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Synthesis method of 2-chloro-4-(piperidylmethyl)pyridine

A technology of chloromethylpyridine and methylpyridine, applied in the field of pharmaceutical synthesis, can solve the problems of long steps and high cost of lafutidine synthesis process, and achieve the effects of simple steps, cheap raw materials, and reduced synthesis cost.

Active Publication Date: 2012-01-04
常州市赛努尔高分子科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In order to solve the above problems, i.e. the problem of high cost and long steps of lafutidine synthesis process, the invention provides a compound 2-chloro-4-(piperidine A simple method for the synthesis of pyridine (pyridylmethyl)pyridine, so that lafutidine can be synthesized with high yield and low cost

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Step 1: Compound 2 Synthesis.

[0025] Add 300 ml of water into the four-neck flask, freeze in an ice-salt bath under stirring, then add 54 ml (1 mol) of concentrated sulfuric acid, and lower the temperature below 0 °C, then add finely ground 2-amino-4-methyl Pyridine 108 g (1 mol), keep the temperature below 5 °C, add NaNO dropwise 2 Aqueous solution (containing 69 g, 1 mol NaNO 2 ), stirred at 0-5°C for 45 minutes after the dropwise addition process was completed, then raised the temperature to 95°C, stopped heating after 15 minutes, adjusted the pH value to 6.5-7.0 with 50% NaOH aqueous solution after cooling, then heated to 60°C, and used Ethyl acetate extracts the hot reaction solution, the consumption of ethyl acetate is equal to the volume of the reaction mixture, extracts twice, and then uses anhydrous MgSO 4 The extract was dried, filtered, rotary evaporated under reduced pressure, and recrystallized to obtain a white solid product, and 153 g (1 mol) POCl wa...

Embodiment 2

[0034] Step 1: Compound 2 Synthesis.

[0035] Add 300ml of water into the four-neck flask, freeze in an ice-salt bath under stirring, then add 85ml (1 mol) of concentrated hydrochloric acid, the temperature drops below 0 ℃, and then add finely ground 2-amino-4-picoline 108 g (1 mol), keep the temperature below 5 ℃, add KNO dropwise 2 solution (containing 85 g, 1 mol KNO 2 ), stirred at 0-5°C for 45 minutes after the dropwise addition process was completed, then heated up to 95°C, and after 30 minutes, stopped heating, adjusted the pH value to 6.5-7.0 with 50% NaOH aqueous solution after cooling, then heated to 60°C, and used Ethyl acetate extracts the hot reaction solution, the consumption of ethyl acetate is equal to the volume of the reaction mixture, extracts twice, and then uses anhydrous MgSO4 The extract was dried, filtered, rotary evaporated under reduced pressure, and recrystallized to obtain a white solid product, and 76.5 g (0.5 mol) POCl was added to the resulting...

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Abstract

The invention relates to a synthesis method of 2-chloro-4-(piperidylmethyl)pyridine, belonging to the field of medicine synthesis. The method comprises the following steps: dropwisely adding a nitrite water solution into acid and 2-amino-4-methylpyridine to react, thereby obtaining a white solid product; adding POCl3 into the white solid to obtain a compound 2-chloro-4-methylpyridine; dropwisely adding SO2Cl2 into the compound 2-chloro-4-methylpyridine while adding a free-radical initiator batch by batch, and distilling under reduced pressure to obtain a compound 2-chloro-4-chloromethylpyridine; and condensing the 2-chloro-4-chloromethylpyridine and piperidine to obtain the 2-chloro-4-(piperidylmethyl)pyridine. Compared with the traditional synthesis method of 2-chloro-4-(piperidylmethyl)pyridine, the synthesis method provided by the invention has the advantages of simpler steps (only three steps) and lower cost of raw materials, and the total yield is higher than 32%. Generally, the invention can greatly lower the synthesis cost of lafutidine.

Description

technical field [0001] The invention relates to an industrializable synthetic process for synthesizing 2-chloro-4-(piperidinylmethyl)pyridine, a key intermediate of lavutidine, and belongs to the field of drug synthesis. Background technique [0002] [0003] Lafutidine (1) is an anti-ulcer drug jointly developed by (Fujirebio) and Dapeng (Taiho). 2 Receptor antagonist, has a unique gastroprotective effect. It has been listed in Japan in April 2000, and the trade names are Storga and Protecadin respectively. With the market share and market share of the anti-ulcer drug lafutidine increasing rapidly in recent years, the demand for the raw material drug of lafutidine will inevitably increase significantly. Therefore, developing a low-cost, low-pollution lafutidine synthetic route has great social and economic benefits. At present, there are many patents and literature reports about the synthetic route of lafutidine bulk drug, but the route is all complicated and the steps...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/61
Inventor 宋国强何其隆黄险峰
Owner 常州市赛努尔高分子科技有限公司
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