KR20070089487A - A method of preparing angiotensin ii antagonist - Google Patents

A method of preparing angiotensin ii antagonist Download PDF

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KR20070089487A
KR20070089487A KR1020060019590A KR20060019590A KR20070089487A KR 20070089487 A KR20070089487 A KR 20070089487A KR 1020060019590 A KR1020060019590 A KR 1020060019590A KR 20060019590 A KR20060019590 A KR 20060019590A KR 20070089487 A KR20070089487 A KR 20070089487A
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formula
azide
compound
hydrochloride
alkyl
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KR1020060019590A
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Korean (ko)
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김문성
김용직
최준호
임홍규
차대원
이재걸
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Abstract

A method for preparing an angiotensin II antagonist is provided to obtain the desired compound with high yield without using trialkyl tin azide or triphenyl tin azide, which is toxic to human body, through a simple synthesizing process. To prepare a compound represented by the formula(1) or a salt thereof, a compound represented by the formula(1) is reacted with an alkali metal azide in an aromatic solvent or an alcoholic solvent in the presence of hydrochloride of an alkyl amine, wherein the alkali metal azide is lithium azide, sodium azide, potassium azide, and cerium azide, the aromatic solvent is toluene, xylene, anisole, and benzene, and the alcoholic solvent is ethanol, n-propanol, 2-propanol, n-butanol, amyl alcohol and hexyl alcohol. In the formula, X is a group represented by the structural formula(1-a), R1 is C3-10 alkyl, R2 is halogen, and R3 is -CHO or -R4OH(wherein R4 is C1-6 alkyl or phenyl).

Description

안지오텐신 Ⅱ 길항제의 제조방법{A method of preparing angiotensin Ⅱ antagonist}A method of preparing angiotensin II antagonist

본 발명은 안지오텐신 II 길항제로서 이용되는 하기 화학식 1의 화합물의 제조방법에 관한 것이다.The present invention relates to a process for the preparation of the compound of formula (1) for use as an angiotensin II antagonist.

<화학식 1><Formula 1>

Figure 112006014928071-PAT00003
Figure 112006014928071-PAT00003

상기 식에서, Where

X는

Figure 112006014928071-PAT00004
이고,X is
Figure 112006014928071-PAT00004
ego,

R1은 C3-10알킬이며,R 1 is C 3-10 alkyl,

R2는 할로겐이고,R 2 is halogen,

R3는 -CHO 또는 -R4OH이며,R 3 is -CHO or -R 4 OH,

R4는 C1-6알킬 또는 페닐기를 나타낸다. R 4 represents a C 1-6 alkyl or phenyl group.

안지오텐신 II는 강한 혈관 수축 작용, 알도스테론-합성 작용 및 세포-증식 작용을 가지고 있어, 각종 순환계 질병의 매개 물질의 하나로 간주되고 있다. 따라서, 안지오텐신 II 길항제는 고혈압, 심장병 및 심근경색증과 같은 심장 질환, 뇌졸중, 신장염, 동맥경화 등을 비롯한 각종 순환계 질병들의 예방 및 치료에 이용된다. Angiotensin II has strong vasoconstrictive action, aldosterone-synthetic action and cell-proliferative action, and is considered to be one of the mediators of various circulatory diseases. Thus, angiotensin II antagonists are used for the prevention and treatment of various circulatory diseases including high blood pressure, heart disease such as heart disease and myocardial infarction, stroke, nephritis, arteriosclerosis and the like.

상기 화학식 1의 화합물은 안지오텐신 II 길항제의 하나로, 혈압 강하제로서 유용하게 사용되고 있는 공지의 화합물이다. 이러한 상기 화학식 1의 화합물 또는 그의 중간체의 제조방법은 미국특허 제5,138,069호, 미국특허 제4,820,843호 및 미국특허 제4,874,867호에 개시되어 있다. The compound of Formula 1 is one of angiotensin II antagonists and is a known compound which is usefully used as a blood pressure lowering agent. Methods of preparing such compounds of Formula 1 or intermediates thereof are disclosed in US Pat. No. 5,138,069, US Pat. No. 4,820,843, and US Pat. No. 4,874,867.

그러나, 상기 언급된 선행기술에서는 화학식 1의 화합물 또는 그의 중간체를 제조함에 있어, 환경유해물질로 알려져 있는 트리알킬틴아지드 또는 트리페닐틴아지드를 필수적인 반응 시약으로서 사용하고 있다. 이들은 인체에 독성을 나타내는 것으로 알려져 있어, 제조 환경상 가능하면 이들을 사용하지 않는 것이 바람직하다. 뿐만 아니라, 상기 언급된 선행기술에 개시된 화학식 1의 화합물의 제조방법은 여러 개의 중간체 합성을 통해 최종 목적 화합물을 얻는 다단계 합성 방식으로 서, 합성 과정이 복잡하고, 오랜 시간을 필요로 한다는 문제점이 있었다. However, in the above-mentioned prior art, in preparing the compound of formula (1) or an intermediate thereof, trialkyltin azide or triphenyltin azide, which is known as an environmentally harmful substance, is used as an essential reaction reagent. Since these are known to be toxic to humans, it is preferable not to use them if possible in the manufacturing environment. In addition, the method of preparing the compound of Formula 1 disclosed in the above-mentioned prior art has a problem that the synthesis process is complicated and requires a long time as a multi-step synthesis method of obtaining the final target compound through the synthesis of several intermediates. .

이에 본 발명에서는, 인체에 독성을 나타내는 트리알킬틴아지드 또는 트리페닐틴아지드를 사용하지 않으면서도 고수율로 목적 화합물을 얻을 수 있고, 합성 과정이 간단한 상기 화학식 1의 화합물의 제조방법을 제공하고자 한다. Accordingly, the present invention provides a method for preparing a compound of Chemical Formula 1, wherein the target compound can be obtained in high yield without using trialkyltin azide or triphenyltin azide, which is toxic to the human body. .

본 발명은 방향족 용매 또는 알코올류 용매 중에서 하기 화학식 2의 화합물과 알칼리금속아지드를 알킬아민 염산염 존재 하에 반응시켜 하기 화학식 1의 화합물 또는 그의 염을 제조하는 방법을 제공한다.The present invention provides a method of preparing a compound of formula 1 or a salt thereof by reacting a compound of formula 2 with an alkali metal azide in the presence of an alkylamine hydrochloride in an aromatic solvent or an alcohol solvent.

<화학식 1><Formula 1>

Figure 112006014928071-PAT00005
Figure 112006014928071-PAT00005

<화학식 2><Formula 2>

Figure 112006014928071-PAT00006
Figure 112006014928071-PAT00006

상기 식에서, Where

X는

Figure 112006014928071-PAT00007
이고,X is
Figure 112006014928071-PAT00007
ego,

R1은 C3-10알킬이며,R 1 is C 3-10 alkyl,

R2는 할로겐이고,R 2 is halogen,

R3는 -CHO 또는 -R4OH이며,R 3 is -CHO or -R 4 OH,

R4는 C1-6알킬 또는 페닐기를 나타낸다. R 4 represents a C 1-6 alkyl or phenyl group.

이하 본 발명에 따른 화학식 1의 화합물의 제조방법을 보다 상세하게 설명하기로 한다.Hereinafter, a method for preparing the compound of Formula 1 according to the present invention will be described in more detail.

본 발명자들은 트리알킬틴아지드 또는 트리페닐틴아지드의 사용을 피하면서도 고수율로 화학식 1의 화합물을 얻을 수 있는 방법을 개발하고자 지속적인 연구를 수행하였다. 그 결과, 방향족 용매 또는 알코올류 용매 중에서 화학식 2의 화합물을 알킬아민 염산염의 존재 하에 알칼리금속아지드와 반응시키면, 중간체 합성 단계 없이 상기 화학식 1의 화합물을 직접 수득할 수 있음을 알아내었다. The present inventors have carried out ongoing studies to develop a method for obtaining the compound of formula 1 in high yield while avoiding the use of trialkyltin azide or triphenyltin azide. As a result, it was found that when the compound of formula 2 is reacted with alkali metal azide in the presence of an alkylamine hydrochloride in an aromatic solvent or an alcoholic solvent, the compound of formula 1 can be directly obtained without an intermediate synthesis step.

따라서, 본 발명의 제조방법은 다단계의 중간체 합성 과정 없이 화학식 2의 화합물로부터 화학식 1의 화합물을 직접 얻을 수 있도록 하여, 선행 기술에서 화학식 1의 화합물의 합성에 요구되던 복잡한 공정을 필요로 하지 않게 하였다. 또한, 본 발명의 제조방법은 화학식 1의 화합물을 우수한 수율로 수득할 수 있게 한다. 따라서, 본 발명은 선행 기술과 비교할 때, 제조 안정성을 높이면서도, 제조 공정은 단순화시키고, 반응 효율을 높였다고 할 수 있다. Therefore, the preparation method of the present invention enables the compound of formula 1 to be obtained directly from the compound of formula 2 without a multi-step intermediate synthesis process, thereby eliminating the complicated process required for the synthesis of the compound of formula 1 in the prior art. . In addition, the preparation method of the present invention makes it possible to obtain the compound of formula 1 in excellent yield. Therefore, the present invention can be said to simplify the manufacturing process and increase the reaction efficiency, while increasing the production stability, compared to the prior art.

본 발명에 있어서, 상기 화학식 1의 화합물을 제조하는데 필요한 출발 물질로서 사용되는 상기 화학식 2의 화합물은 미국특허 제5,138,069호에 공지되어 있으며, 당업계에 공지된 방법 또는 상기 미국특허 제5,138,069호에 기술되어 있는 방법에 따라 제조하여 사용하거나, 당업계에 시판되는 제품을 사용할 수 있다. In the present invention, the compound of Formula 2, which is used as a starting material for preparing the compound of Formula 1, is known from US Pat. No. 5,138,069, and is known in the art or described in US Pat. No. 5,138,069. It can be prepared and used according to the method, or a product commercially available in the art.

본 발명에 있어서, 화학식 1의 화합물의 합성을 위해 사용되는 반응 용매로는, 방향족 용매 또는 알코올류 용매를 사용할 수 있다. 방향족 용매로는 이에 제한되는 것은 아니나, 바람직하게는 톨루엔, 자일렌, 아니솔 또는 벤젠을 사용할 수 있다. 또한, 알코올류 용매로는 이에 제한되는 것은 아니나, 바람직하게는 에탄올, n-프로판올, 2-프로판올, n-부탄올, 아밀알콜 또는 헥실알콜을 사용할 수 있 다. In the present invention, an aromatic solvent or an alcohol solvent may be used as the reaction solvent used for the synthesis of the compound of formula (1). Aromatic solvents include, but are not limited to, toluene, xylene, anisole or benzene. In addition, the alcohol solvent, but is not limited thereto, preferably ethanol, n-propanol, 2-propanol, n-butanol, amyl alcohol or hexyl alcohol can be used.

또한, 본 발명에 있어서, 알킬아민 염산염은 이에 제한되는 것은 아니나 하기 화학식 3의 화합물로 나타낼 수 있다. In addition, in the present invention, the alkylamine hydrochloride may be represented by a compound represented by the following Chemical Formula 3, but is not limited thereto.

<화학식 3><Formula 3>

R5R6R7NHClR 5 R 6 R 7 NHCl

상기 식에서, Where

R5, R6 또는 R7은 서로 동일하거나 상이하며, 각각 H, 탄소수 1 내지 7의 직쇄 또는 분지쇄 알킬 또는 사이클로알킬로부터 선택된다. R 5 , R 6 or R 7 are the same or different from each other and are selected from H, straight or branched chain alkyl or cycloalkyl having 1 to 7 carbon atoms, respectively.

바람직하게는, 알킬아민 염산염은 이에 제한되는 것은 아니나, 트리에틸아민 염산염, 디에틸아민 염산염 또는 디이소프로필 에틸아민 염산염이다. Preferably, the alkylamine hydrochloride is, but is not limited to, triethylamine hydrochloride, diethylamine hydrochloride or diisopropyl ethylamine hydrochloride.

또한, 본 발명에 있어서, 알칼리금속아지드는 이에 제한되는 것은 아니나, 바람직하게는 리튬아지드, 소디움아지드, 칼륨아지드 또는 세륨아지드이다. In addition, in the present invention, the alkali metal azide is not limited thereto, but is preferably lithium azide, sodium azide, potassium azide or cerium azide.

한편, 본 발명의 방법에 따라 제조된 화학식 1의 화합물은 다시 약학적으로 허용가능한 염기와 반응시켜 얻은 약학적으로 허용가능한 염의 형태를 포함한다. 본 발명에 있어서, 화학식 1의 화합물의 약학적으로 허용가능한 염이라 함은 화학식 1의 화합물이 형성할 수 있는 치료상 활성인 무독성의 모든 염 형태를 말한다. 상기 약학적으로 허용가능한 염기는 예를 들어, 알칼리 또는 알칼리금속염, 또는 암모늄염 등일 수 있다. On the other hand, the compound of formula 1 prepared according to the method of the present invention comprises a form of a pharmaceutically acceptable salt obtained by reaction with a pharmaceutically acceptable base again. In the present invention, the pharmaceutically acceptable salts of the compounds of formula (1) refer to all therapeutically active non-toxic salt forms that the compounds of formula (1) can form. The pharmaceutically acceptable base can be, for example, an alkali or alkali metal salt, ammonium salt, or the like.

이하 본 발명을 실시예에 의해 보다 상세히 설명하고자 한다. 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명이 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. The following examples are merely to illustrate the invention, but the invention is not limited thereto.

[실시예 1]Example 1

2-n-부틸-4-2-n-butyl-4- 클로로Chloro -5--5- 하이드록시메틸Hydroxymethyl -1-[(2'-(1H--1-[(2 '-(1H-) 테트라졸Tetrazole -5-일)비페닐-4--5-yl) biphenyl-4- 메틸methyl ]이미다졸의 제조] Preparation of Imidazole

2-n-부틸-4-클로로-1-[(2'-시아노비페닐-4-일)메틸]-5-(하이드록시메틸)이미다졸 (100g, 0.26몰, 1당량), 소디움 아지드 (171g, 2.63몰, 10당량), 및 트리에틸아민염산염 (362.4g, 2.63몰, 10당량)을 톨루엔 (2L)에 현탁시킨 후 반응온도 120℃에서 24시간 환류 교반한다. 반응 종결 후 반응액을 60℃으로 냉각시키고 톨루엔을 감압농축한다. 농축된 반응물에 초산에틸 (4L)을 가하여 희석시키고 1N-수산화나트륨 (1.5L)를 가해 pH 11로 맞춘 후 교반 하고 층 분리한다. 물층에 3N-염산 (1L)을 가하여 pH 2로 맞춘 후 초산에틸 (4L)를 가하여 추출한다. 유기층을 Na2SO4 (500g)으로 탈수, 여과한 후 메탄올 (1L)로 세척하고, 유기층을 외부온도 50℃에서 감압 농축시킨다. 농축물에 메탄올 (2L)를 가하여 용해시킨 후 활성탄 (100g)을 가하고 60℃에서 1시간 동안 교반시키고, 실온으로 냉각후 규조토 545 (500g)로 여과한 후 메탄올 (500mL)로 세척하고, 외부온도 50℃에서 감압 농축시킨다. 농축물에 아세토니트릴 (1L)를 가하고 1시간 동안 실온에서 교반한다. 석출된 결정을 감압 여과하고 아세토니트릴 (500mL)로 세척한다. 결정을 상온에서 12시간 진공 건조하여 2-n-부틸-4-클로로-5-하이드록시메틸-1-[(2'-(1H-테트라졸-5-일)비페닐-4-메틸]이미다졸 (93.2g, 84%)을 얻는다.2-n-butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl) methyl] -5- (hydroxymethyl) imidazole (100 g, 0.26 mol, 1 equiv), sodium azide (171 g, 2.63 mol, 10 equiv) and triethylamine hydrochloride (362.4 g, 2.63 mol, 10 equiv) were suspended in toluene (2 L), followed by stirring under reflux for 24 hours at a reaction temperature of 120 deg. After completion of the reaction, the reaction solution was cooled to 60 ° C. and toluene was concentrated under reduced pressure. Ethyl acetate (4L) was added to the concentrated reaction solution, diluted with 1N-sodium hydroxide (1.5L), adjusted to pH 11, stirred, and the layers separated. 3N hydrochloric acid (1L) was added to the water layer, the pH was adjusted to 2, and ethyl acetate (4L) was added to extract the mixture. The organic layer was dehydrated with Na 2 SO 4 (500 g), filtered and washed with methanol (1 L), and the organic layer was concentrated under reduced pressure at 50 ° C. Methanol (2L) was added to the concentrate to dissolve it, activated carbon (100g) was added thereto, stirred at 60 ° C for 1 hour, cooled to room temperature, filtered through diatomaceous earth 545 (500g), washed with methanol (500mL), and external temperature. Concentrate under reduced pressure at 50 ° C. Acetonitrile (1 L) is added to the concentrate and stirred for 1 hour at room temperature. The precipitated crystals are filtered under reduced pressure and washed with acetonitrile (500 mL). The crystals were vacuum dried at room temperature for 12 hours to give 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2 '-(1H-tetrazol-5-yl) biphenyl-4-methyl] Obtained dazole (93.2 g, 84%).

1H-NMR(DMSO) : δ 7.75-7.48(m-4H) ; 7.07(d,2H) ; 7.04(d,2H) ; 5.24(s,2H) ; 4.34(s,2H) ; 2.48(t,2H) ; 1.48(tt,2H) ; 1.27(qt,2H) ; 0.81(t,3H)1 H-NMR (DMSO): δ 7.75-7.48 (m-4H); 7.07 (d, 2 H); 7.04 (d, 2H); 5.24 (s, 2 H); 4.34 (s, 2 H); 2.48 (t, 2 H); 1.48 (tt, 2 H); 1.27 (qt, 2 H); 0.81 (t, 3H)

[실시예 2] Example 2

2-n-부틸-4-클로로-5-하이드록시메틸-1-[(2'-(1H-테트라졸-5-일)비페닐-4-메틸]이미다졸 칼륨 염의 제조Preparation of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2 '-(1H-tetrazol-5-yl) biphenyl-4-methyl] imidazole potassium salt

2-n-부틸-4-클로로-5-하이드록시메틸-1-[(2'-(1H-테트라졸-5-일)비페닐-4-메틸]이미다졸 (93.2g, 0.22몰, 1당량), 수산화칼륨 (17.3g, 0.31몰, 1.4당량)을 정제수 (9.3mL)과 이소프로필알콜 (466mL)에 현탁시키고, 60℃에서 1시간 교반 후, 반응액에 활성탄 (93.2 g)을 가하고 1시간 동안 교반시킨다. 반응액을 실온으로 냉각시키고 규조토 545 (100g)로 여과한 후 정제수 (100mL)로 세척한다. 여과액을 외부온도 60℃에서 감압 농축 후 농축액을 이소프로필알콜 (195 mL)로 공비한다. 농축액에 이소프로필알콜 (93 ml)와 시클로헥산 (186 mL)을 가하고 외부온도 40℃에서 1시간 교반 후 0℃로 냉각한다. 석출된 결정을 감압여과 하고, IPA (93 mL)로 세척한다. 결정을 60℃에서 진공건조하여 2-n-부틸-4-클로로-5-하이드록시메틸-1- [(2'-(1H-테트라졸-5-일)비페닐-4-메틸]이미다졸 칼륨 염 (90g, 89%)을 얻는다.2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2 '-(1H-tetrazol-5-yl) biphenyl-4-methyl] imidazole (93.2 g, 0.22 mol, 1 Equivalent) and potassium hydroxide (17.3 g, 0.31 mol, 1.4 equivalent) were suspended in purified water (9.3 mL) and isopropyl alcohol (466 mL), and stirred at 60 ° C for 1 hour, and then activated carbon (93.2 g) was added to the reaction solution. Stir for 1 hour The reaction solution is cooled to room temperature, filtered with diatomaceous earth 545 (100 g) and washed with purified water (100 mL) The filtrate is concentrated under reduced pressure at an external temperature of 60 ° C. and the concentrate isopropyl alcohol (195 mL). Isopropyl alcohol (93 ml) and cyclohexane (186 mL) were added to the concentrate, and the mixture was stirred for 1 hour at an external temperature of 40 ° C. and cooled to 0 ° C. The precipitated crystals were filtered under reduced pressure and IPA (93 mL). The crystals were dried in vacuo at 60 ° C. to yield 2-n-butyl-4-chloro-5-hydroxymethyl-1- [(2 '-(1H-tetrazol-5-yl) biphenyl-4- Methyl] imidazole potassium salt (90 g, 89%) to obtain .

1H-NMR(DMSO) : δ 7.54-7.25(m-4H) ; 7.08(d,2H) ; 6.09(d,2H) ; 5.28(s,2H) ; 4.30(s,2H) ; 2.48(t,2H) ; 1.48(tt,2H) ; 1.27(qt,2H) ; 0.81(t,3H)1 H-NMR (DMSO): δ 7.54-7.25 (m-4H); 7.08 (d, 2 H); 6.09 (d, 2 H); 5.28 (s, 2 H); 4.30 (s, 2 H); 2.48 (t, 2 H); 1.48 (tt, 2 H); 1.27 (qt, 2 H); 0.81 (t, 3H)

본 발명의 제조방법에 따르면, 화학식 1의 화합물을 제조함에 있어 필수적으로 사용되던 트리알킬틴아지드 또는 트리페닐틴아지드와 같은 유해한 반응시약을 사용하지 않고도 고수율로 화학식 1의 화합물을 수득할 수 있다. 뿐만 아니라, 본 발명의 제조방법에 따르면 화학식 1의 화합물을 제조하기 위해 필요하던 기존의 다단계 합성 단계 대신 단일단계 합성이 가능하게 된다. 따라서, 본 발명은 제조환경상 안전하고, 제조 공정이 간단하며, 반응 수율이 높은 화학식 1의 화합물의 제조방법을 제공한다. According to the preparation method of the present invention, the compound of Formula 1 can be obtained in high yield without using harmful reaction reagents such as trialkyltin azide or triphenyltin azide, which are essentially used in preparing the compound of Formula 1 . In addition, according to the preparation method of the present invention, a single step synthesis is possible instead of the existing multi step synthesis step required to prepare the compound of Formula 1. Accordingly, the present invention provides a method for preparing the compound of Formula 1, which is safe in the production environment, the manufacturing process is simple, and the reaction yield is high.

Claims (6)

방향족 용매 또는 알코올류 용매 중에서 하기 화학식 2의 화합물을 알킬아민 염산염 존재 하에서 알칼리금속아지드와 반응시켜 하기 화학식 1의 화합물 또는 그의 염을 제조하는 방법.A method of preparing a compound of formula 1 or a salt thereof by reacting a compound of formula 2 with an alkali metal azide in an aromatic solvent or an alcoholic solvent in the presence of an alkylamine hydrochloride. <화학식 1><Formula 1>
Figure 112006014928071-PAT00008
Figure 112006014928071-PAT00008
 <화학식 2><Formula 2>
Figure 112006014928071-PAT00009
Figure 112006014928071-PAT00009
 상기 식에서, Where X는
Figure 112006014928071-PAT00010
이고,X is
Figure 112006014928071-PAT00010
ego, R1은 C3-10알킬이며,R 1 is C 3-10 alkyl, R2는 할로겐이고,R 2 is halogen, R3는 -CHO 또는 -R4OH이며,R 3 is -CHO or -R 4 OH, R4는 C1-6알킬 또는 페닐기를 나타낸다. R 4 represents a C 1-6 alkyl or phenyl group. 제1항에 있어서, 알킬아민 염산염이 하기 화학식 3의 화합물인 방법:The process of claim 1 wherein the alkylamine hydrochloride is a compound of formula <화학식 3><Formula 3> R5R6R7NHClR 5 R 6 R 7 NHCl 상기 식에서, Where R5, R6 또는 R7은 서로 동일하거나 상이하며, 각각 H, 탄소수 1 내지 7의 직쇄 또는 분지쇄 알킬 또는 사이클로알킬로부터 선택된다. R 5 , R 6 or R 7 are the same or different from each other and are selected from H, straight or branched chain alkyl or cycloalkyl having 1 to 7 carbon atoms, respectively. 제2항에 있어서, 알킬아민 염산염이 트리에틸아민 염산염, 디에틸아민 염산염 또는 디이소프로필 에틸아민 염산염인 방법.The method of claim 2 wherein the alkylamine hydrochloride is triethylamine hydrochloride, diethylamine hydrochloride or diisopropyl ethylamine hydrochloride. 제1항 내지 제3항 중 어느 한 항에 있어서, 알칼리금속아지드가 리튬아지드, 소디움아지드, 칼륨아지드 또는 세륨아지드인 방법.The method according to any one of claims 1 to 3, wherein the alkali metal azide is lithium azide, sodium azide, potassium azide or cerium azide. 제1항 내지 제3항 중 어느 한 항에 있어서, 방향족 용매가 톨루엔, 자일렌, 아니솔 또는 벤젠인 방법. The process according to any one of claims 1 to 3, wherein the aromatic solvent is toluene, xylene, anisole or benzene. 제1항 내지 제3항 중 어느 한 항에 있어서, 알코올류 용매가 에탄올, n-프로판올, 2-프로판올, n-부탄올, 아밀알콜 또는 헥실알콜인 방법. The method according to any one of claims 1 to 3, wherein the alcohol solvent is ethanol, n-propanol, 2-propanol, n-butanol, amyl alcohol or hexyl alcohol.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN101402630B (en) * 2008-11-05 2012-05-30 浙江美诺华药物化学有限公司 Preparation of losartan

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN101402630B (en) * 2008-11-05 2012-05-30 浙江美诺华药物化学有限公司 Preparation of losartan

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