Preparation method of abelsilib

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing abesilib through substitution, nucleophilic addition and multi-step coupling reaction by taking 1, 3-dimethyluracil as an initial raw material, which comprises the following six steps: S1, preparing an intermediate II; s2, preparing an intermediate III; s3, preparing an intermediate IV; s4, preparing an intermediate V; s5, preparing an abesilib crude product; and S6, preparing an abesilib product. According to the invention, the core problems of high raw material cost, tedious steps, harsh conditions, poor safety, high environmental protection pressure and the like in the synthesis of the abelsilib are solved, and a technical scheme with extremely high competitiveness is provided for large-scale and green production of the abelsilib.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of drug synthesis, and particularly relates to a method for preparing abemaciclib by taking 1,3-dimethyl uracil as a starting material, and through substitution, nucleophilic addition and multi-step coupling reaction. BACKGROUND

[0002] In the field of tumor treatment, the research and development of cyclin-dependent kinase (CDK) inhibitors as key targets are of great significance to cancer treatment. Abemaciclib, as a representative oral small molecule CDK inhibitor developed by Eli Lilly Company in the United States, exhibits significant anti-tumor activity by targeting CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathways. On September 28, 2017, abemaciclib was approved for marketing by the U.S. Food and Drug Administration (FDA), with the trade name Verzenio, for the treatment of advanced or metastatic breast cancer, filling an important gap in the relevant treatment field. The chemical name of abemaciclib is N-[5-[(4-ethyl-1-piperazinyl) methyl]-2-pyridyl]-5-fluoro-4-[4-fluoro-2-methyl-1-isopropyl-1H-benzimidazol-6-yl]-2-pyrimidinamine, the molecular weight is 506.59, the CAS number is 1231929-97-7, and the structural formula is as follows: .

[0003] Abemaciclib can block the proliferation and reproduction of malignant cells by inhibiting cell cycle, and many studies have confirmed that abemaciclib can effectively improve the non-invasive tumor recurrence survival rate of patients with hormone receptor positive (HR+) early breast cancer at high risk of recurrence. Most of the currently disclosed patent literatures are obtained by coupling reaction of the following two intermediates A and intermediate B to obtain abemaciclib product: ; .

[0004] According to different raw materials used, the synthesis method of abemaciclib intermediate A mainly has the following kinds: The first kind: taking 6-aminonicotinic acid ethyl ester as a starting material, introducing a Boc protecting group through a reaction, reducing, methylsulfonylation, hydrocarbonation and removing the protecting group to obtain intermediate A, and the synthesis route is as follows: ; This route has significant defects: first, the reaction steps are lengthy, and the target intermediate A is prepared after 5 steps; second, the total yield is low, only 32%, which is not conducive to large-scale production; third, the reduction reaction conditions are harsh, and strong reducing agent lithium aluminum hydride (LiAlH4) must be used, and it must be operated in a strict water-free and oxygen-free system, which requires high equipment and operators, and has great production safety hazards; fourth, the raw material 6-amino nicotinic acid ethyl ester and some reagents (such as cesium carbonate) are expensive. The above factors seriously restrict the industrial application of this preparation method.

[0005] The second method is to use 6-bromopyridine-3-carboxaldehyde as the starting material, and the target product is obtained by reductive amination, coupling reaction and removal of the silicon-based protecting group. The synthesis route is as follows: ; This route has obvious shortcomings. The use of Pd2(dba)3, CyJohnPhos and other reagents in the process increases the production cost, which seriously limits its economy. In addition, there is another process route to prepare intermediate A using liquid ammonia or aqueous ammonia as a nitrogen source under the catalysis of cuprous oxide. However, liquid ammonia has a strong irritating odor, strong corrosion and is extremely volatile, which brings great difficulties in the operation process and requires high sealing and corrosion resistance of the production equipment. At the same time, the environmental treatment pressure brought by the volatilization of liquid ammonia is huge, and the process also produces copper metal residue problem, which is difficult to meet the product quality standards. These factors have become the bottleneck for large-scale industrial production.

[0006] The third method is to use 2-chloro-5-chloromethylpyridine as the starting material, and the target product is obtained by hydrocarbonation, coupling reaction and alcoholysis deprotection. The synthesis route is as follows: ; This route also needs to use lithium bis(trimethylsilyl)amide as an amine source reagent during the reaction process. Due to the high market price of this reagent, the production cost is greatly increased. At the same time, its expensive price characteristics are contrary to the economy and scale required by industrial production, which greatly limits the promotion and application of this synthesis process in industrial production.

[0007] According to the different raw materials used, there are also the following methods for the synthesis of abemaciclib intermediate B: The first method is to use 2-propylamine and acetic anhydride as raw materials, and the target product is obtained by acylation, condensation, nucleophilic substitution and suzuki coupling reaction. The synthesis route is as follows: ; The route comprises five steps, wherein a large amount of phosphorus oxychloride is used as a catalyst in the second step of condensation reaction, which is highly toxic and generates a large amount of wastewater after reaction, thereby increasing the environmental treatment cost and putting forward higher requirements for operation safety; the 2,4-dichloro-5-fluoropyrimidine used in the fifth step of coupling reaction is expensive, which directly leads to a significant increase in the cost of industrial production. More importantly, the pyrimidine ring structure contains two chlorine atoms and one fluorine atom, which is easy to cause poor selectivity due to the difference in activity of halogen atoms in the reaction, thereby generating various potential by-products, affecting the quality and yield of the target product, and being difficult to meet the requirements of economic efficiency and product purity in industrial production.

[0008] The second method is a preparation method of abemaciclib key intermediate B disclosed by Zheng et al., which is prepared from N-(4-bromo-2,6-difluorophenyl)acetamide as a starting material through condensation reaction, group exchange reaction and coupling reaction, and the synthetic route is as follows: ; The route comprises four steps, and the total yield is about 60%. Although this method does not need to use expensive palladium catalyst and ligand, which reduces the cost of the catalytic system to some extent, it still has significant defects. The Grignard reagent (such as isopropyl magnesium chloride) needs to be used in the third step of reaction, and the preparation and reaction process must be carried out under strict anhydrous and anaerobic conditions, which has high requirements for the sealing property of the reaction equipment and the operation standard, greatly increases the operation difficulty of industrial production; at the same time, the market prices of reactants 16 and 2,4-dichloro-5-fluoropyrimidine are high, which leads to a high proportion of raw material cost, and seriously restricts the feasibility of large-scale production of this route. The dual restrictions of the above anhydrous operation requirements and high-priced raw materials make it difficult for this method to meet the requirements of economic efficiency, safety and operation convenience in industrial production.

[0009] In combination with the above-mentioned process, the current synthesis methods of abemaciclib have many technical problems to be solved: on the one hand, the cost of some starting materials used in the process is high, which makes it difficult to effectively control the production cost, which is contrary to the economic efficiency required by industrial production; on the other hand, many synthesis routes have the defects of long reaction steps and severe conditions, for example, expensive catalysts (such as palladium complexes and special ligands) or special equipment (such as anhydrous and anaerobic reaction devices) are needed, which not only greatly increases the production operation difficulty, but also significantly increases the process safety risk and cost investment. In addition, the amount of by-products generated in the reaction process of some synthesis methods is large, which leads to a complex separation and purification process, thereby causing low product yield and insufficient purity, which seriously restricts the feasibility of industrial production.

[0010] The prior art has researches on improving the synthesis method of abemaciclib, such as patent CN118063436A-A preparation method of abemaciclib, which uses 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole as a starting material. The raw material is relatively high in price and needs to be specially prepared, which increases the production cost. The key reaction (such as coupling reaction) needs to be carried out under anhydrous and anaerobic conditions, which requires high equipment and complex operation, and is not conducive to industrial production. There are multiple active functional groups (such as chlorine and fluorine) in the raw material, which can easily cause competitive reactions and generate isotope impurities, affecting the quality of the product. Patent CN119431321A-A method for preparing abemaciclib, which uses Miyaura borate, Suzuki coupling, substitution, Buchwald-Hartwig coupling and other multi-step reactions, which is complex in operation and difficult to control the yield. The use of high-toxicity reagents such as phosphorus oxychloride will generate a large amount of phosphorus-containing wastewater, which is high in treatment cost. Patent CN119707834A-A preparation method of abemaciclib and its intermediates, which uses ethyl fluoroacetate as a raw material, and improves the selectivity by activating the pyrimidine ring with a sulfonyl group. However, it needs to be prepared by multi-step condensation and cyclization reaction. The raw materials ethyl fluoroacetate and ethyl formate need to be strictly controlled in temperature reaction, which is complex in operation. In the chlorination reaction, the amount of chlorinating agent needs to be controlled, otherwise multiple chlorinated by-products will be generated, affecting the purity. Patent CN119751416A-A preparation method of abemaciclib, which uses isopropyl magnesium bromide activation and DMFDMA condensation. However, the Grignard reagent requires strict anhydrous and anaerobic conditions, which is high in operation risk and high in energy consumption of high-temperature reaction.

[0011] In summary, the existing synthesis method of abemaciclib generally has the core problems of high cost of raw materials or reagents, long synthesis route leading to low total yield, harsh reaction conditions (especially relying on anhydrous and anaerobic operation and dangerous reagents), poor product selectivity, many by-products, difficult separation and purification, and great environmental pressure. Therefore, the existing process is difficult to meet the requirements of industrial large-scale production in terms of economy, safety, operation convenience, environmental protection and controllability of the final product quality. Therefore, a new technical solution is needed to solve the above technical problems. SUMMARY

[0012] The purpose of the present application is to provide a method for preparing abemaciclib by using 1,3-dimethyl urea pyrimidine as a starting material, through substitution, nucleophilic addition and multi-step coupling reaction, to solve the problems of the existing synthesis method of abemaciclib in economy, safety, operation convenience, environmental protection and controllability of the final product quality, which is difficult to meet the requirements of industrial large-scale production.

[0013] To achieve the above-mentioned purpose, the present application provides the following technical solution: a preparation method of abemaciclib, comprising the following specific steps: S1, taking intermediate I as a starting material, dissolving in a reaction solvent, and reacting with a fluorination reagent at -10-30℃ for 1-5 hours to generate intermediate II by fluorination substitution reaction, wherein the reaction solvent is one of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, the molar ratio of intermediate I to the fluorination reagent is 1:1.5-2.5, and the fluorination reagent is one of 1-chloromethyl-4-fluoro-1,4-diazonium [2.2.2] octane bis (tetrafluoroborate), boron trifluoride ether complex, anhydrous potassium fluoride; S2, intermediate II and guanidine hydrochloride are subjected to nucleophilic addition reaction in a reaction solvent and a base reagent at 20-80℃ for 2-8 hours to generate intermediate III, wherein the reaction solvent is one of methanol, ethanol, tetrahydrofuran, the molar ratio of intermediate II, guanidine hydrochloride and the base reagent is 1:1.05-2.5:1.2-5, and the base reagent is one of potassium carbonate, sodium carbonate or triethylamine; S3, intermediate III is dissolved in a reaction solvent, and subjected to Buchwald-Hartwig coupling reaction with compound 1 in the presence of a palladium catalyst and a ligand at 60-120℃ for 4-12 hours to generate intermediate IV, wherein the reaction solvent is one of toluene, 1,4-dioxane, dichloromethane, the molar ratio of intermediate III to compound 1 is 1:1.2-2.0, the X1 group in the structure of compound 1 is one of Cl, Br and I, the weight ratio of intermediate III to the palladium catalyst and the ligand is 1:0.25-2:0.5-4, the palladium catalyst is one of tetrakis triphenylphosphine palladium, palladium acetate, and bis triphenylphosphine dichloride palladium, and the ligand is one of tri-tert-butyl phosphine, 2-dicyclohexylphosphine-2',6'-dimethoxy biphenyl, and triphenylphosphine; S4, intermediate IV is subjected to substitution reaction in the presence of a reaction solvent and a phosphorus trihalide at 50-100℃ for 5-8 hours to generate intermediate V, wherein the reaction solvent is one of dimethyl sulfoxide, N,N-dimethylformamide, acetone, and acetonitrile, the molar ratio of intermediate IV to the phosphorus trihalide is 1:1.1-2.5, and the phosphorus trihalide is one of phosphorus triiodide, phosphorus tribromide, and phosphorus trichloride; S5, the intermediate V and compound 2 are dissolved in a reaction solvent, and a Suzuki coupling reaction is carried out under the condition of a palladium catalyst, a base reagent and 40-100 DEG C for 3-10 hours to obtain an abemaciclib crude product, wherein the reaction solvent is one of N,N-dimethylformamide, 1,4-dioxane, acetonitrile, water and toluene, the molar ratio of the intermediate V, compound 2 and the base reagent is 1:1.05-1.8:1.5-5, the weight ratio of the intermediate V and the palladium catalyst is 1:0.3-3, the X2 group in the structure of compound 2 is one of Cl, Br and I, the base reagent is one of sodium carbonate, potassium carbonate, potassium acetate, potassium hydroxide and potassium tert-butoxide, and the palladium catalyst is one of tetrakis triphenylphosphine palladium, palladium acetate and bis-triphenylphosphine palladium dichloride; S6, the abemaciclib crude product is recrystallized with a recrystallization solvent to obtain an abemaciclib product with high purity, wherein the recrystallization solvent is methanol and water in a volume ratio of 1:1-5; The synthesis reaction route is as follows: ; Wherein, X1 and X2 can be Cl, Br or I.

[0014] Compared with the prior art, the beneficial effects of the present application are: 1. The present application successfully solves the core problems of high raw material cost, long step, harsh condition, poor safety and great environmental pressure in the synthesis of abemaciclib through the double breakthrough of raw material innovation selection (1,3-dimethyl urea) and path reverse design (halogen-amino direct splicing), and on this basis, through scientific optimization of reaction steps, the preparation of abemaciclib product can be completed in only 5 steps of efficient conversion, which significantly shortens the process flow, greatly reduces the frequency of separation and purification of intermediate products, effectively improves the output efficiency per unit time, and in the aspect of reaction condition optimization, the core coupling reaction innovatively uses a relatively mild reaction system, without relying on high pressure, strong corrosive environment or special equipment, which greatly reduces the equipment purchase cost and production safety risk from the source, greatly enhances the universality and industrialization feasibility of the process, at the same time, with the double advantages of high reaction yield and simplified post-treatment process, the production cost is further compressed while the energy consumption and raw material loss are reduced, which provides a highly competitive technical scheme for the large-scale and green production of abemaciclib; 2. The present application innovatively selects 1,3-dimethyl uracil as a basic raw material, which has the significant advantages of low market price, wide source and easy to obtain, greatly reducing the production cost from the source, effectively solving the technical problems of poor reaction selectivity caused by the structural characteristics of the raw material in the existing process, realizing precise functional group transformation and directional reaction based on the molecular structure characteristics of 1,3-dimethyl uracil through unique reaction design and condition control, significantly improving the selectivity and yield of the target product, and compared with the traditional route, it has cost advantage and technical advancement, and has outstanding industrial application value; 3. The present application breaks through the limitation of traditional synthesis path by ingeniously designing intermediate III, and a new halogen-amino direct splicing coupling route is constructed; on this basis, compound 1 is used as a halogen group raw material, so that the preparation process is more simple and efficient, the production cost is significantly reduced, the use of noble metal catalyst is avoided, the complex post-treatment process caused by metal residue is effectively reduced, and the use of dimethylsilane amine lithium and other special amine sources is also avoided, so that the production cost is greatly reduced from the aspects of raw material cost and process complexity, and the economic and technical advantages are exhibited in industrial application. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1 is the high-resolution mass spectrum of the abemaciclib product of the present application; Figure 2 is the nuclear magnetic hydrogen spectrum (solvent: DMSO-d6) of the abemaciclib product of the present application; Figure 3 is the nuclear magnetic carbon spectrum (solvent: DMSO-d6) of the abemaciclib product of the present application. DETAILED DESCRIPTION The following examples are used to further illustrate the content of the present application, and do not limit the application of the present application. Example 1:

[0016] The present embodiment provides a preparation method of abemaciclib, and the specific preparation steps are as follows: Step one, preparation of intermediate II: 1,3-dimethyl uracil (intermediate I, 10 g, 0.07 mol) was dissolved in 100 mL of acetonitrile, 1-chloromethyl-4-fluoro-1,4-diazonium [2.2.2] octane bis (tetrafluoroborate) (37.9 g, 0.11 mol) was added, and the reaction was stirred at a temperature of-10~0℃ for 4~5 hours. After the reaction was completed, the acetonitrile was removed by reduced pressure distillation, the residue was dissolved in dichloromethane, washed with water and dried to obtain fluorinated intermediate II (9.4 g, yield 85%); Step two, preparation of intermediate III: Fluorinated intermediate II (9.4 g, 0.06 mol) and guanidine hydrochloride (6.0 g, 0.06 mol) were added to methanol, potassium carbonate (10 g, 0.07 mol) was added, and the reaction was carried out at 20-30 °C for 8 h, with TLC monitoring of the reaction progress. After the reaction was completed, the potassium carbonate was removed by filtration, methanol was removed by distillation under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried and concentrated to obtain intermediate III (6.4 g, yield 83%); Step three, preparation of intermediate IV: Intermediate III (6.4 g, 0.05 mol) and 1-[(6-chloropyridin-3-yl)methyl)-4- ethylpiperazine (14.4 g, 0.06 mol) were added to a reaction bottle, toluene was added and stirred until uniform, the reaction was replaced with nitrogen three times, then tetrakis triphenylphosphine palladium (0.15 g, 0.13 mmol) and tri-tert-butyl phosphine (0.05 g, 0.26 mmol) were added to the reaction bottle, and the reaction was carried out at 60-70 °C for 12 h, with TLC monitoring of the reaction progress. After the reaction was completed, the metal catalyst was removed by filtration, and the crude product intermediate IV (18.9 g, 88%) was obtained by concentration under reduced pressure, which was directly used in the next step reaction; Step four, preparation of intermediate V: Intermediate IV (18.9 g, 0.057 mol) and dimethyl sulfoxide were added to a reaction bottle, phosphorus triiodide (25.8 g, 0.063 mol) was added to the reaction bottle, and the reaction was carried out at 50-60 °C for 5 h, with TLC monitoring of the reaction progress. After the reaction was completed, the reaction system was cooled to room temperature, 2 N aqueous sodium hydroxide solution was added to the reaction system under the condition that the pH was 8, and the mixture was stirred and allowed to stand to separate the layers. The organic phase was collected, extracted with toluene (5 V x 2) twice, combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain iodinated yellow solid intermediate V (21.8 g, 86%); Step five, preparation of abemaciclib product: Iodinated intermediate V (21.8 g, 0.049 mol) and compound 2 (16.4 g, 0.051 mol) were added to a reaction bottle, stirred uniformly with N,N-dimethylformamide (DMF), then sodium carbonate (7.8 g, 0.074 mol) was added to the reaction system, the reaction system was replaced with nitrogen three times, then tetra-triphenylphosphonium palladium (0.17 g, 0.15 mmol) was added to the reaction system, then the reaction temperature was increased to 40-50°C for 10 h, the reaction progress was monitored by TLC, after the reaction was completed, the temperature was decreased to room temperature, then water was added dropwise to the reaction system, the solid was stirred to precipitate, the temperature was decreased to 0-10°C, and the crystal was stirred to precipitate for 2 h, then the filter cake was collected by suction filtration and dried in a vacuum drying oven at 50°C to obtain high-purity abemaciclib product (22.8 g, 92%). Example 2:

[0017] The embodiment provides a preparation method of abemaciclib, and the specific preparation steps are as follows: Step one, preparation of intermediate II: 1,3-dimethylurea pyrimidine (intermediate I, 10 g, 0.07 mol) was dissolved in 100 mL N,N-dimethylformamide (DMF), and boron trifluoride ether complex (19.9 g, 0.14 mol) was added, and the reaction was stirred at a temperature of 0-10°C for 3-4 hours, then 50 mL water was added to the reaction bottle, followed by the addition of 100 mL dichloromethane, and the organic phase was collected by stirring and separating the layers, and the organic phase was washed twice with water (100 mL x 2), dried, and concentrated to obtain fluorinated intermediate II (8.3 g, a yield of 75%); Step two, preparation of intermediate III: Fluorinated intermediate II (8.3 g, 0.052 mol) and guanidino hydrochloride (10 g, 0.105 mol) were added to ethanol, and sodium carbonate (13.8 g, 0.13 mol) was added, and the reaction was carried out at a temperature of 45-55°C for 5 h, and the reaction progress was monitored by TLC. After the reaction was completed, the sodium carbonate was removed by filtration, and the ethanol was removed by distillation under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, dried and concentrated to obtain intermediate III (5.9 g, a yield of 88%); Step three, preparation of intermediate IV: Into a reaction flask was placed intermediate III (5.9 g, 0.046 mol), 1-[(6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (19.6 g, 0.069 mol), 1,4-dioxane was added and stirred, the reaction was replaced by nitrogen three times, then palladium acetate (0.1 g, 0.46 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.38 g, 0.9 mmol) were added into the reaction flask, the reaction was carried out at 80-90 °C for 8 h, the reaction progress was monitored by TLC, after the reaction was completed, the metal catalyst was removed by filtration, and the crude product intermediate IV (13.8 g, 90%) was obtained by concentration under reduced pressure, which was directly used in the next step reaction; Step four, preparation of intermediate V: Into a reaction flask was placed intermediate IV (13.8 g, 0.042 mol) and acetone, then phosphorus tribromide (22.7 g, 0.084 mol) was added into the reaction flask, the reaction was carried out at 70-80 °C for 3 h, the reaction progress was monitored by TLC, after the reaction was completed, the reaction system was cooled to room temperature, 2 N sodium hydroxide aqueous solution was added into the reaction system, the reaction pH was adjusted to 8, the reaction system was stirred and separated, the organic phase was collected, the organic phase was extracted with toluene (5 V x 2) for 2 times, the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain brominated yellow solid intermediate V (14.2 g, 85%); Step five, preparation of abemaciclib product: Into a reaction flask was placed brominated intermediate V (14.2 g, 0.036 mol) and compound 2 (17.2 g, 0.054 mol), acetonitrile was added and stirred, then potassium hydroxide (6.1 g, 0.108 mol) was added into the reaction system, the reaction system was replaced by nitrogen three times, then palladium acetate (0.12 g, 0.5 mmol) was added into the reaction system, then the reaction temperature was increased to 70-80 °C, the reaction was carried out for 6 h, the reaction progress was monitored by TLC, after the reaction was completed, the reaction system was cooled to room temperature, then water was added dropwise into the reaction system, the solid was precipitated by stirring, the temperature was decreased to 0-10 °C, the crystal was precipitated by stirring for 2 h, then the crystal was collected by filtration, and the filter cake was dried in a vacuum drying oven at 50 °C to obtain the abemaciclib product (16.2 g, 89%) with high purity. Example 3:

[0018] The present example provides a preparation method of abemaciclib, and the specific preparation steps are as follows: Step one, preparation of intermediate II: Fluorinated intermediate II (8.6 g, 0.054 mol) and guanidino hydrochloride (13 g, 0.135 mol) were added to tetrahydrofuran, triethylamine (27.3 g, 0.27 mol) was added, and the reaction was carried out at a temperature of 70-80 °C for 2 h, with TLC monitoring of the progress of the reaction. After the reaction was completed, the tetrahydrofuran was removed by distillation under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried and concentrated to obtain intermediate III (5.9 g, yield 85%); Step two, preparation of intermediate III: Fluorinated intermediate II (8.6 g, 0.054 mol) and guanidino hydrochloride (13 g, 0.135 mol) were added to tetrahydrofuran, triethylamine (27.3 g, 0.27 mol) was added, and the reaction was carried out at a temperature of 70-80 °C for 2 h, with TLC monitoring of the progress of the reaction. After the reaction was completed, the tetrahydrofuran was removed by distillation under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried and concentrated to obtain intermediate III (5.9 g, yield 85%); Step three, preparation of intermediate IV: Intermediate III (5.9 g, 0.046 mol) and 1-[(6-chloropyridin-3-yl)methyl)-4- ethylpiperazine (22.1 g, 0.092 mol) were added to a reaction flask, 1,4-dioxane was added and stirred until uniform, the reaction was replaced with nitrogen three times, then bis-triphenylphosphine palladium dichloride (0.65 g, 0.92 mmol) and triphenylphosphine (0.48 g, 1.8 mmol) were added to the reaction flask, and the reaction was carried out at a temperature of 80-90 °C for 8 h, with TLC monitoring of the progress of the reaction. After the reaction was completed, the metal catalyst was removed by filtration, and the crude product intermediate IV (12.2 g, 80%) was obtained by concentration under reduced pressure, which was directly used in the next step Step four, preparation of intermediate V: Intermediate IV (12.2 g, 0.037 mol) and DMF were added to a reaction flask, phosphorus trichloride (12.6 g, 0.092 mol) was added, the temperature was raised to 90-100 °C, and the reaction was carried out for 3 h, with TLC monitoring of the progress of the reaction. After the reaction was completed, the reaction system was cooled to room temperature, 2 N sodium hydroxide aqueous solution was added to adjust the pH to 8, and the mixture was stirred and allowed to stand to separate the layers, the organic phase was collected, and the organic phase was extracted twice with toluene (5 V x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain chlorinated yellow solid intermediate V (10.2 g, 78%); Step five, preparation of abemaciclib product: The chloro intermediate V (10.2 g, 0.029 mol) and compound 2 (16.6 g, 0.052 mol) were added to a reaction bottle, toluene was added and stirred until uniform, then potassium tert-butoxide (16.3 g, 0.145 mol) was added to the reaction system, the reaction system was replaced with nitrogen three times, then palladium dichloride bis-triphenylphosphine (0.61 g, 0.87 mmol) was added to the reaction system, then the reaction temperature was increased to 90-100°C and reacted for 3 h, the reaction progress was monitored by TLC, after the reaction was completed, the temperature was lowered to room temperature, then water was added dropwise to the reaction system, the solid was stirred to precipitate, the temperature was lowered to 0-10°C and stirred to crystallize for 2 h, then filtration was performed to obtain the crude abemaciclib; finally, the crude abemaciclib was refined, i.e. the crude abemaciclib was transferred to a reaction bottle, 5 V of methanol was added, the temperature was increased to dissolve the solid, then 1 V of water was added dropwise, the temperature was lowered to room temperature and the solid was stirred to precipitate, then the temperature was lowered to 0-10°C and the solid was stirred to crystallize for 2 h, then filtration was performed, the filter cake was collected and dried in a vacuum drying oven at 50°C to obtain the high-purity abemaciclib product (11.8 g, 80%).

[0019] The high-resolution mass spectrum, the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the abemaciclib product are shown in Figure 1 、 Figure 2 and Figure 3 , and the mass spectrum and the nuclear magnetic hydrogen spectrum data are as follows: The high-resolution mass spectrum data of the abemaciclib product: ESI-MS m / z: 507.2808 [M+H]+.

[0020] The nuclear magnetic resonance hydrogen spectrum data of the abemaciclib product: 1H NMR (600 MHz, DMSO d6) δ: 10.07 (s, 1H), 8.68 (d, J=3.7, 1H), 8.29 (s, 1H), 8.21 (t, J=4.1, 2H), 7.67 (m, 2H), 4.85 (m, 1H), 3.43 (s, 2H), 2.64 (s, 3H), 2.37 (br, 6H), 2.29 (m, 3H), 1.63 (d, J=6.9, 6H), 0.97 (t, J=7.1, 6H).

[0021] Abemaciclib product's nuclear magnetic resonance carbon spectrum data:13C NMR (600MHz, DMSO-d6) δ: 155.34, 154.51, 153.05, 152.11, 151.41, 151.26, 150.07, 150.01, 149.58, 148.07, 147.68, 147.51, 138.17, 136.33, 136.27, 133.29, 133.17, 126.9846, 126.42, 111.71, 108.86, 108.83, 107.10, 107.04, 106.96, 106.91, 58.75, 52.42, 51.51, 48.03, 39.91, 39.78, 39.64, 39.50, 39.36, 39.22, 39.08, 20.87, 14.48, 11.95.

Claims

1. A process for the preparation of abemaciclib, characterized in that, The specific steps include the following: S1, intermediate I is used as a starting material, dissolved in a reaction solvent, and subjected to fluorination substitution reaction with a fluorination reagent to generate intermediate II; S2, intermediate II is subjected to nucleophilic addition reaction with guanidine hydrochloride in a reaction solvent and under the condition of a base reagent to generate intermediate III; S3, intermediate III is dissolved in a reaction solvent, and subjected to Buchwald-Hartwig coupling reaction with compound 1 in the presence of a palladium catalyst and a ligand to generate intermediate IV; S4, intermediate IV is subjected to substitution reaction in the presence of a reaction solvent and phosphorus trihalide to generate intermediate V; S5, intermediate V is dissolved in a reaction solvent with compound 2, and subjected to Suzuki coupling reaction under the condition of a palladium catalyst and a base reagent to obtain abemaciclib crude product; S6, abemaciclib crude product is subjected to recrystallization with a recrystallization solvent to obtain high-purity abemaciclib product; The synthetic reaction route is as follows: ； X1 and X2 can be Cl, Br or I.

2. A process for the preparation of abemaciclib according to claim 1, characterized in that, In S1, the reaction molar ratio of intermediate I to the fluorination reagent is 1:1.5-2.5, wherein the fluorination reagent is one of 1-chloromethyl-4-fluoro-1,4-diazonium bicyclo[2.2.2]octane bis(tetrafluoroborate), boron trifluoride diethyl ether complex and anhydrous potassium fluoride.

3. The process for the preparation of abemaciclib according to claim 1, characterized in that, In S1, the reaction solvent is one of acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide; the fluorination substitution reaction temperature is-10-30°C, and the fluorination substitution reaction time is 1-5 hours.

4. The process for the preparation of abemaciclib according to claim 1, characterized in that, In S2, the reaction solvent is one of methanol, ethanol and tetrahydrofuran; the nucleophilic addition reaction temperature is 20-80°C, the nucleophilic addition reaction time is 2-8 hours; and the reaction molar ratio of intermediate II, guanidine hydrochloride and the base reagent is 1:1.05-2.5:1.2-5, wherein the base reagent is one of potassium carbonate, sodium carbonate or triethylamine.

5. The process for the preparation of abemaciclib according to claim 1, characterized in that, In S3, the reaction molar ratio of intermediate III to compound 1 is 1:1.2-2.0, and the X1 group in the structure of compound 1 is one of Cl, Br and I; and the weight ratio of intermediate III to the palladium catalyst and the ligand is 1:0.25-2:0.5-4, wherein the palladium catalyst is one of tetrakis triphenylphosphine palladium, palladium acetate and bis-triphenylphosphine palladium dichloride, and the ligand is one of tri-tert-butyl phosphine, 2-dicyclohexylphosphine-2',6'-dimethoxy biphenyl and triphenylphosphine.

6. The process for the preparation of abemaciclib according to claim 1, characterized in that, In S3, the reaction solvent is one of toluene, 1,4-dioxane and dichloromethane; the Buchwald-Hartwig coupling reaction temperature is 60-120°C, and the Buchwald-Hartwig coupling reaction time is 4-12 hours.

7. The process for the preparation of abemaciclib according to claim 1, characterized in that, In S4, the reaction solvent is one of dimethyl sulfoxide, N,N-dimethylformamide, acetone and acetonitrile; the substitution reaction temperature is 50-100°C, the substitution reaction time is 5-8 hours; and the reaction molar ratio of intermediate IV to phosphorus trihalide is 1:1.1-2.5, wherein the phosphorus trihalide is one of phosphorus triiodide, phosphorus tribromide and phosphorus trichloride.

8. The process for the preparation of abemaciclib according to claim 1, characterized in that, In S5, the molar ratio of intermediate V, compound 2 and base reagent is 1:1.05-1.8:1.5-5, and the weight ratio of intermediate V and palladium catalyst is 1:0.3-3, wherein the X2 group in the structure of compound 2 is one of Cl, Br and I, the base reagent is one of sodium carbonate, potassium carbonate, potassium acetate, potassium hydroxide and potassium tert-butoxide, and the palladium catalyst is one of tetrakis(triphenylphosphine)palladium, palladium acetate and bis(triphenylphosphine)palladium dichloride.

9. The process for the preparation of abemaciclib according to claim 1, characterized in that, In S5, the reaction solvent is one of N,N-dimethylformamide, 1,4-dioxane, acetonitrile, water and toluene; the temperature of Suzuki coupling reaction is 40-100°C, and the time of Suzuki coupling reaction is 3-10 hours.

10. The process for the preparation of abemaciclib according to claim 1, characterized in that, In S6, the recrystallization solvent is methanol and water in a volume ratio of 1:1-5.

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