A method for preparing zanobrutinib

Abstract

The application belongs to the technical field of organic chemistry and specifically relates to a preparation method of zanabe Ronast. The method comprises the following steps: 1,3-dimethylpyrazole-4-formaldehyde is used as raw material, 4-bromo-piperidine, sodium cyanoborohydride and zinc chloride are used to carry out Borch reduction amination reaction to obtain 4-bromo-1-((1,3-dimethyl-1-H-pyrazole-4-yl)methyl)piperidine; then, 4-methyl 4-cyanobenzoate is used to carry out electrocatalytic synthesis to obtain 4-(1-((1,3-dimethyl-1H-pyrazole-4-yl)methyl)piperidin-4-yl)benzoic acid methyl ester; finally, o-phenylenediamine and potassium tert-butoxide are stirred at room temperature to obtain zanabe Ronast. The application is synthesized through three steps, the reaction condition is mild, the raw material is simple and easy to obtain, the method is green and environment-friendly, the synthesis efficiency is high, the cost is low, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry technology, specifically relating to a method for preparing zebenosatine. Background Technology

[0002] Zabadinostat (CXD101) is an HDAC (histonia deacetylase) inhibitor, initially developed by Celleron Therapeutics Ltd., and currently in Phase II clinical trials globally. HDACs control cell survival, proliferation, angiogenesis, inflammation, and immunity, playing a crucial role in cell signaling. Zabadinostat is a potent, selective, orally active class I HDAC inhibitor with IC50 inhibitory activity against HDAC1, HDAC2, and HDAC3. 50 The effective doses were 63 nM, 570 nM, and 550 nM, respectively, with no activity against class II HDAC. Zabadinostat also exhibits antitumor activity and was approved for clinical trials in January 2021 for relapsed / refractory peripheral T-cell lymphoma. Furthermore, zabadinostat can reverse low or no response or cancer failure to immune checkpoint inhibitors (such as PD-1 and PD-L1), demonstrating broad market potential.

[0003] In existing synthetic processes, 4-pyridin-4-ylbenzoic acid is reacted with N-Boc-o-phenylenediamine to generate N-(2-aminophenyl)-4-(pyridin-4-yl)benzamide, which is then obtained by catalytic hydrogenation or direct pressurized (1-10 bar) hydrogenation. Finally, the desired drug zabenosat is obtained by reductive amination.

[0004] In the aforementioned processes, the hydrogenation step often requires the use of expensive metal catalysts (such as Pd / C, Pd(OH)2 / C, PtO2, Rh, etc.) or is carried out under high-pressure hydrogen gas (1-10 bar) conditions, which undoubtedly increases the cost and risk of the synthesis process. Therefore, there is an urgent need to develop a new synthetic method to solve these problems. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing zebenosstat, specifically adopting the following technical solution:

[0006] A method for preparing zebenosstat includes the following steps:

[0007] Using 1,3-dimethylpyrazol-4-carboxaldehyde as a raw material, 4-bromopiperidine, sodium cyanoborohydride, and zinc chloride were reacted with 4-bromopiperidine, sodium cyanoborohydride, and zinc chloride via a Borch reductive amination reaction to obtain 4-bromo-1-((1,3-dimethyl-1-H-pyrazol-4-yl)methyl)piperidine; then, 4-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)benzoate was synthesized by electrocatalysis with methyl 4-cyanobenzoate; finally, zebenosat was prepared by stirring with o-phenylenediamine and potassium tert-butoxide at room temperature.

[0008] This invention uses 1,3-dimethylpyrazol-4-carboxaldehyde as a raw material, and reacts it with 4-bromopiperidine, sodium cyanoborohydride, and zinc chloride via a Borch reductive amination reaction. The aldehyde condenses with an amine (piperidine) to form an imine, which is then reduced to an amine, yielding 4-bromo-1-((1,3-dimethyl-1-H-pyrazol-4-yl)methyl)piperidine. Then, it is reacted with methyl 4-cyanobenzoate via an electrocatalytic reductive coupling process to synthesize methyl 4-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)benzoate. Finally, it is reacted with o-phenylenediamine and potassium tert-butoxide at room temperature to undergo an amidation reaction, yielding zebenobenostat. This invention utilizes 1,3-dimethylpyrazol-4-carboxaldehyde as a raw material to synthesize zebenobenostat in three steps. The reaction conditions are mild, the raw materials are simple and readily available, the process is environmentally friendly, the synthesis efficiency is high, and the cost is low, making it suitable for industrial production.

[0009] This invention also provides a specific preparation process for the above-mentioned method of preparing zebenosstat, the specific steps of which are as follows:

[0010] Step 1: Add zinc chloride to a methanol solution of 1,3-dimethylpyrazol-4-carboxaldehyde, 4-bromopiperidine, and sodium cyanoborohydride. Stir at room temperature for 1 hour, then cool the reaction system to 0°C in an ice-water bath. Slowly add concentrated hydrochloric acid at 0°C until the pH of the reaction solution is adjusted to 3. Remove the ice-water bath and stir the reaction solution at room temperature for 8 hours. After the reaction is complete, transfer the reaction system to an ice-water bath and slowly add 1M / L NaOH until the pH of the reaction solution is adjusted to 13-14. Then, extract with water and ethyl acetate separately, combine the organic phases, and purify by silica gel rapid chromatography to obtain 4-bromo-1-((1,3-dimethyl-1-H-pyrazol-4-yl)methyl)piperidine.

[0011] Step 2: In a dry electrolytic cell, a zinc sheet is installed as the anode and a PAN-based carbon felt as the cathode. Methyl 4-cyanobenzoate and tetraethylammonium chloride are added to the reaction system, and the air in the reaction system is replaced with nitrogen. Then, 4-bromo-1-((1,3-dimethyl-1H-pyrazole-4-yl)methyl)piperidine and acetonitrile are added. After stirring evenly, electrolysis is carried out at room temperature by passing a direct current. After the reaction is complete, the reaction solution is concentrated and purified by silica gel chromatography to obtain methyl 4-(1-((1,3-dimethyl-1H-pyrazole-4-yl)methyl)piperidine-4-yl)benzoate.

[0012] Step 3: Potassium tert-butoxide was added to a mixed solvent of tetrahydrofuran and water and stirred at room temperature for 5 minutes. Then, methyl 4-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)benzoate and o-phenylenediamine were added and stirred at room temperature for 6 hours. After the reaction was completed, water and dichloromethane were added for extraction, the organic phases were combined, dried with anhydrous Na2SO4, and purified by silica gel chromatography to finally obtain zebenosatine.

[0013] As a further preferred embodiment, the molar ratio of 1,3-dimethylpyrazole-4-carboxaldehyde, 4-bromopiperidine, sodium cyanoborohydride, and zinc chloride in step 1 is 1:1.2:1.2:1.2. 1,3-dimethylpyrazole-4-carboxaldehyde and the target product of step 1, 4-bromo-1-((1,3-dimethyl-1-H-pyrazole-4-yl)methyl)piperidine, are difficult to separate. Reducing the proportion of other reaction raw materials such as 4-bromopiperidine, sodium cyanoborohydride, and zinc chloride will result in residual 1,3-dimethylpyrazole-4-carboxaldehyde, thus increasing the separation difficulty. Increasing the proportion of other reaction raw materials will lead to waste of raw materials.

[0014] As a further preferred embodiment, the molar ratio of methyl 4-cyanobenzoate to 4-bromo-1-((1,3-dimethyl-1-H-pyrazole-4-yl)methyl)piperidine in step 2 is 3:1. Changing the molar ratio of methyl 4-cyanobenzoate to 4-bromo-1-((1,3-dimethyl-1-H-pyrazole-4-yl)methyl)piperidine will lead to a decrease in the reaction yield.

[0015] As a further preferred embodiment, the electrolyte solution in the electrolytic cell in step 2 is an acetonitrile solution of tetraethylammonium chloride, obtained by dissolving tetraethylammonium chloride in acetonitrile in the reaction system. Furthermore, the concentration of the electrolyte solution is 0.2 mol / L. Too high or too low a concentration of the electrolyte solution will lead to a decrease in yield.

[0016] As a further preferred embodiment, the molar ratio of potassium tert-butoxide, methyl 4-(1-((1,3-dimethyl-1H-pyrazole-4-yl)methyl)piperidin-4-yl)benzoate, and o-phenylenediamine in step 3 is 3:1:2. Changing the molar ratio of potassium tert-butoxide, methyl 4-(1-((1,3-dimethyl-1H-pyrazole-4-yl)methyl)piperidin-4-yl)benzoate, and o-phenylenediamine will lead to an increase in byproducts, thereby reducing the reaction yield.

[0017] As a further preferred embodiment, the extraction is performed three times, with the ratio of water to dichloromethane used in each extraction being 1:1.

[0018] As a further preferred embodiment, the ratio of tetrahydrofuran to water in step 3 is 100:1.

[0019] As a further preferred embodiment, the reagents used for rapid silica gel chromatography purification in steps 1, 2 and 3 are petroleum ether and ethyl acetate.

[0020] The beneficial effects of this invention are as follows: This invention uses 1,3-dimethylpyrazol-4-carboxaldehyde as the starting material, and obtains 4-bromo-1-((1,3-dimethyl-1-H-pyrazol-4-yl)methyl)piperidine through reaction. Then, it is electrocatalyzed with methyl 4-cyanobenzoate to synthesize methyl 4-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidine-4-yl)benzoate. Finally, o-phenylenediamine and potassium tert-butoxide are added, and the mixture is stirred at room temperature to obtain zebenobenostat. This invention synthesizes zebenobenostat in three steps under mild reaction conditions, with simple and readily available raw materials, is environmentally friendly, has high synthesis efficiency, and low cost. It solves the problem that existing technologies require expensive metal catalysts or need to be carried out under high-pressure hydrogen conditions, making it suitable for industrial production. Detailed Implementation

[0021] To facilitate understanding of this application, it may be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that the disclosure of this application will be thorough and complete.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the specification of this application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0023] In this document, unless otherwise stated, the term "%" means "mass %"; the term "μg / mL" means micrograms per milliliter. In this document, unless otherwise stated, the term "%" refers to the total weight of the compositions of this application.

[0024] In this article, the term "all ranges" refers to both each specific range within a given range and combinations of subranges between given ranges. For example, the range 1–5 specifically includes 1, 2, 3, 4, and 5, and also includes subranges such as 2–5, 3–5, 2–3, 2–4, and 1–4.

[0025] The preparation method of the present invention uses 1,3-dimethylpyrazole-4-carboxaldehyde as a raw material, and reacts it with 4-bromopiperidine, sodium cyanoborohydride, and zinc chloride via a Borch reduction amination reaction to obtain 4-bromo-1-((1,3-dimethyl-1-H-pyrazole-4-yl)methyl)piperidine; then reacts it with methyl 4-cyanobenzoate via electrocatalysis to synthesize methyl 4-(1-((1,3-dimethyl-1H-pyrazole-4-yl)methyl)piperidin-4-yl)benzoate; finally, it is reacted with o-phenylenediamine and potassium tert-butoxide at room temperature to prepare zebenosatine.

[0026] Example 1

[0027] A method for preparing zebenosstat includes the following steps:

[0028]

[0029] Step 1: Preparation of 4-bromo-1-((1,3-dimethyl-1-H-pyrazol-4-yl)methyl)piperidine

[0030]

[0031] Weighed 1,3-dimethylpyrazole-4-carboxaldehyde (496 mg, 4.0 mmol), 4-bromopiperidine hydrochloride (1.18 g, 4.8 mmol), sodium cyanoborohydride (302 mg, 4.8 mmol), and zinc chloride (653 mg, 4.8 mmol) were added to a 50 mL round-bottom flask equipped with a magnetic stir bar. 20 mL of methanol solution was poured in, and the mixture was stirred at room temperature for 1 hour. The flask was then placed in an ice-water bath, and concentrated hydrochloric acid was slowly added dropwise to the reaction system at 0 °C until the pH of the reaction solution was adjusted to 3. The ice-water bath was then removed, and the mixture was stirred at room temperature for 8 hours. The reaction was monitored by TLC until it was complete. After the reaction was complete, the flask was placed in an ice-water bath, and 1M / L NaOH was slowly added dropwise to the reaction system until the pH of the reaction solution was adjusted to 13. Then, the mixture was extracted separately with water (30 mL) and ethyl acetate (3 × 30 mL), the organic phases were combined, dried over anhydrous Na2SO4, evaporated to dryness, and purified by silica gel rapid chromatography to obtain 682 mg of 4-bromo-1-((1,3-dimethyl-1-H-pyrazol-4-yl)methyl)piperidine, as a colorless liquid, with a yield of 63%.

[0032] The detection results for 4-bromo-1-((1,3-dimethyl-1-H-pyrazol-4-yl)methyl)piperidine were as follows:

[0033] 1 H NMR (400 MHz, CDCl3) δ 7.20 (s, 1H), 4.16 (s, 1H), 3.79 (s, 3H), 3.30 (s, 2H), 2.74 – 2.65 (m, 2H), 2.30 – 2.18 (m, 5H), 2.16 – 2.09 (m, 2H),2.00 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 147.6, 130.5, 115.1, 115.1, 51.8,50.1, 38.4, 36.3, 11.8. FTIR (KBr, cm −1 ) ν: 2942, 2802, 1563, 1447, 1195,1110, 991, 793. HRMS (ESI-TOF) m / z: [M + H] + Calculated for C 11 H 19 BrN3 + 272.0757;Found 272.0756.

[0034] Step 2: Preparation of methyl 4-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)benzoate

[0035]

[0036] In a dry three-necked flask (50 mL with a magnetic induction device), a zinc plate (15 mm × 15 mm × 0.6 mm) was used as the anode and a PAN-based carbon felt (15 mm × 15 mm × 0.6 mm) as the cathode. Methyl 4-cyanobenzoate (966 mg, 6.0 mmol) and tetraethylammonium chloride (994 mg, 6.0 mmol) were added to the reaction system. The air in the reaction system was replaced with nitrogen using a double-row tube. This process was repeated three times. Then, 4-bromo-1-((1,3-dimethyl-1-H-pyrazol-4-yl)methyl)piperidine (540 mg, 2.0 mmol) and acetonitrile (30 mL) were added to the three-necked flask using a syringe. After stirring, the mixture was electrolyzed at room temperature for 15 hours with direct current (12 mA). The reaction was monitored by TLC until it was complete. After the reaction was complete, the reaction solution was concentrated by evaporation and purified by silica gel rapid chromatography to obtain methyl 4-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)benzoate, 331 mg, as a colorless liquid, with a yield of 51%.

[0037] The detection results of methyl 4-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)benzoate are as follows:

[0038] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz, 2H), 7.29 (s, 1H), 7.26(d, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.81(s, 3H), 3.39 (s, 2H), 3.03 (d, J = 12.0Hz, 2H), 2.56 – 2.50 (m, 1H), 2.24 (s, 3H), 2.06 (td, J = 11.2, 3.6 Hz, 2H),1.82 – 1.79 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 167.1, 151.8, 147.9, 130.7,129.8, 128.1, 126.9, 115.0, 53.6, 52.1, 52.0, 42.7, 38.5, 33.1, 11.9. FTIR(KBr, cm −1 ) ν: 2936, 2800, 1723, 1610, 1437, 1279, 1110, 769. HRMS (ESI-TOF)m / z: [M + H] + Calculated for C 19 H 26 N3O2 + 328.2020; Found 328.2014.

[0039] Step 3: Preparation of zebenosatine

[0040]

[0041] Potassium tert-butoxide (336 mg, 3.0 mmol) was added to a mixed solvent of tetrahydrofuran (20 mL) and water (0.2 mL), and stirred at room temperature for 5 minutes. Then, methyl 4-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)benzoate (327 mg, 1.0 mmol) and o-phenylenediamine (216 mg, 2.0 mmol) were added, and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, water (30 mL) and dichloromethane (3 × 30 mL) were added for extraction, the organic phases were combined, dried over anhydrous Na₂SO₄, and purified by rapid silica gel chromatography to give zebenosat, 92.7 mg, as a white solid, in a yield of 23%.

[0042] The test results for Zabadinostat (CXD101) are as follows:

[0043] 1 H NMR (400 MHz, DMSO) δ 9.63 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.44(s, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.17 (s, 1H), 6.96 (t, J = 7.2 Hz, 1H), 6.78 (d, J = 7.2 Hz, 1H), 6.60 (d, J= 7.2 Hz, 1H), 4.90 (s, 2H), 3.71 (s, 3H), 3.28(s, 2H), 2.92 (d, J = 11.2 Hz, 2H), 2.56 (dt, J = 12.0, 3.6 Hz, 1H), 2.12 (s,3H), 1.98 (t, J = 10.4 Hz, 2H), 1.75 (d, J = 11.2 Hz, 2H), 1.66 (td, J = 12.0, 3.6Hz, 2H). 13 C NMR (100 MHz, DMSO) δ 165.7, 150.4, 146.7, 143.5, 132.9, 131.4,128.4, 127.1, 127.1, 126.8, 124.0, 116.7, 116.6, 115.0, 53.6, 52.1, 42.3,38.5, 33.4, 12.1. FTIR (KBr, cm −1 ) ν: 2927, 1647, 1505, 1455, 1315, 127, 1097,750. HRMS (ESI-TOF) m / z: [M + H] + Calculated for C 24 H 30 N5O + 404.2445; Found 404.2454.

[0044] Although the description of the invention has been quite detailed and particularly of several described embodiments, it is not intended to limit it to any of these details or embodiments or any particular embodiment, but should be considered as providing a broad possible interpretation of the claims by referring to the appended claims and taking into account the prior art, thereby effectively covering the intended scope of the invention. Furthermore, the invention has been described above with respect to embodiments foreseeable by the inventors in order to provide a useful description, and non-substantial modifications to the invention that have not yet been foreseen may still represent equivalent modifications.

Claims

1. A method for preparing zebenosstat, characterized in that, Its preparation process specifically includes the following steps: Step 1: Add zinc chloride to a methanol solution of 1,3-dimethylpyrazol-4-carboxaldehyde, 4-bromopiperidine hydrochloride, and sodium cyanoborohydride. Stir at room temperature for 1 hour, then cool the reaction system to 0°C in an ice-water bath. Slowly add concentrated hydrochloric acid at 0°C until the pH of the reaction solution is adjusted to 3. Remove the ice-water bath and stir the reaction solution at room temperature for 8 hours. After the reaction is complete, transfer the reaction system to an ice-water bath and slowly add 1M NaOH until the pH of the reaction solution is adjusted to 13. Then, extract with water and ethyl acetate separately, combine the organic phases, and purify by silica gel rapid chromatography to obtain 4-bromo-1-((1,3-dimethyl-1-H-pyrazol-4-yl)methyl)piperidine. Step 2: In a dry electrolytic cell, a zinc sheet is installed as the anode and a PAN-based carbon felt as the cathode. Methyl 4-cyanobenzoate and tetraethylammonium chloride are added to the reaction system, and the air in the reaction system is replaced with nitrogen. Then, 4-bromo-1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidine and acetonitrile are added. After stirring evenly, electrolysis is carried out by direct current at room temperature. After the reaction is completed, the reaction solution is concentrated and purified by silica gel chromatography to obtain methyl 4-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidine-4-yl)benzoate. Step 3: Potassium tert-butoxide was added to a mixed solvent of tetrahydrofuran and water and stirred at room temperature for 5 minutes. Then, methyl 4-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)benzoate and o-phenylenediamine were added and stirred at room temperature for 6 hours. After the reaction was completed, water and dichloromethane were added for extraction, the organic phases were combined, dried with anhydrous Na2SO4, and purified by silica gel chromatography to finally obtain zebenosatine.

2. The method for preparing zebenostat according to claim 1, characterized in that, In step 1, the molar ratio of 1,3-dimethylpyrazole-4-carboxaldehyde, 4-bromopiperidine hydrochloride, sodium cyanoborohydride, and zinc chloride is 1:1.2:1.2:1.

2.

3. The method for preparing zebenostat according to claim 1, characterized in that, In step 2, the molar ratio of methyl 4-cyanobenzoate and 4-bromo-1-((1,3-dimethyl-1-H-pyrazol-4-yl)methyl)piperidine is 3:

1.

4. The method for preparing zebenostat according to claim 1, characterized in that, In step 2, the electrolyte solution in the electrolytic cell is an acetonitrile solution of tetraethylammonium chloride, which is obtained by dissolving tetraethylammonium chloride in acetonitrile in the reaction system.

5. The method for preparing zebenostat according to claim 4, characterized in that, The concentration of the electrolyte solution is 0.2 mol / L.

6. The method for preparing zebenostat according to claim 1, characterized in that, In step 3, the molar ratio of potassium tert-butoxide, methyl 4-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)benzoate and o-phenylenediamine is 3:1:

2.

7. The method for preparing zebenostat according to claim 1, characterized in that, In steps 1, 2, and 3, the reagents used for rapid silica gel chromatography purification are petroleum ether and ethyl acetate.

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