A chiral acylimidazole cyclopropane carboxamide compound and a preparation method and application thereof

Abstract

The application discloses a chiral acyl imidazole cyclopropane carboxamide compound and a preparation method and application thereof, and belongs to the field of organic synthesis. The cyclopropane skeleton provided by the application contains three continuous chiral centers: 1-methyl-1H-imidazole-2-carbonyl is connected to the C-2 position; an N,N-disubstituted amide group is connected to the C-1 position; and the C-3 position is an aryl group. The preparation method comprises the following steps: taking a sulfoxide ylide and an alpha,beta-unsaturated acyl imidazole as raw materials, and under the catalysis of a chiral metal octahedral rhodium complex, a target product is constructed through an asymmetric [2+1] cyclization reaction in one step. The method has the advantages of mild reaction conditions, low catalyst consumption (up to 2 mol %), wide substrate adaptability and the like, and can efficiently obtain the target chiral cyclopropane derivative with a diastereomeric selectivity of greater than 20:1 and an excellent enantiomeric excess value. The chiral cyclopropane compound prepared by the application can be used as a key chiral synthetic building block and is widely applied in the asymmetric synthesis of natural products, pharmaceutically active molecules and agricultural chemicals, and has important academic value and industrial application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and particularly relates to a chiral acyl imidazole cyclopropane formamide compound, its preparation method and application. Background Technology

[0002] Cyclopropane, being the smallest carbocyclic system, possesses unique ring strain and structural rigidity, making it a crucial and advantageous backbone in medicinal chemistry. Many marketed drugs contain cyclopropane structural units: the antiplatelet drug ticagrelor; the antidepressant levamisole, with chiral cyclopropane formamide as its core backbone; the monoamine oxidase inhibitor transphenylcyclopropane, already used clinically for the treatment of depression; and the antiviral drug sofosbuvir, which also contains a chiral cyclopropane structure. Furthermore, cyclopropane derivatives exhibit a variety of pharmacological activities, including antitumor, antibacterial, antimalarial, and anti-Alzheimer's disease effects. Cyclopropane is highly favored because it imparts conformational rigidity to molecules, improves metabolic stability, enhances membrane permeability, and improves pharmacokinetic properties.

[0003] At the methodological level, the asymmetric synthesis of chiral cyclopropanes still faces challenges. Existing synthetic methods have the following problems: 1. Within the sulfur ylide family, sulfonium ylides have been extensively studied in cyclopropanation reactions, typically achieving moderate to high yields. However, sulfoxide ylides, especially those with amide substituents, exhibit significantly lower reactivity. When the substrate is an α,β-unsaturated acyl imidazolium containing sterically hindered aryl or heterocyclic substituents, the low reactivity of amide sulfoxide ylides often leads to insufficient conversion or a significant decrease in yield. Therefore, effectively activating these low-activity ylides under mild conditions while simultaneously achieving high stereoselectivity is a pressing technical challenge. On the other hand, although asymmetric cyclopropanation reactions catalyzed by chiral rhodium complexes have been reported, there is a lack of systematic preparation methods and readily available mature synthetic routes for specific derivatives containing both acyl imidazolium and N,N-disubstituted amide groups, with a cyclopropane skeleton possessing three consecutive chiral centers.

[0004] 2. Lack of specific solutions for stereoselectivity control of multi-chiral centers: For cyclopropane systems with different large groups attached to the C-1, C-2, and C-3 positions, there is no clear and effective solution in existing published methods for ensuring both high diastereoselectivity (e.g., >20:1dr) and enantioselectivity (high ee value) in a one-step reaction.

[0005] 3. The applicable scope of the substrate and the compatibility of the functional groups need to be verified: whether the previous methods can be compatible with sensitive functional groups such as halogen, alkynyl, and cyano groups on the aromatic ring, as well as diverse substituents such as heterocyclic rings (such as thiophene and dihydrobenzofuran).

[0006] 4. The application direction of the target compound is not yet clear: the specific drug-related targets that this type of chiral acyl imidazole cyclopropane formamide can be used as a lead compound have affected its promotion in new drug development.

[0007] While progress has been made in the asymmetric cyclopropanation reaction catalyzed by chiral metal octahedral rhodium(III) complexes, in-depth research is still lacking in the preparation, diversity construction, and bioactivity evaluation of chiral acyl imidazole cyclopropane formamide compounds.

[0008] Therefore, developing a method for preparing chiral acyl imidazole cyclopropane formamide derivatives that is simple to operate, has mild reaction conditions, a wide range of applicable substrates, and excellent yield and stereoselectivity, and exploring its application in the asymmetric synthesis of drug molecules and natural products, has significant academic value and promising industrial application prospects. Summary of the Invention

[0009] This invention proposes a chiral acylimidazolium cyclopropane formamide compound, its preparation method, and its applications. The invention aims to address the challenges of existing catalytic asymmetric synthesis methods for chiral cyclopropanes. For polysubstituted cyclopropane skeletons with an N,N-disubstituted amide group at C-1, an acylimidazolium group at C-2, and an aryl group at C-3, it is difficult to simultaneously achieve excellent diastereoselectivity and enantioselectivity while constructing three consecutive chiral centers. Particularly when using amide sulfoxide ylide and α,β-unsaturated acylimidazolium as starting materials, the complex substrate coordination environment often leads to reduced reactivity or stereoinduction failure in conventional catalytic systems, making it difficult to obtain target products with both high yield and high optical purity. This invention provides a simple and stereoselective synthetic route for chiral acylimidazolium cyclopropane formamide compounds. The chiral acylimidazolium cyclopropane formamide compound provided by this invention possesses both cyclopropane and imidazole structural units, enabling the construction of diverse compound libraries and providing abundant materials for bioactivity screening. It has significant application value in new drug development and pharmaceutical fields.

[0010] To achieve the above objectives, the present invention provides the following technical solution: This invention provides a chiral acyl imidazole cyclopropane formamide compound having the structure shown in formula (1): Equation (1) In formula (1), R1 is selected from alkyl and substituted aromatic groups, wherein the substituent in the aromatic group is selected from phenyl, benzyl, naphthyl and substituted phenyl, wherein the substituted phenyl is bromine or methyl-substituted phenyl; and the alkyl is selected from methyl or diisobutyl. R2 is selected from alkyl and substituted aromatic groups, wherein the substituent in the aromatic group is selected from phenyl, benzyl and substituted phenyl, wherein the substituted phenyl is a bromine or methyl-substituted phenyl; and the alkyl is diisobutyl. R3 is selected from naphthyl, dihydrobenzofuranyl, 3-methylthiophenyl, phenyl, and substituted phenyl, wherein the substituent in the substituted phenyl is selected from halogen, methyl, methoxy, alkynyl, cyano, or phenyl.

[0011] The structural feature of the chiral acyl imidazolium cyclopropane formamide compound of this invention is a cyclopropane core with a specific chiral configuration of (1R, 2S, 3S), which endows the compound with a rigid three-dimensional structure, facilitating precise stereoselective binding to target proteins. Specifically, the cyclopropane formamide structure unique to this invention is an effective TYK2 (tyrosine kinase 2) inhibitor. It can be used to treat inflammatory bowel disease, cancer, fibrosis, or arthritis. Simultaneously, the cyclopropane formamide derivative can be used as a modulator of cannabinoid CB2 receptors, showing potential in the treatment of pain and neurodegenerative diseases; the imidazolium ring and cyclopropane structure are common skeletons of histamine H3 receptor modulators, associated with brain functions such as cognition and sleep. Furthermore, analogs can serve as positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors for the treatment of schizophrenia, Alzheimer's disease, etc. Therefore, the chiral acyl imidazolium cyclopropane formamide compound provided by this invention is expected to be used in the preparation of drugs for treating inflammation, pain, and central nervous system diseases.

[0012] Furthermore, the chiral acyl imidazole cyclopropane formamide compound has the structure shown in any one of formulas 3a to 3h: .

[0013] Furthermore, the chiral acyl imidazole cyclopropane formamide compound has the structure shown in any one of formulas 4a to 4o: .

[0014] This invention, by introducing an N,N-disubstituted amide group (-CONR1R2) at the C-2 position of cyclopropane, constructs for the first time a novel acylimidazolium cyclopropane formamide skeleton. This is a qualitative structural change, not a simple substituent transformation. The introduction of the amide bond not only alters the electronic properties and polarity of the molecule but also endows the product with a completely different bioactivity spectrum compared to the product described in the paper.

[0015] This invention extends R1 / R2 to alkyl (methyl, diisobutyl) for the first time, and adds alkyne-containing substrates and novel heterocyclic substrates (dihydrobenzofuran) not covered by the prior art, filling the gap in the catalytic system for alkyl thioylide substrates.

[0016] Existing technologies typically employ known chiral rhodium complexes Λ-Rh3 as catalysts; however, this invention is the first to apply a novel chiral rhodium complex containing 3,5-di-tert-butylphenyl to the asymmetric cyclopropanation reaction of thioyl ylide and α,β-unsaturated acyl imidazole, thus developing a completely new catalytic system.

[0017] The present invention also provides a method for preparing the above-mentioned chiral acyl imidazolium cyclopropane formamide compound, comprising the following steps: under the catalysis of a chiral metal rhodium complex catalyst, a sulfoxide ylide having the structure shown in Formula 1 undergoes an asymmetric cycloaddition reaction with an α,β-unsaturated acyl imidazolium having the structure shown in Formula 2 to obtain the chiral acyl imidazolium cyclopropane formamide compound. Formula 1, Equation 2, R1 is selected from alkyl and substituted aromatic groups, wherein the substituent in the aromatic group is selected from phenyl, benzyl, naphthyl and substituted phenyl, wherein the substituted phenyl is bromine or methyl-substituted; the alkyl group is selected from methyl or diisobutyl. R2 is selected from alkyl and substituted aromatic groups, wherein the substituent in the aromatic group is selected from phenyl, benzyl and substituted phenyl, wherein the substituted phenyl is bromine or methyl-substituted; and the alkyl is diisobutyl. R3 is selected from naphthyl, dihydrobenzofuranyl, 3-methylthiophenyl, phenyl, and substituted phenyl, wherein the substituent in the substituted phenyl is selected from halogen, methyl, methoxy, alkynyl, cyano, or phenyl.

[0018] This invention constructs a chiral molecular library containing multi-chiral cyclopropane compounds by precisely splicing acylimidazole and formamide into a cyclopropane backbone. This not only expands structural diversity but also generates potential synergistic pharmacological effects. The chiral acylimidazole cyclopropane formamide compound provided by this invention possesses both acylimidazole and cyclopropane formamide, two advantageous structural units, both of which have potential biological activities. The combination of the conformational rigidity of cyclopropane and the functional diversity of acylimidazole provides abundant material for bioactivity screening and has significant application value in new drug development and pharmaceutical fields.

[0019] Furthermore, the amount of the chiral metal rhodium complex catalyst is 2 to 5 mol of the total amount of sulfoxide ylide with the structure shown in Formula 1 and α,β-unsaturated acyl imidazole with the structure shown in Formula 2.

[0020] Furthermore, the chiral rhodium complex catalyst has the structure shown in formula C(I): Formula C(I).

[0021] Furthermore, the synthetic route for the chiral rhodium metal complex catalyst is as follows: , The specific procedure was as follows: Under nitrogen protection, S1 (10.0 mmol) and S2 (10.0 mmol) were added sequentially to a dry round-bottom flask equipped with a magnetic stir bar. Then, m-xylene (50 mL) was added and stirred until dissolved. The resulting solution was heated to 120 °C and stirred for 30 minutes. 4-Methoxy-TEMPO (90 mg) was added under nitrogen protection, and the reaction was then stirred at 120 °C for 12 hours under an oxygen atmosphere. The reaction progress was monitored by TLC. After the reaction was complete, heating was stopped, and the mixture was cooled to room temperature. After removing the solvent, the residue was directly purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (1:20, v / v) to give a white solid L1 (3.52 g, 80% yield).

[0022] Step 2: Under a nitrogen atmosphere, L1 (4.1 mmol) and RhCl3·3H2O (2.0 mmol) were added sequentially to a dry round-bottom flask equipped with a magnetic stir bar. Then, a mixed solvent of 2-ethoxyethanol and water (92 mL, 3:1, v / v) was added. The mixture was heated to 120 °C and stirred for 24 hours. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, filtered, and washed with cold methanol (3 × 5 mL) to give a green solid dimer-1 (1.16 g, yield 56%).

[0023] Step 3: Under a nitrogen atmosphere, sodium methoxide (0.90 mmol) was dissolved in methanol (50 mL), and L-proline was added at room temperature with stirring for 10 minutes. Then, dimer-1 (1.0 mmol) was added, and the mixture was heated to 50 °C and stirred for 12 hours. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, DCM (50.0 mL) was added, and stirring was continued for 12 hours. The resulting solution was concentrated under reduced pressure, and the crude product was directly purified by silica gel column chromatography, eluting with dichloromethane / methanol (20:1, v / v) to give a yellow solid Λ-(S) (256 mg, yield 32%). Step 4: Under a nitrogen atmosphere and in the dark, Λ-(S) (0.22 mmol) and NH4BF4 (2.8 mmol) were sequentially added to a dry round-bottom flask equipped with a magnetic stir bar. Acetonitrile (50 mL) was then added as a solvent. The mixture was heated to 50 °C and stirred overnight. The reaction was monitored by TLC until complete. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography with gradient elution (DCM / MeOH) to give a yellow solid C(Ⅰ) (164 mg, yield 66%).

[0024] Furthermore, the molar ratio of the sulfoxide ylide having the structure shown in Formula 1 to the α,β-unsaturated acyl imidazole having the structure shown in Formula 2 is (1~1.2):1, preferably 1.2:1.

[0025] Furthermore, the asymmetric cycloaddition reaction is carried out at a temperature of 50 °C for a time of 12 to 24 h, preferably 12 h.

[0026] In a preferred embodiment of the present invention, the solvent used in the asymmetric cycloaddition reaction is selected from one of acetonitrile, tetrahydrofuran, xylene, dichloromethane, 1,2-dichloroethane, and tertiary methyl ether, preferably 1,2-dichloroethane.

[0027] Furthermore, the volume ratio of the amount of sulfoxide ylide having the structure shown in Formula 1 to the volume of the solvent is (0.1 mmol to 0.2 mmol): 1 mL, preferably 0.2 mmol: 1 mL.

[0028] Furthermore, after the asymmetric cycloaddition reaction is completed, the resulting cycloaddition reaction solution is post-processed, which includes the following steps: column chromatography and solvent drying of the cycloaddition reaction solution.

[0029] Furthermore, the column chromatography eluent is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 1:1.

[0030] The present invention also provides the application of the above-mentioned chiral acyl imidazole cyclopropane formamide compound in the preparation of drug lead compounds.

[0031] The present invention also provides the use of the above-mentioned chiral acyl imidazole cyclopropane formamide compound in the preparation of anti-inflammatory drugs, antibacterial drugs, central nervous system drugs or kinase inhibitors.

[0032] Compared with the prior art, the present invention has the following advantages and technical effects: The chiral acyl imidazole cyclopropane formamide compound provided by this invention possesses both cyclopropane and imidazole as advantageous structural units, enabling the construction of diverse compound libraries and providing abundant materials for bioactivity screening. It has significant application value in the fields of new drug development and pharmaceutical manufacturing.

[0033] The preparation method provided by this invention is simple and easy to operate, the raw materials are cheap and readily available, it can be carried out in various organic solvents, it also has good air stability, wide applicability, good compatibility with various substituents, and is easy to realize industrial mass production. Attached Figure Description

[0034] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings: Figure 1 The 1H NMR spectrum of compound 3a is shown. Figure 2 The image shows the carbon NMR spectrum of compound 3a. Figure 3 The image shows the 1H NMR spectrum of compound 3b. Figure 4 The image shows the carbon NMR spectrum of compound 3b. Figure 5 The liquid phase spectrum of compound 3a is shown below. Figure 6 The liquid phase spectrum of compound 3b is shown below. Figure 7 This is a single crystal diagram of compound 3f. Detailed Implementation

[0035] 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.

[0036] 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. Every smaller range between any stated value or intermediate value within a stated range, and 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] The cyclopropane skeleton provided by this invention contains three consecutive chiral centers: a 1-methyl-1H-imidazolium-2-carbonyl group at C-2; an N,N-disubstituted amide group at C-1; and an aryl group at C-3. The preparation method includes: using sulfoxide ylide and α,β-unsaturated acylimidazole as starting materials, the target product is constructed in one step via an asymmetric [2+1] cyclization reaction catalyzed by a chiral metal octahedral rhodium complex. This method has advantages such as mild reaction conditions, low catalyst dosage (up to 2 mol%), and wide substrate adaptability. It can also efficiently obtain the target chiral cyclopropane derivative with a diastereoselectivity >20:1 and excellent enantiomeric excess. The chiral cyclopropane compounds prepared by this invention can serve as key chiral synthetic building blocks and are widely used in the asymmetric synthesis of natural products, pharmaceutical active molecules, and agrochemicals, possessing significant academic value and promising industrial applications.

[0041] Unless otherwise specified, the room temperature in this invention is 25±2℃.

[0042] All raw materials used in the embodiments of the present invention were obtained through commercial purchase.

[0043] It should be noted that any aspects not described in detail in this invention are conventional practices in the field and are not the focus of this invention.

[0044] The technical solution of the present invention will be further illustrated by the following embodiments.

[0045] Example 1 A method for preparing a chiral acyl imidazole cyclopropane formamide compound (3a) is described below: The specific steps are as follows: In a reaction tube, sulfoxide ylide 1a (0.24 mmol) and α,β-unsaturated acylimidazole 2a (0.2 mmol), 1,2-dichloroethane (1.0 mL), and a chiral rhodium complex catalyst were added sequentially. The amount of the chiral metal catalyst was 2 mol% of the total amount of sulfoxide ylide with the structure shown in Formula 1 and α,β-unsaturated acylimidazole with the structure shown in Formula 2. Cyclopropanization was carried out at 50 °C for 12 h. Compound 3a was separated by column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = 1:1). It was a white solid (77.5 mg, 92% yield), melting point: 170.8–172.4 °C, >20:1 dr.

[0046] The results of high-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HDMS) are as follows: HPLC: 97% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 11.99 min, tr (minor) = 10.02 min. [α] D 20 = +21.8 (c = 0.2, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.24 (dt, J = 9.8, 3.8 Hz, 8H), 7.20 - 7.12(m, 6H), 7.03 - 6.97 (m, 3H), 4.02 (s, 3H), 3.55 (dd, J = 9.4, 6.1 Hz, 1H), 3.33 (t, J = 6.3 Hz, 1H), 2.59 (dd, J = 9.4, 6.5 Hz, 1H). 13 C NMR (101 MHz, CDCl3)δ 186.6, 167.9, 143.7, 142.9, 142.6, 138.6, 129.6, 129.3, 128.8, 128.6,128.4, 127.5, 126.9, 126.7, 126.6, 126.4, 126.0, 36.2, 35.9, 35.9, 31.8. HRMS(FTMS +c APCI) calcd for C 27 H 24 N3O2 + (M+H) + 422.1863, found 422.1863. The proton NMR spectrum of compound 3a is shown below. Figure 1 As shown, the carbon NMR spectrum is as follows: Figure 2 As shown. The liquid phase spectrum of compound 3a is shown below. Figure 5 As shown.

[0047] In Examples 2-8 below, compounds 3b-3h are prepared using the same methods as compound 3a.

[0048] Example 2 The difference from Example 1 is that R1 and R2 are 4-methylphenyl.

[0049] 3b was a white solid (79.1 mg, 88% yield), melting point: 223.1–224.7 °C, >20:1 dr. The results of high-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) are as follows: HPLC: 97% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 19.86 min, tr (minor) = 10.62 min. [α] D 20 = -21.9 (c = 0.3, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.24 - 7.15 (m, 4H), 7.12 - 7.01 (m, 10H), 7.00 (s, 1H), 4.02 (s, 3H), 3.56 (dd, J = 9.4, 6.1 Hz, 1H), 3.33 (t, J = 6.3 Hz, 1H), 2.61 (dd, J = 9.4, 6.5 Hz, 1H), 2.28 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 186.7, 167.9,143.7, 140.6, 140.1, 138.7, 137.3, 135.6, 130.1, 129.4, 129.2, 128.3, 128.2,126.8, 126.6, 126.5, 126.2, 36.2, 36.0, 35.9, 35.8, 31.7, 21.0. HRMS (FTMS +cAPCI) calcd for C 29 H 28 N3O2 + (M+H) + 450.2176, found 450.2175. The proton NMR spectrum of compound 3b is shown below. Figure 3 As shown, the carbon NMR spectrum is as follows: Figure 4 As shown. The liquid phase spectrum of compound 3b is as follows. Figure 6 As shown.

[0050] Example 3 The difference from Example 1 is that R1 and R2 are 4-bromophenyl.

[0051] 3c is a white solid (103.1 mg, 89% yield), melting point: 157.0–158.6 °C, >20:1 dr. The results of high-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) are as follows: HPLC: 97% ee (Chiralpak IC column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 26.60 min, tr (minor) = 14.60 min. [α] D 20 = + 88.1 (c = 0.4, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.2 Hz, 4H), 7.25 - 7.17 (m, 4H), 7.08 (d, J =13.1 Hz, 5H), 7.02 - 6.97 (m, 2H), 4.02 (s, 3H), 3.65 (dd, J = 9.4, 6.1 Hz, 1H), 3.27 (t, J = 6.3 Hz, 1H), 2.55 (dd, J = 9.4, 6.5 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 186.3, 167.7, 143.4, 141.5, 141.1, 138.0, 132.9, 132.0, 129.9,129.4, 128.5, 128.0, 127.2, 127.0, 126.2, 36.3, 35.9, 35.8, 32.0. HRMS (FTMS+c APCI) calcd for C 27 H 22 Br2N3O2 + (M+H) + 578.0073, found 578.0073. Example 4 The difference from Example 1 is that R1 is 2-naphthyl.

[0052] 3d was a white solid (78.3 mg, 83% yield), melting point: 185.7–187.3 °C, >20:1dr. High-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) results are as follows: HPLC: 98% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 19.22 min, tr (minor) = 13.55 min. [α] D 20 = + 57.8 (c = 0.4, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.70 - 7.54 (m, 3H), 7.49 (s, 1H), 7.33 (d, J = 12.2 Hz,3H), 7.22 - 7.03 (m, 8H), 6.96 (d, J = 16.6 Hz, 3H), 6.81 (d, J = 6.3 Hz, 1H), 3.94 (s, 3H), 3.50 (dd, J = 9.4, 6.2 Hz, 1H), 3.29 (t, J = 6.3 Hz, 1H), 2.57 (dd, J = 9.4, 6.4 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 186.5, 168.1, 143.6, 142.8,142.6, 140.5, 139.7, 138.3, 133.5, 132.1, 131.6, 129.6, 129.3, 128.8, HRMS (FTMS +c APCI) calcd for C 31 H 26 N3O2 + (M+H) + 472.2020, found 472.2021. Example 5 The difference from Example 1 is that R1 is benzyl.

[0053] 3e was a white solid (73.2 mg, 84% yield), melting point: 117.2–118.8 °C, >20:1dr. High-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) results are as follows: HPLC: >99% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 8.50 min, tr (minor) = 12.25 min. [α] D 20 = +27.3 (c = 0.3, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.18 (dq, J = 7.4, 3.6 Hz, 8H), 7.12 (dt, J = 8.0, 2.9 Hz, 4H),7.04 (s, 1H), 7.01 - 6.96 (m, 4H), 5.09 (d, J = 14.4 Hz, 1H), 4.68 (d, J = 14.5Hz, 1H), 4.03 (s, 3H), 3.46 (dd, J = 9.5, 6.2 Hz, 1H), 3.39 (t, J = 6.3 Hz, 1H), 2.41 (dd, J = 9.5, 6.4 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 186.6, 167.6, 143.7,141.8, 138.6, 137.5, 129.4, 129.2, 128.6, 128.4, 128.3, 128.2, 127.8, 127.2,126.8, 126.6, 126.5, 53.2, 36.2, 35.5, 34.9, 30.9. HRMS (FTMS +c APCI) calcdfor C 28 H 26 N3O2 + (M+H) + 436.2020, found 436.1019. Example 6 The difference from Example 1 is that R1 and R2 are benzyl groups.

[0054] 3f was a white solid (55.8 mg, 63% yield), melting point: 166.4–168.0 °C, >20:1dr. The results of high-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) are as follows: HPLC: 99% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 19.16 min, tr (minor) = 27.36 min. [α] D 20 = -15.1 (c = 0.2, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.34 (t, J = 7.3 Hz, 2H), 7.27 (dd, J = 6.9, 4.8 Hz, 6H), 7.18(td, J = 13.5, 12.5, 7.1 Hz, 8H), 7.05 (s, 1H), 5.16 (d, J = 14.8 Hz, 1H), 4.87(d, J = 16.9 Hz, 1H), 4.23 (d, J = 16.9 Hz, 1H), 4.09 (d, J = 14.8 Hz, 1H), 4.02(s, 3H), 4.00 - 3.93 (m, 1H), 3.61 (t, J = 6.3 Hz, 1H), 2.70 (dd, J = 9.5, 6.6Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 186.2, 167.9, 143.5, 138.5, 137.2, 136.3,129.4, 128.8, 128.5, 128.4, 128.4, 127.5, 127.3, 127.1, 126.8, 126.6, 126.6,49.7, 48.1, 36.2, 34.7, 34.5, 30.7. HRMS (FTMS +c APCI) calcd for C 29 H28 N3O2 + (M+H) + 450.2176, found 450.2174. The single crystal diagram of compound 3f is shown below. Figure 7 As shown, by Figure 7 The exact structure of the compound can be seen, specifically (1) R ,2 S ,3 S )- N,N -dibenzyl-2-(1-methyl-1H-imidazole-2-carbonyl)-3-phenylcyclopropane-1-carboxamide.

[0055] Example 7 The difference from Example 1 is that R1 is methyl.

[0056] 3g was a white solid (61.8 mg, 86% yield), melting point: 134.9~136.5 ℃, >20:1dr. High-performance liquid chromatography, optical rotation, nuclear magnetic resonance, and high-resolution mass spectrometry results are as follows: HPLC: >99% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 9.23 min, tr (minor) = 10.62 min. [α] D 20 = +53.8 (c = 0.3, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.21 - 7.12 (m, 3H), 7.12 - 7.03 (m, 6H), 6.97 (s, 1H), 6.90 -6.86 (m, 2H), 3.96 (s, 3H), 3.40 (dd, J = 9.5, 6.1 Hz, 1H), 3.22 (t, J = 6.3 Hz,1H), 3.18 (s, 3H), 2.32 (dd, J = 9.4, 6.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ186.7, 167.6, 143.6, 143.4, 138.5, 129.5, 129.2, 128.3, 127.5, 127.2, 126.9,126.6, 126.4, 37.5, 36.2, 35.4, 35.2, 31.0. HRMS (FTMS +c APCI) calcd forC 22 H 22 N3O2 + (M+H) + 360.1707, found 360.1708. Example 8 The difference from Example 1 is that R1 and R2 are diisobutyl.

[0057] The product was colorless oil (60.3 mg, 79% yield) after 3 hours, >20:1 dr. High-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) results are as follows: HPLC: 95% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 5.16 min, tr (minor) = 5.97 min. [α] D 20 = -41.0 (c = 0.5, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.25 -7.19 (m, 2H), 7.19 - 7.11 (m, 3H), 7.06 (d, J = 1.0 Hz, 1H), 6.95 (d, J = 0.9 Hz,1H), 3.90 (s, 3H), 3.78 (dd, J = 9.6, 5.9 Hz, 1H), 3.42 - 3.26 (m, 3H), 2.89(dd, J = 14.5, 7.0 Hz, 1H), 2.79 (dd, J = 13.4, 7.7 Hz, 1H), 2.59 (dd, J = 9.6, 6.5Hz, 1H), 1.90 - 1.78 (m, 2H), 0.75 (dd, J= 11.2, 6.7 Hz, 6H), 0.69 (dd, J = 6.7, 2.5 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 186.3, 167.4, 143.6, 138.9, 129.2,128.6, 126.9, 126.7, 126.5, 55.2, 53.1, 36.2, 35.2, 34.7, 30.3, 27.5, 26.3,20.2, 20.1, 20.0, 20.0. HRMS (FTMS +c APCI) calcd for C 23 H 32 N3O2 + (M+H) + 382.2489, found 382.2489. Table 1 Chemical structures and yields of compounds 3a to 3h In Examples 9-23 below, compounds 4a to 4o are prepared in the same way as compound 3a.

[0058] Example 9 The difference from Example 1 is that R3 is 4-methylbenzene.

[0059] 4a was a white solid (74.9 mg, 86% yield), melting point: 194.2–195.8 °C, >20:1 dr. The results of high-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) are as follows: HPLC: 95% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 11.09 min, tr (minor) = 8.25 min. [α] D 20 = -27.7 (c = 0.3, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.28 - 7.17 (m, 9H), 7.13 (s, 2H), 6.99 (d, J = 7.1 Hz, 3H), 6.87(d, J = 7.9 Hz, 2H), 3.99 (s, 3H), 3.50 (dd, J= 9.4, 6.1 Hz, 1H), 3.30 (t, J = 6.3Hz, 1H), 2.55 (dd, J = 9.4, 6.4 Hz, 1H), 2.25 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ186.7, 168.0, 143.7, 142.9, 142.8, 136.3, 135.5, 129.5, 129.2, 129.0, 128.8,128.6, 127.5, 126.9, 126.5, 126.4, 126.0, 36.2, 35.8, 35.7, 31.5, 21.0. HRMS(FTMS +c APCI) calcd for C 28 H 26 N3O2 + (M+H) + 436.2020, found 436.2022. Example 10 The difference from Example 1 is that R3 is 3-methylbenzene.

[0060] 4b was a white solid (65.3 mg, 75% yield), melting point: 133.8–135.4 °C, >20:1 dr. The results of high-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) are as follows: HPLC: 96% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 8.97 min, tr (minor) = 8.25 min. [α] D 20 = +38.6 (c = 0.3, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.25 - 7.20 (m, 8H), 7.12 (d, J = 0.9 Hz, 3H), 7.07 (dd, J = 6.6,1.6 Hz, 2H), 7.03 - 6.98 (m, 2H), 6.86 - 6.82 (m, 1H), 3.99 (s, 3H), 3.44 -3.40 (m, 2H), 2.53 (dd, J= 8.6, 7.3 Hz, 1H), 2.39 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 186.9, 168.6, 143.5, 142.8, 142.7, 138.1, 136.6, 129.8, 129.6,129.2, 128.7, 127.6, 126.9, 126.9, 126.4, 125.8, 125.7, 36.2, 34.4, 33.9,30.1, 19.7. HRMS (FTMS +c APCI) calcd for C 28 H 26 N3O2 + (M+H) + 436.2020, found436.2020. Example 11 The difference from Example 1 is that R3 is 3,4-dimethylbenzene.

[0061] 4c is a white solid (78.2 mg, 87% yield), melting point: 232.3–233.9 °C, >20:1 dr. The results of high-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) are as follows: HPLC: 94% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 13.22 min, tr (minor) = 9.45 min. [α] D 20 = +35.2 (c = 0.3, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.18 (q, J = 12.7, 10.2 Hz, 9H), 7.08 (s, 2H), 6.95 (s, 1H), 6.88(d, J = 7.7 Hz, 1H), 6.70 - 6.62 (m, 2H), 3.95 (s, 3H), 3.45 (dd, J = 9.4, 6.1Hz, 1H), 3.21 (t, J = 6.3 Hz, 1H), 2.49 (dd, J = 9.4, 6.4 Hz, 1H), 2.09 (d, J= 6.2Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 186.8, 168.1, 143.7, 143.0, 142.7, 136.5,135.9, 135.0, 130.0, 129.22, 128.8, 128.6, 127.8, 127.5, 126.9, 126.6, 126.0,123.8, 36.3, 35.9, 35.6, 31.6, 19.7, 19.4. HRMS (FTMS +c APCI) calcd forC 29 H 28 N3O2 + (M+H) + 450.2176, found 450.2176. Example 12 The difference from Example 1 is that R3 is 4-methoxybenzene.

[0062] 4d was a white solid (74.1 mg, 82% yield), melting point: 197.8–199.4 °C, >20:1dr. High-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) results are as follows: HPLC: 94% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 18.59 min, tr (minor) = 12.47 min. [α] D 20 = +56.9 (c = 0.3, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.22 - 7.09 (m, 9H), 7.05 (d, J = 5.1 Hz, 2H), 6.94 (s, 1H), 6.87 - 6.81 (m, 2H), 6.69 - 6.60 (m, 2H), 3.93 (s, 3H), 3.65 (s, 3H), 3.42(dd, J = 9.4, 6.1 Hz, 1H), 3.20 (t, J = 6.3 Hz, 1H), 2.46 (dd, J = 9.4, 6.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 186.7, 168.0, 158.4, 143.6, 142.9, 142.5,130.5, 129.5, 129.2, 128.8, 128.5, 127.5, 126.9, 126.5, 126.0, 113.7, 55.3,36.23, 35.8, 35.7, 31.3. HRMS (FTMS +c APCI) calcd for C 28 H 26 N3O3 + (M+H) + 452.1969, found 452.1966. Example 13 The difference from Example 1 is that R3 is biphenyl.

[0063] 4e was a white solid (86.6 mg, 87% yield), melting point: 166.7–168.3 °C, >20:1 dr. The results of high-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) are as follows: HPLC: 99% ee (Chiralpak IA column, 254 nm, hexane / isopropanol = 80:20, flow rate 1.0 mL / min, tr (major) = 25.38 min, tr (minor) = 23.65 min. [α] D 20 = -88.2 (c = 0.4, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.56 - 7.51 (m, 2H), 7.46 - 7.38 (m, 4H), 7.34 - 7.13 (m, 12H), 7.07(dd, J = 8.3, 2.0 Hz, 2H), 7.02 (s, 1H), 4.02 (s, 3H), 3.64 - 3.56 (m, 1H), 3.40 - 3.35 (m, 1H), 2.68 - 2.58 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 186.5,167.9, 143.7, 142.9, 142.5, 140.7, 139.6, 137.7, 129.6, 129.3, 128.8, 128.6,127.6, 127.3, 127.1, 127.0, 126.9, 126.6, 126.1, 36.2, 35.9, 31.6. HRMS (FTMS+c APCI) calcd for C 33 H 28 N3O2 + (M+H) + 498.2176, found 498.2174. Example 14 The difference from Example 1 is that R3 is 4-fluorobenzene.

[0064] 4f is a white solid (79.1 mg, 90% yield), melting point: 176.9–178.5 °C, >20:1 dr. The results of high-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) are as follows: HPLC: 98% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 13.78 min, tr (minor) = 9.95 min. [α] D 20 = +13.2 (c = 0.3, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.15 (dt, J = 12.8, 5.1 Hz, 9H), 7.06 (s, 2H), 6.94 (s, 1H), 6.89- 6.83 (m, 2H), 6.79 (t, J = 8.7 Hz, 2H), 3.92 (s, 3H), 3.43 (dd, J = 9.4, 6.1Hz, 1H), 3.20 (t, J = 6.3 Hz, 1H), 2.46 (dd, J = 9.4, 6.5 Hz, 1H). 13C NMR (101MHz, CDCl3) δ 186.5, 167.7, 162.9, 160.5, 143.6, 142.84, 142.5, 134.2, 134.2,129.6, 129.3, 128.8, 128.5, 128.0, 127.9, 127.6, 127.0, 126.5, 126.1, 115.3,115.1, 36.2, 35.8, 35.7, 31.1. 19 F NMR (376 MHz, CDCl3) δ -115.9. HRMS (FTMS +cAPCI) calcd for C 27 H 23 FN3O2 + (M+H) + 440.1769, found 44.1769. Example 15 The difference from Example 1 is that R3 is 4-chlorobenzene.

[0065] 4 g was a white solid (81.2 mg, 89% yield), melting point: 201.1~202.7 ℃, >20:1 dr. High-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) results are as follows: HPLC: >99% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 17.74 min, tr (minor) = 12.55 min. [α] D 20 = -16.5 (c = 0.3, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.16 (dq, J = 15.6, 8.3, 6.6 Hz, 9H), 7.08 (dd, J = 6.5, 1.9Hz, 4H), 6.97 (s, 1H), 6.86 - 6.79 (m, 2H), 3.95 (s, 3H), 3.45 (dd, J = 9.4, 6.1 Hz, 1H), 3.19 (t, J = 6.3 Hz, 1H), 2.48 (dd, J = 9.5, 6.5 Hz, 1H).13 C NMR (101MHz, CDCl3) δ 186.3, 167.6, 143.5, 142.8, 142.4, 137.1, 132.4, 129.7, 129.3,128.8, 128.5, 127.8, 127.6, 127.1, 126.5, 126.2, 36.3, 35.9, 35.8, 31.1. HRMS(FTMS +c APCI) calcd for C 27 H 23 ClN3O2 + (M+H) + 456.1473, found 456.1473. Example 16 The difference from Example 1 is that R3 is 4-bromobenzene.

[0066] After 4 hours, it was a white solid (91.1 mg, 91% yield), melting point: 207.6–209.2 °C, >20:1 dr. The results of high-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) are as follows: HPLC: 98% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 20.26 min, tr (minor) = 13.77 min. [α] D 20 = -24.7 (c = 0.3, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 1.7 Hz, 1H), 7.29 -7.17 (m, 9H), 7.15 (s, 2H), 7.03 (s, 1H), 6.88 - 6.82 (m, 2H), 4.01 (s, 3H), 3.52 (dd, J = 9.4, 6.1 Hz, 1H), 3.26 (t, J = 6.3 Hz, 1H), 2.55 (dd, J = 9.4, 6.5Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 186.3, 167.6, 143.6, 142.8, 142.5, 137.7,131.4, 129.6, 129.3, 128.8, 128.5, 128.2, 127.6, 127.0, 126.5, 126.1, 120.5,36.2, 35.8, 35.7, 31.1. HRMS (FTMS +c APCI) calcd for C 27 H 23 BrN3O2 + (M+H) + 500.0968, found 500.0970. Example 17 The difference from Example 1 is that R3 is 4-iodobenzene.

[0067] 4i was a white solid (97.4 mg, 89% yield), melting point: 207.8–209.4 °C, >20:1 dr. The results of high-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) are as follows: HPLC: >99% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 23.77 min, tr (minor) = 16.39 min. [α] D 20 =+20.2 (c = 0.3, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.46 - 7.39 (m, 2H), 7.17 (dt, J = 15.1, 8.1 Hz, 9H), 7.07 (s,2H), 6.96 (s, 1H), 6.67 - 6.57 (m, 2H), 3.94 (s, 3H), 3.44 (dd, J = 9.4, 6.1Hz, 1H), 3.16 (t, J = 6.3 Hz, 1H), 2.48 (dd, J = 9.4, 6.4 Hz, 1H). 13C NMR (101MHz, CDCl3) δ 186.2, 168.0, 143.5, 142.7, 142.4, 138.3, 137.3, 129.6, 129.3,128.8, 128.5, 128.4, 127.6, 127.1, 126.5, 126.1, 91.8, 36.3, 35.8, 35.7,31.2. HRMS (FTMS +c APCI) calcd for C 27 H 23 IN3O2 + (M+H) + 548.0829, found 548.0829. Example 18 The difference from Example 1 is that R3 is 4-ethynylbenzene.

[0068] 4j was a white solid (72.2 mg, 81% yield), melting point: 158.5–160.1 °C, >20:1 dr. The results of high-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) are as follows: HPLC: 97% ee (Chiralpak IA column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 14.02 min, tr (minor) = 11.07 min. [α] D 20 = +64.9 (c = 0.3, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.36 - 7.30 (m, 2H), 7.25 (dd, J = 11.9, 5.7 Hz, 9H), 7.15 (d, J =0.9 Hz, 2H), 7.04 (s, 1H), 6.96 - 6.89 (m, 2H), 4.03 (s, 3H), 3.56 (dd, J =9.4, 6.1 Hz, 1H), 3.29 (t, J = 6.3 Hz, 1H), 3.05 (s, 1H), 2.59 (dd, J = 9.4, 6.5Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 186.3, 167.6, 143.7, 142.9, 142.7, 139.6,132.2, 129.7, 129.4, 128.8, 128.5, 127.6, 127.0, 126.5, 126.4, 126.1, 120.4,83.5, 36.3, 36.1, 36.0, 31.6. HRMS (FTMS +c APCI) calcd for C 29 H 24 N3O2 + (M+H) + 446.1863, found 446.1862. Example 19 The difference from Example 1 is that R3 is 4-cyanobenzene.

[0069] 4K was a white solid (74.1 mg, 83% yield), melting point: 176.0–177.6 °C, >20:1 dr. The results of high-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) are as follows: HPLC: 95% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 23.38 min, tr (minor) = +20.56 min. [α] D 20 = +15.5 (c = 0.3, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.1 Hz, 2H), 7.17 (dq, J = 18.2, 8.7, 7.4 Hz,9H), 7.09 (s, 2H), 7.01 - 6.91 (m, 3H), 3.96 (s, 3H), 3.53 (dd, J = 9.5, 6.0Hz, 1H), 3.23 (t, J = 6.2 Hz, 1H), 2.55 (dd, J = 9.5, 6.5 Hz, 1H). 13C NMR (101MHz, CDCl3) δ 185.7, 167.1, 144.3, 143.4, 142.6, 142.31, 132.2, 129.7, 129.4,128.9, 128.4, 127.7, 127.3, 127.0, 126.4, 126.3, 118.8, 110.3, 36.3, 36.1,36.1, 31.4. HRMS (FTMS +c APCI) calcd for C 28 H 23 N4O2 + (M+H) + 447.1816, found 447.1819. Example 20 The difference from Example 1 is that R3 is 2-naphthalene.

[0070] 4 L was a white solid (80.2 mg, 85% yield), melting point: 213.6–215.2 °C, >20:1 dr. The results of high-performance liquid chromatography (HPLC), optical rotation, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HPLC) are as follows: HPLC: 95% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 19.14 min, tr (minor) = 13.22 min. [α] D 20 = -10.0 (c = 0.3, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.70 - 7.65 (m, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.38 - 7.28(m, 3H), 7.23 - 7.12 (m, 8H), 7.07 (d, J = 6.5 Hz, 3H), 7.01 (dd, J = 8.5, 1.8Hz, 1H), 6.95 (s, 1H), 3.95 (s, 3H), 3.61 (dd, J = 9.4, 6.1 Hz, 1H), 3.39 (t, J =6.3 Hz, 1H), 2.63 (dd, J = 9.4, 6.5 Hz, 1H).13 C NMR (101 MHz, CDCl3) δ 186.6,167.9, 143.6, 142.9, 142.5, 135.9, 133.2, 132.3, 129.6, 129.3, 128.8, 128.5,128.1, 127.6, 127.5, 127.0, 126.5, 126.2, 126.1, 125.6, 125.1, 124.6, 36.3,36.1, 35.7, 32.0. HRMS (FTMS +c APCI) calcd for C 31 H 26 N3O2 + (M+H) + 472.2020, found 472.2021. Example 21 The difference from Example 1 is that R3 is 1-naphthalene.

[0071] 4m is a white solid (79.7 mg, 86% yield), melting point: 203.7~205.3 ℃, >20:1dr. The results of high-performance liquid chromatography, optical rotation, nuclear magnetic resonance, and high-resolution mass spectrometry are as follows: HPLC: 97% ee (Chiralpak IC column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 23.28 min, tr (minor) = 120.53 min. [α] D 20 = +36.8 (c = 0.3, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.4 Hz, 1H), 7.72 (dd, J = 8.2, 1.3 Hz, 1H), 7.62 (d, J = 8.2Hz, 1H), 7.49 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.40 (ddd, J = 8.1, 6.8, 1.2 Hz,1H), 7.20 (dd, J = 5.9, 2.4 Hz, 5H), 7.10 (d, J= 18.8 Hz, 7H), 7.03 (d, J = 7.2Hz, 1H), 6.97 (s, 1H), 3.99 (s, 3H), 3.84 (t, J = 6.5 Hz, 1H), 3.55 (dd, J = 9.3, 6.4 Hz, 1H), 2.51 (dd, J = 9.3, 6.7 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 187.2,168.4, 143.6, 142.8, 142.3, 134.6, 133.5, 133.0, 129.6, 129.4, 128.9, 128.8,128.3, 127.7, 127.1, 126.6, 126.5, 126.1, 126.0, 125.2, 124.8, 123.9, 36.4,34.3, 33.5, 29.9. HRMS (FTMS +c APCI) calcd for C 31 H 26 N3O2 + (M+H) + 472.2020, found472.2020. Example 22 The difference from Example 1 is that R3 is dihydrobenzofuran.

[0072] 4n is a white solid (79.7 mg, 86% yield), melting point: 191.7-193.3 ℃, >20:1dr. The results of high-performance liquid chromatography, optical rotation, nuclear magnetic resonance, and high-resolution mass spectrometry are as follows: HPLC: 96% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 14.90 min, tr (minor) = 10.41 min. [α] D 20 = +55.6 (c = 0.3, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.31 - 7.21 (m, 8H), 7.16 (d, J = 21.4 Hz, 3H), 7.02 (s,1H), 6.83 (d,J = 1.9 Hz, 1H), 6.73 (dd, J = 8.2, 2.0 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 4.49 (t, J = 8.7 Hz, 2H), 4.01 (s, 3H), 3.50 (dd, J = 9.3, 6.1 Hz, 1H), 3.28(t, J = 6.3 Hz, 1H), 3.08 (t, J = 8.7 Hz, 2H), 2.52 (dd, J = 9.4, 6.5 Hz, 1H). 13 CNMR (101 MHz, CDCl3) δ 186.8, 168.0, 159.0, 143.7, 142.9, 142.6, 130.4,129.5, 129.2, 128.7, 128.6, 127.4, 127.1, 126.9, 126.5, 126.3, 126.0, 123.0,108.9, 71.2, 36.2, 35.9, 35.6, 31.7, 29.6. HRMS (FTMS +c APCI) calcd forC 29 H 26 N3O3 + (M+H) + 464.1969, found 464.1968. Example 23 The difference from Example 1 is that R3 is 3-methylthiophene.

[0073] 4O is a white solid (79.5 mg, 90% yield), melting point: 175.5~177.1 ℃, >20:1 dr. The results of high-performance liquid chromatography, optical rotation, nuclear magnetic resonance, and high-resolution mass spectrometry are as follows: HPLC: 95% ee (Chiralpak ADH column, 254 nm, hexane / isopropanol = 70:30, flow rate 1.0 mL / min, tr (major) = 10.87 min, tr (minor) = 9.29 min. [α] D 20 = +16.3 (c = 0.3, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 7.34 - 7.16 (m, 9H), 7.15 (d, J = 0.9 Hz, 2H), 7.02 (s, 1H), 6.46 (s,2H), 4.00 (s, 3H), 3.51 - 3.40 (m, 2H), 2.56 (dd, J = 9.2, 6.5 Hz, 1H), 2.36(s, 3H). 13 C NMR (101 MHz, CDCl3) δ 186.1, 167.6, 143.6, 142.8, 142.4, 140.0,138.0, 129.6, 129.3, 128.8, 128.6, 127.6, 126.9, 126.5, 126.1, 124.7, 124.2,36.8, 36.2, 27.2, 15.3. HRMS (FTMS +c APCI) calcd for C 26 H 24 N3O2S + (M+H) + 442.1584, found 442.1584. Table 2 Chemical structures and yields of compounds 4a to 4o Test Example 1: Evaluation of NO Inhibitory Activity 1. Experimental Methods: A lipopolysaccharide (LPS)-induced inflammation model in mouse macrophage RAW264.7 cells was used to determine the inhibitory activity of the compound of this invention on nitric oxide (NO) production. RAW264.7 cells were seeded in 96-well plates and cultured overnight at 37 °C in a 5% CO2 incubator. The experiment included a blank control group (without LPS and the compound), a negative control group (with LPS but without the compound), and a treatment group (with LPS and the test compound, final concentration 50 μM). Each group was pretreated with the corresponding drug for 1 h, followed by stimulation with LPS (final concentration 1 μg / mL) for 24 h. The cell culture supernatant was collected, and the nitrite content was determined using the Griess method to characterize NO production. Each group had three replicates, and the experiment was repeated three times.

[0074] 2. Inhibition rate calculation Calculate the inhibition rate of each compound on NO generation according to formula (1): Among them, OD 阴性The mean absorbance of the negative control group, OD 空白 The mean absorbance of the blank control group, OD 化合物 The absorbance is the average value of the drug administration group.

[0075] 3. Experimental Results Table 3 shows the inhibition rates of the target compounds against LPS-induced NO production at a concentration of 50 μM. The results indicate that compounds 3h and 4o exhibited relatively strong inhibitory activity, with inhibition rates of (32.0±0.7)% and (28.8±8.2)%, respectively; compounds 3d, 3f, and 4k showed inhibition rates of (21.5±6.5)%, (20.3±4.1)%, and (18.2±3.8)%, respectively, demonstrating moderate anti-inflammatory activity; the inhibition rates of the remaining compounds were below 15% or no significant inhibitory activity was detected.

[0076] Table 3. NO inhibition rates of some target compounds at 50 μM concentration (mean ± SD, n=3) The above results indicate that the chiral acyl imidazole cyclopropane formamide compounds provided by this invention possess a certain degree of NO generation inhibition activity, with compounds 3h and 4o exhibiting relatively superior activity. These compounds can be used as lead compounds for anti-inflammatory drugs for further structural optimization and in-depth pharmacological studies.

[0077] Based on the above results, the present invention draws the following conclusions: 1. A suitable starting material combination was designed (to solve the problem of missing skeleton): sulfoxide ylide (Formula 1) and α,β-unsaturated acylimidazole (Formula 2) were selected as reactants. Utilizing the activating effect of the acylimidazole, this specific skeleton can be constructed through a one-step [2+1] cyclization reaction, rather than relying on multiple cumbersome transformations. This method effectively addresses the problem of "no readily available synthetic method" for this type of polysubstituted cyclopropane skeleton.

[0078] 2. A suitable chiral rhodium catalyst was matched and its dosage optimized (improving stereocontrol): A chiral octahedral rhodium complex with a specific structure (formula C(I)) was selected, and the chiral induction of the cyclization transition state was primarily controlled under 50 °C and 1,2-dichloroethane conditions. Data in the document show that this method achieves diastereoselectivity >20:1 and enantiomeric excess values ​​of 95% to >99% for most substrates, indicating that the catalytic system has good compatibility with these substrates and effectively improves the challenge of simultaneous construction of multiple chiral centers. Simultaneously, the catalyst dosage was controlled at 2–5 mol%, ensuring both effectiveness and economy.

[0079] 3. The system validated the broad compatibility of the substrates (expanding the scope of application): Through Examples 3a-3h and 4a-4o, the variations of R1 / R2 (such as phenyl, benzyl, methyl, diisobutyl, etc.) and R3 (containing halogens, methyl, methoxy, alkynyl, cyano, naphthyl, dihydrobenzofuran, thiophene, etc.) were investigated. The results showed that the yields of most substrates were between 75% and 92%, indicating that the method has good tolerance to substituents with different electronic effects and steric hindrances, and can support the construction of diverse compound libraries, filling the gap in previous validation of the scope of this type of substrate.

[0080] 4. It is associated with specific potential pharmaceutical applications (clear application value): Because the compounds of this invention have both a rigid cyclopropane skeleton and an imidazole heterocyclic structural unit, they have a certain degree of skeletal similarity to some known anti-inflammatory, antibacterial, central nervous system and kinase inhibitor drug molecules. Therefore, they are expected to be used as lead compounds or chiral intermediates for the synthesis and screening of candidate drugs in the above-mentioned related therapeutic areas.

[0081] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. A chiral acylimidazolium cyclopropaneformamide compound, characterized in that, It has the structure shown in equation (1): Equation (1) In formula (1), R1 is selected from alkyl and substituted aromatic groups, wherein the substituent in the aromatic group is selected from phenyl, benzyl, naphthyl and substituted phenyl, wherein the substituted phenyl is bromine or methyl-substituted phenyl; and the alkyl is selected from methyl or diisobutyl. R2 is selected from alkyl and substituted aromatic groups, wherein the substituent in the aromatic group is selected from phenyl, benzyl and substituted phenyl, wherein the substituted phenyl is a bromine or methyl-substituted phenyl; and the alkyl is diisobutyl. R3 is selected from naphthyl, dihydrobenzofuranyl, 3-methylthiophenyl, phenyl, and substituted phenyl, wherein the substituent in the substituted phenyl is selected from halogen, methyl, methoxy, alkynyl, cyano, or phenyl.

2. The chiral acyl imidazolium cyclopropane formamide compound according to claim 1, characterized in that, The chiral acyl imidazole cyclopropane formamide compound has the structure shown in any one of formulas 3a to 3h: 。 3. The chiral acyl imidazolium cyclopropane formamide compound according to claim 1, characterized in that, The chiral acyl imidazole cyclopropane formamide compound has the structure shown in any one of formulas 4a to 4o: 。 4. A method for preparing the chiral acyl imidazolium cyclopropane formamide compound according to any one of claims 1 to 3, characterized in that, Includes the following steps: Under the catalysis of a chiral rhodium complex catalyst, a sulfoxide ylide having the structure shown in Formula 1 undergoes an asymmetric cycloaddition reaction with an α,β-unsaturated acyl imidazole having the structure shown in Formula 2 to obtain the chiral acyl imidazole cyclopropane formamide compound. Formula 1, Equation 2, R1 is selected from alkyl and substituted aromatic groups, wherein the substituent in the aromatic group is selected from phenyl, benzyl, naphthyl and substituted phenyl, wherein the substituted phenyl is bromine or methyl-substituted; the alkyl group is selected from methyl or diisobutyl. R2 is selected from alkyl and substituted aromatic groups, wherein the substituent in the aromatic group is selected from phenyl, benzyl and substituted phenyl, wherein the substituted phenyl is bromine or methyl-substituted; and the alkyl is diisobutyl. R3 is selected from naphthyl, dihydrobenzofuranyl, 3-methylthiophenyl, phenyl, and substituted phenyl, wherein the substituent in the substituted phenyl is selected from halogen, methyl, methoxy, alkynyl, cyano, or phenyl.

5. The preparation method according to claim 4, characterized in that, The amount of the chiral metal rhodium complex catalyst is 2 to 5 mol of the total amount of sulfoxide ylide with the structure shown in Formula 1 and α,β-unsaturated acyl imidazole with the structure shown in Formula 2.

6. The preparation method according to claim 5, characterized in that, The chiral rhodium complex catalyst has the structure shown in formula C(I): Formula C(I).

7. The preparation method according to claim 4, characterized in that, The molar ratio of the sulfoxide ylide having the structure shown in Formula 1 to the α,β-unsaturated acyl imidazole having the structure shown in Formula 2 is (1~1.2):

1.

8. The preparation method according to claim 4, characterized in that, The asymmetric cycloaddition reaction was carried out at a temperature of 50°C for 12–24 h.

9. The use of a chiral acyl imidazole cyclopropane formamide compound as described in any one of claims 1 to 3 in the preparation of a pharmaceutical lead compound.

10. The use of a chiral acyl imidazole cyclopropane formamide compound as described in any one of claims 1 to 3 in the preparation of anti-inflammatory drugs, antibacterial drugs, central nervous system drugs or kinase inhibitors.

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