KR880001054B1 - Process for preparing 1,2-dihydro-6-methyl-20x0-5-(pyridinyl) nicotino-nitriles - Google Patents
Process for preparing 1,2-dihydro-6-methyl-20x0-5-(pyridinyl) nicotino-nitriles Download PDFInfo
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Description
본 발명은 강심제로 유용한 1,2-디하이드로-6-메틸-2-옥소-5-(피리디닐)니코티노니트릴의 제조방법에 관한 것이다.The present invention relates to a process for the preparation of 1,2-dihydro-6-methyl-2-oxo-5- (pyridinyl) nicotinonitrile useful as a cardiac agent.
미국 특허 제 4,276,293호에는 피리디닐메틸 저급 알킬 케톤을 디메틸포름아미드 디-(저급 알킬)아세탈과 반응시켜서 1-(피리디닐)-2-(디메틸아미노)에테닐 저급 알킬 케톤을 얻은 후, 이 케톤을 다시 α-시아노아세트아미드와 반응시킴으로써 1,2-디하이드로-6-(저급 알킬)-2-옥소-5-(피리디닐)니코티노니트릴을 제조하는 방법이 기재되어 있다. 또한, 미국 특허 제 4,223,149호에는 α-(피리디닐)-β-〔디-(저급 알킬)아미노〕-아크롤레인을 저급 알칸올내에서 말로노니트릴과 반응시켜서 1,2-디하이드로-2-옥소-5-(피라디닐)니코티노니트릴을 제조하는 방법이 기재되어 있다.U.S. Patent No. 4,276,293 discloses 1- (pyridinyl) -2- (dimethylamino) ethenyl lower alkyl ketones by reacting pyridinylmethyl lower alkyl ketones with dimethylformamide di- (lower alkyl) acetals to obtain 1- (pyridinyl) -2- (dimethylamino) ethenyl lower alkyl ketones. The process for preparing 1,2-dihydro-6- (lower alkyl) -2-oxo-5- (pyridinyl) nicotinonitrile is described by reacting a back with α-cyanoacetamide. U.S. Patent No. 4,223,149 also discloses the reaction of α- (pyridinyl) -β- [di- (lower alkyl) amino] -acrolein with malononitrile in lower alkanols to 1,2-dihydro-2-oxo- A method for preparing 5- (pyridinyl) nicotinonitrile is described.
본 발명의 방법은 저급 알칸올 내에서 피리디닐메틸 메틸 케톤을 에톡시메틸렌말로노니트릴과 반응시켜서 1,2-디하이드로-6-메틸-2-옥소-5-(피리디닐)니코티노니트릴을 제조하는 것으로 구성되며, 이때 상기 피리디닐은 4-혹은 3-피리디닐, 또는 1개 혹은 2개의 저급 알킬 치환체를 가진 4-혹은 3-피리디닐이다.The process of the present invention reacts pyridinylmethyl methyl ketone with ethoxymethylenemalononitrile in lower alkanols to yield 1,2-dihydro-6-methyl-2-oxo-5- (pyridinyl) nicotinonitrile. Wherein the pyridinyl is 4- or 3-pyridinyl, or 4- or 3-pyridinyl with one or two lower alkyl substituents.
본 발명의 바람직한 실시예에서는 4(혹은 3)-피리디닐메틸 메틸 케톤과 에톡시메틸렌말로노니트릴을 에탄올내에서 가열하여 1,2-디하이드로-6-메틸-2-옥소-5-〔4(혹은 3)-피리디닐〕니코티노니트릴을 제조한다. 본 발명의 특히 바람직한 실시예에 있어서는 4-피리디닐메틸 메틸 케톤과 에톡시메틸렌말로노니트릴을 환류 에탄올내에서 가열하여 1,2-디하이드로-6-메틸-2-옥소-5-(4-피리디닐)니코티노니트릴을 제조한다.In a preferred embodiment of the invention, 4 (or 3) -pyridinylmethyl methyl ketone and ethoxymethylenemalononitrile are heated in ethanol to 1,2-dihydro-6-methyl-2-oxo-5- [4 (Or 3) -pyridinyl] nicotinonitrile is prepared. In a particularly preferred embodiment of the invention, 4-pyridinylmethyl methyl ketone and ethoxymethylenemalononitrile are heated in reflux ethanol to produce 1,2-dihydro-6-methyl-2-oxo-5- (4- Pyridinyl) nicotinonitrile is prepared.
예컨대 피리디닐에 대한 치환체로서 본 명세서내에 사용된 "저급 알킬"이라는 용어는 1개 내지 4개의 탄소원자를 가지고 있는 직쇄 혹은 측쇄의 알킬기를 의미하는 것으로서, 예를 들면 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 2-부틸 혹은 이소부틸이 있다.The term "lower alkyl" as used herein as a substituent to pyridinyl, for example, refers to a straight or branched chain alkyl group having from 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, iso Propyl, n-butyl, 2-butyl or isobutyl.
본 명세서에서 사용된 "저급 알칸올"이라는 용어는 1개 내지 4개의 탄소원자를 가지고 있는 알칸올을 의미하는 것으로서, 예를 들면 메탄올, 에탄올, n-프로판올, 이소프로필 알콜, n-부탄올 등이 있다.As used herein, the term "lower alkanol" refers to an alkanol having from 1 to 4 carbon atoms, for example methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and the like. .
예컨대 반응물인 피리디닐메틸 메틸 케톤에서 사용된, 그리고 본 발명에 의한 니코티노니트릴 생성물의 5-치환체로서 사용된 "피리디닐"이라는 용어는 4-혹은 3-피리디닐, 또는 1개 혹은 2개의 저급 알킬 치환체를 가진 4-혹은 3-피리디닐을 의미하는 것으로서, 에를 들면 2-메틸-4-피리디닐, 3-메틸-4-피리디닐, 2-메틸-3-피리디닐, 2,6-디메틸-4-피리디닐, 6-메틸-3-피리디닐(다른 방법으로서는 2-메틸-5-피리디닐이라고 명명할 수도 있음), 2,3-디메틸-4-피리디닐, 2-에틸-4-피리디닐, 2-이소프로필-4-피리디닐, 2-n-부틸-4-피리디닐, 2,6-디에틸-4-피리디닐, 2,6-디이소프로필-4-피리디닐 등이 있다.The term " pyridinyl " as used, for example, in the reactant pyridinylmethyl methyl ketone and as the 5-substituted product of the nicotinonitrile product according to the invention is 4- or 3-pyridinyl, or one or two lower Means 4- or 3-pyridinyl with alkyl substituents, for example 2-methyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 2,6-dimethyl -4-pyridinyl, 6-methyl-3-pyridinyl (alternatively may be referred to as 2-methyl-5-pyridinyl), 2,3-dimethyl-4-pyridinyl, 2-ethyl-4- Pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2,6-diethyl-4-pyridinyl, 2,6-diisopropyl-4-pyridinyl and the like have.
본 발명의 방법에 따라 제조된 생성물의 분자구조는 적외선 스펙트럼, 핵자기 공명 스펙트럼 및 질량 스펙트럼에 의하여, 또한 크로마토그래프 유동도에 의하여, 그리고 대표적인 실시예에 대한 그 원소 분석에 있어서의 계산치와 실측치 사이의 대응 관계에 의하여 나타난 자료들로 입증되었다.The molecular structure of the product prepared according to the method of the present invention is determined by infrared spectra, nuclear magnetic resonance spectra and mass spectra, also by chromatographic flow, and between calculated and measured values in the elemental analysis for a representative example. The data presented by the correspondence of
본 발명의 방법은 일반적으로 반응물들을 가열함으로써, 즉 피리디닐메틸 메틸 케톤과 에톡시메틸렌말로노니트릴을 저급 알칸올(특히 바람직하게는 환류 에탄올)내에서 약 60℃-120℃의 온도로, 더욱 바람직하게는 약 75℃-100℃의 온도로서 가열함으로써 수행된다.The process of the invention generally involves heating the reactants, ie pyridinylmethyl methyl ketone and ethoxymethylenemalononitrile, at lower temperatures of about 60 ° C.-120 ° C. in lower alkanols (especially reflux ethanol). Preferably by heating at a temperature of about 75 ° C-100 ° C.
본 발명의 방법은 미국 특허 제 4,276,293호에 기재된 바와 같은 종래의 방법을 능가하는 많은 잇점을 가진다. 본 발명에서 반응물로 사용되는 애톡시메틸렌말로노니트릴은 상술한 미국 특허의 방법에서 반응물로 사용되는 디메틸포름아미드 디메틸 아세탈보다 값이 싸고 또한 용이하게 다량으로 구입할 수 있으므로 상업적인 대량 생산에 더욱 적합하다. 뿐만 아니라, 본 발명의 방법에서는 그 반응 단계가 훨씬 감소되어 있으므로, 약제의 사용이 감소하고 반응 시간이 단축됨으로써 공정에 필요한 생산비가 감소된다. 다시 말하면 α-시아노아세트아미드를 사용하는 상술한 종래의 방법은 알칼리 조건하에서 수행되어야만하기 때문에, 필요로 하는 생성물을 얻기 위하여서는 알칼리성 반응 혼합물을 산성화시키는 단계가 반드시 수반되어야만 하였었다. 이에 비하여, 본 발명의 방법을 수행함에 있어서는 알칼리나 산이 전혀 필요하지 않다.The method of the present invention has many advantages over conventional methods as described in US Pat. No. 4,276,293. The ethoxymethylenemalononitrile used as reactant in the present invention is more suitable for commercial mass production because it is cheaper and easier to purchase in large quantities than the dimethylformamide dimethyl acetal used as reactant in the above-described US patent. In addition, in the process of the present invention, since the reaction step is much reduced, the production cost required for the process is reduced by reducing the use of drugs and shortening the reaction time. In other words, since the above-mentioned conventional method using α-cyanoacetamide must be carried out under alkaline conditions, the step of acidifying the alkaline reaction mixture must be accompanied in order to obtain the required product. In contrast, no alkali or acid is required in carrying out the process of the present invention.
이하, 실시예를 통하여 본 발명을 더욱 설명하지만, 본 발명이 이들 실시예에 한정되는 것은 물론 아니다.Hereinafter, although an Example further demonstrates this invention, this invention is not limited to these Examples.
[실시예 1]Example 1
13.5g의 4-피리디닐메틸 메틸 케톤과 12.2g의 에톡시메틸렌말로노니트릴 및 100ml의 에탄올로 이루어진 혼합물을 교반하면서 5시간 동안 환류시킨 후, 실온으로 냉각하였다. 분리된 결정질 생성물을 수집하여 차가운 에탄올로 세척하고, 60℃의 진공 오븐내에서 건조시켜서 14.2g의 1,2-디하이드로-6-메틸-2-옥소-5-(4-피리디닐)니코티노니트릴을 얻었다(융점 ; 300℃이상). 이 화합물에 대한 핵자기 공명 스펙트럼 및 적외선 스펙트럼의 결과는 다른 방법, 즉 1-(4-피리디닐)-2-(디메틸아미노)에테닐 메틸 케톤을 α-시아노아세트아미드와 반응시키는 방법에 의해 얻은 동일 화합물의 상기 스펙트럼 결과와 일치하였다. 또한, 본 발명에 의해 얻은 생성물을 상기 다른 방법에 의한 생성물과 혼합하였을 때에도 그 융점이 전혀 하강하지 않았다.A mixture of 13.5 g of 4-pyridinylmethyl methyl ketone, 12.2 g of ethoxymethylenemalononitrile and 100 ml of ethanol was refluxed for 5 hours with stirring and then cooled to room temperature. The isolated crystalline product was collected, washed with cold ethanol and dried in a vacuum oven at 60 ° C. to 14.2 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotino Nitrile was obtained (melting point: 300 degreeC or more). The results of nuclear magnetic resonance spectra and infrared spectra for this compound were determined by other methods, namely by reacting 1- (4-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone with α-cyanoacetamide. It is consistent with the above spectral result of the same compound obtained. Also, the melting point did not drop at all when the product obtained by the present invention was mixed with the product obtained by the above-mentioned other method.
[실시예 2-5]Example 2-5
4-피리디닐메틸 메틸 케톤 대신에 다음에 기재된 바와 같은 등몰량의 적절한 피리디닐메틸 케톤을 사용한 것을 제외하고는 실시예 1의 과정을 반복함으로써, 대응하는 1,2-디하이드로-6-메틸-2-옥소-5-(피리디닐)니코티노니트릴을 실시예 2-5에서 제조하였다.The procedure of Example 1 was repeated except that an equivalent molar amount of appropriate pyridinylmethyl ketone was used in place of 4-pyridinylmethyl methyl ketone as described below, thereby providing the corresponding 1,2-dihydro-6-methyl- 2-oxo-5- (pyridinyl) nicotinonitrile was prepared in Example 2-5.
실시예 2 ; 3-피리디닐메틸 메틸 케톤을 사용하여서 1,2-디하이드로-6-메틸-2-옥소-5-(2-메틸-4-피리디닐)-2-옥소니코티노니트릴을 제조.Example 2; 1,2-Dihydro-6-methyl-2-oxo-5- (2-methyl-4-pyridinyl) -2-oxonicotinonitrile was prepared using 3-pyridinylmethyl methyl ketone.
실시예 4 ; (2-에틸-4-피리디닐)메틸 메틸 케톤을 사용하여서 5-(2-에틸-4-피리디닐)-1,2-디하이드로-6-메틸-2-옥소니코티노니트릴을 제조.Example 4; 5- (2-ethyl-4-pyridinyl) -1,2-dihydro-6-methyl-2-oxonicotinonitrile was prepared using (2-ethyl-4-pyridinyl) methyl methyl ketone.
실시예 5 : (2,6-디메틸-4-피리디닐)메틸 메틸 케톤을 사용하여서 1,2-디하이드로-6-메틸-5-(2,6-디메틸-4-피리디닐)-2-옥소니코티노니트릴을 제조.Example 5: 1,2-dihydro-6-methyl-5- (2,6-dimethyl-4-pyridinyl) -2- using (2,6-dimethyl-4-pyridinyl) methyl methyl ketone Preparation of oxonicotinonitrile.
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