Preparation method of trirasilil and intermediate thereof

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of trirasilil and an intermediate thereof. The invention firstly provides a simple, efficient, economical and environment-friendly preparation method of a trirasil key intermediate, and the preparation method comprises the following steps: taking a compound shown as a formula I and a compound shown as a formula II as raw materials, and carrying out substitution (SNAr) reaction or Buchwald-Harwig coupling reaction to obtain a compound shown as a formula III. Then, the compound shown in the formula III is sequentially subjected to intramolecular Aldol condensation, reductive dehalogenation, oxidation and substitution, and trirasilil is prepared. The method has the characteristics of short route, cheap and easily available starting materials, safety in operation, high yield, environmental friendliness, suitability for industrial production and the like. The invention provides powerful technical support for industrial production of the trirasilil.

Description

Technical Field

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

[0002] Triasilib hydrochloride is a highly effective, selective, and reversible CDK4 / 6 inhibitor, developed in collaboration with G1 Therapeutics. It is the world's first innovative drug with systemic myeloprotective effects. This drug is indicated for patients with extensive-stage small cell lung cancer who have not previously received systemic chemotherapy. It is administered before platinum-based chemotherapy combined with etoposide to reduce the incidence of chemotherapy-induced myelosuppression.

[0003] Currently, there are few reports on the preparation methods of key intermediates of tricracetam, and those that exist have certain shortcomings. For example, the original process patent CN109789142B discloses two synthetic routes for tricracetam, as follows:

[0004] Route 1:

[0005]

[0006] Route 2:

[0007]

[0008] The patent initially envisioned Route 2 as the process route during its early research stages. This route is characterized by its short length, readily available and inexpensive starting materials, safe operation, and environmental friendliness. However, the following problems were encountered during the research process: ① Column chromatography is required to obtain the product; ② The yield is less than 35%; ③ The reaction is slow and requires heating to 80-85℃; ④ The low reactivity of chlorine in 4-chloro-2-(methylthio)pyridine-5-carboxaldehyde leads to impurities from the reaction of the aldehyde with spironolactam, which are difficult to remove, with a product-to-impurity ratio of approximately 1:1; ⑤ The intermediate is a heavy oil, making scale-up difficult; ⑥ The aldehyde starting compound is not commercially available and requires two synthetic steps derived from the corresponding ester. Although the patent attempted to optimize the process by optimizing the base, material feed ratio, and solvent selection, the results were not ideal. The best result was a product content of 55% and an impurity content of 45% in HPLC.

[0009] Route 2 had problems that rendered it unproductive. Therefore, a new method (Route 1) was developed to synthesize tricrazil using ethyl 4-chloro-2-thiomethylpyrimidinecarboxylate as the starting material. This method involves the substitution of compound 2 with ethyl 4-chloro-2-thiomethylpyrimidinecarboxylate to obtain pyrimidine compound 3. Compound 3 is then protected and cyclized to obtain compound 5. Compound 5 is then introduced with a p-toluenesulfonyl group to enhance its deprotection ability, followed by dehydroxylation and deprotection to obtain compound 8. Compound 8 is then oxidized and substituted with compound 10 to obtain tricrazil. However, using ethyl 4-chloro-2-thiomethylpyrimidinecarboxylate as the starting material for tricrazil has the following drawbacks: ① The synthetic route is lengthy, requiring seven steps; ② It involves multiple protection and deprotection processes, resulting in poor economic efficiency.

[0010] For example, patent CN113788837B discloses a method for synthesizing tricracetam, and its synthetic route is as follows:

[0011]

[0012] This patent uses compound 13 as a starting material, which undergoes condensation with 1-aminomethyl-1-cyclohexanol to obtain compound 15, followed by cyclization to obtain compound 8, and then substitution to obtain tricracetam. While the synthetic process is simple, the raw materials are expensive and not commercially available, requiring multiple steps and making industrial-scale production difficult.

[0013] For example, patent CN114014863B discloses a method for synthesizing tricracetam, and its synthetic route is as follows:

[0014]

[0015] This patent uses compound 16 as a starting material, which undergoes a Williamson reaction with compound 17 to yield compound 18. Compound 19 is then hydrolyzed and subjected to amino-ester exchange to yield compound 8, which is subsequently oxidized and substituted with compound 10 to obtain tricracetam. While this patented route is relatively simple, the starting materials are not commercially available, have limited purchasing channels, and are expensive, making industrial-scale production difficult.

[0016] Therefore, it is necessary to develop a method for the preparation of triasidril that has a short synthetic route, inexpensive and readily available starting materials, high product purity and yield, and can be industrialized. Summary of the Invention

[0017] To address the problems of cumbersome steps, expensive and difficult-to-obtain starting materials, harsh reaction conditions, and unsuitability for industrial production in existing synthesis processes, this invention develops a new method for synthesizing trerazoride and its intermediates, which is more efficient, economical, and environmentally friendly.

[0018] One of the objectives of this invention is to provide a method for preparing a compound of formula III.

[0019] To achieve the above objectives, the present invention adopts the following technical solution:

[0020] The method for preparing compound III involves using compounds of formula I and formula II as raw materials, and obtaining compound III through a substitution (SNAr) reaction or a Buchwald-Hartwig coupling reaction.

[0021] .

[0022] 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 1:1.5.

[0023] Preferably, the Buchwald-Hartwig coupling reaction is carried out in the presence of a palladium catalyst, which includes one or more of bis(triphenylphosphine)palladium dichloride, bis(diphenylphosphine)-ferrocene palladium dichloride, tetra(triphenylphosphine)palladium, and palladium acetate, preferably palladium acetate.

[0024] Preferably, in the Buchwald-Hartwig coupling reaction, the molar ratio of the compound of formula I to the palladium catalyst is 1:0.005~0.2, and the optimal molar ratio is 1:0.01.

[0025] Preferably, the Buchwald-Hartwig coupling reaction is carried out under the action of an alkali, which includes any one or more of sodium carbonate, potassium acetate, triethylamine, cesium carbonate, potassium carbonate, and potassium phosphate, preferably potassium acetate.

[0026] Preferably, in the Buchwald-Hartwig coupling reaction, the molar ratio of compound I to base is 1:1 to 3, with the optimal molar ratio being 1:2.

[0027] Preferably, the reaction solvent for the Buchwald-Hartwig coupling reaction includes one or more of toluene, dioxane, ethylene glycol dimethyl ether, dimethyl sulfoxide, and tetrahydrofuran, with toluene being the most preferred.

[0028] Preferably, in the Buchwald-Hartwig coupling reaction, the volume ratio of the compound of formula I to the reaction solvent is 1:5 to 20, with the optimal volume ratio being 1:10.

[0029] Preferably, the reaction temperature of the Buchwald-Hartwig coupling reaction is 60~100℃, and most preferably 80~85℃.

[0030] Preferably, the Buchwald-Hartwig coupling reaction is carried out under nitrogen protection.

[0031] Preferably, the Buchwald-Hartwig coupling reaction is detected by HPLC until complete. The resulting reaction solution is then filtered, concentrated, pulped, filtered again, and dried to obtain compound III. Preferably, the pulping solvent includes acetonitrile and water.

[0032] Preferably, the solvent for the substitution (SNAr) reaction includes one or more of toluene, dioxane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, N,N-dimethylacetamide, and dichloromethane, with dichloromethane being the most preferred.

[0033] Preferably, in the substitution (SNAr) reaction, the volume ratio of the compound of formula I to the reaction solvent is 1:5 to 20, and the optimal volume ratio is 1:10.

[0034] Preferably, the substitution (SNAr) reaction is carried out under the action of a base, which includes one or more of sodium carbonate, triethylamine, N,N-diisopropylethylamine, potassium carbonate, and potassium phosphate, preferably N,N-diisopropylethylamine.

[0035] Preferably, in the substitution reaction (SNAr), the molar ratio of compound I to base is 1:0.1~2.0, with the optimal ratio being 1:0.5.

[0036] Preferably, in the substitution reaction (SNAr), the reaction temperature is 20~120℃, the preferred temperature is 30~50℃, and the optimal temperature is 40℃.

[0037] Preferably, in the substitution reaction (SNAr), the reaction time is 7 to 15 hours, more preferably 8 to 12 hours, and even more preferably 12 hours.

[0038] Preferably, the substitution (SNAr) reaction is carried out under nitrogen protection.

[0039] Preferably, the substitution (SNAr) reaction is detected by HPLC until complete, then the solvent is evaporated, and the mixture is pulped, filtered, and dried to obtain compound III. Preferably, the pulping solvent includes acetonitrile and water.

[0040] A second objective of this invention is to provide a method for preparing a compound of formula IV.

[0041] To achieve the above objectives, the present invention adopts the following technical solution:

[0042] The preparation method of compound IV includes the following steps:

[0043] (1) Compound III was prepared using the aforementioned method;

[0044] (2) Compound III obtained in step (1) is converted into compound IV by intramolecular Aldol condensation;

[0045] The structural formula of compound IV is as follows:

[0046] .

[0047] Preferably, in step (2), the Aldol condensation reaction is carried out under the action of an alkali, wherein the alkali includes any one or more of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, and DBU, preferably lithium tert-butoxide.

[0048] Preferably, in step (2), the molar ratio of the compound of formula III to the base is 1:1 to 2, and the optimal molar ratio is 1:1.

[0049] Preferably, in step (2), the Aldol condensation reaction temperature is 0~70℃, and more preferably 35~42℃.

[0050] Preferably, in step (2), the Aldol condensation reaction time is 3 to 6 hours, preferably 4 hours.

[0051] Preferably, in step (2), the solvent for the Aldol condensation reaction includes one or more of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, and dichloromethane, with dichloromethane being the most preferred.

[0052] Preferably, in step (2), the volume ratio of the compound of formula III to the reaction solvent is 1:5~20, and the optimal volume ratio is 1:10.

[0053] Preferably, in step (2), the Aldol condensation reaction is detected by HPLC until complete, then the reaction is quenched, the solvent is evaporated, and the mixture is pulped, cooled to crystallize, filtered, and washed to obtain compound IV. Preferably, the quenching solvent is acetic acid and water, and the pulping solvent is acetonitrile.

[0054] A third objective of this invention is to provide a compound of formula IV prepared by the aforementioned method.

[0055] The fourth objective of this invention is to provide a method for preparing a compound of formula V.

[0056] To achieve the above objectives, the present invention adopts the following technical solution:

[0057] The method for preparing compound V includes the following steps:

[0058] S1: Compound IV was prepared using the aforementioned method;

[0059] S2: The compound of formula IV obtained from S1 was reduced and dehalogenated to obtain compound of formula V;

[0060] The structural formula of compound V is as follows:

[0061] .

[0062] Preferably, in S2, the dehalogenation catalyst includes one or more of palladium on carbon, iron powder, and zinc powder, with zinc powder being the most preferred.

[0063] Preferably, in S2, the molar ratio of the compound of formula IV to the dehalogenation catalyst is 1:2 to 6, with the optimal molar ratio being 1:4.

[0064] Preferably, in S2, the hydrogen source includes any one or more of hydrogen gas, hydrochloric acid, glacial acetic acid, and ammonia water, with glacial acetic acid being the most preferred.

[0065] Preferably, in S2, the volume ratio of the compound of formula IV to the hydrogen source is 1:1 to 10; the optimal volume ratio is 1:5.

[0066] Preferably, in S2, the reaction solvent includes tetrahydrofuran.

[0067] Preferably, in S2, the volume ratio of the compound of formula IV to the reaction solvent is 1:20~50, and the optimal volume ratio is 1:25.

[0068] Preferably, in S2, the reaction temperature is 35~55 ℃ and the reaction time is 4~6 hours; more preferably, the reaction is carried out at 40~45 ℃ for 5 hours.

[0069] Preferably, in S2, the reaction is carried out under nitrogen protection.

[0070] As a preferred embodiment, in S2, the reaction is detected by HPLC until complete, and the resulting reaction solution is separated, concentrated, pulped, filtered, and dried to obtain compound V.

[0071] Preferably, the pulping solvent includes methanol.

[0072] Preferably, dichloromethane and water are added, and the mixture is stirred and separated.

[0073] The fifth objective of this invention is to provide a compound of formula V prepared by the aforementioned method.

[0074] The sixth objective of this invention is to provide a method for preparing triasidil.

[0075] To achieve the above objectives, the present invention adopts the following technical solution:

[0076] The preparation method of tricracetam includes the following steps:

[0077] 1) Prepare compound V using the method described in claim 14;

[0078] 2) The compound of formula V obtained in step 1) is oxidized to obtain compound of formula VI;

[0079] 3) The compound of formula VI obtained in step 2) undergoes a substitution reaction with the compound of formula VII to give triasidil;

[0080] The structural formulas of compound VI, compound VII, and tricrazil are as follows:

[0081]

[0082]

[0083] .

[0084] Preferably, in step 2), the oxidant includes potassium peroxymonosulfonate.

[0085] Preferably, in step 2), the molar ratio of compound V to oxidant is 1:2 to 5, with the optimal molar ratio being 1:2.

[0086] Preferably, in step 2), the reaction solvent includes acetonitrile and water; the preferred volume ratio of acetonitrile to water is 1 to 5:1, and the optimal volume ratio of acetonitrile to water is 2:1.

[0087] Preferably, in step 2), the volume ratio of compound V to reaction solvent is 1:20~50; the optimal volume ratio is 1:30.

[0088] Preferably, in step 2), the reaction temperature is 10~50℃, more preferably 20~30℃.

[0089] Preferably, in step 2), the reaction time is 3 to 5 hours, preferably 4 hours.

[0090] Preferably, in step 2), the reaction is carried out under nitrogen protection.

[0091] Preferably, in step 2), the reaction is detected by HPLC until complete, the resulting reaction solution is filtered, extracted with sodium thiosulfate, dichloromethane and water are added, the mixture is stirred and separated, concentrated, slurried with n-heptane and dichloromethane, filtered, and dried to obtain compound VI.

[0092] Preferably, in step 3), the substitution reaction is carried out in the presence of a base, which includes LiHMDS.

[0093] Preferably, in step 3), the molar ratio of compound VI to base is 1:3~5; the optimal amount of base is 1:3.6.

[0094] Preferably, in step 3), the alkali addition temperature is 0~5℃ and the substitution reaction temperature is 13~16℃.

[0095] Preferably, in step 3), the reaction solvent includes tetrahydrofuran.

[0096] Preferably, in step 3), the volume ratio of compound VI to the reaction solvent is 1:30~50, with the optimal volume ratio being 1:30.

[0097] As a preferred embodiment, step 3) specifically includes the following steps:

[0098] ①Preparation of solutions of compound formula VI;

[0099] ② Cool the solution of compound VI obtained in step ① to 0~5℃, replace with nitrogen gas, add LiHMDS dropwise, raise the temperature, and add compound VII to react;

[0100] ③ Repeat step ② twice to obtain triasidil.

[0101] Preferably, the reaction temperature in step ② is 13~16℃ and the reaction time is 1~3 hours, preferably 2 hours.

[0102] Preferably, the reaction solution obtained in step ③ is mixed with dichloromethane, n-butanol and water, filtered and dried to obtain triasidil.

[0103] The beneficial effects of this invention are as follows:

[0104] 1. Using 2-(methylthio)-4,6-dichloro-5-pyrimidinecarboxaldehyde (compound of formula I) as the starting material, only three reaction steps are required to obtain the key intermediate (compound of formula III). This method has advantages such as short route, inexpensive and readily available starting materials, safe operation, high yield, and environmental friendliness. Specifically: ① Compound of formula I has symmetry, and the chlorine at positions 4 and 6 has no regioselectivity; ② The strong electron-withdrawing effect of chlorine increases the reactivity of the chlorine at position 4, thereby increasing the reaction rate; ③ The introduction of the group at position 6 increases steric hindrance, preventing the aldehyde from participating in the reaction; ④ The chlorine at positions 4 and 6 of the pyrimidine can be rapidly removed by simple reduction. ⑤ The yield of the substitution reaction was increased to 85% (the yield in CN109789142B was less than 35%), and the purity was greater than 99%. The total yield of the three steps from compound I to compound V was increased to 60% (the yield of compounds 11 to 8 in route 2 in CN109789142B was 18.6%). ⑥ The reaction temperature was controlled at 38~40℃, which reduced unknown impurities. No impurities generated by aldehydes participating in the reaction were observed. ⑦ The operation is simple. A product with a purity greater than 99% can be obtained by slurrying with acetonitrile and water.

[0105] 2. Currently, there are still few methods for preparing key intermediates of tricrascitabine, and the overall yield is low and the cost is high, which greatly limits the application of tricrascitabine. This invention provides a simple, efficient, economical, and environmentally friendly method for preparing key intermediates of tricrascitabine, providing strong technical support for the industrial production of tricrascitabine.

[0106] 3. This invention avoids the use of expensive starting materials and does not generate a large amount of waste acid, shortens the synthesis steps, improves the synthesis yield, is simple to operate, and is more suitable for industrial production.

[0107] 4. The synthesis process of this invention avoids the generation of waste acid and is more environmentally friendly.

[0108] 5. The method of the present invention uses inexpensive and readily available raw materials, which significantly reduces costs; and the reaction conditions are mild and the operation is simple, making it more suitable for industrial production.

[0109] 6. The synthesis method of the present invention has a high overall yield, which improves the economy and practicality of the product. Attached Figure Description

[0110] Figure 1 The compound of formula III prepared in Example 6 1 H NMR spectrum;

[0111] Figure 2 The compound of formula III prepared in Example 6 13 C NMR spectrum;

[0112] Figure 3 The mass spectrum of the compound of formula III prepared in Example 6;

[0113] Figure 4 The compound of formula IV prepared in Example 11 1 H NMR spectrum;

[0114] Figure 5 The compound of formula IV prepared in Example 11 13 C NMR spectrum;

[0115] Figure 6 The mass spectrum of the compound of formula IV prepared in Example 11;

[0116] Figure 7 The mass spectrum of compound V prepared in Example 15;

[0117] Figure 8 This is a synthetic route diagram for compound V;

[0118] Figure 9 The route map for the overall synthesis of tricracetam. Detailed Implementation

[0119] 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.

[0120] In this embodiment of the invention, the synthetic route of compound V is as follows: Figure 8 As shown, the overall synthetic route of tricracetam is as follows: Figure 9 As shown. This invention yields compound III through a substitution (SNAr) reaction between compound I and compound II, followed by intramolecular Aldol cyclization under the action of lithium tert-butoxide to obtain compound IV. Reduction and dehalogenation under a reducing system yield compound V. The 2-methylthio group of compound V is oxidized to a 2-sulfone group and then undergoes a substitution reaction with compound VII to obtain tricracetam.

[0121] Example 1. Preparation of Compound III

[0122] In a three-necked reaction flask, 4.4 g of compound I, 4.5 g of compound II, and 1.3 g of N,N-diisopropylethylamine were added, followed by 40 mL of dichloromethane. After purging with nitrogen, the mixture was reacted at 38–40 °C for 12 hours. HPLC analysis confirmed the reaction was complete. The solvent was evaporated, and the mixture was slurried with acetonitrile and water, filtered, and dried to obtain 5.7 g of compound III, with a yield of 80% and a purity greater than 99%.

[0123] Example 2. Preparation of Compound III

[0124] In a three-necked reaction flask, 4.4 g of compound I, 4.5 g of compound II, and 1.1 g of sodium carbonate were added, followed by 40 mL of dichloromethane. After purging with nitrogen, the mixture was reacted at 38–40 °C for 12 hours. HPLC analysis confirmed the reaction was complete. The solvent was evaporated, and the mixture was slurried with acetonitrile and water, filtered, and dried to obtain 4.8 g of compound III, with a yield of 68% and a purity greater than 99%.

[0125] Example 3. Preparation of Compound III

[0126] In a three-necked reaction flask, 4.4 g of compound I, 4.5 g of compound II, 0.98 g of potassium acetate, and 0.2 g of bis(diphenylphosphino)-ferrocene palladium dichloride were added, followed by 40 mL of toluene. After purging with nitrogen, the mixture was reacted at 80–85 °C for 8 hours. HPLC analysis confirmed the reaction was complete. The mixture was filtered, concentrated, slurried with acetonitrile and water, filtered again, and dried to obtain 4.6 g of compound III, with a yield of 65% and a purity greater than 99%.

[0127] Example 4. Preparation of Compound III

[0128] In a three-necked reaction flask, 4.4 g of compound I, 4.5 g of compound II, and 2.6 g of N,N-diisopropylethylamine were added, followed by 40 mL of dichloromethane. After purging with nitrogen, the mixture was reacted at 38–40 °C for 10 hours. HPLC analysis confirmed the reaction was complete. The solvent was evaporated, and the mixture was slurried with acetonitrile and water, filtered, and dried to obtain 5.6 g of compound III, with a yield of 80% and a purity greater than 99%.

[0129] Example 5. Preparation of Compound III

[0130] In a three-necked reaction flask, 4.4 g of compound I, 4.5 g of compound II, and 1.3 g of N,N-diisopropylethylamine were added, followed by 40 mL of N,N-dimethylformamide. After purging with nitrogen, the mixture was reacted at 38–40 °C for 12 hours. HPLC analysis confirmed the reaction was complete. The solvent was extracted, evaporated, and the mixture was slurried with acetonitrile and water, filtered, and dried to obtain 5.1 g of compound III, with a yield of 72% and a purity greater than 99%.

[0131] Example 6. Preparation of Compound III

[0132] In a three-necked reaction flask, 494 g of compound I, 558.9 g of compound II, and 85.9 g of N,N-diisopropylethylamine were added, followed by 4940 mL of dichloromethane. After purging with nitrogen, the mixture was reacted at 38–40 °C for 12 hours. HPLC analysis confirmed the reaction was complete. The solvent was evaporated, and the mixture was slurried with acetonitrile and water, filtered, and dried to obtain 666.4 g of compound III, with a yield of 85% and a purity greater than 99%.

[0133] Compound III 1 H NMR image as follows Figure 1 As shown, 1H NMR (500 MHz, CDCl3) δ 10.28 (s,1H), 6.65 (s, 1H), 3.82 (s, 2H), 3.60 (s, 2H), 2.95 (s, 2H), 2.57 (s, 3H),1.57 – 1.49 (m, 6H).

[0134] Compound III 13 C NMR spectrum as shown Figure 2 As shown, 13 C NMR (126 MHz, CDCl3) δ 185.68,173.59, 169.17, 165.79, 162.27, 110.27, 60.27, 55.54, 48.42, 31.97, 25.56,21.57, 14.72.

[0135] The mass spectrum of compound III is as follows Figure 3 As shown, mass spectrometry (ESI): [M+H]=355.1, 357.1 (chlorine isotope peaks).

[0136] Example 7. Preparation of Compound IV

[0137] In a three-necked reaction flask, 6.1 g of compound III, 1.4 g of lithium tert-butoxide, and 61 mL of dichloromethane were added. After purging with nitrogen, the mixture was heated at 35–42 °C for 4 hours. HPLC analysis confirmed the reaction was complete. Acetic acid and water were added to quench the reaction, the solvent was evaporated to dryness, acetonitrile was added and the mixture was stirred until a slurry was formed. The mixture was cooled to allow crystals to precipitate, filtered, and washed to obtain 5.0 g of compound IV, with a yield of 86% and a purity greater than 98%.

[0138] Example 8. Preparation of Compound IV

[0139] In a three-necked reaction flask, 6.1 g of compound III, 2.4 g of potassium tert-butoxide, and 61 mL of dichloromethane were added. After purging with nitrogen, the mixture was heated at 35–42 °C for 4 hours. HPLC analysis confirmed the reaction was complete. Acetic acid and water were added to quench the reaction, the solvent was evaporated to dryness, acetonitrile was added and the mixture was stirred until a slurry was formed. The mixture was then cooled to allow crystallization, filtered, and washed to obtain 3.5 g of compound IV, with a yield of 60% and a purity greater than 98%.

[0140] Example 9. Preparation of Compound IV

[0141] In a three-necked reaction flask, 6.1 g of compound III, 1.7 g of sodium tert-butoxide, and 61 mL of dichloromethane were added. After purging with nitrogen, the mixture was heated at 35–42 °C for 4 hours. HPLC analysis confirmed the reaction was complete. Acetic acid and water were added to quench the reaction, the solvent was evaporated to dryness, acetonitrile was added and the mixture was stirred until a slurry was formed. The mixture was then cooled to allow crystallization, filtered, and washed to obtain 4.0 g of compound IV, with a yield of 69% and a purity greater than 98%.

[0142] Example 10. Preparation of Compound IV

[0143] In a three-necked reaction flask, 6.1 g of compound III, 1.4 g of lithium tert-butoxide, and 61 mL of acetonitrile were added. After purging with nitrogen, the mixture was heated at 35–42 °C for 4 hours. HPLC analysis confirmed the reaction was complete. Acetic acid and water were added to quench the reaction, the solvent was evaporated to dryness, acetonitrile was added and the mixture was stirred until a slurry was formed. The mixture was cooled to allow crystals to precipitate, filtered, and washed to obtain 4.8 g of compound IV, with a yield of 83% and a purity greater than 98%.

[0144] Example 11. Preparation of Compound IV

[0145] In a three-necked reaction flask, 610 g of compound III, 137.6 g of lithium tert-butoxide, and 6100 mL of dichloromethane were added. After purging with nitrogen, the mixture was heated at 35–42 °C for 4 hours. HPLC analysis confirmed the reaction was complete. Acetic acid and water were added to quench the reaction, the solvent was evaporated to dryness, acetonitrile was added and the mixture was stirred until a slurry was formed. The mixture was cooled to allow crystals to precipitate, filtered, and washed to obtain 522.3 g of compound IV, with a yield of 90% and a purity of 99.3%.

[0146] Compounds of Formula IV 1 H NMR image as follows Figure 4 As shown, 1 H NMR (500 MHz, CDCl3) δ 7.33 (s, 1H), 3.83 (s, 2H), 3.01 (td, J = 13.4, 3.7 Hz, 2H), 2.63 (s, 3H), 2.07 – 2.02 (m,2H), 1.88 (d, J = 12.3 Hz, 3H), 1.47 (dt, J = 9.9, 8.1 Hz, 3H).

[0147] Compounds of Formula IV 13 C NMR spectrum as shown Figure 5 As shown, 13C NMR (126 MHz, CDCl3) δ 166.59,161.22, 154.60, 151.75, 128.40, 113.97, 105.30, 60.79, 46.38, 32.31, 25.23,22.88, 14.75.

[0148] The mass spectrum of compound IV is shown below. Figure 6 As shown, the mass spectrometry (ESI) results are: [M+H] = 337.1, 339.1 (chlorine isotope peaks).

[0149] Example 12. Preparation of compound V

[0150] In a three-necked reaction flask, 6.7 g of compound IV, 37.2 g of glacial acetic acid, and 130 mL of tetrahydrofuran were added and stirred until dissolved. Then, 5.2 g of zinc powder was added, and the mixture was purged with nitrogen and heated to 40–45 °C for 5 hours. HPLC analysis confirmed the reaction was complete. Dichloromethane and water were added, and the mixture was stirred, separated, concentrated, slurried with methanol, filtered, and dried to obtain 4.5 g of compound V, with a yield of 75% and a purity greater than 98%.

[0151] Example 13. Preparation of compound V

[0152] In a three-necked reaction flask, 6.7 g of compound IV, 37.2 g of glacial acetic acid, and 130 mL of tetrahydrofuran were added and stirred until dissolved. Then, 9.7 g of iron powder was added, and the mixture was purged with nitrogen and heated to 40–45 °C for 5 hours. HPLC analysis confirmed the reaction was complete. Dichloromethane and water were added, and the mixture was stirred, separated, concentrated, slurried with methanol, filtered, and dried to obtain 3.8 g of compound V, with a yield of 63% and a purity greater than 98%.

[0153] Example 14. Preparation of compound V

[0154] In a three-necked reaction flask, 6.7 g of compound IV, 37.2 g of glacial acetic acid, and 130 mL of tetrahydrofuran were added and stirred until dissolved. Then, 0.67 g of palladium on carbon was added, and the mixture was heated at 40–45 °C for 5 hours to replace the hydrogen gas. HPLC analysis confirmed the reaction was complete. Dichloromethane and water were added, and the mixture was stirred, separated, concentrated, slurried with methanol, filtered, and dried to obtain 2.1 g of compound V, with a yield of 35% and a purity greater than 98%.

[0155] Example 15. Preparation of compound V

[0156] In a three-necked reaction flask, 670 g of compound IV, 3724.0 g of glacial acetic acid, and 13000 mL of tetrahydrofuran were added and stirred until dissolved. Then, 520.18 g of zinc powder was added, and the mixture was purged with nitrogen and heated to 40–45 °C for 5 hours. HPLC analysis confirmed the reaction was complete. Dichloromethane and water were added, and the mixture was stirred, separated, concentrated, slurried with methanol, filtered, and dried to obtain 482.2 g of compound V, with a yield of 80% and a purity greater than 98%. Its mass spectrum is shown below. Figure 7 As shown, the mass spectrometry (ESI) result is [M+H]=303.1.

[0157] Example 16. Preparation of Compound VI

[0158] In a three-necked reaction flask, 440 g of compound V, 1788.8 g of potassium peroxymonosulfonate, 8800 mL of acetonitrile, and 4400 mL of water were added. After purging with nitrogen, the mixture was heated at 20–30 °C for 4 hours. HPLC analysis confirmed the reaction was complete. The mixture was filtered, extracted with sodium thiosulfate, and then dichloromethane and water were added. The mixture was stirred, separated, concentrated, and then slurried with n-heptane and dichloromethane. After filtration and drying, 384.4 g of compound VI was obtained, with a yield of 79% and a purity greater than 78%.

[0159] Example 17. Preparation of Trilacidine

[0160] In a three-necked reaction flask, 360 g of compound VI and 10800 mL of tetrahydrofuran were added. The mixture was cooled to 0–5 °C, nitrogen gas was purged, and 1465.3 g of LiHMDS was added dropwise. The mixture was then heated to 13–16 °C, and 103.5 g of 1-methyl-4-(6-aminopyridin-3-yl)piperazine (compound VII) was added. The reaction was carried out for 2 hours. The mixture was then cooled to 0–5 °C, nitrogen gas was purged, and 1465.3 g of LiHMDS was added dropwise. The mixture was then heated to 13–16 °C, and 103.5 g of 1-methyl-4-(6-aminopyridin-3-yl)piperazine was added. The reaction was carried out for 2 hours. The mixture was then cooled to 0–5 °C, nitrogen gas was purged, and 1465.3 g of LiHMDS was added dropwise. The mixture was then heated to 13–16 °C, and 103.5 g of 1-methyl-4-(6-aminopyridin-3-yl)piperazine was added. The reaction was carried out for 2 hours. The reaction was confirmed to be complete by HPLC. Dichloromethane, n-butanol and water were added, filtered and dried to obtain 216.3 g of triasicil, with a yield of 45% and a purity greater than 99.67%.

Claims

1. A method for preparing the compound of formula III, characterized in that, Using compounds of formula I and formula II as raw materials, compounds of formula III are obtained through substitution reactions or Buchwald-Hartwig coupling reactions. 。 2. The 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 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 bis(triphenylphosphine)palladium dichloride, bis(diphenylphosphine)-ferrocene palladium dichloride, tetra(triphenylphosphine)palladium, and palladium acetate.

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

5. The method according to claim 1, characterized in that, The substitution reaction is carried out under the action of a base, which includes one or more of sodium carbonate, triethylamine, N,N-diisopropylethylamine, potassium carbonate, and potassium phosphate.

6. The method according to claim 1, characterized in that, In the substitution reaction, the molar ratio of compound I to base is 1:0.1~2.

0.

7. The method according to claim 1, characterized in that, In the substitution reaction, the reaction temperature is 20~120℃ and the reaction time is 7~15 hours.

8. A method for preparing the 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) Compound III obtained in step (1) is converted into compound IV by intramolecular Aldol condensation; The structural formula of compound IV is as follows: 。 9. The method according to claim 8, characterized in that, In step (2), the Aldol condensation reaction is carried out under the action of a base, which includes any one or more of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, and DBU.

10. The method according to claim 8, characterized in that, In step (2), the Aldol condensation reaction temperature is 0~70℃ and the reaction time is 3~6 hours.

11. A compound of formula IV prepared by the method according to any one of claims 8 to 10.

12. A method for preparing compound V, characterized by comprising the following steps: S1: Prepare compound of formula IV by the method according to any one of claims 8 to 10; S2: The compound of formula IV obtained from S1 was reduced and dehalogenated to obtain compound of formula V; The structural formula of compound V is as follows: 。 13. The method according to claim 12, characterized in that, In S2, the dehalogenation catalyst includes any one or more of palladium on carbon, iron powder, and zinc powder.

14. The method according to claim 12, characterized in that, In S2, the hydrogen source includes any one or more of hydrogen gas, hydrochloric acid, glacial acetic acid, and ammonia water.

15. A compound of formula V prepared by the method according to any one of claims 12 to 14.

16. A method for preparing tricracetam, characterized by comprising the following steps: 1) Prepare compound V by the method according to any one of claims 12-14; 2) The compound of formula V obtained in step 1) is oxidized to obtain compound of formula VI; 3) The compound of formula VI obtained in step 2) undergoes a substitution reaction with the compound of formula VII to give triasidil; The structural formulas of compound VI, compound VII, and tricrazil are as follows: 。 17. The preparation method according to claim 16, characterized in that, in step 2), the oxidant includes potassium peroxymonosulfonate.

18. The preparation method according to claim 16, characterized in that, in step 3), the substitution reaction is carried out in the presence of a base, wherein the base includes LiHMDS.

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