KR20000063287A - A new process for amlodipine besylate - Google Patents

A new process for amlodipine besylate Download PDF

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KR20000063287A
KR20000063287A KR1020000034180A KR20000034180A KR20000063287A KR 20000063287 A KR20000063287 A KR 20000063287A KR 1020000034180 A KR1020000034180 A KR 1020000034180A KR 20000034180 A KR20000034180 A KR 20000034180A KR 20000063287 A KR20000063287 A KR 20000063287A
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formula
acid
amlodipine besylate
methyl
amlodipine
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KR100374405B1 (en
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안승호
조윤환
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강덕영
한국유나이티드제약 주식회사
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/08—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • 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

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

PURPOSE: A manufacturing method of amlodipine besylate of formula (1) is provided which simplifies existing process by synthesizing amlodipine besylate directly from a novel triazone compound of formula (5) in high yield of more than 90%. CONSTITUTION: A preparation method of amlodipine besylate(2-£(2-(1,3-dimethylhexahydro-2-oxo-1,3,5-triazine-5-yl)ethoxy)-methyl|-4-(2-chlorophenyl)-3- ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine) comprises the steps of: dissolving 5g(17mmol) of ethyl 4-£1,3-dimethylhexahydro-2-oxo-1,3,5-triazine-5-yl|acetoacetate in 50ml of isopropanol(or acoholic solvent like as methanol, ethanol); adding 2.33g of 2-chlorobenzaldehyde and circulating for 1hr; cooling to room temperature, adding small quantity of acetic acid to neutralize; adding 1.97g of methyl 3-aminochlotonate to the solution, and circulating for 18hrs; concentrating under decompression to get brown oily residue; performing silicagel column chromatography to get 4.5g of objective material.

Description

암로디핀 베실레이트의 제조방법{A new process for amlodipine besylate}Method for preparing amlodipine besylate {A new process for amlodipine besylate}

본 발명은 고혈압 치료제로서 유용한 암로디핀 베실레이트(amlodipine besylate)의 새롭고 개량된 제조방법에 관한 것이다.The present invention relates to a new and improved method for preparing amlodipine besylate useful as a therapeutic agent for hypertension.

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 공지되어 있으며, 여러가지 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 프탈이미드화합물로 부터 프탈이미드기를 제거하여 암로디핀을 제조한다. 제조된 암로디핀을 정제하기 위하여, 말레인산을 부가하여 암로디핀 말레이트로 전환하고, 이를 다시 염기로 처리하여 유리형태의 정제된 암로디핀을 얻을 수 있다.Amlodipine besylate material per se is already known and various 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 form amlodipine, or the phthalimide group is removed from the phthalimide compound of Formula 4 to form amlodipine. To prepare. 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 염들 중에서 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.Korean Patent Publication No. 95-6710 discloses that amlodipine besylate has a particularly excellent pharmaceutical property among various salts of amlodipine, and as a preparation method, a benzenesulfonic acid or an ammonium salt solution thereof in the inert solvent can be used to prepare amlodipine in the free base form. A method for recovering amlodipine besylate produced by reaction with is disclosed.

이러한 종래 방법으로 암로디핀 베실레이트를 제조하기 위해서는, 하기의 반응식 1에서 볼 수 있는 바와같이, 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 복잡할뿐만 아니라, 그 과정에서 목적물의 수율이 떨어지게 되는 등의 문제점이 있었다. 또한 수소화반응을 이용함으로써 이미 알려진 바와 같이 압축기체를 다루는 특수한 장치가 요구되며，또한 수소 및 금속촉매를 사용할 경우 상당한 위험성이 내포되어 있다．Therefore, at least four steps have to be processed, and thus, the manufacturing process is not only complicated, but the yield of the target product is reduced in the process. In addition, the use of hydrogenation reactions requires special equipment to deal with the compressor as already known, and there are significant risks when using hydrogen and metal catalysts.

그리고 대한민국 공개특허 제98-31367호에서는 화학식 3의 아지드 화합물을 2 당량이상의 벤젠술폰산과 금속 또는 금속염 촉매하에서 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 of 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 하기 반응식 2에서 볼 수 있는 바와 같이, 암로디핀의 아미노기를 트리틸기로 보호한 상태에서, 벤젠술폰산으로 처리한 후 트리틸기를 제거함으로써 암로디핀 베실레이트를 제조하는 방법이 개시되어 있다.On the other hand, US Patent No. 5,389,654 discloses a process for producing amlodipine besylate by removing trityl group after treatment with benzenesulfonic acid in the state in which the amino group of amlodipine is protected with a trityl group, as shown in Scheme 2 below. It is.

(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 해결하여, 새로운 중간체로부터 보다 단축된 공정으로 90 %이상의 고수율로 암로디핀 베실레이트를 제조하는 개량된 방법을 제공하고자 한다.Accordingly, the present invention is to solve the problems of the prior art, to provide an improved method for producing amlodipine besylate in a high yield of more than 90% in a shorter process from a new intermediate.

이를 위하여 본 발명은 하기 화학식 5의 신규의 트리아존 화합물을 2 당량 이상의 벤젠술폰산과 반응시키거나, 포화 암모늄클로라이드 수용액과 반응시킨 후 벤젠술폰산으로 반응시키는 것을 특징으로 하여 화학식 1의 암로디핀 베실레이트를 얻는 제조방법에 관한 것이다.To this end, the present invention is characterized by reacting a novel triazone compound of Formula 5 with two or more equivalents of benzenesulfonic acid, or a saturated ammonium chloride aqueous solution and then reacting with benzenesulfonic acid to obtain amlodipine besylate of Formula 1 It relates to a manufacturing method.

(반응식 3)(Scheme 3)

(화학식 5) (화학식 1)(Formula 5) (Formula 1)

이하, 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.

본 발명의 화학식 5의 트리아존 화합물은 새로운 화합물로서, 하기의 반응식 4에 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.The triazone compound of Chemical Formula 5 of the present invention was prepared as a new compound by the following Scheme 4. 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 4)(Scheme 4)

(화학식 6) (화학식 7)(Formula 6) (Formula 7)

(화학식 5) (화학식 1)(Formula 5) (Formula 1)

본 발명에 있어서 벤젠술폰산은 화학식 5의 출발물질 1 몰당 2 당량 이상 사용하는 것이 바람직하다. 본 발명의 방법에 있어서는 통상의 유기용매 또는 유기용매와 물과의 혼합용매를 반응용매로 사용할 수 있다.In the present invention, it is preferable to use benzenesulfonic acid at least 2 equivalents per mole of the starting material of the formula (5). In the method of the present invention, a conventional organic solvent or a mixed solvent of organic solvent and water can be used as the reaction solvent.

유기용매의 예로는 메탄올, 에탄올, 이소프로판올, 테트라하이드로푸란, 디옥산 및 아세토니트릴 등을 들 수 있다. 특히 바람직한 용매는 메탄올, 에탄올, 이소프로판올과 같은 알코올류와 테트라하이드로푸란이다.Examples of the organic solvent include methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile and the like. Particularly preferred solvents are alcohols such as methanol, ethanol and isopropanol and tetrahydrofuran.

본 발명의 중요한 특징은 출발물질로서 새로운 트리아존기를 포함하는 화학식 5의 출발물질을 사용함에 있다. 트리아존을 포함하는 출발물질은 벤젠술폰산, 포름산, 트리플루오로아세트산 등의 유기산과 포화암모늄클로라이드 수용액, 질산, 황산, 인산, 염산 등과 같은 무기산 촉매하에서 10 ~ 100 ℃에서 반응시키거나 통상의 비등 환류온도 및 환류조건 하에서 탈보호하여 중화과정을 거쳐 화학식 2의 암로디핀을 제조할 수 있다. 특히 바람직한 산촉매로는 탈보호와 동시에 암로디핀 베실레이트를 제조할 수 있는 벤젠술폰산을 사용하는 것이 바람직하다.An important feature of the present invention is the use of a starting material of formula (5) comprising a new triazone group as starting material. The starting material containing triazone is reacted at 10 to 100 ° C. under an organic acid catalyst such as benzenesulfonic acid, formic acid, trifluoroacetic acid, and an inorganic acid catalyst such as saturated aqueous ammonium chloride solution, nitric acid, sulfuric acid, phosphoric acid, hydrochloric acid, or the like at normal boiling reflux. Amlodipine of Formula 2 may be prepared by neutralization by deprotection under temperature and reflux conditions. As a particularly preferable acid catalyst, it is preferable to use benzenesulfonic acid which can simultaneously prepare dehydroprotection and amlodipine besylate.

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 화합물 확인을 위하여 기지의 방법으로 암로디핀 베실레이트를 합성하고, 합성된 암로디핀 베실레이트로부터 화학식 5의 화합물을 합성하여 비교하였다.To confirm the compound of formula 5 synthesized by 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(또는 메탄올, 에탄올과 같은 알코올성 용매) 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-아미노클로 토네이트 1.97 g을 가하여 18 시간동안 환류하였다. 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) isopropanol (or an alcoholic solvent such as methanol or ethanol) 50 g After dissolving in ml, 2.33 g of 2-chlorobenzaldehyde is added to reflux for 1 hour, and then cooled to room temperature to neutralize by adding a small amount of glacial acetic acid. To this solution was added 1.97 g of methyl 3-aminochlorotonate 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 암로디핀 베실레이트염 1 g을 테트라하이드로푸란 4 ml에 현탁하여 트리에틸아민 0.25 ml를 가하여 1 시간 동안 교반한다. 톨루엔 50 ml와 포화 포르말린 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 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=6.8ㅗHz, 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 이소프로판올 20 ml에 용해시킨 벤젠술폰산(90 %) 4.22 g을 1 시간 동안 적가한 후 가하여 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 4.22 g of benzenesulfonic acid (90%) dissolved 5 g of) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine in 30 ml of isopropanol and dissolved in 20 ml of isopropanol 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 = 14.6HZ, 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 말레이트 염을 제조하는 단계와 그 염을 유리염기 형태로 분리하는 종래 방법에 의한 두단계의 공정을 생략하고, 트리아존기를 포함하는 새로운 중간체를 출발물질로 하여 직접 암로디핀 베실레이트를 합성하므로, 공정이 단축되고 합성공정상의 위험도 또한 현저하게 감소함은 물론 종래의 금속환원제를 사용하는 방법에 의한 경우보다 향상된 수율(90 % 이상)은 물론 보다 환경친화적인 공정으로 암로디핀 베실레이트를 제조할 수 있다.According to the present invention, a step of preparing a maleate salt by reducing from a precursor of amlodipine and a two-step process by a conventional method of separating the salt into free base form are omitted, and a new intermediate including a triazone group is used as a starting material. By directly synthesizing amlodipine besylate, the process is shortened and the risk of the synthesis process is also significantly reduced, as well as an improved yield (90% or more) than the conventional method using a metal reducing agent, as well as a more environmentally friendly process. Amlodipine besylate can be prepared.

Claims (4)

하기의 화학식 5의 트리아존 화합물을 반응용매 존재하에 2 당량 이상의 벤젠술폰산과 산촉매 존재하 또는 부재하 반응시키는 것을 특징으로 하는 화학식 1의 암로디핀 베실레이트의 제조방법.A method for preparing amlodipine besylate of formula (1), wherein the triazone compound represented by the following formula (5) is reacted with two or more equivalents of benzenesulfonic acid in the presence of a reaction solvent, with or without an acid catalyst. (화학식 1)(Formula 1) (화학식 5) (Et: 에틸)(Et: ethyl) 제1항에 있어서, 상기 산촉매로는 벤젠술폰산, 포름산, 트리플루오로아세트산, 암모늄클로라이드, 염산, 질산, 황산, 또는 인산인 것을 특징으로 하는 제조방법.The method of claim 1, wherein the acid catalyst is benzene sulfonic acid, formic acid, trifluoroacetic acid, ammonium chloride, hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid. 제1항에 있어서, 반응용매로 메탄올, 에탄올, 이소프로판올, 테트라하이드로The method of claim 1, wherein the reaction solvent is methanol, ethanol, isopropanol, tetrahydro 푸란, 다이옥산, 혹은 이들 반응용매와 물과의 혼합용매 중 어느 하나를 사용하는 것을 특징으로 하는 제조방법.A production method characterized by using any one of furan, dioxane, or a mixed solvent of these reaction solvents and water. 제1항에 있어서, 반응온도는 10 ℃ 내지 100 ℃에서 반응시키거나 비등환류 시키는 것 중 어느 하나를 선택적으로 사용하는 것을 특징으로 하는 제조방법.The method according to claim 1, wherein the reaction temperature is any one of reacting or boiling reflux at 10 ° C to 100 ° C.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002079158A1 (en) * 2001-03-29 2002-10-10 Hanmi Pharm. Co., Ltd. Novel amlodipine camsylate and method for preparing thereof
KR100538641B1 (en) * 2002-07-30 2005-12-22 씨제이 주식회사 An organic acid salt of amlodipine

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KR100379058B1 (en) * 1998-11-02 2003-11-28 에지스 지오기스제르기아르 알티. Manufacturing method of dihydropyridine derivative

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002079158A1 (en) * 2001-03-29 2002-10-10 Hanmi Pharm. Co., Ltd. Novel amlodipine camsylate and method for preparing thereof
US6936625B2 (en) 2001-03-29 2005-08-30 Hanmi Pharm. Co., Ltd. Amlodipine camsylate and method for preparing thereof
KR100538641B1 (en) * 2002-07-30 2005-12-22 씨제이 주식회사 An organic acid salt of amlodipine

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