JP2000355583A - Production of 2-amino-5-bromopyridine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a 2-amino-5-bromopyridine derivative under mild conditions in high yield advantageously on an industrial scale by brominating an aminopyridine derivative using a specific nitrogen-containing aromatic compound as a brominating agent. SOLUTION: A 2-aminopyridine derivative of formula I [R1 and R2 are each H, an organic sulfonyl, an alkoxycarbonyl, an acyl, a (substituted) alkyl, an aryl or an aralkyl] is brominated by using a solution containing a dibromide hydrobromide of a nitrogen-containing aromatic compound, and a nitrogen- containing aromatic compound, as a brominating agent to produce the objective compound of formula II. Examples of the nitrogen-containing aromatic compound include pyridine, lutidine, picoline, collidine, chloropyridine, quinoline and isoquinoline, and examples of the dibromide hydrobromide of a nitrogen- containing aromatic compound, include pyridine dibromide hydrobromide. The amount of the use of a brominating agent is preferably 0.5-2 mole based on 1 mole of 2-aminopyridine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 2-amino-5-
The present invention relates to a method for producing a bromopyridine derivative. The 2-amino-5-bromopyridine derivative produced according to the present invention can be used, for example, as an intermediate for the synthesis of insecticides [Journal
Of Medicinal Chemistry (Journal
of Medicinal Chemistry), vol. 21, p. 235 (1978)] and HIV
And useful as synthetic intermediates for compounds for the treatment or inhibition of infectious diseases caused by related viruses.
No. 320138].

[0002]

2. Description of the Related Art Conventionally, as a method for producing a 2-amino-5-bromopyridine derivative, for example, 2-amino-5-bromopyridine, 2-aminopyridine or its oxide (N-oxide) is reacted with bromine. [Journal of Organic Chemistry (Journal)
of Organic Chemistry), 4th
8, page 1064 (1983)], and 2-aminopyridine in which the amino group at the 2-position is protected with an acyl group is N-
Bromination with acylaminopyridinium bromide followed by deprotection of the acyl group [JP-A-5-201981
Patent Publication], a method of brominating 2-aminopyridine with tetrabutylammonium tribromide [Canadian Journal of Chemistry (Canad)
ian Journal of Chemistr
y), vol. 67, p. 2061, 1989], 2
A method of brominating aminopyridine with pyridinedibromide hydrobromide [Synthetic Communication (Synthetic Communication);
n), Vol. 23, p. 855 (1993)].

[0003]

However, the above-mentioned method requires an excess of about 2.3 mol times of bromine relative to 2-aminopyridine or its N-oxide, and the yield is 2%. 68% from aminopyridine, its N
From the oxide form, it is as low as 76%, and in addition to the 5-position of the pyridine ring, a dibromo form further brominated at the 3-position is produced in large quantities (23% when using 2-aminopyridine, N-
15% when an oxide form is used). The method requires multiple steps for protecting the amino group of 2-aminopyridine with an acyl group, followed by bromination, and then deprotecting the acyl group. According to the method, tetrabutylammonium tribromide and pyridine dibromide hydrobromide used as brominating agents have low solubility in organic solvents, so tetrabutylammonium tribromide is used as a 0.2 mol / liter chloroform solution.
In this method, pyridine dibromide hydrobromide is used at a low concentration as a 0.04 mol / liter tetrahydrofuran solution, which has a problem of low volumetric efficiency and low productivity. Therefore, the above methods (1) to (4) cannot be said to be industrially advantageous methods for producing 2-amino-5-bromopyridine derivatives. On the other hand, the solubility of a nitrogen-containing aromatic compound dibromide hydrobromide in an organic solvent is dramatically increased by adding a nitrogen-containing aromatic compound. For example, the solubility of pyridine dibromide hydrobromide in dichloromethane is 0 at room temperature. 0.01 mol / l or less, but when 1 mol of pyridine is added to 1 mol of pyridine dibromide hydrobromide, the concentration is about 1 mol / l, which is a concentration sufficient for industrial use. (See JP-A-8-31060). The publication discloses a solution containing a nitrogen-containing aromatic compound dibromide hydrobromide and a nitrogen-containing aromatic compound, wherein the concentration of the nitrogen-containing aromatic compound dibromide hydrobromide is 0.5 mol / liter or more. It is disclosed that 2-bromo-3-methylthiophene can be obtained in high yield by selectively brominating only the 2-position of 3-methylthiophene with the brominating agent. I have. However, there is no mention of a selective bromination reaction at the 5-position of the 2-aminopyridine derivative. Thus, an object of the present invention is to provide 2-amino-5
It is an object of the present invention to provide a method for industrially advantageously producing a bromopyridine derivative with good yield under mild conditions.

[0004]

According to the present invention, the above objects have been achieved by the general formula (I)

[0005]

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(Wherein R ¹ and R ² represent a hydrogen atom, an organic sulfonyl group, an alkoxycarbonyl group, an acyl group or an optionally substituted alkyl group, an aryl group or an aralkyl group). An aminopyridine derivative (hereinafter abbreviated as 2-aminopyridine (I)) is brominated to form a compound represented by the general formula (II):

[0007]

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(Wherein R ¹ and R ² are as defined above) (hereinafter referred to as 2-amino-5-bromopyridine (I)
I)), wherein a solution containing a nitrogen-containing aromatic compound dibromide hydrobromide and a nitrogen-containing aromatic compound is used as a brominating agent. Achieved.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula, the alkyl group represented by R ¹ and R ² is, for example, a methyl group, an ethyl group,
Examples thereof include an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and a tert-butyl group. These alkyl groups may have a substituent. Examples of the substituent include a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; an alkoxyl group such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group. Is mentioned.

The aryl group represented by R ¹ and R ² includes, for example, a phenyl group and a naphthyl group.
These aryl groups may have a substituent, and examples of the substituent include a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; a methyl group, an ethyl group, an n-propyl group, an isopropyl group and an n Alkyl groups such as -butyl group, isobutyl group and tert-butyl group; alkoxyl groups such as methoxy group, ethoxy group, propoxy group and butoxy group; and aryl groups such as phenyl group and paramethoxyphenyl group.

The aralkyl groups represented by R ¹ and R ² include, for example, a benzyl group and a phenethyl group. These aralkyl groups may have a substituent, for example, a halogen atom such as a chlorine atom, a bromine atom, an iodine atom; a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, Alkyl groups such as isobutyl group and tert-butyl group; alkoxyl groups such as methoxy group, ethoxy group, propoxy group and butoxy group; and aryl groups such as phenyl group and paramethoxyphenyl group.

Examples of the organic sulfonyl group represented by R ¹ or R ² include arylsulfonyl groups such as benzenesulfonyl group, paratoluenesulfonyl group and paramethoxyphenylsulfonyl group; and methanesulfonyl group, ethanesulfonyl group and propanesulfonyl group. An alkylsulfonyl group; an aralkylsulfonyl group such as a benzylsulfonyl group and a naphthylethylsulfonyl group.

The alkoxycarbonyl group represented by R ¹ or R ² includes, for example, methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, te
Examples thereof include an rt-amyloxycarbonyl group, a benzyloxycarbonyl group, and a 2,4,6-trimethylbenzyloxycarbonyl group.

The acyl group represented by R ¹ or R ² includes:
For example, a formyl group, an acetyl group, a trichloroacetyl group, a trifluoroacetyl group, a pivaloyl group, a benzoyl group, an orthonitrophenylacetyl group and the like can be mentioned.

In the process of the present invention, when producing 2-amino-5-bromopyridine (II) by brominating 2-aminopyridine (I), a nitrogen-containing aromatic compound dibromide hydrobromide is used as a brominating agent. And a solution containing a nitrogen-containing aromatic compound (hereinafter sometimes simply referred to as a “brominating agent solution”). In addition,
As used herein, the term "nitrogen-containing aromatic compound" that constitutes the brominating agent solution means a compound that contains nitrogen at a ring-constituting atom and exhibits aromaticity, such as pyridine, lutidine, picoline, collidine, and chloro. Pyridine, quinoline, isoquinoline and the like, but in the form of an acceptable salt, for example,
Hydrohalides, sulfates, nitrates, carbonates, phosphates and the like are excluded. These nitrogen-containing aromatic compounds may have a substituent such as an alkyl group such as a methyl group and an ethyl group; and a halogen atom such as a chlorine atom, a bromine atom and an iodine atom. The term "nitrogen-containing aromatic compound dibromide hydrobromide" means a salt composed of hydrobromic acid and bromine of the above-mentioned nitrogen-containing aromatic compound, for example, pyridine dibromide hydrobromide, lutidine dibromide hydrobromide, picoline Dibromide hydrobromide, collidine dibromide hydrobromide, chloropyridine dibromide hydrobromide, quinoline dibromide hydrobromide,
Isoquinoline dibromide hydrobromide and the like.

The reaction is preferably performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aliphatic hydrocarbons such as pentane, hexane, heptane, octane, and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene, and mesitylene Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, and trichloroethane; water, and a mixed solvent thereof. The amount of the solvent used is 2-aminopyridine (I)
Usually, the range of 1 to 50 times by weight is preferable.

The amount of the brominating agent solution used is 0.5 to 2 parts per mole of 2-aminopyridine (I) as the amount of the nitrogen-containing aromatic compound dibromide hydrobromide contained in the brominating agent solution. The molar range is preferably 0.8 to 1.2.
The molar ratio is more preferably in the range of 0.95 to 1.05, particularly preferably in the range of 0.95 to 1.05. When the nitrogen-containing aromatic compound dibromide hydrobromide in the brominating agent solution to be used is present in a molar excess of 2-aminopyridine (I), the resulting 2-amino-5-bromopyridine (I
The 3-position of the pyridine ring of I) is further brominated, and the selectivity of the desired 2-amino-5-bromopyridine (II) tends to decrease.

The reaction is preferably carried out by dissolving 2-aminopyridine (I) in a solvent and adding a brominating agent solution to the solution.

The reaction temperature is preferably in the range of -50 ° C to 50 ° C, more preferably in the range of -20 ° C to 20 ° C.

The 2-amino-5 thus obtained
Bromopyridine (II) can be used to isolate ordinary organic compounds.
It can be isolated and purified by the method used for purification. For example, the reaction mixture is washed with water or an aqueous solution of sodium carbonate to remove water-soluble components, and the organic layer is dried over anhydrous sodium sulfate or the like, and then concentrated. Purify by chromatography.

The nitrogen-containing aromatic compound dibromide hydrobromide constituting the brominating agent solution is obtained, for example, by adding bromine dropwise to a mixture of hydrobromic acid and a nitrogen-containing aromatic compound, and obtaining the resulting nitrogen-containing aromatic compound. The compound dibromide hydrobromide can be produced by recrystallization of a solid (Journal of the Amer Chemical Society).
ican Chemical Society), Chapter 7
0, 417 (1948)).

The reaction temperature for preparing the nitrogen-containing aromatic compound dibromide hydrobromide is preferably in the range of -50 to 50 ° C, more preferably in the range of -20 to 20 ° C. The amount of the nitrogen-containing aromatic compound used is 2 per mole of bromine.
The molar ratio is preferably from 5 to 5 times, more preferably from 2 to 3 times. The amount of hydrobromic acid is 1 to 1 mol of bromine.
A range of 2 to 2 moles is preferred.

The above reaction is carried out in the presence or absence of a solvent. As the solvent, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane and trichloroethane; and hydrocarbons such as pentane, hexane, cyclohexane and heptane are used.
After the reaction, an organic layer is separated from the obtained two-layer solution, whereby a solution of the nitrogen-containing aromatic compound dibromide hydrobromide can be obtained. Further, crystals of the nitrogen-containing aromatic compound dibromide hydrobromide can be isolated from the obtained solution by recrystallization or the like.

In the above-mentioned reaction using a solvent, when hydrobromic acid or a nitrogen-containing aromatic compound is used in excess, these compounds contained in the separated aqueous layer are replaced with the nitrogen-containing aromatic compound diamine. It can be reused for the preparation of bromide hydrobromide.

The crystals of the nitrogen-containing aromatic compound dibromide hydrobromide thus obtained are dissolved in an organic solvent together with the nitrogen-containing aromatic compound and used as a solution. As the organic solvent, it is preferable to use halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, and trichloroethane; and hydrocarbons such as pentane, hexane, cyclohexane, and pentane. The concentration of the nitrogen-containing aromatic compound dibromide hydrobromide is preferably in the range of 0.5 to 3 mol / l.
Concentrations lower than 0.5 mol / l are not preferred from the viewpoint of reducing productivity. Further, the content of the nitrogen-containing aromatic compound is preferably 1 mol or more per 1 mol of the nitrogen-containing aromatic compound dibromide hydrobromide,
More preferably, it is in the range of 1 to 10 times. If the concentration is lower than 1 mol, the solubility of the nitrogen-containing aromatic compound dibromide hydrobromide tends to decrease. If the concentration is higher than 10 mol, the cost of recovering the nitrogen-containing aromatic compound increases, which is not preferable.

When preparing a nitrogen-containing aromatic compound dibromide hydrobromide using an organic solvent, a crystal of the nitrogen-containing aromatic compound dibromide hydrobromide is prepared from a solution of the obtained nitrogen-containing aromatic compound dibromide hydrobromide. Can be added to the solution without separation to prepare a brominating agent solution. In such a case, a nitrogen-containing aromatic compound may be added to the solution of the nitrogen-containing aromatic compound dibromide hydrobromide,
Alternatively, in the step of preparing the nitrogen-containing aromatic compound dibromide hydrobromide, the nitrogen-containing aromatic compound may be added before dropping bromine.

[0027]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention.

Example 1 In a nitrogen atmosphere, a 100 ml three-necked flask equipped with a thermometer, a magnetic stirrer and a dropping funnel was charged with
8.63 g (50.1 mmol) of a 7% aqueous hydrogen bromide solution and 25 ml of dichloromethane were added, and the mixture was cooled to 0 ° C.
7.94 g (100.5 mmol) of pyridine is added to this solution.
Was added dropwise over about 10 minutes while maintaining the internal temperature at 5 ° C. or lower, and then 7.82 g (48.9 mmol) of bromine was added at the same temperature for 3 minutes.
After dropwise addition over 0 minutes, the mixture was further stirred at the same temperature for 1 hour. An organic layer (a dichloromethane solution of pyridine dibromide hydrobromide containing pyridine) was separated from the obtained two-layer reaction mixture. On the other hand, under a nitrogen atmosphere, 4.73 g (50.3 mmol) of 2-aminopyridine and 25 ml of dichloromethane were placed in a 200 ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a dropping funnel, and cooled to -20 ° C. . To this solution, a dichloromethane solution of pyridine dibromide hydrobromide containing pyridine prepared above was added dropwise over about 90 minutes while maintaining the internal temperature at -15 ° C or lower, and the mixture was stirred at the same temperature for 1 hour. Thereafter, the temperature of the reaction mixture was raised to 0 ° C., and 70 ml of a 7% aqueous sodium carbonate solution cooled to 0 ° C. was added dropwise while maintaining the temperature at 5 ° C. or lower, and the organic layer and the aqueous layer of the obtained reaction mixture were separated. . The aqueous layer was extracted twice with 10 ml of dichloromethane. The extract and the organic layer were combined, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate). = 2/1 (volume ratio)) to give 7.75 g (44.8 mmol) of 2-amino-5-bromopyridine having the following physical properties as pale yellow crystals (purity 99).
%, Yield based on 2-aminopyridine: 91.6%).

Melting point: 136-138 ° C. ¹ H-NMR spectrum (270 MHz, CDCl ₃ ,
5. TMS, ppm) δ: 4.26 (br, 2H);
42 (d, 1H, J = 8.5 Hz), 7.49 (dd,
1H, J = 2.5 Hz, 8.5 Hz), 8.10 (d,
1H, J = 2.5Hz)

Example 2 Under a nitrogen atmosphere, a 200-ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a dropping funnel was charged with
17.2 g (99.8 mmol) of a 7% aqueous hydrogen bromide solution and 50 ml of dichloromethane were added, and the mixture was cooled to 0 ° C.
15.8 g (200.0 mmol) of pyridine was added to this solution.
Was added dropwise over about 30 minutes while maintaining the internal temperature at 5 ° C. or lower, and then 15.9 g (99.5 mmol) of bromine was added at the same temperature in 4 parts.
After dropwise addition over 5 minutes, the mixture was further stirred at the same temperature for 1 hour. An organic layer (a dichloromethane solution of pyridine dibromide hydrobromide containing pyridine) was separated from the obtained two-layer reaction mixture. On the other hand, 9.40 g (100.0 mmol) of 2-aminopyridine and 50 ml of dichloromethane were placed in a 300-ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a dropping funnel under a nitrogen atmosphere, and cooled to 0 ° C. To this solution, a dichloromethane solution of pyridine dibromide hydrobromide containing pyridine prepared above was added dropwise over about 120 minutes while maintaining the internal temperature at 5 ° C. or lower, and the mixture was stirred at the same temperature for 1 hour. Thereafter, 150 ml of a 7% aqueous sodium carbonate solution cooled to 0 ° C. was added dropwise while maintaining the temperature at 5 ° C. or lower, and the organic layer and the aqueous layer of the obtained reaction mixture were separated. The aqueous layer was extracted twice with 30 ml of dichloromethane. The extract and the organic layer were combined, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate). = 2/1 (volume ratio)) to obtain 14.4 g (83.3 mmol) of 2-amino-5-bromopyridine as pale yellow crystals (purity 99).
%, Yield based on 2-aminopyridine: 83.7%).

[0031]

Industrial Applicability The present invention provides a method for industrially and advantageously producing a 2-amino-5-bromopyridine derivative under mild conditions with good yield.

Claims (1)

[Claims] 1. A compound of the general formula (I) (Wherein, R ¹ and R ² represent a hydrogen atom, an organic sulfonyl group, an alkoxycarbonyl group, an acyl group or an optionally substituted alkyl group, an aryl group or an aralkyl group). Is brominated to form a compound of the general formula (II) (Wherein, R ¹ and R ² are as defined above.)
Wherein a solution containing a nitrogen-containing aromatic compound dibromide hydrobromide and a nitrogen-containing aromatic compound is used as a brominating agent in the method for producing a 2-amino-5-bromopyridine derivative represented by the formula (1). Method.