Preparation method of abesilib and intermediate thereof

Abstract

The invention relates to the field of medicine synthesis, and particularly discloses a preparation method of abesilib and an intermediate thereof. The invention relates to an abesiril intermediate, which is 4-chloro-5-fluoro-2-(methylsulfonyl) pyrimidine (IV) and 4-fluoro-6-(5-fluoro-2-(methylsulfonyl) pyrimidine-4-yl)-1-isopropyl-2-methyl-1H-benzo [d] imidazole (V). The invention further provides a preparation method of the abesiril intermediate. And carrying out nucleophilic substitution reaction on the abesilib intermediate V and 5-[(4-ethyl piperazine-1-yl) methyl] pyridine-2-amine to prepare the abesilib. According to the preparation method, the raw materials are cheap and easy to obtain, the reaction selectivity of functional groups is high, ectopic impurities generated by a halogen atom competition reaction are effectively avoided, meanwhile, introduction of heavy metal palladium can be reduced, and therefore the cost is reduced. The synthetic route is simple, the atom economy is high, the controllability in production is high, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and in particular relates to an abemaciclib intermediate and an economical and efficient preparation method of abemaciclib. Background Art

[0002] Abemaciclib (also known as Bemaciclib) is the only CDK4 / 6 inhibitor that can treat HR-positive / HER2-negative metastatic advanced or metastatic breast cancer alone. It has been widely used in clinical treatment due to its high inhibition rate. It can be used in combination with aromatase inhibitors for initial endocrine therapy. Abemaciclib was first developed by Eli Lilly and Company, approved by the FDA in 2017, and entered the Chinese market in 2020. The launch of this drug can benefit many patients at home and abroad. Currently, various clinical trials of abemaciclib for the treatment of advanced solid tumors are also underway.

[0003] The chemical name of Abemaciclib (CAS: 1231929-97-7) is: N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-isopropyl-1H-benzimidazol-6-yl]-2-pyrimidinamine, and its structural formula is:

[0004]

[0005] The synthetic route (route 1) published in Eli Lilly's original patent (WO2010075074A1) uses 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole as a starting material, which is coupled with biboronic acid pinacol ester under the action of a palladium catalyst to obtain intermediate 7; then intermediate 7 undergoes a Suzuki coupling reaction with another starting material 2,4-dichloro-5-fluoropyrimidine to obtain intermediate 8; intermediate 11 uses 2-bromo-5-formylpyridine as a starting material, and is reacted with another starting material N-ethylpiperazine through reductive amination and copper oxide-catalyzed Ullmann reaction to obtain it; intermediate 8 is then coupled with intermediate 11 through palladium-catalyzed Buchwald coupling to obtain abemaciclib. When preparing intermediate 8 through this route, since both chlorine atoms in the raw material 2,4-dichloro-5-fluoropyrimidine may participate in the reaction, there will be potential ectopic impurities in the abemaciclib product. In addition, the last step of the Buchwald coupling reaction still requires the use of an expensive Pd catalyst.

[0006]

[0007] Based on the huge market prospects of Abemaciclib, it has attracted the attention of many workers in the field of drug synthesis. Suzhou Mingrui Pharmaceutical Technology Co., Ltd. has disclosed a new method for preparing Abemaciclib (Route 2, CN104529904A / US9969718B2), which uses 12 as the starting material, and obtains intermediate 17 through condensation, amidination, and cyclization reaction; intermediate 18 is guanidated by 5-[(4-ethylpiperazine-1-yl)methyl]pyridine-2-amine; then intermediate 17 and intermediate 18 are subjected to ring closure reaction to obtain the finished product of Abemaciclib. The raw material 12 in this synthetic route is expensive and needs to be made by oneself. Considering the cost factor, it is not conducive to industrial production.

[0008]

[0009] The synthetic route disclosed by Hangzhou Kechao Biotechnology Co., Ltd. (Route 3, CN109761959A) is similar to the original research route, and the last step is a Buchwald coupling reaction between intermediate 8 and intermediate 11, in which intermediate 8 is obtained from 6 via a Kumada coupling reaction. However, when we repeated this route, we found that the yield of the Kumada coupling reaction was low, so this route is not suitable for industrial scale-up.

[0010] Since the above routes mainly have problems such as low yield and difficulty in removing impurities, it is particularly urgent to find a more suitable route to improve the existing process.

[0011] Summary of the invention

[0012] The purpose of the present invention is to provide a simple, green and safe method for preparing abemaciclib and its intermediates. The raw materials of the synthetic route are cheap and readily available, the reaction conditions are mild, the operation is easy to implement, the total yield and purity of the obtained product are high, and the product is suitable for industrial production.

[0013] In order to achieve the above object, the technical scheme of the present invention is: a method for preparing an abemaciclib intermediate compound shown in formula IV,

[0014]

[0015] The following steps are involved:

[0016] (1) In solvent A, in the presence of a base, ethyl fluoroacetate and ethyl formate are first subjected to a condensation reaction, and then subjected to a cyclization reaction with S-methylisothiourea sulfate to obtain a compound of formula II;

[0017]

[0018] (2) in solvent B, in the presence of a base and a chlorinating agent, the compound of formula II undergoes a chlorination reaction with a chlorinating agent to obtain a compound of formula III;

[0019]

[0020] (3) In solvent C, the compound of formula III is oxidized under the action of an oxidant to obtain a compound of formula IV,

[0021]

[0022] A method for preparing an abemaciclib intermediate compound of formula V, comprising steps (1) to (3) of preparing the intermediate compound of formula IV, and further comprising the following step (4):

[0023]

[0024] (4) in solvent D, 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole and the compound of formula IV react in the presence of a base and a palladium catalyst to obtain a compound of formula V;

[0025]

[0026] An abemaciclib intermediate compound represented by formula V has the following structural formula:

[0027]

[0028] A method for preparing abemaciclib, comprising steps (1) to (4) of preparing the intermediate compound of formula V, and further comprising the following step (5):

[0029] (5) In solvent E, formula V reacts with 5-[(4-ethylpiperazine-1-yl)methyl]pyridin-2-amine under the action of a base to prepare abemaciclib,

[0030]

[0031] Preferably, according to the present invention, the solvent A in step (1) is one or more of dichloromethane, methanol, tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide, and acetone, and preferably, the solvent is toluene.

[0032] According to the preferred embodiment of the present invention, the base in step (1) is one or more of sodium carbonate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium carbonate, sodium bicarbonate, potassium acetate, and sodium acetate. Preferably, the base is sodium methoxide.

[0033] Preferably, according to the present invention, in step (1), the molar ratio of ethyl fluoroacetate, ethyl formate, S-methylisothiourea sulfate and the base is 1:(1.1-5.0):(1.0-3.0):(1.0-3.0), preferably, the molar ratio of ethyl fluoroacetate, ethyl formate, S-methylisothiourea sulfate and the base is 1:(1.5-3.0):(1.2-2.0):(1.5-2.5).

[0034] According to the preferred embodiment of the present invention, the solvent B in step (2) is one or more of ethyl acetate, ethanol, 2-methyltetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide, and chlorobenzene, and preferably, the solvent is toluene.

[0035] According to the preferred embodiment of the present invention, the base in step (2) is one or more of triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline and isopropylamine. Preferably, the base is N,N-dimethylaniline.

[0036] Preferably, according to the present invention, the chlorination agent in step (2) is one or more of thionyl chloride, carbon tetrachloride, phosphorus pentachloride, and phosphorus oxychloride. Preferably, the chlorination agent is phosphorus oxychloride.

[0037] Preferably, according to the present invention, in step (2), the molar ratio of the compound of formula II, the chlorination agent and the base is 1:(0.5-3.0):(1.0-3.0), preferably, the molar ratio of the compound of formula II, the chlorination agent and the base is 1:(1.0-1.5):(1.0-2.0).

[0038] Preferably, according to the present invention, the molar ratio of the compound of formula II to phosphorus oxychloride in step (2) is 1:(0.5-3.0), preferably, the molar ratio of the compound of formula II to phosphorus oxychloride is 1:(1.0-1.5).

[0039] According to the preferred embodiment of the present invention, the solvent C in step (3) is one or more of ethyl acetate, n-hexane, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile, dichloromethane and toluene, and preferably, the solvent is dichloromethane.

[0040] Preferably, according to the present invention, the oxidant in step (3) is one or more of hydrogen peroxide, potassium peroxymonosulfonate, and meta-chloroperbenzoic acid. Preferably, the oxidant is meta-chloroperbenzoic acid.

[0041] Preferably, according to the present invention, the molar ratio of the compound of formula III to the oxidant in step (3) is 1:(1.0-5.0), preferably, the molar ratio of the compound of formula III to the oxidant is 1:(2.0-3.0).

[0042] Preferably, according to the present invention, the molar ratio of the compound of formula III to meta-chloroperbenzoic acid in step (3) is 1:(1.0-5.0), preferably, the molar ratio of the compound of formula III to meta-chloroperbenzoic acid is 1:(2.0-3.0).

[0043] According to the preferred embodiment of the present invention, the solvent D in step (4) is one or a combination of dichloromethane, ethyl acetate, acetone, acetonitrile, water, toluene and tetrahydrofuran, and preferably, the solvent is acetonitrile / water.

[0044] Preferably, according to the present invention, the palladium catalyst in step (4) is one or more of palladium acetate, palladium dichloride, tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium dichloride, and bis(acetylacetonate)palladium. Preferably, the palladium catalyst is bistriphenylphosphine palladium dichloride.

[0045] According to the preferred embodiment of the present invention, the base in step (4) is one or more of sodium acetate, sodium carbonate, sodium bicarbonate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium carbonate, and potassium tert-butoxide. Preferably, the base is sodium carbonate.

[0046] Preferably, according to the present invention, in step (4), the molar ratio of the compound of formula IV, the borate compound, the palladium catalyst and the base is 1:(0.5-3.0):(0.001-0.005):(1.5-3.0), preferably, the molar ratio of the compound of formula IV and the borate compound is 1:(0.5-1.5):(0.002-0.004):(2.0-3.0).

[0047] According to the preferred embodiment of the present invention, the solvent E in step (5) is one or more of 1,2-dichloroethane, ethyl acetate, 2-methyltetrahydrofuran, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, and preferably, the solvent is tetrahydrofuran.

[0048] According to the preferred embodiment of the present invention, the base in step (5) is one or more of triethylamine, lithium hexamethyldisilazide, sodium hexamethyldisilazide, N,N-diisopropylethylamine or N,N-dimethylaniline, and preferably, the base is lithium hexamethyldisilazide.

[0049] Preferably, according to the present invention, in step (5), the molar ratio of the compound of formula V, 5-((4-ethylpiperazin-1-yl)methyl)pyridine-2-amine and the base is 1:(0.5-3.0):(1.0-4.0), preferably, the molar ratio of the compound of formula V, 5-((4-ethylpiperazin-1-yl)methyl)pyridine-2-amine and the base is 1:(1.0-1.2):(2.0-3.0).

[0050] In the method of the present invention, the products of each step need to be separated. The following provides a preferred separation and post-treatment method of the products of each step of the present invention:

[0051] After the reaction in step (1) is completed, the reaction system is cooled, 3% HCl aqueous solution is added under stirring to adjust the pH to 2-3, and the mixture is concentrated to dryness, filtered and dried to obtain the compound of formula II.

[0052] After the reaction of step (2) is completed, the reaction system is cooled, quenched with water, extracted with ethyl acetate, and the aqueous layer is extracted with ethyl acetate 2-3 times, and the organic phases are combined. A 3% HCl aqueous solution is added to the organic phase for washing, and the organic phase is concentrated to dryness. Methyl tert-butyl ether is added and heated to reflux, cooled for recrystallization, filtered, and dried to obtain a compound of formula III.

[0053] After the reaction of step (3) is completed, saturated sodium bicarbonate aqueous solution is added to the reaction solution to quench the reaction, the mixture is stirred and separated, dichloromethane is added to the aqueous phase for extraction 2-3 times, the organic phases are combined, and the organic phases are concentrated to dryness. Ethyl acetate is added and stirred, the mixture is heated to dissolve, n-hexane is added dropwise, the mixture is cooled for recrystallization, filtered, and dried to obtain a yellow solid.

[0054] After the reaction of step (4) is completed, water is added to the reaction solution to quench the reaction, dichloromethane is extracted and separated, dichloromethane is added to the aqueous phase for extraction 2-3 times, the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then the organic phase is concentrated to dryness. Isopropanol is added, stirred, heated and dissolved, cooled for recrystallization, filtered, and dried to obtain an off-white solid.

[0055] After the reaction in step (5) is completed, the reaction system is cooled, water is added to quench the reaction, and the layers are separated by dichloromethane extraction. The aqueous phase is extracted with dichloromethane 2-3 times, the organic phases are combined, decolorized with activated carbon at room temperature, filtered, and the filtrate is concentrated to dryness, and then pulped and filtered with methyl tert-butyl ether to obtain a crude product, which is then refined with acetone to obtain abemaciclib.

[0056] Unless otherwise specified, the reagents and raw materials used in the present invention are commercially available. If there is a conflict between the Chinese name of the compound in the present invention and the structural formula, the structural formula shall prevail, unless there is an obvious error in the structural formula.

[0057] The beneficial effects of the present invention are:

[0058] 1. The present invention provides a novel method for preparing abemaciclib, wherein ethyl fluoroacetate and ethyl formate are first subjected to a condensation reaction, and then subjected to a cyclization reaction with S-methylisothiourea sulfate to prepare 5-fluoro-2-(methylthio)pyrimidine-4-ol (II), and then subjected to a chlorination reaction under the action of a base in the presence of a solvent and a chlorination agent to obtain 4-chloro-5-fluoro-2-(methylthio)pyrimidine (III), and then subjected to an oxidation reaction with an oxidant to obtain 4-chloro-5-fluoro-2-(methylsulfonyl)pyrimidine (IV). Formula IV is coupled with 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole under a palladium catalyst to obtain 4-fluoro-6-(5-fluoro-2-(methylsulfonyl)pyrimidin-4-yl)-1-isopropyl-2-methyl-1H-benzo[d]imidazole (V), and finally reacts with 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amine to obtain abemaciclib (I).

[0059] 2. The starting materials used in the method of the present invention are cheap, the intermediate products are easy to separate, the process cost is low, the reaction conditions are mild, the use of precious metal Pd is effectively reduced, and the production cost is reduced.

[0060] 3. The present invention effectively avoids the ectopic impurities generated by the competitive reaction of halogen atoms, has a specific functional group reaction site, high selectivity, reduces the generation of by-products, and has high product purity and yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1 5-fluoro-2-(methylthio)pyrimidin-4-ol (II) 1 H NMR spectrum ( 1 H NMR, DMSO-d6).

[0062] Figure 2 4-chloro-5-fluoro-2-(methylthio)pyrimidine(III) 1 H NMR spectrum ( 1 HNMR, CDCl3).

[0063] Figure 3 4-chloro-5-fluoro-2-(methylsulfonyl)pyrimidine (IV) 1 H NMR spectrum ( 1 H NMR, DMSO-d6).

[0064] Figure 4 4-fluoro-6-(5-fluoro-2-(methylsulfonyl)pyrimidin-4-yl)-1-isopropyl-2-methyl-1H-benzo[d]imidazole (V) 1 H NMR spectrum ( 1H NMR, DMSO-d6).

[0065] Figure 5 For abemaciclib (I) 1 H NMR spectrum ( 1 H NMR, DMSO-d6). DETAILED DESCRIPTION

[0066] The present invention is described below with reference to examples, but the present invention is not limited thereto. In the art, simple replacement or improvement made by technicians in the field to the present invention belongs to the technical solution protected by the present invention.

[0067] Example 1: Preparation of 5-fluoro-2-(methylthio)pyrimidin-4-ol (II)

[0068] Ethyl formate (180g, 2.44mol), sodium methoxide (102g, 1.88mol) and 400mL toluene were added to a three-necked reaction flask, stirred evenly, the reaction system was cooled to 0-10°C, ethyl fluoroacetate (100g, 0.94mol) was slowly added dropwise, and the temperature was raised to 35-40°C for reaction for 20 hours after the addition. After the reaction was completed, the reaction temperature was lowered to 20-25°C, sodium methoxide (102g, 1.88mol) methanol solution and S-methylisothiourea sulfate (265g, 1.41mol) were slowly added in sequence under stirring, the temperature was raised to 35-40°C, the mixture was stirred and reacted for 6-8 hours, and the reaction was complete after TLC monitoring. 3% HCl aqueous solution was added under stirring to adjust the pH to 2-3, concentrated, filtered and dried to obtain 140.5g 5-fluoro-2-(methylthio)pyrimidin-4-ol (II), with a yield of 93.3% and a liquid phase purity of 96.57%.

[0069] Example 2: Preparation of 4-chloro-5-fluoro-2-(methylthio)pyrimidine (III)

[0070] Add 5-fluoro-2-(methylthio)pyrimidin-4-ol (II) (140g, 0.87mol) to a three-necked reaction flask, stir 700mL toluene, slowly drop N,N-dimethylaniline (158.9g, 1.3mol), add phosphorus oxychloride (138.0g, 0.9mol) dropwise under stirring, heat to 55-60℃ and react for 4-6 hours, cool to 20-25℃ after the reaction, add 700mL water to quench the reaction, extract with ethyl acetate (700mL×2), combine the organic phases, add 3% HCl (1.4L) aqueous solution to the organic phases for washing, and concentrate the organic phases to dryness. Add 420mL methyl tert-butyl ether and heat to reflux, cool for recrystallization, filter, and dry to obtain 147.6g of compound III. Yield 95.1%, liquid phase purity 98.71%.

[0071] Example 3: Preparation of 4-chloro-5-fluoro-2-(methylsulfonyl)pyrimidine (IV)

[0072] Add 4-chloro-5-fluoro-2-(methylthio)pyrimidine (III) (145g, 0.81mol) and 1.45L dichloromethane to a three-necked reaction flask and stir evenly. Cool to 0-5°C, add m-chloroperbenzoic acid (140g, 1.62mol) in batches, and react for 16-18 hours. After the reaction is completed, add 725mL of saturated sodium bicarbonate aqueous solution to quench the reaction, separate the layers, add 725mL of dichloromethane to the aqueous phase and extract twice, and concentrate the organic phase to dryness. Add 725mL of ethyl acetate and stir, heat to dissolve, add 145mL of n-hexane dropwise, cool to recrystallize, filter, and dry to obtain 147.0g of compound IV, with a yield of 86.2% and a liquid phase purity of 99.33%.

[0073] Example 4: Preparation of 4-fluoro-6-(5-fluoro-2-(methylsulfonyl)pyrimidin-4-yl)-1-isopropyl-2-methyl-1H-benzo[d]imidazole (V)

[0074] In a three-necked reaction flask, add 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (183.0 g, 0.575 mol), 4-chloro-5-fluoro-2-(methylsulfonyl)pyrimidine (IV) (145 g, 0.69 mol), sodium carbonate (152.6 g, 1.44 mol), PdCl2(PPh3)2 (0.93 g, 1.32 mmol), 1.02 L acetonitrile and 510 mL water, stir evenly, replace with N2 three times. Heat to 80-90°C and react for 4-6 hours. After the reaction is completed, the temperature is lowered to 30-40°C, 1.7L of water and 1.45L of dichloromethane are added, stirred, and separated into layers. The aqueous phase is washed twice with 1.45L of dichloromethane, separated into layers, and the organic phase is washed with 1.16L of saturated brine, and the organic phase is concentrated to dryness. Isopropanol is added, stirred, heated, dissolved, cooled, recrystallized, filtered, and dried to obtain 223.5g of the compound of formula V. The yield is 88.4%, and the liquid phase purity is 99.52%.

[0075] Example 5: Preparation of Abemaciclib (I)

[0076] In a three-necked reaction bottle, the compound of formula V (220g, 0.6mol), 5-((4-ethylpiperazine-1-yl)methyl)pyridine-2-amine (132.3g, 0.6mol) and 2.2L tetrahydrofuran were added and stirred evenly. 1mol / LLiHMDS (1.2L, 1.2mol) was added dropwise under stirring at room temperature in a N2 atmosphere, and the reaction was carried out at 20-30°C for 8-10 hours. After the reaction was completed, the temperature was lowered, 1.1L water was added to quench the reaction, and 1.1L dichloromethane was extracted and layered. The aqueous phase was extracted twice with 1.1L dichloromethane, and 11g activated carbon was added to the combined organic phase for decolorization, filtered, and the filtrate was concentrated to dryness, and methyl tert-butyl ether was added for pulping and filtration. 3.3L acetone was added to the filter cake, the temperature was raised to reflux, cooled and crystallized, and filtered and dried to obtain 276.6g of abecilis. The yield was 91.2%, and the liquid phase purity was 99.85%.

[0077] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A method for preparing an abemaciclib intermediate compound represented by formula IV, characterized in that: The following steps are involved: (1) In solvent A, in the presence of a base, ethyl fluoroacetate and ethyl formate are first subjected to a condensation reaction, and then subjected to a cyclization reaction with S-methylisothiourea sulfate to obtain a compound of formula II; (2) in solvent B, in the presence of a base and a chlorinating agent, the compound of formula II undergoes a chlorination reaction with a chlorinating agent to obtain a compound of formula III; (3) In solvent C, the compound of formula III undergoes oxidation reaction under the action of an oxidant to obtain a compound of formula IV, 2. A method for preparing an abemaciclib intermediate compound represented by formula V, characterized in that: The method comprises the steps (1) to (3) of preparing the intermediate compound of formula IV as claimed in claim 1, and further comprises the following step (4): (4) in solvent D, 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole and the compound of formula IV are reacted in the presence of a base and a palladium catalyst to obtain a compound of formula V; 3. An abemaciclib intermediate compound represented by formula V, characterized in that: The structural formula is as follows:

4. A method for preparing abemaciclib, comprising the steps (1) to (4) of preparing the intermediate compound of formula V according to claim 2, and further comprising the following step (5): (5) In solvent E, formula V reacts with 5-[(4-ethylpiperazine-1-yl)methyl]pyridin-2-amine under the action of a base to prepare abemaciclib, 5. The method for preparing the abemaciclib intermediate compound represented by formula IV according to claim 1, characterized in that: In the step (1), the solvent A is one or more of dichloromethane, methanol, tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide, and acetone; in the step (1), the base is one or more of sodium carbonate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium carbonate, sodium bicarbonate, potassium acetate, and sodium acetate; in the step (1), the molar ratio of ethyl fluoroacetate, ethyl formate, S-methylisothiourea sulfate, and the base is 1:1.1-5.0:1.0-3.0:1.0-3.

0.

6. The method for preparing the abemaciclib intermediate compound represented by formula IV according to claim 1, characterized in that: The solvent B described in step (2) is one or more of ethyl acetate, ethanol, 2-methyltetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide, and chlorobenzene; the base described in step (2) is one or more of triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, and isopropylamine; in step (2), the chlorination agent is one or more of thionyl chloride, carbon tetrachloride, phosphorus pentachloride, and phosphorus oxychloride.

7. The method for preparing the abemaciclib intermediate compound represented by formula IV according to claim 1, characterized in that: In the step (3), the solvent C is one or more of ethyl acetate, n-hexane, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile, dichloromethane, and toluene; in the step (3), the oxidant is one or more of hydrogen peroxide, potassium peroxymonosulfonate, or m-chloroperbenzoic acid.

8. The method for preparing the abemaciclib intermediate compound of formula V according to claim 2, characterized in that: In the step (4), the solvent D is one or a combination of dichloromethane, ethyl acetate, acetone, acetonitrile, water, toluene, and tetrahydrofuran; in the step (4), the palladium catalyst is one or more of palladium acetate, palladium dichloride, tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium dichloride, and di(acetylacetone)palladium; in the step (4), the base is one or more of sodium acetate, sodium carbonate, sodium bicarbonate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium carbonate, and potassium tert-butoxide.

9. The method for preparing abemaciclib according to claim 4, characterized in that: In the step (5), the solvent E is one or more of 1,2-dichloroethane, ethyl acetate, 2-methyltetrahydrofuran, acetonitrile, chloroform, dichloromethane, and tetrahydrofuran; in the step (5), the base is one or more of triethylamine, lithium hexamethyldisilazide, sodium hexamethyldisilazide, N,N-diisopropylethylamine, or N,N-dimethylaniline.

10. The method for preparing abemaciclib according to claim 4, characterized in that: In the step (5), the molar ratio of the compound of formula V, 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine and the base is 1:0.5-3.0:1.0-4.0.

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