A method for synthesizing a pyrrolidine structural unit compound

Abstract

The application discloses a novel pyrrolidine structural unit compound synthesis method, utilizes high-efficiency cross coupling reaction of a Ni catalyst and a 1,6-diene compound, realizes high-yield and high-selectivity synthesis, and the method uses a diene compound as raw material, and through a simple cyclization reaction, can obtain the pyrrolidine structural unit compound in one step under mild conditions. Compared with a traditional synthesis method, the application 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, a plurality of pyrrolidine structural unit compounds with different substituents can be synthesized, and the compounds have wide application potential in multiple fields such as drug research and development, pesticide manufacturing and material science; the synthesis method of the application not only simplifies the cumbersome steps of the traditional synthesis method, but also greatly reduces the production cost, provides strong 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] This invention relates to the field of organic synthesis technology, and specifically to a method for synthesizing compounds with pyrrolidine structural units. Background Technology

[0002] Five-membered nitrogen-containing heterocyclic compounds, especially pyrrolidine structural units, have demonstrated extraordinary importance and broad application potential in both nature and artificial synthesis. These compounds are not only abundantly found 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 synthetic methods often suffer from problems such as cumbersome steps, low yields, expensive raw materials, or environmental unfriendliness, limiting the further application and development of these compounds. Traditional synthetic methods often involve multiple steps and complex reaction conditions, requiring pretreatment of raw materials before constructing the target molecule through multiple steps. This not only increases the complexity of the synthesis but also leads to reduced product purity and yield. Due to difficulties in precisely controlling reaction conditions, poor catalyst performance, or low raw material conversion rates, the product yield is low, increasing production costs and limiting the large-scale production of compounds. The raw materials used are relatively expensive, typically precious metal catalysts or rare chemical reagents. The high cost of these raw materials makes the entire synthetic process uneconomical, limiting the widespread application of the compounds. Furthermore, traditional synthetic methods are environmentally unfriendly.

[0004] Currently, transition metal-catalyzed cross-coupling reactions have become an innovative and efficient method for constructing carbon-carbon bonds. In this field, transition metals such as Pd, Rh, Ru, Co, and Ni have attracted considerable attention due to their superior catalytic performance and coupling capabilities. However, despite the significant achievements of these noble metal catalysts in both laboratory and industrial applications, their scarcity in the Earth's crust, the high difficulty of refining them, and their exorbitant costs severely limit their large-scale and long-term application prospects.

[0005] Given the limitations of precious metal catalysts, the search for and development of inexpensive and efficient metal catalysts has become a research hotspot in the field of catalytic chemistry. Ni catalysts, with their excellent metallic properties and significant catalytic effects, stand out in this field, becoming an ideal alternative to precious metal catalysts. Ni catalysts are not only affordable but also exhibit stable catalytic performance, are easy to handle and recycle, and offer new possibilities for constructing carbon-carbon bonds.

[0006] On the other hand, 1,6-diene compounds, as important raw materials for constructing pyrrolidine structural units, have advantages such as wide availability, ease of obtaining, and atom utilization rate of up to 100%. This characteristic makes 1,6-diene compounds extremely valuable in the synthesis of pyrrolidine derivatives. Summary of the Invention

[0007] Traditional synthetic methods for pyrrolidine compounds suffer from problems such as cumbersome steps, low yields, expensive raw materials, and environmental unfriendliness, which limit the further application and development of these compounds. This invention aims to provide a novel synthetic method for pyrrolidine structural unit compounds. This method fully utilizes the advantages of Ni catalysts and 1,6-diene compounds, achieving high-yield and highly selective synthesis of pyrrolidine structural unit compounds through efficient cross-coupling reactions. This innovative method not only solves the problems existing in traditional synthetic methods but also provides strong support for the large-scale production of pyrrolidine compounds.

[0008] The present invention solves the above-mentioned technical problems through the following technical means:

[0009] This invention provides a method for synthesizing pyrrolidine structural unit compounds. The method uses diene compounds as raw materials, nickel salts as catalysts, triphenylphosphine as ligands, zinc powder as reducing agents, and zinc iodide as additives. The cyclization reaction is carried out in an organic solvent to separate and obtain pyrrolidine structural unit compounds.

[0010] The structural formula of the diene compound is as follows: X is any one of p-toluenesulfonamide, p-trifluoromethylbenzenesulfonamide, benzenesulfonamide, methanesulfonamide, and tert-butylsulfonamide; R1 is any one of alkyl groups having 1 to 3 carbon atoms.

[0011] The nickel salt is any one or a combination of NiCl2, NiBr2, NiI2, and Ni(COD)2.

[0012] Furthermore, the nickel salt is NiCl2.

[0013] In the structural formula of the diene compound, X is any one of p-toluenesulfonamide, p-trifluoromethylbenzenesulfonamide, benzenesulfonamide, methanesulfonamide, and tert-butylsulfonamide; R1 is any one of alkyl groups having 1 to 3 carbon atoms.

[0014] Furthermore, R1 can be any one of methyl, ethyl, or n-propyl.

[0015] Furthermore, the structural formula of the diene compound is as follows: , , , , , , and Any one of them.

[0016] The molar ratio of nickel salt to diene compound is 5~10:100, the molar ratio of zinc powder to diene compound is 1:1, and the molar ratio of zinc iodide to diene compound is 10~50:100.

[0017] The cyclization reaction temperature is 20℃~25℃, and the reaction time is 20 h~26 h.

[0018] The organic solvent is any one or a combination of dichloromethane, trichloromethane, dibromomethane, and dichloroethane.

[0019] The separation was performed by chromatography, with petroleum ether and ethyl acetate in a volume ratio of 40:1 as the eluent.

[0020] The method further includes vacuum distillation or recrystallization of the obtained pyrrolidine structural unit compound to obtain a pure pyrrolidine structural unit compound.

[0021] The present invention provides a method for synthesizing the above-mentioned pyrrolidine structural unit compounds to obtain pyrrolidine structural unit compounds.

[0022] The structural formula of the pyrrolidine structural unit compound is as follows: and Any one of them;

[0023] Wherein, X is any one of p-toluenesulfonamide, p-trifluoromethylbenzenesulfonamide, benzenesulfonamide, methanesulfonamide, and tert-butylsulfonamide; R2 and R3 are any one of alkyl groups having 1 to 2 carbon atoms.

[0024] Furthermore, R2 is any one of hydrogen atom and methyl group; R3 is any one of hydrogen atom and ethyl group.

[0025] The present invention relates to the application of the above-mentioned pyrrolidine structural unit compound in the development of heterocyclic drug molecules, wherein the pyrrolidine structural unit compound is a raw material for the synthesis of heterocyclic drug molecules.

[0026] Compared with the prior art, the present invention achieves the following technical effects:

[0027] The method for synthesizing pyrrolidine structural unit compounds provided by this invention is a novel method for synthesizing pyrrolidine structural unit compounds. Compared with traditional synthesis methods, the method of this invention can obtain the product in one step, simplifying the steps and improving efficiency. This method uses diene compounds as raw materials for constructing pyrrolidine structural units, which are widely available, easy to obtain, and have an atom utilization rate of up to 100%, making the synthesis method more flexible and adaptable in practical applications. The use of nickel salts and ligands for catalysis results in high catalytic efficiency and good chemoselectivity. Compared with traditional noble metal catalysts (such as Pd, Rh, Ru, etc.), Ni catalysts are not only more affordable but also have stable catalytic performance, are easy to operate and recover, and significantly reduce production costs. By utilizing the advantages of Ni catalysts and 1,6-diene compounds, a highly efficient cross-coupling reaction is achieved. This innovation not only simplifies the cumbersome steps of traditional synthesis methods but also significantly improves the product yield (51%-92%) and selectivity. The target product is obtained with high chemoselectivity and excellent yield, and for terminal-substituted alkenes, cycloisomerization products of the inner alkene can be obtained. The raw materials and catalysts used in the synthesis process are environmentally friendly, reducing the use and emission of harmful substances, which is in line with the development trend of green chemistry.

[0028] Furthermore, by adjusting the structural formula of diene compounds, various pyrrolidine structural unit compounds with different substituents can be synthesized. The reaction conditions are simple and mild, with high selectivity. Even with a catalytic dosage of up to 5 mol% and extended reaction time, a considerable yield can be obtained to acquire pyrrolidine structural unit compounds. These pyrrolidine structural unit compounds, with different substituents, can be used to optimize existing drugs such as abuxitinib (Rinvoq) or acalatinib (Calquence) to improve their efficacy, reduce side effects, or expand their indications. Simultaneously, by utilizing the pyrrolidine structural unit compounds with different substituents of this invention and introducing different substituents, the physicochemical properties and biological activities of drugs can be adjusted, thereby developing more advantageous new drug candidates. Therefore, the pyrrolidine structural unit compound synthesis method provided by this invention simplifies traditional synthesis methods, improves product yield and selectivity, reduces production costs, and aligns with the development trend of green chemistry. This method also provides a new avenue for drug development, promoting the optimization of existing drugs and the development of new drugs. Attached Figure Description

[0029] Figure 1 The hydrogen NMR spectrum of the product prepared in Example 2 of this invention;

[0030] Figure 2 The carbon NMR spectrum of the product prepared in Example 2 of this invention;

[0031] Figure 3 The hydrogen NMR spectrum of the product prepared in Example 3 of this invention;

[0032] Figure 4 The carbon NMR spectrum of the product prepared in Example 3 of this invention;

[0033] Figure 5 The NMR fluorine spectrum of the product prepared in Example 3 of this invention;

[0034] Figure 6 The hydrogen NMR spectrum of the product prepared in Example 4 of this invention;

[0035] Figure 7 The carbon NMR spectrum of the product prepared in Example 4 of this invention;

[0036] Figure 8 The hydrogen NMR spectrum of the product prepared in Example 5 of this invention;

[0037] Figure 9 The carbon NMR spectrum of the product prepared in Example 5 of this invention;

[0038] Figure 10 The hydrogen NMR spectrum of the product prepared in Example 6 of this invention;

[0039] Figure 11 The carbon NMR spectrum of the product prepared in Example 6 of this invention;

[0040] Figure 12 The hydrogen NMR spectrum of the product prepared in Example 7 of this invention;

[0041] Figure 13 The carbon NMR spectrum of the product prepared in Example 7 of this invention;

[0042] Figure 14 The hydrogen NMR spectrum of the product prepared in Example 8 of this invention;

[0043] Figure 15 The carbon NMR spectrum of the product prepared in Example 8 of this invention;

[0044] Figure 16 The hydrogen NMR spectrum of the product prepared in Example 9 of this invention;

[0045] Figure 17 The carbon NMR spectrum of the product prepared in Example 9 of this invention;

[0046] Figure 18 The hydrogen NMR spectrum of the product prepared in Example 10 of this invention;

[0047] Figure 19 The carbon NMR spectrum of the product prepared in Example 10 of this invention;

[0048] Figure 20 The hydrogen NMR spectrum of the product prepared in Example 11 of this invention;

[0049] Figure 21 The NMR spectrum of the product prepared in Example 11 of this invention is shown below.

[0050] Figure 22 The NMR fluorine spectrum of the product prepared in Example 11 of this invention. Detailed Implementation

[0051] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0052] Unless otherwise specified, all test materials and reagents used in the following examples are commercially available.

[0053] Unless otherwise specified in the embodiments, the techniques or conditions described in the literature in this field or in accordance with the product manual may be followed.

[0054] Example 1

[0055] This embodiment provides the preparation of diene compounds, which are synthesized according to methods reported in the literature. and ( Adv. Synth. Catal. 2008, 350 , 1073-1080; Chem. Commun 2020, 56 , 7741-7744.), where GP is any one of toluenesulfonyl, p-trifluoromethylbenzenesulfonyl, benzenesulfonyl, methylsulfonyl, tert-butylsulfonyl, R1 is hydrogen atom, methyl, ethyl, n-propyl, and Ts is p-toluenesulfonyl.

[0056] (1) Synthesis of diene compounds

[0057] The reaction formula is as follows:

[0058]

[0059] An amine compound (50 mmol), allyl bromide (60 mmol), potassium carbonate (200 mmol), and acetonitrile (80 mL) were added to a dry round-bottom flask, and the mixture was 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 subjected to column chromatography (eluent: petroleum ether and ethyl acetate in a volume ratio of 30:1) to obtain a diene compound. .

[0060] (2) Synthesis of diene compounds

[0061] The reaction formula is as follows:

[0062]

[0063] Specific steps: Add amine compound (100 mmol), allyl bromide (50 mmol), potassium carbonate (200 mmol), and acetonitrile (80 mL) as solvent to 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, then filter, concentrate under reduced pressure, and perform column chromatography (eluent is petroleum ether and ethyl acetate in a volume ratio of 30:1) to obtain the pure product allyl p-sulfonamide.

[0064] Allyl p-sulfonamide (50 mmol), substituted alkenyl bromide (60 mmol), potassium carbonate (200 mmol), and acetonitrile (80 mL) were added as solvents to a dry round-bottom flask, and the mixture was refluxed in an oil bath at 85 °C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, then filtered, concentrated under reduced pressure, and subjected to column chromatography (eluent: petroleum ether: ethyl acetate) to obtain a pure diene compound. .

[0065] Example 2

[0066] This embodiment, based on Example 1, provides a method for preparing a compound with a pyrrolidine structural unit, as shown in the following reaction formula:

[0067]

[0068] 1,6-diene 10 mmol of NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added to a round-bottom flask, and 20 mL of dichloromethane solvent was added. The mixture was stirred at room temperature for 24 hours. The target product, pyrrolidine, was obtained by column chromatography (eluent was petroleum ether and ethyl acetate in a volume ratio of 40:1) with a yield of 82%.

[0069] See the attached NMR spectrum for confirming the structure of the pyrrolidine compound. Figure 1-2As 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.

[0070] The structural formula of the pyrrolidine structural unit compound is: .

[0071] Example 3

[0072] This embodiment, based on Example 1, provides a method for preparing a compound with a pyrrolidine structural unit, as shown in the following reaction formula:

[0073]

[0074] 1,6-diene 10 mmol of NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added to a round-bottom flask, and 20 mL of dichloromethane solvent was added. The mixture was stirred at room temperature for 24 hours. The target product, pyrrolidine structural unit compound, was obtained by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) with a yield of 88%.

[0075] See the attached NMR spectrum for the structural confirmation of the pyrrolidine structural unit compound. Figure 3-5 The NMR data are as follows: 1H NMR (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).

[0076] The structural formula of the pyrrolidine structural unit compound is: .

[0077] Example 4

[0078] This embodiment, based on Example 1, provides a method for preparing a compound with a pyrrolidine structural unit, as shown in the following reaction formula:

[0079]

[0080] 1,6-diene 10 mmol of NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added to a round-bottom flask, and 20 mL of dichloromethane solvent was added. The mixture was stirred at room temperature for 24 hours. The target product, pyrrolidine structural unit compound, was obtained by column chromatography (eluent: petroleum ether: ethyl acetate, volume ratio = 40:1) with a yield of 92%.

[0081] See the attached NMR spectrum for the structural confirmation of the pyrrolidine structural unit compound. 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.

[0082] The structural formula of the pyrrolidine structural unit compound is:

[0083] Example 5

[0084] This embodiment, based on Example 1, provides a method for preparing a compound with a pyrrolidine structural unit, as shown in the following reaction formula:

[0085]

[0086] 1,6-diene 10 mmol of NiBr2 (0.5 mmol), 0.6 mmol of PPh3 (0.6 mmol), 10 mmol of Zn, and 2 mmol of ZnI2 were added to a round-bottom flask, and 20 mL of dichloromethane solvent was added. The mixture was stirred at room temperature for 24 hours. The target product, pyrrolidine structural unit compound, was obtained by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) with a yield of 77%.

[0087] See the attached NMR spectrum for the structural confirmation of the pyrrolidine structural unit compound. 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.

[0088] The structural formula of the pyrrolidine structural unit compound is: .

[0089] Example 6

[0090] This embodiment, based on Example 1, provides a method for preparing a compound with a pyrrolidine structural unit, as shown in the following reaction formula:

[0091]

[0092] 1,6-diene 10 mmol of NiBr2 (0.5 mmol), 0.6 mmol of PPh3 (0.6 mmol), 10 mmol of Zn, and 2 mmol of ZnI2 were added to a round-bottom flask, along with 20 mL of dichloromethane solvent. The mixture was stirred at room temperature for 24 hours. The target product, pyrrolidine structural unit compound, was obtained by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) with a yield of 61%.

[0093] See the attached NMR spectrum for the structural confirmation of the pyrrolidine structural unit compound. 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.

[0094] The structural formula of the pyrrolidine structural unit compound is: .

[0095] Example 7

[0096] This embodiment, based on Example 1, provides a method for preparing a compound with a pyrrolidine structural unit, as shown in the following reaction formula:

[0097]

[0098] 1,6-diene 10 mmol of NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added to a round-bottom flask, and 20 mL of dichloromethane solvent was added. The mixture was stirred at room temperature for 24 hours. The target product, pyrrolidine structural unit compound, was obtained by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) with a yield of 52%.

[0099] See the attached NMR spectrum for the structural confirmation of the pyrrolidine structural unit compound. 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.

[0100] The structural formula of the pyrrolidine structural unit compound is: .

[0101] Example 8

[0102] This embodiment, based on Example 1, provides a method for preparing a compound with a pyrrolidine structural unit, as shown in the following reaction formula:

[0103]

[0104] 1,6-diene 10 mmol of NiBr2 (0.5 mmol), 0.6 mmol of PPh3 (0.6 mmol), 10 mmol of Zn, and 2 mmol of ZnI2 were added to a round-bottom flask, and 20 mL of dichloromethane solvent was added. The mixture was stirred at room temperature for 24 hours. The target product, pyrrolidine structural unit compound, was obtained by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) with a yield of 55%.

[0105] See the attached NMR spectrum for the structural confirmation of the pyrrolidine structural unit compound. 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.

[0106] The structural formula of the pyrrolidine structural unit compound is: .

[0107] Example 9

[0108] This embodiment, based on Example 1, provides a method for preparing a compound with a pyrrolidine structural unit, as shown in the following reaction formula:

[0109]

[0110] 1,6-diene 10 mmol of NiBr2 (0.5 mmol), PPh3 (0.6 mmol), Zn (10 mmol), and ZnI2 (2 mmol) were added to a round-bottom flask, and 20 mL of dichloromethane solvent was added. The mixture was stirred at room temperature for 24 hours. The target product, pyrrolidine structural unit compound, was obtained by column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 40:1) with a yield of 51%.

[0111] See the attached NMR spectrum for the structural confirmation of the pyrrolidine structural unit compound. 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).

[0112] The structural formula of the pyrrolidine structural unit compound is: .

[0113] Example 10

[0114] This embodiment, based on Example 2, further reacts the pyrrolidine structural unit compound from Example 2 to obtain a pyrrolidine carbonyl compound, as shown in the following reaction formula:

[0115]

[0116] pyrrolidine compounds 10 mmol of RuCl3·H2O (0.2 mmol) and 40 mmol of NaIO4 were added to a round-bottom flask, and 30 mL of CCl4 / H2O / MeCN solvent (v / v ratio 1:1:1) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water (3 × 20 mL), dried over anhydrous Na2SO4, and then separated by column chromatography (eluent: petroleum ether:ethyl acetate, v / v ratio 10:1) to obtain the target product, pyrrolidine carbonyl compound, with a yield of 80%.

[0117] See the attached NMR spectrum for confirming the structure of the pyrrolidine carbonyl compound. 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.

[0118] The structural formula of the pyrrolidine carbonyl compound is: .

[0119] Example 11

[0120] This embodiment, based on Example 2, further reacts the pyrrolidine structural unit compound from Example 2 to obtain a fluorinated pyrrolidine compound, as shown in the following reaction formula:

[0121]

[0122] pyrrolidine compounds 10 mmol of FeNO3·9H2O (12 mmol) and 40 mmol of Selectfluor were added to a round-bottom flask. 15 mL of MeCN solvent was added and stirred to dissolve the mixture. The reaction mixture was degassed and protected. NaBH4 (60 mmol) dissolved in 15 mL of water was added in portions at 0 °C. The mixture was then transferred to room temperature and stirred for 2 hours. After the reaction was completed, the mixture 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, fluorinated pyrrolidine, with a yield of 75%. The product contained two enantiomers in a 1:1 ratio (dr = 1:1).

[0123] See the attached NMR spectrum for the confirmed structure of fluorinated pyrrolidine compounds. 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).

[0124] The structural formula of the fluorinated pyrrolidine compound is: .

[0125] Example 12

[0126] This embodiment, based on Examples 1-2, provides a method for preparing pyrrolidine structural unit compounds, mainly investigating the effect of different nickel salt catalysts on product yield. The reaction formula is as follows:

[0127]

[0128] 1,6-diene 10 mmol of NiCl2 (0.5 mmol), 0.6 mmol of PPh3 (0.6 mmol), 10 mmol of Zn, and 2 mmol of ZnI2 were added to a round-bottom flask, along with 20 mL of dichloromethane solvent. The mixture was stirred at room temperature for 24 hours. The target product, pyrrolidine, was obtained by column chromatography (eluent: petroleum ether: ethyl acetate, volume ratio = 40:1) with a yield of 77%.

[0129] Therefore, when different nickel salt catalysts are used to prepare pyrrolidine compounds (all other conditions are the same), these nickel salts are all divalent metallic nickel salts and are halo-nickel salts, so their properties are similar and have little impact on the yield. The yields of pyrrolidine compounds prepared by NiCl2 and NiBr2 under the action of ligands and additives are similar.

[0130] Example 13

[0131] Based on Examples 1-2, this embodiment mainly examines the effect of additives on the reaction and provides a method for preparing a pyrrolidine structural unit compound, with the following reaction formula:

[0132]

[0133] 1,6-diene 10 mmol of NiBr2 (0.5 mmol), 0.6 mmol of PPh3 (0.6 mmol), and 10 mmol of Zn were added to a round-bottom flask, along with 20 mL of dichloromethane solvent. The mixture was stirred at room temperature for 24 hours. The target product, pyrrolidine, was obtained by column chromatography (eluent: petroleum ether: ethyl acetate, volume ratio = 40:1) with a yield of 35%.

[0134] As can be seen, in this embodiment, no additives were used, and the other conditions were the same as in Example 2 to prepare pyrrolidine compounds. The yield decreased significantly, which indicates that in the synthesis method provided by the present invention, the additive ZnI2 has a significant impact on the reaction. ZnI2 can effectively promote the rate of intermediate reaction process, thereby increasing the yield.

[0135] Comparative Example 1

[0136] Prepared according to the reaction equation shown below:

[0137]

[0138] 1,6-diene 10 mmol of NiBr2 (0.5 mmol), 0.6 mmol of dppp, 10 mmol of Zn, and 2 mmol of ZnI2 were added to a round-bottom flask, and 20 mL of dichloromethane solvent was added. The mixture was stirred at room temperature for 24 hours, but no product was obtained. When the ligands in Example 1 were replaced with dppp, no product was obtained because the complex of the ligand and the nickel salt could not couple with the substrate, thus preventing the reaction. Therefore, the type of ligand is crucial in this reaction.

[0139] Comparative Example 2

[0140] Prepared according to the reaction equation shown below:

[0141]

[0142] 1,6-diene 10 mmol of NiBr2 (0.5 mmol), 0.6 mmol of PPh3 (0.6 mmol), 10 mmol of Zn, and 2 mmol of ZnI2 were added to a round-bottom flask, and 20 mL of dichloromethane solvent was added. The mixture was stirred at room temperature for 24 hours, but no product was obtained. This comparative example shows that the reaction cannot occur when all the alkenes are substituted. In the diene compound used in this invention, one of the two alkenes must be a terminal alkene.

[0143] Comparative Example 3

[0144] Prepared according to the reaction equation shown below:

[0145]

[0146] 1,6-diene 10 mmol of NiBr2 (0.5 mmol), 0.6 mmol of PPh3 (0.6 mmol), 10 mmol of Zn, and 2 mmol of ZnI2 were added to a round-bottom flask, and 20 mL of dichloromethane solvent was added. The mixture was stirred at room temperature for 24 hours, but no product was obtained.

[0147] Compared with Example 2, Comparative Example 3 used different raw materials, while the other reaction conditions were the same. No product was obtained in the end. This indicates that the different nitrogen protecting groups affected the coordination effect, and the different properties of the aryl and sulfonyl substituents also prevented the reaction from proceeding.

[0148] In summary, the reaction mechanism of this invention is as follows:

[0149]

[0150] (1) Coupling reaction

[0151] A double bond (usually a more distant double bond) of a 1,6-diene compound undergoes a coupling reaction with a Ni complex. Coupling 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, forming a Ni-containing alkyl intermediate that is attached to a portion of the 1,6-diene.

[0152] (2) Olefin migration and insertion

[0153] Following 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 carbon atom inserts into the bond between Ni and the previously coupled carbon atom, forming a new alkyl nickel intermediate. This intermediate contains all the carbon atoms of the 1,6-diene and is attached to the Ni complex as a longer alkyl chain.

[0154] (3) β-H removal and pyrrolidine formation

[0155] In the alkyl nickel intermediate, the β-hydrogen on the carbon atom directly bonded to Ni (the more distant carbon atom formed after migration insertion) undergoes a removal reaction. The removal process involves the participation of another ligand or solvent molecule in the Ni complex, forming H2 or the corresponding hydrocarbon byproduct. The removal of β-H leads to the formation of a five-membered ring, namely the pyrrolidine ring. At the same time, the Ni complex dissociates from the product, possibly returning to its original state or undergoing some ligand exchange, preparing for the next catalytic cycle.

[0156] The reaction mechanism is a typical metal-catalyzed olefin coupling and cyclization process that utilizes the catalytic activity of Ni complexes to promote the conversion of 1,6-diene compounds and generates pyrrolidine compounds through a series of ordered steps.

[0157] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

[0158] The above content is only for illustrating the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. Any modifications made to the technical solution based on the technical concept proposed in this invention shall fall within the scope of protection of the claims of this invention.

Claims

1. A method for synthesizing a pyrrolidine building block, characterized by, 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, zinc iodide as an additive, and performs a cyclization reaction in an organic solvent to separate a pyrrolidine structural unit compound; wherein the structure of the diene compound is , R 1 is hydrogen or methyl; and the structure of the pyrrolidine structural unit compound is: or X is any one of p-tolylsulfonamido, benzylsulfonamido, p-trifluoromethylbenzylsulfonamido, methylsulfonamido, and tert-butylsulfonamido.

2. The method for synthesizing a pyrrolidine structural unit compound according to claim 1, characterized in that, The nickel salt is any one or 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, The diene compound has a structural formula of any one of , , , , and .

5. 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.

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

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

8. The method for synthesizing a pyrrolidine structural unit compound according to claim 1, characterized in that, The separation is performed by chromatographic separation, and the eluent is petroleum ether and ethyl acetate at a volume ratio of 40:

1.

9. The method for synthesizing a pyrrolidine structural unit compound according to claim 8, characterized in that, The method further comprises reducing pressure distillation or recrystallization of the obtained pyrrolidine structural unit compound to obtain a pure pyrrolidine structural unit compound.

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