Synthesis method of pyrrolidine structural unit compound

Abstract

The invention discloses a brand-new synthesis method of a pyrrolidine structural unit compound, high-yield and high-selectivity synthesis is realized by utilizing an efficient cross-coupling reaction of a Ni catalyst and a 1, 6-diene compound, the method takes the diene compound as a raw material, and through a simple cyclization reaction, the pyrrolidine structural unit compound is obtained. The pyrrolidine structural unit compound can be obtained in one step under mild conditions. Compared with a traditional synthesis method, the method has the advantages of simple steps, high yield, cheap and easily available raw materials, environmental friendliness and the like; by adjusting the structural formula of the diene compound, multiple pyrrolidine structural unit compounds with different substituent groups can be synthesized, and the compounds have wide application potential in multiple fields of drug research and development, pesticide manufacturing, material science and the like; the synthesis method provided by the invention not only simplifies tedious steps of a traditional synthesis method, but also greatly reduces the production cost, provides powerful support for large-scale production of pyrrolidine compounds, and provides an important raw material source for development of heterocyclic drug molecules.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing a pyrrolidine structural unit compound. Background Art

[0002] Five-membered nitrogen-containing heterocyclic compounds, especially pyrrolidine structural units, have shown extraordinary importance and wide application potential in both nature and artificial synthesis. These compounds are not only abundant and diverse in various natural products and bioactive molecules, but also play an indispensable role in drug development, pesticide manufacturing, and materials science. Therefore, in-depth exploration of efficient synthetic routes for pyrrolidine structural units is of great significance for promoting scientific and technological progress in related fields.

[0003] However, traditional synthesis methods often have problems such as cumbersome steps, low yield, expensive raw materials or environmental unfriendliness, which limit the further application and development of these compounds. Traditional synthesis methods often involve multiple steps and complex reaction conditions. The raw materials need to be pretreated first, and then the target molecule is gradually constructed through multi-step reactions, which not only increases the complexity of the synthesis, but also leads to reduced purity and yield of the product; due to the difficulty in accurately controlling the reaction conditions, poor catalyst effect or low raw material conversion rate, the yield of the product is not high, which not only increases the production cost, but also limits the large-scale production of the compound; the raw materials used are relatively expensive, usually precious metal catalysts or rare chemical reagents. The high cost of these raw materials makes the entire synthesis process uneconomical, limiting the wide application of the compound. In addition, traditional synthesis methods are not environmentally friendly.

[0004] Currently, transition metal-catalyzed cross-coupling reactions have become an innovative and efficient means of constructing carbon-carbon bonds. In this field, transition metals such as Pd, Rh, Ru, Co, and Ni have attracted much attention due to their excellent catalytic performance and coupling ability. However, although these precious metal catalysts have achieved remarkable results in both laboratory and industrial applications, their scarcity in the earth's crust, the difficulty of refining, and the high cost have severely limited their large-scale and long-term application prospects.

[0005] Given the limitations of precious metal catalysts, finding and developing cheap and efficient metal catalysts has become a research hotspot in the current field of catalytic chemistry. Ni catalysts stand out in this field with their excellent metal properties and significant catalytic effects, becoming an ideal choice to replace precious metal catalysts. Ni catalysts are not only affordable, but also have stable catalytic performance, are easy to operate and recycle, and provide new possibilities for building carbon-carbon bonds.

[0006] On the other hand, 1,6-diene compounds, as important raw materials for constructing pyrrolidine structural units, have the advantages of wide sources, easy availability, and up to 100% atomic utilization rate. This characteristic makes 1,6-diene compounds have extremely high application value in the synthesis of pyrrolidine derivatives. Summary of the invention

[0007] In view of the current technical status that traditional synthesis methods of pyrrolidine compounds have the problems of complicated steps, low yield, expensive raw materials and unfriendly environment, which limit the further application and development of these compounds, the present invention aims to provide a new synthesis method of pyrrolidine structural unit compounds, which fully utilizes the advantages of Ni catalyst and 1,6-diene compounds, and realizes the high-yield and high-selectivity synthesis of pyrrolidine structural unit compounds through efficient cross-coupling reaction. This innovative method not only solves the problems existing in traditional synthesis methods, but also provides strong support for the large-scale production of pyrrolidine compounds.

[0008] The present invention solves the above technical problems through the following technical means: The invention provides a method for synthesizing a pyrrolidine structural unit compound. The method uses a diene compound as a raw material, a nickel salt as a catalyst, triphenylphosphine as a ligand, zinc powder as a reducing agent, and zinc iodide as an additive, and performs a cyclization reaction in an organic solvent to separate and obtain the pyrrolidine structural unit compound. Wherein, the structural formula of the diene compound is , X is any one of p-toluenesulfonamide, p-trifluoromethylbenzenesulfonamide, benzenesulfonamide, methylsulfonamide, and tert-butylsulfonamide; and R1 is any one of an alkyl group having 1 to 3 carbon atoms.

[0009] The nickel salt is any one or a combination of NiCl2, NiBr2, NiI2, and Ni(COD)2.

[0010] Furthermore, the nickel salt is NiCl2.

[0011] In the structural formula of the diene compound, X is any one of p-toluenesulfonamide, p-trifluoromethylbenzenesulfonamide, benzenesulfonamide, methylsulfonamide, and tert-butylsulfonamide; and R1 is any one of an alkyl group having 1 to 3 carbon atoms.

[0012] Furthermore, R1 is any one of methyl, ethyl and n-propyl.

[0013] Furthermore, the structural formula of the diene compound is , , , , , , and Any one of .

[0014] The molar ratio of the nickel salt to the diene compound is 5-10:100, the molar ratio of the zinc powder to the diene compound is 1:1, and the molar ratio of the zinc iodide to the diene compound is 10-50:100.

[0015] The cyclization reaction temperature is 20°C to 25°C, and the reaction time is 20 h to 26 h.

[0016] The organic solvent is any one or a combination of dichloromethane, chloroform, dibromomethane and dichloroethane.

[0017] The separation was carried out by chromatography, and the eluent was petroleum ether and ethyl acetate in a volume ratio of 40:1.

[0018] The method further comprises distilling or recrystallizing the obtained pyrrolidine structural unit compound under reduced pressure to obtain a pure product of the pyrrolidine structural unit compound.

[0019] The present invention provides a pyrrolidine structural unit compound obtained by the synthesis method of the pyrrolidine structural unit compound.

[0020] The structural formula of the pyrrolidine structural unit compound is and Any of the following; Wherein, X is any one of p-toluenesulfonamide, p-trifluoromethylbenzenesulfonamide, benzenesulfonamide, methylsulfonamide, and tert-butylsulfonamide; and R2 and R3 are any one of an alkyl group having 1 to 2 carbon atoms.

[0021] Furthermore, R2 is any one of a hydrogen atom and a methyl group; R3 is any one of a hydrogen atom and an ethyl group.

[0022] The pyrrolidine structural unit compound of the present invention is used in the development of heterocyclic drug molecules. The pyrrolidine structural unit compound is a synthetic raw material for heterocyclic drug molecules.

[0023] Compared with the prior art, the present invention achieves the following technical effects: The method for synthesizing a pyrrolidine structural unit compound provided by the present invention is a brand-new method for synthesizing a pyrrolidine structural unit compound. Compared with the traditional synthesis method, the method of the present invention can obtain the product in one step, simplifies the steps and improves the efficiency. This method uses diene compounds as raw materials for constructing pyrrolidine structural units, which have a wide range of sources, are simple and easy to obtain, and have an atomic utilization rate of up to 100%, making the synthesis method more flexible and adaptable in practical applications; nickel salts and ligands are used for catalysis, with high catalytic efficiency and good chemical selectivity. Compared with traditional precious metal catalysts (such as Pd, Rh, Ru, etc.), Ni catalysts are not only affordable, but also have stable catalytic performance, easy to operate and recycle, and greatly reduce production costs; by utilizing the advantages of Ni catalysts and 1,6-diene compounds, efficient cross-coupling reactions are achieved. This innovation not only simplifies the cumbersome steps of traditional synthesis methods, but also significantly improves the yield (51%-92%) and selectivity of the products; the target products are obtained with high chemical selectivity and excellent yield, and for terminal substituted olefins, cycloisomerization products of internal olefins can be obtained; the raw materials and catalysts used in the synthesis process are environmentally friendly, reducing the use and emissions of harmful substances, which is in line with the development trend of green chemistry.

[0024] Furthermore, by adjusting the structural formula of the diene compound, a variety of pyrrolidine structural unit compounds with different substituents can be synthesized; the reaction conditions are simple and mild, and the selectivity is high; the catalytic dosage is up to 5 mol%, and the time is extended to obtain a considerable yield to obtain a pyrrolidine structural unit compound. The pyrrolidine structural unit compound has different substituents and can be used to optimize existing drugs such as abrocitinib Rinvoq or acalabrutinib Calquence to improve their efficacy, reduce side effects or expand their indications; at the same time, the pyrrolidine structural unit compounds with different substituents of the present invention can be used to introduce different substituents to adjust the physicochemical properties and biological activities of the drug, thereby developing more advantageous new drug candidates. Therefore, the synthesis method of the pyrrolidine structural unit compound provided by the present invention simplifies the traditional synthesis method, improves the yield and selectivity of the product, reduces the production cost, and conforms to the development trend of green chemistry. The method also provides a new approach for drug research and development, and promotes the optimization of existing drugs and the development of new drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is the H NMR spectrum of the product prepared in Example 2 of the present invention; Figure 2 This is the NMR carbon spectrum of the product prepared in Example 2 of the present invention; Figure 3 This is the H NMR spectrum of the product prepared in Example 3 of the present invention; Figure 4 This is the NMR carbon spectrum of the product prepared in Example 3 of the present invention; Figure 5 This is the NMR fluorine spectrum of the product prepared in Example 3 of the present invention; Figure 6 This is the H NMR spectrum of the product prepared in Example 4 of the present invention; Figure 7 The NMR carbon spectrum of the product prepared in Example 4 of the present invention; Figure 8 This is the H NMR spectrum of the product prepared in Example 5 of the present invention; Fig. 9 This is the NMR carbon spectrum of the product prepared in Example 5 of the present invention; Fig.10 This is the H NMR spectrum of the product prepared in Example 6 of the present invention; Fig.11 This is the NMR carbon spectrum of the product prepared in Example 6 of the present invention; Fig.12 This is the H NMR spectrum of the product prepared in Example 7 of the present invention; Fig.13 This is the NMR carbon spectrum of the product prepared in Example 7 of the present invention; Fig.14 This is the H NMR spectrum of the product prepared in Example 8 of the present invention; Fig.15 This is the NMR carbon spectrum of the product prepared in Example 8 of the present invention; Fig.16 This is the H NMR spectrum of the product prepared in Example 9 of the present invention; Fig.17 This is the NMR carbon spectrum of the product prepared in Example 9 of the present invention; Fig.18 This is the H NMR spectrum of the product prepared in Example 10 of the present invention; Fig.19 This is the NMR carbon spectrum of the product prepared in Example 10 of the present invention; Fig. 20 This is the H NMR spectrum of the product prepared in Example 11 of the present invention; Fig.21 This is the H-NMR spectrum of the product prepared in Example 11 of the present invention; Fig. 22 This is the NMR fluorine spectrum of the product prepared in Example 11 of the present invention. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0027] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.

[0028] If no specific techniques or conditions are specified in the examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0029] Example 1 This example provides the preparation of a diene compound, and the diene compound is synthesized by referring to the method reported in the literature. and ( Adv. Synth. Catal. 2008, 350 , 1073-1080; Chem. Commun .2020, 56 ,7741-7744.), wherein GP is any one of toluenesulfonyl, p-trifluoromethylbenzenesulfonyl, benzenesulfonyl, methylsulfonyl, and tert-butylsulfonyl, R1 is a hydrogen atom, methyl, ethyl, or n-propyl, and Ts is p-toluenesulfonyl.

[0030] (1) Synthesis of diene compounds

[0031] The reaction formula is as follows:

[0032] Amine compounds (50 mmol), allyl bromide (60 mmol), potassium carbonate (200 mmol), and acetonitrile (80 mL) were added to a dry round-bottom flask as solvent, and refluxed in an oil bath at 85 °C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and column chromatographed (the eluent was petroleum ether and ethyl acetate in a volume ratio of 30:1) to obtain the diene compound. .

[0033] (2) Synthesis of diene compounds

[0034] The reaction formula is as follows:

[0035] Specific steps: add amine compound (100 mmol), allyl bromide (50 mmol), potassium carbonate (200 mmol), and acetonitrile (80 mL) as solvent into a dry round-bottom flask, and reflux in an oil bath at 85 °C for 12 h; after the reaction is completed, cool to room temperature, and then filter, concentrate under reduced pressure, and column chromatography (the eluent is petroleum ether and ethyl acetate in a volume ratio of 30:1) to obtain the pure product allyl p-sulfonamide.

[0036] Allyl p-sulfonamide (50 mmol), substituted alkenyl bromide (60 mmol), potassium carbonate (200 mmol) and acetonitrile (80 mL) were added to a dry round-bottom flask as solvents, and refluxed in an oil bath at 85 °C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and column chromatographed (eluent: petroleum ether: ethyl acetate) to obtain a pure diene compound. .

[0037] Example 2 This example provides a preparation method of a pyrrolidine structural unit compound based on Example 1, and the reaction formula is as follows:

[0038] 1,6-diene (10 mmol), NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added into a round-bottom flask, and 20 mL of dichloromethane solvent was added. The reaction was stirred at room temperature for 24 hours, and the target product, pyrrolidine compound, was separated by column chromatography (the eluent was petroleum ether and ethyl acetate in a volume ratio of 40:1) with a yield of 82%.

[0039] The NMR spectra of the pyrrolidine compound structure confirmation are shown in the attached Figure 1-2 As shown, the NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.70 – 7.64 (m, 2H), 7.30 (d, J = 8.1 Hz, 2H), 4.84 (dt, J =31.7, 2.3 Hz, 2H), 3.93 – 3.88 (m, 1H), 3.74 – 3.68 (m, 1H), 3.54 (dd, J = 8.6,6.8 Hz, 1H), 2.74 – 2.56 (m, 2H), 2.39 (s, 3H), 1.00 (d, J= 6.4 Hz, 3H). 13CNMR (151 MHz, CDCl3) δ 149.3, 143.6, 132.9, 129.7, 127.8, 106.0, 55.1, 52.2,37.4, 21.5, 16.1. The structural formula of the pyrrolidine structural unit compound is: .

[0040] Example 3 This example provides a preparation method of a pyrrolidine structural unit compound based on Example 1, and the reaction formula is as follows:

[0041] 1,6-diene (10 mmol), NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added into a round-bottom flask, and 20 mL of dichloromethane solvent was added. The reaction was stirred at room temperature for 24 hours, and the target product, pyrrolidine structural unit compound, was separated by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) with a yield of 88%.

[0042] The NMR spectra of the pyrrolidine structural unit compound structure confirmation are shown in the attached Figure 3-5 As shown, the NMR data are as follows: 1HNMR (600 MHz, CDCl3) δ 7.94 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 4.88(dq, J = 27.6, 2.3 Hz, 2H), 3.97 (dd, J = 17.6, 3.5 Hz, 1H), 3.77 (dq, J = 14.0,2.0 Hz, 1H), 3.60 (dd, J = 8.9, 7.2 Hz, 1H), 2.78 – 2.53 (m, 2H), 1.03 (d, J =6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 148.6, 140.0, 134.6 (q, J = 32.9 Hz),128.2, 126.4 (q, J= 3.7 Hz), 122.0, 106.7, 55.2, 52.2, 37.6, 16.0. 19F NMR(565 MHz, CDCl3) δ -63.10 (d, J = 14.8 Hz). The structural formula of the pyrrolidine structural unit compound is: .

[0043] Example 4 This example provides a preparation method of a pyrrolidine structural unit compound based on Example 1, and the reaction formula is as follows:

[0044] 1,6-diene (10 mmol), NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added into a round-bottom flask, and 20 mL of dichloromethane solvent was added. The reaction was stirred at room temperature for 24 hours, and the target product, pyrrolidine structural unit compound, was separated by column chromatography (eluent: petroleum ether: ethyl acetate, volume ratio = 40:1), with a yield of 92%.

[0045] The NMR spectra of the pyrrolidine structural unit compound structure confirmation are shown in the attached Figure 6-7 As shown, the NMR data are as follows: 1 HNMR (600 MHz, CDCl3) δ 7.81 (dd, J = 7.7, 1.8 Hz, 2H), 7.63 – 7.57 (m, 1H),7.53 (t, J = 7.7 Hz, 2H), 4.87 (dq, J = 31.1, 2.4 Hz, 2H), 3.98 – 3.92 (m, 1H), 3.78 – 3.73 (m, 1H), 3.58 (dd, J = 9.1, 7.3 Hz, 1H), 2.68 (dt, J = 29.6, 8.1 Hz,2H), 1.03 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 149.2, 136.0, 132.9,129.2, 127.8, 106.2, 55.2, 52.3, 37.6, 16.2. The structural formula of the pyrrolidine structural unit compound is:

[0046] Example 5 This example provides a preparation method of a pyrrolidine structural unit compound based on Example 1, and the reaction formula is as follows:

[0047] 1,6-diene (10 mmol), NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10mmol), and ZnI2 (2 mmol) were added into a round-bottom flask, and 20 mL of dichloromethane solvent was added. The reaction was stirred at room temperature for 24 hours, and the target product, pyrrolidine structural unit compound, was separated by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) with a yield of 77%.

[0048] The NMR spectra of the pyrrolidine structural unit compound structure confirmation are shown in the attached Figure 8-9 As shown, the data is as follows: 1 H NMR (600 MHz, CDCl3) δ 4.94 (q, J = 2.2 Hz, 1H), 4.91 (q, J = 2.4 Hz, 1H), 4.19 (d, J =14.2 Hz, 1H), 4.06 – 3.98 (m, 1H), 3.76 (t, J = 8.7 Hz, 1H), 3.00 (t, J = 9.2 Hz,1H), 2.74 (q, J = 6.8 Hz, 1H), 1.37 (s, 9H), 1.12 (d, J = 6.7 Hz, 3H).13C NMR(151 MHz, CDCl3) δ 150.4, 105.4, 61.3, 56.8, 53.8, 38.4, 24.6, 15.8. The structural formula of the pyrrolidine structural unit compound is: .

[0049] Example 6 This example provides a preparation method of a pyrrolidine structural unit compound based on Example 1, and the reaction formula is as follows:

[0050] 1,6-diene (10 mmol), NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added into a round-bottom flask, and 20 mL of dichloromethane solvent was added. The reaction was stirred at room temperature for 24 hours, and the target product, pyrrolidine structural unit compound, was separated by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) with a yield of 61%.

[0051] The NMR spectra of the pyrrolidine structural unit compound structure confirmation are shown in the attached Figure 10-11 As shown, the data is as follows: 1 HNMR (600 MHz, CDCl3) δ 4.98 (dt, J = 26.9, 2.5 Hz, 2H), 4.08 – 3.98 (m, 1H), 3.90 (dt, J = 14.0, 2.0 Hz, 1H), 3.69 – 3.59 (m, 1H), 2.89 – 2.78 (m, 5H), 1.14(d, J = 6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 149.2, 106.5, 55.0, 52.2, 37.8,34.5, 16.0. The structural formula of the pyrrolidine structural unit compound is: .

[0052] Example 7 This example provides a preparation method of a pyrrolidine structural unit compound based on Example 1, and the reaction formula is as follows:

[0053] 1,6-diene (10 mmol), NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added into a round-bottom flask, and 20 mL of dichloromethane solvent was added. The reaction was stirred at room temperature for 24 hours, and the target product, pyrrolidine structural unit compound, was separated by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) with a yield of 52%.

[0054] The NMR spectra of the pyrrolidine structural unit compound structure confirmation are shown in the attached Figure 12-13 As shown, the data is as follows: 1 HNMR (600 MHz, CDCl3) δ 7.73 – 7.70 (m, 2H), 7.32 (d,J = 7.9 Hz, 2H), 5.58 –5.42 (m, 1H), 5.06 – 4.95 (m, 2H), 3.40 (ddd, J = 10.1, 6.9, 3.2 Hz, 2H), 3.18(dd, J = 10.0, 6.2 Hz, 1H), 2.96 (dd, J = 9.8, 6.1 Hz, 1H), 2.65 (p, J = 6.6 Hz,1H), 2.43 (s, 3H), 2.20 (hept, J = 6.7 Hz, 1H), 0.76 (d, J = 7.0 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 143.4, 135.2, 134.2, 129.8, 127.6, 117.2, 54.1, 51.5,46.4, 36.8, 21.6, 13.7. The structural formula of the pyrrolidine structural unit compound is: .

[0055] Example 8 This example provides a preparation method of a pyrrolidine structural unit compound based on Example 1, and the reaction formula is as follows:

[0056] 1,6-diene (10 mmol), NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added into a round-bottom flask, and 20 mL of dichloromethane solvent was added. The reaction was stirred at room temperature for 24 hours, and the target product, pyrrolidine structural unit compound, was separated by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) with a yield of 55%.

[0057] The NMR spectra of the pyrrolidine structural unit compound structure confirmation are shown in the attached Figure 14-15 As shown, the data is as follows: 1 HNMR (600 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 4.79(p, J = 1.6 Hz, 1H), 4.69 (dt,J = 1.8, 0.9 Hz, 1H), 3.57 (dd, J = 9.7, 7.4 Hz,1H), 3.44 (dd, J = 10.0, 8.1 Hz, 1H), 3.08 (t, J = 9.9 Hz, 1H), 2.76 (t, J = 9.7Hz, 1H), 2.43 (s, 3H), 2.15 (td, J = 10.0, 8.0 Hz, 1H), 2.02 – 1.91 (m, 1H),1.59 (t, J = 1.2 Hz, 3H), 0.87 (d, J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ143.5, 142.1, 134.1, 129.8, 127.6, 113.3, 54.9, 53.5, 52.0, 36.7, 21.7, 19.4,15.7. The structural formula of the pyrrolidine structural unit compound is: .

[0058] Example 9 This example provides a preparation method of a pyrrolidine structural unit compound based on Example 1, and the reaction formula is as follows:

[0059] 1,6-diene (10 mmol), NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added into a round-bottom flask, and 20 mL of dichloromethane solvent was added. The reaction was stirred at room temperature for 24 hours, and the target product, pyrrolidine structural unit compound, was separated by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) with a yield of 51%.

[0060] The NMR spectra of the pyrrolidine structural unit compound structure confirmation are shown in the attached Figure 16-17 As shown, the data is as follows: 1 HNMR (600 MHz, CDCl3) δ 7.72 – 7.69 (m, 2H), 7.32 – 7.31 (m, 2H), 5.40 (dtd, J =15.4, 6.3, 0.9 Hz, 1H), 4.98 (ddt,J = 15.4, 8.7, 1.6 Hz, 1H), 3.40 – 3.35 (m,2H), 3.12 (dd, J = 10.0, 5.9 Hz, 1H), 2.93 (dd, J = 9.7, 6.3 Hz, 1H), 2.62 – 2.54(m, 1H), 2.42 (s, 3H), 2.15 (p, J = 6.4 Hz, 1H), 1.94 – 1.88 (m, 2H), 0.89 (t, J = 7.5 Hz, 3H), 0.73 (d, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 143.4,135.0, 129.7, 127.6, 125.5, 54.1, 52.2, 45.4, 37.0, 25.7, 21.6, 13.7 (twopeaks overlap). The structural formula of the pyrrolidine structural unit compound is: .

[0061] Example 10 In this example, based on Example 2, the pyrrolidine structural unit compound of Example 2 is further reacted to obtain a pyrrolidine carbonyl compound, and the reaction formula is as follows:

[0062] Pyrrolidine compounds (10 mmol), RuCl3·H2O (0.2 mmol), and NaIO4 (40 mmol) were added into a round-bottom flask, and CCl4 / H2O / MeCN (30 mL) solvent with a volume ratio of 1:1:1 was added, and the reaction was stirred at room temperature for 2 hours. After the reaction, it was extracted with ethyl acetate and water (3 × 20 mL), dried over anhydrous Na2SO4, and separated by column chromatography (eluent: petroleum ether: ethyl acetate, volume ratio = 10:1) to obtain the target product pyrrolidine carbonyl compound with a yield of 80%.

[0063] The NMR spectra of the structure confirmation of pyrrolidine carbonyl compounds are shown in the attached Figure 18-19 As shown, the data is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.34 (d, J= 8.0 Hz, 2H), 3.93 (t, J =9.2 Hz, 1H), 3.73 (d, J = 17.5 Hz, 1H), 3.27 (d, J = 17.5 Hz, 1H), 2.81 (t, J = 9.7Hz, 1H), 2.59 – 2.50 (m, 1H), 2.42 (s, 3H), 1.06 (d, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 210.6, 144.5, 131.7, 130.0, 127.9, 53.5, 52.2, 43.0, 21.6,12.1. The structural formula of the pyrrolidine carbonyl compound is: .

[0064] Embodiment 11 In this example, based on Example 2, the pyrrolidine structural unit compound of Example 2 is further reacted to obtain a pyrrolidine fluorine-containing compound, and the reaction formula is as follows:

[0065] Pyrrolidine compounds (10 mmol), FeNO3·9H2O (12 mmol), and Selectfluor (40 mmol) were added into a round-bottom flask, and 15 mL of MeCN solvent was added and stirred to dissolve. The reaction was degassed, and NaBH4 (60 mmol) dissolved in 15 mL of water was added in batches at 0 ℃, and then the reaction was stirred at room temperature for 2 hours. After the reaction, it was extracted with ethyl acetate and water (3 × 20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) to obtain the target product, pyrrolidine fluorine-containing compound, with a yield of 75%. The product has two enantiomers in a ratio of 1:1 (dr = 1:1).

[0066] The NMR spectra of the structure confirmation of pyrrolidine fluorine-containing compounds are shown in the attached Figure 20-22 As shown, the data is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.68 (dd, J = 8.3, 2.3 Hz, 2H), 7.29 (dd, J = 8.3, 2.2 Hz,2H), 3.60 (dd, J= 9.3, 7.8 Hz, 1H), 3.49 – 3.46 (m, 1H), 3.45 – 3.40 (m, 1H), 3.14 (d, J = 2.3 Hz, 1H), 2.92 – 2.86 (m, 1H), 2.39 (s, 3H), 2.21 (dqt, J = 18.9,7.2, 3.6 Hz, 1H), 1.31 (d, J = 11.5 Hz, 1H), 1.28 (d, J = 12.5 Hz, 2H), 0.91 (d, J = 6.8 Hz, 1H), 0.83 (d, J = 7.3 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 143.6 (twopeaks overlap), 133.8, 133.7, 129.7 (two peaks overlap), 127.5, 127.4, 103.5,101.8, 101.2, 99.4, 59.0, 58.8, 56.5, 56.3, 53.8, 53.2, 42.2 (d, J = 4.7 Hz),42.0 (d, J = 5.8 Hz), 21.5, 19.6, 19.3, 18.5, 18.2, 15.3, 15.3, 8.8 (two peaksoverlap). 19F NMR (376 MHz, CDCl3) δ -136.15 – -136.57 (m), -159.81 (ddp, J =35.4, 28.5, 20.9 Hz). The structural formula of the pyrrolidine fluorine-containing compound is: .

[0067] Example 12 This example provides a preparation of a pyrrolidine structural unit compound based on Example 1-2, mainly investigating the effect of different nickel salt catalysts on the product yield. The reaction formula is as follows:

[0068] 1,6-diene (10 mmol), NiCl2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added into a round-bottom flask, and 20 mL of dichloromethane solvent was added. The reaction was stirred at room temperature for 24 hours, and the target product pyrrolidine compound was separated by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) with a yield of 77%.

[0069] It can be seen that when pyrrolidine compounds are prepared using different nickel salt catalysts (other conditions are the same), these nickel salts are all divalent metal nickel salts and are halogenated nickel salts with similar properties, so they have little effect on the yield. The yields of pyrrolidine compounds prepared by NiCl2 and NiBr2 under the action of ligands and additives are similar.

[0070] Example 13 This example mainly investigates the effect of additives on the reaction based on Example 1-2, and provides a preparation method of a pyrrolidine structural unit compound. The reaction formula is as follows:

[0071] 1,6-diene (10 mmol), NiBr2 (0.5 mmol), PPh3 (0.6 mmol), and Zn (10 mmol) were added into a round-bottom flask, and 20 mL of dichloromethane solvent was added. The reaction was stirred at room temperature for 24 hours, and the target product pyrrolidine compound was separated by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) with a yield of 35%.

[0072] It can be seen that this embodiment has no additives, and the other conditions are the same as those in Example 2 to prepare the pyrrolidine compound, and the yield is greatly reduced. This shows that in the synthesis method provided by the present invention, the additive ZnI2 has a greater impact on the reaction, and ZnI2 can effectively promote the rate of the intermediate reaction process, thereby improving the yield.

[0073] Comparative Example 1 Prepare according to the reaction equation shown below:

[0074] 1,6-diene (10 mmol), NiBr2(0.5 mmol), dppp (0.6mmol), Zn (10 mmol), and ZnI2(2 mmol) were added into a round-bottom flask, and 20 mL of dichloromethane solvent was added. The reaction was stirred at room temperature for 24 hours, but no product was obtained. The ligand in Example 1 was replaced. When PPh3 was replaced with dppp, no product was obtained because the complex coordinated by the ligand and the nickel salt could not couple with the substrate, resulting in no reaction. Therefore, the type of ligand is crucial in this reaction.

[0075] Comparative Example 2 Prepare according to the reaction equation shown below:

[0076] 1,6-diene (10 mmol), NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added into a round-bottom flask, and 20 mL of dichloromethane solvent was added. The reaction was stirred at room temperature for 24 hours, but no product was obtained. This comparative example shows that the olefins cannot react when all are substituted. In the diene compound used in the method of the present invention, one of the two olefins must be a terminal olefin.

[0077] Comparative Example 3 Prepare according to the reaction equation shown below:

[0078] 1,6-diene (10 mmol), NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added into a round-bottom flask, and 20 mL of dichloromethane solvent was added. The reaction was stirred at room temperature for 24 hours, but no product was obtained.

[0079] Compared with Example 2, Comparative Example 3 used different raw materials, and the other reaction conditions were the same, but no product was obtained in the end. This shows that the different nitrogen protecting groups affected its coordination effect, and the different properties of the aromatic substituent and the sulfonyl substituent made the reaction unable to proceed.

[0080] Based on the above analysis, the reaction mechanism of the present invention is as follows:

[0081] (1) Coupling reaction A double bond (usually a more distant double bond) of the 1,6-diene compound undergoes a coupling reaction with the Ni complex. The coupling reaction refers to the formation of a chemical bond between a carbon atom of the 1,6-diene and the metal center in the Ni complex to form an alkyl intermediate containing Ni, which is connected to a part of the 1,6-diene.

[0082] (2) Olefin migration insertion After the coupling reaction, the olefin at the other end of the 1,6-diene (i.e., the closer double bond) undergoes a migration insertion reaction, the double bond of the olefin opens, and one of the carbon atoms is inserted into the bond between Ni and the previously coupled carbon atom, forming a new alkyl nickel intermediate that contains all the carbon atoms of 1,6-diene and is connected to the Ni complex in the form of a longer alkyl chain.

[0083] (3) β-H removal and pyrrolidine formation In the alkyl nickel intermediate, the β-hydrogen (i.e., the hydrogen atom separated from the carbon atom by one carbon atom) on the carbon atom directly connected to Ni (the farther carbon atom formed after migration and insertion) undergoes a removal reaction. The removal process involves the participation of another ligand or solvent molecule in the Ni complex to form H2 or the corresponding hydrocarbon by-product; the removal of β-H leads to the formation of a five-membered ring, namely the pyrrolidine ring, and at the same time the Ni complex dissociates from the product, which may return to its original state or undergo some ligand exchange, ready for the next round of catalytic cycle.

[0084] The reaction mechanism is a typical metal-catalyzed olefin coupling and cyclization process, which utilizes the catalytic activity of the Ni complex to promote the conversion of 1,6-diene compounds and generates pyrrolidine compounds through a series of orderly steps.

[0085] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

[0086] The above contents are only for explaining the technical idea of ​​the present invention and cannot be used to limit the protection scope of the present invention. Any changes made on the basis of the technical solution in accordance with the technical idea proposed by the present invention shall fall within the protection scope of the claims of the present invention.

Claims

1. A method for synthesizing a pyrrolidine structural unit compound, characterized in that: The method uses a diene compound as a raw material, a nickel salt as a catalyst, triphenylphosphine as a ligand, zinc powder as a reducing agent, and zinc iodide as an additive, performs a cyclization reaction in an organic solvent, and separates and obtains a pyrrolidine structural unit compound; Wherein, the structural formula of the diene compound is , X is any one of p-toluenesulfonamide, p-trifluoromethylbenzenesulfonamide, benzenesulfonamide, methylsulfonamide, and tert-butylsulfonamide; and R1 is any one of an alkyl group having 1 to 3 carbon atoms.

2. The method for synthesizing a pyrrolidine structural unit compound according to claim 1, characterized in that: The nickel salt is any one or a combination of NiCl2, NiBr2, NiI2, and Ni(COD)2.

3. The method for synthesizing a pyrrolidine structural unit compound according to claim 2, characterized in that: The nickel salt is NiCl2.

4. The method for synthesizing a pyrrolidine structural unit compound according to claim 1, characterized in that: In the structural formula of the diene compound, X is any one of p-toluenesulfonamide, p-trifluoromethylbenzenesulfonamide, benzenesulfonamide, methylsulfonamide, and tert-butylsulfonamide; and R1 is any one of methyl, ethyl, and n-propyl.

5. The method for synthesizing a pyrrolidine structural unit compound according to claim 4, characterized in that: The structural formula of the diene compound is , , , , , , and Any one of .

6. The method for synthesizing a pyrrolidine structural unit compound according to claim 1, characterized in that: The molar ratio of the nickel salt to the diene compound is 5-10:100, the molar ratio of the zinc powder to the diene compound is 1:1, and the molar ratio of the zinc iodide to the diene compound is 20:

100.

7. The method for synthesizing a pyrrolidine structural unit compound according to claim 1, characterized in that: The cyclization reaction temperature is 20-25°C, and the reaction time is 20-26 h.

8. The method for synthesizing a pyrrolidine structural unit compound according to claim 1, characterized in that: The organic solvent is any one or a combination of dichloromethane, chloroform, dibromomethane and dichloroethane.

9. The method for synthesizing a pyrrolidine structural unit compound according to claim 1, characterized in that: The separation was carried out by chromatography, and the eluent was petroleum ether and ethyl acetate in a volume ratio of 40:

1.

10. The method for synthesizing a pyrrolidine structural unit compound according to claim 9, characterized in that: The method further comprises distilling or recrystallizing the obtained pyrrolidine structural unit compound under reduced pressure to obtain a pure product of the pyrrolidine structural unit compound.

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