Preparation method of toelebutinib and intermediate thereof

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of toelebutinib and an intermediate thereof. According to the preparation method, tert-butyl (R)-3-((2-(dibenzylamino)-3-nitropyridine-4-yl) amino) piperidine-1-carboxylic ester is taken as a starting raw material, and toelebutinib is obtained through four-step reaction. The synthetic route comprises the following steps: 1) Buchwald-Harwig coupling reaction, 2) carbonylation reaction, 3) catalytic hydrogenation under an acidic condition, and 4) acryloyl chloride reaction, and the method has the characteristics of short synthetic route, cheap and easily available raw materials, mild conditions, simple operation, high product purity and yield, environmental friendliness and the like, and is more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for preparing toluebutinib and its intermediates. Background Technology

[0002] Tolebrutinib is an orally effective, highly selective, and irreversible Bruton's tyrosine kinase (BTK) inhibitor developed by Sanofi, primarily used to treat multiple sclerosis. Tolebrutinib has excellent blood-brain barrier penetration, allowing it to directly target microglia and B cells in the central nervous system. By inhibiting BTK targets, it effectively blocks signaling pathways leading to neuroinflammation and demyelination, thereby controlling disability progression.

[0003] Currently, there are few reported methods for preparing tolebrutinib. The original compound patent WO2016196840A1 discloses two methods for synthesizing tolebrutinib, as follows:

[0004] Route A:

[0005]

[0006] Route A starts with compound 1-a, which is substituted with (R)-1-tert-butoxycarbonyl-3-aminopyridine and bis-(4-methoxybenzyl)amine to obtain compound 1-c. After reduction with iron powder, compound 1-d is obtained, followed by cyclization to give compound 1-e. This compound 1-f then undergoes a Chan-Lam reaction to yield compound 1-f. After deprotection, it reacts with acrylic acid or acryloyl chloride to give tolebutinib. This process suffers from poor yields in multiple steps, resulting in a low overall yield of only 0.6%, making industrial-scale production difficult.

[0007] Route B:

[0008]

[0009] Route B starts with 1-e as the starting material. After deprotection with p-methoxybenzyl, it undergoes Boc protection to give 1-i, which reacts with DMF-DMA to give the imine compound 1-j. Following a Chan-Lam reaction, it yields the 1-compound 1-k. After deprotection, it reacts with acrylic acid or acryloyl chloride to give tolebutinib. Route B optimizes the coupling method and significantly improves the yield, increasing the overall yield from 0.6% in Route A to 2.4%. However, the yield remains low, and the extended operating time is detrimental to production applications.

[0010] Patent CN119384411A discloses several methods for synthesizing tolebutinib, as follows:

[0011] Route 1:

[0012]

[0013] Route 2:

[0014]

[0015] Route 3:

[0016]

[0017] This patent improves the synthesis process of toneubrutinib, mainly on the amino protecting group of aminopyridine. However, all three routes have certain shortcomings: 1) Route 1 uses p-methoxybenzyl as the protecting group. Due to the electron-donating effect of the methoxy group, the aromatic ring is more electron-rich and easier to remove. To prevent the removal of PMB protective impurities, the iron powder / glacial acetic acid system is replaced with a palladium on carbon / hydrogen system to achieve the reduction of hydroxyl groups. However, palladium on carbon / hydrogen can also lead to the removal of PMB and reduce the yield. The two amino groups of the generated 2,3-diaminopyridine byproducts compete for the Buchwald coupling, resulting in a decrease in yield. The Buchwald coupling step requires the use of expensive tert-amyl methyl ether as a solvent, and the process time is as high as 64 hours, resulting in high material and production costs. The intermediates in each step are oily and difficult to purify, and impurities are difficult to control. 2) In Route 2, 4-c is coupled with 4-bromodiphenyl ether to generate 4-d. However, 2-chloropyridine competes with 3-bromodiphenyl ether for a reaction, producing impurities. Furthermore, the lack of an electron-withdrawing group in the 2-chloropyridine structure of compound 4-e leads to a lower yield for nucleophilic aromatic substitution in this step. 3) Route 3 has a low yield and is not suitable for production. In summary, the direct reaction of compound A with acryloyl chloride (acrylic acid) to synthesize tolebutinib yields a low yield because the amino group in its 2-aminopyridine structure competes for byproducts. The patent improves the yield by reacting A with oxalic acid to generate A oxalate, which then protects the primary amine with oxalic acid, inhibiting byproduct formation. However, this increases the number of reaction steps. Summary of the Invention

[0018] To overcome the problems of long synthetic routes, high costs, low yields, and unsuitability for industrial production in existing technologies, this invention proposes a novel method for preparing tolebutinib and its intermediates. Using tert-butyl(R)-3-((2-(dibenzylamino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylic acid ester as the starting material, this method requires only four reaction steps to obtain tolebutinib. This method features a short route, safe operation, high yield, and environmental friendliness.

[0019] One of the objectives of this invention is to provide a method for preparing a compound of formula III.

[0020] To achieve the above objectives, the present invention adopts the following technical solution:

[0021] The method for preparing compound III involves reacting compound I and compound II via a Buchwald-Hartwig coupling reaction to obtain compound III.

[0022] .

[0023] Preferably, the molar ratio of the compound of formula I to the compound of formula II is 1:1 to 2, and the optimal molar ratio is 1:1.2.

[0024] Preferably, the Buchwald-Hartwig coupling reaction is carried out in the presence of a palladium catalyst, which includes one or more of the following: bis(diphenylphosphine)-ferrocene palladium dichloride or solvate, tetra(triphenylphosphine)-palladium dichloride or solvate, palladium acetate or solvate, and tris(dibenzylacetone)-dipalladium or solvate, preferably tris(dibenzylacetone)-dipalladium.

[0025] Preferably, the molar ratio of the compound of formula I to the palladium catalyst is 1:1%~10%, and the optimal molar ratio is 1:3%.

[0026] Preferably, the Buchwald-Hartwig coupling reaction is carried out in the presence of a base, which includes one or more of sodium carbonate, potassium acetate, triethylamine, cesium carbonate, potassium carbonate, and potassium phosphate, with cesium carbonate being the most preferred.

[0027] Preferably, the mass ratio of the compound of formula I to the base is 1:1 to 3, and the optimal mass ratio is 1:2.

[0028] Preferably, in the Buchwald-Hartwig coupling reaction, the ligand is selected from one or more of XantPhos or its G3 precatalyst, BrettPhos or its G3 precatalyst, and JackiePhos or its G3 precatalyst, with BrettPhos being the most preferred.

[0029] Preferably, the molar ratio of the compound of Formula I to the ligand is 1:2%~12%, and the optimal molar ratio is 1:6%.

[0030] Preferably, in the Buchwald-Hartwig coupling reaction, the solvent includes one or more of toluene, dioxane, ethylene glycol dimethyl ether, dimethyl sulfoxide, and tetrahydrofuran, with toluene being the most preferred.

[0031] Preferably, the volume ratio of the compound of Formula I to the solvent is 1:5 to 20, and the optimal volume ratio is 1:10.

[0032] Preferably, the Buchwald-Hartwig coupling reaction is carried out at a temperature of 90-120°C for 10-20 hours, and more preferably at 100-105°C for 12-15 hours.

[0033] Preferably, the Buchwald-Hartwig coupling reaction is carried out under nitrogen protection.

[0034] As a preferred method, the Buchwald-Hartwig coupling reaction was detected by HPLC until complete; the resulting reaction solution was quenched, separated, extracted, concentrated, crystallized, filtered, and dried to obtain compound III.

[0035] Preferably, the quenching solvent is water.

[0036] Preferably, the extraction solvent is ethyl acetate.

[0037] Preferably, the crystallization solvent is ethyl acetate and n-hexane.

[0038] A second objective of this invention is to provide a method for preparing a compound of formula IV.

[0039] To achieve the above objectives, the present invention adopts the following technical solution:

[0040] The preparation method of compound IV includes the following steps:

[0041] (1) The compound of formula III is prepared by the method of claim 1;

[0042] (2) The compound of formula III obtained in step (1) undergoes a cyclization reaction with a carbonylating agent to obtain the compound of formula IV;

[0043] The structural formula of compound IV is as follows:

[0044] .

[0045] Preferably, in step (2), the carbonylating agent includes one or more of N,N'-carbonyldiimidazole and ditert-butyl dicarbonate, preferably ditert-butyl dicarbonate.

[0046] Preferably, in step (2), the molar ratio of the compound of formula III to the carbonylating agent is 1:1 to 3, and the optimal molar ratio is 1:2.

[0047] Preferably, in step (2), the solvent is any one or more of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, and dichloromethane, with N,N-dimethylformamide being the most preferred.

[0048] Preferably, in step (2), the volume ratio of the compound of formula III to the solvent is 1:5~20; the optimal volume ratio is 1:10.

[0049] Preferably, in step (2), the reaction temperature is 30~80℃ and the reaction time is 5~10 hours, preferably 40~70℃ for 6~8 hours, and more preferably 60~70℃ or 40~50℃ for 6~8 hours.

[0050] Preferably, in step (2), the reaction is carried out under nitrogen protection.

[0051] As a preferred embodiment, in step (2), the reaction is detected by HPLC until complete, and the resulting reaction solution is extracted, the solvent is evaporated, and purified by chromatography column to obtain compound IV.

[0052] A third objective of this invention is to provide a method for preparing compound of formula V.

[0053] To achieve the above objectives, the present invention adopts the following technical solution:

[0054] The preparation method of compound V includes the following steps:

[0055] 1) Prepare compound IV using the method described in claim 6;

[0056] 2) The compound of formula IV obtained in step 1) is catalytically hydrogenated under acidic conditions to obtain compound of formula V;

[0057] The structural formula of compound V is as follows:

[0058] .

[0059] Preferably, in step 2), the acidic additive includes trifluoroacetic acid.

[0060] Preferably, in step 2), the volume ratio of the compound of formula IV to the acidic additive is 1:1 to 5 (or the mass ratio or others), with the optimal volume ratio being 1:2.

[0061] Preferably, in step 2), the catalyst includes one or more of palladium on carbon, palladium hydroxide on carbon, platinum on carbon, and rhodium on carbon, with palladium hydroxide on carbon being the most preferred.

[0062] Preferably, in step 2), the mass ratio of the compound of formula IV to the catalyst is 1:5%~20% (or other mass ratios), with the optimal mass ratio being 1:10%.

[0063] Preferably, in step 2), the solvent includes ethanol.

[0064] Preferably, in step 2), the volume ratio of the compound of formula IV to the solvent is 1:5~20; the optimal ratio is 1:10.

[0065] Preferably, in step 2), the reaction conditions are: heating at 50-70 °C for 3-7 hours in a hydrogen atmosphere, and more preferably heating at 60-65 °C for 4-6 hours in a hydrogen atmosphere.

[0066] Preferably, in step 2), the reaction is detected by HPLC until complete, and the resulting reaction solution is filtered, washed, and concentrated to obtain compound V.

[0067] Preferably, a saturated sodium carbonate solution is used for washing.

[0068] The fourth objective of this invention is to provide a method for preparing toluebutinib.

[0069] To achieve the above objectives, the present invention adopts the following technical solution:

[0070] The preparation method of tolebrutinib includes the following steps:

[0071] S1: Compound V is prepared using the method described in claim 9;

[0072] S2: The compound V obtained in S1 reacts with acryloyl chloride to give tolebutinib;

[0073] The structural formula of tolebutinib is as follows:

[0074] .

[0075] Preferably, in S2, the molar ratio of the compound of formula V to the acryloyl chloride is 1:1 to 1.2, with the optimal ratio being 1:1.

[0076] Preferably, in S2, the reaction is carried out in the presence of a base; the base includes any one or more of sodium hydroxide or its hydrate, potassium hydroxide or its hydrate, sodium carbonate or its hydrate, potassium carbonate or its hydrate, pyridine or its hydrate, 4-dimethylaminopyridine or its hydrate, tert-amyl alcohol or its hydrate, and potassium phosphate or its hydrate, with potassium phosphate being the most preferred.

[0077] Preferably, in S2, the molar ratio of the compound of formula V to the base is 1:1 to 2, with the optimal ratio being 1:1.

[0078] Preferably, in S2, the solvent includes one or more of dichloromethane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and 4-methyl-2-pentanone, with 4-methyl-2-pentanone being the most preferred.

[0079] Preferably, in S2, the volume ratio of the compound of formula V to the solvent is 1:5 to 10, with the optimal volume ratio being 1:10.

[0080] Preferably, S2 comprises: mixing compound of formula V, base and solvent, heating to reflux for 20 to 60 minutes, cooling to -5 to 10 °C and adding acryloyl chloride dropwise to obtain tolebutinib.

[0081] Preferably, the temperature is raised to reflux for 30 minutes, and then cooled to 0-5 °C before adding acryloyl chloride dropwise.

[0082] As a preferred embodiment, in S2, the reaction is detected by HPLC until complete, and the resulting reaction solution is purified by extraction, separation, solvent evaporation, and column chromatography to obtain tolebtinib.

[0083] Preferably, a saturated sodium carbonate solution is used for extraction.

[0084] The beneficial effects of this invention are as follows:

[0085] 1. This invention uses the reaction of compound I with 4-bromodiphenyl ether and selects a suitable ligand (such as BrettPhos) to achieve selective coupling of primary amines, with a yield of up to 90%, which significantly improves the reaction yield.

[0086] 2. The introduction of the Bn protecting group in this invention has several advantages: ① Milder deprotection conditions: The Bn protecting group can be easily removed by catalytic hydrogenation (such as H2 / Pd(OH)2 / C), with mild conditions and good selectivity, and the deprotection time is only 5-6 hours. ② Better compatibility: The Bn protecting group has better stability in the reaction and higher compatibility with reagents and reaction conditions, reducing the formation of byproducts. In reactions with nucleophiles, acids, or bases, Bn-protected primary amines usually remain stable, while PMB interferes with the reaction due to the presence of the methoxy group. In the coupling reaction of CN119384411A, the reaction time requires 64 hours to achieve 96.5% conversion. The synthesis reaction time of the compound of formula III in this invention is shortened to 13 hours, and the use of unconventional solvents such as methyl tert-amyl ether is avoided, resulting in lower production costs and effectively improved product quality.

[0087] 3. This invention uses tert-butyl(R)-3-((2-(dibenzylamino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylic acid ester as the starting material, and tolebtinib can be prepared in only four steps. The overall synthetic route is as follows: Figure 1 As shown. The yield of synthetic formula V in this invention is approximately 82%, and the overall yield is approximately 67%. Compared with the prior art, the synthetic route of this invention is shorter, the raw materials and reagents are inexpensive and readily available, the reaction conditions are mild and reliable, the operation is simple, it is environmentally friendly, and the product has high purity and yield, making it more suitable for industrial production. Attached Figure Description

[0088] Figure 1 This is the overall synthetic route map for tolebrutinib.

[0089] Figure 2 The 1H NMR spectrum of the compound of formula III prepared in Example 1.

[0090] Figure 3 The carbon NMR spectrum of the compound of formula III prepared in Example 1.

[0091] Figure 4 The mass spectrum is that of the compound of formula III prepared in Example 1.

[0092] Figure 5 The 1H NMR spectrum of the compound of formula IV prepared in Example 6.

[0093] Figure 6 The carbon NMR spectrum of the compound of formula IV prepared in Example 6.

[0094] Figure 7 The mass spectrum of the compound of formula IV prepared in Example 6 is shown. Detailed Implementation

[0095] The technical solution of the present invention will be described more clearly and completely below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the protection scope of the present invention.

[0096] Example 1. Preparation of Compound III

[0097] In a three-necked flask, 1.5 g of compound I, 0.9 g of compound II, 3.0 g of cesium carbonate, 0.1 g of tris(dibenzylacetone)palladium, and 0.1 g of BrettPhos were added. 15 mL of toluene was added, and the mixture was purged with nitrogen. The reaction was carried out at 100–105 °C for 12–15 hours. HPLC analysis confirmed the reaction was complete. The mixture was quenched with water, separated, extracted with ethyl acetate, concentrated, and crystallized with ethyl acetate and n-hexane. The crystals were then filtered and dried to obtain 1.8 g of compound III, with a yield of 89% and a purity greater than 98%. The 1H NMR spectrum of the obtained compound III is shown below. Figure 2 As shown, the carbon NMR spectrum is as follows: Figure 3 As shown, the mass spectrometry is as follows Figure 4 As shown. The NMR analysis is as follows:

[0098] 1H NMR (600 MHz, DMSO) δ 7.79 (d, J = 5.6 Hz, 1H), 7.35 – 7.28 (m,2H), 7.22 – 7.12 (m, 6H), 7.13 – 7.08 (m, 4H), 7.06 – 7.00 (m, 1H), 6.93 –6.86 (m, 3H), 6.83 (d, J = 9.0 Hz, 2H), 6.48 (d, J = 8.6 Hz, 2H), 6.38 (d, J= 5.8 Hz, 1H), 5.08 (s, 1H), 4.36 (t, J = 5.0 Hz, 5H), 3.70 (d, J = 24.9 Hz,1H), 3.45 (qd, J = 7.0, 5.1 Hz, 2H), 3.38 (d, J = 3.7 Hz, 1H), 1.43 – 1.31(m, 10H), 1.07 (t, J = 7.0 Hz, 3H). 13 C NMR (151 MHz, DMSO) δ 159.35, 158.71,151.42, 147.08, 142.89, 139.92, 130.12, 128.39, 128.32, 126.85, 122.34,121.31, 116.88, 114.69, 111.43, 101.26, 79.22, 60.22, 56.50, 53.49, 48.03,30.01, 28.49, 19.03. [M+H] + =656.3.

[0099] Example 2. Preparation of Compound III

[0100] In a three-necked reaction flask, 7.0 g of compound I, 4.2 g of compound II, 14.0 g of cesium carbonate, 0.4 g of tris(dibenzylacetone)palladium, and 0.4 g of BrettPhos were added, followed by 70 mL of toluene. After purging with nitrogen, the mixture was reacted at 100–105 °C for 12–15 hours. HPLC analysis confirmed the reaction was complete. The mixture was quenched with water, separated, extracted with ethyl acetate, concentrated, and crystallized with ethyl acetate and n-hexane. After filtration and drying, 8.7 g of compound III was obtained, with a yield of 92% and a purity greater than 98%.

[0101] Example 3. Preparation of Compound III

[0102] In a three-necked reaction flask, 1.5 g of compound I, 0.9 g of compound II, 3.0 g of cesium carbonate, 0.03 g of palladium acetate, and 0.1 g of BrettPhos were added. 15 mL of toluene was added, and the mixture was purged with nitrogen. The reaction was then carried out at 100–105 °C for 12–15 hours. HPLC analysis confirmed the reaction was complete. The mixture was quenched with water, separated, extracted with ethyl acetate, concentrated, and crystallized with ethyl acetate and n-hexane. The crystals were filtered and dried to obtain 1.5 g of compound III, with a yield of 77% and a purity greater than 90%.

[0103] Example 4. Preparation of Compound IV

[0104] In a three-necked reaction flask, 0.5 g of compound III, 0.3 g of N,N'-carbonyldiimidazole, and 20 mL of tetrahydrofuran were added. After purging with nitrogen, the mixture was reacted at 60–70 °C for 6–8 hours. HPLC analysis confirmed the reaction was complete. The solvent was extracted, evaporated, and purified by column chromatography to obtain 0.24 g of compound IV, with a yield of 46% and a purity greater than 98%.

[0105] Example 5. Preparation of Compound IV

[0106] In a three-necked reaction flask, 0.7 g of compound III, 0.5 g of di-tert-butyl dicarbonate, and 0.01 g of 4-dimethylaminopyridine were added, followed by 7 mL of N,N-dimethylformamide. After purging with nitrogen, the mixture was reacted at 40–50 °C for 6–8 hours. HPLC analysis confirmed the reaction was complete. The solvent was extracted, evaporated, and purified by column chromatography to obtain 0.63 g of compound IV, with a yield of 86% and a purity greater than 98%.

[0107] Example 6. Preparation of Compound IV

[0108] In a three-necked flask, 4.2 g of compound III, 3.0 g of di-tert-butyl dicarbonate, and 0.06 g of 4-dimethylaminopyridine were added, followed by 40 mL of N,N-dimethylformamide. After purging with nitrogen, the mixture was reacted at 40–50 °C for 6–8 hours. HPLC analysis confirmed the reaction was complete. The solvent was extracted, evaporated, and purified by column chromatography to obtain 4.0 g of compound IV, with a yield of 91% and a purity greater than 98%. The 1H NMR spectrum of the obtained compound IV is shown below. Figure 5 As shown, the carbon NMR spectrum is as follows: Figure 6 As shown, the mass spectrometry is as follows Figure 7 As shown. The NMR analysis is as follows:

[0109] 1H NMR (600 MHz, DMSO) δ 7.79 (d, J = 5.6 Hz, 1H), 7.35 – 7.28 (m,2H), 7.22 – 7.12 (m, 6H), 7.13 – 7.08 (m, 4H), 7.06 – 7.00 (m, 1H), 6.93 –6.86 (m, 3H), 6.83 (d, J = 9.0 Hz, 2H), 6.48 (d, J = 8.6 Hz, 2H), 6.38 (d, J= 5.8 Hz, 1H), 5.08 (s, 1H), 4.36 (t, J = 5.0 Hz, 5H), 3.70 (d, J = 24.9 Hz,1H), 3.45 (qd, J = 7.0, 5.1 Hz, 2H), 3.38 (d, J = 3.7 Hz, 1H), 1.43 – 1.31(m, 10H), 1.07 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 161.62,160.90, 159.16, 157.90, 150.87, 145.60, 142.79, 142.13, 135.37, 135.22,134.39, 133.88, 133.18, 132.13, 129.01, 124.09, 123.12, 119.78, 105.75,84.32, 61.25, 58.10, 55.55, 53.94, 33.29, 32.04, 23.78. [M+H]+ =682.3.

[0110] Example 7. Preparation of compound V

[0111] In a three-necked reaction flask, 1.0 g of compound IV, 0.1 g of palladium hydroxide on carbon, 10 mL of ethanol, and 2 mL of trifluoroacetic acid were added. The mixture was heated at 60–65 °C for 4–6 hours under a hydrogen atmosphere. HPLC analysis confirmed the reaction was complete. The mixture was filtered, washed with saturated sodium carbonate solution, and concentrated by separation to obtain 0.57 g of compound V, with a yield of 98% and a purity greater than 97%.

[0112] Example 8. Preparation of compound V

[0113] In a three-necked reaction flask, 1.0 g of compound IV, 0.1 g of palladium on carbon, 10 mL of ethanol, and 2 mL of trifluoroacetic acid were added. The mixture was heated at 60–65 °C for 4–6 hours under a hydrogen atmosphere. HPLC analysis confirmed the reaction was complete. The mixture was filtered, washed with saturated sodium carbonate solution, and concentrated by separation to obtain 0.57 g of compound V, with a yield of 94% and a purity greater than 97%.

[0114] Example 9. Preparation of compound V

[0115] In a three-necked reaction flask, 5.0 g of compound IV, 0.5 g of palladium on carbon, 50 mL of ethanol, and 10 mL of trifluoroacetic acid were added. The mixture was heated at 60–65 °C for 4–6 hours under a hydrogen atmosphere. HPLC analysis confirmed the reaction was complete. The mixture was filtered, washed with saturated sodium carbonate solution, and concentrated by separation to obtain 2.9 g of compound V, with a yield of 98% and a purity greater than 98%.

[0116] Example 10. Preparation of tolebrutinib

[0117] In a three-necked reaction flask, 1.0 g of compound V, 0.3 g of N,N-diisopropylethylamine, and 10 mL of tetrahydrofuran were added. The mixture was cooled to 0–5 °C, and 0.2 g of acryloyl chloride was added dropwise. HPLC analysis confirmed the reaction was complete. Extraction was performed using saturated sodium carbonate solution, and the solvent was evaporated to dryness. The mixture was then purified by column chromatography to obtain 0.54 g of tolebutinib, with a yield of 48% and a purity greater than 99%.

[0118] Example 11. Preparation of tolebrutinib

[0119] In a three-necked flask, 1.0 g of compound V, 0.3 g of potassium phosphate, and 10 mL of 4-methyl-2-pentanone were added. The mixture was heated to reflux and reacted for 30 minutes. Then, the temperature was lowered to 0–5 °C, and 0.2 g of acryloyl chloride was added dropwise. The reaction was confirmed to be complete by HPLC. Saturated sodium carbonate solution was added to quench the reaction, and the mixture was separated, the solvent evaporated, and the solution was purified by column chromatography to obtain 0.93 g of tolebrutinib, with a yield of 82% and a purity greater than 99%.

Claims

1. A method for preparing the compound of formula III, characterized in that, Compounds of Formula I and Formula II were coupled via a Buchwald-Hartwig reaction to yield compound of Formula III; 。 2. The preparation method according to claim 1, characterized in that, The molar ratio of the compound of formula I to the compound of formula II is 1:1~2.

3. The preparation method according to claim 1, characterized in that, The Buchwald-Hartwig coupling reaction is carried out in the presence of a palladium catalyst, which includes one or more of the following: bis(diphenylphosphine)-ferrocene palladium dichloride or solvate, tetra(triphenylphosphine)-palladium dichloride or solvate, palladium acetate or solvate, and tris(dibenzylacetone)-palladium dichloride or solvate.

4. The preparation method according to claim 1, characterized in that, The Buchwald-Hartwig coupling reaction is carried out in the presence of a base, which includes one or more of sodium carbonate, potassium acetate, triethylamine, cesium carbonate, potassium carbonate, and potassium phosphate.

5. The preparation method according to claim 1, characterized in that, In the Buchwald-Hartwig coupling reaction, the ligand is selected from one or more of XantPhos or its G3 precatalyst, BrettPhos or its G3 precatalyst, and JackiePhos or its G3 precatalyst.

6. The preparation method according to claim 1, characterized in that, In the Buchwald-Hartwig coupling reaction, the solvent includes one or more of toluene, dioxane, ethylene glycol dimethyl ether, dimethyl sulfoxide, and tetrahydrofuran.

7. The preparation method according to claim 1, characterized in that, The Buchwald-Hartwig coupling reaction is carried out at a temperature of 90-120°C for 10-20 hours.

8. A method for preparing compound of formula IV, characterized in that, Includes the following steps: (1) The compound of formula III is prepared by the method according to any one of claims 1 to 7; (2) The compound of formula III obtained in step (1) undergoes a cyclization reaction with a carbonylating agent to obtain the compound of formula IV; The structural formula of compound IV is as follows: 。 9. The preparation method according to claim 8, characterized in that, In step (2), the carbonylating agent includes one or more of N,N'-carbonyldiimidazole and ditert-butyl dicarbonate.

10. The preparation method according to claim 8, characterized in that, In step (2), the solvent is any one or more of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, and dichloromethane.

11. The preparation method according to claim 8, characterized in that, In step (2), the reaction temperature is 30~80℃ and the reaction time is 5~10 hours.

12. A method for preparing compound V, characterized in that, Includes the following steps: 1) Prepare compound of formula IV by the method according to any one of claims 8 to 11; 2) The compound of formula IV obtained in step 1) is catalytically hydrogenated under acidic conditions to obtain compound of formula V; The structural formula of compound V is as follows: 。 13. The preparation method according to claim 12, characterized in that, In step 2), the acidic additive includes trifluoroacetic acid.

14. The preparation method according to claim 12, characterized in that, In step 2), the catalyst includes any one or more of palladium on carbon, palladium hydroxide on carbon, platinum on carbon, and rhodium on carbon.

15. A method for preparing toluebutinib, characterized in that, Includes the following steps: S1: Compound V is prepared by the method according to any one of claims 12-14; S2: The compound V obtained in S1 reacts with acryloyl chloride to give tolebutinib; The structural formula of tolebutinib is as follows: 。 16. The preparation method according to claim 15, characterized in that, In S2, the molar ratio of the compound of formula V to the acryloyl chloride is 1:1 to 1.

2.

17. The preparation method according to claim 15, characterized in that, In S2, the reaction is carried out in the presence of a base; the base includes any one or more of sodium hydroxide or its hydrate, potassium hydroxide or its hydrate, sodium carbonate or its hydrate, potassium carbonate or its hydrate, pyridine or its hydrate, 4-dimethylaminopyridine or its hydrate, tert-amyl alcohol or its hydrate, and potassium phosphate or its hydrate.

18. The preparation method according to claim 15, characterized in that, In S2, the solvent includes one or more of dichloromethane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and 4-methyl-2-pentanone.

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