A preparation method of Pitobrutinib

Abstract

This invention relates to a method for preparing pyrobrutinib. The preparation method of this invention comprises three steps, using sodium hydroxide and hydrogen peroxide in the reaction route to reduce the operational hazards. Furthermore, the nitro group of the compound shown in Formula 4 reacts with the carboxylic acid of the compound shown in Formula 5 in a single step to generate the product. Compared to the literature method that typically converts the nitro group to an amino group before reacting with the carboxylic acid, this invention reduces the number of reaction steps while maintaining the same yield. The preparation method of this invention has the advantages of simple operation, high yield, and easy purification.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and more specifically, to a method for preparing pyrobrutinib. Background Art

[0002] Pirtobrutinib (also known as pyriturinib, 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, pyriturinib, 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] Formula I

[0005] However, the current preparation 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. Therefore, one object of this invention is to provide a method for preparing pyrobrutinib, a compound of Formula I. Compared to existing technologies, the preparation method of this invention uses sodium hydroxide and hydrogen peroxide, reducing the operational risks during the reaction. It reacts the nitro group with the carboxylic acid in a one-step manner to generate the product, reducing the number of reaction steps while maintaining the same yield. This route has advantages such as simple operation, high yield, and easy purification, and has significant advantages over previous synthetic routes.

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

[0008] (1) Contact the compound shown in Formula 1, the compound shown in Formula 2, Pd(dppf)Cl2, and inorganic salt A to obtain the compound shown in Formula 3;

[0009] (2) Contact the compound shown in Formula 3 with NaOH and H2O2 to obtain the compound shown in Formula 4;

[0010] (3) Contact the compound shown in Formula 4 and the compound shown in Formula 5 with carbon disulfide and DBU to obtain the compound shown in Formula I, pyrobrutinib.

[0011] .

[0012] The inventors have discovered that, using the preparation method described in this invention, with the compounds shown in Formula 1 and Formula 2 as starting materials, the target product pyrobrutinib can be successfully synthesized through a total of 3 reaction steps.

[0013] 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.

[0014] 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.

[0015] According to embodiments of the present invention, the methods for preparing the compounds shown in Formula 3, Formula 4, and Formula I may further include at least one of the following additional technical features:

[0016] 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 3, Formula 4, and Formula 1 is not particularly limited; they can be prepared using any known method or be commercially available. For example, the CAS number of the compound shown in Formula 1 is 2764851-21-8.

[0017] According to an embodiment of the present invention, in step (1), the contact method of the compound shown in Formula 1, the compound shown in Formula 2, Pd(dppf)Cl2, and inorganic salt A is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in Formula 1, the compound shown in Formula 2, Pd(dppf)Cl2, and inorganic salt A can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 3 using this method can be further improved.

[0018] According to an embodiment of the present invention, step (1) includes the following steps: Under N2 protection, the compound shown in Formula 1, the compound shown in Formula 2, Pd(dppf)Cl2, and inorganic salt A solution are added to a flask containing DMF. The reaction mixture is heated to 84°C~92°C and reacted for 10.5 hours~12 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 (4~8):1) to obtain the compound shown in Formula 3. Therefore, the efficiency of the contact reaction between the compound shown in Formula 1, the compound shown in Formula 2, Pd(dppf)Cl2, and inorganic salt A can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula 3 using this method can be further improved.

[0019] According to an embodiment of the present invention, in step (1), the molar ratio of the compound shown in Formula 1, the compound shown in Formula 2, Pd(dppf)Cl2, and inorganic salt A is 1:(1.1~1.2):(0.1~0.2):15, preferably 1:1.15:0.15:15. This further improves the efficiency of preparing the compound shown in Formula 3 using this method.

[0020] According to an embodiment of the present invention, in step (1), inorganic salt A is at least one selected from sodium bicarbonate or potassium bicarbonate.

[0021] According to an embodiment of the present invention, in step (1), it is preferable to heat the reaction mixture to 88°C~90°C and react for 11 hours.

[0022] According to an embodiment of the present invention, in step (1), the volume ratio of the petroleum ether / ethyl acetate mixed solvent is preferably 6:1.

[0023] According to a specific embodiment of the present invention, step (1) includes the following steps: Under N2 protection, the compound shown in Formula 1 (24.80 g, 0.10 mol), the compound shown in Formula 2 (24.84 g, 0.115 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 1M solution) are added to a flask containing DMF (250 mL). The reaction mixture is heated to 88°C~90°C and reacted for 11 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 (300 mL). The aqueous phase is extracted with ethyl acetate (300 mL × 2). The organic phases are combined and washed with saturated brine (300 mL). The mixture is dried over 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 at a volume ratio of 6:1 to obtain the compound shown in Formula 3, with a yield of 27.41. g, yield 80.8%.

[0024] According to an embodiment of the present invention, in step (2), the contact mode between the compound shown in Formula 3 and NaOH and H2O2 is not particularly limited. Therefore, the efficiency of the reaction between the compound shown in Formula 3 and NaOH and H2O2 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 increased.

[0025] According to an embodiment of the present invention, step (2) includes the following steps: dissolving the compound shown in Formula 3 in EtOH and DMSO, adding 5M NaOH aqueous solution and 30% H2O2 solution, reacting the reaction solution at 70°C for 1 hour, cooling to room temperature, concentrating under reduced pressure to remove the organic phase solution, adding ethyl acetate to the concentrate to dissolve it, then adding dilute hydrochloric acid to wash it, combining the aqueous phases, adding an appropriate amount of inorganic base B aqueous solution to adjust the pH to 12, and then adding ethyl acetate to the aqueous phase for extraction to obtain the compound shown in Formula 4. Therefore, the efficiency of the reaction between the compound shown in Formula 3 and NaOH and H2O2 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.

[0026] According to an embodiment of the present invention, in step (2), the molar ratio of the compound shown in Formula 3 to NaOH and H2O2 is 1:(5.0~10.0):(8.0~12.0), preferably 1:7.0:10.0. This further improves the efficiency of preparing the compound shown in Formula 4 using this method.

[0027] According to an embodiment of the present invention, in step (2), inorganic base B is at least one selected from sodium hydroxide or potassium hydroxide.

[0028] According to a specific embodiment of the present invention, step (2) includes the following steps: the compound shown in Formula 3 (3.50 g, 10.32 mmol) is dissolved in EtOH (20 mL) and DMSO (5 mL), and 5M NaOH aqueous solution (14.4 mL, 72.24 mmol) and 30% H2O2 solution (10.5 mL, 103.2 mmol) are added. The reaction solution is reacted at 70°C for 1 hour. After cooling to room temperature, the organic phase solution is removed by vacuum concentration. Ethyl acetate (30 mL) is added to the concentrate to dissolve it, and then dilute hydrochloric acid (4M, 20 mL × 2) is added for washing. The aqueous phases are combined and an appropriate amount of sodium hydroxide aqueous solution is added to adjust the pH to 12. Ethyl acetate (40 mL × 2) is added to the aqueous phase for extraction to obtain the compound shown in Formula 4, with a yield of 2.40 g and a yield of 65.1%.

[0029] According to an embodiment of the present invention, in step (3), the contact mode between the compound shown in Formula 4, the compound shown in Formula 5, carbon disulfide, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is not particularly limited. Therefore, the efficiency of the contact reaction between the compound shown in Formula 4, the compound shown in Formula 5, and carbon disulfide and DBU can be improved, the reaction rate can be accelerated, and the efficiency of preparing the compound shown in Formula I using this method can be further improved.

[0030] According to an embodiment of the present invention, step (3) includes the following steps: adding the compounds shown in Formula 4 and Formula 5, carbon disulfide, DBU, H2O, and DMSO to a sealed tube; reacting the reaction solution at 100°C for 2 hours; washing the reaction solution with water after cooling; extracting with ethyl acetate; combining the organic phases; washing with saturated brine; drying with anhydrous sodium sulfate; concentrating the filtrate 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 compounds shown in Formula 4 and Formula 5 and carbon disulfide and DBU 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.

[0031] According to an embodiment of the present invention, in step (3), the molar ratio of the compound shown in Formula 4, the compound shown in Formula 5, carbon disulfide, and DBU is 1:(1.02~1.1):3:3, preferably 1:1.06:3:3. This further improves the efficiency of preparing the compound shown in Formula I using this method.

[0032] According to an embodiment of the present invention, in step (3), the volume ratio of ethyl acetate to hexane in the mixed solvent of ethyl acetate and hexane is (4~8):1, preferably 6:1.

[0033] According to a specific embodiment of the present invention, step (3) includes the following steps: adding the compound shown in Formula 4 (2.0 g, 5.60 mmol) and the compound shown in Formula 5 (1.01 g, 5.94 mmol), carbon disulfide (1.28 g, 16.8 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.56 g, 16.8 mmol), H2O (3 mL) and DMSO (25 mL) to a 50 mL sealed tube; reacting the reaction solution at 100°C for 2 hours; after cooling the reaction solution, washing with 30 mL of water; extracting with ethyl acetate (30 mL × 2); combining the organic phases; and adding saturated brine (30 mL × 2). The solution was washed with anhydrous sodium sulfate, dried, and the filtrate was 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 pyrobrutinib shown in Formula I, with a yield of 2.13 g, a yield of 79.3%, and an HPLC purity of 99.9%.

[0034] According to a specific embodiment of the present invention, the synthetic route of the compound pyrobrutinib shown in Formula I can be as follows:

[0035] .

[0036] Compared with the prior art, the preparation method of the BTK small molecule inhibitor pyrobrutinib described in this invention has at least the following beneficial effects:

[0037] (1) In the reaction steps, in step (1), the compound shown in Formula 1 and the compound shown in Formula 2 undergo a Suzuki coupling reaction under Pd catalyst conditions to obtain the compound shown in Formula 3; in step (2), under alkaline conditions, hydrogen peroxide is used to convert the cyano group into an amide, and the compound shown in Formula 3 is reacted with NaOH and H2O2 to obtain the compound shown in Formula 4; in step (3), the nitro group (the nitro group of the compound shown in Formula 4) is directly reacted with the carboxylic acid (the carboxylic acid of the compound shown in Formula 5) to obtain the target product pyrobrutinib.

[0038] (2) The Suzuki coupling reaction has the advantages of high yield and convenient post-processing compared with general alkylation reactions. When converting cyano to amide, most literature uses concentrated sulfuric acid for the reaction, which is dangerous; the preparation method described in this invention uses sodium hydroxide and hydrogen peroxide, which reduces the danger of the operation in the reaction.

[0039] (3) The preparation method of the present invention reacts the nitro group of the compound shown in Formula 4 with the carboxylic acid of the compound shown in Formula 5 in one step to generate the product. Compared with the literature, which generally converts the nitro group into an amino group before reacting with the carboxylic acid, the present invention reduces the reaction steps while keeping the yield unchanged.

[0040] (4) In summary, the preparation method of the present invention has the advantages of simple operation, high yield and easy purification. Compared with the previous synthesis route, it has a great advantage and is easy to industrialize, making it very suitable for large-scale industrial production. Detailed Implementation

[0041] 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.

[0042] Example 1: Synthesis of the compound shown in Formula 3

[0043] Under N2 protection, the compound shown in Formula 1 (24.80 g, 0.10 mol), the compound shown in Formula 2 (24.84 g, 0.115 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 250 mL DMF flask. The reaction mixture was heated to 88°C–90°C and reacted for 11 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with water (300 mL), and the aqueous phase was extracted with ethyl acetate (300 mL × 2). The organic phases were combined and washed with saturated brine (300 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography with a 6:1 volume ratio of petroleum ether / ethyl acetate to obtain the compound shown in Formula 3, with a yield of 27.41 g and a yield of 80.8%.

[0044] LC-MS (APCI): m / z = 340.2(M+1) +

[0045] Example 2: Synthesis of the compound shown in Formula 3

[0046] Under N2 protection, the compound shown in Formula 1 (24.80 g, 0.10 mol), the compound shown in Formula 2 (23.76 g, 0.11 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 250 mL DMF flask. The reaction mixture was heated to 90°C–92°C and reacted for 10.5 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with water (300 mL), and the aqueous phase was extracted with ethyl acetate (300 mL × 2). The organic phases were combined and washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography with a 4:1 volume ratio of petroleum ether / ethyl acetate to obtain the compound shown in Formula 3, with a yield of 26.23 g and a yield of 77.3%.

[0047] Example 3 Synthesis of the compound shown in Formula 3

[0048] Under N2 protection, the compound shown in Formula 1 (24.80 g, 0.10 mol), the compound shown in Formula 2 (25.92 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 250 mL DMF flask. The reaction mixture was heated to 84°C–86°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 (300 mL), and the aqueous phase was extracted with ethyl acetate (300 mL × 2). The organic phases were combined and washed with saturated brine (300 mL). The mixture was 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 3, with a yield of 26.84 g and a yield of 79.1%.

[0049] Example 4: Synthesis of the compound shown in Formula 3

[0050] Under N2 protection, the compound shown in Formula 1 (24.80 g, 0.10 mol), the compound shown in Formula 2 (24.84 g, 0.115 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 250 mL DMF flask. The reaction mixture was heated to 88°C–90°C and reacted for 11 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with water (300 mL), and the aqueous phase was extracted with ethyl acetate (300 mL × 2). The organic phases were combined and washed with saturated brine (300 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography with a 6:1 volume ratio of petroleum ether / ethyl acetate to obtain the compound shown in Formula 3, with a yield of 27.14 g and a yield of 80.0%.

[0051] Comparative Example 1: Synthesis of the compound shown in Formula 3

[0052] Under N2 protection, the compound shown in Formula 1 (24.80 g, 0.10 mol), the compound shown in Formula 2 (21.60 g, 0.10 mol), Pd(dppf)Cl2 (5.85 g, 0.008 mol), and sodium bicarbonate solution (containing 84 g (1.0 mol) of sodium bicarbonate, prepared as a 1 M solution) were added to a 250 mL DMF flask. The reaction mixture was heated to 88°C–90°C and reacted for 11 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with water (300 mL), and the aqueous phase was extracted with ethyl acetate (300 mL × 2). The organic phases were combined and washed with saturated brine (300 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography with a 6:1 volume ratio of petroleum ether / ethyl acetate to obtain the compound shown in Formula 3, with a yield of 24.56 g and a yield of 72.4%.

[0053] Comparative Example 2: Synthesis of the compound shown in Formula 3

[0054] Under N2 protection, the compound shown in Formula 1 (24.80 g, 0.10 mol), the compound shown in Formula 2 (29.16 g, 0.135 mol), Pd(dppf)Cl2 (18.29 g, 0.025 mol), and sodium bicarbonate solution (containing 100.8 g (1.2 mol) of sodium bicarbonate, prepared as a 1 M solution) were added to a 250 mL DMF flask. The reaction mixture was heated to 88°C–90°C and reacted for 11 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with water (300 mL), and the aqueous phase was extracted with ethyl acetate (300 mL × 2). The organic phases were combined and washed with saturated brine (300 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography with a 6:1 volume ratio of petroleum ether / ethyl acetate to obtain the compound shown in Formula 3, with a yield of 25.04 g and a yield of 73.8%.

[0055] Example 5: Synthesis of the compound shown in Formula 4

[0056] The compound shown in Formula 3 (3.50 g, 10.32 mmol) was dissolved in EtOH (20 mL) and DMSO (5 mL). 5M NaOH aqueous solution (14.4 mL, 72.24 mmol) and 30% H2O2 solution (10.5 mL, 103.2 mmol) were added. The reaction mixture was reacted at 70°C for 1 hour. After cooling to room temperature, the organic phase solution was concentrated under reduced pressure to remove the organic phase solution. Ethyl acetate (30 mL) was added to the concentrate to dissolve the organic phase. The concentrate was then washed with dilute hydrochloric acid (4M, 20 mL × 2). The aqueous phases were combined, and an appropriate amount of sodium hydroxide aqueous solution was added to adjust the pH to 12. Ethyl acetate (40 mL × 2) was then added to the aqueous phase for extraction to obtain the compound shown in Formula 4, with a yield of 2.40 g and a yield of 65.1%.

[0057] LC-MS (APCI): m / z = 358.2 (M+1) + .

[0058] Example 6 Synthesis of the compound shown in Formula 4

[0059] The compound shown in Formula 3 (3.50 g, 10.32 mmol) was dissolved in EtOH (20 mL) and DMSO (5 mL). 5M NaOH aqueous solution (10.3 mL, 51.60 mmol) and 30% H2O2 solution (8.7 mL, 82.56 mmol) were added. The reaction mixture was reacted at 70°C for 1 hour. After cooling to room temperature, the organic phase solution was removed by vacuum concentration. Ethyl acetate (30 mL) was added to the concentrate to dissolve it, followed by washing with dilute hydrochloric acid (4M, 20 mL × 2). The aqueous phases were combined, and an appropriate amount of sodium hydroxide aqueous solution was added to adjust the pH to 12. Ethyl acetate (40 mL × 2) was then added to the aqueous phase for extraction to obtain the compound shown in Formula 4, with a yield of 2.32 g and a yield of 63.0%.

[0060] Example 7 Synthesis of the compound shown in Formula 4

[0061] The compound shown in Formula 3 (3.50 g, 10.32 mmol) was dissolved in EtOH (20 mL) and DMSO (5 mL). 5M NaOH aqueous solution (20.6 mL, 103.2 mmol) and 30% H2O2 solution (12.6 mL, 123.8 mmol) were added. The reaction mixture was reacted at 70°C for 1 hour. After cooling to room temperature, the organic phase was removed by concentration under reduced pressure. Ethyl acetate (30 mL) was added to the concentrate to dissolve the organic phase. The concentrate was then washed with dilute hydrochloric acid (4M, 20 mL × 2). The aqueous phases were combined, and an appropriate amount of sodium hydroxide aqueous solution was added to adjust the pH to 12. Ethyl acetate (40 mL × 2) was then added to the aqueous phase for extraction to obtain the compound shown in Formula 4, with a yield of 2.37 g and a yield of 64.3%.

[0062] Example 8 Synthesis of the compound shown in Formula 4

[0063] The compound shown in Formula 3 (3.50 g, 10.32 mmol) was dissolved in EtOH (20 mL) and DMSO (5 mL), and 5M NaOH aqueous solution (14.4 mL, 72.24 mmol) and 30% H2O2 solution (10.5 mL, 103.2 mmol) were added. The reaction solution was reacted at 70°C for 1 hour, cooled to room temperature, and concentrated under reduced pressure to remove the organic phase solution. Ethyl acetate (30 mL) was added to the concentrate to dissolve it, and then dilute hydrochloric acid (4M, 20 mL × 2) was added for washing. The aqueous phases were combined, and an appropriate amount of potassium hydroxide aqueous solution was added to adjust the pH to 12. Ethyl acetate (40 mL × 2) was added to the aqueous phase for extraction to obtain the compound shown in Formula 4, with a yield of 2.35 g and a yield of 63.7%.

[0064] Example 9 Synthesis of pyrobrutinib

[0065] Compounds of Formula 4 (2.0 g, 5.60 mmol) and Formula 5 (1.01 g, 5.94 mmol), carbon disulfide (1.28 g, 16.8 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.56 g, 16.8 mmol), H2O (3 mL), and DMSO (25 mL) were added to a 50 mL sealed tube. The reaction solution was reacted at 100°C for 2 hours. After cooling, the reaction solution was washed with 30 mL of water and extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a solid. The solid was recrystallized from the solid using a mixed solvent of ethyl acetate and hexane (6:1 volume ratio). The solid was filtered, and the filter cake was dried to obtain pyrobrutinib, the compound of Formula I, in a yield of 2.13 g. g, yield 79.3%, HPLC purity 99.9%.

[0066] LC-MS(ES) m / z = 480.2(M+1) + .

[0067] Example 10 Synthesis of pitobrutinib

[0068] Compounds of Formula 4 (2.0 g, 5.60 mmol) and Formula 5 (0.97 g, 5.71 mmol), carbon disulfide (1.28 g, 16.8 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.56 g, 16.8 mmol), H2O (3 mL), and DMSO (25 mL) were added to a 50 mL sealed tube. The reaction solution was reacted at 100°C for 2 hours. After cooling, the reaction solution was washed with 30 mL of water and extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a solid. The solid was recrystallized from the solid using a mixed solvent of ethyl acetate and hexane (ethyl acetate to hexane volume ratio 4:1). The solid was filtered, and the filter cake was dried to obtain pyrobrutinib, the compound of Formula I, in a yield of 2.08 g. g, yield 77.6%, HPLC purity 99.6%.

[0069] Example 11 Synthesis of pyrobrutinib

[0070] Compounds of Formula 4 (2.0 g, 5.60 mmol) and Formula 5 (1.05 g, 6.16 mmol), carbon disulfide (1.28 g, 16.8 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.56 g, 16.8 mmol), H2O (3 mL), and DMSO (25 mL) were added to a 50 mL sealed tube. The reaction solution was reacted at 100°C for 2 hours. After cooling, the reaction solution was washed with 30 mL of water and extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a solid. The solid was recrystallized from the solid using a mixed solvent of ethyl acetate and hexane (ethyl acetate to hexane volume ratio of 8:1). The solid was filtered, and the filter cake was dried to obtain pyrobrutinib, the compound of Formula I, in a yield of 2.10 g. g, yield 78.3%, HPLC purity 99.5%.

[0071] Comparative Example 3: Synthesis of Pytobractinib

[0072] Compounds of Formula 4 (2.0 g, 5.60 mmol) and Formula 5 (0.95 g, 5.60 mmol), carbon disulfide (1.28 g, 16.8 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (3.41 g, 22.4 mmol), H2O (3 mL), and DMSO (25 mL) were added to a 50 mL sealed tube. The reaction solution was reacted at 100°C for 2 hours. After cooling, the reaction solution was washed with 30 mL of water and extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure to obtain a solid. The solid was recrystallized from the solid using a mixed solvent of ethyl acetate and hexane (6:1 volume ratio of ethyl acetate to hexane). The solid was filtered, and the filter cake was dried to obtain pyrobrutinib, the compound of Formula I, with a yield of 1.92 g, a yield of 71.5%, and an HPLC purity of 98.6%.

[0073] Comparative Example 4: Synthesis of Pytobrutinib

[0074] Compounds of Formula 4 (2.0 g, 5.60 mmol) and Formula 5 (1.14 g, 6.72 mmol), carbon disulfide (1.71 g, 22.4 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (2.98 g, 19.6 mmol), H2O (3 mL), and DMSO (25 mL) were added to a 50 mL sealed tube. The reaction solution was reacted at 100°C for 2 hours. After cooling, the reaction solution was washed with 30 mL of water and extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate and the filtrate was 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 pyrobrutinib, the compound of Formula I, with a yield of 1.95 g, a yield of 72.6%, and an HPLC purity of 99.0%.

[0075] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are 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.

[0076] 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 preparing pyrobrutinib, characterized in that, include: (1) Contact the compound shown in Formula 1, the compound shown in Formula 2, Pd(dppf)Cl2, and inorganic salt A to obtain the compound shown in Formula 3; (2) Contact the compound shown in Formula 3 with NaOH and H2O2 to obtain the compound shown in Formula 4; (3) Contact the compound shown in Formula 4, the compound shown in Formula 5, with carbon disulfide and DBU to obtain pyrobrutinib. ， In step (1), the inorganic salt A 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: Under N2 protection, the compound shown in Formula 1, the compound shown in Formula 2, Pd(dppf)Cl2 and inorganic salt A solution are added to a flask containing DMF. The reaction mixture is heated to 84°C~92°C and reacted for 10.5 hours~12 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 (4~8):1 to obtain the compound shown in Formula 3.

3. The method according to claim 2, characterized in that, In step (1), the molar ratio of the compound shown in Formula 1, the compound shown in Formula 2, Pd(dppf)Cl2, and inorganic salt A is 1:(1.1~1.2):(0.1~0.2):

15.

4. The method according to claim 3, characterized in that, In step (1), the molar ratio of the compound shown in Formula 1, the compound shown in Formula 2, Pd(dppf)Cl2, and inorganic salt A is 1: 1.15: 0.15:

15.

5. The method according to claim 2, characterized in that, In step (1), the reaction mixture is heated to 88°C~90°C and reacted for 11 hours.

6. The method according to claim 2, characterized in that, In step (1), the volume ratio of the petroleum ether / ethyl acetate mixed solvent is 6:

1.

7. The method according to claim 1, characterized in that, Step (2) includes the following steps: Dissolve the compound shown in Formula 3 in EtOH and DMSO, add 5M NaOH aqueous solution and 30% H2O2 solution, react the reaction solution at 70°C for 1 hour, cool to room temperature and concentrate under reduced pressure to remove the organic phase solution, add ethyl acetate to the concentrate to dissolve, then add dilute hydrochloric acid to wash, combine the aqueous phases and add an appropriate amount of inorganic base B aqueous solution to adjust the pH to 12, then add ethyl acetate to the aqueous phase for extraction to obtain the compound shown in Formula 4.

8. The method according to claim 7, characterized in that, In step (2), the molar ratio of the compound shown in Formula 3 to NaOH and H2O2 is 1:(5.0~10.0):(8.0~12.0).

9. The method according to claim 8, characterized in that, In step (2), the molar ratio of the compound shown in Formula 3 to NaOH and H2O2 is 1:7.0:10.

0.

10. The method according to claim 7, characterized in that, In step (2), inorganic base B is at least one selected from sodium hydroxide or potassium hydroxide.

11. The method according to claim 1, characterized in that, Step (3) includes the following steps: adding the compounds shown in Formula 4 and Formula 5, carbon disulfide, DBU, H2O and DMSO to a sealed tube, reacting the reaction solution at 100°C for 2 hours, washing the reaction solution with water after cooling, extracting with ethyl acetate, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating the filtrate 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.

12. The method according to claim 11, characterized in that, In step (3), the molar ratio of the compound shown in Formula 4, the compound shown in Formula 5, carbon disulfide, and DBU is 1:(1.02~1.1):3:

3.

13. The method according to claim 12, characterized in that, In step (3), the molar ratio of the compound shown in Formula 4, the compound shown in Formula 5, carbon disulfide, and DBU is 1:1.06:3:

3.

14. The method according to claim 11, characterized in that, In step (3), the volume ratio of ethyl acetate to hexane in the mixed solvent of ethyl acetate and hexane is (4~8):

1.

15. The method according to claim 14, characterized in that, In step (3), the volume ratio of ethyl acetate to hexane is 6:

1.

16. The method according to claim 1, characterized in that, Step (1) includes the following steps: Under N2 protection, 24.80 g of the compound shown in Formula 1, 24.84 g of the compound shown in Formula 2, 10.98 g of Pd(dppf)Cl2 and a 1M sodium bicarbonate solution containing 126 g of sodium bicarbonate were added to a 250 mL DMF flask. The reaction mixture was heated to 88°C~90°C and reacted for 11 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 300 mL of water. The aqueous phase was extracted with 300 mL × 2 ethyl acetate. The organic phases were combined and washed with 300 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 6:1 to obtain the compound shown in Formula 3, with a yield of 27.41 g and a yield of 80.8%. Step (2) includes the following steps: 3.50 g of the compound shown in Formula 3 was dissolved in 20 mL of EtOH and 5 mL of DMSO, 14.4 mL of 5M NaOH aqueous solution and 10.5 mL of 30% H2O2 solution were added, the reaction solution was reacted at 70°C for 1 hour, cooled to room temperature and concentrated under reduced pressure to remove the organic phase solution, 30 mL of ethyl acetate was added to the concentrate to dissolve it, and then 20 mL of 4M dilute hydrochloric acid was added twice each time to wash it. The aqueous phases were combined and an appropriate amount of sodium hydroxide aqueous solution was added to adjust the pH to 12. Then 40 mL × 2 ethyl acetate was added to the aqueous phase for extraction to obtain the compound shown in Formula 4, with a yield of 2.40 g and a yield of 65.1%. Step (3) includes the following steps: 2.0 g of the compound shown in Formula 4 and 1.01 g of the compound shown in Formula 5, 1.28 g of carbon disulfide, 2.56 g of 1,8-diazabicyclo[5.4.0]undec-7-ene, 3 mL of H2O and 25 mL of DMSO are added to a 50 mL sealed tube. The reaction solution is reacted at 100°C for 2 hours. After the reaction solution is cooled, 30 mL of water is added for washing, and then 30 mL × 2 ethyl acetate is added for extraction. After the organic phases are combined, 30 mL of saturated brine is added for washing, and the solution is dried with anhydrous sodium sulfate. The filtrate is concentrated under reduced pressure to obtain a solid. The solid is recrystallized with a mixed solvent of ethyl acetate and hexane in a volume ratio of 6:

1. The solid is filtered, the filter cake is dried, and pitobrutinib is obtained with a yield of 2.13 g, a yield of 79.3%, and an HPLC purity of 99.9%.

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