阅读说明：本技术 一种2-氨基-5-碘吡啶的制备方法 (Preparation method of 2-amino-5-iodopyridine ) 是由 梅姜平 张永飞 陆金华 于 2021-07-23 设计创作，主要内容包括：一种2-氨基-5-碘吡啶的制备方法,包括、将700-800g的2-氨基-5-溴吡啶、80-85g碘化亚铜、1300-1500g碘化钾、80-90gN,N-二甲基乙二胺和3600-3800ml的DMF投入10L反应瓶中,搅拌,真空置换氮气,升温,T=100℃保温反应约5h,HPLC检测原料<5%。降温至T<40℃,加入自来水搅拌,过滤；该合成方法具有反应高效、快速,条件温和,底物简单易得、适用性较广,反应时间短、收率高等优点,路线设计合理,实验操作简单,易于实现,且得到的产物收率较高,而且不产生有机废液,反应过程安全无污染。(A preparation method of 2-amino-5-iodopyridine comprises the steps of putting 800g of 700-amino-5-bromopyridine, 80-85g of cuprous iodide, 1300-1500g of potassium iodide, 80-90g of N, N-dimethylethylenediamine and 3600-3800ml of DMF into a 10L reaction bottle, stirring, replacing nitrogen in vacuum, heating, keeping the temperature at T =100 ℃ for reaction for about 5h, and detecting the raw material by HPLC (high performance liquid chromatography) < 5%. Cooling to T <40 deg.C, adding tap water, stirring, and filtering; the synthesis method has the advantages of high-efficiency and rapid reaction, mild conditions, simple and easily-obtained substrate, wide applicability, short reaction time, high yield and the like, the route design is reasonable, the experimental operation is simple, the implementation is easy, the yield of the obtained product is high, no organic waste liquid is generated, and the reaction process is safe and pollution-free.)

1. A preparation method of 2-amino-5-iodopyridine is characterized by comprising the following steps:

step 1, putting 800g of 700-amino-5-bromopyridine, 80-85g of cuprous iodide, 1300-1500g of potassium iodide, 80-90g of N, N-dimethylethylenediamine and 3800ml of DMF in a 10L reaction bottle, stirring, vacuum-replacing nitrogen, heating, keeping the temperature at T =100 ℃ for about 5h, detecting the raw material by HPLC (high performance liquid chromatography), cooling to T <40 ℃, adding tap water, stirring and filtering;

step 2, washing the filter cake with 5L multiplied by 3 tap water, and drying by blowing air at 60 ℃ to obtain 600-680g of crude product 1; standing the filtrate for layering, extracting the water layer with 2L × 2 toluene, mixing the organic phases, washing with 3L water, and concentrating under reduced pressure at 60 deg.C to dry to obtain 250g of crude product 2;

and 3, dissolving the crude product 1 and the crude product 2 in 6L of methanol, adding 70-80g of activated carbon, stirring at room temperature, filtering, washing filter residues with 1L of hot methanol, combining the filtrates, concentrating under reduced pressure to dryness, and drying by blowing at 60 ℃ to obtain 750g of product 700-.

2. The process for preparing 2-amino-5-iodopyridine according to claim 1, comprising the steps of:

step 1, putting 750g of 2-amino-5-bromopyridine, 82.6g of cuprous iodide, 1440g of potassium iodide, 83g of N, N-dimethylethylenediamine and 3750ml of DMF (dimethyl formamide) into a 10L reaction bottle, stirring, performing vacuum nitrogen replacement, heating, keeping the temperature at T =100 ℃ for reaction for about 5 hours, detecting by HPLC (high performance liquid chromatography), reducing the temperature to T <40 ℃, adding tap water, stirring and filtering;

step 2, washing the filter cake with 5L multiplied by 3 tap water, and drying by blowing air at 60 ℃ to obtain 645g of crude product; standing the filtrate for layering, extracting the water layer with 2L × 2 toluene, mixing the organic phases, washing with 3L water, and concentrating under reduced pressure at 60 deg.C to dry to obtain 250g crude product;

and 3, dissolving 645g and 250g of crude product in 6L of methanol, adding 75g of activated carbon, stirring at room temperature, filtering, washing filter residue with 1L of hot methanol, combining the filtrates, concentrating under reduced pressure to dryness, and drying by blowing at 60 ℃ to obtain 720g of product.

3. The method for preparing 2-amino-5-iodopyridine according to claim 2, wherein 20L of tap water is added in step 1 and stirred for 0.5 h.

4. The process for preparing 2-amino-5-iodopyridine according to claim 2, wherein the stirring in step 3 is performed at room temperature for 1 hour.

Technical Field

The invention relates to the technical field of synthesis of medical intermediates, in particular to a preparation method of 2-amino-5-iodopyridine.

Background

The 2-amino-5-iodopyridine is also named as 2-amino-5-iodopyridine, 5-iodo-2-aminopyridine and CAS (CAS: 20511-12-0), is an important intermediate for organic synthesis, is mainly used for a medical intermediate, and is also used for dye production, pesticide production, perfume and other aspects.

The general process is that 2-aminopyridine reacts with iodine in a solvent to synthesize the product, the yield is about 83 percent, and organic waste liquid is generated in the preparation process, which brings pressure to the environment. Another common synthetic route is to use 2-amino-5-bromopyridine as a raw material, which is expensive and not easily available, and organic waste liquid is still generated during synthesis.

Disclosure of Invention

Technical problem to be solved

Aiming at the defects of the prior art, the invention provides a preparation method of 2-amino-5-iodopyridine

(II) technical scheme

In order to achieve the purpose, the invention provides the following technical scheme: a preparation method of 2-amino-5-iodopyridine comprises the following steps:

step 1, putting 800g of 700-amino-5-bromopyridine, 80-85g of cuprous iodide, 1300-1500g of potassium iodide, 80-90g of N, N-dimethylethylenediamine and 3600-3800ml of DMF into a 10L reaction bottle, stirring, replacing nitrogen in vacuum, heating, keeping the temperature at T =100 ℃ for reaction for about 5h, and detecting the raw material by HPLC (high performance liquid chromatography) < 5%. Cooling to T <40 deg.C, adding tap water, stirring, and filtering;

step 2, washing the filter cake with 5L multiplied by 3 tap water, and drying by blowing air at 60 ℃ to obtain 600-680g of crude product 1; standing the filtrate for layering, extracting the water layer with 2L × 2 toluene, mixing the organic phases, washing with 3L water, and concentrating under reduced pressure at 60 deg.C to dry to obtain 250g of crude product 2;

and 3, dissolving the crude product 1 and the crude product 2 in 6L of methanol, adding 70-80g of activated carbon, stirring at room temperature, filtering, washing filter residues with 1L of hot methanol, combining the filtrates, concentrating under reduced pressure to dryness, and drying by blowing at 60 ℃ to obtain 750g of product 700-.

The improvement of the invention comprises the following steps:

step 1, putting 750g of 2-amino-5-bromopyridine, 82.6g of cuprous iodide, 1440g of potassium iodide, 83g of N, N-dimethylethylenediamine and 3750ml of DMF into a 10L reaction bottle, stirring, replacing nitrogen in vacuum, heating, keeping the temperature at T =100 ℃ for reaction for about 5h, and detecting the raw material by HPLC (high performance liquid chromatography) to be less than 5%. Cooling to T <40 deg.C, adding tap water, stirring, and filtering;

step 2, washing the filter cake with 5L multiplied by 3 tap water, and drying by blowing air at 60 ℃ to obtain 645g of crude product; standing the filtrate for layering, extracting the water layer with 2L × 2 toluene, mixing the organic phases, washing with 3L water, and concentrating under reduced pressure at 60 deg.C to dry to obtain 250g crude product;

and 3, dissolving 645g and 250g of crude product in 6L of methanol, adding 75g of activated carbon, stirring at room temperature, filtering, washing filter residue with 1L of hot methanol, combining the filtrates, concentrating under reduced pressure to dryness, and drying by blowing at 60 ℃ to obtain 720g of product.

The invention is improved in that 20L of tap water is added in the step 1 and stirred for 0.5 h.

The invention is improved in that in the step 3, the mixture is stirred for 1 hour at room temperature.

(III) advantageous effects

Compared with the prior art, the invention provides a preparation method of 2-amino-5-iodopyridine, which has the following beneficial effects:

the new method is simple in reaction operation, and can synthesize the 2-amino-5-iodopyridine through simple steps, the synthesis method has the advantages of high reaction efficiency, high speed, mild conditions, simple and easily-obtained substrate, wide applicability, short reaction time, high yield and the like, the route design is reasonable, the experimental operation is simple and easy to realize, the yield of the obtained product is high, no organic waste liquid is generated, and the reaction process is safe and pollution-free.

Drawings

FIG. 1 is a schematic diagram of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the 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-5-iodopyridine comprises the following steps:

step 1, putting 700g of 2-amino-5-bromopyridine, 80g of cuprous iodide, 1300g of potassium iodide, 80g of N, N-dimethylethylenediamine and 3600ml of DMF into a 10L reaction bottle, stirring, replacing nitrogen in vacuum, heating, keeping the temperature at T =100 ℃ for reaction for about 5h, and detecting by HPLC that the raw material is less than 5%. Cooling to T <40 deg.C, adding tap water, stirring, and filtering;

step 2, washing the filter cake with 5L multiplied by 3 tap water, and drying by blowing air at 60 ℃ to obtain 600-680g of crude product 1; standing the filtrate for layering, extracting the water layer with 2L × 2 toluene, mixing the organic phases, washing with 3L water, and concentrating under reduced pressure at 60 deg.C to dry to obtain 250g of crude product 2;

and 3, dissolving the crude product 1 and the crude product 2 in 6L of methanol, adding 70g of activated carbon, stirring at room temperature, filtering, washing filter residues with 1L of hot methanol, combining the filtrates, concentrating under reduced pressure to dryness, and drying by blowing at 60 ℃ to obtain 750g of product 700-.

Example 2

A preparation method of 2-amino-5-iodopyridine comprises the following steps:

750g 2-amino-5-bromopyridine, 82.6g cuprous iodide, 1440g potassium iodide, 83g N, N-dimethylethylenediamine and 3750ml DMF were put into a 10L reaction flask, stirred, vacuum-substituted with nitrogen, warmed, incubated at T =100 ℃ for about 5h, and HPLC checked to find that the starting material was < 5%. Cooling to T <40 deg.C, adding tap water, stirring, and filtering;

step 2, washing the filter cake with 5L multiplied by 3 tap water, and drying by blowing air at 60 ℃ to obtain 645g of crude product; standing the filtrate for layering, extracting the water layer with 2L × 2 toluene, mixing the organic phases, washing with 3L water, and concentrating under reduced pressure at 60 deg.C to dry to obtain 250g crude product;

and 3, dissolving 645g and 250g of crude product in 6L of methanol, adding 75g of activated carbon, stirring at room temperature, filtering, washing filter residue with 1L of hot methanol, combining the filtrates, concentrating under reduced pressure to dryness, and drying by blowing at 60 ℃ to obtain 720g of product.

Example 3

A preparation method of 2-amino-5-iodopyridine comprises the following steps:

step 1, putting 800g of 2-amino-5-bromopyridine, 85g of cuprous iodide, 1500g of potassium iodide, 90g of N, N-dimethylethylenediamine and 3800ml of DMF into a 10L reaction bottle, stirring, replacing nitrogen in vacuum, heating, keeping the temperature at T =100 ℃ for reaction for about 5h, and detecting by HPLC that the raw material is less than 5%. Cooling to T <40 deg.C, adding tap water, stirring, and filtering;

step 2, washing the filter cake with 5L multiplied by 3 tap water, and drying by blowing air at 60 ℃ to obtain 600-680g of crude product 1; standing the filtrate for layering, extracting the water layer with 2L × 2 toluene, mixing the organic phases, washing with 3L water, and concentrating under reduced pressure at 60 deg.C to dry to obtain 250g of crude product 2;

and 3, dissolving the crude product 1 and the crude product 2 in 6L of methanol, adding 80g of activated carbon, stirring at room temperature, filtering, washing filter residues by using 1L of hot methanol, combining the filtrates, concentrating under reduced pressure to dryness, and drying by blowing at 60 ℃ to obtain 750g of product 700-.

The invention is improved in that 20L of tap water is added in the step 1 and stirred for 0.5 h.

The invention is improved in that in the step 3, the mixture is stirred for 1 hour at room temperature.

(HPLC conditions: MeOH: 0.1% TFA =30: 70, 220nm), preparative HPLC of the product was > 90%.

The metering in specific example 2 can be referred to the following table

Material(s)	Molecular weight	Weight (D)	Number of moles	Molar ratio of	Remarks for note
						2-amino-5-bromopyridine	173.01	750g	4.335	1.00
Potassium iodide	166.00	1440g	8.670	2.00
						Cuprous iodide	190.45	82.6g	0.434	0.10
N, N-dimethylethylenediamine	88.15	83.0g	0.941	0.22
						Methanol		7.0L			Recycle sleeve
Activated carbon		75g
						DMF		3750ml
Toluene		4L			Recycle sleeve
						2-amino-5-iodopyridines	220.01	720g	3.272

Molar yield: 75.5 percent

Weight yield: 96.0 percent

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.