A method of synthesizing an lxr agonist

Abstract

The application provides a synthesis method of an LXR agonist 4-phenyl-8-trifluoromethylquinoline-3-benzophenone, which can overcome the defects of existing LXR agonist synthesis methods, such as expensive starting material, many and complex steps, and the need to use noble metal palladium, and the synthesis method adopts mild reaction conditions, and LXR agonist is synthesized by nickel instead of palladium catalysis, and is suitable for large-scale industrial production.

Description

[Technical Field]

[0001] This invention belongs to the field of catalytic organic synthesis, and specifically relates to the synthesis of an LXR (liver X receptor) agonist, 4-phenyl-8-trifluoromethylquinoline-3-benzophenone. [Background Technology]

[0002] LXRs are a type of nuclear hormone receptor involved in the regulation of cholesterol and lipid metabolism. They are ligand-activated transcription factors that bind to DNA as a heterodimer specific to the retinoic acid X receptor (RXR). Several commonly used LXR agonists include the natural ligand 24-(S),25-epoxycholesterol, and two structurally different synthetic nonsteroidal ligands (GW3965) and (TO901317). One adverse effect observed in these known LXR compounds is a significant increase in serum and hepatic triglyceride levels by upregulating SREBP-1c and other adipogenic genes in the liver. The LXR agonist 4-phenyl-8-trifluoromethylquinoline-3-benzophenone effectively addresses these issues (J. Med. Chem. 2006, 49, 6151-6154).

[0003] Existing synthetic methods suffer from drawbacks such as expensive starting materials, numerous and complex steps, and the need for the precious metal palladium. Here, we present a consensual method for the synthesis of LXR agonists under mild conditions using nickel catalysis. The LXR agonist is generated by acylation of a quinoline derivative at C3-H under Ni catalysis, followed by trifluoromethylation at the C8 position. Furthermore, this method can be applied to the gram-scale synthesis of LXR agonists. [Summary of the Invention]

[0004] To address the technical problems existing in the prior art, this invention provides a method for synthesizing the LXR agonist 4-phenyl-8-trifluoromethylquinoline-3-benzophenone. This method overcomes the disadvantages of existing LXR agonist synthesis methods, such as expensive starting materials, numerous and complex steps, and the need for the noble metal palladium. The synthesis method uses mild reaction conditions and achieves the synthesis of LXR agonists through nickel catalysis instead of palladium, making it suitable for large-scale industrial production.

[0005] To achieve the above-mentioned objectives, the present invention proposes the following technical solution:

[0006] A method for synthesizing an LXR agonist comprises the following steps: synthetic intermediate I, synthetic intermediate II, and synthesis of the LXR agonist.

[0007] Synthesis of intermediate I: Using N-(4-phenylquinoline)-8-tert-butylamide as a starting material, Ni catalyst and C7H were added under argon atmosphere. 15MgBr, tBuOK, and diethylene glycol dimethyl ether solvent were added. The mixture was stirred at room temperature for 20 min. Then, benzaldehyde was added, and the mixture was stirred at room temperature for 20 min. The reaction solution was then extracted, dried, and 1,2-dichloro-4,5-dicyanbenzidone (DDQ) was added. The mixture was stirred for 10 min, and column chromatography was used to obtain intermediate I.

[0008]

[0009] In the synthesis of intermediate I, the amount of Ni catalyst used is 0.05 equivalents, C7H 15 The amount of MgBr used was 2.0 equivalents, the amount of tBuOK used was 2.5 equivalents, the amount of benzaldehyde used was 5.0 equivalents, and the amount of DDQ used was 1.0 equivalent. The reaction time was 50 min, and the reaction temperature was room temperature.

[0010] Synthesis of intermediate II: Sodium hydroxide was added to a methanol solution of intermediate I, and the mixture was heated at 100°C for 12 h. The mixture was then concentrated under reduced pressure. Intermediate II was obtained by silica gel chromatography.

[0011]

[0012] In the synthesis of intermediate II, the amount of NaOH was 10 equivalents, the reaction time was 24 h, and the reaction temperature was 100 °C.

[0013] Synthesis of the LXR agonist: Hydrochloric acid was added to an acetonitrile solution of intermediate II at 0°C and stirred for 5 min. Then, tBuONO was added and stirred for 15 min. Subsequently, a freshly prepared AgCF3 solution at -78°C was added, and the mixture was stirred at -78°C for 3 h. The temperature was then raised to room temperature and stirred for another 1 h. After the reaction was complete, the solvent was removed, and the mixture was extracted with dichloromethane and water. After evaporation to dryness, the mixture was purified by silica gel column chromatography to obtain the LXR agonist.

[0014]

[0015] In the synthesis of the LXR agonist, the amount of HCl used is 2 equivalents, the amount of tBuONO is 1.1 equivalents, and the amount of AgCF3 is 3 equivalents.

[0016] Compared with existing technologies, the advantages of this invention are as follows: It provides a novel method for synthesizing LXR agonists, starting from simple quinoline derivatives, selectively achieving acylation of quinoline C-3 to generate intermediate I, followed by simple amide deprotection and trifluoromethylation to generate the LXR agonist. Furthermore, the generation of intermediate I is achieved through Ni catalysis. [Attached Image Description]

[0017] Figure 1This diagram illustrates the specific synthetic method for LXR agonists.

[0018] Figure 2 This is the spectrum of the LXR agonist.

Detailed Implementation Methods

[0019] To provide a clearer understanding of the technical features, objectives, and effects of this invention, the specifics of this invention are now described:

[0020] Preparation of intermediate I

[0021] Under argon atmosphere, 20.5 mmol of Ni(acac), 10 mmol of tBuOK, 10 mmol of N-(4-phenylquinoline)-8-tert-butylamide, and 50.0 mL of anhydrous DEDM were added sequentially to a dry reaction tube. Then, 25 mmol of magnesium heptabromide solution was added dropwise using a syringe. The solution was stirred at room temperature for 20 min. Next, 50 mmol of benzaldehyde was added. After stirring at room temperature for 30 min, the reaction was quenched by adding 125 mL of saturated ammonium chloride aqueous solution. The aqueous layer was separated by extraction with ethyl acetate (3 × 250 mL), and the combined organic layer was dried on anhydrous sodium sulfate. Then, 10 mmol of 1,2-dichloro-4,5-dicyanbenziquinone (DDQ) was added. The mixture was stirred for 10 min. Finally, the solvent was removed under reduced pressure, and the product was purified by silica gel chromatography using PE / EtOAc as the eluent to give 2.49 g of the target product as a white solid, with a yield of 61%.

[0022] Preparation of intermediate II

[0023] Intermediate I (6 mmol, 2.45 g) was dissolved in EtOH (20.0 mL) solution, and sodium hydroxide (30 mmol, 1.20 g) was added. The mixture was heated at 100 °C for 12 hours. Then, the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (5%–10% ethyl acetate, n-hexane) gave 1.36 g of a yellow solid in 70% yield. 1 H NMR (400MHz, CDCl3) δ8.83 (s, 1H), 7.61 (d, J = 7.4Hz, 2H), 7.43 (t, J = 7.4Hz, 1H), 7.35-7.23 (m, 8H), 7.03 (dd, J = 16.9, 8.0Hz, 2H), 5.17 (d, J = 35.9Hz, 2H).

[0024] Preparation of LXR agonists

[0025] The specific process for preparing AgCF3 is as follows: 14.0 mmol of AgF was added to 30.0 ml of anhydrous and oxygen-free EtCN under nitrogen atmosphere, cooled to -78°C, 14 mmol of TMSCF3 was added, and then the mixture was brought to room temperature and stirred for 15 min to form a gray solution.

[0026] Under nitrogen atmosphere, intermediate II (4 mmol, 1.3 g) was added and dissolved in 20.0 mL of acetonitrile. The compound was cooled to 0 °C, and hydrochloric acid (8.0 mmol) was added. After stirring for 5 min, tBuONO (4.4 mmol, 0.46 g) was added, and stirring was continued at 0 °C for 15 min. The solution was degassed with liquid nitrogen, and then heated to -78 °C under nitrogen atmosphere. The freshly prepared AgCF3 was also cooled to -78 °C and slowly added to the solution. The mixture was stirred at -78 °C for 3 h, then heated to room temperature and stirred for another 1 h. The solvent was removed, and the mixture was extracted with dichloromethane and water, dried, and concentrated. Finally, the mixture was purified by silica gel chromatography (5%–10% ethyl acetate, n-hexane) to give 1.10 g of a yellow solid, with a yield of 73%. 1 H NMR (400MHz, CDCl3) δ9.13 (s, 1H), 8.18 (d, J = 7.2Hz, 1H), 7.99 (d, J = 8.5Hz, 1H), 7.61 (dd, J = 13.3, 7.9Hz, 3H), 7.47 (t, J = 7.4Hz, 1H), 7.36-7.20 (m, 7H).

[0027] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method of synthesis of an LXR agonist, characterized by, The synthesis method comprises the following steps: synthesizing intermediate I, synthesizing intermediate II, and synthesizing the LXR agonist The synthesis of the intermediate II comprises the following steps: adding sodium hydroxide into a methanol solution of the intermediate I, heating at 100 DEG C for 12 h, then concentrating under reduced pressure, and purifying by silica gel chromatography to obtain the intermediate II The synthesis of the intermediate I: N-(4-phenylquinoline)-8-tert-butylamide as a starting material, under argon, Ni catalyst, C7H 15 MgBr, tBuOK and solvent diglycol dimethyl ether were added, stirred at room temperature for 20 min, then benzaldehyde was added, stirred at room temperature for 20 min, then the reaction solution was extracted, dried, then 1,2-dichloro-4,5-dicyanoquinone DDQ was added, stirred for 10 min, and column chromatography was performed to obtain the intermediate I: ； The synthesis of the LXR agonist comprises the following steps: adding hydrochloric acid into an acetonitrile solution of the intermediate II at 0 DEG C, stirring for 5 min, then adding tBuONO, stirring for 15 min, then adding a freshly prepared AgCF3 solution at -78 DEG C, stirring at -78 DEG C for 3 h, then warming to room temperature and stirring for 1 h, removing the solvent after the reaction is completed, extracting with dichloromethane and water, drying and purifying by silica gel column to obtain the LXR agonist ； In the synthesis of the intermediate II, the amount of NaOH is 10 equivalents, the reaction time is 24 h, and the reaction temperature is 100 DEG C ； The amount of Ni catalyst used in the synthesis of the intermediate I is 0.05 equivalents, the amount of C7H 15 The amount of MgBr used is 2.5 equivalents, the amount of tBuOK used is 2.0 equivalents, the amount of benzaldehyde used is 5.0 equivalents, the amount of DDQ used is 1.0 equivalent, the reaction time is 50 min, and the reaction temperature is room temperature. In the synthesis of the LXR agonist, the amount of HCl is 2 equivalents, the amount of tBuONO is 1.1 equivalents, and the amount of AgCF3 is 3 equivalents. ​

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