KR790000938B1 - Process for the preparation of indazole derivatives - Google Patents
Process for the preparation of indazole derivatives Download PDFInfo
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- KR790000938B1 KR790000938B1 KR7501076A KR750001076A KR790000938B1 KR 790000938 B1 KR790000938 B1 KR 790000938B1 KR 7501076 A KR7501076 A KR 7501076A KR 750001076 A KR750001076 A KR 750001076A KR 790000938 B1 KR790000938 B1 KR 790000938B1
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Abstract
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Description
본 발명은 일반식The present invention is a general formula
(식중 X는 수소원자, 할로겐원자 또는 저급알킬기, R는 저급알킬렌기를 나타냄)으로 표시되는 인다졸유도체의 제법에 관한 것이다.(In the formula, X represents a hydrogen atom, a halogen atom or a lower alkyl group, R represents a lower alkylene group).
본 발명에 의하면 I의 화합물은, 일반식According to the present invention, the compound of I is a general formula
(식중 X 및 R는 전기의 의미를 갖고, R'은 수소원자 또는 메틸기를 나타냄)Wherein X and R have the meaning of electricity and R 'represents a hydrogen atom or a methyl group.
으로 표시되는 화합물을 메틸화함으로써 제조된다.It is manufactured by methylating the compound represented by.
본 발명에 사용되는 식 II의 화합물은 신규화합물이며, 예를 들면 다음의 반응에 의해 제조된다.The compound of formula II used for this invention is a novel compound, For example, it is manufactured by the following reaction.
식중 X,R 및 R'는 전기의 의미를 갖고, X'는 할로겐원자, R"는 저급알킬기 또는 수소원자를 나타내고, n는 1~4의 정수를 나타낸다.Wherein X, R and R 'have the meaning of electricity, X' represents a halogen atom, R "represents a lower alkyl group or a hydrogen atom, and n represents an integer of 1-4.
식 II의 화합물로서는, 예를들면 1-메틸아미노프로필-3-페닐-5-메틸인다졸, 1-아미노프로필-3-페닐인다졸, 1-아미노프로필-3-페닐-5-클로로인다졸, 1-메틸아미노프로필-3-페닐-5-클로로인다졸, 1-아미노프로필-3-페닐-5-브로모인다졸, 1-아미노에틸-3-페닐-5-인다졸, 1-아미노에틸-3-페닐-5-메틸인다졸, 1-아미노부틸-3-페닐인다졸 등이 사용된다.As the compound of Formula II, for example, 1-methylaminopropyl-3-phenyl-5-methylindazole, 1-aminopropyl-3-phenylindazole, 1-aminopropyl-3-phenyl-5-chloroindazole , 1-methylaminopropyl-3-phenyl-5-chloroindazole, 1-aminopropyl-3-phenyl-5-bromidazole, 1-aminoethyl-3-phenyl-5-indazole, 1-aminoethyl 3-phenyl-5-methylindazole, 1-aminobutyl-3-phenylindazole and the like are used.
본 발명을 실시함에 있어서는 식 II의 화합물을 메틸화제, 예를 들면 포름알데히드와 의산 혹은 포름알데히드와 나트륨보론하이드라이드등과 반응시킨다. 이때에 사용되는 포름알데히드는 중합체 또는 그의 반응성유도체의 형이어도 사용 할 수 있지만, 반응하기 쉬운 점을 고려하면 포르말린을 사용하는 것이 바람직하다. 반응은 식 II의 화합물을 용매, 예를 들면 메타놀, 에타놀등에 용해시키든가 또는 무용매로 행하고, 실온 내지 가온하에 통상 20분 내지 5시간, 바람직하기로는 30분 내지 3시간 행한다. 식 II의 화합물에 대해서 메틸화제를 당몰량 또는 과잉몰량 사용하는 것이 바람직하다.In carrying out the present invention, the compound of formula II is reacted with a methylating agent such as formaldehyde and acid, or formaldehyde and sodium boron hydride. The formaldehyde used at this time can be used in the form of a polymer or a reactive derivative thereof, but it is preferable to use formalin in view of easy reaction. The reaction is carried out by dissolving the compound of formula II in a solvent such as methanol, ethanol or the like, or without solvent, and usually 20 minutes to 5 hours, preferably 30 minutes to 3 hours at room temperature to warm. It is preferable to use the molar amount or excess molar amount of a methylating agent with respect to the compound of Formula II.
반응 혼합물로 부터 목적화합물 I을 단리함에는, 반응액에 유기용매, 예를 들면 벤젠, 에에테르, 클로로포름 등을 가하고, 유기층을 분취, 수세, 건조한 후 감압하에 농축하면 목적 화합물이 얻어진다.To isolate the target compound I from the reaction mixture, an organic solvent such as benzene, ether, chloroform or the like is added to the reaction mixture, and the organic layer is preparated, washed with water, dried and concentrated under reduced pressure to obtain the target compound.
수득된 목적화합물 I은 일반적으로 유상물이며 상법에 의해 무기산 또는 유기산에 의한 염, 예를 들면 염산염, 수산염으로 할 수도 있다.Obtained target compound I is generally an oily substance, and can also be salted with inorganic or organic acids, for example, hydrochloride or oxalate, by a conventional method.
본 발명에 의해 수득되는 식 I의 화합물은 신규화합물이며, 중추억제작용, 항우울작용, 항염증작용 등을 갖는 의약품으로서 유용하다.The compound of formula I obtained by the present invention is a novel compound and is useful as a medicine having central inhibitory action, antidepressant action, anti-inflammatory action and the like.
[원료화합물 II의 제조예][Preparation Example of Raw Material Compound II]
3-페닐-5-메틸인다졸 7.7g을 디메틸포름 아미드 100ml에 용해하고, 50% 함유 수소화나트륨 2.0g을 가해서 실온에서 10분간 교반한다. 이어서 이것에 브로모프로피온산에틸에스테르 8.7g을 가해서 실온에서 30분간 교반한다. 반응액을 물에 주입하고, 클로로포름으로 추출하고, 수세, 건조한 후 농축하면 1-에톡시카아보닐- 에틸-3-페닐-5-메틸인다졸 13.5g가 수득된다. 수득된 1-에톡시카아보닐에틸-3-페닐-5-메틸인다졸 13.5g을 에타놀 100ml에 용해하고, 40% 모노메틸아민 수용액 15ml를 가하고, 20시간 50℃에서 가온한 후 감압농축한다. 잔사를 클로로포름에 용해하고, 수세하고, 황산나트륨으로 건조한 후 감압농축하면, 1-N-모노메틸카아바모일에틸-3-페닐-5-메틸인다졸 9.0g이 수득된다. 이것을 에타놀로부터 재결정하여 수득되는 화합물은 융점 128 130℃를 나타낸다.7.7 g of 3-phenyl-5-methylindazole is dissolved in 100 ml of dimethylformamide, 2.0 g of 50% -containing sodium hydride is added and stirred at room temperature for 10 minutes. Subsequently, 8.7 g of ethyl bromopropionate is added to this, and it stirred at room temperature for 30 minutes. The reaction solution was poured into water, extracted with chloroform, washed with water, dried and concentrated to give 13.5 g of 1-ethoxycarbonyl-ethyl-3-phenyl-5-methylindazole. 13.5 g of 1-ethoxycarbonylethyl-3-phenyl-5-methylindazole obtained is dissolved in 100 ml of ethanol, 15 ml of a 40% monomethylamine aqueous solution is added, and heated at 50 ° C for 20 hours, followed by concentration under reduced pressure. The residue was dissolved in chloroform, washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain 9.0 g of 1-N-monomethylcarbamoylethyl-3-phenyl-5-methylindazole. The compound obtained by recrystallizing this from ethanol has a melting point of 128 130 ° C.
수득된 1-N-모노메틸카아바모일에틸-3-페닐-5-메틸인다졸 5.0g을 무수테트라하이드로푹란 40ml에 용해하고, 이것에 리튬알미늄하이드 1.5g을 빙냉하에 가해서 20분간 가열 환류하에 교반한다. 이어서 반응액에 함수예에테르 및 수산화나트륨 수용액을 가하고, 유기층을 분취한다. 다시 이 유기층에 10% 염산수를 가해 상징액을 분취하고, 수산화나트륨수용액을 가해서 염기성으로 한다. 이것을 벤젠으로 추출하고, 유기층을 수세하고, 황산나트륨으로 건조한후 감압농축하면, 1-모노메틸아미노프로필-3-페닐-5-메틸인다졸염산염 1.8g이 얻어진다. 이것을 에타놀에에테르 혼합용매로 부터 재결정하여 수득되는 화합물은 융점 148~149℃를 나타낸다.5.0 g of 1-N-monomethyl carbamoylethyl-3-phenyl-5-methylindazole obtained was dissolved in 40 ml of anhydrous tetrahydrofuran, 1.5 g of lithium aluminum hydride was added thereto under ice cooling, and heated under reflux for 20 minutes. Stir. Subsequently, hydrous ether and aqueous sodium hydroxide solution are added to the reaction solution, and the organic layer is separated. Again, 10% hydrochloric acid is added to the organic layer, the supernatant is separated, and sodium hydroxide aqueous solution is added to make it basic. This was extracted with benzene, the organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure, whereby 1.8 g of 1-monomethylaminopropyl-3-phenyl-5-methylindazole hydrochloride was obtained. The compound obtained by recrystallizing this from an ethanol ether mixed solvent shows melting | fusing point 148-149 degreeC.
[실시예 1]Example 1
1-모노메틸아미노프로필-3-페닐-5-메틸인다졸 1.1g을 메타놀 20ml에 용해하고, 이것에 포르말린수용액(37% 포름알데히드 함유) 0.63(을 가하고, 실온에서 20분간 교반한다.1.1 g of 1-monomethylaminopropyl-3-phenyl-5-methylindazole is dissolved in 20 ml of methanol, and an aqueous formalin solution (containing 37% formaldehyde) 0.63 (to this is added) and stirred at room temperature for 20 minutes.
이어서 나트륨보론하이드라이드 0.30g을 빙냉하에 가해 실온에서 10분간 교반한다. 수득된 반응액 감압농축하고, 잔류물에 벤젠을 가해서 수세하고, 황산나트륨으로 건조한 후 감압 농축하면 1-디메틸 아미노프로필-3-페닐-5-메틸인다졸 0.9g이 유상물로서 수득된다. 이것을 상법에 의해 수산으로 처리하면 수산염이 수득된다. 이것을 에타놀로 부터 재결정하여 수득되는 화합물은 융점 184~185℃를 나타낸다.Subsequently, 0.30 g of sodium boron hydride is added under ice-cooling, followed by stirring at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, benzene was added to the residue, washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain 0.9 g of 1-dimethylaminopropyl-3-phenyl-5-methylindazole as an oily substance. When this is treated with hydroxyl by the conventional method, the hydroxide is obtained. The compound obtained by recrystallizing this from ethanol shows melting | fusing point 184-185 degreeC.
[실시예 2]Example 2
1-아노노프로필-3-페닐인다졸 2.0g, 포르말린 수용액 1.0g 및 나트륨보론하이드라이드 0.55g을 사용하고, 그 외는 실시예 1과 동일하게 처리하면, 1-디메틸아노노프로필-3-페닐인다졸 1.6g이 유상물로서 수등된다. 이것을 상법에 의해 염산염으로 하고, 또 에타놀에에테르 혼합용매로 부터 재결정하여 수득하는 화합물은 융점 141~143℃를 나타낸다.When 2.0 g of 1-anonopropyl-3-phenylindazole, 1.0 g of formalin aqueous solution and 0.55 g of sodium boron hydride were used, and else the same treatment as in Example 1, 1-dimethylanonopropyl-3-phenyl 1.6 g of indazole is graded as an oil. The compound obtained as a hydrochloride by the conventional method and recrystallized from the ethanol ether mixed solvent shows melting | fusing point 141-143 degreeC.
[실시예 3]Example 3
1-아노노프로필-3-페닐-5-클로로인다졸 3.0g에 포르말린 수용액(37% 포름알데히드 함유) 7.5g 및 의산 1.4g을 가하고, 3시간 가열 환류한 후, 수산화나트륨수용액을 가해서 염기성으로 한다. 이어서 벤젠 20ml를 가해서 유기층을 분취하고, 수세하고, 황산 나트륨으로 건조한 후 감압농축하면, 1-디메틸아노프로필-3-페닐-5-클로로인다졸 2.9g이 유상물로서 얻어진다. 이것을 상법에 의해 에에테르염산으로 처리하면 염산염이 얻어진다. 이것을 에타놀에에테르 혼합용매로 부터 재결정하여 수득되는 화합물은 융점 158~160℃를 나타낸다.To 3.0 g of 1-anonopropyl-3-phenyl-5-chloroindazole, 7.5 g of formalin aqueous solution (containing 37% formaldehyde) and 1.4 g of acid were added thereto, and the mixture was heated and refluxed for 3 hours. do. Then, 20 ml of benzene is added, the organic layer is separated, washed with water, dried over sodium sulfate, and concentrated under reduced pressure, whereby 2.9 g of 1-dimethylanopropyl-3-phenyl-5-chloroindazole is obtained as an oily substance. When this is treated with ether hydrochloric acid by the conventional method, hydrochloride is obtained. The compound obtained by recrystallizing this from an ethanol ether mixed solvent shows melting | fusing point 158-160 degreeC.
[실시예 4]Example 4
1-모노메틸아노노프로필-3-페닐-5-클로로인다졸 2.0g, 의산 0.95g 및 포르말린 수용액(37% 포름알데히드 함유) 4.0g을 사용하고, 그 외는 실시예 3과 동일하게 처, 하면 1-디메틸 아미노프로필-3-페닐-5-클로로인다졸 1.8g이 유상물로서 수득된다. 이것을 상법에 의해 염산염으로 할 수가 있다.2.0 g of 1-monomethylanonopropyl-3-phenyl-5-chloroindazole, 0.95 g of phosphate, and 4.0 g of an aqueous solution of formalin (containing 37% formaldehyde) were used. 1.8 g of 1-dimethyl aminopropyl-3-phenyl-5-chloroindazole is obtained as an oil. This can be made into a hydrochloride by the conventional method.
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