Synthetic method of pyrazole derivative
By using Gphos Pd G6 catalyst and sodium trimethylsilanol base to carry out CN coupling reaction under nitrogen protection, the problem of catalyst poisoning was solved, and the efficient and selective synthesis of pyrazole derivatives was achieved, which reduced the cost and expanded the substrate applicability.
Patent Information
- Application Number
- CN202510720802.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-30
- Publication Date
- 2025-10-10
AI Technical Summary
The problem of catalyst poisoning in existing CN coupling reactions makes it impossible to directly couple the compounds. In addition, transition metal palladium catalysts are expensive, the reaction conditions are harsh, and the yield and selectivity are low.
Gphos Pd G6 was used as a catalyst and sodium trimethylsilanol as a base. The reaction was carried out under nitrogen protection, the reaction material ratio was optimized, the subsequent treatment steps were simplified, and the CN coupling reaction was carried out under mild conditions.
The yield and selectivity of the reaction are improved, the processing steps are simplified, the production cost is reduced, the applicable scope of the substrate is broadened, and a new synthetic strategy is provided.
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Figure CN120757538A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for synthesizing a pyrazole derivative. Background Art
[0002] Nitrogen heterocycles are the most common substructures found in pharmaceuticals, agrochemicals, and natural products, and they play a key role in many drugs. A survey of all small molecule drugs conducted by the US Food and Drug Administration between 2015 and June 2020 found that 88% contained one or more N-heterocyclic subunits, with pyridine, piperidine, pyrimidine, pyrazole, and indole being the five most representative N-heterocycles. Nitrogen heterocycles are ubiquitous in drug design because these functional groups can modulate the polarity, solubility, lipophilicity, and hydrogen bonding properties of small molecules, thereby regulating their corresponding ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties. Therefore, the incorporation of nitrogen heterocycles into synthetic building blocks is crucial. Numerous methods exist for the introduction of nitrogen heterocycles into a structure, with the CN coupling reaction being the most straightforward. Previous research has led to continuous improvements in reaction conditions and catalysts, expanding the range of substrates suitable for CN coupling, and thus facilitating the incorporation of nitrogen heterocycles.
[0003] The CN cross-coupling reaction is an important method for forming the CN bond of aromatic amines. The CN coupling to construct aromatic amine derivatives has attracted the interest of many organic chemists and has become a research hotspot in this field. Finding a simple and efficient method to construct aromatic amine derivatives is the goal pursued by organic synthesis workers. The classic methods for synthesizing aromatic amines include nitration reduction method, Jourdan synthesis method
[11] , Ullmann synthesis method, Goldberg synthesis method, etc. However, the reaction conditions of these methods are relatively harsh, and the yield of such reactions is relatively low and the selectivity of the reaction is poor. In the 1990s, Hartwig of Yale University and Buchwald of Massachusetts Institute of Technology almost simultaneously and independently developed the palladium-catalyzed CN bond formation reaction and developed an important method for CN bond construction, which was later called Buchwald-Hartwig cross-coupling reaction. As a result, transition metal-catalyzed CN coupling reaction has developed rapidly. In the current research on CN coupling, domestic researchers have carried out the design and synthesis of a variety of catalysts, such as transition metal catalysts, organic small molecule catalysts and photocatalysts. Among them, palladium-catalyzed CN coupling reaction is one of the most common and effective methods. Professor Xue Dong's team has achieved photopromoted nickel-catalyzed direct CN coupling reactions of nitroarenes with aromatic halides. This CN coupling reaction has been used to synthesize a variety of pharmaceutically active compounds, such as anticancer, antiviral, and antibacterial drugs. Stephen Buchwald is dedicated to developing highly efficient catalysts, such as palladium catalysts and copper catalysts. Furthermore, new catalysts, such as iron and gold catalysts, have been proposed, enabling the synthesis of numerous important pharmaceutical molecules, such as anti-inflammatory, anticancer, and antibacterial drugs, through CN coupling reactions. Furthermore, research is focused on synthetic drug libraries and high-throughput screening.
[0004] Overall, the CN coupling reaction has received extensive attention and research both domestically and internationally, with new catalysts and reaction conditions continually being discovered and developed. These studies have provided important support and impetus for the development of synthetic organic chemistry and related fields.
[0005] The CN coupling reaction is a type of organic synthesis reaction, typically referring to the chemical reaction that forms bonds between carbon and nitrogen atoms in aromatic or heterocyclic compounds. This reaction can be used to construct carbon-nitrogen bonds in nitrogen-containing organic molecules and is a widely used method in modern organic chemistry. The mechanism of the CN coupling reaction involves coordination between an organic substrate and a nitrogen-source ligand, generating an intermediate that is then eliminated and reacts with another organic substrate to form a CN bond. The choice of nitrogen-source ligand significantly influences the reaction rate and yield; commonly used ligands include various amines, ammonia, and thiazole. The CN coupling reaction has broad application prospects and continues to attract significant attention. Previous research has further improved the reaction conditions, enabling the reaction to proceed even at low catalyst loadings and room temperature using a soluble neutral base with good yields. Continuous improvements in catalysts have broadened the scope of its substrate applicability. However, challenges remain, such as catalyst selectivity for a given compound class and the need for CN coupling of polynitrogen compounds and substrates with multiple nucleophilic groups, which require consideration of regioselectivity and various mechanistic considerations. Secondly, the price of transition metal palladium catalyst is relatively expensive. Summary of the Invention
[0006] The present invention provides a method for synthesizing pyrazole derivatives, so as to solve the common problem of catalyst poisoning encountered in the CN coupling reaction of existing heterocyclic compounds and the problem that the coupling cannot be directly achieved.
[0007] The present invention provides a method for synthesizing a pyrazole derivative, comprising:
[0008] Under nitrogen protection, 5-bromo-3-(4-chlorophenyl)-1-methyl-1H-pyrazole represented by formula (1) and 3-(Boc-amino)pyrrolidine represented by formula (2) are reacted as reactants in the presence of a catalyst, a base and a solvent to obtain a coupling product of formula (3);
[0009]
[0010] Among them, R is Cl, OCH3, CH3, H.
[0011] The present invention efficiently promotes the CN coupling reaction: Under nitrogen protection, through a carefully designed material ratio, including specific reactants, catalysts, and base, the method effectively promotes the occurrence of the CN coupling reaction. This reaction method can be carried out under mild conditions, avoiding harsh conditions such as high temperature or high pressure, thereby improving the safety and operability of the reaction.
[0012] Improving reaction yield and selectivity: Using Gphos Pd G6 as catalyst can significantly improve the yield and selectivity of the reaction. This catalyst has excellent catalytic performance, which can accelerate the progress of key steps during the reaction process, while reducing the generation of by-products, thereby improving the purity and yield of the target product.
[0013] Simplifying subsequent processing steps: Through reasonable subsequent processing steps, including quenching, extraction, drying, vacuum distillation and purification, the method can efficiently separate and purify the target product. The simplification of these steps not only improves the efficiency of the entire synthesis process, but also reduces production cost and environmental pollution.
[0014] Broadening the scope of substrate application: The reactants and conditions used in this method have certain universality, which can be applied to the synthesis of various polyazacyclic compounds. This means that this method not only applies to the specific reaction system described at present, but also can be further extended to the synthesis of other similar compounds, providing a new synthesis strategy for the field of organic chemical synthesis.
[0015] In summary, this technical method realizes the efficient and high-selectivity synthesis of polyazacyclic compound target products by optimizing reaction conditions, selecting appropriate catalysts and ligands, and simplifying subsequent processing steps, providing a new technical approach and solution for the field of organic chemical synthesis. BRIEF DESCRIPTION OF DRAWINGS
[0016] Figure 1 Synthesis route map provided for the embodiments of the present application;
[0017] Figure 2 Product prepared for Example 1 of the present application 1 H NMR chart;
[0018] Figure 3 Product prepared for Example 1 of the present application 13 C NMR chart;
[0019] Figure 4 Product prepared for Example 2 of the present application 1 H NMR chart;
[0020] Figure 5 Product prepared for Example 2 of the present application 13 C NMR chart;
[0021] Figure 6 Product prepared for Example 3 of the present application 1 H NMR chart;
[0022] Figure 7 Product prepared for Example 3 of the present application 13 C NMR chart;
[0023] Figure 8 The product prepared by Example 4 of the present invention 1 H NMR spectrum;
[0024] Figure 9 The product prepared by Example 4 of the present invention 13 C NMR spectrum. DETAILED DESCRIPTION
[0025] The invention is illustrated by the following examples.
[0026] like Figure 1 As shown, the present invention first investigates how to achieve C-N coupling of nitrogen heterocyclic substrates. After determining a method, various conditions are screened, including catalysts, ligands, bases, and solvents. Ultimately, Gphos PdG6 is determined as a catalyst and sodium trimethylsilanol is used as a base. The reaction is carried out under heating conditions. The methyl-substituted pyrazole ring is successfully coupled with the five-membered pyrrole ring to obtain the target product in good yield. If the hydrogen on the nitrogen of the pyrazole ring is exposed or protected by a relatively sterically hindered protecting group, the reaction still cannot proceed.
[0027] The structural formula of the catalyst is:
[0028]
[0029] Technical route:
[0030] After the synthesis method is determined, the applicability of the method is verified by replacing different groups.
[0031]
[0032] Wherein, R is CH3, H, OCH3, Cl.
[0033] like Figure 1 The following compounds were synthesized using the current synthetic method using the experimental scheme shown in the figure, and all obtained good yields.
[0034]
[0035] The method for the CN coupling reaction of polynitrogen heterocyclic compounds provided by the present invention has a high yield and mild reaction conditions based on current coupling results, and has good applicability to such substrates. At the same time, the research interest in CN coupling is only increasing, and there is sufficient literature as a reference.
[0036] Example 1
[0037]
[0038] 0.24mmol of 3-(Boc-amino)pyrrolidine, 0.20mmol of 5-bromo-1-methyl-3-(p-tolyl)-1H-pyrazole, 0.01mmol of catalyst and 0.21mmol of sodium trimethylsilanolate were added to a dry reaction tube, nitrogen was replaced to expel oxygen from the system, nitrogen was protected, and an appropriate amount of toluene was added with a long needle to dissolve the above substrates. The reaction tube was placed in a casserole and stirred at 70°C for 4 hours. After the reaction was completed, dilute hydrochloric acid was added dropwise to quench the reaction, extracted with dichloromethane and water, and the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. After purification, the coupling product (24.94mg, 35%) was obtained, as shown in FIG. Figure 2 and Figure 3 shown.
[0039] 1 H NMR (800MHz, CDCl3) δ7.55–7.48(m,2H),7.23–7.15(m,2H),7.03(d,J=7.5Hz,1H),6.93(s,1H),4.18(s,1H),3.79(s,3H),3.09(d ,J=4.9Hz,1H),2.93–2.78(m,2H),2.64(d,J=7.3Hz,1H),2.31(s,3H),2.22(d,J=7.5Hz,1H),1.65(d,J=6.2Hz,1H),1.37(s,9H). 13 C NMR (201 MHz, CDCl3) δ
[0040] 154.30(s),140.96(s),136.78(s),132.91(s),131.95(s),127.12(s),126.86(s),126.84(s),123.44 (s),117.84(s),78.39(s),58.33(s),50.04(s),49.15(s),38.21(s),31.64(s),27.40(s),20.48(s).
[0041] Example 2
[0042]
[0043] 0.24mmol of 3-(Boc-amino)pyrrolidine, 0.20mmol of 5-bromo-3-(4-chlorophenyl)-1-methyl-1H-pyrazole, 0.01mmol of catalyst and 0.21mmol of sodium trimethylsilanol were added to a dry reaction tube, nitrogen was replaced to expel oxygen from the system, nitrogen was protected, and an appropriate amount of toluene was added with a long needle to dissolve the above substrates. The reaction tube was placed in a casserole and stirred at 90°C for 8 hours. After the reaction was completed, dilute hydrochloric acid was added dropwise to quench the reaction, extracted with dichloromethane and water, and the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. After purification, the coupling product (32.35mg, 43%) was obtained, as shown in FIG. Figure 4 and Figure 5 shown.
[0044] 1 H NMR (800MHz, CDCl3) δ7.59(d,J=7.9Hz,2H),7.12(d,J=7.9Hz,2H),6.93(s,1H),4.15(d,J=31.5Hz,1H),3.79(s,3H),3.41(d,J=6.0Hz,1H),2.90 (dd,J=9.6,6.1Hz,1H),2.81(d,J=7.3Hz,1H),2.62(d,J=7.2Hz,1H),2.30(s,1H),2.17–2.13(m,1H),1.94(dd,J=12.7,7.0Hz,1H),1.38(s,9H). 13 C NMR(201MHz, CDCl3)δ154.32(s),139.83(s),132.06(s),131.78(s),131.51(s),128.87(s),127.44( s),125.56(s),100.76(s),78.53(s),58.43(s),50.18(s),49.12(s),34.91(s),33.30(s),27.40(s).
[0045] Example 3
[0046]
[0047] 0.24mmol of 3-(Boc-amino)pyrrolidine, 0.20mmol of 5-bromo-3-(4-methoxyphenyl)-1-methyl-1H-pyrazole, 0.01mmol of catalyst and 0.21mmol of sodium trimethylsilanol were added to a dry reaction tube, nitrogen was replaced to expel oxygen from the system, nitrogen was protected, and an appropriate amount of toluene was added with a long needle to dissolve the above substrates. The reaction tube was placed in a casserole and stirred at 85°C for 4 hours. After the reaction was completed, dilute hydrochloric acid was added dropwise to quench the reaction, extracted with dichloromethane and water, and the organic layers were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. After purification, the coupling product (23.82mg, 32%) was obtained, as shown in FIG. Figure 6 and Figure 7 shown.
[0048] 1 H NMR (800MHz, CDCl3) δ7.63(d,J=8.7Hz,2H),6.92(s,1H),6.86(d,J=8.8Hz,2H),4.75(s,1H),4.18(s,1H),3.78(s,3H),3.76(s,3H), 3.07(d,J=4.9Hz,1H), 2.91(dd,J=9.7,6.2Hz,1H), 2.79(d,J=7.7Hz,1H), 2.62(d,J=7.2Hz,1H), 2.21(d,J=7.1Hz,1H), 1.38(s,9H). 13 C NMR (201 MHz, CDCl3) δ
[0049] 157.76(s),154.32(s),140.79(s),131.63(s),127.52(s),125.69(s),117.80(s),112.66 (s),78.40(s),58.31(s),54.22(s),50.10(s),49.13(s),38.15(s),31.60(s),27.41(s).
[0050] Example 4
[0051]
[0052] Into a dry reaction vial, 0.24 mmol of 3-(Boc-amino)pyrrolidine, 0.20 mmol of 5-bromo-1-methyl-3-phenyl-1H-pyrazole, 0.01 mmol of catalyst and 0.21 mmol of sodium trimethylsilanolate were added. The system was purged with nitrogen to remove oxygen, and the substrates were dissolved in an appropriate amount of toluene using a long needle. The reaction vial was placed in a sand bath at 90 °C and stirred for 5 hours. After the reaction was completed, the reaction was quenched by adding dilute hydrochloric acid dropwise, extracted with dichloromethane and water, and the organic layers were combined and dried over anhydrous sodium sulfate and then distilled under reduced pressure. The coupling product (27.38 mg, 40%) was obtained after purification, as shown in Figure 8 and Figure 9
[0053] 1 H NMR (800 MHz, CDC13) δ 7.86 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.19 (s, 1H), 6.99 (s, 1H), 4.19 (s, 1H), 3.81 (s, 3H), 3.08 (s, 1H), 2.95 - 2.89 (m, 1H), 2.83 (d, J = 8.2 Hz, 1H), 2.65 (d, J = 7.1 Hz, 1H), 1.66 (dd, J = 12.0, 5.1 Hz, 1H), 1.56 (dd, J = 14.8, 7.5 Hz, 1H), 1.38 (s, 9H). 13 C NMR (201 MHz, CDC13) δ 154.32 (s), 139.48 (s), 136.58 (s), 132.53 (s), 126.13 (s), 124.18 (d, J = 3.0 Hz), 118.39 (s), 106.59 (s), 78.57 (s), 58.55 (s), 50.27 (s), 49.15 (s), 38.38 (s), 31.45 (s), 27.38 (s).
[0054] Example 5: Synthesis of pyrazole derivatives using potassium carbonate as inorganic base
[0055] Into a dry reaction vial, 0.24 mmol of 3-(Boc-amino)pyrrolidine (Formula 2), 0.20 mmol of 5-bromo-3-(4-chlorophenyl)-1-methyl-1H-pyrazole (Formula 1, R = CI), 0.01 mmol of Gphos Pd G6 catalyst and 0.21 mmol of potassium carbonate (K2CO3, inorganic base) were added. The system was purged with nitrogen three times to remove oxygen, and a nitrogen atmosphere was maintained. An appropriate amount of anhydrous toluene was added using a long needle to dissolve the substrates. The reaction vial was placed in a 90 °C oil bath and stirred for 4 hours.
[0056] After the reaction, the mixture was cooled to room temperature and quenched by the dropwise addition of 1 M hydrochloric acid solution. The mixture was extracted with dichloromethane (3 × 10 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain the product as a white solid (21.5 mg, 29% yield).
[0057] 1 H NMR (800MHz, CDCl3) δ7.58(d,J=8.0Hz,2H),7.13(d,J=8.0Hz,2H),6.92(s,1H),4.16(br s,1H),3.79(s,3H),3.40(d,J=6.2Hz,1H),2.90(dd,J=9.6,6.2Hz,1H),2.81(d,J=7.2Hz,1H),2.62(d,J=7.2Hz,1H),2.30(br s,1H),2.17–2.13(m,1H),1.94(dd,J=12.8,7.0Hz,1H),1.38(s,9H).
[0058] 13C NMR(201MHz, CDCl3)δ154.31(s),139.82(s),132.05(s),131.77(s),131.50(s),128.86(s),127.43( s),125.55(s),100.75(s),78.52(s),58.42(s),50.17(s),49.11(s),34.90(s),33.29(s),27.39(s).
[0059] Example 6: Synthesis of pyrazole derivatives with a molar ratio of 1:1
[0060] Add 0.20 mmol of 3-(Boc-amino)pyrrolidine (Formula 2), 0.20 mmol of 5-bromo-3-(4-chlorophenyl)-1-methyl-1H-pyrazole (Formula 1, R=Cl), 0.01 mmol of Gphos Pd G6 catalyst, and 0.21 mmol of sodium trimethylsilanol to a dry, sealed reaction tube. After purging the reaction mixture with nitrogen three times, add 2.0 mL of anhydrous toluene and stir at 90°C for 4 hours.
[0061] After treatment, the residue was purified by column chromatography to obtain the desired product (25.6 mg, 34% yield).
[0062] 1 The H NMR and 13C NMR data were the same as those in Example 2.
[0063] Example 7: Synthesis of pyrazole derivatives with a molar ratio of 1:3
[0064] Add 0.60 mmol of 3-(Boc-amino)pyrrolidine (Formula 2), 0.20 mmol of 5-bromo-3-(4-chlorophenyl)-1-methyl-1H-pyrazole (Formula 1, R=Cl), 0.01 mmol of Gphos Pd G6 catalyst, and 0.21 mmol of sodium trimethylsilanol to a dry, sealed reaction tube. After purging the reaction mixture with nitrogen three times, add 2.0 mL of anhydrous toluene and stir at 90°C for 4 hours.
[0065] After treatment, the residue was purified by column chromatography to obtain the desired product (38.7 mg, 52% yield).
[0066] 1 The H NMR and 13C NMR data were the same as those in Example 2.
[0067] Example 8: Synthesis of pyrazole derivatives with a molar ratio of 1:5
[0068] Add 1.0 mmol of 3-(Boc-amino)pyrrolidine (Formula 2), 0.20 mmol of 5-bromo-3-(4-chlorophenyl)-1-methyl-1H-pyrazole (Formula 1, R=Cl), 0.01 mmol of Gphos Pd G6 catalyst, and 0.21 mmol of sodium trimethylsilanol to a dry, sealed reaction tube. After purging the reaction chamber with nitrogen three times, add 2.0 mL of anhydrous toluene and stir at 90°C for 4 hours.
[0069] After treatment, the residue was purified by column chromatography to obtain the desired product (40.1 mg, 54% yield).
[0070] 1 The H NMR and 13C NMR data were the same as those in Example 2.
Claims
1. A method for synthesizing a pyrazole derivative, characterized in that: include: Under nitrogen protection, 5-bromo-3-(4-chlorophenyl)-1-methyl-1H-pyrazole represented by formula (1) and 3-(Boc-amino)pyrrolidine represented by formula (2) are reacted as reactants in the presence of a catalyst, a base and a solvent to obtain a coupling product of formula (3); Among them, R is Cl, OCH3, CH3, H.
2. The method according to claim 1, characterized in that The molar ratio of 5-bromo-3-(4-chlorophenyl)-1-methyl-1H-pyrazole represented by formula (1) to 3-(Boc-amino)pyrrolidine represented by formula (2) is 1:1-5.
3. The method according to any one of claims 1-2, characterized in that The catalyst is a palladium catalyst.
4. The method according to claim 3, characterized in that The structural formula of the palladium catalyst is:
5. The method according to any one of claims 1-2, characterized in that The base is an inorganic base or an organic base.
6. The method according to claim 5, characterized in that The organic base is sodium trimethylsilanol, and the inorganic base is potassium carbonate.
7. The method according to any one of claims 1-2, characterized in that The solvent is toluene.
8. The method according to any one of claims 1-2, characterized in that The temperature is 70°C-90°C.
9. The method according to any one of claims 1-2, characterized in that The reaction time is 4-8 hours.