Compound as shown in formula I, preparation method and application thereof, and preparation method of abelsilib intermediate compound A

Abstract

The invention relates to the technical field of medical chemistry, in particular to a compound shown in a formula I and a preparation method and application thereof, and a preparation method of an abelsilil intermediate compound A. The preparation method of the abesilib intermediate compound A comprises the following steps: taking 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole as an initial raw material, and carrying out a coupling reaction to obtain a compound as shown in a formula I; and carrying out a fluorination reaction on the compound shown in the formula I and a fluorination reagent to synthesize the abesilil intermediate compound A. The method has the advantages of low cost, simple operation, mild reaction conditions, high yield and good repeatability.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to a compound of formula I, a preparation method and application thereof, and a preparation method of an abemaciclib intermediate compound A. Background Art

[0002] Abemaciclib, chemically named N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-isopropyl-1H-benzimidazol-6-yl]-2-pyrimidinamine, is a novel oral targeted CDK4 / 6 inhibitor that blocks signal transduction inside cells, thereby preventing the growth and spread of cancer cells. The drug is used to treat advanced or metastatic breast cancer, and its trade name is Verzenio. The synthesis and process improvement of the drug have been one of the hot topics in recent years.

[0003] Chinese invention patent publication number CN110218189A discloses a method for preparing abemaciclib, wherein the intermediate 2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazol-6-yl)ethane-1-one is used to synthesize abemaciclib. The specific synthesis route of abemaciclib is as follows:

[0004]

[0005] The method discloses a method for synthesizing the intermediate 2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazol-6-yl)ethane-1-one using 3,5-difluoro-4-nitrobenzonitrile as a starting material. The first step: 3,5-difluoro-4-nitrobenzonitrile and isopropylamine react with potassium carbonate to obtain 3-fluoro-5-(isopropylamino)-4-nitrobenzenebenzonitrile; the second step: 3-fluoro-5-(isopropylamino)-4-nitrobenzenebenzonitrile is hydrogenated with palladium carbon to reduce the nitro group to amino group, and then reacts with acetic anhydride to undergo intramolecular cyclization to obtain 4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole-6-carbonitrile; the third step: 4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole-6-carbonitrile reacts with fluoromethylmagnesium chloride to obtain 2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole-6-yl)ethane-1-one. The specific synthesis route is as follows:

[0006]

[0007] However, this method for synthesizing the intermediate has the following disadvantages: (1) the starting material 3,5-difluoro-4-nitrobenzonitrile is relatively expensive; (2) the second step of palladium carbon hydrogenation and cyclization is relatively cumbersome in industrial operation; and (3) the third step of the Grignard reagent reaction has poor reproducibility and is not suitable for large-scale production.

[0008] U.S. invention patent publication number US2017 / 0305884 A1 designed a method for synthesizing 2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazol-6-yl)ethane-1-one using 2,6-difluoroaniline as the starting material. The first step: 2,6-difluoroaniline reacts with fluoroacetonitrile under the catalysis of trifluoromethanesulfonic acid to generate 1-(4-amino-3,5-difluorophenyl)-2-fluoroethane-1-one; the second step: 1-(4-amino-3,5-difluorophenyl)-2-fluoroethane-1-one reacts with N-isopropylacetamide under the catalysis of phosphine trichloride to generate N-(2,6-difluoro-4-(2-fluoroacetyl)phenyl)-N'-isopropylacetimide; the third step: N-(2,6-difluoro-4-(2-fluoroacetyl)phenyl)-N'-isopropylacetimide is heated and refluxed in sodium hydride and toluene to obtain 2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazol-6-yl)ethane-1-one. The specific synthesis route is as follows:

[0009]

[0010] However, this method of synthesizing intermediates has the following disadvantages: (1) The first step of this route is a Friedel-Crafts reaction catalyzed by a strong acid, trifluoromethanesulfonic acid. The amino group of the starting material will form a salt, resulting in a reduced localization effect, poor reaction activity, low purity of the reaction system, difficulty in purification, and a large amount of wastewater. (2) Both the second and third steps require reactions at relatively high temperatures, resulting in the decomposition of the fluoroacetyl group, which is not conducive to large-scale production.

[0011] Therefore, it is very necessary to develop a method for preparing the abemaciclib intermediate compound A, which can solve the above technical problems, and a compound of formula I for preparing the abemaciclib intermediate compound A. Summary of the invention

[0012] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a method for preparing an abemaciclib intermediate compound A with low cost, simple operation, mild reaction conditions and high yield. Specifically, the abemaciclib intermediate compound A is prepared by a new compound of formula I: 2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazol-6-yl)ethane-1-one.

[0013] The present invention is achieved through the following technical solutions:

[0014] The first aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof:

[0015]

[0016] In the formula, R is a C1-C6 alkyl group.

[0017] In some embodiments of the present invention, R is a C2-C4 alkyl group.

[0018] In some embodiments of the present invention, the compound of formula I is selected from the following compounds:

[0019]

[0020]

[0021] The second aspect of the present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0022] Using 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole as a starting material, a coupling reaction is carried out with a compound of formula II to obtain a compound of formula I;

[0023] Wherein, the compound of formula II is:

[0024]

[0025] In the formula, m is selected from H, SnBu3 group;

[0026] R is the same as R in formula I and is a C1-C6 alkyl group, preferably a C2-C4 alkyl group, and more preferably an ethyl group, a n-propyl group, or a n-butyl group.

[0027] In some embodiments of the present invention, the coupling reaction further comprises one or more of the following conditions:

[0028] i1) It is also necessary to add a catalyst and a base;

[0029] i2) the coupling reaction is carried out in solvent A;

[0030] i3) the coupling reaction is carried out in an inert atmosphere;

[0031] i4) the molar ratio of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole to the compound of formula I is 1:1-10, preferably 1:2-10;

[0032] i5) The reaction temperature of the coupling reaction is 70-150° C., and the reaction time is 8-12 h.

[0033] In some preferred embodiments of the present invention, the catalyst comprises a palladium-based catalyst.

[0034] Further preferably, the palladium catalyst comprises at least one of Pd(dppf)Cl2, Pd(PPh3)2Cl2, PdOAc2, PdCl2, Pd(PPh3)4 and Pd2(dba)3

[0035] In some preferred embodiments of the present invention, the molar ratio of the catalyst to 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole is 0.005-0.015:1.

[0036] In some preferred embodiments of the present invention, the molar ratio of the base to 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole is 2-4:1.

[0037] In some preferred embodiments of the present invention, the base comprises an inorganic base.

[0038] Further preferably, the inorganic base includes at least one of potassium carbonate, sodium carbonate, sodium bicarbonate and potassium phosphate.

[0039] In some preferred embodiments of the present invention, the solvent A comprises an organic solvent.

[0040] Further preferably, the solvent A comprises at least one of anhydrous DMF, 1,4-dioxane, acetonitrile, tetrahydrofuran and toluene.

[0041] In some preferred embodiments of the present invention, the inert atmosphere includes at least one of nitrogen and argon.

[0042] In some embodiments of the present invention, after the coupling reaction is completed, the temperature is cooled to room temperature, water and an organic solvent B are added, and the organic phase is dried to obtain a crude compound of formula I, which is then purified by column chromatography to obtain a compound of formula I.

[0043] In some preferred embodiments of the present invention, the organic solvent B is ethyl acetate.

[0044] In some preferred embodiments of the present invention, the eluent used in the column chromatography is petroleum ether:ethyl acetate:triethylamine in a volume ratio of 10:1:0.01-1:1:0.01.

[0045] The third aspect of the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof in the preparation of abemaciclib intermediate compound A and / or abemaciclib;

[0046] The structure of the abemaciclib intermediate compound A is as follows:

[0047]

[0048] The structural formula of abemaciclib is as follows:

[0049]

[0050] The fourth aspect of the present invention provides a method for preparing an abemaciclib intermediate compound A, comprising the steps of: using 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole as a starting material, carrying out a coupling reaction with a compound of formula II to obtain a compound of formula I; and then carrying out a fluorination reaction between the compound of formula I and a fluorination agent to obtain an abemaciclib intermediate compound A.

[0051] In some embodiments of the present invention, the fluorination reaction further comprises one or more of the following conditions:

[0052] ii1) before the fluorination reaction, the compound of formula I is dissolved in solvent C and the temperature is lowered; the fluorination agent is dissolved in water;

[0053] ii2) the molar ratio of the compound of formula I to the fluorinating agent is 1:1.15-1:3;

[0054] ii3) the reaction temperature of the fluorination reaction is 20-30°C and the reaction time is 1-6h;

[0055] ii4) After the fluorination reaction is completed, water and an organic solvent D are added, wherein the organic solvent D is insoluble in water, and the obtained organic phase is dried and purified to obtain the abemaciclib intermediate compound A.

[0056] In some preferred embodiments of the present invention, the compound of formula I is dissolved in solvent C and cooled to -20 to 25°C.

[0057] In some preferred embodiments of the present invention, the fluorination reagent includes at least one of Selectfluor, perfluoropiperidine, and Umist reagent.

[0058] In some preferred embodiments of the present invention, the solvent D comprises ethyl acetate.

[0059] In some preferred embodiments of the present invention, the purification operation includes beating and / or column chromatography, the solvent used for beating is n-heptane and ethyl acetate, and the eluent used for column chromatography is petroleum ether:ethyl acetate in a volume ratio of 3:1-1:1.

[0060] The beneficial effects of the present invention are:

[0061] The invention uses 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole as a starting material, and can synthesize an abemaciclib intermediate compound A through a one-step coupling reaction and a one-step fluorination reaction, has low cost, avoids the use of strong acid and strong base, and also avoids the decomposition of fluoroacetyl groups caused by high temperature reaction conditions.

[0062] The first step of the coupling reaction of the method of the present invention uses precious metal palladium, but through condition optimization, a higher yield can be obtained with only 0.5-1.5% catalyst equivalent, and the operation is simple. The second step of the fluorination reaction can be carried out at a relatively mild room temperature, and the yield is high, the repeatability is good, and it is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 This is the H NMR spectrum of compound 1 prepared in Example 1.

[0064] Figure 2 This is the NMR fluorine spectrum of compound 1 prepared in Example 1.

[0065] Figure 3 This is the NMR carbon spectrum of compound 1 prepared in Example 1.

[0066] Figure 4 This is the H NMR spectrum of the abemaciclib intermediate compound A prepared in Example 1.

[0067] Figure 5 This is the H NMR spectrum of compound 3 prepared in Example 2.

[0068] Figure 6 This is the NMR fluorine spectrum of compound 3 prepared in Example 2.

[0069] Figure 7 This is the NMR carbon spectrum of compound 3 prepared in Example 2. DETAILED DESCRIPTION

[0070] The present invention will be further described below in conjunction with specific embodiments, and the advantages and features of the present invention will become clearer as the description proceeds. However, these embodiments are exemplary only and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the scope of protection of the present invention.

[0071] Example 1

[0072] Step A: Preparation of 6-(1-ethoxyvinyl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole (Compound 1)

[0073]

[0074] 10.0 g (36.9 mmol, 1.0 eq.) of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole and 26.7 g (74.0 mmol, 2.0 eq.) of tributyl (1-ethoxyethylene) tin (CAS: 97674-02-7), 270 mg (0.369 mmol, 0.01 eq.) of Pd (dppf) Cl2, and 15.3 g (110.7 mmol, 3.0 eq.) of potassium carbonate were dissolved in 100 mL of anhydrous DMF. After evacuating and replacing the nitrogen three times, the mixture was heated to 70° C. and stirred for 12 hours under nitrogen protection. LCMS confirmed that the raw material reacted completely. After cooling to room temperature, 100 mL of water and 100 mL of ethyl acetate were added to separate the organic phase. The aqueous phase was extracted once with 100 mL of ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: triethylamine = 10: 1: 0.01) to obtain a white solid, which was compound 1 (9.21 g, yield = 95%). The H NMR, F NMR, and C NMR spectra of compound 1 are shown as follows: Figure 1-Figure 3 shown.

[0075] LC-MS:(M+1) + ; m / z = 263.09;

[0076] 1 H NMR (400MHz, CDCl3) δ7.54 (d, J=1.4Hz, 1H), 7.21 (d, J=11.8Hz, 1H), 4.76-4.60 (m, 2H), 4.23 (d, J=2.8Hz, 1H) , 3.97 (qd, J=7.0, 3.1Hz, 2H), 2.64 (d, J=3.4Hz, 3H), 1.65 (dd, J=7.0, 3.4Hz, 6H), 1.47 (td, J=7.0, 3.1Hz, 3H).

[0077] 19 F NMR (376MHz, CDCl3) δ-129.72 (d, J=10.0Hz).

[0078] 13 C NMR (100 MHz, CDCl3) δ 159.63, 159.61, 154.31, 151.96, 151.83, 136.40, 136.30, 131.56, 131.49, 105.30, 105.11, 104.17, 104.13, 82.38, 63.54, 48.28, 21.41, 15.08, 14.55. Step B: Preparation of 2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazol-6-yl)ethan-1-one (abecibizole intermediate compound A)

[0079]

[0080] 5.00g (19.1mmol, 1.0eq.) 6-(1-ethoxyvinyl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole was dissolved in 100mL acetonitrile, cooled to 0°C, and then 7.78g (22.0mmol, 1.15eq.) Selectfluor was dissolved in 20mL water and slowly added dropwise to the above reaction system. After the addition, the temperature was naturally raised to room temperature and stirred for 2 hours. TLC confirmed that the raw material reaction was complete, 100mL of water and 100mL of ethyl acetate were added to separate the organic phase, and the aqueous phase was extracted twice with 100mL of ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by beating with (n-heptane: ethyl acetate = 3:1) to obtain the target product as a white solid, which was abemaciclib intermediate compound A (4.47g, purity 95%, yield = 93%). The nuclear magnetic hydrogen spectrum of abemaciclib intermediate compound A is as follows Figure 4 shown.

[0081] LC-MS:(M+1) + ; m / z = 253.04;

[0082] 1 H NMR (400MHz, DMSO-d6) δ8.01 (d, J=1.2Hz, 1H), 7.50 (dd, J=11.4, 1.3Hz, 1H), 5. 93 (d, J=46.1Hz, 2H), 4.86 (p, J=7.0Hz, 1H), 2.65 (s, 3H), 1.60 (d, J=7.0Hz, 6H).

[0083] Example 2

[0084] Step A: Preparation of 6-(1-butoxyvinyl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole (Compound 3)

[0085]

[0086] 1.0 g (3.69 mmol, 1.0 eq.) of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole and 3.69 g (36.9 mmol, 10.0 eq.) of vinyl n-butyl ether (CAS: 111-34-2), 27 mg (0.0369 mmol, 0.01 eq.) of Pd(dppf)Cl2, and 1.53 g (11.1 mmol, 3.0 eq.) of potassium carbonate were added to a 25 mL sealed tube, followed by 5 mL of anhydrous DMF. After bubbling nitrogen with a long needle for ten minutes, the seal was tightened and the reaction solution was heated to 110°C and stirred for 12 hours. LCMS confirmed that the raw material was completely reacted. After cooling to room temperature, 20 mL of water and 20 mL of ethyl acetate were added to separate the organic phase. The aqueous phase was extracted once with 20 mL of ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: triethylamine = 10: 1: 0.01) to obtain a light yellow oily substance, which was compound 3 (0.7 g, yield = 65%). The H NMR, F NMR, and C NMR spectra of compound 3 are shown as follows: Figure 5-Figure 7 shown.

[0087] LC-MS:(M+1) + ; m / z = 291.24;

[0088] 1 H NMR (400MHz, CDCl3) δ7.52 (d, J=1.3Hz, 1H), 7.17 (dt, J=11.8, 1.4Hz, 1H), 4.70-4.54 (m, 2H), 4.20 (t, J=2.1Hz, 1H), 3.86 (td, J=6.4, 1.8Hz, 2H), 2.59 (d, J=2.0Hz, 3H), 1.86-1.73 (m, 2H), 1.60 (dd, J=7.0, 1.9Hz, 6H), 1.51 (dtd, J=14.7, 7.4, 1.6Hz, 2H), 0.98 (td, J=7.4, 1.7Hz, 3H).

[0089] 19 F NMR (376MHz, CDCl3) δ-129.74 (d, J=2.8Hz).

[0090] 13C NMR (100 MHz, CDCl3) δ 159.64, 159.62, 154.28, 151.97, 136.32, 131.60, 131.53, 105.20, 105.00, 104.22, 104.19, 82.24, 67.69, 48.29, 31.09, 21.34, 19.52, 14.98, 13.90. Step B: Preparation of 2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazol-6-yl)ethan-1-one (abecib intermediate compound A)

[0091]

[0092] 0.7g (2.41mmol, 1.0eq.) 6-(1-butoxyvinyl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole was dissolved in 10mL acetonitrile, cooled to 0°C, and then 0.98g (2.77mmol, 1.15eq.) Selectfluor (CAS: 140681-55-6) was dissolved in 2mL water and slowly added dropwise to the above reaction system. After the addition, the temperature was naturally raised to room temperature and stirred for 2 hours. TLC confirmed that the raw material reaction was complete, 10mL of water and 10mL of ethyl acetate were added to separate the organic phase, and the aqueous phase was extracted twice with 10mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product as a white solid (0.55g, purity 95%, yield = 90%).

[0093] LC-MS:(M+1) + ; m / z = 253.04.

[0094] Example 3

[0095] Step A: Preparation of 6-(1-ethoxyvinyl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole (Compound 1)

[0096] 10.0 g (36.9 mmol, 1.0 eq.) of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole and 66.6 g (184.5

[0097] mmol, 5.0eq.) tributyl (1-ethoxyethylene) tin (CAS: 97674-02-7), 125mg (0.552mmol, 0.015eq.) PdOAc2, 8.0g (75.5mmol, 2.0eq.) sodium carbonate, dissolved in 100mL 1,4-dioxane, vacuumed and replaced with argon three times, heated to 100°C under argon protection and stirred for 10 hours. LCMS confirmed that the raw material reaction was complete, and after cooling to room temperature, 100mL of water and 100mL of ethyl acetate were added to separate the organic phase, the aqueous phase was extracted once with 100mL of ethyl acetate, the organic phases were combined, the organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate:

[0098] Triethylamine = 10:1:0.01) to give a white solid (8.32 g, yield = 86%).

[0099] Step B: Preparation of 2-fluoro-1-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazol-6-yl)ethan-1-one (abecibizole intermediate compound A)

[0100] 5.00g (19.1mmol, 1.0eq.) 6-(1-ethoxyvinyl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole was dissolved in 100mL tetrahydrofuran, cooled to -20°C, and then 24.8mmol (1.3eq.) Selectfluor was dissolved in 20mL water and slowly added to the above reaction system, and the temperature was naturally raised to room temperature and stirred for 2 hours. TLC confirmed that the raw material reaction was complete, 100mL of water and 100mL of ethyl acetate were added to separate the organic phase, and the aqueous phase was extracted twice with 100mL of ethyl acetate, and the organic phase was combined. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by beating with (n-heptane: ethyl acetate = 3:1) to obtain the target product as a white solid (4.52g, purity 95%, yield 94%).

[0101] Example 4

[0102] The only difference from Example 2 is that the fluorination agent in step B is different, that is, perfluoropiperidine, and the other conditions are the same. The yield of the finally prepared abemaciclib intermediate compound A is 91%, and the purity is 95%.

[0103] Example 5

[0104] The only difference from Example 2 is that the fluorination reagent in step B is different, that is, Umist reagent, and the other conditions are the same. The yield of the finally prepared abemaciclib intermediate compound A is 90%, and the purity is 95%.

[0105] Comparative Example 1-1

[0106] The only difference from Example 1 is that the molar ratio of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole to tributyl(1-ethoxyethylene)tin in step A is different, which is 1:12, and the other conditions are the same. The yield of the final prepared compound 1 is 95%.

[0107] Comparative Example 1-2

[0108] The only difference from Example 1 is that the molar ratio of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole to tributyl(1-ethoxyethylene)tin in step A is different, which is 1:15, and the other conditions are the same. The yield of the final prepared compound 1 is 95%.

[0109] Comparative Examples 1-1 and 1-2 show that increasing the amount of tributyl(1-ethoxyethylene)tin on the basis of Example 1 does not increase the yield, but causes a waste of raw materials and increases costs.

[0110] Comparative Example 2

[0111] The only difference from Example 1 is that the molar ratio of 6-(1-ethoxyvinyl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole to Selectfluor in step B is different, which is 1:0.8, and the other conditions are the same. The final prepared abemaciclib intermediate compound A has a yield of 52% and a purity of 94%.

[0112] Comparative Example 3

[0113] The only difference from Example 1 is that the fluorination agent in step B is different, that is, TBAF, and the other conditions are the same. The yield of the finally prepared abemaciclib intermediate compound A is 34% and the purity is 92%.

[0114] The above detailed description is a specific description of one feasible embodiment of the present invention. The embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound of formula I is: In the formula, R is a C1-C6 alkyl group.

2. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: R is a C2-C4 alkyl group.

3. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: The compound of formula I is selected from the following compounds:

4. A method for preparing a compound of formula I or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof according to any one of claims 1 to 3, characterized in that: The method comprises the following steps: using 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole as a starting material and performing a coupling reaction with a compound of formula II to obtain a compound of formula I; Wherein, the compound of formula II is: In the formula, m is selected from H and SnBu3.

5. The preparation method according to claim 4, characterized in that: The coupling reaction also includes one or more of the following conditions: i1) It is also necessary to add a catalyst and a base; i2) the coupling reaction is carried out in solvent A; i3) the coupling reaction is carried out in an inert atmosphere; i4) the molar ratio of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole to the compound of formula II is 1:1-10; i5) The reaction temperature of the coupling reaction is 70-150° C., and the reaction time is 8-12 h.

6. The preparation method according to claim 5, characterized in that: The catalyst comprises a palladium-based catalyst; the molar ratio of the catalyst to 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole is 0.005-0.015:1; the molar ratio of the base to 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole is 2-4:1; the base comprises an inorganic base; the solvent A comprises an organic solvent; and the inert atmosphere comprises at least one of nitrogen and argon.

7. The preparation method according to claim 6, characterized in that: The palladium-based catalyst includes at least one of Pd(dppf)Cl2, Pd(PPh3)2Cl2, PdOAc2, PdCl2, Pd(PPh3)4 and Pd2(dba)3; the inorganic base includes at least one of potassium carbonate, sodium carbonate, sodium bicarbonate and potassium phosphate; and the solvent A includes at least one of anhydrous DMF, 1,4-dioxane, acetonitrile, tetrahydrofuran and toluene.

8. The preparation method according to any one of claims 4 to 7, characterized in that: After the coupling reaction is completed, the temperature is lowered to room temperature, and water and an organic solvent B are added. The organic solvent B is insoluble in water. The obtained organic phase is dried to obtain a crude product of the compound of formula I, and then subjected to column chromatography to obtain the compound of formula I.

9. The preparation method according to claim 8, characterized in that: The organic solvent B is ethyl acetate; the eluent used in the column chromatography is petroleum ether:ethyl acetate:triethylamine in a volume ratio of 10:1:0.01-1:1:0.

01.

10. Use of the compound of formula I or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof according to any one of claims 1 to 3 in the preparation of abemaciclib intermediate compound A and / or abemaciclib; The structural formula of the abemaciclib intermediate compound A is as follows: The structural formula of abemaciclib is as follows:

11. A method for preparing abemaciclib intermediate compound A, characterized in that: The method comprises the following steps: a compound of formula I is subjected to a fluorination reaction with a fluorination agent to obtain an abemaciclib intermediate compound A.

12. The preparation method according to claim 11, characterized in that: The fluorination reaction also includes one or more of the following conditions: ii1) before the fluorination reaction, the compound of formula I is dissolved in solvent C and cooled to -20 to 25°C; the fluorination agent is dissolved in water; ii2) the molar ratio of the compound of formula I to the fluorinating agent is 1:1.15-1:3; ii3) the reaction temperature of the fluorination reaction is 20-30°C and the reaction time is 1-6h; ii4) After the fluorination reaction is completed, water and an organic solvent D are added, wherein the organic solvent D is insoluble in water, and the obtained organic phase is dried and purified to obtain the abemaciclib intermediate compound A.

13. The preparation method according to claim 12, characterized in that: The solvent C includes at least one of acetonitrile, tetrahydrofuran and 1,4-dioxane; the fluorination reagent includes at least one of Selectfluor, perfluoropiperidine and Umist reagent; the solvent D includes ethyl acetate; the purification operation is to use n-heptane and ethyl acetate for slurrying, and / or to use an eluent of a solvent system with a volume ratio of petroleum ether:ethyl acetate = 3:1-1:1 for column chromatography.

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