阅读说明：本技术 一种2-氨基-3-羟甲基吡啶的制备方法 (Preparation method of 2-amino-3-hydroxymethylpyridine ) 是由 马魁 闫永平 胡海威 于 2021-11-17 设计创作，主要内容包括：本发明公开了一种2-氨基-3-羟甲基吡啶的制备方法,包括以下步骤：在无水无氧操作下,在1L三口瓶中加入无水四氢呋喃150ml,搅拌下加入50g原料2-氨基吡啶-3-甲酸,在冰盐浴下控温10℃以下滴加70％甲苯溶液的红铝209克,滴加完毕后撤去冰盐浴,升至室温搅拌反应16小时,反应完毕滴加饱和氯化铵淬灭并过滤,将滤饼用四氢呋喃洗涤,合并母液并用硫酸镁干燥,过滤除去硫酸镁,旋干得到产品38.2克,收率85％。本药物中间体2-氨基-3-羟甲基吡啶的制备方法,整个工艺流程设计合理,条件温和,操作简便,原料易得,生成效率高,十分适合大规模的工业化生产。(The invention discloses a preparation method of 2-amino-3-hydroxymethyl pyridine, which comprises the following steps: under the anhydrous and anaerobic operation, 150ml of anhydrous tetrahydrofuran is added into a 1L three-necked bottle, 50g of raw material 2-aminopyridine-3-formic acid is added under stirring, 209 g of red aluminum of 70% toluene solution is dropwise added under the condition that the temperature is controlled below 10 ℃ in an ice salt bath, the ice salt bath is removed after the dropwise addition is finished, the temperature is raised to room temperature, the reaction is stirred for 16 hours, saturated ammonium chloride is dropwise added after the reaction is finished, the reaction is quenched and filtered, a filter cake is washed by the tetrahydrofuran, mother liquor is combined and dried by magnesium sulfate, the magnesium sulfate is filtered and removed, and the product is dried by spinning to obtain 38.2 g of product with the yield of 85%. The preparation method of the drug intermediate 2-amino-3-hydroxymethylpyridine has the advantages of reasonable design of the whole process flow, mild conditions, simple and convenient operation, easily obtained raw materials and high generation efficiency, and is very suitable for large-scale industrial production.)

1. A preparation method of 2-amino-3-hydroxymethyl pyridine is characterized by comprising the following steps: the method comprises the following steps: under the anhydrous and anaerobic operation, 150ml of anhydrous tetrahydrofuran is added into a 1L three-necked bottle, 50g of raw material 2-aminopyridine-3-formic acid is added under stirring, 209 g of red aluminum of 70% toluene solution is dropwise added under the condition that the temperature is controlled below 10 ℃ in an ice salt bath, the ice salt bath is removed after the dropwise addition is finished, the temperature is raised to room temperature, the reaction is stirred for 16 hours, saturated ammonium chloride is dropwise added after the reaction is finished, the reaction is quenched and filtered, a filter cake is washed by the tetrahydrofuran, mother liquor is combined and dried by magnesium sulfate, the magnesium sulfate is filtered and removed, and the product is dried by spinning to obtain 38.2 g of product with the yield of 85%.

2. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: 150ml of anhydrous tetrahydrofuran is added into the 1L three-necked bottle, 50g of raw material 2-aminopyridine-3-formic acid is added under stirring, and a glass rod is used for drainage during stirring and the raw material is stirred in the same direction.

3. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: 209 g of red aluminum of 70% toluene solution is dropwise added when the temperature of the ice salt bath is controlled to be 7 ℃, and the ice salt bath is removed after the dropwise addition.

4. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: and (3) dropwise adding 209 g of red aluminum and 2 g of ethanol in 70% toluene solution at the temperature of below 10 ℃ in the ice salt bath, withdrawing the ice salt bath after dropwise adding, heating to room temperature, and stirring for reacting for 16 hours.

5. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: upon quenching by dropwise addition of the saturated ammonium chloride and filtration, the filter cake was washed with tetrahydrofuran, the mother liquors were combined and dried over magnesium sulfate, the magnesium sulfate was removed by filtration and dried on a rotary to give 38.2 g of product in 85% yield.

Technical Field

The invention relates to the technical field of intermediate synthesis, and particularly relates to a preparation method of 2-amino-3-hydroxymethylpyridine.

Background

2-amino-3-hydroxymethylpyridine is widely used as a medical intermediate in the synthesis of medicines. The medicine AFN-1252 taking 2-amino-3-hydroxymethylpyridine as an important fragment is a FabI efficient inhibitor, can inhibit staphylococcus aureus, and is a novel antibiotic medicine. At the same time he is an important organic intermediate of the antidepressant mirtazapine. Therefore, the development of a simple, convenient, efficient and safe synthesis process for synthesizing the 2-amino-3-hydroxymethylpyridine has important significance.

The product is obtained by using 2-amino-pyridine-3-formic acid or formic ester as a raw material and reducing the raw material by using lithium aluminum hydride on the conventional route (WO 2011156811, WO 2002034745). Or 2-aminopyridine-3-ethyl formate is taken as a raw material, sodium borohydride or potassium borohydride is used for reduction to obtain a product, the 2-aminopyridine-3-formic acid is taken as a raw material, one-step esterification reaction is needed, and the yield is not high.

Disclosure of Invention

In view of the problems mentioned in the background, it is an object of the present invention to provide a process for preparing 2-amino-3-hydroxymethylpyridine, which solves the problems mentioned in the background.

The technical purpose of the invention is realized by the following technical scheme:

a preparation method of 2-amino-3-hydroxymethyl pyridine comprises the following steps: under the anhydrous and anaerobic operation, 150ml of anhydrous tetrahydrofuran is added into a 1L three-necked bottle, 50g of raw material 2-aminopyridine-3-formic acid is added under stirring, 209 g of red aluminum of 70% toluene solution is dropwise added under the condition that the temperature is controlled below 10 ℃ in an ice salt bath, the ice salt bath is removed after the dropwise addition is finished, the temperature is raised to room temperature, the reaction is stirred for 16 hours, saturated ammonium chloride is dropwise added after the reaction is finished, the reaction is quenched and filtered, a filter cake is washed by the tetrahydrofuran, mother liquor is combined and dried by magnesium sulfate, the magnesium sulfate is filtered and removed, and the product is dried by spinning to obtain 38.2 g of product with the yield of 85%.

Preferably, 150ml of anhydrous tetrahydrofuran is added into the 1L three-necked flask, 50g of the raw material 2-aminopyridine-3-formic acid is added under stirring, and a glass rod is used for drainage while stirring and the raw material is stirred in the same direction.

Preferably, 209 g of red aluminum in 70% toluene solution is added dropwise when the temperature of the ice salt bath is controlled to be 7 ℃, and the ice salt bath is removed after the addition is finished.

Preferably, 209 g of red aluminum and 2 g of ethanol in 70% toluene solution are dropwise added in the ice salt bath at the temperature controlled below 10 ℃, the ice salt bath is removed after the dropwise addition, and the mixture is heated to room temperature and stirred for reaction for 16 hours.

Preferably, upon quenching with the dropwise addition of the saturated ammonium chloride and filtration, the filter cake is washed with tetrahydrofuran, the mother liquors are combined and dried over magnesium sulfate, the magnesium sulfate is removed by filtration and dried by spin drying to give 38.2 g of product in 85% yield.

In summary, the invention mainly has the following beneficial effects:

the preparation method of the drug intermediate 2-amino-3-hydroxymethylpyridine has the advantages of reasonable design of the whole process flow, mild conditions, simple and convenient operation, easily obtained raw materials and high generation efficiency, and is very suitable for large-scale industrial production; the 2-aminopyridine-3-formic acid is used as a raw material and is subjected to a one-step red aluminum reaction to obtain a 2-amino-3-hydroxymethylpyridine product, so that lithium aluminum hydride is not used as a reducing agent, and the industrial scale-up production is facilitated.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

A preparation method of 2-amino-3-hydroxymethyl pyridine comprises the following steps: under the anhydrous and anaerobic operation, 150ml of anhydrous tetrahydrofuran is added into a 1L three-necked bottle, 50g of raw material 2-aminopyridine-3-formic acid is added under stirring, 209 g of red aluminum of 70% toluene solution is dropwise added under the condition that the temperature is controlled below 10 ℃ in an ice salt bath, the ice salt bath is removed after the dropwise addition is finished, the temperature is raised to room temperature, the reaction is stirred for 16 hours, saturated ammonium chloride is dropwise added after the reaction is finished, the reaction is quenched and filtered, a filter cake is washed by the tetrahydrofuran, mother liquor is combined and dried by magnesium sulfate, the magnesium sulfate is filtered and removed, and the product is dried by spinning to obtain 38.2 g of product with the yield of 85%.

Wherein, 150ml of anhydrous tetrahydrofuran is added into the 1L three-necked flask, 50g of raw material 2-aminopyridine-3-formic acid is added under stirring, and a glass rod is used for drainage during stirring and the raw material is stirred in the same direction.

209 g of red aluminum of 70% toluene solution is dropwise added when the temperature of the ice salt bath is controlled to be 7 ℃, and the ice salt bath is removed after the dropwise addition.

209 g of red aluminum and 2 g of ethanol in 70% toluene solution are dropwise added in the ice salt bath at the temperature controlled below 10 ℃, the ice salt bath is removed after the dropwise addition, and the mixture is heated to room temperature and stirred for reaction for 16 hours.

Wherein, while the saturated ammonium chloride is added dropwise to quench and filter, the filter cake is washed with tetrahydrofuran, the mother liquors are combined and dried over magnesium sulfate, the magnesium sulfate is removed by filtration and dried by spinning to obtain 38.2 g of product with 85% yield.

The preparation method of the drug intermediate 2-amino-3-hydroxymethylpyridine has the advantages of reasonable design of the whole process flow, mild conditions, simple and convenient operation, easily available raw materials and high generation efficiency, and is very suitable for large-scale industrial production; the 2-aminopyridine-3-formic acid is used as a raw material and is subjected to a one-step red aluminum reaction to obtain a 2-amino-3-hydroxymethylpyridine product, so that lithium aluminum hydride is not used as a reducing agent, and the industrial scale-up production is facilitated.

Example 2

A preparation method of 2-amino-3-hydroxymethyl pyridine comprises the following steps: under the operation of anhydrous and oxygen-free, 150ml of anhydrous tetrahydrofuran is added into a 1L three-necked bottle, 50g of raw material 2-aminopyridine-3-formic acid is added under stirring, 209 g of red aluminum of 70% toluene solution is dropwise added under the condition that the temperature is controlled below 10 ℃ in an ice salt bath, the ice salt bath is removed after the dropwise addition is finished, the temperature is raised to room temperature, the reaction is stirred and reacted for 14 hours, saturated ammonium chloride is dropwise added after the reaction is finished, the reaction solution is quenched and filtered, a filter cake is washed by the tetrahydrofuran, mother liquor is combined and dried by magnesium sulfate, the magnesium sulfate is filtered and removed, the product is dried by spinning to obtain 38.2 g of product, and the yield is 85%.

Wherein, 150ml of anhydrous tetrahydrofuran is added into the 1L three-necked flask, 50g of raw material 2-aminopyridine-3-formic acid is added under stirring, and a glass rod is used for drainage during stirring and the raw material is stirred in the same direction.

209 g of red aluminum of 70% toluene solution is dropwise added when the temperature of the ice salt bath is controlled to be 9 ℃, and the ice salt bath is removed after the dropwise addition.

209 g of red aluminum of 70% toluene solution is dropwise added in the ice salt bath at the temperature controlled below 8 ℃, the ice salt bath is removed after the dropwise addition, and the mixture is heated to room temperature and stirred for reaction for 16 hours.

Wherein, while the saturated ammonium chloride is added dropwise to quench and filter, the filter cake is washed with tetrahydrofuran, the mother liquors are combined and dried over magnesium sulfate, the magnesium sulfate is removed by filtration and dried by spinning to obtain 38.2 g of product with 85% yield.

The preparation method of the drug intermediate 2-amino-3-hydroxymethylpyridine has the advantages of reasonable design of the whole process flow, mild conditions, simple and convenient operation, easily available raw materials and high generation efficiency, and is very suitable for large-scale industrial production; the 2-aminopyridine-3-formic acid is used as a raw material and is subjected to a one-step red aluminum reaction to obtain a 2-amino-3-hydroxymethylpyridine product, so that lithium aluminum hydride is not used as a reducing agent, and the industrial scale-up production is facilitated.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.