KR102220011B1 - Method for preparing azilsartan with environment-friendly solvent, and key intermediate compounds thereof - Google Patents
Method for preparing azilsartan with environment-friendly solvent, and key intermediate compounds thereof Download PDFInfo
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- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
Description
본 발명은 효율적인 One-pot 반응으로 핵심 중간체인 아질사탄 다이헥실아민 염을 합성한 후, 친환경 용매인 이온성 액체와 공융용매를 매개로 아질사탄 메독소밀을 합성하는 것에 관한 것이다.The present invention relates to synthesizing azyl satan dihexylamine salt, which is a core intermediate through an efficient one-pot reaction, and then synthesizing azyl satan medoxomil through an ionic liquid and a eutectic solvent, which are environmentally friendly solvents.
고혈압 치료제는 혈관 확장제와 교감 신경 억제제로 나뉘는데, 혈관 확장제의 한 종류인 ARB 계열의 치료제가 전체 고혈압 치료제 처방액 중 70% 이상으로 압도적으로 시장을 점유하고 있는 추세이다.Hypertension treatments are divided into vasodilators and sympathetic nerve inhibitors, and ARB-based treatments, a type of vasodilator, have overwhelmingly dominated the market with more than 70% of the total prescriptions for hypertension treatment.
이 중에서도, 아질사탄 메독소밀은 아래 도시한 것과 같은 구조의 칸데살탄의 화학구조를 변경한 물질로서, AT1 수용체에 강력하게 결합하고 천천히 해리하는 약리학적 특성을 가지는 물질이다.Among them, azylsartan medoxomil is a substance having a chemical structure of candesartan having a structure as shown below, and has a pharmacological property that strongly binds to AT1 receptors and dissociates slowly.
즉, 안지오텐신 Ⅱ와 AT1 수용체 간의 결합을 억제시킴으로써 혈관 수축을 일으키고, 알도스테론의 분비 작용을 억제하여 혈압을 낮추는 역할을 한다. 아질사탄 메독소밀은 동일 기전의 약물들에 비해 최저 효과/최대 효과비를 가지고 있어 24시간 혈압 조절에 유리하다는 장점을 가지고 있는 물질이다. 이에 따라, 아질사탄 메독소밀에 대한 수요가 점차 늘어가고 있으며, 이에 대한 경제적이고 효율적인 다양한 제조 방법이 연구되고 있는 실정이다.That is, by inhibiting the binding between angiotensin II and AT1 receptor, blood vessel constriction is caused, and aldosterone secretion is suppressed to lower blood pressure. Agilent Medoxomil is a substance that is advantageous in controlling blood pressure for 24 hours because it has the lowest/maximum effect ratio compared to drugs of the same mechanism. Accordingly, the demand for azil satan medoxomil is gradually increasing, and various economical and efficient manufacturing methods for this are being studied.
이에 대한 종래의 아질사탄 메독소밀의 제법에 대해서는, "Org . Process Res. Dev . 2013, 17, 1, 77-86" 에 하기 [반응식 1]에 따른 아질사탄 메독소밀 제조 방법을 들 수 있다.Regarding the conventional method for preparing azyl satan medoxomil for this, there may be mentioned a method for preparing azyl satan medoxomil according to the following [Reaction Scheme 1] in "Org . Process Res. Dev . 2013, 17, 1, 77-86".
[반응식 1][Scheme 1]
이 제법은 P-3 화합물을 히드록실 아민 수용액과 반응하여 아미도옥심 형태의 P-2 화합물을 제조하고, 다이메틸설폭사이드 용매 하에 N,N'-카르보닐다이이미다졸와 1,8-디아자비시클로[5.4.0]운데센-7 (DBU)를 첨가하여 고리화 반응을 진행시켜 P-1 화합물을 제조하였다. 제조한 P-1 화합물에 수산화나트륨 수용액을 가하여 가수분해 반응을 진행하여 아질사탄을 제조하였고, 메독소밀 알코올과 4-톨루엔 술포닐 클로라이드를 반응시켜 아질사탄메독소밀을 제조하였다.This preparation method reacts a P-3 compound with an aqueous hydroxyl amine solution to prepare an amidooxime-type P-2 compound, and N,N'-carbonyldiimidazole and 1,8-dia in a dimethylsulfoxide solvent. A cyclization reaction was carried out by adding zabicyclo[5.4.0]undecene-7 (DBU) to prepare a P-1 compound. To the prepared P-1 compound, an aqueous solution of sodium hydroxide was added to carry out a hydrolysis reaction to prepare azile satan, and azyl satan medoxomil was prepared by reacting medoxomil alcohol and 4-toluene sulfonyl chloride.
그러나, 아질사탄 메독소밀을 제조하기 위한 상기의 기술은 4단계의 긴 공정을 거쳐 아질사탄 메독소밀을 합성하였는 바, P-1 화합물을 합성할 때, 비싸고, 수분에 약한 불안정한 N,N'-카르보닐다이이미다졸(CDI) 시약을 사용한다는 문제점이 있다. 또한, 값이 저렴한 메독소밀 클로라이드를 사용하는 것이 아니라, 비싼 메독소밀 알코올을 사용하여 단가 상승의 문제를 초래하였다.However, the above-described technology for preparing azyl satan medoxomil synthesized azyl satan medoxomil through a long process of 4 steps.When synthesizing the P-1 compound, it was expensive and unstable N,N'- There is a problem in using a carbonyldiimidazole (CDI) reagent. In addition, not using medoxomil chloride, which is inexpensive, but using medoxomil alcohol, which is inexpensive, caused a problem of increasing the unit price.
또한, EP특허 제 2 119 715호에는 아질사탄메독소밀의 제조 방법이 기재되어 있다. 하기 [반응식 2]에 따라 아질사탄과 4-Chloro-1,3-dioxolan-2-one이 DMF 용매 하에 90℃에서 12시간 이상 반응하여 아질사탄 메독소밀을 합성하고, 컬럼크로마토그래피를 사용하여 정제하는 기술이다.In addition, EP Patent No. 2 119 715 discloses a method for producing azil satan medoxomil. According to the following [Reaction Scheme 2], azile satan and 4-Chloro-1,3-dioxolan-2-one reacted at 90° C. for 12 hours or longer in a DMF solvent to synthesize azile satan medoxomil, and purified using column chromatography. It is a skill to do.
[반응식 2][Scheme 2]
그러나, 이는 고온에서 반응이 진행되므로 불순물이 발생할 가능성이 농후하며, 컬럼크로마토그래피를 사용한 정제 공정을 포함하므로 대량 생산이 불가능하며, 상업적으로 용이하지 않다는 문제점을 가지고 있다. However, since the reaction proceeds at a high temperature, the possibility of occurrence of impurities is rich, and since it includes a purification process using column chromatography, mass production is impossible, and it is not commercially easy.
또한, EP 특허 제 0 520 423호에는 하기 [반응식 3]에 따라 P-4 화합물을 디메틸설폭사이드 용매 하에 히드록실 아민과 메톡사이드나트륨 또는 트리에틸아민을 반응시켜 P-3 화합물을 합성하고, 에틸클로로포메이트와 트리에틸아민 또는 피리딘을 반응시켜 P-2화합물을 합성한다. 또한, 자일렌 용매 하에서 환류하여 화합물 P-1을 제조하고, 수산화리튬 또는 수산화나트륨을 사용하여 아질사탄을 합성한다. 이 후, 메독소밀을 알코올을 사용하여 아질사탄 메독소밀을 합성한다. In addition, in EP Patent No. 0 520 423, a P-4 compound was synthesized by reacting a hydroxyl amine with sodium methoxide or triethylamine in a dimethyl sulfoxide solvent according to the following [Reaction Scheme 3], and ethyl The P-2 compound is synthesized by reacting chloroformate with triethylamine or pyridine. Further, by refluxing in a xylene solvent, compound P-1 is prepared, and nitrous satan is synthesized using lithium hydroxide or sodium hydroxide. After that, the medoxomil is synthesized by using alcohol to synthesize azile satan medoxomil.
[반응식 3][Scheme 3]
그러나, 이 제법은 5단계의 긴 공정을 거쳐서 아질사탄 메독소밀까지 합성을 진행해야 하며, 인체에 유해한 발암물질인 자일렌을 고온에서 반응시켜야 하므로, 대량생산에 적합하지 않은 프로세스이다.However, this method is a process that is not suitable for mass production, since it must undergo synthesis through a 5-step long process to nitrous oxide medoxomil and react with xylene, a carcinogen harmful to humans, at high temperatures.
또한, 에틸클로로포메이트 시약은 발암물질로 인체에 유해한 시약을 사용한다는 문제점을 가지고 있으며, 메독소밀 알코올을 사용하여 제조 단가상승의 문제를 초래하였다.In addition, the ethyl chloroformate reagent has a problem that it uses a reagent that is harmful to the human body as a carcinogen, and the use of medoxomil alcohol has caused a problem of an increase in manufacturing cost.
그러므로 안전하고, 효율적인 대량생산에 적합한 고순도 고수율의 아질사탄 메독소밀을 제조하는 공정 개발 연구가 필요하다.Therefore, research is needed to develop a process for producing high-purity, high-yield nitrite medoxomil suitable for safe and efficient mass production.
본 발명의 목적은 대량생산이 가능한 고순도 고수율의 아질사탄 메독소밀을 합성하는 방법을 제공하기 위함으로, 단계별로 진행되던 기존의 방법과 달리 효율적인 One-pot 반응으로 핵심 중간체인 Azilsartan dicyclohexylamine salt를 합성하고, 친환경 용매인 이온성 액체와 공융용매를 매개체로 사용하여 고순도, 고수율의 효율적인 Azilsartan Medoxomil을 제조하는 것이다.The object of the present invention is to provide a method for synthesizing high purity and high yield nitrous oxide medoxomil that can be mass-produced. Unlike the conventional method, which was carried out step by step, an efficient one-pot reaction to synthesize Azilsartan dicyclohexylamine salt, a key intermediate And, by using eco-friendly solvents such as ionic liquid and eutectic solvent as mediators, high-purity, high-yield efficient Azilsartan Medoxomil is prepared.
본원발명은 상술한 종래기술의 문제점을 해결하기 위해 안출된 것으로서,The present invention was devised to solve the problems of the prior art described above,
하기 화학식 1로 표현되는 아질사탄 디시클로헥실아민염 화합물을 제공한다:It provides an azylsartan dicyclohexylamine salt compound represented by the following Formula 1:
[화학식 1][Formula 1]
또한, 1) 하기 화학식 3의 화합물과 하기 화학식 4의 아민 화합물을 반응시켜 아질사탄 아민염을 제조하는 제1단계; 및In addition, 1) a first step of reacting a compound represented by the following formula (3) and an amine compound represented by the following formula (4) to prepare an nitrous satan amine salt; And
2) 상기 제조된 아질사탄 아민염을, 이온성 액체 또는 공융용매 하에서, 하기 화학식 5의 메독소밀 할라이드와 반응시키는 제2단계를 포함하는 것을 특징으로 하는, 하기 화학식 2의 아질사탄 메독소밀의 제조방법을 제공한다:2) Preparation of azyl satan medoxomil of the following formula (2), characterized in that it comprises a second step of reacting with the medoxomil halide of the following formula (5) under an ionic liquid or a eutectic solvent Provides a way:
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
여기서, R1, R2, 및 R3는, 각각 독립적으로, 수소, 탄소수 C1 내지 C6의 직쇄, 분지쇄, 또는 고리형의 알킬, 또는 그의 1가 알코올이며, R1, R2, 및 R3가 동시에 모두 수소인 경우는 제외한다.Here, R 1 , R 2 , and R 3 are each independently hydrogen, C 1 to C 6 straight chain, branched chain, or cyclic alkyl, or a monohydric alcohol thereof, R 1 , R 2 , And R 3 are both hydrogen at the same time, except for the case.
[화학식 5][Formula 5]
여기서, X는 불소, 염소, 브롬, 또는 요오드이다.Where X is fluorine, chlorine, bromine, or iodine.
또한, 하기 화학식 6으로 표현되고, 이온성 액체 또는 공융용매 하에서, 메독소밀 할라이드와 반응시켜 아질사탄 메독소밀의 합성에 사용되는 중간체 화합물을 제공한다:In addition, it is represented by the following formula (6), in an ionic liquid or a eutectic solvent, reacting with medoxomiyl halide to provide an intermediate compound used in the synthesis of azylsartan medoxomil:
[화학식 6][Formula 6]
여기서, R1, R2, 및 R3는, 각각 독립적으로, 수소, 탄소수 C1 내지 C6의 직쇄, 분지쇄, 또는 고리형의 알킬, 또는 그의 1가 알코올이며, R1, R2, 및 R3가 동시에 모두 수소인 경우는 제외한다.Here, R 1 , R 2 , and R 3 are each independently hydrogen, C 1 to C 6 straight chain, branched chain, or cyclic alkyl, or a monohydric alcohol thereof, R 1 , R 2 , And R 3 is both hydrogen at the same time, except for the case.
본 발명은 아질사탄 메독소밀 제조시 고리화 반응 및 가수분해 반응을 연속적으로 진행하여 반응 시간 단축 및 제조 단가 절감의 효과를 거두며, One-Pot 반응으로 핵심 중간체인 아질사탄 디사이클로헥실아민염을 합성하고, 유기 용매 대신 친환경적인 용매인 이온성 액체와 공융용매를 사용하여 50℃ 미만에서도 반응이 가능하도록 반응성을 증가시켜 유연물질의 생성을 감소시키고, 고순도, 고수율 및 경쟁력 있는 아질사탄 메독소밀을 대량 생산 할 수 있다.The present invention achieves the effect of shortening the reaction time and reducing the manufacturing cost by continuously proceeding the cyclization reaction and the hydrolysis reaction during the production of azyl satan medoxomil, and synthesizes azyl satan dicyclohexylamine salt, a key intermediate, through a one-pot reaction. And, instead of organic solvents, environmentally friendly solvents such as ionic liquids and eutectic solvents are used to increase reactivity so that reactions are possible at less than 50°C to reduce the generation of related substances, and to produce high purity, high yield, and competitive nitrous oxide medoxomil. Can be mass produced.
도 1은, 아질사탄의 XRD 그래프이다.
도 2는, 아질사탄 디사이클로헥실아민염의 XRD 그래프이다.
도 3은, 아질사탄 에탄올아민염의 XRD 그래프이다.1 is an XRD graph of azil satan.
Fig. 2 is an XRD graph of azylsartan dicyclohexylamine salt.
Fig. 3 is an XRD graph of the nitrite ethanolamine salt.
이하, 본 발명에 대해서 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은,The present invention,
1) 하기 화학식 3의 화합물과 하기 화학식 4의 아민 화합물을 반응시켜 아질사탄 아민염을 제조하는 제1단계; 및1) a first step of reacting a compound represented by the following formula (3) with an amine compound represented by the following formula (4) to prepare an nitrous acid amine salt; And
2) 상기 제조된 아질사탄 아민염을, 이온성 액체 또는 공융용매 하에서, 하기 화학식 5의 메독소밀 할라이드와 반응시키는 제2단계를 포함하는 것을 특징으로 하는, 하기 화학식 2의 아질사탄 메독소밀의 제조방법이다:2) Preparation of azyl satan medoxomil of the following formula (2), characterized in that it comprises a second step of reacting with the medoxomil halide of the following formula (5) under an ionic liquid or a eutectic solvent It's the way:
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
여기서, R1, R2, 및 R3는, 각각 독립적으로, 수소, 탄소수 C1 내지 C6의 직쇄, 분지쇄, 또는 고리형의 알킬, 또는 그의 1가 알코올이며, R1, R2, 및 R3가 동시에 모두 수소인 경우는 제외한다.Here, R 1 , R 2 , and R 3 are each independently hydrogen, C 1 to C 6 straight chain, branched chain, or cyclic alkyl, or a monohydric alcohol thereof, R 1 , R 2 , And R 3 is both hydrogen at the same time, except for the case.
[화학식 5][Formula 5]
여기서, X는 불소, 염소, 브롬, 또는 요오드이다.Where X is fluorine, chlorine, bromine, or iodine.
본 발명은 상술한 종래 기술들의 문제점을 해결하기 위한 것으로, 하기 [반응식 4]에서 보는 바와 같이 P-1 화합물에서 One-Pot 반응으로 수산화나트륨과 디메틸카보네이트를 적가한 후, 디사이클로헥실아민을 가하여 핵심중간체인 아질사탄 디사이클로헥실아민염을 합성하고, 친환경 용매인 이온성 액체와 공융용매를 사용하여 메독소밀 클로라이드를 효율적이고 간단한 방법으로 고순도, 고수율로 합성하는 것을 주된 특징으로 한다.The present invention is to solve the problems of the prior art described above, as shown in the following [Reaction Scheme 4], sodium hydroxide and dimethyl carbonate are added dropwise in a One-Pot reaction in the P-1 compound, and then dicyclohexylamine is added. It is characterized by synthesizing azylsartan dicyclohexylamine salt, which is a core intermediate, and synthesizing medoxomyl chloride in an efficient and simple manner with high purity and high yield using an eco-friendly ionic liquid and eutectic solvent.
[반응식 4][Scheme 4]
특히, 본 발명에 있어서, 이온성 액체 또는 공융용매 하에서, 메독소밀 할라이드와 반응시켜 아질사탄 메독소밀의 합성에 사용되는 중간체는 하기 화학식 6으로 표현되는 화합물을 사용할 수 있다:In particular, in the present invention, the intermediate used for the synthesis of azylsartan medoxomil by reacting with medoxomil halide under an ionic liquid or a eutectic solvent may be a compound represented by the following formula (6):
[화학식 6][Formula 6]
여기서, R1, R2, 및 R3는, 각각 독립적으로, 수소, 탄소수 C1 내지 C6의 직쇄, 분지쇄, 또는 고리형의 알킬, 또는 그의 1가 알코올이며, R1, R2, 및 R3가 동시에 모두 수소인 경우는 제외한다.Here, R 1 , R 2 , and R 3 are each independently hydrogen, C 1 to C 6 straight chain, branched chain, or cyclic alkyl, or a monohydric alcohol thereof, R 1 , R 2 , And R 3 is both hydrogen at the same time, except for the case.
아질사탄에 관한 염에 대해서는, 리튬, 나트륨 등의 무기염과, 이소프로필 알코올 등의 탄화수소 기반의 유기염 등이 있지만, 유기아민염은 높은 안정성 및 용해도, 반응성 등등과 같이 물성적인 측면에서 여러 장점이 있다.There are inorganic salts such as lithium and sodium, and organic salts based on hydrocarbons such as isopropyl alcohol, for salts related to nitrite, but organic amine salts have several advantages in terms of physical properties such as high stability, solubility, and reactivity. There is this.
상기 메독소밀 할라이드와 반응시켜 아질사탄 메독소밀의 합성에 사용되는 중간체로 가장 바람직한 것은, 하기 화학식 1로 표현되는 아질사탄 디시클로헥실아민염인 것이다.The most preferable intermediate used in the synthesis of azyl satan medoxomil by reacting with the medoxomiyl halide is an azyl satan dicyclohexylamine salt represented by the following formula (1).
[화학식 1][Formula 1]
합성과정에 아질사탄 디시클로엑실아민염은 수율이 높고, 무엇보다, 결정성을 나타내기 때문에, 안정성이 높은 이점이 있다. 이에 대한 보다 상세한 이해는 후술할 실시예 등을 통하여 행하여질 수 있을 것이다.In the synthesis process, azylsartan dicycloexylamine salt has a high yield and, above all, crystallinity, and thus has a high stability. A more detailed understanding of this may be made through examples and the like to be described later.
본 발명에 있어서, 상기 제1단계는 상온에서 이루어질 수 있으며, 상기 제2단계 조차도 약 60℃ 이하, 약 50℃ 이하, 또는 더 나아가 그 이하의 저온 범위에서도 이루어질 수 있다.In the present invention, the first step may be performed at room temperature, and even the second step may be performed in a low temperature range of about 60° C. or less, about 50° C. or less, or even lower.
이러한 저온 범위 합성은 유연물질 생성이 감소되어 고순도, 고수율의 아질사탄 메독소밀 생산을 가능케 하며, 에너지 비용도 절감되어 대량생산 시 경제적으로도 매우 유리하다. 이러한 저온 합성이 가능한 것은 핵심 중간체로서 아질사탄 유기아민염이 메독소밀 할라이드와 이온성 액체 또는 공융용매 하에서 높은 반응성을 나타내는 것에 기인한다.This low-temperature synthesis reduces the generation of related substances, enabling the production of high purity and high yield nitrous oxide medoxomil, and energy costs are also reduced, which is economically advantageous in mass production. This low-temperature synthesis is possible due to the high reactivity of the medoxomyl halide and the medoxomyl halide in the ionic liquid or eutectic solvent as a core intermediate.
상기 이온성 액체 화합물은, 당해 기술분야에 널리 알려진 이온성 액체 화합물을 비제한적으로 사용할 수 있고, 이에 대한 예시로, 1-에틸-3-메틸 이미다졸륨 에틸 설페이트, 1-에틸-3-메틸이미다졸리움 브로마이드, 1-에틸-3-메틸이미다졸리움 헥사플루오로포스페이트, N-부틸-N- 메틸피롤리디움 브로마이드, N-부틸-N-메틸피롤리디움 헥사플루오로포스페이트, N-부틸-3-메틸피리디움 브로마이드, N-부틸-3-메틸피리디움 헥사플루오로포스페이트, 테트라-N-부틸암모늄 브로마이드, 테트라-N-부틸암모늄 헥사플루오로포스페이트, 테트라-N-부틸포스포늄 브로마이드, 테트라-N-부틸포스포늄 헥사플루오로포스페이트에서 선택되는 1종 이상인 것을 들 수 있으며, 1-에틸-3-메틸 이미다졸륨 에틸 설페이트인 것이 바람직하다.As the ionic liquid compound, an ionic liquid compound well known in the art may be used without limitation, and examples thereof include 1-ethyl-3-methyl imidazolium ethyl sulfate, 1-ethyl-3-methyl Imidazolium bromide, 1-ethyl-3-methylimidazolium hexafluorophosphate, N-butyl-N-methylpyrrolidium bromide, N-butyl-N-methylpyrrolidium hexafluorophosphate, N-butyl -3-methylpyridinium bromide, N-butyl-3-methylpyridinium hexafluorophosphate, tetra-N-butylammonium bromide, tetra-N-butylammonium hexafluorophosphate, tetra-N-butylphosphonium bromide, And one or more selected from tetra-N-butylphosphonium hexafluorophosphate, and 1-ethyl-3-methyl imidazolium ethyl sulfate is preferred.
상기 공융용매 화합물은, 콜린 클로라이드 및 우레아 혼합용매, 콜린 클로라이드 및 구연산 혼합용매, 또는 구연산 및 글루코스 혼합용매 등인 것을 사용할 수 있고, 바람직하게는, 콜린 클로라이드와 우레아를 1:2 비율로 섞은 용매, 콜린 클로라이드와 구연산을 1:1 또는 2:1 비율로 섞은 용매, 구연산과 글루코스를 1:1 비율로 섞은 용매, 또는 콜린 클로라이드와 글루코스를 1:1 비율로 섞은 용매 등인 것을 사용할 수 있으며, 더 바람직하게는, 콜린 클로라이드와 우레아를 1:2 비율로 섞은 용매를 사용할 수 있다.The eutectic solvent compound may be a mixed solvent of choline chloride and urea, a mixed solvent of choline chloride and citric acid, or a mixed solvent of citric acid and glucose, and preferably, a solvent in which choline chloride and urea are mixed in a ratio of 1:2, choline A solvent in which chloride and citric acid are mixed in a 1:1 or 2:1 ratio, a solvent in which citric acid and glucose are mixed in a 1:1 ratio, or a solvent in which choline chloride and glucose are mixed in a 1:1 ratio may be used, and more preferably It is possible to use a solvent in which choline chloride and urea are mixed in a ratio of 1:2.
이와 같이 본원발명은 유기용매 대신에 이온성 액체 화합물이나 공융용매 화합물을 사용하므로, 환경적인 측면에서도 바람직하며, 종래에 알려진 물질의 합성방법을 보다 친환경적으로 바꾸려는 녹색 화학(green chemistry)의 하나가 될 것이다.As described above, since the present invention uses an ionic liquid compound or a eutectic solvent compound instead of an organic solvent, it is also preferable from an environmental point of view, and one of the green chemistry to change the conventionally known synthesis method of substances to be more environmentally friendly. Will be
이하, 본 발명에 대하여 실시예를 들어 보다 더 상세히 설명한다. 다만, 이하의 실시예는 발명의 상세한 설명을 위한 것일뿐 이에 의해 권리범위를 제한하려는 의도가 아님을 분명히 해둔다.Hereinafter, the present invention will be described in more detail with reference to examples. However, it should be clarified that the following embodiments are for detailed description of the invention and are not intended to limit the scope of the rights thereby.
실시예Example
아질사탄Asil Satan 아민염의Amine salt 합성 synthesis
1-1. 2- 에톡시 -1-((2'-(5- oxo -4,5- 디하이드로 -1,2,4- 옥사다이아졸 -3-일)비페닐-4-일)메틸)- 1H -벤조[ d ]이미다졸-7-카르복실 엑시드 다이사이클로헥실아민 염의 합성 1-1. 2-ethoxy -1 - ((2 '- (5- oxo -4,5- dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) methyl) - 1H - Benzo[ d ]imidazole-7-carboxyl acid Synthesis of dicyclohexylamine salt
플라스크에 메틸-2-에톡시-1-((2'-N'-하이드록시카바미미도일)비페닐-4-일-메틸)-1H-벤조[d]-이미다졸-7카르복실레이트 4.8g, 다이메틸설폭사이드 24ml, 다이메틸카보네이트 1.36ml를 가한 후, 상온(23~28℃)에서 30분간 교반하고, 소듐하이드록사이드 2.81g을 가한다. 이 반응액을 상온(23~28℃)에서 2시간 교반한 후, 반응이 완료 되면 에틸아세테이트 24ml, 정제수 24ml 가한 후, 염산 24ml를 적가하여 pH를 2~3으로 조절한다. 유기층을 분리한 후, 다이사이클로헥실아민 2.37ml를 투입한다. 이 반응액을 상온(23~28℃)에서 15시간 이상 교반한 후, 여과하여 실온에서 진공건조하여 2-에톡시-1-((2'-(5-oxo-4,5-디하이드로-1,2,4-옥사다이아졸-3-일)비페닐-4-일)메틸)-1H-벤조[d]이미다졸-7-카르복실 엑시드 다이사이클로헥실아민 염 5.8g(84.2%)을 얻는다.In-2-on-ethoxy flask -1 - ((2'- N '- hydroxy cover insignificant degree yl) biphenyl-4-yl-methyl) - 1H-benzo [d] - imidazol -7-carboxylate After adding 4.8 g, 24 ml of dimethyl sulfoxide and 1.36 ml of dimethyl carbonate, the mixture was stirred at room temperature (23-28° C.) for 30 minutes, and 2.81 g of sodium hydroxide was added. The reaction solution was stirred at room temperature (23~28℃) for 2 hours, and when the reaction was completed, 24ml of ethyl acetate and 24ml of purified water were added, and then 24ml of hydrochloric acid was added dropwise to adjust the pH to 2~3. After separating the organic layer, 2.37 ml of dicyclohexylamine is added. After stirring the reaction solution at room temperature (23 to 28°C) for 15 hours or more, it was filtered and dried under vacuum at room temperature to obtain 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-). benzo [d] imidazole-7-carboxylic acid dicyclohexyl amine salt 5.8g (84.2%) - 1,2,4- oxadiazol-3-yl) biphenyl-4-yl) methyl) - 1H Get
1H NMR (DMSO)(ppm):13.17 (bs, 1H, OH or NH), 12.42 (bs, 1H, OH or NH), 7.70-7.60 (m, 3H, Ar), 7.57-7.50 (m, 2H,Ar), 7.50-7.44 (m, 1H, Ar), 7.23 (d, J = 8.3 Hz, 2H, Ar), 7.18 (t, J = 7.9 Hz, 1H, Ar), 7.05 (d, J= 8.3 Hz, 2H, Ar), 5.68 (s, 2H, N-CH2-Ar), 4.58 (q, J = 7.1 Hz, 2H, OCH2CH3), 1.38 (t, J = 7.1Hz, 3H, OCH2CH3 1 H NMR (DMSO)(ppm):13.17 (bs, 1H, OH or NH), 12.42 (bs, 1H, OH or NH), 7.70-7.60 (m, 3H, Ar), 7.57-7.50 (m, 2H) ,Ar), 7.50-7.44 (m, 1H, Ar), 7.23 (d, J = 8.3 Hz, 2H, Ar), 7.18 (t, J = 7.9 Hz, 1H, Ar), 7.05 (d, J = 8.3 Hz, 2H, Ar), 5.68 (s, 2H, N-CH2-Ar), 4.58 (q, J = 7.1 Hz, 2H, OCH2CH3), 1.38 (t, J = 7.1Hz, 3H, OCH2CH3
1-2. 2- 에톡시 -1-((2'-(5- oxo -4,5- 디하이드로 -1,2,4- 옥사다이아졸 -3-일)비페닐-4-일)메틸)- 1H -벤조[ d ]이미다졸-7-카르복실 엑시드 디에틸아민 염의 합성 1-2. 2-ethoxy -1 - ((2 '- (5- oxo -4,5- dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) methyl) - 1H - Synthesis of benzo[ d ]imidazole-7-carboxyl acid diethylamine salt
상기 1-1에서, 다이시클로헥실아민을 디에틸아민으로 대체한 것 이외에 모두 동일한 절차와 과정을 거쳐 아질사탄 아민염을 합성하였다.In 1-1 above, azylsartan amine salt was synthesized through the same procedure and procedure except that dicyclohexylamine was replaced with diethylamine.
1-3. 2- 에톡시 -1-((2'-(5- oxo -4,5- 디하이드로 -1,2,4- 옥사다이아졸 -3-일)비페닐-4-일)메틸)- 1H -벤조[ d ]이미다졸-7-카르복실 엑시드 에탄올아민 염의 합성 1-3. 2-ethoxy -1 - ((2 '- (5- oxo -4,5- dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) methyl) - 1H - Synthesis of benzo[ d ]imidazole-7-carboxyl acid ethanolamine salt
상기 1-1에서, 다이시클로헥실아민을 에탄올아민으로 대체한 것 이외에 모두 동일한 절차와 과정을 거쳐 아질사탄 아민염을 합성하였다.In 1-1 above, azylsartan amine salt was synthesized through the same procedure and procedure except that dicyclohexylamine was replaced with ethanolamine.
1-4. 2- 에톡시 -1-((2'-(5- oxo -4,5- 디하이드로 -1,2,4- 옥사다이아졸 -3-일)비페닐-4-일)메틸)- 1H -벤조[ d ]이미다졸-7-카르복실 엑시드 디이소프로필에틸아민 염의 합성 1-4. 2-ethoxy -1 - ((2 '- (5- oxo -4,5- dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) methyl) - 1H - Benzo[ d ]imidazole-7-carboxyl acid Synthesis of diisopropylethylamine salt
상기 1-1에서, 다이시클로헥실아민을 디이소프로필에틸아민으로 대체한 것 이외에 모두 동일한 절차와 과정을 거쳐 아질사탄 아민염을 합성하였다.In 1-1 above, azylsartan amine salt was synthesized through the same procedure and procedure except that dicyclohexylamine was replaced with diisopropylethylamine.
1-4. 2- 에톡시 -1-((2'-(5- oxo -4,5- 디하이드로 -1,2,4- 옥사다이아졸 -3-일)비페닐-4-일) 메 틸)- 1H -벤조[ d ]이미다졸-7-카르복실 엑시드 디메틸에탄올아민 염의 합성 1-4. 2-ethoxy -1 - ((2 '- (5- oxo -4,5- dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl) methyl) - 1H -Synthesis of benzo[ d ]imidazole-7-carboxyl acid dimethylethanolamine salt
상기 1-1에서, 다이시클로헥실아민을 디메틸에탄올아민으로 대체한 것 이외에 모두 동일한 절차와 과정을 거쳐 아질사탄 아민염을 합성하였다.In 1-1 above, azyl satanamine salt was synthesized through the same procedure and procedure except that dicyclohexylamine was replaced with dimethylethanolamine.
각 아민염 합성 수율은 하기 표1에서 보는 바와 같았고, 그 중 디사이클로헥실아민염이 가장 높은 수율로 확보되었다.The synthesis yield of each amine salt was as shown in Table 1 below, of which dicyclohexylamine salt was secured in the highest yield.
XRD 분석 결과, 기존 아질사탄의 경우 도 1과 같은 결정형을 가지며, 회절각(2Θ)은 8.85, 9.19, 21.53, 23.59인 것을 특징으로 하는 결정형화물이었다.As a result of XRD analysis, in the case of the conventional azile satan, it has a crystal form as shown in FIG. 1, and the diffraction angles (2Θ) were 8.85, 9.19, 21.53, and 23.59.
아질사탄 디사이클로헥실아민염의 경우, 도 2와 같은 결정형을 가지며, 회절각(2Θ)은 7.34, 8.89, 19.05, 19.78, 20.74, 21.92인 것을 특징으로 하는 결정형화물이 생성된 것을 확인하였다.In the case of azylsartan dicyclohexylamine salt, it was confirmed that a crystalline product, characterized in that it had a crystal form as shown in FIG. 2, and the diffraction angles (2Θ) were 7.34, 8.89, 19.05, 19.78, 20.74, and 21.92.
아질사탄 에탄올아민염의 경우, 도 3과 같은 비정질 형태를 갖는 무정형화물이 생성된 것을 확인하였다.In the case of the nitrite ethanolamine salt, it was confirmed that an amorphous product having an amorphous form as shown in FIG. 3 was generated.
이에 따라, 결정형 아질사탄 디사이클로헥실아민염이 무정형의 아질사탄 에탄올아민염 보다 안정성이 좋을 것은, 당해 기술분야 상식에 비추어 자명할 것이다.Accordingly, it will be apparent in the light of common knowledge in the art that the crystalline azile satan dicyclohexylamine salt is more stable than the amorphous nitrite ethanolamine salt.
아질사탄Asil Satan 메독소밀의Medoxomil 합성 synthesis
2-1. (5- 메틸 -2-옥소-1,3- 다이옥솔 -4-일) 메틸 2-에톡시-1-[[2'-(5-oxo-4,5-디하이드로-1,2,4-옥사다이아졸-3-일)비페닐-4-일]메틸]-1H-벤즈이미다졸-7-카르복실레이트의 합성 2-1. (5- methyl -2-oxo-1,3- dioxol -4-yl) methyl 2-ethoxy-1-[[2'-(5-oxo-4,5-dihydro-1,2,4) Synthesis of -oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate
플라스크에 2-에톡시-1-((2'-(5-oxo-4,5-디하이드로-1,2,4-옥사다이아졸-3-일)비페닐-4-일)메틸)-1H-벤조[d]이미다졸-7-카르복실 엑시드 다이사이클로헥실아민 염 5.8g, 1-에틸-3-메틸 이미다졸륨 에틸 설페이트 34.8ml, 소디움카보네이트 1.54g을 가한 후, 상온(23~28℃)에서 30분 교반한다. 메독소밀클로라이드 1.41ml, 포타슘아이오다이드 0.21g을 가한 후, 50℃에서 3시간 교반한다. 반응이 완료된 후, 에틸아세테이트 34.8ml, 정제수 34.8ml를 가하여 10분간 교반하고 유기층을 분리한다. 분리한 유기층에 소듐설페이트를 가하여 탈수한 후, 여과한다. 감압농축하고, 결정화하여 (5-메틸-2-옥소-1,3-다이옥솔-4-일)메틸 2-에톡시-1-[[2'-(5-oxo-4,5-디하이드로-1,2,4-옥사다이아졸-3-일)비페닐-4-일]메틸]-1H-벤즈이미다졸-7-카르복실레이트 3.93g(76.0%)을 얻는다.In a flask 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1H -benzo[ d ]imidazole-7-carboxyl acid dicyclohexylamine salt 5.8 g, 1-ethyl-3-methyl imidazolium ethyl sulfate 34.8 ml, sodium carbonate 1.54 g were added, and then at room temperature (23-28 ℃) for 30 minutes. 1.41 ml of medoxomil chloride and 0.21 g of potassium iodide were added, followed by stirring at 50° C. for 3 hours. After the reaction was completed, 34.8 ml of ethyl acetate and 34.8 ml of purified water were added, stirred for 10 minutes, and the organic layer was separated. After dehydration by adding sodium sulfate to the separated organic layer, it is filtered. Concentrated under reduced pressure, crystallized (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl 2-ethoxy-1-[[2'-(5-oxo-4,5-dihydro) -1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate 3.93 g (76.0%) are obtained.
1H NMR (500 MHz, DMSO)(ppm): 12.37 (bs, 1H, NH), 7.73 (dd, J = 7.9, 1.2, 1H, Ar), 7.69-7.62 (m, 2H, Ar), 7.55(dd, J = 7.6, 1.2, 1H, Ar), 7.52 (dd, J = 7.9, 1.2, 1H, Ar), 7.50-7.44 (m, 1H, Ar), 7.22 (d, J = 8.2Hz, 2H, Ar), 7.24-7.19 (m, 1H, Ar), 7.00 (d, J = 8.2 Hz, 2H, Ar), 5.55 (s, 2H, N-CH2-Ar), 5.12(s, 2H, COOCH2-R), 4.60 (q, J = 7.0 Hz, 2H, OCH2CH3), 2.16 (s, 3H, CH3), 1.38 (t, J = 7.0 Hz, 3H, OCH2CH3). 1 H NMR (500 MHz, DMSO) (ppm): 12.37 (bs, 1H, NH), 7.73 (dd, J = 7.9, 1.2, 1H, Ar), 7.69-7.62 (m, 2H, Ar), 7.55( dd, J = 7.6, 1.2, 1H, Ar), 7.52 (dd, J = 7.9, 1.2, 1H, Ar), 7.50-7.44 (m, 1H, Ar), 7.22 (d, J = 8.2Hz, 2H, Ar), 7.24-7.19 (m, 1H, Ar), 7.00 (d, J = 8.2 Hz, 2H, Ar), 5.55 (s, 2H, N-CH2-Ar), 5.12 (s, 2H, COOCH2-R ), 4.60 (q, J = 7.0 Hz, 2H, OCH2CH3), 2.16 (s, 3H, CH3), 1.38 (t, J = 7.0 Hz, 3H, OCH2CH3).
2-2. (5- 메틸 -2-옥소-1,3- 다이옥솔 -4-일) 메틸 2-에톡시-1-[[2'-(5-oxo-4,5-디하이드로-1,2,4-옥사다이아졸-3-일)비페닐-4-일]메틸]-1H-벤즈이미다졸-7-카르복실레이트의 합성 2-2. (5- methyl -2-oxo-1,3- dioxol -4-yl) methyl 2-ethoxy-1-[[2'-(5-oxo-4,5-dihydro-1,2,4) Synthesis of -oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate
플라스크에 2-에톡시-1-((2'-(5-oxo-4,5-디하이드로-1,2,4-옥사다이아졸-3-일)비페닐-4-일)메틸)-1H-벤조[d]이미다졸-7-카르복실 엑시드 다이사이클로헥실아민 염 5.8g, 콜린 클로라이드와 우레아를 1:2 비율로 섞은 용매 34.8ml, 소디움카보네이트 1.54g을 가한 후, 상온(23~28℃)에서 30분 교반한다. 메독소밀클로라이드 1.41ml, 포타슘아이오다이드 0.21g을 가한 후, 50℃에서 3시간 교반한다. 반응이 완료된 후, 에틸아세테이트 34.8ml, 정제수 34.8ml를 가하여 10분간 교반하고 유기층을 분리한다. 분리한 유기층에 소듐설페이트를 가하여 탈수한 후, 여과한다. 감압농축하고, 결정화하여 (5-메틸-2-옥소-1,3-다이옥솔-4-일)메틸 2-에톡시-1-[[2'-(5-oxo-4,5-디하이드로-1,2,4-옥사다이아졸-3-일)비페닐-4-일]메틸]-1H-벤즈이미다졸-7-카르복실레이트 3.78g(73.2%)을 얻는다. 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- in a flask 1H -benzo[ d ]imidazole-7-carboxyl acid dicyclohexylamine salt 5.8g, a solvent mixed with choline chloride and urea in a ratio of 1:2 After adding 34.8ml and 1.54g of sodium carbonate, the mixture was stirred at room temperature (23~28℃) for 30 minutes. 1.41 ml of medoxomil chloride and 0.21 g of potassium iodide were added, followed by stirring at 50° C. for 3 hours. After the reaction was completed, 34.8 ml of ethyl acetate and 34.8 ml of purified water were added, stirred for 10 minutes, and the organic layer was separated. After dehydration by adding sodium sulfate to the separated organic layer, it is filtered. Concentrated under reduced pressure, crystallized (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl 2-ethoxy-1-[[2'-(5-oxo-4,5-dihydro) -1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate 3.78 g (73.2%) are obtained.
1H NMR (500 MHz, DMSO)(ppm): 12.37 (bs, 1H, NH), 7.73 (dd, J = 7.9, 1.2, 1H, Ar), 7.69-7.62 (m, 2H, Ar), 7.55(dd, J = 7.6, 1.2, 1H, Ar), 7.52 (dd, J = 7.9, 1.2, 1H, Ar), 7.50-7.44 (m, 1H, Ar), 7.22 (d, J = 8.2Hz, 2H, Ar), 7.24-7.19 (m, 1H, Ar), 7.00 (d, J = 8.2 Hz, 2H, Ar), 5.55 (s, 2H, N-CH2-Ar), 5.12(s, 2H, COOCH2-R), 4.60 (q, J = 7.0 Hz, 2H, OCH2CH3), 2.16 (s, 3H, CH3), 1.38 (t, J = 7.0 Hz, 3H, OCH2CH3). 1 H NMR (500 MHz, DMSO) (ppm): 12.37 (bs, 1H, NH), 7.73 (dd, J = 7.9, 1.2, 1H, Ar), 7.69-7.62 (m, 2H, Ar), 7.55( dd, J = 7.6, 1.2, 1H, Ar), 7.52 (dd, J = 7.9, 1.2, 1H, Ar), 7.50-7.44 (m, 1H, Ar), 7.22 (d, J = 8.2Hz, 2H, Ar), 7.24-7.19 (m, 1H, Ar), 7.00 (d, J = 8.2 Hz, 2H, Ar), 5.55 (s, 2H, N-CH2-Ar), 5.12 (s, 2H, COOCH2-R ), 4.60 (q, J = 7.0 Hz, 2H, OCH2CH3), 2.16 (s, 3H, CH3), 1.38 (t, J = 7.0 Hz, 3H, OCH2CH3).
2-1, 및 2-2에서 상술한 것과 같은 방법으로, 다양한 용매를 사용하여 아질사탄 메독소밀을 합성한 방법을 하기 표 2와 같은 용매를 사용하여 아질사탄 메독소밀을 합성하였고, 수율 및 순도 결과는 하기 표 2와 같았다.In the same manner as described above in 2-1 and 2-2, a method for synthesizing azyl satan medoxomil using various solvents was synthesized using a solvent as shown in Table 2 below, and yield and purity The results were shown in Table 2 below.
(MEK: Methyl Ethyl Ketone; DMAC: Dimethylacetamide; EMIES: 1-ethyl-3-methylimidazolium ethylsulfate; EMIB: 1-ethyl-3-methylimidazolium bromide; EMIA:: 1-ethyl-3-methylimidazolium acetate; BMIA: 1-butyl-3-methylimidazolium acetate)(MEK: Methyl Ethyl Ketone; DMAC: Dimethylacetamide; EMIES: 1-ethyl-3-methylimidazolium ethylsulfate; EMIB: 1-ethyl-3-methylimidazolium bromide; EMIA:: 1-ethyl-3-methylimidazolium acetate; BMIA: 1-butyl -3-methylimidazolium acetate)
동일한 조건에서 유기용매를 사용한 경우 아질사탄 메독소밀이 합성되지 않았지만, 이온성 액체들 중 1-에틸-3-메틸 이미다졸륨 에틸설페이트, 공융용매로 콜린 클로라이드와 우레아를 1:2로 섞어 사용한 경우 50℃ 미만의 반응 조건에서 고순도, 고수율로 아질사탄 메독소밀이 합성됨을 확인할 수 있었다.In the case of using an organic solvent under the same conditions, nitrous oxide medoxomil was not synthesized, but 1-ethyl-3-methyl imidazolium ethyl sulfate among ionic liquids, choline chloride and urea as a eutectic solvent were mixed in a ratio of 1:2. It was confirmed that azil satan medoxomil was synthesized with high purity and high yield under reaction conditions of less than 50°C.
Claims (10)
[화학식 1]
[Formula 1]
2) 상기 제조된 아질사탄 아민염을, 이온성 액체 또는 공융용매 하에서, 하기 화학식 5의 메독소밀 할라이드와 반응시키는 제2단계를 포함하는 것을 특징으로 하는, 하기 화학식 2의 아질사탄 메독소밀의 제조방법:
[화학식 2]
[화학식 3]
[화학식 4]
여기서, R1, R2, 및 R3는, 각각 독립적으로, 수소, 탄소수 C1 내지 C6의 직쇄, 분지쇄, 또는 고리형의 알킬, 또는 그의 1가 알코올이며, R1, R2, 및 R3가 동시에 모두 수소인 경우는 제외한다.
[화학식 5]
여기서, X는 불소, 염소, 브롬, 또는 요오드이다.1) a first step of preparing azyl satan from a compound of the following formula (3), and reacting it with an amine compound of the following formula (4) to prepare an azyl satan amine salt; And
2) Preparation of azyl satan medoxomil of the following formula (2), characterized in that it comprises a second step of reacting with the medoxomil halide of the following formula (5) under an ionic liquid or a eutectic solvent Way:
[Formula 2]
[Formula 3]
[Formula 4]
Here, R 1 , R 2 , and R 3 are each independently hydrogen, C 1 to C 6 straight chain, branched chain, or cyclic alkyl, or a monohydric alcohol thereof, R 1 , R 2 , And R 3 is both hydrogen at the same time, except for the case.
[Formula 5]
Where X is fluorine, chlorine, bromine, or iodine.
[화학식 1]
[Formula 1]
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| EP0520423A2 (en) | 1991-06-27 | 1992-12-30 | Takeda Chemical Industries, Ltd. | Heterocyclic compounds, their production and use as angiotensin II antagonists |
| US20050032854A1 (en) * | 2001-12-03 | 2005-02-10 | Kiminori Kawahara | Insulin resistance improving agents |
| EP2119715A1 (en) | 2004-02-25 | 2009-11-18 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and its use as aii receptor antagonist |
| US20120238606A1 (en) * | 2009-11-30 | 2012-09-20 | Jiangsu Hans Pharmaceutial Group Co., Ltd. | Azilsartan organic amine salts, preparation method and use thereof |
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| EP0520423A2 (en) | 1991-06-27 | 1992-12-30 | Takeda Chemical Industries, Ltd. | Heterocyclic compounds, their production and use as angiotensin II antagonists |
| US20050032854A1 (en) * | 2001-12-03 | 2005-02-10 | Kiminori Kawahara | Insulin resistance improving agents |
| EP2119715A1 (en) | 2004-02-25 | 2009-11-18 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and its use as aii receptor antagonist |
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