KR920007270B1 - Method of preparing for pyridine - Google Patents

Method of preparing for pyridine Download PDF

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KR920007270B1
KR920007270B1 KR1019920010695A KR920010695A KR920007270B1 KR 920007270 B1 KR920007270 B1 KR 920007270B1 KR 1019920010695 A KR1019920010695 A KR 1019920010695A KR 920010695 A KR920010695 A KR 920010695A KR 920007270 B1 KR920007270 B1 KR 920007270B1
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formula
pyridine
preparing
iii
pyridine derivative
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KR1019920010695A
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Korean (ko)
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문순구
이관순
문영호
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한미약품공업 주식회사
임성기
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom

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

Abstract

A process for preparing pyridine derics. of formula (I) comprises (a) reacting 3,5-dimethyl pyridine-N-oxide of formula (II) with a halogenating agent to obtain 3,5-dimethyl-4-chloro pyridine of formula (III), and (b) reacting (III) with an oxidizing agent and a base. Pref. the halogenating agent is POCl3; the oxidizing agent is H2O2; the base is potassium methoxide. Cpds. (I) are intermediates in the prepn. of omeprazole which is useful as an antiulcer drug.

Description

피리딘 유도체의 제조방법Method for preparing pyridine derivative

본 발명은 다음 구조식(Ⅰ)로 표시되는 피리딘 유도체의 새로운 제조방법에 관한 것이다.The present invention relates to a new method for preparing a pyridine derivative represented by the following structural formula (I).

상기 구조식(Ⅰ)의 화합물은 항궤양제로 유용한 다음 구조식(Ⅱ)로 표시되는 오메프라졸(Omeprazole)의 제조에 유용하게 사용될 수 있는 중간체이다.The compound of formula (I) is an intermediate that can be usefully used for the preparation of omeprazole represented by the following formula (II), which is useful as an anti-ulcer agent.

구조식(Ⅰ)의 화합물을 제조하는 방법은 대한민국 특허공고 제88-91호에 예시되어 있는바, 이 방법에 의하면 하기 구조식(Ⅲ)의 3,5-디메틸피리딘-N-옥사이드에 니트로화제(진한황산-진한질산)을 작용시켜 하기 구조식 (Ⅳ)의 3.5-디메틸-4-니트로피리딘-N-옥사치드를 얻고 여기에 염기를 작용시켜 구조식(Ⅰ)의 3,5-디메틸-4-메톡시피리딘-N-옥사이드를 제조하였다.The method for preparing the compound of formula (I) is illustrated in Korean Patent Publication No. 88-91. According to this method, the nitrating agent (concentration) in 3,5-dimethylpyridine-N-oxide of formula (III) Sulfuric acid-concentrated nitric acid) to give 3.5-dimethyl-4-nitropyridine-N-oxazide of formula (IV) and to a base to which 3,5-dimethyl-4-me of formula (I) Oxypyridine-N-oxide was prepared.

그러나, 상기 제조방법에서는 구조식(Ⅲ)→구조식(Ⅳ)의 니트로화반응시 고온에서 장시간(90℃, 철야반응)반응시켜야 하며, 과량의 강산을 사용하므로 유독기체(SO2,NO2등)가 다량생성되어 대량생산에 문제점이 있으며, 구조식(Ⅰ)화합물의 수율이 50% 정도로 비교적 낮은 단점이 있었다.However, in the above manufacturing method, and it needs a long period of time (90 ℃, overnight reaction) to react at a high temperature during nitration reaction of formula (Ⅲ) → formula (Ⅳ), because it uses an excess of strong acid toxic gases (SO 2, NO 2, etc.) There is a problem in mass production because a large amount is produced, the yield of the compound of formula (I) was relatively low, such as 50%.

본 발명자들은 전술한 방법에서 야기되는 제반 문제점을 해결하기 위해 오랜동안의 연구를 행한 결과, 구조식(Ⅳ)화합물에 할로겐화제를 반응시켜 구조식(Ⅴ) 화합물을 제조하고 여기에 산화제 및 염기를 반응시키면 구조식(Ⅰ) 화합물을 고수율로 제조할 수 있다는 사실을 발견하여 본 발명을 완성하게 된 것이다.The present inventors have conducted a long study to solve the problems caused by the above-described method, and as a result, reacting a halogenating agent with a compound of formula (IV) to produce a compound of formula (V) and reacting an oxidizing agent and a base The present invention was completed by discovering that the compound of formula (I) can be prepared in high yield.

따라서, 본 발명은 항궤양제로 유용한 오메프라졸을 제조하는데 유용한 피리딘 유도체를 고수율로 제조할 수 있는 개선된 제조방법을 제공하는데 그 목적이 있다.It is therefore an object of the present invention to provide an improved process for the production of pyridine derivatives useful for preparing omeprazole useful as anti-ulcer agents in high yield.

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

본 발명은 다음 구조식(Ⅲ)으로부터 다음 구조식(Ⅰ)로 표시되는 피리딘 유도체를 제조함에 있어서, 다음 구조식(Ⅲ)의 3,5-디메틸피리딘-N-옥사이드를 할로겐화제인 POCl3와 반응시켜 다음 구조식(Ⅴ)의 3,5-디메틸-4-클로로피리딘을 제조하고, 이를 산화제인 H2O2및 염기와 반응시키는 것을 특징으로 하는 다음 구조식(Ⅰ)로 표시되는 3,5-디메틸-4-메톡시피리딘-N-옥사이드의 제조방법에 관한 것이다.In the present invention, in preparing a pyridine derivative represented by the following structural formula (I) from the following structural formula (III), by reacting 3,5-dimethylpyridine-N-oxide of the following structural formula (III) with POCl 3 as a halogenating agent 3,5-dimethyl-4-chloropyridine of (V) is prepared and reacted with H 2 O 2 and a base, which is an oxidizing agent, 3,5-dimethyl-4- represented by the following structural formula (I) It relates to a method for preparing methoxypyridine-N-oxide.

본 발명을 실시함에 있어서, 상기 구조식(Ⅲ)화합물 1당량에 대하여 POCl3를 1 내지 4당량 사용할 수 있으나, 바람직하기로는 1.5 내지 3당량을 사용하는 것이 좋다. 또한 상기 구조식(Ⅴ) 화합물로부터 구조식(Ⅰ)화합물을 제조하는 단계에 있어서, 우선 1단계 산화반응에서는 산화제로서 과산화수소, 질산, 메타클로 로퍼옥시벤조익산, 디니트로겐-테트라옥사이드 등을 사용할 수 있으나, 이 중에서 과산화수소를 사용하는 것이 가장 바람직하다. 2단계인 할로겐 치환반응에서는 소듐 알콕사이드 또는 포타슘알콕사이드 등을 사용할 수 있으나, 이중에서 포타슘알콕사이드(클라이센염기)를 사용하는 것이 바람직하다.In carrying out the present invention, 1 to 4 equivalents of POCl 3 may be used per 1 equivalent of the compound of formula (III), but it is preferable to use 1.5 to 3 equivalents. In addition, in the step of preparing the compound of formula (I) from the compound of formula (V), in the first stage of the oxidation reaction, hydrogen peroxide, nitric acid, methachloroperoxybenzoic acid, dinitrogen-tetraoxide, etc. may be used. Of these, hydrogen peroxide is most preferably used. In the two-step halogen substitution reaction, sodium alkoxide or potassium alkoxide may be used, but it is preferable to use potassium alkoxide (clisen base).

다음의 실시예는 본 발명을 보다 상세하게 설명하기 위한 것이며, 본 발명이 이에 한정되는 것은 아니다.The following examples are intended to illustrate the present invention in more detail, but the present invention is not limited thereto.

[실시예 1]Example 1

[4-클로로-3,5-디메틸피리딘의 제조][Production of 4-chloro-3,5-dimethylpyridine]

상기 구조식(Ⅰ)의 3,5-디메틸피리딘-N-옥사이드 12.3g을 250㎖ 플라스크에 넣고 그 온도를 60℃로 조절하여 완전히 용융시킨 후, 여기에다 POCl320㎖를 30분간에 걸쳐서 서서히 가한다. 반응이 진행되면서 생성되는 HCl 기체는 NaOH트랩을 사용하여 제거하고, 반응액의 온도를 80-90℃로 유지시키면서 약1시간 동안 반응시킨다. 용액의 온도를 5℃이하로 냉각시키고 포화탄산나트륨 용액을 사용하여 PH 7.0으로 조절한다. 디클로로메탄 150㎖, 100㎖를 각각 사용하여 각각 생성물을 추출해내고, 증류수 200㎖ 및 포화 소금물 200㎖로 디클로로메탄층을 세척하여 MgSO4상에서 건조시켜 용매를 증발시키면 목적하는 무색오일 상의 4-클로로-3,5-디메틸피리딘이 얻어진다.12.3 g of 3,5-dimethylpyridine-N-oxide of the above formula (I) was added to a 250 ml flask, and the temperature was adjusted to 60 ° C. to completely melt the mixture. 20 ml of POCl 3 was slowly added thereto over 30 minutes. . As the reaction proceeds, HCl gas generated is removed using a NaOH trap, and reacted for about 1 hour while maintaining the temperature of the reaction solution at 80-90 ° C. The temperature of the solution is cooled below 5 ° C. and adjusted to PH 7.0 using saturated sodium carbonate solution. Extract the product using 150 ml and 100 ml of dichloromethane, respectively, wash the layer of dichloromethane with 200 ml of distilled water and 200 ml of saturated brine, dry over MgSO 4 and evaporate the solvent to give 4-chloro- on the colorless oil of interest. 3,5-dimethylpyridine is obtained.

수율 : 11.7g(82%)Yield: 11.7 g (82%)

1H NMR(CDCl3/TMS) ppd(δ), 2.30 (6H,s), 8.21(2H, s) 1 H NMR (CDCl 3 / TMS) ppd (δ), 2.30 (6H, s), 8.21 (2H, s)

[실시예 2]Example 2

[3,5-디메틸-4-메톡시피리딘-N-옥사이드의 제조][Preparation of 3,5-dimethyl-4-methoxypyridine-N-oxide]

상기 제조예 1에 따라 제조된 4-클로로-3,5-디메틸피리딘 7.0g(0.049M)을 빙초산 15㎖에 녹이고, 이를 서서히 가열하여 60℃로 조절한다. 여기에 30% 과산화수소용액 5.3㎖를 3시간에 걸쳐 서서히 가한후, 동일한 온도에서 3시간 더 반응시킨다. 미응물질과 용매를 감압하에서 증류하여 제거하고, 10M-NaOH를 가하여 pH를 10.0으로 조절한다.7.0 g (0.049M) of 4-chloro-3,5-dimethylpyridine prepared according to Preparation Example 1 was dissolved in 15 ml of glacial acetic acid, which was slowly heated to adjust to 60 ° C. 5.3 ml of 30% hydrogen peroxide solution was slowly added over 3 hours, followed by further reaction at the same temperature for 3 hours. Uncoagulant and solvent are distilled off under reduced pressure, and the pH is adjusted to 10.0 by addition of 10M-NaOH.

잔사에 CH3CN 30㎖을 가하고 생성되는 염을 여과하여 제거한 후, CH3CN을 증류하여 제거한다. 이어서 CHCl250㎖로 2회 추출하고, MgSO4상에서 건조하여 용매를 감압증발시키면, 오일상의 4-클로로-3,5-디메틸피리딘-N-옥사이드 7.75g(100%)가 얻어진다.30 ml of CH 3 CN was added to the residue, and the resulting salt was filtered off. Then, CH 3 CN was distilled off. Then extracted twice with 50 ml of CHCl 2 , dried over MgSO 4 and evaporated under reduced pressure to give 7.75 g (100%) of 4-chloro-3,5-dimethylpyridine-N-oxide as an oil.

이렇게하여 얻어진 조생성물을 MeOH 50㎖에 녹이고, 클라이센염기_(KOH 35.2g을 증류수 25.2㎖에 용해시키고, 여기에 MeOH를 가하여 100㎖로 한 용액) 30㎖를 환류온도에서 2시간 동안 적가한다. 계속 해서 환류온도에서 2시간 더 반응을 시키고 20℃로 냉각시킨 후, 30% HCl을 사용하여 PH 9.0으로 조절한다. 감압하에 MeOH를 증류시키고, 디클로로메탄 100㎖로 잔사를 2회 추출한 후, 활성탄으로 탈색하고 여 과하여 용매를 감압하에 증류시키면 목적하는 3,5-디메틸-4-메톡시피리딘-N-옥사치드가 흰색의 결정성 고체로 얻어진다.The crude product thus obtained is dissolved in 50 ml of MeOH, and 30 ml of chrysene base _ (35.2 g of KOH is dissolved in 25.2 ml of distilled water, and 100 ml of MeOH is added thereto) is added dropwise at reflux for 2 hours. . The reaction was then continued for 2 hours at reflux, cooled to 20 ° C., and adjusted to PH 9.0 using 30% HCl. The MeOH was distilled off under reduced pressure, the residue was extracted twice with 100 ml of dichloromethane, decolorized with activated charcoal, filtered and the solvent was distilled off under reduced pressure. Obtained as a white crystalline solid.

수율 : 5.9g(78%)Yield: 5.9 g (78%)

m.p. : 79-80℃m.p. : 79-80 ℃

1H NMR(CDCl3/TMS) ppm(δ), 2.23(6H,s), 3.81(3H,s), 7.94(2H,s) 1 H NMR (CDCl 3 / TMS) ppm (δ), 2.23 (6H, s), 3.81 (3H, s), 7.94 (2H, s)

Claims (4)

다음 구조식(Ⅲ)으로 표시되는 화합물로부터 다음 구조식(Ⅰ)로 표시되는 피리딘 유도체를 제조함에 있어서, 다음 구조식(Ⅲ)의 3,5-디메틸피리딘-N-옥사이드를 할로겐화제와 반응시켜 다음 구조식(Ⅴ)의 3,5-디메틸-4-클로로피리딘을 제조하고, 이를 산화제 및 염기와 반응시키는 것을 특징으로 하는 피리딘 유도체의 제조방법.In preparing the pyridine derivative represented by the following formula (I) from the compound represented by the following formula (III), by reacting the 3,5-dimethylpyridine-N-oxide of the following formula (III) with a halogenating agent A process for producing a pyridine derivative characterized in that 3,5-dimethyl-4-chloropyridine of V) is prepared and reacted with an oxidizing agent and a base. 제1항에 있어서, 상기 할로겐화제로서 POCl3를 사용하는 것을 특징으로 하는 피리딘 유도체의 제조 방법.The method for producing a pyridine derivative according to claim 1, wherein POCl 3 is used as the halogenating agent. 제1항에 있어서, 상기 산환제로서 과산화수소(H2O2)를 사용하는 것을 특징으로 하는 피리딘 유도체의 제조방법.The method for producing a pyridine derivative according to claim 1, wherein hydrogen peroxide (H 2 O 2 ) is used as the conversion agent. 제1항에 있어서, 상기 염기로서 포타슘메톡사이드를 사용하는 것을 특징으로 하는 피리딘 유도체의 제조방법.The method for producing a pyridine derivative according to claim 1, wherein potassium methoxide is used as the base.
KR1019920010695A 1988-01-27 1992-06-19 Method of preparing for pyridine KR920007270B1 (en)

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KR1019880000637A KR910010079B1 (en) 1988-01-27 1988-01-27 Process for the preparation of benzimidazol derivatives
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