KR100473652B1 - The process for preparing 4-chloropyridine derivatives - Google Patents

Abstract

The present invention relates to a novel method for preparing a pyridine derivative, characterized in that a pyridine derivative, which is an intermediate compound useful in the process for producing benzimidazole derivatives having gastric acid secretion properties, is prepared by injecting high-efficiency chlorine gas in the presence of alkali. As a result, it is possible to replace conventional nitropyridine oxide to overcome economic hazards such as human hazards and low yield, and to provide new processes of high purity and high yield and simplified useful processes.

Description

The process for preparing 4-chloropyridine derivatives}

The present invention provides a novel production method that can be produced in high purity and high yield using chlorine gas having high economical efficiency in the production of pyridine derivatives which are intermediates used in the preparation of benzimidazole derivatives having gastric acid secretion inhibitory properties. will be.

Benzimidazole derivatives having a pyridine parent nucleus represented by the following general formula (IV) are known in various literatures (British patent 1,500,043, UK patent 1,525,989, US patent 4,182,766, US patent 4,255,431). (H), a compound used for gastric acid protection as well as gastric acid secretion in mammals and humans is known to have an excellent effect in treating inflammation of the gastrointestinal system such as gastric ulcer and duodenal ulcer.

(Ⅳ)

In general formula (IV), omeprazole wherein R ₂ and R ₃ are methyl groups and R ₄ and X are methoxy groups is the most representative compound among benzimidazole derivatives, and in general, gastric acid secretion is released at the final stage of the acid secretion pathway. By regulating it is known to be useful in suppressing gastric acid secretion in mammals and humans. In a more general sense, omeprazole can be used for the prevention and treatment of gastric acid-related diseases in mammals and humans, including reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer, and also requires gastric acid inhibitory effects. For example, gastrinoma causing non-steroidal anti-inflammatory drugs (NSAIDs), non-ulcer dyspepsia, patients with symptomatic gastroesophageal reflux disease, and refractory digestive ulcers caused by hyperacidosis. It can be used for the treatment of gastrinomas, and it can be used preoperatively and postoperatively to prevent gastric aspiration and to prevent and treat stress ulceration in patients requiring intensive treatment and patients with acute upper gastrointestinal bleeding. Also, the treatment of psoriasis as well as Helicobacter pylori (Helicobacter) may be useful in the treatment or prevention of inflammatory diseases in a mammal, including the treatment and human infection and related diseases, a method is described in various patents and publications ( Korean Patent Publication No. 88-91, Korean Patent Publication No. 1995-0014070, and Korean Patent Registration No. 1997-0008316).

In addition, in the general formula (IV), lansoprazole wherein R ₂ is a methyl group, R ₃ and R ₄ are hydrogen atoms, and X is a 2,2,2-trifluoroethoxy group is used for gastric acid secretion inhibition and gastric mucosal protection. As anti-ulcer agents exhibiting excellent effects, a number of papers and patent documents have described manufacturing methods (Korean Patent Publication No. 92-2128, Korean Patent Publication No. 96-0047, Korean Patent Publication No. 97-6299, Europe Patent Nos. 0,174,726, European Patent No. 0,446,961, US Patent No. 4,689,333, US Patent No. 5,374,730, International Patent Publication No. 95/12590, and International Patent Publication No. 97/29103.

In addition, in said general formula (IV), pantoprazole or R <_2> is a methyl group, R <_2> is a methoxy group, R <_3> is a hydrogen atom, R <_4> is a ₂ , 2- difluoromethoxy group, and X is a methoxy group. , R ₃ and R ₄ are hydrogen atoms, X is 2-methoxypropoxy group, rabeprazole are effective compounds for the treatment of diseases caused by increased gastric acid secretion, the preparation method is described in the patent literature (international patent) Application 97/41114).

These benzimidazole derivatives are formed by combining a benzimidazole derivative portion and a pyridine methyl moiety with sulfide or sulfoxide, and a manufacturing process has been disclosed in US Patent No. 4,255,431 (European Patent No. 1005-129). One or more solvents were used, the isolation of intermediates to obtain the final product was required, and the resulting product was contaminated with starting materials and by-products, which made it difficult to obtain pure compounds as well as the need for separation processes to be involved. .

In addition, US Pat. No. 5,391,752 describes only an oxidation step using magnesium monoperoxyphthalate as the oxidant, which likewise shows low yield and purity because the product is contaminated with starting materials and by-products.

Meanwhile, a known method for preparing 4-methoxy-3,5-dimethylpyridine-N-oxide, which is a key intermediate in preparing benzimidazole derivative compounds, is described in Korean Patent Publication No. 88-91, Looking at these manufacturing methods are as follows.

3,5-dimethylpyridine (1) is reacted with hydrogen peroxide to obtain 3,5-dimethylpyridine-N-oxide (2), which is then reacted with a nitrating agent such as nitric acid and subsequently with an alkali to produce the desired methoxy group. Was introduced to obtain 3,5-dimethyl-4-methoxypyridine-N-oxide (4).

However, such a known production method requires a continuous operation such as oxidation, reduction, introduction, and substitution reaction to selectively introduce an appropriate group at each position of the pyridine ring, so that the reaction operation is complicated and ineffective. The yield was poor at about 65%, and due to the carcinogenic and mutant properties of the N-oxide compound (3) of nitropyridine, which is produced as a synthetic intermediate in the reaction pathway, it is harmful to humans ( Acta Chemica Scandinavica , B48 , pp524-525, 1988), an efficient and high yield method without toxicity is required.

In order to make up for the shortcomings of the above-mentioned known method, Korean Patent Publication No. 1991-0009816 discloses the following manufacturing method.

However, the reaction process is not only long in three stages, but also expensive phosphoryl chloride as a chloroating agent, which is toxic and excessive production cost to the human body, and the reaction temperature is very high and unsuitable for mass production, and also 4-chloropyridine- Since the one-step oxidation process was added at the time of manufacture of N-oxide (4), there was much room for improvement (pre-process yield: 65%).

In view of the above, there is still a need for a new production method for preparing intermediates of benzimidazole derivatives which are efficient, simple and economical, which eliminates the disadvantages of the known methods, thereby providing chlorine gas in the presence of organic solvents and alkalis. By injecting, the existing three-step process is simplified to two stages, and a new method can be prepared in high purity and high yield using inexpensive chlorine gas instead of phosphoryl chloride to use as a chloroating agent. It was.

It is an object of the present invention to provide a novel process for the preparation of 4-chloropyridine derivative compounds which are intermediate compounds used in the preparation of benzimidazole derivatives having gastric acid secretion inhibitory properties.

In order to achieve the above object, the present invention oxidizes the pyridine of general formula (II) with an oxidizing agent to obtain pyridine-N-oxide of general formula (III), and then chlorine gas is injected as a chloroating agent in the presence of a solvent and an alkali. It provides a method for producing 4-chloropyridine derivative represented by the following structural formula (I) which is an intermediate used in the preparation of benzimidazole derivatives characterized in that.

(Ⅰ)

(Ⅱ)

(Ⅲ)

In the above formula,

R ₁ , R ₂ and R ₃ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, which are different from or the same as each other.

The oxidizing agent which can be used in the above production process is peracid, sodium bromide, sodium hypochlorite, preferably hydrogen peroxide, and the reaction solvent is a solvent selected from halogenated hydrocarbons, ethers, amides, alcohols, water, preferably glacial acetic acid.

In addition, the chloroating agent that can be used in the above process is chlorine gas, methylene chloride, carbon tetrachloride, preferably chloroform as the organic solvent, sodium hydroxide, potassium hydroxide powder or aqueous solution thereof, preferably sodium carbonate powder Can be used.

Likewise, the amount of alkali used in the process is 0.5 to 5 equivalents, preferably 1 to 2 equivalents, per mole of formula (III), the reaction temperature is 0 to 40 ° C, preferably 0 to 30 ° C, and the reaction The time is 30 minutes to 10 hours, preferably 1 hour to 6 hours.

Hereinafter, the manufacturing process of the present invention will be described in detail with the following reaction scheme.

The preparation process of the present invention can be chemically synthesized by the method shown in the following scheme, but is not limited to this example, it can be prepared by appropriate changes in the reagents and starting materials known to those skilled in the art.

As in Scheme 1, pyridine of formula (II) is oxidized using hydrogen peroxide and glacial acetic acid to obtain pyridine-N-oxide of formula (III), and then chlorine gas is used as a chloroating agent in the presence of a solvent and an alkali. By injection, 4-chloropyridine-N-oxide derivative of general formula (I) which is a benzimidazole intermediate can be prepared.

The first step is to prepare a pyridine-N-oxide which is a compound of the general formula (III) by oxidizing the pyridine of the general formula (II) by a known method, the hydrogen peroxide of the oxidizing agent used in the above process is about 20 to 50% It is common to use aqueous solution, but it is not limited to the said range.

The amount of hydrogen peroxide used is 0.95 to 2.0 equivalents, preferably 0.95 to 1.4 equivalents, more preferably 1.0 to 1.1 equivalents based on the compound of formula (II). Reaction solvents include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; Ethers such as tetrahydrofuran, dioxane; Amide, alcohol, water or glacial acetic acid.

Subsequently, the second step is to prepare a pyridine-N-oxide of the general formula (III) using a chloroating agent in the presence of alkali to prepare a 4-chloropyridine oxide compound of the general formula (I).

The chloroating agent that can be used in the above process is chlorine gas, the organic solvent is methylene chloride, carbon tetrachloride, chloroform, the alkali means a powder of sodium hydroxide, potassium hydroxide or sodium carbonate or an aqueous solution thereof.

In addition, the usage-amount of alkali in the said process is 1-2 equivalent per mole of general formula (III) compound, and reaction temperature is 0-30 degreeC.

As described above, the present invention is not only an effective method harmless to the human body in the manufacturing process by using chloropyridine-N-oxide in place of the harmful nitropyridine-N-oxide derivative used in the known method, but also a two-step process. Unlike conventional reaction processes, the compound of general formula (I) can be prepared in a higher yield than a known method by using only one step, which does not require a separate oxidation process, and chlorine gas is used instead of phosphoryl chloride as a chloroating agent. Economical use and yield are also superior to known methods by use.

The invention can be better understood by the following examples, which are intended to illustrate the invention and are not intended to limit the scope of protection.

Example 1. Preparation of 3,5-dimethylpyridine-N-oxide (1)

7.80 g (72.8 mM) of 3,5-dimethylpyridine and 4 ml of toluene were added to the reactor, followed by reacting with 14 ml of glacial acetic acid while maintaining 0 to 10 DEG C, followed by dropwise addition of 9.4 ml of 30% hydrogen peroxide solution for 4 hours. . After the temperature was lowered to room temperature, the mixture was adjusted to pH 8-9 with 10M aqueous sodium hydroxide solution, extracted twice with 40 ml of methylene chloride, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain 3,5-dimethylpyridine-N-oxide. Compound 8.51 g (yield 95.0%) was obtained (see Table 1).

Example 2. Preparation of 2,3-dimethylpyridine-N-oxide (2)

7.80 g (72.8 mM) of 2,3-dimethylpyridine and 4 ml of toluene were placed in a reactor, followed by reacting with 14 ml of glacial acetic acid while maintaining 0 to 10 DEG C, followed by dropwise addition of 9.4 ml of 30% hydrogen peroxide solution for 4 hours. . After the temperature was lowered to room temperature, the mixture was adjusted to pH 8-9 with 10M aqueous sodium hydroxide solution, extracted twice with 40 ml of methylene chloride, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to give 2,3-dimethylpyridine-N-oxide. 8.11 g (yield 90.0%) of compound was obtained (see Table 1).

(Ⅲ)

compound R ₁ R ₂ R ₃ Yield (%) One H CH ₃ CH ₃ 95.0 2 CH ₃ CH ₃ H 90.0

Example 3. Preparation of 4-chloro-3,5-dimethylpyridine-N-oxide (3)

1.23 g (9.99 mM) of 3,5-dimethylpyridine-N-oxide prepared in Example 1 of the present application was dissolved in 40 ml of chloroform, followed by adding 1.06 g (10.00 mM) of sodium carbonate powder and maintaining 0 to 5 ° C. Chlorine gas was injected for 3.5 hours. After the reaction, nitrogen gas was flowed to remove the chlorine gas dissolved in the solvent, and then filtered to remove the insoluble matters and washed twice with saturated aqueous sodium bicarbonate solution. 6 ml of ethyl acetate was added to the residue obtained by washing, drying and evaporation. After stirring, 18 ml of hexane was added dropwise for 1 hour to crystallize, followed by filtration to give 4-chloro-3,5-dimethylpyridine-N-oxide compound ( 1.31 g) was obtained (see Table 2).

Example 4. Preparation of 4-chloro-2,3-dimethylpyridine-N-oxide (4)

1.23 g (9.99 mM) of 2,3-dimethylpyridine-N-oxide prepared in Example 2 of the present application was dissolved in 40 ml of chloroform, followed by addition of 1.06 g (10.00 mM) of sodium carbonate powder and chlorine gas at room temperature for 30 hours. Was injected during. After the reaction, nitrogen gas was injected to remove the chlorine gas dissolved in the solvent, followed by filtration to remove the insolubles, and washed twice with saturated aqueous sodium bicarbonate solution. The residue obtained by washing, drying and evaporating was subjected to a silica gel column using a developing solvent (EtoAc: MeOH = 6: 1), and 1.02 g of 4-chloro-2,3-dimethylpyridine-N-oxide compound (yield 65.0%). ) Was obtained (see Table 2).

(Ⅰ)

compound R ₁ R ₂ R ₃ Yield (%) ¹ H-NMR (CDCl ₃ ) δ: 3 H CH ₃ CH ₃ 83.0 2.32 (s, 6H), 8.00 (s, 2H) 4 CH ₃ CH ₃ H 65.0 2.66 (s, 3H), 2.85 (s, 3H), 7.62 (d, 1H), 8.85 (d, 1H)

As a result, the novel preparation method of the 4-chloropyridine derivative compound, which is an intermediate compound used in the preparation of benzimidazole derivatives having gastric acid secretion inhibitory properties, simplifies the process from the existing three-step reaction to two steps. Compared with the yield using the method (old method: 65%), it showed a significant effect (new method: 79%), it was confirmed that the invention is economically and industrially useful.

In the method for preparing 4-chloropyridine derivative of the present invention, chlorine gas is injected in the presence of an organic solvent and an alkali to simplify the existing process, and to convert chlorine gas into a highly toxic and relatively expensive phosphoryl chloride. Substitution can simplify the process and economically produce high purity, high yield compounds.

Claims (4)

The pyridine of the general formula (II) is oxidized with an oxidizing agent selected from hydrogen peroxide, sodium bromide and sodium hypochlorite to obtain pyridine- N -oxide of the general formula (III), followed by a solvent and hydroxide selected from methylene chloride, chloroform and carbon tetrachloride. A process for preparing 4-chloropyridine- N -oxide derivative of general formula (I) characterized by injecting chlorine gas as a chloroating agent at a temperature of 0 to 30 ° C in the presence of an alkali selected from sodium, potassium hydroxide and sodium carbonate: In the above formula, R ₁ , R ₂ and R ₃ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, which are different from or the same as each other. delete delete delete