KR20060069048A - Novel process for preparing 3,4-dihydro-pyrano[3,4-c]pyridin-1-one derivatives - Google Patents

Novel process for preparing 3,4-dihydro-pyrano[3,4-c]pyridin-1-one derivatives Download PDF

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KR20060069048A
KR20060069048A KR1020040108136A KR20040108136A KR20060069048A KR 20060069048 A KR20060069048 A KR 20060069048A KR 1020040108136 A KR1020040108136 A KR 1020040108136A KR 20040108136 A KR20040108136 A KR 20040108136A KR 20060069048 A KR20060069048 A KR 20060069048A
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김형욱
류제호
정재윤
이남규
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에스케이케미칼주식회사
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Abstract

본 발명은 3,4-디히드로-피라노[3,4-c]피리딘-1-온 유도체의 신규 제조방법에 관한 것으로, 더욱 상세하게는 4-메틸-니코티노니트릴 화합물을 출발물질로 사용하고, C-4 메틸기를 직접 히드록시에틸기로 전환한 후에 산성 조건에서 고리화함으로써 목적하는 3,4-디히드로-피라노[3,4-c]피리딘-1-온 유도체를 경제적으로 합성하게 되는 신규 제조방법에 관한 것이다.
The present invention relates to a novel process for preparing 3,4-dihydro-pyrano [3,4-c] pyridin-1-one derivatives, and more particularly, using 4-methyl-nicotinonitrile compounds as starting materials. And converting the C-4 methyl group directly into a hydroxyethyl group and then cyclizing in acidic conditions to economically synthesize the desired 3,4-dihydro-pyrano [3,4-c] pyridin-1-one derivative. It relates to a new manufacturing method.

3,4-디히드로-피라노[3,4-c]피리딘-1-온, 히드록시에틸기, 고리화, 락톤화3,4-dihydro-pyrano [3,4-c] pyridin-1-one, hydroxyethyl group, cyclized, lactonated

Description

3,4-디히드로-피라노[3,4-ｃ]피리딘-1-온 유도체의 신규 제조방법{Novel process for preparing 3,4-dihydro-pyrano[3,4-c]pyridin-1-one derivatives}New process for preparing 3,4-dihydro-pyrano [3,4-c] pyridin-1-one derivatives {Novel process for preparing 3,4-dihydro-pyrano [3,4-c] pyridin-1-one derivatives}

본 발명은 3,4-디히드로-피라노[3,4-c]피리딘-1-온 유도체의 신규 제조방법에 관한 것으로, 더욱 상세하게는 4-메틸-니코티노니트릴 화합물을 출발물질로 사용하고, C-4 메틸기를 직접 히드록시에틸기로 전환한 후에 산성 조건에서 고리화함으로써 목적하는 다음 화학식 1로 표시되는 3,4-디히드로-피라노[3,4-c]피리딘-1-온 유도체를 경제적으로 합성하게 되는 신규 제조방법에 관한 것이다.The present invention relates to a novel process for preparing 3,4-dihydro-pyrano [3,4-c] pyridin-1-one derivatives, and more particularly, using 4-methyl-nicotinonitrile compounds as starting materials. And converting the C-4 methyl group directly into a hydroxyethyl group and then cyclizing in acidic conditions to give the desired 3,4-dihydro-pyrano [3,4-c] pyridin-1-one represented by the following general formula (1). It relates to a novel process for economically synthesizing derivatives.

Figure 112004059740890-PAT00001
Figure 112004059740890-PAT00001

상기 화학식 1로 표시되는 3,4-디히드로-피라노[3,4-c]피리딘-1-온 유도체는 강력한 소염진통 효과를 갖는 화합물로서, 본 발명자들에 의해 개발되어 대한민국 특허출원 제2003-100132호로서 특허출원한 바 있다. 상기 화학식 1로 표시되는 유도체들은 화학구조상 피리딘 고리의 C-3 및 C-4 위치의 탄소가 락톤 고리와 융합되어 있는 특징을 갖는다.The 3,4-dihydro-pyrano [3,4-c] pyridin-1-one derivative represented by Chemical Formula 1 is a compound having a strong anti-inflammatory analgesic effect, which was developed by the present inventors and is a Korean Patent Application No. 2003 Patent application as -100132. The derivatives represented by the formula (1) has the characteristic that the carbon in the C-3 and C-4 position of the pyridine ring in the chemical structure is fused with the lactone ring.

상기한 대한민국 특허출원 제2003-100132호에 기재된 제조방법에서는, 다음 화학식 2로 표시되는 4-메틸-니코티노니트릴 화합물을 염기 존재 하에서 알킬 에스테르 화합물과 반응시킨 다음, 환원 반응하여 다음 화학식 3a로 표시되는 알코올 화합물을 얻고, 그런 다음 상기 화학식 3a로 표시되는 알코올 화합물을 고리화 반응하여 다음 화학식 1로 표시되는 3,4-디히드로-피라노[3,4-c]피리딘-1-온 유도체를 얻고 있다.In the above-described method of Korean Patent Application No. 2003-100132, the 4-methyl-nicotinonitrile compound represented by the following Chemical Formula 2 is reacted with an alkyl ester compound in the presence of a base, and is then reduced to the following Chemical Formula 3a. To obtain an alcohol compound, and then cyclize the alcohol compound represented by Chemical Formula 3a to obtain a 3,4-dihydro-pyrano [3,4-c] pyridin-1-one derivative represented by the following Chemical Formula 1. Getting

Figure 112004059740890-PAT00002
Figure 112004059740890-PAT00002

상기한 선행 방법에서는 화학식 3a로 표시되는 알코올 화합물을 얻기 위하여 상기 화학식 2로 표시되는 4-메틸-니코티노니트릴 화합물로부터 2 단계 반응을 수행하고 있다. 즉, 상기 화학식 2로 표시되는 4-메틸-니코티노니트릴 화합물을 알킬 에스테르 화합물로 알킬화 반응하고 이를 다시 환원 반응하여 상기 화학식 3a로 표시되는 알코올 화합물을 얻고 있다. 그러나, 상기한 선행 제조방법은 2 단계 반응을 거치면서 대체로 고가의 시약들을 사용하게 되므로 경제적이고 효율적인 제법이라 할 수 없고 특히, 상기 피리딘 유도체들의 대량합성에 적용하기에도 그다지 용이한 방법이 아니다. In the preceding method, a two-step reaction is performed from the 4-methyl-nicotinonitrile compound represented by Chemical Formula 2 to obtain an alcohol compound represented by Chemical Formula 3a. That is, the 4-methyl-nicotinonitrile compound represented by the formula (2) is alkylated with an alkyl ester compound and reduced again to obtain an alcohol compound represented by the formula (3a). However, the above-described preparation method is not an economical and efficient method because it uses expensive reagents through a two-step reaction, and is not particularly easy to apply to the mass synthesis of the pyridine derivatives.                         

따라서, 좀 더 경제적이고 효율적으로 합성하고 대량합성에도 적용할 수 있는 개량된 제조방법의 개발이 요구된다.
Therefore, there is a need for the development of an improved manufacturing method that can be synthesized more economically and efficiently and applied to mass synthesis.

본 발명자들은 상기 화학식 2로 표시되는 4-메틸-니코티노니트릴 화합물로부터 직접 알코올 화합물을 합성하는 제조방법을 개발하게됨으로써 본 발명을 완성하게 되었다.The present inventors have completed the present invention by developing a production method for synthesizing an alcohol compound directly from the 4-methyl-nicotinonitrile compound represented by Chemical Formula 2.

따라서, 본 발명은 상기 화학식 1로 표시되는 화합물을 경제적이며 효율적으로 합성하는 신규 제조방법을 제공하는데 그 목적이 있다.
Accordingly, an object of the present invention is to provide a novel production method for synthesizing the compound represented by Formula 1 economically and efficiently.

본 발명의 제조방법은The manufacturing method of the present invention

다음 화학식 2로 표시되는 4-메틸-니코티노니트릴 화합물을 포름알데히드 시약 또는 R4 함유 알콕시메틸 알킬화제로 알킬화 반응시켜 다음 화학식 3으로 표시되는 화합물을 얻는 과정, 및A process of alkylating the 4-methyl-nicotinonitrile compound represented by the following formula (2) with a formaldehyde reagent or an R 4 -containing alkoxymethyl alkylating agent to obtain a compound represented by the following formula (3), and

상기 화학식 3으로 표시되는 화합물을 고리화 반응하여 다음 화학식 1로 표시되는 3,4-디히드로-피라노[3,4-c]피리딘-1-온 유도체를 얻는 과정을 포함하여 이루어지는 것을 그 특징으로 한다. Cyclizing the compound represented by Chemical Formula 3 to obtain a 3,4-dihydro-pyrano [3,4-c] pyridin-1-one derivative represented by the following Chemical Formula 1; It is done.                     

Figure 112004059740890-PAT00003
Figure 112004059740890-PAT00003

상기 반응식 1에서, In Scheme 1,

R1, R2, 및 R3는 독립적으로 수소원자, 할로겐원자, 시아노, 니트로, 아실, 히드록시, 아미노, C1-C6 저급알킬, C2-C6 저급알케닐, C 1-C6 저급알콕시, C1-C6 알킬티오, C1-C6 알킬아미노, 아릴아미노, 아실아미노, 아실옥시, C1-C 6 알킬설피닐, C1-C6 알킬설포닐, C1-C6 알킬설포닐아미노, 아릴설피닐, 아릴설포닐, 아릴설포닐아미노, 아릴, 헤테로아릴, 아랄킬, 헤테로아랄킬, 아릴옥시 및 헤테로아릴옥시기 중에서 선택되거나, 또는 이들은 각각 서로 이웃하는 치환기와 결합하여 환을 형성할 수 있고; R4는 수소원자, C1-C6 저급알킬, C2-C6 저급알케닐, 아실 및 아릴기 중에서 선택된다.R 1 , R 2 , and R 3 are independently hydrogen atom, halogen atom, cyano, nitro, acyl, hydroxy, amino, C 1 -C 6 lower alkyl, C 2 -C 6 lower alkenyl, C 1- C 6 lower alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, arylamino, acylamino, acyloxy, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylamino, arylsulfinyl, arylsulfonyl, arylsulfonylamino, aryl, heteroaryl, aralkyl, heteroaralkyl, aryloxy and heteroaryloxy groups, or they are each adjacent to each other Combine with a substituent to form a ring; R 4 is selected from a hydrogen atom, C 1 -C 6 lower alkyl, C 2 -C 6 lower alkenyl, acyl and aryl groups.

상기 반응식 1에 따른 본 발명의 제조방법을 더욱 상세히 설명하면 다음과 같다.Referring to the production method of the present invention according to the reaction scheme 1 in more detail as follows.

본 발명의 제조방법에서 출발물질로 사용하는 상기 화학식 2로 표시되는 4-메틸-니코티노니트릴 화합물은 공지의 방법(J. Org. Chem., Vol. 41, No. 15, 2542, 1976; Pharmazie, 38(9), 591, 1983)에 의해 쉽게 제조하여 사용할 수 있다.4-methyl-nicotinonitrile compound represented by the formula (2) used as a starting material in the production method of the present invention is known methods ( J. Org. Chem ., Vol. 41, No. 15, 2542, 1976; Pharmazie , 38 (9), 591, 1983).

본 발명에 따른 제조방법에서는 먼저, 상기 화학식 2로 표시되는 4-메틸-니 코티노니트릴 화합물을 무수의 불활성 비양자성 용매 중에 녹이고, -100 ℃ 내지 -40 ℃의 온도에서 포름알데히드 시약 또는 R4 함유 알콕시메틸 알킬화제를 적가하고 -78 ℃ 내지 실온에서 2시간 내지 8시간 동안 반응시켜 상기 화학식 3으로 표시되는 화합물을 얻는다. 상기 반응에서 비양자성 용매는 테트라히드로푸란(THF), 디에틸 에테르, 디옥산 등이 포함될 수 있고, 그 중 THF가 특히 바람직하다. 포름알데히드 시약은 반응 내에서 포름알데히드를 생성시킬 수 있는 파라포름알데히드, 트리옥산 등이 포함될 수 있다. R4 함유 알콕시메틸 알킬화제는 R4OCH2X(이때, R4는 상기에서 정의한 바와 같고, X는 할로겐원자)로 표시되는 알콕시메틸 할라이드 시약이 포함될 수 있다. 또한, 상기한 알킬화 반응은 염기의 부재 하에서 또는 적절한 염기를 선택 사용하여 수행할 수 있다. 상기한 알킬화 반응에서 사용이 가능한 염기로는 리튬 비스(트리메틸실릴)아미드(LHMDS), 포타슘 비스(트리메틸실릴)아미드(KHMDS), 리튬 디이소프로필아미드(LDA), 소듐 히드리드(NaH), 포타슘 히드리드(KH), 리튬 히드리드(LiH), 소듐 히드록시드(NaOH), 소듐 카보네이트(Na2CO3), 소듐 바이카보네이트(NaHCO3), 포타슘 카보네이트(K 2CO3), 포타슘 바이카보네이트(KHCO3) 등이 포함될 수 있다. 바람직하기로는 NaOH, KOH, Na2CO3, K2CO3, NaHCO3, 또는 KHCO3 등을 염기로 사용하여 포름알데히드 수용액과 반응시키는 것이다. 더욱 바람직하게는, 염기 부재 하에서 포름알데히드 수용액 과 반응시키는 것이다.In the production method according to the present invention, first, 4-methyl-nicotinonitrile compound represented by the formula (2) is dissolved in anhydrous inert aprotic solvent, -100 ℃ to -40 Add formaldehyde reagent or R 4 containing alkoxymethyl alkylating agent at a temperature of < RTI ID = 0.0 > Reaction is carried out for 2 hours to 8 hours at ℃ to room temperature to obtain a compound represented by the formula (3). The aprotic solvent in the reaction may include tetrahydrofuran (THF), diethyl ether, dioxane and the like, of which THF is particularly preferred. Formaldehyde reagents may include paraformaldehyde, trioxane, and the like, which can produce formaldehyde in the reaction. The R 4 containing alkoxymethyl alkylating agent may include an alkoxymethyl halide reagent represented by R 4 OCH 2 X wherein R 4 is as defined above and X is a halogen atom. In addition, the above alkylation reaction can be carried out in the absence of a base or by using an appropriate base. Bases usable in the above alkylation reaction include lithium bis (trimethylsilyl) amide (LHMDS), potassium bis (trimethylsilyl) amide (KHMDS), lithium diisopropylamide (LDA), sodium hydride (NaH), potassium Hydride (KH), lithium hydride (LiH), sodium hydroxide (NaOH), sodium carbonate (Na 2 CO 3 ), sodium bicarbonate (NaHCO 3 ), potassium carbonate (K 2 CO 3 ), potassium bicarbonate (KHCO 3 ), and the like. Preferably, NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , or KHCO 3 is used as a base to react with an aqueous formaldehyde solution. More preferably, it is reacted with an aqueous formaldehyde solution in the absence of a base.

그런 다음, 상기 화학식 3으로 표시되는 화합물을 산성 조건에서 고리화 반응하여 상기 화학식 1로 표시되는 3,4-디히드로-피라노[3,4-c]피리딘-1-온 유도체을 얻는다. 산성 조건은 염산, 황산 등의 무기산을 사용하거나, 또는 아세트산 등의 유기산을 사용하여 반응용액의 pH를 0 내지 3 범위로 유지함으로써 조절된다. 바람직하게는 진한 염산 용액을 사용하여 6시간 내지 18시간 동안 환류시킴으로써 고리화 반응은 용이하게 이루어진다.Then, the compound represented by Chemical Formula 3 is cyclized under acidic conditions to obtain a 3,4-dihydro-pyrano [3,4-c] pyridin-1-one derivative represented by Chemical Formula 1. Acidic conditions are controlled by using inorganic acids such as hydrochloric acid and sulfuric acid, or by maintaining the pH of the reaction solution in the range of 0 to 3 using organic acids such as acetic acid. Preferably the cyclization reaction is facilitated by refluxing for 6-18 hours with concentrated hydrochloric acid solution.

상기한 본 발명의 제조방법에서 합성되는 반응 중간체로서 상기 화학식 3으로 표시되는 화합물 및 최종 목적 화합물로서 생성되는 상기 화학식 1로 표시되는 화합물 각각은 크로마토그래피와 재결정화와 같은 통상적인 방법에 의하여 분리 및 정제될 수 있다.As a reaction intermediate synthesized in the above-described preparation method of the present invention, each of the compound represented by Chemical Formula 3 and the compound represented by Chemical Formula 1 produced as a final target compound are separated and separated by conventional methods such as chromatography and recrystallization. It can be purified.

이와 같은 본 발명은 다음의 실시예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이들에 의해 한정되는 것은 아니다.
Such a present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

실시예 1: 4-(2-히드록시-에틸)-5-비닐-니코티노니트릴의 합성 Example 1 Synthesis of 4- (2-hydroxy-ethyl) -5-vinyl-nicotinonitrile

4-메틸-5-비닐-니코티노니트릴 58.87 g(0.408 mol)을 37% 포름알데히드 수용액 600 mL에 녹이고 20 시간 동안 가열 환류하였다. 반응액을 실온으로 냉각한 후 염화나트륨 포화수용액(200 mL)을 가하고 메틸렌클로라이드(300 mL×3)로 추출하였다. 유기용매층을 무수 황산나트륨으로 건조하여 여과한 후 여액을 감압 농축하여 얻은 잔사를 에틸아세테이트-헥산(1:1, v/v)의 혼합 용출액으로 칼럼 크 로마토그래피하여 4-(2-히드록시-에틸)-5-비닐-니코티노니트릴 56.56 g(80%)을 백색 고체로 얻었다.58.87 g (0.408 mol) of 4-methyl-5-vinyl-nicotinonitrile were dissolved in 600 mL of 37% aqueous formaldehyde solution and heated to reflux for 20 hours. After cooling the reaction solution to room temperature, saturated aqueous sodium chloride solution (200 mL) was added, followed by extraction with methylene chloride (300 mL × 3). The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by column chromatography with a mixed eluent of ethyl acetate-hexane (1: 1, v / v) to give 4- (2-hydroxy). 56.56 g (80%) of -ethyl) -5-vinyl-nicotinonitrile was obtained as a white solid.

1H NMR(300MHz, CDCl3) 8.92(s, 1H), 8.84(s, 1H), 7.05(dd, 1H, J=17.4Hz, 11.1Hz), 5.96(d, 1H, J=17.4Hz), 5.55(d, 1H, J=11.1Hz), 3.61(t, 2H, J=6.6Hz), 3.04(t, 2H, J=6.6Hz).
 1 H NMR (300 MHz, CDCl 3 ) 8.92 (s, 1 H), 8.84 (s, 1 H), 7.05 (dd, 1 H, J = 17.4 Hz, 11.1 Hz), 5.96 (d, 1H, J = 17.4 Hz), 5.55 (d, 1H, J = 11. 1 Hz), 3.61 (t, 2H, J = 6.6 Hz), 3.04 (t, 2H, J = 6.6 Hz).

실시예 2: 5-비닐-3,4-디히드로-피라노[3,4-c]피리딘-1-온의 합성 Example 2: Synthesis of 5-vinyl-3,4-dihydro-pyrano [3,4-c] pyridin-1-one

4-(2-히드록시-에틸)-5-비닐-니코티노니트릴 56.56 g(0.325 mol)에 농염산 500 mL를 가하여 pH를 0∼3으로 조절한 후에, 15 시간 동안 가열 환류하였다. 반응액을 감압 농축하여 얻은 잔사를 물에 녹인 후 0 ℃ 상에서 교반하며 탄산수소나트륨 포화수용액을 서서히 가해 중화하고 에틸아세테이트(500 mL×2)로 추출하였다. 유기용매층을 염화나트륨 포화수용액으로 세척하고 무수 황산나트륨으로 건조하여 여과한 후 여액을 감압 농축하여 얻은 잔사를 에틸아세테이트-헥산(1:2, v/v)의 혼합 용출액으로 칼럼 크로마토그래피하여 5-비닐-3,4-디히드로-피라노[3,4-c]피리딘-1-온 51.76 g(91%)을 백색 고체로 얻었다. To 56.56 g (0.325 mol) of 4- (2-hydroxy-ethyl) -5-vinyl-nicotinonitrile, 500 mL of concentrated hydrochloric acid was added to adjust the pH to 0 to 3, and then heated to reflux for 15 hours. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in water, and then 0. Stirred slowly over saturated aqueous sodium hydrogen carbonate, neutralized and extracted with ethyl acetate (500 mL × 2). The organic solvent layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by column chromatography with a mixed eluent of ethyl acetate-hexane (1: 2, v / v) to 5-vinyl. 51.76 g (91%) of -3,4-dihydro-pyrano [3,4-c] pyridin-1-one was obtained as a white solid.

1H NMR(300MHz, CDCl3) 9.17(s, 1H), 8.84(s, 1H), 6.81(dd, 1H, J=17.7Hz, 11.1Hz), 5.81(d, 1H, J=17.7Hz), 5.59(d, 1H, J=11.1Hz), 4.56(t, 2H, J=6.0Hz), 3.09(t, 2H, J=6.0Hz)
1 H NMR (300 MHz, CDCl 3 ) 9.17 (s, 1 H), 8.84 (s, 1 H), 6.81 (dd, 1 H, J = 17.7 Hz, 11.1 Hz), 5.81 (d, 1H, J = 17.7 Hz), 5.59 (d, 1H, J = 11.1 Hz), 4.56 (t, 2H, J = 6.0 Hz), 3.09 (t, 2H, J = 6.0 Hz)

실시예 3: 4-(2-메톡시에틸)-5-비닐-피리딘-3-카르보니트릴의 합성Example 3: Synthesis of 4- (2-methoxyethyl) -5-vinyl-pyridine-3-carbonitrile

무수 THF 15 mL에 4-메틸-5-비닐-니코티노니트릴 2.0 g(13.87 mmol)을 녹이고 -78 ℃에서 1M 리튬 비스(트리메틸실릴)아미드(LHMDS) 용액 15.26 mL를 적가하고 1시간 교반하였다. 동일한 온도에서 메톡시메틸클로라이드(MOMCl) 1.37 mL를 적가하고 1시간 교반한 후 0 ℃로 가온하여 2시간 더 교반하였다. 반응액에 염화암모늄 포화수용액 5 mL를 가하여 에틸아세테이트 300 mL로 희석하고, 유기용매층은 물, 염화나트륨 포화수용액으로 세척한 후 무수 황산나트륨으로 건조한 후 여과하였다. 여액을 감압농축하여 얻은 잔사를 에틸아세테이트-헥산(1:3, v/v) 혼합용출액으로 실리카겔 칼럼 크로마토그래피하여 4-(2-메톡시에틸)-5-비닐-피리딘-3-카르보니트릴 1.7 g(65%)을 무색 오일로 얻었다.Dissolve 2.0 g (13.87 mmol) of 4-methyl-5-vinyl-nicotinonitrile in 15 mL of dry THF and -78 15.26 mL of a 1M lithium bis (trimethylsilyl) amide (LHMDS) solution was added dropwise at 占 폚 and stirred for 1 hour. At the same temperature, 1.37 mL of methoxymethyl chloride (MOMCl) was added dropwise and stirred for 1 hour, followed by 0 Warmed to C and stirred for 2 h. 5 mL of saturated aqueous ammonium chloride solution was added to the reaction mixture, diluted with 300 mL of ethyl acetate. The organic solvent layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography with an ethyl acetate-hexane (1: 3, v / v) mixed eluent to give 4- (2-methoxyethyl) -5-vinyl-pyridine-3-carbonitrile 1.7. g (65%) was obtained as a colorless oil.

1H NMR(300MHz, CDCl3) 8.90(s, 1H), 8.85(s, 1H), 7.05(dd, 1H, J=17.4Hz, 11.1Hz), 5.95(d, 1H, J=17.4Hz), 5.56(d, 1H, J=11.1Hz), 3.60(t, 2H, J=6.6Hz), 3.30(s, 3H), 3.02(t, 2H, J=6.6Hz).
 1 H NMR (300 MHz, CDCl 3 ) 8.90 (s, 1 H), 8.85 (s, 1 H), 7.05 (dd, 1 H, J = 17.4 Hz, 11.1 Hz), 5.95 (d, 1H, J = 17.4 Hz), 5.56 (d, 1H, J = 11. 1 Hz), 3.60 (t, 2H, J = 6.6 Hz), 3.30 (s, 3H), 3.02 (t, 2H, J = 6.6 Hz).

실시예 4:Example 4: 5-비닐-3,4-디히드로-피라노[3,4-c]피리딘-1-온의 합성Synthesis of 5-vinyl-3,4-dihydro-pyrano [3,4-c] pyridin-1-one

4-(2-히드록시-에틸)-5-비닐-니코티노니트릴 대신 4-(2-메톡시에틸)-5-비닐-피리딘-3-카르보니트릴 1.0 g을 사용한 것을 제외하고 상기 실시예 2와 동일한 방 법으로 5-비닐-3,4-디히드로-피라노[3,4-c]피리딘-1-온 837 mg(90%)을 백색 고체로 얻었다.Example 2 above, except that 1.0 g of 4- (2-methoxyethyl) -5-vinyl-pyridine-3-carbonitrile was used instead of 4- (2-hydroxy-ethyl) -5-vinyl-nicotinonitrile In the same manner as in, 837 mg (90%) of 5-vinyl-3,4-dihydro-pyrano [3,4-c] pyridin-1-one was obtained as a white solid.

1H NMR(300MHz, CDCl3) 8.92(s, 1H), 8.84(s, 1H), 7.05(dd, 1H, J=17.4Hz, 11.1Hz), 5.96(d, 1H, J=17.4Hz), 5.55(d, 1H, J=11.1Hz), 3.61(t, 2H, J=6.6Hz), 3.04(t, 2H, J=6.6Hz).
 1 H NMR (300 MHz, CDCl 3 ) 8.92 (s, 1 H), 8.84 (s, 1 H), 7.05 (dd, 1 H, J = 17.4 Hz, 11.1 Hz), 5.96 (d, 1H, J = 17.4 Hz), 5.55 (d, 1H, J = 11. 1 Hz), 3.61 (t, 2H, J = 6.6 Hz), 3.04 (t, 2H, J = 6.6 Hz).

이상에서 설명한 바와 같이, 본 발명의 제조방법에 의하면 상기 화학식 2로 표시되는 4-메틸-니코티노니트릴 화합물로부터 1 단계 반응을 통해 직접 상기 화학식 3으로 표시되는 화합물을 합성하는 것이 가능하여 공정 단순화 효과가 크고, 또한 상기 화학식 3으로 표시되는 화합물은 산성 조건에서 고리화 반응에 의해 상기 화학식 1로 표시되는 3,4-디히드로-피라노[3,4-c]피리딘-1-온 유도체를 용이하게 합성 할 수 있어, 전체적인 제조공정이 경제적이며 효율적이어서 산업적으로 그 유용성이 매우 크다.As described above, according to the preparation method of the present invention, it is possible to directly synthesize the compound represented by Chemical Formula 3 through the one-step reaction from the 4-methyl-nicotinonitrile compound represented by Chemical Formula 2, thereby simplifying the process. In addition, the compound represented by the formula (3) is easy to 3,4-dihydro-pyrano [3,4-c] pyridin-1-one derivative represented by the formula (1) by a cyclization reaction in acidic conditions It can be synthesized easily, and the overall manufacturing process is economical and efficient, so its usefulness is very industrially.

Claims (8)

다음 화학식 2로 표시되는 4-메틸-니코티노니트릴 화합물을 포름알데히드 시약 또는 R4 함유 알콕시메틸 알킬화제로 알킬화 반응시켜 다음 화학식 3으로 표시되는 화합물을 얻는 과정, 및A process of alkylating the 4-methyl-nicotinonitrile compound represented by the following formula (2) with a formaldehyde reagent or an R 4 -containing alkoxymethyl alkylating agent to obtain a compound represented by the following formula (3), and 상기 화학식 3으로 표시되는 화합물을 고리화 반응하여 다음 화학식 1로 표시되는 3,4-디히드로-피라노[3,4-c]피리딘-1-온 유도체를 얻는 과정Cyclic reaction of the compound represented by Formula 3 to obtain a 3,4-dihydro-pyrano [3,4-c] pyridin-1-one derivative represented by the following Formula 1 을 포함하여 이루어지는 것을 특징으로 하는 제조방법 :Manufacturing method characterized in that comprises a:
Figure 112004059740890-PAT00004
Figure 112004059740890-PAT00004
Figure 112004059740890-PAT00005
Figure 112004059740890-PAT00005
 [화학식 1][Formula 1]
Figure 112004059740890-PAT00006
Figure 112004059740890-PAT00006
 상기 화학식들에서, In the above formulas, R1, R2, 및 R3는 독립적으로 수소원자, 할로겐원자, 시아노, 니트로, 아실, 히드록시, 아미노, C1-C6 저급알킬, C2-C6 저급알케닐, C 1-C6 저급알콕시, C1-C6 알킬티오, C1-C6 알킬아미노, 아릴아미노, 아실아미노, 아실옥시, C1-C 6 알킬설피닐, C1-C6 알킬설포닐, C1-C6 알킬설포닐아미노, 아릴설피닐, 아릴설포닐, 아릴설포닐아미노, 아릴, 헤테로아릴, 아랄킬, 헤테로아랄킬, 아릴옥시 및 헤테로아릴옥시기 중에서 선택되거나, 또는 이들은 각각 서로 이웃하는 치환기와 결합하여 환을 형성할 수 있고; R4는 수소원자, C1-C6 저급알킬, C2-C6 저급알케닐, 아실 및 아릴기 중에서 선택된다.R 1 , R 2 , and R 3 are independently hydrogen atom, halogen atom, cyano, nitro, acyl, hydroxy, amino, C 1 -C 6 lower alkyl, C 2 -C 6 lower alkenyl, C 1- C 6 lower alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, arylamino, acylamino, acyloxy, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylamino, arylsulfinyl, arylsulfonyl, arylsulfonylamino, aryl, heteroaryl, aralkyl, heteroaralkyl, aryloxy and heteroaryloxy groups, or they are each adjacent to each other Combine with a substituent to form a ring; R 4 is selected from a hydrogen atom, C 1 -C 6 lower alkyl, C 2 -C 6 lower alkenyl, acyl and aryl groups. 제 1 항에 있어서, 상기 R4는 수소원자, C1-C6 저급알킬 및 아릴기 중에서 선택되는 것을 특징으로 하는 제조방법.The method according to claim 1, wherein R 4 is selected from a hydrogen atom, a C 1 -C 6 lower alkyl, and an aryl group. 제 1 항에 있어서, 상기 알킬화 반응에 사용되는 포름알데히드 시약은 파라포름알데히드 및 트리옥산 중에서 선택되고, R4 함유 알콕시메틸 알킬화제는 R4OCH2X(이때, R4는 상기 청구항 1에서 정의한 바와 같고, X는 할로겐원자 임)로 표시되는 화합물 중에서 선택되는 것을 특징으로 하는 제조방법. The method of claim 1, wherein the formaldehyde reagent used in the alkylation reaction is selected from paraformaldehyde and trioxane, the R 4 containing alkoxymethyl alkylating agent is R 4 OCH 2 X (wherein R 4 is as defined in claim 1 above) And X is a halogen atom). 제 1 항에 있어서, 상기 알킬화 반응은 염기 존재 또는 부재 하에서 수행하는 것을 특징으로 하는 제조방법.The method of claim 1, wherein the alkylation reaction is carried out in the presence or absence of a base. 제 4 항에 있어서, 상기 염기는 리튬 비스(트리메틸실릴)아미드(LHMDS), 포타슘 비스(트리메틸실릴)아미드(KHMDS), 리튬 디이소프로필아미드(LDA), 소듐 히드리드(NaH), 포타슘 히드리드(KH), 리튬 히드리드(LiH), 소듐 히드록시드(NaOH), 소듐 카보네이트(Na2CO3), 소듐 바이카보네이트(NaHCO3), 포타슘 카보네이트(K 2CO3), 및 포타슘 바이카보네이트(KHCO3) 중에서 선택되는 것을 특징으로 하는 제조방법.The method of claim 4, wherein the base is lithium bis (trimethylsilyl) amide (LHMDS), potassium bis (trimethylsilyl) amide (KHMDS), lithium diisopropylamide (LDA), sodium hydride (NaH), potassium hydride (KH), lithium hydride (LiH), sodium hydroxide (NaOH), sodium carbonate (Na 2 CO 3 ), sodium bicarbonate (NaHCO 3 ), potassium carbonate (K 2 CO 3 ), and potassium bicarbonate ( KHCO 3 ) The production method, characterized in that selected from. 제 1 항에 있어서, 상기 고리화 반응은 pH 0 내지 3 범위의 산성 조건에서 수행하는 것을 특징으로 하는 제조방법.The method according to claim 1, wherein the cyclization reaction is performed under acidic conditions in the range of pH 0-3. 제 6 항에 있어서, 상기 산성 조건은 염산 및 황산을 포함하는 무기산 또는 아세트산을 포함하는 유기산을 사용하여 조절하는 것을 특징으로 하는 제조방법The method of claim 6, wherein the acidic conditions are controlled by using an inorganic acid including hydrochloric acid and sulfuric acid or an organic acid including acetic acid. 제 6 항에 있어서, 상기 산성 조건은 진한 염산 용액을 사용하여 조절하는 것을 특징으로 하는 제조방법.7. The process according to claim 6, wherein the acidic conditions are controlled using concentrated hydrochloric acid solution.
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