Synthesis method of Elafibranor
The E-configuration intermediate was generated through triphenylphosphine construction and condensation reaction, and combined with the alkylation reaction, the problem of close polarity of intermediate mixtures in the existing Elafibranor synthesis was solved, and an efficient and simple synthesis route was achieved, suitable for industrialization. Production.
Patent Information
- Application Number
- CN202411324863.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-23
- Publication Date
- 2025-01-03
AI Technical Summary
In the existing synthesis method of Elafibranor, the Z-type and E-type mixtures of intermediates IV and II are difficult to avoid, resulting in close polarity of the product, difficult to crystallize and purify, which is not conducive to industrial production.
The construction reaction with compound 1 was performed to form intermediate 2, and then condensed with compound 3 to form intermediate 4 in the E configuration, and finally alkylated with compound 5 to obtain Elafibranor.
Through this method, the synthesis efficiency and simplicity of purification of Elafibranor are improved, suitable for industrial production, and have good cost-effectiveness.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of biomedicine, and in particular to a method for synthesizing 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 synthesis methods of the prior art, such as US20060142611 or US20050176808, are to condense 4-methylthioacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde to obtain intermediate IV of Elafibranor, which is then reacted with tert-butyl 2-bromoisobutyrate to obtain intermediate II, and then obtain Elafibranor.
[0008]
[0009] Among them, in the process of forming double bonds during the condensation of 4-methylthioacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde, it is difficult to avoid the formation of a mixture of Z-form and E-form of intermediate IV, and the intermediate II obtained by the reaction with tert-butyl 2-bromoisobutyrate is also a mixture of Z-form and E-form. The polarity of the E-form isomer is very close to that of the Z-form, and it is difficult to crystallize and purify. The product requires very precise column chromatography, which is not conducive to industrial production.
[0010] Therefore, the current synthesis method for Elafibranor still needs to be improved. Summary of the invention
[0011] 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 method for synthesizing the compound Elafibranor represented by Formula I. Compared with the prior art, the method described in the present invention selects the compound represented by Formula 1 and triphenylphosphine to construct the intermediate compound represented by Formula 2, which is then subjected to a condensation reaction with the compound represented by Formula 3 to obtain the compound represented by Formula 4, wherein the compound represented by Formula 4 is of E-formula configuration, and finally the compound represented by Formula 4 is subjected to an alkylation reaction with the compound represented by Formula 5 to obtain the product Elafibranor.
[0012] In one aspect of the present invention, the present invention provides a method for synthesizing Elafibranor, a compound represented by Formula I. According to an embodiment of the present invention, the synthesis process comprises:
[0013] (1) contacting the compound represented by Formula 1 with triphenylphosphine to obtain the compound represented by Formula 2;
[0014] (2) contacting the compound represented by Formula 2 with the compound represented by Formula 3 to obtain the compound represented by Formula 4;
[0015] (3) The compound represented by Formula 4 is mixed with the compound represented by Formula 5, Cs 2 CO 3 , CuI, so as to obtain the compound Elafibranor represented by formula I,
[0016]
[0017] The inventors have found that, using the synthesis method of the present invention, the compound shown in Formula 1 and triphenylphosphine are used as starting materials, and a total of three steps of reaction are performed to successfully synthesize and prepare the target product Elafibranor.
[0018] 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.
[0019] 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.
[0020] According to an embodiment of the present invention, the method for preparing the compound represented by Formula 2, the compound represented by Formula 4, and the compound represented by Formula I may also have at least one of the following additional technical features:
[0021] According to an embodiment of the present invention, the chemical reaction described in 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 2, the compound shown in Formula 4, and the compound shown in Formula 1 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: 42445-46-5, the CAS of the compound shown in Formula 2 is: 603-35-0, and the CAS of the compound shown in Formula 3 is: 400822-47-1.
[0022] According to an embodiment of the present invention, in step (1), the contacting method of the compound represented by Formula 1 and triphenylphosphine is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 1 and triphenylphosphine can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 2 by using this method can be further improved.
[0023] According to an embodiment of the present invention, in step (1), the following steps are included: dissolving triphenylphosphine in benzene at room temperature, adding the compound shown in Formula 1, maintaining room temperature and continuing stirring for 6 to 7 hours, monitoring the complete reaction of the compound shown in Formula 1 by thin layer chromatography (TLC), filtering the reaction solution, washing the filter cake with an appropriate amount of benzene, and drying under reduced pressure to obtain the compound shown in Formula 2. Thus, the efficiency of the contact reaction between the compound shown in Formula 1 and triphenylphosphine can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound shown in Formula 2 by using this method can be further improved.
[0024] According to an embodiment of the present invention, in step (1), the molar ratio of the compound represented by Formula 1 to triphenylphosphine is 1:(1.0-1.2), and preferably the molar ratio of the compound represented by Formula 1 to triphenylphosphine is 1:1.03. Thus, the efficiency of preparing the compound represented by Formula 2 by this method can be further improved.
[0025] According to an embodiment of the present invention, in step (1), preferably the stirring is continued at room temperature for 6.5 hours.
[0026] According to a specific embodiment of the present invention, in step (1), the following steps are included: at room temperature, triphenylphosphine (11.02 g, 42.01 mmol) is dissolved in benzene (120 mL), and then the compound represented by formula 1 (10.0 g, 40.79 mmol) is added, and the mixture is stirred at room temperature for 6.5 hours, and the complete reaction of the compound represented by formula 1 is monitored by thin layer chromatography (TLC), the reaction solution is filtered, the filter cake is washed with an appropriate amount of benzene, and the mixture is dried under reduced pressure to obtain the compound represented by formula 2, with an amount of 17.26 g and a yield of 99.2%.
[0027] According to an embodiment of the present invention, in step (2), the contacting method of the compound represented by Formula 2 and the compound represented by Formula 3 is not particularly limited. Thus, the efficiency of the contact reaction between the compound represented by Formula 2 and the compound represented by Formula 3 can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound represented by Formula 4 by using this method can be further improved.
[0028] According to an embodiment of the present invention, in step (2), the following steps are included: at room temperature, the compound of formula 2 and the compound of formula 3 are dissolved in anhydrous tetrahydrofuran, kept at room temperature, and the reaction solution is stirred for 45 to 55 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent to obtain a compound of formula 4. In this way, the efficiency of the contact reaction between the compound of formula 2 and the compound of formula 3 can be improved, the reaction speed can be accelerated, and the efficiency of preparing the compound of formula 4 using this method can be further improved.
[0029] According to an embodiment of the present invention, in step (2), the molar ratio of the compound represented by Formula 2 to the compound represented by Formula 3 is (2.5-4):1, and preferably the molar ratio of the compound represented by Formula 2 to the compound represented by Formula 3 is 3:1. Thus, the efficiency of preparing the compound represented by Formula 4 by this method can be further improved.
[0030] According to an embodiment of the present invention, in step (2), the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate mixed solvent is (6-12):1, and preferably the volume ratio of petroleum ether / ethyl acetate mixed solvent is 10:1.
[0031] According to an embodiment of the present invention, in step (2), the reaction solution is preferably stirred for 48 hours.
[0032] 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 2 (15.0 g, 35.17 mmol) and the compound represented by formula 3 (2.5 g, 11.73 mmol) are dissolved in anhydrous tetrahydrofuran (150 ml), kept at room temperature, and the reaction solution is stirred for 48 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 10:1 to obtain a compound represented by formula 4, with an amount of 4.10 g and a yield of 96.7%.
[0033] LC-MS (APCI): m / z = 361.0 (M+1) + .
[0034] 1 H NMR (400 MHz, CDCl 3 )δ7.99(d,J=8.6Hz,1H);7.75(d,J=15.4Hz,2H);7.42(d,J=15.5Hz,1H);7.36-7.28(m,4H);2.57(s,3H);2.32(s,6H).
[0035] According to Scifinder search, the compound represented by formula 4 is a new compound that has not been reported in the literature.
[0036] According to a specific embodiment of the present invention, the use of the compound represented by Formula 4 is as an intermediate compound for preparing the compound represented by Formula I, Elafibranor.
[0037] According to an embodiment of the present invention, in step (3), the compound represented by formula 4, the compound represented by formula 5, Cs 2 CO 3 The contacting method of the compound represented by Formula 4 and the compound represented by Formula 5, Cs 2CO 3 , the efficiency of the CuI contact reaction, accelerate the reaction speed, and further improve the efficiency of preparing the compound represented by formula I using this method.
[0038] According to an embodiment of the present invention, in step (3), the following steps are included: under a nitrogen atmosphere, adding the compound represented by formula 4 and the compound represented by formula 5 to DMF, stirring, adding Cs 2 CO 3 , cuprous iodide (CuI), the reaction solution was heated to 90-110°C and stirred for 10-13 hours. TLC showed that the compound shown in Formula 4 was completely reacted. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, DMF was removed as much as possible, ethyl acetate was added to dissolve the remaining liquid, and then HCl solution was added for washing. The organic phase was concentrated under reduced pressure, and a petroleum ether / ethyl acetate mixed solvent was added for recrystallization, filtration, and drying under reduced pressure to obtain the compound Elafibranor shown in Formula I. Thus, the compound shown in Formula 4 and the compound shown in Formula 5, Cs 2 CO 3 , the efficiency of the CuI contact reaction, accelerate the reaction speed, and further improve the efficiency of preparing the compound represented by formula I using this method.
[0039] According to an embodiment of the present invention, in step (3), the compound represented by formula 4, the compound represented by formula 5, Cs 2 CO 3 , CuI is 1:(1.1-1.6):(1.2-2.5):(0.15-0.4), preferably the compound represented by formula 4 and the compound represented by formula 5, Cs 2 CO 3 The molar ratio of CuI is 1:1.3:1.5:0.2. Thus, the efficiency of preparing the compound represented by formula I by this method can be further improved.
[0040] According to an embodiment of the present invention, in step (3), the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate mixed solvent is 10:1.
[0041] According to an embodiment of the present invention, in step (3), the reaction solution is preferably heated to 98-100° C. and then stirred for 10 hours.
[0042] According to a specific embodiment of the present invention, in step (3), the following steps are included: under a nitrogen atmosphere, the compound represented by formula 4 (35.0 g, 96.87 mmol) and the compound represented by formula 5 (13.1 g, 125.9 mmol) are added to DMF (400 mL), stirred, and Cs 2 CO 3(47.34 g, 145.3 mmol), cuprous iodide (CuI) (3.70 g, 19.4 mmol), the reaction solution was heated to 98-100°C and stirred for 10 hours. TLC showed that the compound shown in Formula 4 was completely reacted. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove DMF as much as possible. The remaining liquid was dissolved in 500 mL of ethyl acetate, and then 1M HCl solution (about 300 mL) was added for washing. The organic phase was concentrated under reduced pressure, and 300 mL of petroleum ether / ethyl acetate mixed solvent (volume ratio of 10:1) was added for recrystallization, filtered, and dried under reduced pressure to obtain the compound shown in Formula I, Elafibranor, with an amount of 31.47 g, a yield of 84.5%, and a purity of 99.7% (HPLC).
[0043] According to a specific embodiment of the present invention, the synthesis route of the compound Elafibranor represented by Formula I can be as follows:
[0044]
[0045] Compared with the prior art, the synthesis method of Elafibranor described in the present invention has at least the following beneficial effects:
[0046] 1. Compared with the prior art, the method described in the present invention selects the compound shown in Formula 1 and triphenylphosphine to construct the intermediate compound shown in Formula 2, which is then subjected to a condensation reaction with the compound shown in Formula 3 to obtain the compound shown in Formula 4, wherein the compound shown in Formula 4 is an E-configuration, and finally the compound shown in Formula 4 is subjected to an alkylation reaction with the compound shown in Formula 5 to obtain the product Elafibranor.
[0047] 2. Prior art In the process of forming double bonds during the condensation of 4-methylthioacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde, it is difficult to avoid the production of a Z-form and E-form mixture of intermediate IV, and the intermediate II obtained by reacting with tert-butyl 2-bromoisobutyrate is also a Z-form and E-form mixture. The polarity of the E-form isomer is very close to that of the Z-form, and it is difficult to crystallize and purify. The product requires very precise column chromatography, which is not conducive to industrial production. The present invention uses triphenylphosphine to construct the intermediate compound 2 of the condensation process, and then generates the E-form configuration with compound 3. In addition, the use of triphenylphosphine intermediates can effectively improve the yield in the condensation process, is suitable for industrial production and has good cost-effectiveness. In short, the synthesis method described in the present invention has the advantages of high yield, simple purification, etc., is easy to realize industrialization, and is very suitable for large-scale industrial production. DETAILED DESCRIPTION
[0048] 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.
[0049] Example 1 Synthesis of the compound represented by formula 2
[0050] At room temperature, triphenylphosphine (11.02 g, 42.01 mmol) was dissolved in benzene (120 mL), and the compound represented by formula 1 (10.0 g, 40.79 mmol) was added, and the mixture was stirred at room temperature for 6.5 hours. The reaction of the compound represented by formula 1 was monitored by thin layer chromatography (TLC). The reaction solution was filtered, the filter cake was washed with an appropriate amount of benzene, and the mixture was dried under reduced pressure to obtain the compound represented by formula 2. The yield was 17.26 g, and the yield was 99.2%.
[0051] LC-MS (APCI): m / z = 427.1 (M+1) + .
[0052] Example 2 Synthesis of the compound represented by formula 2
[0053] At room temperature, triphenylphosphine (10.7 g, 40.79 mmol) was dissolved in benzene (120 mL), and the compound represented by formula 1 (10.0 g, 40.79 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction of the compound represented by formula 1 was monitored by thin layer chromatography (TLC). The reaction solution was filtered, the filter cake was washed with an appropriate amount of benzene, and dried under reduced pressure to obtain the compound represented by formula 2, with an amount of 17.05 g and a yield of 98.0%.
[0054] Example 3 Synthesis of the compound represented by formula 2
[0055] At room temperature, triphenylphosphine (12.84 g, 48.95 mmol) was dissolved in benzene (120 mL), and the compound represented by formula 1 (10.0 g, 40.79 mmol) was added, and the mixture was stirred at room temperature for 7 hours. The reaction of the compound represented by formula 1 was monitored by thin layer chromatography (TLC). The reaction solution was filtered, the filter cake was washed with an appropriate amount of benzene, and the mixture was dried under reduced pressure to obtain the compound represented by formula 2. The yield was 17.20 g, and the yield was 98.9%.
[0056] LC-MS (APCI): m / z = 427.1 (M+1) + .
[0057] Comparative Example 1 Synthesis of the Compound Represented by Formula 2
[0058] At room temperature, triphenylphosphine (14.98 g, 57.11 mmol) was dissolved in benzene (120 mL), and the compound represented by formula 1 (10.0 g, 40.79 mmol) was added, and the mixture was stirred at room temperature for 7 hours. The reaction of the compound represented by formula 1 was monitored by thin layer chromatography (TLC). The reaction solution was filtered, and the residue was washed with benzene and dried under reduced pressure to obtain the compound represented by formula 2. The yield was 17.03 g, and the yield was 97.9%.
[0059] Changing the molar ratio of the compound represented by Formula 1 to triphenylphosphine to 1:1.4 did not further improve the efficiency (yield) of preparing the compound represented by Formula 2.
[0060] Example 4 Synthesis of the compound represented by formula 4
[0061] The synthetic route is as follows:
[0062]
[0063] At room temperature, the compound represented by formula 2 (15.0 g, 35.17 mmol) and the compound represented by formula 3 (2.5 g, 11.73 mmol) were dissolved in anhydrous tetrahydrofuran (150 ml), kept at room temperature, and the reaction solution was stirred for 48 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography with a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 10:1 to obtain the compound represented by formula 4, with an amount of 4.10 g and a yield of 96.7%.
[0064] LC-MS (APCI): m / z = 361.0 (M+1) + .
[0065] 1 H NMR (400 MHz, CDCl 3 )δ7.99(d,J=8.6Hz,1H);7.75(d,J=15.4Hz,2H);7.42(d,J=15.5Hz,1H);7.36-7.28(m,4H);2.57(s,3H);2.32(s,6H).
[0066] Example 5 Synthesis of the compound represented by formula 4
[0067] At room temperature, the compound represented by formula 2 (12.51 g, 29.33 mmol) and the compound represented by formula 3 (2.5 g, 11.73 mmol) were dissolved in anhydrous tetrahydrofuran (150 ml), kept at room temperature, and the reaction solution was stirred for 45 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography with a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 6:1 to obtain the compound represented by formula 4, with an amount of 3.98 g and a yield of 94.0%.
[0068] Example 6 Synthesis of the compound represented by formula 4
[0069] At room temperature, the compound represented by formula 2 (20.01 g, 46.92 mmol) and the compound represented by formula 3 (2.5 g, 11.73 mmol) were dissolved in anhydrous tetrahydrofuran (150 ml), kept at room temperature, and the reaction solution was stirred for 55 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography with a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 12:1 to obtain the compound represented by formula 4, with an amount of 4.05 g and a yield of 95.5%.
[0070] Comparative Example 2 Synthesis of the Compound Represented by Formula 4
[0071] At room temperature, the compound represented by formula 2 (7.50 g, 17.60 mmol) and the compound represented by formula 3 (2.5 g, 11.73 mmol) were dissolved in anhydrous tetrahydrofuran (150 ml), kept at room temperature, and the reaction solution was stirred for 42 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography with a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 10:1 to obtain the compound represented by formula 4, with an amount of 3.92 g and a yield of 92.5%.
[0072] It can be seen that changing the molar ratio of the compound represented by Formula 2 to the compound represented by Formula 3 to 1.5:1 and adjusting the stirring reaction to 42 hours did not further improve the efficiency (yield) of preparing the compound represented by Formula 4.
[0073] Example 7 Synthesis of Elafibranor, a compound represented by Formula I
[0074] Under nitrogen atmosphere, the compound represented by Formula 4 (35.0 g, 96.87 mmol) and the compound represented by Formula 5 (13.1 g, 125.9 mmol) were added to DMF (400 mL) and stirred. Cs 2 CO 3 (47.34 g, 145.3 mmol), cuprous iodide (CuI) (3.70 g, 19.4 mmol), the reaction solution was heated to 98-100°C and stirred for 10 hours. TLC showed that the compound shown in Formula 4 was completely reacted. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove DMF as much as possible. The remaining liquid was dissolved in 500 mL of ethyl acetate, and then washed with 1M HCl solution (about 300 mL). The organic phase was concentrated under reduced pressure, and 300 mL of petroleum ether / ethyl acetate (volume ratio of 10:1) was added for recrystallization, filtered, and dried under reduced pressure to obtain the compound Elafibranor shown in Formula I, with an amount of 31.47 g, a yield of 84.5%, and a purity of 99.7% (HPLC).
[0075] LC-MS (APCI): m / z = 385.1 (M+1) + .
[0076] 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).
[0077] Example 8 Synthesis of Elafibranor, a compound represented by Formula I
[0078] Under nitrogen atmosphere, the compound represented by Formula 4 (35.0 g, 96.87 mmol) and the compound represented by Formula 5 (11.19 g, 106.56 mmol) were added to DMF (400 mL) and stirred. Cs 2 CO 3 (37.87 g, 116.24 mmol), CuI (2.77 g, 14.53 mmol), the reaction solution was heated to 90-95°C and stirred for 13 hours. TLC showed that the compound shown in formula 4 was completely reacted. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove DMF as much as possible. The remaining liquid was dissolved in 500 mL of ethyl acetate, and then 1M HCl solution (about 300 mL) was added for washing. The organic phase was concentrated under reduced pressure, and 300 mL of petroleum ether / ethyl acetate mixed solvent (volume ratio of 10:1) was added for recrystallization, filtered, and dried under reduced pressure to obtain the compound shown in formula I, Elafibranor, with an amount of 30.09 g, a yield of 80.8%, and a purity of 99.5% (HPLC).
[0079] Example 9 Synthesis of Elafibranor, a compound represented by Formula I
[0080] Under nitrogen atmosphere, the compound represented by Formula 4 (35.0 g, 96.87 mmol) and the compound represented by Formula 5 (16.13 g, 155.0 mmol) were added to DMF (400 mL) and stirred. Cs 2 CO 3(78.91 g, 242.2 mmol), CuI (7.38 g, 38.75 mmol), the reaction solution was heated to 105-110°C and stirred for 11 hours. TLC showed that the compound shown in formula 4 was completely reacted. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove DMF as much as possible. The remaining liquid was dissolved in 500 mL of ethyl acetate, and then washed with 1M HCl solution (about 300 mL). The organic phase was concentrated under reduced pressure, and 300 mL of petroleum ether / ethyl acetate mixed solvent (volume ratio of 10:1) was added for recrystallization, filtered, and dried under reduced pressure to obtain the compound shown in formula I, Elafibranor, with an amount of 31.13 g, a yield of 83.6%, and a purity of 99.4% (HPLC).
[0081] Comparative Example 3 Synthesis of Elafibranor, a Compound Represented by Formula I
[0082] Under nitrogen atmosphere, the compound represented by Formula 4 (35.0 g, 96.87 mmol) and the compound represented by Formula 5 (10.08 g, 96.87 mmol) were added to DMF (400 mL) and stirred. Cs 2 CO 3 The reaction solution was heated to 98-100°C and stirred for 10 hours. TLC showed that the compound shown in Formula 4 was completely reacted. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove DMF as much as possible. The remaining liquid was dissolved in 500 mL of ethyl acetate, and then washed with 1M HCl solution (about 300 mL). The organic phase was concentrated under reduced pressure, and 300 mL of petroleum ether / ethyl acetate mixed solvent (volume ratio of 10:1) was added for recrystallization, filtered, and dried under reduced pressure to obtain the compound shown in Formula I, Elafibranor, with an amount of 28.57 g, a yield of 76.7%, and a purity of 98.1% (HPLC).
[0083] It can be seen that the compound shown in Formula 4, the compound shown in Formula 5, and Cs 2 CO 3 After the molar ratio of cuprous iodide is changed to 1:1.0:1.0:0.1, the yield of the compound represented by formula I is not further improved, and the purity of the compound represented by formula I is reduced.
[0084] Comparative Example 4 Synthesis of Elafibranor, a Compound Represented by Formula I
[0085] Under nitrogen atmosphere, the compound represented by Formula 4 (35.0 g, 96.87 mmol) and the compound represented by Formula 5 (18.15 g, 174.4 mmol) were added to DMF (400 mL) and stirred. Cs 2 CO 3The reaction solution was heated to 105-110°C and stirred for 13 hours. TLC showed that the compound shown in Formula 4 was completely reacted. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove DMF as much as possible. The remaining liquid was dissolved in 500 mL of ethyl acetate, and then washed with 1M HCl solution (about 300 mL). The organic phase was concentrated under reduced pressure, and 300 mL of petroleum ether / ethyl acetate mixed solvent (volume ratio of 10:1) was added for recrystallization, filtered, and dried under reduced pressure to obtain the compound shown in Formula I, Elafibranor, with an amount of 29.87 g, a yield of 80.2%, and a purity of 99.0% (HPLC).
[0086] It can be seen that the compound shown in Formula 4, the compound shown in Formula 5, and Cs 2 CO 3 After the molar ratio of cuprous iodide is changed to 1:1.8:3.0:0.5, the yield of the compound represented by formula I is not further improved, and the purity of the compound represented by formula I is reduced.
[0087] 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.
[0088] 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 method for synthesizing Elafibranor, characterized in that: include: (1) contacting the compound represented by Formula 1 with triphenylphosphine to obtain the compound represented by Formula 2; (2) contacting the compound represented by Formula 2 with the compound represented by Formula 3 to obtain the compound represented by Formula 4; (3) contacting the compound represented by Formula 4 with the compound represented by Formula 5, Cs2CO3, and CuI 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: at room temperature, triphenylphosphine is dissolved in benzene, and then the compound shown in formula 1 is added, and stirring is continued at room temperature for 6 to 7 hours, and the complete reaction of the compound shown in formula 1 is monitored by thin layer chromatography (TLC), the reaction solution is filtered, the filter cake is washed with an appropriate amount of benzene, and the filter cake is dried under reduced pressure to obtain the compound shown in formula 2.
3. The method according to claim 2, characterized in that In step (1), the molar ratio of the compound represented by formula 1 to triphenylphosphine is 1:(1.0-1.2), preferably the molar ratio of the compound represented by formula 1 to triphenylphosphine is 1:1.03; Optionally, in step (1), stirring is preferably continued for 6.5 hours while maintaining room temperature.
4. The method according to claim 1, characterized in that: In step (2), the following steps are included: at room temperature, dissolving the compound represented by formula 2 and the compound represented by formula 3 in anhydrous tetrahydrofuran, maintaining the mixture at room temperature, stirring the reaction solution for 45 to 55 hours, and after the reaction is completed, concentrating the reaction solution under reduced pressure, and purifying the concentrate by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent to obtain a compound represented by formula 4.
5. The method according to claim 4, characterized in that In step (2), the molar ratio of the compound represented by formula 2 to the compound represented by formula 3 is (2.5-4):1, preferably the molar ratio of the compound represented by formula 2 to the compound represented by formula 3 is 3:1; Optionally, in step (2), the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate mixed solvent is (6-12):1, preferably the volume ratio of petroleum ether / ethyl acetate mixed solvent is 10:1; Optionally, in step (2), the reaction solution is preferably stirred for 48 hours.
6. The method according to claim 1, characterized in that In step (3), the following steps are included: under a nitrogen atmosphere, adding the compound represented by formula 4 and the compound represented by formula 5 to DMF, stirring, adding Cs2CO3 and cuprous iodide (CuI), heating the reaction solution to 90-110°C and stirring for 10-13 hours, TLC showing that the compound represented by formula 4 is completely reacted, filtering the reaction solution with diatomaceous earth, concentrating the filtrate under reduced pressure, removing DMF as much as possible, adding ethyl acetate to dissolve the remaining liquid, then adding HCl solution for washing, concentrating the organic phase under reduced pressure, adding a petroleum ether / ethyl acetate mixed solvent for recrystallization, filtering, and drying under reduced pressure to obtain the compound represented by formula I, Elafibranor.
7. The method according to claim 6, characterized in that In step (3), the molar ratio of the compound represented by formula 4 to the compound represented by formula 5, Cs2CO3, and CuI is 1:(1.1-1.6):(1.2-2.5):(0.15-0.4), preferably the molar ratio of the compound represented by formula 4 to the compound represented by formula 5, Cs2CO3, and CuI is 1:1.3:1.5:0.2; Optionally, in step (3), the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate mixed solvent is 10:1; Optionally, in step (3), the reaction solution is preferably heated to 98-100° C. and stirred for 10 hours.
8. The method according to claim 1, characterized in that In step (1), the following steps are included: at room temperature, triphenylphosphine (11.02 g, 42.01 mmol) is dissolved in benzene (120 mL), and then the compound represented by formula 1 (10.0 g, 40.79 mmol) is added, and the mixture is stirred at room temperature for 6.5 hours, and the reaction of the compound represented by formula 1 is completely monitored by thin layer chromatography (TLC), the reaction solution is filtered, the filter cake is washed with an appropriate amount of benzene, and the mixture is dried under reduced pressure to obtain the compound represented by formula 2, with an amount of 17.26 g and a yield of 99.2%; In step (2), the following steps are included: at room temperature, the compound represented by formula 2 (15.0 g, 35.17 mmol) and the compound represented by formula 3 (2.5 g, 11.73 mmol) are dissolved in anhydrous tetrahydrofuran (150 ml), kept at room temperature, and the reaction solution is stirred for 48 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 10:1 to obtain a compound represented by formula 4, with an amount of 4.10 g and a yield of 96.7%; In step (3), the following steps are included: under a nitrogen atmosphere, the compound represented by formula 4 (35.0 g, 96.87 mmol) and the compound represented by formula 5 (13.1 g, 125.9 mmol) are added to DMF (400 mL), stirred, Cs2CO3 (47.34 g, 145.3 mmol) and cuprous iodide (CuI) (3.70 g, 19.4 mmol) are added, the reaction solution is heated to 98-100° C. and stirred for 10 hours, and TLC shows that the compound represented by formula 4 is The reaction mixture was completely reacted, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to remove DMF as much as possible, and the remaining liquid was dissolved in 500 mL of ethyl acetate, and then washed with 1 M HCl solution (about 300 mL). The organic phase was concentrated under reduced pressure, and 300 mL of a mixed solvent of petroleum ether / ethyl acetate (volume ratio of 10:1) was added for recrystallization, filtered, and dried under reduced pressure to obtain Elafibranor, a compound of formula I, with an amount of 31.47 g, a yield of 84.5%, and a purity of 99.7% (HPLC).
9. A compound having a chemical structure as shown in Formula 4:
10. The compound of formula 4 according to claim 9, which is used as an intermediate compound for preparing Elafibranor, a compound of formula I.