KR100710548B1 - Method for preparing s-3-amino-2,3,4,5- tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid and ester compound thereof - Google Patents
Method for preparing s-3-amino-2,3,4,5- tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid and ester compound thereof Download PDFInfo
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Abstract
본 발명은 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화합물의 제조방법에 관한 것으로서, 유기용매, 염기 촉매 및 상전이 촉매의 존재 하에서 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-2-온을 할로겐화아세트산 에스테르 화합물과 N-알킬화 반응을 시켜 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물을 제조하는 단계; 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물을 암모니아와 반응시키는 아미노기 치환반응을 통해 3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물을 제조하는 단계; 및 3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물을 광학활성 유기산과의 부분입체이성질체 형성을 통해 광학활성을 갖도록 하는 단계를 포함하는 광학적으로 순수한 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화합물의 제조방법에 관한 것이다.The present invention relates to a method for preparing (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid and ester compounds thereof, wherein the organic solvent , N-alkylation of 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-2-one with a halogenated acetic acid ester compound in the presence of a base catalyst and a phase transfer catalyst To prepare 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester compound; 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester 3-amino-2,3, Preparing a 4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester compound; And 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester compound to have optical activity through diastereoisomer formation with an optically active organic acid. A method for preparing optically pure (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid and ester compounds thereof comprising the step will be.
벤자제핀, 알킬화반응, 암모니아, 테트라히드로, 아세트산, 상이동촉매.Benzazepine, alkylation, ammonia, tetrahydro, acetic acid, phase transfer catalyst.
Description
본 발명은 하기 화학식 1로 표시되는 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화합물의 제조방법에 관한 것으로, 더욱 상세하게는 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-2-온을 원료 물질로 하여 상이동 촉매를 이용한 락탐기의 온화한 N-알킬화반응을 수행한 후 암모니아를 이용한 직접적인 아미노기 치환 반응을 진행하고 광학 활성 유기산을 이용하여 광학 활성을 갖도록 한 경제적이고 효율적이며 산업적 생산이 가능한 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화합물의 제조방법에 관한 것이다. The present invention provides a method for preparing (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid and ester compounds thereof represented by the following general formula (1): In more detail, a lactam group using a phase transfer catalyst using 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-2-one as a raw material (S) -3-amino-2,3 which is economical, efficient and industrially produced by conducting a direct amino group substitution reaction using ammonia and performing optical activity using optically active organic acids after mild N-alkylation of It relates to a method for producing 4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid and ester compounds thereof.
상기 화학식 1에서 R은 탄소수 1 내지 10의 직쇄 또는 측쇄의 포화 또는 불포화 탄소사슬, 포화 또는 불포화 탄소고리, 또는 벤젠고리를 포함하고 있는 탄소사슬 또는 고리이다.In Formula 1, R is a carbon chain or ring containing a straight or branched, saturated or unsaturated carbon chain of 1 to 10 carbon atoms, a saturated or unsaturated carbon ring, or a benzene ring.
상기 화학식 1로 표시되는 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화학물은 광학 활성 의약품의 제조에 유용한 물질로 알려져있다.(S) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid and ester chemicals thereof represented by Chemical Formula 1 may be used as Known as a useful material for manufacturing.
(s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화학물의 종래 제조방법을 살펴보면 다음과 같다.A conventional method for preparing (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid and ester chemicals thereof is as follows.
2,3,4,5-테트라히드로1H-1-벤자제핀-2-온을 원료 물질로 하여 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화학물을 얻는 종래 방법은(미국특허 제4,410,520호, 제4,473,575호, 및 제4,575,503호) 오염화인을 통한 염소화 반응에서 이중염소치환 화합물을 제조한 후 치환된 2개의 염소 원자 중 한 원자를 수소화반응을 통해 다시 제거하여 단일염소치환 화합물을 제조하고 아지도나트륨을 사용한 아지도 치환반응을 거쳐 이를 다시 수소화를 통해 아미노기를 도입해야 하므로 반응단계가 길어지고 경제적으로도 비효율적이다. 또 한, 나트륨히드리드 같은 강염기를 사용한 락탐의 N-알킬화반응은 산업적인 생산이 용이하지 않다. (S) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H using 2,3,4,5-tetrahydro1H-1-benzazepin-2-one as a starting material Conventional methods for obtaining -1-benzazepine-1-acetic acid and ester chemicals thereof (US Pat. Nos. 4,410,520, 4,473,575, and 4,575,503) have been described for preparing dichlorine-substituted compounds in chlorination reactions with phosphorus pentachloride. After removing one of the two substituted chlorine atoms through hydrogenation, a single chlorine-substituted compound was prepared and an azido substitution using azido sodium was required to introduce an amino group through hydrogenation. It is economically inefficient. In addition, N-alkylation of lactams with strong bases such as sodium hydride is not easy for industrial production.
미국특허 제4,692,522호에서 언급한 방법도 3-브롬화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-2-온을 아지도나트륨과 반응시킨 후 이를 수소화하므로 상술한 문헌과 같은 문제를 갖는다.The method mentioned in US Pat. No. 4,692,522 also reacts with 3-bromide-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-2-one after reacting with azido sodium. Therefore, it has the same problem as the above-mentioned document.
광학적으로 순수한 L-키누레닌을 이용한 고리화반응을 통해 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화학물을 얻는 방법은(미국특허 제4,410,520호, 제4,473,575호, 및 제4,575,503호) 고가의 원료물질을 사용해야 하고 L-키누레닌에서 유도된 불필요한 카르보닐기를 환원시켜 제거해야 하는 문제가 있다.(S) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid and its by cyclization with optically pure L-kynurenine The process for obtaining ester chemicals (US Pat. Nos. 4,410,520, 4,473,575, and 4,575,503) requires the use of expensive raw materials and the need to reduce and remove unnecessary carbonyl groups derived from L-kynurenine.
또 다른 방법으로 Helvetica Chimica Acta vol.71, 페이지 337-343 (1988) 및 미국특허 제5,677,297호에 언급된 반응은 3-브롬화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-2-온을 프탈이미드칼륨과 반응시킨 후 이를 가수분해하여 아미노기를 도입하는데 이때 분자량이 큰 프탈이미드칼륨을 반응시켜 원자 효율성(atom efficiency)의 감소와 가수분해라는 또 다른 반응을 진행시켜야 하므로 단계가 보다 길어져 경제적이지 못한 문제가 있다.Alternatively, the reactions mentioned in Helvetica Chimica Acta vol. 71, pages 337-343 (1988) and U.S. Pat. No. 5,677,297 are described as 3-brominated-2,3,4,5-tetrahydro-2-oxo-1H- After reacting 1-benzazepin-2-one with potassium phthalimide potassium and hydrolyzing it to introduce an amino group, it reacts potassium phthalimide with high molecular weight to reduce atomic efficiency and hydrolysis. There is a problem that it is not economical because the step is longer because other reactions must proceed.
이에 본 발명에서는 상술한 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화학물의 제조 방법상의 문제를 해결하기 위해 연구를 수행한 결과, 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤 자제핀-2-온을 원료 물질로 하여 상이동 촉매를 이용한 락탐기의 온화한 N-알킬화반응을 수행한 후 암모니아를 이용한 직접적인 아미노기 치환반응을 진행하고 광학활성 유기산을 이용해 광학활성을 갖도록하여 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화합물을 경제적이고 효율적이며 산업적 생산이 가능하게 제조하여 본 발명을 완성하였다. Accordingly, the present invention addresses the problem of the above-described method for preparing (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid and ester chemicals thereof. In order to solve this problem, lactam using a phase transfer catalyst using 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-2-one as a raw material After mild N-alkylation of the group, a direct amino group substitution reaction using ammonia was carried out, and optical activity was performed using an optically active organic acid to give (s) -3-amino-2,3,4,5-tetrahydro- The present invention has been completed by preparing 2-oxo-1H-1-benzazepine-1-acetic acid and ester compounds thereof to enable economical, efficient and industrial production.
따라서 본 발명의 목적은 온화한 반응조건과 반응공정의 단축을 통하여 효율적이며 경제적인 방법으로 상업적 생산이 가능한 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화학물을 제조하는 방법을 제공하는데 있다.Accordingly, an object of the present invention is to provide (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H which can be commercially produced in an efficient and economical manner through mild reaction conditions and shortening of the reaction process. A method for preparing -1-benzazepine-1-acetic acid and ester chemicals thereof is provided.
상기 목적을 달성하기 위한 본 발명의 하기 화학식 1로 표시되는 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화합물을 제조하는 방법은 유기용매, 염기 촉매 및 상전이 촉매의 존재 하에서 하기 화학식 2로 표시되는 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-2-온을 하기 화학식 5로 표시되는 할로겐화아세트산 에스테르 화합물과 N-알킬화 반응시켜 하기 화학식 3으로 표시되는 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물을 제조하는 단계; 하기 화학식 3으로 표시되는 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물을 암모니아와 반응시켜 아미노기 치환반응을 통해 하기 화학식4로 표시되는 3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물을 제조하는 단계; 및 하기 화학식 4로 표시되는 3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물을 광학활성 유기산과의 부분입체이성질체 형성을 통해 광학활성을 갖도록 하는 단계를 포함한다.(S) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid represented by the following general formula (1) of the present invention for achieving the above object and Method for preparing an ester compound thereof is a 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzase represented by the following formula (2) in the presence of an organic solvent, a base catalyst and a phase transfer catalyst 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1 represented by the following general formula (3) by reacting pin-2-one with a halogenated acetic acid ester compound represented by the following formula (5): Preparing a benzazepine-1-acetic acid ester compound; The 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester compound represented by the following Chemical Formula 3 is reacted with ammonia to perform an amino group substitution reaction. Preparing a 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester compound represented by 4; And forming a diastereomer of the 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester compound represented by the following formula (4) with an optically active organic acid: To have optical activity through.
화학식 1Formula 1
여기서, R은 탄소수 1 내지 10의 직쇄 또는 측쇄의 알킬기이다.Here, R is a C1-C10 linear or branched alkyl group.
여기서, X는 염소, 브롬, 또는 요오드이다.Where X is chlorine, bromine, or iodine.
여기서, X는 염소, 브롬, 또는 요오드이고, R은 탄소수 1 내지 10의 직쇄 또는 측쇄의 알킬기이다.Here, X is chlorine, bromine, or iodine, and R is a straight or branched alkyl group having 1 to 10 carbon atoms.
여기서, R은 탄소수 1 내지 10의 직쇄 또는 측쇄의 알킬기이다.
여기서, X는 염소, 브롬 또는 요오드이며, R은 탄소수 1 내지 10의 직쇄 또는 측쇄의 알킬기이다.Here, R is a C1-C10 linear or branched alkyl group.
Wherein X is chlorine, bromine or iodine, and R is a straight or branched alkyl group having 1 to 10 carbon atoms.
이하 본 발명을 더욱 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in more detail.
전술한 바와 같이, 본 발명에서는 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-2-온으로부터 상이동 촉매와 상업적 활용이 가능한 염기를 사용하여 온화한 조건에서 높은 수율로 N-알킬화 반응을 수행하여 강염기에 의한 상업적 생산이 어려운 문제를 해결하였으며 암모니아를 이용하여 직접적으로 아미노기를 도입해서 아지도기를 도입한 후 수소화하는 공정이나 프탈이미드칼륨과의 반응 후 가수분해 공정 등 추가 공정이 필요한 문제를 해결하여 반응단계가 길어지는 문제를 해결하였다.As described above, in the present invention, a phase transfer catalyst and a commercially available base are used from 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-2-one. This solution solved the problem of difficult commercial production by strong base by performing N-alkylation reaction at high yield under mild conditions, and introduced azido groups by directly introducing amino groups using ammonia or by hydrogenation with potassium phthalimide. After the reaction to solve the problem that the additional step, such as a hydrolysis step to solve the problem of longer reaction step.
다시 말하면, 본 발명은 상기 화학식 2로 표시되는 3-할로겐화-2,3,4,5-테트 라히드로-2-옥소-1H-1-벤자제핀-2-온을 원료물질로하여 상이동 촉매를 이용한 락탐기의 온화한 N-알킬화반응을 수행한 후 암모니아를 이용한 직접적인 아미노기 치환반응을 진행한 후 광학활성 유기산을 이용하여 광학활성을 갖도록 함으로서 경제적이고 효율적이며 산업적 생산이 가능한 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화합물의 제조방법에 관한 것이다. In other words, the present invention is a phase transfer using the 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-2-one represented by the formula (2) as a raw material After the mild N-alkylation reaction of the lactam group using a catalyst, the amino group substitution reaction using ammonia is carried out, and the optical activity is carried out using an optically active organic acid, thereby enabling economical, efficient and industrial production (s) -3. -Amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid and a method for producing an ester compound thereof.
첫번째 반응과정은 상기 화학식 2로 표시된 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-2-온과 상기 화학식 5로 표시된 할로겐화아세트산 에스테르와의 N-알킬화 반응이다. 유기용매 하에서 상기 화학식 2로 표시된 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-2-온과 할로겐화아세트산 에스테르를 염기촉매와 상이동 촉매를 이용하여 반응시킨다. 상이동 촉매를 사용하게 되면 상업적 생산에 활용 가능한 값싼 염기를 사용하여도 반응속도가 빨라지며 부반응이 억제되는 효과가 있다. The first reaction process is the reaction of 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-2-one represented by Chemical Formula 2 with the halogenated acetic acid ester represented by Chemical Formula 5. N-alkylation reaction. 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-2-one and a halogenated acetic acid ester represented by Chemical Formula 2 under a organic solvent were subjected to a phase transfer catalyst To react. The use of phase transfer catalysts has the effect of speeding up reactions and suppressing side reactions even when using cheap bases available for commercial production.
이때 사용 가능한 염기촉매는 수산화나트륨, 수산화칼륨, 수산화리튬 등의 다양한 알칼리 금속 수산화물; 나트륨메톡사이드, 나트륨에톡사이드, 나트륨삼차부톡사이드 등의 다양한 알카리금속의 알콕사이드; 나트륨히드리드, 리튬히드리드등의 알칼리 금속 히드리드; 리튬디이소프로필아미드, 또는 부틸리튬등이며 바람직하게는 수산화나트륨, 수산화칼륨, 또는 수산화리튬이다. The base catalyst which can be used at this time is various alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide; Alkoxides of various alkali metals such as sodium methoxide, sodium ethoxide and sodium tert-butoxide; Alkali metal hydrides such as sodium hydride and lithium hydride; Lithium diisopropylamide, or butyllithium and the like, preferably sodium hydroxide, potassium hydroxide, or lithium hydroxide.
사용 가능한 상이동 촉매는 R1R2R3R4NX(이때 R1, R2, R3, 및 R4는 서로 같거나 다르게 탄소원자수 1∼4의 알킬 또는 아릴기, X는 염소, 브롬 또는 요오드)인 군으 로부터 선택되며, 보다 구체적으로는 염화벤질트리메틸암모늄, 염화벤질트리에틸암모늄, 염화벤질트리부틸암모늄, 염화테트라메틸암모늄, 염화테트라에틸암모늄, 염화테트라부틸암모늄, 브롬화벤질트리메틸암모늄, 브롬화벤질트리에틸암모늄, 브롬화벤질트리부틸암모늄, 브롬화테트라메틸암모늄, 브롬화테트라에틸암모늄, 브롬화테트라부틸암모늄, 요오드화벤질트리메틸암모늄, 요오드화벤질트리에틸암모늄, 요오드화벤질트리부틸암모늄, 요오드화테트라메틸암노늄, 요오드화테트라에틸암모늄, 요오드화테트라부틸암모늄, 황산수소벤질트리메틸암모늄, 황산수소벤질트리에틸암모늄, 황산수소벤질트리부틸암모늄, 황산수소테트라메틸암모늄, 황산수소테트라에틸암모늄, 또는 황산수소테트라부틸암모늄등이며, 바람직하게는 염화벤질트리메틸암모늄, 염화벤질트리에틸암모늄, 또는 염화벤질트리부틸암모늄이다.Phase transfer catalysts that can be used are R 1 R 2 R 3 R 4 NX (where R 1 , R 2 , R 3 , and R 4 are the same or different alkyl or aryl groups of 1 to 4 carbon atoms, X is chlorine, bromine Or iodine), and more specifically benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium chloride, benzyltrimethylammonium bromide, Benzyl triethylammonium bromide, benzyl tributylammonium bromide, tetramethylammonium bromide, tetraethylammonium bromide, tetrabutylammonium bromide, benzyl trimethylammonium iodide, benzyl triethylammonium iodide, benzyltributylammonium iodide, tetramethylammonium iodide, Tetraethylammonium Iodide, Tetrabutylammonium Iodide, Hydrogen Benzyl Trimethylammonium, Hydrogen Benzyl Triethylammonium Benzyl trimethylammonium sulfate, tetrahydrogen ammonium sulfate, tetraethylammonium sulfate, or tetrabutylammonium sulfate, and the like, preferably benzyltrimethylammonium chloride, benzyltriethylammonium chloride, or benzyltributylammonium chloride. to be.
반응 용매는 아세토니트릴, 테트라히드로퓨란, N,N-디메틸포름아미드, 또는 디메틸술폭사이드; 메탄올, 및 에탄올등의 알코올류 용매; 또는 벤젠, 톨루엔, 및 자일렌 등의 방향족 용매중 하나 또는 그 이상을 사용할 수 있으며 바람직하게는 아세토니트릴이다.The reaction solvent may be acetonitrile, tetrahydrofuran, N, N-dimethylformamide, or dimethyl sulfoxide; Alcohol solvents such as methanol and ethanol; Or one or more of aromatic solvents such as benzene, toluene, and xylene may be used, preferably acetonitrile.
상기 화학식 2로 표시된 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-2-온과 상기 화학식 5로 표시된 할로겐화아세트산 에스테르와의 당량비는 1 : 1.0 ∼ 3.0이며 바람직하게는 1 : 1.0 ∼ 1.1이다. 할로겐화아세트산 에스테르와의 당량비가 1.0 미만이면 반응 전환률이 감소하며 1 : 3.0을 초과하면 불필요하게 많이 사용하는 것으로 비경제적이다. 반응온도는 -50 ∼ 100℃이며 바람직하게는 0 ∼ 50℃이고, 가장 바람직하게는 15 ∼ 35℃이다. 반응온도가 -50℃ 미만이면 반응속도가 느려질 뿐만 아니라 경제적으로 바람직하지 못하며 반응온도가 100℃를 초과하면 부반응이 많이 생겨 비효율적이다. 상기 화학식 2로 표시된 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-2-온과 염기촉매의 당량비는 1 : 1.0 ∼ 2.0이며 바람직하게는 1 : 1.0 ∼ 1.2이다. 염기촉매의 당량비가 1.0미만이면 반응이 완결되지 않으며 2.0을 초과하면 부반응물 생성이 많아진다. 상기 화학식 2로 표시된 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-2-온과 상이동 촉매의 당량비는 1 : 0.1 ∼ 1.0이며 바람직하게는 1 : 0.2 ∼ 0.5이다. 상이동 촉매의 당량비가 0.1미만이면 반응속도가 느려져 비효율적이고 1.0을 초과하면 과량으로 사용하는 것임으로 경제적이지 못하다. The equivalent ratio of 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-2-one represented by Formula 2 with the halogenated acetic acid ester represented by Formula 5 is 1: 1.0-3.0, Preferably it is 1: 1.0-1.1. When the equivalent ratio with the halogenated acetic acid ester is less than 1.0, the reaction conversion rate decreases, and when it exceeds 1: 3.0, it is uneconomically unnecessary to use a lot. Reaction temperature is -50-100 degreeC, Preferably it is 0-50 degreeC, Most preferably, it is 15-35 degreeC. If the reaction temperature is less than -50 ℃ not only slow the reaction rate but also economically undesirable, if the reaction temperature exceeds 100 ℃ a lot of side reactions are inefficient. The equivalent ratio of 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-2-one represented by the formula (2) and the base catalyst is 1: 1.0 to 2.0, preferably 1: 1.0 to 1.2. If the equivalence ratio of the base catalyst is less than 1.0, the reaction is not completed. If the equivalent ratio of the base catalyst is more than 2.0, the side reaction product is increased. The equivalent ratio of 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-2-one represented by the formula (2) and the phase transfer catalyst is 1: 0.1 to 1.0 and preferably Is 1: 0.2 to 0.5. If the equivalence ratio of the phase transfer catalyst is less than 0.1, the reaction rate is slow and inefficient.
다음 반응단계는 상기 화학식 3으로 표시된 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물의 할로겐기를 암모니아와 반응시켜 아미노기를 도입하는 반응이다. In the next reaction step, the halogen group of the 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester compound represented by Chemical Formula 3 is reacted with ammonia to form an amino group. It is reaction to introduce.
유기용매 하에서 상기 화학식 3으로 표시된 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물과 암모니아를 가압 조건에서 반응시킨다. 이때 사용되는 암모니아는 암모니아 기체 또는 암모니아수를 사용할 수 있으며 바람직하게는 암모니아 기체이다. Under an organic solvent, the 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester compound represented by Formula 3 is reacted with ammonia under pressurized conditions. At this time, ammonia used may be ammonia gas or ammonia water, preferably ammonia gas.
반응압력은 3 ∼ 30기압이며 바람직하게는 10 ∼ 20기압이다. 반응압력이 3기압미만이면 반응속도가 현저히 느려지고 30기압을 초과하면 지나치게 고압이므로 상업적 생산이 어려워진다. 반응온도는 50 ∼ 150℃이며 바람직하게는 70 ∼ 110℃이다. 반응온도가 50℃미만이면 반응속도가 느려지고 110℃를 초과하면 부반응이 많이 생겨 효율적이지 못하다.The reaction pressure is 3 to 30 atm, preferably 10 to 20 atm. If the reaction pressure is less than 3 atm, the reaction rate is significantly slower, and if it exceeds 30 atm, it is too high pressure, making commercial production difficult. Reaction temperature is 50-150 degreeC, Preferably it is 70-110 degreeC. If the reaction temperature is less than 50 ℃ the reaction rate is slow and exceeds 110 ℃ a lot of side reactions are not efficient.
다음 반응단계는 상기 화학식 4로 표시된 3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물을 광학활성 유기산과 반응시켜 부분입체이성질체를 형성시킨 후 적절한 용매에서 용해도 차이를 이용하여 광학적으로 순수한 키랄 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물의 광학활성 유기산 염을 제조한 후 중화반응을 통해 광학활성 유기산을 제거하여 상기 화학식 1로 표시되는 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화합물을 제조하는 반응이다. The next reaction step is a diastereomer by reacting the 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester compound represented by Chemical Formula 4 with an optically active organic acid. Optically pure chiral (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1- using the solubility difference in a suitable solvent after isomer formation (S) -3-amino-2,3,4,5-tetrahydro-2-oxo represented by Chemical Formula 1 by preparing an optically active organic acid salt of an acetic acid ester compound and then removing the optically active organic acid through a neutralization reaction -1H-1-benzazepine-1-acetic acid and ester compounds thereof.
유기용매 하에서 상기 화학식 4로 표시된 3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물을 광학활성 유기산과 반응시켜 부분입체이성질체를 형성시킨 후 적절한 용매에서 용해도 차이를 이용하여 광학적으로 순수한 키랄 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물의 광학활성 유기산 염을 제조한 후 중화반응을 통해 광학활성 유기산을 제거하여 상기 화학식 1로 표시되는 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화합물을 제조한다. Diastereomers by reacting 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester compound represented by Formula 4 with an optically active organic acid in an organic solvent Optically pure chiral (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid using solubility differences in a suitable solvent after (S) -3-amino-2,3,4,5-tetrahydro-2-oxo- represented by Chemical Formula 1 by preparing an optically active organic acid salt of an ester compound and then removing the optically active organic acid through a neutralization reaction. 1H-1-benzazepine-1-acetic acid and ester compounds thereof are prepared.
이때 사용되는 광학활성 유기산은 L-타르타르산, 디아릴타르타르산, 말릭산, 캄포릭산, 캄포술폰산, 또는 만델릭산등을 사용할 수 있으며, 바람직하게는 L-타르타르산이다. 반응용매는 메탄올, 에탄올, 프로판올, 이소프로판올, 부탄올, 또는 삼차부탄올등을 사용할 수 있으며 바람직하게는 에탄올 또는 이소프로판올이다. The optically active organic acid used may be L- tartaric acid, diaryl tartaric acid, malic acid, camphoric acid, camphorsulfonic acid, or mandelic acid, and the like, and preferably L-tartaric acid. The reaction solvent may be methanol, ethanol, propanol, isopropanol, butanol, tert-butanol and the like, preferably ethanol or isopropanol.
광학활성 유기산염을 제거하기 위해 사용되는 염기는 암모니아수, 메틸아민, 에틸아민, 프로필아민, 및 부틸아민등의 1차아민; 디메틸아민, 디에틸아민, 및 디이소프로필아민등 2차아민; 트리메틸아민, 트리에틸아민, 및 디에틸이소프로필아민등 3차아민; 피리딘등의 고리형 아민; 또는 탄산나트륨, 탄산수소나트륨, 수산화나트륨, 및 수산화칼륨등의 무기염등이며 바람직하게는 암모니아수 및 수산화나트륨이다. Bases used for removing the optically active organic acid salt include primary amines such as ammonia water, methylamine, ethylamine, propylamine, and butylamine; Secondary amines such as dimethylamine, diethylamine, and diisopropylamine; Tertiary amines such as trimethylamine, triethylamine, and diethylisopropylamine; Cyclic amines such as pyridine; Or inorganic salts such as sodium carbonate, sodium bicarbonate, sodium hydroxide, and potassium hydroxide, and the like, preferably ammonia water and sodium hydroxide.
광학활성 유기산염을 제거하고 난 후 상기 화학식 1로 표시되는 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화합물을 추출하기 위해 사용되는 유기용매는 디클로로메탄, 클로로포름, 사염화탄소, 및 디클로로에탄등의 할로겐류 용매; 메틸초산, 에틸초산, 및 부틸초산등의 초산계 용매; 벤젠, 톨루엔, 및 자일렌등의 방향족 용매; 또는 에틸에테르, 및 프로필에테르등의 에테르계 용매와 같은 물과 혼합되지 않는 다양한 용매가 사용 가능하다.(S) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid represented by Formula 1 after removing the optically active organic acid salt and Organic solvents used for extracting the ester compounds thereof include halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane; Acetic acid solvents such as methyl acetic acid, ethyl acetate, and butyl acetic acid; Aromatic solvents such as benzene, toluene, and xylene; Or various solvents which are not mixed with water such as ether solvents such as ethyl ether and propyl ether can be used.
한편 상기 화학식 4로 표시된 3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물을 광학활성 유기산과 반응시켜 부분입체이성질체를 형성시킬 경우 상기 화학식 4로 표시된 3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물의 S폼으로부터 유도된 부분입체이성질체만이 용해도 차이에 의해 결정으로 석출되고 반대 광학이성질체인 R폼으로부터 유도된 부분입체이성질체는 용액상에 그대로 존재하여 광학적으로 순수한 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물의 광학활성 유기산 염을 선택적으로 얻을 수 있지만 이론적 수율은 50%를 넘지 못하게 된다. 그러나 반응용매 중에 녹아있는 R폼의 3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물에서 유도된 부분입체이성질체를 알데히드 화합물과 반응시켜 이민화합물을 형성시킨 후 이를 라세미화시키면 R폼의 일부가 S폼의 3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물의 부분입체이성질체로 전환된다. 이 물질은 용해도 차이로 인해 다시 결정으로 석출되므로 이론적으로 R폼을 S폼으로 100% 전환시킬 수 있게 되어 전체적인 수율을 높일 수 있다. Meanwhile, the 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester compound represented by Chemical Formula 4 is reacted with an optically active organic acid to form diastereomers. In this case, only the diastereomers derived from S-form of 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester compound represented by Formula 4 above The diastereomers, which are precipitated as crystals by the difference in solubility and derived from the opposite optical isomer, Rform, remain in solution and are thus optically pure (s) -3-amino-2,3,4,5-tetrahydro-2. Optically active organic acid salts of oxo-1H-1-benzazepine-1-acetic acid ester compounds can be selectively obtained, but the theoretical yield will not exceed 50%. However, the diastereomers derived from 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester compound of R-form dissolved in the reaction solvent are aldehyde compounds. And an imine compound to form an racemic compound, and then racemize it to form part of the R-form as 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1- Converted to diastereomers of acetic acid ester compounds. Because of the difference in solubility, the material precipitates back into crystals, which theoretically allows 100% conversion of the R-form to the S-form, thus increasing the overall yield.
(s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 삼차부틸에스테르의 경우 염화수소 기체와의 반응을 통해 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산을 얻을 수 있었다.(s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid through tertiary butyl ester through reaction with hydrogen chloride gas (s)- 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid was obtained.
또한, 다양한 ( s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 에스테르 화합물들은 가수분해를 통해 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산으로 제조될 수 있었으며 이 중 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 벤질에스테르의 경우에는 가수분해대신 수소화를 통해서도 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산의 제조가 가능하였다.In addition, various (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid ester compounds may be hydrolyzed to (s) -3- Amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid, of which (s) -3-amino-2,3,4,5 In the case of tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid benzyl ester, it is also possible to (s) -3-amino-2,3,4,5-tetrahydro-2 by hydrogenation instead of hydrolysis. Oxo-1H-1-benzazepine-1-acetic acid was possible.
이하 실시예를 통하여 본 발명을 좀 더 구체적으로 설명하지만, 하기 실시예에 본 발명의 범주가 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following Examples, but the scope of the present invention is not limited to the following Examples.
실시예1 Example 1
100㎖ 반응기에 아세토니트릴 (30㎖), 3-브롬화-2,3,4,5-테트라히드로-2-옥 소-1H-1-벤자제핀-2-온(10g)과 클로로아세트산 삼차부틸에스테르(6.6g)을 넣고 교반하였다. 염화벤질트리에틸암모늄(0.38g)을 상이동 촉매로 넣어준 후 수산화나트륨(1.8g)을 천천히 투입하고 25℃에서 1시간 동안 교반하였다. 반응액을 물(90g)에 천천히 투입한 후 생성된 고체를 여과하여 3-브롬화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 삼차부틸에스테르 (14.1g)를 얻었다.Acetonitrile (30 mL), 3-brominated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-2-one (10 g) and tert-butyl chloroacetate in a 100 mL reactor Ester (6.6 g) was added and stirred. Benzyltriethylammonium chloride (0.38g) was added as a phase transfer catalyst, and sodium hydroxide (1.8g) was slowly added thereto, and stirred at 25 ° C for 1 hour. The reaction solution was slowly poured into water (90 g), and then the resulting solid was filtered to 3-bromide-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid tert-butyl Ester (14.1 g) was obtained.
실시예 2 Example 2
100㎖ 고압 반응기에 아세토니트릴(30㎖), 3-브롬화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 삼차부틸에스테르(2g)를 넣고 암모니아 기체를 10기압으로 가압한 후 반응 온도를 100℃로 승온한 후 10시간 동안 교반하였다. 용매를 감압증류하여 제거한 후 크로마토그래피로 분리하여 3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 삼차부틸에스테르(1.2g)를 얻었다.Acetonitrile (30 mL) and 3-brominated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid tert-butyl ester (2 g) were added to a 100 mL high-pressure reactor. After pressurizing the ammonia gas to 10 atm, the reaction temperature was raised to 100 ° C. and stirred for 10 hours. The solvent was distilled off under reduced pressure, and then chromatographed to separate 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid tert-butyl ester (1.2 g). Got it.
실시예 3 Example 3
100㎖ 반응기에 이소프로필알코올 (25.0g)과 3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 삼차부틸에스테르(6.0g)를 넣은 후 70℃로 승온하였다. L-타르타르산(3.2g)을 넣고 1시간 동안 교반한 후 살리실알데히드(0.13g)를 투입하고 18시간 동안 환류하였다. 생성된 고체를 여과하고 이소프로필알코올로 세척하여 광학적으로 순수한 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 삼차부틸에스테르 타르타르산 염을 얻었다. 얻어진 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 삼차부틸에스테르 타르타르산 염을 물(10㎖) 및 28% 암모니아수(11㎖)와 혼합한 후 디클로로메탄으로 추출하고 수층을 제거하였다. 추출된 유기층을 무수황산마그네슘으로 수분을 제거한 후 감압증류하여 광학적으로 순수한 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 삼차부틸에스테르 (4.3g)를 얻었다(m.p. 111 ∼ 113℃, [α]25 D = -272.6℃(C=1.0, 에탄올)). Isopropyl alcohol (25.0 g) and 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid tert-butyl ester (6.0 g) were added to a 100 ml reactor. It heated up at 70 degreeC after putting. L-tartaric acid (3.2g) was added and stirred for 1 hour, then salicylic aldehyde (0.13g) was added and refluxed for 18 hours. The resulting solid was filtered and washed with isopropyl alcohol to obtain optically pure (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid tertiary Butyl ester tartaric acid salt was obtained. The resulting (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid tert-butyl ester tartaric acid salt (10 mL) and 28% aqueous ammonia (11 mL), followed by extraction with dichloromethane and removal of the aqueous layer. The extracted organic layer was dried with anhydrous magnesium sulfate, and then distilled under reduced pressure to obtain optically pure (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1. - to obtain ethyl tert-butyl ester (4.3g) (mp 111 ~ 113 ℃, [α] 25 D = -272.6 ℃ (C = 1.0, ethanol)).
실시예 4 Example 4
100㎖ 반응기에 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 삼차부틸에스테르(4.0g)와 디클로로메탄(30㎖)을 넣고 상온을 유지하면서 염화수소 기체를 2시간 불어넣어 주었다. 디클로로메탄을 감압증류하여 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산(4.1g) 염산염을 얻었다. 에틸초산 30㎖ 과 물 30㎖을 상기 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산(4.1g) 염산염에 넣고 수산화나트륨을 사용하여 수용액의 pH를 7로 조정한 후 추출하였다(에틸초산 30㎖ ×2). 상기 에틸초산 용액을 무수황산마그네슘을 사용하여 수분을 제거하고 감압증류하여 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산을 얻었다(m.p. 275 ∼ 276℃).In a 100 ml reactor, (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid tert-butyl ester (4.0 g) and dichloromethane (30 Ml) and hydrogen chloride gas was blown for 2 hours while maintaining the room temperature. Dichloromethane was distilled under reduced pressure to obtain (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid (4.1 g) hydrochloride. 30 ml of ethyl acetate and 30 ml of water were added to (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid (4.1 g) hydrochloride. The pH of the aqueous solution was adjusted to 7 using sodium hydroxide, and extracted (30 ml of ethyl acetate x 2). The ethyl acetate solution was evaporated under reduced pressure using anhydrous magnesium sulfate, followed by (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1. Acetic acid was obtained (mp 275 to 276 ° C).
실시예 5Example 5
100㎖ 반응기에 메탄올(70㎖)과 활성탄에 담지된 5% 팔라튬 촉매(0.03g) 및 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 벤질에스테르(3.0g)을 투입하고 3기압의 수소하에서 25℃를 유지하며서 3시간 동안 교반하였 다. 촉매를 여과하여 제거한 후 메탄올을 감압증류하여 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산(1.6g)을 얻었다(m.p. 274.9 ∼ 275.4℃, [α]20D = -295.5℃(C=0.71, 1N HCl)).
5% palladium catalyst (0.03 g) supported on methanol (70 mL) and activated carbon in a 100 mL reactor and (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1 Benzazepine-1-acetic acid benzyl ester (3.0 g) was added thereto, and the mixture was stirred for 3 hours while maintaining 25 ° C under hydrogen at 3 atmospheres. The catalyst was filtered off and the methanol was distilled under reduced pressure to afford (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid (1.6 g). (Mp 274.9-275.4 degreeC, [(alpha)] 20D = -295.5 degreeC (C = 0.71, 1N HCl).
상술한 바와 같이 본 발명에 따른 (s)-3-아미노-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-1-아세트산 및 이의 에스테르 화합물의 제조방법은 3-할로겐화-2,3,4,5-테트라히드로-2-옥소-1H-1-벤자제핀-2-온을 원료 물질로하여 상이동 촉매를 이용한 락탐기의 온화한 N-알킬화반응을 수행한 후 암모니아를 이용한 직접적인 아미노기치환반응을 진행한 후 광학활성 유기산을 이용하여 광학활성을 갖도록 하는 매우 경제적이고 효율적이며 산업적 생산이 가능한 제조 방법이다.As described above, the method of preparing (s) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid and ester compounds thereof according to the present invention Gentle N-alkylation of lactam group using phase transfer catalyst using 3-halogenated-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-2-one as a starting material After a direct amino-substituted reaction using ammonia, it is a very economical, efficient and industrial production method that has optical activity using optically active organic acid.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4410520A (en) | 1981-11-09 | 1983-10-18 | Ciba-Geigy Corporation | 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids |
| KR900001190B1 (en) * | 1981-08-11 | 1990-02-28 | 칼 에프. 조르다 | Preparation process for 3-amino-(1)benzazepin-2-one-1-alkanoic acid |
| JPH05301859A (en) * | 1991-09-23 | 1993-11-16 | Hoechst Roussel Pharmaceut Inc | Substituted 3-amino-2,3,4,5-tetrahydro-1-aryloxy-3-benzazepines |
| KR960034178A (en) * | 1995-03-23 | 1996-10-22 | 디터 라우어 | Benzazepine-benzoxazepine- and benzothiazepine-N-acetic acid derivatives, their preparation and pharmaceutical compositions containing them |
| US5610153A (en) | 1992-12-11 | 1997-03-11 | Ciba-Geigy Corporation | Benzazepinone derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR900001190B1 (en) * | 1981-08-11 | 1990-02-28 | 칼 에프. 조르다 | Preparation process for 3-amino-(1)benzazepin-2-one-1-alkanoic acid |
| US4410520A (en) | 1981-11-09 | 1983-10-18 | Ciba-Geigy Corporation | 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids |
| JPH05301859A (en) * | 1991-09-23 | 1993-11-16 | Hoechst Roussel Pharmaceut Inc | Substituted 3-amino-2,3,4,5-tetrahydro-1-aryloxy-3-benzazepines |
| US5610153A (en) | 1992-12-11 | 1997-03-11 | Ciba-Geigy Corporation | Benzazepinone derivatives |
| KR960034178A (en) * | 1995-03-23 | 1996-10-22 | 디터 라우어 | Benzazepine-benzoxazepine- and benzothiazepine-N-acetic acid derivatives, their preparation and pharmaceutical compositions containing them |
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