KR910009956B1 - Process for preparation of benzimidazol derivatives - Google Patents

Abstract

A process for preparing a benzimidazole derivative of formula (I) comprises (a) reacting a cpd. of formula (II) with a cpd. of formula (III) in the presence of a base to obtain a phosphate ester cpd., (b) reacting the obtd. cpd. with benzimidazole-2-thiol of formula (IV), and (c) oxidizing the resulting cpd. to form (I). In the formulas, Y = O or S; R = C1-4 lower alkyl or opt. substd. phenyl. Pref. the cpd. of formula (III) is diethylchlorophosphate, diphenylchlorophosphate, diethylchlorothiophosphate or diphenylchlorothiophosphate. The base is selected from NaH or triethylamine. Cpd. (I) is useful as an antiulcer drug.

Description

Novel Method for Preparing Benzimidazole Derivatives

The present invention relates to a novel process for preparing benzimidazole derivatives represented by the following general formula (I), which is useful as an anti-ulcer agent.

The compound represented by the structural formula (I) is a compound named under the general name of omeprazole, and has been reported to have a particularly excellent effect in the treatment of gastric ulcer.

Conventionally, various methods for preparing benzimidazole derivatives represented by the following structural formula (Ia) have been introduced, for example, British Patent Nos. 1,500,043 and 2,134,523, Japanese Patent Publication Nos. 57-053,406 and 57- 039,622, etc., and these methods can be summarized into the following three categories.

In the structural formula, n represents an integer of 0 or 1.

<Method I>

A method for preparing a compound of formula (I ′) by reacting a pyridine derivative of formula (A) with a substituted benzimidazole-2-thiol of formula (B)

In the above structural formula, X means leaving groups such as chloro, bromo, iodine, paratoluenesulfonyloxy and methanesulfonyloxy.

[Method I] is a widely used method, but has a disadvantage in that the yield of the reaction is poor because the compound of formula (A), which is an intermediate, is unstable and easily decomposed.

<Method II>

A method for preparing the compound of formula (I ′) by cyclization of the substituted 2-pyridylmethyl thioformic acid of formula (C) with the substituted phenylenediamine of formula (D).

In Method II, a method of preparing the compound of formula (C) is very difficult, and the yield of the compound of formula (I ′), which is a target compound, is extremely low because the compound of formula (C) is very unstable.

<Method III>

Method for preparing the compound of formula (I) by reacting the substituted 2-substituted pyridine of formula (E) with the compound of formula (F)

In the structural formula X is as described above, M means an alkali metal, such as lithium sodium, potassium.

In <Method III>, too, the production of the compound of formula (F) is difficult and the yield of the compound of formula (I) is poor because the compound itself is very unstable.

In addition to the above-mentioned method, several manufacturing methods are disclosed in Korean Patent Publication Nos. 88-1714, 89-1405, and 89-1404, but there are disadvantages as described above.

Thus, the methods used in the prior art have a problem that the production of the target compound is extremely poor because the production of the reactant is very difficult or the intermediate compound is very unstable, and there is room for improvement.

Accordingly, the present invention provides a novel preparation method for producing a benzimidazole derivative of the above formula (I), which is usefully used as an anti-ulcer agent, so that a series of manufacturing processes are easier than the conventional methods, and the yield of the target compound is greatly improved. The purpose is to provide.

Hereinafter, the present invention will be described in detail.

In the present invention, in preparing the benzimidazole derivative of formula (I), the alcohol of the following formula (II) is reacted with phosphate of the following formula (III) in the presence of a base to obtain a phosphate ester compound of the following formula (IV), In addition, benzimidazole-2-thiol of Structural Formula (B) is reacted to obtain Structural Formula (I ′), which is oxidized to produce Structural Formula (I).

In the above structural formulas, Y represents oxygen or a sulfur atom, and R represents C _1-4 lower alkyl or a phenyl group which may be substituted.

In the present invention, the solvent for preparing the compound of formula (IV) is a polar solvent except alcohols, that is, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, diethyl ether, tetrahydrofuran , 1.4-dioxane and the like can be used, but the most preferred are the bicyclic ethers tetrahydrofuran and 1.4-dioxane.

In addition, the compound of formula (III) may be used in the amount of 1 to 2 equivalents based on the alcohol of the formula (II), about 1.2 equivalents is most preferred.

The base used at this time is triethylamine, N, N'-tetramethyl ethylenediamine (TMEDA), trimethylamine, pyridine, sodium hydride (NaH), sodium alkoxide (NaOR ¹ ), sodium amide (NaNH ₂ ), lithium Diisopropylamide (LDA), normal butyllithium (n-BuLi), etc. may be used, but triethylamine, trimethylamine when Y is an oxygen atom, and sodium hydride (NaH) when Y is a sulfur atom Most preferred.

And, the reaction temperature may be carried out at 0 ℃ to reflux temperature, but it is preferable to proceed at room temperature.

On the other hand, the compound of formula (IV) is stable in a protic solvent (aqueous solution, such as an aqueous solution or alcohol) and hardly decomposes on silica gel.

In addition, the compound of formula IV can be used for the next reaction in a one-pot reaction without separation.

In the present invention, in order to prepare the compound of formula (I ′), the compound of formula (B) is reacted with the formula (IV), wherein the solvent used is methanol, ethanol, isopropyl alcohol, N, N-dimethyl. Formamide, N, N-dimethylacetamide, tetrahydrofuran, 1.4-dioxane and the like can be used, but alcohols such as methanol and ethanol are most preferred.

In addition, sodium alkoxide (NaOR ¹ ) may be most preferably used as the base used in this reaction, and the reaction is completed in 1 to 5 hours at reflux temperature.

The oxidation reaction for preparing the compound of formula (I) from the compound of formula (I ′) prepared in this manner uses a known method, wherein meta-chloroperbenzoic acid, perbenzoic acid, hydrogen peroxide, sodium metaperiodate, etc. Although it can be used, it is most preferable to use meta-chloroperbenzoic acid, perbenzoic acid, and the like.

The present invention is characterized by the high yield of the desired compound of formula (I) using the compound of formula (IV), which is a new and stable phosphate ester intermediate as compared to existing methods.

Hereinafter, the present invention will be described in more detail with reference to the following examples, and the present invention is not necessarily limited to the following examples.

Example 1

[Preparation of 3, 5-dimethyl-4-methoxy-2- (diphenylphosphoryloxy) methyl pyridine]

3, 5-Dimethyl-4-methoxy-2-hydroxymethylpyridine (1.67 g, 10 mM) is dissolved in tetrahydrofuran (20 ml) and triethylamine (1.68 ml, 12 mM) is added.

After stirring the solution for 10 minutes at room temperature, diphenylchlorophosphate (2.49ml, 12mM) is added dropwise over 30 minutes.

Thereafter, the reaction solution is stirred at room temperature for 2 hours, and when the reaction is completed, the solvent is removed by distillation under reduced pressure. Then, distilled water (30 ml) was added to the residue, followed by extraction with dichloromethane (2 × 30 ml). The extracts were combined and washed sequentially with saturated sodium hydrogen carbonate solution (30 ml) and saturated brine (30 ml). To obtain the title compound.

Analytical samples are obtained by purification by column chromatography (developing solvent ethyl acetate / hexane = 1: 1).

Example 2

[Production of 3,5-dimethyl-4-methoxy-2- (diethylthiophosphoryloxy) methyl pyridine]

3, 5-dimethyl-4-methoxy-2-hydroxymethylpyridine (3.34g, 20mM) was dissolved in tetrahydrofuran (30ml), cooled to 0 ° C and NaH (0.58g, 24mM) in solid state. Add.

After that, the reaction solution was heated to room temperature and reacted for 2 hours, and the solvent was distilled off under reduced pressure. Then, distilled water (40 ml) was added to the residue, ethyl acetate (2 × 40 ml) was added, the extracts were combined, and washed with saturated brine (40 ml). MgSO ₄ was added to dehydrate and filtered to distill the filtrate under reduced pressure to give the title compound as a colorless oil.

Example 3

[Preparation of 5-methoxy-2-[(3.5-dimethyl-4-methoxypyridylmethyl) thio]-(1H) -benzimidazole]

5-methoxy-2-mercaptobenzimidazole (5.94 g, 33 mM) and NaOH (1.58 g, 40 mM) are turbid in methanol (100 ml) and heated to reflux.

To the solution was added dropwise a solution of 3.5-dimethyl-4-methoxy-2- (diethylthiophosphoryloxy) methyl pyridine (10.51g, 33mM) prepared in Example 2 in methanol (30ml) for 30 minutes. .

Thereafter, the reaction solution was heated to reflux for 2 hours and cooled to room temperature to remove the solvent by distillation under reduced pressure. Then, distilled water (100 ml) was added to the residue, dichloromethane (2 × 50 ml) was extracted, dehydrated and distilled under reduced pressure to obtain the title compound as a light brown oil.

Analytical samples are obtained using column chromatography (developing solvent ethyl acetate / hexane = 2: 1).

Example 4

[Preparation of 5-methoxy-2-[(3,5-dimethyl-4-methoxypyridylmethyl) thio]-(1H) -benzimidazole]

3, 5-dimethyl-4-methoxy-2-hydroxymethylpyridine (1.67 g, 10 mM) is dissolved in tetrahydrofuran (20 ml), 1.68 ml (12 mM) of triethylamine is added and stirred at room temperature for 10 minutes.

Diphenylchlorophosphate (2.49ml, 12mM) was added dropwise to the solution over 30 minutes, reacted at room temperature for 2 hours, and the resulting crystals were filtered off.

Meanwhile, in the other reaction vessel, 5-methoxy-2-mercaptobenzimidazole (1.80 g, 10 mM) and NaOH (0.48 g, 12 mM) were dissolved in methanol (20 ml) and heated to reflux to prepare the phosphate ester solution prepared above. Drop for 30 minutes.

Thereafter, the mixture was heated to reflux for 1 hour, cooled to room temperature, the pH was adjusted to neutral (pH 7.0), and the solvent was removed by distillation under reduced pressure.

Then, distilled water (50 ml) was added to the residue, followed by extraction with dichloromethane (2 x 50 ml), followed by washing with saturated brine (50 ml), dehydration with MgSO ₄ , and evaporation under reduced pressure to obtain a pale brown title compound as an oil phase.

Example 5

[Preparation of 5-methoxy-2-[(3,5-dimethyl-4-methoxypyridylmethyl) sulfinyl]-(1H) -benzimidazole]

5-methoxy-2-[(3,5-dimethyl-4-methoxypyridylmethyl) thio]-(1H) -benzimidazole (0.83 g, 2.52 mM) prepared in Example 3 was added to chloroform ( 10 ml) and cooled to -15 ° C to -20 ° C.

To the solution, a solution of 85% meta-chloroperbenzoic acid (0.52 g, 2.52 mM) in chloroform (5 ml) was added dropwise at the same temperature for 30 minutes.

After stirring for 20 minutes at the same temperature, saturated sodium hydrogen carbonate solution (10 ml) was added and washed. The chloroform layer was dehydrated with MgSO ₄ , filtered and evaporated under reduced pressure. Then, acetone (10 ml) was added to the residue, crystallized and filtered to give the title compound as white crystals.

Claims (3)

In preparing the benzimidazole derivative, an alcohol of the following structural formula (II) is reacted with a compound of the following structural formula (III) in the presence of a base to obtain a phosphate ester compound of the following structural formula (IV), and a compound of the following structural formula (B) A reaction method for producing a benzimidazole derivative, characterized in that the compound of formula (I ') is obtained by oxidizing to form a compound of formula (I).

In the formulas, Y represents oxygen or a sulfur atom, and R represents C _1-4 lower alkyl or a phenyl group which may be substituted. The method for producing benzimidazole derivatives according to claim 1, wherein diethylchlorophosphate, diphenylchlorophosphate, diethylchlorothiophosphate, or diphenylchlorothiophosphate is used as the compound of the formula (III). The base used in the preparation of the compound of the formula (IV) is NaH when Y in the formulas (III) and (IV) is a sulfur atom, and triethyl when Y is an oxygen atom. A method for producing a benzimidazole derivative, characterized by using an amine.