Ibrutinib and its synthesis method

Abstract

The present invention discloses ibrutinib and a synthesis method thereof, comprising the following steps: (1) using SM1 (4-phenoxybenzoyl chloride) as a raw material, and carrying out a coupling reaction with SM2 (4,6-dichloropyrimidine) under the condition of a catalyst to obtain an intermediate M1 ((4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methyl ketone); (2) carrying out a cyclization reaction between M1 and SM3 (1-(3R-hydrazino-1-piperidinyl)-2-propylene-1-one) to obtain to the intermediate M2 (1-((R)-3-(4-chloro-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one); (3) subjecting M2 to a chlorination amination reaction to obtain ibrutinib (1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one). The ibrutinib synthesis method provided by the present invention has a reasonable route design, mild reaction conditions in each step, strong operability, low cost, high yield, simple process operation, is suitable for large-scale industrial production, and is of great significance.

Description

Technical Field

[0001] The present invention relates to the technical field of ibrutinib pharmaceuticals, and in particular to ibrutinib and a synthesis method thereof. Background Art

[0002] Ibrutinib, also known as ibrutinib, is the first small molecule BTK (Bruton's tyrosine kinase) inhibitor. BTK is expressed in B lymphocytes from the pre-B cell to the mature B cell stage. It regulates B cell development and differentiation by activating positive cell cycle regulators and differentiation factors, and also regulates B cell survival and proliferation by modulating the expression of pro-apoptotic and anti-apoptotic proteins. BTK is a potential therapeutic target for B cell-related malignancies, including CLL (chronic lymphocytic leukemia), NHL (non-Hodgkin's lymphoma), and mantle cell lymphoma.

[0003] Ibrutinib was developed and produced by Catalent CTS LLC / Johnson & Johnson / AbbVie. It was approved for marketing by the U.S. FDA in 2013, the European EMA in 2014, the Japanese PMDA in 2016, and the Chinese CFDA in 2017. It is included in the Class B medical insurance program and is marketed under the trade name The chemical name is: 1-{(3R)-3-[4-amino-3-(4-phenoxyphenol)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one, the molecular formula is: C 25 H 24 N6O2, structural formula (I) is as follows:

[0004]

[0005] WO2008039218A first disclosed a method for synthesizing ibrutinib and its analogs. The starting material is 4-phenoxybenzoyl chloride, which is condensed with malononitrile and then cyclized with anhydrous hydrazine to produce a pyrazole intermediate. This intermediate is then cyclized with formamide to yield a 4-aminopyrazolo[3,4-d]pyrimidine nucleus. The product is then condensed with a chiral alcohol via a Mitsunobu reaction, followed by removal of the Boc protecting group and acryloylation. This method is relatively long and has a low overall yield. Furthermore, the fourth step requires a high temperature of 180°C, making it unsuitable for industrial production. The synthetic route is as follows:

[0006]

[0007] CN105622613B reports that 4,6-dihydroxypyrimidine is used as the starting material, and the intermediate 4,6-dichloro-5-pyrimidinecarboxaldehyde is prepared by reacting phosphorus oxychloride and DMF. The intermediate 4,6-dichloro-5-pyrimidinecarboxaldehyde is then subjected to nucleophilic addition reaction with lithium salt formed by 4-phenoxybromobenzene at low temperature, or magnesium salt formed by Grignard reagent; the intermediate 4,6-dichloro-5-pyrimidinecarboxaldehyde is then reacted with an oxidant (including Jones reagent, PCC, PDC, hydrogen peroxide, Dess-Martin reagent, etc.) to form the corresponding ketone; the intermediate 4,6-dichloro-5-pyrimidinecarboxaldehyde is then reacted with hydrazine hydrate to form a key intermediate after chloroamination; the intermediate 4,6-dichloro-5-pyrimidinecarboxaldehyde is then subjected to Mitsunobu reaction, and the intermediate 4,6-dichloro-5-pyrimidinecarboxaldehyde is then deprotected with hydrochloric acid to form a salt, and finally acryloylation is performed to obtain ibrutinib. This scheme still has the disadvantages of a long route and low yield. The synthetic route is as follows:

[0008]

[0009] CN103626774B reports that 4-phenoxybenzoyl chloride is used as the starting material, which is condensed with malononitrile and dimethyl sulfate, and then cyclized with 1-(3R-hydrazino-1-piperidinyl)-2-propen-1-one to obtain the key pyrazole intermediate, which is then cyclized with DMF-DMA to obtain ibrutinib. After optimization, the reaction steps of this scheme are significantly reduced, but the highly toxic reagent dimethyl sulfate needs to be used during the reaction; at the same time, the last two steps of the reaction require high temperature conditions. Under these conditions, the stability of the acrylic acid fragment poses a greater challenge to the control of impurities during the reaction. The synthetic route is as follows:

[0010]

[0011] Therefore, it is of great significance to develop a route with reasonable design, mild reaction conditions, strong operability, low cost and high yield, which provides an important basis for the feasibility of commercial production of ibrutinib.

[0012] In view of this, this application is hereby filed. Summary of the Invention

[0013] The problem with the existing technology is that the current synthesis method of ibrutinib has problems such as long route, low yield, harsh reaction conditions and reagent safety. The present invention provides ibrutinib and its synthesis method, which have a reasonable route design, mild reaction conditions in each step, strong operability, low cost, high yield, simple process operation, and are suitable for large-scale industrial production, and are of great significance.

[0014] The present invention is achieved through the following technical solutions:

[0015] In a first aspect, the present invention provides a method for synthesizing ibrutinib, and the synthetic route is as follows:

[0016]

[0017] In a specific embodiment, the method for synthesizing ibrutinib comprises the following steps:

[0018] (1) Adding the raw materials SM1 (4-phenoxybenzoyl chloride) and SM2 (4,6-dichloropyrimidine) to an organic solvent, a coupling reaction occurs under the condition of a catalyst, and after completion of the reaction monitored by TLC, the intermediate M1 ((4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methyl ketone) is obtained through post-treatment;

[0019] (2) M1 and SM3 (1-(3R-hydrazino-1-piperidinyl)-2-propen-1-one) were added to an organic solvent, and a base was added to cause a cyclization reaction. After the reaction was completed under TLC monitoring, the intermediate M2 (1-((R)-3-(4-chloro-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one) was obtained after post-treatment;

[0020] (3) M2 is subjected to a chlorination reaction to obtain ibrutinib (1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one).

[0021] In a specific embodiment, in step (1), the organic solvent for the coupling reaction is one or a combination of two or more of tetrahydrofuran, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, and toluene; preferably tetrahydrofuran;

[0022] The catalyst comprises TMP2Zn·2MgCl2·2LiCl and CuCN·2LiCl; and the TMP is 2,2,6,6-tetramethylpiperidine.

[0023] In a specific embodiment, in step (1), the molar ratio of SM1 to SM2 is 1:0.9 to 1.5, preferably 1:1.1;

[0024] The molar ratio of SM1 to TMP2Zn·2MgCl2·2LiCl and CuCN·2LiCl is 1:0.5-1.0:0.05-1.2, 1:0.55:1.1.

[0025] In a specific embodiment, in step (2),

[0026] The organic solvent for the cyclization reaction is N,N-dimethylaminoformamide, N,N-dimethylaminoacetamide, dimethyl sulfoxide, acetonitrile, toluene, xylene or tetrahydrofuran, preferably ethanol;

[0027] The base is triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate or cesium carbonate, preferably triethylamine.

[0028] In a specific embodiment, in step (2), the molar ratio of intermediate M1 to SM3 is 1.0:0.5-1.2, preferably 1.0:0.8, and the molar ratio of intermediate M1 to base is 1:0.5-1.5, preferably 1.0:1.0.

[0029] In a specific embodiment, in step (3), the amination reagent used in the amination reaction is one or a combination of two or more of ammonia water, ammonium chloride, ammonium carbonate, ammonium nitrate, ammonium sulfate, ammonium acetate, ammonia gas / ethanol solution, ammonia gas / methanol solution, ammonia gas / isopropanol solution, ammonia gas / toluene solution, ammonia water / methanol solution, ammonia water / ethanol solution, and ammonia water / isopropanol solution, preferably ammonia water, ammonia gas / ethanol solution, and ammonia water / ethanol solution.

[0030] In a specific embodiment, in step (3), the molar ratio of the intermediate M2 to the aminating agent is 1.0:1.0-30, preferably 1.0:15.

[0031] In a specific embodiment, in step (3), the solvent for the cyclization reaction is methanol, ethanol, isopropanol, toluene, xylene, acetonitrile, N,N-dimethylaminoformamide, N,N-dimethylaminoacetamide or dimethyl sulfoxide, preferably ethanol;

[0032] In step (3), the reaction temperature is -10 to 50°C, preferably 0 to 10°C.

[0033] In a second aspect, the present invention provides ibrutinib, which is prepared using the synthetic method.

[0034] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0035] The embodiments of the present invention provide ibrutinib and a synthesis method thereof, which have a reasonable route design, mild reaction conditions in each step, strong operability, low cost, high yield, simple process operation, and are suitable for large-scale industrial production, and are of great significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without making any creative efforts.

[0037] Figure 1The compound prepared by the synthesis method of the present invention 1 HNMR spectrum;

[0038] Figure 2 The compound prepared by the synthesis method of the present invention 13 CNMR image. DETAILED DESCRIPTION

[0039] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with examples. The illustrative embodiments of the present invention and their descriptions are only used to explain the present invention and are not intended to limit the present invention.

[0040] In the following description, numerous specific details are set forth to provide a thorough understanding of the present invention. However, it will be apparent to one of ordinary skill in the art that these specific details are not necessarily employed to practice the present invention. In other embodiments, well-known materials or methods are not specifically described to avoid obscuring the present invention.

[0041] Throughout this specification, references to "one embodiment," "an embodiment," "an example," or "an example" mean that a particular feature, structure, or characteristic described in connection with the embodiment or example is included in at least one embodiment of the present invention. Thus, appearances of the phrases "one embodiment," "an embodiment," "an example," or "an example" in various places throughout this specification are not necessarily all referring to the same embodiment or example. Furthermore, the particular features, structures, or characteristics may be combined in any suitable combinations and / or subcombinations in one or more embodiments or examples. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0042] As used herein, "ranges" are defined in terms of lower and upper limits. A given range is defined by selecting a lower limit and an upper limit, the selected lower and upper limits defining the boundaries of the particular range. Ranges defined in this manner may be inclusive or exclusive and may be combined arbitrarily, i.e., any lower limit may be combined with any upper limit to form a range.

[0043] In the description of the present invention, unless otherwise specified, all embodiments and optional embodiments of the present application can be combined with each other to form a new technical solution.

[0044] In the description of the present invention, unless otherwise specified, all technical features and optional technical features of this application can be combined with each other to form a new technical solution.

[0045] In the description of the present invention, unless otherwise specified, the terms "include" and "comprising" mentioned in this application may be open-ended or closed-ended. For example, the terms "include" and "comprising" may mean that other components not listed may also be included or that only the listed components are included.

[0046] In a first aspect, the present invention provides a method for synthesizing ibrutinib, comprising the following steps:

[0047] A method for synthesizing ibrutinib, characterized in that the synthetic route is as follows:

[0048]

[0049] In a specific embodiment, the method for synthesizing ibrutinib comprises the following steps:

[0050] (1) Adding the raw materials SM1 (4-phenoxybenzoyl chloride) and SM2 (4,6-dichloropyrimidine) to an organic solvent, a coupling reaction occurs under the condition of a catalyst, and after completion of the reaction monitored by TLC, the intermediate M1 ((4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methyl ketone) is obtained through post-treatment;

[0051] (2) M1 and SM3 (1-(3R-hydrazino-1-piperidinyl)-2-propen-1-one) were added to an organic solvent, and a base was added to cause a cyclization reaction. After the reaction was completed under TLC monitoring, the intermediate M2 (1-((R)-3-(4-chloro-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one) was obtained after post-treatment;

[0052] (3) M2 is subjected to a chlorination reaction to obtain ibrutinib (1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one).

[0053] In a specific embodiment, in step (1), the organic solvent is one or a combination of two or more selected from tetrahydrofuran, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, and toluene; preferably tetrahydrofuran;

[0054] The catalyst comprises TMP2Zn·2MgCl2·2LiCl and CuCN·2LiCl; and the TMP is 2,2,6,6-tetramethylpiperidine.

[0055] In a specific embodiment, in step (1), the molar ratio of SM1 to SM2 is 1:0.9 to 1.5, preferably 1:1.1;

[0056] The molar ratio of SM1 to TMP2Zn·2MgCl2·2LiCl and CuCN·2LiCl is 1:0.5-1.0:0.05-1.2, 1:0.55:1.1.

[0057] In a specific embodiment, in step (2),

[0058] The organic solvent is N,N-dimethylaminoformamide, N,N-dimethylaminoacetamide, dimethyl sulfoxide, acetonitrile, toluene, xylene or tetrahydrofuran, preferably ethanol;

[0059] The base is triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate or cesium carbonate, preferably triethylamine.

[0060] In a specific embodiment, in step (2), the molar ratio of intermediate M1 to SM3 is 1.0:0.5-1.2, preferably 1.0:0.8, and the molar ratio of intermediate M1 to base is 1:0.5-1.5, preferably 1.0:1.0.

[0061] In a specific embodiment, in step (3), the amination reagent used in the amination reaction is one or a combination of two or more of ammonia water, ammonium chloride, ammonium carbonate, ammonium nitrate, ammonium sulfate, ammonium acetate, ammonia gas / ethanol solution, ammonia gas / methanol solution, ammonia gas / isopropanol solution, ammonia gas / toluene solution, ammonia water / methanol solution, ammonia water / ethanol solution, and ammonia water / isopropanol solution, preferably ammonia water, ammonia gas / ethanol solution, and ammonia water / ethanol solution.

[0062] In a specific embodiment, in step (3), the molar ratio of the intermediate M2 to the aminating agent is 1.0:1.0-30, preferably 1.0:15.

[0063] In a specific embodiment, in step (3), after M2 is dissolved in a solvent, an aminating agent is added for amination, and the solvent used is methanol, ethanol, isopropanol, toluene, xylene, acetonitrile, N,N-dimethylaminoformamide, N,N-dimethylaminoacetamide or dimethyl sulfoxide, preferably ethanol;

[0064] In step (3), the reaction temperature is -10 to 50°C, preferably 0 to 10°C.

[0065] In a second aspect, the present invention provides ibrutinib, which is prepared using the synthetic method.

[0066] Example 1

[0067] An embodiment of the present invention provides a method for synthesizing ibrutinib, comprising the following steps:

[0068] (1) 14.9 g (0.10 mol, 1.0 eq) of 4,6-dichloropyrimidine was dissolved in 180 ml of dry tetrahydrofuran and added dropwise to a tetrahydrofuran solution containing TMP2Zn·2MgCl2·2LiCl (0.79 M, 0.055 mol, 0.55 eq) at room temperature. After stirring for 1 hour, the temperature was lowered to -20°C; a tetrahydrofuran solution containing CuCN·2LiCl (1.0 M, 0.11 mol, 1.1 eq) was added dropwise at -20°C, and stirring was maintained for 1 hour; then, a tetrahydrofuran solution containing 25.6 g (0.11 mol, 1.1 eq) of 4-phenoxybenzoyl chloride (100 ml) was added dropwise while maintaining the temperature. After completion of the addition, the temperature was slowly raised to room temperature, and the reaction was continued with stirring until the starting material essentially disappeared as determined by TLC (dichloromethane:methanol = 1:10); the reaction solution was added to 1 L of a saturated aqueous ammonium chloride solution, and extracted multiple times with appropriate amounts of ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, and concentrated; the concentrate was recrystallized from an appropriate amount of methanol to obtain 27.5 g of solid M1 (yield 79.6%, chemical purity ≥99%).

[0069] The hydrogen spectrum data of M1 are as follows:

[0070] 1 H-NMR (DMSO-d6, 400MHz, δppm): 7.08 (d, 2H), 7.22 (d, 2H), 7.29 (t, 1H), 7.50 (d, 2H), 8.00 (d, 2H), 9.12 (s, 1H).

[0071] (2) 17.3 g of M1 (0.05 mol, 1.0 eq) and 6.8 g of SM3 (0.04 mol, 0.8 eq) were added to 300 ml of ethanol and stirred evenly. 5.0 g of triethylamine (0.05 mol, 1.0 eq) was then added dropwise. The temperature was raised to reflux and the reaction was continued until TLC (dichloromethane:methanol = 1:10) monitoring indicated that the starting material had essentially disappeared. The reaction solution was cooled to room temperature, 400 ml of water was slowly added, and the mixture was stirred for 1 hour. The solid was filtered and dried. The resulting solid was recrystallized from a 50% aqueous ethanol solution, filtered, and dried to obtain 17.4 g of solid M2 (yield 75.6%, chemical purity ≥99%).

[0072] The hydrogen spectrum data of M2 are as follows:

[0073] 1H-NMR (DMSO-d6, 400MHz, δppm): 1.52-1.64 (m, 1H), 1.91-1.95 (m, 1H), 2.11-2.14 (m, 1H), 2.22-2.33 (m, 1H), 3.01 (t, 0.5H), 3.16-3.24 (m, 1H), 3.71 (t, 0.5H), 4.08 (d, 0.5H), 4.21 (m, 1H), 4.56 (d, 0.5H), 4.71 (m, 1H), 5.65 (dd, 1H), 6.05-6.16 (m, 1H), 6.69-6.91(m, 1H), 7.32-7.72(m, 5H), 7.74(t, 2H), 8.07(d, 2H), 9.16(s, 1H).

[0074] (3) Dissolve 4.6 g (10 mmol) of compound M2 in 50 ml of ethanol, and then add 30 ml of 3 M ammonia / ethanol solution. Cool the reaction solution to 5-10°C and stir the reaction until TLC shows that the starting material disappears. Concentrate the reaction solution under reduced pressure to about 10 ml, and then add 100 ml of deionized water. Separate the aqueous phase, and add appropriate amount of deionized water to wash the residue several times until it is neutral. After drying, recrystallize from ethyl acetate / n-heptane and dry to obtain 4.1 g of white solid ibrutinib (yield 93.2%, chemical purity ≥99%).

[0075] The proton spectrum data of ibrutinib are as follows:

[0076] 1 H-NMR (CD3OD, 400MHz, δppm): 1.72-1.76 (m, 1H), 2.07-2.10 (m, 1H), 2.21-2.24 (m, 1H), 2.3 1-2.42(m, 1H), 3.22(t, 0.5H), 3.51(t, 0.5H), 3.85-3.91(m, 0.5H), 4.11(d, 0.5H), 4.20-4 .30 (m, 1H), 4.60-4.66 (t, 0.5H), 4.85 (m, 1H), 5.63-5.79 (dd, 1H), 6.13-6.24 (m, 1H), 6.64 -6.87(m, 1H), 7.08-7.21(m, 5H), 7.29-7.44(t, 2H), 7.67-7.69(d, 2H), 8.25-8.27(d, 1H).

[0077] The carbon spectrum data of ibrutinib are as follows:

[0078] 13C-NMR (CD3OD, 100MHz, δppm): 23.14, 24.61, 29.23, 29.70, 42.18, 45.85, 49.66, 52.33, 52.9 5, 97.82, 118.55, 119.14, 123.68, 127.64, 129.68, 129.85, 155.30, 156.56, 158.49, 158.54.

[0079] Example 2

[0080] An embodiment of the present invention provides a method for synthesizing ibrutinib, comprising the following steps:

[0081] (1) Dissolve 14.9 g (0.10 mol, 1.0 eq) of 4,6-dichloropyrimidine in 180 ml of dry tetrahydrofuran and add dropwise to a tetrahydrofuran solution containing TMP2Zn·2MgCl2·2LiCl (0.79 M, 0.055 mol, 0.55 eq) at room temperature. Stir at room temperature for 0.5 hour, then cool to -20°C. Add dropwise a tetrahydrofuran solution containing CuCN·2LiCl (1.0 M, 0.11 mol, 1.1 eq) at -20°C, and continue stirring for 0.5 hour. Then, add dropwise a tetrahydrofuran solution containing 25.6 g (0.11 mol, 1.1 eq) of 4-phenoxybenzoyl chloride (100 ml) while maintaining the temperature. After completion of the addition, slowly warm the temperature to room temperature and continue stirring until the starting material disappears as shown by TLC (dichloromethane:methanol = 1:10). The reaction mixture was added to 1 L of saturated aqueous ammonium chloride solution, and then extracted multiple times with appropriate amounts of ethyl acetate. The organic phases were combined, dried over anhydrous NaSO, and concentrated. The concentrate was recrystallized from an appropriate amount of methanol to obtain 25.8 g of solid M1 (yield 74.7%, chemical purity ≥99%).

[0082] (2) 17.3 g of M1 (0.05 mol, 1.0 eq) and 6.8 g of SM3 (0.05 mol, 1.0 eq) were added to 300 ml of acetonitrile and stirred evenly. 5.5 g of triethylamine (0.05 mol, 1.1 eq) was then added dropwise. The temperature was raised to reflux and the reaction was continued until TLC (dichloromethane:methanol = 1:10) monitoring indicated that the starting material had essentially disappeared. The reaction solution was cooled to room temperature, 400 ml of water was slowly added, and the mixture was stirred for 1 hour. The solid was filtered and dried. The resulting solid was recrystallized from 50% aqueous ethanol, filtered, and dried to obtain 18.3 g of solid M2 (yield 79.6%, chemical purity ≥99%).

[0083] (3) Dissolve 4.6 g (10 mmol) of compound M2 in 50 ml of methanol, and then add 20 ml of 7 M ammonia / methanol solution. Cool the reaction solution to 5-10°C and stir the reaction until TLC shows that the starting material disappears. Concentrate the reaction solution to dryness under reduced pressure, then add 100 ml of deionized water and an appropriate amount of dichloromethane and extract three times. Combine the organic phases, dry over anhydrous Na2SO4, and concentrate under reduced pressure. The concentrate is then recrystallized from ethyl acetate / n-heptane and dried to obtain 3.9 g of a white solid (yield 88.6%, chemical purity and optical purity ≥99%).

[0084] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing ibrutinib, characterized in that: The synthetic route is as follows:

2. The method for synthesizing ibrutinib according to claim 1, wherein: The steps include: (1) SM1 (4-phenoxybenzoyl chloride) is used as a raw material and undergoes a coupling reaction with SM2 (4,6-dichloropyrimidine) under catalyst conditions to obtain the intermediate M1 ((4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methyl ketone); (2) M1 is cyclized with SM3 (1-(3R-hydrazino-1-piperidinyl)-2-propen-1-one) to obtain the intermediate M2 (1-((R)-3-(4-chloro-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one); (3) M2 is subjected to a chlorination reaction to obtain ibrutinib (1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one).

3. The method for synthesizing ibrutinib according to claim 2, wherein: In step (1), The solvent for the coupling reaction is one or more of tetrahydrofuran, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, and toluene; The catalyst comprises TMP2Zn·2MgCl2·2LiCl and CuCN·2LiCl; and the TMP is 2,2,6,6-tetramethylpiperidine.

4. The method for synthesizing ibrutinib according to claim 2, wherein: In step (1), The molar ratio of SM1 to SM2 is 1:0.9-1.5; The molar ratio of SM1 to TMP2Zn·2MgCl2·2LiCl and CuCN·2LiCl is 1:0.5-1.0:0.05-1.

2.

5. The method for synthesizing ibrutinib according to claim 2, wherein: In step (2), the solvent for the cyclization reaction is N,N-dimethylaminoformamide, N,N-dimethylaminoacetamide, dimethyl sulfoxide, acetonitrile, toluene, xylene or tetrahydrofuran; the cyclization reaction is carried out under the action of a base, and the base is triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate or cesium carbonate.

6. The method for synthesizing ibrutinib according to claim 2, wherein: In step (2), the molar ratio of the intermediate M1 to SM3 is 1.0:0.5-1.2, and the molar ratio of the intermediate M1 to the base is 1:0.5-1.

5.

7. The method for synthesizing ibrutinib according to claim 2, wherein: In step (3), the amination reagent used in the amination reaction is one or more of ammonia water, ammonium chloride, ammonium carbonate, ammonium nitrate, ammonium sulfate, ammonium acetate, ammonia / ethanol solution, ammonia / methanol solution, ammonia / isopropanol solution, ammonia / toluene solution, ammonia water / methanol solution, ammonia water / ethanol solution, and ammonia water / isopropanol solution.

8. The method for synthesizing ibrutinib according to claim 2, wherein: In step (3), the molar ratio of the intermediate M2 to the aminating agent is 1.0:1.0-30.

9. The method for synthesizing ibrutinib according to claim 2, wherein: In step (3), the solvent for the amination reaction is methanol, ethanol, isopropanol, toluene, xylene, acetonitrile, N,N-dimethylaminoformamide, N,N-dimethylaminoacetamide or dimethyl sulfoxide; In step (3), the reaction temperature is -10 to 50°C.

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