CN114262293B - Preparation method of 2-amino-3-bromopyridine - Google Patents
Preparation method of 2-amino-3-bromopyridine Download PDFInfo
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Abstract
The application relates to a preparation method of 2-amino-3-bromopyridine, which is environment-friendly, low in production cost and high in product purity, wherein a mass-produced 2-amino-3-nitropyridine is taken as a starting material, an amino protecting group is introduced to protect the amino of the 2-amino-3-nitropyridine, then the nitro is reduced into amino, the amino obtained by reduction is replaced by bromine atoms, and finally the amino protecting group is removed to obtain the 2-amino-3-bromopyridine. In each reaction step for synthesizing the 2-amino-3-bromopyridine, the raw materials are common environment-friendly chemical reagents for mass production, the reaction conditions are mild, and the production cost is low. In addition, the amino group of the 2-amino-3-nitropyridine is protected and deprotected, so that the purity of the product is improved.
Description
Technical Field
The application relates to the technical field of medicine and organic synthesis, in particular to a preparation method of 2-amino-3-bromopyridine.
Background
2-amino-3-bromopyridine is an important bromo-aminopyridine compound, is an intermediate for preparing pesticides, medicines and animal feeds, and can be used for synthesizing plant growth regulators and preparing medicines for protecting neurons, easing pain, resisting drug dependence, resisting parkinsonism and the like.
The Chinese patent application No. 201710133812.7 discloses a method for synthesizing 2-amino-3-bromopyridine, which comprises the following steps: (1) Dissolving 2-aminopyridine in an organic solvent, stirring at a temperature below 0 ℃ and dropwise adding half of liquid bromine, heating to 10-20 ℃, dropwise adding acetic acid, cooling to a temperature below 0 ℃, dropwise adding the other half of liquid bromine, heating and reacting for a period of time to obtain a mixed solution; (2) Adding sodium hydroxide solution to adjust pH value to neutral, mixing the mixed solution with water, extracting for three times, and concentrating under reduced pressure to obtain 2-amino-3-bromopyridine.
Application number 201510489585.2 discloses a process for the synthesis of 2-amino-3-bromopyridine which comprises starting from 3-bromo-iodopyridin-2-amine and then deiodinating at the 5-position to give 2-amino-3-bromopyridine, the deiodination step being specifically a hydrodereduction of the 3-bromo-iodopyridin-2-amine or reacting the 3-bromo-iodopyridin-2-amine with a formative reagent and then with an acidic hydrogen provider such as ammonium chloride.
There is also a disclosure of the preparation of 2-amino-3-bromopyridine by Huffman degradation starting from 3-bromo-2-carboxamide pyridine.
The disclosed synthesis methods require the use of hazardous chemical reagents such as liquid bromine, and some are prone to the formation of more by-products. For this reason, there is a continuous need in the art to develop a process for preparing 2-amino-3-bromopyridine that is environmentally friendly, inexpensive to produce, and has few by-products.
Disclosure of Invention
The application aims to provide a preparation method of 2-amino-3-bromopyridine, which is environment-friendly, low in production cost and high in product purity, so that the technical problems are solved. Specifically, the application takes mass-produced 2-amino-3-nitropyridine as a starting material, introduces an amino protecting group to protect the amino of the 2-amino-3-nitropyridine, reduces the nitro group into amino, replaces the amino obtained by reduction with bromine atoms, and finally removes the amino protecting group to obtain the 2-amino-3-bromopyridine.
In order to solve the technical problems, the application provides the following technical scheme.
In a first aspect, the present application provides a process for the preparation of 2-amino-3-bromopyridine, said process comprising the steps of:
s1: reacting 2-amino-3-nitropyridine with an amino protecting reagent to obtain a first intermediate comprising an amino protecting group, the pyridine ring of the first intermediate comprising a nitro group;
s2: carrying out hydrogenation reduction reaction on the first intermediate, and reducing nitro on the pyridine ring of the first intermediate into amino to obtain a second intermediate, wherein the pyridine ring of the second intermediate comprises amino;
s3: reacting the second intermediate with a brominating reagent to enable amino groups on pyridine rings of the second intermediate to be replaced by bromine atoms, so as to obtain a third intermediate;
and, S4: and (3) carrying out deprotection reaction on the third intermediate, and removing the amino protecting group to obtain the 2-amino-3-bromopyridine.
In one embodiment of the first aspect, the first intermediate has a structure represented by the following general formula (I):
the second intermediate has a structure represented by the following general formula (II):
the third intermediate has a structure represented by the following general formula (III):
wherein R represents an amino protecting group.
In one embodiment of the first aspect, R represents one or more of pivaloyl, acetyl, benzoyl, benzenesulfonyl, p-toluenesulfonyl and p-nitrobenzenesulfonyl.
In one embodiment of the first aspect, in step S1, reacting the 2-amino-3-nitropyridine with the amino-protecting reagent comprises reacting the 2-amino-3-nitropyridine with pivaloyl chloride in a first organic solvent at a reaction temperature of 0-10 ℃ and in the presence of an amine catalyst for a first predetermined period of time.
In one embodiment of the first aspect, the amine catalyst is triethylamine and the molar ratio of triethylamine to 2-amino-3-nitropyridine is 3-5:1.
In one embodiment of the first aspect, in step S2, subjecting the first intermediate to a hydrogenation reduction reaction comprises reacting the first intermediate with hydrogen in a second organic solvent under pressurized conditions at a reaction temperature of 45-50 ℃ and in the presence of a palladium catalyst for a second predetermined period of time.
In one embodiment of the first aspect, in step S3, reacting the second intermediate with a brominating reagent comprises reacting the second intermediate with hydrobromic acid in a nitrite solution in the presence of cuprous bromide at a reaction temperature of 0-5 ℃ for a third predetermined period of time.
In one embodiment of the first aspect, the brominating reagent is hydrobromic acid;
the nitrite solution is sodium nitrite solution or potassium nitrite solution.
In one embodiment of the first aspect, in step S4, the deprotecting the third intermediate comprises reacting a solution of the third intermediate in a fourth organic solvent with an alkali metal hydroxide solution at a reaction temperature of 75-80 ℃ for a fourth predetermined period of time.
In one embodiment of the first aspect, the fourth organic solvent is methanol.
Compared with the prior art, the application has the beneficial effects that: in each reaction step for synthesizing the 2-amino-3-bromopyridine, the raw materials are common environment-friendly chemical reagents for mass production, the reaction conditions are mild, and the production cost is low. In addition, the amino group of the 2-amino-3-nitropyridine is protected and deprotected, so that the purity of the product is improved.
Drawings
FIG. 1 shows a synthetic route for 2-amino-3-bromopyridine in accordance with one embodiment of the application.
FIG. 2 shows the synthetic route for 2-amino-3-bromopyridine of example 1 according to the application.
Detailed Description
As described above, the existing synthesis methods of 2-amino-3-bromopyridine have more or less defects, some require dangerous chemical agents such as liquid bromine, some have more side reactions, and the product purity is not high enough, or the cost is high, so that the industrial production value is limited.
Therefore, the application provides a preparation method of high-purity 2-amino-3-bromopyridine, which is environment-friendly and low in production cost. In one embodiment, the preparation method described herein uses a mass-produced 2-amino-3-nitropyridine as a starting material, introduces an amino protecting group to protect the 2-amino-3-nitropyridine amino group, then reduces the nitro group to an amino group, replaces the reduced amino group with a bromine atom, and finally removes the amino protecting group to obtain the 2-amino-3-bromopyridine.
In one embodiment, the present application provides a process for preparing 2-amino-3-bromopyridine. Referring to fig. 1, the method may include the steps of:
s1: reacting 2-amino-3-nitropyridine with an amino protecting reagent to obtain a first intermediate comprising an amino protecting group, the pyridine ring of the first intermediate comprising a nitro group;
s2: carrying out hydrogenation reduction reaction on the first intermediate, and reducing nitro on the pyridine ring of the first intermediate into amino to obtain a second intermediate, wherein the pyridine ring of the second intermediate comprises amino;
s3: reacting the second intermediate with a brominating reagent to enable amino groups on pyridine rings of the second intermediate to be replaced by bromine atoms, so as to obtain a third intermediate;
and, S4: and (3) carrying out deprotection reaction on the third intermediate, and removing the amino protecting group to obtain the 2-amino-3-bromopyridine.
In the synthetic route shown in fig. 1, the first intermediate has a structure represented by the following general formula (I):
the second intermediate has a structure represented by the following general formula (II):
the third intermediate has a structure represented by the following general formula (III):
wherein R represents an amino protecting group.
In one embodiment, R may represent one or more of pivaloyl, acetyl, benzoyl, benzenesulfonyl, p-toluenesulfonyl, and p-nitrobenzenesulfonyl. Those skilled in the art will appreciate that R may also be other suitable amino protecting groups.
Next, the method for producing 2-amino-3-bromopyridine described herein will be described in detail with pivaloyl as an amino protecting group.
In step S1, 2-amino-3-nitropyridine is reacted with pivaloyl chloride in a first organic solvent at a reaction temperature of 0-10 ℃ and in the presence of an amine catalyst for a first predetermined period of time. In this embodiment, the amine catalyst may be triethylamine and the molar ratio of triethylamine to 2-amino-3-nitropyridine is 3-5:1. For example, the molar ratio of amine catalyst to 2-amino-3-nitropyridine may be 3:1, 3.5:1, 4.5:1, or 5:1. In this step, the first organic solvent may preferably be a nonpolar organic solvent, such as methylene chloride. The first predetermined period of time may be 0.5-1 hour.
The chemical reaction of step S1 causes one hydrogen atom on the amino group of 2-amino-3-nitropyridine to be substituted with an amino protecting group, thereby protecting the amino group on the pyridine ring from being reduced in the subsequent nitroreduction reaction and from participating in the reaction when the amino group is substituted with a bromine atom.
In step S2, the first intermediate may be reacted with hydrogen in a second organic solvent under pressurized conditions at a reaction temperature of 45-50 ℃ and in the presence of a palladium catalyst for a second predetermined period of time. The second organic solvent may be an alcohol solvent, for example, methanol. The second predetermined period of time may be 10-15 hours. The pressure at the time of the reaction may preferably be 1.0MPa.
The chemical reaction of step S2 is a common hydrogenation reduction reaction, and is mainly used for reducing the nitro group on the pyridine ring of the first intermediate to amino group. The amount of catalyst used and other reaction parameters can be adjusted as is practical by the person skilled in the art.
In step S3, the second intermediate may be reacted with hydrobromic acid in a nitrite solution at a reaction temperature of 0-5 ℃ and in the presence of cuprous bromide for a third predetermined period of time. In one embodiment, the brominating agent is hydrobromic acid. In one embodiment, the nitrite solution is a sodium nitrite solution or a potassium nitrite solution. The third predetermined period of time may be 0.5-1 hour.
The chemical reaction of step S3 is used to replace the amino group on the pyridine ring of the second intermediate with a bromine atom.
In step S4, a solution of the third intermediate in a fourth organic solvent may be reacted with an alkali metal hydroxide solution at a reaction temperature of 75-80 ℃ for a fourth predetermined period of time. The fourth organic solvent may be methanol. The fourth predetermined period of time may be 3-5 hours, for example, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, or a range and subrange between any two of the values thereof.
The step S4 chemical reaction is deprotection reaction for removing amino protecting group, and hydrogen atom is used for replacing amino protecting group of amino on pyridine ring of third intermediate, so as to obtain final product 2-amino-3-bromopyridine.
Examples
The present application will be further described and illustrated with reference to examples. Unless otherwise indicated, all chemical raw materials used can be purchased from the market. Those skilled in the art will appreciate that the following examples are illustrative only.
Example 1
This example relates to the synthesis of 2-amino-3-bromopyridine using pivaloyl as an amino protecting group. The synthetic route for this example is shown in FIG. 2, and specific experimental procedures are described below.
The first step:
to the reaction flask were successively added 2-amino-3-nitropyridine (200.00 g,1.44mol,1.00 eq), methylene chloride (1.60L, 8.00V), triethylamine (437.00 g,4.31mol,3.00 eq). The temperature of the reaction flask is reduced to 0-5 ℃ by ice bath, and pivaloyl chloride (520.00 g,4.31mol,3.00 eq) is slowly added dropwise under the temperature of 10 ℃. After the dripping is finished, the temperature is controlled to be 0-10 ℃ and stirring is carried out reverselyShould be 1h. Then the ice bath is removed, naturally warmed to room temperature and stirred for reaction for 15h. The reaction was monitored by sample TLC, after the starting material was complete, 0.5L was added to quench the reaction, and stirring was carried out for 15min. The mixture was allowed to stand for separation, the organic phase was collected, the aqueous phase was extracted with 300mL of dichloromethane, and all the organic phases were combined. The organic phase was washed successively with 500 Ml. Times.3 times of saturated aqueous sodium bicarbonate solution and 500 Ml. Times.2 times of saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 40-45℃to remove the solvent, yielding 272.8g of crude N- (3-nitropyridin-2-yl) pivalamide in 85% yield. 2.8g of crude product is taken for column chromatography, and 2.5g of pure product is obtained. Sampling and feeding 1 H NMR, nuclear magnetic resonance spectroscopy data were as follows: 1 H NMR(400MHz,CDCl 3 )δ10.07(s,1H),8.73(dd,J＝4.6,1.6Hz,1H),8.48(dd,J＝8.3,1.7Hz,1H),7.23(dd,J＝8.3,4.7Hz,1H),1.38(s,9H)。
and a second step of:
n- (3-nitropyridin-2-yl) pivalamide (270.00 g,1.21mol,1.00 eq), methanol (1.08L, 4.00V), 10% Pd/C (27.0 g,10% wt) were added sequentially to the autoclave. And (3) introducing high-pressure nitrogen to replace the system for three times, and then introducing high-pressure hydrogen to replace the system for three times, so that the pressure of hydrogen in the kettle is pressurized to 1.0Mpa. Then, the reaction kettle is heated to 45-50 ℃ and stirred for reaction for 10-15h. Sampling TLC to monitor the reaction, after the raw materials are reacted completely, directly filtering out the reaction liquid by pumping to remove the solid insoluble catalyst, collecting the filtrate, and concentrating the filtrate under reduced pressure at 40-45 ℃ to remove the solvent to obtain 210.5g of crude N- (3-aminopyridine-2-yl) pivalamide product with the yield of 90%. 2.5g of crude product is taken for column chromatography, and 2.3g of pure product is obtained. Sampling and feeding 1 H NMR, nuclear magnetic resonance spectroscopy data were as follows: 1 HNMR(400MHz,CDCl 3 )δ8.22(s,1H),7.83(dd,J＝4.6,1.3Hz,1H),7.10(dd,J＝7.9,1.3Hz,1H),7.02(dd,J＝7.9,4.6Hz,1H),4.34(s,2H),1.36(s,9H)。
and a third step of:
n- (3-aminopyridin-2-yl) pivalamide (200.00 g,1.03mol,1.00 eq), 48% hydrobromic acid aqueous solution (400 mL, 2.00V) and brominated polyketone (155.14 g,1.08mol,1.05 eq) were added in this order to the reaction flask, and the mixture was stirred and dissolved and cooled to 0-5 ℃. An aqueous sodium nitrite solution (85.28 g,1.24mol,1.20eq,400mL of water) was slowly added dropwise to the flask at a temperature below 5 ℃. After the dripping is completedStirring and reacting for 0.5-1.0h at the temperature of 0-5 ℃. Sampling TLC to monitor the reaction, pouring the reaction solution into 1.00L of ice water directly after the reaction is completed, stirring for 15min to quench the reaction, extracting the reaction solution with dichloromethane 500mL multiplied by 3 times, and collecting an organic phase. The organic phase was washed successively with 500 mL. Times.3 times of saturated aqueous sodium bicarbonate solution and 500 mL. Times.2 times of saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 40-45℃to remove the solvent, yielding 227.8g of crude N- (3-bromopyridin-2-yl) pivalamide in 86% yield. 3.8g of crude product is taken for column chromatography, and 3.5g of pure product is obtained. Sampling and feeding 1 H NMR, nuclear magnetic resonance spectroscopy data were as follows: 1 H NMR(400MHz,CDCl 3 )δ8.42(s,1H),8.06(s,1H),7.86(dd,J＝7.9,1.2Hz,1H),6.97(s,1H),1.35(s,9H)。
fourth step:
n- (3-bromopyridin-2-yl) pivalamide (220.00 g,0.86mol,1.00 eq) and methanol (440 mL, 2.00V) were sequentially added to the reaction flask, stirred until clear, and aqueous potassium hydroxide (72.24 g,1.29mol,1.50eq,350mL of water) was added. The temperature of the reaction flask is raised to 75-80 ℃ and the reaction is stirred for 4 hours. Sampling TLC to monitor the reaction, cooling the reaction solution to room temperature after the reaction of the raw materials is completed, extracting the reaction solution with dichloromethane 500mL multiplied by 3 times, collecting an organic phase, and washing the organic phase with saturated sodium chloride aqueous solution 500mL multiplied by 2 times. The organic phase is dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 40-45 ℃ to remove the solvent, thus obtaining crude product. Recrystallizing the crude product by using an ethyl acetate/petroleum ether system, and vacuum drying at 45-50 ℃ to obtain 128.7g of refined 2-amino-3 bromopyridine with the yield of 87%. Sampling and feeding 1 H NMR, nuclear magnetic resonance spectroscopy data were as follows: 1 H NMR(400MHz,CDCl3)δ8.06-7.97(m,1H),7.65(dd,J＝7.7,1.3Hz,1H),6.54(ddd,J＝7.7,4.9,1.8Hz,1H),4.98(s,2H)。
the embodiments are described above in order to facilitate the understanding and application of the present application by those of ordinary skill in the art. It will be apparent to those skilled in the art that various modifications can be made to these embodiments and that the general principles described herein may be applied to other embodiments without the use of inventive faculty. Therefore, the present application is not limited to the embodiments herein, and those skilled in the art, based on the present disclosure, may make improvements and modifications within the scope and spirit of the present application without departing from the scope and spirit of the present application.
Claims (8)
1. A process for the preparation of 2-amino-3-bromopyridine, said process comprising the steps of:
s1: reacting 2-amino-3-nitropyridine with an amino protecting reagent to obtain a first intermediate comprising an amino protecting group, the pyridine ring of the first intermediate comprising a nitro group;
s2: carrying out hydrogenation reduction reaction on the first intermediate, and reducing nitro on the pyridine ring of the first intermediate into amino to obtain a second intermediate, wherein the pyridine ring of the second intermediate comprises amino;
s3: reacting the second intermediate with a brominating reagent to enable amino groups on pyridine rings of the second intermediate to be replaced by bromine atoms, so as to obtain a third intermediate;
and, S4: deprotection reaction is carried out on the third intermediate, and the amino protecting group is removed to obtain 2-amino-3-bromopyridine;
the first intermediate has a structure represented by the following general formula (I):
the second intermediate has a structure represented by the following general formula (II):
the third intermediate has a structure represented by the following general formula (III):
wherein R represents a pivaloyl group;
the amino protecting agent is pivaloyl chloride.
2. The method of claim 1, wherein step S1 comprises reacting 2-amino-3-nitropyridine with pivaloyl chloride in a first organic solvent at a reaction temperature of 0-10 ℃ and in the presence of an amine catalyst for a first predetermined period of time.
3. The process according to claim 2, wherein the amine catalyst is triethylamine and the molar ratio of triethylamine to 2-amino-3-nitropyridine is 3-5:1.
4. The method of any one of claims 1-3, wherein in step S2, the subjecting the first intermediate to the hydrogenation reduction reaction comprises reacting the first intermediate with hydrogen in a second organic solvent under pressurized conditions at a reaction temperature of 45-50 ℃ and in the presence of a palladium catalyst for a second predetermined period of time.
5. A process according to any one of claims 1 to 3, wherein step S3 comprises reacting the second intermediate with hydrobromic acid in a nitrite solution at a reaction temperature of 0 to 5 ℃ and in the presence of cuprous bromide for a third predetermined period of time.
6. The method of claim 5, wherein the nitrite solution is a sodium nitrite solution or a potassium nitrite solution.
7. A method according to any one of claims 1 to 3, wherein in step S4, the deprotection reaction of the third intermediate comprises reacting a solution of the third intermediate in a fourth organic solvent with an alkali metal hydroxide solution at a reaction temperature of 75-80 ℃ for a fourth predetermined period of time.
8. The method of claim 7, wherein the fourth organic solvent is methanol.
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Effective date of registration: 20230821 Address after: Room 403-72, No. 1831 Dongjing Road, Pudong New Area, Shanghai, August 2012 Applicant after: Shanghai Youji Pharmaceutical Chemical Co.,Ltd. Address before: 246005 Room 501, building 3, Phoenix Science Park, No. 8, Huangguan Road, Daguan District, Anqing City, Anhui Province Applicant before: Anhui Youji Pharmaceutical Technology Co.,Ltd. |
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