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KR900001619B1 - Process for the preparation of n-ethyl-n-(2-methylphenyl)-2-butenamide - Google Patents

Process for the preparation of n-ethyl-n-(2-methylphenyl)-2-butenamide Download PDF

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KR900001619B1
KR900001619B1 KR1019860010743A KR860010743A KR900001619B1 KR 900001619 B1 KR900001619 B1 KR 900001619B1 KR 1019860010743 A KR1019860010743 A KR 1019860010743A KR 860010743 A KR860010743 A KR 860010743A KR 900001619 B1 KR900001619 B1 KR 900001619B1
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KR880007437A (en
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최현웅
장복현
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태평양제약 주식회사
정명진
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00Carboxylic acid amides
    • C07C233/01Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/33Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00Carboxylic acid amides
    • C07C233/01Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/55Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton

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Abstract

내용 없음.No content.

Description

카르복실산 아미드의 제조방법Process for preparing carboxylic acid amide

본 발명은 기생성 피부질환 치료에 유용한 다음 구조식(1)의 α,β-불포화 카르복실산 아미드의 제조방법에 관한 것이다.The present invention relates to a method for preparing α, β-unsaturated carboxylic acid amide of the following structural formula (1) useful for treating parasitic skin diseases.

Figure kpo00001
Figure kpo00001

위 식에서 R1은 수소 또는 메틸기를 의미하며, R2는 메틸기를 의미한다.In the above formula, R 1 means hydrogen or methyl group, R 2 means methyl group.

현재까지 구조식(1)의 화합물을 제조하기 위한 여러 가지 방법이 특허와 문헌에 발표되어 있는데 선행기술의 방법중 대표적인 것들을 검토하다 보면,To date, various methods for preparing the compound of formula (1) have been published in patents and literature.

CH3CH=CHCOOH (2)CH 3 CH = CHCOOH (2)

상기 유기산(2)의 산염화물을 거쳐 구조식(1)의 화합물을 제조하는 방법들은 Chemical abstract Vol. 90-P121239b(폴란드 특허 제87388호), 영국특허 제615137호 등의 명세서에 기재되어 있는데 이들 방법에 의하면 유기산(2)의 카르복실산기를 염화티오닐클로라이드, 오염확인, 옥시염화인 등을 사용하여 산염화물을 제조하고 이를 아실화 반응시켜 구조식(1)의 화합물을 제조하였다.Methods of preparing the compound of formula (1) via the acid chloride of the organic acid (2) are described in Chemical abstract Vol. 90-P121239b (Poland Patent No. 87388), British Patent No. 615137, etc. According to these methods, the carboxylic acid group of the organic acid (2) uses thionyl chloride, contamination confirmation, phosphorus oxychloride, or the like. An acid chloride was prepared and acylated to prepare a compound of formula (1).

그러나, 이들 방법은 티오닐크롤라이드, 오염화인, 옥시염화인 등을 사용하기 때문에 상기 반응물질들이 수분과의 반응이 민감하고 수분이 많은 공기중에서 취급하기 불편할 뿐만 아니라 반응부생물로써 염화수소가스와 아황산가스 등 유독한 가스가 생성되므로 반응기가 쉽게 부식되고 이들을 완전히 처리하지 못하는 경우에는 공해를 유발시키는 문제점이 있다. 또한 영국 특허 제615137호에서는 아실화 과정에서 130℃ 이상의 고온에서 반응시키므로 공업화하기에 어려운 점들이 있었다.However, these methods use thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, etc., so that the reactants are sensitive to water reactions and are inconvenient to handle in humid air, as well as hydrogen chloride gas and sulfurous acid as reaction byproducts. Toxic gases such as gases are generated, so that the reactor is easily corroded and there is a problem of causing pollution when not fully processed. In addition, in British Patent No. 615137, it is difficult to industrialize because it is reacted at a high temperature of 130 ℃ or more in the acylation process.

그리고, 이 특허에서는 무수물로써 반응시킬 수 있다는 통념의 제법에 관하여 단지 서술적인 언급이 표현되고 있으나 구체적인 실시예나 방법이 전혀 기록되어 있지 못하다.In this patent, only descriptive references are made to the conventional method of reacting with anhydrides, but no specific examples or methods are recorded.

유기산(2)의 저금 에스테르를 경유하여 구조식(1)의 화합물을 제조하는 방법은 일본국 특허 제3468호에 기재되어 있으며 이 방법에서는 구조식(1)의 유기산을 에틸에스터로 전환한 다음 이를 아실화시켜 구조식(1)의 화합물을 제조하였다.The process for preparing the compound of formula (1) via the low-ester ester of organic acid (2) is described in Japanese Patent No. 3468, which converts the organic acid of formula (1) to ethyl ester and then acylates it. To prepare a compound of formula (1).

그러나 상기의 아실화 반응은 밀폐된 용기에서 100℃이상 가열하는 고온고압 반응이므로 공업화하기 어렵다. 실제로 이 과정을 150℃정도에서 가열하여 실시해 본 결과 순조로운 반응을 얻지 못하였으며 단지 반응물들의 변색만 초래하였다.However, the acylation reaction is difficult to industrialize because it is a high temperature and high pressure reaction that is heated to 100 ℃ or more in a sealed container. In fact, this process was carried out by heating at about 150 ℃, did not get a smooth reaction and only caused discoloration of the reactants.

이에 본 발명자는 구조식(1)의 화합물의 제조방법에 관하여 예의 연구를 행한 결과 전술한 선행기술들의 단점을 제거한 방법으로써 상온, 상압 조건 그리고 취급하기 쉬운 원료를 사용하여 손쉽게 구조식(1)의 화합물을 얻기에 이르렀다.Thus, the present inventors have made intensive studies on the preparation method of the compound of the formula (1). As a result of eliminating the disadvantages of the above-mentioned prior art, the compound of the formula (1) can be easily prepared using normal temperature, atmospheric pressure and easy to handle raw materials. I got it.

본 발명은 구조식(2)의 유기산을 유기용매와 염기 존재하에 알킬클로로카보네이트인 다음 구조식(3)의 화합물과 반응시켜 혼합산 무수물(4)를 얻고 이것을 상온에서 다음 구조식(5)의 화합물과 아실화 반응시키는 것을 특징으로하여 구조식(1)의 화합물을 만들었다.The present invention reacts an organic acid of formula (2) with a compound of formula (3), which is an alkylchlorocarbonate in the presence of an organic solvent and a base, to obtain a mixed acid anhydride (4), which is reacted with the compound of formula (5) at room temperature. The compound of Structural Formula (1) was prepared by carrying out the misfire reaction.

Figure kpo00002
Figure kpo00002

위 각 식에서 R1은 수소, 또는 메틸기를 의미하며, R2는 메틸기를 의미하고, R3는 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸기를 나타낸다.In each formula, R 1 means hydrogen or methyl group, R 2 means methyl group, R 3 represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl group.

본 발명을 반응식으로 간단히 도해하면 다음과 같다.The present invention is briefly illustrated as a reaction scheme as follows.

Figure kpo00003
Figure kpo00003

이 반응공정중 혼합산 무수물(4)를 얻기 위한 반응은 유기용매중에서 진행하는데 바람직한 용매로서는 메틸알콜, 에틸알콜, 이소프로필알콜, 테트라히드로푸란 등이 있는데 이중에서 메틸알콜이 바람직하다.The reaction for obtaining the mixed acid anhydride (4) in this reaction step is carried out in an organic solvent. Preferred solvents include methyl alcohol, ethyl alcohol, isopropyl alcohol, tetrahydrofuran, and methyl alcohol is preferable.

이 반응에서 사용되는 염기로써는 유기염기와 무기염기가 사용되는데 바람직한 유기염기에는 트리메틸아민, 트리에틸아민, 이소프로필아민, 디메틸아민 등이 있고, 무기염기로써는 수산화나트륨, 수산화칼륨 등이 있다. 염기의 사용량은 유기산(2)에 대해 동몰량 이상을 사용하는 것이 바람직하다.As the base used in this reaction, organic bases and inorganic bases are used. Preferred organic bases include trimethylamine, triethylamine, isopropylamine, dimethylamine, and the like. The inorganic bases include sodium hydroxide and potassium hydroxide. It is preferable that the usage-amount of a base uses more than equimolar amount with respect to the organic acid (2).

알킬클로로카보네트(3)로써는 메틸클로로카보네이트, 에틸클로로카보네이트, 프로필클로로카보네이트, 부틸클로로카보네이트, 이소부틸클로로카보네이트 등이 사용되며 이중에서 메틸클로로카보네이트, 에틸클로로카보네이트가 바람직하다.As the alkyl chlorocarbonet (3), methylchlorocarbonate, ethylchlorocarbonate, propylchlorocarbonate, butylchlorocarbonate, isobutylchlorocarbonate and the like are used, of which methylchlorocarbonate and ethylchlorocarbonate are preferable.

유기산(2)에 대한 알킬클로로카보네이트(3)의 사용량은 1 내지 1.1몰비가 바람직하며 이 반응은 상온에서 행하고 반응시간은 30분 내지 1시간이면 충분하다.The amount of alkylchlorocarbonate (3) used relative to the organic acid (2) is preferably 1 to 1.1 molar ratio, the reaction is carried out at room temperature and the reaction time is sufficient 30 minutes to 1 hour.

다음 반응인 혼합산 무수술(4)의 화합물과 아민화합물(5)와의 아실화 반응은 반응에 무관한 용매이면 전부 가능하나 주로 알킬할라이드류의 유기용매중에서 진행하는데 적당한 용매로서는 클로로포름, 디클로로메탄, 디클로로에탄, 트리클로로에탄, 사염화탄소 등이 사용되며 이중에서 클로로포름, 디클로로메탄이 바람직하다.The acylation reaction between the compound of the mixed acid anhydride (4) and the amine compound (5), which is the next reaction, can be carried out in all solvents irrelevant to the reaction, but it is mainly carried out in the organic solvents of alkyl halides. Dichloroethane, trichloroethane, carbon tetrachloride and the like are used, of which chloroform and dichloromethane are preferred.

혼합산 무수물(4)에 대해 아민화합물(5)에 대해 아민화합물(5)의 사용량은 1.05 내지 1.1몰비를 사용하는 것이 바람직하다.It is preferable that the usage-amount of the amine compound (5) with respect to the amine compound (5) with respect to the mixed acid anhydride (4) uses 1.05 to 1.1 molar ratio.

반응은 상온에서 1시간 내지 2시간 행하여지며 혼적량의 미반응 아민화합물(5)는 10% 염산으로 추출하여 쉽게 제거할 수 있다.The reaction is carried out at room temperature for 1 to 2 hours, and the unreacted amine compound (5) in a mixed amount can be easily removed by extracting with 10% hydrochloric acid.

여기에서 특징지울 수 있는 방법은 혼합산 무수물(4)를 단리해 내지 않고 직접 용매만 치환시켜 줌으로써(처음 용매는 날려서 제거시킴) 목적물까지 한단계로 얻을 수 있다는 점이다.A method that can be characterized here is that the target acid can be obtained in one step by directly dissolving the solvent (the first solvent is blown off) without isolating the mixed acid anhydride (4).

이상에서 알 수 있는 바와 같이 본 발명은 (1) 취급이 용이하고 반응상 유독가스 배출위험이 없는 알킬클로로카보네이트를 사용하였으며, (2) 모든 반응이 실온에서 진행될 수 있고, (3) 반응공정이 간단하여 공업화하기에 어려운 점이 전혀 없다.As can be seen from the above, the present invention used (1) alkylchlorocarbonate, which is easy to handle and has no risk of toxic gas emissions from reaction, (2) all reactions can proceed at room temperature, and (3) It is so simple that it is not difficult to industrialize.

따라서, 본 발명의 방법에서는 종전의 방법에 비하여 제조시설을 간략화 할 수 있고 목적물을 고수율로 순쉽게 얻기 때문에 상업적으로 가치가 있는 방법을 제공할 수 있는 것이다.Therefore, the method of the present invention can provide a commercially valuable method because it is possible to simplify the manufacturing facilities compared to the previous method and to easily obtain the target product in high yield.

다음의 실시예들은 본 발명을 좀더 상세히 또는 이를 예시하기 위한 것으로 본 발명을 한정하기 위한 것은 아니다.The following examples are intended to illustrate the invention in more detail or not to limit the invention.

[실시예 1]Example 1

크로톤산 2그람(0.023몰)을 메탄올 10밀리리터에 녹이고 트리에틸아민 3.2밀리리터를 가한다. 이 용액에 메틸클로로카보네이트 1.9밀리리터(0.024몰)를 적가한 다음 상온에서 1시간 교반한다. 반응 후 감압농축하여 메탄올을 제거하고 잔사에 클로로포롬 10밀리리터를 가하고 5% 수산화나트륨수용액 15밀리리터로 추출하고 다시 정제수 15밀리리터로 2번 추출 후 유기용매층을 무수황산나트륨으로 건조시키고 감압농축하여 액체상태의 혼합산 무수율 3.2그람을 얻었다.Two grams of crotonic acid (0.023 mol) are dissolved in 10 milliliters of methanol and 3.2 milliliters of triethylamine are added. 1.9 milliliter (0.024 mol) of methylchlorocarbonate was added dropwise to this solution, followed by stirring at room temperature for 1 hour. After the reaction, the mixture was concentrated under reduced pressure to remove methanol, and 10 ml of chloroform was added to the residue, followed by extraction with 15 ml of 5% aqueous sodium hydroxide solution, followed by extraction twice with 15 ml of purified water. 3.2 grams of mixed acid anhydride was obtained.

수율 : 96%Yield: 96%

박층크로마토그라피 : 시클로헥산 : 아세톤 =3 : 1Thin layer chromatography: cyclohexane: acetone = 3: 1

Rf=0.48Rf = 0.48

[실시예 2]Example 2

메틸클로로카보네이트 대신에 에틸클로로카보네이트 2.3밀리리터를 사용하는 것을 제외하고는 실시예 1의 방법을 반복실시하여 액체상태의 혼합한 무수물 3.7그람을 얻었다.The procedure of Example 1 was repeated except that 2.3 milliliters of ethylchlorocarbonate was used instead of methylchlorocarbonate to obtain 3.7 grams of mixed anhydride in a liquid state.

수율 : 95%Yield: 95%

박층크로마토그라피 : 시클로헥산 : 아세톤 =3 : 1Thin layer chromatography: cyclohexane: acetone = 3: 1

Rf=0.49Rf = 0.49

[실시예 3]Example 3

크로톤산 2그람(0.023몰)를 메탄올 10밀리터에 녹이고 메틸클로로카보네이트 1.9밀리리터(0.024)을 가한다. 여기서 1그람의 수산화나트륨을 정제수 1밀릴터에 녹인 용액을 적가한다. 1시간 상온에서 교반하고 감압농축하여 메탄올을 제거한 후 정제수 15밀리리터를 가하고 10밀리리터의 클로로포름으로 추출한다. 다시 정제수 15밀리리터로 2번 추출한 후 클로로포름층을 무수황산나트륨으로 건조시킨 후 감압농축하여 3.1그람의 액체상태인 혼합산 무수물을 얻었다.Two grams of crotonic acid (0.023 mol) are dissolved in 10 milliliters of methanol and 1.9 milliliters (0.024) of methylchlorocarbonate are added. Here, a solution of 1 gram of sodium hydroxide dissolved in 1 milliliter of purified water is added dropwise. After stirring for 1 hour at room temperature, concentrated under reduced pressure to remove methanol, 15 milliliters of purified water was added and extracted with 10 milliliters of chloroform. After extraction twice with 15 milliliters of purified water, the chloroform layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.1 gram of mixed acid anhydride in a liquid state.

수율 : 93%Yield: 93%

박층크로마토그라피 : 시클로헥산 : 아세톤 =3 : 1Thin layer chromatography: cyclohexane: acetone = 3: 1

Rf=0.48Rf = 0.48

[실시예 4]Example 4

N-에틸-O-톨루이딘 3.2그람(0.0236몰)과 클로로포름 6밀리리터의 용액에 실시예 1의 혼합산 무수물 3.2그람(0.022몰)을 가한 후 상온에서 1시간 교반시킨다. 반응 후 10% 염산 10밀리리터로 추출한 후 10% 탄산수소나트륨수용액 10밀리리터, 10% 소금물로 추출한다. 클로로포름층을 무수황산나트륨으로 건조시킨 후 감압농축하여 4.1그람의 액체 N-에틸-O-크로토노톨루다이드를 얻었다.3.2 grams (0.0236 mol) of N-ethyl-O-toluidine and 6 milliliters of chloroform were added to 3.2 grams (0.022 mol) of the mixed acid anhydride of Example 1, followed by stirring at room temperature for 1 hour. After the reaction, the mixture was extracted with 10 ml of 10% hydrochloric acid, followed by extraction with 10 ml of 10% sodium hydrogen carbonate solution and 10% brine. The chloroform layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 4.1 grams of liquid N-ethyl-O-crotonotolide.

수율 : 91%Yield: 91%

bp5:132°-135℃bp 5 : 132 ° -135 ° C

박층크로마토그라피 : 시클로헥산 : 아세톤 =3 : 1Thin layer chromatography: cyclohexane: acetone = 3: 1

Rf=0.36Rf = 0.36

[실시예 5]Example 5

N-에틸-O-톨루이딘 대신에 N-에틸-m-톨루이딘 0.2그람을 사용하는 것을 제외하고는 실시예4의 방법을 반복 실시하여 4.14그람의 N-에틸-m-크로토노톨루다이드를 얻었다.The procedure of Example 4 was repeated except that 0.2 grams of N-ethyl-m-toluidine was used instead of N-ethyl-O-toluidine to obtain 4.14 grams of N-ethyl-m-crotonotoludide. .

수율 : 92%Yield: 92%

bp5: 139°-142℃bp 5 : 139 ° -142 ° C

박층크로마토그라피 : 시클로헥산 : 아세톤 =3 : 1Thin layer chromatography: cyclohexane: acetone = 3: 1

Rf=0.34Rf = 0.34

Claims (1)

다음 구조식(2)의 유기산을 유기용매와 염기 존재하에 알킬클로로카보네이트(3)과 반응시켜 반응성 혼합산 무수물(4)를 얻고 이것을 상온에서 다음 구조식(5)의 화합물과 아실화 반응시키는 것을 특징으로 하는 다음 구조식(1)의 카르복실산아미드의 제조방법.The organic acid of the following formula (2) is reacted with alkylchlorocarbonate (3) in the presence of an organic solvent and a base to obtain a reactive mixed acid anhydride (4), which is acylated with a compound of the following formula (5) at room temperature. Method for producing a carboxylic acid amide of the following formula (1).
Figure kpo00004
Figure kpo00004
위 각식에서 R1은 수소 또는 메틸기를 의미하고, R2는 메틸기를 의미하며, R3는 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸기를 의미한다.In the above formula, R 1 means hydrogen or methyl group, R 2 means methyl group, R 3 means methyl, ethyl, propyl, isopropyl, butyl, isobutyl group.
KR1019860010743A 1986-12-16 1986-12-16 Process for the preparation of n-ethyl-n-(2-methylphenyl)-2-butenamide Expired KR900001619B1 (en)

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