KR20120129317A - Manufacturing Method Of Hetero Cyclic Compound - Google Patents

Abstract

PURPOSE: A manufacturing method of heterocyclic compounds is provided to shorten operation time and to simplify the operation process and to manufacture the compounds at high purity and high yield. CONSTITUTION: A manufacturing method of heterocyclic compounds of chemical formula 1 comprises a step of reacting a compound of chemical formula 2 with active materials. The active material is inorganic base or pyridine. The inorganic base is hydroxysalt of alkali metal. The hydroxysalt of the alkali metal is NaOH, lithium hydroxide or potassium hydroxide. 1-10 equivalent of the inorganic base is used based on 1 equivalent of the compound of chemical formula 2. 1-30 ml of the pyridine is used based on 1g of the compound of the chemical formula 2. 0.5-200 equivalent of pyridine is used based on 1 equivalent of inorganic base. The reaction temperature is 0-100 deg. Celsius. The compound of the chemical formula 2 is manufactured by reacting a compound of chemical formula 3 with alkylchloroformate.

Description

Manufacturing Method Of Hetero Cyclic Compound

The present invention relates to a method for preparing a heterocyclic compound in which a reaction proceeds continuously (one-pot reaction) in one reactor unlike in the conventional stepwise process.

Heterocyclic compounds represented by the following formula (1), in particular azylartan represented by R ₂ is an ethyl group, such as 2-ethoxy-1-[[2`- (2,5-dihydro-5-oxo-1,2 , 4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid is an antagonist of the angiotensin II receptor.

Angiotensin II causes vasoconstriction and promotes aldosterone secretion, leading to sodium and water retention, leading to increased fluids and increased blood pressure. This vasoconstriction is fatal to patients suffering from hypertension.

Since azilartan is an antagonist of angiotensin II receptor, it inhibits blood vessel contraction and aldosterone secretion by inhibiting binding between angiotensin II and AT ₁ receptor. In addition, azylsartan shows an excellent blood pressure lowering effect compared to commercially available diovan (component name: valsartan) and olmetec (component name: olmesartan).

The US Food and Drug Administration (FDA) has approved azilsartan medoxomil, a pro-drug of azilsartan, for the treatment of hypertension.

Conventional Korean Patent No. 233,689 (registered on September 14, 1999) was prepared azylartan according to the method of Scheme 1. As shown in Scheme 1, compound (III) was prepared by reacting compound (I) with ethylchloroformate (ECC) to prepare compound (II) and refluxing in a xylene solvent to proceed with a cyclization reaction. Prepared. Further, compound (IV) (azylsartan) was prepared by adding lithium hydroxide (LiOH) to compound (III) to proceed with a hydrolysis reaction. However, such a prior art includes a purification process using column chromatography, so mass production is not possible and is not commercially easy.

[Reaction Scheme 1]

In addition, the Journal of Medicinal Chemistry 1996, 39 , 5228 ~ 5235 discloses a method for preparing azilsartan according to the following scheme 2. This technique is carried out by reacting compound (I) with 2-ethylhexylchloroformate (EHC) to produce compound (V) and refluxing in a xylene solvent to proceed with the cyclization reaction as shown in Scheme 2. Compound (III) was prepared. Furthermore, compound IV was prepared by adding sodium hydroxide (NaOH) to compound (III) to proceed with a hydrolysis reaction.

Scheme 2

The prior arts for preparing acetylsartan may be exposed to xylene gas by heating and refluxing xylene, a carcinogen harmful to the human body, at a high temperature, and distilling the xylene under reduced pressure after the cyclization reaction is completed. There is a problem that it is difficult to treat the waste xylene during removal. In addition, since the reaction proceeds at a high temperature, impurities are generated to lower purity and yield. The cyclization reaction with xylene yields a low yield of 23%, which results in lower yield of nitsarartan.

The present invention provides a method for preparing a heterocyclic compound in which a cyclization reaction and a hydrolysis reaction can be continuously performed (one-pot reaction) by using water and an active substance in a compound having an acyl derivative, which has been progressed step by step. It aims to provide.

Another object of the present invention is to provide a method for producing a heterocyclic compound having high purity and high yield.

In order to achieve the above object, the method for preparing a heterocyclic compound of the present invention includes preparing a heterocyclic compound of Chemical Formula 1 by reacting a compound of Chemical Formula 2 with water and an active substance.

[Formula 1]

Wherein R ₁ is selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and a cycloalkyl group having 3 to 6 carbon atoms, and R ₂ and R ₃ are selected from the group consisting of an alkyl group having 1 to 8 carbon atoms.

The active substance is at least one selected from the group consisting of inorganic bases and pyridine.

The inorganic base is a hydroxy salt of an alkali metal, the hydroxy salt of an alkali metal is at least one selected from the group consisting of sodium hydroxide, lithium hydroxide and potassium hydroxide.

The inorganic base is used in an amount of 1 to 10 equivalents based on 1 equivalent of the compound of Formula 2, and pyridine is used in an amount of 1 to 30 ml based on 1 g of the compound of Formula 2. When an inorganic base and pyridine are used together, pyridine is used in an amount of 0.5 to 200 equivalents based on 1 equivalent of the inorganic base.

In addition, the compound of formula 3 is reacted with alkylchloroformate to produce formula 2.

Wherein R ₁ is selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and a cycloalkyl group having 3 to 6 carbon atoms, and R ₂ is selected from the group consisting of an alkyl group having 1 to 8 carbon atoms.

The alkylchloroformate is ethylchloroformate or 2-ethylhexylchloroformate.

In the present invention, since the cyclization reaction and the hydrolysis reaction proceed continuously from the compound having an acyl derivative to the one-pot reaction, the work process is simple and mass production is possible, and the process time is halved compared with the conventional process. It is shortened.

The present invention also provides 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4- Since the purity of the mono] methyl] benzimidazole-7-carboxylic acid is 98% or more, no further purification step is required, and if necessary, it may be purified and manufactured to have a purity of 99.5% or more.

In addition, the present invention, unlike the prior art using xylene refluxed at a high temperature, because the reaction proceeds under mild conditions and one-pot can obtain a high yield.

According to the present invention, a cyclization reaction and a hydrolysis reaction are performed in a reactor using water and an active substance to a compound having an acyl derivative, thereby performing a one-pot reaction unlike a conventional step-by-step process. It is possible to simplify the working process and shorten the process time, and to prepare a heterocyclic compound of Formula 1 which can obtain a compound with high purity (more than 98%) and high yield (70 to 85%) without additional purification process. will be.

Hereinafter, the present invention will be described in detail.

The present invention is a heterocyclic compound represented by Chemical Formula 1 as a one-pot reaction in which a cyclization reaction and a hydrolysis reaction are continuously performed by reacting a compound of Chemical Formula 2 having an acyl derivative with water and an active substance. Is manufactured.

Here, the one-pot reaction means that the reaction proceeds continuously in one reactor.

 [Formula 1]

[Formula 2]

Wherein R ₁ is selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and a cycloalkyl group having 3 to 6 carbon atoms, and R ₂ and R ₃ are selected from the group consisting of an alkyl group having 1 to 8 carbon atoms.

The active substance is to perform a cyclization reaction and a hydrolysis reaction, and specific examples thereof include one or two or more selected from the group consisting of inorganic bases and pyridine.

Specific examples of the inorganic base may include a hydroxy salt of an alkali metal, and more specifically, may include one or two or more selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, and the like. Sodium hydroxide is used.

The inorganic base is used in an amount of 1 to 10 equivalents, preferably 4 to 5 equivalents, based on 1 equivalent of the compound of formula (2). If the inorganic base is less than 1 equivalent to 1 equivalent of the compound of Formula 2, the yield may be lowered, and if it is more than 10 equivalents, the impurities may be increased.

In addition, pyridine is used in an amount of 1 to 30 ml, preferably 10 to 20 ml, based on 1 g of the compound of formula (2). When the active substance is less than 1 ml with respect to 1 g of the compound of Formula 2, the stirring may not be smooth and the yield may be reduced. When the active substance is more than 30 ml, the reaction time increases or the delay of removing the solvent after completion of the reaction yields the yield. This can be degraded.

When the inorganic base and the pyridine are used as the active substance, the amount of the pyridine is 0.5 to 200 equivalents, preferably 10 to 40 equivalents, based on 1 equivalent of the inorganic base. If the pyridine is less than 0.5 equivalent to 1 equivalent of the inorganic base, the stirring may not be smooth and the yield may be reduced. If the pyridine is more than 200 equivalent, the reaction time may increase or the yield may be lowered.

The compound of Formula 1 is prepared by adding water and an active substance to the compound of Formula 2, followed by stirring for 1 to 10 hours at a temperature of 0 to 100 ℃, preferably 40 to 80 ℃. If the temperature is less than 0 ° C., there is a problem that the yield is lowered. If the temperature is above 100 ° C., impurities tend to increase.

In addition, the compound represented by the formula (2) is prepared by reacting the compound of formula (3) with alkylchloroformate.

(3)

Wherein R ₁ is selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and a cycloalkyl group having 3 to 6 carbon atoms, and R ₂ is selected from the group consisting of an alkyl group having 1 to 8 carbon atoms.

The alkylchloroformate is an acylated amine alcohol, and specific examples thereof include ethylchloroformate or 2-ethylhexylchloroformate, preferably ethylchloroformate.

The compound of formula 2 is prepared by adding alkylchloroformate to the compound of formula 3, followed by stirring for 1 to 3 hours at -10 to 25 ℃, preferably 0 to 25 ℃.

When the cyclization reaction and the hydrolysis reaction from the compound of Formula 2 to the compound of Formula 1 are completed, the compound represented by Formula 1 is separated by adjusting the pH value to be in the range of 2 to 3 using an acid. In addition, if necessary, it can be separated by using a water-immiscible solvent, specifically, ethyl acetate.

According to the preparation method of the present invention, 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) represented by Chemical Formula 1) Biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid is prepared in high yield (70-85%) and high purity (98% or more).

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the present invention. Such variations and modifications are intended to be within the scope of the appended claims.

Production Example 1

10.0 g of methyl 2-ethoxy-1-[[2`-hydroxycarbaimidoyl] biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate was added to the container, followed by pyridine. Methyl 2-ethoxy-1-[[2′-ethoxycarbonyloxy] having an acyl derivative was added by dissolving 200 ml and then slowly adding 2.4 ml of ethylchloroformate at 5 ° C. and stirring the mixture at 25 ° C. for 1 hour. Carbamimidoyl] biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate was prepared.

Production Example 2

10.0 g of methyl 2-ethoxy-1-[[2`-hydroxycarbamidomiyl] biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate was added to the container, followed by After dissolving by adding 3.5 ml of ethylamine, 2.36 ml of ethylchloroformate was slowly added at 5 ° C, and stirred at 25 ° C for 1 hour. Solid was filtered out from the reaction mixture, the solution was concentrated under reduced pressure at 40 ℃ and crystallized with ethyl acetate and hexane to give a compound 10.8g (yield: 93.0%) having an acyl derivative.

Preparation Example 3.

10.0 g of ethyl 2-ethoxy-1-[[2`-hydroxycarbamidomiyl] biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate was added to the container, followed by pyridine. 200 ml of ethyl 2-ethoxy-1-[[2′-ethoxycarbonyloxy having an acyl derivative was obtained by slowly adding 2.3 ml of ethylchloroformate at 5 ° C. and stirring the mixture at 25 ° C. for 1.5 hours. Carbamimidoyl] biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate was prepared.

Preparation Example 4.

10.0 g of ethyl 2-ethoxy-1-[[2′-hydroxycarbamidomiyl] biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate and tetrahydrofuran 150 in a container After adding ml and dissolving, 3.4 ml of triethylamine was added, and 2.3 ml of ethylchloroformate was slowly added at 5 ° C, and stirred at 25 ° C for 1 hour. Solid was filtered out from the reaction mixture, the solution was concentrated under reduced pressure at 40 ℃ and crystallized with ethyl acetate and hexane to give a compound 10.6g (yield: 92.0%) having an acyl derivative.

Example 1: 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl Preparation of Benzimidazole-7-carboxylic Acid

100 ml of an aqueous 1 M sodium hydroxide solution was added to a vessel containing pyridine and a compound having an acyl derivative prepared in Preparation Example 1, followed by stirring at 50 ° C. for 4 hours. Thereafter, the reaction solution to which 1 M aqueous sodium hydroxide solution was added was cooled to 25 ° C, and 100 ml of water and 400 ml of ethyl acetate were added. The reaction product to which water and ethyl acetate was added was cooled to 5 ° C. and adjusted to a pH value of 3 with 6M aqueous hydrochloric acid solution. The separated organic layer was washed with 100 ml of 1M hydrochloric acid aqueous solution and 100 ml of water, and then the organic layer was concentrated under reduced pressure at 40 ° C. and crystallized to obtain 7.59 g (yield: 75.5%) of the target compound.

¹ H NMR (400 MHz, DMSO) δ : 1.38 (3H, t, J = 7.2), 4.59 (2H, q, J = 7.2), 5.68 (2H, s), 7.03-7.56 (11H, m).

Purity Measurement (HPLC): 98.7%

Example 2: 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl Preparation of Benzimidazole-7-carboxylic Acid

10.8 g of the compound having an acyl derivative prepared in Preparation Example 2 was added to the vessel, followed by addition of 200 ml of pyridine and 100 ml of 1M sodium hydroxide aqueous solution, followed by stirring at 50 ° C. for 4 hours. The stirred reaction was then cooled to 25 ° C. and 100 ml of water and 400 ml of ethyl acetate were added. The reaction product to which water and ethyl acetate was added was cooled to 5 ° C. and adjusted to a pH value of 3 with 6M aqueous hydrochloric acid solution. The separated organic layer was washed with 100 mL of 1M hydrochloric acid aqueous solution and 100 mL of water, and then the organic layer was concentrated under reduced pressure at 40 ° C. and crystallized to obtain 7.7 g (yield: 84.4%) of the target compound.

¹ H NMR (400 MHz, DMSO) δ : 1.38 (3H, t, J = 7.2), 4.59 (2H, q, J = 7.2), 5.68 (2H, s), 7.03-7.56 (11H, m).

Purity Measurement (HPLC): 99.04%

Example 3: 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl Preparation of Benzimidazole-7-carboxylic Acid

100 ml of an aqueous 1 M sodium hydroxide solution was added to a container containing pyridine and a compound having an acyl derivative prepared in Preparation Example 3, followed by stirring at 50 ° C. for 7 hours. Thereafter, the reaction solution to which 1 M aqueous sodium hydroxide solution was added was cooled to 25 ° C, and 100 ml of water and 400 ml of ethyl acetate were added. The reaction product to which water and ethyl acetate was added was cooled to 5 ° C. and adjusted to a pH value of 3 with 6M aqueous hydrochloric acid solution. The separated organic layer was washed with 100 ml of 1 M aqueous hydrochloric acid solution and 100 ml of water, and then the organic layer was concentrated under reduced pressure at 40 ° C. and crystallized to prepare 7.4 g (yield: 77.2%) of the title compound.

¹ H NMR (400 MHz, DMSO) δ : 1.38 (3H, t, J = 7.2), 4.59 (2H, q, J = 7.2), 5.67 (2H, s), 7.03-7.68 (11H, m).

Purity Measurement (HPLC): 98.7%

Example 4: 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl Preparation of Benzimidazole-7-carboxylic Acid

10.6 g of a compound having an acyl derivative prepared in Preparation Example 4 was added to a container, followed by addition of 200 ml of pyridine and 100 ml of a 1M sodium hydroxide aqueous solution, followed by stirring at 50 ° C. for 7 hours. The stirred reaction was then cooled to 25 ° C. and 100 ml of water and 400 ml of ethyl acetate were added. The reaction product to which water and ethyl acetate was added was cooled to 5 ° C. and adjusted to a pH value of 3 with 6M aqueous hydrochloric acid solution. The separated organic layer was washed with 100 mL of 1M hydrochloric acid aqueous solution and 100 mL of water, and then the organic layer was concentrated under reduced pressure at 40 ° C. and crystallized to prepare 6.8 g of a target compound (yield: 78.0%).

¹ H NMR (400 MHz, DMSO) δ : 1.38 (3H, t, J = 7.2), 4.59 (2H, q, J = 7.2), 5.67 (2H, s), 7.03-7.68 (11H, m).

Purity measurement (HPLC): 99.5%

Example 5: 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl Preparation of Benzimidazole-7-carboxylic Acid

10.0 g of the compound having an acyl derivative prepared in Preparation Example 2 was added to a container, and then 100 ml of a 1 M sodium hydroxide aqueous solution was added thereto, followed by stirring at 80 ° C. for 2 hours. The stirred reaction was then cooled to 25 ° C. and 100 ml of water and 400 ml of ethyl acetate were added. The reaction product to which water and ethyl acetate was added was cooled to 5 ° C. and adjusted to a pH value of 3 with 6M aqueous hydrochloric acid solution. The separated organic layer was washed with 100 ml of 1M hydrochloric acid aqueous solution and 100 ml of water, and then the organic layer was concentrated under reduced pressure at 40 ° C. and crystallized to prepare 6.2 g (yield: 71.0%) of the target compound.

¹ H NMR (400 MHz, DMSO) δ : 1.38 (3H, t, J = 7.2), 4.59 (2H, q, J = 7.2), 5.68 (2H, s), 7.03-7.56 (11H, m).

Purity Measurement (HPLC): 94.4%

Example 6: 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl Preparation of Benzimidazole-7-carboxylic Acid

10.0 g of the compound having an acyl derivative prepared in Preparation Example 2 was added to a container, and then 100 ml of an aqueous 1 M sodium hydroxide solution was added thereto, followed by stirring at 80 ° C. for 4 hours. The stirred reaction was then cooled to 25 ° C. and 100 ml of water and 400 ml of ethyl acetate were added. The reaction product to which water and ethyl acetate was added was cooled to 5 ° C. and adjusted to a pH value of 3 with 6M aqueous hydrochloric acid solution. The separated organic layer was washed with 100 mL of 1M hydrochloric acid aqueous solution and 100 mL of water, and the organic layer was concentrated under reduced pressure at 40 ° C. and crystallized to prepare 6.0 g (yield: 74.0%) of the target compound.

¹ H NMR (400 MHz, DMSO) δ : 1.38 (3H, t, J = 7.2), 4.59 (2H, q, J = 7.2), 5.68 (2H, s), 7.03-7.56 (11H, m).

Purity Measurement (HPLC): 88.0%

Comparative Example 1: Methyl 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] Preparation of Methyl] benzimidazole-7-carboxylate

30 ml of tetrahydrofuran (THF), 0.2 g of triethylamine and methyl 2-ethoxy-1-[[2-hydroxycarbamidomiyl) biphenyl) -4-yl] methyl] -1H-benzimidazole To the stirred suspension of 0.90 g of -7-carboxylate, 0.22 g of ethylchlorocarbonate and 2 ml of methylene chloride are added dropwise under ice-cooling. The mixture is stirred at room temperature for 2 hours, the insoluble material is filtered off and the filtrate is concentrated to dryness. 5 ml of ethyl acetate was added to the concentrate, the insoluble matter was filtered off, and the filtrate was concentrated to dryness. The mixture of residue in 10 ml of xylene is heated at reflux for 1.5 h. Ethyl acetate is added to the reaction mixture, which is washed with water, concentrated to dryness and dried again. The residue is purified by silica gel column chromatography to give crystals. 0.22 g (yield: 23%) of colorless footnotes were prepared by recrystallization from ethyl acetate-isopropyl ether.

Comparative Example 2: 2-Ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl ] Preparation of Benzimidazole-7-carboxylic Acid

0.166 g of the compound obtained in Comparative Example 1 was dissolved in 12 ml of methanol, and 1 ml of 2N aqueous LiOH solution was added thereto, followed by heating under reflux for 3 hours. After adjusting to pH3 using 2N HCl, the solvent is evaporated and dried. The residue is separated into 20 ml of water and 50 ml of chloroform, and then the organic layer is washed with water and dried. The solvent was evaporated to dryness and the crystalline product was recrystallized from ethyl acetate to give 0.135 g (yield: 84%) of colorless footnotes.

Purity Measurement (HPLC): 91.0%

Claims (10)

A method for preparing a heterocyclic compound of Formula 1 comprising reacting a compound of Formula 2 with water and an active substance:
[Formula 1]

(2)

Wherein R ₁ is selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and a cycloalkyl group having 3 to 6 carbon atoms, and R ₂ and R ₃ are selected from the group consisting of an alkyl group having 1 to 8 carbon atoms.
The method of claim 1, wherein the active material is at least one member selected from the group consisting of inorganic bases and pyridine.
The method for producing a heterocyclic compound according to claim 2, wherein the inorganic base is a hydroxy salt of an alkali metal.
The method for producing a heterocyclic compound according to claim 3, wherein the hydroxy salt of the alkali metal is at least one selected from the group consisting of sodium hydroxide, lithium hydroxide and potassium hydroxide.
The method for producing a heterocyclic compound according to any one of claims 2 to 4, wherein the inorganic base is used in an amount of 1 to 10 equivalents based on 1 equivalent of the compound of the formula (2).
The method for preparing a heterocyclic compound according to claim 2, wherein pyridine is used in an amount of 1 to 30 ml based on 1 g of the compound of Formula 2.
The method for preparing a heterocyclic compound according to claim 2, wherein pyridine is used in an amount of 0.5 to 200 equivalents based on 1 equivalent of the inorganic base.
The method for producing a heterocyclic compound according to any one of claims 1 to 4, wherein the reaction temperature is higher than 0 ° C and 100 ° C.
The method for preparing a heterocyclic compound according to claim 1, wherein the compound of Formula 3 is reacted with alkylchloroformate to prepare the compound of Formula 2.
(3)

Wherein R ₁ is selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and a cycloalkyl group having 3 to 6 carbon atoms, and R ₂ is selected from the group consisting of an alkyl group having 1 to 8 carbon atoms.
The method of claim 9, wherein the alkylchloroformate is ethylchloroformate or 2-ethylhexylchloroformate.