2 nucleophilic substitution reaction and hydrolysis reaction through a one-pot method to generate pemafibrate. The synthesis route is as follows:

[0009] The one-pot method for preparing pemafibrate is characterized in that the reaction solvent in step one is acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran, and the inorganic base is sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. Preferably, the reaction solvent is acetonitrile, and the inorganic base is potassium carbonate.

[0010] The one-pot method for preparing pemafibrate, characterized in that the molar ratio of PM02 to the inorganic base in step one is 1:1.0-1.4, and the ratio of the mass of PM02 to the volume of the reaction solvent is 1:5-15, the unit of mass being g and the unit of volume being mL. Preferably, the molar ratio of PM02 to the inorganic base is 1:1.2, and the ratio of the mass of PM02 to the volume of the reaction solvent is 1:10.

[0011] The one-pot method for preparing pemafibrate, characterized in that the molar ratio of PM02 in step one to PM03 in step two is 1:1.0-1.2. Preferably, it is 1:1.1.

[0012] The one-pot method for preparing pemafibrate, characterized in that the ratio of the mass of PM03 to the volume of acetonitrile in step two is 1:2-4, the unit of mass being g and the unit of volume being mL. Preferably, it is 1:3.

[0013] The one-pot method for preparing pemafibrate, characterized in that the time of the room temperature reaction in step two is 22 h-26 h. Preferably, it is 24 h.

[0014] The one-pot method for preparing pemafibrate, characterized in that the molar ratio of PM02 in step one to potassium trimethylsilanol in step three is 1:1.4-1.8, and the time of the room temperature reaction is 2 h-3 h. Preferably, the molar ratio is 1:1.6, and the time of the room temperature reaction is 2.5 h.

[0015] The one-pot method for preparing pemafibrate, characterized in that the ratio of the mass of PM02 in step one to the volume of methyl tert-butyl ether, ethyl acetate in step three is 1:4-8:6-10, the unit of mass being g and the unit of volume being mL. Preferably, it is 1:6:8.

[0016] The one-pot method for preparing pemafibrate, characterized in that the ratio of the mass of PM02 in step one to the volume of water, the volume of saturated brine, the mass of anhydrous sodium sulfate in step three is 1:2-4:2-4:0.5-1.5, the unit of mass being g and the unit of volume being mL. Preferably, it is 1:3:3:1.

[0017] The one-pot method for preparing pemafibrate, characterized in that the volume ratio of ethyl acetate in step three to n-heptane in step four is 1:2. The volume of the n-heptane is the total volume of the n-heptane added twice.

[0018] The room temperature reaction temperature in the present application is generally 20℃-25℃.

[0019] PM02 is the abbreviation of 3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenol, PM03 is the abbreviation of (S)-butyl 2-(((trifluoromethyl)sulfonyl)oxy)butanoate, and PM04 is the abbreviation of (R)-butyl 2-(3-((benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxy)butanoate.

[0020] Compared with the prior art, the present application has the following advantages: 1. The one-pot method is used to prepare pemafibrate, PM02 and PM03 are reacted at room temperature to generate (R)-butyl 2-(3-((benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxy)butanoate (PM04), and the SN2 nucleophilic substitution reaction generates few impurities which can be removed by post-treatment of hydrolysis reaction, so that the hydrolysis reaction can be directly carried out without separation and purification, the operation is simple, easy to control, and suitable for industrial production.

[0021] 2. The subsequent reaction is directly carried out in the PM04 reaction system, so that the separation and purification of the oily intermediate PM04 is avoided, the reaction time is shortened, the amount of waste solid and waste water generated in the reaction process is reduced, and the production cost is reduced.

[0022] 3. The pemafibrate product prepared by the one-pot method has good quality and high yield.

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

[0024] Example 1 This example includes the following steps: Step one, 12.6g of PM02, 63mL of acetonitrile and 5.0g of potassium carbonate are added to a 250mL reaction bottle, and stirring is carried out under nitrogen protection; Step two, 10.0g of PM03 and 20mL of acetonitrile are added to a 250mL reaction bottle, and stirring is carried out to dissolve and prepare a PM03-acetonitrile mixture, which is then added dropwise into the stirred system in step one for room temperature reaction for 22h; Step three, 6.4 g of potassium trimethylsilanol was added to the system after the reaction in step two was completed at room temperature, and the reaction was continued for 2 h at room temperature. After the reaction was completed, the obtained filtrate was adjusted to neutral PH = 6-7 with 3 mol / L dilute hydrochloric acid, the solvent was removed by rotary evaporation, then 1 mol / L sodium hydroxide solution was used to adjust the PH to 12-13, and 101 mL of methyl tert-butyl ether was used for extraction to remove impurities, then hydrochloric acid was used to adjust the PH to 3-4, and 76 mL of ethyl acetate was used for extraction, followed by washing with 26 mL of water twice, 26 mL of saturated brine once, 6.3 g of anhydrous sodium sulfate drying and filtration, to obtain a pemetrexed ethyl acetate solution; Step four, 100 mL of n-heptane was added to the pemetrexed ethyl acetate solution in step three and heated to 65°C, and activated carbon was used for decolorization for 30 min, then filtered while hot. 100 mL of n-heptane was added to the obtained filtrate and incubated for 1 h, and the temperature was lowered to induce crystallization, to obtain 14.5 g of pemetrexed, with a molar yield of 94.9%, an HPLC purity of 99.91%, and an ee value of 99.97% (ee value = pemetrexed R configuration content - S configuration content).

[0025] Comparative Example 1 This comparative example includes the following steps: Step one, 12.6 g of PM02, 63 mL of acetonitrile and 5.0 g of potassium carbonate were added to a 250 mL reaction bottle and stirred under nitrogen protection; Step two, 10.0 g of PM03, 20 mL of acetonitrile were added to a 250 mL reaction bottle and stirred to dissolve to form a PM03-acetonitrile mixture, then the mixture was added dropwise to the stirred system in step one and reacted at room temperature for 22 h; Step three, 1.5 g of lithium hydroxide monohydrate was added to the system after the reaction in step two was completed at room temperature, and the reaction was continued for 2 h at room temperature. TLC monitoring showed that the reaction was not complete, 1.5 g of lithium hydroxide monohydrate was added to continue the hydrolysis reaction for 2 h, and TLC monitoring showed that about 30% of the raw material remained, indicating that the reaction was not complete under the reaction conditions.

[0026] Comparative Example 2 This comparative example includes the following steps: Step one, 12.6 g of PM02, 63 mL of acetonitrile and 5.0 g of potassium carbonate were added to a 250 mL reaction bottle and stirred under nitrogen protection; Step two, 10.0 g of PM03, 20 mL of acetonitrile were added to a 250 mL reaction bottle and stirred to dissolve to form a PM03-acetonitrile mixture, then the mixture was added dropwise to the stirred system in step one and reacted at room temperature for 22 h; Step three, 6.4g of potassium trimethylsilanolate was added to the system after the reaction in step two was completed at room temperature, and the reaction was continued for 2h at room temperature. After the reaction was completed, the obtained filtrate was adjusted to neutral PH = 6-7 with 3mol / L dilute hydrochloric acid, the solvent was removed by rotary evaporation, then 1mol / L sodium hydroxide solution was used to adjust the PH to 12-13, and 101mL of methyl tert-butyl ether was used for extraction to remove impurities, then hydrochloric acid was used to adjust the PH to 3-4, and 76mL of ethyl acetate was used for extraction, then it was washed with 26mL of water twice, 26mL of saturated brine once, 6.3g of anhydrous sodium sulfate was used for drying, and suction filtration was performed to obtain the ethyl acetate solution of pemafibrate; Step four, 100mL of toluene was added to the ethyl acetate solution of pemafibrate in step three and heated to 65℃, and activated carbon was used for decolorization for 30min, then hot filtration was performed, 100mL of toluene was added to the obtained filtrate and kept for 1h, and the temperature was lowered to induce crystallization, and oil was precipitated, but the crystallization failed, and pemafibrate was not obtained.

[0027] Comparing the present example 1 with the comparative examples 1-2, it can be seen that the reaction in comparative example 1 is not complete using lithium hydroxide monohydrate instead of potassium trimethylsilanolate, and the toluene used in comparative example 2 instead of n-heptane cannot achieve smooth crystallization, which shows that the use of potassium trimethylsilanolate for hydrolysis reaction in step two of the present application and the use of n-heptane for crystallization in step four can achieve one-pot preparation of pemafibrate, and the yield and purity of the product are high.

[0028] Example 2 The present example includes the following steps: Step one, 12.6g of PM02, 189mL of tetrahydrofuran and 5.0g of sodium carbonate were added to a 500mL reaction bottle, and stirring was performed under nitrogen protection; Step two, 10.0g of PM03, 40mL of acetonitrile were added to a 500mL reaction bottle and stirred to dissolve to prepare a PM03-acetonitrile mixture, then the mixture was added dropwise to the stirred system in step one to perform room temperature reaction for 26h; Step three, 6.4g of potassium trimethylsilanolate was added to the system after the reaction in step two was completed at room temperature, and the reaction was continued for 2.5h at room temperature. After the reaction was completed, the obtained filtrate was adjusted to neutral PH = 6-7 with 3mol / L dilute hydrochloric acid, the solvent was removed by rotary evaporation, then 1mol / L sodium hydroxide solution was used to adjust the PH to 12-13, and 80mL of methyl tert-butyl ether was used for extraction to remove impurities, then hydrochloric acid was used to adjust the PH to 3-4, and 103mL of ethyl acetate was used for extraction, then it was washed with 38mL of water twice, 38mL of saturated brine once, 12.6g of anhydrous sodium sulfate was used for drying, and suction filtration was performed to obtain the ethyl acetate solution of pemafibrate; Step four, 103 mL of n-heptane was added to the ethyl acetate solution of pemafibrate in step three and heated to 65°C, and then decolorized with activated carbon for 30 min, and then filtered while hot. 103 mL of n-heptane was added to the obtained filtrate and incubated for 1 h, and then cooled to precipitate crystals, to obtain 14.6 g of pemafibrate, with a molar yield of 95.5%, an HPLC purity of 99.98%, and an ee value of 99.92%.

[0029] Example 3 This example includes the following steps: Step one, 12.6 g of PM02, 126 mL of 2-methyltetrahydrofuran, and 2.5 g of sodium bicarbonate were added to a 250 mL reaction bottle and stirred under nitrogen protection; Step two, 10.9 g of PM03, 30 mL of acetonitrile were added to a 250 mL reaction bottle and stirred to dissolve, to form a PM03-acetonitrile mixture, which was then added dropwise to the stirred system in step one and reacted at room temperature for 24 h; Step three, 6.4 g of potassium trimethylsilanol was added to the system after the room temperature reaction in step two was completed, and the reaction was continued at room temperature for 2 h. After the reaction was completed, the filtrate was obtained, and then 3 mol / L dilute hydrochloric acid was used to adjust the pH to 6-7. The solvent was removed by rotary evaporation, and then 1 mol / L sodium hydroxide solution was used to adjust the pH to 12-13. 75.6 mL of methyl tert-butyl ether was used for extraction and impurity removal, followed by adjustment of the pH to 3-4 with hydrochloric acid, extraction with 100 mL of ethyl acetate, and then washing with 38 mL of water twice, 38 mL of saturated brine once, drying with 12.6 g of anhydrous sodium sulfate, and vacuum filtration to obtain an ethyl acetate solution of pemafibrate; Step four, 100 mL of n-heptane was added to the ethyl acetate solution of pemafibrate in step three and heated to 65°C, and then decolorized with activated carbon for 30 min, and then filtered while hot. 100 mL of n-heptane was added to the obtained filtrate and incubated for 1 h, and then cooled to precipitate crystals, to obtain 14.7 g of pemafibrate, with a molar yield of 96.2%, an HPLC purity of 99.97%, and an ee value of 99.91%.

[0030] Example 4 This example includes the following steps: Step one, 50 g of PM02, 500 mL of acetonitrile, and 17.5 g of potassium bicarbonate were added to a 1 L reaction bottle and stirred under nitrogen protection; Step two, 40.0 g of PM03, 100 mL of acetonitrile were added to a 250 mL reaction bottle and stirred to dissolve, to form a PM03-acetonitrile mixture, which was then added dropwise to the stirred system in step one and reacted at room temperature for 22 h; Step three, 22.3g of potassium trimethylsilanolate was added to the system after the reaction in step two was completed at room temperature, and the reaction was continued at room temperature for 2.5h. After the reaction was completed, the filtrate was obtained by filtering, and then 3mol / L dilute hydrochloric acid was used to adjust the pH to neutral PH=6~7. The solvent was removed by rotary evaporation, and then 1mol / L sodium hydroxide solution was used to adjust the pH to 12~13. Then 400mL of methyl tert-butyl ether was used to extract the impurities, followed by adjusting the pH to 3~4 with hydrochloric acid and extracting with 450mL of ethyl acetate. Then, 200mL of water was used to wash twice, 200mL of saturated brine was used to wash once, 75g of anhydrous sodium sulfate was used for drying, and then the filtrate was obtained by suction filtration. Finally, the ethyl acetate solution of pemafibrate was obtained. Step four, 450mL of n-heptane was added to the ethyl acetate solution of pemafibrate in step three, and heated to 65℃. After decolorizing with activated carbon for 30min, the hot filtrate was obtained by filtering. Then 450mL of n-heptane was added to the filtrate and kept for 1h. The temperature was lowered to obtain 57.5g of pemafibrate, with a molar yield of 94.8%, a HPLC purity of 99.95%, and an ee value of 99.93%.

[0031] Example 5 This example includes the following steps: Step one, 50g of PM02, 500mL of acetonitrile and 20.5g of potassium carbonate were added to a 1L reaction bottle and stirred under nitrogen protection. Step two, 40.0g of PM03, 120mL of acetonitrile were added to a 250mL reaction bottle and stirred to dissolve to form a PM03-acetonitrile mixture. Then the mixture was added dropwise to the stirred system in step one and reacted at room temperature for 22h. Step three, 28.6g of potassium trimethylsilanolate was added to the system after the reaction in step two was completed at room temperature, and the reaction was continued at room temperature for 3h. After the reaction was completed, the filtrate was obtained by filtering, and then 3mol / L dilute hydrochloric acid was used to adjust the pH to neutral PH=6~7. The solvent was removed by rotary evaporation, and then 1mol / L sodium hydroxide solution was used to adjust the pH to 12~13. Then 300mL of methyl tert-butyl ether was used to extract the impurities, followed by adjusting the pH to 3~4 with hydrochloric acid and extracting with 400mL of ethyl acetate. Then, 150mL of water was used to wash twice, 150mL of saturated brine was used to wash once, 50g of anhydrous sodium sulfate was used for drying, and then the filtrate was obtained by suction filtration. Finally, the ethyl acetate solution of pemafibrate was obtained. Step four, 400mL of n-heptane was added to the ethyl acetate solution of pemafibrate in step three, and heated to 65℃. After decolorizing with activated carbon for 30min, the hot filtrate was obtained by filtering. Then 400mL of n-heptane was added to the filtrate and kept for 1h. The temperature was lowered to obtain 56.8g of pemafibrate, with a molar yield of 93.7%, a HPLC purity of 99.93%, and an ee value of 99.92%.

[0032] The above merely describes preferred embodiments of the present application, and is not intended to limit the present application. Any simple modification, change and equivalent variation of the above embodiments according to the technical essence of the present application are still within the protection scope of the technical scheme of the present application.

Claims

1. A process for the one-pot preparation of pemafibrate, characterized in that, The method comprises the following steps: Step one, stirring PM02, reaction solvent and inorganic base under nitrogen protection; Step two, dissolving PM03 and acetonitrile to prepare a PM03-acetonitrile mixture, then dropping into the stirred system in step one for room temperature reaction; Step three, adding potassium trimethylsilanol to the system after the room temperature reaction in step two, continuing the room temperature reaction, filtering after the reaction, adjusting the obtained filtrate to neutral PH=6~7 with 3mol / L dilute hydrochloric acid, removing the solvent by rotary evaporation, then adjusting to PH=12~13 with 1mol / L sodium hydroxide solution, and extracting impurities with methyl tert-butyl ether, then adjusting to PH=3~4 with hydrochloric acid and extracting with ethyl acetate, then washing twice with water, once with saturated brine, drying with anhydrous sodium sulfate and filtering, to obtain a pemetrexed ethyl acetate solution; Step four, adding n-heptane to the pemetrexed ethyl acetate solution in step three and heating, decolorizing with activated carbon and filtering while hot, adding n-heptane to the obtained filtrate and keeping warm, cooling and crystallizing, to obtain pemetrexed.

2. The process for one pot preparation of pemafibrate as claimed in claim 1 wherein, The reaction solvent in step one is acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran, and the inorganic base is sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.

3. The process for one pot preparation of pemafibrate as claimed in claim 1 wherein, The molar ratio of PM02 to inorganic base in step one is 1:1.0~1.4, and the mass ratio of PM02 to the volume of reaction solvent is 1:5~15, the unit of mass is g and the unit of volume is mL.

4. The process for one pot preparation of pemafibrate as claimed in claim 1 wherein, The molar ratio of PM02 in step one to PM03 in step two is 1:1.0~1.

2.

5. The process for one pot preparation of pemafibrate as claimed in claim 1 wherein, The mass ratio of PM03 to the volume of acetonitrile in step two is 1:2~4, the unit of mass is g and the unit of volume is mL.

6. The process for one pot preparation of pemafibrate as claimed in claim 1 wherein, The time of room temperature reaction in step two is 22h~26h.

7. The process for one pot preparation of pemafibrate as claimed in claim 1 wherein, The molar ratio of PM02 in step one to potassium trimethylsilanol in step three is 1:1.4~1.8, and the time of room temperature reaction is 2h~3h.

8. The process for one pot preparation of pemafibrate as claimed in claim 1 wherein, The mass ratio of PM02 in step one to the volume of methyl tert-butyl ether and ethyl acetate in step three is 1:4~8:6~10, the unit of mass is g and the unit of volume is mL.

9. The process for one pot preparation of pemafibrate as claimed in claim 1 wherein, The mass ratio of PM02 in step one to the volume of water, the volume of saturated brine and the mass of anhydrous sodium sulfate in step three is 1:2~4:2~4:0.5~1.5, the unit of mass is g and the unit of volume is mL.

10. The process for one pot preparation of pemafibrate as claimed in claim 1 wherein, The volume ratio of ethyl acetate in step three to n-heptane in step four is 1:2.

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