Synthesis method of atavapam

Abstract

The invention provides a synthesis method of atavapam, which comprises the following steps: carrying out nucleophilic addition-elimination reaction on commercially available raw materials and 4-methyl-3-trifluoromethylaniline under alkaline conditions, carrying out Suzuki coupling reaction under the action of a catalyst, carrying out pressurized hydrogenation, and carrying out chiral resolution, thereby obtaining the atavapam. And condensing with 2-fluoro-6-methyl benzoyl chloride under an alkaline condition, and further removing a Boc protecting group under an acidic condition to finish synthesis of the atavapam. According to the invention, a convergent synthesis process is adopted, tedious synthesis steps in the original process are shortened, and post-treatment is simpler and more controllable.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and relates to avacopane, and more particularly to a method for synthesizing avacopane with shortened synthesis steps, simpler and more controllable post-processing, and high yield. Background Technology

[0002] Avacopan is an orally active, selective complement 5a receptor (C5aR1) antagonist that inhibits the interaction between C5aR and anaphylactic toxin C5a, blocking C5a-mediated neutrophil activation and migration. Notably, avacopan is the first FDA-approved oral complement 5a receptor antagonist, receiving FDA approval in October 2021 for use in combination with standard treatment regimens, including glucocorticoids, to treat active, severe ANCA-associated vasculitis (MPA and GPA) in adults. Its structural formula is shown in Formula I.

[0003]

[0004] Patent CN102264227A, published on November 30, 2011, entitled "C5aR Antagonist," discloses a method for synthesizing avacopan (structural formula I) from Chimosentrix Co., Ltd. This method follows the original research route (as shown below). Compound 1 (ethyl 2-chloronicotinate) and 4-(N-Boc-amino)phenylboronic acid undergo a Suzuki coupling reaction under palladium catalysis to obtain intermediate 2. This intermediate is then subjected to PdO2-catalyzed pressurized hydrogenation reduction to obtain racemic intermediate 3: (ethyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)piperidine-3-carboxylate). Chiral resolution with L-(-)-dibenzoyl tartaric acid yields the target configuration (2R, 3S) intermediate 4. Compound 4 is condensed with 2-fluoro-6-methylbenzoyl chloride to obtain intermediate 5. Intermediate 5 is further deprotected with the Boc protecting group under acidic conditions to generate intermediate 6, which is then subjected to a reductive amination reaction with cyclopentanone under NaBH(OAc)3 conditions to obtain intermediate 7. Intermediate 7 is then condensed with 4-methyl-3-trifluoromethylaniline under trimethylaluminum catalysis to obtain the target product avacopan.

[0005]

[0006] However, the above method for synthesizing avacopan involves lengthy reaction steps, cumbersome post-processing (such as post-processing with trimethylaluminum), and low resolution yield, resulting in high cost of the final synthesized product.

[0007] Patent CN106999481A, published on August 1, 2017, discloses several other synthetic methods for avacopan, one of which is shown below. Compound 8 (ethyl p-nitrobenzoyl acetate) is cyclized with a chiral fragment (R)-(-)-2-phenylglycine and acrolein diethyl acetal fragment to obtain intermediate 9. Subsequently, hydrogenation reduction of the double bond and removal of the chiral side chain, followed by one-pot reduction of the nitro group, and reductive amination with cyclopentanone yields intermediate 10. Resolution with L-(-)-dibenzoyl tartaric acid further increases the ee value. Intermediate 10 is condensed with 2-fluoro-6-methylbenzoyl chloride to obtain intermediate 7, which is then condensed with 4-methyl-3-trifluoromethylaniline to obtain the target product.

[0008]

[0009] The above method for synthesizing avacopan has fewer reaction steps compared to the original route. The introduction of a cofactor makes the hydrogenation reaction surface-selective, but chiral resolution is still required to further improve the ee value, resulting in a higher cost of the final product.

[0010] Patent CN114262291A, published on April 1, 2022, is a method for asymmetric hydrogenation synthesis of avacopan provided by Chongqing Medical University. The synthetic route is as follows: the method obtains intermediate 12 by condensation cyclization reaction of fragments 11 and 8, obtains intermediate 6 by rhodium-catalyzed asymmetric hydrogenation reaction, and then completes the synthesis of avacopan by reductive amination and ammonolysis reaction.

[0011] The preparation process of avacopan described above bypasses chiral resolution, but requires the use of expensive rhodium di-(1,5-cyclooctadiene)-tetrafluoroborate and ligands, making it impossible to effectively control costs.

[0012] Patent WO2023158722 A1, published on August 24, 2023, discloses a synthetic method for avacopan using several similar synthetic routes, as reported by Teva Pharmaceuticals. This method is very similar to the original synthetic route published by Chimosentex Corporation (as shown in A below), except for the method used to resolve racemic intermediate 3. This method uses an imine reductase and coenzyme regeneration system to resolve racemic intermediate 3, as shown in B below. Under the action of the enzyme and coenzyme regeneration system, one isomer of racemic intermediate 3 is oxidized to imine intermediate 3a, while the other chiral isomer 4 does not participate in the reaction. 3a is unstable and tautomerizes to 3b, which can be further hydrogenated and recycled back to racemic intermediate 3. Furthermore, to avoid using trimethylaluminum, this method first hydrolyzes intermediate 7 to intermediate 13, which is then condensed with 4-methyl-3-trifluoromethylaniline to obtain the product avacopan.

[0013] The above method synthesizes avacopane, and the enzymatic resolution effectively solves the problem of low resolution yield. However, the overall reaction steps are lengthy, the post-processing is cumbersome, and the cost of synthesizing the final product is not low. Summary of the Invention

[0014] To address the shortcomings of existing synthetic avacopan processes, such as linear, cumbersome, lengthy steps, low yield, and high cost, this invention provides a synthetic method for avacopan. The method involves reacting a commercially available compound of formula 14 (2-chloronicotinyl chloride) with 4-methyl-3-trifluoromethylaniline under alkaline conditions via a nucleophilic addition-elimination reaction to obtain an intermediate of formula 15. The intermediate of formula 15 then undergoes a Suzuki coupling reaction with the intermediate of formula 16 under a palladium catalyst to obtain an intermediate of formula 17. After obtaining intermediate 17, pressurized hydrogenation yields a racemic intermediate of formula 18. Finally, chiral resolution with L-(-)-dibenzoyl tartaric acid is used to obtain the target configuration (2R, 3S) intermediate of formula 19. The compound shown in intermediate formula 19 is condensed with 2-fluoro-6-methylbenzoyl chloride under alkaline conditions to obtain the compound shown in intermediate formula 20. Further removal of the Boc protecting group under acidic conditions completes the synthesis of avacopan.

[0015] The preparation method of the compound represented by intermediate formula 16 is as follows: the compound represented by starting material formula 21 (p-bromoaniline) undergoes a reductive amination reaction with cyclopentanone to obtain the compound represented by intermediate formula 22 (4-bromo-N-cyclopentylaniline). The secondary amine of the compound represented by intermediate formula 22 is protected with Boc to obtain the compound represented by intermediate formula 23. The compound represented by intermediate formula 23 is subjected to lithium halide exchange and boron-lithium exchange to obtain the compound represented by intermediate formula 16.

[0016] To achieve the above objectives, the present invention adopts the following technical solution:

[0017] This invention provides a method for synthesizing avacopane, the method comprising the following steps:

[0018] 1) The compound shown in Formula 14 reacts with 4-methyl-3-trifluoromethylaniline under alkaline conditions to give the compound shown in Formula 15;

[0019] 2) The compound shown in Formula 15 and the compound shown in Formula 16 undergo a coupling reaction under the action of a catalyst to obtain the compound shown in Formula 17;

[0020] 3) The compound shown in Formula 17 is hydrogenated under pressure to obtain the compound shown in Formula 18;

[0021] 4) The compound shown in Formula 18 is chirally resolved to obtain the compound shown in Formula 19;

[0022] 5) The compound shown in Formula 19 reacts with 2-fluoro-6-methylbenzoyl chloride under alkaline conditions to give the compound shown in Formula 20;

[0023] 6) The compound shown in Formula 20 is reacted under acidic conditions to give the target product, the compound shown in Formula I;

[0024] The preparation method of the compound shown in Formula 16 is as follows: the compound shown in Formula 21 undergoes a reducing amination reaction with cyclopentanone to obtain the compound shown in Formula 22, the compound shown in Formula 22 is protected with Boc to obtain the compound shown in Formula 23, and the compound shown in Formula 23 is obtained by lithium halide exchange and boron-lithium exchange to obtain the compound shown in Formula 16.

[0025] The structural formula of the compound shown in Formula 14 is as follows: The structural formula of the compound shown in Formula 15 is as follows: The structural formula of the compound shown in Formula 16 is as follows: The structural formula of the compound shown in Formula 17 is as follows: The structural formula of the compound shown in Formula 18 is as follows: The structural formula of the compound shown in Formula 19 is as follows:

[0026] The structural formula of the compound shown in Formula 20 is as follows:

[0027] The structural formula of the compound shown in Formula 21 is as follows:

[0028] The structural formula of the compound shown in Formula 22 is as follows:

[0029] The structural formula of the compound shown in Formula 23 is as follows:

[0030] The structural formula of the compound represented by Formula I is as follows:

[0031] As a preferred embodiment of the present invention, in step 1), the base in the alkaline conditions includes triethylamine, pyridine, DIPEA or 2,4-dimethylpyridine.

[0032] In a preferred embodiment of the present invention, in step 2), the catalyst used consists of a metal catalyst and a ligand, wherein the metal catalyst includes tetratetraphenylphosphine palladium, palladium acetate, diphenylphosphine ferrocene palladium dichloride, bis(triphenylphosphine) palladium dichloride, or tris(dibenzylacetone)dipalladium; and the ligand used includes PPh3, AsPh3, n - Bu3P, (MeO)3P, bidentate ligand Ph2P(CH2)2PPh2(dppe) or bidentate ligand Ph2P(CH2)3PPh2(dppp).

[0033] In a preferred embodiment of the present invention, the metal catalyst is tetraphenylphosphine palladium and the ligand is PPh3.

[0034] As a preferred embodiment of the present invention, in step 2), the base used includes K2CO3, Cs2CO3, KOAc, NaOAc, KHCO3, NaHCO3 or CsF; the solvent used in the reaction includes a single or mixed system of DME, 1,4-dioxane, toluene, DMF, DMSO, ethanol, methanol and water, and the reaction system is an anaerobic system.

[0035] More preferably, the base used is K2CO3, and the reaction system is a mixture of 1,4-dioxane and water.

[0036] As a preferred embodiment of the present invention, in step 3), the reaction temperature is 50-70°C and the hydrogen pressure is 0.5-1.5 MPa.

[0037] More preferably, the reaction temperature is 55-60℃ and the hydrogen pressure is 0.7-1.0MPa.

[0038] As a preferred embodiment of the present invention, in step 4), the reagent used for separation is L-(-)-dibenzoyl tartaric acid.

[0039] As a preferred embodiment of the present invention, in step 5), the base used includes triethylamine, pyridine, DIPEA, 2,4-dimethylpyridine, sodium carbonate, or potassium carbonate.

[0040] As a preferred embodiment of the present invention, in step 6), the acid used under acidic conditions includes TFA, HCl-1,4-dioxane solution, HCl-H2O solution, HCl-EtOH solution, HCl-MeOH solution or HCl-EA solution.

[0041] As a preferred embodiment of the present invention, in the preparation of the compound of Formula 22 from the compound of Formula 21, the reducing agent used includes sodium triacetoxyborohydride or sodium cyanoborohydride, and the solvent used includes tetrahydrofuran, methanol, ethanol, 1,4-dioxane or dichloromethane; in the preparation of the compound of Formula 23 from the compound of Formula 22, the protecting group is introduced under the condition of Boc2O / base / solvent, and the base used includes NaHMDS, LiHMDS, DIPEA, Et3N, pyridine or 2,4-dimethylpyridine, and the solvent includes THF, toluene or pyridine; in the preparation of the compound of Formula 16 from the compound of Formula 23, the bromine substituent is converted into boric acid, and the corresponding boric acid intermediate is obtained by lithium halide exchange reaction with borate ester and then hydrolysis.

[0042] More preferably, in the preparation of the compound shown in Formula 23 from the compound shown in Formula 22, the base used is NaHMDS and the solvent used is THF.

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] 1) This invention has made groundbreaking innovations in the synthesis route, adopting a convergent synthesis process, which shortens the cumbersome and lengthy synthesis steps in the original process, and the post-processing is simpler and more controllable.

[0045] 2) The intermediate shown in Formula 16 of the present invention can be coupled with Suzuki reaction to avoid the introduction of impurities in the step of reducing amination of cyclopentanone with higher intermediates.

[0046] 3) The synthesis method of the present invention shortens the synthesis steps, makes the post-processing simpler and more controllable, and has a high yield. Attached Figure Description

[0047] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0048] Figure 1 This is the NMR spectrum of the compound shown in Formula 15.

[0049] Figure 2 This is the NMR spectrum of the compound shown in Formula 16.

[0050] Figure 3 This is the NMR spectrum of the compound shown in Formula 17.

[0051] Figure 4 This is the NMR spectrum of the compound shown in Formula 18.

[0052] Figure 5 This is the NMR spectrum of the compound represented by Formula I.

[0053] Figure 6 This is the NMR spectrum of the compound shown in Formula 22.

[0054] Figure 7 This is the NMR spectrum of the compound shown in Formula 23.

[0055] Figure 8 This is a diagram showing the enantiomer content of the compound represented by Formula 19.

[0056] Figure 9 This is a diagram showing the enantiomer content of the compound represented by Formula I. Detailed Implementation

[0057] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0058] This invention provides a method for synthesizing avacopan. The method involves reacting a commercially available compound of formula 14 (2-chloronicotinyl chloride) with 4-methyl-3-trifluoromethylaniline under alkaline conditions via a nucleophilic addition-elimination reaction to yield an intermediate of formula 15. The intermediate of formula 15 then undergoes a Suzuki coupling reaction with the intermediate of formula 16 under a palladium catalyst to yield an intermediate of formula 17. After obtaining intermediate 17, pressurized hydrogenation yields a racemic intermediate of formula 18. This intermediate is then chirally resolved by L-(-)-dibenzoyl tartaric acid to obtain the target configuration (2R, 3S) intermediate of formula 19. The intermediate of formula 19 is condensed with 2-fluoro-6-methylbenzoyl chloride under alkaline conditions to yield an intermediate of formula 20. Further removal of the Boc protecting group under acidic conditions completes the synthesis of avacopan.

[0059] The preparation method of the compound represented by intermediate formula 16 is as follows: the compound represented by starting material formula 21 (p-bromoaniline) undergoes a reductive amination reaction with cyclopentanone to obtain the compound represented by intermediate formula 22 (4-bromo-N-cyclopentylaniline). The secondary amine of the compound represented by intermediate formula 22 is protected with Boc to obtain the compound represented by intermediate formula 23. The compound represented by intermediate formula 23 is subjected to lithium halide exchange and boron-lithium exchange to obtain the compound represented by intermediate formula 16.

[0060] The synthetic route of this invention is shown below:

[0061] Example 1

[0062] This embodiment provides a method for synthesizing avacopane, including the following steps:

[0063] Step 1: Pyridine (100 mL) and dichloromethane (100 mL) were added to a reaction flask. At 15-25°C, the starting material compound (100 g, 1.0 eq) of formula 14 was added, and the mixture was purged with nitrogen. Then, 4-methyl-3-trifluoromethylbenzene (97.5 g, 0.98 eq) was slowly added while cooling to 0°C. The reaction was continued at 15-25°C for 6 hours. After confirming complete reaction of the starting materials, stirring was stopped, and the reaction was quenched with saturated sodium bicarbonate, at which point a large amount of solid precipitated. The mixture was filtered, the filter cake was washed with water, and dried under vacuum. The filter cake was then recrystallized from acetonitrile, filtered again, and dried to obtain the target intermediate compound of formula 15.

[0064] See Figure 1 , 1 H NMR (400MHz, DMSO-d6) δ 10.88(s,1H),8.59-8.51(m,1H),8.16-8.04(m,2H),7.80(d,J=8.3Hz,1H),7.64-7.53(m,1H),7.44(d,J=8.3Hz,1H),2.41(s,3H).

[0065] Step 2: The compound shown in intermediate formula 15 (100 g, 1.0 eq) and the compound shown in intermediate formula 16 (116 g, 1.2 eq) were added to a reaction flask, dissolved in 600 mL of 1,4-dioxane and 600 mL of water. At room temperature, tetraphenylphosphine palladium (1.10 g, 0.003 eq) and K₂CO₃ (132 g, 3.0 eq) were added sequentially. After switching to nitrogen, the reaction system was heated to 100 °C and reacted for 72 h. The reaction solution was cooled to room temperature, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the compound shown in intermediate formula 17.

[0066] See Figure 3 , 1 H NMR(400MHz,Chloroform-d)δ8.74(dd,J=4.8,1.7Hz,1H),8.03(dd,J=7.8,1.7Hz ,1H),7.90(s,1H),7.67(d,J=8.5Hz,2H),7.57-7.49(m,2H),7.47-7.43(m,1H),7. 39-7.33(m,1H),7.13(d,J=8.4Hz,2H),4.43(ddd,J=17.0,9.5,7.6Hz,1H),2.45-2 .34(m,3H),1.88-1.77(m,2H),1.48-1.41(m,4H),1.38-1.32(m,2H),1.28(s,9H).

[0067] Step 3: The obtained intermediate compound of formula 17 (100 g, 1.0 eq) was added to a high-pressure reactor, dissolved in acetic acid (800 ml), followed by the addition of 10% palladium on carbon (2.5 g). The reactor was sealed, hydrogen gas was switched, and the hydrogen pressure was set to 1.0 MPa. The temperature was raised to 55-65 °C, and the hydrogenation reaction system was hydrogenated for 36 h. After the reaction was completed, the reaction system was cooled to 25 °C, and the filtrate was filtered through diatomaceous earth, washed with CH2Cl2, and quenched with saturated sodium carbonate. CH2Cl2 was extracted three times, the organic phase was dried with anhydrous sodium sulfate, concentrated, and then dragged with ethyl acetate. Finally, the mixture was slurried in an ethyl acetate / n-heptane mixture, filtered, and the filter cake was dried to obtain the target intermediate compound of formula 18.

[0068] See Figure 4 , 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),7.80(d,J=2.2Hz,1H),7.41(dd,J=8.3,2.2Hz,1H),7.34(d,J=8.4Hz,2H),7.26 (d,J=8.3Hz,1H),6.97(d,J=8.4Hz,2H),4.29(p,J=8.1,7.7Hz,1H),4.02(d,J=2.9Hz,1H),3. 27(d,J=12.6Hz,1H),2.95-2.88(m,1H),2.79-2.69(m,1H),2.36-2.27(m,3H),2.11-1.91(m, 2H),1.87-1.73(m,1H),1.73-1.60(m,2H),1.56-1.47(m,1H),1.38-1.17(m,7H),1.14(s,9H).

[0069] Step 4, Chiral Resolution: The obtained intermediate compound of formula 18 (60.0 g, 1.0 eq) and L-(-)-dibenzoyl tartaric acid (39.9 g, 1.0 eq) were added to a reaction flask, dissolved in ethanol (600 mL), concentrated to a clear solution and aspirated to dryness. Ethyl acetate (250 mL) was then added to form a clear solution. TBME (500 mL) was slowly added to this solution. After the addition was complete, the mixture was allowed to stand at room temperature for 3 days without disturbance. A large amount of white crystals were produced. The crystals were filtered and washed with TBME (100 mL) to obtain a white solid. The obtained white solid was dissolved in THF (500 mL), and TBME (500 mL) was slowly added to this solution. After the addition was complete, the mixture was allowed to stand at room temperature for 3 days without disturbance and filtered to obtain a white solid. At 0°C, a saturated sodium bicarbonate aqueous solution (200 mL) was added to a CH2Cl2 suspension (200 mL). After stirring at room temperature for 30 min, the mixture was separated, and the aqueous phase was extracted with CH₂Cl₂. The combined organic phases were washed with saturated sodium bicarbonate solution, dried, and concentrated under reduced pressure to give the intermediate compound of formula 19. (See also...) Figure 8 If the enantiomer content is ≥99.5%, it can be used for the next reaction. If the enantiomer content is less than 99.5%, repeat the above operation until the enantiomer content is ≥99.5%.

[0070] Step 5: The obtained intermediate compound of formula 19 (100.0 g, 1.0 eq) was added to a reaction flask, and toluene (500 mL) and water (1000 mL) were added as solvents. Sodium carbonate (97.1 g, 5.0 eq) and 2-fluoro-6-methylbenzoyl chloride (36.3 g, 1.15 eq) were added sequentially at 20-25 °C, and the reaction was maintained at 20-25 °C for 6 h. After confirming that the reactants had reacted completely, stirring was stopped, the mixture was extracted with ethyl acetate, separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product compound of formula 20, which was directly used in the next reaction step.

[0071] Step 6: Dissolve the crude product (Formula 20) obtained in the previous step in 1,4-dioxane (100 mL), then add 1,4-dioxane solution in 4N HCl (100 mL). After the addition is complete, maintain the reaction at 20-25°C for 6 hours. Once the reaction of the starting material is confirmed to be complete, stop stirring. Cool to 0°C, neutralize with saturated sodium bicarbonate, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then purify by recrystallization to obtain the product (Formula I).

[0072] See Figure 5 , 1 H NMR (400MHz, TFA-d) δ8.02 (dd, J=8.6, 2.5Hz, 1H), 7.94 (dd, J=8.6, 2.4Hz, 1H), 7.70-7.61 (m, 2H), 7.60-6.97 (m, 7H), 6.94-6. 84(m,1H),4.23-4.04(m,1H),3.74-3.62(m,1H),3.60-3.49(m,1H),3.47-3.32(m,1H),2.60-2.30(m,7H),2.23-1.71(m,13H).

[0073] See Figure 9 By chiral separation of the intermediate compound shown in Formula 18, and then through two-step transformation, the ee value of the final compound I can reach 99.9%.

[0074] The synthesis of the compound represented by intermediate formula 16 includes the following steps:

[0075] Step 1': 100 g (1.0 eq) of p-bromoaniline (formula 21) and cyclopentanone (147 g, 3.0 eq) were placed in a reaction flask, followed by the addition of methanol (500 mL) and acetic acid (17.5 g, 0.5 eq) as solvents. Sodium cyanoborohydride (54.8 g, 1.5 eq) was added at 25°C, and the reaction was maintained at 25°C for 20 h. TLC analysis showed that a small amount of unreacted reactant remained. Subsequently, sodium cyanoborohydride (18.3 g, 0.5 eq) was added at 25°C, and the reaction was maintained at 25°C for another 20 h. Stirring was stopped, and the reaction was quenched with saturated sodium bicarbonate. The mixture was extracted with CH2Cl2, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the product compound (formula 22).

[0076] See Figure 6 , 1 H NMR (400MHz, Chloroform-d) δ7.26-7.20(m,2H),6.50-6.44(m,2H),3.90-3.60(m,2H),2.08-1.93(m,2H),1.79-1.56(m,4H),1.51-1.38(m,2H).

[0077] Step 2': Dissolve 100 g (1.0 eq) of the compound of formula 22 obtained in the previous step in THF (500 mL), add NaHMDS (2.0 M THF solution, 250 mL, 1.2 eq) at 25 °C, and maintain the reaction at 25 °C for 1 h. Then add Boc2O (182 g, 2.0 eq) at 0-10 °C, and raise the temperature to 25 °C and react for 24 h. Quench the reaction with saturated sodium bicarbonate, extract with ethyl acetate, wash three times with water, and wash once with saturated sodium chloride solution. Filter, concentrate under reduced pressure, and slurry with n-heptane to obtain the compound of formula 23.

[0078] See Figure 7 , 1 H NMR (400MHz, DMSO-d6) δ 7.59-7.51(m,2H),7.10-7.04(m,2H),4.41-4.25(m,1H),1.88-1.75(m,2H),1.51-1.38(m,4H),1.37-1.25(m,11H).

[0079] Step 3': Add 100 g (1.0 eq) of the intermediate compound (formula 23) to a dry reaction flask, purge with nitrogen, dissolve in anhydrous THF (800 mL), then cool to -78 °C and add n dropwise. -BuLi (2.4M hexane solution, 159 mL, 1.3 eq) was added while maintaining an internal temperature below -70°C. The reaction mixture was stirred at -78°C for 1 h, followed by the addition of B(OEt)3 (94.4 g, 2.2 eq) while maintaining an internal temperature below -70°C. After the addition was complete, the reaction was continued at -78°C for another 1 h, followed by a warming to 0°C for 2 h. The reaction was quenched by the addition of saturated ammonium chloride aqueous solution and stirred at 20–25°C for 2 h. The mixture was extracted with ethyl acetate, washed once with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and then slurried in n-heptane / ethyl acetate (40 / 1) to give the product shown in Formula 16.

[0080] See Figure 2 , 1 H NMR (400MHz, DMSO-d6) δ 8.07(s,1H),7.76(d,J=8.3Hz,1H),7.05(d,J=8.3Hz,1H),4.40-4.29(m,1H),1.87-1.75(m,2H),1.49-1.35(m,6H),1.30(s,9H).

[0081] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any form or substance. It should be noted that those skilled in the art can make various improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention. Any modifications, alterations, and equivalent changes made by those skilled in the art based on the above-disclosed technical content without departing from the spirit and scope of the present invention are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and evolutions made to the above embodiments based on the essential technology of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing avacopane, characterized in that, The synthesis method includes the following steps: 1) The compound shown in Formula 14 reacts with 4-methyl-3-trifluoromethylaniline under alkaline conditions to give the compound shown in Formula 15; 2) The compound shown in Formula 15 and the compound shown in Formula 16 undergo a coupling reaction under the action of a catalyst to obtain the compound shown in Formula 17; 3) The compound shown in Formula 17 is hydrogenated under pressure to obtain the compound shown in Formula 18; 4) The compound shown in Formula 18 is chirally resolved to obtain the compound shown in Formula 19; 5) The compound shown in Formula 19 reacts with 2-fluoro-6-methylbenzoyl chloride under alkaline conditions to give the compound shown in Formula 20; 6) The compound shown in Formula 20 is reacted under acidic conditions to give the target product, the compound shown in Formula I; The preparation method of the compound shown in Formula 16 is as follows: the compound shown in Formula 21 undergoes a reducing amination reaction with cyclopentanone to obtain the compound shown in Formula 22, the compound shown in Formula 22 is protected with Boc to obtain the compound shown in Formula 23, and the compound shown in Formula 23 is obtained by lithium halide exchange and boron-lithium exchange to obtain the compound shown in Formula 16. The structural formula of the compound shown in Formula 14 is as follows: The structural formula of the compound shown in Formula 15 is as follows: The structural formula of the compound shown in Formula 16 is as follows: The structural formula of the compound shown in Formula 17 is as follows: The structural formula of the compound shown in Formula 18 is as follows: The structural formula of the compound shown in Formula 19 is as follows: The structural formula of the compound shown in Formula 20 is as follows: The structural formula of the compound shown in Formula 21 is as follows: The structural formula of the compound shown in Formula 22 is as follows: The structural formula of the compound shown in Formula 23 is as follows: The structural formula of the compound represented by Formula I is as follows:

2. The method for synthesizing avacopane according to claim 1, characterized in that, In step 1), the base in the alkaline conditions includes triethylamine, pyridine, DIPEA, or 2,4-dimethylpyridine.

3. The method for synthesizing avacopane according to claim 1, characterized in that, In step 2), the catalyst used consists of a metal catalyst and a ligand. The metal catalyst includes tetratetraphenylphosphine palladium, palladium acetate, diphenylphosphine ferrocene palladium dichloride, bis(triphenylphosphine) palladium dichloride, or tris(dibenzylacetone) dipalladium. The ligands used include PPh3, AsPh3, n-Bu3P, (MeO)3P, bidentate ligand Ph2P(CH2)2PPh2(dppe), or bidentate ligand Ph2P(CH2)3PPh2(dppp).

4. The method for synthesizing avacopane according to claim 1, characterized in that, The metal catalyst is tetrakis(triphenylphosphine)palladium, and the ligand is PPh3.

5. The method for synthesizing avacopane according to claim 1, characterized in that, In step 2), the base used includes K2CO3, Cs2CO3, KOAc, NaOAc, KHCO3, NaHCO3 or CsF; the solvent used in the reaction includes single or mixed systems of DME, 1,4-dioxane, toluene, DMF, DMSO, ethanol, methanol and water, and the reaction system is an anaerobic system.

6. The method for synthesizing avacopane according to claim 1, characterized in that, In step 3), the reaction temperature is 50-70℃ and the hydrogen pressure is 0.5-1.5MPa.

7. The method for synthesizing avacopane according to claim 1, characterized in that, In step 4), the reagent used for separation is L-(-)-dibenzoyl tartaric acid.

8. The method for synthesizing avacopane according to claim 1, characterized in that, In step 5), the base used includes triethylamine, pyridine, DIPEA, 2,4-dimethylpyridine, sodium carbonate, or potassium carbonate.

9. The method for synthesizing avacopane according to claim 1, characterized in that, In step 6), the acids used under acidic conditions include TFA, HCl-1,4-dioxane solution, HCl-H2O solution, HCl-EtOH solution, HCl-MeOH solution, or HCl-EA solution.

10. A method for synthesizing avacopane according to any one of claims 1-9, characterized in that, In the preparation of the compound shown in Formula 22 from the compound shown in Formula 21, the reducing agent used includes sodium triacetoxyborohydride or sodium cyanoborohydride, and the solvent used includes tetrahydrofuran, methanol, ethanol, 1,4-dioxane, or dichloromethane; In the preparation of the compound shown in Formula 23 from the compound shown in Formula 22, the protecting group is introduced under the condition of Boc2O / base / solvent, and the base used includes NaHMDS, LiHMDS, DIPEA, Et3N, pyridine, or 2,4-dimethylpyridine, and the solvent includes THF, toluene, or pyridine; In the preparation of the compound shown in Formula 16 from the compound shown in Formula 23, the bromine substituent is converted into boric acid, and the corresponding boric acid intermediate is obtained by lithium halide exchange reaction with borate ester followed by hydrolysis.

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