KR100421282B1 - Process for preparing 1-methylhexahydro-4-azepinone hydrochloride - Google Patents
Process for preparing 1-methylhexahydro-4-azepinone hydrochloride Download PDFInfo
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- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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
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Abstract
본 발명은 천식 및 알레르기 비염 치료제인 아젤라스틴 염산염의 핵심 중간체인 화학식 1의 1-메틸헥사히드로-4-아제피논 염산염의 새로운 제조방법에 관한 것이다.The present invention relates to a novel process for preparing 1-methylhexahydro-4-azpinone hydrochloride of formula 1, which is a key intermediate of azelastine hydrochloride, a therapeutic agent for asthma and allergic rhinitis.
본 발명에서 아젤라스틴 염산염의 핵심 중간체인 화학식 1의 1-메틸헥사히드로-4-아제피논 염산염을 화학식 5의 알킬 4-[(2-시아노-에틸)-메틸-아미노]부트릭 에스테르를 출발물질로 하여 디엑크만(Dieckmann) 반응을 이용하여 고수율로 간편하고 경제적으로 합성하였다.In the present invention, 1-methylhexahydro-4-azinone hydrochloride of formula 1, which is a key intermediate of azelastine hydrochloride, is substituted with alkyl 4-[(2-cyano-ethyl) -methyl-amino] butyric ester of formula 5. The starting material was synthesized simply and economically in high yield using the Dieckmann reaction.
[화학식 1][Formula 1]
[화학식 5][Formula 5]
Description
본 발명은 기관지 천식 및 알레르기성 비염, 피부염 치료제인 아젤라스틴 염산염의 핵심 중간체인 화학식 1의 1-메틸헥사히드로-4-아제피논 염산염을 간편하고 우수한 수율로 제조하는 새로운 제조방법에 관한 것이다.The present invention relates to a novel process for preparing 1-methylhexahydro-4-azinonon hydrochloride of formula (I), which is a key intermediate of azelastine hydrochloride, a therapeutic agent for bronchial asthma and allergic rhinitis, dermatitis.
본 발명에서는 아젤라스틴 염산염의 핵심 중간체인 화학식 1의 1-메틸헥사히드로-4-아제피논을 화학식 5의 알킬 4-[(2-시아노-에틸)-메틸-아미노]부트릭 에스테르를 출발물질로 하여 디엑크만 반응을 이용하여 고수율로 간편하고 경제적으로 합성하였다.In the present invention, 1-methylhexahydro-4-azinone of formula (I), which is a key intermediate of azelastine hydrochloride, is used to start alkyl 4-[(2-cyano-ethyl) -methyl-amino] butyric ester of formula (5). The material was synthesized simply and economically in high yield using the Diekmann reaction.
일본공개특허공보(JP 07-089936)에는 (2-알콕시카보닐에칠)-N-(3-알콕시카보닐프로필)알킬아민을 불활성 가스하에서 염기 존재하에 환화축합시킨 후 산처리하여 화학식 1의 1-메틸헥사히드로-4-아제피논을 제조하는 방법이 공지되어 있다. 상기 일본특허도 화학식 1의 1-메틸헥사히드로-4-아제피논을 고수율로 제조하기 위한 것이긴 하지만 수율이 여전히 미흡하고 용매를 크실렌을 사용함으로써 경비의 상승을 초래하며 높은 가열환류 온도(크실렌 b.p.: 137∼144℃, 톨루엔 b.p.: 110℃)로 인한 이유로 제조공정상의 어려움이 있었다.Is (2-alkoxycarbonyl to fill) Japanese Unexamined Patent Publication (JP 07-089936) - N - ( 3- alkoxycarbonyl-propyl) alkylamine of formula (I) by the acid treatment after condensation cyclization in the presence of a base under an inert gas Processes for preparing 1-methylhexahydro-4-azinone are known. Although the Japanese patent is also intended to prepare 1-methylhexahydro-4-azepone of Formula 1 in high yield, the yield is still insufficient, and the solvent is used to increase the cost by using xylene and high heating reflux temperature ( Xylene bp: 137-144 ° C., toluene bp: 110 ° C.) had difficulties in the manufacturing process.
이에 본 발명자는 화학식 5의 알킬 4-[(2-시아노-에틸)-메틸-아미노]-부트릭 에스테르를 출발물질로 하여 디엑크만 반응을 이용하여 환화축합 함으로써 고수율과 간편한 공정으로 1-메틸헥사히드로-4-아제피논을 합성하였다.Accordingly, the present inventors have a high yield and a simple process by cyclization condensation using Dieckman reaction using alkyl 4-[(2-cyano-ethyl) -methyl-amino] -butyric ester of Formula 5 as a starting material. -Methylhexahydro-4-azinone was synthesized.
디엑크만 반응(Dieckmann reaction)은 diester를 염기하에서 분자내 축합반응시켜 환 형태의 ketoester를 제조하는 반응을 말하며, 보통 디엑크만 반응을 수행하여 ketoester를 제조한 후 가수분해 하여 탈카르복시 반응을 수행하여 환 형태의 케톤을 제조하는데 많이 이용된다. 본 발명에서는 디엑크만 반응을 이용하여 화학식 1의 1-메틸헥사히드로-4-아제피논 염산염을 보다 간편한 공정으로 고수율로 제조함으로써 본 발명을 완성하였다.The Dieckmann reaction refers to a reaction in which a diester is intramolecularly condensed under a base to produce a cyclic ketoester. Usually, the Dieckmann reaction produces a ketoester by hydrolysis, followed by hydrolysis to perform a decarboxylation reaction. It is widely used to prepare a ketone in the form of a ring. In the present invention, the present invention was completed by preparing the 1-methylhexahydro-4-azinone hydrochloride of Formula 1 in a high yield using a Dieckman reaction in a simpler process.
[화학식 5][Formula 5]
상기 식에서 R은 메틸, 에틸, 프로필, 이소프로필, 부틸기를 나타낸다.In the formula, R represents a methyl, ethyl, propyl, isopropyl, butyl group.
화학식 5의 알킬 4-[(2-시아노-에틸-아미노]부트릭 에스테르를 합성하기 위한 도식은 다음과 같다.N-메틸피롤리돈으로 부터 유도된 화학식 2의N-메틸아미노부트릭산을 두가지 경로에 의하여 합성한다.The scheme for synthesizing alkyl 4-[(2-cyano-ethyl-amino] butyric ester of formula 5 is as follows: N -methylaminobutyric acid of formula 2 derived from N -methylpyrrolidone Is synthesized by two paths.
화학식 3의 화합물은 화학식 2의 화합물을 산 촉매하에서 에스테르화하여 제조한다. 이때 R은 메틸, 에틸, 프로필, 이소프로필, 부틸 등의 저급 알킬이며 산은 황산, 염산, 인산 등의 무기산과 파라-톨루엔술폰산, 벤젠술폰산, 메탄술폰산 등의 유기산이다. 이때 쓰이는 용매로는 메탄올, 에탄올, 이소프로판올, 부탄올 등의 저급 알코올이 직접 과량 사용되거나 벤젠, 톨루엔, 자일렌 등이 사용된다.Compounds of formula 3 are prepared by esterifying compounds of formula 2 under acid catalyst. In this case, R is lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl and the like, and acids are inorganic acids such as sulfuric acid, hydrochloric acid and phosphoric acid and organic acids such as para-toluenesulfonic acid, benzenesulfonic acid and methanesulfonic acid. At this time, as the solvent, a lower alcohol such as methanol, ethanol, isopropanol, butanol is directly used in excess, or benzene, toluene, xylene or the like is used.
화학식 5의 화합물은 화학식 3의 화합물을 유기 또는 무기 염기하에서 아크릴로니트릴을 사용하여 제조할 수 있다. 이때 용매는 메탄올, 에탄올, 프로판올, 이소프로판올, 부탄올 등의 저급 알코올 또는 테트라히드로푸란, 이염화메탄, 클로로포름,N,N-디메틸포름아미드 등을 사용할 수 있고, 염기로는 중조, 탄산나트륨, 탄산칼슘, 탄산칼륨 등의 무기 염기 또는 트리에틸아민,N-메틸몰폴린 등의 유기 염기일 수 있다. 반응온도는 0℃에서 각 용매의 환류 온도까지 이다. 이때 R은 메틸, 에틸, 프로필, 이소프로필, 부틸 등의 저급 알킬이다.The compound of formula 5 may be prepared using acrylonitrile under the organic or inorganic base. At this time, the solvent may be lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol, or tetrahydrofuran, methane dichloride, chloroform, N, N -dimethylformamide, and the like. Inorganic bases such as potassium carbonate or organic bases such as triethylamine and N -methylmorpholine. The reaction temperature is from 0 deg. C to the reflux temperature of each solvent. R is lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl.
또한, 화학식 5의 화합물은 화학식 4의 화합물을 거쳐서 제조할 수 있다. 화학식 4의 화합물은 화학식 2의 화합물을 염기 촉매하에서 아크릴로니트릴을 사용하여 합성할 수 있다. 이때 용매와 염기는 화학식 3에서 화학식 5의 화합물을 합성할 때와 같은 조건으로 수행할 수 있다. 화학식 5의 화합물은 화학식 4의 화합물을 에스테르화 하여 제조할 수 있으며 이때 사용하는 용매, 온도는 화학식 2의 화합물로부터 화학식 3의 화합물을 제조하는 경우와 같다.In addition, the compound of Formula 5 may be prepared via the compound of Formula 4. The compound of formula 4 can be synthesized using acrylonitrile under a base catalyst. In this case, the solvent and the base may be performed under the same conditions as those of synthesizing the compound of Chemical Formula 5 in Chemical Formula 3. The compound of Formula 5 may be prepared by esterifying the compound of Formula 4, wherein the solvent and temperature used are the same as the case of preparing the compound of Formula 3 from the compound of Formula 2.
화학식 1의 화합물인 1-메틸헥사히드로-4-아제피논 염산염은 화학식 5의 화합물로부터 디엑크만 반응과 가수분해를 통해 제조할 수 있다. 본 발명의 디엑크만 반응시 사용되는 염기는 수산화나트륨, 칼륨t-부톡사이드, 소듐 에톡사이드, 소듐 메톡사이드 등이며 용매로는 톨루엔을 사용하며 반응수행시 온도는 용매의 가열환류 온도에서 수행한다. 가수분해는 염기 또는 산을 촉매로 하여 수행되며 염기로는 수산화나트륨, 수산화칼륨 등을, 산 촉매로는 염산, 인산, 황산 등을 사용할 수 있다.1-Methylhexahydro-4-azinone hydrochloride, a compound of Formula 1, may be prepared from the compound of Formula 5 through Dieckman reaction and hydrolysis. The base used in the Diekman reaction of the present invention is sodium hydroxide, potassium t -butoxide, sodium ethoxide, sodium methoxide, and the like. Toluene is used as a solvent, and the reaction temperature is performed at the reflux temperature of the solvent. . Hydrolysis is performed using a base or an acid as a catalyst, and sodium hydroxide, potassium hydroxide, and the like may be used as the base, and hydrochloric acid, phosphoric acid, sulfuric acid and the like may be used as the acid catalyst.
[제조예 1][Production Example 1]
에틸 4-[(2-시아노-에틸)-메틸-아미노]-부트릭산 에스테르Ethyl 4-[(2-cyano-ethyl) -methyl-amino] -butyric ester
(4-[(2-Cyano-ethyl)-methyl-amino]-butyric acid ethyl ester)의 합성Synthesis of (4-[(2-Cyano-ethyl) -methyl-amino] -butyric acid ethyl ester)
N-메틸피롤리돈 100g을 물 500ml와 농염산 100ml와 함께 놓고 24시간 가열 환류한 다음 감압 증류하여 용매를 제거 후 감압 건조하여 화합물N-메틸아미노부트릭산(N-methyl amino butyric acid)을 얻었다.N-메틸아미노부트릭산을 에탄올 1.2L에 현탁시키고 0℃에서 냉각시키고 질소 기류하에 SOCl2(thionyl chloride) 142ml를 적가하였다. 이 온도를 계속 유지하면서 피리딘 300ml를 적가하였다. 실온에서 7시간 교반 후 감압 증류하여 조화합물N-메틸카보에톡시 아미노부트릭산을 얻은 후 정제과정 없이 에탄올 160ml, 아크릴로니트릴 173ml에 녹이고 0℃로 냉각 후 트리에틸아민 920ml를 적가하였다. 실온에서 10시간 교반 후 용매를 감압 증류하고 초산에틸 1L로 2회 추출한 후 무수 황산나트륨으로 탈수 여과하여 감압 증류한 다음 진공 증류하여 화합물 에틸 4-[(2-시아노-에틸)-메틸-아미노]-부트릭산 에스테르 155g을 얻었다. N-methyl-pyrrolidone 100g water 500ml and 100ml of concentrated hydrochloric acid with a place to reflux 24 hours and then was evaporated under reduced pressure and dried under reduced pressure to afford N after removal of the solvent - methyl amino acid unit trick (N -methyl amino butyric acid) a Got it. N -methylaminobutyric acid was suspended in 1.2 L of ethanol, cooled to 0 ° C. and 142 ml of SOCl 2 (thionyl chloride) was added dropwise under nitrogen stream. 300 ml of pyridine was added dropwise while maintaining this temperature. After stirring for 7 hours at room temperature, the mixture was distilled under reduced pressure to obtain crude compound N -methyl carboethoxy aminobutyric acid, which was dissolved in 160ml of ethanol and 173ml of acrylonitrile without purification, and cooled to 0 ° C, and 920ml of triethylamine was added dropwise. After stirring for 10 hours at room temperature, the solvent was distilled off under reduced pressure, extracted twice with 1 L of ethyl acetate, filtered by dehydration with anhydrous sodium sulfate, distillation under reduced pressure, and then vacuum distilled to remove the compound ethyl 4-[(2-cyano-ethyl) -methyl-amino]. 155 g of butyric acid ester were obtained.
수율 : 77%Yield: 77%
1H-NMR(CDCl3) : 1.27(3H, t,J=7.2Hz), 1.79(2H, quintet,J=7.2Hz), 2.27(3H, s), 1 H-NMR (CDCl 3 ): 1.27 (3H, t, J = 7.2 Hz), 1.79 (2H, quintet, J = 7.2 Hz), 2.27 (3H, s),
2.36(2H, t,J=7.2Hz), 2.44(2H, t,J=7.2Hz), 2.47(2H, t,J=7.2Hz),2.36 (2H, t, J = 7.2 Hz), 2.44 (2H, t, J = 7.2 Hz), 2.47 (2H, t, J = 7.2 Hz),
2.71(2H, t,J=7.2Hz), 4.13(2H, quartet,J=7.2Hz)2.71 (2H, t, J = 7.2 Hz), 4.13 (2H, quartet, J = 7.2 Hz)
[실시예 1]Example 1
1-메틸헥사히드로-4-아제피논 염산염의 합성Synthesis of 1-methylhexahydro-4-azpinone hydrochloride
질소기류하에 무수 톨루엔 6L에 칼륨t-부톡사이드 54.9g을 넣고 가열환류하고 곧바로 에틸4-[(2-시아노-에틸)-메틸-아미노]부트릭산에스테르(4-[(2-cyano-ethyl)-methyl-amino]-butyric acid ethyl ester) 150g을 무수 톨루엔 2.5L에 녹이고 60시간 동안 적가하였다. 적가완료 후 냉각한 다음 3N-HCl 200ml로 3회 추출 후 수층을 다시 24시간 가열환류 하였다. 냉각 후 감압 증류하여 용매를 제거하고 얼음냉각하에 탄산나트륨으로 pH=11로 맞춘다. 이염화메탄으로 4회 추출하고 무수 황산나트륨으로 탈수, 여과 감압 증류하여 조화합물을 얻었다. 얻어진 조화합물에 디에칠에테르 500ml를 가하고 무수 염산 가스를 통과시킨 후 생긴 결정을 여과하여 최종화합물 99g을 얻었다.Under nitrogen stream, 54.9 g of potassium t -butoxide was added to 6 L of anhydrous toluene, and the mixture was heated and refluxed immediately to give ethyl 4-[(2-cyano-ethyl) -methyl-amino] butyric acid ester (4-[(2-cyano-). 150 g of ethyl) -methyl-amino] -butyric acid ethyl ester) was dissolved in 2.5 L of anhydrous toluene and added dropwise for 60 hours. After completion of the dropwise cooling, the mixture was extracted three times with 200 ml of 3N-HCl, and the aqueous layer was heated to reflux for 24 hours. After cooling, the solvent was removed by distillation under reduced pressure, and adjusted to pH = 11 with sodium carbonate under ice cooling. Extracted four times with methane dichloride, dehydrated with anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain a crude compound. 500 ml of ethyl ether was added to the obtained crude compound, and crystals formed after passing through anhydrous hydrochloric acid gas were filtered to obtain 99 g of the final compound.
수율 : 80%Yield: 80%
m.p. : 166∼167℃m.p. : 166 to 167 ° C
1H-NMR(DMSO-d6) : 1.96(1H, m), 2.12(1H, m), 2.48∼2.265(3H, m), 1 H-NMR (DMSO-d 6 ): 1.96 (1H, m), 2.12 (1H, m), 2.48-2.265 (3H, m),
2.76(3H, d,J=3.85Hz), 3.16∼3.38(2H, m), 3.37∼3.50(3H, m), 11.53(1H, s)2.76 (3H, d, J = 3.85 Hz), 3.16-3.38 (2H, m), 3.37-3.50 (3H, m), 11.53 (1H, s)
13C-NMR(DMSO-d6): 210.3, 58.3, 51.3, 44.1, 42.4, 39.6, 20.3 13 C-NMR (DMSO-d 6 ): 210.3, 58.3, 51.3, 44.1, 42.4, 39.6, 20.3
본 발명은 천식 및 알레르기 비염치료제인 아젤라스틴 염산염의 핵심 중간체인 화학식 1의 1-메틸헥사히드로-4-아제피논의 새로운 제조방법에 관한 것으로 본 발명에서 화학식 5의 알킬 4-[(2-시아노-에틸)-메틸-아미노]-부트릭 에스테르를 출발물질로 하여 디엑크만 반응을 이용하여 환화축합 함으로써 고수율과 간편한 공정으로 1-메틸헥사히드로-4-아제피논을 합성할 수 있다.The present invention relates to a novel process for preparing 1-methylhexahydro-4-azinone of formula (I), which is a key intermediate of azelastine hydrochloride, a therapeutic agent for asthma and allergic rhinitis. 1-methylhexahydro-4-azepine can be synthesized by high yield and simple process by cyclization and condensation using Dieckman reaction with no-ethyl) -methyl-amino] -butyric ester as a starting material. .
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| KR10-2001-0050606A KR100421282B1 (en) | 2001-08-22 | 2001-08-22 | Process for preparing 1-methylhexahydro-4-azepinone hydrochloride |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4197241A (en) * | 1977-12-22 | 1980-04-08 | John Wyeth & Brother Limited | Hexahydroazepine, piperidine and pyrrolidine derivatives |
| JPH0789936A (en) * | 1993-09-24 | 1995-04-04 | Koei Chem Co Ltd | Production of 1-alkylhexahydroazepine-4-one |
| US5760221A (en) * | 1993-12-18 | 1998-06-02 | Asta Medica Aktiengesellschaft | Method for the preparation of hexahydroazepinones and hexahydroazepinoles |
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2001
- 2001-08-22 KR KR10-2001-0050606A patent/KR100421282B1/en active IP Right Grant
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4197241A (en) * | 1977-12-22 | 1980-04-08 | John Wyeth & Brother Limited | Hexahydroazepine, piperidine and pyrrolidine derivatives |
| JPH0789936A (en) * | 1993-09-24 | 1995-04-04 | Koei Chem Co Ltd | Production of 1-alkylhexahydroazepine-4-one |
| US5760221A (en) * | 1993-12-18 | 1998-06-02 | Asta Medica Aktiengesellschaft | Method for the preparation of hexahydroazepinones and hexahydroazepinoles |
Non-Patent Citations (1)
| Title |
|---|
| John Wiley & Sons Inc., Advanced organic chemistry,Book vol 4, 1992, p. 494 * |
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