KR940006531B1 - Process for preparation of pyridine derivatives - Google Patents

Abstract

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Description

Method for preparing pyridine derivative

The present invention relates to a process for the preparation of pyridine derivatives represented by the following general formula (I '), which is an important intermediate for preparing omeprazole.

In the above formula, X represents a methoxy group or halogen.

Omeprazole and its derivatives are excellent in inhibiting gastric acid secretion and are useful for treating gastrointestinal inflammatory diseases, including wee ulcer and duodenal ulcer, and have the following structural formula.

Wherein A and B are the same or different and each represents hydrogen, alkyl, halogen carbomethoxy, alkoxy or alkanoyl, wherein the compound in which A is a 5-methoxy group and B is hydrogen is an omeprazole.

The compound of the general formula (I ′) of the present invention is an important intermediate for synthesizing oeprazole and derivatives, which is very important in preparing omeprazole and its derivatives.

Korean Patent Publication No. 88-91 discloses a method for synthesizing a compound of the above general formula (I ') derivative. For example, the reaction operation is complicated and the synthesis conditions are difficult due to the synthetic route of selectively introducing a suitable group at each position of the pyridine ring by using a pyridine derivative such as 2,3,5-collidine as a starting material. . This is represented by the following reaction scheme. The final product, 2-hydroxymethyl pyridine derivative, is further reacted with halogen or the like to pyridine methyl radical to synthesize pyridine derivative for preparing omeprazole.

This conventional patent method, first, the synthesis of 2,3,5-collidine and pyridine derivatives used as starting material is not easy to position the substituted methyl, in fact starting materials such as 3,5-lutidine The reaction to selectively introduce an alkyl group at position 2 into the material must be preceded.

Secondly, the overall synthesis route has complex and difficult synthesis conditions due to the continuous operation of oxidation, reduction, introduction, and monocyclic reaction for selectively introducing an appropriate group at each position of the pyridine ring.

Therefore, the process is long due to the selection of the starting material in the pyridine derivative and the selective introduction of a suitable group at each position, the process is long, the synthesis conditions are difficult, and the manufacturing cost of the starting material is expensive.

However, the present invention is characterized in that a compound of the general formula (I ′) can be easily synthesized by reacting a diene and a dienopyrocarbodiimide compound already substituted with a desired group at each appropriate position.

The present inventors have completed the present invention by finding that the desired material can be prepared simply by forming pyridine as soon as the reaction is carried out using a starting material that already contains desired groups at a suitable position through the following synthetic route. It was.

In the above formula, R ¹ is an alkyloxycarbonyl group having ¹ to 6 carbon atoms, R ² is a methanesulfonyl group, and X is as defined above.

At this time, R ¹ is alkyl having 1-6 carbon atoms to protect the carboxyl group, and R ² is a group having a strong electron affinity such as p-toluenesulfonyl, benzenesulfonyl or ethanesulfonyl, to easily cause 6-membered ring formation reaction. Along with their role, they aid in the dehydrogenation of the pyridine ring.

Most preferably, R ¹ is -COOBu and R ² is a p-toluenesulfonyl group.

That is, a heteroaromatic six-membered ring containing one nitrogen atom of formula (D) by reacting a diene compound of formula (B) and a carbodiimide compound of formula (C) with the desired groups introduced at an appropriate position thereof. When preparing the compound, and proceed with the pyridine ring forming reaction in the presence of a hydroxyl group by continuous while up with the hydrolysis and release reaction of the R ² of the R ¹ easily for manufacture of an intermediate of omeprazole and their derivatives of the above formula (I ') Pyridine derivatives can be synthesized.

The compound of formula (I ′) thus prepared may be converted to the corresponding hydroxymethyl group by reduction with a conventional reducing agent such as lithium aluminum hydride or sodium boron hydride.

In addition, the corresponding hydroxymethyl compounds thus prepared can be prepared with the corresponding methyl halide compounds by treatment with conventional hydrogen halides.

The reaction of the present invention is preferably reacted in the presence of a catalyst such as anhydrous aluminum chloride or the like.

In other words, a diene compound of formula (B) was synthesized from 2-methyl-1-penten-3-one and aluminium chloride was used as a catalyst, for example, Nn-butyloxycarbonyl, which is one of compounds of formula (C). Reaction with methylene-p-toluenesulfonamide yields the pyridine compound of formula (D) in high yield and then the reaction derivatives are added to a solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide to react with the compound of formula (I '). Compounds are readily obtained and if necessary reduce the carboxyl group to the hydroxymethyl group with a reducing agent throughout.

Nn-butyloxycarbomethylene-p-toluenesulfonamide, which is a starting material used in the present invention, is synthesized by a known method and used as a reactant, 3-methoxy-2-ethyl- 1,3-pentadiene is synthesized by reacting 2-methyl-1-penten-3-one with triethylamine, trimethylamine and methyl iodine as follows. Similarly other reactants or starting materials are readily prepared and used in a similar manner to these reactions.

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

Example 1

130 g of n-butylglyoxylate and 220 g of N-sulfinyl-p-toluenesulfonamide were dissolved in 1,000 ml of benzene and refluxed for 3 hours while slowly dropping 45 g of aluminum chloride into a solution dissolved in 250 ml of nitrobenzene.

The reactant was cooled to room temperature, washed once with 250 ml of distilled water, and the solvent was distilled off under reduced pressure. Then, 190 g of pure Nn-butyloxycarbonylethylene-p-toluenesulfonamide with a boiling point of 130-135 ° C. was purified at 10 ⁻³ torr. Material was obtained.

C ₁₃ H ₁₇ NO ₄ S (283.4):

Theoretical: C; 55.14, H; 6.12, N; 5.04 S; 11.14

Found: C; 55.10 H; 6.05 N; 4.95 S; 11.32

Example 2

1.5 g of cupric chloride anhydride was added to 85 g of triethylamine, and the mixture was stirred at room temperature for 1 hour. The solution was slowly added to a solution of 35 g of 2-methyl-1-penten-3-one dissolved in 85 ml of benzene.

100 g of methyl iodine was added to the reaction vessel and stirred for 3 hours, followed by stirring for 1 hour at 40 ° C., and the reaction mixture was cooled to room temperature and extracted with ether.

The solvent was distilled off under reduced pressure, followed by distillation under reduced pressure to obtain 27 g of pure 3-methoxy-2-methyl-pentadiene distilled at 45-49 ° C. at 10 mmHg.

NMR (CDCl ₃ ): 1.62 (d, 3H), 1.70 (s, 3H), 3.20 (s, 2H) 3.68 (s, 3H), 4.79 (q, 1H)

Example 3

After dissolving 27 g of 3-methoxy-2-methyl-pentadiene in 250 ml of dichloroethane and adding 10.7 g of aluminum chloride, 68 g of Nn-butyloxycarbonylethylene-p-toluenesulfonamide synthesized in Example 1 was prepared at room temperature. I put it slowly.

The reaction mixture was stirred for 3 hours, filtered through Celite 545, the solvent was distilled off under reduced pressure, and 250 ml of ethane and 27 g of potassium hydroxide were added to reflux for 10 hours. The reaction mixture was cooled to room temperature and extracted with ether to give 15 g of 3,5-dimethyl-4-methoxy-pyridine-2-carboxylic acid.

NMR (CDCl ₃ ): 2.21 (s, 3H), 2.29 (s, 3H), 3.81 (s, 3H), 4.56 (br, 1H), 8.18 (s, 1H)

Claims (1)

A compound of formula (B) and a compound of formula (C) are reacted in the presence of AlCl ₃ to form a cyclic compound of formula (D), and subsequently refluxed in a solution of an alkali metal hydroxide to pyridine derivative of formula (I ′). How to prepare. In the above formulas, R ¹ is an alkyloxycarbonyl group having 1-6 carbon atoms, R ² is a p-toluenesulfonyl group, a benzenesulfonyl group or a methanesulfonyl groupimmer, and X is a methoxy group or a halogen atom.