WO2012157977A9 - Manufacturing method of heterocyclic compound - Google Patents

Manufacturing method of heterocyclic compound Download PDF

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WO2012157977A9
WO2012157977A9 PCT/KR2012/003902 KR2012003902W WO2012157977A9 WO 2012157977 A9 WO2012157977 A9 WO 2012157977A9 KR 2012003902 W KR2012003902 W KR 2012003902W WO 2012157977 A9 WO2012157977 A9 WO 2012157977A9
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formula
compound
compound represented
carbon atoms
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PCT/KR2012/003902
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WO2012157977A2 (en
WO2012157977A3 (en
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Nam-Hyun Jo
Young Ju Lee
Junho Chu
Jiweon Jeong
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Hanmi Fine Chemical Co., Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a method of manufacturing a heterocyclic compound by continuously proceeding a reaction (one-pot reaction) in a single reactor, compared to typical processes known in prior art which are generally carried out in steps.
  • a heterocyclic compound represented by Formula 1 below, in particular, azilsartan having R 2 denoted as an ethyl group, i.e. , 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 angiotensin II receptor blocker (ARB).
  • Angiotensin II causes vasoconstriction, promotes secretion of aldosterone leading to sodium and water content retention, which in turn causes an increase in body fluid, thus raising blood pressure. Vasoconstriction described above is fatal to patients suffering from hypertension.
  • Azilsartan is a blocker of angiotensin II receptors and hence inhibits combination of angiotensin II with AT 1 receptor, to control vasoconstriction and aldosterone secretion and thereby lower blood pressure. Also, azilsartan exhibits excellent anti-hypertensive effects, compared to Diovan (name of component: valsartan) or Olmetec (name of component; Olmesartan) which are commercially available in the market.
  • the Food and Drug Administration in the United States has approved azilsartan medoxomil as a hypertension drug, which is a prodrug of azilsartan.
  • Korean Patent Registration No. 233,689 (registered on September 14, 1999) disclosed production of azilsartan according to a process illustrated in Reaction Scheme 1 below.
  • Reaction Scheme 1 the foregoing technique has produced a compound III by reacting a compound I with ethyl chloroformate (ECC) to form a compound II and refluxing the same in the presence of a xylene solvent to execute a cyclization reaction.
  • ECC ethyl chloroformate
  • the compound IV was prepared by adding lithium hydroxide (LiOH) to the compound III to progress hydrolysis.
  • LiOH lithium hydroxide
  • an object of the present invention is to provide a method of manufacturing a heterocyclic compound capable of continuously proceeding cyclization and hydrolysis (one-pot reaction) by treating a compound containing an acyl derivative with an active material as well as water.
  • Another object of the present invention is to provide a method of manufacturing a heterocyclic compound with high purity and yield.
  • a method of manufacturing a heterocyclic compound represented by the following Formula 1 which includes reacting a compound represented by the following Formula 2 with water and an active material.
  • R 1 is selected from a group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms
  • R 2 and R 3 are each selected from a group consisting of alkyl groups having 1 to 8 carbon atoms.
  • the above active material may be at least one selected from a group consisting of inorganic bases and pyridine.
  • the inorganic base may be a hydroxyl salt of an alkali metal wherein the hydroxyl salt of the alkali metal may be at least one selected from sodium hydroxide, lithium hydroxide and potassium hydroxide.
  • the inorganic base may be used in an amount of 1 to 10 equivalents to 1 equivalent of the compound represented by Formula 2, while pyridine may be used in amount of 1 to 30 ml to 1g of the compound represented by Formula 2. If the inorganic base and pyridine are used together, pyridine may be used in an amount of 0.5 to 200 equivalents to 1 equivalent of the inorganic base.
  • a compound represented by the following Formula 3 may react with alkyl chloroformate to prepare the compound represented by Formula 2.
  • R 1 is selected from a group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms
  • R 2 is selected from a group consisting of alkyl groups having 1 to 8 carbon atoms
  • the alkyl chloroformate may be ethyl chloroformate or 2-ethylhexyl chloroformate.
  • the present invention adopts a one-pot reaction starting from a compound containing an acyl derivative wherein cyclization and hydrolysis are continuously carried out, and therefore, may have advantages such as a simple working process, mass-production and short processing time by as much as half that of typical processes.
  • 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid produced according to the present invention may have purity of not less than 98% and does not need further purification. Moreover, if necessary, it may have higher purity of 99.5% or more through purification.
  • the present invention may perform a one-pot reaction under mild conditions, compared to typical processes using xylene through refluxing at a high temperature, thereby accomplishing higher yield.
  • the present invention describes a method of manufacturing a heterocyclic compound represented by Formula 1, which includes conducting cyclization and hydrolysis in a single reactor treating a compound containing an acyl derivative with water and an active material, to proceed a 'one-pot' reaction, compared to typical processes proceeding in steps, thereby attaining various advantages such as a simple and convenient working process, decrease in processing time, and production of a final compound with high purity (not less than 98%) and high yield (70 to 85%) without additional purification.
  • the heterocyclic compound represented by Formula 1 may be prepared by a one-pot reaction wherein cyclization and hydrolysis are continuously proceeded by reacting the compound containing an acyl derivative represented by Formula 2 with water and an active material.
  • 'one-pot' reaction denotes continuous progress of a reaction(s) in a single reactor.
  • R 1 is selected from a group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms
  • R 2 and R 3 are each selected from a group consisting of alkyl groups having 1 to 8 carbon atoms.
  • the active material is used for cyclization and hydrolysis, and more particularly, may be at least one or two or more selected from a group consisting of inorganic bases and pyridine.
  • the inorganic base may include hydroxyl salts of alkali metals, and more particularly, at least one or two or more selected from a group consisting of sodium hydroxide, lithium hydroxide and potassium hydroxide. More preferably, sodium hydroxide may be used.
  • the inorganic base may be used in an amount of 1 to 10 equivalents, and preferably, 4 to 5 equivalents to 1 equivalent of the compound represented by Formula 2. If the amount of the inorganic base is less than 1 equivalent to 1 equivalent of the compound represented by Formula 2, yield may be decreased. On the other hand, when the amount exceeds 10 equivalents, impurities may be increased.
  • pyridine may be used in an amount of 1 to 30 ml, and preferably, 10 to 20 ml to 1g of the compound represented by Formula 2. If an amount of the active material is less than 1 ml to 1g of the compound represented by Formula 2, agitation is not efficient while a yield may be decreased. On the other hand, when the amount is more than 30 ml, a reaction time may be prolonged or, after completing the reaction, a time for removing a solvent may be delayed to cause a decrease in yield.
  • an inorganic base and pyridine are used together as the active material
  • 0.5 to 200 equivalents, and preferably, 10 to 40 equivalents of pyridine to 1 equivalent of the inorganic base may be used. If an amount of pyridine is less than 0.5 equivalent to 1 equivalent of the inorganic base, agitation is not efficient while a yield may be decreased. On the other hand, when the amount exceeds 200 equivalents, a reaction time may be prolonged or a yield may be decreased.
  • the compound represented by Formula 1 may be prepared by adding water and an active material to the compound represented by Formula 2 then agitating the mixture at a temperature of more than 0 to 100°C, and preferably, 40 to 80°C, for 1 to 10 hours. If the temperature is less than 0°C, a yield may be decreased. On the other hand, when the temperature is more than 100°C, impurities tend to increase with time.
  • the compound represented by Formula 2 may be prepared by reacting a compound represented by Formula 3 with alkyl chloroformate.
  • R 1 is selected from a group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms
  • R 2 is selected from a group consisting of alkyl groups having 1 to 8 carbon atoms
  • Alkyl chloroformate described above is used for acylation of amine alcohol and may include, for example, ethyl chloroformate or 2-ethylhexyl chloroformate. More preferably, ethyl chloroformate is used.
  • the compound represented by Formula 2 may be prepared by adding alkyl chloroformate to the compound represented by Formula 3 and agitating the mixture at -10 to 25°C, and preferably, more than 0 to 25°C for 1 to 3 hours.
  • a pH value may be adjusted in the range of 2 to 3 using acid, so as to separate the compound represented by Formula 1.
  • a water-immiscible solvent more particularly, ethyl acetate may be optionally used to separate the above compound.
  • 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid may be produced with high yield (70 to 85%) and high purity (not less than 98%).

Abstract

Disclosed is a method of manufacturing a heterocyclic compound, which treats a compound containing an acyl derivative with water and an active material to concurrently proceed cyclization and hydrolysis, so that one-pot reaction may be performed to hence achieve advantages such as a simple and convenient working process, reduction in processing time, and production of a compound with high purity of more than 98% and high yield, compared to typical stepwise processes known in related art.

Description

MANUFACTURING METHOD OF HETEROCYCLIC COMPOUND
The present invention relates to a method of manufacturing a heterocyclic compound by continuously proceeding a reaction (one-pot reaction) in a single reactor, compared to typical processes known in prior art which are generally carried out in steps.
A heterocyclic compound represented by Formula 1 below, in particular, azilsartan having R2 denoted as an ethyl group, i.e., 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 angiotensin II receptor blocker (ARB).
[Formula 1]
Figure PCTKR2012003902-appb-I000001
Angiotensin II causes vasoconstriction, promotes secretion of aldosterone leading to sodium and water content retention, which in turn causes an increase in body fluid, thus raising blood pressure. Vasoconstriction described above is fatal to patients suffering from hypertension.
Azilsartan is a blocker of angiotensin II receptors and hence inhibits combination of angiotensin II with AT1 receptor, to control vasoconstriction and aldosterone secretion and thereby lower blood pressure. Also, azilsartan exhibits excellent anti-hypertensive effects, compared to Diovan (name of component: valsartan) or Olmetec (name of component; Olmesartan) which are commercially available in the market.
The Food and Drug Administration (FDA) in the United States has approved azilsartan medoxomil as a hypertension drug, which is a prodrug of azilsartan.
Conventionally, Korean Patent Registration No. 233,689 (registered on September 14, 1999) disclosed production of azilsartan according to a process illustrated in Reaction Scheme 1 below. As shown in Reaction Scheme 1, the foregoing technique has produced a compound III by reacting a compound I with ethyl chloroformate (ECC) to form a compound II and refluxing the same in the presence of a xylene solvent to execute a cyclization reaction. In addition, the compound IV (azilsartan) was prepared by adding lithium hydroxide (LiOH) to the compound III to progress hydrolysis. However, since the above known technique includes purification using column chromatography, it cannot be used in mass-production and may entail difficulties in commercial application.
[Reaction Scheme 1]
[Rectified under Rule 91 20.06.2012]
Figure PCTKR2012003902-appb-I000002
Further, The Journal of Medicinal Chemistry 1996, 39, 5228~5235, disclosed a method for production of azilsartan based on Reaction Scheme 2 below. This includes reacting a compound I with 2-ethylhexyl chloroformate (EHC) to prepare a compound V and refluxing the prepared compound in the presence of a xylene solvent to proceed cyclization reaction, thus forming a compound III, as shown in Reaction Scheme 2. In addition, by adding sodium hydroxide (NaOH) to the compound III, hydrolysis occurs to form a compound IV (azilsartan).
[Reaction Scheme 2]
[Rectified under Rule 91 20.06.2012]
Figure PCTKR2012003902-appb-I000003
Conventional technologies used for preparation of azilsartan, as described above, generally use xylene, which is a carcinogenic material harmful to a human body, by heating and refluxing the same at a high temperature and hence may cause a worker to be exposed to xylene gas. Further, when xylene is removed through vacuum distillation after completing a cyclization reaction, difficulties may be encountered in relation to generation of xylene waste which is hard to treat and/or dispose of. Furthermore, since the reaction is conducted at a high temperature, impurities may occur to deteriorate purity and yield. The cyclization reaction (hereinafter referred to as 'cyclization') using xylene involves a low yield of 23%, hence causing a decrease in yield of azilsartan.
Therefore, compared to typical stepwise processes known in the related art, an object of the present invention is to provide a method of manufacturing a heterocyclic compound capable of continuously proceeding cyclization and hydrolysis (one-pot reaction) by treating a compound containing an acyl derivative with an active material as well as water.
Also, another object of the present invention is to provide a method of manufacturing a heterocyclic compound with high purity and yield.
In order to achieve the above objects, there is provided a method of manufacturing a heterocyclic compound represented by the following Formula 1, which includes reacting a compound represented by the following Formula 2 with water and an active material.
[Formula 1]
Figure PCTKR2012003902-appb-I000004
[Formula 2]
Figure PCTKR2012003902-appb-I000005
(wherein R1 is selected from a group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms, and R2 and R3 are each selected from a group consisting of alkyl groups having 1 to 8 carbon atoms).
The above active material may be at least one selected from a group consisting of inorganic bases and pyridine.
The inorganic base may be a hydroxyl salt of an alkali metal wherein the hydroxyl salt of the alkali metal may be at least one selected from sodium hydroxide, lithium hydroxide and potassium hydroxide.
The inorganic base may be used in an amount of 1 to 10 equivalents to 1 equivalent of the compound represented by Formula 2, while pyridine may be used in amount of 1 to 30 ml to 1g of the compound represented by Formula 2. If the inorganic base and pyridine are used together, pyridine may be used in an amount of 0.5 to 200 equivalents to 1 equivalent of the inorganic base.
Meanwhile, a compound represented by the following Formula 3 may react with alkyl chloroformate to prepare the compound represented by Formula 2.
[Formula 3]
Figure PCTKR2012003902-appb-I000006
(wherein R1 is selected from a group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms, and R2 is selected from a group consisting of alkyl groups having 1 to 8 carbon atoms).
The alkyl chloroformate may be ethyl chloroformate or 2-ethylhexyl chloroformate.
The present invention adopts a one-pot reaction starting from a compound containing an acyl derivative wherein cyclization and hydrolysis are continuously carried out, and therefore, may have advantages such as a simple working process, mass-production and short processing time by as much as half that of typical processes.
In addition, 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid produced according to the present invention may have purity of not less than 98% and does not need further purification. Moreover, if necessary, it may have higher purity of 99.5% or more through purification.
The present invention may perform a one-pot reaction under mild conditions, compared to typical processes using xylene through refluxing at a high temperature, thereby accomplishing higher yield.
The present invention describes a method of manufacturing a heterocyclic compound represented by Formula 1, which includes conducting cyclization and hydrolysis in a single reactor treating a compound containing an acyl derivative with water and an active material, to proceed a 'one-pot' reaction, compared to typical processes proceeding in steps, thereby attaining various advantages such as a simple and convenient working process, decrease in processing time, and production of a final compound with high purity (not less than 98%) and high yield (70 to 85%) without additional purification.
Hereinafter, the present invention will be described in detail.
According to the present invention, the heterocyclic compound represented by Formula 1 may be prepared by a one-pot reaction wherein cyclization and hydrolysis are continuously proceeded by reacting the compound containing an acyl derivative represented by Formula 2 with water and an active material.
Herein, 'one-pot' reaction denotes continuous progress of a reaction(s) in a single reactor.
[Formula 1]
Figure PCTKR2012003902-appb-I000007
[Formula 2]
Figure PCTKR2012003902-appb-I000008
(wherein R1 is selected from a group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms, and R2 and R3 are each selected from a group consisting of alkyl groups having 1 to 8 carbon atoms).
The active material is used for cyclization and hydrolysis, and more particularly, may be at least one or two or more selected from a group consisting of inorganic bases and pyridine.
Specific examples of the inorganic base may include hydroxyl salts of alkali metals, and more particularly, at least one or two or more selected from a group consisting of sodium hydroxide, lithium hydroxide and potassium hydroxide. More preferably, sodium hydroxide may be used.
The inorganic base may be used in an amount of 1 to 10 equivalents, and preferably, 4 to 5 equivalents to 1 equivalent of the compound represented by Formula 2. If the amount of the inorganic base is less than 1 equivalent to 1 equivalent of the compound represented by Formula 2, yield may be decreased. On the other hand, when the amount exceeds 10 equivalents, impurities may be increased.
Also, pyridine may be used in an amount of 1 to 30 ml, and preferably, 10 to 20 ml to 1g of the compound represented by Formula 2. If an amount of the active material is less than 1 ml to 1g of the compound represented by Formula 2, agitation is not efficient while a yield may be decreased. On the other hand, when the amount is more than 30 ml, a reaction time may be prolonged or, after completing the reaction, a time for removing a solvent may be delayed to cause a decrease in yield.
Alternatively, in the case where an inorganic base and pyridine are used together as the active material, 0.5 to 200 equivalents, and preferably, 10 to 40 equivalents of pyridine to 1 equivalent of the inorganic base may be used. If an amount of pyridine is less than 0.5 equivalent to 1 equivalent of the inorganic base, agitation is not efficient while a yield may be decreased. On the other hand, when the amount exceeds 200 equivalents, a reaction time may be prolonged or a yield may be decreased.
The compound represented by Formula 1 may be prepared by adding water and an active material to the compound represented by Formula 2 then agitating the mixture at a temperature of more than 0 to 100℃, and preferably, 40 to 80℃, for 1 to 10 hours. If the temperature is less than 0℃, a yield may be decreased. On the other hand, when the temperature is more than 100℃, impurities tend to increase with time.
Meanwhile, the compound represented by Formula 2 may be prepared by reacting a compound represented by Formula 3 with alkyl chloroformate.
[Formula 3]
Figure PCTKR2012003902-appb-I000009
(wherein R1 is selected from a group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms, and R2 is selected from a group consisting of alkyl groups having 1 to 8 carbon atoms).
Alkyl chloroformate described above is used for acylation of amine alcohol and may include, for example, ethyl chloroformate or 2-ethylhexyl chloroformate. More preferably, ethyl chloroformate is used.
The compound represented by Formula 2 may be prepared by adding alkyl chloroformate to the compound represented by Formula 3 and agitating the mixture at -10 to 25℃, and preferably, more than 0 to 25℃ for 1 to 3 hours.
After completing cyclization and hydrolysis starting from the compound represented by Formula 2 into the compound represented by Formula 1, a pH value may be adjusted in the range of 2 to 3 using acid, so as to separate the compound represented by Formula 1. In addition, a water-immiscible solvent, more particularly, ethyl acetate may be optionally used to separate the above compound.
According to the manufacturing method of the present invention, 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid may be produced with high yield (70 to 85%) and high purity (not less than 98%).
Hereinafter, preferred embodiments of the present invention will be described in detail to more concretely understand the present invention with reference to examples, comparative examples, practical examples and experimental examples. However, it will be apparent to those skilled in the art that such embodiments are provided for illustrative purposes and do not limit subject matters to be protected as defined by the appended claims.
Preparative Example 1
10.0g of methyl 2-ethoxy-1-[[2'-hydroxycarbamimidoyl]biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate was introduced into a vessel and then 200 ml of pyridine was added thereto and dissolved therein. Thereafter, 2.4 ml of ethyl chloroformate was slowly added thereto at 5℃, followed by agitating the same at 25℃ for 1 hour, to thereby prepare methyl 2-ethoxy-1-[[2'-etoxy carbonyloxycarbamimidoyl]biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate having an acyl derivative.
Preparative Example 2
10.0g of methyl 2-ethoxy-1-[[2'-hydroxycarbamimidoyl]biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate was introduced into a vessel and then 3.5 ml of triethylamine was added thereto and dissolved therein. Thereafter, 2.36 ml of ethyl chloroformate was slowly added thereto at 5℃, followed by agitating the same at 25℃ for 1 hour. Following this, solids were removed from the agitated reaction mixture by filtration and the remaining solution was concentrated under reduced pressure at 40℃, followed by crystallization using ethyl acetate and hexane, thereby yielding 10.8g (yield: 93.0%) of a compound having an acyl derivative.
Preparative Example 3
10.0g of ethyl 2-ethoxy-1-[[2'-hydroxycarbamimidoyl]biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate was introduced into a vessel and then 200 ml of pyridine was added thereto and dissolved therein. Thereafter, 2.3 ml of ethyl chloroformate was slowly added thereto at 5℃, followed by agitating the same at 25℃ for 1.5 hours, to thereby prepare ethyl 2-ethoxy-1-[[2'-etoxy carbonyloxycarbamimidoyl]biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate having an acyl derivative.
Preparative Example 4
10.0g of ethyl 2-ethoxy-1-[[2'-hydroxycarbamimidoyl]biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate was introduced into a vessel and then 150 ml of tetrahydrofuran was added thereto and dissolved therein. Thereafter, 2.3 ml of ethyl chloroformate was slowly added thereto at 5℃, followed by agitating the same at 25℃ for 1 hour. Following this, solids were removed from the agitated reaction mixture by filtration and the remaining solution was concentrated under reduced pressure at 40℃, followed by crystallization using ethyl acetate and hexane, thereby yielding 10.6g (yield: 92.0%) of a compound having an acyl derivative.
Example 1: Preparation of 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid
To the vessel including the compound having an acyl derivative prepared in Preparative Example 1 as well as pyridine, 100 ml of a 1M sodium hydroxide solution was added and agitated at 50℃ for 4 hours. Then, the reaction mixture containing the 1M sodium hydroxide solution was cooled to 25℃ and provided with 100 ml of water and 400 ml of ethyl acetate. The reaction mixture containing water and ethyl acetate was further cooled to 5℃ and controlled to reach pH 3 using a 6M hydrochloric acid solution. After washing an isolated organic layer with 100 ml of a 1M hydrochloric acid solution and 100 ml of water, the organic layer was concentrated under reduced pressure at 40℃, followed by crystallization, thereby yielding 7.59g of a purposed compound (yield: 75.5%).
1H 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).
Measurement of purity (HPLC): 98.7%
Example 2: Preparation of 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid
To the vessel including 10.8g of the compound having an acyl derivative prepared in Preparative Example 2, 200 ml of pyridine and 100 ml of a 1M sodium hydroxide solution were added and agitated at 50℃ for 4 hours. Then, the agitated reaction mixture was cooled to 25℃ and provided with 100 ml of water and 400 ml of ethyl acetate. The reaction mixture containing water and ethyl acetate was further cooled to 5℃ and controlled to reach pH 3 using a 6M hydrochloric acid solution. After washing a separated organic layer with 100 ml of a 1M hydrochloric acid solution and 100 ml of water, the organic layer was concentrated under reduced pressure at 40℃, followed by crystallization, thereby yielding 7.7g of a purposed compound (yield: 84.4%).
1H 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).
Measurement of purity (HPLC): 99.04%
Example 3: Preparation of 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid
To the vessel including the compound having an acyl derivative prepared in Preparative Example 3 as well as pyridine, 100 ml of a 1M sodium hydroxide solution was added and agitated at 50℃ for 7 hours. Then, the reaction mixture containing the 1M sodium hydroxide solution was cooled to 25℃ and provided with 100 ml of water and 400 ml of ethyl acetate. The reaction mixture containing water and ethyl acetate was further cooled to 5℃ and controlled to reach pH 3 using a 6M hydrochloric acid solution. After washing a separated organic layer with 100 ml of a 1M hydrochloric acid solution and 100 ml of water, the organic layer was concentrated under reduced pressure at 40℃, followed by crystallization, thereby yielding 7.4g of a purposed compound (yield: 77.2%).
1H 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).
Measurement of purity (HPLC): 98.7%
Example 4: Preparation of 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid
To the vessel including 10.6g of the compound having an acyl derivative prepared in Preparative Example 4, 200 ml of pyridine and 100 ml of a 1M sodium hydroxide solution were added and agitated at 50℃ for 7 hours. Then, the agitated reaction mixture was cooled to 25℃ and provided with 100 ml of water and 400 ml of ethyl acetate. The reaction product containing water and ethyl acetate was further cooled to 5℃ and controlled to reach pH 3 using a 6M hydrochloric acid solution. After washing a separated organic layer with 100 ml of a 1M hydrochloric acid solution and 100 ml of water, the organic layer was concentrated under reduced pressure at 40℃, followed by crystallization, thereby yielding 6.8g of a purposed compound (yield: 78.0%).
1H 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).
Measurement of purity (HPLC): 99.5%
Example 5: Preparation of 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid
To the vessel including 10.0g of the compound having an acyl derivative prepared in Preparative Example 2, 100 ml of a 1M sodium hydroxide solution was added and agitated at 80℃ for 2 hours. Then, the agitated reaction mixture was cooled to 25℃ and provided with 100 ml of water and 400 ml of ethyl acetate. The reaction mixture containing water and ethyl acetate was further cooled to 5℃ and controlled to reach pH 3 using a 6M hydrochloric acid solution. After washing a separated organic layer with 100 ml of a 1M hydrochloric acid solution and 100 ml of water, the organic layer was concentrated under reduced pressure at 40℃, followed by crystallization, thereby yielding 6.2g of a purposed compound (yield: 71.0%).
1H 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).
Measurement of purity (HPLC): 94.4%
Example 6: Preparation of 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid
To the vessel including 10.0g of the compound having an acyl derivative prepared in Preparative Example 2, 100 ml of a 1M sodium hydroxide solution was added and agitated at 80℃ for 4 hours. Then, the agitated reaction mixture was cooled to 25℃ and provided with 100 ml of water and 400 ml of ethyl acetate. The reaction mixture containing water and ethyl acetate was further cooled to 5℃ and controlled to reach pH 3 using a 6M hydrochloric acid solution. After washing a separated organic layer with 100 ml of a 1M hydrochloric acid solution and 100 ml of water, the organic layer was concentrated under reduced pressure at 40℃, followed by crystallization, thereby yielding 6.0g of a purposed compound (yield: 74.0%).
1H 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).
Measurement of purity (HPLC): 88.0%
Comparative Example 1: Preparation of methyl 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate
To a suspension prepared by blending and agitating 30 ml of tetrahydrofuran (THF), 0.2g of trimethylamine and 0.90g of methyl 2-ethoxy-1-[[(2-(hydroxycarbamimidoyl)biphenyl)-4-yl]methyl]-1H-benzimidazole-7-carboxylate, 0.22g of ethyl chlorocarbonate and 2 ml of methylene chloride were added under ice cooling. The mixture was agitated at room temperature for 2 hours and, after removing an insoluble material by filtration, the remaining filtrate was concentrated and dried. 5 ml of ethyl acetate was added to the concentrated reaction mixture and, after removing an insoluble material by filtration, the remaining filtrate was concentrated and dried again. A mixture of residue in 10 ml of xylene was heated for 1.5 hours under refluxing. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, dried and concentrated, and then dried again. The residue was purified through a silica gel column-chromatography to obtain crystals. The crystals were subjected to recrystallization using ethyl acetate-isopropylether, thus yielding 0.22g of a colorless prism type product (yield: 23%).
Comparative Example 2: Preparation of 2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid
0.166g of the compound prepared in Comparative Example 1 was dissolved in 12 ml of methanol and 1 ml of a 2N LiOH solution was added thereto, followed by heating the same for 3 hours under refluxing. Using 2N HCl, the heated mixture was controlled to reach pH 3. Then, the solvent was evaporated to dryness. After separating the remaining residue using 20 ml of water and 50 ml of chloroform, an organic layer was washed with water then dried. After distilling and drying the solvent, the remaining crystalline product was subjected to recrystallization using ethyl acetate, thus yielding in 0.135g of a colorless prism type product (yield: 84%).
Measurement of purity (HPLC): 91.0%.
Although preferred embodiments of the present invention have been described above in conjunction with the accompanying examples and experimental examples, those skilled in the art will appreciate that various modifications and alterations are possible without departing from the scope and spirit of the invention, based on the foregoing description and the appended claims.

Claims (10)

  1. A method of manufacturing a heterocyclic compound represented by the following Formula 1, comprising reacting a compound represented by the following Formula 2 with water and an active material:
    [Formula 1]
    Figure PCTKR2012003902-appb-I000010
    [Formula 2]
    Figure PCTKR2012003902-appb-I000011
    (wherein R1 is selected from a group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms, and R2 and R3 are each selected from a group consisting of alkyl groups having 1 to 8 carbon atoms).
  2. The method according to claim 1, wherein the active material is at least one selected from a group consisting of inorganic bases and pyridine.
  3. The method according to claim 2, wherein the inorganic base is a hydroxyl salt of alkali metal.
  4. The method according to claim 3, wherein the hydroxyl salt of alkali metal is at least one selected from a group consisting of sodium hydroxide, lithium hydroxide and potassium hydroxide.
  5. The method according to any one of claims 2 to 4, wherein the inorganic base is used in an amount of 1 to 10 equivalents to 1 equivalent of the compound represented by Formula 2.
  6. The method according to claim 2, wherein the pyridine is used in an amount of 1 to 30 ml to 1g of the compound represented by Formula 2.
  7. The method according to claim 2, wherein the pyridine is used in an amount of 0.5 to 200 equivalents to 1 equivalent of the inorganic base.
  8. The method according to any one of claims 1 to 4, wherein a reaction temperature is more than 0 to 100℃.
  9. The method according to claim 1, wherein the compound represented by Formula 2 is prepared by reacting a compound represented by the following Formula 3 with alkyl chloroformate:
    [Formula 3]
    Figure PCTKR2012003902-appb-I000012
    (wherein R1 is selected from a group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms, and R2 is selected from a group consisting of alkyl groups having 1 to 8 carbon atoms).
  10. The method according to claim 9, wherein the alkyl chloroformate is ethyl chloroformate or 2-ethylhexyl chloroformate.
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