KR20040100520A - Process for preparing 2-thiophenecarboxaldehyde derivatives - Google Patents

Process for preparing 2-thiophenecarboxaldehyde derivatives Download PDF

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KR20040100520A
KR20040100520A KR1020030032908A KR20030032908A KR20040100520A KR 20040100520 A KR20040100520 A KR 20040100520A KR 1020030032908 A KR1020030032908 A KR 1020030032908A KR 20030032908 A KR20030032908 A KR 20030032908A KR 20040100520 A KR20040100520 A KR 20040100520A
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formula
derivatives
thiophenecarboxaldehyde
thiophene
derivative
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Korean (ko)
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윤석균
김경애
김봉찬
김성지
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주식회사 엘지생명과학
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/08—Hydrogen atoms or radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom

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  • Organic Chemistry (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

PURPOSE: A process for preparing 2-thiophenecarboxaldehyde derivatives is provided, thereby high selectively preparing 2-thiophenecarboxaldehyde derivatives with a high yield without use of harmful substances. CONSTITUTION: The process for preparing 2-thiophenecarboxaldehyde derivatives represented by formula (1) comprises the steps of: reacting thiopen derivatives of formula (2) in solvent such as methylene chloride in the presence of oxalylchloride with formamide derivatives of formula (3) at 40 to 80 deg. C and hydrolyzing the resulting product, wherein R1 and R2 are independently hydrogen, alkyl or aryl, or morpholine together with nitrogen atom; and R is halogen, alkyl, alkoxy, aryl, dialkylamino, alkylcarbonylamino, carboxy or alkoxycarbonyl.

Description

2-티오펜카복스알데히드 유도체의 제조 방법 {Process for preparing 2-thiophenecarboxaldehyde derivatives}Process for preparing 2-thiophene carboxaldehyde derivatives

본 발명은 포름아미드 유도체와 옥살릴 클로라이드를 사용하여 티오펜을 포밀화시킴을 특징으로 하여 하기 화학식 1의 2-티오펜카복스알데히드 유도체를 제조하는 방법에 관한 것이다:The present invention relates to a process for preparing 2-thiophenecarboxaldehyde derivatives of the general formula (1), characterized by formylation of thiophene using formamide derivatives and oxalyl chloride:

[화학식 1][Formula 1]

상기식에서,In the above formula,

R은 할로겐, 알킬, 알콕시, 아릴, 디알킬아미노, 알킬카보닐아미노, 카복실 또는 알콕시카보닐을 나타낸다.R represents halogen, alkyl, alkoxy, aryl, dialkylamino, alkylcarbonylamino, carboxyl or alkoxycarbonyl.

이와 같은 본 발명의 방법에 따르면, 옥시염화인이나 포스겐과 같은 물질을 사용할 필요 없이, 선택적이며 고수율로 2-티오펜카복스알데히드 유도체를 공업적으로 유리하게 제조할 수 있다.According to this method of the present invention, it is possible to industrially advantageously prepare 2-thiophenecarboxaldehyde derivatives in an optional and high yield without the need for using a substance such as phosphorus oxychloride or phosgene.

종래에는 2-티오펜카복스알데히드 유도체를 제조하기 위하여 포름아미드 유도체와 옥시염화인을 이용한 빌스마이어 반응을 이용하거나(USP 2,853,493), 포름아미드 유도체와 포스겐의 반응을 이용하였다(EP 0,595,328 A1). 그러나 옥시염화인을 이용하는 빌스마이어 반응에서는 다량의 인을 포함하는 폐수가 발생하며, 옥시염화인 대신에 포스겐을 사용하는 방법에서는 유독한 포스겐을 취급하기 어렵다는 어려움이 있었다.Conventionally, the Vilsmeier reaction using formamide derivatives and phosphorus oxychloride was used to prepare 2-thiophene carboxaldehyde derivatives (USP 2,853,493), or the reaction of formamide derivatives with phosgene was used (EP 0,595,328 A1). However, in the Vilsmeier reaction using phosphorus oxychloride, wastewater containing a large amount of phosphorus is generated, and it is difficult to handle toxic phosgene by using phosgene instead of phosphorus oxychloride.

따라서 본 발명자들은 종래 방법에서 문제를 야기시켰던 옥시염화인이나 포스겐을 사용하지 않고 간편하면서도 효율적으로 2-티오펜카복스알데히드 유도체를 제조하기 위하여 집중적인 연구를 수행하였으며, 그 결과 옥살릴클로라이드를 사용하면 이러한 문제가 해결될 수 있음을 발견하고 본 발명을 완성하였다. 즉, 본 발명에서는 액체 상태의 옥살릴클로라이드를 반응에 사용하는데, 이 물질은 취급이 용이하고 안정성 측면에서 탁월하여 대량생산에 유리할 뿐 아니라, 선택적으로 티오펜의 2번 위치에만 알데히드를 도입시키며, 고수율로 목적하는 2-티오펜카복스 알데히드 유도체를 수득할 수 있게 한다. 또한, 본 발명의 방법에 따르면 폐수 문제에 있어서도 유리한 효과를 기대할 수 있다.Therefore, the present inventors conducted an intensive study to prepare 2-thiophene carboxaldehyde derivatives simply and efficiently without using phosphorus oxychloride or phosgene, which caused problems in the conventional method, and as a result, oxalyl chloride was used. The present invention was found to be able to solve this problem. That is, in the present invention, the liquid oxalyl chloride is used for the reaction, which is easy to handle and excellent in terms of stability, which is advantageous for mass production, and selectively introduces aldehyde only at the second position of thiophene, It is possible to obtain the desired 2-thiophenecarbox aldehyde derivative in high yield. In addition, according to the method of the present invention, an advantageous effect can be expected even in the waste water problem.

따라서 본 발명은 하기 화학식 2의 티오펜 유도체를 용매중에서 옥살릴클로라이드의 존재하에 하기 화학식 3의 포름아미드 유도체와 반응시키고 가수분해시킴을 특징으로 하여 하기 화학식 1의 2-티오펜카복스알데히드 유도체를 제조하는 효율적이고도 새로운 방법을 제공한다Accordingly, the present invention is characterized by reacting and hydrolyzing a thiophene derivative represented by the following Chemical Formula 2 with a formamide derivative represented by the following Chemical Formula 3 in the presence of oxalyl chloride in a solvent to obtain a 2-thiophenecarboxaldehyde derivative represented by the following Chemical Formula 1 Provide an efficient and new way to manufacture

[화학식 1][Formula 1]

상기식에서,In the above formula,

R1및 R2는 각각 독립적으로 수소, 알킬 또는 아릴을 나타내거나 이들이 부착되어 있는 질소원자와 함께 모폴린을 나타낼 수 있고,R 1 and R 2 may each independently represent hydrogen, alkyl or aryl or may represent morpholine with the nitrogen atom to which they are attached,

R은 할로겐, 알킬, 알콕시, 아릴, 디알킬아미노, 알킬카보닐아미노, 카복시 또는 알콕시카보닐을 나타낸다.R represents halogen, alkyl, alkoxy, aryl, dialkylamino, alkylcarbonylamino, carboxy or alkoxycarbonyl.

본 발명에 따른 상기 치환기 정의에서 알킬은 단독으로 사용될 때나, 알콕시와 같이 조합하여 사용되거나, 예를 들어 메틸, 에틸, 프로필, 이소프로필, t-부틸과 같은 직쇄 또는 측쇄의 탄소수 1 내지 6의 알킬, 또는 예를 들어 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실과 같은 탄소수 3 내지 6의 사이클로알킬을 의미하며, 아릴은 예를 들어 페닐 또는 나프틸과 같은 탄소수 6 내지 10의 방향족을 의미한다.Alkyl in the above substituent definition according to the invention is used alone or in combinations such as alkoxy, or straight or branched chain alkyl such as methyl, ethyl, propyl, isopropyl, t-butyl, for example. Or cycloalkyl having 3 to 6 carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and aryl means aromatic having 6 to 10 carbon atoms such as, for example, phenyl or naphthyl.

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

본 발명에 따른 방법에서 출발물질로 사용되는 티오펜 유도체의 구체적인 예로는 알킬 치환된 티오펜으로서 2-메틸티오펜, 2-t-부틸티오펜, 2-사이클로프로필티오펜 등이 있고, 아릴 치환된 티오펜으로서 2-페닐티오펜 등이 있으며, 할로겐 치환된 티오펜으로서 2-클로로티오펜, 2-브로모티오펜 등이 있고, 디알킬아미노 치환된 티오펜으로서 2-디메틸아미노티오펜 등이 있으며, 알킬카보닐아미노 치환된 티오펜으로서 2-아세토아미노티오펜 등이 있고, 카복시 또는 알콕시카보닐 치환된 티오펜으로서 2-카복시티오펜, 2-메톡시카보닐티오펜 등이 있다. 이와 같이 2-번 위치에 치환기를 갖는 티오펜 유도체를 이용하여 반응시키면 선택적으로 티오펜 환의 5-번 위치에 치환기를 갖는 목적화합물을 수득할 수 있다.Specific examples of thiophene derivatives used as starting materials in the process according to the present invention include alkyl substituted thiophenes, such as 2-methylthiophene, 2-t-butylthiophene, 2-cyclopropylthiophene, and aryl substitution. 2-phenylthiophene and the like as the substituted thiophene; 2-chlorothiophene, 2-bromothiophene and the like as the halogen-substituted thiophene; 2-dimethylaminothiophene and the like as the dialkylamino substituted thiophene; And 2-acetoaminothiophene as alkylcarbonylamino substituted thiophene, and 2-carboxythiophene, 2-methoxycarbonylthiophene and the like as carboxy or alkoxycarbonyl substituted thiophene. By reacting with a thiophene derivative having a substituent at the 2-position as described above, a target compound having a substituent at the 5-position of the thiophene ring can be obtained.

반응물질로 사용되는 화학식 3의 포름아미드 유도체의 구체적인 예로는 N,N-디메틸포름아미드, N,N-디에틸포름아미드, N-메틸포름아미드, N-에틸포름아미드, N-페닐-N-메틸포름아미드, 모폴리닐포름아미드 등을 들 수 있다. 이중에서도 특히 바람직한 것은 N,N-디메틸포름아미드이다. 포름아미드 유도체는 화학식 2의 티오펜 유도체를 기준으로 하여 1 내지 10당량 사용하며, 바람직하게는 1.2당량 사용한다.Specific examples of formamide derivatives of formula (3) used as reactants include N, N-dimethylformamide, N, N-diethylformamide, N-methylformamide, N-ethylformamide, and N-phenyl-N- Methylformamide, morpholinylformamide, etc. are mentioned. Especially preferred among these is N, N-dimethylformamide. The formamide derivative is used in the amount of 1 to 10 equivalents, preferably 1.2 equivalents, based on the thiophene derivative of the formula (2).

옥살릴클로라이드 역시 화학식 2의 티오펜 유도체를 기준으로 하여 1 내지10당량 사용하며, 바람직하게는 1.2당량 사용한다.Oxalyl chloride is also used in the amount of 1 to 10 equivalents, preferably 1.2 equivalents, based on the thiophene derivative of the formula (2).

반응용매로는 반응에 악영향을 미치지 않는 어떤 유기용매라도 사용할 수 있으며, 바람직하게는 헥산, 헵탄 등의 지방족탄화수소, 메틸렌클로라이드, 클로로포름, 1,1-디클로로에탄, 1,2-디클로로에탄, 1,1,2-트리클로로에탄, 1,1,2,2-테트라클로로에탄 등의 할로겐화탄화수소, 아세토니트릴, 또는 디알킬에테르 등을 사용한다. 가장 바람직한 용매는 메틸렌클로라이드이다.As the reaction solvent, any organic solvent which does not adversely affect the reaction may be used. Preferably, aliphatic hydrocarbons such as hexane and heptane, methylene chloride, chloroform, 1,1-dichloroethane, 1,2-dichloroethane, 1, Halogenated hydrocarbons such as 1,2-trichloroethane, 1,1,2,2-tetrachloroethane, acetonitrile, dialkyl ether and the like. Most preferred solvent is methylene chloride.

본 발명에 따른 방법은 0 내지 90℃의 온도에서 수행될 수 있으며, 바람직하게는 40 내지 80℃의 온도에서 수행된다.The process according to the invention can be carried out at a temperature of 0 to 90 ° C., preferably at a temperature of 40 to 80 ° C.

상기 화학식 2의 화합물과 화학식 3의 화합물의 반응이 종료되면, 반응액 중에 존재하는 하기 화학식 4의 빌스마이어 중간체를 가수분해하여 목적하는 화학식 1의 화합물을 얻는다.When the reaction of the compound of Formula 2 and the compound of Formula 3 is complete, the Vilsmeier intermediate of Formula 4 present in the reaction solution is hydrolyzed to obtain the desired compound of Formula 1.

이때, 가수분해 반응은 통상의 조건하에 수행될 수 있으나, 바람직하게는 물 또는 염화암모늄 수용액을 반응액에 가하거나, 수산화나트륨, 탄산나트륨 또는 수산화칼륨 등의 염기성 수용액을 반응액에 가함으로써 수행된다. 가수분해 후 유기용매로 추출하여 화학식 1의 2-티오펜카복스알데히드 화합물을 얻을 수 있으며, 추출에는 반응에 사용한 것과 동일한 용매을 사용하거나 물과 혼화되지 않는 기타 유기용매를 사용할 수 있다.At this time, the hydrolysis reaction may be carried out under ordinary conditions, but preferably, water or an ammonium chloride aqueous solution is added to the reaction solution, or a basic aqueous solution such as sodium hydroxide, sodium carbonate or potassium hydroxide is added to the reaction solution. After hydrolysis it can be extracted with an organic solvent to obtain a 2-thiophene carboxaldehyde compound of the formula (1), and the same solvent used in the reaction may be used for extraction or other organic solvents that are not miscible with water.

이하 본 발명을 하기 실시예에 의거하여 좀더 구체적으로 설명한다. 그러나 이 실시예는 본 발명에 대한 이해를 돕기 위한 것일 뿐, 어떤 의미로든 실시예가 본 발명의 기술적 범위를 한정하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, this embodiment is only for better understanding of the present invention, the embodiment in any sense does not limit the technical scope of the present invention.

실시예 1Example 1

5-메틸-2-티오펜카복스알데히드의 제조Preparation of 5-methyl-2-thiophenecarboxaldehyde

2-메틸티오펜 39.27g (0.40mol)을 메틸렌클로라이드 250㎖에 용해시키고 N,N-디메틸포름아미드 35.01g (0.48mol)를 반응 용액에 가한 다음 10℃로 냉각시켰다. 여기에 옥살릴클로라이드 60.93g (0.48mol)을 1시간 동안 적가하였다. 적가가 완료되면 온도를 40℃로 승온시켜 4시간 동안 환류 교반하였다. 반응이 완료되면 물 65g을 첨가하였으며, 이때 발열에 주의하였다. 반응용액에 15%의 수산화나트륨 수용액을 적가하면서 반응용액의 pH를 7~8로 조정하였다. 유기층과 수층을 분리하고, 수층을 메틸렌클로라이드 100㎖로 2회 추출하여 처음 유기층과 합하였다. 합해진 유기층을 물 100㎖로 세척한 후 무수 망초로 건조시키고, 여과하고, 감압증류하여 98% 수율로 5-메틸-2-티오펜카복스알데히드 49.46g (97.68 HPLC Area %)을 얻었다.39.27 g (0.40 mol) of 2-methylthiophene was dissolved in 250 ml of methylene chloride, 35.01 g (0.48 mol) of N, N-dimethylformamide was added to the reaction solution, and then cooled to 10 ° C. To this was added 60.93 g (0.48 mol) of oxalyl chloride dropwise for 1 hour. When the addition was completed, the temperature was raised to 40 ℃ and stirred under reflux for 4 hours. When the reaction was completed, 65 g of water was added, and attention was paid to exotherm. 15% sodium hydroxide aqueous solution was added dropwise to the reaction solution to adjust the pH of the reaction solution to 7-8. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted twice with 100 ml of methylene chloride and combined with the first organic layer. The combined organic layers were washed with 100 mL of water, dried over anhydrous manganese, filtered and distilled under reduced pressure to give 49.46 g (97.68 HPLC Area%) of 5-methyl-2-thiophenecarboxaldehyde in 98% yield.

[HPLC]: 260nm, 1.0㎖/분, Capcell pak C18 [HPLC]: 260 nm, 1.0 ml / min, Capcell pak C 18

화합물: 2-메틸티오펜 5-메틸-2-티오펜카복스알데히드Compound: 2-methylthiophene 5-methyl-2-thiophenecarboxaldehyde

RT : 13.87 6.10RT: 13.87 6.10

면적% : 0.00 97.68Area%: 0.00 97.68

[gradient 조건] 초기: 75/25 (H2O/MeCN, 0.1% TFA), 15분: 75/25, 25분: 65/35, 27분: 75/25[gradient condition] Initial: 75/25 (H 2 O / MeCN, 0.1% TFA), 15 minutes: 75/25, 25 minutes: 65/35, 27 minutes: 75/25

1H NMR (CDCl3, ppm); 9.74 (1H, d), 7.52 (1H, d), 5.82 (1H, t), 2.51 (3H, s) 1 H NMR (CDCl 3 , ppm); 9.74 (1H, d), 7.52 (1H, d), 5.82 (1H, t), 2.51 (3H, s)

상기 설명한 바와 같이, 본 발명의 방법에 따르면 옥시염화인이나 포스겐과 같이 취급이 어렵고 독성이 강한 물질을 사용하지 않고도 3-티오펜카복스알데히드 유도체와 같은 부산물의 생성 없이 고수율 및 높은 선택성으로 2-티오펜 카복스알데히드 유도체를 공업적으로 유리하게 제조할 수 있다.As described above, the method of the present invention provides high yield and high selectivity without generating by-products such as 3-thiophenecarboxaldehyde derivatives without the use of difficult to handle and toxic substances such as phosphorus oxychloride or phosgene. -Thiophene carboxaldehyde derivatives can be produced industrially advantageously.

Claims (6)

하기 화학식 2의 티오펜 유도체를 용매중에서 옥살릴클로라이드의 존재하에 하기 화학식 3의 포름아미드 유도체와 반응시키고 가수분해시킴을 특징으로 하여 하기 화학식 1의 2-티오펜카복스알데히드 유도체를 제조하는 방법:A method for preparing the 2-thiophene carboxaldehyde derivative of the general formula (I) according to claim 1, wherein the thiophene derivative of the general formula (II) is reacted and hydrolyzed with a formamide derivative of the general formula (3) in the presence of oxalyl chloride in a solvent: [화학식 2][Formula 2] [화학식 3][Formula 3] [화학식 1][Formula 1] 상기식에서,In the above formula, R1및 R2는 각각 독립적으로 수소, 알킬 또는 아릴을 나타내거나 이들이 부착되어 있는 질소원자와 함께 모폴린을 나타낼 수 있고,R 1 and R 2 may each independently represent hydrogen, alkyl or aryl or may represent morpholine with the nitrogen atom to which they are attached, R은 할로겐, 알킬, 알콕시, 아릴, 디알킬아미노, 알킬카보닐아미노, 카복시 또는 알콕시카보닐을 나타낸다.R represents halogen, alkyl, alkoxy, aryl, dialkylamino, alkylcarbonylamino, carboxy or alkoxycarbonyl. 제1항에 있어서, 화학식 3의 포름아미드 유도체가 N,N-디메틸포름아미드인 방법.The method of claim 1 wherein the formamide derivative of formula 3 is N, N-dimethylformamide. 제1항에 있어서, 화학식 3의 포름아미드 유도체를 화학식 2의 티오펜 유도체를 기준으로 하여 1.2당량 사용하는 방법.The method of claim 1, wherein the formamide derivative of formula 3 is used based on 1.2 equivalents of the thiophene derivative of formula 2. 제1항에 있어서, 옥살릴클로라이드를 화학식 2의 티오펜 유도체를 기준으로 하여 1.2당량 사용하는 방법.The method of claim 1, wherein oxalylchloride is used in the amount of 1.2 equivalents based on the thiophene derivative of formula (2). 제1항에 있어서, 용매가 메틸렌클로라이드인 방법.The method of claim 1 wherein the solvent is methylene chloride. 제1항에 있어서, 반응온도가 40~80℃인 방법.The method according to claim 1, wherein the reaction temperature is 40 to 80 ° C.
KR1020030032908A 2003-05-23 2003-05-23 Process for preparing 2-thiophenecarboxaldehyde derivatives KR20040100520A (en)

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