KR100662110B1 - Preparation of tetrazol derivatives - Google Patents

Preparation of tetrazol derivatives Download PDF

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KR100662110B1
KR100662110B1 KR1020050097226A KR20050097226A KR100662110B1 KR 100662110 B1 KR100662110 B1 KR 100662110B1 KR 1020050097226 A KR1020050097226 A KR 1020050097226A KR 20050097226 A KR20050097226 A KR 20050097226A KR 100662110 B1 KR100662110 B1 KR 100662110B1
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formula
azide
compound represented
alkali metal
present
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임근조
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켐젠주식회사
동아제약주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • 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
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin

Abstract

A method for preparation of tetrazole derivatives is provided to prevent production of impurities and increase preparation yield by shortening the preparation process, and to avoid environmental pollution and harmful effects to worker by using nontoxic raw materials. The tetrazole derivatives represented by the formula(1) are prepared by reacting a compound represented by the formula(2) with alkali metal azide in the presence of nontoxic zinc chloride in pyridine solvent, wherein Y is aldehyde or hydroxymethyl group; and the alkali metal azide is lithium azide, sodium azide, potassium azide or cerium azide.

Description

테트라졸 유도체의 제조방법{Preparation of tetrazol derivatives}Preparation method of tetrazole derivatives {Preparation of tetrazol derivatives}

본 발명은 하기 화학식 1로 표시되는 테트라졸 유도체의 제조방법에 관한 것이다.The present invention relates to a method for producing a tetrazole derivative represented by the following formula (1).

[화학식 1][Formula 1]

Figure 112005058271822-pat00003
Figure 112005058271822-pat00003

상기 화학식 1로 표시되는 테트라졸 유도체는 안지오텐신 II 길항제로서 안지오텐신에 의해 유발되는 고혈압 치료에 유용하게 사용되는 약물이다. 상기 화학식 1의 테트라졸 유도체는 표적 세포상의 안지오텐신 II 수용체에서 안지오텐신 II 활성을 억제하므로써 호르몬-수용체 상호작용에 의해 유발되는 혈압의 증가를 방지 하는 것으로 알려져 있다.Tetrazole derivatives represented by the formula (1) is an angiotensin II antagonist is a drug that is useful in the treatment of hypertension induced by angiotensin. Tetrazole derivatives of Formula 1 are known to prevent an increase in blood pressure caused by hormone-receptor interactions by inhibiting angiotensin II activity at angiotensin II receptors on target cells.

상기 화학식 1로 표시되는 화합물은 미국특허 제5,138,069호, 미국특허 제4,820,843호, 미국특허 제4,874,867호, 대한민국 특허등록 제37,180호, 대한민국 특허등록 제37,181호 및 대한민국 특허등록 제107,764호에 그 제조방법이 개시되어 있다.The compound represented by Chemical Formula 1 is prepared in US Patent No. 5,138,069, US Patent No. 4,820,843, US Patent No. 4,874,867, Republic of Korea Patent No. 37,180, Republic of Korea Patent No. 37,181 and Republic of Korea Patent No. 107,764. Is disclosed.

상기 종래 기술에 개시되어 있는 화학식 1로 표시되는 화합물의 제조방법은 크게 다음과 같은 2가지의 반응식으로 나타낼 수 있다.Method for preparing a compound represented by the formula (1) disclosed in the prior art can be largely represented by the following two schemes.

<반응식 1><Scheme 1>

Figure 112005058271822-pat00004
Figure 112005058271822-pat00004

상기 반응식 1은 미국특허 제5,138,069호에 개시되어 있다.Scheme 1 is disclosed in US Pat. No. 5,138,069.

그러나, 상기 제조방법은 높은 수율로 목적하는 테트라졸 유도체를 제조할 수 있는 장점은 있으나, 다단계의 제조과정을 통하여 목적물을 제조하는 것일 뿐만 아니라, 제조공정 중에 매우 독성이 큰 트리알킬 또는 트리페닐틴아지드를 필수적으로 사용하여야 하므로 제조자의 피부 발진 등을 일으키게 되며, 제조환경을 악화시키는 단점을 지니고 있다.However, the manufacturing method has the advantage of producing the desired tetrazole derivatives in a high yield, but not only to prepare the target product through a multi-step manufacturing process, but also very toxic trialkyl or triphenyltin in the manufacturing process Since the use of the jide is necessary to cause skin rash of the manufacturer, etc. has a disadvantage of worsening the manufacturing environment.

또한 미국특허 제5,138,069호에는 하기 화학식 2로 표시되는 화합물을 하기 반응식 2에 의하여 상기 화학식 1로 표시되는 화합물의 제조방법이 개시되어 있다. 그러나, 실질적으로는 하기 반응식 2에 의해서는 상기 화학식 1로 표시되는 화합물이 제조되지 않으므로 상기 화학식 1로 표시되는 화합물을 제조방법으로는 이용될 수 없다.In addition, US Patent No. 5,138,069 discloses a method for preparing a compound represented by the formula (1) to the compound represented by the following formula (2). However, since the compound represented by the formula (1) is not substantially prepared by the following Reaction Scheme 2, the compound represented by the formula (1) cannot be used as a production method.

[화학식 2][Formula 2]

Figure 112005058271822-pat00005
Figure 112005058271822-pat00005

상기 식에서 Y는 알데히드, 히드록시메틸기를 나타낸다.In the formula, Y represents an aldehyde or hydroxymethyl group.

<반응식 2><Scheme 2>

Figure 112005058271822-pat00006
Figure 112005058271822-pat00006

한편, 유럽공개특허공보 EP 0838458A1호에는 염화아연을 이용한 테트라졸 유도체의 제조방법이 개시되어 있다.On the other hand, European Patent Publication No. EP 0838458A1 discloses a method for producing a tetrazole derivative using zinc chloride.

상기 종래기술에는 DMF, 아밀알콜, 헥실알콜, 에탄올, 이소프로필알콜, 헵틸알콜, 1,4-디옥산, DMSO, 클로로포름, 디클로로에탄, THF, t-부틸메틸에테르, 1,3-디메틸이미다졸리디온, n-메틸피롤리돈, n-부탄올, 아세토니트릴 및 메틸에틸케톤 중에서 선택되는 용매를 사용하여 염화아연을 이용한 테트라졸 유도체의 제조방법을 개시하고 있으나, 본 발명자는 본 발명에 따른 화학식 1로 표시되는 화합물은 상기 제조방법으로는 제조할 수 없음을 알게 되었다.The prior art includes DMF, amyl alcohol, hexyl alcohol, ethanol, isopropyl alcohol, heptyl alcohol, 1,4-dioxane, DMSO, chloroform, dichloroethane, THF, t-butylmethyl ether, 1,3-dimethylimida Although a method for preparing a tetrazole derivative using zinc chloride is disclosed using a solvent selected from zolidione, n-methylpyrrolidone, n-butanol, acetonitrile and methyl ethyl ketone, the present inventors have described the formula according to the present invention. It was found that the compound represented by 1 could not be produced by the above production method.

상기 유럽공개특허공보 EP 0838458A1호를 이용하여 본 발명에 따른 화학식 1로 표시되는 화합물의 제조를 시도하였으나, 상기 종래기술에서 언급한 용매를 사용하여 염화아연의 존재하에 상기 화학식 2로 표시되는 화합물과 알칼리금속아지드를 반응시키더러도 반응이 거의 일어나지 않거나 반응이 일어나더라도 불순물이 많 이 발생하여 실질적으로 목적하는 화학식 1로 표시되는 화합물을 제조할 수 없다.An attempt was made to prepare a compound represented by Chemical Formula 1 according to the present invention using EP 0838458A1, but the compound represented by Chemical Formula 2 in the presence of zinc chloride using a solvent mentioned in the prior art. Even when the alkali metal azide is reacted, the reaction hardly occurs or a large amount of impurities are generated even when the reaction occurs, so that the compound represented by Chemical Formula 1 cannot be prepared.

본 발명자는 매우 독성이 큰 트리알킬 또는 트리페닐틴아지드를 사용하지 않고 직접 화학식 1로 표시되는 화합물의 제조방법을 연구하기 위하여 상기 유럽공개특허공보 EP 0838458A1호에 기재되어 있는 염화아연을 이용한 화학식 1로 표시되는 화합물의 제조방법을 연구하던 중, 놀랍게도 피리딘 용매에서 화학식 2로 표시되는 화합물을 반응시키면 직접 화학식 1로 표시되는 테트라졸 유도체를 불순물 없이 고수율로 제조할 수 있음을 확인하고 본 발명을 완성하였다.The present inventors formulated using zinc chloride as described in EP 0838458A1 to study a method for preparing a compound represented by the formula (1) directly without using a highly toxic trialkyl or triphenyltin azide. While studying a method for preparing a compound represented by the above, it was surprisingly confirmed that the reaction of the compound represented by the formula (2) in a pyridine solvent can directly prepare the tetrazole derivative represented by the formula (1) in high yield without impurities. Completed.

본 발명은 하기 화학식 1로 표시되는 테트라졸 유도체의 제조공정을 단축하고 고수율로 목적물을 획득할 수 있는 제조방법을 제공하는 것을 목적으로 한다.An object of the present invention is to shorten the manufacturing process of the tetrazole derivative represented by the following formula (1) and to provide a production method capable of obtaining the target product in high yield.

또한 본 발명은 제조공정을 친환경적으로 제조할 수 있는 화학식 1로 표시되는 화합물의 제조방법을 제공하는 것을 목적으로 한다.In addition, an object of the present invention is to provide a method for preparing a compound represented by the formula (1) that can be produced environmentally friendly manufacturing process.

상기와 같은 목적을 달성하기 위하여, 본 발명은 피리딘 용매 중에서 하기 화학식 2로 표시되는 화합물을 반응시키므로서 직접 화학식 1로 표시되는 테트라졸 유도체를 제조할 수 있는 제조방법을 제공한다.In order to achieve the above object, the present invention provides a method for producing a tetrazole derivative represented by the formula (1) by reacting the compound represented by the formula (2) in a pyridine solvent.

보다 구체적으로 본 발명은 피리딘 용매를 사용하여 염화아연의 존재하에 하기 화학식 1로 표시되는 화합물과 알칼리금속아지드를 반응시키므로써 직접 하기 화학식 1로 표시되는 테트라졸를 제조할 수 있다.More specifically, the present invention may directly prepare tetrazole represented by the following Chemical Formula 1 by reacting a compound represented by the following Chemical Formula 1 with an alkali metal azide in the presence of zinc chloride using a pyridine solvent.

[화학식 1][Formula 1]

Figure 112005058271822-pat00007
Figure 112005058271822-pat00007

[화학식 2][Formula 2]

Figure 112005058271822-pat00008
Figure 112005058271822-pat00008

상기 식에서 Y는 알데히드, 히드록시메틸기를 나타낸다.In the formula, Y represents an aldehyde or hydroxymethyl group.

이하 본 발명에 따른 제조방법을 상세하게 설명하기로 한다.Hereinafter, the manufacturing method according to the present invention will be described in detail.

본 발명에 따른 화학식 1로 표시되는 테트라졸 유도체는 염화아연의 존재하에 화학식 2로 표시되는 화합물과 알칼리금속아지드를 반응시키므로써 직접 제조된다.The tetrazole derivatives represented by Formula 1 according to the present invention are prepared directly by reacting the compound represented by Formula 2 with alkali metal azide in the presence of zinc chloride.

놀랍게도 이러한 반응은 피리딘 용매 중에서 0 ∼ 150℃에서 수행함으로써 달성된다.Surprisingly this reaction is achieved by performing at 0-150 ° C. in pyridine solvent.

종래기술로 언급된 유럽공개특허공보 EP 0838458A1호에는 염화아연의 존재하에 알칼리금속아지드을 DMF, 아밀알콜, 헥실알콜, 에탄올, 이소프로필알콜, 헵틸알콜, 1,4-디옥산, DMSO, 클로로포름, 디클로로에탄, THF, t-부틸메틸에테르, 1,3-디메틸이미다졸리디온, n-메틸피롤리돈, n-부탄올, 아세토니트릴 및 메틸에틸케톤 중에서 반응시켜 테트라졸 유도체를 제조하는 방법이 공지되어 있으나, 예를들면, n-부탄올을 용매로 하여 ZnCl2/NaN3을 사용하여 반응을 진행하면 목적하는 본 발명에 따른 화학식 1로 표시되는 테트라졸 유도체의 반응이 완결되지 않을 뿐만 아니라, ZnCl2/NaN3을 과량 사용하여 반응이 완결되더라도 n-부탄올이 치환된 구조의 불순물이 동시에 생성되므로 상기 용매들은 본 발명의 범주에 포함되지 않는다.European Patent Publication No. EP 0838458A1 referred to in the prior art discloses alkali metal azides in the presence of zinc chloride, such as DMF, amyl alcohol, hexyl alcohol, ethanol, isopropyl alcohol, heptyl alcohol, 1,4-dioxane, DMSO, chloroform, Known methods for preparing tetrazole derivatives by reacting in dichloroethane, THF, t-butylmethylether, 1,3-dimethylimidazolidione, n-methylpyrrolidone, n-butanol, acetonitrile and methylethylketone However, for example, when the reaction proceeds using ZnCl 2 / NaN 3 with n-butanol as a solvent, not only the reaction of the tetrazole derivative represented by Formula 1 according to the present invention is not completed, and ZnCl Even when the reaction is completed by using an excess of 2 / NaN 3 , the impurities are not simultaneously included in the scope of the present invention because impurities of the structure substituted with n-butanol are simultaneously produced.

놀랍게도 본 발명은 피리딘을 용매로 사용하여 염화아연의 존재하에 화학식 2로 표시되는 화합물과 알칼리금속아지드을 반응시킬 때, 직접 본 발명에 따른 화학식 1로 표시되는 테트라졸 유도체를 불순물이 생성되지 않고 고수율로 획득할 수 있다.Surprisingly, when the compound represented by the formula (2) and the alkali metal azide are reacted in the presence of zinc chloride using pyridine as a solvent, the present invention does not directly generate the tetrazole derivative represented by the formula (1) without impurities. Can be obtained in yield.

본 발명에 따른 화학식 1로 표시되는 테트라졸 유도체를 제조하는데 필요한 상기 화학식 2로 표시되는 화합물은 미국특허 제5,138,069호에 공지되어 있으며, 상기 미국특허에 제5,138,069호에 기술되어 있는 방법에 의해 제조된 화합물을 사 용할 수 있다.Compounds represented by Formula 2 required to prepare tetrazole derivatives represented by Formula 1 according to the present invention are known in US Pat. No. 5,138,069 and prepared by the methods described in US Pat. No. 5,138,069. Compounds can be used.

본 발명에서 상기 알칼리 금속아지드는 특별한 제한을 받지 않으나 리튬아지드, 소디움아지드, 칼륨아지드, 세륨아지드의 군에서 선택되는 것이 바람직하다.In the present invention, the alkali metal azide is not particularly limited, but is preferably selected from the group of lithium azide, sodium azide, potassium azide and cerium azide.

본 발명은 또한 친환경적으로 제조할 수 있는 제조공정과 제조공정 중에 제조자의 신체를 보호할 수 있는 본 발명에 따른 화학식 1로 표시되는 테트라졸 유도체의 제조방법을 제공한다.The present invention also provides a manufacturing process that can be environmentally friendly and a method for producing a tetrazole derivative represented by the formula (1) according to the invention that can protect the body of the manufacturer during the manufacturing process.

종래 미국특허 제5,138,069호, 미국특허 제4,820,843호, 미국특허 제4,874,867호, 대한민국 특허등록 제37,180호, 대한민국 특허등록 제37,181호 및 대한민국 특허등록 제107,764호에서 언급된 화학식 2로 표시되는 화합물을 이용하여 화학식 1로 표시되는 화합물을 제조하는 경우에는 매우 독성이 큰 트리알킬 또는 트리페닐틴아지드를 필수적으로 사용하여야 하므로 제조자의 피부 발진 등을 일으키게 되며, 제조환경을 악화시키는 단점을 지니고 있었다.Using a compound represented by Formula 2 mentioned in the prior US Patent No. 5,138,069, US Patent No. 4,820,843, US Patent No. 4,874,867, Republic of Korea Patent No. 37,180, Republic of Korea Patent No. 37,181 and Republic of Korea Patent No. 107,764 In the case of preparing the compound represented by Formula 1, it is necessary to use a very toxic trialkyl or triphenyltin azide because it is necessary to cause the skin rash of the manufacturer, and had a disadvantage in deteriorating the manufacturing environment.

그러나, 본 발명은 놀랍게도 화학식 2로 표시되는 화합물을 이용하더라도 피리딘을 용매로 사용하여 독성이 없는 염화아연의 존재하에 알칼리금속아지드과 반응시키면 직접 본 발명에 따른 화학식 1로 표시되는 테트라졸 유도체를 불순물 없이 고수율로 획득할 수 있다.However, the present invention surprisingly, even when using the compound represented by the formula (2), when pyridine is used as a solvent and reacted with the alkali metal azide in the presence of non-toxic zinc chloride, the tetrazole derivative represented by the formula (1) according to the present invention directly impurity Can be obtained in high yield without.

또한 본 발명은 화학식 1로 표시되는 화합물을 약학적으로 허용 가능한 염 즉, 수산화칼륨, 탄산칼륨, 탄산수소칼륨과 같이 약학적으로 허용 가능한 염기와 반응시켜 염 형태로 전환하여 제조될 수 있다.In addition, the present invention may be prepared by converting the compound represented by Formula 1 into a salt form by reacting with a pharmaceutically acceptable salt, that is, a pharmaceutically acceptable base such as potassium hydroxide, potassium carbonate, potassium hydrogen carbonate.

상술한 바와 같은 본 발명에 따른 화학식 1로 표시되는 테트라졸 유도체와 약학적으로 허용 가능한 그의 염은 안지오텐신 II 길항제로서 안지오텐신에 의해 유발되는 고혈압 치료에 유용하게 사용될 수 있다.As described above, the tetrazole derivative represented by Formula 1 according to the present invention and a pharmaceutically acceptable salt thereof may be usefully used for the treatment of hypertension induced by angiotensin as an angiotensin II antagonist.

본 발명에 따라 제조되는 화합물들의 분자구조는 적외선 분광법, 자외선 분광법, 가시광선 분광법, 핵자기공명 스펙트럼, 질량 분광법과 대표적인 화합물의 원소분석 실측치와 계산치의 비교에 의해 확인하였다.The molecular structure of the compounds prepared according to the present invention was confirmed by comparison between infrared spectroscopy, ultraviolet spectroscopy, visible light spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy and elemental analysis of the typical compounds and calculated values.

이하 본 발명을 실시예에 의거하여 좀 더 상세히 설명하기로 하며, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명이 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, and the following Examples are merely illustrative of the present invention, and the present invention is not limited by the Examples.

<실시예 1> 2-n-부틸-4- 클로로 -5- 히드록시메틸 -1-[(2'-(1H- 테트라졸 -5-일)비페닐-4-일)메틸]이미다졸의 제조 Example 1 of 2-n-butyl-4 -chloro- 5 -hydroxymethyl- 1-[(2 '-(1H- tetrazol -5-yl) biphenyl-4-yl) methyl] imidazole Produce

2-n-부틸-4-클로로-5-히드록시메틸-1-[(2'-시아노비페닐-4-일)메틸]이미다졸 20g을 피리딘 200ml에 가하고 염화아연 28g 및 소디움아지드 27g을 가한 후, 환류교반한다. 반응 종료 후 감압증류하고, 이의 잔사물에 디클로메탄과 이소프로판올의 혼합액 300ml 및 3N-수산화나트륨의 용액 500ml을 가한 후 유기층을 분리한다. 다시 물 200ml을 가한후 물층을 분리한다. 이의 물층을 묽은염산을 가하여 pH을 2로 조정한후에 에틸아세테이트와 이소프로판올의 혼합액 400ml을 가하고 유기층을 분리한다. 유기층을 망초로 탈수후, 여과하고, 농축한다. 이의 잔사물에 아세톤 200ml을 가하여 결정화하고 이를 여과함으로서 목적물 20.1g(수율 : 89%)을 획득한다.20 g of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-cyanobiphenyl-4-yl) methyl] imidazole were added to 200 ml of pyridine, and 28 g of zinc chloride and 27 g of sodium azide were added. After the addition, the mixture is stirred at reflux. After completion of the reaction, distillation under reduced pressure, 300 ml of a mixture of dichloromethane and isopropanol and 500 ml of 3N-sodium hydroxide were added to the residue, and the organic layer was separated. 200 ml of water is added again, and the water layer is separated. The aqueous layer was diluted with hydrochloric acid to adjust the pH to 2, and then 400 ml of a mixture of ethyl acetate and isopropanol was added to separate the organic layer. The organic layer is dehydrated with forget-me-not, filtered and concentrated. To the residue was added 200 ml of acetone to crystallize and filtered to obtain 20.1 g of a target product (yield: 89%).

1H-NMR(DMSO-d6) : 7.76-7.47(m, 4H), 7.08(d, 2H, J=9Hz), 7.02(d, 2H, J=9Hz), 5.23(s, 2H), 4,31(s, 2H), 2.47(t, 2H), 1.45(m, 2H), 1.25(m, 2H), 0.79(t, 3H) 1 H-NMR (DMSO-d 6 ): 7.76-7.47 (m, 4H), 7.08 (d, 2H, J = 9 Hz), 7.02 (d, 2H, J = 9 Hz), 5.23 (s, 2H), 4 , 31 (s, 2H), 2.47 (t, 2H), 1.45 (m, 2H), 1.25 (m, 2H), 0.79 (t, 3H)

mp : 184.3 - 186.1℃mp: 184.3-186.1 ℃

<실시예 2> 2-n-부틸-4- 클로로 -5- 히드록시메틸 -1-[(2'-(1H- 테트라졸 -5-일) 비페닐4 -일)메틸]이미다졸·칼륨염의 제조 Example 2 2-n-butyl-4 -chloro- 5 -hydroxymethyl- 1-[(2 '-(1H -tetrazol -5-yl) biphenyl4 -yl) methyl] imidazole potassium Preparation of Salt

실시예 1에서 제조된 2-n-부틸-4-클로로-5-히드록시메틸-1-[(2'-(1H-테트라졸-5-일)비페닐4-일)메틸]이미다졸 1Kg을 메탄올과 이소프로판올 혼합용액 20L에 가한 후, 탄산수소칼륨 237g을 첨가하고, 실온에서 교반한다. 반응 종료 후 반응액을 여과하고 이소프로판올으로 세척하고, 여과액을 감압 농축한다. 이의 잔사물에 메탄올과 헥산을 가하여 생성된 고체를 여과함으로서 목적물을 1.0Kg(수율 : 92%)을 획득한다.1 Kg of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2 '-(1H-tetrazol-5-yl) biphenyl4-yl) methyl] imidazole prepared in Example 1 Was added to 20 L of a mixed solution of methanol and isopropanol, and then 237 g of potassium hydrogen carbonate was added and stirred at room temperature. After the reaction was completed, the reaction solution was filtered, washed with isopropanol, and the filtrate was concentrated under reduced pressure. 1.0 Kg (yield: 92%) of the target product was obtained by filtering the solid produced by adding methanol and hexane to the residue.

13C-NMR(DMSO-d6) : 160.5, 147.3, 141.1, 139.7, 134.4, 132.5, 130.3, 129.8, 129.4, 127.3, 126.6, 125.4, 125.3, 125.1, 51.4, 46.5, 29.2, 25.9, 21.9, 13.6 13 C-NMR (DMSO-d 6 ): 160.5, 147.3, 141.1, 139.7, 134.4, 132.5, 130.3, 129.8, 129.4, 127.3, 126.6, 125.4, 125.3, 125.1, 51.4, 46.5, 29.2, 25.9, 21.9, 13.6

원소분석(C22H22ClKN6O) : 이론치 C : 57.32%, H : 4.81%, N : 18.23%Elemental analysis (C 22 H 22 ClKN 6 O): Theoretical C: 57.32%, H: 4.81%, N: 18.23%

실측치 C : 57.27%, H : 4.90%, N : 18.25%                       Found C: 57.27%, H: 4.90%, N: 18.25%

본 발명에 따른 화학식 1로 표시되는 테트라졸 유도체는 공지된 화학식 2로 표시되는 화합물에 의하여 제조공정을 단축하여 1 단계 제조공정에 의해서 불순물을 생성하지 않고 고수율로 획득할 수 있다.The tetrazole derivative represented by Chemical Formula 1 according to the present invention can be obtained in a high yield without producing impurities by a one-step manufacturing process by shortening the production process by a known compound represented by Chemical Formula 2.

또한 본 발명은 피리딘을 용매로 사용하여 독성이 없는 염화아연 존재하에 알칼리금속아지드와 반응시키는 것이므로 친환경적으로 제조할 수 있는 제조공정과 제조공정 중에 제조자의 신체를 보호할 수 있는 제조방법을 제공한다.In another aspect, the present invention provides a manufacturing method that can protect the manufacturer's body during the manufacturing process and manufacturing process that can be environmentally friendly because it uses pyridine as a solvent to react with alkali metal azide in the presence of non-toxic zinc chloride. .

Claims (2)

염화아연 존재하에 알칼리금속아지드와 반응시켜 테트라졸 유도체의 제조방법에 있어서,In the method for producing a tetrazole derivative by reacting with an alkali metal azide in the presence of zinc chloride, 염화아연 존재하에 하기 화학식 2로 표시되는 화합물과 알칼리금속아지드를 피리딘 용매 중에서 반응시킴을 특징으로 하는 하기 화학식 1로 표시되는 테트라졸 유도체 및 그의 염의 제조방법.A method for preparing a tetrazole derivative represented by the following formula (1) and a salt thereof, wherein the compound represented by the following formula (2) and an alkali metal azide are reacted in a pyridine solvent in the presence of zinc chloride. <화학식 1><Formula 1>
Figure 112005058271822-pat00009
Figure 112005058271822-pat00009
 <화학식 2><Formula 2>
Figure 112005058271822-pat00010
Figure 112005058271822-pat00010
 상기식에서 Y는 알데히드 또는 히드록시메틸기를 나타낸다.In the formula, Y represents an aldehyde or hydroxymethyl group. 제 1 항에 있어서, 알칼리금속아지드는 리튬아지드, 소디움아지드, 칼륨아지드, 세륨아지드 중에서 선택되는 어느 하나 인 것을 특징으로 하는 화학식 1로 표시되는 테트라졸 유도체 및 그의 염의 제조방법.The method of claim 1, wherein the alkali metal azide is any one selected from lithium azide, sodium azide, potassium azide and cerium azide.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101009383B1 (en) * 2008-04-30 2011-01-19 켐젠주식회사 Preparation of high purity 2-butyl-3-[[2?-1H-tetrazol-5-yl[1,1?-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4,4]non-1-en-4-on
KR101009404B1 (en) * 2008-04-30 2011-01-19 켐젠주식회사 Preparation of high purity S-N-1-carboxy-2-methyl-pro-1-phyl-N-pentanoyl-N-[2?-1H-tetrazol-5-ylbiphenyl-4-yl-methyl]amine
KR101091734B1 (en) * 2009-06-05 2011-12-08 케이에스랩(주) Process for preparing of 5-(4`-methylbiphenyl-2-yl)-1H-tetrazole

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101009383B1 (en) * 2008-04-30 2011-01-19 켐젠주식회사 Preparation of high purity 2-butyl-3-[[2?-1H-tetrazol-5-yl[1,1?-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4,4]non-1-en-4-on
KR101009404B1 (en) * 2008-04-30 2011-01-19 켐젠주식회사 Preparation of high purity S-N-1-carboxy-2-methyl-pro-1-phyl-N-pentanoyl-N-[2?-1H-tetrazol-5-ylbiphenyl-4-yl-methyl]amine
KR101091734B1 (en) * 2009-06-05 2011-12-08 케이에스랩(주) Process for preparing of 5-(4`-methylbiphenyl-2-yl)-1H-tetrazole

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