A process for the preparation of tetrahydropyridine and hexahydropyridine derivatives

Abstract

The application discloses a preparation method of tetrahydropyridine derivatives and hexahydropyridine derivatives. The preparation method comprises the following steps: subjecting pyridine salt shown in formula III or formula IV to catalytic hydrogenation reaction with hydrogen in the presence of a catalyst and an alkali, so as to obtain 1,2,3,6-tetrahydropyridine derivatives shown in formula I and 1,2,3,4,5,6-hexahydropyridine derivatives shown in formula II respectively. The pyridine salt is reacted with hydrogen in the presence of a catalyst and an alkali in a solvent, so that the synthesis of 1,2,3,6-tetrahydropyridine derivatives and 1,2,3,4,5,6-hexahydropyridine derivatives is realized.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for preparing tetrahydropyridine derivatives and hexahydropyridine derivatives. Background Technology

[0002] 1,2,3,6-Tetrahydropyridine derivatives and 1,2,3,4,5,6-Hexahydropyridine derivatives are a very important class of nitrogen-containing heterocyclic compounds. They are important structural units for constructing a variety of natural products and physiologically active molecules, and are also important intermediates for analgesics such as opioid receptor antagonists and dyes. They have significant research value and broad application prospects in the fields of medicine, chemical engineering and organic synthesis.

[0003] In existing technologies, the most direct method for preparing 1,2,3,6-tetrahydropyridine derivatives and 1,2,3,4,5,6-hexahydropyridine derivatives is the hydrogenation reduction of nitrogen-containing heterocycles in N-alkylpyridine salts. Currently, methods for preparing 1,2,3,6-tetrahydropyridine derivatives and 1,2,3,4,5,6-hexahydropyridine derivatives via hydrogenation reactions typically use precious metal catalysts, which have disadvantages such as high catalyst cost, significant toxicity, and poor biocompatibility. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing 1,2,3,6-tetrahydropyridine derivatives and 1,2,3,4,5,6-hexahydropyridine derivatives.

[0005] The 1,2,3,6-tetrahydropyridine derivative has the structural formula shown in Formula I:

[0006]

[0007] In formula I, R n Independently indicates monosubstituted, disubstituted, trisubstituted, tetrasubstituted, or unsubstituted;

[0008] R nEach element is independently selected from: hydrogen, deuterium, halogen, alkyl (specifically, alkyl groups having 1-20 carbon atoms), cycloalkyl (specifically, cycloalkyl groups having 3-20 cyclic carbon atoms), heteroalkyl (alkyl substituents containing heteroatoms, such as -CH2CH2N(CH3)2, -CF3) (specifically, heteroalkyl groups having 1-20 carbon atoms), aralkyl (alkyl substituents containing aryl groups, such as the simplest benzyl, PhCH2- is an aralkyl group containing 7 carbon atoms) (specifically, aralkyl groups having 7-30 carbon atoms), alkoxy (specifically... It can be an alkoxy group having 1-20 carbon atoms, an aryloxy group (specifically, an aryloxy group having 6-30 carbon atoms), an acyloxy group (specifically, an acyloxy group having 6-30 carbon atoms), an amino group (specifically, a primary amino group, an alkyl-substituted secondary amino group, a tertiary amino group, or an acyl-substituted amino group), an aryl group (specifically, an aryl group having 6-30 carbon atoms, an aryl group fused with a benzene ring, or an aryl group fused with a pyridine ring), a cyano group, an ester group (specifically, an ester group having 6-30 carbon atoms), an amide group (specifically, an amide group having 6-30 carbon atoms), and combinations thereof.

[0009] Specifically, R n It can be hydrogen;

[0010] R 1 Selected from: hydrogen, deuterium, alkyl (specifically, alkyl with 1-20 carbon atoms), cycloalkyl (specifically, cycloalkyl with 3-20 cyclic carbon atoms), heteroalkyl (alkyl substituents containing heteroatoms, such as -CH2CH2N(CH3)2, -CF3) (specifically, heteroalkyl with 1-20 carbon atoms), aralkyl (alkyl substituents with aryl groups, such as the simplest benzyl, PhCH2- is an aralkyl with 7 carbon atoms) (specifically, aralkyl with 7-30 carbon atoms).

[0011] Specifically, R 1 It can be benzyl;

[0012] R 2Selected from: halogens, alkyl groups (specifically, alkyl groups having 1-20 carbon atoms), cycloalkyl groups (specifically, cycloalkyl groups having 3-20 cyclic carbon atoms), heteroalkyl groups (alkyl substituents containing heteroatoms, such as -CH2CH2N(CH3)2, -CF3) (specifically, heteroalkyl groups having 1-20 carbon atoms), aralkyl groups (alkyl substituents containing aryl groups, such as the simplest benzyl, PhCH2-, which is an aralkyl group containing 7 carbon atoms) (specifically, aralkyl groups having 7-30 carbon atoms), alkoxy groups (specifically, alkyl groups having 7-30 carbon atoms). Alkoxy groups having 1-20 carbon atoms, aryloxy groups (specifically aryloxy groups having 6-30 carbon atoms), acyloxy groups (specifically acyloxy groups having 6-30 carbon atoms), amino groups (specifically primary amino groups, alkyl-substituted secondary and tertiary amino groups, acyl-substituted amino groups), aryl groups (specifically aryl groups having 6-30 carbon atoms, aryl groups fused with a benzene ring, or aryl groups fused with a pyridine ring), cyano groups, ester groups (specifically ester groups having 6-30 carbon atoms), and amide groups (specifically amide groups having 6-30 carbon atoms).

[0013] Specifically, R 2 It can be halogen, methyl, tert-butyl, phenyl, benzyl, trifluoromethyl, ester (specifically CH2CO2Et, CO2Me), C1-C6 alkoxy (specifically methoxy), acyl-substituted amino (specifically 4-tert-butyloxycarbonylamino), etc.

[0014] The 1,2,3,4,5,6-hexahydropyridine derivatives have the structural formula shown in Formula II:

[0015]

[0016] In Equation II, R n Independently indicates monosubstituted, disubstituted, trisubstituted, tetrasubstituted, or unsubstituted.

[0017] R nEach element is independently selected from: hydrogen, deuterium, halogen, alkyl (specifically, alkyl groups having 1-20 carbon atoms), cycloalkyl (specifically, cycloalkyl groups having 3-20 cyclic carbon atoms), heteroalkyl (alkyl substituents containing heteroatoms, such as -CH2CH2N(CH3)2, -CF3) (specifically, heteroalkyl groups having 1-20 carbon atoms), aralkyl (alkyl substituents containing aryl groups, such as the simplest benzyl, PhCH2- is an aralkyl group containing 7 carbon atoms) (specifically, aralkyl groups having 7-30 carbon atoms), alkoxy (specifically... It can be an alkoxy group having 1-20 carbon atoms, an aryloxy group (specifically, an aryloxy group having 6-30 carbon atoms), an acyloxy group (specifically, an acyloxy group having 6-30 carbon atoms), an amino group (specifically, a primary amino group, an alkyl-substituted secondary amino group, a tertiary amino group, or an acyl-substituted amino group), an aryl group (specifically, an aryl group having 6-30 carbon atoms, an aryl group fused with a benzene ring, or an aryl group fused with a pyridine ring), a cyano group, an ester group (specifically, an ester group having 6-30 carbon atoms), an amide group (specifically, an amide group having 6-30 carbon atoms), and combinations thereof;

[0018] Specifically, R n It can be methyl or phenyl;

[0019] R 1 Selected from: hydrogen, deuterium, alkyl (specifically, alkyl with 1-20 carbon atoms), cycloalkyl (specifically, cycloalkyl with 3-20 cyclic carbon atoms), heteroalkyl (alkyl substituents containing heteroatoms, such as -CH2CH2N(CH3)2, -CF3) (specifically, heteroalkyl with 1-20 carbon atoms), aralkyl (alkyl substituents with aryl groups, such as the simplest benzyl, PhCH2- is an aralkyl with 7 carbon atoms) (specifically, aralkyl with 7-30 carbon atoms).

[0020] Specifically, R 1 It can be benzyl.

[0021] The preparation methods of 1,2,3,6-tetrahydropyridine derivatives and 1,2,3,4,5,6-hexahydropyridine derivatives provided by the present invention include the following steps:

[0022] In the presence of a catalyst and a base, the pyridine salt compound shown in Formula III or the pyridine salt compound shown in Formula IV is catalytically hydrogenated with hydrogen to obtain the 1,2,3,6-tetrahydropyridine compound shown in Formula I or the 1,2,3,4,5,6-hexahydropyridine compound shown in Formula II.

[0023]

[0024] In Equation III above, R nIndependently indicates monosubstituted, disubstituted, trisubstituted, tetrasubstituted, or unsubstituted;

[0025] R n Each element is independently selected from: hydrogen, deuterium, halogen, alkyl (specifically, alkyl groups having 1-20 carbon atoms), cycloalkyl (specifically, cycloalkyl groups having 3-20 cyclic carbon atoms), heteroalkyl (alkyl substituents containing heteroatoms, such as -CH2CH2N(CH3)2, -CF3) (specifically, heteroalkyl groups having 1-20 carbon atoms), aralkyl (alkyl substituents containing aryl groups, such as the simplest benzyl, PhCH2- is an aralkyl group containing 7 carbon atoms) (specifically, aralkyl groups having 7-30 carbon atoms), alkoxy (specifically... It can be an alkoxy group having 1-20 carbon atoms, an aryloxy group (specifically, an aryloxy group having 6-30 carbon atoms), an acyloxy group (specifically, an acyloxy group having 6-30 carbon atoms), an amino group (specifically, a primary amino group, an alkyl-substituted secondary amino group, a tertiary amino group, or an acyl-substituted amino group), an aryl group (specifically, an aryl group having 6-30 carbon atoms, an aryl group fused with a benzene ring, or an aryl group fused with a pyridine ring), a cyano group, an ester group (specifically, an ester group having 6-30 carbon atoms), an amide group (specifically, an amide group having 6-30 carbon atoms), and combinations thereof;

[0026] Specifically, R n It can be hydrogen;

[0027] R 1 Selected from: hydrogen, deuterium, alkyl (specifically, alkyl with 1-20 carbon atoms), cycloalkyl (specifically, cycloalkyl with 3-20 cyclic carbon atoms), heteroalkyl (alkyl substituents containing heteroatoms, such as -CH2CH2N(CH3)2, -CF3) (specifically, heteroalkyl with 1-20 carbon atoms), aralkyl (alkyl substituents with aryl groups, such as the simplest benzyl, PhCH2- is an aralkyl with 7 carbon atoms) (specifically, aralkyl with 7-30 carbon atoms);

[0028] Specifically, R 1 It can be benzyl;

[0029] R 2Selected from: halogens, alkyl groups (specifically, alkyl groups having 1-20 carbon atoms), cycloalkyl groups (specifically, cycloalkyl groups having 3-20 cyclic carbon atoms), heteroalkyl groups (alkyl substituents containing heteroatoms, such as -CH2CH2N(CH3)2, -CF3) (specifically, heteroalkyl groups having 1-20 carbon atoms), aralkyl groups (alkyl substituents containing aryl groups, such as the simplest benzyl, PhCH2- is an aralkyl group containing 7 carbon atoms) (specifically, aralkyl groups having 7-30 carbon atoms), alkoxy groups (specifically, alkyl substituents containing aryl groups, such as the simplest benzyl, PhCH2- is an aralkyl group containing 7 carbon atoms). Alkoxy groups with 1-20 carbon atoms, aryloxy groups (specifically, aryloxy groups with 6-30 carbon atoms), acyloxy groups (specifically, acyloxy groups with 6-30 carbon atoms), amino groups (specifically, primary amino groups, alkyl-substituted secondary and tertiary amino groups, acyl-substituted amino groups), aryl groups (specifically, aryl groups with 6-30 carbon atoms, aryl groups fused with a benzene ring, or aryl groups fused with a pyridine ring), cyano groups, ester groups (specifically, ester groups with 6-30 carbon atoms), and amide groups (specifically, amide groups with 6-30 carbon atoms).

[0030] Specifically, R 2 It can be halogen, methyl, tert-butyl, phenyl, benzyl, trifluoromethyl, ester, etc.;

[0031] X is selected from: fluorine, chlorine, bromine, and iodine;

[0032] Specifically, X can be chlorine, bromine, or iodine.

[0033] In equation IV above, R n Independently indicates monosubstituted, disubstituted, trisubstituted, tetrasubstituted, or unsubstituted;

[0034] R nEach element is independently selected from: hydrogen, deuterium, halogen, alkyl (specifically, alkyl groups having 1-20 carbon atoms), cycloalkyl (specifically, cycloalkyl groups having 3-20 cyclic carbon atoms), heteroalkyl (alkyl substituents containing heteroatoms, such as -CH2CH2N(CH3)2, -CF3) (specifically, heteroalkyl groups having 1-20 carbon atoms), aralkyl (alkyl substituents containing aryl groups, such as the simplest benzyl, PhCH2- is an aralkyl group containing 7 carbon atoms) (specifically, aralkyl groups having 7-30 carbon atoms), alkoxy (specifically... It can be an alkoxy group having 1-20 carbon atoms, an aryloxy group (specifically, an aryloxy group having 6-30 carbon atoms), an acyloxy group (specifically, an acyloxy group having 6-30 carbon atoms), an amino group (specifically, a primary amino group, an alkyl-substituted secondary amino group, a tertiary amino group, or an acyl-substituted amino group), an aryl group (specifically, an aryl group having 6-30 carbon atoms, an aryl group fused with a benzene ring, or an aryl group fused with a pyridine ring), a cyano group, an ester group (specifically, an ester group having 6-30 carbon atoms), an amide group (specifically, an amide group having 6-30 carbon atoms), and combinations thereof;

[0035] Specifically, R n It can be methyl or phenyl;

[0036] R 1 Selected from: hydrogen, deuterium, alkyl (specifically, alkyl with 1-20 carbon atoms), cycloalkyl (specifically, cycloalkyl with 3-20 cyclic carbon atoms), heteroalkyl (alkyl substituents containing heteroatoms, such as -CH2CH2N(CH3)2, -CF3) (specifically, heteroalkyl with 1-20 carbon atoms), aralkyl (alkyl substituents with aryl groups, such as the simplest benzyl, PhCH2-, which is an aralkyl with 7 carbon atoms) (specifically, aralkyl with 7-30 carbon atoms);

[0037] Specifically, R 1 It can be benzyl;

[0038] X is selected from: fluorine, chlorine, bromine, and iodine;

[0039] Specifically, X can be chlorine, bromine, or iodine.

[0040] In the above preparation method, the catalyst can be a manganese complex.

[0041] The manganese complex contains at least one carbonyl ligand and one manganese metal center;

[0042] The manganese complex may specifically be pentacarbonyl manganese bromide and / or decacarbonyl dimanganese;

[0043] The amount of the manganese complex is 1-30 mol% of the molar amount of the pyridine salt compound shown in Formula III or Formula IV, specifically 5 mol%.

[0044] In the above preparation method, the base can be an organic amine compound;

[0045] The organic amine compounds may specifically be trialkylamines, such as triethylamine and N,N'-tetramethylethylenediamine;

[0046] The amount of the organic amine compound used is 100-1000 mol% of the molar amount of the pyridine salt compound shown in Formula III or Formula IV, specifically 150 mol%.

[0047] In the above preparation method, the pressure of the hydrogen gas can be 1-10 MPa.

[0048] The pressure of the hydrogen gas can be specifically 3 MPa.

[0049] In the above preparation method, the catalytic hydrogenation reaction is carried out in an organic solvent;

[0050] The organic solvent may be one or a mixture of several of the following: tetrahydrofuran, anisole, isopropyl ether, methyl tert-butyl ether, 1,4-dioxane, n-butyl ether, diethylene glycol dimethyl ether, and dimethoxyethane, specifically tetrahydrofuran.

[0051] In the above preparation method, the molar concentration of the pyridine salt shown in Formula III or Formula IV in the catalytic hydrogenation reaction system can be 0.05 to 2 mol / L, specifically 0.25 to 0.5 mol / L, 0.25 mol / L, or 0.5 mol / L.

[0052] In the above preparation method, the temperature of the catalytic hydrogenation reaction can be 20-150℃, and the time can be 5 min-72 h. Specifically, the reaction can be carried out at 80℃ for 8 h.

[0053] The preparation method disclosed in this invention utilizes pyridine salts and hydrogen in a solvent in the presence of a manganese catalyst and a base to synthesize 1,2,3,6-tetrahydropyridine derivatives and 1,2,3,4,5,6-hexahydropyridine derivatives. These two nitrogen-containing heterocyclic compounds have important applications in natural products and pharmaceuticals. Existing catalytic hydrogenation synthesis methods require noble metals as catalysts. This invention utilizes monovalent manganese, which has low toxicity and good biocompatibility, as a catalyst to synthesize 1,2,3,6-tetrahydropyridine derivatives and 1,2,3,4,5,6-hexahydropyridine derivatives. It has a broad substrate range, mild reaction conditions, and high yields of these derivatives, making it valuable for pharmaceutical synthesis applications.

[0054] Therefore, the novel method developed in this invention for preparing 1,2,3,6-tetrahydropyridine derivatives and 1,2,3,4,5,6-hexahydropyridine derivatives using manganese catalysts is of great significance. Detailed Implementation

[0055] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0056] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0057] The pyridine salts described in Formulas III and IV were synthesized according to literature in the art (see Efficient and Chemoselective Reduction of Pyridines to Tetrahydropyridines and Piperidines via Rhodium-Catalyzed Transfer Hydrogenation. Jianjun Wu, Weijun Tang, Alan Pettman, and Jianliang Xiao. Advanced Synthesis & Catalysis. 2013, 355, 35-40), with the specific synthetic method shown in Formula V:

[0058]

[0059] In the above formula V, R n Independently indicates monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted or unsubstituted;

[0060] R n Each element is independently selected from: hydrogen, deuterium, halogen, alkyl (specifically, alkyl groups having 1-20 carbon atoms), cycloalkyl (specifically, cycloalkyl groups having 3-20 cyclic carbon atoms), heteroalkyl (alkyl substituents containing heteroatoms, such as -CH2CH2N(CH3)2, -CF3) (specifically, heteroalkyl groups having 1-20 carbon atoms), aralkyl (alkyl substituents containing aryl groups, such as the simplest benzyl, PhCH2- is an aralkyl group containing 7 carbon atoms) (specifically, aralkyl groups having 7-30 carbon atoms), alkoxy (specifically... It can be an alkoxy group having 1-20 carbon atoms, an aryloxy group (specifically, an aryloxy group having 6-30 carbon atoms), an acyloxy group (specifically, an acyloxy group having 6-30 carbon atoms), an amino group (specifically, a primary amino group, an alkyl-substituted secondary amino group, a tertiary amino group, or an acyl-substituted amino group), an aryl group (specifically, an aryl group having 6-30 carbon atoms, an aryl group fused with a benzene ring, or an aryl group fused with a pyridine ring), a cyano group, an ester group (specifically, an ester group having 6-30 carbon atoms), an amide group (specifically, an amide group having 6-30 carbon atoms), and combinations thereof;

[0061] Specifically, R n It can be methyl, tert-butyl, benzyl, trifluoromethyl, phenyl, methoxy, cyano, dimethylamino, tert-butoxycarbonylamino, ethoxyester, alkyl ester, bromine, etc.

[0062] R 1 Selected from: hydrogen, deuterium, alkyl (specifically, alkyl with 1-20 carbon atoms), cycloalkyl (specifically, cycloalkyl with 3-20 cyclic carbon atoms), heteroalkyl (alkyl substituents containing heteroatoms, such as -CH2CH2N(CH3)2, -CF3) (specifically, heteroalkyl with 1-20 carbon atoms), aralkyl (alkyl substituents with aryl groups, such as the simplest benzyl, PhCH2- is an aralkyl with 7 carbon atoms) (specifically, aralkyl with 7-30 carbon atoms);

[0063] Specifically, R 1 It can be benzyl;

[0064] X is selected from: fluorine, chlorine, bromine, and iodine;

[0065] Specifically, X can be chlorine, bromine, or iodine.

[0066] Procedure: Under a nitrogen atmosphere, add pyridine (10 mmol, 1.0 eq.), anhydrous acetonitrile (10 mL), and a haloalkane (10 mmol, 1.0 eq.) sequentially to a two-necked flask equipped with a condenser. Reflux at 80 °C for 12 hours. After the reaction is complete, cool to room temperature, filter the resulting precipitate, and wash five times with anhydrous diethyl ether. Dry the precipitate in a vacuum oven for 12 hours (30 °C) to prepare the pyridine salt represented by Formula III or Formula IV.

[0067] Example 1: Preparation of 1-benzyl-4-methyl-1,2,3,6-tetrahydropyridine (Formula I-a)

[0068]

[0069] To a 14 mL polytetrafluoroethylene-lined reaction tube, the catalyst manganese pentacarbonyl bromide (0.025 mmol, 6.9 mg), solvent tetrahydrofuran (1.0 mL), triethylamine (0.75 mmol, 75.8 mg), and substrate 1-benzyl-4-methylpyridine bromide (0.5 mmol, 132.0 mg) were added sequentially. The reaction tube was placed in an autoclave and purged with hydrogen gas at 3 MPa. The reaction was carried out at 80 °C for 8 h. After cooling to room temperature, the gas was released, the reaction tube was rinsed with ethyl acetate, passed through a short silica gel column, and evaporated to dryness. After purification by column chromatography (eluent: petroleum ether:triethylamine = 30 / 1, v / v), 81 mg of the target product (formula I-a) was obtained, with a yield of 87%.

[0070] The target product is characterized as follows: 1 H NMR (300MHz, CDCl3) δ7.38-7.22(m,5H),5.37-5.33(m,1H),3.56(s,2H),2.96-2.88(m,2H),2.54(t,J=5.8Hz,2H),2.11–2.02(m,2H),1.67(s,3H). 13 C NMR (101MHz, CDCl3) δ 138.6, 132.8, 129.3, 128.3, 127.1, 119.5, 63.0, 53.1, 50.1, 31.0, the structure is correct.

[0071] Example 2: 1-Benzyl-4-tert-butyl-1,2,3,6-tetrahydropyridine (Formula I-b)

[0072]

[0073] To a 14 mL polytetrafluoroethylene-lined reaction tube, the catalyst manganese pentacarbonyl bromide (0.025 mmol, 6.9 mg), solvent tetrahydrofuran (1.0 mL), triethylamine (0.75 mmol, 75.8 mg), and substrate 1-benzyl-4-tert-butylpyridine bromide (0.5 mmol, 153.0 mg) were added sequentially. The reaction tube was placed in an autoclave and purged with hydrogen gas at 3 MPa. The reaction was carried out at 80 °C for 8 h. After cooling to room temperature, the gas was released, the reaction tube was rinsed with ethyl acetate, passed through a short silica gel column, and evaporated to dryness. After purification by column chromatography (eluent: petroleum ether:triethylamine = 30 / 1, v / v), 110 mg of the target product (Formula I-b) was obtained, with a yield of 96%.

[0074] The target product is characterized as follows: 1 H NMR (400MHz, CDCl3) δ7.39-7.27(m,4H),7.27-7.20(m,1H),5.41-5.39(m,1H),3 .57(s,2H),3.00(m,2H),2.52(t,J=5.7Hz,2H),2.21–2.11(m,2H),1.02(s,9H). 13 C NMR (101MHz, CDCl3) δ 144.3, 138.6, 129.3, 128.3, 127.1, 116.0, 63.0, 53.6, 50.3, 35.0, 28.9, 25.6, the structure is correct.

[0075] Example 3: 1-Benzyl-4-benzyl-1,2,3,6-tetrahydropyridine (Formula I-c)

[0076]

[0077] To a 14 mL polytetrafluoroethylene-lined reaction tube, the catalyst manganese pentacarbonyl bromide (0.025 mmol, 6.9 mg), solvent tetrahydrofuran (1.0 mL), triethylamine (0.75 mmol, 75.8 mg), and substrate 1-benzyl-4-benzylpyridine bromide (0.5 mmol, 170.0 mg) were added sequentially. The reaction tube was placed in an autoclave and purged with hydrogen gas at 3 MPa. The reaction was carried out at 80 °C for 8 h. After cooling to room temperature, the gas was released, the reaction tube was rinsed with ethyl acetate, passed through a short silica gel column, and evaporated to dryness. After purification by column chromatography (eluent: petroleum ether:triethylamine = 30 / 1, v / v), 130 mg of the target product (formula I-c) was obtained, with a yield of 99%.

[0078] The target product is characterized as follows: 1H NMR (400MHz, CDCl3) δ7.36-7.21(m,7H),7.21-7.13(m,3H),5.37-5.36(m,1H),3.5 5(s,2H),3.27(s,2H),2.99-2.96(m,2H),2.51(t,J=5.7Hz,2H),2.08-1.98(m,2H). 13 C NMR (101MHz, CDCl3) δ 139.7, 138.5, 136.0, 129.3, 129.2, 128.4, 128.3, 127.1, 126.1, 121.0, 62.9, 53.1, 50.0, 43.6, 29.1, the structure is correct.

[0079] Example 4: 1-Benzyl-4-trifluoromethyl-1,2,3,6-tetrahydropyridine (Formula I-d)

[0080]

[0081] To a 14 mL polytetrafluoroethylene-lined reaction tube, the catalyst manganese pentacarbonyl bromide (0.025 mmol, 6.9 mg), solvent tetrahydrofuran (1.0 mL), triethylamine (0.75 mmol, 75.8 mg), and substrate 1-benzyl-4-trifluoromethylpyridine bromide (0.5 mmol, 159.0 mg) were added sequentially. The reaction tube was placed in an autoclave and purged with hydrogen gas at 3 MPa. The reaction was carried out at 80 °C for 8 h. After cooling to room temperature, the gas was released, the reaction tube was rinsed with ethyl acetate, passed through a short silica gel column, and evaporated to dryness. After purification by column chromatography (eluent: petroleum ether:triethylamine = 30 / 1, v / v), 91 mg of the target product (formula I-d) was obtained, with a yield of 76%.

[0082] The target product is characterized as follows: 1 H NMR (300MHz, CDCl3) δ7.34-7.28(m,5H),6.27(s,1H),3.62(s,2H),3.16–3.02(m,2H),2.63(t,J=5.7Hz,2H),2.29(s,2H). 13 C NMR (126MHz, CDCl3) δ 137.9, 129.2, 128.51, 128.48 (q, J = 6.3Hz), 127.4, 127.0 (q, J = 31.5Hz), 123.7 (q, J = 270.9Hz), 62.4, 51.6, 48.6, 23.4, the structure is correct.

[0083] Example 5: 1-Benzyl-4-ethoxycarbonylmethyl-1,2,3,6-tetrahydropyridine (Formula I-e)

[0084]

[0085] To a 14 mL polytetrafluoroethylene-lined reaction tube, the catalyst manganese pentacarbonyl bromide (0.025 mmol, 6.9 mg), solvent tetrahydrofuran (1.0 mL), triethylamine (0.75 mmol, 75.8 mg), and substrate 1-benzyl-4-tert-butylpyridine bromide (0.5 mmol, 168.0 mg) were added sequentially. The reaction tube was placed in an autoclave and purged with hydrogen gas at 3 MPa. The reaction was carried out at 80 °C for 8 h. After cooling to room temperature, the gas was released, the reaction tube was rinsed with ethyl acetate, passed through a short silica gel column, and evaporated to dryness. After purification by column chromatography (eluent: petroleum ether:triethylamine = 30 / 1, v / v), 110 mg of the target product (formula I-e) was obtained, with a yield of 85%.

[0086] The target product is characterized as follows: 1 H NMR (400MHz, CDCl3) δ7.38–7.27(m,4H),7.27–7.22(m,1H),5.61–5.50(m,1H),4.13(q,J=7.1Hz,2H ),3.57(s,2H),3.00-2.98(m,4H),2.58(t,J=5.7Hz,2H),2.25–2.14(m,2H),1.25(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ171.6,138.5,129.9,129.3,128.3,127.1,123.7,62.7,60.6,52.8,49.8,42.6,29.3,14.3, the structure is correct.

[0087] Example 6: 1-Benzyl-4-phenyl-1,2,3,6-tetrahydropyridine (Formula I-f)

[0088]

[0089] To a 14 mL polytetrafluoroethylene-lined reaction tube, the catalyst manganese pentacarbonyl bromide (0.025 mmol, 6.9 mg), solvent tetrahydrofuran (1.0 mL), triethylamine (0.75 mmol, 75.8 mg), and substrate 1-benzyl-4-phenylpyridine bromide (0.5 mmol, 163.0 mg) were added sequentially. The reaction tube was placed in an autoclave and purged with hydrogen gas at 3 MPa. The reaction was carried out at 80 °C for 8 h. After cooling to room temperature, the gas was released, the reaction tube was rinsed with ethyl acetate, passed through a short silica gel column, and evaporated to dryness. After purification by column chromatography (eluent: petroleum ether:triethylamine = 30 / 1, v / v), 123 mg of the target product (formula I-f) was obtained, with a yield of 99%.

[0090] The target product is characterized as follows: 1 H NMR (400MHz, CDCl3) δ7.41–7.35(m,4H),7.35–7.25(m,5H),7.25–7.19(m,1H),6.07-6 .04(m,1H),3.64(s,2H),3.18-3.16(m,2H),2.71(t,J=5.7Hz,2H),2.60–2.54(m,2H). 13 C NMR (101MHz, CDCl3) δ 141.1, 138.4, 135.1, 129.4, 128.4, 127.2, 127.1, 125.0, 122.1, 62.9, 53.5, 50.1, 28.2. The structure is correct.

[0091] Example 7: 1-Benzyl-4-methoxy-1,2,3,6-tetrahydropyridine (Formula I-g)

[0092]

[0093] To a 14 mL polytetrafluoroethylene-lined reaction tube, the catalyst manganese pentacarbonyl bromide (0.025 mmol, 6.9 mg), solvent tetrahydrofuran (1.0 mL), triethylamine (0.75 mmol, 75.8 mg), and substrate 1-benzyl-4-methoxypyridine bromide (0.5 mmol, 140.0 mg) were added sequentially. The reaction tube was placed in an autoclave and purged with hydrogen gas at 3 MPa. The reaction was carried out at 80 °C for 8 h. After cooling to room temperature, the gas was released, the reaction tube was rinsed with ethyl acetate, passed through a short silica gel column, and evaporated to dryness. After purification by column chromatography (eluent: petroleum ether:triethylamine = 30 / 1, v / v), 62 mg of the target product (Formula I-g) was obtained, with a yield of 61%.

[0094] The target product is characterized as follows: 1 H NMR (400MHz, CDCl3) δ7.37–7.28(m,4H),7.25-7.23(m,1H),4.58-4.56(m,1H),3.5 9(s,2H),3.51(s,3H),3.06-3.02(m,2H),2.60(t,J=5.9Hz,2H),2.22-2.19(m,2H). 13 C NMR (101MHz, CDCl3) δ 154.1, 138.6, 129.3, 128.4, 127.2, 62.5, 54.2, 51.7, 28.5. The structure is correct.

[0095] Example 8: 1-Benzyl-4-tert-Butoxycarbonylamino-1,2,3,6-Tetrahydropyridine (Formula I-h)

[0096]

[0097] To a 14 mL polytetrafluoroethylene-lined reaction tube, the catalyst manganese pentacarbonyl bromide (0.025 mmol, 6.9 mg), solvent tetrahydrofuran (1.0 mL), triethylamine (0.75 mmol, 75.8 mg), and substrate 1-benzyl-4-tert-butoxycarbonylaminopyridine bromide (0.5 mmol, 182.5 mg) were added sequentially. The reaction tube was placed in an autoclave and purged with hydrogen gas at 3 MPa. The reaction was carried out at 80 °C for 8 h. After cooling to room temperature, the gas was released, the reaction tube was rinsed with ethyl acetate, passed through a short silica gel column, and evaporated to dryness. After purification by column chromatography (eluent: petroleum ether: ethyl acetate: triethylamine = 20 / 4 / 1, v / v), 115 mg of the target product (Formula I-h) was obtained, with a yield of 95%.

[0098] The target product is characterized as follows: 1 H NMR (500MHz, CDCl3) δ7.38–7.27(m,4H),7.25-7.22(m,1H),5.78-5.75(m,2H),3.5 9(s,2H),3.05-3.03(m,2H),2.59(t,J=5.8Hz,2H),2.26–2.17(m,2H),1.45(s,9H). 13 C NMR (126MHz, CDCl3) δ 152.8, 138.5, 131.0, 129.1, 128.3, 127.1, 106.0, 80.0, 62.4, 51.7, 49.4, 28.6, 28.4. The structure is correct.

[0099] Example 9: 1-Benzyl-4-bromo-1,2,3,6-tetrahydropyridine (Formula I-i)

[0100]

[0101] To a 14 mL polytetrafluoroethylene-lined reaction tube, the catalyst manganese pentacarbonyl bromide (0.025 mmol, 6.9 mg), solvent tetrahydrofuran (1.0 mL), triethylamine (0.75 mmol, 75.8 mg), and substrate 1-benzyl-4-bromopyridine bromide (0.5 mmol, 165.0 mg) were added sequentially. The reaction tube was placed in an autoclave and purged with hydrogen gas at 3 MPa. The reaction was carried out at 80 °C for 8 h. After cooling to room temperature, the gas was released, the reaction tube was rinsed with ethyl acetate, passed through a short silica gel column, and evaporated to dryness. After purification by column chromatography (eluent: petroleum ether:triethylamine = 30 / 1, v / v), 58 mg of the target product (formula I-i) was obtained, with a yield of 46%.

[0102] The target product is characterized as follows: 1 H NMR (300MHz, CDCl3) δ7.36–7.27(m,5H),5.99-5.96(m,1H),3.57(s,2H),3.01-2.98(m,2H),2.65(t,J=5.6Hz,2H),2.60–2.49(m,2H). 13 C NMR (101MHz, CDCl3) δ 138.1, 129.2, 128.5, 127.4, 126.9, 119.9, 62.1, 54.1, 50.9, 35.8. The structure is correct.

[0103] Example 10: 1-Benzyl-4-methoxycarbonyl-1,2,3,6-tetrahydropyridine (Formula I-j)

[0104]

[0105] To a 14 mL polytetrafluoroethylene-lined reaction tube, the catalyst manganese pentacarbonyl bromide (0.025 mmol, 6.9 mg), solvent tetrahydrofuran (1.0 mL), triethylamine (0.75 mmol, 75.8 mg), and substrate 1-benzyl-4-methoxycarbonylpyridine bromide (0.5 mmol, 154.0 mg) were added sequentially. The reaction tube was placed in an autoclave and purged with hydrogen gas at 3 MPa. The reaction was carried out at 80 °C for 8 h. After cooling to room temperature, the gas was released, the reaction tube was rinsed with ethyl acetate, passed through a short silica gel column, and evaporated to dryness. After purification by column chromatography (eluent: petroleum ether:triethylamine = 30 / 1, v / v), 50 mg of the target product (Formula I-j) was obtained, with a yield of 43%.

[0106] The target product is characterized as follows: 1 H NMR (400MHz, CDCl3) δ7.36–7.27(m,5H),6.89-6.86(m,1H),3.73(s,3H),3.61(s,2H),3.14-3.12(m,2H),2.61(t,J=5.7Hz,2H),2.45–2.38(m,2H). 13 C NMR (101MHz, CDCl3) δ 167.3, 138.2, 137.1, 129.2, 128.8, 128.5, 127.3, 62.5, 52.8, 51.8, 49.4, 25.4. The structure is correct.

[0107] Example 11: 1-Benzyl-2-phenyl-1,2,3,4,5,6-hexahydropyridine (Formula I-a)

[0108]

[0109] To a 14 mL polytetrafluoroethylene-lined reaction tube, the catalyst manganese pentacarbonyl bromide (0.025 mmol, 6.9 mg), solvent tetrahydrofuran (1.0 mL), triethylamine (0.75 mmol, 75.8 mg), and substrate 1-benzyl-2-phenylpyridine bromide (0.5 mmol, 163.0 mg) were added sequentially. The reaction tube was placed in an autoclave and purged with hydrogen gas at 3 MPa. The reaction was carried out at 80 °C for 8 h. After cooling to room temperature, the gas was released, the reaction tube was rinsed with ethyl acetate, passed through a short silica gel column, and evaporated to dryness. After purification by column chromatography (eluent: petroleum ether:triethylamine = 30 / 1, v / v), 125 mg of the target product (formula II-a) was obtained, with a yield of 99%.

[0110] The target product is characterized as follows: 1 H NMR(500MHz, CDCl3)δ7.47-7.44(m,2H),7.34-7.31(m,2H),7.29–7.16(m,6H),3.78-3.75(m,1H),3.12–3.09(m,1H) ,2.98–2.94(m,1H),2.82-2.78(m,1H),1.99–1.88(m,1H),1.83–1.71(m,2H),1.67–1.51(m,3H),1.43–1.31(m,1H). 13 C NMR (126MHz, CDCl3) δ 145.9, 134.0, 128.8, 128.6, 128.1, 127.6, 127.0, 126.6, 69.3, 59.9, 53.5, 37.2, 26.2, 25.4. The structure is correct.

[0111] The present invention has been described in detail above. Those skilled in the art will recognize that the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope, and without requiring unnecessary experiments. While specific embodiments have been provided, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including changes made using conventional techniques known in the art that depart from the scope disclosed herein.

Claims

1. A method for preparing 1,2,3,6-tetrahydropyridine derivatives or 1,2,3,4,5,6-hexahydropyridine derivatives, The 1,2,3,6-tetrahydropyridine derivative has the structural formula shown in Formula I: In formula I, R n Independently indicates monosubstituted, disubstituted, trisubstituted, tetrasubstituted, or unsubstituted; R n Each is independently selected from: hydrogen, deuterium, halogens and combinations thereof; R 1 Selected from: hydrogen, deuterium, benzyl; R 2 Selected from: halogens, alkyl groups with 1-20 carbon atoms, cycloalkyl groups with 3-20 cyclic carbon atoms, heteroalkyl groups with 1-20 carbon atoms, benzyl groups, alkoxy groups with 1-20 carbon atoms, aryloxy groups with 6-30 carbon atoms, ester groups, cyano groups, amide groups, 4-tert-butoxycarbonylamino groups. The 1,2,3,4,5,6-hexahydropyridine derivatives have the structural formula shown in Formula II: In Equation II, R n Independently indicates monosubstituted, disubstituted, trisubstituted, tetrasubstituted, or unsubstituted; R n Each is independently selected from: hydrogen, deuterium, halogen, alkyl, phenyl and combinations thereof having 1-20 carbon atoms; R 1 Selected from: hydrogen, deuterium, benzyl; characterized in that: The method includes the following steps: in the presence of a catalyst and a base, the pyridine salt compound of Formula III or the pyridine salt compound of Formula IV is catalytically hydrogenated with hydrogen to obtain the 1,2,3,6-tetrahydropyridine compound of Formula I or the 1,2,3,4,5,6-hexahydropyridine compound of Formula II. In Formula III, R n R 1 R 2 In the same formula I, R n R 1 R 2 ; In formula IV, R n R 1 In formula II, R n R 1 ; X is selected from: fluorine, chlorine, bromine, and iodine; The catalyst is manganese pentacarbonyl bromide and / or manganese decacarbonyl; The base is a trialkylamine.

2. The method according to claim 1, characterized in that: The amount of the manganese complex is 1-30 mol of the molar amount of the pyridinium salt compound shown in Formula III or Formula IV.

3. The method according to claim 1 or 2, characterized in that: The amount of the base used is 100-1000 mol of the molar amount of the pyridine salt compound shown in Formula III or Formula IV.

4. The method according to claim 1 or 2, characterized in that: The pressure of the hydrogen gas is 1-10 MPa.

5. The method according to claim 1 or 2, characterized in that: The catalytic hydrogenation reaction is carried out in an organic solvent; The organic solvent is one or a mixture of several of the following: tetrahydrofuran, anisole, isopropyl ether, methyl tert-butyl ether, 1,4-dioxane, n-butyl ether, diethylene glycol dimethyl ether, and dimethoxyethane.

6. The method according to claim 1 or 2, characterized in that: In the system of the catalytic hydrogenation reaction, the molar concentration of the pyridine salt shown in Formula III or Formula IV is 0.05~2 mol / L.

7. The method according to claim 1 or 2, characterized in that: The catalytic hydrogenation reaction is carried out at a temperature of 20–150 °C for a time of 5 min–72 h.

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