Synthesis method of 2-bromo-4-(piperidinyl methyl) pyridine

Abstract

The invention discloses a synthesis method of 2-bromine-4-(piperidinyl methyl) pyridine, which comprises the following steps: by taking 2-bromine-4-methylpyridine as a raw material, carrying out bromination to obtain a mixture of 2-bromine-4-dibromomethylpyridine and 2-bromine-4-bromomethylpyridine; according to the method, 2-bromo-4-dibromomethylpyridine is taken as a raw material, separation is not needed, 2-bromo-4-dibromomethylpyridine is converted into 2-bromo-4-bromomethylpyridine under the action of a reducing agent, then the 2-bromo-4-bromomethylpyridine reacts with piperidine to prepare 2-bromo-4-(piperidyl methyl) pyridine, and the method has the advantages of being few in step, simple in purification and high in yield.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing 2-bromo-4-(piperidinylmethyl)pyridine. Background Art

[0002] Lafutidine (A) is a long-acting, potent H2 receptor antagonist jointly developed by Fujirebio and Taihb of Japan. It was first launched in Japan in 2000. Lafutidine has a sustained anti-secretory effect and potential mucosal protective effect. It is mainly used for the treatment of gastric ulcer, duodenal ulcer and gastritis. As a second-generation H2 receptor antagonist, it has certain advantages over ranitidine, famotidine and cimetidine in terms of efficacy and has a good market prospect. At present, the synthesis process of lafutidine has the problems of long steps, high cost and low yield. The synthesis process of its key intermediate 2-bromo-4-(piperidinylmethyl)pyridine (B) has low yield and difficult purification, which needs to be solved urgently.

[0003] Structural formula (A) Lafutidine Structural formula (B) 2-Bromo-4-(piperidinylmethyl)pyridine Regarding the synthesis of 2-bromo-4-(piperidinylmethyl)pyridine, there are two methods in the literature: Document US 4977267 A uses 2-bromo-4-methylpyridine as a raw material and obtains the target molecule through four steps of oxidation, reduction, oxidation, and substitution reaction. This method has a long route and low yields in each step, with the yields of the third and fourth steps being only 15% and the total yield being only 10%, which is not suitable for industrialization.

[0004] Journal of Jiangxi Normal University (Natural Science Edition), 2007, 31 The above route was improved by using benzenesulfonyl chloride to react with 2-bromo-pyridine-4-methanol to generate a sulfonate intermediate, which was then substituted with piperidine to obtain the target molecule with a total yield of 40%, which is not conducive to industrial production.

[0005] We assumed that 2-bromo-4-(piperidinylmethyl)pyridine could also be prepared by reacting 2-bromo-4-bromomethylpyridine with piperidine; therefore, we searched for the synthesis method of 2-bromo-4-bromomethylpyridine and found that the existing method had a low yield and was difficult to industrialize.

[0006] US 1999 / 5962458 reports that 2-bromo-4-methylpyridine is used as a raw material, and a free radical reaction occurs with NBS under the action of an initiator to generate 2-bromo-4-dibromomethylpyridine and 2-bromo-4-bromomethylpyridine, and the products are separated by column chromatography, with a yield of only 28%. This method has a long reaction time, is difficult to purify, and has a low yield, and is not suitable for industrial scale-up.

[0007] US 2013 / 252938 reports that 2-bromo-4-pyridinemethanol is used as a raw material, reacts with carbon tetrabromide under the action of triphenylphosphine to prepare 2-bromo-4-bromomethylpyridine, and the product is separated by column chromatography with a yield of 60%. The raw material 2-bromo-4-pyridinemethanol in this method needs to be prepared from 2-bromo-4-methylpyridine, which is expensive, resulting in increased production costs. Summary of the invention

[0008] The purpose of the present invention is to solve the problems of low yield, high cost and difficult purification in the preparation of 2-bromo-4-(piperidinylmethyl)pyridine, and to provide a synthesis method of 2-bromo-4-(piperidinylmethyl)pyridine, which has the characteristics of few steps, simple purification and high yield.

[0009] The technical solution adopted by the present invention to solve its technical problem is: A method for synthesizing 2-bromo-4-(piperidinylmethyl)pyridine comprises the following steps: (1) Bromination reaction: 2-bromo-4-methylpyridine is subjected to bromination reaction to obtain a mixture of 2-bromo-4-dibromomethylpyridine and 2-bromo-4-bromomethylpyridine; (2) Reduction reaction: Under the action of a reducing agent, 2-bromo-4-dibromomethylpyridine in the mixture is directly and selectively converted into 2-bromo-4-bromomethylpyridine; (3) Substitution reaction: 2-Bromo-4-bromomethylpyridine reacts with piperidine to obtain 2-bromo-4-(piperidinylmethyl)pyridine.

[0010] In step (1), the reagents used in the bromination reaction include a bromination reagent, a free radical initiator and a reaction solvent; the molar ratio of the bromination reagent to 2-bromo-4-methylpyridine is 1:1 to 3:1, and the molar ratio of the free radical initiator to 2-bromo-4-methylpyridine is 1:3 to 1:12.

[0011] The bromination reagent is one of NBS, DBDMH and PyHBr3.

[0012] The free radical initiator is one of dimethyl azobisisobutyrate, azobisisobutyronitrile, dibenzoyl peroxide and tert-butyl peroxide.

[0013] The reaction solvent is one or more of carbon tetrachloride, trifluorotoluene, chlorobenzene, chloroform and dichloromethane.

[0014] In step (1), the reaction temperature is 0-120°C and the reaction time is 2-6 hours. The reaction temperature is preferably 40-80°C; the reaction time is preferably 3 hours.

[0015] In step (2), the reducing agent is one of diethyl phosphite, diethyl ethyl phosphate, and diethyl phosphate; and the reaction solvent is one of tetrahydrofuran, acetonitrile, dichloromethane, methanol, and dioxane.

[0016] In step (2), the molar ratio of reducing agent to mixture is 1:1 to 3:1; the reaction temperature is 0 to 60°C and the reaction time is 4 to 8 hours. The reaction temperature is preferably 10 to 20°C; the reaction time is preferably 6 hours.

[0017] In step (3), the molar ratio of piperidine to 2-bromo-4-bromomethylpyridine is 1:1 to 2:1; the reaction temperature is 0 to 60°C, and the reaction time is 3 to 6 hours. The reaction temperature is preferably 10 to 20°C; and the reaction time is preferably 5 hours.

[0018] In step (3), the reaction solvent is selected from one of tetrahydrofuran, acetonitrile, dichloromethane, methanol and dioxane.

[0019] The specific synthesis method of the present invention is specifically operated as follows: (1) Under nitrogen protection, the bromination reagent, free radical initiator and solvent are placed in a reaction flask, 2-bromo-4-methylpyridine is added dropwise, the temperature is raised and the reaction is continued for 2 to 6 hours, the solvent is removed under reduced pressure, the residue is extracted with ethyl acetate, the organic phase is washed with saturated sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain a mixture of 2-bromo-4-dibromomethylpyridine and 2-bromo-4-bromomethylpyridine.

[0020] (2) Under nitrogen protection, a mixture of 2-bromo-4-dibromomethylpyridine and 2-bromo-4-bromomethylpyridine, an acid-binding agent (DIPEA) and a solvent are placed in a reaction flask, and a reducing agent is added dropwise. After the addition is complete, the reaction is continued with stirring for 4 to 8 hours. After the reaction is completed, the filtrate is filtered and the solvent is removed under reduced pressure. The residue is extracted with ethyl acetate, and the organic phase is washed with a saturated sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain 2-bromo-4-bromomethylpyridine. The molar ratio of the acid-binding agent: the mixture is 2.0 to 3.0:1.

[0021] (3) 2-bromo-4-bromomethylpyridine, potassium carbonate and solvent are added to a reaction flask, and piperidine is added dropwise. The reaction is continued for 3 to 6 hours. After the reaction is completed, the filtrate is filtered and the filter cake is washed with ethyl acetate. The solvent is removed by decompression of the filtrate. The residue is extracted with dilute hydrochloric acid (1.0 mol / L) and ethyl acetate, and the organic layer is discarded. The pH of the aqueous layer is adjusted to about 10 to 11 with alkali. 2-bromo-4-bromomethylpyridine is extracted three times with ethyl acetate. The organic phases are combined and the solvent is removed by decompression to obtain the final product 2-bromo-4-(piperidinylmethyl)pyridine. The molar ratio of potassium carbonate:2-bromo-4-bromomethylpyridine is 1.0 to 3.0:1.

[0022] The invention has the following beneficial effects: the invention uses 2-bromo-4-methylpyridine as a raw material, obtains a mixture of 2-bromo-4-dibromomethylpyridine and 2-bromo-4-bromomethylpyridine through bromination; 2-bromo-4-dibromomethylpyridine is converted into 2-bromo-4-bromomethylpyridine under the action of a reducing agent without separation, and then reacts with piperidine to obtain 2-bromo-4-(piperidinylmethyl)pyridine, and the invention has the characteristics of fewer steps, simple purification and high yield. DETAILED DESCRIPTION

[0023] The technical solution of the present invention is further described in detail below through specific embodiments.

[0024] In the present invention, unless otherwise specified, the raw materials and equipment used can be purchased from the market or are commonly used in the art. The methods in the following embodiments, unless otherwise specified, are all conventional methods in the art.

[0025] Embodiment 1: Step 1: Synthesis of a mixture of 2-bromo-4-dibromomethylpyridine 2 and 2-bromo-4-bromomethylpyridine 3.

[0026] In a three-necked flask, 53.4 g (0.30 mol) of NBS, 1.6 g (0.01 mol) of azobisisobutyronitrile and trifluorotoluene (200 ml) were added in sequence, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 40°C for 30 min, and then 20.0 g (0.12 mol) of 2-bromo-4-methylpyridine was added dropwise over 30 min. After the addition was completed, the mixture was heated to 80°C and stirred for 3 hours. The reaction solution was decompressed to remove the solvent, and the residue was washed with saturated sodium bicarbonate. The organic phase was extracted with ethyl acetate and washed with saturated sodium chloride. The organic phase was separated and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 36.4 g of a mixture of 2-bromo-4-dibromomethylpyridine 2 and 2-bromo-4-bromomethylpyridine 3. HPLC analysis showed that the content of 2-bromo-4-methylpyridine in the raw material was less than 1%, the content of 2-bromo-4-dibromomethylpyridine 2 was greater than 51%, and the content of 2-bromo-4-bromomethylpyridine 3 was greater than 39%. The yield was 95%.

[0027] Step 2: Synthesis of 2-bromo-4-bromomethylpyridine 3.

[0028] At 20°C, dichloromethane (370 ml) was added to a mixture of 2-bromo-4-dibromomethylpyridine 2 and 2-bromo-4-bromomethylpyridine 3 (37.0 g, 0.11 mol), and the mixture was replaced with nitrogen three times. Then, DIPEA (N, N-diisopropylethylamine) 42.7 g (0.33 mol) and diethyl phosphite 33.1 g (0.24 mol) were added in sequence. The mixture was stirred for 6 hours. After the reaction was completed, the mixture was filtered, the filter cake was washed with ethyl acetate, and the solvent was removed from the filtrate under reduced pressure. The residue was extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 2-bromo-4-bromomethylpyridine 31.9 g. The content was greater than 85% and the yield was 84% ​​as determined by HPLC.

[0029] 1 H NMR (500 MHz, CDCl3): δ 8.40 (d, J = 5.0 Hz, 1H), 7.23 (dd, J 1 = 5.0Hz, J 2 = 1.0 Hz, 1H), 6.98 (d, J = 5.0 Hz, 1H), 4.57 (s, 2H). .

[0030] Step 3: Synthesis of 2-bromo-4-(piperidinylmethyl)pyridine.

[0031] At 10°C, 29.0 g (0.11 mol) of 2-bromo-4-bromomethylpyridine, 31.8 g (0.23 mol) of potassium carbonate, and tetrahydrofuran (120 ml) were added to a three-necked flask in sequence, followed by dropwise addition of 14.8 g (0.17 mol) of piperidine. After the addition was completed, the mixture was stirred and reacted at 20°C for 5 hours. After the reaction was completed, the mixture was filtered and the filter cake was washed with ethyl acetate. The solvent was removed from the filtrate under reduced pressure. The residue was extracted with 100 mL of dilute hydrochloric acid (1.0 mol / L) and ethyl acetate, the organic layer was discarded, the pH of the aqueous layer was adjusted to about 10 to 11 with sodium bicarbonate, and the mixture was extracted with ethyl acetate three times. The organic phases were combined and the solvent was removed under reduced pressure to obtain 22.5 g of the final product 2-bromo-4-(piperidinylmethyl)pyridine, with an HPLC purity of >98%, a yield of 92%, and a total yield of 73% in three steps.

[0032] 1 H NMR (500 MHz, CDCl3): δ 8.35 (d, J= 5.0 Hz, 1H), 7.15 (dd, J 1 = 5.0Hz, J 2 = 1.0 Hz, 1H), 6.94 (d, J = 5.0 Hz, 1H), 3.59 (s, 2H), 2.50 (m, 4H), 1.55(m, 4H), 1.45 (m, 2H).

[0033] Embodiment 2: Step 1: Synthesis of a mixture of 2-bromo-4-dibromomethylpyridine 2 and 2-bromo-4-bromomethylpyridine 3.

[0034] In a three-necked flask, 48.6 g (0.17 mol) of DBDMH, 4.8 g (0.02 mol) of dibenzoyl peroxide and 150 ml of chlorobenzene were added in sequence. The atmosphere was replaced with nitrogen three times and stirred at 50°C for 30 min. Then, 15.0 g (0.09 mol) of 2-bromo-4-methylpyridine was added dropwise over 30 min. After the addition was completed, the temperature was raised to 70°C and the reaction was continued with stirring for 3 hours. The solvent was removed from the reaction solution under reduced pressure. The residue was washed with saturated sodium bicarbonate and extracted with ethyl acetate to obtain an organic phase, which was washed with saturated sodium chloride. The organic phase was separated and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a mixture of 27.4 g of 2-bromo-4-dibromomethylpyridine 2 and 2-bromo-4-bromomethylpyridine 3. g, and HPLC detection showed that the content of raw material 2-bromo-4-methylpyridine was less than 2%, the content of 2-bromo-4-dibromomethylpyridine 2 was greater than 48%, and the content of 2-bromo-4-bromomethylpyridine 3 was greater than 40%, with a yield of 93%.

[0035] Step 2: Synthesis of 2-bromo-4-bromomethylpyridine 3.

[0036] 10 o At 37.4 g (0.08 mol) of a mixture of 2-bromo-4-dibromomethylpyridine 2 and 2-bromo-4-bromomethylpyridine 3, tetrahydrofuran (270 ml) was added at 40 °C, and the mixture was replaced with nitrogen three times. Then, 22.0 g (0.17 mol) of DIPEA and 26.6 g (0.16 mol) of diethyl ethyl phosphate were added in sequence, and the mixture was stirred for 6 hours. After the reaction was completed, the mixture was filtered, the filter cake was washed with ethyl acetate, and the solvent was removed by decompression. The residue was extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed by decompression to obtain 28.6 g of 2-bromo-4-bromomethylpyridine. The content was greater than 84% and the yield was 83% as determined by HPLC.

[0037] Step 3: Synthesis of 2-bromo-4-(piperidinylmethyl)pyridine.

[0038] 15 o C, 2-bromo-4-bromomethylpyridine 30 g (0.12 mol), potassium carbonate 24.9 g (0.18 mol), acetonitrile (120 ml) were added in sequence to a three-necked flask, followed by piperidine 10.2 g (0.12 mol) dropwise. After the addition was complete, 20 o C and stirred for 5 hours. After the reaction, the mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was decompressed to remove the solvent. The residue was extracted with 100 mL of dilute hydrochloric acid (1.0 mol / L) and ethyl acetate, and the organic layer was discarded. The aqueous layer was adjusted to a pH of about 10 to 11 with sodium bicarbonate, and extracted with ethyl acetate three times. The organic phases were combined and the solvent was removed under reduced pressure to obtain 22.0 g of the final product 2-bromo-4-(piperidinylmethyl)pyridine, with an HPLC purity of >97%, a yield of 90%, and a total yield of 70% in three steps.

[0039] Embodiment 3: Step 1: Synthesis of a mixture of 2-bromo-4-dibromomethylpyridine 2 and 2-bromo-4-bromomethylpyridine 3.

[0040] In a three-necked flask, 86.4 g (0.27 mol) of PyHBr3, 7.3 g (0.03 mol) of dibenzoyl peroxide and 150 ml of chlorobenzene were added in sequence. The atmosphere was replaced with nitrogen three times and stirred at 45°C for 30 min. Then, 15.0 g (0.09 mol) of 2-bromo-4-methylpyridine was added dropwise over 30 min. After the addition was completed, the temperature was raised to 75°C and the reaction was continued with stirring for 3 hours. The solvent was removed from the reaction solution under reduced pressure. The residue was washed with saturated sodium bicarbonate and extracted with ethyl acetate to obtain an organic phase, which was washed with saturated sodium chloride. The organic phase was separated and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a mixture of 26.9 g of 2-bromo-4-dibromomethylpyridine 2 and 2-bromo-4-bromomethylpyridine 3. g, and HPLC detection showed that the content of raw material 2-bromo-4-methylpyridine was less than 1%, the content of 2-bromo-4-dibromomethylpyridine 2 was greater than 47%, and the content of 2-bromo-4-bromomethylpyridine 3 was greater than 42%, with a yield of 94%.

[0041] Step 2: Synthesis of 2-bromo-4-bromomethylpyridine 3.

[0042] 15 oAt 37 °C, tetrahydrofuran (270 ml) was added to a mixture of 26.9 g (0.08 mol) of 2-bromo-4-dibromomethylpyridine 2 and 2-bromo-4-bromomethylpyridine 3, and the mixture was replaced with nitrogen three times. Then, 25.8 g (0.2 mol) of DIPEA and 18.5 g (0.12 mol) of diethyl phosphate were added in sequence, and the mixture was stirred for 6 hours. After the reaction was completed, the mixture was filtered, the filter cake was washed with ethyl acetate, and the solvent was removed from the filtrate under reduced pressure. The residue was extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 25.2 g of 2-bromo-4-bromomethylpyridine. The content was greater than 84% and the yield was 80% as determined by HPLC.

[0043] Step 3: Synthesis of 2-bromo-4-(piperidinylmethyl)pyridine.

[0044] 15 o C, 25.0 g (0.1 mol) of 2-bromo-4-bromomethylpyridine, 27.6 g (0.2 mol) of potassium carbonate, and dichloromethane (120 ml) were added to a three-necked flask in sequence, followed by dropwise addition of 12.8 g (0.15 mol) of piperidine. After the addition was complete, 25 o C and stirred for 5 hours. After the reaction, the mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was evaporated under reduced pressure, and the residue was extracted with 100 mL of dilute hydrochloric acid (1.0 mol / L) and ethyl acetate. The organic layer was discarded, and the pH of the aqueous layer was adjusted to about 10-11 with sodium bicarbonate. The mixture was extracted with ethyl acetate three times, and the organic phases were combined. The solvent was removed under reduced pressure to obtain 18.3 g of the final product 2-bromo-4-(piperidinylmethyl)pyridine, with an HPLC purity of >98%, a yield of 91%, and a total yield of 72% in three steps.

[0045] Embodiment 4: The difference between this embodiment and embodiment 1 is that: In step 1: the amount of NBS used is 0.12 mol, and dimethyl azobisisobutyrate replaces azobisisobutyronitrile; the reaction temperature is 40°C, and the reaction time is 6 hours.

[0046] In step 2: the amount of diethyl phosphite used is 0.11 mol, acetonitrile replaces dichloromethane; the reaction temperature is 10°C, and the reaction time is 8 hours.

[0047] In step 3: dichloromethane replaces tetrahydrofuran.

[0048] The total yield of the final product 2-bromo-4-(piperidinylmethyl)pyridine was 73%.

[0049] Embodiment 5: The difference between this embodiment and embodiment 1 is that: In step 1: tert-butyl peroxide replaces azobisisobutyronitrile; the reaction temperature is 80° C. and the reaction time is 2 hours.

[0050] In step 2: the amount of diethyl phosphite used is 0.33 mol, methanol replaces dichloromethane; the reaction temperature is 20°C, and the reaction time is 4 hours.

[0051] In step 3: the amount of piperidine used is 0.33 mol, and methanol replaces tetrahydrofuran.

[0052] The total yield of the final product 2-bromo-4-(piperidinylmethyl)pyridine is 70%.

[0053] Embodiment 6: The difference between this embodiment and embodiment 1 is that: In step 1: carbon tetrachloride replaces trifluorotoluene.

[0054] In step 2: dioxane replaced dichloromethane.

[0055] In step 3: tetrahydrofuran is replaced by dioxane; the reaction temperature is 10°C and the reaction time is 6 hours.

[0056] The total yield of the final product 2-bromo-4-(piperidinylmethyl)pyridine was 71%.

[0057] Embodiment 7: The difference between this embodiment and embodiment 1 is that: In step 1: chloroform replaces trifluorotoluene.

[0058] In step 3: the reaction temperature is 20°C and the reaction time is 3 hours.

[0059] The total yield of the final product 2-bromo-4-(piperidinylmethyl)pyridine was 72%.

[0060] The above-described embodiment is only a preferred solution of the present invention and does not limit the present invention in any form. There are other variations and modifications without exceeding the technical solution described in the claims.

Claims

1. A method for synthesizing 2-bromo-4-(piperidinylmethyl)pyridine, characterized in that: The steps include: (1) Bromination reaction: 2-bromo-4-methylpyridine is subjected to bromination reaction to obtain a mixture of 2-bromo-4-dibromomethylpyridine and 2-bromo-4-bromomethylpyridine; (2) Reduction reaction: Under the action of a reducing agent, 2-bromo-4-dibromomethylpyridine in the mixture is directly and selectively converted into 2-bromo-4-bromomethylpyridine; (3) Substitution reaction: 2-Bromo-4-bromomethylpyridine reacts with piperidine to obtain 2-bromo-4-(piperidinylmethyl)pyridine.

2. The synthesis method according to claim 1, characterized in that In step (1), the reagents used in the bromination reaction include a bromination reagent, a free radical initiator and a reaction solvent; the molar ratio of the bromination reagent to 2-bromo-4-methylpyridine is 1:1 to 3:1, and the molar ratio of the free radical initiator to 2-bromo-4-methylpyridine is 1:3 to 1:

12.

3. The synthesis method according to claim 2, characterized in that The bromination reagent is one of NBS, DBDMH and PyHBr3.

4. The synthesis method according to claim 2, characterized in that The free radical initiator is one of dimethyl azobisisobutyrate, azobisisobutyronitrile, dibenzoyl peroxide and tert-butyl peroxide.

5. The synthesis method according to claim 2, characterized in that The reaction solvent is one or more of carbon tetrachloride, trifluorotoluene, chlorobenzene, chloroform and dichloromethane.

6. The synthesis method according to claim 1, characterized in that In step (1), the reaction temperature is 0-120° C. and the reaction time is 2-6 hours.

7. The synthesis method according to claim 1 or 2, characterized in that: In step (2), the reducing agent is one of diethyl phosphite, diethyl ethyl phosphate, and diethyl phosphate; and the reaction solvent is one of tetrahydrofuran, acetonitrile, dichloromethane, methanol, and dioxane.

8. The synthesis method according to claim 1 or 2, characterized in that: In step (2), the molar ratio of reducing agent to mixture is 1:1 to 3:1; the reaction temperature is 0 to 60°C, and the reaction time is 4 to 8 hours.

9. The synthesis method according to claim 1 or 2, characterized in that: In step (3), the molar ratio of piperidine to 2-bromo-4-bromomethylpyridine is 1:1 to 2:1; the reaction temperature is 0 to 60° C., and the reaction time is 3 to 6 hours.

10. The synthesis method according to claim 1 or 2, characterized in that: In step (3), the reaction solvent is selected from one of tetrahydrofuran, acetonitrile, dichloromethane, methanol and dioxane.

Images