KR880001849B1 - Preparing process for new compounds for synthesis of heterocyclic aromatic amides - Google Patents

Preparing process for new compounds for synthesis of heterocyclic aromatic amides Download PDF

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KR880001849B1
KR880001849B1 KR1019850008972A KR850008972A KR880001849B1 KR 880001849 B1 KR880001849 B1 KR 880001849B1 KR 1019850008972 A KR1019850008972 A KR 1019850008972A KR 850008972 A KR850008972 A KR 850008972A KR 880001849 B1 KR880001849 B1 KR 880001849B1
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나경주
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일양약품공업 주식회사
정형식
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms

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Abstract

A novel compd. of formula (I), used for synthesizing heterocyclic aromatic amide, is prepd. by reacting carboxylic halogen ide with azole derivs. in the presence of solvent i.e. THF, chloroform, benzene or similar inert solvent at 0 deg.C to below b.p. of solvent. In the formula, R1 is lower alkyl, alkenyl, X is Cl or Br, Az is azole compd. i.e. imidazole, trirazole, benzimidazole or their substd. derivs., R5 is amino, acylamino gp..

Description

헤테로 고리 방향족 아마이드 합성용 신규화합물의 제조방법Process for the preparation of novel compounds for the synthesis of heterocyclic aromatic amides

본 발명은 일반식(Ⅰ)로 표시되는 도파민 수용체 차단제인 헤테로 고리 방향족 아마이드 합성에 이용되는 일반식(Ⅱ)의 화합물을 제조하는 방법에 관한 것이다.The present invention relates to a method for producing a compound of formula (II) used for the synthesis of a heterocyclic aromatic amide which is a dopamine receptor blocker represented by formula (I).

Figure kpo00001
Figure kpo00001

여기에서 X는 C1 또는 Br이며, R1은 저급알킬 또는 알케닐을 표시하며, R2,R3는 모두 수소이거나 3,4위치의 C1 또는 3,4위치의 메틸렌디옥시 그룹, 4위치의 메톡시 그룹과 수소이고, R5는 아미노, 아실아미노기를 표시하며, AZ는 아졸화합물로서 이미다졸, 파이라졸, 트라이아졸, 벤즈이미다졸, 벤조트라이아졸 및 이들의 치환 유도체를 나타낸다.Wherein X is C1 or Br, R 1 represents lower alkyl or alkenyl, R 2 , R 3 are all hydrogen or C 1 or 3,4 methylenedioxy group of 4, 4 A methoxy group and hydrogen, R 5 represents an amino, acylamino group, and A Z represents an azole compound as imidazole, pyrazole, triazole, benzimidazole, benzotriazole and substituted derivatives thereof.

본 발명의 화합물(Ⅱ)는 신규의 화합물로서 유리한 조건에서 고순도 및 고수율의 벤즈 아마이드 합성에 이용될 뿐만 아니라 지금까지 보고된 바가 없는 신규의 물질이다.Compound (II) of the present invention is a novel compound which is used for the synthesis of benzamide of high purity and high yield under favorable conditions as well as a novel substance which has not been reported so far.

본 발명을 보다 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.

본 발명의 화합물(Ⅱ)는 공지의 화합물(Ⅲ)의 카르복실산과 공지의 디아졸화합물(Ⅳ)와 용매 존재하에서 반응시켜 얻을 수 있다. 이때 사용되는 용매는 테트라 하이드로 퓨란, 클로로포름, 벤젠 및 기타 유산한 불활성용매의 존재하에서 0℃ 내지 용매의 비등점 이하에서 반응되지만 실온이 가장 바람직하다.Compound (II) of the present invention can be obtained by reacting a carboxylic acid of known compound (III) with a known diazole compound (IV) in the presence of a solvent. The solvent used here is reacted at temperatures between 0 ° C. and below the boiling point of the solvent in the presence of tetrahydrofuran, chloroform, benzene and other lactic inert solvents, but room temperature is most preferred.

또한, 본 발명의 화합물(Ⅱ)는 화합물(Ⅲ)의 카르복실산 할로겐화물과 아졸화합물(V)을 1 : 2몰비로 반응시켜서 상술한 용매 및 온도 조건하에서 얻을 수 있다.The compound (II) of the present invention can be obtained under the solvent and temperature conditions described above by reacting the carboxylic acid halide of the compound (III) with the azole compound (V) in a 1: 2 molar ratio.

또한, 화합물(Ⅱ)는 화합물(Ⅲ)의 카르복실산 할로겐화물을 N-트리메틸실릴 아졸 화합물(Ⅵ)과 상기한 조건하에서 반응시켜 얻을 수 있으며 화합물(Ⅲ)의 카르복실산 할로겐화물을 아졸의 Ag염과 상기한 조건에서 반응시켜서도 화합물(Ⅱ)을 얻을 수 있다.Further, compound (II) can be obtained by reacting the carboxylic acid halide of compound (III) with N-trimethylsilyl azole compound (VI) under the conditions described above. Compound (II) can also be obtained by making it react with Ag salt on the conditions mentioned above.

Figure kpo00002
Figure kpo00002

여기에서 X, R1,R5는 상술한 바와 같고, R4는 카르복실산, 카르복실산, 할로겐화물, 카르복실산의 저급알킬 에스테르를 표시하며, Y는 카르보닐, 티오카르보닐, 티오닐, 설퍼릴기를 표시한다.Wherein X, R 1 , R 5 are as described above, R 4 represents a carboxylic acid, carboxylic acid, halide, lower alkyl ester of carboxylic acid, Y is carbonyl, thiocarbonyl, tee O'Neill, Sulfuryl group is indicated.

이것을 화학반응식으로 표시하면 다음과 같다.If this is expressed as chemical reaction formula, it is as follows.

Figure kpo00003
Figure kpo00003

여기에서, R1,R5,X,Az는 상술한 바와 같다.Here, R 1 , R 5 , X, and Az are as described above.

본 발명의 반응에 사용되는 용매는 불활성 무수 용매로서 방향족 하이드로카본, 할로겐화 하이드로 카본, 알카노익산의 저급 알킬에스테르, 저급 알킬케톤, 저급알킬에테르, 테트라하이드로 퓨란이나 다이옥산 같은 환상에테르, 저급 지방산의 저급알킬 에스테르, 수소화하이드로 카본, 저급알킬 시아나이드, 피리딘 등을 사용하며, 반응온도는 0℃ 내지 용매의 비등점이하에서 반응시키면 실온이 가장 바람직하다.The solvent used in the reaction of the present invention is an inert anhydrous solvent which is aromatic hydrocarbon, halogenated hydrocarbon, lower alkyl ester of alkanoic acid, lower alkyl ketone, lower alkyl ether, cyclic ether such as tetrahydrofuran or dioxane, lower fatty acid. Alkyl esters, hydrogenated hydrocarbons, lower alkyl cyanide, pyridine and the like are used, and the reaction temperature is most preferably at a reaction temperature of 0 ° C to below the boiling point of the solvent.

본 발명을 보다 상세히 설명하기 위해 화합물(Ⅱ)를 합성하는 방법중의 하나인 일반식(Ⅲ)의 카르복실산과 일반식(Ⅳ)의 디아졸 화합물의 반응에서 일반식(Ⅲ)과 (Ⅳ)에서 R1이 메칠, X가 염소이고 Az이 이미다졸, Y가 카보닐기이며 R4가 카르복실산, R5가 아미노기일때를 예로 들어 메카니즘을 설명하면 다음과 같다.In order to explain the present invention in more detail, in the reaction of the carboxylic acid of general formula (III) and the diazole compound of general formula (IV), which is one of methods for synthesizing compound (II), general formulas (III) and (IV) In the case where R 1 is methyl, X is chlorine, Az is imidazole, Y is carbonyl group, R 4 is carboxylic acid and R 5 is amino group, the mechanism is as follows.

Figure kpo00004
Figure kpo00004

Figure kpo00005
Figure kpo00005

위의 화학 반응식에서 보는 바와 같이 구조식(Ⅲ-1)의 카르복실산과 N,N'-카르보닐디이미다졸(Ⅳ-1)화합물을 1 : 1로 반응시켰을 경우 1몰의 아실이미다졸(Ⅱ-1)을 형성하면서 1몰의 이미다졸과 CO2를 발생시킨다.As shown in the above chemical reaction formula, 1 mole of acylimidazole (1: 1) when the carboxylic acid of the structural formula (III-1) and the N, N'-carbonyldiimidazole (IV-1) compound is reacted 1: 1. 1 mole of imidazole and CO 2 are generated while forming II-1).

여기에서 중간체인(Ⅷ)과 (Ⅸ)은 분리해 내지 못했으며 최종 화합물(Ⅱ-1)은 분리해 내는데 성공했다.Intermediates (Ⅷ) and (Ⅸ) could not be separated here and the final compound (II-1) succeeded in separating.

본 발명을 실시예로서 상세히 설명하면 다음과 같다. 그러나, 본 발명의 범위가 이 실시예에 국한되는 것은 아니다.The present invention will be described in detail as examples. However, the scope of the present invention is not limited to this embodiment.

[실시예 1]Example 1

2-메톡시-4-아미노-5-클로로 벤조일 이미다졸의 제조방법.Process for the preparation of 2-methoxy-4-amino-5-chloro benzoyl imidazole.

기계적 교반기와 첨가 깔때기가 설치된 반응기를 장치하고 이 반응기에 2-메톡시-4-아미노-5-클로로 벤조산 20.4g(0.1mole)을 무수 테트라하이드로 퓨란 300ml로 완전히 용해한다. 실온을 유지하면서 무수 테트라하이드로 퓨란 100ml에 녹인 N,N'-카보닐디이미다졸 16.2g(0.1mole)을 가한다. 실온에서 1시간 동안 교반한다. 감압하에서 테트라하이드로 퓨란이

Figure kpo00006
정도 남을 때까지 증발시킨 후 에틸에테르를 넣어 결정화 시킨다.A reactor equipped with a mechanical stirrer and an addition funnel was installed, and 20.4 g (0.1 mole) of 2-methoxy-4-amino-5-chlorobenzoic acid was completely dissolved in 300 ml of anhydrous tetrahydrofuran. 16.2 g (0.1 mole) of N, N'-carbonyldiimidazole dissolved in 100 ml of anhydrous tetrahydrofuran was added while maintaining the room temperature. Stir at room temperature for 1 hour. Tetrahydrofuran under reduced pressure
Figure kpo00006
Evaporate until the residue remains and add ethyl ether to crystallize.

결정이 석출되면 여과하고 얼음물로 세척한다.After crystals precipitate, they are filtered and washed with ice water.

건조시키면 백색의 2-메톡시-4-아미노-5-클로로 벤조일 이미다졸 결정 23.4g을 얻는다. 수율 : 92% mp : 119°~121℃ 참조 : 적외선 스펙트럼 그라프.Drying affords 23.4 g of white 2-methoxy-4-amino-5-chloro benzoyl imidazole crystals. Yield: 92% mp: 119 ° to 121 ° C. Reference: infrared spectral graph.

Claims (5)

일반식(Ⅲ)의 화합물을 아졸유도체와 용매 존재하에 0℃ 내지 용매의 비점이하에서 반응시키는 것을 특징으로 하여 일반식(Ⅱ)의 헤테로 고리 방향족 아마이드 합성용 신규화합물의 제조방법.A process for producing a novel compound for the synthesis of heterocyclic aromatic amides of formula (II), wherein the compound of formula (III) is reacted with an azole derivative in the presence of a solvent at 0 ° C. to below the boiling point of the solvent.
Figure kpo00007
Figure kpo00007
 여기에서 R1은 저급알킬, 알케닐을 표시하며, X는 C1이나 Br이며, Az는 아졸화합물로서 이미다졸, 파이라졸, 트라이라졸, 벤즈 이미다졸, 벤조 트라이아졸 및 이들의 치환 유도체를 타나내며, R5는 아미노, 아실아미노기를 나타낸다.Wherein R 1 represents lower alkyl, alkenyl, X is C1 or Br, and Az is an azole compound, which represents imidazole, pyrazole, triazole, benz imidazole, benzo triazole and substituted derivatives thereof. R 5 represents an amino or acylamino group. 1항에 있어서, 아졸유도체로서는 일반식(Ⅳ)의 화합물을 사용함을 특징으로 하는 제 1 항기재의 헤테로 고리 방향족 아마이드 합성용 신규화합물의 제조방법.The method for producing a novel compound for synthesizing a heterocyclic aromatic amide according to claim 1, wherein the compound of formula (IV) is used as the azole derivative. 1항에 있어서, 아졸유도체로서는 일반식(Ⅴ)의 화합물을 사용함을 특징으로 하는 제 1 항기재의 헤테로 고리 방향족 아마이드 합성용 신규화합물의 제조방법.The method for producing a novel compound for synthesizing a heterocyclic aromatic amide according to claim 1, wherein the compound of formula (V) is used as the azole derivative. 1항에 있어서, 아졸유도체로서는 일반식(Ⅵ)의 화합물을 사용함을 특징으로 하는 제 1 항기재의 헤테로 고리 방향족 아마이드 합성용 신규화합물의 제조방법.The method for producing a novel compound for synthesizing a heterocyclic aromatic amide according to claim 1, wherein the compound of formula (VI) is used as the azole derivative. 1항에 있어서, 아졸유도체로서는 일반식(Ⅶ)의 화합물을 사용함을 특징으로 하는 제 1 항기재의 헤테로 고리 방향족 아마이드 합성용 신규화합물의 제조방법.The method for producing a novel compound for synthesizing a heterocyclic aromatic amide according to claim 1, wherein the compound of formula (III) is used as the azole derivative.
Figure kpo00008
Figure kpo00008
KR1019850008972A 1985-11-30 1985-11-30 Preparing process for new compounds for synthesis of heterocyclic aromatic amides KR880001849B1 (en)

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