Arylpiperidine compounds and methods for their preparation

Abstract

The application provides an arylpiperidine compound and a preparation method thereof, and belongs to the technical field of organic synthesis. The arylpiperidine compound has a structure shown in formula Xx. The application takes a commercial and cheap piperidine carboxylic acid compound as a starting material, prepares a redox active ester with an N-hydroxy dicarboxylic imide compound, then undergoes decarboxylation coupling reaction with an aryl boronic acid compound or decarboxylation reduction coupling reaction with an aryl iodine compound, quickly and effectively constructs a connecting arm between C-sp2 (the aryl boronic acid compound or the aryl iodine compound) and C-sp3 (the piperidine), and realizes economical synthesis of the arylpiperidine compound. The raw material adopted by the application is cheap and easy to obtain, avoids using an expensive platinum group noble metal catalyst and a high-pressure reaction condition, and further reduces production cost and adverse effects on the environment.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to an arylpiperidine compound and its preparation method. Background Technology

[0002] Arylpiperidine compounds are one of the important building blocks in the field of medicinal chemistry, and are widely distributed in the core skeleton of important drug molecules (including pharmaceuticals and pesticides). For example, they are key arylpiperidine intermediates involved in the synthesis of important drug molecules such as Niraparib, Preclamol, and Ampreloxetine. These molecular skeletons have also received widespread attention in lead optimization and the discovery of new drug molecules.

[0003] Arylpiperidine compounds, as molecular fragments in the structures of niraparib (an analgesic) and dopamine autoreceptor agonists, involve lengthy and cumbersome reactions in traditional synthesis, involving noble metal coupling and transaminase reactions. For example, the anticancer drug Niraparib contains a β-arylpiperidine core skeleton. This drug is a class I PARP inhibitor, and its synthesis involves bromophenylpiperidine or aminophenylpiperidine compounds in both medicinal chemistry research and chemical preparation stages. Current routes primarily involve the Suzuki coupling of arylboronic acid and halopyridine compounds catalyzed by the noble metal palladium, followed by noble metal-catalyzed hydrogenation or enzyme-catalyzed reduction of pyridine to ultimately prepare the desired arylpiperidine building blocks.

[0004] However, the above synthesis strategies have drawbacks such as multiple reaction steps and the use of precious metal catalysts, and the raw materials are not easy to obtain, which greatly limits the efficiency of the synthesis and preparation of such important drug building blocks and is not conducive to their application in the field of medicinal chemistry. Summary of the Invention

[0005] In view of this, the purpose of this invention is to provide an arylpiperidine compound and a method for preparing the same. The preparation method provided by this invention has short steps, uses inexpensive and readily available raw materials, and avoids the use of precious metal catalysts.

[0006] To achieve the above objectives, the present invention provides the following solution:

[0007] This invention provides an arylpiperidine compound having the structure shown in formula Xx:

[0008]

[0009] Ar in formula Xx includes phenyl, halophenyl, haloalkylphenyl, alkyloxyphenyl, alkylphenyl, benzyloxyphenyl, biphenyl, cyanophenyl, pyridyl, thiophene, benzothiophene, or oxofluorenyl;

[0010] The substitution site of Ar is the α, β, or γ position of the N atom.

[0011] Preferably, the halophenyl includes fluorophenyl, chlorophenyl, bromophenyl or iodophenyl; the haloalkylphenyl includes fluoroalkylphenyl; the alkyloxyphenyl includes alkoxyphenyl, with the alkyl carbon number being 1 to 6; the alkylphenyl includes alkylphenyl, with the alkyl carbon number being 1 to 6.

[0012] Preferably, the arylpiperidine compound has the structure shown in any one of formulas X2 to X21:

[0013]

[0014] This invention provides a method for preparing the arylpiperidine compounds described above, comprising the following steps:

[0015] N-hydroxyphthalimide compounds, N-Boc piperidine carboxylic acid, organic base catalyst, condensing agent and first organic solvent are mixed and subjected to condensation reaction to obtain redox active ester;

[0016] Under the protection of a first protective gas, the redox active ester, arylboronic acid compound, second organic solvent, basic activator and first nickel-based catalyst are mixed and subjected to a decarboxylation coupling reaction to obtain the arylpiperidine compound;

[0017] Alternatively, under the protection of a second protective gas, the redox-active ester, the aryl iodide compound, the reducing agent, the second nickel-based catalyst, and the third organic solvent are mixed and subjected to a decarboxylation-reduction coupling reaction to obtain the arylpiperidine compound; the reducing agent includes metal reducing agents and organosilicon reducing agents.

[0018] The N-Boc piperidine carboxylic acid has the structure shown in Formula 1; the redox-active ester has the structure shown in Formula X1; the arylboronic acid compound has the structure shown in Formula 2; and the aryl iodinated compound has the structure shown in Formula 3.

[0019] Ar-B(OH)2 formula 2; Ar-I formula 3;

[0020]

[0021] In equation X1, R1, R2, R3, and R4 are independently H or Cl.

[0022] Preferably, the organic base catalyst comprises 4-dimethylaminopyridine; the condensing agent comprises EDCI-HCl or DCC.

[0023] Preferably, the molar ratio of the N-hydroxyphthalimide compound to N-Boc piperidine carboxylic acid is 1:(0.8-1.5).

[0024] Preferably, the condensation reaction is carried out at a temperature of 0°C to room temperature for 10 to 40 hours.

[0025] Preferably, the temperature of the decarboxylation coupling reaction is 50–95°C and the time is 10–20 h; the temperature of the decarboxylation reduction coupling reaction is -5–5°C and the time is 1–5 h.

[0026] Preferably, the molar ratio of the redox active ester to the arylboronic acid compound is 1:(3-4); the molar ratio of the redox active ester to the aryl iodide compound is 2:(1-1.2).

[0027] Preferably, the first nickel-based catalyst comprises a nickel salt-dinitrogen ligand complex; the second nickel-based catalyst comprises a nickel salt-dinitrogen ligand complex; the metal reducing agent comprises zinc powder and manganese powder; and the organosilicon reducing agent comprises PhMeSiCl2.

[0028] This invention provides an arylpiperidine compound having the structure shown in formula Xx; where Ar in formula Xx includes phenyl, halophenyl, haloalkylphenyl, alkyloxyphenyl, alkylphenyl, benzyloxyphenyl, biphenyl, cyanophenyl, pyridyl, thiophene, benzothiophene, or oxofluorenyl; the substitution site of Ar is at the α, β, or γ position of the N atom. This invention uses commercially available and inexpensive piperidine carboxylic acids as starting materials, preparing redox-active esters with N-hydroxydicarboxylimide compounds, followed by decarboxylation coupling reactions with arylboronic acid compounds or decarboxylation-reductive coupling reactions with aryl iodide compounds, rapidly and efficiently constructing a linker arm between C-sp2 (arylboronic acid compound or aryl iodide compound) and C-sp3 (piperidine), achieving the economical synthesis of arylpiperidine compounds. The raw materials used in this invention are inexpensive and readily available, avoiding the use of expensive platinum group metal catalysts and high-pressure reaction conditions, further reducing production costs and adverse environmental impacts.

[0029] The arylpiperidine compounds prepared by this invention can be used to prepare key arylpiperidine intermediates involved in the synthesis of drug molecules such as Niraparib, Preclamol, Ampreloxetine, OSU-6162, Elsubrutinib, and Pridopidine. Detailed Implementation

[0030] This invention provides an arylpiperidine compound having the structure shown in formula Xx:

[0031]

[0032] Ar in formula Xx includes phenyl, halophenyl, haloalkylphenyl, alkyloxyphenyl, alkylphenyl, benzyloxyphenyl, biphenyl, cyanophenyl, pyridyl, thiophene, benzothiophene, or oxofluorenyl;

[0033] The substitution site of Ar is the α, β, or γ position of the N atom.

[0034] In this invention, the halophenyl preferably includes fluorophenyl, chlorophenyl, bromophenyl, or iodophenyl. The halophenyl in this invention preferably includes mono- to penta-substituted halogens.

[0035] In this invention, the haloalkylphenyl group preferably includes fluoroalkylphenyl group; the fluoroalkylphenyl group preferably includes m-trifluoromethylphenyl or p-trifluoromethylphenyl.

[0036] In this invention, the alkyloxyphenyl preferably includes alkoxyphenyl, with the alkyl carbon number being 1 to 6; the alkoxyphenyl preferably includes methoxyphenyl or propoxyphenyl; the alkylphenyl preferably includes alkylphenyl, with the alkyl carbon number being 1 to 6; the alkylphenyl preferably includes methylphenyl.

[0037] In this invention, the arylpiperidine compound preferably has the structure shown in any one of formulas X2 to X21:

[0038]

[0039]

[0040] This invention provides a method for preparing the arylpiperidine compounds described above, comprising the following steps:

[0041] N-hydroxyphthalimide compounds, N-Boc piperidine carboxylic acid, organic base catalyst, condensing agent and first organic solvent are mixed and subjected to condensation reaction to obtain redox active ester;

[0042] Under the protection of a first protective gas, the redox active ester, arylboronic acid compound, second organic solvent, basic activator and first nickel-based catalyst are mixed and subjected to a decarboxylation coupling reaction to obtain the arylpiperidine compound;

[0043] Alternatively, under the protection of a second protective gas, the redox-active ester, the aryl iodide compound, the reducing agent, the second nickel-based catalyst, and the third organic solvent are mixed and subjected to a decarboxylation-reduction coupling reaction to obtain the arylpiperidine compound; the reducing agent includes metal reducing agents and organosilicon reducing agents.

[0044] The N-Boc piperidine carboxylic acid has the structure shown in Formula 1; the redox-active ester has the structure shown in Formula X1; the arylboronic acid compound has the structure shown in Formula 2; and the aryl iodinated compound has the structure shown in Formula 3.

[0045] Ar-B(OH)2 formula 2; Ar-I formula 3;

[0046]

[0047] In equation X1, R1, R2, R3, and R4 are independently H or Cl.

[0048] Unless otherwise specified, all raw materials and equipment used in this invention are commercially available products.

[0049] This invention involves mixing an N-hydroxyphthalimide compound, an N-Boc piperidine carboxylic acid, an organic base catalyst, a condensing agent, and a first organic solvent to carry out a condensation reaction, thereby obtaining a redox-active ester.

[0050] In this invention, the N-hydroxyphthalimide compound preferably includes N-hydroxytetrachlorophthalimide or N-hydroxyphthalimide; the N-Boc piperidine carboxylic acid preferably includes N-Boc piperidine-3-carboxylic acid or N-Boc piperidine-4-carboxylic acid; the organic base catalyst preferably includes 4-dimethylaminopyridine; the condensing agent preferably includes EDCI-HCl or DCC; and the first organic solvent preferably includes dichloromethane, dichloroethane, tetrahydrofuran, N,N'-dimethylformamide, or toluene.

[0051] In this invention, the molar ratio of the N-hydroxyphthalimide compound to N-Boc piperidine carboxylic acid is preferably 1:(0.8-1.5), and in the embodiments of this invention, it can specifically be 1:0.8, 1:1, 1:1.1, 1:1.2 or 1:1.5; the molar ratio of the N-Boc piperidine carboxylic acid to the organic base catalyst is preferably (1-1.2):0.2, and in the embodiments of this invention, it can specifically be 1:0.2 or 1.2:0.2; the molar ratio of the N-Boc piperidine carboxylic acid to the condensing agent is preferably (1-1.2):1.2, and in the embodiments of this invention, it can specifically be 1:1, 1.1:1.2 or 1:1.2; the molar amount of the N-Boc piperidine carboxylic acid to the volume ratio of the first organic solvent is preferably (1-1.2) mmol:5 mL, and in the embodiments of this invention, it can specifically be 1 mmol:5 mL, 1.1 mmol:5 mL or 1.2 mmol:5 mL.

[0052] In this invention, the temperature of the condensation reaction is preferably 0°C to room temperature (25°C), and the time is preferably 10 to 40 hours. In the embodiments of this invention, it can be 10 hours, 15 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 30 hours, 35 hours, or 40 hours.

[0053] In the condensation reaction process described in this invention, N-hydroxyphthalimide compounds and N-Boc piperidine carboxylic acid undergo dehydration condensation to generate redox-active esters.

[0054] After the condensation reaction is completed, the present invention preferably performs post-treatment on the resulting reaction mixture.

[0055] The present invention does not have special requirements for the post-processing steps; any steps well-known in the art that can yield the redox-active ester pure substance are acceptable. In an embodiment of the present invention, the post-processing preferably includes: adding an organic solvent to the obtained reaction mixture, then washing the organic phase of the reaction system sequentially with water and saturated sodium chloride, drying the washed organic phase sequentially with anhydrous sodium sulfate, filtering under reduced pressure and concentrating to obtain a crude product, and finally purifying it by silica gel column chromatography.

[0056] After obtaining the redox-active ester, the present invention, under the protection of a first protective gas, mixes the redox-active ester, an arylboronic acid compound, a second organic solvent, a basic activator, and a first nickel-based catalyst to carry out a decarboxylation coupling reaction to obtain the arylpiperidine compound.

[0057] In this invention, the first protective gas preferably includes nitrogen.

[0058] In this invention, the arylboronic acid compound has the structure shown in Formula 2, Ar-B(OH)2; the types of Ar groups in Formula 2 are the same as those in Formula Xx described above, and will not be repeated here.

[0059] In this invention, the arylboronic acid compound has the structure shown in any one of Formulas 2-X2 to 2-X19 or the structure shown in Formulas 2-X21:

[0060]

[0061]

[0062] In this invention, when the N-Boc piperidine carboxylic acid is N-Boc piperidine-3-carboxylic acid, the arylboronic acid compound has the structure shown in any one of formulas 2-X2 to 2-X19 or the structure shown in formulas 2 to X21.

[0063] In this invention, when the N-Boc piperidine carboxylic acid is N-Boc piperidine-4-carboxylic acid, the arylboronic acid compound has the structure shown in Formula 2-X2.

[0064] In this invention, the second organic solvent preferably comprises 1,4-dioxane; the basic activator preferably comprises triethylamine. In this invention, the basic activator is capable of activating arylboronic acid compounds.

[0065] In this invention, the first nickel-based catalyst preferably comprises a nickel salt-dinitrogen ligand complex; the nickel salt in the nickel salt-dinitrogen ligand complex preferably comprises triphenylphosphine nickel chloride (NiCl(PPh3)2); the dinitrogen ligand (Ligand) in the nickel salt-dinitrogen ligand complex preferably comprises bipyridine compounds, alkyloxy-substituted bipyridines, alkyl-substituted bipyridines, alkylamino-substituted bipyridines, or o-phenanthroline; the alkyloxy-substituted bipyridines preferably comprise 4,4'-dimethoxybipyridine (L13) or 5,5'-dimethoxybipyridine.

[0066] In this invention, the molar ratio of the redox active ester to the arylboronic acid compound is preferably 1:(3-4), and in specific embodiments of this invention, it can be 1:3, 1:3.5, or 1:4; the molar ratio of the redox active ester to the basic activator is preferably 1:10; the molar ratio of the redox active ester to the nickel salt in the first nickel-based catalyst is preferably 1:0.2; the molar ratio of the redox active ester to the dinitrogen ligand in the first nickel-based catalyst is preferably 1:0.2; and the concentration of the redox active ester in the organic solvent (including the second and fourth organic solvents) is preferably 0.023 mol / L.

[0067] In this invention, the nickel salt-dinitrogen ligand complex is preferably obtained by mixing a nickel salt, a dinitrogen ligand, and a fourth organic solvent. In this invention, the fourth organic solvent preferably comprises N,N-dimethylformamide. In this invention, the molar ratio of the nickel salt to the dinitrogen ligand is preferably 1:1; the volume ratio of the second organic solvent to the fourth organic solvent is preferably 10:1. In this invention, the first nickel-based catalyst is preferably added in solution form.

[0068] In this invention, the temperature of the decarboxylation coupling reaction is preferably 50-95°C. In the embodiments of this invention, it can be 50°C, 60°C, 70°C, 75°C, 80°C, 90°C, or 95°C. The time is preferably 10-20 hours. In the embodiments of this invention, it can be 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, or 20 hours.

[0069] After the decarboxylation coupling reaction is completed, the present invention preferably performs post-treatment on the obtained reaction mixture; the present invention does not have special requirements for the post-treatment process, and any method known in the art can be used to obtain the arylpiperidine compound.

[0070] In an embodiment of the present invention, the post-processing preferably includes cooling the obtained reaction mixture to room temperature, then diluting it with an organic solvent, washing the organic phase of the reaction system sequentially with saturated ammonium chloride, water and saturated brine, drying the washed organic phase with anhydrous sodium sulfate and concentrating it, and finally purifying it by silica gel column chromatography.

[0071] Alternatively, after obtaining the redox-active ester, the present invention, under the protection of a second protective gas, mixes the redox-active ester, the aryl iodide compound, the reducing agent, the second nickel-based catalyst, and the third organic solvent to carry out a decarboxylation-reduction coupling reaction to obtain the aryl piperidine compound; the reducing agent includes a metal reducing agent and an organosilicon reducing agent.

[0072] In this invention, the second protective gas preferably includes nitrogen. In this invention, the aryl iodide compound has the structure shown in Formula 3, Ar-I Formula 3; the types of Ar groups in Formula 3 are the same as those in Formula Xx described above, and will not be repeated here. In this invention, the aryl iodide compound preferably includes iodobenzene.

[0073] In this invention, the metal reducing agent preferably includes zinc powder and manganese powder; the organosilicon reducing agent preferably includes PhMeSiCl2. In this invention, the reducing agent is used to reduce nickel catalysts, redox-active esters, and aryl iodinated compounds.

[0074] The second nickel-based catalyst preferably comprises a nickel salt-dinitrogen ligand complex; the nickel salt-dinitrogen ligand complex preferably comprises NiCl2(bpy)2 or comprises the nickel salt-dinitrogen ligand complex described above, which will not be repeated here. In this invention, the third organic solvent preferably comprises N,N-dimethylacetamide (DMA).

[0075] In this invention, the molar ratio of the redox active ester to the aryl iodide compound is preferably 2:(1-1.2), and in the embodiments of this invention, it can specifically be 2:1, 2:1.1, or 2:1.2; the molar ratio of the aryl iodide compound to the reducing agent is preferably (1-1.2):11, and in the embodiments of this invention, it can specifically be 1:11, 1.1:11, or 1.2:11; the molar ratio of the aryl iodide compound to the second nickel-based catalyst is preferably (1-1.2):0.1, and in the embodiments of this invention, it can specifically be 1:0.1, 1.1:0.1, or 1.2:0.1; the molar amount of the aryl iodide compound in the third organic solvent is preferably 0.2 mol / L; the molar ratio of the metal reducing agent to the organosilicon reducing agent is preferably 8:3; and the molar ratio of the zinc powder to the manganese powder is preferably 1:1.

[0076] In this invention, the temperature of the decarboxylation reduction coupling reaction is preferably -5 to 5°C. In the embodiments of this invention, it can be -5°C, -3°C, 0°C, 2°C, 3°C or 5°C. The time is preferably 1 to 5 hours. In the embodiments of this invention, it can be 1 hour, 2 hours, 3 hours, 4 hours or 5 hours.

[0077] After completing the decarboxylation reduction coupling reaction, the present invention preferably performs post-treatment on the obtained reaction solution; the present invention does not have special requirements for the post-treatment steps, and any method well known in the art can be used to obtain pure substances of arylpiperidine compounds.

[0078] In an embodiment of the present invention, the post-processing preferably includes: adding an organic solvent to dilute the reaction solution, and then adding saturated ammonium chloride to quench the reaction. After separation, the inorganic phase is extracted with ethyl acetate (5×2 mL), and the combined organic phases are washed sequentially with saturated ammonium chloride, water, and saturated brine. The washed organic phases are dried over anhydrous sodium sulfate and concentrated, and finally purified by silica gel column chromatography.

[0079] This invention uses commercially available and inexpensive piperidine carboxylic acids as starting materials, preparing redox-active esters with N-hydroxydicarboximides. These esters then undergo decarboxylation coupling reactions with arylboronic acids or decarboxylation-reductive coupling reactions with aryl iodides to rapidly and efficiently construct a linker arm between C-sp2 (arylboronic acid or aryl iodide) and C-sp3 (piperidine), achieving the economical synthesis of arylpiperidine compounds. The raw materials used in this invention are inexpensive and readily available, avoiding the use of expensive platinum group metal catalysts and high-pressure reaction conditions, further reducing production costs and adverse environmental impacts.

[0080] The arylpiperidine compounds prepared by this invention can be used to prepare key arylpiperidine intermediates involved in the synthesis of drug molecules such as Niraparib, Preclamol, Ampreloxetine, OSU-6162, Elsubrutinib, and Pridopidine.

[0081] To further illustrate the present invention, the following detailed description, in conjunction with embodiments, of an arylpiperidine compound and its preparation method provided by the present invention, should not be construed as limiting the scope of protection of the present invention.

[0082] Example 1

[0083] Synthesis of redox-active ester X1

[0084]

[0085] Following the chemical reaction equation shown in formula a, N-hydroxytetrachlorophthalimide (1 mmol, 1.0 equiv) and catalyst DMAP (0.2 mmol, 0.2 equiv) were added to a round-bottom flask. 5 mL of dichloromethane was added to dissolve the mixture, and the mixture was stirred vigorously. Then, N-Boc piperidine-3-carboxylic acid (1 mmol, 1.0 equiv) and condensing agent 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCl, 1.2 mmol, 1.2 equiv) were added to initiate a condensation reaction. The reaction was carried out in an ice bath (0 °C) and gradually reduced to room temperature (25 °C). After the reaction was completed (after 24 h) by thin-layer chromatography, 10 mL of dichloromethane (DCM) was added to dilute the reaction mixture. The organic phase of the reaction system was then washed successively with water and saturated sodium chloride. The washed organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated to obtain the crude product. Finally, the crude product was eluent: V 石油醚 / V 二氯甲烷 Purified by silica gel column chromatography at a ratio of 2:1, yielding redox-active ester X1. Yield 75%, white solid.

[0086] Preparation of the target compound β-phenylpiperidine compound X2

[0087]

[0088] Following the chemical reaction equation shown in formula b, redox-active ester X1 (0.2 mmol, 101 mg, 1.0 equiv) and phenylboronic acid (0.6 mmol, 3.0 equiv) were added to a Shrek tube. The Shrek tube was then evacuated and backfilled with N2 (air and oxygen are detrimental to the reaction). This process was repeated three times. 1,4-Dioxane (8 mL) of organic solvent was added, and the resulting mixture was stirred for 1 min. Then, Et3N (0.27 mL, 10.0 equiv; triethylamine is a base and can activate phenylboronic acid) was added, and the mixture was stirred for 2–5 min until the solid was uniformly dissolved. Finally, the catalyst [Ni] was added using a syringe. 2+ The complex of [Ligand] (0.05 M in DMF, 0.8 mL, 20 mol%) was added to a Shrek tube. The tube was immediately placed in a preheated 75°C metal heating sleeve and stirred for 12 h to carry out the decarboxylation coupling reaction. After 12 h, the reaction mixture was cooled to room temperature and then diluted with EtOAc (50 mL). The organic phase of the reaction system was washed successively with saturated ammonium chloride (20 mL), water (20 mL), and saturated brine (20 mL). The washed organic phase was dried over anhydrous sodium sulfate and concentrated, then eluent: V 石油醚 / V 二氯甲烷 Purification by silica gel column chromatography at a ratio of 20:1 yielded β-phenylpiperidine compound X2, with a yield of 59%. Structural identification data are as follows:

[0089] 1H NMR(400MHz, CDCl3)δ7.28-7.20(m,2H),7.18-7.11(m,3H),4.09(s,2H),2.81-2.5 0(m,3H),2.04-1.84(m,1H),1.72-1.66(m,1H),1.57-1.47(m,2H),1.39(s,9H).13C NMR (101MHz, CDCl3) δ154.9,143.6,128.5,127.1,126.6,79.5,50.9,42.6,31.8,28.5,25.5,24.5.

[0090] Examples 2-20

[0091] The preparation method is the same as in Example 1, except that phenylboronic acid is replaced with the corresponding arylboronic acid compound to prepare β-arylpiperidine compounds of formulas X3 to X19 and X21;

[0092] Arylboronic acid compounds have structures shown in formulas 2-X3 to 2-X19 and 2-X21 (corresponding to products of formulas X3 to X19 and X21 respectively):

[0093]

[0094] The preparation method is the same as in Example 1, except that N-Boc piperidine-3-carboxylic acid is replaced with N-Boc piperidine-4-carboxylic acid to prepare γ-arylpiperidine compound X20;

[0095] The yield data of arylpiperidine compounds of formulas X2 to X21 are shown in Table 1.

[0096] Table 1 Yield data for arylpiperidine compounds of formulas X2 to X21

[0097] compound Formula X2 Formula X3 Formula X4 Formula X5 Formula X6 Formula X7 Formula X8 Yield / % 59 53 54 34 59 32 8 compound Formula X9 Formula X10 Formula X11 Formula X12 Formula X13 Formula X14 Formula X15 Yield / % 86 73 10 63 64 88 37 compound Formula X16 Formula X17 Formula X18 Formula X19 Formula X20 Formula X21 / Yield / % 12 58 59 86 68 50 /

[0098] Example 21

[0099]

[0100] Following the chemical reaction equation shown in formula c, redox-active ester X1 (0.4 mmol, 202 mg, 2.0 equiv), iodobenzene (0.20 mmol, 1.0 equiv), zinc powder (52 mg, 0.80 mmol, 4.0 equiv), manganese powder (44 mg, 0.80 mmol, 4.0 equiv), and nickel catalyst NiCl2(bpy)2 (5.8 mg, 0.020 mmol, 0.10 equiv) were added to a Shrek tube. The Shrek tube was then evacuated and backfilled with N2 (air and oxygen are detrimental to the reaction), and this process was repeated three times. Under a nitrogen atmosphere, a DMA solution (DMA 1.0 mL, iodobenzene 0.20 M) containing organosilicon reducing agent PhMeSiCl2 (98 μL, 0.60 mmol, 3.0 equiv) was added to the Shrek tube. The reaction tube was placed in an ice bath at 0°C and magnetically stirred to carry out the decarboxylation reduction coupling reaction. The reaction progress was monitored by TLC. After 2 hours, the reaction was complete. 10 mL of ethyl acetate was added to dilute the reaction solution, followed by 5 mL of saturated ammonium chloride to quench the reaction. After separation, the inorganic phase was extracted with ethyl acetate (5 × 2 mL). The combined organic phases were washed successively with 10 mL of saturated ammonium chloride, 10 mL of water, and 10 mL of saturated brine. The washed organic phases were dried over anhydrous sodium sulfate and concentrated. Finally, the product was purified by silica gel column chromatography with an eluent of 20:1 (V petroleum ether / V dichloromethane) to give β-phenylpiperidine compound X2, in 54% yield.

[0101] Product X2 was obtained. The structural identification data are as follows:

[0102] 1H NMR(400MHz, CDCl3)δ7.28-7.20(m,2H),7.18-7.11(m,3H),4.09(s,2H),2.81-2.5 0(m,3H),2.04-1.84(m,1H),1.72-1.66(m,1H),1.57-1.47(m,2H),1.39(s,9H).13C NMR (101MHz, CDCl3) δ154.9,143.6,128.5,127.1,126.6,79.5,50.9,42.6,31.8,28.5,25.5,24.5.

[0103] Examples 22-40

[0104] The preparation steps are the same as in Example 21, except that the iodobenzene is replaced with the corresponding aryl iodo compound, or N-Boc piperidine-3-carboxylic acid is replaced with N-Boc piperidine-4-carboxylic acid, to obtain aryl piperidine compounds of formula X3 to X21, with yields of 10 to 85%.

[0105] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing an arylpiperidine compound, comprising the following steps: N-hydroxyphthalimide compounds, N-Boc piperidine carboxylic acid, organic base catalyst, condensing agent and first organic solvent are mixed and subjected to condensation reaction to obtain redox active ester; Under the protection of a first protective gas, the redox active ester, arylboronic acid compound, second organic solvent, basic activator and first nickel-based catalyst are mixed and subjected to a decarboxylation coupling reaction to obtain the arylpiperidine compound; Alternatively, under the protection of a second protective gas, the redox-active ester, the aryl iodide compound, the reducing agent, the second nickel-based catalyst, and the third organic solvent are mixed and subjected to a decarboxylation-reduction coupling reaction to obtain the arylpiperidine compound; the reducing agent includes metal reducing agents and organosilicon reducing agents. The first nickel-based catalyst comprises a nickel salt-dinitrogen ligand complex; the second nickel-based catalyst comprises a nickel salt-dinitrogen ligand complex; the metal reducing agent comprises zinc powder and manganese powder; The N-Boc piperidine carboxylic acid has the structure shown in Formula 1; the redox-active ester has the structure shown in Formula X1; the arylboronic acid compound has the structure shown in Formula 2; and the aryl iodinated compound has the structure shown in Formula 3. Formula 1; Ar-B(OH)2 Formula 2; Ar-I Formula 3; Formula X1; In formula X1, R1, R2, R3 and R4 are independently H or Cl; The arylpiperidine compounds have the structure shown in formula Xx: Formula Xx; Ar in formula Xx includes phenyl, halophenyl, haloalkylphenyl, alkyloxyphenyl, alkylphenyl, benzyloxyphenyl, biphenyl, cyanophenyl, pyridyl, thiophene, benzothiophene, or oxofluorenyl; The substitution site of Ar is the α, β, or γ position of the N atom.

2. The preparation method according to claim 1, characterized in that, The halophenyl includes fluorophenyl, chlorophenyl, bromophenyl or iodophenyl; the haloalkylphenyl includes fluoroalkylphenyl; the alkyloxyphenyl includes alkoxyphenyl, with the alkyl carbon number being 1 to 6; the alkylphenyl includes alkylphenyl, with the alkyl carbon number being 1 to 6.

3. The preparation method according to claim 1 or 2, characterized in that, The arylpiperidine compounds have the structures shown in any one of formulas X2 to X21: X2; X3; X4; X5; X6; X7; X8; X9; X10; X11; X12; X13; X14; X15; X16; X17; X18; X19; X20; X21。 4. The preparation method according to claim 1, characterized in that, The organic base catalyst includes 4-dimethylaminopyridine; the condensing agent includes EDCI-HCl or DCC.

5. The preparation method according to claim 1, characterized in that, The molar ratio of the N-hydroxyphthalimide compound to N-Boc piperidine carboxylic acid is 1:(0.8~1.5).

6. The preparation method according to claim 1, 4, or 5, characterized in that, The condensation reaction is carried out at a temperature of 0°C to room temperature for 10 to 40 hours.

7. The preparation method according to claim 1, characterized in that, The decarboxylation coupling reaction is carried out at a temperature of 50~95℃ for 10~20h; the decarboxylation reduction coupling reaction is carried out at a temperature of -5~5℃ for 1~5h.

8. The preparation method according to claim 1, characterized in that, The molar ratio of the redox-active ester to the arylboronic acid compound is 1:(3~4); the molar ratio of the redox-active ester to the aryl iodide compound is 2:(1~1.2).

9. The preparation method according to claim 1 or 8, characterized in that, The organosilicon reducing agent includes PhMeSiCl2.

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