Synthesis method of chiral 3-aryl-2-piperidone compound

Abstract

The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a synthesis method of a chiral 3-aryl-2-piperidone compound. Comprising the following steps: by taking an aryl halogenated compound or a trifluoromethanesulfonate compound and a chlorinated lactam electrophilic compound as raw materials, carrying out reductive coupling reaction at room temperature in a protective atmosphere in a reaction system formed by a nickel-based catalyst, a ligand, manganese and a solvent, so as to obtain the chiral 3-aryl-2-piperidone compound. According to the invention, based on a reduction coupling strategy of nickel catalysis, an aryl halogenated compound or a trifluoromethanesulfonate compound and a simple and easily available 3-chloro-2-piperidone electrophilic reagent are used as initial raw materials, so that the defects of harsh reaction conditions of noble metals, biological enzymes and the like, complex substrate synthesis, limited range and the like are overcome; a series of chiral 3-aryl-2-piperidone compounds are efficiently, mildly and conveniently synthesized.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for synthesizing chiral 3-aryl-2-piperidone compounds. Background Art

[0002] As a six-membered nitrogen-containing saturated heterocycle, 2-piperidone can provide a rigid framework, and the presence of chiral centers endows the compound with significant steric selectivity and stereochemical properties. This property is crucial for the design of bioactive molecules because most biological systems are highly sensitive to chirality. In medicinal chemistry, chiral piperidone compounds are widely used as active molecules or drug precursors. Their stereostructures can significantly affect the interactions with biological targets such as enzymes and receptors, thus determining the efficacy, metabolic pathways, and toxicity of drugs. Currently, chiral 3-substituted piperidone compounds are widely present in various drug molecules and bioactive molecules, but their acquisition remains a challenge, especially for the piperidone structure with an aryl substitution at the chiral 3-position.

[0003] Currently, there are relatively few reports on chiral 3-substituted piperidones, and only a few successful cases. In 1998, the Koga research group reported the use of chiral tetradentate lithium amide and lithium bromide to obtain enantioselective alkylation of lactams in the form of enol lithium, enabling the synthesis of chiral 3-substituted-2-piperidone compounds. However, this reaction only yielded alkyl-substituted chiral 2-piperidone compounds.

[0004] 。

[0005] In 2022, the Chen Yifeng research group reported a nickel-catalyzed intramolecular asymmetric alkylacylation reaction of alkenes, which can synthesize various chiral 3-substituted piperidone compounds. However, this reaction is mainly used to obtain chiral 3-substituted benzopiperidone compounds, and only 3 alkyl-substituted chiral 2-piperidone compounds were obtained.

[0006] 。

[0007] In summary, the current synthesis methods for chiral 3-substituted piperidones have harsh reaction conditions, poor substrate compatibility, and low product enantioselectivity. Summary of the Invention

[0008] To solve the above problems, the present invention provides a method for synthesizing chiral 3-aryl-2-piperidone compounds. Based on a nickel-catalyzed reductive coupling strategy, aryl halide compounds or trifluoromethanesulfonate compounds and readily available 3-chloro-2-piperidone electrophilic reagents are used as starting materials, overcoming obstacles such as harsh reaction conditions of precious metals and biological enzymes, and limited scope of complex substrate synthesis. A series of chiral 3-aryl-2-piperidone compounds are efficiently, mildly and conveniently synthesized. Through a reduction reaction, chiral 3-arylpiperidine compounds can be rapidly obtained, which can be used in the synthesis of key intermediates of related chiral 3-arylpiperidine drug molecules.

[0009] The present invention solves the above technical problems through the following technical solutions.

[0010] The object of the present invention is to provide a method for synthesizing chiral 3-aryl-2-piperidone compounds, comprising the following steps: Using an aryl halide compound or a trifluoromethanesulfonate compound and a chloroamide electrophilic compound as raw materials, in a reaction system composed of a nickel-based catalyst, a chiral biimidazole ligand, a metal-based reducing agent and a solvent, a reductive coupling reaction is carried out at room temperature under a protective atmosphere to obtain a chiral 3-aryl-2-piperidone compound.

[0011] Further, the molar ratio of the chloroamide electrophilic compound to the aryl halide compound is 0.1:0.2 - 0.5, and the molar ratio of the chloroamide electrophilic compound to the trifluoromethanesulfonate compound is 0.1:0.2 - 0.5.

[0012] Further, the molar ratio of the chloroamide compound to the nickel-based catalyst is 0.1:0.01 - 0.025; the molar ratio of the chloroamide compound to the ligand is 0.1:0.015 - 0.03; the molar ratio of the chloroamide compound to the metal reducing agent is 0.1:0.3 - 0.5, and the metal-based reducing agent is manganese.

[0013] Further, the nickel-based catalyst is nickel bromide dimethoxyethane.

[0014] Further, the structural formula of the chiral biimidazole ligand is as follows: .

[0015] Further, the time of the reductive coupling reaction is 12 h - 24 h.

[0016] Further, the chloroamide electrophilic compound is 3-chloro-1-pivaloylpiperidin-2-one, 3-chloro-1-pivaloyl-3,4-dihydropyridin-2(1H)-one, 3-chloro-1-pivaloylpyrrolidin-2-one, 3-chloro-1-pivaloylazepan-2-one or 3-chloro-1-pivaloyl-3,4-dihydroquinolin-2(1H)-one.

[0017] Further, the structural formula of the aryl halide compound is as follows: or ; wherein, R1 is benzene, biphenyl, benzothiophene, tert-butyl indole-1-carboxylate, thiophene, substituted pyridine, substituted phenyl, substituted pyrimidine, , , or ; " " is the connection site; The substituents of the phenyl group are selected from halogen, C1-C3 alkenyl, -R3COOR4, -NHR3COOR4, -R3COR4, cyano, C1-C3 aldehyde group, C1-C3 trifluoroalkoxy group, C1-C3 alkynylsilane, C1-C4 alkyl group, C1-C4 alkoxy group, C1-C3 alkylthio group or dioxolane ring, R3 is a C1-C3 alkyl group, and R4 is a C1-C4 alkyl group; The substituents of the pyridine are selected from halogen, C1-C4 alkoxy group; The substituents of the pyrimidine are selected from C1-C4 alkoxy group; wherein, R2 is indene or C1-C3 alkenylphenyl, and the alkene in indene or C1-C3 alkenylphenyl is the connection site.

[0018] Further, the trifluoromethanesulfonate compound is cyclohex-1-en-1-yl trifluoromethanesulfonate.

[0019] Further, the aryl halide compounds are iodobenzene, p-fluoroiodobenzene, p-chloroiodobenzene, p-iodostyrene, methyl p-iodobenzoate, p-iodobenzonitrile, p-iodobenzaldehyde, 1-iodo-4-trifluoromethoxybenzene, ((4-iodophenyl)ethynyl)trimethylsilane, 4-iodo-1,1'-biphenyl, 1-iodo-4-methylbenzene, 1-(tert-butyl)-4-iodobenzene, 1-iodo-4-methoxybenzene, (4-iodophenyl)(methyl)thiane), tert-butyl (4-iodophenyl)carbamate, 1-iodo-3-methoxybenzene, 2-iodonaphthalene, 1-(3-iodophenyl)-1-ethanone, 1-iodo-3,4-methylenedioxbenzene, 1-iodo-2-methylbenzene, 4-iododibenzo[b,d]thiophene, 5-iodo-1H-indole-1-carboxylic acid tert-butyl ester, 3-iodothiophene, 2-fluoro-4-iodopyridine, 5-iodo-2-methoxypyridine, 2-chloro-6-iodopyridine, 5-iodo-2-methoxypyrimidine, 2-bromo-1H-indene, 3-bromo-1,2-dihydronaphthalene, (2-bromovinyl)benzene, ethyl 4-(8-iodo-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylate, (3 aR , 5R , 6 S , 6 aR )-5-(( R )-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl 4-iodobenzoate, ( S )-1-(4-fluorophenyl)-3-((2 S , 3 R )-1-(4-fluorophenyl)-2-(4-iodophenyl)-4-oxazolidin-3-yl)propyl acetate or (1 R , 2 S , 5 R )-2-isopropyl-5-methylcyclohexyl 3-iodobenzoate.

[0020] The present invention has the following beneficial effects compared with the prior art: The present invention provides a method for synthesizing chiral 3-aryl-2-piperidone compounds. Based on the nickel-catalyzed reductive coupling strategy, using aryl halide compounds or trifluoromethanesulfonate compounds, and simple and readily available 3-chloro-2-piperidone electrophilic reagents as starting materials, aryl iodide / bromide / trifluoromethanesulfonate reagents and simple and readily available chloroamide electrophilic reagents as starting materials, it overcomes the obstacles such as harsh reaction conditions of precious metals and biological enzymes, and limited scope of complex substrate synthesis, and efficiently, mildly and conveniently synthesizes a series of chiral piperidine compounds at the 3-position. It is the first time to complete the modular synthesis of chiral piperidine compounds at the 3-position through the reductive coupling strategy. The chiral 3-arylpiperidine compounds can be rapidly obtained through the reduction reaction and can be used in the synthesis of key intermediates of related chiral 3-arylpiperidine drug molecules.

[0021] The method for synthesizing chiral 3-aryl-2-piperidone compounds prepared by the present invention provides a simple method and realizes the modular synthesis of chiral piperidine compounds at the 3-position under mild reaction conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is the 1 1H NMR spectrum of 2,2'-(2-phenylpropane-1,3-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) prepared in Example 1 of the present invention.

[0023] Figure 2 is the 13 13C NMR spectrum of 2,2'-(2-phenylpropane-1,3-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) prepared in Example 1 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0024] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0025] At present, regarding the synthetic methods of chiral 3-substituted piperidinones, the reaction conditions are harsh, and the substrate compatibility and product enantioselectivity are relatively poor. And chiral 3-aryl-2-piperidinone compounds, as a structure widely existing in drug molecules and bioactive molecules, are also the reduction precursors of chiral 3-arylpiperidine structures and have high practical value. Therefore, it is necessary to develop a strategy for the efficient synthesis of chiral 3-aryl-2-piperidinones.

[0026] Based on this, the present invention provides a synthetic method for chiral 3-aryl-2-piperidinone compounds, including the following steps: Using aryl halide compounds or trifluoromethanesulfonate compounds and chloroamide electrophilic compounds as raw materials, in a reaction system composed of a nickel-based catalyst, a chiral biimidazole ligand, a metal-based reducing agent, and a solvent, a reductive coupling reaction is carried out at room temperature under a protective atmosphere to obtain chiral 3-aryl-2-piperidinone compound aryls.

[0027] As a preferred embodiment of the present invention, the chloroamide electrophilic compound can be 3-chloro-1-pivaloylpiperidin-2-one, 3-chloro-1-pivaloyl-3,4-dihydropyridin-2(1H)-one, 3-chloro-1-pivaloylpyrrolidin-2-one, 3-chloro-1-pivaloylazepan-2-one, or 3-chloro-1-pivaloyl-3,4-dihydroquinolin-2(1H)-one. The reaction routes and mechanisms of the above-mentioned chloroamide electrophilic compounds as raw materials for reductive coupling reactions with aryl halide compounds or trifluoromethanesulfonate compounds are the same. The present invention takes 3-chloro-1-pivaloylpiperidin-2-one as the chloroamide electrophilic compound as an example to further illustrate the reaction route and mechanism of the reductive coupling reaction. The synthetic route of its chiral 3-aryl-2-piperidinone compound is as follows:

[0028] 。

[0029] The reaction mechanism is as follows: 。

[0030] Using metallic manganese as a reducing agent, by reducing the Ni II pre-catalyst to form Ni 0 L n catalyst. Subsequently, Ni 0L n The catalyst undergoes oxidative addition with the aryl iodide compound to form X-Ni II L n (Ar) species, X-Ni II / L n The (Ar) species is oxidized by the alkyl radical IV, and single electron transfer occurs to generate X-Ni III L n (Ar) intermediate. Subsequently, X-Ni III L n The (Ar) intermediate undergoes reductive elimination to obtain X-Ni II L n species V. Then, through the halogen atom transfer reduction between the alkyl chloride and X-Ni II L n species V, X-Ni II L n (Cl) complex VI is obtained. Finally, the Ni 0 L n catalyst is regenerated by reduction with the metal manganese reductant, thus ending the catalytic cycle.

[0031] This is further illustrated by the following specific examples.

[0032] Example 1 ( R ) Preparation method of ( )-3-phenyl-1-pivaloylpiperidin-2-one (Compound 3a), comprising the following steps:

[0033] .

[0034] Characterize Compound 3a, 1 1H NMR (400 MHz, CDCl3) is as Figure 1 shown, 13 13C NMR (400 MHz, CDCl3) spectrum is as Figure 2 shown, and fromFigure 1 and Figure 2 It can be seen that compound 3a was successfully synthesized.

[0035] 1H NMR characterization: 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.34 (m, 2H), 7.33 – 7.25 (m, 3H), 3.76 – 3.62 (m, 3H), 2.33 – 2.23 (m, 1H), 2.15 – 2.05 (m, 2H), 2.04 – 1.94 (m, 1H), 1.31 (s, 9H).

[0036] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 174.4, 139.6, 128.8, 128.6, 127.3, 50.9, 47.7, 44.1, 30.9, 28.0, 22.5. HRES (ESI+): Calcd for [C 16 H 21 NO2, M+Na] + : 282.14645; Found: 282.14774.

[0037] Example 2 ( R )- Preparation of 3-(4-fluorophenyl)-1-pivaloylpiperidin-2-one (Compound 3b) The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) was replaced with p-fluoroiodobenzene (2b, 0.2 mmol), and the target chiral piperidine compound 3b was obtained by column chromatography separation and purification. Compound 3b is a white solid, with an enantioselectivity ratio of 98:2 and a yield of 82%. The synthetic route is as follows:

[0038] .

[0039] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.23 – 7.16 (m, 2H), 7.08 – 7.00 (m, 2H), 3.74 – 3.58 (m, 3H), 2.27 – 2.20 (m, 1H), 2.11 – 1.93 (m, 3H), 1.27 (s, 9H). 13C NMR characterization: 1313C NMR (100 MHz, CDCl3) δ 190.3, 174.3, 163.3, 160.9, 135.3 (d, J J = 3.33 Hz), 130.2 (d, J J = 8.02 Hz), 115.6 (d, J J = 21.45 Hz), 50.1, 47.7, 44.1, 30.9, 28.0, 22.6.

[0040] Example 3 ( R )-3-(4-Chlorophenyl)-1-pivaloylpiperidin-2-one (Compound 3c) Preparation The difference between this example and Example 1 is only that: Iodobenzene (2a, 0.2 mmol) is replaced with p-Chloroiodobenzene (2c, 0.2 mmol). The target chiral piperidine compound 3c was obtained by column chromatography separation and purification. Compound 3c is a white solid, with an enantioselectivity ratio of 99:1 and a yield of 85%. The synthetic route is as follows:

[0041] .

[0042] 1H NMR characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J J = 8.4 Hz, 2H), 7.19 –7.14 (m, 2H), 3.72 – 3.58 (m, 3H), 2.25 – 2.20 (m, 1H), 2.09 – 1.94 (m, 3H), 1.26 (s, 9H).

[0043] 13C NMR characterization: 13 13C NMR (100 MHz, CDCl3) δ 190.2, 174.0, 138.0, 133.2, 130.0, 128.9, 50.2, 47.7, 47.7, 44.3, 44.1, 30.7, 28.0, 22.6.

[0044] Example 4 ( R )-1-Pivaloyl-3-(4-vinylphenyl)piperidin-2-one (Compound 3d) Preparation The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced by methyl 4-iodobenzoate (2e, 0.2 mmol). The target chiral piperidine compound 3e was obtained by column chromatography separation and purification. Compound 3e is a white solid, with an enantioselectivity ratio of 99:1 and a yield of 46%. The synthetic route is as follows:

[0045] 。

[0046] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J J = 7.9 Hz, 2H), 7.19(d, J J = 7.8 Hz, 2H), 6.70 (dd, J J = 17.6, 10.9 Hz, 1H), 5.72 (d, J J = 17.6 Hz, 1H),5.23 (d, J J = 10.9 Hz, 1H), 3.67 (ddd, J J = 12.3, 8.5, 5.7 Hz, 3H), 2.21 (d, J J = 8.1Hz, 1H), 2.05 (tdd, J J = 14.0, 7.3, 3.9 Hz, 3H), 1.27 (s, 9H).。

[0047] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.2, 174.3, 139.1, 136.7,136.5, 128.7, 126.6, 113.9, 50.6, 47.7, 44.1, 30.7, 28.0, 22.5.。

[0048] Example 5 ( R )-Methyl 4-(2-oxo-1-pivaloylpiperidin-3-yl)benzoate (Compound 3e) Preparation The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced by methyl 4-iodobenzoate (2e, 0.2 mmol). The target chiral piperidine compound 3e was obtained by column chromatography separation and purification. Compound 3e is a white solid, with an enantioselectivity ratio of 99:1 and a yield of 46%. The synthetic route is as follows:

[0049] 。

[0050] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 8.03 – 7.98 (m, 2H), 7.32 –7.28 (m, 2H), 3.89 (s, 3H), 3.77 – 3.58 (m, 3H), 2.23 (dtt, J J = 10.7, 4.6, 2.2Hz, 1H), 2.11 – 1.93 (m, 3H), 1.26 (s, 9H).

[0051] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.2 173.6, 166.9, 144.8,130.0, 129.1, 128.7, 52.2, 50.7, 47.7, 44.1, 30.6, 27.9, 22.4.

[0052] Example 6 ( R ) Preparation of (S)-4-(2-oxo-1-pivaloylpiperidin-3-yl)benzonitrile (Compound 3f) The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) was replaced with 4-iodobenzonitrile (2f, 0.2 mmol). The target chiral piperidine compound 3f was obtained by column chromatography separation and purification. Compound 3f is a white solid, with an enantioselectivity ratio of 98:2 and a yield of 35%. The synthetic route is as follows:

[0053] .

[0054] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.68 – 7.57 (m, 2H), 7.38 –7.29 (m, 2H), 3.78 – 3.66 (m, 2H), 3.59 (dtd, J J = 12.5, 4.6, 1.6 Hz, 1H), 2.24(dt, J J = 7.8, 5.5 Hz, 1H), 2.12 – 1.96 (m, 3H), 1.25 (s, 9H).

[0055] 13C NMR characterization: 1313C NMR (100 MHz, CDCl3) δ 190.1, 173.0, 144.9, 132.5, 129.6, 118.8, 111.2, 50.7, 47.7, 44.0, 30.5, 27.9, 22.5.

[0056] Example 7 ( R ) Preparation of ( )-4-(2-Oxo-1-pivaloylpiperidin-3-yl)benzaldehyde (Compound 3g)

[0057] .

[0058] 1H NMR characterization: 1 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.89 – 7.85 (m, 2H), 7.43 – 7.39 (m, 2H), 3.81 – 3.69 (m, 2H), 3.63 (dtd, J J = 9.3, 4.8, 2.3 Hz, 1H), 2.27 (dddd, J J = 14.2, 8.0, 5.1, 2.0 Hz, 1H), 2.12 – 1.98 (m, 3H), 1.28 (s, 9H).

[0059] 13C NMR characterization: 13 13C NMR (100 MHz, CDCl3) δ 192.0, 190.2, 173.4, 146.6, 135.6, 130.2, 129.5, 51.0, 47.7, 44.1, 30.7, 28.0, 22.6.

[0060] Example 8 ( R ) Preparation of ( The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced by 1-iodo-4-trifluoromethoxybenzene (2h, 0.2 mmol). The target chiral piperidine compound 3h was obtained by column chromatography separation and purification. Compound 3h is a white solid, with an enantioselectivity ratio of 99:1 and a yield of 70%. The synthetic route is as follows:

[0061] 。

[0062] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.28 – 7.23 (m, 2H), 7.21 –7.15 (m, 2H), 3.79 – 3.54 (m, 3H), 2.24 (dtt, J J = 10.3, 4.5, 2.1 Hz, 1H), 2.11– 1.90 (m, 3H), 1.28 (s, 9H).。

[0063] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 173.9, 148.4 (q, J J = 2.01Hz), 138.3, 130.0, 129.8, 121.3, 50.2, 47.9, 47.8, 44.1, 31.0, 28.0, 22.6.。

[0064] Example 9 ( R )-1-Pivaloyl-3-(4-((trimethylsilyl)ethynyl)phenyl)piperidin-2-one (Compound 3i) Preparation The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced by ((4-iodophenyl)ethynyl)trimethylsilane (2i, 0.2 mmol). The target chiral piperidine compound 3i was obtained by column chromatography separation and purification. Compound 3i is a white solid, with an enantioselectivity ratio of 98:2 and a yield of 89%. The synthetic route is as follows:

[0065] 。

[0066] 1H NMR characterization: 11H NMR (400 MHz, CDCl3) δ 7.47 – 7.38 (m, 2H), 7.20 – 7.13 (m, 2H), 3.73 – 3.57 (m, 3H), 2.25 – 2.16 (m, 1H), 2.09 – 1.91 (m, 3H), 1.26 (s, 9H), 0.23 (s, 9H).。

[0067] 13C NMR characterization: 13 13C NMR (100 MHz, CDCl3) δ 190.3, 173.9, 140.0, 132.3, 128.5, 122.2, 105.0, 94.4, 50.7, 47.7, 44.1, 30.6, 28.0, 22.4, 0.1.。

[0068] Example 10 ( R )-3-( [1,1'-Biphenyl]-4-yl)-1-piperidin-2-one (Compound 3j) Preparation The difference between this example and Example 1 is only that: Iodobenzene (2a, 0.2 mmol) is replaced with ((4-iodophenyl)ethynyl)trimethylsilane (2j, 0.2 mmol). The target chiral piperidine compound 3j is obtained by column chromatography separation and purification. Compound 3j is a white solid, with an enantioselectivity ratio of 98:2 and a yield of 89%. Its synthetic route is as follows:

[0069] 。

[0070] 1H NMR characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J J = 7.6 Hz, 4H), 7.43(t, J J = 7.5 Hz, 2H), 7.33 (dd, J J = 14.9, 7.6 Hz, 3H), 3.80 – 3.62 (m, 3H), 2.30 – 2.24 (m, 1H), 2.09 (tq, J J = 9.2, 5.1 Hz, 2H), 2.04 – 1.96 (m, 1H), 1.30 (s, 9H).。

[0071] 13C NMR characterization: 1313C NMR (100 MHz, CDCl3) δ 190.4, 174.5, 141.0, 140.3, 138.6, 129.0, 128.9, 127.6, 127.4, 127.3, 50.6, 47.8, 44.1, 30.9, 28.0, 22.6.

[0072] Example 11 ( R ) Preparation of ( )-1-pivaloyl-3-(p-tolyl)piperidin-2-one (Compound 3k)

[0073] .

[0074] 1H NMR characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.14 (q, J J = 8.2 Hz, 4H), 3.72 – 3.37 (m, 3H), 2.33 (d, J J = 3.6 Hz, 3H), 2.27 – 2.17 (m, 1H), 2.12 – 1.88 (m, 3H), 1.28 (s, 9H).

[0075] 13C NMR characterization: 13 13C NMR (100 MHz, CDCl3) δ 190.3, 174.7, 136.9, 136.5, 129.4, 128.4, 50.6, 47.7, 44.0, 30.8, 28.0, 22.6, 21.2.

[0076] Example 12 ( R ) Preparation of methyl 4-(2-oxo-1-pivaloylpiperidin-3-yl)benzoate (Compound 3l) The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) was replaced with 1-(tert-butyl)-4-iodobenzene (2l, 0.2 mmol). The target chiral piperidine compound 3l was obtained by column chromatography separation and purification. Compound 3l is a white solid, with an enantioselectivity ratio of 97:3 and a yield of 35%. The synthetic route is as follows:

[0077] 。

[0078] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.33 (m, 2H), 7.20 –7.13 (m, 2H), 3.73 – 3.58 (m, 3H), 2.22 (dddd, J = 14.1, 7.5, 3.7, 1.7 Hz, 1H),1.95 (s, 3H), 1.31 (s, 9H), 1.29 (s, 9H).。

[0079] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.4, 174.6, 149.9, 136.5,128.2, 125.7, 50.4, 47.7, 44.0, 34.5, 31.4, 30.9, 28.0, 22.5.。

[0080] Example 13 ( R )-3-(4-Methoxyphenyl)-1-pivaloylpiperidin-2-one (Compound 3m) Preparation The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced by 1-iodo-4-methoxybenzene (2m, 0.2 mmol). The target chiral piperidine compound 3m was obtained by column chromatography separation and purification. Compound 3m is a white solid, with an enantioselectivity ratio of 99:1 and a yield of 90%. The synthetic route is as follows:

[0081] 。

[0082] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.18 – 7.13 (m, 2H), 6.91 –6.85 (m, 2H), 3.79 (s, 3H), 3.69 – 3.59 (m, 3H), 2.26 – 2.18 (m, 1H), 2.10 –1.92 (m, 3H), 1.27 (s, 9H).。

[0083] 13C NMR characterization: 1313C NMR (100 MHz, CDCl3) δ 190.3, 174.8, 158.8, 131.6, 129.6, 114.2, 55.4, 50.1, 47.7, 44.1, 30.8, 28.0, 22.6.

[0084] Example 14 ( R ) Preparation of methyl ( )-4-(2-oxo-1-pivaloylpiperidin-3-yl)benzoate (Compound 3n)

[0085] .

[0086] 1H NMR characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.26 – 7.21 (m, 2H), 7.18 – 7.12 (m, 2H), 3.72 – 3.57 (m, 3H), 2.46 (s, 3H), 2.26 – 2.16 (m, 1H), 2.10 – 1.89 (m, 3H), 1.27 (s, 9H).

[0087] 13C NMR characterization: 13 13C NMR (100 MHz, CDCl3) δ 190.3, 174.4, 141.0, 140.2, 138.6, 129.0, 128.8, 127.5, 127.2, 50.6, 47.8, 44.1, 30.9, 28.0, 22.6.

[0088] Example 15 ( R ) Preparation of methyl ( )-4-(2-oxo-1-pivaloylpiperidin-3-yl)benzoate (Compound 3o)

[0089] 。

[0090] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J J = 8.1 Hz, 2H), 7.16 –7.11 (m, 2H), 3.70 – 3.58 (m, 3H), 2.19 (tt, J J = 8.4, 5.7 Hz, 1H), 2.03 (tdd, J J =12.9, 5.5, 2.4 Hz, 2H), 1.97 – 1.90 (m, 1H), 1.50 (s, 9H), 1.26 (s, 9H).。

[0091] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 174.6, 152.9, 137.5,134.0, 129.0, 118.9, 80.5, 50.2, 47.7, 44.0, 30.7, 28.4, 28.0, 22.4.。

[0092] Example 16 ( R )-3-(3-Methoxyphenyl)-1-pivaloylpiperidin-2-one (Compound 3p) Preparation The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) was replaced with 1-iodo-3-methoxybenzene (2p, 0.2 mmol). The target chiral piperidine compound 3p was obtained by column chromatography separation and purification. Compound 3p is a white solid, with an enantioselectivity ratio of 98:2 and a yield of 65%. Its synthetic route is as follows:

[0093] 。

[0094] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.26 (d, J J = 15.9 Hz, 1H), 6.85 –6.75 (m, 3H), 3.79 (s, 3H), 3.71 – 3.61 (m, 3H), 2.28 – 2.18 (m, 1H), 2.06(ddt, J= 12.8, 6.6, 2.5 Hz, 2H), 1.98 – 1.90 (m, 1H), 1.28 (s, 9H).。

[0095] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 174.2, 159.8, 141.1,129.7, 120.9, 114.6, 112.5, 55.3, 50.9, 47.7, 44.1, 30.8, 28.0, 22.4.。

[0096] Example 17 ( R )- Preparation of 3-(naphthalen-2-yl)-1-pivaloylpiperidin-2-one (Compound 3q) The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced by 2-iodonaphthalene (2q, 0.2 mmol). The target chiral piperidine compound 3q was obtained by column chromatography separation and purification. Compound 3q is a white solid, with an enantioselectivity ratio of 99:1 and a yield of 78%. The synthetic route is as follows:

[0097] 。

[0098] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.86 – 7.78 (m, 3H), 7.71 (d, J =1.9 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.36 (dd, J = 8.5, 1.9 Hz, 1H), 3.88 (dd, J =10.7, 6.3 Hz, 1H), 3.82 – 3.62 (m, 2H), 2.34 – 2.25 (m, 1H), 2.23 – 2.06 (m,2H), 2.06 – 1.95 (m, 1H), 1.31 (s, 9H).。

[0099] 13C NMR characterization: 1313C NMR (100 MHz, CDCl3) δ 190.3, 174.4, 137.0, 133.5, 132.7, 128.4, 127.8, 127.7, 127.4, 126.6, 126.2, 125.9, 51.0, 47.8, 44.1, 30.8, 28.0, 22.6.

[0100] Example 18 ( R ) Preparation of ( ) -3-(3-Acetylphenyl)-1-pivaloylpiperidin-2-one (Compound 3r)

[0101] .

[0102] 1H NMR characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.92 – 7.79 (m, 2H), 7.45 (dd, J J = 4.7, 2.1 Hz, 2H), 3.80 – 3.68 (m, 2H), 3.67 – 3.60 (m, 1H), 2.60 (s, 3H), 2.30 – 2.21 (m, 1H), 2.15 – 2.04 (m, 2H), 2.04 – 1.98 (m, 1H), 1.27 (s, 9H).

[0103] 13C NMR characterization: 13 13C NMR (100 MHz, CDCl3) δ 198.0, 190.3, 173.9, 140.3, 137.6, 133.5, 129.0, 128.4, 127.6, 50.8, 47.8, 44.1, 30.9, 28.0, 26.8, 22.6.

[0104] Example 19 ( R ) Preparation of Methyl 4-(2-oxo-1-pivaloylpiperidin-3-yl)benzoate (Compound 3s) The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced by 1-iodo-3,4-methylenedioxybenzene (2s, 0.2 mmol). The target chiral piperidine compound 3s is obtained through column chromatography separation and purification. Compound 3s is a white solid, with an enantioselectivity ratio of 98:2 and a yield of 82%. The synthetic route is as follows:

[0105] 。

[0106] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 6.81 – 6.74 (m, 1H), 6.74 –6.66 (m, 2H), 5.93 (dq, J = 5.1, 1.5 Hz, 2H), 3.70 – 3.50 (m, 3H), 2.25 – 2.17(m, 1H), 2.09 – 1.91 (m, 3H), 1.27 (s, 9H).。

[0107] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 174.6, 147.9, 146.9,133.3, 121.9, 109.0, 108.5, 101.2, 50.6, 47.7, 44.1, 30.9, 28.0, 22.6.。

[0108] Example 20 ( R )-Preparation of (1S,3S)-1-pivaloyl-3-(o-tolyl)piperidin-2-one (Compound 3t) The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced by 1-iodo-2-methylbenzene (2t, 0.2 mmol). The target chiral piperidine compound 3t is obtained through column chromatography separation and purification. Compound 3t is a white solid, with an enantioselectivity ratio of 98:2 and a yield of 37%. The synthetic route is as follows:

[0109] 。

[0110] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.24 – 7.12 (m, 4H), 3.97 –3.85 (m, 1H), 3.72 (ddd, J = 12.3, 9.7, 4.1 Hz, 1H), 3.63 (dtd,J = 12.3, 4.7, 1.7 Hz, 1H), 2.33 (s, 3H), 2.26 – 1.99 (m, 3H), 2.03 – 1.89 (m, 1H), 1.30 (s, 9H).

[0111] 1H NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.5, 174.2, 138.2, 136.2, 130.9, 128.2, 127.3, 126.4, 47.9, 47.4, 44.1, 30.0, 28.0, 22.8, 20.0.

[0112] Example 21 ( R )-3-(Dibenzo[b,d]thiophen-4-yl)-1-pivaloylpiperidin-2-one (Compound 3u) Preparation The difference between this example and Example 1 is only that: Iodobenzene (2a, 0.2 mmol) is replaced by 4-iododibenzo[b,d]thiophene (2u, 0.2 mmol). The target chiral piperidine compound 3u is obtained by column chromatography separation and purification. Compound 3u is a white solid, with an enantioselectivity ratio of 98:2 and a yield of 58%. Its synthetic route is as follows:

[0113] .

[0114] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 8.18 – 8.12 (m, 1H), 8.09 (dd, J = 7.9, 1.1 Hz, 1H), 7.88 – 7.82 (m, 1H), 7.52 – 7.42 (m, 3H), 7.34 (dd, J = 7.4, 1.1 Hz, 1H), 4.05 (dd, J = 10.5, 6.8 Hz, 1H), 3.82 (ddd, J = 12.5, 10.0, 4.5 Hz, 1H), 3.68 (dtd, J = 12.5, 4.8, 1.3 Hz, 1H), 2.42 – 2.27 (m, 2H), 2.17 – 2.00 (m, 2H), 1.32 (s, 9H).

[0115] 13C NMR characterization:13 13C NMR (100 MHz, CDCl3) δ 190.3, 172.8, 139.4, 138.8, 136.4, 136.2, 134.3, 127.0, 126.3, 125.1, 124.6, 122.8, 121.9, 120.7, 50.2, 47.9, 44.1, 29.1, 28.0, 22.9.

[0116] Example 22 ( R ) Preparation of tert-Butyl 5-(2-oxo-1-pivaloylpiperidin-3-yl)-1H-indole-1-carboxylate (Compound 3v) The difference between this example and Example 1 is only that: Iodobenzene (2a, 0.2 mmol) was replaced with tert-Butyl 5-iodo-1H-indole-1-carboxylate (2v, 0.2 mmol). The target chiral piperidine compound 3v was obtained by column chromatography separation and purification. Compound 3v is a white solid, with an enantioselectivity ratio of 99:1 and a yield of 58%. The synthetic route is as follows:

[0117] .

[0118] 1H NMR characterization: 1 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J J = 8.6 Hz, 1H), 7.58 (d, J J = 3.8 Hz, 1H), 7.43 (d, J J = 1.8 Hz, 1H), 7.18 (dd, J J = 8.6, 1.8 Hz, 1H), 6.53 (d, J J = 3.7 Hz, 1H), 3.79 (dd, J J = 10.4, 6.2 Hz, 1H), 3.68 (pd, J J = 12.4, 4.8 Hz, 2H), 2.27 (dq, J J = 11.7, 5.6 Hz, 1H), 2.15 – 2.05 (m, 2H), 1.98 (ddt, J J = 14.6, 9.5, 4.8 Hz, 1H), 1.66 (s, 9H), 1.28 (s, 9H).

[0119] 13C NMR characterization: 1313C NMR (100 MHz, CDCl3) δ 190.3, 174.9, 149.8, 134.4, 133.9, 131.0, 126.4, 124.8, 120.9, 115.5, 107.4, 83.8, 50.8, 47.7, 44.1, 31.1, 28.3, 28.0, 22.6.

[0120] Example 23 ( R ) Preparation of ( ) -1-Pivaloyl-3-(thiophen-3-yl)piperidin-2-one (3w) (Compound 3w)

[0121] .

[0122] 1H NMR characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.27 (m, 1H), 7.14 (dt, J J = 3.0, 1.0 Hz, 1H), 7.04 (dd, J J = 5.0, 1.3 Hz, 1H), 3.84 (dd, J J = 9.3, 6.1 Hz, 1H), 3.61 (dd, J J = 6.9, 5.0 Hz, 2H), 2.28 – 2.20 (m, 1H), 2.13 – 2.02 (m, 2H), 1.98 – 1.89 (m, 1H), 1.27 (s, 9H).

[0123] 13C NMR characterization: 13 13C NMR (100 MHz, CDCl3) δ 190.3, 173.9, 139.3, 127.8, 125.9, 122.2, 47.6, 45.7, 44.1, 29.7, 28.0, 22.1.

[0124] Example 24 ( R ) Preparation of ( The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced by 3-iodothiophene 2-fluoro-4-iodopyridine (2x, 0.2 mmol). The target chiral piperidine compound 3x was obtained by column chromatography separation and purification. Compound 3x is a white solid, with an enantioselective ratio of 93:7 and a yield of 70%. The synthetic route is as follows:

[0125] .

[0126] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 8.17 (dd, J J = 10.0, 5.2 Hz, 1H),7.07 (ddt, J J = 5.2, 3.4, 1.7 Hz, 1H), 6.82 (t, J J = 1.7 Hz, 1H), 3.82 – 3.65 (m,2H), 3.65 – 3.56 (m, 1H), 2.29 – 2.18 (m, 1H), 2.13 – 1.92 (m, 3H), 1.27 (s,9H).

[0127] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.1, 172.1, 164.1 (d, J J=238.6 Hz), 154.0 (d, J J = 7.9 Hz), 147.9 (d, J J = 15.3 Hz), 121.7 (d, J J = 4.2 Hz),109.8 (d, J J = 37.9 Hz), 49.8, 49.8, 47.6, 44.1, 30.0, 27.9, 22.3. 19 F NMR (376MHz, CDCl3) δ -66.22.

[0128] Example 25 ( R S)-3-(6-Methoxypyridin-3-yl)-1-pivaloylpiperidin-2-one (Compound 3y) Preparation The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced by 5-iodo-2-methoxypyridine (2y, 0.2 mmol). The target chiral piperidine compound 3y was obtained by column chromatography separation and purification. Compound 3y is a white solid, with an enantioselectivity ratio of 97:3 and a yield of 64%. The synthetic route is as follows:

[0129] 。

[0130] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 8.02 (d, J J = 2.5 Hz, 1H), 7.48 –7.41 (m, 1H), 6.73 (d, J J = 8.6 Hz, 1H), 3.91 (s, 3H), 3.73 – 3.58 (m, 3H), 2.21(q, J J = 7.2 Hz, 1H), 2.09 – 1.95 (m, 3H), 1.26 (s, 9H).。

[0131] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.2, 174.1, 163.6, 146.6,138.8, 127.8, 111.1, 53.6, 47.7, 47.6, 44.1, 30.6, 28.0, 22.7.。

[0132] Example 26 ( R )-Preparation of 3-(6-chloropyridin-2-yl)-1-pivaloylpiperidin-2-one (Compound 3z) The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced by 2-chloro-6-iodopyridine (2z, 0.2 mmol). The target chiral piperidine compound 3z was obtained by column chromatography separation and purification. Compound 3z is a white solid, with an enantioselectivity ratio of 98:2 and a yield of 58%. The synthetic route is as follows:

[0133] 。

[0134] 1H NMR characterization: 1 H NMR(400 MHz, CDCl3) δ 7.62 (t, J J = 7.8 Hz, 1H), 7.21(dd, J= 9.6, 7.7 Hz, 2H), 3.86 (dd, J = 9.2, 7.1 Hz, 1H), 3.75 – 3.55 (m, 2H), 2.25 (dq, J = 10.4, 4.7 Hz, 2H), 2.12 (dq, J = 14.5, 4.8 Hz, 1H), 1.93 (ddq, J =14.1, 9.2, 4.8 Hz, 1H), 1.26 (s, 9H).。

[0135] 1H NMR characterization: 13 C NMR(100 MHz, CDCl3) δ 190.3, 172.6, 160.0, 151.0, 139.2, 122.9, 122.4, 52.2, 47.7, 44.2, 28.9, 28.0, 22.1.。

[0136] Example 27 ( R )-3-(2-Methoxypyrimidin-5-yl)-1-pivaloylpiperidin-2-one (Compound 3aa) Preparation The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced by 5-iodo-2-methoxypyrimidine (2aa, 0.2 mmol). The target chiral piperidine compound 3aa was obtained by column chromatography separation and purification. Compound 3aa is a white solid, with an enantioselectivity ratio of 97:3 and a yield of 71%. Its synthetic route is as follows:

[0137] 。

[0138] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 2H), 4.00 (s, 3H), 3.78 – 3.57 (m, 3H), 2.29 – 2.20 (m, 1H), 2.12 – 1.98 (m, 3H), 1.27 (s, 9H).。

[0139] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 189.9, 173.0, 165.1, 159.2, 125.9, 55.1, 47.7, 45.3, 44.1, 30.1, 27.9, 22.7.。

[0140] Example 28 ( R ) Preparation of -3-(cyclohex-1-en-1-yl)-1-piperidin-2-one pentanoylpiperidine (Compound 3ab) The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) was replaced with cyclohex-1-en-1-yl trifluoromethanesulfonate (2ab, 0.2 mmol). The target chiral piperidine compound 3ab was obtained by column chromatography separation and purification. Compound 3ab is a white solid, and the enantioselectivity ratio is 96:4, and the yield is 30%. The synthetic route is as follows:

[0141] .

[0142] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 5.57 (tt, J J = 3.7, 1.5 Hz, 1H), 3.58 – 3.46 (m, 2H), 3.02 (dd, J J = 9.5, 6.5 Hz, 1H), 1.97 (s, 7H), 1.67 – 1.52(m, 5H), 1.27 (s, 9H).

[0143] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.6, 174.5, 135.9, 125.7, 52.6, 47.6, 44.1, 28.0, 27.4, 26.6, 25.4, 22.9, 22.4, 22.3.

[0144] Example 29 ( R ) Preparation of -3-(1H-inden-2-yl)-1-piperidin-2-one pentanoylpiperidine (Compound 3ac) The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) was replaced with 2-bromo-1H-indene (2ac, 0.2 mmol). The target chiral piperidine compound 3ac was obtained by column chromatography separation and purification. Compound 3ac is a white solid, and the enantioselectivity ratio is 95:5, and the yield is 59%. The synthetic route is as follows:

[0145] .

[0146] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, J= 7.4 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.23 (td, J = 7.4, 1.1 Hz, 1H), 7.15 (td, J = 7.4, 1.2 Hz, 1H), 6.76 – 6.72 (m, 1H), 3.66 (dd, J = 9.2, 6.0 Hz, 1H), 3.63 – 3.57 (m, 2H), 3.53 (d, J = 3.8 Hz, 1H), 3.46 (dd, J = 22.6, 1.6 Hz, 1H), 2.23 – 2.13 (m, 1H), 2.13 – 2.00 (m, 2H), 1.94 (ddt, J = 15.1, 8.1, 2.8 Hz, 1H), 1.29 (s, 9H).。

[0147] 1H NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 173.7, 146.3, 144.6, 143.4, 129.4, 126.4, 124.6, 123.7, 120.8, 47.5, 46.3, 44.1, 40.4, 28.4, 28.0, 22.0.。

[0148] Example 30 ( R )-3-(3,4-Dihydronaphthalen-2-yl)-1-pivaloylpiperidin-2-one (Compound 3ad) Preparation The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced by 3-bromo-1,2-dihydronaphthalene (2ad, 0.2 mmol). The target chiral piperidine compound 3ad was obtained by column chromatography separation and purification. Compound 3ad is a white solid, with an enantioselectivity ratio of 94:6 and a yield of 52%. The synthetic route is as follows:

[0149] 。

[0150] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.14 – 7.07 (m, 3H), 7.00 (d, J= 6.7 Hz, 1H), 6.37 (s, 1H), 3.63 – 3.53 (m, 2H), 3.32 (dd, J = 9.8, 5.8 Hz, 1H), 2.94 – 2.75 (m, 2H), 2.30 (t, J = 8.1 Hz, 2H), 2.06 – 1.91 (m, 4H), 1.30 (s, 9H).。

[0151] 1H NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.4, 173.9, 138.8, 135.0, 134.2, 127.3, 127.0, 126.5, 126.0, 126.0, 52.2, 47.6, 44.1, 28.3, 28.0, 27.4, 26.0, 22.3.。

[0152] Example 31 ( R , E )-1-Pivaloyl-3-styrylpiperidin-2-one (Compound 3ae) Preparation The difference between this example and Example 1 is only that: Iodobenzene (2a, 0.2 mmol) is replaced by (2-bromovinyl)benzene (2ae, 0.2 mmol). The target chiral piperidine compound 3ae was obtained by column chromatography separation and purification. Compound 3ae is a white solid, with an enantioselectivity ratio of 93:7 and a yield of 75%. The synthetic route is as follows:

[0153] 。

[0154] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.37 – 7.27 (m, 5H), 6.71 (d, J = 11.5 Hz, 1H), 5.72 (dd, J = 11.5, 9.9 Hz, 1H), 3.69 – 3.57 (m, 2H), 3.50 (dtd, J = 12.4, 5.1, 1.6 Hz, 1H), 1.99 (ddt, J = 17.8, 9.7, 3.8 Hz, 2H), 1.79 (dddd, J= 23.8, 12.7, 9.2, 3.8 Hz, 2H), 1.30 (s, 9H).。

[0155] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.1, 175.0, 136.8, 132.2, 128.9, 128.7, 128.5, 127.4, 47.7, 44.0, 43.5, 29.4, 28.1, 21.9.。

[0156] Example 32 ( R )-Methyl 4-(2-oxo-1-pivaloylpiperidin-3-yl)benzoate (Compound 3ba) Preparation The difference between this example and Example 1 is only that: 3-chloro-1-pivaloylpiperidin-2-one (1a, 0.1 mmol) is replaced by 3-chloro-1-pivaloyl-3,4-dihydropyridin-2(1H)-one (1b, 0.1 mmol). The target chiral piperidine compound 3ba was obtained by column chromatography separation and purification. Compound 3ba is a white solid, with an enantioselectivity ratio of 99:1 and a yield of 53%. The synthetic route is as follows:

[0157] 。

[0158] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, Chloroform-d) δ 7.39 – 7.33 (m, 2H), 7.33 – 7.27 (m, 3H), 6.50 (dd, J = 7.9, 1.7 Hz, 1H), 5.37 (ddt, J = 8.6, 5.6, 2.8 Hz, 1H), 3.86 (t, J = 8.6 Hz, 1H), 2.74 – 2.66 (m, 2H), 1.25 (s, 9H).。

[0159] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 186.8, 171.5, 137.9, 128.8, 128.3, 127.8, 127.4, 107.4, 77.5, 77.2, 76.8, 48.7, 44.0, 29.0, 27.8.。

[0160] Example 33 (R ) Preparation of methyl 4-(2-oxo-1-pivaloylpiperidin-3-yl)benzoate (Compound 3ca) The difference between this example and Example 1 is only that: 3-chloro-1-pivaloylpiperidin-2-one (1a, 0.1 mmol) is replaced by 3-chloro-1-pivaloylpyrrolidin-2-one (1c, 0.1 mmol). The target chiral piperidine compound 3ca was obtained by column chromatography separation and purification. Compound 3ca is a white solid, and the enantioselectivity ratio is 90:10, with a yield of 95%. The synthetic route is as follows:

[0161] .

[0162] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.38 (dd, J = 8.2, 6.6 Hz, 2H), 7.31 – 7.23 (m, 3H), 3.98 (ddd, J = 11.5, 8.4, 2.9 Hz, 1H), 3.89 – 3.75 (m, 2H), 2.51 (dddd, J = 13.0, 8.8, 7.0, 2.9 Hz, 1H), 2.29 – 2.15 (m, 1H), 1.35 (s, 9H).

[0163] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 180.5, 173.8, 138.0, 129.0, 128.1, 127.6, 51.2, 46.1, 41.8, 27.0, 26.2.

[0164] Example 34 ( R ) Preparation of methyl 4-(2-oxo-1-pivaloylpiperidin-3-yl)benzoate (Compound 3da) The difference between this example and Example 1 is only that: 3-chloro-1-pivaloylpiperidin-2-one (1a, 0.1 mmol) is replaced by 3-chloro-1-pivaloylazepan-2-one (1d, 0.1 mmol). The target chiral piperidine compound 3da was obtained by column chromatography separation and purification. Compound 3da is a white solid, and the enantioselectivity ratio is 95:5, with a yield of 74%. The synthetic route is as follows:

[0165] .

[0166] 1H NMR characterization: 11H NMR (400 MHz, CDCl3) δ 7.35 (dd, J = 8.1, 6.7 Hz, 2H), 7.30 – 7.24 (m, 1H), 7.24 – 7.19 (m, 2H), 3.99 – 3.88 (m, 2H), 3.50 (dd, J = 15.1, 10.5 Hz, 1H), 2.19 – 2.04 (m, 3H), 2.02 – 1.94 (m, 1H), 1.77 – 1.61 (m, 2H), 1.26 (s, 9H).

[0167] 13C NMR characterization: 13 13C NMR (100 MHz, CDCl3) δ 191.0, 177.9, 140.8, 128.5, 128.5, 127.1, 52.1, 47.0, 44.2, 31.3, 29.1, 29.0, 28.1.

[0168] Example 35 ( R )-3-Phenyl-1-pivaloyl-3,4-dihydroquinolin-2(1H)-one (Compound 3ea) Preparation The difference between this example and Example 1 is only that: 3-chloro-1-pivaloylpiperidin-2-one (1a, 0.1 mmol) is replaced by 3-chloro-1-pivaloyl-3,4-dihydroquinolin-2(1H)-one (1e, 0.1 mmol). The target chiral piperidine compound 3ea was obtained by column chromatography separation and purification. Compound 3ea is a white solid, with an enantioselective ratio of 95:5 and a yield of 68%. The synthetic route is as follows:

[0169] .

[0170] 1H NMR characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.30 (m, 2H), 7.29 – 7.18 (m, 5H), 7.07 (td, J J = 7.5, 1.1 Hz, 1H), 6.73 (dd, J J = 8.0, 1.1 Hz, 1H), 3.88 (dd, J J = 10.4, 6.0 Hz, 1H), 3.36 – 3.20 (m, 2H), 1.33 (s, 9H).

[0171] 13C NMR characterization: 1313C NMR (100 MHz, CDCl3) δ 188.5, 171.0, 137.3, 137.0, 128.8, 128.7, 128.3, 127.9, 127.6, 124.9, 124.2, 115.6, 47.1, 44.7, 33.4, 27.9.

[0172] Example 36 ( R ) - Ethyl 4-(8-(2-oxo-1-pivaloylpiperidin-3-yl)-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylate (Compound 3af) Preparation The difference between this example and Example 1 is only that: Iodobenzene (2a, 0.2 mmol) is replaced with ethyl 4-(8-iodo-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylate (2af, 0.2 mmol). The target chiral piperidine compound 3af is obtained by column chromatography separation and purification. Compound 3af is a white solid, with an enantioselectivity ratio of 99:1 and a yield of 95%. Its synthetic route is as follows:

[0173] .

[0174] 1H NMR characterization: 1 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J J = 4.8 Hz, 1H), 7.42(d, J J = 7.6 Hz, 1H), 7.15 (d, J J = 7.8 Hz, 1H), 7.07 (dd, J J = 7.7, 4.8 Hz, 1H), 7.00(d, J J = 5.4 Hz, 2H), 4.12 (q, J J = 7.1 Hz, 2H), 3.80 (s, 2H), 3.63 (pd, J J = 12.4,4.0 Hz, 3H), 3.44 – 3.29 (m, 2H), 3.10 (ddt, J J = 13.2, 9.7, 4.9 Hz, 2H), 2.82(p, J J = 7.1 Hz, 2H), 2.44 – 2.36 (m, 2H), 2.31 – 2.15 (m, 2H), 1.98 (ddp,J = 26.2, 16.8, 4.7 Hz, 4H), 1.26 (s, 12H).

[0175] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.5, 174.3, 157.9, 155.6, 146.6, 138.8, 138.7, 137.8, 137.4, 136.9, 135.0, 133.9, 129.9, 122.3, 61.4, 50.6, 47.8, 45.0, 44.1, 32.2, 31.6, 31.2, 30.9, 30.8, 29.8, 28.0, 22.6, 14.8.

[0176] Example 37 (3 aR , 5 R , 6 S , 6 Ar )-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl 4-((R)-2-oxo-1-piperidin-3-yl)benzoate (Compound 3ag) Preparation The difference between this example and Example 1 is only that: Iodobenzene (2a, 0.2 mmol) is replaced by 3 aR , 5 R , 6 S , 6 aR )-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl 4-iodobenzoate (2ag, 0.2 mmol). The target chiral piperidine compound 3ag was obtained by column chromatography separation and purification. Compound 3ag is a white solid, with an enantioselectivity ratio of 99:1 and a yield of 95%. Its synthetic route is as follows:

[0177] .

[0178] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 5.93 (d, J = 3.6 Hz, 1H), 5.49 (d, J= 2.6 Hz, 1H), 4.59 (d, J = 3.7 Hz, 1H), 4.37 – 4.29 (m, 2H), 4.13 – 4.06 (m, 2H), 3.79 – 3.60 (m, 3H), 2.28 – 2.19 (m, 1H), 2.12 – 1.97 (m, 3H), 1.55 (s, 3H), 1.41 (s, 3H), 1.31 (s, 3H), 1.27 (s, 12H).。

[0179] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.2, 173.5, 165.0, 145.5, 130.2, 128.9, 128.6, 112.5, 109.6, 105.3, 83.5, 80.1, 76.7, 72.7, 67.4, 50.8, 47.7, 44.1, 30.6, 28.0, 27.0, 26.9, 26.3, 25.3, 22.5.。

[0180] Example 38 (3 S )-1-(4-Fluorophenyl)-3-((3 R ,4 S )-1-(4-Fluorophenyl)-2-oxo-4-(4-((R)-2-oxo-1-pivaloylpiperidin-3-yl)phenyl)azetidin-3-yl)propyl acetate (Compound 3ah) Preparation The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced with ( S )-1-(4-Fluorophenyl)-3-((2 S ,3 R )-1-(4-Fluorophenyl)-2-(4-iodophenyl)-4-oxazolidin-3-yl)propyl acetate (2ah, 0.2 mmol). The target chiral piperidine compound 3ah was obtained by column chromatography separation and purification. Compound 3ah is a white solid, with an enantioselective ratio of 98:2 and a yield of 38%. Its synthetic route is as follows:

[0181] 。

[0182] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.26 (s, 8H), 7.02 (t, J= 8.6 Hz, 2H), 6.97 – 6.88 (m, 2H), 5.69 (td, J = 6.8, 1.9 Hz, 1H), 4.58 (d, J = 2.3 Hz, 1H), 3.78 – 3.53 (m, 4H), 3.06 (tt, J = 7.8, 2.6 Hz, 1H), 2.22 (dd, J = 7.9, 4.6 Hz, 1H), 2.05 (s, 3H), 2.04 – 1.91 (m, 4H), 1.90 – 1.80 (m, 2H), 1.27 (d, J = 2.4 Hz, 9H).。

[0183] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.4, 174.0, 170.3, 167.1, 167.0, 162.6 (d, J = 245.8 Hz), 159.1 (d, J = 241.8 Hz), 140.3, 136.4, 135.8 (d, J = 3.3 Hz), 133.9 (d, J = 2.6 Hz), 129.6 (d, J = 1.8 Hz), 128.4 (d, J = 8.4 Hz), 126.2, 118.6, 118.5, 116.1, 115.9, 115.8, 115.5, 75.0, 61.1, 60.2, 50.5, 47.8, 44.1, 33.8, 31.0, 28.0, 25.1, 22.6, 21.3.。

[0184] Example 39 (1 R ,2 S ,5 R )-2-Isopropyl-5-methylcyclohexyl 3-((R)-2-oxo-1-pivaloylpiperidin-3-yl)benzoate (Compound 3ai) Preparation The difference between this example and Example 1 is only that: iodobenzene (2a, 0.2 mmol) is replaced with (1 R ,2 S ,5 R)-2-Isopropyl-5-methylcyclohexyl 3-iodobenzoate (2ai, 0.2 mmol). The target chiral piperidine compound 3ah was obtained by column chromatography purification. Compound 3ah is a white solid, with an enantioselectivity ratio of 98:2 and a yield of 78%. The synthetic route is as follows:

[0185] .

[0186] 1H NMR characterization: 1 H NMR (400 MHz, CDCl3) δ 7.99 – 7.90 (m, 2H), 7.44 –7.38 (m, 2H), 4.93 (tt, J J = 10.9, 4.1 Hz, 1H), 3.80 – 3.57 (m, 3H), 2.30 – 2.20(m, 1H), 2.16 – 1.78 (m, 6H), 1.75 – 1.69 (m, 2H), 1.59 – 1.49 (m, 2H), 1.27(s, 9H), 1.15 – 1.05 (m, 2H), 0.91 (t, J J = 7.0 Hz, 6H), 0.78 (dd, J J = 6.9, 1.8Hz, 3H).

[0187] 13C NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 174.0, 166.0, 140.0,133.1, 131.3, 129.7, 128.7, 128.6, 75.0, 50.7, 47.7, 47.3, 44.1, 41.1, 34.4,31.6, 30.8, 28.0, 26.5, 23.7, 22.5, 22.2, 20.9, 16.6.

[0188] It should be noted that when the present invention involves a numerical range, it should be understood that both endpoints of each numerical range and any value between the two endpoints can be selected. Since the steps and methods adopted are the same as those in the embodiments, in order to prevent repetition, the present invention describes the preferred embodiments. Although the preferred embodiments of the present invention have been described, those skilled in the art can make additional changes and modifications to these embodiments once they know the basic creative concept. Therefore, the appended claims are intended to be construed as including the preferred embodiments and all changes and modifications falling within the scope of the present invention.

[0189] Obviously, those skilled in the art can make various modifications and variations to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention also intends to include these modifications and variations.

Claims

1. A method for synthesizing a chiral 3-aryl-2-piperidone compound, characterized in that, It includes the following steps: Using an aryl halide compound or a trifluoromethanesulfonate compound and a chloroamide electrophilic compound as raw materials, in a reaction system composed of a nickel-based catalyst, a chiral biimidazole ligand, a metal-based reducing agent and a solvent, a reductive coupling reaction is carried out at room temperature under a protective atmosphere to obtain a chiral 3-aryl-2-piperidone compound.

2. The synthesis method of the chiral 3-aryl-2-piperidone compound according to claim 1, and the synthesis method of the 1,3-diboron compound, characterized in that, The molar ratio of the chloroamide electrophilic compound to the aryl halide compound is 0.1:0.2 - 0.5, and the molar ratio of the chloroamide electrophilic compound to the trifluoromethanesulfonate compound is 0.1:0.2 - 0.

5.

3. The synthesis method of the chiral 3-aryl-2-piperidone compound according to claim 1, characterized in that, The molar ratio of the chloroamide compound to the nickel-based catalyst is 0.1:0.01 - 0.025; the molar ratio of the chloroamide compound to the ligand is 0.1:0.015 - 0.03; the molar ratio of the chloroamide compound to the metal reducing agent is 0.1:0.3 - 0.5, and the metal-based reducing agent is manganese.

4. The method for synthesizing the chiral 3-aryl-2-piperidone compound according to claim 1, characterized in that, The nickel-based catalyst is nickel bromide in ethylene glycol dimethyl ether.

5. The synthesis method of the chiral 3-aryl-2-piperidone compound according to claim 1, characterized in that, The structural formula of the chiral biimidazole ligand is as follows: 。 6. The synthetic method of the chiral 3-aryl-2-piperidone compound according to claim 1, characterized in that, The time of the reductive coupling reaction is 12h - 24h.

7. The method for synthesizing the chiral 3-aryl-2-piperidone compound according to claim 1, characterized in that, The chloroamide electrophilic compound is 3-chloro-1-pivaloylpiperidin-2-one, 3-chloro-1-pivaloyl-3,4-dihydropyridin-2(1H)-one, 3-chloro-1-pivaloylpyrrolidin-2-one, 3-chloro-1-pivaloylazepan-2-one or 3-chloro-1-pivaloyl-3,4-dihydroquinolin-2(1H)-one.

8. The synthetic method of the chiral 3-aryl-2-piperidone compound according to claim 1, wherein, The structural formula of the aryl halide compound is as follows: or ; Among them, R1 is benzene, biphenyl, benzothiophene, tert-butyl indole-1-carboxylate, thiophene, pyridine with substituents, phenyl with substituents, pyrimidine with substituents, , , or ;" " is the connection site; The substituents of the phenyl group are selected from halogen, C1 - C3 alkenyl, -R3COOR4, -NHR3COOR4, -R3COR4, cyano, C1 - C3 aldehyde group, C1 - C3 trifluoroalkoxy group, C1 - C3 alkynylsilane, C1 - C4 alkyl group, C1 - C4 alkoxy group, C1 - C3 alkylthio group or dioxolane ring, R3 is a C1 - C3 alkyl group, and R4 is a C1 - C4 alkyl group; The substituents of the pyridine are selected from halogen, C1 - C4 alkoxy group; The substituents of the pyrimidine are selected from C1 - C4 alkoxy group; Wherein, R2 is indene or a C1 - C3 alkenylphenyl group, and the alkene in indene or the C1 - C3 alkenylphenyl group is the connection site.

9. The synthetic method of the chiral 3-aryl-2-piperidone compound according to claim 1, wherein The trifluoromethanesulfonate compound is cyclohex-1-en-1-yl trifluoromethanesulfonate.

10. The method for synthesizing the chiral 3-aryl-2-piperidone compound according to claim 8, wherein, The aryl halide compounds are iodobenzene, p-fluoroiodobenzene, p-chloroiodobenzene, p-iodostyrene, methyl p-iodobenzoate, p-iodobenzonitrile, p-iodobenzaldehyde, 1-iodo-4-trifluoromethoxybenzene, ((4-iodophenyl)ethynyl)trimethylsilane, 4-iodo-1,1'-biphenyl, 1-iodo-4-methylbenzene, 1-(tert-butyl)-4-iodobenzene, 1-iodo-4-methoxybenzene, (4-iodophenyl)(methyl)sulfane, tert-butyl (4-iodophenyl)carbamate, 1-iodo-3-methoxybenzene, 2-iodonaphthalene, 1-(3-iodophenyl)-1-ethanone, 1-iodo-3,4-methylenedioxybenzene, 1-iodo-2-methylbenzene, 4-iododibenzo[b,d]thiophene, tert-butyl 5-iodo-1H-indole-1-carboxylate, 3-iodothiophene, 2-fluoro-4-iodopyridine, 5-iodo-2-methoxypyridine, 2-chloro-6-iodopyridine, 5-iodo-2-methoxypyrimidine, 2-bromo-1H-indene, 3-bromo-1,2-dihydronaphthalene, (2-bromovinyl)benzene, ethyl 4-(8-iodo-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylate, ( aR , 5 R , 6 S , 6 aR )-5-(( R )-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl 4-iodobenzoate, ( S )-1-(4-fluorophenyl)-3-((2 S , 3 R )-1-(4-fluorophenyl)-2-(4-iodophenyl)-4-oxazolidin-3-yl)propyl acetate or (1 R , 2 S , 5 R )-2-isopropyl-5-methylcyclohexyl 3-iodobenzoate.

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