A kind of synthetic method of 4-amino-1-methylpiperidine

Abstract

The present invention belongs to the field of medicine, and in particular to a kind of synthetic method of 4-amino-1-methylpiperidine. Nitromethane and ethylene oxide generate 3-nitropropane-1-alcohol through ring-opening reaction, product and thionyl chloride generate 1-chloro-3-nitropropane through substitution reaction, product and methylamine generate N-methyl-3-nitropropane-1-amine through substitution reaction, then generate 5-(methylamino)-3-nitropentane-1-alcohol through ring-opening reaction, product and thionyl chloride generate 5-chloro-N-methyl-3-nitropentane-1-amine through substitution reaction, then cyclize to generate 1-methyl-4-nitropiperidine under the catalysis of potassium bromide, finally, under the catalysis of palladium carbon, reduction reaction occurs with hydrogen to generate intermediate 4-amino-1-methylpiperidine. The inventive method reaction conditions are mild, equipment requirements are not high, energy consumption is low, and post-processing is simple. New method is provided for the industrial production of Pimarserine intermediates.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and particularly relates to a method for synthesizing 4-amino-1-methylpiperidine. Background Art

[0002] There are three methods for synthesizing 4-amino-1-methylpiperidine (9) depending on the raw materials:

[0003]

[0004] Route 1

[0005] 4-amino-1-benzylpiperidine is used as a raw material. Diethyl ether is used as a solvent. This method is a nationally controlled reagent with a narrow source and is difficult to obtain. The reagent is relatively expensive. A hazardous reagent is used, and the yield is low.

[0006]

[0007] Route 2

[0008] There are many synthetic methods using 1-methyl-4-piperidone as the raw material, but there are also many problems. The source of 1-methyl-4-pyridone is difficult to obtain, controlled solvents are used, and the process is relatively dangerous. For example, most methods first generate a Schiff base intermediate and then reduce it to the target product.

[0009]

[0010] Route 3

[0011] The process uses ethyl 4-amino-1-piperidinylcarboxylate as raw material, which is difficult to obtain. Controlled and hazardous reagents, such as lithium aluminum hydride, are used. The solid and solution of this substance are highly flammable, so they must be isolated from air and moisture. In addition, hydrogen can be released under conditions of high temperature, water, acid, oxidant, etc., which places high demands on its use and storage, and the yield is not high. Summary of the Invention

[0012] In order to overcome the deficiencies of the prior art, the present invention provides a method for synthesizing 4-amino-1-methylpiperidine: nitromethane (2) and ethylene oxide undergo a ring-opening reaction to generate 3-nitropropane-1-ol (3); (3) undergoes a substitution reaction with thionyl chloride to generate 1-chloro-3-nitropropane (4); (4) undergoes a substitution reaction with methylamine to generate N-methyl-3-nitropropane-1-amine (5); (5) undergoes a ring-opening reaction with ethylene oxide to generate 5-(methylamino)-3-nitropentan-1-ol (6); (6) undergoes a substitution reaction with thionyl chloride to generate 5-chloro-N-methyl-3-nitropentan-1-amine (7); (7) undergoes cyclization under the catalysis of potassium bromide to generate 1-methyl-4-nitropiperidine (8); and (8) undergoes a reduction reaction with hydrogen under the catalysis of palladium on carbon to generate the key intermediate 4-amino-1-methylpiperidine.

[0013] Product 4-(4-fluorobenzylamino)-1-methylpiperidine (1) (Formula 1):

[0014]

[0015] The specific synthesis steps of the Pimarserine intermediate are as follows:

[0016] (1) Synthesis of 3-nitropropane-1-ol 3

[0017] Nitromethane was added to a 50 mL round-bottom flask and dissolved in tetrahydrofuran. Ethylene oxide, triethylamine, and cuprous chloride were then added and stirred at 50°C. After 12 hours, TLC confirmed the reaction was complete. The catalyst was removed by filtration and the mixture was rinsed three times with 30 mL of tetrahydrofuran. The organic solvents were combined and concentrated under reduced pressure to yield Compound 3 as a pale yellow oil.

[0018] The molar ratio of nitromethane, ethylene oxide, triethylamine and cuprous chloride is 1:1.15-1.35:1.2:0.05.

[0019] (2) Synthesis of 1-chloro-3-nitropropane 4

[0020] Compound 3 was added to a 50 mL round-bottom flask, followed by thionyl chloride. The mixture was heated at 45°C with stirring. After 4 h, TLC indicated that the starting materials had essentially reacted. The mixed solvent was evaporated under reduced pressure to afford compound 4 as a yellow oil.

[0021] The molar ratio of compound 3 to thionyl chloride is 1:1.15-1.35.

[0022] (3) Synthesis of N-methyl-3-nitropropane-1-amine 5

[0023] A 40% aqueous methylamine solution was added to a 50 mL round-bottom flask, followed by the slow addition of a methanol solution of compound 4. After the addition was complete, the mixture was refluxed and the reaction was complete after 40 min of TLC analysis. The mixture was concentrated under reduced pressure, followed by the addition of 10% sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried, and concentrated under reduced pressure to afford compound 5 as a yellow oil.

[0024] The molar ratio of compound 4 to methylamine is 1:2-8.

[0025] (4) Synthesis of 5-(methylamino)-3-nitropentan-1-ol 6

[0026] Compound 5 was added to a 50 mL round-bottom flask and dissolved in tetrahydrofuran. Ethylene oxide, triethylamine, and cuprous chloride were then added and stirred at 50°C. After 12 hours, TLC confirmed the reaction was complete. The catalyst was removed by filtration and the mixture was rinsed three times with 30 mL of tetrahydrofuran. The organic solvents were combined and concentrated under reduced pressure to yield compound 6 as a yellow oil.

[0027] The molar ratio of compound 5, ethylene oxide, triethylamine and cuprous chloride is 1:1.15-1.35:1.2:0.05.

[0028] (5) Synthesis of 5-chloro-N-methyl-3-nitropentan-1-amine 7

[0029] Compound 6 was added to a 50 mL round-bottom flask, followed by thionyl chloride. The mixture was heated and stirred at 45°C. After 4 h, TLC indicated that the starting materials had essentially reacted. The mixed solvent was evaporated under reduced pressure to afford compound 7 as a yellow oil.

[0030] The molar ratio of compound 6 to thionyl chloride is 1:1.15-1.35.

[0031] (6) Synthesis of 1-methyl-4-nitropiperidine

[0032] Compound 7 was added to a 50 mL round-bottom flask and dissolved in DMF. Potassium bromide and sodium carbonate were then added and stirred under reflux. After 3 h, the reaction was complete as determined by TLC. The mixture was concentrated under reduced pressure, diluted with 10% sodium hydroxide solution, and the aqueous phase was extracted three times with ethyl acetate. The organic phase was collected, washed with saturated brine, dried, and concentrated under reduced pressure to yield compound 8 as a white oil.

[0033] The molar ratio of compound 7, potassium bromide and potassium carbonate is 1:0.5 to 1.5:1.

[0034] (7) Synthesis of 4-amino-1-methylpiperidine 1

[0035] Compound 8 was added to a 50 mL round-bottom flask and dissolved in methanol. Palladium on carbon was then added and stirred at room temperature under a hydrogen atmosphere (50 psi). After 3 h, TLC confirmed the reaction was complete. The catalyst was removed by filtration, and the combined organic solvents were rinsed with 30 mL of methanol and concentrated under reduced pressure to yield Compound 1 as a yellow oil.

[0036] The molar ratio of compound 8 to palladium carbon is 1:0.1~1.

[0037] Beneficial effects:

[0038] The present invention utilizes novel raw materials to generate 4-amino-1-methylpiperidine, resulting in mild reaction conditions, low equipment requirements, low energy consumption, simple post-processing, and a simple and easy reaction, without the use of state-regulated reagents. More importantly, the present invention provides a novel synthesis method for the industrial production of the intermediate of pimaserin, an anti-Parkinson's disease drug, and the anti-tumor drug TAK-960 by first generating 4-amino-1-methylpiperidine and then further synthesizing the intermediate. This opens up a new source of acquisition, which is of great significance for the diversified synthesis and production of pimaserin and TAK-960. DETAILED DESCRIPTION

[0039] The present invention is described in detail below with reference to specific embodiments.

[0040] Example 1

[0041] (1) Synthesis of compound 3

[0042] Nitromethane (1.0 g, 16.38 mmol) was added to a 50 mL round-bottom flask and dissolved in tetrahydrofuran (30 mL). Ethylene oxide (0.9 g, 20.48 mmol), triethylamine (2.0 g, 19.66 mmol), and cuprous chloride (0.08 g, 0.82 mmol) were then added and stirred at 50°C. After 12 h, TLC confirmed the reaction was complete. The catalyst was removed by filtration and rinsed three times with 30 mL of tetrahydrofuran. The organic solvents were combined and concentrated under reduced pressure to afford 1.719 g of compound 3 as a light yellow oil (99.88% yield).

[0043] (2) Synthesis of compound 4

[0044] To a 50 mL round-bottom flask, compound 3 (1.719 g, 16.36 mmol) was added, followed by thionyl chloride (2.43 g, 20.45 mmol). The mixture was heated and stirred at 45°C. After 4 h, TLC confirmed that the starting materials had essentially reacted. The mixed solvent was evaporated under reduced pressure to dryness, affording 2.01 g of compound 4 as a yellow oil, with a yield of 99.51%.

[0045] (3) Synthesis of compound 5

[0046] A 50 mL round-bottom flask was added with 40% aqueous methylamine solution (6.33 ml, 81.4 mmol), followed by the slow addition of a solution of compound 4 (2.01 g, 16.28 mmol) in methanol (10 mL). After the addition was complete, the mixture was refluxed and the reaction was complete after 40 min of TLC analysis. The mixture was concentrated under reduced pressure, followed by the addition of 10% sodium hydroxide solution, and the aqueous phase was extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried, and concentrated under reduced pressure to afford 1.81 g of compound 5 as a yellow oil, with a yield of 93.98%.

[0047] (4) Synthesis of Compound 6

[0048] Compound 5 (1.81 g, 15.30 mmol) was added to a 50 mL round-bottom flask and dissolved in tetrahydrofuran (30 mL). Ethylene oxide (0.84 g, 19.125 mmol), triethylamine (1.86 g, 18.36 mmol), and cuprous chloride (0.06 g, 0.765 mmol) were then added and stirred at 50°C. After 12 h, TLC confirmed the reaction was complete. The catalyst was removed by filtration and the mixture was rinsed three times with 30 mL of tetrahydrofuran. The organic solvents were combined and concentrated under reduced pressure to afford 2.47 g of compound 6 as a yellow oil in a 99.7% yield.

[0049] (5) Synthesis of Compound 7

[0050] To a 50 mL round-bottom flask, compound 6 (2.47 g, 15.254 mmol) was added, followed by thionyl chloride (2.27 g, 19.07 mmol). The mixture was heated and stirred at 45°C. After 4 h, TLC confirmed that the starting materials had essentially reacted. The mixed solvent was evaporated under reduced pressure to dryness, affording 2.74 g of compound 7 as a yellow oil (99.6% yield).

[0051] (6) Synthesis of Compound 8

[0052] Compound 7 (2.74 g, 15.19 mmol) was added to a 50 mL round-bottom flask and dissolved in DMF (30 mL). Potassium bromide (1.81 g, 15.19 mmol) and sodium carbonate (1.61 g, 15.19 mmol) were then added and stirred under reflux. After 3 h, TLC confirmed the reaction was complete. The mixture was concentrated under reduced pressure, diluted with 10% sodium hydroxide solution, and the aqueous phase was extracted three times with ethyl acetate. The organic phase was collected, washed with saturated brine, dried, and concentrated under reduced pressure to obtain 2.15 g of compound 8 as a white oil in a yield of 98.42%.

[0053] (7) Synthesis of Compound 1

[0054] Compound 8 (2.15 g, 14.93 mmol) was added to a 50 mL round-bottom flask and dissolved in methanol (30 mL). Palladium on carbon (0.80 g, 7.47 mmol) was then added and stirred at room temperature under a hydrogen atmosphere (50 psi). After 3 h, TLC confirmed the reaction was complete. The catalyst was removed by filtration, and the combined organic solvents were rinsed with 30 mL of methanol and concentrated under reduced pressure to afford 1.69 g of compound 1 as a yellow oil, with a yield of 98.86%.

[0055] Example 2

[0056] (1) Synthesis of compound 3

[0057] Nitromethane (1.0 g, 16.38 mmol) was added to a 50 mL round-bottom flask and dissolved in tetrahydrofuran (30 mL). Ethylene oxide (0.83 g, 18.84 mmol), triethylamine (2.0 g, 19.66 mmol), and cuprous chloride (0.08 g, 0.82 mmol) were then added and stirred at 50°C. After 12 h, TLC confirmed the reaction was complete. The catalyst was removed by filtration and rinsed three times with 30 mL of tetrahydrofuran. The organic solvents were combined and concentrated under reduced pressure to afford 1.67 g of compound 3 as a light yellow oil (97.01% yield).

[0058] (2) Synthesis of compound 4

[0059] Compound 3 (1.67 g, 15.89 mmol) and thionyl chloride (2.17 g, 18.27 mmol) were added to a 50 mL round-bottom flask and heated with stirring at 45°C. After 4 h, TLC confirmed the reaction was complete. The mixed solvent was evaporated under reduced pressure to afford 1.90 g of compound 4 as a yellow oil, with a yield of 96.85%.

[0060] (3) Synthesis of compound 5

[0061] A 50 mL round-bottom flask was added with 40% aqueous methylamine solution (2.39 ml, 30.78 mmol), followed by the slow addition of a solution of compound 4 (1.9 g, 15.39 mmol) in methanol (10 mL). After the addition was complete, the mixture was refluxed and the reaction was complete after 40 min of TLC analysis. The mixture was concentrated under reduced pressure, and 10% sodium hydroxide solution was added. The aqueous phase was extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried, and concentrated under reduced pressure to afford 1.44 g of compound 5 as a yellow oil, with a yield of 79.34%.

[0062] (4) Synthesis of Compound 6

[0063] Compound 5 (1.44 g, 12.21 mmol) was added to a 50 mL round-bottom flask and dissolved in tetrahydrofuran (30 mL). Ethylene oxide (0.62 g, 14.04 mmol), triethylamine (1.86 g, 18.36 mmol), and cuprous chloride (0.06 g, 0.765 mmol) were then added and stirred at 50°C. After 12 h, TLC confirmed the reaction was complete. The catalyst was removed by filtration and the mixture was rinsed three times with 30 mL of tetrahydrofuran. The organic solvents were combined and concentrated under reduced pressure to afford 1.90 g of compound 6 as a yellow oil in a 95.90% yield.

[0064] (5) Synthesis of Compound 7

[0065] To a 50 mL round-bottom flask, compound 6 (1.90 g, 11.71 mmol) was added, followed by thionyl chloride (1.6 g, 13.47 mmol). The mixture was heated and stirred at 45°C. After 4 h, TLC confirmed the reaction was complete. The mixed solvent was evaporated under reduced pressure to dryness, affording 2.04 g of compound 7 as a yellow oil (yield: 96.24%).

[0066] (6) Synthesis of Compound 8

[0067] Compound 7 (2.04 g, 11.27 mmol) was added to a 50 mL round-bottom flask and dissolved in DMF (30 mL). Potassium bromide (0.67 g, 5.64 mmol) and sodium carbonate (1.61 g, 15.19 mmol) were then added and stirred under reflux. After 3 h, TLC confirmed the reaction was complete. The mixture was concentrated under reduced pressure, diluted with 10% sodium hydroxide solution, and the aqueous phase was extracted three times with ethyl acetate. The organic phase was collected, washed with saturated brine, dried, and concentrated under reduced pressure to obtain 1.28 g of compound 8 as a white oil with a yield of 78.26%.

[0068] 7) Synthesis of Compound 1

[0069] Compound 8 (1.28 g, 8.85 mmol) was added to a 50 mL round-bottom flask and dissolved in methanol (30 mL). Palladium on carbon (0.1 g, 0.89 mmol) was then added and stirred at room temperature under a hydrogen atmosphere (50 psi). After 3 h, TLC confirmed the reaction was complete. The catalyst was removed by filtration, and the combined organic solvents were rinsed with 30 mL of methanol and concentrated under reduced pressure to afford 0.73 g of compound 1 as a yellow oil, with a yield of 72.66%.

[0070] Example 3

[0071] (1) Synthesis of compound 3

[0072] Nitromethane (1.0 g, 16.38 mmol) was added to a 50 mL round-bottom flask and dissolved in tetrahydrofuran (30 mL). Ethylene oxide (0.97 g, 22.11 mmol), triethylamine (2.0 g, 19.66 mmol), and cuprous chloride (0.08 g, 0.82 mmol) were then added and stirred at 50°C. After 12 h, TLC confirmed the reaction was complete. The catalyst was removed by filtration and rinsed three times with 30 mL of tetrahydrofuran. The organic solvents were combined and concentrated under reduced pressure to afford 1.69 g of compound 3 as a light yellow oil (97.85% yield).

[0073] (2) Synthesis of compound 4

[0074] To a 50 mL round-bottom flask, compound 3 (1.69 g, 16.03 mmol) was added, followed by thionyl chloride (2.57 g, 21.64 mmol). The mixture was heated and stirred at 45°C. After 4 h, TLC confirmed that the starting materials had essentially reacted. The mixed solvent was evaporated under reduced pressure to afford 1.94 g of compound 4 as a yellow oil, with a yield of 97.94%.

[0075] (3) Synthesis of compound 5

[0076] A 50 mL round-bottom flask was added with a 40% aqueous methylamine solution (9.77 ml, 125.6 mmol), followed by the slow addition of a methanol solution (10 mL) of compound 4 (1.94 g, 15.70 mmol). After the addition was complete, the mixture was refluxed and the reaction was complete after 40 min of TLC analysis. The mixture was concentrated under reduced pressure, and then 10% sodium hydroxide solution was added. The aqueous phase was extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried, and concentrated under reduced pressure to afford 1.68 g of compound 5 as a yellow oil, with a yield of 90.45%.

[0077] (4) Synthesis of Compound 6

[0078] Compound 5 (1.68 g, 14.20 mmol) was added to a 50 mL round-bottom flask and dissolved in tetrahydrofuran (30 mL). Ethylene oxide (0.81 g, 18.46 mmol), triethylamine (1.86 g, 18.36 mmol), and cuprous chloride (0.06 g, 0.765 mmol) were then added and stirred at 50°C. After 12 h, TLC confirmed the reaction was complete. The catalyst was removed by filtration and the mixture was rinsed three times with 30 mL of tetrahydrofuran. The organic solvents were combined and concentrated under reduced pressure to afford 2.24 g of compound 6 as a yellow oil in a yield of 97.32%.

[0079] (5) Synthesis of Compound 7

[0080] To a 50 mL round-bottom flask, compound 6 (2.24 g, 13.82 mmol) was added, followed by thionyl chloride (2.22 g, 18.66 mmol). The mixture was heated and stirred at 45°C. After 4 h, TLC confirmed that the starting materials had essentially reacted. The mixed solvent was evaporated under reduced pressure to afford 2.43 g of compound 7 as a yellow oil, with a yield of 97.47%.

[0081] (6) Synthesis of Compound 8

[0082] Compound 7 (2.43 g, 13.47 mmol) was added to a 50 mL round-bottom flask and dissolved in DMF (30 mL). Potassium bromide (2.40 g, 20.21 mmol) and sodium carbonate (1.61 g, 15.19 mmol) were then added and stirred under reflux. After 3 h, TLC confirmed the reaction was complete. The mixture was concentrated under reduced pressure, diluted with 10% sodium hydroxide solution, and the aqueous phase was extracted three times with ethyl acetate. The organic phase was collected, washed with saturated brine, dried, and concentrated under reduced pressure to obtain 1.88 g of compound 8 as a white oil with a yield of 96.65%.

[0083] 7) Synthesis of Compound 1

[0084] Compound 8 (1.88 g, 13.02 mmol) was added to a 50 mL round-bottom flask and dissolved in methanol (30 mL). Palladium on carbon (1.39 g, 13.02 mmol) was then added and stirred at room temperature under a hydrogen atmosphere (50 psi). After 3 h, TLC confirmed the reaction was complete. The catalyst was removed by filtration, and the combined organic solvents were rinsed with 30 mL of methanol and concentrated under reduced pressure to afford 11.45 g of the compound as a yellow oil (yield: 97.54%).

Claims

1. A method for synthesizing 4-amino-1-methylpiperidine, characterized in that: The synthesis method comprises the following steps: nitromethane and ethylene oxide undergo a ring-opening reaction to generate 3-nitropropane-1-ol; 3-nitropropane-1-ol and thionyl chloride undergo a substitution reaction to generate 1-chloro-3-nitropropane; 1-chloro-3-nitropropane and methylamine undergo a substitution reaction to generate N-methyl-3-nitropropane-1-amine; N-methyl-3-nitropropane-1-amine and ethylene oxide undergo a ring-opening reaction to generate 5-(methylamino)-3-nitropentan-1-ol; 5-(methylamino)-3-nitropentan-1-ol and thionyl chloride undergo a substitution reaction to generate 5-chloro-N-methyl-3-nitropentan-1-amine; 5-chloro-N-methyl-3-nitropentan-1-amine forms a ring under the catalysis of potassium bromide to generate 1-methyl-4-nitropiperidine; and 1-methyl-4-nitropiperidine undergoes a reduction reaction with hydrogen under the catalysis of palladium on carbon to generate 4-amino-1-methylpiperidine.

2. The synthetic method of 4-amino-1-methylpiperidine according to claim 1, wherein The synthesis method steps are as follows: (1) Synthesis of 3-nitropropane-1-ol 3 Nitromethane was added to a round-bottom flask and dissolved in tetrahydrofuran. Ethylene oxide, triethylamine, and cuprous chloride were then added and stirred at 50°C. After 12 h, the reaction was complete as determined by TLC. The catalyst was removed by filtration and the mixture was rinsed three times with tetrahydrofuran. The organic solvents were combined and concentrated under reduced pressure to obtain compound 3 as a light yellow oil. (2) Synthesis of 1-chloro-3-nitropropane 4 Compound 3 was added to a round-bottom flask, followed by thionyl chloride. The mixture was heated and stirred at 45°C. After 4 h, TLC was performed to confirm that the reaction of the raw materials was complete. The mixed solvent was evaporated under reduced pressure to obtain compound 4 as a yellow oily liquid. (3) Synthesis of N-methyl-3-nitropropane-1-amine 5 A 40% aqueous methylamine solution was added to a round-bottom flask, and then a methanol solution of compound 4 was added thereto. After the addition was complete, the mixture was refluxed for 40 minutes and then detected by TLC. The reaction was complete and concentrated under reduced pressure. A 10% sodium hydroxide solution was then added, and the aqueous phase was extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried, and concentrated under reduced pressure to obtain compound 5 as a yellow oil. (4) Synthesis of 5-(methylamino)-3-nitropentan-1-ol 6 Compound 5 was added to a round-bottom flask and dissolved in tetrahydrofuran. Ethylene oxide, triethylamine, and cuprous chloride were then added and stirred at 50°C. After 12 h, the reaction was complete as determined by TLC. The catalyst was removed by filtration and the mixture was rinsed three times with tetrahydrofuran. The organic solvents were combined and concentrated under reduced pressure to obtain compound 6 as a yellow oil. (5) Synthesis of 5-chloro-N-methyl-3-nitropentan-1-amine 7 Compound 6 was added to a round-bottom flask, followed by thionyl chloride. The mixture was heated and stirred at 45°C. After 4 h, TLC was performed to confirm that the reaction of the raw materials was complete. The mixed solvent was evaporated under reduced pressure to obtain compound 7 as a yellow oily liquid. (6) Synthesis of 1-methyl-4-nitropiperidine Compound 7 was added to a round-bottom flask and dissolved in DMF. Potassium bromide and sodium carbonate were then added and refluxed with stirring. After 3 h, the reaction was complete as determined by TLC. The mixture was concentrated under reduced pressure and diluted with 10% sodium hydroxide solution. The aqueous phase was extracted three times with ethyl acetate. The organic phase was collected, washed with saturated brine, dried, and concentrated under reduced pressure to obtain compound 8 as a white oily liquid. (7) Synthesis of 4-amino-1-methylpiperidine 1 Compound 8 was added to a round-bottom flask and dissolved in methanol. Palladium carbon was then added and stirred at room temperature under a hydrogen atmosphere. After 3 h, the reaction was detected by TLC. The catalyst was removed by filtration, and the organic solvent was washed with methanol and combined, and concentrated under reduced pressure to obtain compound 1 as a yellow oil.

3. The synthetic method of 4-amino-1-methylpiperidine according to claim 1, wherein In step (1), the molar ratio of nitromethane, ethylene oxide, triethylamine and cuprous chloride is 1:1.15-1.35:1.2:0.

05.

4. The synthetic method of 4-amino-1-methylpiperidine according to claim 1, wherein In step (2), the molar ratio of 3-nitropropane-1-ol to thionyl chloride is 1:1.15-1.

35.

5. The synthetic method of 4-amino-1-methylpiperidine according to claim 1, characterized in that, In step (3), the molar ratio of 1-chloro-3-nitropropane to methylamine is 1:2-8.

6. The method for synthesizing 4-amino-1-methylpiperidine according to claim 1, wherein In step (4), the molar ratio of compound 5, ethylene oxide, triethylamine, and cuprous chloride is 1:1.15-1.35:1.2:0.

05.

7. The method for synthesizing 4-amino-1-methylpiperidine according to claim 1, wherein In step (5), the molar ratio of compound 6 to thionyl chloride is 1:1.15~1.

35.

8. The method for synthesizing 4-amino-1-methylpiperidine according to claim 1, wherein In step (6), the molar ratio of compound 7, potassium bromide and sodium carbonate is 1:0.5~1.5:

1.

9. The method for synthesizing 4-amino-1-methylpiperidine according to claim 1, wherein In step (7), the molar ratio of compound 8 to palladium carbon is 1:0.1~1.

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