A method for synthesizing a pyrrolidine compound

Abstract

The application belongs to the technical field of pyrrolidine compound synthesis, and specifically discloses a synthesis method of pyrrolidine compounds. In the method, α-amino ketone compounds and 2-methylene propane-1,3-diacetyloxy are used as raw materials, and in the presence of a catalyst, a ligand, an additive and a solvent, through continuous N-allylation and intramolecular C-allylation processes, C-N and C-C bonds are constructed in one step, thereby directly synthesizing functionalized pyrrolidine compounds with exocyclic methylene. The method has the advantages of simple reaction process, mild reaction conditions, low economic burden in the synthesis process, high yield, easy purification of products and the like, and provides an effective strategy for constructing a pyrrolidine skeleton.

Description

Technical Field

[0001] This invention relates to the field of pyrrolidine compound synthesis technology, and in particular to a method for synthesizing pyrrolidine compounds. Background Technology

[0002] Pyrrolidines, as an important class of five-membered nitrogen-containing heterocyclic structural units, occupy a significant position in medicinal chemistry research. Based on their well-defined molecular conformation, moderate skeletal rigidity, and abundant modifiable sites, these structures are widely used in the design and optimization of drug lead compounds. Furthermore, pyrrolidine compounds exhibit diverse biological activities, including antitumor, anti-infective, nervous system modulation, and antidiabetic pharmacological effects. Some drugs with pyrrolidine as their core structure, such as piracetam and pyrotinib, have been successfully used in clinical treatment.

[0003] Although the synthesis of pyrrolidine compounds has a long history and various classic methods have been developed, such as the Hofmann-Löffler-Freytag synthesis, the aza-Michael reaction synthesis, and the Mitsunobu reaction synthesis, these traditional synthetic methods generally have the following problems: (1) The substrate usually needs to be functionalized in advance, which leads to lengthy raw material preparation steps and reduced overall synthesis efficiency; (2) The reaction route is generally long and the steps are not economical enough, making it difficult to build a complex pyrrolidine skeleton from simple and readily available starting materials in one step; (3) The reaction system often involves harsh conditions such as strong acids, strong bases, strong oxidants, or high temperatures, which not only limits the compatibility of substrates containing sensitive functional groups, but also significantly narrows the scope of application of the method; (4) Corrosive or toxic reagents are often used in traditional routes, resulting in large amounts of waste emissions, which does not conform to the concept of green chemistry and sustainable development.

[0004] Based on the above problems, there is an urgent need to develop a new method for synthesizing pyrrolidine compounds that is highly selective, has a high yield, is mild under mild conditions, and is environmentally friendly, in order to meet the demand for efficient synthetic tools in modern medicinal chemistry and the construction of functional molecules. Summary of the Invention

[0005] To address the shortcomings of traditional methods, such as low synthesis efficiency, low step economy, poor functional group compatibility, and environmental hazards, this invention provides a method for directly synthesizing pyrrolidine compounds by constructing C–N and C–C bonds in one step through continuous N-allylation and intramolecular C-allylation processes.

[0006] To achieve the above objectives, the present invention provides the following solution: This invention provides a method for synthesizing pyrrolidine compounds, comprising the following steps: The pyrrolidine compound was obtained by reacting an α-aminoketone compound with 2-methylenepropane-1,3-diacetoxy in the presence of a catalyst, ligand, additive and solvent. The structural formula of the α-aminoketone compound is shown in formula (I): ; In equation (I), (R1) r This represents r substituents on the benzene ring, where r is an integer greater than or equal to 0; R1 is selected from hydrogen atom, C 1～6 Alkyl, C 1～6 Alkoxy, C 6～12 One of aryl, trifluoromethyl, and halogen, wherein each of the above groups is optionally unsubstituted or substituted by one or more C1 groups. 1~4 Alkyl, C 1～4 Substituents consisting of alkyl halogens, halogens, or phenyl groups; When r is an integer greater than or equal to 2, R1 is independently selected from the above groups, and R1 may be the same or different; R2 is selected from hydrogen, halogens, and C. 1～6 Alkyl, C 1～6 One of the alkoxy groups.

[0007] In a preferred embodiment of the present invention, the α-aminoketone compound includes at least one of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0008] In a preferred embodiment of the present invention, the structural formula of the 2-methylenepropane-1,3-diacetoxy (CAS: 3775-29-9) is as follows: .

[0009] In a preferred embodiment of the present invention, the catalyst is selected from at least one of bis(triphenylphosphine)palladium dichloride, palladium acetate, tris(dibenzylacetone)palladium, and tetra(triphenylphosphine)palladium (preferably, the catalyst is palladium acetate).

[0010] In a preferred embodiment of the present invention, the ligand is selected from at least one of triphenylphosphine, 1,1'-bis(diphenylphosphine)ferrocene, 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl, 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene, and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (preferably, the ligand is triphenylphosphine).

[0011] In a preferred embodiment of the present invention, the additive is selected from at least one of potassium acetate, potassium hydroxide, cesium carbonate, cesium acetate, cesium fluoride, and sodium carbonate (preferably, the additive is potassium carbonate).

[0012] In a preferred embodiment of the present invention, the solvent is selected from at least one of acetonitrile, hexafluoroisopropanol, tetrahydrofuran, methanol, 2,2,2-trifluoroethanol, ethanol, dichloromethane, dimethyl sulfoxide, and N,N-dimethylformamide (preferably, the solvent is 2,2,2-trifluoroethanol).

[0013] In a preferred embodiment of the present invention, the reaction temperature is 60-120°C and the reaction time is 12-24h (preferably, the reaction temperature is 90°C and the reaction time is 12h).

[0014] In a preferred embodiment of the present invention, based on 1 molar equivalent of an α-aminoketone compound, the molar equivalent of 2-methylenepropane-1,3-diacetoxy is 1.0-2.0, the molar equivalent of the catalyst is 0.01-0.2, the molar equivalent of the ligand is 0.1-0.5, and the molar equivalent of the additive is 1.0-4.0.

[0015] In a preferred embodiment of the present invention, the reaction is further complicated by a separation and purification step.

[0016] The structural formula of the pyrrolidine compounds prepared by the method of the present invention is shown in formula (II): In equation (II), (R1) r This represents r substituents on the benzene ring, where r is an integer greater than or equal to 0; R1 is selected from hydrogen atom, C 1～6 Alkyl, C 1～6 Alkoxy, C 6～12 One of aryl, trifluoromethyl, and halogen, wherein each of the above groups is optionally unsubstituted or substituted by one or more C1 groups. 1～4 Alkyl, C 1～4 Substituents consisting of alkyl halogens, halogens, or phenyl groups; When r is an integer greater than or equal to 2, R1 is independently selected from the above groups, and R1 may be the same or different; R2 is selected from hydrogen, halogens, and C. 1～6 Alkyl, C 1～6 One of the alkoxy groups.

[0017] In some embodiments, the pyrrolidine compound includes at least one of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0018] The reaction mechanism of the method of the present invention is as follows: Figure 1As shown: First, in the presence of a phosphine ligand and a base, Pd(OAc)₂ generates an active Pd(0) species in situ. Pd(0) undergoes oxidative addition to allyl diacetate 2a to generate π-allyl palladium intermediate A, which is subsequently captured by the nitrogen atom of α-amino ketone 1aa to give N-allylated intermediate B. Under basic reaction conditions, the carbonyl α-position is deprotonated to generate the corresponding enol anion intermediate. Subsequently, the remaining allyl acetate moiety is activated by Pd(0) to form an intramolecular π-allyl palladium species C. Immediately afterwards, the α-carbon undergoes intramolecular nucleophilic attack on the π-allyl palladium intermediate, achieving C-C bond formation and cyclization, thereby giving the 3-methylenepyrrolidine product 3aa. Overall, this reaction achieves the sequential construction of CN and C-C bonds in a single operation through successive N-allylation and intramolecular C-allylation processes.

[0019] Compared with the prior art, the present invention has the following beneficial effects: In the method of this invention, using α-aminoketone compounds and 2-methylenepropane-1,3-diacetoxy as starting materials, and in the presence of a catalyst, ligand, additives, and solvent, C–N and C–C bonds are constructed in one step through a series of N-allylation and intramolecular C-allylation processes, thereby directly synthesizing functionalized pyrrolidine compounds with exocyclic methylene groups. This method has advantages such as a simple reaction process, mild reaction conditions, low economic burden in the synthesis process, high yield, and easy product purification, providing an effective strategy for constructing pyrrolidine skeletons. Attached Figure Description

[0020] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0021] Figure 1 This is a schematic diagram illustrating the mechanism of the synthesis method of pyrrolidine compounds of the present invention. Detailed Implementation

[0022] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0023] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0024] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0025] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0026] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0027] Unless otherwise specified, the experimental methods used in the preparation examples and embodiments of this invention are conventional methods; the materials and reagents used are commercially available unless otherwise specified.

[0028] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0029] Preparation Examples 1-28 The synthetic steps for preparing α-aminoketone compounds are as follows: (1) Add 7.5 mmol of aniline compound and 8 mL of DMF solvent to a 50 mL round-bottom flask equipped with a magnetic stirrer. Slowly add 2 mL of DMF solution containing 5.0 mmol of 2-bromoacetophenone compound to the flask under stirring at 25 °C. After the addition is complete, react at 25 °C for 30 min. After 30 min, monitor the reaction by thin-layer chromatography (petroleum ether: ethyl acetate = 10:1) to confirm that the reaction is complete.

[0030] (2) Quench the reaction with 10 mL of water, then extract the mixture with ethyl acetate (25 mL x 3 times), combine the organic phases, wash three times with water (50 mL) and once with saturated brine (50 mL). Place the organic phase in an Erlenmeyer flask, add an appropriate amount of anhydrous sodium sulfate, stir and dry for 30 min. Concentrate under reduced pressure to remove the solvent, and obtain the crude product.

[0031] (3) The crude product was purified by reverse-phase column (C18)(MeCN / H2O) gradient elution, and the resulting fraction was concentrated and evaporated to obtain the final product.

[0032] (4) The reaction formula for preparing Example 1-28 is shown below: .

[0033] (5) The chemical structures of the aniline compounds prepared in Examples 1-21, the chemical structures of the products, the product yields, and the product characterization data are shown in Table 1 below. Among them, the 2-bromoacetophenone compound is 2-bromoacetophenone, with the structural formula [structure omitted]. .

[0034] (6) The chemical structures of the 2-bromoacetophenone compounds in Examples 22-28, the chemical structures of the products, the product yields, and the product characterization data are shown in Table 2 below. The structural formula of the aniline compounds is as follows: .

[0035] Table 1

[0036] Table 2

[0037] Examples 1-19: Optimization of Synthetic Conditions for Pyrrolidine Compounds A method for synthesizing a pyrrolidine compound, comprising the following steps: (1) Add α-amino ketone compound (0.5 mmol), 2-methylenepropane-1,3-diacetoxy (0.65 mmol), palladium acetate (0.071 mmol), ligand (0.22 mmol), and additive (2.0 mmol) to a reaction tube (10 mL) equipped with a magnetic stir bar. Finally, add 5.0 mL of solvent, seal the reaction tube, and place it in an oil bath for stirring and heating for 12 h. After the reaction cools to room temperature, confirm the completeness of the reaction by thin-layer chromatography (petroleum ether: ethyl acetate = 10:1). (2) After the reaction (heat treatment) is completed, the resulting reaction solution is concentrated under reduced pressure, and the residue is purified by rapid silica gel column chromatography. The chromatographic purification method is as described in Section 0512 Column Chromatography of the 2020 edition of the Chinese Pharmacopoeia, Part IV. The specific operation is as follows: 200-300 mesh silica gel is used as the packing material, and the column is packed by wet method; the sample is dissolved in ethyl acetate, mixed, and then loaded by dry method; a mixed solution of petroleum ether and ethyl acetate is used as the mobile phase for elution, and the ratio of the mobile phase is predetermined by thin-layer chromatography (TLC) according to the polarity of the target product. The volume ratio of petroleum ether to ethyl acetate is 50:1; the fraction containing the target product is collected, combined, and concentrated under reduced pressure to obtain the final pure product. The product yield is calculated based on the ratio of the mass of the purified product obtained by separation to the theoretical yield. The same applies below.

[0038] The reaction formulas in Examples 1-19 are shown below: The catalysts, ligands, additives, solvents, reaction temperatures, and yields in Examples 1-19 are shown in Table 3.

[0039] Table 3

[0040] As shown in Table 3, the highest yield of the target product, reaching 87%, was achieved using palladium acetate (Pd(OAc)2) as a catalyst, triphenylphosphine (PPh3) as a ligand, potassium carbonate (K2CO3) as an additive, 2,2,2-trifluoroethanol (TFE) as a reaction solvent, a reaction temperature of 90℃, and a reaction time of 12 hours. Therefore, these conditions were determined to be the optimal reaction conditions for the synthesis of pyrrolidine compounds.

[0041] Examples 20-46: Substrate expansion of pyrrolidine derivatives The method for synthesizing pyrrolidine compounds using the reaction conditions of Example 17 is as follows: (1) Add α-amino ketone compound (0.5 mmol), 2-methylenepropane-1,3-diacetoxy (0.65 mmol), palladium acetate (0.071 mmol), triphenylphosphine (0.22 mmol), and potassium carbonate (2.0 mmol) to a reaction tube (10 mL) equipped with a magnetic stir bar. Finally, add 5.0 mL of trifluoroethanol (TFE) solvent. After sealing the reaction tube, place it in a 90°C oil bath and stir and heat for 12 h. (2) After the reaction solution was cooled to room temperature, thin-layer chromatography (petroleum ether: ethyl acetate = 10:1) was used to confirm that the reaction was complete; then the solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column chromatography (50:1) to obtain the final product.

[0042] The chemical structures of the α-aminoketone compounds in Examples 17 and Examples 20-46, the chemical structures of the products, the product yields, and the product characterization data are shown in Table 4 below.

[0043] The chemical reaction formulas for Examples 20-46 are as follows: Table 4

[0044] This invention achieves one-step construction of C–N and C–C bonds through a series of N-allylation and intramolecular C-allylation processes, thereby directly synthesizing functionalized pyrrolidine compounds with exocyclic methylene groups. This method offers advantages such as high bonding efficiency, a simple reaction process, and broad compatibility of the product's functional groups, providing an effective strategy for constructing pyrrolidine skeletons.

[0045] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for synthesizing pyrrolidine compounds, characterized in that, Includes the following steps: The pyrrolidine compound was obtained by reacting an α-aminoketone compound with 2-methylenepropane-1,3-diacetoxy in the presence of a catalyst, ligand, additive and solvent. The structural formula of the α-aminoketone compound is shown in formula (I): ； In equation (I), (R1) r This represents r substituents on the benzene ring, where r is an integer greater than or equal to 0; R1 is selected from hydrogen atom, C 1～6 Alkyl, C 1～6 Alkoxy, C 6～12 One of aryl, trifluoromethyl, and halogen, wherein each of the above groups is optionally unsubstituted or substituted by one or more C groups. 1~4 Alkyl, C 1～4 Substituents consisting of alkyl halogens, halogens, or phenyl groups; When r is an integer greater than or equal to 2, R1 is independently selected from the above groups, and R1 may be the same or different; R2 is selected from hydrogen, halogens, and C. 1～6 Alkyl, C 1～6 One of the alkoxy groups.

2. The synthesis method according to claim 1, characterized in that, The α-aminoketone compounds include at least one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 3. The synthesis method according to claim 1, characterized in that, The structural formula of the 2-methylenepropane-1,3-diacetoxy group is shown below: 。 4. The synthesis method according to claim 1, characterized in that, The catalyst is selected from at least one of bis(triphenylphosphine)palladium dichloride, palladium acetate, tris(dibenzylideneacetone)palladium, and tetra(triphenylphosphine)palladium.

5. The synthesis method according to claim 1, characterized in that, The ligand is selected from at least one of triphenylphosphine, 1,1'-bis(diphenylphosphine)ferrocene, 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl, 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene, and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl.

6. The synthesis method according to claim 1, characterized in that, The additive is selected from at least one of potassium acetate, potassium hydroxide, cesium carbonate, cesium acetate, cesium fluoride, and sodium carbonate.

7. The synthesis method according to claim 1, characterized in that, The solvent is selected from at least one of acetonitrile, hexafluoroisopropanol, tetrahydrofuran, methanol, 2,2,2-trifluoroethanol, ethanol, dichloromethane, dimethyl sulfoxide, and N,N-dimethylformamide.

8. The synthesis method according to claim 1, characterized in that, The reaction temperature is 60-120℃, and the reaction time is 12-24h.

9. The synthesis method according to claim 1, characterized in that, Based on 1 molar equivalent of an α-aminoketone compound, the molar equivalent of 2-methylenepropane-1,3-diacetoxy is 1.0-2.0, the molar equivalent of the catalyst is 0.01-0.2, the molar equivalent of the ligand is 0.1-0.5, and the molar equivalent of the additive is 1.0-4.

0.

10. The synthesis method according to claim 1, characterized in that, The reaction is followed by a separation and purification step.

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