Aryl piperidine compound and preparation method thereof

Abstract

The invention provides an aryl piperidine compound and a preparation method thereof, and belongs to the technical field of organic synthesis. The aryl piperidine compound has a structure as shown in a formula Xx. The method comprises the following steps: by taking a commercially available and cheap piperidine carboxylic acid compound as an initial raw material, preparing oxidation-reduction active ester from the piperidine carboxylic acid compound and an N-hydroxydicarboximide compound, and then carrying out decarboxylation coupling reaction on the oxidation-reduction active ester and an arylboronic acid compound or carrying out decarboxylation reduction coupling reaction on the oxidation-reduction active ester and an aryl iodo-compound to obtain the compound. A connecting arm between C-sp2 (arylboronic acid compounds or aryl iodo compounds) and C-sp3 (piperidine) is rapidly and effectively constructed, and economical synthesis of the aryl piperidine compounds is achieved. The raw materials adopted by the invention are cheap and easy to obtain, use of expensive platinum group noble metal catalysts and high-pressure reaction conditions are avoided, and the production cost and adverse effects on the environment are further reduced.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to an arylpiperidine compound and a preparation method thereof. Background Art

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

[0003] As molecular fragments of structures such as niraparib analgesics and dopamine autoreceptor agonists, arylpiperidine compounds involve reactions with noble metals in traditional synthesis steps, such as coupling reactions and transaminase reactions, and the reaction steps are long and cumbersome. For example, the anticancer drug Niraparib contains a β-arylpiperidine core skeleton. This drug is the first class of PARP inhibitors and involves the synthesis of bromophenylpiperidine or aminophenylpiperidine compounds in both the pharmaceutical chemistry research stage and the chemical engineering preparation stage. The existing routes mainly involve Suzuki coupling of arylboronic acid with halogenated pyridine compounds catalyzed by noble metal palladium, and then reduction of pyridine by noble metal-catalyzed hydrogenation or enzyme catalysis to finally prepare the required arylpiperidine synthetic building blocks.

[0004] However, the above synthesis strategies have disadvantages such as multiple reaction steps and the use of noble metal catalysts, and the raw materials are not easily available, which greatly limits the synthesis efficiency 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 the present invention is to provide an arylpiperidine compound and a preparation method thereof. The preparation method provided by the present invention has short steps, cheap and easily available raw materials, and avoids the use of noble metal catalysts.

[0006] To achieve the above purpose, the present invention provides the following solutions:

[0007] The present invention provides an arylpiperidine compound having the structure shown in Formula Xx:

[0008]

[0009] In Formula Xx, Ar includes phenyl, halogenated phenyl, halogenated hydrocarbon phenyl, alkoxyphenyl, hydrocarbon phenyl, benzyloxyphenyl, biphenyl, cyanophenyl, pyridyl, thienyl, benzothienyl, or fluorenyl.

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

[0011] Preferably, the halogenated phenyl group includes fluorophenyl, chlorophenyl, bromophenyl or iodophenyl; the halogenated alkylphenyl group includes fluorinated alkylphenyl; the alkoxyphenyl group includes alkoxyphenyl with 1 to 6 carbon atoms in the alkyl group; the alkylphenyl group includes alkylphenyl with 1 to 6 carbon atoms in the alkyl group.

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

[0013]

[0014] The present invention provides a method for preparing the arylpiperidine compound described in the above solution, comprising the following steps:

[0015] Mix an N-hydroxyphthalimide compound, an N-Boc piperidine carboxylic acid, an organic base catalyst, a condensing agent and a first organic solvent, and carry out a condensation reaction to obtain a redox active ester;

[0016] Under the protection of a first protective gas, mix the redox active ester, an arylboronic acid compound, a second organic solvent, a basic activator and a first nickel-based catalyst, and carry out a decarboxylative coupling reaction to obtain the arylpiperidine compound;

[0017] Or under the protection of a second protective gas, mix the redox active ester, an aryl iodide compound, a reducing agent, a second nickel-based catalyst and a third organic solvent, and carry out a decarboxylative reductive coupling reaction to obtain the arylpiperidine compound; the reducing agent includes a metal reducing agent and an organosilicon reducing agent;

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

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

[0020]

[0021] In Formula X1, R 1 , R 2 , R 3 and R 4 are independently H or Cl.

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

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

[0024] Preferably, the temperature of the condensation reaction is 0°C to room temperature, and the time is 10 - 40 h.

[0025] Preferably, the temperature of the decarboxylative coupling reaction is 50 - 95°C, and the time is 10 - 20 h; the temperature of the decarboxylative reductive 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 includes a nickel salt-diazine ligand complex; the second nickel-based catalyst includes a nickel salt-diazine ligand complex; the metal reducing agent includes zinc powder and manganese powder; the organosilicon reducing agent includes PhMeSiCl 2 .

[0028] The present invention provides an arylpiperidine compound having the structure shown in Formula Xx; in Formula Xx, Ar includes phenyl, halogenated phenyl, halogenated hydrocarbon-based phenyl, alkoxyphenyl, hydrocarbon-based phenyl, benzyloxyphenyl, biphenyl, cyanophenyl, pyridyl, thienyl, benzothienyl or fluorenyl; the substitution site of the Ar is the α, β or γ position of the N atom. The present invention uses a commercially available and inexpensive piperidinecarboxylic acid compound as a starting material, prepares a redox-active ester with an N-hydroxydicarboximide compound, and then undergoes a decarboxylative coupling reaction with an arylboronic acid compound or a decarboxylative reductive coupling reaction with an aryl iodide compound to rapidly and effectively construct a linker between C-sp2 (arylboronic acid compound or aryl iodide compound) and C-sp3 (piperidine), realizing the economical synthesis of arylpiperidine compounds. The raw materials used in the present invention are inexpensive and readily available, avoiding the use of expensive platinum group noble metal catalysts and high-pressure reaction conditions, further reducing the production cost and the adverse impact on the environment.

[0029] The arylpiperidine compounds prepared by the present invention can be used for the synthesis of key arylpiperidine intermediates involved in the synthesis of drug molecules such as Niraparib, Preclamol, Ampreloxetine, OSU-6162, Elsubrutinib, Pridopidine, etc. Specific Embodiments

[0030] The present invention provides an arylpiperidine compound having the structure shown in Formula Xx:

[0031]

[0032] In Formula Xx, Ar includes phenyl, halogenated phenyl, halogenated hydrocarbon-based phenyl, alkoxy phenyl, hydrocarbon-based phenyl, benzyloxy phenyl, biphenyl, cyano phenyl, pyridyl, thienyl, benzothienyl or fluorenyl;

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

[0034] In the present invention, the halogenated phenyl preferably includes fluorophenyl, chlorophenyl, bromophenyl or iodophenyl. The halogenation in the halogenated phenyl of the present invention preferably includes mono-substitution to penta-substitution.

[0035] In the present invention, the halogenated hydrocarbon-based phenyl preferably includes fluorinated hydrocarbon-based phenyl; the fluorinated hydrocarbon-based phenyl preferably includes m-trifluoromethylphenyl or p-trifluoromethylphenyl.

[0036] In the present invention, the alkoxy phenyl preferably includes alkoxy phenyl with 1 to 6 carbon atoms in the alkyl group; the alkoxy phenyl preferably includes methoxy phenyl or propoxy phenyl; the hydrocarbon-based phenyl preferably includes alkyl phenyl with 1 to 6 carbon atoms in the alkyl group; the alkyl phenyl preferably includes methyl phenyl.

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

[0038]

[0039]

[0040] The present invention provides a preparation method of the arylpiperidine compound described in the above solution, including the following steps:

[0041] Mix an N-hydroxyphthalimide compound, N-Boc piperidine carboxylic acid, an organic base catalyst, a condensing agent and a first organic solvent, and carry out a condensation reaction to obtain a redox active ester;

[0042] Under the protection of a first protective gas, mix the redox active ester, an arylboronic acid compound, a second organic solvent, a basic activator and a first nickel-based catalyst, and carry out a decarboxylative coupling reaction to obtain the arylpiperidine compound;

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

[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; the aryl iodide compound has the structure shown in Formula 3;

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

[0046]

[0047] In Formula X1, R 1 , R 2 , R 3 and R 4 are independently H or Cl.

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

[0049] In the present invention, the N-hydroxyphthalimide compound, N-Boc piperidine carboxylic acid, organic base catalyst, condensing agent, and first organic solvent are mixed to carry out a condensation reaction to obtain a redox active ester.

[0050] In the present invention, the N-hydroxyphthalimide compound preferably includes N-hydroxy tetrachlorophthalimide 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; the first organic solvent preferably includes dichloromethane, dichloroethane, tetrahydrofuran, N,N'-dimethylformamide, or toluene.

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

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

[0053] In the process of the condensation reaction of the present invention, the N-hydroxyphthalimide compound and the N-Boc piperidine carboxylic acid undergo dehydration condensation to form a redox-active ester.

[0054] After completing the condensation reaction, the present invention preferably performs post-treatment on the obtained reaction mixture.

[0055] The present invention has no special requirements for the steps of the post-treatment, and a redox-active ester pure substance can be obtained by using the steps well-known in the art. In the examples of the present invention, the post-treatment preferably includes: adding an organic solvent to the obtained reaction mixture, then washing the organic phase of the reaction system with water and saturated sodium chloride in sequence, drying the washed organic phase with anhydrous sodium sulfate, performing vacuum filtration and concentration to obtain a crude product, and finally purifying it by silica gel column chromatography.

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

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

[0058] In the present invention, the arylboronic acid compound has the structure shown in Formula 2, Ar-B(OH) 2Formula 2; the type of the Ar group in Formula 2 is the same as that of the Ar group in Formula Xx described above, and will not be elaborated here.

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

[0060]

[0061]

[0062] In the present 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 Formula 2-X2 to Formula 2-X19 or has the structure shown in Formula 2-X21.

[0063] In the present 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 the present invention, the second organic solvent preferably includes 1,4-dioxane; the basic activator preferably includes triethylamine. In the present invention, the basic activator can activate the arylboronic acid compound.

[0065] In the present invention, the first nickel-based catalyst preferably includes a nickel salt-diazine ligand complex; the nickel salt in the nickel salt-diazine ligand complex preferably includes nickel chloride triphenylphosphine (NiCl(PPh 3 ) 2 )); the diazine ligand (Ligand) in the nickel salt-diazine ligand complex preferably includes bipyridine compounds, alkoxy-substituted bipyridines, alkyl-substituted bipyridines, alkylamino-substituted bipyridines or phenanthroline; the alkoxy-substituted bipyridines preferably include 4,4'-dimethoxy bipyridine (L13) or 5,5'-dimethoxy bipyridine.

[0066] In the present invention, the molar ratio of the redox active ester to the arylboronic acid compound is preferably 1:(3-4), and can specifically be 1:3, 1:3.5 or 1:4 in the examples of the present invention; 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 diazine ligand in the first nickel-based catalyst is preferably 1:0.2; the concentration of the redox active ester in the organic solvent (including the second organic solvent and the fourth organic solvent) is preferably 0.023 mol / L.

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

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

[0069] After completing the decarboxylative coupling reaction, the present invention preferably subjects the obtained reaction mixture to post-treatment; the present invention has no special requirements for the process of the post-treatment, and the arylpiperidine compounds can be obtained by using a method well-known in the art.

[0070] In the examples of the present invention, the post-treatment 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 successively with saturated ammonium chloride, water, and saturated brine, drying the washed organic phase with anhydrous sodium sulfate and then concentrating it, and finally purifying it by silica gel column chromatography.

[0071] Alternatively, after obtaining the redox-active ester, under the protection of a second protective gas, the redox-active ester, an aryl iodide compound, a reducing agent, a second nickel-based catalyst, and a third organic solvent are mixed to carry out a decarboxylative reductive coupling reaction to obtain the arylpiperidine compounds; the reducing agent includes a metal reducing agent and an organosilicon reducing agent.

[0072] In the present invention, the second protective gas preferably includes nitrogen. In the present invention, the aryl iodide compound has the structure shown in Formula 3, Ar-I Formula 3; the type of the Ar group in Formula 3 is the same as that of the Ar group in Formula Xx described above and will not be elaborated here. In the present invention, the aryl iodide compound preferably includes iodobenzene.

[0073] In the present invention, the metal reducing agent preferably includes zinc powder and manganese powder; the organosilicon reducing agent preferably includes PhMeSiCl 2 . In the present invention, the reducing agent is used to reduce the nickel catalyst, the redox-active ester, and the aryl iodide compound.

[0074] The second nickel-based catalyst preferably includes a nickel salt-diazine ligand complex; the nickel salt-diazine ligand complex preferably includes NiCl2 (bpy) 2 Or it includes the nickel salt - di-nitrogen ligand complex described above, which will not be elaborated here. In the present invention, the third organic solvent preferably includes N,N-dimethylacetamide (DMA).

[0075] In the present invention, the molar ratio of the redox active ester to the aryl iodide compound is preferably 2:(1 - 1.2). In the examples of the present 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. In the examples of the present 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. In the examples of the present invention, it can specifically be 1:0.1, 1.1:0.1, or 1.2:0.1; the concentration of 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; the molar ratio of zinc powder to manganese powder is preferably 1:1.

[0076] In the present invention, the temperature of the decarboxylative reductive coupling reaction is preferably -5 to 5 °C. In the examples of the present invention, it can specifically be -5 °C, -3 °C, 0 °C, 2 °C, 3 °C, or 5 °C, and the time is preferably 1 to 5 h. In the examples of the present invention, it can specifically be 1 h, 2 h, 3 h, 4 h, or 5 h.

[0077] After completing the decarboxylative reductive coupling reaction, the present invention preferably performs post-treatment on the obtained reaction solution; the present invention has no special requirements for the steps of the post-treatment, and a pure substance of the arylpiperidine compound can be obtained by using a method well-known in the art.

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

[0079] The present invention uses commercially available and inexpensive piperidine carboxylic acid compounds as starting materials, prepares redox active esters with N-hydroxy dicarboximides, and then undergoes decarboxylative coupling reactions with arylboronic acid compounds or decarboxylative reductive coupling reactions with aryl iodide compounds to rapidly and effectively construct a linker between C-sp2 (arylboronic acid compounds or aryl iodide compounds) and C-sp3 (piperidine), achieving the economical synthesis of arylpiperidine compounds. The raw materials used in the present invention are inexpensive and readily available, avoiding the use of expensive platinum group noble metal catalysts and high-pressure reaction conditions, further reducing production costs and adverse environmental impacts.

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

[0081] To further illustrate the present invention, the following examples will be used to describe in detail an arylpiperidine compound and its preparation method provided by the present invention, but they should not be construed as limiting the protection scope of the present invention.

[0082] Example 1

[0083] Synthesis of Redox Active Ester X1

[0084]

[0085] According to the chemical reaction equation shown in Formula a, add N-hydroxy tetrachlorophthalimide (1 mmol, 1.0 equiv) and catalyst DMAP (0.2 mmol, 0.2 equiv) to a round-bottom flask. Add 5 mL of organic solvent dichloromethane to dissolve and vigorously stir the mixture, then add 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) for condensation reaction, and the reaction temperature is an ice bath (0 °C) and gradually returns to room temperature (25 °C). After determining that the reaction is complete by thin layer chromatography (after 24 h), add 10 mL of dichloromethane (DCM) to dilute the reaction mixture, and the organic phase of the reaction system is washed successively with water and saturated sodium chloride. The washed organic phase is dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated to obtain a crude product. Finally, use an eluent: V 石油醚 / V 二氯甲烷 = 2:1 silica gel column chromatography purification to obtain redox active ester X1. The yield is 75%, white solid.

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

[0087]

[0088] According to the chemical reaction equation shown in Formula b, add redox-active ester X1 (0.2 mmol, 101 mg, 1.0 equiv) and phenylboronic acid (0.6 mmol, 3.0 equiv) into a Schlenk tube. Then evacuate the Schlenk tube and backfill it with N 2 (Air and oxygen are adverse to the reaction). This process is repeated three times in total. Add the organic solvent 1,4-dioxane (8 mL), stir the resulting mixture for 1 min, and then add Et 3 N (0.27 mL, 10.0 equiv, triethylamine is the base that can activate phenylboronic acid). Stir the mixture for 2 - 5 min until the solid dissolves evenly. Finally, use a syringe to add the catalyst: [Ni 2+ (Ligand)] complex (0.05 M in DMF, 0.8 mL, 20 mol%) into the Schlenk tube. Immediately place the tube in a preheated metal heating mantle at 75 °C and stir for 12 h to carry out the decarboxylative coupling reaction. After 12 h, cool the reaction mixture to room temperature, then dilute the reaction mixture with EtOAc (50 mL). The organic phase of the reaction system is washed successively with saturated ammonium chloride (20 mL), water (20 mL), and saturated brine (20 mL). The washed organic phase is dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography with an eluent: V 石油醚 / V 二氯甲烷 = 20:1 to obtain the product β-phenylpiperidine compound X2 with a yield of 59%. The structure identification data are as follows:

[0089] 1H NMR (400 MHz, CDCl3) δ 7.28 - 7.20 (m, 2H), 7.18 - 7.11 (m, 3H), 4.09 (s, 2H), 2.81 - 2.50 (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 (101 MHz, CDCl3) δ 154.9, 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 that of Example 1, except that phenylboronic acid is replaced with the corresponding arylboronic acid compounds to prepare β-arylpiperidine compounds of Formula X3 to Formula X19 and Formula X21;

[0092] The arylboronic acid compounds have the structures shown in Formula 2-X3 to Formula 2-X19, Formula 2-X21 (corresponding to the product Formulas X3 to X19 and Formula X21 in sequence):

[0093]

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

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

[0096] Table 1 Yield data of arylpiperidine compounds of Formula X2 to Formula 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] According to the chemical reaction equation shown in Formula c, add redox active ester X1 (0.4 mmol, 202 mg, 2.0 equiv), iodobenzene (0.20 mmol, 1.0 equiv), metal reducing agent zinc powder (52 mg, 0.80 mmol, 4.0 equiv), metal reducing agent manganese powder (44 mg, 0.80 mmol, 4.0 equiv) and nickel catalyst NiCl 2 (bpy) 2 (5.8 mg, 0.020 mmol, 0.10 equiv) into a Schlenk tube. Then evacuate the Schlenk tube and backfill it with N 2 backfill the pipeline (air and oxygen are adverse to the reaction), and this process is repeated three times in total. Under a nitrogen atmosphere, add organosilicon reducing agent PhMeSiCl 2A DMA solution (98 μL, 0.60 mmol, 3.0 equiv) in DMA (1.0 mL, with iodobenzene at 0.20 M). The reaction tube was placed in an ice bath at 0 °C and stirred magnetically for the decarboxylative reductive coupling reaction. The reaction progress was monitored by TLC. After 2 h, the reaction was complete. 10 mL of ethyl acetate was added to dilute the reaction solution, and then saturated ammonium chloride (5 mL) was added to quench the reaction. After liquid separation, the inorganic phase was extracted with ethyl acetate (5 × 2 mL). The combined organic phases were washed successively with saturated ammonium chloride (10 mL), water (10 mL), and saturated brine (10 mL). The washed organic phase was dried over anhydrous sodium sulfate and concentrated. Finally, it was purified by silica gel column chromatography with an eluent of V petroleum ether / V dichloromethane = 20:1 to obtain the product β-phenylpiperidine compound X2 with a yield of 54%.

[0101] The product X2 was obtained. The structure identification data are as follows:

[0102] 1H NMR (400 MHz, CDCl3) δ 7.28 - 7.20 (m, 2H), 7.18 - 7.11 (m, 3H), 4.09 (s, 2H), 2.81 - 2.50 (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 (101 MHz, CDCl3) δ 154.9, 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 were the same as those in Example 21, except that iodobenzene was replaced with the corresponding aryl iodide compound, or N-Boc piperidine-3-carboxylic acid was replaced with N-Boc piperidine-4-carboxylic acid to obtain arylpiperidine compounds of formula X3 - formula X21 with yields ranging from 10% to 85%.

[0105] Although the above examples have described the present invention in detail, they are only a part of the embodiments of the present invention, not all embodiments. People can also obtain other embodiments based on these embodiments without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. An aryl piperidine compound, characterized in that: It has the structure shown in formula Xx: In the formula Xx, Ar includes phenyl, halogenated phenyl, halogenated alkylphenyl, alkoxyphenyl, alkylphenyl, benzyloxyphenyl, biphenyl, cyanophenyl, pyridyl, thienyl, benzothienyl or oxazolidinyl; The substitution site of Ar is the α, β or γ position of the N atom.

2. The aryl piperidine compound according to claim 2, characterized in that: The halogenated phenyl group includes fluorophenyl, chlorophenyl, bromophenyl or iodophenyl; the halogenated alkylphenyl group includes fluoroalkylphenyl; the alkyloxyphenyl group includes alkoxyphenyl, the alkyl group has 1 to 6 carbon atoms; the alkylphenyl group includes alkylphenyl, the alkyl group has 1 to 6 carbon atoms.

3. The aryl piperidine compound according to claim 1, 2, characterized in that: The aryl piperidine compound has a structure shown in any one of Formula X2 to Formula X21:

4. The method for preparing the arylpiperidine compound according to any one of claims 1 to 3, comprising the following steps: Mixing an N-hydroxyphthalimide compound, N-Boc piperidine carboxylic acid, an organic base catalyst, a condensation agent and a first organic solvent to carry out a condensation reaction to obtain a redox-active ester; Under the protection of a first protective gas, the redox-active ester, the aryl boronic acid compound, the second organic solvent, the alkaline activator and the first nickel-based catalyst are mixed to perform a decarboxylation coupling reaction to obtain the aryl piperidine 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 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; The N-Boc piperidine carboxylic acid has a structure shown in Formula 1; the redox-active ester has a structure shown in Formula X1; the aryl boronic acid compound has a structure shown in Formula 2; and the aryl iodide compound has a structure shown in Formula 3; Ar-B(OH)2 Formula 2; Ar-I Formula 3; In formula X1, R1, R2, R3 and R4 are independently H or Cl.

5. The preparation method according to claim 4, characterized in that: The organic base catalyst includes 4-dimethylaminopyridine; the condensation agent includes EDCI-HCl or DCC.

6. The preparation method according to claim 4, characterized in that: The molar ratio of the N-hydroxyphthalimide compound to N-Boc piperidine carboxylic acid is 1:(0.8-1.5).

7. The preparation method according to claim 4, 5 or 6, characterized in that: The condensation reaction temperature is 0°C to room temperature, and the reaction time is 10 to 40 hours.

8. The preparation method according to claim 4, characterized in that: The temperature of the decarboxylation coupling reaction is 50-95° C., and the time is 10-20 hours; the temperature of the decarboxylation reduction coupling reaction is -5-5° C., and the time is 1-5 hours.

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

10. The preparation method according to claim 4 or 9, characterized in that: The first nickel-based catalyst includes a nickel salt-dinitrogen ligand complex; the second nickel-based catalyst includes a nickel salt-dinitrogen ligand complex; the metal reducing agent includes zinc powder and manganese powder; and the organosilicon reducing agent includes PhMeSiCl2.

Images