KR101205570B1 - The new process for the preparation of 2-n-propyl-4-methyl-6- 1-methyl benzimidazole-2-yl-1H-benzimidazole - Google Patents
The new process for the preparation of 2-n-propyl-4-methyl-6- 1-methyl benzimidazole-2-yl-1H-benzimidazole Download PDFInfo
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Abstract
Description
본 발명은 텔미사르탄 핵심 중간체인 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸의 공업적인 대량생산에 적합한 개량된 새로운 제조방법에 관한 것이다.
The present invention provides an improved novel preparation for industrial mass production of telmisartan core intermediate 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole. It is about a method.
2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)은 참고 문헌 J. Med. Chem. (1993), 36(25), 4040-4051, 국제 공개 특허 00/63158에 의해 알려진대로 N-메틸-O-페닐렌-디아민 다이하이드로클로라이드(4)와 2-n-프로필-4-메틸-1H-벤즈이미다졸-6-카복실산(2)의 반응에 의해 제조된다.2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1) is described in reference to J. Med. Chem. (1993), 36 (25), 4040-4051, N-methyl-O-phenylene-diamine dihydrochloride (4) and 2-n-propyl-4-methyl- as known by International Publication No. 00/63158. It is prepared by the reaction of 1H-benzimidazole-6-carboxylic acid (2).
2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)은 약리 활성 물질인 텔미사르탄(Drugs of the future 1997, 22(10), 1112-1116)의 중요 구성 블록으로 공업적으로 생산하는 데 있어서 중간체로써 큰 중요성을 갖는다. 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1) is a pharmacologically active substance called the drug of the future (Drugs of the future 1997, 22 ( 10), 1112-1116), an important building block of great importance as an intermediate in industrial production.
[반응식 1][Reaction Scheme 1]
2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 합성하는 상기 [반응식 1]은 국제 공개 특허 2007/010558 실시예 1에 기재 되어 있고, 이 반응식에 따르면 2-n-프로필-4-메틸-1H-벤즈이미다졸-6-카복실산(2)을 폴리인산에 현탁 시키고, 온도를 70~75℃로 가열한 후 N-메틸-O-페닐렌-디아민 다이하이드로클로라이드(4)를 첨가 하고, 130~135℃에서 10시간 동안 반응을 진행한 후 온도를 70℃로 냉각하여 상수를 서서히 첨가하고, 암모니아수로 중화시킨 뒤 생성된 고체를 50~55℃에서 여과하여 원하는 생성물인 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 얻는다. (수율 77.4%)
Scheme 1, which synthesizes 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1), is described in International Publication No. 2007/010558. 1, according to this scheme, 2-n-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (2) is suspended in polyphosphoric acid, heated to 70-75 ° C. and then N -Methyl-O-phenylene-diamine dihydrochloride (4) was added, the reaction was carried out at 130-135 ° C. for 10 hours, the temperature was cooled to 70 ° C. and a constant was slowly added thereto, and neutralized with ammonia water. The resulting solid is filtered at 50-55 ° C. to afford 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1) as desired. (Yield 77.4%)
[반응식 2]Scheme 2
2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 합성하는 [반응식 2]는 국제 공개 특허 2006/044754 실시예 2에도 기재 되어 있고, 상기 반응식에 따르면 2-n-프로필-4-메틸-1H-벤즈이미다졸-6-카복실산(2)과 N-메틸-O-페닐렌-디아민 모노하이드로클로라이드(5)를 폴리인산에 현탁 시키고, 온도를 150~155℃로 한 후 반응을 진행한 후 온도를 90~100℃로 냉각한 후 상수를 서서히 첨가하고, 다시 60~70℃로 냉각한 후 반응 혼합물을 교반 시키고, 40~45℃에서 상수를 첨가한 뒤 50% 수산화나트륨 수용액으로 pH를 약산성으로 한 뒤 고체를 여과하여 원하는 생성물인 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 얻는다. (수율 60.5%)
Scheme 2, which synthesizes 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1), is described in International Publication No. 2006/044754 Example 2 According to the above scheme, 2-n-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (2) and N-methyl-O-phenylene-diamine monohydrochloride (5) Suspended in phosphoric acid, the temperature was set to 150 ~ 155 ℃, the reaction proceeds to cool the temperature to 90 ~ 100 ℃ and then slowly added a constant, and then cooled to 60 ~ 70 ℃ again, the reaction mixture is stirred, After adding a constant at 40-45 ° C., the pH was slightly acidic with 50% aqueous sodium hydroxide solution, and the solid was filtered to give 2-n-propyl-4-methyl-6- (1-methylbenzimidazole-2 as a desired product. -Yl) -1H-benzimidazole (1) is obtained. (Yield 60.5%)
상기 [반응식 1], [반응식 2]는 다음과 같은 단점을 가진다.
[Scheme 1], [Scheme 2] has the following disadvantages.
첫째, 반응에 사용하는 폴리인산의 경우 점도가 높아 상온에서 다루기 어려운 문제가 있다.
First, in the case of polyphosphoric acid used in the reaction there is a problem that is difficult to handle at room temperature due to the high viscosity.
둘째, 반응 후 처리 과정에서는 반응 온도(135~155℃)로 부터 온도를 단계별로 낮추면서 상수를 서서히 첨가하여 과량으로 사용된 폴리인산의 불균일한 반응 혼합물의 상태를 균일하게 해야 하는 불편함이 있다.
Second, in the post-reaction treatment process, it is inconvenient to uniformize the state of the heterogeneous reaction mixture of polyphosphoric acid used in excess by gradually adding a constant while lowering the temperature from the reaction temperature (135 ~ 155 ° C) step by step. .
셋째, 용매 겸 반응 시약으로 사용하는 과량의 폴리인산을 중화하기 위해 필요량 이상의 시약을 추가로 사용해야 한다.
Third, more reagent than necessary should be used to neutralize the excess polyphosphoric acid used as solvent and reaction reagent.
넷째, 일반적으로 공업적인 반응에서 사용하는 유기 용매들 보다 필요 이상의 높은 135~155℃에서 반응이 진행되어 상대적으로 생성물에 대해 가혹하다.
Fourth, in general, the reaction proceeds at 135 to 155 ° C. higher than necessary than the organic solvents used in the industrial reaction, which is relatively harsh to the product.
다섯째, 수율이 60~77%로 저조하여 대량 생산에서는 효율적이지 못하다.
Fifth, yields are low at 60-77%, making them inefficient in mass production.
[반응식 3] Scheme 3
미국 공개 특허 2003/0139608 실시예 1 또한 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 제조하는 방법을 개시한다. 상기 반응식에 따르면 메탄술폰산에 용해된 오산화인을 125~145℃로 가열하고, 2-n-프로필-4-메틸-1H-벤즈이미다졸-6-카복실산(2)과 N-메틸-O-페닐렌-디아민(3)을 첨가하고 125~145℃에서 반응시킨 뒤 80℃로 냉각하고 상수를 첨가하여 과량의 오산화인/메탄술폰산의 활성을 억제한 뒤 50% 수산화나트륨 수용액으로 pH를 조절하고, 활성탄 처리 과정을 3회 반복한 뒤 50% 수산화나트륨 수용액으로 pH를 재조절하여 생성된 침전물을 여과하여 원하는 생성물인 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 얻는다. (수율 85%) US Patent Publication 2003/0139608 Example 1 also discloses a process for preparing 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1). . According to the above scheme, phosphorus pentoxide dissolved in methanesulfonic acid was heated to 125-145 ° C, 2-n-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (2) and N-methyl-O-phenyl Len-diamine (3) was added and reacted at 125-145 ° C., cooled to 80 ° C., and a constant was added to inhibit excess phosphorus pentoxide / methanesulfonic acid activity, and then the pH was adjusted with 50% aqueous sodium hydroxide solution. After repeated treatment of activated carbon three times, the pH was adjusted with 50% aqueous sodium hydroxide solution and the resulting precipitate was filtered to give the desired product, 2-n-propyl-4-methyl-6- (1-methylbenzimidazole-2 -Yl) -1H-benzimidazole (1) is obtained. (Yield: 85%)
상기 [반응식 3]의 오산화인/메탄술폰산을 사용하여 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 제조하는 경우는 다음과 같은 단점을 갖는다.
To prepare 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1) using the phosphorus pentoxide / methanesulfonic acid of [Scheme 3] The case has the following disadvantages.
첫째, 실제 125~145℃의 고온에서 2-n-프로필-4-메틸-1H-벤즈이미다졸-6-카복실산(2)과 N-메틸-O-페닐렌-디아민(3)을 첨가해야 하므로 작업자의 안전에 영향을 줄 수 있는 위험한 공정을 포함한다.
First, since 2-n-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (2) and N-methyl-O-phenylene-diamine (3) should be added at a high temperature of 125 to 145 ° C. Contains hazardous processes that may affect worker safety.
둘째, 필요 이상 온도의 고온에서 반응이 진행 되어 생성물에 대해 가혹하다.
Second, the reaction proceeds at higher temperatures than necessary, which is harsh for the product.
셋째, 오산화인/메탄술폰산 활성 억제시 생성되는 부산물인 무수메탄술폰산은 생성물을 오염 시킬 가능성이 있다.
Third, methanesulfonic anhydride, a by-product produced by inhibiting phosphorus pentoxide / methanesulfonic acid activity, may contaminate the product.
넷째, 반응에 사용되는 용매 겸 반응시약인 과량의 오산화인/메탄술폰산을 중화하기 위해 과량의 시약을 추가로 사용하여야 하므로 경제적이지도 못하다. Fourth, it is not economical because an excess reagent must be additionally used to neutralize the excess phosphorus pentoxide / methanesulfonic acid, which is a solvent and a reagent used in the reaction.
기존에 공지된 방법 및 상기 언급된 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 제조하는 방법들은 취급하기 어려우며 작업자의 안전에 영향을 주는 위험한 공정을 포함하며 수율이 저조하고, 필요 이상의 고온에서 반응이 진행되어 생성물에 대해 가혹하며 경제성 및 공정상 효율성이 떨어져 공업적인 대량생산에는 적합하지 않다.
The known methods and methods for preparing the aforementioned 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1) are difficult to handle and It contains hazardous processes that affect worker safety, yields are low, reactions are carried out at higher temperatures than necessary, they are harsh on products, and are not suitable for industrial mass production due to low economic and process efficiency.
이와 같이 텔미사르탄의 핵심 중간체인 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 제조하는 방법은 취급하기 어려운 시약을 사용하며 위험한 공정을 포함하고 효율적이지 못하며, 수율이 저조하여 공업적인 대량생산을 위한 방법으로 적합하지 않음에도 다양한 제조방법이 존재하지 않기 때문에, 본 발명은 기존에 공지된 방법들의 단점을 개선한 새로운 제조 공정으로 높은 수율로 공업적으로 대량생산이 용이한 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 제조하는 밥법을 제공하는데 그 목적이 있다.
Thus, the method for preparing 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1), which is a key intermediate of telmisartan, is difficult to handle. The present invention improves the disadvantages of the known methods because they contain reagents, contain dangerous processes, are not efficient, and have low yields and are not suitable for industrial mass production. A new manufacturing process provides 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1), which is easy to mass produce in high yield. The purpose is to provide a recipe for manufacturing.
본 발명자들은 기존 공지된 선행 기술들의 문제점들을 극복하면서 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 공업적으로 용이하게 높은 수율로 제조할 수 있는 방법을 찾기 위한 다양한 연구를 진행하였다.
The inventors have industrially employed 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1) while overcoming the problems of the known prior art. Various studies have been conducted to find a method that can be easily produced in high yield.
그 결과 기존 공지된 폴리인산(PPA, polyphosphoric acid)이나 오산화인/메탄술폰산(P2O5/methanesulfonic acid)을 대신하여 옥시염화인(POCl3)을 비극성 용매에서 사용한 결과 비극성 용매에서 옥시염화인을 처리하여 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 제조 하는 방법은 기존 선행 기술의 단점을 개선한 공업적으로 대량생산이 용이한 새로운 제조 방법임을 발견하였다.
As a result, phosphorus oxychloride (POCl 3 ) was used in a nonpolar solvent in place of the known polyphosphoric acid (PPA) or phosphorus pentoxide / methanesulfonic acid (P 2 O 5 / methanesulfonic acid). The process for preparing 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1) by treatment of It has been found that it is a new manufacturing method that is easy to mass production.
본 발명자들의 신규한 제조 방법은 다음과 같은 장점을 가진다. The novel manufacturing method of the present inventors has the following advantages.
첫째, 폴리인산, 옥시염화인/메탄술폰산의 물리적 성질 때문에 발생하는 부가적인 반응 제어 과정이 필요하지 않아 작업 과정이 편리하고 안전하다.
First, the process is convenient and safe because no additional reaction control process occurs due to the physical properties of polyphosphoric acid and phosphorus oxychloride / methanesulfonic acid.
둘째, 용매 겸 시약으로 필요량 이상으로 사용하는 폴리인산, 오산화인/메탄술폰산 대신 필요 당량 만큼의 시약을 사용하므로 효율적이고 경제적이다.
Second, it is efficient and economical because it uses the equivalent amount of reagent instead of polyphosphoric acid and phosphorus pentoxide / methanesulfonic acid, which are used as necessary as solvent and reagent.
셋째, 필요 온도 이상까지 반응 온도를 상승시키지 않으므로 생성물에 대해 가혹하지 않다.
Third, the reaction temperature is not raised above the required temperature, so it is not harsh on the product.
넷째, 기존 선행 기술에 비해 상대적으로 온화한 조건에서 고순도의 높은 수율로 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 제조할 수 있다. Fourth, 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1) in high yield with high purity under relatively mild conditions compared to the prior art. Can be prepared.
따라서 본 발명은 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)의 신규한 제조 방법 및 대량생산에 적합한 제조 방법을 제공한다.
Therefore, the present invention provides a novel process for preparing 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1) and a process suitable for mass production. to provide.
상기한 바와 같이, 본 발명은 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)의 새로운 제조 방법을 제공한다.
As mentioned above, the present invention provides a new process for the preparation of 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1).
본 발명은 비극성 용매 중에서 옥시염화인을 사용하여 N-메틸-O-페닐렌-디아민(3)과 2-n-프로필-4-메틸-1H-벤즈이미다졸-6-카복실산(2)을 반응시켜 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 제조하는 방법으로 첫째, 기존 선행기술처럼 상온에서 취급하기 어려운 시약과 고온에서 시약을 첨가하지 않으므로 작업자의 안전에 영향을 끼치는 위험한 공정을 포함하지 않아 유용하고, 둘째, 필요량 만큼의 시약을 사용하므로 용매 겸 시약으로 이론량 이상의 과량을 사용하는 기존 선행 기술에 비하여 경제적이고, 셋째로 필요 이상의 온도 이상에서 반응을 진행하지 않아 생성물에 대해 가혹하지 않아 순도가 높고 효율적이며, 결과적으로 높은 수율로 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 제조할 수 있는 효과를 제공한다.
The present invention reacts N-methyl-O-phenylene-diamine (3) with 2-n-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (2) using phosphorus oxychloride in a nonpolar solvent. To prepare 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1), which is difficult to handle at room temperature as in the prior art. It is useful because it does not add reagents and reagents at high temperatures, so it does not include dangerous processes that affect the safety of the operator. Second, since it uses the required amount of reagents, it is useful as compared to the existing prior art which uses more than theoretical amount as a solvent and reagent. Economical, thirdly, it does not proceed above the required temperature, so it is not harsh on the product, so it is high in purity and efficient, resulting in 2-n-propyl-4-methyl-6- (1-methylbenzimine in high yield Effect of the preparation of dazol-2-yl) -1H-benzimidazole (1) Lt; / RTI >
이하, 본 발명이 이루고자하는 기술적 과제를 자세히 설명한다.Hereinafter, the technical problem to be achieved by the present invention will be described in detail.
[반응식 4]Scheme 4
본 발명은 상기 [반응식 4]와 같이 비극성 용매 중에서 옥시염화인을 사용하여 N-메틸-O-페닐렌-디아민(3)과 2-n-프로필-4-메틸-1H-벤즈이미다졸-6-카복실산(2)과의 반응을 통하여 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 제조한다. The present invention relates to N-methyl-O-phenylene-diamine (3) and 2-n-propyl-4-methyl-1H-benzimidazole-6 using phosphorus oxychloride in a nonpolar solvent as shown in [Scheme 4]. 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1) is prepared via reaction with carboxylic acid (2).
본 발명은 비극성 용매 중에서 옥시염화인을 사용하여 공업적인 대량 생산에 적용하기 용이한 조건으로 고순도, 고수율로 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 제조할 수 있다.
The present invention utilizes phosphorus oxychloride in a non-polar solvent in a high purity, high yield in 2-n-propyl-4-methyl-6- (1-methylbenzimidazole-2- in conditions that are easy to apply to industrial mass production. I) -1H-benzimidazole (1) can be prepared.
상기 [반응식 4]에서 비극성 용매로는 자일렌, 1,4-디옥산, 톨루엔으로부터 선택되는 단일 용매 또는 2가지 이상으로 구성된 혼합 용매를 사용할 수 있고, 가장 바람직하게는 톨루엔을 사용한다.
As the non-polar solvent in [Scheme 4], a single solvent selected from xylene, 1,4-dioxane, toluene, or a mixed solvent composed of two or more may be used, and most preferably toluene is used.
상기 [반응식 4]에서 이용되는 옥시염화인 사용량은 2-n-프로필-4-메틸-1H-벤즈이미다졸-6-카복실산(2) 몰당량의 1.0 내지 약 6.0 몰당량이 바람직 하며, 가장 바람직하게는 4.0 당량이다.
The amount of phosphorus oxychloride used in [Scheme 4] is preferably 1.0 to about 6.0 molar equivalents of 2-n-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (2), and most preferably It is 4.0 equivalent.
상기 [반응식 4]에서 비극성 용매에 용해된 N-메틸-O-페닐렌-디아민(3)에 옥시염화인을 처리한 후 2-n-프로필-4-메틸-1H-벤즈이미다졸-6-카복실산(2)을 첨가한 후 반응 온도는 100~110℃, 반응 시간은 5시간~15시간 동안 진행하는 것이 바람직하다.
Phosphorous oxychloride was treated with N-methyl-O-phenylene-diamine (3) dissolved in a nonpolar solvent in [Scheme 4], followed by 2-n-propyl-4-methyl-1H-benzimidazole-6- After adding carboxylic acid (2), it is preferable that reaction temperature is 100-110 degreeC, and reaction time advances for 5 to 15 hours.
이러한 반응 공정을 통해 제조된 생성물은 후처리 반응(work up) 과정 후 반응 용매를 감압하에 농축하여 제거하고 중성화 한 후 비수성 유기용매를 사용하여 결정화할 수 있으며, 바람직한 비수성 유기용매는 에틸 아세테이트, 이소프로필 아세테이트이며 에틸 아세테이트가 가장 바람직하다.
The product prepared through this reaction process can be removed by neutralization after removal of the reaction solvent under reduced pressure after work-up process and neutralization, and the preferred non-aqueous organic solvent is ethyl acetate. Isopropyl acetate and ethyl acetate is most preferred.
본 발명의 방법에서 적용되는 반응 조건은 기존 선행 기술들의 제조 방법상 존재하는 상온에서 취급하기 어려운 시약을 사용하거나 고온에서 시약을 첨가하여 작업자의 안전에 영향을 끼치는 위험한 공정을 포함하지 않으며, 필요 이상의 온도에서 반응이 진행되지 않아 생성물에 대해 온화하며 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)을 훨씬 더 높은 수율로 얻으면서 공업적인 규모에 적합화 될 수 있다.
The reaction conditions applied in the method of the present invention do not include dangerous processes that affect the safety of the operator by using reagents that are difficult to handle at room temperature or by adding reagents at high temperature, which exist in the manufacturing methods of the existing prior art, The reaction does not proceed at temperature, which is mild to the product and yields much higher yield of 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1). Can be adapted to industrial scale.
또한, 본 발명에 따른 제조 방법에 의해 얻어진 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)로부터 텔미사르탄을 제조한 결과 고순도, 고수율의 텔미사르탄을 얻을 수 있음을 확인 하였다.
Further, telmisartan is prepared from 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1) obtained by the production method according to the present invention. As a result, it was confirmed that telmisartan of high purity and high yield was obtained.
이하 본 발명을 다음의 실시 예에 의거하여 더욱 상세히 설명하는 바, 본 발명이 이에 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
실시예 1 : 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)의 제조
Example 1 Preparation of 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1)
N-메틸-O-페닐렌-디아민(3) 50.01g을 자일렌 560mL에 용해하고, 5℃로 냉각한 뒤 옥시염화인 76.5mL를 가하고 상온에서 1시간 교반하고, 2-n-프로필-4-메틸-1H-벤즈이미다졸-6-카복실산(2) 44.75g을 첨가 한 뒤 환류 교반하여 반응을 진행 시킨다. 반응액을 5℃로 냉각한 후 수산화 나트륨 수용액 560mL를 가한 뒤 염산 수용액을 사용하여 중성화 한다. 반응 혼합물의 유기용매를 감압 농축하여 유기용매를 제거한 뒤 에틸 아세테이트 220mL를 첨가하여 생성된 결정을 상온에서 2시간 교반 시킨 후 여과하고 상수 450mL와 에틸 아세테이트 100mL로 세척하고 60℃에서 건조하여 표제 화합물 58.03g(수율: 93%)을 얻었다.
50.01 g of N-methyl-O-phenylene-diamine (3) was dissolved in 560 mL of xylene, cooled to 5 ° C., 76.5 mL of phosphorus oxychloride was added, stirred at room temperature for 1 hour, and 2-n-propyl-4. 44.75 g of methyl-1H-benzimidazole-6-carboxylic acid (2) is added, followed by stirring under reflux to proceed with the reaction. After the reaction solution was cooled to 5 ° C, 560 mL of sodium hydroxide aqueous solution was added and neutralized with an aqueous hydrochloric acid solution. The organic solvent of the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and 220 mL of ethyl acetate was added thereto. The resulting crystals were stirred at room temperature for 2 hours, filtered, washed with a constant 450 mL and 100 mL of ethyl acetate, dried at 60 ° C., and the title compound 58.03 g (yield: 93%) was obtained.
실시예 2 : 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)의 제조
Example 2 Preparation of 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1)
N-메틸-O-페닐렌-디아민(3) 30.0g을 1,4-디옥산 및 톨루엔 혼합용매 400mL에 용해하고, 5℃로 냉각한 뒤 옥시염화인 46mL를 가하고 상온에서 1시간 교반하고, 2-n-프로필-4-메틸-1H-벤즈이미다졸-6-카복실산(2) 26.9g을 첨가 한 뒤 환류 교반하여 반응을 진행 시킨다. 반응액을 5℃로 냉각한 후 수산화 나트륨 수용액 270mL를 가한 뒤 염산 수용액을 사용하여 중성화 한다. 반응 혼합물의 유기용매를 감압 농축하여 유기용매를 제거한 뒤 에틸 아세테이트 135mL를 첨가하여 생성된 결정을 상온에서 2시간 교반 시킨 후 여과하고 상수 300mL와 에틸 아세테이트 70mL로 세척하고 60℃에서 건조하여 표제 화합물 34.7g(수율: 92.5%)을 얻었다.
30.0 g of N-methyl-O-phenylene-diamine (3) was dissolved in 400 mL of a mixed solvent of 1,4-dioxane and toluene, cooled to 5 ° C, 46 mL of phosphorus oxychloride was added, and stirred at room temperature for 1 hour, 26.9 g of 2-n-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (2) was added, followed by stirring under reflux to proceed with the reaction. After the reaction solution was cooled to 5 ° C., 270 mL of an aqueous sodium hydroxide solution was added and neutralized with an aqueous hydrochloric acid solution. The organic solvent of the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and 135 mL of ethyl acetate was added thereto. The resulting crystals were stirred at room temperature for 2 hours, filtered, washed with a constant 300 mL and 70 mL of ethyl acetate, dried at 60 ° C., and the title compound 34.7. g (yield: 92.5%) was obtained.
실시예 3 : 2-n-프로필-4-메틸-6-(1-메틸벤즈이미다졸-2-일)-1H-벤즈이미다졸(1)의 제조
Example 3 Preparation of 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (1)
N-메틸-O-페닐렌-디아민(3) 626.2g을 톨루엔 5.6L에 용해하고, 5℃로 냉각한 뒤 옥시염화인 956mL를 가하고 상온에서 1시간 교반하고, 2-n-프로필-4-메틸-1H-벤즈이미다졸-6-카복실산(2) 559.4g을 첨가 한 뒤 환류 교반하여 반응을 진행 시킨다. 반응액을 5℃로 냉각한 후 수산화 나트륨 수용액 5.6L를 가한 뒤 염산 수용액을 사용하여 중성화 한다. 반응 혼합물의 유기용매를 감압 농축하여 유기용매를 제거한 뒤 에틸 아세테이트 2.8L를 첨가하여 생성된 결정을 상온에서 2시간 교반 시킨 후 여과하고 상수 6L와 에틸 아세테이트 1.4L로 세척하고 60℃에서 건조하여 표제 화합물 741.3g(수율: 95%)을 얻었다. 626.2 g of N-methyl-O-phenylene-diamine (3) was dissolved in 5.6 L of toluene, cooled to 5 ° C., 956 mL of phosphorus oxychloride was added and stirred at room temperature for 1 hour, and 2-n-propyl-4- 559.4 g of methyl-1H-benzimidazole-6-carboxylic acid (2) is added thereto, followed by stirring under reflux to proceed with the reaction. After the reaction solution was cooled to 5 ° C., 5.6 L of sodium hydroxide aqueous solution was added thereto, followed by neutralization with an aqueous hydrochloric acid solution. The organic solvent of the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and 2.8 L of ethyl acetate was added thereto. The resulting crystals were stirred at room temperature for 2 hours, filtered, washed with a constant 6 L and 1.4 L of ethyl acetate, and dried at 60 ° C. 741.3 g (yield 95%) of compound was obtained.
1H-NMR(CDCl3) δ 0.9(t,3H), 1.7(m,2H), 2.6(s,3H), 2.8 (t,2H), 3.9(s,3H), 1 H-NMR (CDCl 3 ) δ 0.9 (t, 3H), 1.7 (m, 2H), 2.6 (s, 3H), 2.8 (t, 2H), 3.9 (s, 3H),
7.3-7.5(m,4H) 7.8(d,2H)
7.3-7.5 (m, 4H) 7.8 (d, 2H)
Claims (4)
N-methyl-O-phenylene-diamine (3) and 2-n-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (2) were reacted with phosphorus oxychloride in a nonpolar solvent to give 2- Method for preparing n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -1H-benzimidazole (Compound 1)
The method according to claim 1, wherein the nonpolar solvent is a solvent composed of at least one selected from xylene, 1,4-dioxane and toluene.
The method according to claim 1 or 2, wherein the amount of phosphorus oxychloride used is 1.0 to 6.0 molar equivalents relative to molar equivalents of 2-n-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid.
The process according to claim 1 or 2, wherein the reaction proceeds at 100 to 110 ° C. for 5 to 15 hours.
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| WO2007010558A1 (en) | 2005-07-19 | 2007-01-25 | Matrix Laboratories Limited | A process for the preparation of telmisartan |
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| WO2007010558A1 (en) | 2005-07-19 | 2007-01-25 | Matrix Laboratories Limited | A process for the preparation of telmisartan |
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