Preparation method of abelsilib

Abstract

The invention relates to the field of medicine synthesis, in particular to a preparation method of abelsilib. The preparation method comprises the following steps: based on 2-chloro-4-chloromethylpyridine (a compound R-1) as a raw material, carrying out a substitution reaction on N-ethyl piperazine to obtain 5-(4-ethyl piperazine-1-yl) methyl-2-chloropyridine (a compound R-2); then, 2-amino-5-fluoro-4-[4-fluoro-2-methyl-1-isopropyl-1H-benzimidazole-6-yl] pyrimidine (a compound R-2) and the compound R-2 are subjected to a reaction, and the abesilib is obtained. The preparation method provided by the invention is simple and convenient to operate, safe, green, low in cost, small in pollution, stable in process, high in yield, high in product purity and more beneficial to industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemicals, and more particularly to a method for preparing abemaciclib. Background Art

[0002] Abemaciclib, chemically known as 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 primarily blocks intracellular signaling, thereby preventing the growth and spread of cancer cells. This drug is used to treat advanced or metastatic breast cancer, and its synthesis and process improvement have been a hot topic in recent years.

[0003] Chinese patent CN102264725 uses 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[D]imidazole, 2,4-dichloro-5-fluoropyrimidine, and 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine to prepare abemaciclib through three steps of palladium catalysis. The process is as follows:

[0004]

[0005] The main disadvantage of this route is that all three steps of the synthesis use heavy metal palladium catalysts, which increases the risk of introduction into abemaciclib and ingestion by humans. In addition, the use of palladium catalysts increases costs, making it unsuitable for commercial production.

[0006] WO2016110224 and US7855211 use 5-(4-ethyl-piperazin-1-yl-methyl)-2-aminopyridine as a raw material to undergo a guanidination reaction with monocyanamide to produce the intermediate guanidine, which is then cyclized with the intermediate 1-isopropyl-2-methyl-4-fluoro-6-(3-dimethylamino-fluoro)acryloyl-1H-benzimidazole under base catalysis to prepare abemaciclib. The patent also reports two synthetic methods for the intermediate 1-isopropyl-2-methyl-4-fluoro-6-(3-dimethylamino-fluoro)acryloyl-1H-benzimidazole, both of which use 1-(4-amino-2,6-difluorophenyl)-2-fluoroethanone as the starting material. Method 1 involves a condensation reaction between the raw material 1-(4-amino-2,6-difluorophenyl)-2-fluoroethanone and N,N-dimethylformamide dimethyl acetal. This reaction then undergoes an amidination reaction with N-isopropylacetamide in the presence of a halogenating agent and an acid-binding agent. The amidination product then undergoes an intramolecular cyclization reaction to produce the target intermediate. Method 2 involves a condensation reaction between the raw material 1-(4-amino-2,6-difluorophenyl)-2-fluoroethanone and N-isopropylacetamide in the presence of a halogenating agent and an acid-binding agent. The amidination product then undergoes an intramolecular cyclization reaction. The cyclization product then undergoes a condensation reaction with N,N-dimethylformamide dimethyl acetal to produce the target intermediate. This process involves relatively expensive raw materials, poor reaction selectivity, low purity, and a large amount of wastewater, making it unsuitable for industrial production. Summary of the Invention SUMMARY OF THE INVENTION

[0008] In view of the shortcomings of the existing technology, the present invention provides a preparation method of abemaciclib with simple operation, safety, greenness, low cost, low pollution, stable process, high yield and high purity.

[0009] On the one hand, the present invention provides a method for preparing abemaciclib, and the preparation route is shown as follows:

[0010]

[0011] The present invention provides a method for preparing abemaciclib. The method comprises the following steps: using 2-chloro-4-chloromethylpyridine (compound R-1) as a raw material, first performing a substitution reaction with N-ethylpiperazine to obtain 5-(4-ethylpiperazin-1-yl)methyl-2-chloropyridine (compound R-2); and then reacting 2-amino-5-fluoro-4-[4-fluoro-2-methyl-1-isopropyl-1H-benzimidazol-6-yl]pyrimidine (compound R-6) with compound R-2 to obtain abemaciclib.

[0012] On the other hand, the present invention provides a method for preparing abemaciclib, wherein the preparation route of the compound R-6 is shown as follows:

[0013]

[0014] The preparation method of compound R-6 provided by the present invention is based on 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[D]imidazole (compound R-3) as a starting material, performing a Miyaura borylation reaction to obtain 4-fluoro-2-methyl-1-(isopropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (compound R-4), and then performing a Suzuki coupling reaction between compound R-4 and 4-chloro-5-fluoropyrimidin-2-amine (compound R-5) to obtain compound R-6. Compound R-6 reacts with compound R-2 to obtain abemaciclib.

[0015] The preparation method provided by the present invention is simple to operate, safe and green, low in cost, low in pollution, stable in process, high in yield, high in product purity, and more conducive to industrial production.

[0016] Definition of terms

[0017] The present invention is intended to encompass all alternatives, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0018] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0019] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0020] Unless otherwise indicated, the following definitions apply. For the purposes of this invention, the chemical elements are as described in the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th edition, 1994. The terms "comprising" or "including" are open-ended expressions, meaning that the present invention includes the contents specified, but does not exclude other aspects.

[0021] The term “THF” means tetrahydrofuran; the term “DME” means ethylene glycol dimethyl ether; the term “DMSO” means dimethyl sulfoxide; the term “DMF” means dimethylformamide; the term “Bn” means phenyl; the term “Cbz” means formylbenzyl ester; the term “PMB” means 4-methoxybenzyl; the term “NaH” means sodium hydride; the term “DIPEA” means diisopropylethylamine; the term “DMAP” means dimethylaminopyridine; and the term “DBU” means 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0022] Ruphos represents 2-dicyclohexylphosphino-2',6'-diisopropyloxy-1,1'-biphenyl; X-phos represents 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; Xant-phos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;

[0023] The term "Pd(OAc)2" means palladium acetate; the term "PdCl2(PhCN)2" means trans-dichlorobis(phenylcyanide)palladium; the term "Pd2(dba)3" means tris(dibenzylidene-BASE acetone)dipalladium; the term "P(O-Tol)2PdCl2" means dichloro(di-o-tolylphosphine)palladium.

[0024] g stands for gram, mg for milligram, °C for degree Celsius, h for hour, mL for milliliter, min for minute, mol for mole, and mmol for millimole. In the description of the present invention, it should be understood that the terms "first" and "second" are used for descriptive purposes only and should not be construed to indicate or imply relative importance or implicitly specify the quantity of the technical features indicated. Therefore, features specified as "first" or "second" may explicitly or implicitly include one or more of such features. In the description of the present invention, "plurality" means two or more, unless otherwise specifically defined. Throughout this specification, references to the terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples" mean that the specific features, structures, materials, or characteristics described in connection with such embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of these terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined as appropriate in any one or more embodiments or examples. In addition, those skilled in the art may combine and combine different embodiments or examples described in this specification, as well as features of different embodiments or examples, unless they are mutually inconsistent. In the present invention, expressions such as "Compound A" and "the compound represented by Formula A" refer to the same compound. Detailed Description of the Invention

[0026] In one aspect, the present invention provides a method for preparing abemaciclib, characterized in that it comprises the following steps:

[0027]

[0028] Compound R-6 reacts with compound R-2 in the presence of a first solvent and a first base to obtain abemaciclib.

[0029] In some embodiments, the first solvent comprises at least one of acetonitrile, ethyl acetate, tetrahydrofuran, toluene, xylene, ethanol, and ethylene glycol dimethyl ether.

[0030] In some embodiments, the first solvent is toluene.

[0031] In some embodiments, the first solvent is xylene.

[0032] In some embodiments, the first base comprises at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, cesium carbonate, potassium tert-butoxide, and DBU.

[0033] In some embodiments, the first base is cesium carbonate.

[0034] In some embodiments, the first base is potassium carbonate.

[0035] In some embodiments, the molar ratio of compound R-2 to compound R-6 is 0.9-3.0:1.

[0036] In some embodiments, the molar ratio of compound R-2 to compound R-6 is 1.0-2.0:1.

[0037] In some embodiments, the molar ratio of compound R-2 to compound R-6 is 1.2-1.5:1.

[0038] In some embodiments, the molar ratio of the first base to compound R-6 is 0.9-3.0:1.

[0039] In some embodiments, the molar ratio of the first base to compound R-6 is 1.0-2.0:1.

[0040] In some embodiments, the molar ratio of the first base to compound R-6 is 1.2-1.5:1.

[0041] In some embodiments, the reaction temperature is 30°C-150°C.

[0042] In some embodiments, the reaction temperature is 50°C-130°C.

[0043] In some embodiments, the reaction temperature is 90°C-110°C.

[0044] In some embodiments, the reaction is carried out in the presence of a ligand and a first catalyst to produce abemaciclib through a coupling reaction.

[0045] In some embodiments, the ligand comprises at least one of Ruphos, X-phos, Xant-phos, tricyclohexylphosphine, and triphenylphosphine.

[0046] In some embodiments, the ligand is Xant-phos.

[0047] In some embodiments, the ligand is Ruphos.

[0048] In some embodiments, the first catalyst comprises at least one of Pd(OAc)2, PdCl2(PhCN)2, tetraphenylphosphine palladium dichloride, Pd2(dba)3, P(O-Tol)2PdCl2, palladium acetate, and palladium dichloride.

[0049] In some embodiments, the first catalyst is palladium acetate.

[0050] In some embodiments, the ratio of the ligand to compound R-6 is 0.001eq-0.05eq:1.0eq.

[0051] In some embodiments, the ratio of the ligand to compound R-6 is 0.005eq-0.03eq:1.0eq.

[0052] In some embodiments, the ratio of the ligand to compound R-6 is 0.01eq-0.02eq:1.0eq.

[0053] In some embodiments, the ratio of the first catalyst to compound R-6 is 0.001eq-0.05eq:1.0eq.

[0054] In some embodiments, the ratio of the first catalyst to compound R-6 is 0.005eq-0.03eq:1.0eq.

[0055] In some embodiments, the ratio of the first catalyst to compound R-6 is 0.01eq-0.02eq:1.0eq.

[0056] On the other hand, the present invention provides a method for preparing abemaciclib, wherein the preparation of the compound R-6 comprises the following steps:

[0057]

[0058] (1) Compound R-3 reacts with biboronic acid pinacol ester in a second base, a second catalyst, and a second solvent to obtain compound R-4;

[0059] (2) Compound R-4 reacts with compound R-5 in a third base and a third solvent to obtain compound R-6.

[0060] In some embodiments, the second base includes at least one of potassium acetate, potassium phosphate, sodium acetate, sodium carbonate, potassium 2-ethylhexanoate, and potassium carbonate.

[0061] In some embodiments, the second base is potassium acetate.

[0062] In some embodiments, the molar ratio of the second base to compound R-3 is 0.9-3.0:1.

[0063] In some embodiments, the molar ratio of the second base to compound R-3 is 1.0-2.0:1.

[0064] In some embodiments, the molar ratio of the second base to compound R-3 is 1.2-1.5:1.

[0065] In some embodiments, the second catalyst comprises at least one of Pd(OAc)2, PdCl2(PhCN)2, tetraphenylphosphine palladium dichloride, Pd2(dba)3, and P(O-Tol)2PdCl2.

[0066] In some embodiments, the second catalyst is PdCl2(PhCN)2.

[0067] In some embodiments, the ratio of the second catalyst to compound R-3 is 0.001eq-0.05eq:1.0eq.

[0068] In some embodiments, the ratio of the second catalyst to compound R-3 is 0.005eq-0.03eq:1.0eq.

[0069] In some embodiments, the ratio of the second catalyst to compound R-3 is 0.01eq-0.02eq:1.0eq.

[0070] In some embodiments, the second solvent comprises at least one of acetonitrile, ethyl acetate, tetrahydrofuran, toluene, xylene, ethanol, and DME.

[0071] In some embodiments, the second solvent is tetrahydrofuran.

[0072] In some embodiments, the reaction temperature of the compound R-3 and pinacol diboronate is 30°C-100°C.

[0073] In some embodiments, the reaction temperature of the compound R-3 and pinacol diboronate is 50°C-90°C.

[0074] In some embodiments, the reaction temperature of the compound R-3 and pinacol diboronate is 60°C-80°C.

[0075] In some embodiments, the third base includes at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and sodium bicarbonate.

[0076] In some embodiments, the third base is potassium carbonate.

[0077] In some embodiments, the third solvent comprises at least one of methanol, ethanol, isopropanol, DMSO, DMF, tetrahydrofuran, and water.

[0078] In some embodiments, the third solvent is water.

[0079] In some embodiments, the molar ratio of the third base to compound R-4 is 0.9-3.0:1.

[0080] In some embodiments, the molar ratio of the third base to compound R-4 is 1.0-2.0:1.

[0081] In some embodiments, the molar ratio of the third base to compound R-4 is 1.2-1.5:1.

[0082] In some embodiments, the reaction temperature of the compound R-4 and the compound R-5 is 30°C-100°C.

[0083] In some embodiments, the reaction temperature of the compound R-4 and the compound R-5 is 50°C-80°C.

[0084] In some embodiments, the reaction temperature of the compound R-4 and the compound R-5 is 60°C-70°C.

[0085] In some embodiments, the preparation of compound R-2 comprises the following steps:

[0086]

[0087] Compound R-1 reacts with N-ethylpiperazine in a fourth base and a fourth solvent to obtain compound R-2.

[0088] In some embodiments, the fourth base comprises at least one of triethylamine, DIPEA, pyridine, and N-ethylpiperazine.

[0089] In some embodiments, the fourth base is triethylamine.

[0090] In some embodiments, the fourth solvent includes at least one of toluene, THF, ethyl acetate, dichloromethane, cyclohexane, and n-hexane.

[0091] In some embodiments, the fourth solvent is toluene.

[0092] Those skilled in the art, under the conception of the present invention, can adjust the reaction conditions appropriately according to the disclosed content as needed, such as selecting other appropriate reaction solvents, adjusting the reaction temperature, and appropriately extending the reaction time to obtain better reaction effects.

[0093] Compared with the prior art, the technical solution provided by the present invention has the following advantages:

[0094] 1. The starting materials in this process, compound R-1, compound R-3 and compound R-5, are all available on the market at relatively low prices, which is conducive to reducing costs.

[0095] 2. The intermediate compounds in the process are relatively stable. The reaction liquid of compound R-4 directly reacts with compound R-5 to obtain compound R-6 in a one-pot process, avoiding unstable intermediates and reducing the use of precious metal catalysts.

[0096] 3. The preparation method provided by the present invention is simple to operate, safe and green, low in cost, low in pollution, stable in process, high in yield, high in product purity, and more conducive to industrial production. DETAILED DESCRIPTION

[0097] In order to enable those skilled in the art to better understand the technical solutions of the present invention, the present invention provides some preparation examples by way of example, and further discloses some non-limiting examples below to further illustrate the present invention in detail.

[0098] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0099] Example 1 Preparation of Compound R-2

[0100] A mixture of 2-chloro-4-chloromethylpyridine (Compound R-1, 50.0 g), N-ethylpiperazine (42.3 g), and triethylamine (37.5 g) in toluene (250 mL) was stirred thoroughly, then heated to approximately 50°C and stirred for 3 hours. After completion of the reaction, as monitored by TLC, the mixture was cooled to approximately 25°C, washed with water (50 mL) and stirred. The mixture was allowed to stand for separation, and the organic phase was collected. The organic phase was concentrated under reduced pressure to remove the solvent, yielding 5-(4-ethylpiperazin-1-yl)methyl-2-chloropyridine (Compound R-2, 72.1 g; yield: 97.5%; HPLC purity: 99.1%) as a pale yellow oil.

[0101] Example 2 Preparation of Compound R-4

[0102] A mixture of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[D]imidazole (Compound R-3, 10.0 g), pinacol diboron (11.24 g), potassium acetate (5.43 g), and PdCl[PhCN] (141 mg) in THF (60 mL) was stirred thoroughly. The air in the system was then displaced with nitrogen. Under nitrogen, the system was heated to reflux (external temperature 80°C) and allowed to react for approximately 16 hours. The system was then cooled to approximately 25°C and, under nitrogen, was set aside. (Compound R-4, 11.7 g, yield: 100%).

[0103] Example 3 Preparation of Compound R-6

[0104] To the reaction solution containing compound R-4, 4-chloro-5-fluoropyrimidin-2-amine (compound R-5, 9.21 g), potassium carbonate (16.13 g), and water (60 mL) were added and stirred evenly. The system was heated to 60°C and stirred for about 16 hours. The reaction was stopped, the system was cooled to about 10°C, filtered, and stirred for crystallization for about 2 hours. The filter cake was rinsed with water (10 mL) to obtain a wet product, which was then dried in vacuo at 60°C for about 10 hours to obtain 2-amino-5-fluoro-4-[4-fluoro-2-methyl-1-isopropyl-1H-benzimidazol-6-yl]pyrimidine (compound R-6, 10.93 g, yield: 97.7%, HPLC purity: 99.2%) as a gray solid.

[0105] Example 4 Preparation of Abemaciclib (Method 1)

[0106] A mixture of 2-amino-5-fluoro-4-[4-fluoro-2-methyl-1-isopropyl-1H-benzimidazol-6-yl]pyrimidine (Compound R-6, 10.0 g), 5-(4-ethylpiperazin-1-yl)methyl-2-chloropyridine (Compound R-2, 9.49 g), and cesium carbonate (16.11 g) in toluene (100 mL) was stirred uniformly. The system was then heated to 100°C and stirred for approximately 16 hours. The reaction was stopped, and water (50 mL) was added. After stirring uniformly, the mixture was allowed to stand for separation. The organic phase was collected, cooled to approximately 10°C, and stirred for approximately 2 hours to allow crystallization. Filtration afforded abemaciclib as a pale yellow solid (16.5 g, yield: 98.79%, HPLC purity: 99.5%).

[0107] Example 5 Preparation of Abemaciclib (Method 2)

[0108] A mixture of 2-amino-5-fluoro-4-[4-fluoro-2-methyl-1-isopropyl-1H-benzimidazol-6-yl]pyrimidine (Compound R-6, 10.0 g), 5-(4-ethylpiperazin-1-yl)methyl-2-chloropyridine (Compound R-2, 9.49 g), RuPhos (308 mg), palladium acetate (150 mg), and potassium carbonate (6.83 g) in toluene (100 mL) was stirred uniformly. The mixture was then heated to 100°C and stirred for approximately 16 hours. The reaction was terminated, the mixture was cooled to approximately 50°C, and the mixture was filtered while hot. The organic phase was collected, cooled to approximately 10°C, and stirred for approximately 2 hours to allow crystallization. Filtration afforded abemaciclib (16.3 g, 97.6% yield, 99.6% HPLC purity) as a pale yellow solid.

[0109] The methods of the present invention have been described through preferred embodiments. It is apparent that those skilled in the art will be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and spirit of the present invention to implement and apply the technology of the present invention. Those skilled in the art may refer to the disclosure herein and appropriately modify the process parameters to achieve the desired effect. It is particularly important to note that all similar substitutions and modifications apparent to those skilled in the art are considered encompassed by the present invention.

Claims

1. A method for preparing abemaciclib, characterized in that: The following steps are involved: Compound R-6 reacts with compound R-2 in the presence of a first solvent and a first base to obtain abemaciclib.

2. The preparation method according to claim 1, characterized in that The first solvent includes at least one of acetonitrile, ethyl acetate, tetrahydrofuran, toluene, xylene, ethanol and ethylene glycol dimethyl ether; or, the first solvent is toluene or xylene.

3. The preparation method according to claim 1, characterized in that The first base includes at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, cesium carbonate, potassium tert-butoxide and DBU; or, the first base is cesium carbonate or potassium carbonate.

4. The preparation method according to claim 1, characterized in that The molar ratio of the compound R-2 to the compound R-6 is 0.9-3.0:1; or, the molar ratio of the compound R-2 to the compound R-6 is 1.0-2.0:1; or, the molar ratio of the compound R-2 to the compound R-6 is 1.2-1.5:

1.

5. The preparation method according to claim 1, characterized in that The molar ratio of the first base to the compound R-6 is 0.9-3.0:1; or the molar ratio of the first base to the compound R-6 is 1.0-2.0:1; or the molar ratio of the first base to the compound R-6 is 1.2-1.5:

1.

6. The preparation method according to claim 1, characterized in that The reaction temperature of the reaction is 30°C-150°C; alternatively, the reaction temperature of the reaction is 50°C-130°C; alternatively, the reaction temperature of the reaction is 80°C-120°C; alternatively, the reaction temperature of the reaction is 90°C-110°C.

7. The preparation method according to claim 1, characterized in that The reaction is carried out in the presence of a ligand and a first catalyst to produce abemaciclib through a coupling reaction.

8. The preparation method according to claim 7, characterized in that The ligand includes at least one of Ruphos, X-phos, Xant-phos, tricyclohexylphosphine and triphenylphosphine; or, the ligand is Xant-phos or Ruphos.

9. The preparation method according to claim 7, characterized in that The first catalyst includes at least one of Pd(OAc)2, PdCl2(PhCN)2, tetraphenylphosphine palladium dichloride, Pd2(dba)3, P(O-Tol)2PdCl2, palladium acetate and palladium dichloride; or, the first catalyst is palladium acetate.

10. The preparation method according to claim 7, characterized in that The usage ratio of the ligand to the compound R-6 is 0.001eq-0.05eq:1.0eq; or, the usage ratio of the ligand to the compound R-6 is 0.005eq-0.03eq:1.0eq; or, the usage ratio of the ligand to the compound R-6 is 0.01eq-0.02eq:1.0eq.

11. The preparation method according to claim 7, characterized in that The usage ratio of the first catalyst to compound R-6 is 0.001eq-0.05eq:1.0eq; or, the usage ratio of the first catalyst to compound R-6 is 0.005eq-0.03eq:1.0eq; or, the usage ratio of the first catalyst to compound R-6 is 0.01eq-0.02eq:1.0eq.

12. The preparation method according to claim 1, characterized in that The preparation of the compound R-6 comprises the following steps: (1) Compound R-3 reacts with biboronic acid pinacol ester in a second base, a second catalyst, and a second solvent to obtain compound R-4; (2) Compound R-4 reacts with compound R-5 in a third base and a third solvent to obtain compound R-6.

13. The preparation method according to claim 12, characterized in that The second base includes at least one of potassium acetate, potassium phosphate, sodium acetate, sodium carbonate, potassium 2-ethylhexanoate and potassium carbonate; or the second base is potassium acetate.

14. The preparation method according to claim 12, characterized in that The molar ratio of the second base to the compound R-3 is 0.9-3.0:1; or the molar ratio of the second base to the compound R-3 is 1.0-2.0:1; or the molar ratio of the second base to the compound R-3 is 1.2-1.5:

1.

15. The preparation method according to claim 12, characterized in that The second catalyst includes at least one of Pd(OAc)2, PdCl2(PhCN)2, tetraphenylphosphine palladium dichloride, Pd2(dba)3 and P(O-Tol)2PdCl2; or, the second catalyst is PdCl2(PhCN)2.

16. The preparation method according to claim 12, characterized in that The usage ratio of the second catalyst to compound R-3 is 0.001eq-0.05eq:1.0eq; or, the usage ratio of the second catalyst to compound R-3 is 0.005eq-0.03eq:1.0eq; or, the usage ratio of the second catalyst to compound R-3 is 0.01eq-0.02eq:1.0eq.

17. The preparation method according to claim 12, characterized in that The second solvent includes at least one of acetonitrile, ethyl acetate, tetrahydrofuran, toluene, xylene, ethanol and DME; or, the second solvent is tetrahydrofuran.

18. The preparation method according to claim 12, characterized in that: The reaction temperature of the compound R-3 and biboric acid pinacol ester is 30°C-100°C; or, the reaction temperature of the compound R-3 and biboric acid pinacol ester is 50°C-90°C; or, the reaction temperature of the compound R-3 and biboric acid pinacol ester is 60°C-80°C.

19. The preparation method according to claim 12, characterized in that: The third base includes at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and sodium bicarbonate; or, the third base is potassium carbonate; the third solvent includes at least one of methanol, ethanol, isopropanol, DMSO, DMF, tetrahydrofuran and water; or, the third solvent is water.

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