A preparation method of ibrutinib

Abstract

The present invention belongs to the technical field of drug synthesis, and in particular to a method for preparing ibrutinib. The present invention uses 3-bromo-1H-pyrazolo[3,4-D]pyrimidine-4-amine as a raw material, and reacts with 4-phenoxyphenylboronic acid under amine catalysis to obtain 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine; 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine is reacted with 1-[(S)-3-hydroxy-1-piperidinyl]-2-propylene-1-one under the catalysis of phosphine oxide to obtain ibrutinib through Mitsunobu reaction. This process uses amine catalysts instead of precious metal palladium to catalyze the Suzuki coupling reaction, which solves the problems of low yield and expensive catalysts in traditional reactions of this type. It uses phosphine oxide as a catalyst to catalyze the Mitsunobu reaction, avoiding the use of equivalent triphenylphosphine in the Mitsunobu reaction, and solves the harsh conditions of the reaction itself that require the acidity of the nucleophilic reagent. The process is simple to operate, and the target product obtained is of high purity, which is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing ibrutinib. Background Art

[0002] Ibrutinib, also known as Ibrutinib, has a chemical name of 1-[3(R)-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propene-1-one. It is an oral heavyweight Bruton's tyrosine kinase (BTK) inhibitor anticancer drug developed by Pharmacyclics and Johnson & Johnson. The drug selectively covalently binds to the cysteine ​​residues at the active site of the target protein BTK to irreversibly inhibit BTK, thereby effectively preventing tumors from migrating from cells to lymphoid tissues that adapt to the tumor growth environment. Since its launch, ibrutinib has been granted 4 breakthrough drug designations by the FDA, and has broad research and development prospects. The chemical structure is as follows:

[0003]

[0004] Due to its good clinical performance, Ibrutinib has attracted great attention from pharmacists and organic synthesizers to develop its synthesis method. According to the chemical structure of Ibrutinib itself, people have conducted a retrosynthetic analysis on it. Its structure consists of three fragments, namely piperidine ring fragment A, pyrazolopyrimidineamine fragment B and diphenyl ether fragment C:

[0005]

[0006] The CN bond connection of the existing process fragments A and B is mainly achieved through Mitsunobu reaction or SN2 substitution reaction. There are two main methods reported in the prior art:

[0007] Method 1: achieved through Mitsunobu reaction, such as Liu Meixia. Synthesis, structural modification and biological activity evaluation of ibrutinib [D]. Shandong University, and Chinese patent applications CN105859728B, CN103121999, and patent WO2017163257 all reported that intermediate IV and compound 11, i.e., (S)-2-(hydroxymethyl)piperidin-1-carboxylic acid tert-butyl ester, under the catalyst triphenylphosphine and diisopropyl azodicarboxylate, underwent Mitsunobu reaction to obtain compound X. However, since a large amount of diisopropyl azodicarboxylate (DIAD) was used in the reaction, a large amount of by-products were produced in the reaction, and many impurities needed to be removed in the post-treatment process. Therefore, it is not an atom-economical and green process route:

[0008]

[0009] Method 2: Through SN2 reaction, Chinese patent application CN105820168 and international applications WO2016132383, WO2016151438, etc. have successively reported that the chiral raw material reacts with methylsulfonyl chloride to obtain compound 11 containing a leaving functional group, 11 and halogen-substituted pyrazolopyrimidine heterocyclic compound 10 are subjected to substitution reaction under alkaline conditions to prepare intermediate 12, and 12 is subjected to multi-step reaction to obtain ibrutinib, thereby avoiding the Mitsunobu reaction. However, the control of the chiral center of the SN2 substitution reaction is worse than that of the Mitsunobu reaction, which is not conducive to the control of the chiral purity of the final product:

[0010]

[0011] The construction of the CC bond between fragments B and C can be achieved by a metal-catalyzed coupling reaction. For example, in U.S. Pat. No. 2008108636, heterocyclic compound 4 is used as a starting material, and an iodination reaction is carried out with N-iodosuccinimide to obtain compound 10. 10 is subjected to a Suzuki coupling reaction with p-methoxyphenylboronic acid III under the catalysis of a transition metal catalyst to obtain the key intermediate IV. The synthetic route is as follows:

[0012]

[0013] Chinese patent application CN105859728 uses 4-bromoanisole to prepare silicon-containing compound 15, and 15 and compound II are reacted by Paterson coupling reaction to prepare key intermediate IV:

[0014]

[0015] The above CC bond construction reactions have the following problems: 1) precious metal catalysts are used, which increases production costs; 2) metal-catalyzed coupling reactions require harsh reaction conditions and low yields.

[0016] In summary, the currently reported preparation methods of ibrutinib mainly have the following problems:

[0017] 1. The product yield of the Mitsunobu reaction is not high (<80%), and an equivalent amount of triphenylphosphine is required, which produces an equivalent amount of triphenylphosphine, which is difficult to remove;

[0018] 2. The Mitsunobu reaction itself has requirements for the acidity of the nucleophile. Basically, pKa <= 15, and less than 11 is the most ideal choice;

[0019] 3. The metal-catalyzed coupling reaction of the CC bond between fragments B and C uses a precious metal catalyst, which increases production costs and is prone to palladium metal residues.

[0020] In summary, the current preparation methods for ibrutinib have many shortcomings in terms of process safety, complicated operation, low yield, and high production cost. Therefore, researching and finding a reaction route suitable for industrial production with mild reaction conditions, simple operation process, high product yield, high purity, and low production cost is still a problem that needs to be solved. Summary of the invention

[0021] In order to solve the problems in the prior art that the product yield of Mitsunobu reaction in the synthesis process of ibrutinib is low, the acidity of nucleophilic reagents is required, and the Suzuki coupling reaction requires a precious metal catalyst, the present invention provides a new method for preparing ibrutinib; the method avoids the need for a precious metal catalyst in the Suzuki reaction, and at the same time, the Mitsunobu reaction uses a new catalyst without the generation of by-products, has a high reaction yield, a short cycle, a wider range of applicable conditions, and safer operation and production.

[0022] The specific technical solutions of the present invention are as follows:

[0023]

[0024] A method for preparing ibrutinib, comprising the following steps:

[0025] Preparation of Compound IV

[0026] The preparation method of the compound IV specifically comprises the following steps: adding compound II, compound III, a base and catalyst A to an organic solution A at room temperature, heating and stirring until the reaction is completed to obtain compound IV.

[0027] Preferably, the base is selected from potassium carbonate, cesium carbonate, sodium bicarbonate, potassium tert-butoxide, and sodium hydride, among which potassium carbonate is particularly preferred.

[0028] Preferably, the catalyst A is an amine catalyst selected from 2-methyl-N 1 ,N 3 - one of di-o-tolylbenzene-1,3-diamine, 3-methyldiphenylamine, 2-methylaniline, and 2,6-diaminotoluene, among which 2-methyl-N 1 ,N 3 -Di-o-tolylbenzene-1,3-diamine.

[0029] Preferably, the molar ratio of compound II, compound III, base and catalyst is 1:1.0-1.8:2.5-3.5:0.02-0.1, among which 1:1.2:3.0:0.05 is particularly preferred.

[0030] Preferably, the organic solvent A is selected from one of xylene, toluene, dimethyl sulfoxide, N-methylpyrrolidone or a combination thereof.

[0031] Preferably, the reaction temperature is 100°C to 130°C.

[0032] In a preferred embodiment, after the reaction is completed, post-treatment is required. The specific operation is as follows: after the detection reaction is completed, the organic solvent is evaporated, purified water and dichloromethane are added for slurrying, filtering, and drying to obtain compound IV.

[0033] Preparation of Compound I

[0034] The preparation of compound I specifically includes the following steps: adding compound IV, compound V and catalyst B into organic solvent B, controlling the temperature and refluxing the reaction, and obtaining ibrutinib after the reaction is completed.

[0035] Preferably, the catalyst B is a phosphine oxide, selected from one of (2-methoxybenzyl)diphenylphosphine oxide, (2-hydroxybenzyl)diphenylphosphine oxide, and (2-hydroxyphenyl)diphenylphosphine oxide, among which (2-methoxybenzyl)diphenylphosphine oxide is particularly preferred.

[0036] Preferably, the molar ratio of compound IV, compound V and catalyst B is 1:1.0-1.8:0.08-0.20, with 1:1.2:0.1 being particularly preferred.

[0037] Preferably, the organic solvent B is selected from one of xylene, toluene, N,N-dimethylformamide, dimethyl sulfoxide or a combination thereof.

[0038] In a preferred embodiment, after the reaction is completed, post-treatment is required, and the specific operation is as follows: after the detection reaction is completed, the organic solvent is evaporated and acetone-n-heptane is added at -5°C for recrystallization to obtain compound I.

[0039] Beneficial effects of the present invention:

[0040] 1. The present invention provides a new method for preparing ibrutinib, which uses an amine catalyst instead of precious metal palladium to catalyze the Suzuki coupling reaction, thereby solving the problems of low yield and expensive catalysts in traditional reactions of this type;

[0041] 2. The preparation process of the present invention uses phosphine oxide as a catalyst to catalyze the Mitsunobu reaction, avoids the use of an equivalent amount of triphenylphosphine in the Mitsunobu reaction, solves the harsh conditions of the reaction itself requiring the acidity of the nucleophilic reagent, is easy to operate, and the obtained target product has high purity. DETAILED DESCRIPTION

[0042] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention all fall within the scope of protection claimed by the present invention.

[0043] The structure of the product obtained by the present invention is characterized:

[0044] The present invention uses HPLC to determine the purity of the intermediate compound IV and Ibrutinib, and the chromatographic conditions are as follows:

[0045] Chromatographic column:Phenomenex Kinetex C 18 (150 mm × 4.6 mm, 5 μm);

[0046] Mobile phase: water-acetonitrile (volume ratio 1:1);

[0047] Detection wavelength: 260nm;

[0048] Flow rate: 1.0 mL min -1 ;

[0049] Column temperature: 30°C;

[0050] Injection volume: 20 μl

[0051] NMR characterization of compound IV:

[0052] 1 H NMR (400MHz, DMSO-d6): δ13.58(s,1H),8.22(s,1H),7.67(d,J=8.8Hz,2H),7.43(t,J=8.0Hz,2H),7.20-7.11(m,5H). 13 C NMR (100MHz, DMSO-d6): δ158.11,157.04,156.33,155.82,143.99,130.17,128.48,123.82,119.05,96.95.

[0053] The structure of ibrutinib was confirmed as follows:

[0054] HR-ESI-MS(m / z):441.2015[M+H] + ; 1H-NMR (400Mz, DMSO-d6): δ8.26(s,1H),7.64(d,J=8.0Hz,2H),7.44(t,J=7.5Hz,2H),7.19-7.09(m,5H),6.85(t,J =13.2,0.5H),6.69(t,J=15.6Hz,0.5H),6.16-6.06(m,1H),5.70(d,J=10.2Hz,0.5H),5.59(d,J=9.6Hz,0.5H),4.7 9-4.71(m,1H),4.56(d,J=10.8Hz,1H),4.19(brs,1H),4.06(d,J=13.2Hz,0.5H),3.71(t,J=10.8Hz,0.5H),3.26-3 .19(m,1H),3.04(t,J=12.0Hz,0.5H),2.30-2.23(m,1H),2.15-2.13(m,1H),1.95-1.92(m,1H),1.66-1.54(m,1H); 13 C NMR (100MHz, DMSO-d6): δ164.6,157.5,156.1,152.7,144.7,130.1,128.3,127.5,127.2,127.0 ,126.1,123.9,119.0,115.8,97.1,53.0,52.4,49.2,45.7,45.1,41.5,29.5,29.27,24.7,23.1.

[0055] Ibrutinib chiral detection method

[0056] Chromatographic column: AD-H column (4.6 mm × 250 mm, 5 μm);

[0057] Mobile phase: n-hexane-ethanol (35:65);

[0058] Detection wavelength: 258nm;

[0059] Flow rate: 0.5 ml / min;

[0060] Column temperature: 35°C;

[0061] Retention time: Compound I: 20.92 min, (S)-form: 28.29 min

[0062] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0063] Preparation of Compound IV

[0064] Example 1

[0065] In a 200 ml single-necked bottle, compound II (2.14 g, 10 mmol), 4-phenoxyphenylboronic acid (2.57 g, 12 mmol), 2-methyl-N 1 ,N 3 -Di-o-tolylbenzene-1,3-diamine (15 mg, 0.05 mmol), potassium carbonate (3.85 g, 30 mmol) and p-xylene (80 ml) were stirred at 110°C. After the reaction was completed, the solvent was removed under reduced pressure. 30 ml of purified water and 80 ml of dichloromethane were added to the reaction mixture for slurrying. The mixture was filtered and the solid was dried in vacuo to obtain intermediate V with a yield of 98.5% and a HPLC purity of 99.98%.

[0066] Example 2

[0067] In a 200 ml single-necked bottle, compound II (2.14 g, 10 mmol), 4-phenoxyphenylboronic acid (2.14 g, 10 mmol), 3-methyldiphenylamine (9.87 mg, 0.05 mmol), potassium carbonate (3.46 g, 25 mmol) and p-xylene (80 ml) were added, and the reaction was stirred at 110 ° C. After the reaction was completed, the solvent was removed under reduced pressure. 30 ml of purified water and 80 ml of dichloromethane were added to the reaction to slurry, filtered, and the solid was vacuum dried to obtain intermediate V with a yield of 94.1% and HPLC purity of 99.62%.

[0068] Example 3

[0069] In a 200 ml single-necked bottle, compound II (2.14 g, 10 mmol), 4-phenoxyphenylboronic acid (3.85 g, 18 mmol), 2-methylaniline (5.36 mg, 0.05 mmol), potassium carbonate (4.84 g, 35 mmol) and p-xylene (80 ml) were added, and the reaction was stirred at 110 ° C. After the reaction was completed, the solvent was removed under reduced pressure, 30 ml of purified water and 80 ml of dichloromethane were added to the reaction, and the mixture was slurried. The mixture was filtered and the solid was dried in vacuo to obtain intermediate V with a yield of 93.6% and an HPLC purity of 99.56%.

[0070] Example 4

[0071] In a 200 ml single-necked bottle, compound II (2.14 g, 10 mmol), 4-phenoxyphenylboronic acid (4.30 g, 20 mmol), 2,6-diaminotoluene (6.11 mg, 0.05 mmol), potassium carbonate (5.11 g, 37 mmol) and p-xylene (80 ml) were added, and the reaction was stirred at 110 ° C. After the reaction was completed, the solvent was removed under reduced pressure, 30 ml of purified water and 80 ml of dichloromethane were added to the reaction, and the mixture was slurried, filtered, and the solid was vacuum dried to obtain intermediate V with a yield of 88.7% and an HPLC purity of 98.86%.

[0072] Example 5

[0073] In a 200 ml single-necked bottle, compound II (2.14 g, 10 mmol), 4-phenoxyphenylboronic acid (2.57 g, 12 mmol), 2-methyl-N 1 ,N 3 -Di-o-tolylbenzene-1,3-diamine (6.05 mg, 0.02 mmol), cesium carbonate (9.77 g, 30 mmol) and m-xylene (80 ml) were stirred at 100°C. After the reaction was completed, the solvent was removed under reduced pressure. 30 ml of purified water and 80 ml of dichloromethane were added to the reaction mixture for slurrying. The mixture was filtered and the solid was dried under vacuum to obtain intermediate V with a yield of 93.3% and a HPLC purity of 99.60%.

[0074] Example 6

[0075] In a 200 ml single-necked bottle, compound II (2.14 g, 10 mmol), 4-phenoxyphenylboronic acid (2.57 g, 12 mmol), 2-methyl-N 1 ,N 3 -Di-o-tolylbenzene-1,3-diamine (30.24 mg, 0.1 mmol), sodium bicarbonate (2.52 g, 30 mmol) and dimethyl sulfoxide (80 ml) were stirred at 130°C for reaction. After the reaction was completed, the solvent was removed under reduced pressure. 30 ml of purified water and 80 ml of dichloromethane were added to the reaction mixture for slurrying. The mixture was filtered and the solid was dried under vacuum to obtain intermediate V with a yield of 94.2% and a HPLC purity of 99.52%.

[0076] Example 7

[0077] In a 200 ml single-necked bottle, compound II (2.14 g, 10 mmol), 4-phenoxyphenylboronic acid (2.57 g, 12 mmol), 2-methyl-N 1 ,N 3-Di-o-tolylbenzene-1,3-diamine (3.02 mg, 0.01 mmol), potassium tert-butoxide (3.37 g, 30 mmol) and toluene (80 ml) were stirred at 95 °C. After the reaction was completed, the solvent was removed under reduced pressure. 30 ml of purified water and 80 ml of dichloromethane were added to the reaction mixture for slurrying. The mixture was filtered and the solid was dried under vacuum to obtain intermediate V with a yield of 88.2% and a HPLC purity of 98.92%.

[0078] Example 8

[0079] In a 200 ml single-necked bottle, compound II (2.14 g, 10 mmol), 4-phenoxyphenylboronic acid (2.57 g, 12 mmol), 2-methyl-N 1 ,N 3 -Di-o-tolylbenzene-1,3-diamine (36.26 mg, 0.12 mmol), sodium hydride (0.72 g, 30 mmol) and N-methylpyrrolidone (80 ml) were stirred at 135°C. After the reaction was completed, the solvent was removed under reduced pressure. 30 ml of purified water and 80 ml of dichloromethane were added to the reaction mixture for slurrying. The mixture was filtered and the solid was dried in vacuo to obtain intermediate V with a yield of 86.6% and a HPLC purity of 98.63%.

[0080] Example 9

[0081] Compound IV (3.03 g, 10 mmol), compound V (1.86 g, 12 mmol), (2-hydroxybenzyl) diphenylphosphine oxide (0.31 g, 1.0 mmol) and 80 ml of p-xylene were added to a single-necked bottle and refluxed under controlled temperature. After the reaction was completed by TLC detection, the organic solvent was evaporated and the obtained solid was recrystallized at -5 ° C with 60 ml of isopropanol-n-heptane (2: 3, volume ratio) and dried to obtain ibrutinib with a yield of 97.3%, HLPC purity of 99.88%, and ee value of 99.97%.

[0082] Example 10

[0083] Compound IV (3.03 g, 10 mmol), compound V (1.55 g, 10 mmol), (2-hydroxybenzyl) diphenylphosphine oxide (0.31 g, 1.0 mmol) were added to a single-necked bottle and refluxed under controlled temperature. After the reaction was completed by TLC detection, the organic solvent was evaporated and the obtained solid was recrystallized at -5 ° C with 60 ml of isopropanol-n-heptane (2: 3, volume ratio) and dried to obtain ibrutinib with a yield of 93.2%, HLPC purity of 99.62%, and ee value of 99.84%.

[0084] Embodiment 11

[0085] Compound IV (3.03 g, 10 mmol), compound V (2.79 g, 18 mmol), (2-hydroxyphenyl) diphenylphosphine oxide (0.29 g, 1.0 mmol) and 80 ml of o-xylene were added to a single-necked bottle and refluxed under controlled temperature. After the reaction was completed by TLC detection, the organic solvent was evaporated and the obtained solid was recrystallized at -5 ° C with 60 ml of isopropanol-n-heptane (2: 3, volume ratio) and dried to obtain ibrutinib with a yield of 94.3%, HLPC purity of 99.51%, and ee value of 99.75%.

[0086] Example 12

[0087] Compound IV (3.03 g, 10 mmol), compound V (1.86 g, 12 mmol), (2-hydroxybenzyl) diphenylphosphine oxide (0.25 g, 0.8 mmol) were added to 80 ml of toluene in a single-necked bottle, and the reaction was refluxed under controlled temperature. After the reaction was completed by TLC detection, the organic solvent was evaporated and the obtained solid was recrystallized with 60 ml of isopropanol-n-heptane (2:3, volume ratio) at -5°C and dried to obtain ibrutinib with a yield of 94.5%, a HLPC purity of 99.66%, and an ee value of 99.89%.

[0088] Example 13

[0089] Compound IV (3.03 g, 10 mmol), compound V (1.86 g, 12 mmol), (2-hydroxybenzyl) diphenylphosphine oxide (0.62 g, 2.0 mmol) and 80 ml of N,N-dimethylformamide were added to a single-necked bottle and refluxed under controlled temperature. After the reaction was completed by TLC detection, the organic solvent was evaporated and the obtained solid was recrystallized with 60 ml of isopropanol-n-heptane (2:3, volume ratio) at -5°C and dried to obtain ibrutinib with a yield of 93.2%, HLPC purity of 99.45% and ee value of 99.66%.

[0090] Embodiment 14

[0091] Compound IV (3.03 g, 10 mmol), compound V (1.86 g, 12 mmol), (2-hydroxybenzyl) diphenylphosphine oxide (0.18 g, 0.6 mmol) were added to 80 ml of toluene in a single-necked bottle and refluxed under controlled temperature. After the reaction was completed by TLC detection, the organic solvent was evaporated and the obtained solid was recrystallized with 60 ml of isopropanol-n-heptane (2:3, volume ratio) at -5°C and dried to obtain ibrutinib with a yield of 88.5%, HLPC purity of 98.85%, and ee value of 97.66%.

[0092] Embodiment 15

[0093] Compound IV (3.03 g, 10 mmol), compound V (3.1 g, 20 mmol), (2-hydroxybenzyl) diphenylphosphine oxide (0.92 g, 3.0 mmol) and 80 ml of dimethyl sulfoxide were added to a single-necked bottle and refluxed under controlled temperature. After the reaction was completed by TLC detection, the organic solvent was evaporated and the obtained solid was recrystallized at -5 ° C with 60 ml of isopropanol-n-heptane (2: 3, volume ratio) and dried to obtain ibrutinib with a yield of 82.3%, HLPC purity of 97.44%, and ee value of 96.35%.

[0094] Comparative Example

[0095] Weigh 3-bromo-1H-pyrazolo[3,4-d]pyrimidine-4-amine, 4-phenoxyphenylboronic acid (1.5 g, 7.01 mmol), Pd(PPh3)4 (540 mg, 0.47 mmol), K3PO4·3H2O (2.49 g, 9.34 mmol), add to a 250 ml two-necked flask, add 50 ml of solvent (1,4-dioxane: water = 4:1) to dissolve, remove oxygen from the solution by ultrasonication, replace the air in the device with nitrogen, heat under reflux at 135 ° C, react for 30 hours, and detect by TLC that the reaction is basically complete. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure to obtain a yellow solid. Silica gel column chromatography (dichloromethane:methanol 100:1) was performed to obtain compound 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid with a yield of 72.3% and a HPLC purity of 97.32%.

[0096] The compound 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.65 mmol) was weighed and placed in a 100 ml eggplant-shaped bottle, PPh3 (1.3 g, 4.95 mmol) and (S)-1-Boc-3-hydroxypyrazol (0.5 g, 2.47 mmol) were added, and stirred in an ice bath for 10 min. min, and then DIAD (1.0 g, 4.95 mmol) was added dropwise until the solution was clear. TLC detection showed that the reaction was complete, and the solvent was evaporated and the reaction was performed by silica gel column chromatography (dichloromethane:methanol=300:1-100:1). (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester was obtained as a white solid with a yield of 47.5%, a HPLC purity of 97.22%, and an ee value of 96.25%.

Claims

1. A method for preparing ibrutinib, characterized in that: The preparation method comprises the following steps: (1) Add compound II, compound III, base and catalyst A to organic solution A at room temperature, heat and stir until the reaction is complete to obtain compound IV; (2) adding compound IV, compound V and catalyst B into organic solvent B, controlling the temperature and subjecting the mixture to reflux reaction, and completing the reaction to obtain ibrutinib; The synthetic route is as follows: ； Step (1) The catalyst A is an amine catalyst selected from 2-methyl-N 1 ,N 3 - one of di-o-tolylbenzene-1,3-diamine, 3-methyldiphenylamine, 2-methylaniline, and 2,6-diaminotoluene; The catalyst B in step (2) is a phosphine oxide, selected from one of (2-methoxybenzyl)diphenylphosphine oxide, (2-hydroxybenzyl)diphenylphosphine oxide and (2-hydroxyphenyl)diphenylphosphine oxide.

2. The preparation method according to claim 1, characterized in that: The base in step (1) is selected from potassium carbonate, cesium carbonate, sodium bicarbonate, potassium tert-butoxide, and sodium hydride.

3. The preparation method according to claim 1, characterized in that: In step (1), the feed ratio of compound II, compound III, base and catalyst is 1:1.0~1.8:2.5~3.5:0.02~0.

1.

4. The preparation method according to claim 1, characterized in that: The organic solvent A in step (1) is selected from xylene, toluene, dimethyl sulfoxide, N -Methyl pyrrolidone or a combination thereof.

5. The preparation method according to claim 1, characterized in that: The reaction temperature in step (1) is 100°C to 130°C.

6. The preparation method according to claim 1, characterized in that: In step (2), the molar ratio of compound IV, compound V and compound VI is 1:1.0~1.8:0.08~0.

20.

7. The preparation method according to claim 1, characterized in that: In step (2), the organic solvent B is selected from one of xylene, toluene, N,N-dimethylformamide, dimethyl sulfoxide or a combination thereof.

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