Synthesis method of abesilib intermediate and synthesis method of abesilib

Abstract

The invention relates to a synthesis method of an abesilib intermediate, which comprises the following steps of: performing Grignard reagent treatment on 3, 5-difluorobromobenzene serving as a raw material, and reacting with 2-fluoro-N-methoxy-N-methylacetamide to obtain 1-(3, 5-difluorophenyl)-2-fluoroethane-1-ketone; then, carrying out nitration reaction to obtain 1-(3, 5-difluoro-4-nitrophenyl)-2-fluoroethane-1-ketone; in the presence of hydrogen and a catalyst, carrying out hydrogenation reduction to obtain 1-(4-amino-3, 5-difluorophenyl)-2-fluoroethane-1-ketone; the preparation method comprises the following steps: introducing acetyl through acetyl chloride, and condensing with N, N-dimethylformamide dimethyl acetal to prepare (Z)-N-(4-(3-(dimethylamino)-2-fluoroacryloyl)-2, 6-difluorophenyl) acetamide; the preparation method comprises the following steps: carrying out cyclization on 2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole-6-yl) prop-2-en-1-one and isopropylamine under an alkali condition to obtain an abesiril intermediate (Z)-3-(dimethylamino)-2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole-6-yl) prop-2-en-1-one; and finally, under an alkaline condition, carrying out cyclization on the compound and N-(5-(4-ethyl-piperazine-1-yl methyl) pyridine-2-yl) guanidine nitrate to obtain abesilib.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of pharmaceutical compounds, and specifically refers to a method for synthesizing an abemaciclib intermediate and a method for synthesizing abemaciclib. Background Art

[0002] Abemaciclib, whose structural formula is as shown in Formula I and chemical name is N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-1-(1-isopropyl)-2-methyl-1H-benzoimidazol-6-yl)-2-methoxybenzylamine, was approved by the US FDA for marketing in 2017. It is an oral cell cycle inhibitor developed by Eli Lilly and Company, with good anti-tumor activity. Currently, it is used for the treatment of advanced or metastatic breast cancer and has good safety and effectiveness.

[0003]

[0004] The original research patent WO2010075074 of Eli Lilly and Company discloses a preparation method of abemaciclib and its intermediate. Some synthesis steps are shown in Figure 1 Synthesis Route 1. In the coupling reaction of the final intermediate, expensive palladium metal catalysts and other special ligands are used, resulting in extremely high synthesis costs. Moreover, side reactions are difficult to control during the coupling reaction, and the yield is relatively low, which is not conducive to industrial production.

[0005] In view of the deficiencies of the original research route, Xu Xuenong disclosed the patent WO2016 / 110224A1. Using 2,6-difluoroaniline as a raw material, reacting with fluoroacetonitrile under the catalysis of trifluoromethanesulfonic acid to obtain 1-(4-amino-2,6-difluorophenyl)-2-fluoroethanone, and then through condensation, amidation, and cyclization to obtain the intermediate (Z)-3-(dimethylamino)-2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazol-6-yl)prop-2-en-1-one (VI), and finally cyclizing with N-(5-(4-ethyl-piperazin-1-ylmethyl)pyridin-2-yl)guanidine nitrate (VII) to obtain abemaciclib. Specifically, see Figure 2 Synthesis Route 2. This route avoids the use of a large amount of precious metal palladium catalysts and greatly reduces the production cost. However, in the first step of this route, using 2,6-difluoroaniline as a raw material and reacting with fluoroacetonitrile under the catalysis of trifluoromethanesulfonic acid to obtain 1-(4-amino-2,6-difluorophenyl)-2-fluoroethanone, fluoroacetonitrile, as a reactant, is expensive and highly toxic. Moreover, under the strong acid condition of trifluoromethanesulfonic acid, the amino group is converted into an ammonium salt, resulting in a decrease in the Friedel-Crafts reaction activity, poor regioselectivity, more by-products, and lower purity and yield. In addition, among the subsequent intermediate steps, the isopropyl acetimidate has poor stability and poor operability, which is not conducive to production. Additionally, the yield of the final step of cyclization to prepare abemaciclib disclosed in the patent is reduced.

[0006] Therefore, for the synthesis method of abemaciclib, further improvements are needed. Summary of the Invention

[0007] The first technical problem to be solved by the present invention is to provide a synthesis method of the above-mentioned abemaciclib intermediate in view of the current situation of the prior art.

[0008] The second technical problem to be solved by the present invention is to provide a synthesis method of abemaciclib in view of the current situation of the prior art, which has low production cost, good selectivity, high purity and high yield.

[0009] The technical solution adopted by the present invention to solve at least one of the above technical problems is as follows:

[0010] An abemaciclib intermediate, wherein the abemaciclib intermediate is (Z)-3-(dimethylamino)-2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazol-6-yl)prop-2-en-1-one, and the structural formula is as follows Formula VI,

[0011]

[0012] A synthesis method of an abemaciclib intermediate, comprising the following steps:

[0013] (1) 3,5-Difluorobromobenzene first undergoes a Grignard reaction with a Grignard reagent in the presence of a solvent, and then reacts with 2-fluoro-N-methoxy-N-methylacetamide to obtain Compound II 1-(3,5-difluorophenyl)-2-fluoroethan-1-one;

[0014]

[0015] (2) In the presence of a solvent, Compound II undergoes a nitration reaction with a nitrating reagent to obtain Compound III 1-(3,5-difluoro-4-nitrophenyl)-2-fluoroethan-1-one;

[0016]

[0017] (3) In a solvent, in the presence of hydrogen and a catalyst, Compound III undergoes a reduction hydrogenation reaction to obtain Compound IV 1-(4-amino-3,5-difluorophenyl)-2-fluoroethan-1-one;

[0018]

[0019] (4) In the presence of a solvent, an acid-binding agent and acetyl chloride, the compound of formula IV first undergoes an acylation reaction, and then undergoes a condensation reaction with N,N-dimethylformamide dimethyl acetal in a solvent to obtain the compound of formula V, (Z)-N-(4-(3-(dimethylamino)-2-fluoropropenoyl)-2,6-difluorophenyl)acetamide;

[0020]

[0021] (5) In the presence of a solvent and a base, the compound of formula V undergoes a cyclization reaction with isopropylamine to obtain the compound of formula VI, namely the abemaciclib intermediate (Z)-3-(dimethylamino)-2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazol-6-yl)prop-2-en-1-one.

[0022] Preferably, in step (1), the solvent is one or more of tetrahydrofuran and diethyl ether; preferably tetrahydrofuran. The Grignard reagent is one or more of isopropylmagnesium chloride and ethylmagnesium bromide; preferably isopropylmagnesium chloride. The molar ratio of 3,5-difluorobromobenzene to the Grignard reagent is 1:(1-4); preferably 1:2. The molar ratio of 3,5-difluorobromobenzene to 2-fluoro-N-methoxy-N-methylacetamide is 1:(1-4); preferably 1:2. The reaction temperature is 0-20°C, preferably 0-5°C.

[0023] Preferably, in step (2), the solvent is one or more of concentrated sulfuric acid and acetic acid; preferably concentrated sulfuric acid. The nitrating reagent is one or more of concentrated nitric acid and potassium nitrate; preferably concentrated nitric acid. The molar ratio of the compound of formula II to the nitrating reagent is 1:(1-4); preferably 1:1.5. The reaction temperature is 0-20°C, preferably 0-5°C.

[0024] Preferably, in step (3), the solvent is one or more of methanol, ethanol, isopropanol and tetrahydrofuran; preferably methanol. The catalyst is one or more of palladium on carbon and Raney nickel; preferably palladium on carbon. The weight ratio of the compound of formula III to the catalyst is 1:(1%-10%); preferably 1:(1%-5%). The reaction temperature is 20-80°C; preferably 40-50°C. The hydrogen pressure is 0.1-0.5 MPa, preferably 0.2 MPa.

[0025] Preferably, in step (4), the acylation reaction solvent is one or more of dichloromethane, chloroform, and toluene; preferably dichloromethane. The acid-binding agent for the acylation reaction is one or more of triethylamine, diisopropylamine, and sodium carbonate; preferably triethylamine. The molar ratio of the compound of formula (IV) in the acylation reaction to the acid-binding agent is 1:(1-4); preferably 1:2. The molar ratio of the compound of formula (IV) in the acylation reaction to acetyl chloride is 1:(1-4); preferably 1:1.5. The acylation reaction temperature is 0-20°C; preferably 5-10°C. The condensation reaction solvent is one or more of N,N-dimethylformamide, dimethyl sulfoxide, chloroform, and toluene; preferably N,N-dimethylformamide. The molar ratio of the compound of formula IV to N,N-dimethylformamide dimethyl acetal is 1:(1-4); preferably 1:2. The condensation reaction temperature is 40-100°C, preferably 60-70°C.

[0026] Preferably, in step (5), the reaction solvent is one or more of N,N-dimethylformamide, dimethyl sulfoxide, xylene, toluene, and dioxane; preferably N,N-dimethylformamide. The base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and sodium amide; preferably potassium carbonate or potassium tert-butoxide. The molar ratio of the compound of formula V to the base is 1:(1-4); preferably 1:2. The molar ratio of the compound of formula V to isopropylamine is 1:(1-4); preferably 1:2. The reaction temperature is 60-120°C, preferably 80-100°C.

[0027] In the synthesis process of the abemaciclib intermediate above, the intermediates in each synthesis step are obtained by simple post-treatment and separation and purification. The specific methods are as follows: After the reaction in step (1) is completed, water and dichloromethane are added for extraction, and after layering, the solvent is removed by reduced pressure distillation, and then dried to obtain the compound of formula II with a liquid phase purity of more than 98.5%. After the reaction in step (2) is completed, ice water and dichloromethane are added for extraction, and after layering, it is washed with a 10% sodium carbonate solution, and after layering, the solvent in the organic layer is removed by reduced pressure distillation, and then dried to obtain the compound of formula III with a liquid phase purity of more than 98%. After the reaction in step (3) is completed, the reactant is cooled, filtered, the solvent in the filtrate is removed by reduced pressure distillation, methyl tert-butyl ether is added and stirred, filtered, and dried to obtain the compound of formula IV with a liquid phase purity of more than 99%. After the acylation reaction in step (4) is completed, water and dichloromethane are added for extraction, and after layering, the solvent in the organic layer is removed by reduced pressure distillation, and directly subjected to the condensation reaction; after the condensation reaction is completed, the solvent is removed by reduced pressure distillation and dried, dichloromethane and n-heptane are added and stirred, filtered, and dried to obtain the compound of formula V with a liquid phase purity of more than 99%. After the reaction in step (5) is completed, the reactant is cooled, filtered, the solvent in the filtrate is removed by reduced pressure distillation, ethyl acetate and n-heptane are added and stirred, filtered, and dried to obtain the compound of formula VI with a liquid phase purity of more than 99%.

[0028] A method for synthesizing abemaciclib. In a solvent and under the action of a base, guanidine nitrate of the following formula VII, N-(5-(4-ethyl-piperazin-1-ylmethyl)pyridin-2-yl), and the abemaciclib intermediate (Z)-3-(dimethylamino)-2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1 imidazol-6-yl)prop-2-en-1-one described in claims 1 to 8 are directly cyclized to obtain the compound of formula I,

[0029]

[0030] The compound of formula I is the target product abemaciclib.

[0031] Preferably, the solvent is one or more of ethanol, isopropanol, n-butanol, N,N-dimethylformamide, dimethyl sulfoxide, xylene, toluene; preferably n-butanol or toluene. The base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide; preferably potassium carbonate or potassium hydroxide. The molar ratio of the compound of formula VI to the base is 1:(1-5); preferably 1:2. The molar ratio of the compound of formula VI to the compound of formula VII is 1:(1-2); preferably 1:1.5. The reaction temperature is 70-140°C, preferably 80-100°C.

[0032] In the above synthesis process of abemaciclib, after the reaction is completed, the reactants are cooled, water is added, filtered, the crude product is recrystallized with acetone, filtered, and dried to obtain off-white abemaciclib with a liquid phase purity of 99.6-99.8%.

[0033] Compared with the prior art, the advantages of the present invention are as follows: The present invention uses 3,5-difluorobromobenzene as a raw material, undergoes Grignard reagent formation, and then reacts with 2-fluoro-N-methoxy-N-methylacetamide to obtain 1-(3,5-difluorophenyl)-2-fluoroethan-1-one; then undergoes nitration reaction to obtain 1-(3,5-difluoro-4-nitrophenyl)-2-fluoroethan-1-one; under hydrogen and a catalyst, undergoes hydrogenation reduction to obtain 1-(4-amino-3,5-difluorophenyl)-2-fluoroethan-1-one; introduces an acetyl group through acetyl chloride, and then condenses with N,N-dimethylformamide dimethyl acetal to obtain (Z)-N-(4-(3-(dimethylamino)-2-fluoropropenoyl)-2,6-difluorophenyl)acetamide; under alkaline conditions, cyclizes with isopropylamine to obtain the abemaciclib intermediate (Z)-3-(dimethylamino)-2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazol-6-yl)prop-2-en-1-one; finally, under alkaline conditions, cyclizes with guanidine nitrate of N-(5-(4-ethyl-piperazin-1-ylmethyl)pyridin-2-yl) to obtain abemaciclib;

[0034] The present invention has developed a new synthetic method for an abemaciclib intermediate compound, and further developed a method for synthesizing abemaciclib via this intermediate compound. This method has simple operations, low prices for reaction raw materials and auxiliary materials, no harsh reaction conditions, good reaction conversion rate and selectivity, high yield, low cost, and is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 It is Synthetic Route 1 in the background art of the present invention;

[0036] Figure 2 It is Synthetic Route 2 in the background art of the present invention;

[0037] Figure 3 For the abemaciclib in Example 1 of the present invention 13 13C NMR detection spectrum. DETAILED DESCRIPTION OF THE INVENTION

[0038] The present invention will be further described in detail below with reference to the accompanying drawings and examples.

[0039] The abemaciclib intermediate in the embodiment of the present invention is (Z)-3-(dimethylamino)-2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazol-6-yl)prop-2-en-1-one, and the structural formula is as follows Formula VI,

[0040]

[0041] Example 1:

[0042] The synthetic method of the abemaciclib intermediate in this example is as follows:

[0043] (1) Add 100 ml of tetrahydrofuran to a 500-ml four-necked reaction flask, add 19.3 g (0.1 mol) of 3,5-difluorobromobenzene, stir to dissolve clearly, and cool the reaction system to 0-5 °C. Dropwise add 120 ml (0.12 mol) of 1 mol / L isopropylmagnesium chloride tetrahydrofuran solution. After dropping, keep the reaction at 0-5 °C for 0.5 hour. Dropwise add 18.2 g of 2-fluoro-N-methoxy-N-methylacetamide. After dropping, keep the reaction at 0-5 °C for 1 hour. Add 100 ml of water, stir, add 200 ml of dichloromethane for extraction, separate the layers, and collect the dichloromethane layer. The organic phase layer is distilled under reduced pressure to remove the solvent, and dried to obtain 14.85 g of 1-(3,5-difluorophenyl)-2-fluoroethan-1-one solid, with a yield of 85.3% and a liquid phase purity of 98.55%.

[0044] (2) Add 14 g (0.08 mol) of the prepared 1-(3,5-difluorophenyl)-2-fluoroethan-1-one solid to a 250 mL four-necked reaction flask, add 30 mL of concentrated sulfuric acid, stir to dissolve, and cool the reaction system to 0 - 5 °C. Dropwise add 8.2 g of concentrated nitric acid. After the addition is complete, keep the temperature at 0 - 5 °C and react for 1 hour. Slowly add the reaction solution to 100 mL of ice water, add 100 mL of dichloromethane for extraction, separate the layers, and wash the organic layer with 100 mL of 10% sodium carbonate solution. Separate the layers, distill the organic layer to dryness under reduced pressure, and dry to obtain 15.7 g of 1-(3,5-difluoro-4-nitrophenyl)-2-fluoroethan-1-one solid, with a yield of 89.2% and a liquid phase purity of 98.62%.

[0045] (3) Add 15 g (0.068 mol) of the prepared 1-(3,5-difluoro-4-nitrophenyl)-2-fluoroethan-1-one solid, 60 mL of methanol, and 0.3 g of 5% palladium on carbon catalyst to a 250 mL stainless steel pressure reaction kettle. Seal the reaction kettle, displace it three times with nitrogen and hydrogen, introduce hydrogen and maintain the pressure at about 0.2 MPa, heat up to 45 - 50 °C, and stir and react for 6 hours. Cool down, filter the palladium on carbon catalyst, distill off the solvent from the filtrate under reduced pressure, add 20 mL of methyl tert-butyl ether and stir, filter by suction, and dry to obtain 12 g of 1-(4-amino-3,5-difluorophenyl)-2-fluoroethan-1-one solid, with a yield of 92.7% and a liquid phase purity of 99.3%.

[0046] (4) Add 11.3 g (0.06 mol) of the prepared (Z)-N-(4-(3-(dimethylamino)-2-fluoropropenoyl)-2,6-difluorophenyl)acetamide to a 250 mL four-necked reaction flask, add 50 mL of dichloromethane, stir to dissolve, add 9.1 g of triethylamine, and cool down to 5 - 10 °C. Dropwise add 5.7 g of acetyl chloride. After the addition is complete, react at 20 - 25 °C for 2 hours, add 25 mL of water, separate the layers, and collect the dichloromethane layer. Concentrate it to dryness under reduced pressure, add 10 mL of N,N-dimethylformamide, stir to dissolve, add 14.3 g of N,N-dimethylformamide dimethyl acetal, heat up to 65 °C, and stir and react for 2 hours. Distill off the solvent under reduced pressure, add 10 mL of dichloromethane and 30 mL of n-heptane and stir, filter, and dry to obtain 15.7 g of (Z)-N-(4-(3-(dimethylamino)-2-fluoropropenoyl)-2,6-difluorophenyl)acetamide solid, with a yield of 91.6% and a liquid phase purity of 99.1%.

[0047] (5) Add 15 g (0.052 mol) of the prepared solid of (Z)-N-(4-(3-(dimethylamino)-2-fluoropropenoyl)-2,6-difluorophenyl)acetamide to a 250 mL stainless steel pressure reactor, add 60 mL of N,N-dimethylformamide, 11 g of sodium carbonate, and 3.7 g of isopropylamine. Seal the reactor, heat it to 90 °C, and react for 10 h. Cool to room temperature, filter the reaction material, distill off the solvent under reduced pressure for the filtrate, add 10 mL of ethyl acetate and 30 mL of n-heptane, filter, and dry to obtain 15.2 g of (Z)-3-(dimethylamino)-2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazol-6-yl)prop-2-en-1-one, with a yield of 95.1% and a purity of 99.0%.

[0048] The synthetic method of abemaciclib in this example is as follows:

[0049] (1) Add 22 g (0.1 mol) of 5-(4-ethylpiperazin-1-ylmethyl)pyridin-2-amine to a 500 mL four-necked reaction flask, add 250 mL of absolute ethanol, cool to 0 °C, and sequentially dropwise add 4.5 mL of 65% nitric acid and 10 mL of 50% aqueous monocyanamide solution. After dropping, slowly heat to 80 °C and stir and react for 10 h. Cool to 0 °C, dropwise add 4.5 mL of 65% nitric acid and 10 mL of 50% monocyanamide solution again. After dropping, slowly heat to 80 °C and keep the temperature for reaction for 8 h again. Cool to room temperature, and a solid precipitates. Filter, recrystallize the filter cake with ethyl acetate and n-heptane, filter, and dry to obtain 29.6 g of solid, with a yield of 91% and a liquid phase purity of 98.3%.

[0050] (2) Add 5 g (0.0163 mol) of the prepared (Z)-3-(dimethylamino)-2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazol-6-yl)prop-2-en-1-one and 5.83 g of N-(5-(4-ethylpiperazin-1-ylmethyl)pyridin-2-yl)guanidine nitrate prepared in Example 6 to a 250 mL four-necked reaction flask, add 50 mL of n-butanol, stir to dissolve, add 1.83 g of potassium hydroxide, heat to 100 °C, and stir and react for 15 h. Cool down, add 50 mL of water, filter, recrystallize the wet product with acetone, filter, and dry to obtain 7.24 g of off-white solid abemaciclib, with a yield of 87.6% and a liquid phase purity of 99.7%.

[0051] The 13 13C NMR spectrum of the obtained product is shown in Figure 3 , and this compound is the target product.

[0052] Example 2:

[0053] The synthetic method of abemaciclib in this example is as follows:

[0054] Into a 250 mL four-necked reaction flask, 5 g (0.0163 mol) of (Z)-3-(dimethylamino)-2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazol-6-yl)prop-2-en-1-one prepared in Example 1, 5.83 g of N-(5-(4-ethylpiperazin-1-ylmethyl)pyridin-2-yl)guanidine nitrate were added. 50 mL of n-butanol was added and stirred until dissolved. 8 g of cesium carbonate was added, and the temperature was raised to 100 °C, and the mixture was stirred and reacted for 12 hours. After cooling, 50 mL of water was added, and the mixture was filtered. The wet product was recrystallized from acetone, filtered, and dried to obtain 7.32 g of a white solid abemaciclib, with a yield of 88.6% and a liquid phase purity of 99.6%.

[0055] Example 3:

[0056] The synthetic method of abemaciclib in this example is as follows:

[0057] Into a 250 mL four-necked reaction flask, 5 g (0.0163 mol) of (Z)-3-(dimethylamino)-2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazol-6-yl)prop-2-en-1-one prepared in Example 1, 5.83 g of N-(5-(4-ethylpiperazin-1-ylmethyl)pyridin-2-yl)guanidine nitrate were added. 50 mL of toluene was added and stirred until dissolved. 1.83 g of potassium hydroxide was added, and the temperature was raised to 100 °C, and the mixture was stirred and reacted for 16 hours. After cooling, 50 mL of water was added, and the mixture was filtered. The wet product was recrystallized from acetone, filtered, and dried to obtain 7 g of a white solid abemaciclib, with a yield of 84.6% and a liquid phase purity of 99.8%.

Claims

1. A method for synthesizing an abemaciclib intermediate, characterized in that It includes the following steps: (1) 3,5-Difluorobromobenzene first undergoes a Grignard reaction with a Grignard reagent in the presence of a solvent, and then reacts with 2-fluoro-N-methoxy-N-methylacetamide to obtain the compound of formula II, 1-(3,5-difluorophenyl)-2-fluoroethan-1-one; (2) In the presence of a solvent, the compound of formula II undergoes a nitration reaction with a nitrating reagent to obtain the compound of formula III, 1-(3,5-difluoro-4-nitrophenyl)-2-fluoroethan-1-one; (3) In a solvent, in the presence of hydrogen and a catalyst, the compound of formula III undergoes a reduction hydrogenation reaction to obtain the compound of formula IV, 1-(4-amino-3,5-difluorophenyl)-2-fluoroethan-1-one; (4) In the presence of a solvent, an acid-binding agent and acetyl chloride, the compound of formula IV first undergoes an acylation reaction, and then undergoes a condensation reaction with N,N-dimethylformamide dimethyl acetal in a solvent to obtain the compound of formula V, (Z)-N-(4-(3-(dimethylamino)-2-fluoropropenoyl)-2,6-difluorophenyl)acetamide; (5) In the presence of a solvent and a base, the compound of formula V undergoes a cyclization reaction with isopropylamine to obtain the compound of formula VI, which is the abemaciclib intermediate (Z)-3-(dimethylamino)-2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazol-6-yl)prop-2-en-1-one, 2. The synthesis method of the abemaciclib intermediate according to claim 1, wherein: In step (1), the solvent is one or more of tetrahydrofuran and diethyl ether; The Grignard reagent is one or more of isopropylmagnesium chloride and ethylmagnesium bromide; The molar ratio of 3,5-difluorobromobenzene to the Grignard reagent is 1:(1 - 4); The molar ratio of 3,5-difluorobromobenzene to 2-fluoro-N-methoxy-N-methylacetamide is 1:(1 - 4); The reaction temperature is 0 - 20 °C.

3. The synthesis method of the abemaciclib intermediate according to claim 1, characterized in that: In step (2), the solvent is one or more of concentrated sulfuric acid and acetic acid; The nitrating reagent is one or more of concentrated nitric acid and potassium nitrate; The molar ratio of the compound of formula II to the nitrating reagent is 1:(1 - 4); The reaction temperature is 0 - 20 °C.

4. The synthesis method of the abemaciclib intermediate according to claim 1, characterized in that: In step (3), the solvent is one or more of methanol, ethanol, isopropanol and tetrahydrofuran; The catalyst is one or more of palladium on carbon and Raney nickel; The weight ratio of the compound of formula III to the catalyst is 1:(1% - 10%); The reaction temperature is 20 - 80 °C; The hydrogen pressure is 0.1 - 0.5 MPa.

5. The synthetic method of the abemaciclib intermediate according to claim 1, wherein: In step (4), the solvent for the acylation reaction is one or more of dichloromethane, chloroform and toluene; The acid-binding agent for the acylation reaction is one or more of triethylamine, diisopropylamine and sodium carbonate; The molar ratio of the compound of formula (IV) in the acylation reaction to the acid-binding agent is 1:(1 - 4); The molar ratio of the compound of formula (IV) in the acylation reaction to acetyl chloride is 1:(1 - 4); The acylation reaction temperature is 0 - 20 °C; The solvent for the condensation reaction is one or more of N,N-dimethylformamide, dimethyl sulfoxide, chloroform and toluene; The molar ratio of the compound of formula IV to N,N-dimethylformamide dimethyl acetal is 1:(1 - 4); The condensation reaction temperature is 40 to 100 °C.

6. The synthesis method of the abemaciclib intermediate according to claim 1, wherein: In step (5), the reaction solvent is one or more of N,N-dimethylformamide, dimethyl sulfoxide, xylene, toluene, and dioxane; The base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and sodium amide; The molar ratio of the compound of formula V to the base is 1:(1 to 4); The molar ratio of the compound of formula V to isopropylamine is 1:(1 to 4); The reaction temperature is 60 to 120 °C.

7. A synthesis method of abemaciclib, characterized in that: In a solvent, under the action of a base, the compound of formula VII N-(5-(4-ethyl-piperazin-1-ylmethyl)pyridin-2-yl)guanidine nitrate reacts with the abemaciclib intermediate (Z)-3-(dimethylamino)-2-fluoro-1-(4 -fluoro-1- isopropyl-2-methyl-1H-benzoimidazol-6-yl)prop-2-en-1-one directly undergoes cyclization to obtain the compound of formula I, The compound of formula I is the target product abemaciclib.

8. The synthesis method of abemaciclib according to claim 7, characterized in that: The solvent is one or more of ethanol, isopropanol, n-butanol, N,N-dimethylformamide, dimethyl sulfoxide, xylene, and toluene; The base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, and sodium tert-butoxide; The molar ratio of the compound of formula VI to the base is 1:(1 to 5); The molar ratio of the compound of formula VI to the compound of formula VII is 1:(1 to 2); The reaction temperature is 70 to 140 °C.

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