Ibrutinib and synthesis method thereof

Abstract

The invention discloses ibrutinib and a synthetic method thereof, and the synthetic method comprises the following steps: (1) taking SM1 (4-phenoxybenzoyl chloride) as a raw material, and carrying out a coupling reaction with SM2 (4, 6-dichloropyrimidine) in the presence of a catalyst to obtain an intermediate M1 ((4, 6-dichloropyrimidine-5-yl) (4-phenoxyphenyl) methyl ketone); (2) the M1 and SM3 (1-(3R-hydrazino-1-piperidyl)-2-propylene-1-ketone) are subjected to a cyclization reaction, and an intermediate M2 (1-((R)-3-(4-chloro-3-(4-phenoxy phenyl)-1H-pyrazolo [3, 4-d] pyrimidine-1-yl) piperidin-1-yl) prop-2-ene-1-ketone) is obtained; and (3) the M2 is subjected to an ammonolysis reaction of chlorine, such that ibrutinib (1-((R)-3-(4-amino-3-(4-phenoxy phenyl)-1H-pyrazolo [3, 4-d] pyrimidine-1-yl) piperidine-1-yl) prop-2-en-1-one) is obtained. The ibrutinib synthesis method provided by the invention is reasonable in route design, mild in reaction condition of each step, high in operability, low in cost, high in yield, simple in process operation and suitable for industrial mass production, and has very important significance.

Description

Technical Field

[0001] The present invention relates to the technical field of ibrutinib pharmaceutical preparation, 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 the pre-B cell to B cell maturation stage of B lymphocytes. It can regulate the development and differentiation of B cells by activating cell cycle positive regulators and differentiation factors, and regulate the survival and proliferation of B cells by regulating 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 was included in the Class B medical insurance program and its trade name is 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 the synthesis method of ibrutinib and its analogs, using 4-phenoxybenzoyl chloride as the starting material, condensing with malononitrile, and then cyclizing with anhydrous hydrazine to obtain a pyrazole intermediate, which is then cyclized with formamide to obtain a 4-aminopyrazolo[3,4-d]pyrimidine mother nucleus, and then condensing with chiral alcohol by Mitsunobu reaction, removing the Boc protecting group and acryloylating to obtain the product. This scheme has a long route and a low total yield; and the fourth step reaction requires a high temperature of 180°C, which is not suitable for industrial production. The synthesis 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 the reaction of phosphorus oxychloride and DMF, and then the lithium salt formed by 4-phenoxybromobenzene at low temperature, or the magnesium salt formed by Grignard reagent, is subjected to nucleophilic addition reaction; then the corresponding ketone is reacted with an oxidant (including Jones reagent, PCC, PDC, hydrogen peroxide, Dess-Martin reagent, etc.); after the chlorination reaction, the key intermediate is prepared by the ring-closing reaction with hydrazine hydrate; after the Mitsunobu reaction, the Boc protection is removed by hydrochloric acid to form a salt, and finally ibrutinib is obtained after acryloylation. This scheme still has the disadvantages of long route and low yield. The synthesis route is as follows:

[0008]

[0009] CN103626774B reported that 4-phenoxybenzoyl chloride was used as the starting material, and after condensation with malononitrile and dimethyl sulfate, it was cyclized with 1-(3R-hydrazino-1-piperidinyl)-2-propene-1-one to obtain the key intermediate of pyrazole, and then closed with DMF-DMA to obtain ibrutinib. After optimization, the reaction steps of this scheme were significantly reduced, but the highly toxic reagent dimethyl sulfate needed to be used in the reaction process; at the same time, the last two steps of the reaction required high temperature conditions, under which the stability of the acrylic acid fragment poses a great 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 can provide 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 prior art is that the current synthesis method of ibrutinib has the problems of long route, low yield, harsh reaction conditions and reagent safety. The present invention provides ibrutinib and a synthesis method thereof, which has a reasonable route design, mild reaction conditions in each step, strong operability, low cost, high yield, simple process operation, and is suitable for large-scale industrial production, and is 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 synthesis method of ibrutinib comprises the following steps:

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

[0019] (2) M1 and SM3 (1-(3R-hydrazino-1-piperidinyl)-2-propene-1-one) are added to an organic solvent, and a base is added to cause a cyclization reaction. After the reaction is 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) is obtained through 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 1:0.9-1.5, 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 by the synthesis 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 reasonable route design, mild reaction conditions in each step, strong operability, low cost, high yield, simple process operation, 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 drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

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

[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 purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with embodiments. The illustrative embodiments of the present invention and their description are only used to explain the present invention and are not intended to limit the present invention.

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

[0041] Throughout the specification, references to "one embodiment," "an embodiment," "an example," or "an example" mean that a particular feature, structure, or characteristic described in conjunction with the embodiment or example is included in at least one embodiment of the present invention. Therefore, the phrases "one embodiment," "an embodiment," "an example," or "an example" appearing in various places throughout the specification do not necessarily all refer to the same embodiment or example. In addition, particular features, structures, or characteristics may be combined in one or more embodiments or examples in any suitable combination and / or subcombination. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0042] The "range" disclosed in this application is defined in the form of a lower limit and an upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of the particular range. The range defined in this way can be inclusive or exclusive of the end values, and can be arbitrarily combined, that is, any lower limit can 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 the present 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 words "include" and "comprising" mentioned in the present application may be open-ended or closed-ended. For example, the words "include" and "comprising" may mean that other components not listed may also be included or comprised, or may only include or comprise the listed components.

[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 synthesis route is as follows:

[0048]

[0049] In a specific embodiment, the synthesis method of ibrutinib comprises the following steps:

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

[0051] (2) M1 and SM3 (1-(3R-hydrazino-1-piperidinyl)-2-propene-1-one) are added to an organic solvent, and a base is added to cause a cyclization reaction. After the reaction is 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) is obtained through 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 1:0.9-1.5, 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 by the synthesis method.

[0066] Example 1

[0067] The 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; at -20°C, a tetrahydrofuran solution containing CuCN·2LiCl (1.0M, 0.11mol, 1.1eq) was added dropwise, and stirring was maintained for 1 hour; then 100ml of a tetrahydrofuran solution containing 25.6g (0.11mol, 1.1eq) of 4-phenoxybenzoyl chloride was added dropwise while maintaining the temperature, and the temperature was slowly raised to room temperature after the addition was completed, and the reaction was continued to be stirred until the raw material basically disappeared according to TLC (dichloromethane: methanol = 1:10); the reaction solution was added to 1L of a saturated aqueous solution of ammonium chloride, and an appropriate amount of ethyl acetate was added for multiple extractions, the organic phases were combined, dried over anhydrous Na2SO4, and concentrated; the concentrate was recrystallized with an appropriate amount of methanol to obtain 27.5g 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) Add 17.3 g of M1 (0.05 mol, 1.0 eq) and 6.8 g of SM3 (0.04 mol, 0.8 eq) to 300 ml of ethanol, stir evenly, and then drop 5.0 g of triethylamine (0.05 mol, 1.0 eq). Heat to reflux reaction until TLC (dichloromethane: methanol = 1:10) monitoring shows that the raw material is basically gone. The reaction solution is cooled to room temperature, 400 ml of water is slowly added, stirred for 1 hour, and the solid is filtered and dried. The obtained solid is recrystallized with 50% ethanol aqueous 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 3M ammonia / ethanol solution. Cool the reaction solution to 5-10°C and stir the reaction until TLC shows that the raw 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 then add an appropriate amount of deionized water to wash the residue several times until it is neutral. After drying, recrystallize with 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] The embodiment of the present invention provides a method for synthesizing ibrutinib, comprising the following steps:

[0081] (1) Take 14.9 g (0.10 mol, 1.0 eq) of 4,6-dichloropyrimidine and dissolve it in 180 ml of dry tetrahydrofuran. Then, add it dropwise to a tetrahydrofuran solution containing TMP2Zn·2MgCl2·2LiCl (0.79 M, 0.055 mol, 0.55 eq) at room temperature. After stirring for 0.5 hour, cool to -20°C. Add a tetrahydrofuran solution containing CuCN·2LiCl (1.0 M, 0.11 mol, 1.1 eq) dropwise at -20°C and keep stirring for 0.5 hour. Then, add 100 ml of a tetrahydrofuran solution containing 25.6 g (0.11 mol, 1.1 eq) of 4-phenoxybenzoyl chloride dropwise while keeping warm. After the addition is complete, slowly warm the temperature to room temperature. Continue stirring the reaction until the raw material disappears as shown by TLC (dichloromethane: methanol = 1:10). The reaction solution was added to 1 L of saturated aqueous solution of ammonium chloride, and then an appropriate amount of ethyl acetate was added for multiple extractions. The organic phases were combined, dried over anhydrous Na2SO4, and concentrated. The concentrate was recrystallized with an appropriate amount of methanol to obtain 25.8 g of solid M1 (yield 74.7%, chemical purity ≥99%).

[0082] (2) Add 17.3 g M1 (0.05 mol, 1.0 eq) and 6.8 g SM3 (0.05 mol, 1.0 eq) to 300 ml acetonitrile, stir evenly, and then drop 5.5 g triethylamine (0.05 mol, 1.1 eq). Heat to reflux reaction until TLC (dichloromethane: methanol = 1:10) monitoring shows that the raw material is basically gone. The reaction solution is cooled to room temperature, 400 ml water is slowly added, stirred for 1 hour, and the solid is filtered and dried. The obtained solid is recrystallized with 50% ethanol aqueous solution, filtered, and dried to obtain 18.3 g 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 raw material disappears. Concentrate the reaction solution to dryness under reduced pressure, then add 100 ml of deionized water and an appropriate amount of dichloromethane to 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 a coupling reaction is carried out with SM2 (4,6-dichloropyrimidine) under the condition of a catalyst to obtain the intermediate M1 ((4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methyl ketone); (2) M1 is subjected to a cyclization reaction with SM3 (1-(3R-hydrazino-1-piperidinyl)-2-propene-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, 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 intermediate M1 to SM3 is 1.0:0.5-1.2, and the molar ratio of intermediate M1 to base is 1:0.5-1.

5.

7. The method for synthesizing ibrutinib according to claim 2, wherein: In step (3), the aminating reagent used in the aminating 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.

10. Ibrutinib, characterized in that The compound is prepared by the synthesis method according to any one of claims 1 to 9.

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