A synthetic method for the BTK inhibitor pirobrutinib

Abstract

This invention relates to a method for synthesizing the BTK inhibitor pyrobrutinib. Compared to common synthetic routes in the literature, which typically involve eight or more steps, this route is shortened to five steps. This invention directly utilizes ammonia borane to convert the ester group to an amide, shortening the reaction by one to two steps. The subsequent substitution reaction of the amide effectively improves the yield. In the final step, instead of using methanesulfonic acid to convert the cyano group to an amide as commonly found in the literature, this invention uses concentrated sulfuric acid, increasing the yield from approximately 80% in existing techniques to 89.5% in this invention. Furthermore, the purification of the five-step reaction is mostly achieved through recrystallization, reducing purification difficulty and offering good economic efficiency and operability.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to a method for synthesizing the BTK inhibitor pyrobrutinib. Background Technology

[0002] Pirtobrutinib (also known as pyritobactinib, research code: LOXO-305, trade name: Jaypirca) is a small molecule BTK inhibitor. On January 27, 2023, Eli Lilly announced accelerated approval from the FDA for its next-generation BTK inhibitor, pyritobactinib, for adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least two lines of systemic therapy (including BTK inhibitors). Pirtobrutinib is also the first and, to date, the only non-covalent (reversible) BTK inhibitor approved by the FDA. Previously marketed small molecule BTK inhibitors were all covalent BTK inhibitors, which mainly exert their inhibitory effect by forming a covalent bond with cysteine ​​residues at the BTK active site. However, covalent binding is prone to resistance mutations. Pirtobrutinib can re-establish BTK inhibition in MCL patients who have previously been treated with covalent BTK inhibitors (ibrutinib, acalabrutinib, or zanubrutinib).

[0003] The chemical structure of pitobrutinib is shown in Formula I:

[0004]

[0005] However, the current synthetic methods for pitobrutinib still need improvement. Summary of the Invention

[0006] This invention aims to at least partially solve one of the technical problems in related technologies. To this end, one object of this invention is to provide a method for synthesizing pyrobrutinib, a compound of Formula I. Compared to existing technologies, this route is shorter, consisting of five reaction steps. This invention directly utilizes ammonia borane to convert the ester group to an amide, which can shorten the reaction by one or two steps. The subsequent substitution reaction of the amide can effectively improve the yield. In the final step, compared to the general use of methanesulfonic acid to convert the cyano group to an amide in the literature, this invention replaces the acid with concentrated sulfuric acid, increasing the reaction yield from approximately 80% in existing technologies to 89.5% in this invention.

[0007] In one aspect of the invention, a method for synthesizing pyrobrutinib, a compound of formula I, is provided. According to an embodiment of the invention, the synthesis method includes:

[0008] (1) Contact the compound shown in Formula 1, iodomethane, and acid-binding agent A to obtain the compound shown in Formula 2;

[0009] (2) Contact the compound shown in Formula 2 with ammonia borane (NH3BH3) and sodium bis(trimethylsilyl)amino to obtain the compound shown in Formula 3;

[0010] (3) Contact the compound shown in Formula 3, pentamethyldiethylenetriamine (PMDETA), copper bromide, organic base B, and the compound shown in Formula 7 to obtain the compound shown in Formula 4;

[0011] (4) Contact the compound shown in Formula 4, the compound shown in Formula 5, Pd(dppf)Cl2, and inorganic salt C to obtain the compound shown in Formula 6.

[0012] (5) Contact the compound shown in Formula 5 with concentrated sulfuric acid to obtain the compound shown in Formula I, pitobrutinib.

[0013]

[0014] The inventors have discovered that by using the synthetic method described in this invention, with the compound shown in Formula 1 and iodomethane as starting materials, the target product pyrobrutinib can be successfully synthesized and prepared through a total of 5 reaction steps.

[0015] The term "contact" as used herein should be interpreted broadly, encompassing any method that enables at least two reactants to undergo a chemical reaction, such as mixing two reactants under appropriate conditions. If necessary, reactants requiring contact can be mixed under stirring; therefore, the type of stirring is not particularly limited, such as mechanical stirring, i.e., stirring under mechanical force.

[0016] In this document, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of this invention, "a plurality of" means two or more, unless otherwise explicitly specified.

[0017] According to embodiments of the present invention, the methods for preparing the compounds shown in Formula 2, Formula 3, Formula 4, Formula 6, and Formula 1 may further have at least one of the following additional technical features:

[0018] According to embodiments of the present invention, the chemical reaction described herein can be carried out according to any method known in the art. The source of the starting materials for the compounds shown in Formula 2, Formula 3, Formula 4, Formula 6, and Formula 1 is not particularly limited; they can be prepared by any known method or be commercially available. For example, the CAS number of the compound shown in Formula 1 is 345-16-4, and the CAS number of the compound shown in Formula 5 is 2764851-21-8.

[0019] According to an embodiment of the present invention, in step (1), the contact mode of the compound shown in Formula 1, iodomethane, and acid-binding agent A is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in Formula 1, iodomethane, and acid-binding agent A can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 2 using this method can be further improved.

[0020] According to an embodiment of the present invention, step (1) includes the following steps: sealing the reaction system containing the compound shown in Formula 1, iodomethane, acid-binding agent A, and DMF in a tube, reacting at 100°C for 10 hours, cooling the reaction system after the reaction, performing post-treatment, quenching with saturated ammonium chloride solution, diluting with ethyl acetate, washing the organic phase sequentially with water and saturated brine, drying with anhydrous sodium sulfate, and distilling the solvent off the filtrate under reduced pressure to obtain the compound shown in Formula 2. Therefore, the efficiency of the contact reaction between the compound shown in Formula 1, iodomethane, and acid-binding agent A can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 2 using this method can be further improved.

[0021] According to an embodiment of the present invention, in step (1), the molar ratio of the compound shown in Formula 1, iodomethane, and acid-binding agent A is 1:4:(4.0 to 5.0), preferably 1:4:4.5. This further improves the efficiency of preparing the compound shown in Formula 2 using this method.

[0022] According to an embodiment of the present invention, in step (1), the acid-binding agent A is at least one selected from potassium carbonate, N,N-diisopropylethylamine, N,N-diisopropylethylenediamine or triethylamine.

[0023] According to a specific embodiment of the present invention, step (1) includes the following steps: sealing a reaction system containing the compound shown in Formula 1 (1.56 g, 0.01 mol), iodomethane (5.68 g, 0.04 mol), potassium carbonate (6.22 g, 0.045 mol), and DMF (50 mL), and reacting at 100 °C for 10 hours. After the reaction is completed, the reaction system is cooled, quenched with saturated ammonium chloride solution (10 mL), diluted with ethyl acetate (50 mL), and the organic phase is washed successively with water (50 mL) and saturated brine (50 mL), dried with anhydrous sodium sulfate, and the solvent is evaporated from the filtrate under reduced pressure to obtain the compound shown in Formula 2, with a yield of 1.810 g and a yield of 98.3%.

[0024] According to an embodiment of the present invention, in step (2), the contact mode between the compound of Formula 2 and ammonia borane (NH3BH3) and sodium bis(trimethylsilyl)amino (NaHMDS) is not particularly limited. Therefore, the efficiency of the contact reaction between the compound of Formula 2 and NH3BH3 and sodium bis(trimethylsilyl)amino can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound of Formula 3 using this method can be further improved.

[0025] According to an embodiment of the present invention, step (2) includes the following steps: The compound shown in Formula 2, NH3BH3, sodium bis(trimethylsilyl)amino, and THF solution are added sequentially to a Schlenk tube. The Schlenk tube is sealed, and the reaction is stirred at 25°C under a nitrogen atmosphere for 14–18 minutes. After the reaction is complete, water is added to quench the reaction, and the mixture is extracted with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and directly filtered to obtain the compound shown in Formula 3. This improves the efficiency of the reaction between the compound shown in Formula 2 and NH3BH3 and sodium bis(trimethylsilyl)amino, accelerates the reaction rate, and further enhances the efficiency of preparing the compound shown in Formula 3 using this method.

[0026] According to an embodiment of the present invention, in step (2), the molar ratio of the compound shown in Formula 2 to NH3BH3 and sodium bis(trimethylsilyl)amino is 1:(1.1-1.2):(1.4-1.6), preferably 1:1.15:1.5. This further improves the efficiency of preparing the compound shown in Formula 3 using this method.

[0027] According to an embodiment of the present invention, in step (2), the reaction is preferably stirred for 15 minutes.

[0028] According to a specific embodiment of the present invention, step (2) includes the following steps: 1.84 g (0.01 mol) of the compound shown in Formula 2, NH3BH3 (0.355 g (0.0115 mol), sodium bis(trimethylsilyl)amino (2.75 g (0.015 mol), and THF solution (20 mL) are added sequentially to a 50 mL Schlenk tube. The Schlenk tube is sealed, and the reaction is stirred at 25 °C for 15 minutes under a nitrogen atmosphere. After the reaction is completed, water (10 mL) is added to quench the reaction, and the mixture is extracted with ethyl acetate (20 mL × 2). The organic phases are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and directly filtered to separate the solid of the compound shown in Formula 3, with a yield of 1.52 g and a yield of 89.8%.

[0029] According to an embodiment of the present invention, in step (3), the contact mode of the compound shown in Formula 3, pentamethyldiethylenetriamine (PMDETA), copper bromide, organic base B, and the compound shown in Formula 7 is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in Formula 3, pentamethyldiethylenetriamine, copper bromide, organic base B, and the compound shown in Formula 7 can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 4 using this method can be further improved.

[0030] According to an embodiment of the present invention, step (3) includes the following steps: at room temperature, toluene and pentamethyldiethylenetriamine are added to a flask containing copper bromide, organic base B, and the compound shown in Formula 3. Under N2 protection, a mixed solution of the compound shown in Formula 7 and toluene is slowly added dropwise over 30 minutes. After the addition is complete, the reaction mixture is stirred at room temperature for 8-9 hours. After the reaction is complete, ethyl acetate is added for dilution. The organic phase is washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to remove the solvent. The concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of (8-12):1 to obtain the compound shown in Formula 4. Therefore, the efficiency of the contact reaction between the compound shown in Formula 3, pentamethyldiethylenetriamine, copper bromide, potassium tert-butoxide, and the compound shown in Formula 7 can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 4 using this method can be further improved.

[0031] According to an embodiment of the present invention, in step (3), the molar ratio of the compound shown in Formula 3, pentamethyldiethylenetriamine, copper bromide, organic base B, and the compound shown in Formula 7 is 1:(0.04~0.05):(0.04~0.05):(1.1~1.2):(1.0~1.2), preferably 1:0.045:0.045:1.15:1.1. This further improves the efficiency of preparing the compound shown in Formula 4 using this method.

[0032] According to an embodiment of the present invention, in step (3), the organic base B is at least one selected from potassium tert-butoxide, sodium tert-butoxide, or butyllithium.

[0033] According to an embodiment of the present invention, in step (3), the reaction mixture is preferably stirred at room temperature for 8.5 hours.

[0034] According to an embodiment of the present invention, in step (3), the volume ratio of the petroleum ether / ethyl acetate mixed solvent is preferably 10:1.

[0035] According to a specific embodiment of the present invention, step (3) includes the following steps: at room temperature, toluene (200 mL) and pentamethyldiethylenetriamine (7.80 g, 0.045 mol) are added to a flask containing copper bromide (10.05 g, 0.045 mol), potassium tert-butoxide (12.90 g, 0.115 mol), and the compound shown in Formula 3 (16.92 g, 0.1 mol). Under N2 protection, the compound shown in Formula 7 (22.60 g, 0.11 mol) is slowly added dropwise. A mixed solution of toluene (80 mL) was added dropwise over 30 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 8.5 hours. After the reaction was complete, ethyl acetate (200 mL) was added to dilute the mixture. The organic phase was washed successively with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixture at a volume ratio of 10:1 to obtain the compound shown in Formula 4, with a yield of 22.59 g and a yield of 76.9%.

[0036] According to an embodiment of the present invention, in step (4), the contact method of the compound shown in Formula 4, the compound shown in Formula 5, Pd(dppf)Cl2, and inorganic salt C is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in Formula 4, the compound shown in Formula 5, Pd(dppf)Cl2, and inorganic salt C can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 6 using this method can be further improved.

[0037] According to an embodiment of the present invention, step (4) includes the following steps: Under N2 protection, the compound shown in Formula 4, the compound shown in Formula 5, Pd(dppf)Cl2, and inorganic salt C solution are added to a flask containing DMF. The reaction mixture is heated to 84°C–92°C and reacted for 11.5–13 hours. After the reaction is complete, the reaction solution is cooled to room temperature. The reaction solution is filtered with diatomaceous earth and washed with water. The aqueous phase is extracted with ethyl acetate. The organic phases are combined and washed with saturated brine. The mixture is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of (2–6):1 to obtain the compound shown in Formula 6. Therefore, the efficiency of the contact reaction between the compound shown in Formula 4, the compound shown in Formula 5, Pd(dppf)Cl2, and inorganic salt C can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 6 using this method can be further improved.

[0038] According to an embodiment of the present invention, in step (4), the molar ratio of the compound shown in Formula 4, the compound shown in Formula 5, Pd(dppf)Cl2, and inorganic salt C is 1:(1.0~1.2):(0.1~0.2):15, preferably 1:1.1:0.15:15. This further improves the efficiency of preparing the compound shown in Formula 6 using this method.

[0039] According to an embodiment of the present invention, in step (4), the inorganic salt C is at least one selected from sodium bicarbonate or potassium bicarbonate.

[0040] According to an embodiment of the present invention, in step (4), it is preferable to heat the reaction mixture to 86°C to 90°C and react for 12 hours.

[0041] According to an embodiment of the present invention, in step (4), the volume ratio of the petroleum ether / ethyl acetate mixed solvent is preferably 4:1.

[0042] According to a specific embodiment of the present invention, step (4) includes the following steps: under N2 protection, the compound shown in Formula 4 (29.4 g, 0.1 mol), the compound shown in Formula 5 (27.3 g, 0.11 mol), Pd(dppf)Cl2 (10.98 g, 0.015 mol), and sodium bicarbonate solution (containing 126 g (1.5 mol) of sodium bicarbonate, prepared as a 1 M solution) are added to a flask containing DMF (300 mL), and the reaction mixture is stirred. The compound was heated to 86℃~90℃ and reacted for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth and washed with water (500 mL). The aqueous phase was extracted with ethyl acetate (500 mL × 2). The organic phases were combined and washed with saturated brine (500 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixture at a volume ratio of 4:1 to obtain the compound shown in Formula 6, with a yield of 35.71 g and a yield of 77.4%.

[0043] According to an embodiment of the present invention, in step (5), the contact mode between the compound of Formula 6 and concentrated sulfuric acid is not particularly limited. Therefore, the efficiency of the reaction between the compound of Formula 6 and concentrated sulfuric acid can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound of Formula I using this method can be further increased.

[0044] According to an embodiment of the present invention, step (5) includes the following steps: adding the compound shown in Formula 6 and toluene to a reaction flask, controlling the temperature below 20°C, slowly adding concentrated sulfuric acid dropwise, and after the addition is complete, heating the mixture to 60°C, stirring vigorously for 3 hours, cooling the reaction solution, performing post-treatment, slowly adding ice-cold saturated NaHCO3 solution, and then adding ethyl acetate, DCM and THF:EtOAc (v / v = 1:1) for extraction, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a solid, recrystallizing the solid with a mixed solvent of ethyl acetate and hexane, filtering, drying the filter cake to obtain the compound pyrobrutinib shown in Formula I. Therefore, the efficiency of the reaction between the compound shown in Formula 6 and concentrated sulfuric acid can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound pyrobrutinib shown in Formula I using this method can be further improved.

[0045] According to an embodiment of the present invention, in step (5), the molar ratio of the compound shown in Formula 6 to concentrated sulfuric acid is 1:(8-10), preferably 1:9. This further improves the efficiency of preparing the compound shown in Formula I using this method.

[0046] According to an embodiment of the present invention, in step (5), the volume ratio of ethyl acetate to hexane in the mixed solvent of ethyl acetate and hexane is (5-8):1, preferably 6:1.

[0047] According to a specific embodiment of the present invention, step (5) includes the following steps: adding the compound shown in Formula 6 (46.14 g, 0.1 mol) and toluene (500 ml) to a reaction flask, controlling the temperature below 20°C, slowly adding concentrated sulfuric acid (88.2 g, 0.9 mol), after the addition is complete, heating the mixture to 60°C, stirring vigorously for 3 hours, and after the reaction solution cools, slowly adding a saturated NaHCO3 solution (600 ml) in ice, and then adding ethyl acetate (2 × 600 mL) respectively. Extracted with DCM (2 × 600 mL) and THF:EtOAc (v / v = 1:1, 2 × 600 mL), the organic phases were combined and washed with saturated brine (600 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a solid, which was recrystallized from the solid with a mixed solvent of ethyl acetate and hexane (volume ratio of ethyl acetate to hexane 6:1), filtered, and the filter cake was dried to obtain the compound pyrobrutinib shown in Formula I, with a yield of 42.91 g, a yield of 89.5%, and an HPLC purity of 99.6%.

[0048] According to a specific embodiment of the present invention, the synthetic route of the compound pyrobrutinib shown in Formula I can be as follows:

[0049]

[0050] Compared with existing technologies, the method for synthesizing the BTK small molecule inhibitor pyrobrutinib described in this invention has at least the following beneficial effects:

[0051] 1. Innovation in reaction steps: In step (1), the compound shown in formula 1 undergoes a substitution reaction with iodomethane to obtain the compound shown in formula 2; in step (2), the compound shown in formula 2 reacts with ammonia borane (NH3BH3) to generate an amide, obtaining the compound shown in formula 3; in step (3), the compound shown in formula 3 undergoes an alkylation reaction with a haloalkane under alkaline conditions to generate the compound shown in formula 4; in step (4), the compound shown in formula 4 and the compound shown in formula 5 react under a Pd catalyst. Under chemical agent conditions The Suzuki coupling reaction yields the compound shown in Formula 6; in step (5), the compound shown in Formula 6... The cyano group in the product reacts under strong acid (H2SO4) conditions to yield the product pyrobrutinib. Compared to common synthetic routes in the literature, which mostly involve more than 8 steps, this route shortens the steps, reducing the reaction from 8 steps in the prior art to 5 steps in this invention.

[0052] 2. Technological Innovation: The starting material chosen in this invention is 5-fluoro-2-hydroxybenzoic acid, which is about 20% cheaper than 5-fluoro-2-methoxybenzoic acid, resulting in good economic benefits. Compared to the conversion of methyl 5-fluoro-2-methoxybenzoate to amides, which requires first converting it to the corresponding benzoic acid and then reacting it with an amino group, this invention directly uses ammonia borane (NH3BH3) to convert the ester group to the amide, shortening the reaction by one or two steps. Subsequent substitution reactions of the amide in this invention can effectively improve the yield. In the final step, compared to the common use of methanesulfonic acid to convert the cyano group to the amide in the literature, this invention replaces the acid with concentrated sulfuric acid, increasing the reaction yield from approximately 80% in existing technologies to 89.5% in this invention. Furthermore, the purification of most of the five-step reaction is achieved through recrystallization, avoiding column chromatography purification, reducing purification difficulty, and demonstrating good economic efficiency and operability.

[0053] 3. In summary, this route has the advantages of low raw material cost, high yield, and simple purification, making it easy to industrialize and very suitable for large-scale industrial production. Detailed Implementation

[0054] The embodiments of the present invention are described in detail below. These embodiments are exemplary and are only used to explain the present invention, and should not be construed as limiting the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products.

[0055] Synthesis of the compound shown in Formula 2 in Example 1

[0056] The reaction system containing the compound shown in Formula 1 (1.56 g, 0.01 mol), iodomethane (5.68 g, 0.04 mol), potassium carbonate (6.22 g, 0.045 mol), and DMF (50 mL) was sealed in a tube and reacted at 100 °C for 10 hours. After the reaction was completed, the reaction system was cooled and quenched with saturated ammonium chloride solution (10 mL). Ethyl acetate (50 mL) was added for dilution. The organic phase was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated from the filtrate under reduced pressure to obtain the compound shown in Formula 2. The yield was 1.810 g, with a yield of 98.3%.

[0057] LC-MS (APCI): m / z = 185.2(M+1) + .

[0058] 1H-NMR (300MHz, CDCl3): δ7.5 (m, 1H), 7.17 (m, 1H), 6.91 (dd, 1H), 3.88 (d, 6H).

[0059] Example 2: Synthesis of the compound shown in Formula 2

[0060] The reaction system containing the compound shown in Formula 1 (1.56 g, 0.01 mol), iodomethane (5.68 g, 0.04 mol), potassium carbonate (5.53 g, 0.04 mol), and DMF (50 mL) was sealed in a tube and reacted at 100 °C for 10 hours. After the reaction was completed, the reaction system was cooled and quenched with saturated ammonium chloride solution (10 mL). Ethyl acetate (50 mL) was added for dilution. The organic phase was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated from the filtrate under reduced pressure to obtain the compound shown in Formula 2. The yield was 1.805 g, with a yield of 98.0%.

[0061] Example 3 Synthesis of the compound shown in Formula 2

[0062] The reaction system containing the compound shown in Formula 1 (1.56 g, 0.01 mol), iodomethane (5.68 g, 0.04 mol), potassium carbonate (6.91 g, 0.05 mol), and DMF (50 mL) was sealed in a tube and reacted at 100 °C for 10 hours. After the reaction was completed, the reaction system was cooled and quenched with saturated ammonium chloride solution (10 mL). Ethyl acetate (50 mL) was added for dilution. The organic phase was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated from the filtrate under reduced pressure to obtain the compound shown in Formula 2. The yield was 1.790 g, with a yield of 97.2%.

[0063] Example 4: Synthesis of the compound shown in Formula 2

[0064] Experiments in which acid-binding agent A was replaced with N,N-diisopropylethylamine:

[0065] The reaction system containing the compound shown in Formula 1 (1.56 g, 0.01 mol), iodomethane (5.68 g, 0.04 mol), N,N-diisopropylethylamine (5.82 g, 0.045 mol), and DMF (50 mL) was sealed in a tube and reacted at 100 °C for 10 hours. After the reaction was completed, the reaction system was cooled and quenched with saturated ammonium chloride solution (10 mL). Ethyl acetate (50 mL) was added for dilution. The organic phase was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated from the filtrate under reduced pressure to obtain the compound shown in Formula 2. The yield was 1.801 g, with a yield of 97.8%.

[0066] Example 5: Synthesis of the compound shown in Formula 2

[0067] Experiments involving replacing acid-binding agent A with N,N-diisopropylethylenediamine:

[0068] The reaction system containing the compound shown in Formula 1 (1.56 g, 0.01 mol), iodomethane (5.68 g, 0.04 mol), N,N-diisopropylethylenediamine (6.49 g, 0.045 mol), and DMF (50 mL) was sealed in a tube and reacted at 100 °C for 10 hours. After the reaction was completed, the reaction system was cooled and quenched with saturated ammonium chloride solution (10 mL). Ethyl acetate (50 mL) was added for dilution. The organic phase was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated from the filtrate under reduced pressure to obtain the compound shown in Formula 2. The yield was 1.796 g, with a yield of 97.5%.

[0069] Example 6 Synthesis of the compound shown in Formula 2

[0070] Experiment where acid-binding agent A is replaced with triethylamine:

[0071] The reaction system containing the compound shown in Formula 1 (1.56 g, 0.01 mol), iodomethane (5.68 g, 0.04 mol), triethylamine (6.49 g, 0.045 mol), and DMF (50 mL) was sealed in a tube and reacted at 100 °C for 10 hours. After the reaction was completed, the reaction system was cooled and quenched with saturated ammonium chloride solution (10 mL). Ethyl acetate (50 mL) was added for dilution. The organic phase was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated from the filtrate under reduced pressure to obtain the compound shown in Formula 2. The yield was 1.784 g, with a yield of 96.9%.

[0072] Comparative Example 1: Synthesis of the compound shown in Formula 2

[0073] The reaction system containing the compound shown in Formula 1 (1.56 g, 0.01 mol), iodomethane (5.68 g, 0.04 mol), potassium carbonate (7.60 g, 0.055 mol), and DMF (50 mL) was sealed in a tube and reacted at 95 °C for 12 hours. After the reaction was completed, the reaction system was cooled and quenched with saturated ammonium chloride solution (10 mL). The mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed successively with water (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated from the filtrate under reduced pressure to obtain the compound shown in Formula 2. The yield was 1.715 g, with a yield of 93.1%.

[0074] Example 7 Synthesis of the compound shown in Formula 3

[0075] To a 50 mL Schlenk tube, the compound shown in Formula 2 (1.84 g, 0.01 mol), NH3BH3 (0.355 g, 0.0115 mol), sodium bis(trimethylsilyl)amino(NaHMDS) (2.75 g, 0.015 mol), and THF solution (20 mL) were added sequentially. The Schlenk tube was sealed, and the reaction was stirred at 25 °C for 15 minutes under a nitrogen atmosphere. After the reaction was completed, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and directly filtered to separate the solid of the compound shown in Formula 3. The yield was 1.52 g, with a yield of 89.8%.

[0076] LC-MS (APCI): m / z = 170.2(M+1) + .

[0077] Example 8: Synthesis of the compound shown in Formula 3

[0078] To a 50 mL Schlenk tube, the compound shown in Formula 2 (1.84 g, 0.01 mol), NH3BH3 (0.340 g, 0.011 mol), sodium bis(trimethylsilyl)amino(NaHMDS) (2.57 g, 0.014 mol), and THF solution (20 mL) were added sequentially. The Schlenk tube was sealed, and the reaction was stirred at 25 °C for 14 minutes under a nitrogen atmosphere. After the reaction was completed, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and directly filtered to separate the solid of the compound shown in Formula 3. The yield was 1.48 g, with a yield of 87.6%.

[0079] Example 9: Synthesis of the compound shown in Formula 3

[0080] To a 50 mL Schlenk tube, the compound shown in Formula 2 (1.84 g, 0.01 mol), NH3BH3 (0.370 g, 0.012 mol), sodium bis(trimethylsilyl)amino(NaHMDS) (2.93 g, 0.016 mol), and THF solution (20 mL) were added sequentially. The Schlenk tube was sealed, and the reaction was stirred at 25 °C for 18 minutes under a nitrogen atmosphere. After the reaction was completed, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and directly filtered to separate the solid of the compound shown in Formula 3. The yield was 1.50 g, with a yield of 88.7%.

[0081] Comparative Example 2: Synthesis of the compound shown in Formula 3

[0082] To a 50 mL Schlenk tube, the compound shown in Formula 2 (1.84 g, 0.01 mol), NH3BH3 (0.309 g, 0.01 mol), sodium bis(trimethylsilyl)amino(NaHMDS) (2.38 g, 0.013 mol), and THF solution (20 mL) were added sequentially. The Schlenk tube was sealed, and the reaction was stirred at 25 °C for 15 minutes under a nitrogen atmosphere. After the reaction was completed, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and directly filtered to separate the solid of the compound shown in Formula 3. The yield was 1.43 g, with a yield of 84.5%.

[0083] Comparative Example 3: Synthesis of the compound shown in Formula 3

[0084] To a 50 mL Schlenk tube, the compound shown in Formula 2 (1.84 g, 0.01 mol), NH3BH3 (0.401 g, 0.013 mol), sodium bis(trimethylsilyl)amino(NaHMDS) (3.30 g, 0.018 mol), and THF solution (20 mL) were added sequentially. The Schlenk tube was sealed, and the reaction was stirred at 25 °C for 16 minutes under a nitrogen atmosphere. After the reaction was completed, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and directly filtered to separate the solid of the compound shown in Formula 3. The yield was 1.44 g, with a yield of 85.1%.

[0085] Synthesis of the compound shown in Formula 4 in Example 10

[0086] At room temperature, toluene (200 mL) and pentamethyldiethylenetriamine (7.80 g, 0.045 mol) were added to a flask containing copper bromide (10.05 g, 0.045 mol), potassium tert-butoxide (12.90 g, 0.115 mol), and the compound shown in Formula 3 (16.92 g, 0.1 mol). Under N2 protection, a mixed solution of the compound shown in Formula 7 (22.60 g, 0.11 mol) and toluene (80 mL) was slowly added dropwise. The reaction mixture was added dropwise over 30 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 8.5 hours. After the reaction was complete, ethyl acetate (200 mL) was added to dilute the mixture. The organic phase was washed successively with water (200 mL) and saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by silica gel column chromatography with a 10:1 (v / v) mixture of petroleum ether and ethyl acetate to give the compound shown in Formula 4, with a yield of 22.59 g and a yield of 76.9%.

[0087] LC-MS (APCI): m / z = 294.2(M+1)+ .

[0088] Example 11 Synthesis of the compound shown in Formula 4

[0089] At room temperature, toluene (200 mL) and pentamethyldiethylenetriamine (6.93 g, 0.04 mol) were added to a flask containing copper bromide (8.93 g, 0.04 mol), potassium tert-butoxide (12.34 g, 0.11 mol), and the compound shown in Formula 3 (16.92 g, 0.1 mol). Under N2 protection, a mixed solution of the compound shown in Formula 7 (20.55 g, 0.10 mol) and toluene (80 mL) was slowly added dropwise over 30 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 8 hours. After the reaction was complete, ethyl acetate (200 mL) was added to dilute the mixture. The organic phase was washed successively with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixture at a volume ratio of 8:1 to obtain the compound shown in Formula 4, with a yield of 21.76 g and a yield of 74.1%.

[0090] Synthesis of the compound shown in Formula 4 in Example 12

[0091] At room temperature, toluene (240 mL) and pentamethyldiethylenetriamine (8.67 g, 0.05 mol) were added to a flask containing copper bromide (11.17 g, 0.05 mol), potassium tert-butoxide (13.47 g, 0.12 mol), and the compound shown in Formula 3 (16.92 g, 0.1 mol). Under N2 protection, a mixed solution of the compound shown in Formula 7 (24.66 g, 0.12 mol) and toluene (100 mL) was slowly added dropwise over 30 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 9 hours. After the reaction was complete, ethyl acetate (240 mL) was added to dilute the mixture. The organic phase was washed successively with water (240 mL) and saturated brine (240 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixture at a volume ratio of 12:1 to obtain the compound shown in Formula 4, with a yield of 22.12 g and a yield of 75.3%.

[0092] Synthesis of the compound shown in Formula 4 in Example 13

[0093] At room temperature, toluene (200 mL) and pentamethyldiethylenetriamine (7.80 g, 0.045 mol) were added to a flask containing copper bromide (10.05 g, 0.045 mol), sodium tert-butoxide (11.0 g, 0.114 mol), and the compound shown in Formula 3 (16.92 g, 0.1 mol). Under N2 protection, a mixed solution of the compound shown in Formula 7 (22.60 g, 0.11 mol) and toluene (80 mL) was slowly added dropwise. The reaction mixture was added dropwise over 30 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 8.5 hours. After the reaction was complete, ethyl acetate (200 mL) was added to dilute the mixture. The organic phase was washed successively with water (200 mL) and saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixture at a volume ratio of 10:1 to obtain the compound shown in Formula 4, with a yield of 21.91 g and a yield of 74.6%.

[0094] Example 14 Synthesis of the compound shown in Formula 4

[0095] At room temperature, toluene (200 mL) and pentamethyldiethylenetriamine (7.80 g, 0.045 mol) were added to a flask containing copper bromide (10.05 g, 0.045 mol), butyllithium (7.40 g, 0.116 mol), and the compound shown in Formula 3 (16.92 g, 0.1 mol). Under N2 protection, a mixed solution of the compound shown in Formula 7 (22.60 g, 0.11 mol) and toluene (80 mL) was slowly added dropwise over 30 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 8.5 hours. After the reaction was complete, ethyl acetate (200 mL) was added to dilute the mixture. The organic phase was washed successively with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixture at a volume ratio of 10:1 to obtain the compound shown in Formula 4, with a yield of 21.71 g and a yield of 73.9%.

[0096] Comparative Example 4: Synthesis of the compound shown in Formula 4

[0097] At room temperature, toluene (200 mL) and pentamethyldiethylenetriamine (7.80 g, 0.03 mol) were added to a flask containing copper bromide (6.70 g, 0.03 mol), potassium tert-butoxide (14.59 g, 0.13 mol), and the compound shown in Formula 3 (16.92 g, 0.1 mol). Under N2 protection, a mixed solution of the compound shown in Formula 7 (26.71 g, 0.13 mol) and toluene (80 mL) was slowly added dropwise over 30 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 8.5 hours. After the reaction was complete, ethyl acetate (200 mL) was added to dilute the mixture. The organic phase was washed successively with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixture at a volume ratio of 4:1 to obtain the compound shown in Formula 4, with a yield of 20.18 g and a yield of 68.7%.

[0098] Synthesis of the compound shown in Formula 6 in Example 15

[0099] Under N2 protection, the compound shown in Formula 4 (29.4 g, 0.1 mol), the compound shown in Formula 5 (27.3 g, 0.11 mol), Pd(dppf)Cl2 (10.98 g, 0.015 mol), and sodium bicarbonate solution (containing 126 g (1.5 mol) of sodium bicarbonate, prepared as a 1 M solution) were added to a flask containing DMF (300 mL). The reaction mixture was heated to 86 °C–90 °C and reacted for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with water (500 mL), and the aqueous phase was extracted with ethyl acetate (500 mL × 2). The organic phases were combined and washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixture at a volume ratio of 4:1 to obtain the compound shown in Formula 6, with a yield of 35.71 g and a yield of 77.4%.

[0100] LC-MS (APCI): m / z = 462.3(M+1) + .

[0101] Example 16 Synthesis of the compound shown in Formula 6

[0102] Under N2 protection, the compound shown in Formula 4 (29.4 g, 0.1 mol), the compound shown in Formula 5 (24.8 g, 0.10 mol), Pd(dppf)Cl2 (7.32 g, 0.01 mol), and sodium bicarbonate solution (containing 126 g (1.5 mol) of sodium bicarbonate, prepared as a 1 M solution) were added to a flask containing DMF (300 mL). The reaction mixture was heated to 90 °C–92 °C and reacted for 11.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with water (500 mL), and the aqueous phase was extracted with ethyl acetate (500 mL × 2). The organic phases were combined and washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixed solvent at a volume ratio of 2:1 to obtain the compound shown in Formula 6, with a yield of 34.47 g and a yield of 74.7%.

[0103] Example 17 Synthesis of the compound shown in Formula 6

[0104] Under N2 protection, the compound shown in Formula 4 (29.4 g, 0.1 mol), the compound shown in Formula 5 (29.76 g, 0.12 mol), Pd(dppf)Cl2 (14.63 g, 0.02 mol), and sodium bicarbonate solution (containing 126 g (1.5 mol) of sodium bicarbonate, prepared as a 1 M solution) were added to a flask containing DMF (300 mL). The reaction mixture was heated to 84 °C–86 °C and reacted for 13 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with water (500 mL), and the aqueous phase was extracted with ethyl acetate (500 mL × 2). The organic phases were combined and washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixture at a volume ratio of 6:1 to obtain the compound shown in Formula 6, with a yield of 35.21 g and a yield of 76.3%.

[0105] Synthesis of the compound shown in Formula 6 in Example 18

[0106] Under N2 protection, the compound shown in Formula 4 (29.4 g, 0.1 mol), the compound shown in Formula 5 (27.3 g, 0.11 mol), Pd(dppf)Cl2 (10.98 g, 0.015 mol), and potassium bicarbonate solution (containing 150 g (1.5 mol) of potassium bicarbonate, prepared as a 1 M solution) were added to a flask containing DMF (300 mL). The reaction mixture was heated to 86 °C–90 °C and reacted for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with water (500 mL), and the aqueous phase was extracted with ethyl acetate (500 mL × 2). The organic phases were combined and washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixture at a volume ratio of 4:1 to obtain the compound shown in Formula 6, with a yield of 35.48 g and a yield of 76.9%.

[0107] Comparative Example 5: Synthesis of the compound shown in Formula 6

[0108] Under N2 protection, the compound shown in Formula 4 (29.40 g, 0.1 mol), the compound shown in Formula 5 (32.24 g, 0.13 mol), Pd(dppf)Cl2 (21.95 g, 0.03 mol), and sodium bicarbonate solution (containing 126 g (1.5 mol) of sodium bicarbonate, prepared as a 1 M solution) were added to a flask containing DMF (300 mL). The reaction mixture was heated to 86 °C–90 °C and reacted for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with water (500 mL), and the aqueous phase was extracted with ethyl acetate (500 mL × 2). The organic phases were combined and washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixture at a volume ratio of 8:1 to obtain the compound shown in Formula 6, with a yield of 33.45 g and a yield of 72.5%.

[0109] Example 19: Synthesis of pyrobrutinib, the compound shown in Formula I

[0110] The compound shown in Formula 6 (46.14 g, 0.1 mol) and toluene (500 ml) were added to a reaction flask. The temperature was controlled below 20 °C, and concentrated sulfuric acid (88.2 g, 0.9 mol) was slowly added dropwise. After the addition was complete, the mixture was heated to 60 °C and stirred vigorously for 3 hours. After the reaction solution was cooled, a saturated NaHCO3 solution (600 ml) was slowly added to the mixture. Then, ethyl acetate (2 × 600 mL), DCM (2 × 600 mL), and THF:EtOAc (v / v = 1:1, 2 × 600 mL) were added for extraction. The organic phases were combined and washed with saturated brine (600 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a solid. The solid was recrystallized from the solid using a mixed solvent of ethyl acetate and hexane (volume ratio of ethyl acetate to hexane was 6:1). The solid was filtered, and the filter cake was dried to obtain the compound shown in Formula I, pyrobrutinib, with a yield of 42.91 g, a yield of 89.5%, and an HPLC purity of 99.6%.

[0111] LC-MS(ES)m / z=480.2(M+1) + .

[0112] Example 20: Synthesis of pyrobrutinib, the compound shown in Formula I

[0113] The compound shown in Formula 6 (46.14 g, 0.1 mol) and toluene (500 ml) were added to a reaction flask. The temperature was controlled below 20 °C, and concentrated sulfuric acid (78.4 g, 0.8 mol) was slowly added dropwise. After the addition was complete, the mixture was heated to 60 °C and stirred vigorously for 3 hours. After the reaction solution was cooled, a saturated NaHCO3 solution (600 ml) was slowly added to the mixture. Then, ethyl acetate (2 × 600 mL), DCM (2 × 600 mL), and THF:EtOAc (v / v = 1:1, 2 × 600 mL) were added for extraction. The organic phases were combined and washed with saturated brine (600 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a solid. The solid was recrystallized from the solid using a mixed solvent of ethyl acetate and hexane (volume ratio of ethyl acetate to hexane was 8:1). The solid was filtered, and the filter cake was dried to obtain the compound shown in Formula I, pyrobrutinib, with a yield of 41.80 g, a yield of 87.2%, and an HPLC purity of 99.5%.

[0114] Example 21 Synthesis of pyrobrutinib, the compound shown in Formula I

[0115] The compound shown in Formula 6 (46.14 g, 0.1 mol) and toluene (500 ml) were added to a reaction flask. The temperature was controlled below 20 °C, and concentrated sulfuric acid (98.0 g, 1.0 mol) was slowly added dropwise. After the addition was complete, the mixture was heated to 60 °C and stirred vigorously for 3 hours. After the reaction solution was cooled, a saturated NaHCO3 solution (600 ml) was slowly added to the mixture. Then, ethyl acetate (2 × 600 mL), DCM (2 × 600 mL), and THF:EtOAc (v / v = 1:1, 2 × 600 mL) were added for extraction. The organic phases were combined and washed with saturated brine (600 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a solid. The solid was recrystallized from the solid using a mixed solvent of ethyl acetate and hexane (volume ratio of ethyl acetate to hexane was 5:1). The solid was filtered, and the filter cake was dried to obtain the compound shown in Formula I, pyrobrutinib, with a yield of 42.48 g, a yield of 88.6%, and an HPLC purity of 99.3%.

[0116] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0117] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for synthesizing pyrobrutinib, characterized in that, include: (1) Contact the compound shown in Formula 1, iodomethane, and acid-binding agent A to obtain the compound shown in Formula 2; (2) Contact the compound shown in Formula 2 with NH3BH3 and sodium bis(trimethylsilyl)amino to obtain the compound shown in Formula 3; (3) Contact the compound shown in Formula 3, pentamethyldiethylenetriamine, copper bromide, organic base B, and the compound shown in Formula 7 to obtain the compound shown in Formula 4; (4) Contact the compound shown in Formula 4, the compound shown in Formula 5, Pd(dppf)Cl2, and inorganic salt C to obtain the compound shown in Formula 6. (5) Contact the compound shown in Formula 6 with concentrated sulfuric acid to obtain pitobrutinib. ； In step (1), the acid-binding agent A is at least one selected from potassium carbonate, N,N-diisopropylethylamine, N,N-diisopropylethylenediamine or triethylamine; In step (3), the organic base B is at least one selected from potassium tert-butoxide, sodium tert-butoxide, or butyllithium; In step (4), the inorganic salt C is at least one selected from sodium bicarbonate or potassium bicarbonate.

2. The method according to claim 1, characterized in that, Step (1) includes the following steps: sealing the reaction system containing the compound shown in Formula 1, iodomethane, acid-binding agent A and DMF in a tube, reacting at 100°C for 10 hours, cooling the reaction system after the reaction is completed, performing post-treatment, quenching with saturated ammonium chloride solution, adding ethyl acetate for dilution, washing the organic phase sequentially with water and saturated brine, drying with anhydrous sodium sulfate, and distilling the solvent off the filtrate under reduced pressure to obtain the compound shown in Formula 2.

3. The method according to claim 2, characterized in that, In step (1), the molar ratio of the compound shown in Formula 1, iodomethane, and acid-binding agent A is 1:4:(4.0~5.0).

4. The method according to claim 3, characterized in that, In step (1), the molar ratio of the compound shown in Formula 1, iodomethane, and acid-binding agent A is 1:4:4.

5.

5. The method according to claim 1, characterized in that, Step (2) includes the following steps: the compound shown in Formula 2, NH3BH3, sodium bis(trimethylsilyl)amino, and THF solution are added sequentially to a Schlenk tube. The Schlenk tube is sealed and stirred at 25°C for 14-18 minutes under a nitrogen atmosphere. After the reaction is completed, water is added to quench the reaction, and the mixture is extracted with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and filtered directly to obtain the compound shown in Formula 3.

6. The method according to claim 5, characterized in that, In step (2), the molar ratio of the compound shown in Formula 2 to NH3BH3 and sodium bis(trimethylsilyl)amino is 1:(1.1~1.2):(1.4~1.6).

7. The method according to claim 6, characterized in that, In step (2), the molar ratio of the compound shown in Formula 2 to NH3BH3 and sodium bis(trimethylsilyl)amino is 1:1.15:1.

5.

8. The method according to claim 5, characterized in that, In step (2), the reaction is stirred for 15 minutes.

9. The method according to claim 1, characterized in that, Step (3) includes the following steps: At room temperature, toluene and pentamethyldiethylenetriamine are added to a flask containing copper bromide, organic base B and the compound shown in Formula 3. Under N2 protection, a mixed solution of the compound shown in Formula 7 and toluene is slowly added dropwise over 30 minutes. After the addition is complete, the reaction mixture is stirred at room temperature for 8-9 hours. After the reaction is complete, ethyl acetate is added to dilute the mixture. The organic phase is washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure to remove the solvent. The concentrate is purified by silica gel column chromatography using a mixed solvent of petroleum ether / ethyl acetate with a volume ratio of (8-12):1 to obtain the compound shown in Formula 4.

10. The method according to claim 9, characterized in that, In step (3), the molar ratio of the compound shown in Formula 3, pentamethyldiethylenetriamine, copper bromide, organic base B, and the compound shown in Formula 7 is 1:(0.04~0.05):(0.04~0.05):(1.1~1.2):(1.0~1.2).

11. The method according to claim 10, characterized in that, In step (3), the molar ratio of the compound shown in Formula 3, pentamethyldiethylenetriamine, copper bromide, organic base B, and the compound shown in Formula 7 is 1: 0.045: 0.045: 1.15: 1.

1.

12. The method according to claim 9, characterized in that, In step (3), the reaction mixture is stirred at room temperature for 8.5 hours.

13. The method according to claim 9, characterized in that, In step (3), the volume ratio of the petroleum ether / ethyl acetate mixed solvent is 10:

1.

14. The method according to claim 1, characterized in that, Step (4) includes the following steps: Under N2 protection, the compound shown in Formula 4, the compound shown in Formula 5, Pd(dppf)Cl2 and inorganic salt C solution are added to a flask containing DMF. The reaction mixture is heated to 84°C~92°C and reacted for 11.5 hours~13 hours. After the reaction is completed, the reaction solution is cooled to room temperature. The reaction solution is filtered with diatomaceous earth and washed with water. The aqueous phase is extracted with ethyl acetate. The organic phases are combined and washed with saturated brine. The mixture is dried with anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixed solvent with a volume ratio of (2~6):1 to obtain the compound shown in Formula 6.

15. The method according to claim 14, characterized in that, In step (4), the molar ratio of the compound shown in Formula 4, the compound shown in Formula 5, Pd(dppf)Cl2, and inorganic salt C is 1:(1.0~1.2):(0.1~0.2):

15.

16. The method according to claim 15, characterized in that, In step (4), the molar ratio of the compound shown in Formula 4, the compound shown in Formula 5, Pd(dppf)Cl2, and inorganic salt C is 1: 1.1: 0.15:

15.

17. The method according to claim 14, characterized in that, In step (4), the reaction mixture is heated to 86°C~90°C and reacted for 12 hours.

18. The method according to claim 14, characterized in that, In step (4), the volume ratio of the petroleum ether / ethyl acetate mixed solvent is 4:

1.

19. The method according to claim 1, characterized in that, Step (5) includes the following steps: adding the compound shown in Formula 6 and toluene to a reaction flask, controlling the temperature below 20°C, slowly adding concentrated sulfuric acid, and after the addition is complete, heating the mixture to 60°C, stirring vigorously for 3 hours, cooling the reaction solution, performing post-treatment, slowly adding ice-saturated NaHCO3 solution, and then adding ethyl acetate, DCM and a mixed solvent of THF and EtOAc in a volume ratio of 1:1 for extraction, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a solid, recrystallizing the solid with a mixed solvent of ethyl acetate and hexane, filtering, drying the filter cake to obtain pitobrutinib.

20. The method according to claim 19, characterized in that, In step (5), the molar ratio of the compound shown in Formula 6 to concentrated sulfuric acid is 1:(8~10).

21. The method according to claim 20, characterized in that, In step (5), the molar ratio of the compound shown in Formula 6 to concentrated sulfuric acid is 1:

9.

22. The method according to claim 19, characterized in that, In step (5), the volume ratio of ethyl acetate to hexane in the mixed solvent of ethyl acetate and hexane is (5~8):

1.

23. The method according to claim 22, characterized in that, In step (5), the volume ratio of ethyl acetate to hexane is 6:

1.

24. The method according to claim 1, characterized in that, Step (1) includes the following steps: sealing the reaction system containing 1.56g of the compound shown in Formula 1, 5.68g of iodomethane, 6.22g of potassium carbonate and 50 mL of DMF in a tube, reacting at 100°C for 10 hours, cooling the reaction system after the reaction is completed, quenching with 10 mL of saturated ammonium chloride solution, diluting with 50 mL of ethyl acetate, washing the organic phase successively with 50 mL of water and 50 mL of saturated brine, drying with anhydrous sodium sulfate, and diluting the solvent off the filtrate under reduced pressure to obtain the compound shown in Formula 2, with a yield of 1.810g and a yield of 98.3%; Step (2) includes the following steps: 1.84 g of the compound shown in Formula 2, 0.355 g of NH3BH3, 2.75 g of sodium bis(trimethylsilyl)amino, and 20 mL of THF solution are added sequentially to a 50 mL Schlenk tube. The Schlenk tube is sealed, and the reaction is stirred at 25°C for 15 minutes under a nitrogen atmosphere. After the reaction is completed, 10 mL of water is added to quench the reaction. The mixture is extracted with 20 mL × 2 ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and directly filtered to separate the solid of the compound shown in Formula 3. The yield is 1.52 g, with a yield of 89.8%. Step (3) includes the following steps: At room temperature, 200 mL of toluene and 7.80 g of pentamethyldiethylenetriamine were added to a flask containing 10.05 g of copper bromide, 12.90 g of potassium tert-butoxide and 16.92 g of the compound shown in Formula 3. Under N2 protection, a mixed solution of 22.60 g of the compound shown in Formula 7 and 80 mL of toluene was slowly added dropwise over 30 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 8.5 hours. After the reaction was complete, 200 mL of ethyl acetate was added to dilute the mixture. The organic phase was washed successively with 200 mL of water and 200 mL of saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixed solvent at a volume ratio of 10:1 to obtain the compound shown in Formula 4, with a yield of 22.59 g and a yield of 76.9%. Step (4) includes the following steps: Under N2 protection, 29.4 g of the compound shown in Formula 4, 27.3 g of the compound shown in Formula 5, 10.98 g of Pd(dppf)Cl2 and 126 g of sodium bicarbonate were prepared into a 1M sodium bicarbonate solution and added to a flask containing 300 mL of DMF. The reaction mixture was heated to 86°C~90°C and reacted for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was filtered with diatomaceous earth and washed with 500 mL of water. The aqueous phase was extracted with 500 mL × 2 ethyl acetate. The organic phases were combined and washed with 500 mL of saturated brine. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography with a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 4:1 to obtain the compound shown in Formula 6. The yield was 35.71 g and the yield was 77.4%. Step (5) includes the following steps: 46.14 g of the compound shown in Formula 6 and 500 mL of toluene are added to a reaction flask. The temperature is controlled below 20°C. 88.2 g of concentrated sulfuric acid is slowly added dropwise. After the addition is complete, the mixture is heated to 60°C and stirred vigorously for 3 hours. After the reaction solution is cooled, 600 mL of ice-saturated NaHCO3 solution is slowly added. Then, 2 × 600 mL of ethyl acetate, 2 × 600 mL of DCM and 2 × 600 mL of a mixed solvent of THF and EtOAc with a volume ratio of 1:1 are added for extraction. After the organic phases are combined, 600 mL of saturated brine is added for washing. The mixture is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a solid. The solid is recrystallized from a mixed solvent of ethyl acetate and hexane with a volume ratio of 6:

1. The solid is filtered, the filter cake is dried, and pyrobrutinib is obtained with a yield of 42.91 g, a yield of 89.5%, and an HPLC purity of 99.6%.

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