Novel synthesis method of trirasilil
By combining the substitution reaction of compounds 4 and 5 with oxidation and substitution aminolysis reactions in the presence of a base and a phase transfer catalyst, the problems of expensive starting materials and harsh reaction conditions in the prior art are solved, and efficient and economical tricrasciline synthesis is achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SPH NO 1 BIOCHEM & PHARMA CO LTD
- Filing Date
- 2026-01-13
- Publication Date
- 2026-05-12
AI Technical Summary
Existing methods for synthesizing tricraceticil involve expensive and difficult-to-obtain starting materials, use precious metal palladium catalysts, have harsh reaction conditions, involve many steps, and have low overall yields, making them unsuitable for industrial production.
The synthetic route is simplified by using the substitution reaction of compounds 4 and 5 in the presence of a base and a phase transfer catalyst, combined with oxidation and substitution aminolysis reactions, and using commercially available starting materials and mild conditions.
A method for synthesizing treasidrili has been developed that is simple to operate, has mild reaction conditions, uses inexpensive and readily available raw materials, is suitable for large-scale production, and has a high overall yield.
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Figure CN122010959A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic compound technology and relates to a new method for preparing triabocitric acid. Background Technology
[0002] Trilacilib, developed by G1 Therapeutics, is the world's first innovative drug with systemic myeloprotective effects, administered before chemotherapy. It received FDA approval on February 12, 2021, and is marketed by G1 Therapeutics Inc. under the brand name Cosela. On July 12, 2022, it received NMPA approval from the China National Medical Products Administration (NMPA) and is marketed by Jiangsu Simcere Pharmaceutical Co., Ltd. under the brand name Cosela. Trilacilib has broad application prospects, therefore, developing a simple and efficient route is essential. The synthesis of trilacilib involved in this invention is simple and efficient, and of significant value.
[0003] The literature reports the following main synthetic routes for tricrazil: Method 1 - Original Patent WO2012061156A1: The synthetic method of tricrazil reported in the original patent WO2012061156A1 is as follows: using N-[1-(aminomethyl)cyclohexyl]carbamate benzyl ester as a starting material, after Boc protection and debenzylation, the intermediate N-[(1-aminocyclohexyl)methyl]carbamate tert-butyl ester is obtained. Then, it is reacted with 5-bromo-2,4-dichloropyrimidine through nucleophilic substitution, coupling, cyclization, hydrolysis, and oxidation to obtain the key parent nucleus. Finally, it undergoes Buchwald-Hartwig coupling with 5-(4-methylpiperazin-1-yl)pyridin-2-amine to generate tricrazil. This route does not provide the yields of each reaction step, the starting materials are rarely commercially available and expensive, and there are very few reported synthetic methods.
[0004]
[0005] Method 2 - Original Patent WO2018005865A1: Subsequently, the original research reported the production process of tricrazolidone in patent WO2018005865A1: using ethyl 4-chloro-2-(methylthio)pyrimidin-5-carboxylate as a raw material, it undergoes a substitution reaction with 1,4-diazaspiro[5.5]undecane-3-one to obtain the intermediate ethyl 2-(methylthio)-4-(3-oxo-1,4-diazaspiro[5.5]undecane-1-yl)pyrimidin-5-carboxylate, and then undergoes an eight-step reaction of amino protection, cyclization, sulfonation, reduction, deBoc removal, oxidation, and coupling to obtain tricrazolidone, with a yield of 16.8%. However, the starting material 1,4-diazaspiro[5.5]undecane-3-one is expensive and requires two additional steps to be prepared in-house (yield of 35%).
[0006]
[0007] Method 3 - Patent CN114014863: Patent CN114014863 discloses a method for preparing tricrazil, using methyl 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate as a starting material through substitution, hydrolysis, condensation, and coupling reactions to obtain tricrazil, with an overall yield of 61.4%. This synthetic route is relatively short, with mild reaction conditions in each step, requiring no column chromatography purification, and exhibits good yield and purity. However, it does not provide the synthetic methods for the key intermediates used, and the starting material is not commercially available.
[0008]
[0009] Method 4 - Patent CN113788837A: The route reported in Method 4 is currently the shortest method for synthesizing trilaciclib. It uses 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid and 1-aminomethyl-1-cyclohexanol as starting materials, undergoing a condensation reaction to obtain an amide product. This product is then intramolecularly cyclized to obtain the key parent nucleus. Finally, the parent nucleus is substituted with 1-methyl-4-(6-aminopyridin-3-yl)piperazine to obtain Trilaciclib, with an overall yield as high as 65%. However, the starting materials are scarce and very expensive, and the reaction conditions are harsh, making it unsuitable for industrial production.
[0010]
[0011] Method 5 - Patent CN 117903147 A: Recently, a patent reported a method for preparing tricrazil using 5-bromo-2,4-dichloropyrimidine as a starting material. The tricrazil core is obtained through substitution, cyclization, esterification, and reductive aminolysis reactions. Finally, it is coupled with 1-methyl-4-(6-aminopyridin-3-yl)piperazine to obtain tricrazil, with an overall yield of 15%. This reaction has a low yield, resulting in high production costs.
[0012] Summary of the Invention
[0013] The purpose of this invention is to overcome the shortcomings of existing technologies, such as expensive and difficult-to-obtain starting materials, use of precious metal palladium catalysts, harsh reaction conditions, multiple steps, low overall yield, and unsuitability for industrial production. This invention provides a new synthetic method for tricracetam; this method is simple to operate, has mild reaction conditions, and uses inexpensive and readily available raw materials, making it suitable for scale-up production.
[0014] This invention provides a method for preparing triasidil, which includes the following steps:
[0015] In a solvent, in the presence of a base and a phase transfer catalyst, compounds 4 and 5 undergo a substitution reaction to give tricracene;
[0016] .
[0017] In some embodiments of the present invention, the solvent in the substitution reaction is a conventional solvent for such reactions in the art; preferably an amide solvent; more preferably N,N-dimethylformamide or N,N-dimethylacetamide; for example, N,N-dimethylformamide.
[0018] In some embodiments of the present invention, the base in the substitution reaction is an alkali metal carbonate; preferably potassium carbonate or cesium carbonate; for example, cesium carbonate.
[0019] In some embodiments of the present invention, in the substitution reaction, the phase transfer catalyst is a quaternary ammonium salt phase transfer agent or a quaternary phosphate salt phase transfer agent; the quaternary ammonium salt phase transfer agent is preferably tetrabutylammonium halide; more preferably tetra-n-butylammonium iodide, tetra-n-butylammonium bromide or tetra-n-butylammonium chloride; for example, tetra-n-butylammonium bromide; the quaternary phosphate salt phase transfer catalyst is preferably triphenylmethylphosphine halide or tetraphenylphosphine halide; for example, triphenylmethylphosphine bromide or tetraphenylphosphine bromide.
[0020] In some embodiments of the present invention, in the substitution reaction, the molar volume ratio of compound 4 to the solvent is 0.1-1 mol / L; preferably 0.2-0.6 mol / L; for example, 0.4 mol / L.
[0021] In some embodiments of the present invention, in the substitution reaction, the molar ratio of the base to the compound 4 is (1-2):1; preferably (1.2-1.8):1; for example, 1.5:1.
[0022] In some embodiments of the present invention, in the substitution reaction, the molar ratio of the phase transfer catalyst to the compound 4 is (0.02-0.3):1; preferably (0.05-0.15):1; for example, 0.1:1.
[0023] In some embodiments of the present invention, the temperature of the substitution reaction is the conventional reaction temperature for such reactions in the art; preferably 80-120 °C; more preferably 90-110 °C; for example 100 °C.
[0024] In some embodiments of the present invention, the substitution reaction time is the conventional reaction time for such reactions in the art, usually ending when the raw materials disappear or the product no longer increases; preferably 12-48 h; more preferably 18-30 h; for example 24 h.
[0025] In some embodiments of the present invention, the substitution reaction further includes the following post-processing steps: cooling to room temperature, adding water and ethyl acetate, stirring and separating the liquid, extracting the aqueous phase with ethyl acetate, washing the combined organic layers sequentially with water and saturated sodium chloride, and removing the solvent by rotary evaporation to obtain the crude product; preferably, it further includes: slurrying the crude product with ethyl acetate, filtering, and vacuum drying the filter cake to obtain triasidil.
[0026] In some embodiments of the present invention, the method for preparing tricracetam further includes the following steps:
[0027] ;
[0028] In a solvent, in the presence of an oxidizing agent, compound 3 undergoes an oxidation reaction to give compound 4.
[0029] In some embodiments of the present invention, in the oxidation reaction, the solvent is a conventional solvent for such reactions in the art; preferably, it is a mixed solvent of a nitrile solvent and water; the nitrile solvent is preferably acetonitrile; more preferably, the solvent is an equal volume mixed solvent of a nitrile solvent and water; preferably, it is an equal volume mixed solvent of acetonitrile and water.
[0030] In some embodiments of the present invention, the oxidant in the oxidation reaction is a conventional oxidant for such reactions in the art; for example, potassium persulfate double salt.
[0031] In some embodiments of the present invention, in the oxidation reaction, the molar volume ratio of compound 3 to the solvent is 0.05-0.5 mol / L; preferably 0.1-0.3 mol / L; for example, 0.17 mol / L.
[0032] In some embodiments of the present invention, in the oxidation reaction, the molar ratio of the oxidant to the compound 3 is (2-8):1; preferably (4-6):1; for example, 5:1.
[0033] In some embodiments of the present invention, the temperature of the oxidation reaction is the conventional reaction temperature for such reactions in the art; preferably 20-30 °C.
[0034] In some embodiments of the present invention, the oxidation reaction time is the conventional reaction time for such reactions in the art, usually ending when the raw materials disappear or the products no longer increase; preferably 2-12 h; more preferably 4-6 h; for example 5 h.
[0035] In some embodiments of the present invention, the oxidation reaction further includes the following post-processing steps: removing most of the acetonitrile by rotary evaporation, extracting the aqueous phase with ethyl acetate, washing the combined organic layers sequentially with water and saturated sodium chloride, and removing the solvent by rotary evaporation to obtain the crude product.
[0036] In some embodiments of the present invention, after the oxidation reaction is completed, the crude product containing compound 4 is used to carry out the aforementioned substitution reaction to obtain triasidil; the amount of compound 4 depends on the amount of compound 3 used in the oxidation reaction.
[0037] In some embodiments of the present invention, in the substitution reaction, the molar volume ratio of compound 3 to the solvent is 0.1-1 mol / L; preferably 0.2-0.6 mol / L; for example, 0.4 mol / L.
[0038] In some embodiments of the present invention, in the substitution reaction, the molar ratio of the base to the compound 3 is (1-2):1; preferably (1.2-1.8):1; for example, 1.5:1.
[0039] In some embodiments of the present invention, in the substitution reaction, the molar ratio of the phase transfer catalyst to the compound 3 is (0.02-0.3):1; preferably (0.05-0.15):1; for example, 0.1:1.
[0040] In some embodiments of the present invention, the method for preparing tricracetam further includes the following steps:
[0041] ,
[0042] Where X is a halogen;
[0043] In a solvent and in the presence of a base, compound 1 and compound 2a undergo a substitution aminolysis reaction to give compound 3.
[0044] In some embodiments of the present invention, in compound 2a, X is Cl or Br.
[0045] In some embodiments of the present invention, in the substituted aminolysis reaction, the solvent is a polar aprotic solvent; preferably an amide solvent or a sulfone solvent; more preferably N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or sulfolane; for example, N,N-dimethylformamide.
[0046] In some embodiments of the present invention, in the substituted aminolysis reaction, the base is an alkali metal carbonate or an alkali metal alkoxide; preferably potassium carbonate, cesium carbonate, sodium tert-amyloxide, or potassium tert-amyloxide; for example, potassium carbonate.
[0047] In some embodiments of the present invention, in the substituted aminolysis reaction, the molar volume ratio of compound 2a to the solvent is 0.2-3 mol / L; preferably 0.5-1.5 mol / L; for example, 1 mol / L.
[0048] In some embodiments of the present invention, in the substituted aminolysis reaction, the molar ratio of compound 2a to compound 1 is (0.9-1.5):1; preferably (1-1.2):1; for example, 1:1.
[0049] In some embodiments of the present invention, in the substituted aminolysis reaction, the molar ratio of the base to the compound 1 is (1-5):1; preferably (2-4):1; for example, 3:1.
[0050] In some embodiments of the present invention, the temperature of the substitution aminolysis reaction is a conventional reaction temperature for such reactions in the art; preferably 80-120°C. o C; more preferably 90-110 o C; for example, 100 o C.
[0051] In some embodiments of the present invention, the time for the substitutional aminolysis reaction is the conventional reaction time for such reactions in the art, usually ending when the starting material disappears or the product no longer increases; preferably 5-20 h; more preferably 8-12 h; for example 10 h.
[0052] In some embodiments of the present invention, the substituted aminolysis reaction further includes the following post-processing steps: after cooling to room temperature, saturated ammonium chloride is added to quench the reaction, ethyl acetate is used for extraction, and the organic phases are combined and the solvent is removed by rotary evaporation to obtain a crude product; preferably, it further includes: the crude product is pulped with methyl tert-butyl ether, filtered, and the filter cake is vacuum dried to obtain compound 3.
[0053] In some embodiments of the present invention, the method for preparing tricracetam further includes the following steps:
[0054] In a solvent, in the presence of a halogenating agent, compound 2 undergoes a halogenation reaction to give compound 2a; said compound 2 is 1-aminomethyl-1-cyclohexanol hydrochloride.
[0055] In some embodiments of the present invention, the solvent in the halogenation reaction is a polar aprotic solvent; preferably an amide solvent or a sulfone solvent; more preferably N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or sulfolane; for example, N,N-dimethylformamide.
[0056] In some embodiments of the present invention, the halogenating agent in the halogenation reaction is thionyl chloride or phosphorus tribromide.
[0057] In some embodiments of the present invention, in the halogenation reaction, the molar volume ratio of compound 2 to the solvent is 0.2-3 mol / L; preferably 0.5-1.5 mol / L; for example, 1 mol / L.
[0058] In some embodiments of the present invention, in the halogenation reaction, the molar ratio of the halogenating reagent to the compound 2 is (1-2):1; preferably (1.2-1.8):1; for example, 1.5:1.
[0059] In some embodiments of the present invention, the halogenating reagent is added dropwise during the halogenation reaction.
[0060] In some embodiments of the present invention, the temperature of the halogenation reaction is a conventional reaction temperature for such reactions in the art; preferably 40-80°C. o C; more preferably 50-70 o C; for example, 60 o C.
[0061] In some embodiments of the present invention, the halogenation reaction time is the conventional reaction time for such reactions in the art, usually ending when the raw materials disappear or the product no longer increases; preferably 1-8 h; more preferably 2-6 h; for example 4 h.
[0062] In some embodiments of the present invention, after the halogenation reaction is completed, the aforementioned substitution aminolysis reaction is carried out using the reaction solution containing compound 2a to obtain compound 3.
[0063] In some embodiments of the present invention, the amount of compound 2a depends on the amount of compound 2 used in the halogenation reaction, and in the substitution aminolysis reaction, the molar volume ratio of compound 2 to the solvent is 0.2-3 mol / L; preferably 0.5-1.5 mol / L; for example, 1 mol / L.
[0064] In some embodiments of the present invention, in the substituted aminolysis reaction, the molar ratio of compound 2 to compound 1 is (0.9-1.5):1; preferably (1-1.2):1; for example, 1:1.
[0065] This invention provides a method for preparing compound 3, which includes the following steps:
[0066] ,
[0067] Where X is a halogen;
[0068] In a solvent and in the presence of a base, compound 1 and compound 2a undergo a substitution aminolysis reaction to give compound 3.
[0069] In some embodiments of the present invention, the reaction conditions for the substitution aminolysis reaction are as described above.
[0070] In some embodiments of the present invention, the preparation method of compound 3 further includes the following steps:
[0071] In a solvent, in the presence of a halogenating agent, compound 2 undergoes a halogenation reaction to give compound 2a; said compound 2 is 1-aminomethyl-1-cyclohexanol hydrochloride.
[0072] In some embodiments of the present invention, the reaction conditions for the halogenation reaction are as described above.
[0073] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.
[0074] The reagents and raw materials used in this invention are all commercially available.
[0075] This invention has one or more of the following positive and progressive effects:
[0076] (1) Simple to operate;
[0077] (2) The reaction conditions are mild;
[0078] (3) Raw materials are inexpensive and readily available;
[0079] (4) No precious metal catalysts are used;
[0080] (5) Suitable for large-scale production;
[0081] (6) Fewer steps, higher overall yield. Detailed Implementation
[0082] The present invention will be further described in detail below with reference to specific embodiments. However, the scope of protection of the present invention is not limited to these embodiments. All variations and advantages that can be conceived by those skilled in the art without departing from the inventive concept and scope are included in the present invention and are protected by the appended claims. The processes, conditions, reagents, experimental methods, etc., for carrying out the present invention, except as specifically mentioned below, are all common knowledge and general knowledge in the art, and the present invention does not have any particular limitations. Furthermore, product purity is determined by HPLC (area normalization method).
[0083] Example 1: Preparation of Compound 3
[0084]
[0085] Add 10 mmol (1.66 g) of 1-aminomethyl-1-cyclohexanol hydrochloride and 10 mL of DMF to a 50 mL single-necked reaction flask, followed by slow dropwise addition of thionyl chloride (15 mmol (1.78 g)). Heat to 60°C. o The reaction was carried out at C for 4 hours. After cooling to room temperature, pyrimidine-pyrrole compound 1 (10 mmol, 2.23 g) and potassium carbonate (30 mmol, 4.15 g) were added sequentially. After the addition was complete, the temperature was raised to 100°C.o The reaction was carried out at C for 10 hours. After cooling to room temperature, 15 mL of saturated ammonium chloride was added to quench the reaction. The mixture was then extracted with ethyl acetate (10 x 3 mL), and the organic phases were combined and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was then slurried with methyl tert-butyl ether, filtered, and the filter cake was dried under vacuum to obtain a pale yellow solid compound 3 (2.18 g, 72%, purity 98.9%). 1 H NMR (400MHz, DMSO-d6) δ 8.96 (s, 1H), 8.31 (d, J = 3.3 Hz, 1H), 7.15 (s, 1H), 3.68(d, J = 3.2 Hz, 2H), 2.87 (td, J = 13.3, 4.0 Hz, 2H), 2.57 (s, 3H), 1.92 (d,J = 13.1 Hz, 2H), 1.79 – 1.70 (m, 3H), 1.46 (tdd, J = 13.7, 10.4, 3.5 Hz,3H).
[0086] Example 2: Preparation of Compound 4
[0087]
[0088] Compound 3 (4 mmol, 1.18 g), the product from the previous step, and potassium persulfate double salt (20 mmol, 6.92 g) were added to a 50 mL reaction flask, followed by 12 mL of water and acetonitrile. After stirring at room temperature for 5 h, most of the acetonitrile was removed by rotary evaporation. The aqueous phase was extracted with ethyl acetate (10 x 3 mL), and the combined organic layers were washed successively with water (10 x 2 mL) and saturated sodium chloride (20 mL). The solvent was removed by rotary evaporation to obtain crude compound 4 with a purity of 95.7%, which can be used directly in the next step. 1 H NMR (400 MHz, Chloroform-d) δ 9.22 (s, 1H), 7.45 (s, 1H), 7.16 (s, 1H), 3.87 (d, J = 3.1Hz, 2H), 3.42 (s, 3H), 3.00 (td, J = 12.6, 4.4 Hz, 2H), 2.15 – 2.07 (m, 2H), 1.93 – 1.83 (m, 4H), 1.49 (t, J = 9.2 Hz, 3H).
[0089] Example 3: Preparation of Triasidril
[0090]
[0091] Cesium carbonate (6 mmol, 2.93 g), TBAB (0.4 mmol, 128.8 mg), and 1-methyl-4-(6-aminopyridin-3-yl)piperazine (compound 5) (6 mmol, 1.15 g) were added to the crude compound 4 from the previous step, followed by the addition of 10 mL of DMF. The mixture was heated to 100 °C and reacted for approximately 24 h. After cooling to room temperature, 10 mL of water and ethyl acetate were added, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate (10 x 3 mL). The combined organic layers were washed successively with water (10 x 2 mL) and saturated sodium chloride (20 mL). The solvent was removed by rotary evaporation, and the crude product was slurried with ethyl acetate, filtered, and the filter cake was dried under vacuum to obtain a brownish-yellow solid, triasidrili (1.46 g, two-step yield 82%, purity 99.5%). 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.48 (s, 1H), 8.21 (dd, J = 9.6, 2.9 Hz, 1H), 8.02 (d, J = 2.9 Hz, 1H), 7.67(d, J = 9.5 Hz, 1H), 7.31 (s, 1H), 3.85 (d, J = 10.1 Hz, 2H), 3.69 (d, J =2.9 Hz, 2H), 3.52 (d, J = 9.0 Hz, 2H), 3.24 (d, J = 9.8 Hz, 4H), 2.83 (d, J =8.7 Hz, 5H), 1.93 (d, J = 13.3 Hz, 3H), 1.78 – 1.72 (m, 4H), 1.48 (d, J =13.7 Hz, 2H).
[0092] Comparative Example 1: Preparation of Trivacoride
[0093] Cesium carbonate (6 mmol, 2.93 g) and 1-methyl-4-(6-aminopyridin-3-yl)piperazine (compound 5) (6 mmol, 1.15 g) were added to the crude product 4 from the previous step, and finally 10 mL of DMF was added. After reacting at 100 °C for about 24 h, the mixture was cooled to room temperature, and 10 mL of water and ethyl acetate were added respectively. The mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate (10 x 3 mL), and the combined organic layers were washed successively with water (10 x 2 mL) and saturated sodium chloride (20 mL). The solvent was removed by rotary evaporation, and the crude product was slurried with ethyl acetate, filtered, and the filter cake was dried under vacuum to obtain a brownish-yellow solid triasilimide (0.91 g, two-step yield 51%, purity 99.5%).
Claims
1. A method for preparing triasidil, comprising the following steps: In a solvent, in the presence of a base and a phase transfer catalyst, compounds 4 and 5 undergo a substitution reaction to give tricracene; 。 2. The preparation method according to claim 1, characterized in that, Meet one or more of the following conditions: (1) In the substitution reaction, the solvent is an amide solvent; preferably N,N-dimethylformamide or N,N-dimethylacetamide; for example, N,N-dimethylformamide; (2) In the substitution reaction, the base is an alkali metal carbonate; preferably potassium carbonate or cesium carbonate; for example, cesium carbonate; (3) In the substitution reaction, the phase transfer catalyst is a quaternary ammonium salt phase transfer agent or a quaternary phosphate salt phase transfer agent; the quaternary ammonium salt phase transfer agent is preferably tetrabutylammonium halide; more preferably tetra-n-butylammonium iodide, tetra-n-butylammonium bromide or tetra-n-butylammonium chloride; for example, tetra-n-butylammonium bromide; the quaternary phosphate salt phase transfer catalyst is preferably triphenylmethylphosphine halide or tetraphenylphosphine halide; for example, triphenylmethylphosphine bromide or tetraphenylphosphine bromide; (4) In the substitution reaction, the molar volume ratio of compound 4 to the solvent is 0.1-1 mol / L; preferably 0.2-0.6 mol / L; for example, 0.4 mol / L; (5) In the substitution reaction, the molar ratio of the base to the compound 4 is (1-2):1; preferably (1.2-1.8):1; for example, 1.5:1; (6) In the substitution reaction, the molar ratio of the phase transfer catalyst to compound 4 is (0.02-0.3):1; preferably (0.05-0.15):1; for example, 0.1:1; (7) The temperature of the substitution reaction is 80-120 °C; preferably 90-110 °C; for example, 100 °C; (8) The substitution reaction takes 12-48 h; preferably 18-30 h; for example, 24 h; (9) The substitution reaction further includes the following post-processing steps: cooling to room temperature, adding water and ethyl acetate, stirring and separating the liquid, extracting the aqueous phase with ethyl acetate, washing the combined organic layers with water and saturated sodium chloride in sequence, and removing the solvent by rotary evaporation to obtain the crude product; preferably, it further includes: slurrying the crude product with ethyl acetate, filtering, and vacuum drying the filter cake to obtain triasidil.
3. The preparation method according to claim 1, characterized in that, The method for preparing tricracetam further includes the following steps: ； In a solvent, in the presence of an oxidizing agent, compound 3 undergoes an oxidation reaction to give compound 4; Preferably, the preparation method satisfies one or more of the following conditions: (1) In the substitution reaction, the molar volume ratio of compound 3 to the solvent is 0.1-1 mol / L; preferably 0.2-0.6 mol / L; for example, 0.4 mol / L; (2) In the substitution reaction, the molar ratio of the base to the compound 3 is (1-2):1; preferably (1.2-1.8):1; for example, 1.5:1; (3) In the substitution reaction, the molar ratio of the phase transfer catalyst to the compound 3 is (0.02-0.3):1; preferably (0.05-0.15):1; for example, 0.1:
1.
4. The preparation method according to claim 3, characterized in that, Meet one or more of the following conditions: (1) In the oxidation reaction, the solvent is a mixture of nitrile solvent and water; the nitrile solvent is preferably acetonitrile; more preferably, the solvent is an equal volume mixture of nitrile solvent and water; preferably, an equal volume mixture of acetonitrile and water. (2) In the oxidation reaction, the oxidant is potassium persulfate double salt; (3) In the oxidation reaction, the molar volume ratio of compound 3 to the solvent is 0.05-0.5 mol / L; preferably 0.1-0.3 mol / L; for example, 0.17 mol / L; (4) In the oxidation reaction, the molar ratio of the oxidant to the compound 3 is (2-8):1; preferably (4-6):1; for example, 5:1; (5) The temperature of the oxidation reaction is 20-30 °C; (6) The oxidation reaction takes 2-12 h; more preferably 4-6 h; for example 5 h; (7) The oxidation reaction also includes the following post-treatment steps: removing most of the acetonitrile, extracting the aqueous phase with ethyl acetate, washing the combined organic layers with water and saturated sodium chloride in sequence, and removing the solvent to obtain the crude product.
5. The preparation method according to claim 3, characterized in that, The method for preparing tricracetam further includes the following steps: ， Where X is a halogen; In a solvent and in the presence of a base, compound 1 and compound 2a undergo a substitution aminolysis reaction to give compound 3.
6. The preparation method according to claim 5, characterized in that, Meet one or more of the following conditions: (1) In compound 2a, X is Cl or Br; (2) In the substituted aminolysis reaction, the solvent is a polar aprotic solvent; preferably an amide solvent or a sulfone solvent; more preferably N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or sulfolane; for example, N,N-dimethylformamide; (3) In the substituted aminolysis reaction, the base is an alkali metal carbonate or an alkali metal alkoxide; preferably potassium carbonate, cesium carbonate, sodium tert-amyloxide or potassium tert-amyloxide; for example, potassium carbonate; (4) In the substituted aminolysis reaction, the molar volume ratio of compound 2a to the solvent is 0.2-3 mol / L; preferably 0.5-1.5 mol / L; for example, 1 mol / L; (5) In the substituted aminolysis reaction, the molar ratio of compound 2a to compound 1 is (0.9-1.5):1; preferably (1-1.2):1; for example, 1:1; (6) In the substituted aminolysis reaction, the molar ratio of the base to compound 1 is (1-5):1; preferably (2-4):1; for example, 3:1; (7) The temperature of the substitution aminolysis reaction is 80-120°C. o C; preferably 90-110 o C; for example, 100 o C; (8) The time for the substitution aminolysis reaction is 5-20 h; preferably 8-12 h; for example 10 h; (9) The substituted aminolysis reaction further includes the following post-processing steps: after cooling to room temperature, saturated ammonium chloride is added to quench the reaction, ethyl acetate is used for extraction, and the organic phases are combined and the solvent is removed by rotary evaporation to obtain the crude product; preferably, it further includes: the crude product is pulped with methyl tert-butyl ether, filtered, and the filter cake is dried under vacuum to obtain compound 3.
7. The preparation method according to claim 5, characterized in that, The method for preparing tricracetam further includes the following steps: In a solvent, in the presence of a halogenating agent, compound 2 undergoes a halogenation reaction to give compound 2a; said compound 2 is 1-aminomethyl-1-cyclohexanol hydrochloride; Preferably, the preparation method satisfies one or two of the following conditions: (1) In the substituted aminolysis reaction, the molar volume ratio of compound 2 to the solvent is 0.2-3 mol / L; preferably 0.5-1.5 mol / L; for example, 1 mol / L; (2) In the substituted aminolysis reaction, the molar ratio of compound 2 and compound 1 is (0.9-1.5):1; preferably (1-1.2):1; for example, 1:
1.
8. The preparation method according to claim 7, characterized in that, Meet one or more of the following conditions: (1) In the halogenation reaction, the solvent is a polar aprotic solvent; preferably an amide solvent or a sulfone solvent; more preferably N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or sulfolane; for example, N,N-dimethylformamide; (2) In the halogenation reaction, the halogenating agent is thionyl chloride or phosphorus tribromide; (3) In the halogenation reaction, the halogenating reagent is added dropwise; (4) In the halogenation reaction, the molar volume ratio of compound 2 to the solvent is 0.2-3 mol / L; preferably 0.5-1.5 mol / L; for example, 1 mol / L; (5) In the halogenation reaction, the molar ratio of the halogenating reagent to the compound 2 is (1-2):1; preferably (1.2-1.8):1; for example, 1.5:1; (6) The temperature of the halogenation reaction is 40-80°C. o C; preferably 50-70 o C; for example, 60 o C; (7) The halogenation reaction takes 1-8 h; preferably 2-6 h; for example 4 h.
9. A method for preparing compound 3, comprising the following steps: ， Where X is a halogen; In a solvent and in the presence of a base, compound 1 and compound 2a undergo a substitution aminolysis reaction to give compound 3.
10. The preparation method according to claim 9, characterized in that, The preparation method of compound 3 further includes the following steps: In a solvent, in the presence of a halogenating agent, compound 2 undergoes a halogenation reaction to give compound 2a; said compound 2 is 1-aminomethyl-1-cyclohexanol hydrochloride; Preferably, the reaction conditions for the substitution aminolysis reaction are as described in claim 6 or 7; More preferably, the reaction conditions for the halogenation reaction are as described in claim 8.