KR960005828B1 - Process for preparation of pyridine derivatives - Google Patents

Abstract

The pyridine derivative, 3,5-dimethyl-4-methoxy-2-hydroxymethyl pyridine(I), is prepared by : (a) making pyridinon derivative(VIII) from pentenon derivative(IV); (b) making chloropyridine derivative(IX) from the reaction with POCl3 or PCl5; (c) making methoxy pyridine derivative(X) from the reaction with metal alkoxyde such as sodium alkoxyde or potassium alkoxyde; (d) hydrogenating under the catalyst of Pd/C and 1-20 kg/cm3 hydrogen pressure.

Description

Method for preparing pyridine derivative

The present invention relates to a method for preparing a pyridine derivative of formula (I) below used in the preparation of benzimidazole derivatives having gastric acid secretion inhibitory properties.

Benmidimidazole derivatives of the following structural formula (A) are compounds used for the purpose of protecting the gastrointestinal tract, including gastric ulcer and duodenal ulcer, and methods for preparing the same are described in British Patent Nos. 1,500,043, 1,525,958, US Pat. No. 4,182,766 and No. 4,255,431 and the like are known compounds whose common name is omeprazole.

Benzimidazole derivatives of the above structural formula (A) are generally compounds formed by combining mercapto benzimidazole derivatives with chloromethyl pyridine, and in the preparation of omeprazole, 4-methoxy-3,5-dimethyl-2-hydroxy Methyl pyridine is an essential intermediate, and a known method for preparing the same is described in Korean Patent Publication No. 88-91, which is described below.

The above known method is reacted with hydrogen peroxide using 3,5-lutidine or 2,3,5-collidine as a starting material to obtain pyridine-N-oxide, and reacted with a nitrating agent to introduce pyridine-N into which a methoxy group is introduced. After obtaining -oxide compound, using dimethyl sulfate and free radicals or reacting with acetic anhydride [(CH ₃ CO) ₂ O] and then hydrolysis reaction to obtain the desired product.

However, such a known method requires a continuous operation such as oxidation, reduction, introduction, and substitution reaction in order to selectively introduce an appropriate group at each position of the pyridine ring, so that the reaction operation is complicated and ineffective, and yield is low. I have a problem. In addition, the nitro-pyridine-N-oxide compound produced as a synthetic intermediate has the disadvantage of being harmful to the human body having carcinogenic and mutagenic properties, and 2,3,5-collidine is expensive and 3, There is a disadvantage that a reaction of selectively introducing a methyl group at position 2 with a starting material such as 5-lutidine must be preceded.

Therefore, the inventors of the present invention provide a novel method for preparing 4-methoxy-3,5-dimethyl-2-hydroxymethyl pyridine of general formula (I), in which the disadvantages of the above known method are eliminated. Invented to complete the present invention. In other words, specifically, the present invention condensates an aliphatic ene-one compound and an acetyl radical derivative, which is substituted with a desired group at a suitable position, and is represented by the structural formula (I) through a cyclosubstitution reaction and a hydrogenation reaction. It is an efficient and new manufacturing method for preparing target compound

In more detail, the compound of formula (I) is prepared by the following process.

In the reaction route of the present invention, the first reaction step, 3-pentanone of the formula (II) and ethyl formate is reacted using sodium methoxide and treated with aqueous hydrochloric acid to form a compound of the formula (III) The reaction proceeds to a process of synthesizing 2,4-dimethyl-1-methoxy-1-penten-3-one of formula (IV) below by reacting with a methoxide anion.

In the second reaction step, the pentenone derivative of the above formula (IV) is subjected to a low temperature reaction with the acetyl radical of the following formula (V) by adding a metal catalyst to form an intermediate of the following formulas (V) and (VII), and ammonia hydro Reaction of Si with reflux or pressurization with ammonia (NH ₃ ) to produce 3,5-dimethyl-2-benzyloxymethyl-4-pyridinone compound of the following formula (VIII), wherein the acetyl radical is benzyloxyacetyl chloride. , Bromides, iodides and anhydrides may be used and are characteristic reaction steps in the present invention.

Wherein X is Cl, Br, I or to be.

The third reaction step is a reaction for substituting a methoxy group at position 4 of the pyridine ring, by reacting a pyridinone derivative of the above formula (VIII) with a chlorinating agent under an inert solvent to form 4-chloro-3, 5-Dimethyl-6-benzyloxymethyl pyridine is prepared and reacted with a methoxide anion in a polar aprotic organic solvent to introduce a methoxy group at position 4 of the pyridine ring to form 4-methoxy-3 of formula (X) below. , 5-dimethyl-6-benzyloxymethyl pyridine.

The final reaction step of preparing the pyridine derivative of formula (I), which is the target compound of the present invention and an important starting material for the synthesis of omeprazole of formula (A), is the hydrogenation of pyridine derivative of formula (X) in a non-acidic solvent. This is a method for producing 3,5-dimethyl-4-methoxy-2-hydroxymethyl pyridine of formula (I) by advancing to remove benzyloxy group.

Referring to the reaction process of the present invention as described above in more detail as follows.

The pentenone derivative of formula (IV) is a compound in which 3-pentenone is conveniently reacted with ethyl formate using sodium methoxide in an aprotic organic solvent such as diethyl ether or tetrahydrofuran, and acidified with aqueous hydrochloric acid solution. After the addition of methoxide anion it can be prepared by reflux reaction. The condensation reaction is carried out for 1-6 hours at a temperature between 0 ° C. and room temperature. In order to introduce a methoxy group from the compound of formula (III), a methoxide anion is formed from concentrated sulfuric acid and methanol, and an inert organic solvent such as benzene and toluene. It can be manufactured by making it react for 3-6 hours from 50 degreeC to reflux temperature under the following. In the present invention, the conditions for the preparation of the structural formula (VIII), which is a characteristic reaction step, are carried out using the pentenone derivative of the structural formula (IV) using a metal catalyst such as lithium bis (trimethylsilyl) amide, boron trichloride, zinc chloride and the like. By reacting with a benzyloxyacetyl chloride, benzyloxyacetyl bromide or benzyloxyacetyl anhydride as a radical, a benzyloxyacetyl group is selectively introduced at the fourth position of the compound of formula (IV) to obtain the compounds of formulas (VI) and (VII). It can manufacture. The reaction is subjected to a low temperature reaction for 1-3 hours at -78 to -20 ° C using an aprotic organic solvent such as diethyl ether or tetrahydrofuran. At this time, a mixture of pentenone derivatives of formula (VI) and pyranone derivatives of formula (VII) is produced. Such compounds can be separated by using a developing solvent of hexane / ethyl acetate (3/1) and performing column chromatography. It is convenient to proceed to the next reaction in the form of a mixture without any manipulation. The compound of formula (VIII) can be easily prepared by adding ammonium hydroxy alcohol solution to the mixture and proceeding to reflux without any separate separation operation.

The pyridinone derivative of formula (VIII) prepared in the above reaction forms 4-methoxy-3,5-dimethyl-6-benzyloxymethylpyridine of formula (IX) through suitable chlorination and alkoxy substitution reaction. The chlorination reaction is carried out for 1-6 hours at 70-150 ° C. using a chlorinating agent such as phosphorus octacycloide (POCl ₅ ) or phosphorus pentachloride (PCl ₃ ) in an inert organic solvent such as benzene or toluene. The compound of formula (X) was reacted with a metal alkoxide such as sodium methoxide and potassium methoxide in a polar aprotic organic solvent such as dimethyl formamide, dimethyl acetamide or dimethyl sulfoxide at a temperature of 50-80 ° C. It can be prepared by introducing a methoxy group at position 4 with warm stirring for -6 hours.

In the present invention, the pyridine derivative of formula (I), which is the target compound, can be obtained in high purity and high yield by removing benzyl oxy group through ordinary hydrogenation reaction conditions, and thus, a catalyst such as palladium or zinc in an alcohol solution such as ethanol can be obtained. Can be prepared by reacting under hydrogen pressure. The hydrogenation reaction is stirred for 7-12 hours at a hydrogen pressure of 1-20kg / cm ² and preferably reacted under 10% Pd / C ethanol solution.

The compound of formula (I) obtained in high yield by the advanced manufacturing process of the present invention is reacted with thionyl chloride by the known method disclosed in German Patent Nos. 2,428,294 and 3,040,248, and the chloro of formula (XI) Methyl pyridine derivatives can be obtained.

As described above, the present invention is a known method for obtaining the compound of formula (I) through the operation of oxidation, substitution reaction, etc. using 3,5-lutidine or 2,3,5-collidine as a starting material Not only is the reaction process more useful, it is economical to obtain 4-methoxy-3,5-dimethyl-2-hydroxymethyl pyridine, the target compound of formula (I), in high yield, without the formation of intermediates harmful to the human body. It is an advanced new manufacturing method.

The following examples illustrate the invention in detail, and do not limit the invention.

Example 1

Preparation of 2,4-dimethyl-1-methoxy-1-penten-3-one (IV)

1 L of anhydrous diethyl ether was added to a reactor equipped with a reflux condenser and agitator, 60 g of sodium methoxide was added thereto, and the temperature of the solution was cooled to 0 ° C. Then, 110 ml of 3-pentenone and 89 ml of ethyl formate were added at the same temperature. After stirring for 3 hours at the same temperature, the resulting precipitate was filtered, washed and dried. The compound was dissolved in water, acidified with 1N-HCl, extracted three times with dichloromethane, and the obtained organic layer was dried over magnesium sulfate and concentrated to obtain a pale yellow solid material of formula (III). 250 ml of benzene was added thereto to dissolve, 45 ml of methanol and 10 ml of concentrated sulfuric acid were added thereto, and the mixture was stirred under reflux for 5 hours. The benzene layer was dried over magnesium sulfate and concentrated under reduced pressure to remove benzene to give 123.3 g of the titled compound (IV) as a colorless liquid.

Yield: 87%

H NMR (CDCl ₃ ) δ: 7.25 (s, 1H), 3.85 (s, 3H), 2.64 (m, 2H), 1.80 (s, 3H), 1.20 (s, 3H)

Example 2

Preparation of 3,5-dimethyl-2-benzyloxymethyl-4-pyridionone (VIII)

After dissolving 26 g in 2,4-dimethyl-1-methoxy-1-penten-3-one (IV) in 500 ml of tetrahydrofuran and cooling the reaction solution to -78 ° C, lithium bus (trimethylsilyl (amide) After adding 38 ml and stirring for 30 minutes, 20 g of benzyloxyacetyl chloride was slowly added thereto, stirred at the same temperature for 1 hour, and then saturated ammonium chloride solution was added thereto, extracted with diethyl ether, and the organic layer was concentrated under reduced pressure. As a liquid, a mixture of structural formulas (VI) and (VII) was obtained, and 200 ml of methanol and ammonium hydroxy were added to the mixed compound to dissolve, and the mixture was stirred under reflux for 3 hours, the solvent was concentrated under reduced pressure, and 500 ml of ethyl acetate was added. The precipitate was added to form a precipitate, which was filtered and dried to yield 18.4 g (yield: 75%) of the title compound (VIII) as a yellow solid.

Melting Point: 148-150 ℃

H NMR (CDCl ₃ ) δ: 10.50 (s, NH), 9.4 (m, 6H), 4.51 (d, 4H), 2.00 (d, 6H)

Example 3

The reaction was carried out using the same reaction conditions as in Example 2, but in the process of synthesizing pyridinone derivatives, the reaction was carried out at a reaction temperature of 100 ° C. using ammonia gas pressure of 5 kg / cm ² instead of ammonium hydroxy. The resulting 3,5-dimethyl-2-benzyloxymethyl-4-pyridion (VIII) was obtained in a yield of 82%.

Example 4

Preparation of 3,5-dimethyl-4-chloro-6-benzyloxymethylpyridine (IX)

20 g of 3,5-dimethyl-2-benzyloxymethyl-4-pyridinone obtained in Example 2 was dissolved in 100 ml of toluene, and 22 ml of phosphorus oxcyclolide was added thereto, followed by stirring under reflux for 2 hours. After completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent, and extracted with diethyl ether and saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and distilled under reduced pressure to obtain 3,5-dimethyl-4 of the title compound (IX). 18.86 g of -chloro-6-benzyloxymethyl pyridine was obtained.

Yield: 91%

H NMR (CDCl ₃ ) δ: 8.22 (s, 1H), 7.33 (m, 5H), 4.70 (d, 4H), 2.33 (d, 6H)

Example 5

Preparation of 3,5-dimethyl-4-methoxy-6-benzyloxymethyl pyridine (X)

6.2 g of sodium methoxide was added to 500 ml of dimethyl sulfoxide to form methoxide anion, 20 g of 4-chloro-3,5-dimethyl-6-benzyloxymethyl pyridine was added thereto, followed by stirring at 60 ° C. for 6 hours, followed by di Extraction with ethyl ether and concentration gave 17.4 g of the title compound (X) as a colorless liquid substance.

Yield: 89%

H NMR (CDCl ₃ ) δ: 8.24 (s, 1H), 7.35 (m, 5H), 4.62 (d, 4H), 3.76 (d, 3H), 2.30 (d, 6H)

Example 6

Preparation of 3,5-dimethyl-4-methoxy-2-hydroxymethyl pyridine (I)

In a pressure reactor, 15.8 g of 3.5-dimethyl-4-methoxy-6-benzyloxymethyl pyridine (X) was added to 600 ml of 10% Pd / C ethanol solution and stirred for 12 hours under hydrogen pressure of 5 kg / cm ² to complete the reaction. After Pd / C was filtered off, the solvent was concentrated under reduced pressure to obtain 9.2 g of the target compound (I) as a colorless liquid substance.

Yield: 92%

H NMR (CDCl ₃ ): 8.17 (s, 1H), 4.60 (s, 3H), 3.76 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H)

Example 7

Preparation of 3,5-dimethyl-4-methoxy-2-chloromethyl pyridine hydrochloride (XI)

Put 100ml of dichloromethane into the reaction tank to which the cooling tank was attached, and add 12g of 3,5-dimethyl-4-methoxy-2-hydroxymethyl pyridine to dissolve it, and then cool the reaction solution to 0 ° C and 12ml of thionyl chloride. Was added slowly and stirred at room temperature for 5 hours. Unreacted thionyl chloride and the solvent were distilled off under reduced pressure to obtain 15.2 g of the title compound as a white solid.

Yield: 95%

H NMR (CDCl ₃ ): 8.21 (s, 1H), 4.92 (s, 2H), 3.75 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H)

Comparative Example 1

According to the method described in Korean Patent Publication No. 88-91, 100 g of 2,3,5-collidine was reacted with acetic acid to synthesize 2,3,5-collidine-N-oxide, and nitration of a sulfuric acid and nitric acid mixed solution was performed. After reacting with the solution, it was reacted with methoxide anion in methanol to prepare 4-methoxy-2,3,5-trimethyl-pyridine-N-oxide. After reacting with acetic anhydride according to a known method, hydrolyzing with sodium hydroxide and proceeding with reaction with thionyl chloride, 56.9 g of the target compound 3,5-dimethyl-4-methoxy-2-chloromethyl pyridine (yield: 31 %) Was obtained.

Claims (9)

In preparing the hydroxymethyl pyridine derivative represented by the following structural formula (I), a pyridinone derivative of the following structural formula (VIII) is synthesized from the pentenone derivative of the following structural formula (IV), and reacted with a chlorinating agent to give the following structural formula (IX) Chloropyridine derivatives of n) were prepared and reacted with metal alkoxides to produce methoxide pyridine derivatives of the following formula (X), followed by hydrogenation to give 3,5-dimethyl-4-methoxy-2-hydroxymethyl A process for producing pyridine (I). The process of claim 1, wherein the preparation of the compound of formula (VIII) comprises reacting the compound of formula (IV) with a benzyloxyazyl radical of formula (V) under a catalyst to react the compounds of formulas (IV) and (VII) And then reacting with the ammonia derivative in an alcohol solvent. Wherein X is Cl, Br, I or to be. The process for preparing a compound of formula (I) according to claim 1, wherein the metal alkoxide is sodium methoxide or potassium methoxide. The method according to claim 1, wherein POCl ₃ or PCl ₃ is used as the chlorinating agent. The method according to claim 1, wherein the dehydration reaction is carried out at a hydrogen pressure of 1-20 kg / cm ² using Pd / C as a catalyst. The method according to claim 2, wherein the reaction with the ammonia derivative is reacted with ammonium hydroxy at normal pressure or under ammonia (NH ₃ ) pressure of 5-10 kg / cm ² . 3. The process according to claim 2, wherein the benzyloxyacetyl radical is benzyloxyacetyl chloride, benzyloxyacetyl bromide or benzyloxyacetyl anhydride. The process for preparing a compound of formula (I) according to claim 2, wherein the catalyst is lithium bis (trimethylsilyl) amide, boron trifluoride or zinc chloride. The process for preparing the compound of formula (I) according to claim 2, wherein the alcohol is methanol or ethanol.