KR930009817B1 - Process for preparation of pyridine derivatives - Google Patents
Process for preparation of pyridine derivatives Download PDFInfo
- Publication number
- KR930009817B1 KR930009817B1 KR1019910013002A KR910013002A KR930009817B1 KR 930009817 B1 KR930009817 B1 KR 930009817B1 KR 1019910013002 A KR1019910013002 A KR 1019910013002A KR 910013002 A KR910013002 A KR 910013002A KR 930009817 B1 KR930009817 B1 KR 930009817B1
- Authority
- KR
- South Korea
- Prior art keywords
- pyridine
- compound
- preparing
- alkali metal
- metal base
- Prior art date
Links
Classifications
-
- 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
- C07D213/60—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 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
본 발명은 피리딘 유도체의 새로운 제조방법에 관한 것으로서, 더욱 상세하게는 방향족화합물과 치환된 피리딘으로부터 종래의 제조방법보다 간단하고 경제적인 공정으로 피리딘 유도체를 제조하는 방법에 관한 것이다.The present invention relates to a novel process for preparing pyridine derivatives, and more particularly, to a process for preparing pyridine derivatives from aromatic compounds and substituted pyridine in a simpler and more economical process than conventional methods.
종래의 방향족화합물과 치환된 피리딘으로부터 피리딘 유도체를 제조하는 방법으로는 다음 반응식(A)와 같이 소디움아미드를 사용하여 110∼120℃에서 약 1시간 반응시켜 제조하는 방법이 미국특허 제2,507,631호에 제시되어 있다.As a method for preparing a pyridine derivative from a conventional aromatic compound and a substituted pyridine, a method of preparing a pyridine derivative by reacting at about 1 hour at 110 to 120 ° C. using sodium amide is shown in US Pat. It is.
[반응식 A]Scheme A
이러한 방법은 염기로 사용되는 소디움아미드가 다른염기보다 값이 비싸며, 반응과정중에 암모니아 등의 유독가스를 발생하고, 폭발의 위험이 있어서 취급이 곤란하여 산업용으로 이용하기에는 어려웠다. 또한 수율이 낮고 반응공정이 복잡한 문제점을 안고 있다.In this method, sodium amide, which is used as a base, is more expensive than other bases, generates toxic gases such as ammonia during the reaction process, and is difficult to handle due to the risk of explosion, making it difficult for industrial use. In addition, the yield is low and the reaction process has a complex problem.
따라서, 본 발명은 피리딘 유도체를 제조함에 있어서, 종래의 소디움아미드 대신 알카리금속염기를 사용하므로써, 경제적이고 간단한 공정을 통하여 고수율로 피리딘 유도체를 제조하는 방법을 제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide a method for preparing a pyridine derivative in high yield through an economical and simple process by using an alkali metal base instead of conventional sodium amide in preparing a pyridine derivative.
이하, 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
본 발명은 방향족화합물과 치환된 피리딘으로부터 피리딘 유도체를 제조함에 있어서, 다음 구조식(Ⅱ)의 화합물과 다음 구조식(Ⅲ)의 화합물을 알칼리금속염기의 존재하에 유기용매중에서 반응시켜서 다음 구조식 (Ⅰ)의 화합물을 제조하는 것을 특징으로 한다.In the preparation of the pyridine derivative from the aromatic compound and the substituted pyridine, the compound of formula (II) and the compound of formula (III) are reacted in an organic solvent in the presence of an alkali metal base, It is characterized by preparing a compound.
상기식에서, Ar은 탄소수 5~10개의 방향족 탄화수소기, Py는 피리딘기, X는 수소 또는 저급알킬기, Y는 할로겐원자, R은 니트릴기, 에스테르화 또는 아미드화된 카르복실기, 또는 카르복실산기를 나타낸다.Wherein Ar represents an aromatic hydrocarbon group having 5 to 10 carbon atoms, Py represents a pyridine group, X represents a hydrogen or lower alkyl group, Y represents a halogen atom, R represents a nitrile group, an esterified or amidated carboxyl group, or a carboxylic acid group. .
이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.
본 발명은 방향족화합물과 치환된 피리딘으로부터 피리딘 유도체를 제조함에 있어서, 방향족화합물과 치환된 피리딘을 알칼리금속염기의 존재하에서 유기용매에 현탁시킨 후 6~15시간 환류시킨 다음 물을 부가하고 나서 다시 유기용매로 추출하고, 추출된 유기층을 감압 농축한 다음 유기용매중에서 결정화시켜 피리딘 유도체를 제조하는 것이다.In the present invention, in preparing a pyridine derivative from an aromatic compound and a substituted pyridine, the aromatic compound and the substituted pyridine are suspended in an organic solvent in the presence of an alkali metal base, refluxed for 6 to 15 hours, and then water is added to the organic compound. Extraction with a solvent, concentration of the extracted organic layer under reduced pressure and crystallization in an organic solvent to prepare a pyridine derivative.
이와 같은 본 발명은 방향족화합물과 치환된 피리딘을 이용하여 피리딘 유도체를 제조함에 있어서 종래의 소디움아미드 대신에 알칼리금속염기를 사용하는 것을 특징으로 하는바, 본 발명에서 알칼리금속염기로서는 수산화나트륨 또는 수산화칼륨을 사용한다.As described above, the present invention is characterized by using an alkali metal base in place of conventional sodium amide in preparing a pyridine derivative using an aromatic compound and a substituted pyridine. In the present invention, the alkali metal base is sodium hydroxide or potassium hydroxide. Use
이러한 알칼리금속염기는 방향족화합물에 대하여 1~3당량을 첨가하는바, 그 첨가량이 너무 적으면 반응이 완결이 안되어 수율이 적어지는 문제가 있고, 너무 많으면 부생성물이 다량 생기는 문제가 있다.When the alkali metal base is added in an amount of 1 to 3 equivalents to the aromatic compound, if the addition amount is too small, the reaction is not completed and the yield is low. If the amount is too high, a large amount of by-products are generated.
또한, 본 발명에서 방향족화합물은 일반적 방향족화합물이나 관능기를 가진 방향족화합물을 사용하는바, 그 대표적인 예로서 페닐아세토니트릴, 메틸페닐아세테이트 등을 들 수 있다.In the present invention, the aromatic compound generally uses an aromatic compound or an aromatic compound having a functional group, and examples thereof include phenylacetonitrile and methylphenyl acetate.
그리고, 치환된 피리딘으로서는 주로 2-클로로피리딘, 2-브로모피리딘을 사용한다.As the substituted pyridine, 2-chloropyridine and 2-bromopyridine are mainly used.
한편, 유기용매로서는 제 1 단계의 반응용매로서 톨루엔 또는 메틸설폭시드, 제 2 단계의 추출용매로서 에틸아세테이트 또는 클로로포름, 그리고 제 3 단계의 결정화용매로서 에틸아세테이트 또는 석유에테르 등이 유용한바, 특히 반응용매로는 톨루엔, 추출 및 결정화 용매로는 석유에틸아세테이트 또는 석유에테르를 사용할 경우에 효과적이다.As the organic solvent, toluene or methyl sulfoxide as the reaction solvent of the first stage, ethyl acetate or chloroform as the extraction solvent of the second stage, and ethyl acetate or petroleum ether as the crystallization solvent of the third stage are particularly useful. It is effective when toluene is used as the solvent and petroleum ethyl acetate or petroleum ether is used as the extraction and crystallization solvent.
본 발명에 의하면 방향족화합물과 치환된 피리딘 반응할 때 알칼리금속염기의 작용에 의해 목적하는 피리딘 유도체가 생성되는 것으로서, 본 발명의 방법에 따라 제조된 피리딘 유도체는 그 전체수율이 70~80%로서 종래의 50~70%보다 수율면에서 우수하다.According to the present invention, when a pyridine reaction is substituted with an aromatic compound, a desired pyridine derivative is produced by the action of an alkali metal base. The pyridine derivative prepared according to the method of the present invention has a total yield of 70 to 80%. It is better in yield than 50 ~ 70% of.
이와 같은 본 발명의 방법에 따라 제조된 피리딘 유도체는 예컨데 미국특허 제2,507,631호 및 미국특허 제2,957,880호등에 기재된 공지방법을 이용하여 중추신경 홍분제로서 유용한 약리학적인 작용을 갖는 페닐-피페리딜-2-아세트산 메틸에스테르 염산염을 제조하는 중간체로 유용한 것으로서, 본 발명은 이러한 피리딘 유도체를 종래보다 경제적이고도 간단한 공정을 통하여 제조할 수 있는 것이다.Such pyridine derivatives prepared according to the method of the present invention are phenyl-piperidyl-2 having a pharmacological action useful as a central nerve lubricating agent using, for example, known methods described in US Pat. Nos. 2,507,631 and 2,957,880. Useful as an intermediate for producing acetic acid methyl ester hydrochloride, the present invention can produce such pyridine derivatives through a simpler and more economical process than before.
이하, 본 발명을 실시예를 통해 더욱 상세히 설명하겠는바, 실시예에 의해 본 발명이 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by Examples.
[실시예 1]Example 1
페닐-피리딜-2-아세토니트릴의 제조Preparation of Phenyl-pyridyl-2-acetonitrile
페닐아세토니트릴 30.0g과 2-클로로피리딘 29.1g을 메틸설폭시드 70ml와 톨루엔 80ml의 혼합용액에 넣어 현탁시킨 후 교반시킨다. 40℃에서 수산화나트륨 20.5g을 넣고 90℃에서 9시간 동안 환류시킨다. 이 반응물에 물 150g을 부가하고 에틸아세테이트 150ml로 2회 추출한다. 추출된 유기층은 감압농축하여 오일형태의 물질을 얻고 이것을 에틸아세테이트와 석유에테르에서 결정화시켜 미색결정의 페닐-피리딜-2-아세토니트릴 36.2g을 얻었다(수율 72%).30.0 g of phenylacetonitrile and 29.1 g of 2-chloropyridine are added to a mixed solution of 70 ml of methyl sulfoxide and 80 ml of toluene, and then suspended and stirred. 20.5 g of sodium hydroxide was added at 40 ° C and refluxed at 90 ° C for 9 hours. 150 g of water is added to the reaction and extracted twice with 150 ml of ethyl acetate. The extracted organic layer was concentrated under reduced pressure to obtain an oily substance, which was crystallized in ethyl acetate and petroleum ether to obtain 36.2 g of off-white phenyl-pyridyl-2-acetonitrile (yield 72%).
융점 : 89.4~91.2℃Melting Point: 89.4 ~ 91.2 ℃
핵자기공명스펙트럼(100MHz, CDCl3) : δ 8.60(d,1H,J=4.8Hz), 7.70(td,1H,J=7.7,1.8Hz), 7.52~7.17(m7H), 5.32(s,1H)ppmNuclear Magnetic Resonance Spectrum (100MHz, CDCl 3 ): δ 8.60 (d, 1H, J = 4.8Hz), 7.70 (td, 1H, J = 7.7,1.8Hz), 7.52 ~ 7.17 (m7H), 5.32 (s, 1H ) ppm
[실시예 2]Example 2
페닐-피리딜-2-아세산 메틸에스테르의 제조Preparation of Phenyl-pyridyl-2-acetic Acid Methyl Ester
메틸페닐아세테이트 15.0g과 2-브로모피리딘 15.8g을 메틸설폭시드 30ml 톨루엔 50ml의 혼합용액에 넣어 현탁시킨 후 교반한다. 상온에서 수산화나트륨 8.0g을 넣고 110℃에서 11시간 동안 환류시킨다. 이 반응물에 물 100g을 부가하고 에틸아세테이트 150ml로 3회 추출한다. 추출된 유기층은 감압농축하여 오일 형태의 물질을 얻고 이것을 에틸아세테이트와 석유에테르에서 결정화시켜 백색결정을 페닐-피리딜-2-아세트산 메틸에스테르 18.3g을 얻는다.(수율 81%)15.0 g of methylphenyl acetate and 15.8 g of 2-bromopyridine are placed in a mixed solution of 50 ml of methyl sulfoxide 30 ml toluene, suspended and stirred. Add 8.0 g of sodium hydroxide at room temperature and reflux at 110 ° C. for 11 hours. To the reaction was added 100 g of water and extracted three times with 150 ml of ethyl acetate. The extracted organic layer was concentrated under reduced pressure to obtain an oily substance, which was crystallized in ethyl acetate and petroleum ether to give 18.3 g of white phenyl-pyridyl-2-acetic acid methyl ester (yield 81%).
융점 : 74.3~75.1℃Melting Point: 74.3 ~ 75.1 ℃
핵자기공명스펙트럼(100MHz, CDCl3) : δ 8.56(d,1H,J=4.0Hz), 7.63(td,1H)7.34(m,7H), 5.26(s,1H), 3.76(s,3H)ppmNuclear Magnetic Resonance Spectrum (100MHz, CDCl 3 ): δ 8.56 (d, 1H, J = 4.0Hz), 7.63 (td, 1H) 7.34 (m, 7H), 5.26 (s, 1H), 3.76 (s, 3H) ppm
[비교예 1]Comparative Example 1
페닐-피리딜-2-아세토니트릴의 제조Preparation of Phenyl-pyridyl-2-acetonitrile
페닐아세토니트릴 117g과 2-클로로피리딘 113g을 무수톨루엔 400ml에 넣고 소디움아미드 80g을 상온에서 부가하고 110~120℃까지 서서히 가열한 후 1시간동안 환류시켰다. 이 반응물을 급히 냉각시킨 후 물을 부가하고 묽은 염산 수용액으로 톨루엔용액을 3~4회 추출한다. 산추출물은 수산화나트륨으로 건조시킨 후 감압하에서 농축하고 감압증류한 후 에틸아세테이트에서 결정화시켜 미색 결정의 페닐-2-피리딜아세토니트릴 135g을 얻는다(수율 70%).117 g of phenylacetonitrile and 113 g of 2-chloropyridine were added to 400 ml of anhydrous toluene, 80 g of sodium amide was added at room temperature, and the mixture was slowly heated to 110 to 120 ° C. and refluxed for 1 hour. After cooling the reaction product rapidly, water is added and the toluene solution is extracted 3-4 times with dilute hydrochloric acid aqueous solution. The acid extract was dried over sodium hydroxide, concentrated under reduced pressure, distilled under reduced pressure, and crystallized from ethyl acetate to obtain 135 g of off-white crystals of phenyl-2-pyridylacetonitrile (yield 70%).
[비교예 2]Comparative Example 2
페닐-피리딜-2-아세트산 메틸에스테르의 제조Preparation of Phenyl-pyridyl-2-acetic Acid Methyl Ester
상기 비교예에 1에서와 같은 방법으로 페닐-2-피리딘아세토니트릴의 제조한 후 페닐-피리딜-2-아세토니트릴의 100g에 진한 황산용액 400ml를 조금씩 부가하고 50℃에서 12시간동안 교반시켰다.After preparing phenyl-2-pyridineacetonitrile in the same manner as in Comparative Example 1, 400 ml of concentrated sulfuric acid solution was added little by little to 100 g of phenyl-pyridyl-2-acetonitrile and stirred at 50 ° C. for 12 hours.
반응물을 묽은 수산화나트륨 수용액으로 알칼리화시키고 생성된 고체는 감압여과하여 얻은 후에 에틸아세테이트에 의해서 결정화시켜 백색결정의 페닐-2-피리딜아세트아미드 96g을 얻는다(수율 88%).The reaction was alkalized with dilute aqueous sodium hydroxide solution, and the resulting solid was filtered under reduced pressure and crystallized with ethyl acetate to give 96 g of white phenyl-2-pyridylacetamide (yield 88%).
페닐-피리딜-2-아세트아미드 90g을 무수메탄올 800ml에 녹인 후 염화수소기체를 통과시키면서 6시간동안 환류시켰다. 반응물을 냉각시킨 후 감압하에서 농축시키고 물에 녹인 후 수산화나트륨으로 알칼리화시킨다. 생성된 고체는 감압여과하여 얻으며, 50% 메탄올로 재결정하여 백색결정의 페닐-피리딜-2-아세트산 에틸에스테르 81g을 얻는다(수율 84%).90 g of phenyl-pyridyl-2-acetamide was dissolved in 800 ml of anhydrous methanol and refluxed for 6 hours while passing through a hydrogen chloride gas. The reaction is cooled and then concentrated under reduced pressure, dissolved in water and alkalinized with sodium hydroxide. The resulting solid was obtained by filtration under reduced pressure, and recrystallized with 50% methanol to obtain 81 g of white phenyl-pyridyl-2-acetic acid ethyl ester (yield 84%).
상기의 비교예는 앞서 종래기술로 언급한 미국특허 제2,507,631호에 제시된 방법에 의한 것으로써 3단계의 복잡한 공정을 거쳐서 이루어지며 수율 또한 실시예에 비하여 매우 낮다. 비교예 2의 경우 전체 수율은 52%이다.The comparative example is based on the method described in US Pat. No. 2,507,631, referred to in the prior art, and is made through a complicated three-step process. The yield is also very low compared to the examples. In the case of Comparative Example 2, the overall yield is 52%.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019910013002A KR930009817B1 (en) | 1991-07-29 | 1991-07-29 | Process for preparation of pyridine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019910013002A KR930009817B1 (en) | 1991-07-29 | 1991-07-29 | Process for preparation of pyridine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR930002315A KR930002315A (en) | 1993-02-22 |
| KR930009817B1 true KR930009817B1 (en) | 1993-10-11 |
Family
ID=19317926
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019910013002A KR930009817B1 (en) | 1991-07-29 | 1991-07-29 | Process for preparation of pyridine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR930009817B1 (en) |
-
1991
- 1991-07-29 KR KR1019910013002A patent/KR930009817B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR930002315A (en) | 1993-02-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE69723846T2 (en) | Process for the preparation of sildenafil | |
| KR940006764B1 (en) | Process for the preparation of (z)-1-phenyl-1-diethyl amino carbonyl 2-amino methyl cyclo propane hydrochloride | |
| JPS60190753A (en) | Manufacture of intermediate | |
| KR930009817B1 (en) | Process for preparation of pyridine derivatives | |
| JP3378745B2 (en) | Method for producing 4-acylamino-2,2,6,6-tetramethylpiperidine | |
| KR0141482B1 (en) | Process for the preparation of o-carboxypyridyl and o-carboxyquinolylimidazolinones | |
| CA1314898C (en) | Method for producing 1-propargyl-2,4-dioxoimidazolidine | |
| US3435047A (en) | Process for preparing 3-aminoisoxazole derivatives | |
| JP2001521498A (en) | Method for producing O- (3-amino-2-hydroxy-propyl) -hydroxymic acid halide | |
| US4521616A (en) | Method for the preparation of fluoroanthranilic acids | |
| KR890001241B1 (en) | Process for preparing 4-acetyl isoquinolinone | |
| JP2815654B2 (en) | Novel 4-substituted-3,5-dimethylpicolinic acid compound and method for producing the same | |
| CH651031A5 (en) | PROCESS FOR THE PREPARATION OF (TRIALCOXY BENZYL) -1 PIPERAZINES. | |
| US4029664A (en) | Process for interconversion of heteroyohimbane alkaloids | |
| CA2287566A1 (en) | 9,10-diazatricyclo¬4.2.1.12,5|decane and 9,10-diazatricyclo¬3.3.1.12,6|decane derivatives having analgesic activity | |
| US4343951A (en) | Method for the preparation of fluoroaniline | |
| US3948915A (en) | 2-Halopyrimidine derivatives and a method for their preparation | |
| KR20000055711A (en) | A method of preparing 5-halobutyl-1-cyclohexyltetrazole | |
| HU195485B (en) | Process for producing aromatic carboxylic acid derivatives and -carboxamide derivatives | |
| KR910003636B1 (en) | Process for the preparation of benzophenon oxime compounds | |
| EP0079740B1 (en) | Anthraniloyloxyalkanoates | |
| US4220794A (en) | Synthetic intermediates for the preparation of diaromatic O-(amino-alkyl)oximes | |
| US4189444A (en) | Process for the preparation of N,N'-disubstituted 2-naphthaleneethanimidamide and intermediates used therein | |
| US4923993A (en) | Process for the preparation of 2-pyridinecarboxylic acid derivatives and 1-amino-1,4-dihydropyridine-2-carboxylic acid derivatives | |
| US2724714A (en) | 2 methyl-3 acetyl-4, 5 pyridine dicarboxylic acid, lower alkyl esters thereof and intermediates |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| G160 | Decision to publish patent application | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| FPAY | Annual fee payment |
Payment date: 20060918 Year of fee payment: 14 |
|
| LAPS | Lapse due to unpaid annual fee |