KR930007381B1 - Process for preparation of imidazole derivatives - Google Patents

Process for preparation of imidazole derivatives Download PDF

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KR930007381B1
KR930007381B1 KR1019900017165A KR900017165A KR930007381B1 KR 930007381 B1 KR930007381 B1 KR 930007381B1 KR 1019900017165 A KR1019900017165 A KR 1019900017165A KR 900017165 A KR900017165 A KR 900017165A KR 930007381 B1 KR930007381 B1 KR 930007381B1
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iodide
general formula
phosphonium
compound
imidazole
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KR920008010A (en
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김상호
이경주
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주식회사 코오롱
하기주
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Imidazole derivs. of formula (I) and their pharmaceutically acceptable salts are prepd. by the reaction of 1-Ar-2-haloethanone (II) with imidazole using the catalyst, of formula (III), which is quaternary ammonium or phosphonium salt in organic solvent at room temp. The organic solvent is one of the following cpds. aromatic carbohydrates like benzene, toluene, or methylbenzene, ethers like tetrahydrofuran, dioxane or dimethylether, acetonitrile, methanol, N,N-dimethyl formamide, N,N-dimethyl acetamide, and dimethyl sulfoxide. Imidazole derivs and their salts are useful as an intermediate in the prepn. of antifungal agents.

Description

이미다졸 유도체의 제조방법Method for preparing imidazole derivative

본 발명은 이미다졸 유도체 및 제약학적으로 허용되는 그 산부가염의 제조방법에 관한 것으로서, 상세하게는 목적화합물을 온화한 반응조건하에서 고수율로 얻을 수 있어 매우 경제성이 우수한 동시에 공정상에 있어 간단한 하기일반식(I)로 나타내어지는 이미다졸 유도체 및 제약학적으로 허용되는 그 산부가염(이하"염"이라고만 칭함)의 제조방법에 관한 것이다 :The present invention relates to a method for preparing an imidazole derivative and a pharmaceutically acceptable acid addition salt thereof. Specifically, the target compound can be obtained in a high yield under mild reaction conditions, and thus it is very economical and simple in process. And a process for preparing an imidazole derivative represented by formula (I) and a pharmaceutically acceptable acid addition salt thereof (hereinafter referred to only as "salt"):

(상기식에서, X1는 할로겐 원자로서, 바람직하게는 Br 또는 C1로 나타내거나 혹은 이들 할로겐 원자에 의해 이치화된 것을 나타낸다).(Wherein, X 1 is a halogen atom, preferably represented by Br or C1, or represented by a halogen atom).

더욱 상세하게는, 본 발명은, 이미다졸 유도체 및 그의 염을 제조함에 있어 하기일반식(Ⅲ)으로 나타내어지는 제4 암모늄염 또는 제4 포스포늄(quaternary ammonium 또는 phosphonium salt)을 촉매로서 사용하여 상온에서 단시간내에 효과적으로 반응을 완료시키기 때문에 목적화합물을 고수율로 얻을 수 있어 경제성이 우수한 이미다졸 유도체 및 그 산부가염의 제조방법에 관한 것이다 :More specifically, the present invention, in the preparation of the imidazole derivatives and salts thereof at room temperature using a fourth ammonium salt or quaternary ammonium or phosphonium salt represented by the following general formula (III) as a catalyst The present invention relates to a method for preparing an imidazole derivative and an acid addition salt thereof having excellent economic efficiency because the target compound can be obtained in high yield because the reaction is effectively completed in a short time.

(상기식에서, R1, R2, R3및 R4는 같거나 다를 수 있으며, 각각은 C1∼C6인 알킬기 또는 아릴기이고, W는 N 또는 P이다).(Wherein R 1 , R 2 , R 3 and R 4 may be the same or different, each is a C 1 -C 6 alkyl or aryl group, and W is N or P).

본 발명의 방법에 의해 제공되는 이미다졸 유도체 및 그의 산부가염은 향진균제의 합성시 중간체로서 사용되는 매우 유용한 물질이라는 것이 알려져 있다.It is known that the imidazole derivatives and acid addition salts thereof provided by the process of the invention are very useful substances used as intermediates in the synthesis of antifungal agents.

종래에 대한민국 특허공고공보 제86-1315호 및 미합중국 특허 제4, 141, 908호에는, 이미다졸을 1-Ar-2-할로에탄올과 적당한 유기용매중에서 반응시켜 일반식(I)의 이미다졸 유도체 및 그의 산부가염을 제조하는 방법이 개시되어 있다.Conventionally, Korean Patent Publication Nos. 86-1315 and US Pat. Nos. 4, 141, and 908 disclose imidazole derivatives of general formula (I) by reacting imidazole with 1-Ar-2-haloethanol in a suitable organic solvent. And methods for preparing acid addition salts thereof are disclosed.

또한, 이와같은 방법에 있어서는 10∼24시간 정도 반응을 진행시켜야만 소망하는 목적물을 얻을수 있어 반응시간이 길고, 반응속도를 높이기 위해서는 약간의 고온, 예를 들어서 반응혼합물의 환류온도에서 반응 시키는 가열조작이 필요하기 때문에 제조공정이 번거롭고 복잡하다는 문제점이 있다.In addition, in such a method, a reaction of about 10 to 24 hours can be obtained in order to obtain a desired target. The reaction time is long, and in order to increase the reaction speed, a heating operation for reacting at a slight temperature, for example, at a reflux temperature of the reaction mixture, There is a problem that the manufacturing process is cumbersome and complicated because it is necessary.

더욱이, 이와같은 방법에서는 반응물로서 사용하는 이미다졸을 5몰 이상 과량으로 첨가하여야만 소망하는 목적물을 얻을 수 있기 때문에 제조원가면에 있어 경제적이지 못할 뿐말 아니라, 반응물을 과량으로 사용함에도 불구하고 수율도 양호하지 못하다는 문제점이 있다.Moreover, in such a method, since the desired object can be obtained only by adding an imidazole used as a reactant in an excess of 5 moles, it is not economical in terms of manufacturing cost, and the yield is not good even though the reactant is used in excess. There is a problem.

따라서, 본 발명의 발명자들은 제조공정이 간단할 뿐만 아니라, 목적화합물의 수율도 더 향상시키는 경제적이 우수한 이미다졸 유도체 및 그 산부가염의 제법을 개발하고자 부단히 연구, 검토한 결과 본 발명을 완성하기에 이르렀다.Therefore, the inventors of the present invention have studied and studied to develop an economical imidazole derivative and its acid addition salt which not only simplify the manufacturing process but also improve the yield of the target compound. Reached.

즉, 본 발명은 상기한 바와같은 종래기술의 문제점을 해결하기 위하여 안출된 것으로서 본 발명의 목적은, 이미다졸 유도체 및 그의 산부가염을 제조함에 있어서, 상온, 상압 등의 온화한 반응조건하에서 단시간내에 효과적으로 반응을 진행시킴으로써 목적화합물을 고수율로 얻을 수 있어 경제성이 우수한 일반식(I)로 나타내어지는 이미다졸 유도체 및 제약적으로 허용되는 그의 산부가염의 제조방법을 제공하는데에 있다.That is, the present invention has been made to solve the problems of the prior art as described above, the object of the present invention, in the preparation of imidazole derivatives and acid addition salts thereof, in a short time under a mild reaction conditions such as room temperature, atmospheric pressure effectively It is an object of the present invention to provide a method for producing an imidazole derivative represented by the general formula (I) having excellent economical efficiency by obtaining a target compound in a high yield, and a pharmaceutically acceptable acid addition salt thereof.

더욱 상세하게 설명하면, 본 발명의 목적은, 이미다졸 유도체 및 그의 산부가 염을 제조함에 있어서, 일반식(Ⅲ)으로 나타내어지는 제4 유기암모늄염 또는 제4 유기포스포늄염을 촉매로서 사용하여 반응을 진행시킴으로써 반응시간을 단축시키고 반응속도를 높일 뿐만 아니라, 가열조작이 필요없기 때문에 제조공정상의 번거러움을 해결한 간편하고 경제성이 우수한 일반식(Ⅰ)로 나타내어지는 이미다졸 유도체 및 그의 산부가염을 제공하는데에 있다.In more detail, it is an object of the present invention to produce an imidazole derivative and an acid addition salt thereof by using a fourth organoammonium salt or fourth organophosphonium salt represented by the general formula (III) as a catalyst. Providing the imidazole derivative represented by Formula (I) and acid addition salt thereof, which is simple and economically effective, which not only shortens the reaction time and speeds up the reaction, but also eliminates the inconvenience of the manufacturing process because no heating operation is required. It is in

상기한 바와같은 목적을 달성하기 위하여, 본 발명은, 하기일반식(Ⅱ)로 나타내어지는 1-Ar-2-할로에탄온 화합물을 유기용매중에서 하기일반식(Ⅲ)으로 나타내어지는 화합물을 촉매로서 사용하여 이미다졸과 상온에서 반응시키는 것을 특징으로 하는 하기일반식(Ⅰ)로 나타내어지는 이미다졸 유도체의 제조방법을 제공한다.In order to achieve the above object, the present invention provides a 1-Ar-2-haloethanone compound represented by the following general formula (II) as a catalyst in a compound represented by the following general formula (III) in an organic solvent: It provides a method for producing an imidazole derivative represented by the following general formula (I), characterized in that the reaction with imidazole at room temperature.

(상기식에서, X2는 할로겐 원자로서, 바람직하게는 Br 또는 C1을 나타내고, X1, R1, R2, R3, R4및 W는 상기에서 정의된 바와같은 의미를 갖는다).(Wherein X 2 represents a halogen atom, preferably Br or C1, and X 1 , R 1 , R 2 , R 3 , R 4 and W have the meaning as defined above).

또한, 본 발명에서는, 상기한 일반식(Ⅲ)으로 나타내어지는 화합물은 제4유기암모늄염 또는 제4유기포스포늄염으로서, 요오드와 사메틸암모늄, 요오드화 사에틸암모늄, 요오드와 사프로필암모늄, 요오드화 사이소프로필암모늄, 요오드화 사부틸암모늄, 요오드화 사sec.-부틸암모늄, 요오드화 사tret.-부틸암모늄, 요오드화 사펜틸암모늄, 요오드화 사헥실암모늄, 요오드화 사페닐포스포늄, 요오드화 사벤질포스포늄, 요오드화 사메틸벤질포스포늄, 요오드화 사디메틸벤질포스포늄, 요오드화 사톨릴포스포늄, 요오드화 사크실릴포스포늄 중에서 선택되는 어느 1종의 화합물인 것이 바람직하다.In the present invention, the compound represented by the general formula (III) described above is a fourth organic ammonium salt or a fourth organic phosphonium salt, wherein iodine and samethyl ammonium, iodide tetraethylammonium, iodine and sapropyl ammonium, and iodide Isopropyl ammonium, tetrabutyl ammonium iodide, tetrasulfide sec.-butylammonium iodide, tetrat-butylammonium iodide, sapentyl ammonium iodide, tetrahexyl iodide, saphenyl phosphonium iodide, sabenzyl phosphonium iodide, samethyl iodide It is preferable that it is any 1 type compound chosen from benzyl phosphonium, the tetradimethyl benzyl phosphonium iodide, the satolyl phosphonium iodide, and the sacylyl phosphonium iodide.

또한, 본 발명에 있어서, 상기한 유기용매는 벤젠, 톨루엔 또는 메틸벤젠과 같은 방향족 탄화수소, 테트라히드로푸란, 디옥산 또는 디에틸 에테르와 같은 에테르류, 아세토니트릴, 메탄올, N,N-디메틸포름아미드, N,N-디메틸아세트아미드, 디메틸술폭시드 중에서 선택되는 어느 1종의 화학물인 것이 바람직하다.In addition, in the present invention, the organic solvent is an aromatic hydrocarbon such as benzene, toluene or methylbenzene, ethers such as tetrahydrofuran, dioxane or diethyl ether, acetonitrile, methanol, N, N-dimethylformamide It is preferable that it is any 1 type of chemicals chosen from among N, N- dimethylacetamide and dimethyl sulfoxide.

즉, 본 발명은 적당한 유기용매, 바람직하게는 아세토니트릴 중에서 이미다졸 2∼2.5몰 및 일반식(Ⅱ)의 1-Ar-2-할로에탄온 화합물 1몰을 촉매로서 일반식(Ⅲ)의 화합물, 바람직하게는 요오드화 사부틸암모늄이나 혹은 요오드화 사케닐포스포늄을 사용하여 상온에서 1∼5시간 동안, 바람직하게는 2∼3시간 동안 반응시켜 일반식(Ⅰ)로 나타내어지는 이미다졸 유도체를 제조하는 방법으로서, 이를 반응식으로 표시하면 다음과 같다 :That is, the present invention is a compound of the general formula (III) as a catalyst using 2 to 2.5 moles of imidazole and 1 mole of 1-Ar-2-haloethanone compound of the general formula (II) in a suitable organic solvent, preferably acetonitrile. To prepare an imidazole derivative represented by the general formula (I) by reacting for 1 to 5 hours at room temperature, preferably for 2 to 3 hours, preferably using tetrabutylammonium iodide or sakenylphosphonium iodide. As a method, it can be expressed as a reaction scheme as follows:

(상기식에서, X1, X2, R1, R2, R3, R4및 W는 상기에서 정의된 바와같은 의미를 갖는다).(Wherein X 1 , X 2 , R 1 , R 2 , R 3 , R 4 and W have the meaning as defined above).

더욱 상세하게 설명하면, 본 발명에서는 일반식(Ⅲ)의 화합물을 촉매로 사용함으로써 하기일반식(Ⅳ)로 나타내어지는 화합물과 하기일반식(Ⅴ)로 나타내어지는 화합물이 생성되고, 여기에 다시 반응물로서 이미다졸을 첨가하게 되면 하기일반식(Ⅵ)으로 나타내어지는 중간체가 생성되면서 반응이 계속 진행되어, 목적화합물인 일반식(Ⅰ)의 이미다졸 유도체의 화합물과 함께 다시 촉매로서 사용가능한 일반식(Ⅲ)의 화합물이 생성되기 때문에, 이렇게 생성된 일반식(Ⅲ)의 화합물이 다시 반응의 촉매로 작용하는 연속적인 반응에 의해 일반식(Ⅰ)의 목적화합물을 고수율로 온화한 반응조건하에서 얻을 수 있다 :In more detail, in the present invention, by using the compound of the general formula (III) as a catalyst, the compound represented by the following general formula (IV) and the compound represented by the following general formula (V) are produced, and the reactant is again added thereto. When the imidazole is added as an intermediate, the intermediate is represented by the following general formula (VI), and the reaction proceeds continuously, and the compound can be used as a catalyst together with the compound of the imidazole derivative of general formula (I) Since the compound of III) is produced, the target compound of the formula (I) can be obtained under mild reaction conditions in high yield by a continuous reaction in which the compound of formula (III) thus formed acts as a catalyst for the reaction again. have :

본 발명에서 촉매로서 사용되는 일반식(Ⅲ)의 화합물에 있어서, R1, R2, R3및 R4가 저급알킬기인 경우에는 측쇄 또는 직쇄일 수 있다. 이와같은 저급알킬킬기로는 메틸기, 에틸기, 프로필기, 이소프로필기, 1-메틸에틸기, 1,1-디메틸에틸기, 부틸기, sec.-부틸기, tert.-부틸기, 펜틸기, 헥실기 등이 바람직하다.In the compound of general formula (III) used as a catalyst in the present invention, when R 1 , R 2 , R 3 and R 4 are lower alkyl groups, they may be branched or straight chain. Such lower alkyl kill groups include methyl, ethyl, propyl, isopropyl, 1-methylethyl, 1,1-dimethylethyl, butyl, sec.-butyl, tert.-butyl, pentyl and hexyl groups. Etc. are preferable.

R1, R2, R3및 R4가 아릴기인 경우에는 페닐기, 벤질기, 메틸벤질기, 디메틸벤질기, 톨릴기, 크실릴기 등이 바람직하다.When R 1 , R 2 , R 3 and R 4 are aryl groups, a phenyl group, benzyl group, methylbenzyl group, dimethylbenzyl group, tolyl group, xylyl group and the like are preferable.

본 발명에서는 사용가능한 일반식(Ⅲ)의 화합물로는 요오드화 사메틸암모늄, 요오드화 사에틸암모늄, 요오드화 사프로필암모늄, 요오드화 사이소프로필암모늄, 요오드화 사부틸암모늄, 요오드화 사sec.-부틸암모늄, 요오드화 사.tert.-부틸암모늄, 요오드화 사펜틸암모늄, 요오드화 사헥실암모늄, 요오드화 사페닐포스포늄, 요오드화 사벤질포스포늄, 요오드화 사메틸벤질포스포늄, 요오드화 사디메틸벤질포스포늄, 요오드화 사톨릴포스포늄, 요오드화 사크실릴포스포늄 등을 들 수 있다.Compounds of the general formula (III) which can be used in the present invention include tetramethylammonium iodide, tetraethylammonium iodide, tetrapropyl ammonium iodide, isopropyl ammonium iodide, tetrabutyl ammonium iodide, tetrabutyl ammonium iodide, and tetrabutyl iodide tert.-Butyl ammonium iodide, sapentyl ammonium iodide, tetrahexyl iodide, iodide tetraphenyl phosphonium, iodide tetraphenyl phosphonium iodide sabenzyl phosphonium iodide, tetramethylbenzyl phosphonium iodide, dimethylbenzyl phosphonium iodide, satolyl phosphonium iodide, iodide Saxylyl phosphonium etc. are mentioned.

이와같은 암모늄 화합물 또는 포스포늄 화합물은 당 기술분야에서 통상적으로 공지된 방법에 의해 실험실이나 연구소에서 합성하여 사용하거나 혹은 시중에서 시판되는 제품을 정재하여 사용가능하다.Such ammonium compounds or phosphonium compounds may be synthesized in a laboratory or a laboratory by methods commonly known in the art, or may be used by commercially available products.

한편, 이와같은 일반식(III)의 화합물은 직접 합성하거나 구입하여 사용하는 대신에 일반식(V)의 화합물과 요오드 화합물을 사용하여 반응도중에 일반식(III)의 화합물을 생성시켜 사용하는 것도 가능하며, 이와같은 반응을 진행시키는 경우에도 본 발명에 의한 작용효과가 동일하게 얻어질 수 있다.Meanwhile, instead of directly synthesizing or purchasing and using the compound of the general formula (III), it is also possible to generate and use the compound of the general formula (III) during the reaction using the compound of the general formula (V) and the iodine compound. In addition, even when such a reaction proceeds, the effect of the present invention can be obtained in the same manner.

또한, 본 발명에서 출발물질로서 사용되는 일반식(II)의 1-Ar-2-할로에탄온 화합물에 있어서, X1및 X2는 서로 같거나 다를 수 있으며, 플루오르, 염소, 브롬, 요오드를 나타내며, 바람직하게는 염소 또는 브롬을 나타내거나 혹은 이들에 의해 이치환된 것을 나타낸다.In addition, in the 1-Ar-2-haloethanone compound of the general formula (II) used as a starting material in the present invention, X 1 and X 2 may be the same or different from each other, fluorine, chlorine, bromine, iodine And preferably chlorine or bromine or disubstituted by them.

본 발명에서 사용가능한 일반식(II)의 화합물로는 2',4'-디클로로-2-브로모- 또는 2',4'-디클로로-2-클로로아세토페논, 2'-브로모-, 3'-브로모- 또는 4'-브로모-2-브로모-아세토페논, 2'-클로로-, 3'-클로로- 또는 4'-클로로-2-브로모-아세토페논 등을 들 수 있으며, 이들 화합물들도, 상기일반식(III)의 화합물과 마찬가지로, 통상의 방법에 의해 합성하거나 혹은 시판되는 제품을 정제하여 사용가능하다.Compounds of the general formula (II) usable in the present invention include 2 ', 4'-dichloro-2-bromo- or 2', 4'-dichloro-2-chloroacetophenone, 2'-bromo-, 3 '-Bromo- or 4'-bromo-2-bromo-acetophenone, 2'-chloro-, 3'-chloro- or 4'-chloro-2-bromo-acetophenone and the like. These compounds, like the compound of the general formula (III), can also be used by purifying a product synthesized by a conventional method or commercially available.

한편, 본 발명의 방법에 의한 일련의 반응은 통상적으로 사용되는 유기용매중에서 수행하는 것이 바람직하다. 이와같은 유기용매의 실례로서는 벤젠, 톨루엔 또는 메틸벤젠과 같은 방향족 탄화수소, 테트라히드로 푸란, 디옥산 또는 디에틸에테르와 같은 에테르류, 아세토니트릴, 메탄올, N,N-디메틸포름아미드, N,N-디메틸아세트아미드, 디메틸술폭시드 등을 들 수 있다. 그중에서도 아세토니트릴이 가장 바람직하다.On the other hand, it is preferable to perform a series of reactions by the method of this invention in the organic solvent normally used. Examples of such organic solvents include aromatic hydrocarbons such as benzene, toluene or methylbenzene, ethers such as tetrahydrofuran, dioxane or diethyl ether, acetonitrile, methanol, N, N-dimethylformamide, N, N- Dimethyl acetamide, dimethyl sulfoxide, etc. are mentioned. Among them, acetonitrile is most preferred.

또한, 본 발명에서 출발물질로서 사용되는 이미다졸 화합물은 무색의 결정으로서 통상적으로 글리옥살, 포름알데히드 및 암모니아의 축합에 의해 얻어질 수 있다.In addition, the imidazole compound used as the starting material in the present invention can be obtained by condensation of glyoxal, formaldehyde and ammonia as colorless crystals.

한편, 본 발명의 방법에 의해 얻어지는 일반식(I)의 화합물은 염기성 성질을 띠고 있으므로, 적당한 산, 예를 들어서 염산, 브롬산 또는 요오드산과 같은 할로겐화산 ; 황산, 질산 또는 티오시안산, 인산과 같은 무기산 ; 혹은 예를 들어서, 아세트산, 프로판산, 히드록시아세트산, 2-히드록시프로판산, 2-옥소프로판산, 벤조산, 3-페닐-2-프로펜산, α-히드록시벤젠아세트산, 메탄술폰산, 에탄술폰산, 2-히드록시에탄술폰산, 4-메톡시벤젠술폰산 등과 같은 유기산으로 처리하여 제약학적으로 허용되는 비독성 산부가염 형태로 전환시킬 수 있다. 한편, 이와같이 얻어지는 산부가염은 당 기술분야에서 공지된 알칼리로 처리하여 유리 염기 형태로 전환시킬 수도 있다.On the other hand, since the compound of the general formula (I) obtained by the method of the present invention has basic properties, a suitable acid such as a halogenated acid such as hydrochloric acid, bromic acid or iodic acid; Inorganic acids such as sulfuric acid, nitric acid or thiocyanic acid, phosphoric acid; Or, for example, acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, benzoic acid, 3-phenyl-2-propenic acid, α-hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid It can be converted into a pharmaceutically acceptable non-toxic acid addition salt form by treating with an organic acid such as 2-hydroxyethanesulfonic acid, 4-methoxybenzenesulfonic acid and the like. On the other hand, the acid addition salt thus obtained may be converted into the free base form by treating with an alkali known in the art.

본 발명에서 사용가능한 반응조건, 예를들어서 온도, 압력, 시간등에 대해서는 어떠한 특별한 제한은 주어지지 않지만, 본 발명의 반응은 통상 상온에서, 상압하에서 반응물에 사용된 치환체의 종류에 따라 1∼5시간 동안, 바람직하게는 2∼3시간 동안 수행하는 것이 바람직하다.No particular limitation is imposed on the reaction conditions usable in the present invention, such as temperature, pressure, time, etc., but the reaction of the present invention is usually carried out at room temperature for 1 to 5 hours depending on the type of substituents used in the reactants under normal pressure. Is preferably carried out for 2 to 3 hours.

한편, 본 발명에서 이미다졸 화합물은 사용된 일반식(II)의 화합물 1몰에 대해 2∼2.5몰의 양으로 사용하는 것이 바람직하다.Meanwhile, in the present invention, the imidazole compound is preferably used in an amount of 2 to 2.5 moles with respect to 1 mole of the compound of the general formula (II).

본 발명의 방법에 의해 최종적으로 얻어지는 생성물은 당 기술분야에서 공지된 방법, 이를테면 추출, 세척, 건조등의 공정에 의해 분리·정제될 수 있다.The product finally obtained by the method of the present invention can be separated and purified by methods known in the art, such as extraction, washing, drying and the like.

다음에 본 발명의 바람직한 실시예를 기재한다.Next, a preferred embodiment of the present invention is described.

그러나, 하기의 실시예는 본 발명은 더욱 상세히 예증하기 위하여 제공된 것일뿐, 본 발명의 범위가 이들 실시예에만 한정되는 것은 아니다. 달리 언급이 없다면, 다음에 사용되는 모든 % 및 부(part)는 각각 중량% 및 중량부를 의미한다.However, the following examples are provided only to illustrate the present invention in more detail, the scope of the present invention is not limited only to these examples. Unless otherwise stated, all percentages and parts used in the following mean weight percent and parts by weight, respectively.

[실시예 1]Example 1

2',4'-디클로로-2-브로모아세토페논 1부와 이미다졸 0.6부를 아세토릴트릴 15부에 녹인 후, 이어서 여기에 요오드화 사부틸암모늄 0.1부를 첨가하고 상온에서 약 2시간 동안 교반하에 반응시켰다.After dissolving 1 part of 2 ', 4'-dichloro-2-bromoacetophenone and 0.6 parts of imidazole in 15 parts of acetolyltrile, 0.1 part of tetrabutylammonium iodide was added thereto and reacted under stirring at room temperature for about 2 hours. I was.

상기 반응후 얻어지는 반응 혼합물을 6N 수산화나트륨 용액으로 염기화하고, 염화 메틸렌으로 추출하였다.The reaction mixture obtained after the reaction was basified with 6N sodium hydroxide solution and extracted with methylene chloride.

추출후 얻어지는 추출물을 물로 세척하고, 무수황산마그네슘상에서 건조하고, 여과하여 감압하에서 농축시켰다.The extract obtained after extraction was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.

잔류물을 아세톤에 녹이고, 여기에 과량의 질산을 첨가하고, 이렇게하여 얻어지는 침전된 고체염을 여과 분리하고 건조시켜 0.9부의 하기일반식(I)"로 나타내어지는 1-(2',4'-디클로로페닐)-2-(1H-이미다졸릴)에탄온 나이트레이트(융점 : 180∼182℃)를 얻었다 :The residue was dissolved in acetone, and excess nitric acid was added thereto, and the precipitated solid salt thus obtained was separated by filtration and dried to yield 1- (2 ', 4'- represented by 0.9 parts of the following general formula (I) ". Dichlorophenyl) -2- (1H-imidazolyl) ethanone nitrate (melting point: 180-182 ° C.) was obtained:

[실시예 2]Example 2

요오드화 사부틸암모늄 대신에 요오드화 사페닐포스포늄을 동일량으로 사용한 점을 제외하고는 상기한 실시예 1과 실질적으로 동일한 방법으로 처리하여 0.85부의 1-(2',4'-디클로로페닐)-2-(1H-이미다졸릴)에탄온 나이트레이트를 얻었다.Subsequently, 0.85 parts of 1- (2 ', 4'-dichlorophenyl) -2 were treated in the same manner as in Example 1, except that the same amount of tetraphenylammonium iodide was used in place of tetrabutylammonium iodide. -(1H-imidazolyl) ethanone nitrate was obtained.

[실시예 3]Example 3

2',4'-디클로로-2-브로모아세토페논 대신에 4'-브로모-2-브로모-아세토페논을 동일량으로 사용한점을 제외하고는 상기한 실시예 1과 실질적으로 동일한 방법으로 처리하여 0.7부의 하기일반식(I)"로 나타내어지는 1-(4'-브로모)-2-(1H-이미다졸릴)에탄온 나이트레이트(융점 : 175∼176℃)을 얻었다 :In substantially the same manner as in Example 1, except that 4'-bromo-2-bromo-acetophenone was used in the same amount instead of 2 ', 4'-dichloro-2-bromoacetophenone. The mixture was treated with 0.7 parts of 1- (4'-bromo) -2- (1H-imidazolyl) ethanone nitrate represented by the following general formula (I) "(melting point: 175-176 degreeC):

이상에서 상세히 기재한 바와같이, 본 발명은 온화한 반응조건하에서 일반식(Ⅲ)으로 나타내어지는 유기암모늄염 또는 유기포스포늄염을 사용하여 이미다졸 유도체 및 그의 산부가염을 제조하는 방법으로서, 종래의 이미다졸 유도체의 제조방법보다 낮은 온도에서 높은 수율로 최종 목적화합물을 얻을 수 있게 하는 간편하고 경제적인 방법으로 제공한다.As described in detail above, the present invention is a method for preparing an imidazole derivative and an acid addition salt thereof using an organoammonium salt or an organophosphonium salt represented by General Formula (III) under mild reaction conditions. It provides a simple and economical way to obtain the final target compound in high yield at a lower temperature than the preparation method of the derivative.

Claims (3)

하기일반식(II)로 나타내어지는 1Ar-2-할로에탄온 화합물을, 유기용매중에서 하기일반식(III)으로 나타내어지는 화합물을 촉매로서 사용하여, 이미다졸과 상온에서 반응시키는 것을 특징으로 하는 하기 일반식(I)로 나타내어지는 이미다졸 유도체의 제조방법 :The 1Ar-2-haloethanone compound represented by the following general formula (II) is reacted at room temperature with imidazole using the compound represented by the following general formula (III) in an organic solvent as a catalyst. Process for preparing imidazole derivative represented by general formula (I): (상기식에서, X1및 X2는 같거나 다를 수 있으며, 각각은 할로겐 원자나 혹은 이들에 의해 이치환된 것을 나타내고, R1,R2,R3, 및 R4는 같거나 다를 수 있으며, 각각은 C1∼C6인 저급알킬기 또는 아릴기를 나타내며, W는 N 또는 P를 나타낸다).Wherein X 1 and X 2 may be the same or different, each represent a halogen atom or disubstituted by them, R 1 , R 2 , R 3 , and R 4 may be the same or different, respectively Represents a lower alkyl group or an aryl group which is C 1 to C 6 , and W represents N or P). 제1항에 있어서, 상기한 일반식(III)의 화합물은 요오드화 사메틸암모늄, 요오드화 사에틸암모늄, 요오드화 사프로필암모늄, 요오드화 사이소프필암모늄, 요오드화 사부틸암모늄, 요오드화 사sec.-부틸암모늄, 사tert.-부틸암모늄, 요오드화 사펜틸암모늄, 요오드화 사헥실암모늄, 요오드화 사페닐포스포늄, 요오드화 사벤질포스포늄, 요오드화 사메틸벤질포스포늄, 요오드화 사디메틸포스포늄, 요오드화 사토릴포스포늄, 요오드화 사크실릴포스포늄 중에서 선택되는 어느 1종의 제4유기암모늄염 또는 제4유기포스포늄염인 것을 특징으로 하는 이미다졸 유도체의 제조방법.The compound of formula (III) according to claim 1, wherein the compound of the general formula (III) is tetramethylammonium iodide, tetraethylammonium iodide, tetrapropyl ammonium iodide, cysulfide iodide, tetrabutylammonium iodide, tetrasulfoxide iodide, Tert.-Butyl ammonium iodide, sapentyl ammonium iodide, hexyl iodide, iodide tetraphenyl phosphonium iodide saphenyl phosphonium iodide, sabenzyl phosphonium iodide, samethylbenzyl phosphonium iodide, dimethyl satriphosphonium iodide, satolyl iodide phosphide iodide A method for producing an imidazole derivative, characterized in that any one of the fourth organic ammonium salt or the fourth organic phosphonium salt selected from silyl phosphonium. 제1항에 있어서, 상기한 유기용매는 벤젠, 톨루엔 또는 메틸벤젠과 같은 방향족 탄화수소, 테트라히드로푸란, 디옥산 또는 디메틸 에테르와 같은 에테르류, 아세토니트릴, 메타올, N, N-디메틸포름아미드, N, N-디메틸아세트아미드, 디메틸술폭시드 중에서 선택되는 어느 1종의 화합물인 것을 특징으로 하는 이미다졸 유도체의 제조방법.The method of claim 1, wherein the organic solvent is an aromatic hydrocarbon such as benzene, toluene or methylbenzene, ethers such as tetrahydrofuran, dioxane or dimethyl ether, acetonitrile, metaol, N, N-dimethylformamide, A method for producing an imidazole derivative, which is any one compound selected from N, N-dimethylacetamide and dimethyl sulfoxide.
KR1019900017165A 1990-10-25 1990-10-25 Process for preparation of imidazole derivatives KR930007381B1 (en)

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