KR100354806B1 - New intermediate for the preparation of amlodipine besylate and its process - Google Patents
New intermediate for the preparation of amlodipine besylate and its process Download PDFInfo
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
본 발명은 암로디핀 베실레이트를 제조하기 위한 신규 중간체 및 그의 제조방법에 관한 것으로, 화학식 5의 신규 중간체인 트리아존 화합물을 사용하면 화학식 1의 암로디핀 베실레이트를 간편한 공정으로 고수율로 얻을 수 있다.The present invention relates to a novel intermediate for preparing amlodipine besylate and a method for preparing the same, and by using a triazone compound as a novel intermediate of Formula 5, the amlodipine besylate of Formula 1 can be obtained in a high yield in a simple process.
(화학식 1)(Formula 1)
(화학식 5)(Formula 5)
(Et: 에틸)(Et: ethyl)
Description
본 발명은 고혈압 치료제로서 유용한 암로디핀 베실레이트의 제조시 유용한 신규의 트리아존 유도체 및 그의 제조방법에 관한 것이다.The present invention relates to novel triazone derivatives useful in the preparation of amlodipine besylate useful as therapeutic agents for hypertension and methods of making the same.
하기 화학식 1로 표시되는 암로디핀 베실레이트(amlodipine besylate)는 하기 화학식 2로 표시되는 암로디핀(amlodipine)의 벤젠술폰산염의 일반명칭으로서, 화학명은 3-에틸-5-메틸-2-[2-아미노에톡시메틸]-4-[2-클로로페닐]-6-메틸-1,4-디하이드로피리딘-3,5-디카르복실레이트 벤젠술폰산염이고, 장기간에 걸쳐 활성을 나타내는 디하이드로피리딘-디카르복실레이트 형태의 강력한 칼슘길항제(Calcium Channel Blocker)이다.Amlodipine besylate represented by the following formula (1) is a general name of benzenesulfonate salt of amlodipine (amlodipine) represented by the following formula (2), the chemical name is 3-ethyl-5-methyl-2- [2-aminoethoxy Methyl] -4- [2-chlorophenyl] -6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulfonate, dihydropyridine-dicarboxyl showing long term activity It is a powerful calcium channel blocker in the form of latex.
(화학식 1)(Formula 1)
(화학식 2)(Formula 2)
(Et: 에틸)(Et: ethyl)
암로디핀 베실레이트 물질 자체는 이미 공지이며, 여러 가지 제조방법들이 소개되어 있다. 먼저, 대한민국 특허공고 제87-809호에는 화학식 2의 암로디핀을 제조할 수 있는 여러가지 방법들이 개시되어 있다. 예를 들어, 화학식 3의 아지드 화합물을, 트리페닐포스핀이나 아연 및 염산, 또는 H2/Pd등으로 환원시켜 암로디핀을 제조하거나 화학식 4의 프탈이미드화합물로부터 프탈이미드기를 제거하여 암로디핀을 제조한다. 제조된 암로디핀을 정제하기 위하여, 말레인산을 부가하여 암로디핀 말레이트로 전환하고, 이를 다시 염기로 처리하여 유리형태의 정제된 암로디핀을 얻을 수 있다.The amlodipine besylate material itself is already known and several preparation methods are introduced. First, Korean Patent Publication No. 87-809 discloses various methods for preparing amlodipine of Formula 2. For example, the azide compound of Formula 3 is reduced to triphenylphosphine, zinc and hydrochloric acid, or H 2 / Pd to prepare amlodipine, or the phthalimide group is removed from the phthalimide compound of Formula 4 Manufacture. In order to purify the prepared amlodipine, maleic acid may be added to convert to amlodipine maleate, which may then be treated with a base to obtain purified amlodipine in the free form.
(화학식 3)(Formula 3)
(화학식 4)(Formula 4)
(Et: 에틸)(Et: ethyl)
그리고 대한민국 특허공고 제95-6710호에서는, 암로디핀의 여러가지 염들중And in Korean Patent Publication No. 95-6710, among the various salts of amlodipine
에서 암로디핀 베실레이트가 특이하게 우수한 약제학적 특성을 갖는다고 밝히고, 그 제조방법으로서 유리염기 형태의 암로디핀을 불활성용매 중에서 벤젠술폰산 또는 그의 암모늄염 용액과 반응시켜 생성된 암로디핀 베실레이트를 회수하는 방법을 개시하고 있다.Discloses a method for recovering amlodipine besylate produced by reacting amlodipine in free base form with benzenesulfonic acid or its ammonium salt solution in an inert solvent. have.
이러한 종래 방법으로 암로디핀 베실레이트를 제조하기 위해서는, 하기의 반응식 1에서 볼 수 있는 바와 같이, 먼저 화학식 3의 아지드화합물을 환원시켜 암로디핀 염기를 제조하고, 이어서 암로디핀 말레이트를 이용하여 정제된 유리형태의 암로디핀을 얻은 다음, 이를 다시 벤젠술폰산과 반응시켜 암로디핀 베실레이트를 수득하게 된다.In order to prepare amlodipine besylate by this conventional method, as can be seen in Scheme 1 below, the azide compound of Formula 3 is first reduced to prepare amlodipine base, and then purified glass form using amlodipine maleate. Amlodipine is obtained and then reacted with benzenesulfonic acid again to obtain amlodipine besylate.
(반응식 1)(Scheme 1)
(화학식 3) (화학식 2)(Formula 3) (Formula 2)
(화학식 2)(Formula 2)
(화학식 1) (Et: 에틸)(Et: ethyl)
따라서, 적어도 4 단계 이상의 공정을 거쳐야 하므로 제조과정이 복잡할뿐만아니라, 그 과정에서 목적물의 수율이 떨어지게 되는 등의 문제점이 있었다. 또한 수소화반응을 이용함으로써 이미 알려진 바와같이 압축기체를 다루는 특수한 장치가 요구되며，또한 수소 및 금속촉매를 사용할 경우 상당한 위험성이 내포되어 있다．Therefore, there is a problem that the manufacturing process is not only complicated, but the yield of the target drops in the process because it must go through at least four steps. In addition, the use of hydrogenation reactions requires special equipment to deal with the compressor as is known, and there is a significant risk of using hydrogen and metal catalysts.
그리고 대한민국 공개특허 제98-31367호에서는 화학식 3의 아지드 화합물을 2 당량이상의 벤젠술폰산과 금속 또는 금속염 촉매 하에서 반응시켜 화학식 1의 암로디핀 베실레이트를 제조하는 방법이 개시되어 있다. 아지드화합물을 사용하는 이러한 종래의 방법들은 아지드 화합물류의 폭발성(C.A. 105, 11321t)으로 인하여 또한 상당한 위험성이 내포되어 있다. In Korean Patent Application Laid-Open No. 98-31367, there is disclosed a method of preparing amlodipine besylate of Chemical Formula 1 by reacting an azide compound represented by Chemical Formula 3 with two equivalents of benzenesulfonic acid under a metal or metal salt catalyst. These conventional methods using azide compounds also pose significant risks due to the explosive nature of the azide compounds (C.A. 105, 11321t).
한편, 미합중국 특허 제5,389,654호에는 암로디핀의 아미노기를 트리틸기로 보호한 상태에서, 벤젠술폰산으로 처리한 후 트리틸기를 제거함으로써 암로디핀 베실레이트를 제조하는 제3의 방법이 개시되어 있다.U.S. Pat.
(반응식 2)(Scheme 2)
그러나 이러한 방법에서도, 정제공정이 까다롭고 복잡하며, 수율도 저조한 문제점이 있었다.However, even in this method, the purification process is difficult and complicated, the yield was also a problem.
이에, 본 발명에서는 종래기술이 가지는 문제점을 해결하고자, 새로운 중간체로부터 보다 단축된 공정으로 90 %이상의 고수율로 암로디핀 베실레이트를 제조하는 방법을 연구하던중, 신규의 합성중간유도체인 하기 화학식 5의 트리아존 화합물을 합성하기에 이르렀는바, 본 발명의 신규 중간유도체를 합성에 이용하면 종래방법 보다 간편한 공정으로 고수율로 합성이 가능하였다.Thus, in the present invention, to solve the problems of the prior art, while studying a method for producing amlodipine besylate in a high yield of more than 90% by a shorter process from a new intermediate, a novel synthetic intermediate derivative of the formula (5) Since the triazone compound was synthesized, the new intermediate derivative of the present invention was synthesized in a high yield by a simpler process than the conventional method.
(화학식 5)(Formula 5)
Et: 에틸(ethyl)Et: ethyl
본 발명의 암로디핀 베실레이트의 제조시 유용한 신규의 트리아존 화합물은 하기의 화학식 5의 구조를 갖는 화합물로서 그 합성공정을 요약하면 다음과 같다.The novel triazone compounds useful in the preparation of the amlodipine besylate of the present invention are compounds having the structure of Formula 5 below.
(화학식 5)(Formula 5)
Et: 에틸(ethyl)Et: ethyl
화학식 5의 트리아존 화합물은 새로운 화합물로서 하기의 반응식 3에 의하여 제조되었다. 일급 아미노기를 보호하는 공정은 이미 알려진 공정으로, J. Org. Chem. 1992, 57, 6239와 유사한 공정에 의해 제조하였다. 화학식 5의 트리아존 화합물은 일반적인 한츠(Hantzsch) 합성법에 의해 합성하였다.Triazone compound of Formula 5 was prepared according to Scheme 3 below as a new compound. The process of protecting the primary amino group is a known process, J. Org. Chem. Prepared by a process similar to 1992, 57, 6239. Triazone compounds of Formula 5 were synthesized by a general Hanzsch synthesis method.
(반응식 3)(Scheme 3)
(화학식 6) (화학식 7)(Formula 6) (Formula 7)
(화학식 5) (화학식 1)(Formula 5) (Formula 1)
Et: 에틸(ethyl)Et: ethyl
즉, 상기 반응식 3에 따라 에탄올아민을 출발물질로하여 화학식 6의 화합물을 경유하여 케토에스테르기가 도입된 화학식 7의 화합물을 제조한후, 얻어진 화학식 7의 화합물인 에틸 4-[1,3-디메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일]아세토아세테이트를 저급알코올과 같은 유기용매에 용해시킨후 2-클로로벤즈알데히드를 가하여 환류, 중화한 용액에 메틸 3-아미노클로토네이트를 가하여 다시 환류시키고 감압, 농축하여 화학식 5의 신규한 트리아존 화합물을 제조하는 것이다.That is, according to Scheme 3, a ethanolamine is used as a starting material, and then a compound of Formula 7 having a keto ester group introduced therein is obtained through the compound of Formula 6, and then ethyl 4- [1,3-dimethyl is a compound of Formula 7 obtained. Hexahydro-2-oxo-1,3,5-triazin-5-yl] acetoacetate was dissolved in an organic solvent such as lower alcohol, and 2-chlorobenzaldehyde was added to reflux to neutralize the solution with methyl 3-aminochloro. Tonic acid is added again to reflux, and the resultant is concentrated under reduced pressure to prepare a novel triazone compound represented by Chemical Formula 5.
본 발명에서의 저급알코올과 같은 유기용매로는 메탄올, 에탄올 또는 이소프로판올이 속하며, 이중 이소프로판올이 합성에 더욱 적합하였다.Organic solvents such as lower alcohols in the present invention include methanol, ethanol or isopropanol, of which isopropanol was more suitable for synthesis.
본 발명에 따른 화합물의 제조방법을 하기의 실시예로서 보다 상세히 설명한다. 그러나 이들 실시예에 의하여 본 발명의 영역 또는 분야를 제한하고자 하는 것은 아니다.The preparation method of the compound according to the present invention is described in more detail by the following examples. However, these examples are not intended to limit the scope or field of the present invention.
본 발명에 의하여 합성된 화학식 5의 화합물의 확인을 위하여 기지의 방법으로 암로디핀 베실레이트를 합성하고, 합성된 암로디핀 베실레이트로부터 화학식 5의 화합물을 합성하여 비교하였다.In order to identify the compound of formula 5 synthesized according to the present invention, amlodipine besylate was synthesized by a known method, and the compound of formula 5 was synthesized from the synthesized amlodipine besylate and compared.
(실시예 1)(Example 1)
2-[(2-(1,3-디메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시)-메틸]-4-(2-클로로페닐)-3-에톡시카보닐-5-메톡시카보닐-6-메틸-1,4-디하이드로피리딘의 제조방법2-[(2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy) -methyl] -4- (2-chlorophenyl) -3- Process for preparing ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine
에틸 4-[1,3-디메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일]아세토아세테이트(화학식 7) 5 g을 이소프로판올 50 ml에 녹인 후 2-클로로벤즈알데히드 2.33 g을 가하여 1 시간 동안 환류시킨 후 실온으로 냉각하여 소량의 빙초산을 가해 중화한다. 이 용액에 메틸 3-아미노클로토네이트 1.97 g을 가하여 18 시간동안 환류 하였다. 반응용액을 감압농축하여 갈색 오일성 잔사를 얻는다. 잔사는 일반적인 실리카겔 칼럼크로마토그래피를 통해 오일성의 화학식 5의 표제화합물 4.5 g을 얻는다.(수율: 52 %)5 g of ethyl 4- [1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl] acetoacetate (Formula 7) were dissolved in 50 ml of isopropanol, and 2.33 g of 2-chlorobenzaldehyde. The mixture was refluxed for 1 hour, cooled to room temperature, and neutralized by addition of a small amount of glacial acetic acid. To this solution was added 1.97 g of methyl 3-aminoclotonate and refluxed for 18 hours. The reaction solution is concentrated under reduced pressure to give a brown oily residue. The residue was subjected to general silica gel column chromatography to obtain 4.5 g of an oily title compound of formula 5 (yield: 52%).
1H NMR(CDCl3): δ1.18(t, 3H, J=6.8Hz, OCH2CH3), 2.30(s, 3H, C-6), 2.90(s, 6H, NCH3), 3.05(t, 2H, J=4.8Hz, OCH2CH2N), 3.61(s, 3H, OCH3), 3.67(t, 2H, J=4.8Hz, OCH2CH2N), 4.05(q, 2H, J=7.2Hz, OCH2CH3), 4.21(s, 4H, NCH2N), 4.76(m, 2H, CCH2O), 5.40(s, 1H, C-4), 7.05-7.44(m, 4H, Ar) 1 H NMR (CDCl 3 ): δ 1.18 (t, 3H, J = 6.8 Hz, OCH 2 CH 3 ), 2.30 (s, 3H, C-6), 2.90 (s, 6H, NCH 3 ), 3.05 ( t, 2H, J = 4.8 Hz, OCH 2 CH 2 N), 3.61 (s, 3H, OCH 3 ), 3.67 (t, 2H, J = 4.8 Hz, OCH 2 CH 2 N), 4.05 (q, 2H, J = 7.2 Hz, OCH 2 CH 3 ), 4.21 (s, 4H, NCH 2 N), 4.76 (m, 2H, CCH 2 O), 5.40 (s, 1H, C-4), 7.05-7.44 (m, 4H, Ar)
(실시예 2)(Example 2)
2-[(2-(1,3-디메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시)-메틸]-4-(2-클로로페닐)-3-에톡시카보닐-5-메톡시카보닐-6-메틸-1,4-디하이드로피리딘의 제조방법2-[(2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy) -methyl] -4- (2-chlorophenyl) -3- Process for preparing ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine
기지의 방법에 의하여 제조된 시중 암로디핀 베실레이트염 1 g을 테트라하이드로푸란 4 ml에 현탁하여 트리에틸아민 0.25 ml를 가하여 1 시간 동안 교반한다. 톨루엔 50 ml와 포화포르말린 수용액 8 ml, 1,3-디메틸우레아 0.16 g을 가하여 3 시간동안 아조트로픽 증류하여 물을 완전히 제거한다. 이 용액을 감압증류하여 테트라하이드로푸란을 제거하고 증류수로 2 회 세척한다. 무수 마그네슘설페이트를 이용하여 잔존하는 물을 제거하고 감압농축하여 오일성의 잔사를 얻는다. 잔사는 일반적인 실리카겔 칼럼크로마토그래피를 통해 화학식 5의 표제화합물 0.9 g을 얻는다.(수율 : 99 %)1 g of commercial amlodipine besylate salt prepared by a known method is suspended in 4 ml of tetrahydrofuran, 0.25 ml of triethylamine is added, and stirred for 1 hour. 50 ml of toluene, 8 ml of saturated formalin aqueous solution, and 0.16 g of 1,3-dimethylurea were added thereto, followed by azotropic distillation for 3 hours to completely remove water. The solution is distilled under reduced pressure to remove tetrahydrofuran and washed twice with distilled water. The remaining water is removed using anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oily residue. The residue was subjected to general silica gel column chromatography to obtain 0.9 g of the title compound of formula (5). (Yield: 99%)
1H NMR(CDCl3): δ1.18(t, 3H, J=6.8Hz, OCH2CH3), 2.30(s, 3H, C-6), 2.90(s, 6H, NCH3), 3.05(t, 2H, J=4.8Hz, OCH2CH2N), 3.61(s, 3H, OCH3), 3.67(t, 2H, J=4.8Hz, OCH2CH2N), 4.05(q, 2H, J=7.2Hz, OCH2CH3), 4.21(s, 4H, NCH2N), 4.76(m, 2H, CH2OCH2CH2NH2), 5.40(s, 1H, C-4), 7.05-7.44(m, 4H, Ar) 1 H NMR (CDCl 3 ): δ 1.18 (t, 3H, J = 6.8 Hz, OCH 2 CH 3 ), 2.30 (s, 3H, C-6), 2.90 (s, 6H, NCH 3 ), 3.05 ( t, 2H, J = 4.8 Hz, OCH 2 CH 2 N), 3.61 (s, 3H, OCH 3 ), 3.67 (t, 2H, J = 4.8 Hz, OCH 2 CH 2 N), 4.05 (q, 2H, J = 7.2 Hz, OCH 2 CH 3 ), 4.21 (s, 4H, NCH 2 N), 4.76 (m, 2H, CH 2 OCH 2 CH 2 NH 2 ), 5.40 (s, 1H, C-4), 7.05 -7.44 (m, 4H, Ar)
(실시예 3)(Example 3)
암로디핀 베실레이트의 제조방법Method for preparing amlodipine besylate
실시예 1에서 얻은 2-[(2-1,3-디메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시)-메틸]-4-(2-클로로페닐)-3-에톡시카보닐-5-메톡시카보닐-6-메틸-1,4-디하이드로피리딘 5 g을 이소프로판올 30 ml에 용해시키고, 별도로 이소프로판올 20 ml에 용해시킨 벤젠술폰산(90 %) 4.22 g을 1 시간 동안 적가한 후, 6 시간동안 비등환류한다. 용액을 상온으로 냉각한 다음 감압농축시켰다. 이 잔류물에 에틸아세테이트 50 ml를 가하여 1 시간 동안 교반하고, 이 혼합물에 물 10 ml를 가하여 다시 3 시간 동안 교반 후 생성되는 고체를 감압여과하여 건조시켰다. 건조된 생성물은 메탄올에서 재결정시켜서 암로디핀 베실레이트 4.95 g을 수득하였다.(수율: 91 %) 융점: 199 ~ 202 ℃2-[(2-1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy) -methyl] -4- (2-chlorophenyl as obtained in Example 1 5 g of) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine was dissolved in 30 ml of isopropanol and separately dissolved in 20 ml of isopropanol (90%). 4.22 g is added dropwise for 1 hour followed by boiling reflux for 6 hours. The solution was cooled to room temperature and then concentrated under reduced pressure. 50 ml of ethyl acetate was added to the residue, followed by stirring for 1 hour. 10 ml of water was added to the mixture, followed by further stirring for 3 hours, and the resulting solid was dried under reduced pressure. The dried product was recrystallized in methanol to give 4.95 g of amlodipine besylate. (Yield: 91%) Melting Point: 199-202 캜
1H NMR(CDCl3): δ1.17(t, 3H, J=6.8Hz, OCH2CH3), 2.10(s, 3H, C-6), 3.09(br, s, 2H, OCH2CH2NH2), 3.56(s, 3H, OCH3), 3.63(br, S, 2H, OCH2CH2NH2), 4.03(q, 2H, J=6.8Hz, OCH2CH3), 4.63(q, 2H, J=14.6Hz, CH2OCH2CH2NH2), 5.33(s, 1H, C-4), 6.9-7.9(m, 7H, Ar), 7.85(dd, 2H, J=7.5Hz, Ar), 8.01(br, s, 3H, NH2) 1 H NMR (CDCl 3 ): δ 1.17 (t, 3H, J = 6.8 Hz, OCH 2 CH 3 ), 2.10 (s, 3H, C-6), 3.09 (br, s, 2H, OCH 2 CH 2 NH 2 ), 3.56 (s, 3H, OCH 3 ), 3.63 (br, S, 2H, OCH 2 CH 2 NH 2 ), 4.03 (q, 2H, J = 6.8 Hz, OCH 2 CH 3 ), 4.63 (q , 2H, J = 14.6 Hz, CH 2 OCH 2 CH 2 NH 2 ), 5.33 (s, 1H, C-4), 6.9-7.9 (m, 7H, Ar), 7.85 (dd, 2H, J = 7.5 Hz , Ar), 8.01 (br, s, 3H, NH 2 )
본 발명에 의하면 암로디핀의 전구체로부터 환원하여 말레이트를 제조하는 단계와 그 염을 유리염기 형태로 분리하는 종래 방법에 의한 두단계의 공정을 생략하고, 트리아존기를 포함하는 새로운 중간체(화학식 5 유도체)를 출발물질로하여 직접 암로디핀 베실레이트를 합성하므로, 공정이 단축되고 합성공정상의 위험도 또한 현저하게 감소함은 물론 종래의 금속환원제를 사용하는 방법에 의한 경우보다 향상된 수율은 물론 보다 환경친화적인 공정으로 암로디핀 베실레이트를 제조할 수 있는 새로운 합성중간체인 화학식 5의 트리아존 화합물을 얻을 수 있는 특장점이 있다.According to the present invention, a new intermediate comprising a triazone group is omitted, omitting the two-step process by the conventional method of reducing maleate by reducing the precursor of amlodipine and separating the salt into a free base form. Since amlodipine besylate is directly synthesized using as a starting material, the process is shortened and the risk of the synthesis process is also significantly reduced, as well as an improved yield and a more environmentally friendly process than the conventional method using a metal reducing agent. There is a merit of obtaining a triazone compound represented by Chemical Formula 5, which is a new synthetic intermediate capable of producing amlodipine besylate.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5352684A (en) * | 1990-04-10 | 1994-10-04 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Pyridines as medicaments |
| US5438145A (en) * | 1992-11-26 | 1995-08-01 | Lek, Tovarna Farmecevtskih In Kemicnih Izdelkov | Process for the preparation of amlodipine benzenesulphonate |
| KR20000030984A (en) * | 1998-11-02 | 2000-06-05 | 사바 키스 | Method of preparation of dihydropyridine derivatives |
| WO2001002360A1 (en) * | 1999-07-05 | 2001-01-11 | Richter Gedeon Vegyészeti Gyár Rt. | Process for preparing amlodipine benzenesulphonate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5352684A (en) * | 1990-04-10 | 1994-10-04 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Pyridines as medicaments |
| US5438145A (en) * | 1992-11-26 | 1995-08-01 | Lek, Tovarna Farmecevtskih In Kemicnih Izdelkov | Process for the preparation of amlodipine benzenesulphonate |
| KR20000030984A (en) * | 1998-11-02 | 2000-06-05 | 사바 키스 | Method of preparation of dihydropyridine derivatives |
| WO2001002360A1 (en) * | 1999-07-05 | 2001-01-11 | Richter Gedeon Vegyészeti Gyár Rt. | Process for preparing amlodipine benzenesulphonate |
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