KR910000481B1 - Process for preparing pyridine derivatives - Google Patents

Abstract

A method for preparing 2-hydroxymethylpyridine derivs. of formula (I) comprises a reduction of pyridine carboxylic acid methyl(ethyl)-ester of formula (II) with NaBH4 in the presence of alcoholic solvent. And a method for preparing (II) comprises hydrolyzing (III) and reacting the resulting cpd. with MeOH(EtOH) in the presence of acid catalyst. In the formulas, R1 and R2 each= H or CH3; and R3= CH3 or C2H5.

Description

Method for preparing pyridine derivative

The present invention relates to a novel process for the preparation of pyridine derivatives of formula (I) for use as a synthetic intermediate of benzimidazole derivatives of formula (II) useful as a therapeutic agent for gastric ulcers.

Wherein R is a methoxy group or a trifluoromethyl group, n is an integer of 0 or 1, and R ¹ and R ² are each independently selected from hydrogen or methyl group.

Among the compounds of formula (I), a method for preparing 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine free base of formula (I) 'wherein R ¹ and R ² are methyl groups is disclosed in Korea. No. 84-5718), which will be described in more detail as follows.

First, a 2-acetoxymethyl pyridine derivative of formula (IV) is prepared by reacting 4-methoxy-2,3,5-trimethylpyridine N-oxide compound of formula (III) with acetic anhydride, and then hydrolyzing it To prepare a compound of formula (I) '.

Second, the 4-methoxy-3,5-dimethylpyridine N-oxide compound of formula (V) is reacted with dimethyl sulfate to prepare an N-methoxy derivative of formula (VI), which is then reacted with a free radical agent. To a method of preparing the compound of formula (I) '.

The development team of the present inventors developed a novel manufacturing method for the target compound of the present invention and filed the patent application No. 86-8700 and is currently pending. This method is represented by the following scheme.

However, the above method converts the compound of formula (I) into hydrogen peroxide and converts it to N-oxide of the pyridine nucleus to prepare the compound of formula (C), and then converts the nitro group (NO ₂ ) to the methoxy group (CH ₃ O). After substitution, N-oxide was reduced again to go through a cumbersome process in which the compound of formula (M) had to be prepared. In addition, in this method, the first and fifth processes were not improved, and the overall yield was only a low yield of about 28%.

The present inventors have conducted a further study, were in the group of pyridine-4-NO ₂ mohaek Sikkim substituted methoxy (CH ₃ O) discovered the surprising fact that substitution is possible without the use of a compound of pyridine N- oxide mohaek, thus Not only does the N-oxide generation process and the N-oxide reduction process after replacing 4-NO ₂ group with a methoxy group are necessary, but the first and final reduction processes are also improved, so that the overall yield is higher than about 67%. The discovery of new facts on the preparation of compounds has led to the completion of the present invention.

It is therefore an object of the present invention to provide a process for the preparation of compounds of formula (I) in new and advanced methods.

In the present invention, a compound of formula (VII) is introduced into a compound of formula (VII) to prepare a compound of formula (VIII), and then a nitro group is substituted with a methoxy group to prepare a compound of formula (IX), followed by hydrolysis in a basic aqueous solution. The compound of (X) was prepared and reacted with methanol or ethanol under an acid catalyst to prepare a methyl ester or ethyl ester compound of the pyridine carboxylic acid of formula (XI), followed by esterification using sodium borohydride as a reducing agent. The method for preparing 2-hydroxymethyl pyridine derivative of formula (I) by reducing the oxidized portion was completed and the present invention was completed.

(Wherein R ¹ and R ² are each hydrogen or methyl group and R ³ is methyl or ethyl group).

The compound of formula (VII), which is the starting material of the present invention, can be prepared by the methods described in Acta Cryst, B33, 1549-1556 (1977) and German Laid-open Patent No. 2,112,832. Is reacted with sodium cyanide or potassium cyanide using the Reissert-Kaufmann reaction to obtain a 2-cyano pyridine derivative of formula (VIII). In this reaction, when the excess amount of dimethyl sulfate serving as a catalyst and a reaction solvent is used, the yield of the cyanide compound is significantly increased. Subsequently, the nitro group was substituted with a methoxy group using sodium methoxide to prepare the compound of formula (IX) in high yield. Furthermore, the hydrolysis reaction of the compound of formula (IX) can be carried out in an aqueous solution. In the acidic aqueous solution, the decarboxylation reaction is likely to occur, so that the reaction was carried out in a basic aqueous solution such as potassium hydroxide and sodium hydroxide to prepare a compound of formula (X).

The compound of formula (X) is reacted with lower alcohols such as methanol and ethanol under an acid catalyst such as sulfuric acid, hydrochloric acid or methanesulfonic acid to obtain an ester compound of formula (XI), which is then reduced to sodium borohydride. When sodium borohydride is used for the reduction of the compound of formula (XI), the reduction reaction occurs easily at room temperature in a solvent of alcohols such as methanol, and the reduction reaction can be carried out even in the presence of moisture. It is very important for use. In the case of using lithium aluminum hydride, the reaction should be carried out with great caution because it should be carried out in an ether solvent having a very low flash point in anhydrous state, and even after mass production, the lithium aluminum hydride must be decomposed. there is a problem. Therefore, sodium borohydride is preferably used as the reducing agent. By reacting in this way, the compound of formula (I) was obtained in high yield, and the reaction of thionyl chloride with the method described in German Patent Publication Nos. 2,428,294 and 3,040,248 could also prepare the compound of formula (XII).

The present invention is explained in more detail in the following examples.

Example 1

Preparation of 2-cyano-3,5-dimethyl-4-nitropyridine

168 g of 3,5-dimethyl-4-nitropyridine N-oxide was added to 250 g of dimethyl sulfate, refluxed for 2 hours, and the resulting solid was filtered and dissolved in 500 ml of purified water. Then, 100 g of potassium cyanide was dissolved in 700 ml of purified water. The solution was added dropwise while maintaining the temperature at 0-3 ° C. for 2 hours, and then the resulting precipitate was filtered to give 156 g of the brown title compound.

Melting Point: 70-72 ℃

Elemental Analysis C ₈ H ₇ N ₃ O ₂

Theoretical (%): C; 54,24, H; 3.98, N; 23.72

Found (%): C; 53.87, H; 3.92, N; 24.02

IR: γKBr cm ^-1 : 2,220, 1,550, 1,370, 1,290, 1,045

NMR (CDCl ₃ ) δ: 8.16 (s, 1H), 2.27 (s, 3H), 2.17 (s, 3H)

Example 2

Preparation of 2-cyano-3,5-dimethyl-4-methoxy pyridine

While passing nitrogen gas through the reactor, 25 g of sodium metal was dissolved in 800 ml of methanol, and 177 g of 2-cyano-3,5-dimethyl-4-nitropyridine was added to reflux for 1 hour, and the resulting precipitate was filtered off. The filtrate was concentrated under reduced pressure, 1500 ml of ethyl acetate and 500 ml of purified water were added to the residue, followed by stirring for 30 minutes. The ethyl acetate layer was separated, water was removed with a forget-me-not, and the solvent was removed under reduced pressure. After addition, the mixture was granulated, cooled, stirred for 2 hours, and filtered to obtain 154 g of a pale brown title compound.

Melting Point: 57-59 ℃

Elemental Analysis C ₉ H ₁₀ N ₂ O

Theoretical value (%): C; 66.65, H; 6.21, N; 17.27

Found (%): C; 66.64, H; 6.22, N; 17.31

IR: γKBr cm ^-1 : 2,219, 1,560, 1,470, 1,250, 1,080, 865

NMR (CDCl ₃ ) δ: 8.16 (s, 1H), 3.75 (s, 3H), 2.27 (s, 3H), 2.18 (s, 3H)

Example 3

Preparation of (3,5-dimethyl-4-methoxy-2-pyridyl) carboxylic acid

After refluxing for 3 hours by adding 48 g of 2-cyano-3,5-dimethyl-4-methoxypyridine to 500 ml of 20% aqueous sodium hydroxide solution, the mixture was neutralized with cyclic sulfuric acid, water was removed under reduced pressure, and then 500 ml of methanol was added to the residue. After adding to the filtrate to remove the insolubles, the filtrate was removed under reduced pressure, and the residue was crystallized by adding normal hexane to the residue, followed by filtration to obtain 53 g of a pale brown title compound.

Melting Point: 130-134 ℃

Elemental Analysis C ₉ H ₁₁ NO ₃

Theoretical (%): C; 59.66, H; 6.12, N; 7.73

Found (%): C; 59.68, H; 6.14, N; 7.78

IR: γKBr cm ^-1 : 1,700, 1,570, 1,250, 1,060, 778

NMR (d ₆ -DMSO) δ: 8.16 (s, 1H), 3.75 (s, 3H), 2.27 (s, 3H), 2.18 (s, 3H)

Example 4

Preparation of (3,5-dimethyl-4-methoxy-2-pyridyl) carboxylic acid methyl ester

163 g of (3,5-dimethyl-4-methoxy-2-pyridyl) carboxylic acid and 18 g of concentrated sulfuric acid were added to 1 L of anhydrous methanol, and the mixture was refluxed for 10 hours. Then, methanol was removed under reduced pressure, and 1 L of chloroform was added to the residue. After neutralizing with aqueous potassium carbonate solution, the chloroform layer was separated to completely remove water with a forget-me-not, and the solvent was removed under reduced pressure to obtain 158 g of the title compound in a syrup state.

Elemental Analysis C ₁₀ H ₁₃ NO ₃

Theoretic value (%): C; 61.53, H; 6.71, N; 7.17

Found (%): C; 61.58, H; 6.82, N; 7.22

IR: γKBr cm ^-1 : 2,970, 1,725, 1,565, 1,392, 1,062

NMR (CDCl ₃ ) δ: 8.16 (s, 1H), 3.75 (s, 3H), 3.55 (s, 3H), 2.27 (s, 3H), 2.18 (s, 3H)

Example 5

Preparation of 2-hydroxymethyl-3,5-dimethyl-4-methoxypyridine hydrochloride

97 g of (3,5-dimethyl-4-methoxy-2-pyridyl) carboxylic acid methyl ester and 17 g of sodium borohydride were added to 800 ml of methanol, the mixture was stirred at room temperature for 3 hours, and the residue was removed under reduced pressure. 200 ml of purified water and 1 l of chloroform were added to separate an organic layer, and water was removed with a forget-me-not. Then, the solvent was removed under reduced pressure. 200 ml of methyl ethyl ketone and 50 ml of concentrated hydrochloric acid were added to the residue, which was then cooled and filtered to give 91 g of the title compound as a white solid. Got.

Melting Point: 126-127 ℃

IR: γKBr cm ^-1 : 3,200, 1,608, 1,520, 1,466, 1,200

NMR (d ₆ -DMSO) δ: 8.41 (s, 1H), 4.65 (s, 3H), 3.75 (s, 3H), 2.27 (s, 3H), 2.18 (s, 3H)

Example 6

Preparation of Hydrochloride of 2-Chloromethyl-4-methoxy-3,5-dimethyl Pyridine

102 g of 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine hydrochloride was added to 500 ml of chloroform and cooled to 0-5 ° C., and then 100 ml of thionyl chloride was added while maintaining the temperature below 20 ° C., and 3 at 20 ° C. After stirring for an hour, unreacted thionyl chloride is completely removed by reduced pressure. 250 ml of chloroform was added to the residue, followed by filtration. 750 ml of ethyl ether was added to the filtrate to form particles, which were cooled, stirred for 2 hours, filtered, and the filtrate was washed with ether and dried to give 106 g of the title compound.

Melting Point: 128 ℃

IR: γKBr cm ^-1 : 3,020, 1,785, 1,614, 1,480, 1,310

NMR (CDCl ₃ + d ₆ -DMSO) δ: 8.41 (s, 1H), 4.65 (s, -2H), 3.75 (s, 3H), 2.27 (s, 3H), 2.18 (s, 3H).

Claims (3)

2-hydroxymethylpyridine of formula (I), characterized in that the ester portion of the methyl ester or the ethyl ester compound of the pyridine carboxylic acid represented by formula (XI) is reduced to sodium borohydride in the presence of an alcoholic solvent. Process for the preparation of derivatives.

(Wherein R ¹ and R ² are each hydrogen or methyl group and R ³ is methyl or ethyl group). The preparation of the compound of formula (XI) is characterized in that the compound of formula (IX) is hydrolyzed in a basic aqueous solution to prepare a compound of formula (X), and then reacted with methanol or ethanol under an acid catalyst. How to.

(Herein, R ₃ of R ₁ and R ₂ are as described above.) The preparation of the compound of formula (IX) according to claim 2 is carried out by reacting the compound of formula (VII) with a cyanide of an alkali metal in the presence of an excess of dimethylsulfate to prepare the compound of formula (VIII), and then directly using a nitro group as a methoxy group. A substitution reaction.

(Wherein R ¹ and R ² are as described above).