KR920000049B1 - Process for the preparation of 2-chloromethyl pridine derivatives - Google Patents
Process for the preparation of 2-chloromethyl pridine derivatives Download PDFInfo
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- KR920000049B1 KR920000049B1 KR1019900004400A KR900004400A KR920000049B1 KR 920000049 B1 KR920000049 B1 KR 920000049B1 KR 1019900004400 A KR1019900004400 A KR 1019900004400A KR 900004400 A KR900004400 A KR 900004400A KR 920000049 B1 KR920000049 B1 KR 920000049B1
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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
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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
- C07D213/89—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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Abstract
Description
본 발명은 위산 분비 억제제를 제조할때 유용한 중간체로 사용되는 다음 구조식(Ⅰ)로 표시되는 2 - 클로로메틸피리딘 유도체의 새로운 제조 방법에 관한 것으로서, 더욱 상세하게는 2 - 메틸피리딘 유도체로부터 옥시염화인과 아민화합물을 사용하여 경제적이고도 고수율로 2 - 클로로메틸피리딘 유도체를 제조하는 방법에 관한 것이다.The present invention relates to a novel process for preparing 2-chloromethylpyridine derivatives represented by the following structural formula (I), which is used as an intermediate useful in the preparation of gastric acid secretion inhibitors, and more particularly, to phosphorus oxychloride from 2-methylpyridine derivatives. The present invention relates to a method for producing a 2 -chloromethylpyridine derivative in an economical and high yield using an amine compound.
상기 식에서 R은 수소 원자 또는 메톡시기를 나타낸다.In the formula, R represents a hydrogen atom or a methoxy group.
종래에 2 - 클로로메틸피리딘 유도체를 제조하는 대표적인 방법으로는 다음과 같은 방법이 있었다. 첫째, 2 - 메틸피리딘의 유도체로부터 2 - 아세톡시메틸피리딘 유도체를 제조한 후, 이를 가수분해하여 2 - 히드록시 메틸피리딘 유도체를 제조하고, 이를 다시 클로로화하여 2 - 클로로메틸피리딘 유도체를 제조하는 방법이 있다(국내 특허 공고 제88 - 91호).Conventionally, as a representative method for preparing a 2-chloromethylpyridine derivative, the following method has been used. First, 2-acetoxymethylpyridine derivatives are prepared from derivatives of 2-methylpyridine, and then hydrolyzed to prepare 2-hydroxymethylpyridine derivatives, which are then chlorolated to prepare 2-chloromethylpyridine derivatives. There is a method (Domestic Patent Publication Nos. 88-91).
상기의 방법을 반응 메카니즘으로 나타내면 다음과 같다.The above method is represented by the reaction mechanism as follows.
상기 식에서 R은 수소원자 또는 메톡시기를 나타낸다.In the formula, R represents a hydrogen atom or a methoxy group.
다른 또 하나의 방법으로는, 오르쏘(ortho)위치에 치환체가 없는 피리딘 N - 옥사이드 유도체로부터 O - 메틸화된 화합물을 제조한 다음 유리라디칼의 존재하에서 2 - 히드록시메틸피리딘 유도체를 제조하고 이를 클로로화하여 2 - 클로로메틸피리딘 유도체를 제조하는 방법이 개시되어 있다(국내 특허 공고 제88 - 91호).In another method, O-methylated compounds are prepared from pyridine N-oxide derivatives having no substituents at the ortho position, followed by preparation of 2-hydroxymethylpyridine derivatives in the presence of free radicals and chloro To prepare a 2-chloromethylpyridine derivative. (Korean Patent Publication No. 88-91).
상기의 방법을 반응 메카니즘으로 나타내면 다음과 같다.The above method is represented by the reaction mechanism as follows.
상기 식에서 R은 수소 원자 또는 메톡시기를 나타낸다.In the formula, R represents a hydrogen atom or a methoxy group.
그러나 상기와 같은 방법들은 모두가 3가지 공정을 거쳐야 하므로 수율이 낮고 또한 제조공정이 복잡하여 비경제적이라는 단점이 있다.However, all of the above methods have a disadvantage in that the yield is low and the manufacturing process is complicated because it has to go through three processes.
이에 본 발명은 2 - 클로로메틸피리딘 유도체를 제조함에 있어서, 단 하나의 공정만을 거침으로써 경제적이고도 고수율로 목적 화합물을 제조하는 방법을 제공하는데 그 목적이 있는 것이다.Accordingly, an object of the present invention is to provide a method for producing a target compound in an economical and high yield by only one process in preparing a 2-chloromethylpyridine derivative.
이하 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
본 발명은 다음 구조식(Ⅱ)로 나타낸 2 - 메틸피리딘 유도체로부터 다음 구조식(Ⅰ)로 나타낸 2 - 클로로메딜피리딘 유도체를 제조함에 있어서, 상기 2 - 메틸피리딘 유도체에 옥시염화인과 아민 화합물을 사용하는 것을 특징으로 하는 2 - 클로로 메틸피리딘 유도체의 제조방법이다.The present invention uses the phosphorus oxychloride and the amine compound as the 2-methylpyridine derivative in the preparation of the 2-chloromedylpyridine derivative represented by the following structural formula (I) from the 2-methylpyridine derivative represented by the following structural formula (II). It is a method for producing a 2-chloromethylpyridine derivative, characterized in that.
이때 반응은 20∼60℃ 온도에서 3∼6시간 동안 실시하는 것이 가장 좋다.At this time, the reaction is best carried out for 3 to 6 hours at a temperature of 20 ~ 60 ℃.
기 식에서 R은 수소 원자 또는 메톡시기를 나타낸다.R represents a hydrogen atom or a methoxy group.
본 발명은 아래의 반응식으로 나타냈듯이 상기 구조식(Ⅱ)로 표시되는 2 - 메틸피리딘 유도체에 옥시염화인과 트리메틸 아민이나 트리에틸아민 또는 피리딘 등의 아민 화합물을 첨가시켜 반응시킨 다음, 수산화나트륨으로 알카리화하여 유기 용매층을 추출, 감압 증류시켜서 상기 구조식(Ⅰ)로 표시되는 2 - 클로로메틸피리딘 유도체를 제조하는 것이다.The present invention reacts by adding an amine compound such as phosphorus oxychloride and trimethyl amine, triethylamine or pyridine to the 2-methylpyridine derivative represented by the structural formula (II) as shown by the following reaction formula, followed by sodium hydroxide. Alkalineization, the organic solvent layer is extracted, and distillation under reduced pressure is carried out to produce the 2-chloromethylpyridine derivative represented by the above formula (I).
이때 사용되는 아미노화합물은 PO2Cl2와 착물을 만드는 모든 아민류가 사용 가능하지만 특히 트리메틸아민, 트리에틸아민 또는 피리딘을 사용하는 것이 가장 바람직하다.The amino compound used at this time can be used all amines complexed with PO 2 Cl 2 It is most preferable to use trimethylamine, triethylamine or pyridine.
상기 식에서 R은 수소 원자 또는 메톡시기를 나타낸다.In the formula, R represents a hydrogen atom or a methoxy group.
이러한 본 발명은 2 - 클로로메틸피리딘 유도체를 제조함에 있어서, 단 하나의 공정만을 거치기 때문에 공정이 간단할뿐 아니라 경제적으로 유용하고, 더불어 높은 수율로 목적물을 제조할 수 있는 효과가 있는 것이다.In the present invention, in the preparation of the 2-chloromethylpyridine derivative, only one process is required, and thus the process is not only simple but economically useful, and also has the effect of producing a target product in high yield.
이하, 본 발명을 실시예에 의거 상세히 설명하겠는바, 본 발명이 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by Examples.
[실시예 1]Example 1
환류 컬럼과 교반기가 장치된 플라스크에 2,3,5 - 트리메틸 - 4 - 메톡시피리딘 - 1 - 옥사이드 50.0g, 디클로로메탄 300ml를 넣은후 교반기를 사용하여 교반을 하면서 온도를 40℃까지 올렸다. 40℃에서 옥시염화인 50.4g을 디클로로메탄 300ml에 녹인 용매를 적가하기 시작하였다. 잠시후 트리에틸아민 30.3g을 디클로로메탄 300ml에 녹인 용액을 상기의 용액과 동시에 적가하였다. 적가하는데 소요된 시간은 3시간이었다. 적가가 끝난후 2시간 동안 환류시키고 디클로로메탄은 감압 증류로 제거한후, 테트라하이드로퓨란 100ml에 녹이고 녹지 아니한 침전물을 여과하여 제거하였다. 이 과정을 2회 반복한후 감압 농축하여 목적 화합물인 3,5 - 디메틸 - 4 - 메톡시 - 2 - 클로로메틸피리딘 50.0g(90.0%)을 얻었다.In a flask equipped with a reflux column and a stirrer, 20.0 g of 3,5-trimethyl-4-methoxypyridine-1 oxide and 300 ml of dichloromethane were added thereto, and the temperature was raised to 40 ° C. while stirring using a stirrer. At 40 ° C., a solvent in which 50.4 g of phosphorus oxychloride was dissolved in 300 ml of dichloromethane was added dropwise. After a while, a solution of 30.3 g of triethylamine in 300 ml of dichloromethane was added dropwise simultaneously with the above solution. The time required for dropping was three hours. After the addition, the mixture was refluxed for 2 hours, dichloromethane was removed by distillation under reduced pressure, dissolved in 100 ml of tetrahydrofuran, and the undissolved precipitate was removed by filtration. This process was repeated twice, followed by concentration under reduced pressure, to obtain 50.0 g (90.0%) of the target compound, 3,5-dimethyl-4-methoxy-2-2-chloromethylpyridine.
[실시예 2]Example 2
상기 실시예 1과 동일하게 실시하되 반응물을 교반하면서 온도 30℃까지 올리고. 트리에틸아민은 17.7g을 사용하였다. 그 결과 목적 화합물을 45.5g(82.0%) 얻었다.Do the same as in Example 1, but raise the temperature to 30 ℃ while stirring the reactants. 17.7 g of triethylamine was used. As a result, 45.5 g (82.0%) of the target compounds were obtained.
[실시예 3]Example 3
상기 실시예 1과 동일하게 실시하되 트리에틸아민 대신 피리딘을 23.6g 사용하였다. 그 결과 목적 화합물을 48.0g(86.5%) 얻었다.In the same manner as in Example 1, 23.6 g of pyridine was used instead of triethylamine. As a result, 48.0 g (86.5%) of the title compound was obtained.
[비교예][Comparative Example]
2,3,5 - 트리메틸 - 4 - 메톡시피리딘 - N - 옥사이드 1268g을 초산에 용해시킨후 90℃로 가열된 아세틱언안하이드라이드(acetic anhydride, (CH3CO)2O) 2140ml에 적가하였다.1268 g of 2,3,5-trimethyl-4-methoxypyridine-N-oxide was dissolved in acetic acid and added dropwise to 2140 ml of acetic anhydride (CH 3 CO) 2 O heated to 90 ° C. .
이때 적가하는 동안에는 가열을 계속하지 않았다 적가가 끝나면 130℃로 승온시켜서 반응액을 1시간 동안 교반하고, 이어서 80℃로 냉각시킨 다음 메탄올 2640ml를 첨가한후 반응액을 증발시켰다. 증발시키고 남은 잔유물에 수산화나트륨 3300ml를 첨가하고 냉각시켜 디클로로메탄 8l로 추출한 다음 각 층을 분리하여 수층을 디클로로메탄 4l로 2회 추출하였다. 추출된 용액을 황산 마그네슘으로 건조시켜 디클로로메탄을 제거시키고 발색 탄소 소량과 함께 환류시킨 다음 여과하여 3,5 - 디메틸 - 2 - 히드록시메틸피리딘을 941g(74.2%) 얻었다. 얻어진 3,5 - 디메틸 - 2 - 히드록시메틸피리딘에 SOCl2를 반응시켜 3,5 - 디메틸 - 4 - 메톡시 - 2 - 클로로메틸피리딘을 제조하였다.At this time, heating was not continued during the dropwise addition. When the dropwise addition was completed, the reaction solution was heated to 130 ° C, stirred for 1 hour, cooled to 80 ° C, and then 2640ml of methanol was added, and the reaction solution was evaporated. After evaporation, 3300 ml of sodium hydroxide was added to the remaining residue, and the mixture was cooled, extracted with 8 l of dichloromethane, and each layer was separated, and the aqueous layer was extracted twice with 4 l of dichloromethane. The extracted solution was dried over magnesium sulfate to remove dichloromethane, refluxed with a small amount of colored carbon and filtered to give 941 g (74.2%) of 3,5-dimethyl- 2-hydroxymethylpyridine. SOCl 2 was reacted with the obtained 3,5-dimethyl-2-hydroxymethylpyridine to prepare 3,5-dimethyl-4 methoxy-2-chloromethylpyridine.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019900004400A KR920000049B1 (en) | 1990-03-31 | 1990-03-31 | Process for the preparation of 2-chloromethyl pridine derivatives |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019900004400A KR920000049B1 (en) | 1990-03-31 | 1990-03-31 | Process for the preparation of 2-chloromethyl pridine derivatives |
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| Publication Number | Publication Date |
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| KR910016698A KR910016698A (en) | 1991-11-05 |
| KR920000049B1 true KR920000049B1 (en) | 1992-01-06 |
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| KR1019900004400A KR920000049B1 (en) | 1990-03-31 | 1990-03-31 | Process for the preparation of 2-chloromethyl pridine derivatives |
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