KR20060104761A - Process for preparing lercanidipine hydrochloride - Google Patents
Process for preparing lercanidipine hydrochloride Download PDFInfo
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- KR20060104761A KR20060104761A KR1020050027175A KR20050027175A KR20060104761A KR 20060104761 A KR20060104761 A KR 20060104761A KR 1020050027175 A KR1020050027175 A KR 1020050027175A KR 20050027175 A KR20050027175 A KR 20050027175A KR 20060104761 A KR20060104761 A KR 20060104761A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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Abstract
본 발명은 하기 화학식 1의 레르카니디핀 염산염을 제조하는 방법에 관한 발명으로서, 상세하게는 a) 2,6-디메틸-5-메톡시카르보닐-4-(3-니트로페닐)-1,4-디히드로피리딘-3-카르복실산(화학식 2)과 디할라이드알킬포스포란 또는 디할라이드아릴포스포란으로부터 선택되는 할로겐화제(화학식 3)를 반응시켜 화학식 4의 카르복실산 할라이드를 생성시키는 단계; b) 화학식 4의 카르복실산 할라이드와 하기 화학식 5의 2-N-디메틸-N-(3,3-디페닐프로필)-1-아미노-2-프로필 알콜과의 에스테르화 반응에 의하여 화학식 1의 레르카니디핀을 제조하는 단계; c) 제조된 화학식 1의 레르카니디핀을 무수 염산염으로 분리하는 단계; 를 특징으로 한다. 본 발명에 따른 제조방법은 연속적인 반응에 의하여 높은 수율과 순도로서 레르카니디핀 무수 염산염을 제조할 수 있어 경제적인 장점이 있다.The present invention relates to a method for preparing lercanidipine hydrochloride of formula (1), specifically, a) 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4 Reacting the dihydropyridine-3-carboxylic acid (Formula 2) with a halogenating agent selected from dihalidealkylphosphorane or dihalidearylphosphorane (Formula 3) to produce a carboxylic acid halide of Formula 4; b) by the esterification of the carboxylic acid halide of formula 4 with 2-N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propyl alcohol of formula 5 Preparing lercanidipine; c) separating the prepared lercanidipine with anhydrous hydrochloride; It is characterized by. The production method according to the present invention is economically advantageous in that lercanidipine anhydrous hydrochloride can be prepared in high yield and purity by continuous reaction.
[화학식 1][Formula 1]
레르카니디핀, 레르카니디핀 염산염, 할로겐화제, 디할라이드알킬포스포란, 디할라이드아릴포스포란 Lercanidipine, lercanidipine hydrochloride, halogenating agent, dihalidealkylphosphorane, dihalidearylphosphoran
Description
본 발명은 레르카니디핀이라고 하는 하기 화학식 1의 메틸 1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸-1,4-디하이드로-2,6-디메틸-4-(3-니트로페닐)피리딘-3,5-디카르복실레이트의 염산염 제조방법에 관한 발명이다.The present invention relates to methyl 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl-1,4-dihydro-2,6-dimethyl of the following general formula (1) called lercanidipine. The invention relates to a method for preparing hydrochloride of 4- (3-nitrophenyl) pyridine-3,5-dicarboxylate.
[화학식 1][Formula 1]
화학식1의 메틸 1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸-1,4-디하이드로-2,6-디메틸-4-(3-니트로페닐)피리딘-3,5-디카르복실레이트(레르카니디핀이라고 함) 및 그 염산염은 미국특허공보 제4,705,797호에 공지된 바와 같이 디히 드로피리딘계 L-칼슘 채널 길항물질이고, 항고혈압제 및 안기나(인후 편도선의 염증 등)와 관상동맥 질환을 치료하는데 사용되는 물질로 잘 알려져 있으며, 높은 친유성과 높은 막 계수(Membrane coefficient)로 인하여 작용 지속 기간이 길어지고 혈관 선택성이 높아지는 특성을 나타낸다.Methyl 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl-1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) of formula Pyridine-3,5-dicarboxylate (called lercanidipine) and its hydrochloride are dihydropyridine-based L-calcium channel antagonists, as known in U.S. Patent No. 4,705,797, and include antihypertensive agents and Inflammation of the tonsils of the throat, etc.) and coronary artery disease are well known. Due to the high lipophilic and high membrane coefficients, the duration of action and the vascular selectivity are high.
상기 화학식 1의 레르카니디핀의 제조방법에 대하여 한국특허공보 제91-5231호에는 하기 반응식 1의 반응단계를 거쳐 화학식 1의 레르카니디핀을 제조하는 방법이 공지되어 있다.Korean Patent Publication No. 91-5231 discloses a method for preparing lercanidipine of Chemical Formula 1 through a reaction step of Scheme 1 below.
[반응식 1]Scheme 1
상기 반응식 1에 도시된 바와 같이 아미노 알콜(V)을 디케텐과 반응시켜 아세토아세테이트(VI)을 제조하고, 제조된 아세토아세테이트 화합물(VI)을 3-니트로벤잘알데히드와 반응시켜 α-아세틸-3-니트로페닐신나메이트(VII)를 제조하고, 이 를 메틸 3-아미노 크로토네이트와 고리화 반응을 통하여 화합물 (I)를 수득하는 방법으로서, 상기와 같은 공정에 따르면 최종단계에서 사용되는 Hanzsch 고리화반응의 특성에 의해 여러 가지 부산물이 생성되어, 이로 인해 원하는 화합물의 수득률이 감소하고, 부산물을 제거하기 위해서는 컬럼 크로마토그래피를 사용해야 하는 등 대규모 생산에 적용하기에 난점이 있는 정제기술을 요구하게 된다. 또한 수득되는 생성물은 흡습성이 있어 제약학적 조성물을 만드는 과정에서 취급하기 어려운 수화물(Hemi-Hydrated)인 무정형의 레르카니디핀 염산염으로 수득함에 있어서 수득률은 35%이고 전반적인 공정 수득률은 23%에 불과하다. As shown in Scheme 1, amino alcohol (V) was reacted with diketene to prepare acetoacetate (VI), and the acetoacetate compound (VI) was reacted with 3-nitrobenzalaldehyde to produce α -acetyl- A process for preparing 3-nitrophenylcinnamate (VII), which is obtained by cyclization with methyl 3-amino crotonate to obtain compound (I), according to the above process Hanzsch Due to the nature of the cyclization reaction, various by-products are produced, which reduces the yield of the desired compound and requires purification techniques that are difficult to apply to large-scale production, such as the use of column chromatography to remove the by-products. do. In addition, the obtained product is hygroscopic and is obtained in the form of amorphous lercanidipine hydrochloride, a hydrate (Hemi-Hydrated) which is difficult to handle in the preparation of a pharmaceutical composition, the yield is 35% and the overall process yield is only 23%.
한편 한국특허공보 제395441호에는 하기의 반응식 2의 반응단계를 거쳐 화학식 1의 레르카니디핀을 제조하는 방법이 공지되어 있다.Meanwhile, Korean Patent No. 395441 discloses a method for preparing lercanidipine of Chemical Formula 1 through a reaction step of Scheme 2 below.
[반응식 2]Scheme 2
상기 반응식 2에서 도시된 바와 같이 디클로로메탄 중에서 디메틸포름아미드를 촉매로 사용한 2,6-디메틸-5-메톡시카르보닐-4-(3-니트로페닐)-1,4-디히드로피리딘-3-카르복실산(II)의 할로겐화 반응을 통하여 카르복실산 클로라이드를 생성시 킨 후 2-N-디메틸-N-(3,3-디페닐프로필)-1-아미노-2-프로필 알콜(V)과 15시간동안 에스테르화 반응을 수행하고 생성된 화학식 1의 레르카니디핀을 염산염으로 분리하는 방법으로써, 상기의 제조방법은 무수의 비흡습성의 결정형인 레르카니디핀 염산염을 더 높은 수득률로 생성시키는 것이 가능하고, 부산물의 생성을 억제하는 것이 가능하나, 반응시간이 매우 길고, 결정형 레르카니디핀 염산의 정제 및 분리단계가 매우 복잡하다. 또한 산업적으로 사용하기에 쉽지 않은 화합물인 염화티오닐을 사용해야 하며, 이 화합물을 사용하기 위해 반드시 반응계가 무수 조건(Anhydrous condition) 하에서 제조해야 하는 문제점이 있다.2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3- using dimethylformamide as catalyst in dichloromethane as shown in Scheme 2 above Carboxylic acid chloride is produced through halogenation of carboxylic acid (II), followed by 2-N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propyl alcohol (V). By performing the esterification reaction for 15 hours and separating the resulting lercanidipine of the formula (1) with hydrochloride, the above production method is capable of producing anhydrous non-hygroscopic crystalline lercanidipine hydrochloride in higher yield. It is possible to suppress the production of by-products, but the reaction time is very long, and the purification and separation steps of crystalline lercanidipine hydrochloric acid are very complicated. In addition, thionyl chloride, which is a compound that is not easy to use industrially, must be used, and there is a problem that a reaction system must be prepared under anhydrous conditions in order to use the compound.
본 발명의 목적은 상기에서 언급한 바 있는 공지 방법의 비경제성, 비상용성 등의 단점을 극복할 수 있는 신규한 레르카니디핀 염산염의 제조 방법을 제공하는 것이며, 본 발명의 또 다른 목적은 2,6-디메틸-5-메톡시카르보닐-4-(3-니트로페닐)-1,4-디히드로피리딘-3-카르복실산과 산업적으로 사용하기에 어렵지 않은 디할라이드포스포란을 할로겐화제로 사용하여 반응시켜 카르복실산 할라이드를 생성시키고, 2-N-디메틸-N-(3,3-디페닐프로필)-1-아미노-2-프로필 알콜과의 에스테르화 반응을 짧은 시간 내에 완결하는 것을 특징으로 하는 제조방법을 제공하는 것이다.It is an object of the present invention to provide a novel method of preparing lercanidipine hydrochloride that can overcome the disadvantages of the above-mentioned known methods, such as inefficiency, incompatibility, and another object of the present invention is 2, Reaction with 6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid and dihalidephosphorane which is not difficult to industrially use as halogenating agent To form a carboxylic acid halide and to complete the esterification reaction with 2-N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propyl alcohol in a short time. It is to provide a manufacturing method.
본 발명은 종래의 레르카니디핀 염산염의 제조방법의 문제점을 해결하기 위 해 안출된 것으로서 본 발명에 따른 레르카니디핀 염산염의 제조방법은 a) 하기 화학식 2의 2,6-디메틸-5-메톡시카르보닐-4-(3-니트로페닐)-1,4-디히드로피리딘-3-카르복실산과 하기 화학식 3의 할로겐화제를 반응시켜 화학식 4의 카르복실산 할라이드를 생성시키는 단계; b) 화학식 4의 카르복실산 할라이드와 하기 화학식 5의 2-N-디메틸-N-(3,3-디페닐프로필)-1-아미노-2-프로필 알콜과의 에스테르화 반응에 의하여 화학식 1의 레르카니디핀을 제조하는 단계; c) 제조된 화학식 1의 레르카니디핀을 무수 염산염으로 분리하는 단계; 를 특징한다.The present invention has been made to solve the problems of the conventional method for preparing lercanidipine hydrochloride, the method for preparing lercanidipine hydrochloride according to the present invention is a) 2,6-dimethyl-5-methoxy of formula (2) Reacting carbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid with a halogenating agent of Formula 3 to produce a carboxylic acid halide of Formula 4; b) by the esterification of the carboxylic acid halide of formula 4 with 2-N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propyl alcohol of formula 5 Preparing lercanidipine; c) separating the prepared lercanidipine with anhydrous hydrochloride; It features.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 5][Formula 5]
(상기 식 중 R은 1 내지 6개의 탄소원자를 갖는 알킬 또는 아릴기를 나타내고, X는 할로겐을 나타낸다.)(Wherein R represents an alkyl or aryl group having 1 to 6 carbon atoms and X represents a halogen.)
본 발명에 따른 제조방법을 반응식으로 도시하면 하기의 반응식 3과 같이 나타낼 수 있다.When the manufacturing method according to the present invention is shown in Scheme 3, it may be represented as Scheme 3 below.
[반응식 3]Scheme 3
(상기 반응식 3에서, R은 1 내지 6개의 탄소원자를 갖는 알킬 또는 아릴기를 나타 내고, X는 할로겐을 나타낸다.)(In Scheme 3, R represents an alkyl or aryl group having 1 to 6 carbon atoms, and X represents a halogen.)
본 발명에 따른 레르카니디핀 염산염의 제조방법에 있어서 a) 단계에서 사용되는 카르복실산의 할로겐화제로는 디할로겐화 포스포란을 사용하며, 상기 할로겐화제는 직접 사용할 수 있고 원료화합물을 이용하여 반응 전에 제조하여 사용할 수 있다. 본 발명의 제조방법에서 사용되는 할로겐화를 예시하면 디클로로트리부틸포스포란, 디브로모트리부틸포스포란, 디요오드트리부틸포스포란 등의 디할라이드트리알킬포스포란, 디클로로트리페닐포스포란, 디브로모트리페닐포스포란, 디요오드트리페닐포스포란 등의 디할라이드트리아릴포스포란가 있으며, 바람직하기로는 디브로모트리페닐포스포란이며, 상기 할로겐화제의 사용량은 화학식 (II)의 화합물에 대해 동량 이상, 바람직하게는 1.05 내지 1.35 당량이다.In the method for preparing lercanidipine hydrochloride according to the present invention, as the halogenating agent of carboxylic acid used in step a), dihalogenated phospholane is used, and the halogenating agent can be used directly and prepared before the reaction using the raw material compound. Can be used. Examples of the halogenation used in the production method of the present invention include dihalide trialkylphosphoranes such as dichlorotributylphosphoran, dibromotributylphosphoran and diiotritributylphosphoran, dichlorotriphenylphosphoran and dibromo. Dihalidetriarylphosphorane, such as triphenylphosphorane and diiotritriphenylphosphoran, and preferably dibromotriphenylphosphoran, and the amount of the halogenating agent used is equal to or greater than that of the compound of formula (II), Preferably it is 1.05-1.35 equivalent.
할로겐화 단계에서 사용되는 용매의 예로는 디클로로메탄, 클로로포름, 1,2-디클로로에탄, 1,1-디클로로에탄 등과 같은 할로겐형 용매, 테트라히드로푸란, 1,2-디메톡시에탄 등과 같은 에테르형 용매, 벤젠 및 톨루엔과 같은 탄화수소형 용매가 있으며, 바람직하게는 디클로로메탄, 클로로포름, 1,2-디클로로에탄, 1,1-디클로로에탄 등과 같은 할로겐형 용매이다.Examples of the solvent used in the halogenation step include halogenated solvents such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1-dichloroethane, ether type solvents such as tetrahydrofuran, 1,2-dimethoxyethane, There are hydrocarbon type solvents such as benzene and toluene, preferably halogen type solvents such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1-dichloroethane and the like.
할로겐화 단계의 반응은 불활성 용매 중에서 -10 내지 40℃, 5분에서 12시간동안 수행되며, 바람직하게는 0 내지 10℃의 온도에서 2시간에서 6시간동안 수행된다. The reaction of the halogenation step is carried out in an inert solvent at -10 to 40 DEG C for 5 minutes to 12 hours, preferably at a temperature of 0 to 10 DEG C for 2 to 6 hours.
화학식 (II)의 화합물과 카르복실산의 할로겐화제(III)와의 반응에서 생성된 카르복실산 할라이드(IV)는 -10~ 내지 0℃로 온도를 유지하면서 상기에서 언급된 불활성 용매에 용해된 2-N-디메틸-N-(3,3-디페닐프로필)-1-아미노-2-프로필 알콜(V)을 첨가하여 에스테르화 반응이 완료될 때까지 2시간에서 4시간동안 지속시킨다. TLC 또는 HPLC와 같은 분석기술을 이용하여 반응이 완료됨을 알 수 있다. 상기 단계에서의 바람직한 반응조건은 0 내지 10℃의 온도에서 1시간에서 3시간동안 수행하는 것이다.The carboxylic acid halide (IV) produced in the reaction of the compound of formula (II) with the halogenating agent (III) of the carboxylic acid was dissolved in the above-mentioned inert solvent while maintaining the temperature between -10 and 0 ° C. -N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propyl alcohol (V) is added and continued for 2 to 4 hours until the esterification reaction is complete. It can be seen that the reaction is completed using analytical techniques such as TLC or HPLC. Preferred reaction conditions in this step is to carry out for 1 to 3 hours at a temperature of 0 to 10 ℃.
본 발명에 따른 제조방법은 할로겐화 단계인 a) 단계와 에스테르화 반응인 b) 단계를 하나의 반응기에서 동일 용매조건하에서 분리하지 않고 연속적으로 진행하는 것이 가능하다. In the production method according to the present invention, it is possible to continuously proceed the halogenation step a) and the esterification step b) without separating under the same solvent conditions in one reactor.
본 발명은 하기의 실시 예에 의해 더욱 구체적으로 설명되어지고, 본 발명의 영역 또는 분야가 이에 한정되는 것은 아니다.The invention is described in more detail by the following examples, which are not intended to limit the scope or field of the invention.
[실시예 1]Example 1
메틸 1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸-1,4-디하이드로-2,6-디메틸-4-(3-니트로페닐)피리딘-3,5-디카르복실레이트 염산염의 제조 Methyl 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl-1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3 Of 5-, dicarboxylate hydrochloride
디클로로메탄 25㎖에 2,6-디메틸-5-메톡시카르보닐-4-(3-니트로페닐)-1,4-디히드로피리딘-3-카르복실산 4.82g을 현탁하여 0~5℃에서 교반하고 이 용액에 온도를 유 지하면서 디브로모트리페닐포스포란 7.66g을 가하고 4시간동안 교반한다. 디클로로메탄 12㎖에 용해시킨 2-N-디메틸-N-(3,3-디페닐프로필)-1-아미노-2-프로필 알콜 4.32g을 30분 동안 적가하고 2시간동안 교반였다. 감압 증발로 용매를 제거 하고, 잔사에 초산에틸 100㎖을 가한다. 이 용액을 포화 염화나트륨 용액, 10% 탄산칼륨 용액, 포화 염화나트륨 용액, 1N HCl용액, 포화 염화나트륨 용액으로 각각 세척한 후 건조하고 감압 증발하여 초기 부피의 1/3정도로 농축시킨 후 소량의 종자 결정을 가하고 0~5℃에서 12시간동안 방치하였다. 생성된 고체를 여과 하고 이소프로판올에서 재결정하여 순수한 메틸 1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸-1,4-디하이드로-2,6-디메틸-4-(3-니트로페닐)피리딘-3,5-디카르복실레이트 염산염 7.32g(78%, HPLC purity 99.2%)을 얻었다.4.82 g of 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid was suspended in 25 ml of dichloromethane at 0-5 占 폚. Stir and add 7.66 g of dibromotriphenylphosphorane to the solution while maintaining the temperature and stir for 4 hours. 4.32 g of 2-N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propyl alcohol dissolved in 12 ml of dichloromethane was added dropwise for 30 minutes and stirred for 2 hours. The solvent was removed by evaporation under reduced pressure, and 100 ml of ethyl acetate was added to the residue. The solution was washed with saturated sodium chloride solution, 10% potassium carbonate solution, saturated sodium chloride solution, 1N HCl solution, saturated sodium chloride solution, dried, evaporated under reduced pressure, concentrated to about one third of the initial volume, and a small amount of seed crystals was added. It was left for 12 hours at 0-5 ° C. The resulting solid was filtered and recrystallized from isopropanol to give pure methyl 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl-1,4-dihydro-2,6-dimethyl- 7.32 g (78%, HPLC purity 99.2%) of 4- (3-nitrophenyl) pyridine-3,5-dicarboxylate hydrochloride were obtained.
mp : 186 ~ 187℃mp: 186 ~ 187 ℃
H1NMR (300MHz, DMSO) :1.5(s, 6H, CO(CH 3 )2CH2N) 2.6 (s, 3H, NCH 3 ), 2.1~3.2 (m, 13H), 3.3~4.1(m, 6H), 5.0 (s, 1H, 3-NO2phCH), 7.2~7.5(m, 10H, Ar), 7.6~7.8(m, 2H,Ar), 8.0~8.3(m, 2H, Ar), 9.5(bs, 1H), 9.4~10.7(bb, 1H, Ar)H 1 NMR (300MHz, DMSO): 1.5 (s, 6H, CO ( CH 3 ) 2 CH 2 N) 2.6 (s, 3H, N CH 3 ), 2.1 ~ 3.2 (m, 13H), 3.3 ~ 4.1 (m , 6H), 5.0 (s, 1H, 3-NO 2 phC H ), 7.2 to 7.5 (m, 10H, Ar), 7.6 to 7.8 (m, 2H, Ar), 8.0 to 8.3 (m, 2H, Ar) , 9.5 (bs, 1H), 9.4-10.7 (bb, 1H, Ar)
[실시예 2]Example 2
메틸 1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸-1,4-디하이드로-2,6-디메틸-4-(3-니트로페닐)피리딘-3,5-디카르복실레이트 염산염의 제조 Methyl 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl-1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3 Of 5-, dicarboxylate hydrochloride
디클로로메탄 7㎖에 트리페닐포스핀 2.1g을 녹인 용액을 0~5℃에서 30분 동안 교반하고 이 용액에 브롬(0.37㎖)을 디클로로메탄 3㎖에 녹인 용액을 30분 동안 적가하였다. 이 혼합용액을 30분 동안 같은 온도에서 교반하고 2,6-디메틸-5-메톡시카르보닐-4-(3-니트로페닐)-1,4-디히드로피리딘-3-카르복실산 2.17g을 가하고 4시간동안 교반였다. 이 혼합용액에 2-N-디메틸-N-(3,3-디페닐프로필)-1-아미노-2-프로필 알콜(1.94g)을 디클로로메탄 5㎖에 녹인 용액을 30분 동안 적가하고 2시간동안 교반하였다. 실시예 1과 같은 방법으로 순수한 메틸 1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸-1,4-디하이드로-2,6-디메틸-4-(3-니트로페닐)피리딘-3,5-디카르복실레이트 염산염 3.08g(73%, HPLC purity 99.3%)을 얻었다.A solution of 2.1 g of triphenylphosphine in 7 ml of dichloromethane was stirred at 0-5 ° C. for 30 minutes, and a solution of bromine (0.37 ml) in 3 ml of dichloromethane was added dropwise to the solution for 30 minutes. The mixed solution was stirred for 30 minutes at the same temperature and 2.17 g of 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid was added. It was added and stirred for 4 hours. To this mixed solution, a solution of 2-N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propyl alcohol (1.94 g) in 5 ml of dichloromethane was added dropwise for 30 minutes, followed by 2 hours. Was stirred. Pure methyl 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl-1,4-dihydro-2,6-dimethyl-4- ( 3.08 g (73%, HPLC purity 99.3%) of 3-nitrophenyl) pyridine-3,5-dicarboxylate hydrochloride were obtained.
mp : 186~189℃mp: 186 ~ 189 ℃
본 발명의 공정은 기존 기술의 공정과 비교하여 보면 부산물이 거의 생성되지 않고 반응 시간의 단축 및 후 공정을 단순화 할 수 있으며, 분리 및 정제 공정이 매우 간단한 장점이 있으며, 레르카니디핀 염산염을 고순도, 고수율로 수득할 수 있게 되므로 공업적으로 매우 가치가 있다. Compared with the process of the prior art, the process of the present invention produces little by-products and can shorten the reaction time and simplify the post-process, and the separation and purification process has a very simple advantage, and the high purity of lercanidipine hydrochloride, It is very valuable industrially because it can be obtained in high yield.
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| WO2008082041A1 (en) * | 2006-12-29 | 2008-07-10 | Dongwoo Syntech Co., Ltd | Process for preparing lercanidipine hydrochloride |
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