Preparation process of Elafibranor

Abstract

The invention relates to a preparation process of an Elafibranor. According to the preparation technology, a compound shown in a formula 1 and a compound shown in a formula 2 are selected to be subjected to an alkylation reaction to obtain a compound shown in a formula 3, the compound shown in the formula 3 and a compound shown in a formula 4 are subjected to a condensation process under the acidic condition, ester group hydrolysis is conducted at the same time, and finally configuration conversion is conducted under the alkaline condition to obtain a single-configuration product Elafibranor. By adding the compound shown in the formula 2 in batches, a good reaction yield can be obtained while the alpha-hydroxy tert-butyl isobutyrate with the equivalent weight not higher than 1.5 is used; the reaction product in each step can be directly obtained through recrystallization, due to the fact that the yield is high, complex aftertreatment is not needed, and the preparation method is suitable for batch production of the Elafibranor raw material medicine.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a preparation process of Elafibranor. Background Art

[0002] In June 2024, the U.S. FDA accelerated the approval of Ipsen's Iqirvo (elafibranor) 80 mg tablets in combination with ursodeoxycholic acid (UDCA) for the treatment of adult primary biliary cholangitis (PBC) who have an insufficient response to UDCA, or as a monotherapy for patients who are intolerant to UDCA. The approval of this therapy is mainly based on the positive results of the pivotal Phase 3 trial ELATIVE. The analysis showed that the primary composite endpoint achieved significant treatment benefit. The analysis showed that the difference between patients who achieved biochemical response in the 80 mg elafibranor group (51%) and the placebo group (4%) was 47% (P<0.001). In the trial, biochemical response was defined as alkaline phosphatase (ALP) <1.67×upper limit of normal (ULN) at week 52, ALP reduction ≥15%, and total bilirubin (TB) ≤ULN. ALP and bilirubin are important predictors of PBC disease progression. Reduced levels of both may indicate reduced cholestatic damage and improved liver function. In addition, only patients receiving elafibranor achieved normal ALP values ​​at week 52, including 15% of the drug group (P = 0.002), which was a key secondary endpoint of the trial. Elafibranor's significant biochemical effect was also shown in the rapid reduction of patients' ALP levels from baseline.

[0003] A decrease in ALP levels was observed as early as week 4 in patients in the elafibranor group and continued until week 52, with a 41% reduction in ALP in the elafibranor group compared with the placebo group.

[0004] PBC is a serious chronic liver disease. Due to chronic damage to the bile duct, the liver's ability to clear toxins from the body is reduced, leading to cirrhosis and liver failure. Currently, about 50% of PBC patients respond poorly to existing therapies or cannot tolerate the toxic side effects of the therapy. There is still a great unmet need in this field. Iqirvo is the first new drug approved in nearly a decade for the treatment of the rare liver disease primary biliary cholangitis.

[0005] The chemical structure of Elafibranor is shown in Formula I:

[0006]

[0007] The existing literature preparation process for synthesizing Elafibranor is to reflux 2,6-dimethylphenol and bromoisobutyrate in potassium carbonate / acetonitrile to obtain an ester intermediate, and then treat with 10 times the equivalent of trifluoroacetic acid to obtain Elafibranor. Among them, the first step of alkylation reaction requires the use of more than 3 times the equivalent of bromoisobutyrate, the reaction time is long, and after the reaction is completed, the phenol intermediate cannot be completely reacted, and a large amount of by-products are generated (such as the elimination product of bromoisobutyrate), which greatly affects the separation of the product and requires column chromatography for further purification. The second step of ester hydrolysis reaction requires the use of excessive trifluoroacetic acid, which is troublesome to post-process, and also increases the discharge of waste acid, which has environmental risks.

[0008] Therefore, the current preparation process of Elafibranor still needs to be improved. Summary of the invention

[0009] The present invention aims to solve at least one of the technical problems in the related art to a certain extent. To this end, one object of the present invention is to propose a preparation process of the compound Elafibranor represented by Formula I. Compared with the prior art, the preparation process of the present invention selects the compound represented by Formula 1 and the compound represented by Formula 2 to undergo alkylation reaction to obtain the compound represented by Formula 3, and the compound represented by Formula 3 and the compound represented by Formula 4 undergo condensation process under acidic conditions, and the ester group is hydrolyzed at the same time, and finally a configuration conversion occurs under alkaline conditions to obtain a single-configuration product Elafibranor.

[0010] In one aspect of the present invention, the present invention provides a preparation process of Elafibranor, a compound represented by Formula I. According to an embodiment of the present invention, the synthesis process comprises:

[0011] (1) The compound represented by Formula 1, the compound represented by Formula 2, and Cs 2 CO 3 Contacting to obtain the compound represented by formula 3;

[0012] (2) contacting the compound represented by Formula 3 with the compound represented by Formula 4 to obtain the compound represented by Formula 5;

[0013] (3) contacting the compound represented by Formula 5 with sodium tert-butoxide to obtain Elafibranor, a compound represented by Formula I,

[0014]

[0015] The inventors found that, using the preparation process of the present invention, the compound represented by Formula 1 and the compound represented by Formula 2, Cs 2 CO 3 As the starting material, it can be smoothly synthesized to obtain the target product Elafibranor through a total of 3 steps of reaction.

[0016] The term "contact" as used herein should be understood in a broad sense, and can be any manner that allows at least two reactants to undergo a chemical reaction, such as mixing the two reactants under appropriate conditions. If necessary, the reactants to be contacted can be mixed under stirring, and thus, the type of stirring is not particularly limited, and can be mechanical stirring, i.e. stirring under the action of mechanical force.

[0017] In this document, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features. In the description of the present invention, the meaning of "plurality" is two or more, unless otherwise clearly and specifically defined.

[0018] According to an embodiment of the present invention, the method for preparing the compound represented by Formula 3, the compound represented by Formula 5, and the compound represented by Formula I may also have at least one of the following additional technical features:

[0019] According to an embodiment of the present invention, the chemical reaction of the present invention can be carried out according to any method known in the art. The source of the raw materials of the compound shown in Formula 3, the compound shown in Formula 5, and the compound shown in Formula I is not particularly limited, and it can be prepared by any known method or commercially available. For example, the CAS of the compound shown in Formula 1 is: 400822-47-1, and the CAS of the compound shown in Formula 2 is: 36293-63-7.

[0020] According to an embodiment of the present invention, in step (1), the compound represented by formula 1, the compound represented by formula 2, Cs 2 CO 3 The contacting method is not particularly limited. Thus, the compound represented by Formula 1 and the compound represented by Formula 2, Cs 2 CO 3 The efficiency of the contact reaction is improved, the reaction speed is accelerated, and the efficiency of preparing the compound represented by Formula 3 by using this method is further improved.

[0021] According to an embodiment of the present invention, in step (1), the following steps are included: adding the compound represented by formula 1 and the compound represented by formula 2 to acetonitrile at room temperature, and then adding Cs 2 CO 3 The reaction solution was heated to 78-82°C and stirred for 9-12 hours, and the compound shown in Formula 2 and Cs 2 CO 3, continue to maintain the stirring reaction at 78-82°C for 9-12 hours, TLC shows that the compound shown in Formula 1 is completely reacted, the reaction solution is filtered through diatomaceous earth, the filtrate is concentrated under reduced pressure, the residue is dissolved in dichloromethane, washed with water, separated, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, the solid is recrystallized by adding petroleum ether / ethyl acetate mixed solvent, filtered, and dried under reduced pressure to obtain the compound shown in Formula 3. Thus, the compound shown in Formula 1 and the compound shown in Formula 2, Cs 2 CO 3 The efficiency of the contact reaction is improved, the reaction speed is accelerated, and the efficiency of preparing the compound represented by Formula 3 by using this method is further improved.

[0022] According to an embodiment of the present invention, in step (1), the compound represented by formula 1, the compound represented by formula 2, Cs 2 CO 3 The molar ratio is 1:(1.1-1.4):(2.4-4), preferably the compound represented by formula 1 and the compound represented by formula 2, Cs 2 CO 3 The molar ratio of is 1:1.2:3. Thus, the efficiency of preparing the compound represented by Formula 3 by this method can be further improved.

[0023] According to an embodiment of the present invention, in step (1), in the petroleum ether / ethyl acetate mixed solvent used for recrystallization, the volume ratio of petroleum ether to ethyl acetate is 10:1.

[0024] According to an embodiment of the present invention, in step (1), it is preferred that the reaction solution is heated to 78-82° C. and then stirred for reaction for 10 hours.

[0025] According to a specific embodiment of the present invention, in step (1), the following steps are included: at room temperature, the compound represented by formula 1 (15.0 g, 70.40 mmol) and the compound represented by formula 2 (6.77 g, 42.24 mmol) are added to acetonitrile (250 mL), and then Cs 2 CO 3 (34.41 g, 105.60 mmol), the reaction solution was heated to 78-82°C and stirred for 10 hours, and the compound shown in formula 2 (6.77 g, 42.24 mmol) and Cs 2 CO 3The mixture was stirred at 78-82°C for 10 hours. TLC showed that the compound of Formula 1 was completely reacted. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was dissolved in 200 mL of dichloromethane and washed with 400 mL of water. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness. The solid was recrystallized by adding 200 mL of a mixed solvent of petroleum ether / ethyl acetate (the volume ratio of petroleum ether to ethyl acetate was 10:1). The solid was filtered and dried under reduced pressure to obtain the compound of Formula 3. The yield was 15.71 g and the yield was 76.3%.

[0026] According to an embodiment of the present invention, in step (2), the contacting method of the compound represented by Formula 3 and the compound represented by Formula 4 is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 3 and the compound represented by Formula 4 can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 5 by using this method can be further improved.

[0027] According to an embodiment of the present invention, in step (2), the following steps are included: at room temperature, the compound of formula 3 and the compound of formula 4 are added to a methanol solution containing hydrogen chloride, maintained at 30°C and stirred for 3 hours, then cooled to 10°C, continued to stir for 1 hour, filtered the reaction solution, and dried the residue to obtain the compound of formula 5. In this way, the efficiency of the contact reaction between the compound of formula 3 and the compound of formula 4 can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 5 by using this method can be further improved.

[0028] According to an embodiment of the present invention, in step (2), the molar ratio of the compound represented by Formula 3 to the compound represented by Formula 4 is 1:(1.0-1.2), and preferably the molar ratio of the compound represented by Formula 3 to the compound represented by Formula 4 is 1:1.05. Thus, the efficiency of preparing the compound represented by Formula 5 using this method can be further improved.

[0029] According to a specific embodiment of the present invention, in step (2), the following steps are included: at room temperature, the compound represented by formula 3 (13.0 g, 44.46 mmol) and the compound represented by formula 4 (7.76 g, 46.68 mmol) are added to 56 mL of methanol solution containing hydrogen chloride, maintained at 30° C. and stirred for 3 hours, then cooled to 10° C., and stirred for 1 hour, the reaction solution is filtered, and the filter residue is dried to obtain the compound represented by formula 5, with an amount of 15.90 g and a yield of 93.0%.

[0030] According to an embodiment of the present invention, in step (3), the contacting method of the compound represented by Formula 5 and sodium tert-butoxide is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 5 and sodium tert-butoxide can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula I by using this method can be further improved.

[0031] According to an embodiment of the present invention, in step (3), the following steps are included: adding the compound shown in Formula 5 to toluene at 10°C, stirring, adding sodium tert-butoxide, heating the reaction solution to 50°C for reaction for 2 hours, and then post-processing, specifically adding water washing, layering, washing the organic phase with saturated brine, drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, adding methanol to the residue, maintaining the temperature at 10°C for pulping and purification, stirring for 1 hour, filtering the mixture, and vacuum drying the filter residue at 40°C to obtain the compound Elafibranor shown in Formula I. Thus, the efficiency of the contact reaction between the compound shown in Formula 5 and sodium tert-butoxide can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound shown in Formula I by using this method can be further improved.

[0032] According to an embodiment of the present invention, in step (3), the molar ratio of the compound represented by Formula 5 to sodium tert-butoxide is 1:1.3. Thus, the efficiency of preparing the compound represented by Formula I by this method can be further improved.

[0033] According to a specific embodiment of the present invention, in step (3), the following steps are included: at 10°C, the compound represented by formula 5 (12.3 g, 32.0 mmol) is added to 100 mL of toluene, stirred, sodium tert-butoxide (4.0 g, 41.6 mmol) is added, the reaction solution is heated to 50°C for reaction for 2 hours, 60 mL of water is added for washing, layering is performed, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase is concentrated under reduced pressure, 200 mL of methanol is added to the residue, the temperature is maintained at 10°C for pulping and purification, stirred for 1 hour, the mixture is filtered, and the filter residue is dried under vacuum at 40°C to obtain the compound represented by formula I, Elafibranor, with an amount of 11.7 g, a yield of 97.5%, HPLC: 99.52% (based on E configuration, Z configuration isomer accounts for 0.15%, and other largest single impurities account for 0.15%).

[0034] According to a specific embodiment of the present invention, the synthesis route of the compound Elafibranor represented by Formula I can be as follows:

[0035]

[0036] Compared with the prior art, the preparation process of Elafibranor described in the present invention has at least the following beneficial effects:

[0037] 1. Compared with the prior art, the preparation process described in the present invention selects the compound represented by Formula 1 and the compound represented by Formula 2 to undergo an alkylation reaction to obtain the compound represented by Formula 3, and the compound represented by Formula 3 and the compound represented by Formula 4 undergo a condensation process under acidic conditions, and the ester group is hydrolyzed at the same time, and finally a configuration conversion occurs under alkaline conditions to obtain a single-configuration product Elafibranor.

[0038] 2. Compared with the prior art methods, the present invention has the following significant advantages: (1) By adding the compound shown in Formula 2 in batches, a good reaction yield can be obtained while using no more than 1.5 equivalents of tert-butyl α-hydroxyisobutyrate. (2) The use of hydrochloric acid / methanol can not only cause the condensation process, but also the ester hydrolysis reaction. At the same time, the post-treatment of this step of the reaction only requires filtration, which has simpler operability than TFA. (3) The product of each step of the reaction can be directly obtained by recrystallization. Thanks to the high yield, there is no need for complicated post-treatment. The preparation method described in the present invention is suitable for the mass production of Elafibranor API. DETAILED DESCRIPTION

[0039] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used that do not specify the manufacturer are all conventional products that can be obtained commercially.

[0040] Example 1 Synthesis of the compound represented by formula 3

[0041] At room temperature, the compound represented by Formula 1 (15.0 g, 70.40 mmol) and the compound represented by Formula 2 (6.77 g, 42.24 mmol) were added to acetonitrile (250 mL), and then Cs 2 CO 3 (34.41 g, 105.60 mmol), the reaction solution was heated to 78-82°C and stirred for 10 hours, and the compound shown in formula 2 (6.77 g, 42.24 mmol) and Cs 2 CO 3 The mixture was stirred at 78-82°C for 10 hours. TLC showed that the compound of Formula 1 was completely reacted. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was dissolved in 200 mL of dichloromethane and washed with 400 mL of water. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness. The solid was recrystallized by adding 200 mL of a mixed solvent of petroleum ether / ethyl acetate (the volume ratio of petroleum ether to ethyl acetate was 10:1). The solid was filtered and dried under reduced pressure to obtain the compound of Formula 3. The yield was 15.71 g and the yield was 76.3%.

[0042] LC-MS (APCI): m / z = 293.2 (M+1) + .

[0043] Example 2 Synthesis of the compound represented by formula 3

[0044] At room temperature, the compound represented by Formula 1 (15.0 g, 70.40 mmol) and the compound represented by Formula 2 (6.20 g, 38.72 mmol) were added to acetonitrile (250 mL), and Cs 2 CO 3 (27.53 g, 84.48 mmol), the reaction solution was heated to 78-82°C and stirred for 9 hours, and the compound shown in formula 2 (6.20 g, 38.72 mmol) and Cs 2 CO 3 27.53 g, 84.48 mmol, continue to maintain stirring at 78-82 ° C for 9 hours, TLC shows that the compound shown in formula 1 is completely reacted, the reaction solution is filtered with diatomaceous earth, the filtrate is concentrated under reduced pressure, 200 mL of dichloromethane is added to the residue to dissolve, 400 mL of water is added to wash, the layers are separated, saturated brine is added to the organic phase to wash, and anhydrous sodium sulfate is dried, the organic phase is concentrated to dryness, 200 mL of petroleum ether / ethyl acetate mixed solvent (the volume ratio of petroleum ether to ethyl acetate is 10:1) is added to the solid for recrystallization, filtration, and drying under reduced pressure to obtain the compound shown in formula 3, with an amount of 15.29 g and a yield of 74.3%.

[0045] Example 3 Synthesis of the compound represented by formula 3

[0046] At room temperature, the compound represented by Formula 1 (15.0 g, 70.40 mmol) and the compound represented by Formula 2 (7.90 g, 49.28 mmol) were added to acetonitrile (250 mL), and then Cs 2 CO 3 (45.88 g, 140.8 mmol), the reaction solution was heated to 78-82°C and stirred for 12 hours, and the compound shown in formula 2 (7.90 g, 49.28 mmol) and Cs 2 CO 3 The mixture was stirred at 78-82°C for 12 hours. TLC showed that the compound of Formula 1 was completely reacted. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was dissolved in 200 mL of dichloromethane and washed with 400 mL of water. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness. The solid was recrystallized by adding 200 mL of a mixed solvent of petroleum ether / ethyl acetate (the volume ratio of petroleum ether to ethyl acetate was 10:1). The solid was filtered and dried under reduced pressure to obtain the compound of Formula 3. The yield was 15.60 g and the yield was 75.8%.

[0047] Comparative Example 1 Synthesis of the Compound Represented by Formula 3

[0048] At room temperature, the compound represented by Formula 1 (15.0 g, 70.40 mmol) and the compound represented by Formula 2 (5.64 g, 35.2 mmol) were added to acetonitrile (250 mL), and then Cs 2 CO 3 (18.35 g, 56.32 mmol), the reaction solution was heated to 78-82°C and stirred for 9 hours, and the compound shown in formula 2 (5.64 g, 35.2 mmol) and Cs 2 CO 3 The reaction was continued at 78-82°C with stirring for 9 hours. TLC showed that the compound of Formula 1 was completely reacted. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 200 mL of dichloromethane, washed with 400 mL of water, and separated. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness, and the solid was recrystallized by adding 200 mL of a mixed solvent of petroleum ether / ethyl acetate (the volume ratio of petroleum ether to ethyl acetate was 10:1). The solid was filtered and dried under reduced pressure to obtain the compound of Formula 3. The yield was 15.17 g and the yield was 73.7%.

[0049] The compound represented by Formula 1, the compound represented by Formula 2, and Cs 2 CO 3 After the molar ratio was changed to 1:1.0:1.6, the yield of the compound represented by Formula 3 was not further improved.

[0050] Example 4 Synthesis of the compound represented by formula 5

[0051] At room temperature, the compound represented by formula 3 (13.0 g, 44.46 mmol) and the compound represented by formula 4 (7.76 g, 46.68 mmol) were added to 56 mL of methanol solution containing hydrogen chloride, stirred at 30 ° C for 3 hours, then cooled to 10 ° C, and stirred for 1 hour. The reaction solution was filtered and the residue was dried to obtain the compound represented by formula 5, with an amount of 15.90 g and a yield of 93.0%.

[0052] LC-MS (APCI): m / z = 385.1 (M+1) + .

[0053] Example 5 Synthesis of the compound represented by formula 5

[0054] At room temperature, the compound represented by formula 3 (13.0 g, 44.46 mmol) and the compound represented by formula 4 (7.39 g, 44.46 mmol) were added to 56 mL of methanol solution containing hydrogen chloride, stirred at 30 ° C for 3 hours, then cooled to 10 ° C, and stirred for 1 hour. The reaction solution was filtered and the residue was dried to obtain the compound represented by formula 5, with an amount of 15.57 g and a yield of 91.1%.

[0055] Example 6 Synthesis of the compound represented by formula 5

[0056] At room temperature, the compound represented by formula 3 (13.0 g, 44.46 mmol) and the compound represented by formula 4 (8.87 g, 53.35 mmol) were added to 56 mL of methanol solution containing hydrogen chloride, stirred at 30 ° C for 3 hours, then cooled to 10 ° C, and stirred for 1 hour. The reaction solution was filtered and the residue was dried to obtain the compound represented by formula 5, with an amount of 15.80 g and a yield of 92.4%.

[0057] Comparative Example 2 Synthesis of the Compound Represented by Formula 5

[0058] At room temperature, the compound represented by formula 3 (13.0 g, 44.46 mmol) and the compound represented by formula 4 (7.10 g, 42.68 mmol) were added to 56 mL of methanol solution containing hydrogen chloride, stirred at 30 ° C for 3 hours, then cooled to 10 ° C, and stirred for 1 hour. The reaction solution was filtered and the residue was dried to obtain the compound represented by formula 5, with an amount of 14.97 g and a yield of 87.6%.

[0059] Changing the molar ratio of the compound represented by Formula 3 to the compound represented by Formula 4 to 1:0.96 did not further improve the yield of the compound represented by Formula 5.

[0060] Comparative Example 3 Synthesis of the Compound Represented by Formula 5

[0061] At room temperature, the compound represented by formula 3 (13.0 g, 44.46 mmol) and the compound represented by formula 4 (10.35 g, 62.24 mmol) were added to 56 mL of methanol solution containing hydrogen chloride, stirred at 30 ° C for 3 hours, then cooled to 10 ° C, stirred for 1 hour, the reaction solution was filtered, and the filter residue was dried to obtain the compound represented by formula 5, with an amount of 15.73 g and a yield of 92.0%.

[0062] Changing the molar ratio of the compound represented by Formula 3 to the compound represented by Formula 4 to 1:1.4 did not further improve the yield of the compound represented by Formula 5.

[0063] Example 7 Preparation of Elafibranor, a compound of formula I

[0064] At 10°C, the compound represented by Formula 5 (12.3 g, 32.0 mmol) was added to 100 mL of toluene and stirred. Sodium tert-butoxide (4.0 g, 41.6 mmol) was added, and the reaction solution was heated to 50°C for 2 hours. 60 mL of water was added for washing and layering. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. 200 mL of methanol was added to the residue. The temperature was maintained at 10°C for pulping and purification. Stirring for 1 hour, the mixture was filtered, and the filter residue was dried under vacuum at 40°C to obtain the compound represented by Formula I, Elafibranor, with an amount of 11.7 g and a yield of 97.5%. HPLC: 99.52% (based on E configuration, Z configuration isomer accounts for 0.15%, and other largest single impurities account for 0.15%).

[0065] LC-MS (APCI): m / z = 385.1 (M+1) + .

[0066] 1 H NMR(400MHz,DMSO-d6)d ppm 12.96(s,1H)8.11(m,J=8.56Hz,2H)7.85(d,J=15.55Hz,1H)7.65(d,J=15.53H z,1H)7.58(s,2H)7.40(m,J=8.58Hz,2H)2.59(s,3H)2.24(s,6H)1.40(s,6H).

[0067] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0068] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A process for preparing Elafibranor, characterized in that: include: (1) contacting the compound represented by Formula 1 with the compound represented by Formula 2 and Cs2CO3 to obtain the compound represented by Formula 3; (2) contacting the compound represented by Formula 3 with the compound represented by Formula 4 to obtain the compound represented by Formula 5; (3) contacting the compound represented by Formula 5 with sodium tert-butoxide to obtain Elafibranor, a compound represented by Formula I, 2. The method according to claim 1, characterized in that In step (1), the following steps are included: adding the compound of formula 1 and the compound of formula 2 to acetonitrile at room temperature, and then adding Cs2CO3, raising the temperature of the reaction solution to 78-82°C and stirring the reaction for 9-12 hours, adding the compound of formula 2 and Cs2CO3 again, and continuing to stir the reaction at 78-82°C for 9-12 hours, TLC showing that the compound of formula 1 is completely reacted, filtering the reaction solution with diatomaceous earth, concentrating the filtrate under reduced pressure, adding dichloromethane to dissolve the residue, washing with water, layering, washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, concentrating the organic phase, adding a petroleum ether / ethyl acetate mixed solvent to recrystallize the solid, filtering, and drying under reduced pressure to obtain a compound of formula 3.

3. The method according to claim 2, characterized in that In step (1), the molar ratio of the compound represented by formula 1 to the compound represented by formula 2 and Cs2CO3 is 1:(1.1-1.4):(2.4-4), and preferably the molar ratio of the compound represented by formula 1 to the compound represented by formula 2 and Cs2CO3 is 1:1.2:

3.

4. The method according to claim 2, characterized in that: In step (1), in the petroleum ether / ethyl acetate mixed solvent used for recrystallization, the volume ratio of petroleum ether to ethyl acetate is 10:

1.

5. The method according to claim 2, characterized in that: In step (1), it is preferred that the reaction solution is heated to 78-82°C and then stirred for 10 hours each time.

6. The method according to claim 1, characterized in that In step (2), the following steps are included: at room temperature, adding the compound represented by formula 3 and the compound represented by formula 4 to a methanol solution containing hydrogen chloride, maintaining the temperature at 30°C and stirring for 3 hours, then cooling to 10°C, continuing stirring for 1 hour, filtering the reaction solution, and drying the filter residue to obtain the compound represented by formula 5.

7. The method according to claim 6, characterized in that In step (2), the molar ratio of the compound represented by formula 3 to the compound represented by formula 4 is 1:(1.0-1.2), and preferably the molar ratio of the compound represented by formula 3 to the compound represented by formula 4 is 1:1.

05.

8. The method according to claim 1, characterized in that In step (3), the following steps are included: adding the compound represented by formula 5 to toluene at 10°C, stirring, adding sodium tert-butoxide, heating the reaction solution to 50°C for reaction for 2 hours, and then performing post-treatment, specifically adding water washing, layering, washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, adding methanol to the residue, maintaining the temperature at 10°C for pulping and purification, stirring for 1 hour, filtering the mixture, and vacuum drying the filter residue at 40°C to obtain the compound Elafibranor represented by formula I.

9. The method according to claim 8, characterized in that In step (3), the molar ratio of the compound represented by formula 5 to sodium tert-butoxide is 1:1.

3.

10. The method according to claim 1, characterized in that In step (1), the following steps are included: at room temperature, the compound represented by formula 1 (15.0 g, 70.40 mmol) and the compound represented by formula 2 (6.77 g, 42.24 mmol) are added to acetonitrile (250 mL), and then Cs2CO3 (34.41 g, 105.60 mmol) is added, the reaction solution is heated to 78-82° C. and stirred for 10 hours, the compound represented by formula 2 (6.77 g, 42.24 mmol) and Cs2CO3 (34.41 g, 105.60 mmol) are added again, and the reaction mixture is stirred for 10 hours. The mixture was stirred and reacted at 78-82°C for 10 hours. TLC showed that the compound of Formula 1 was completely reacted. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 200 mL of dichloromethane, washed with 400 mL of water, separated, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness, and the solid was recrystallized by adding 200 mL of a mixed solvent of petroleum ether / ethyl acetate (the volume ratio of petroleum ether to ethyl acetate was 10:1), filtered, and dried under reduced pressure to obtain the compound of Formula 3, with an amount of 15.71 g and a yield of 76.3%; In step (2), the following steps are included: at room temperature, the compound represented by formula 3 (13.0 g, 44.46 mmol) and the compound represented by formula 4 (7.76 g, 46.68 mmol) are added to 56 mL of methanol solution containing hydrogen chloride, maintained at 30° C. and stirred for 3 hours, then cooled to 10° C. and stirred for 1 hour, the reaction solution is filtered, and the filter residue is dried to obtain the compound represented by formula 5, with an amount of 15.90 g and a yield of 93.0%; In step (3), the following steps are included: at 10°C, the compound represented by formula 5 (12.3 g, 32.0 mmol) is added to 100 mL of toluene, stirred, sodium tert-butoxide (4.0 g, 41.6 mmol) is added, the reaction solution is heated to 50°C for reaction for 2 hours, 60 mL of water is added for washing, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase is concentrated under reduced pressure, 200 mL of methanol is added to the residue, the temperature is maintained at 10°C for pulping and purification, stirred for 1 hour, the mixture is filtered, and the filter residue is vacuum dried at 40°C to obtain the compound represented by formula I, Elafibranor, with an amount of 11.7 g, a yield of 97.5%, HPLC: 99.52% (based on E configuration, Z configuration isomer accounts for 0.15%, and other largest single impurities account for 0.15%). .

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