KR100559800B1 - Methyl 1,1, nitrogen-trimethyl- (3,3-diphenylpropyl) -2-aminoethyl-1,4-dihydro-2,6-dimethyl-4 (3-nitrophenyl) -pyridine-3,5 -New Method for Making Dicarboxylate Hydrochloride - Google Patents
Methyl 1,1, nitrogen-trimethyl- (3,3-diphenylpropyl) -2-aminoethyl-1,4-dihydro-2,6-dimethyl-4 (3-nitrophenyl) -pyridine-3,5 -New Method for Making Dicarboxylate Hydrochloride Download PDFInfo
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Abstract
본 발명은 구조식(I)의 항고혈압제인 메틸 1,1,N-트리메틸-(3,3-디페닐프로필)-2-아미노에틸-1,4-디하이드로-2,6-디메틸-4(3-니트로페닐)-피리딘-3,5-디카르복실레이트(레르카니디핀) 또는 그 염의 개량된 제조방법에 관한 것이다. 본 발명은 전체적인 반응공정과 시간이 비교적 짧으며, 양성자성 용매하에서 새로운 중간체인 1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸-3-아미노크로토네이트를 메틸 α-아세틸-3-니트로신나메이트와 반응시킴으로써 까다로운 정제공정 없이 높은 수율로 목적하는 화합물을 합성할 수 있는 신규의 개량된 방법이다.The present invention relates to methyl 1,1, N-trimethyl- (3,3-diphenylpropyl) -2-aminoethyl-1,4-dihydro-2,6-dimethyl-4, which is an antihypertensive agent of formula (I) It relates to an improved process for the preparation of 3-nitrophenyl) -pyridine-3,5-dicarboxylate (lercanidipine) or salts thereof. The present invention is relatively short in overall reaction process and time, and is a new intermediate 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl-3-aminocroto under protic solvent. It is a novel and improved process that allows the reaction of a nate with methyl α-acetyl-3-nitrocinnamate to synthesize the desired compound in high yield without the demanding purification process.
새로운 중간체, 1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸-3-아미노크로토네이트, 레르카니디핀 하이드로클로라이드New intermediates, 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl-3-aminocrotonate, lercanidipine hydrochloride
Description
본 발명은 구조식(I)의 메틸 1,1,N-트리메틸-(3,3-디페닐프로필)-2-아미노에틸-1,4-디하이드로-2,6-디메틸-4(3-니트로페닐)-피리딘-3,5-디카르복실레이트(일반명 : 레르카니디핀) 하이드로클로라이드를 제조하는 새롭고 개량된 방법에 관한 것이다.The present invention relates to methyl 1,1, N-trimethyl- (3,3-diphenylpropyl) -2-aminoethyl-1,4-dihydro-2,6-dimethyl-4 (3-nitro of formula (I) Phenyl) -pyridine-3,5-dicarboxylate (common name: lercanidipine) hydrochloride relates to a new and improved process for preparing hydrochloride.
[구조식(I)][Structure Formula (I)]
레르카니디핀은 미국 특허 제4705797호에 상술된 바 있는데, 이는 제 3세대 디하이드로피리딘 계열의 칼슘채널차단제(L-형태의 칼슘채널 길항물질)로 항고혈압제 및 안기나(인후 편도선의 염증 등)와 관상동맥 질환을 치료하는데 사용되는 물질로 밝혀졌다.Lercanidipine has been described in U.S. Patent No. 4705797, which is a third-generation dihydropyridine-based calcium channel blocker (L-type calcium channel antagonist) and an antihypertensive agent and angina (such as inflammation of the throat tonsil). And substances that have been used to treat coronary artery disease.
레르카니디핀의 제조방법은 미국 특허 제4705797호에 기술되어 있는데, 이것은 다음의 반응식과 같다.A method for preparing lercanidipine is described in US Pat. No. 4705797, which is represented by the following scheme.
[반응식 1]Scheme 1
이 반응식에 따르면 아미노알콜(1)은 디케텐과 에스테르화 반응을 하여 아세토아세테이트(2)가 형성되고, 이것을 3-니트로벤즈알데히드와 반응시켜 1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸 α-아세틸-3-니트로신나메이트(3)를 만든다. 그 다음 이것을 이소프로판올 용매하에서 메틸 3-아미노크로토네이트와 환류교반하여 고리를 형성함으로써 레르카니디핀을 합성하였다. According to this scheme, aminoalcohol (1) is esterified with diketene to form acetoacetate (2), which is reacted with 3-nitrobenzaldehyde to react with 1,1, N-trimethyl-N- (3,3- Diphenylpropyl) -2-aminoethyl α-acetyl-3-nitrocinnamate (3) is prepared. Lercanidipine was synthesized by then refluxing with methyl 3-aminocrotonate in isopropanol solvent to form a ring.
이와 같은 공정은 여러 가지 단점이 있다. 첫 번째로 중간체(3)을 합성하는 단계에서 반응시간만 3일이나 걸리는 것과 두 번째로 아세토아세테이트(2)를 합성하는 단계와 최종 단계에서 각각 부산물을 제거하기 위해 칼럼 크로마토그래피와 같은 정제기술이 요구되는데 이는 대규모 생산에 적용하기에는 난점이 있다. 또한 최종 단계의 수득률은 36%이고 전반적인 공정 수득률은 26%로 비교적 수율이 낮다. 세 번째로 이 공정에 의해 수득된 생성물은 녹는점이 119~123℃인 레르카니디핀 하이드로클로라이드 헤미하이드레이트로 흡습 성질이 있어 조성물에는 부적절하고 제약학적 조성물을 만드는 과정에서 취급이 어려우며, 안정성도 만족스럽지 못한 것으로 알려져 있다(한국 공개특허 특1999-008378).Such a process has several disadvantages. First, the reaction time takes three days in the synthesis of the intermediate (3), and second, purification techniques such as column chromatography to remove by-products in the synthesis and acetoacetate (2) stages. This is a challenge for large-scale production. In addition, the final step yield is 36% and overall process yield is 26%, which is relatively low in yield. Third, the product obtained by this process is ercanidipine hydrochloride hemihydrate with melting point of 119 ~ 123 ℃, which is inadequate for the composition, difficult to handle in the process of making pharmaceutical composition, and unstable in stability. It is known that (Korean Patent Laid-Open Patent No. 1999-008378).
본 발명에서는 목적 화합물을 합성하는데 있어 공지방법의 단점인 비교적 긴 공정시간, 칼럼 크로마토그래피를 통한 정제공정 및 낮은 수율, 최종 물질이 하이드로클로라이드 헤미하이드레이트 형태의 결정형으로 얻어짐으로써 발생하는 문제점 등을 개선하고 공업적인 생산을 용이하게 하기 위하여 공지방법과 상이한 제조공정 및 새로운 중간체를 통하여 비교적 단시간에 칼럼 크로마토그래피 등의 정제공정 없이 높은 수율 및 바람직한 결정형인 하이드로클로라이드 무수물로의 목적화합물을 제조하는데 그 목적이 있다.
In the present invention, a relatively long process time, a purification process through column chromatography, and a low yield, which are disadvantages of the known method for synthesizing the target compound, improve the problems caused by obtaining the final material in the form of a hydrochloride hemihydrate form In order to facilitate the industrial production and to prepare the target compound in the hydrochloride anhydride, which is a high yield and the preferred crystalline form, without the purification process such as column chromatography in a relatively short time through a different manufacturing process and a new intermediate than the known method. have.
본 발명은 새로운 중간체 1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸-3-아미노크로토네이트(4)의 합성과 이 중간체를 이용하여 새로운 공정으로 레르카니디핀을 제조하는 것을 특징으로 한다.The present invention provides the synthesis of a new intermediate 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl-3-aminocrotonate (4) and a new process using this intermediate. It is characterized by preparing lercanidipine.
본 발명의 공정은 다음의 반응식에 의해 설명될 수 있다.The process of the present invention can be illustrated by the following scheme.
[반응식 2]Scheme 2
본 발명은 레르카니디핀을 제조하는데 있어 [반응식 2]에 나타낸 바와 같이 아미노알콜(1)을 2,2,6-트리메틸-4H-1,3-디옥신-4-온(디케텐 아세톤 부가물)으로 에스테르화 반응시켜 아세토아세테이트(2)를 합성하고, 이것을 알콜 용매하에서 암모늄 아세테이트 촉매를 사용하여 암모니아수와 반응시켜 새로운 중간체인 1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸-3-아미노크로토네이트(4)를 합성한다. 그다음 이것을 양성자성 용매하에서 메틸 α-아세틸-3-니트로신나메이트와 고리화반응을 시켜서 레르카니디핀을 합성한다.In the present invention, in the preparation of lercanidipine, aminoalcohol (1) is used as 2,2,6-trimethyl-4H-1,3-dioxin-4-one (diketene acetone adduct) as shown in [Scheme 2]. Esterification reaction to synthesize acetoacetate (2), which was then reacted with aqueous ammonia using an ammonium acetate catalyst in an alcoholic solvent to form a new intermediate, 1,1, N-trimethyl-N- (3,3-diphenylpropyl). ) -2-aminoethyl-3-aminocrotonate (4) is synthesized. This is then cyclized with methyl α-acetyl-3-nitrocinnamate in a protic solvent to synthesize lercanidipine.
에스테르화 반응에서는 디케텐을 사용하지 않고 디케텐의 아세톤 부가물인 2,2,6-트리메틸-4H-1,3-디옥신-4-온을 사용하였다. 이때 용매는 벤젠, 톨루엔, 크실렌, 1,4-디옥산 등을 사용할 수 있고, 촉매로 트리에틸아민을 사용할 수 있으며, 바람직하게는 크실렌 용매를 사용하는 것이고, 제일 바람직한 것은 1,4-디옥산을 용매로 하고 트리에틸아민을 촉매로 사용하는 것이다.In the esterification reaction, 2,2,6-trimethyl-4H-1,3-dioxin-4-one, which is an acetone adduct of diketene, was used without diketene. In this case, benzene, toluene, xylene, 1,4-dioxane, etc. may be used, and triethylamine may be used as a catalyst, and preferably, xylene solvent is used. Most preferably, 1,4-dioxane is used. Is used as a solvent and triethylamine is used as a catalyst.
새로운 중간체인 아미노크로토네이트(4)의 합성반응에서는 용매로써 암모니아수 또는 선택적으로 에틸 아세테이트나 메탄올, 에탄올, n-프로판올, i-프로판올, n-부탄올, s-부탄올, t- 부탄올 등의 양성자성 용매를 혼합용매로 사용할 수 있으며, 촉매로 빙초산 또는 암모늄 아세테이트를 사용할 수 있고, 바람직하게는 에탄올 용매와 촉매로 암모늄 아세테이트를 사용하여 암모니아수와 반응시키는 것이 좋다. In the synthesis of the new intermediate aminocrotonate (4), the proticity of ammonia water or optionally ethyl acetate or methanol, ethanol, n-propanol, i-propanol, n-butanol, s-butanol, t-butanol, etc. The solvent may be used as a mixed solvent, glacial acetic acid or ammonium acetate may be used as a catalyst, preferably ammonium acetate as the ethanol solvent and the catalyst is preferably reacted with ammonia water.
최종 단계에서는 새로운 중간체인 아미노크로토네이트(4)를 메틸 α-아세틸-3-니트로신나메이트와 고리화반응을 시킴으로써 레르카니디핀을 합성할 수 있는데, 이때의 용매로는 메탄올, 에탄올, n-프로판올, i-프로판올, n-부탄올, s-부탄올, t-부탄올 등의 양성자성 용매를 사용할 수 있으며, 그 중에서 메탄올과 에탄올이 가장 적합한 용매이다.In the final step, lercanidipine can be synthesized by cyclization of a new intermediate, aminocrotonate (4), with methyl α-acetyl-3-nitrocinnamate. Protic solvents such as propanol, i-propanol, n-butanol, s-butanol and t-butanol can be used, of which methanol and ethanol are the most suitable solvents.
본 발명에 따라 제조된 레르카니디핀은 알콜성 염화수소, 에틸 아세테이트나 에테르성 염화수소 등을 이용하여 염화처리 할 수 있고, 다음의 두 가지 방법에 의하여 하이드로클로라이드 무수 결정형으로 얻을 수 있다. Lercanidipine prepared according to the present invention can be chlorinated using alcoholic hydrogen chloride, ethyl acetate or ethereal hydrogen chloride, etc., and can be obtained in hydrochloride anhydrous crystalline form by the following two methods.
가) 에틸 아세테이트, 메틸 아세테이트, 아세톤 같은 반 양성자성 용매로부터 결정화한 후에 메탄올, 에탄올, n-프로판올, i-프로판올, n-부탄올, s-부탄올, t-부탄올 등의 양성자성 용매를 하나 또는 선택적으로 혼합해서 사용하여 재결정함으로써 얻는다. A) one or selective protic solvents such as methanol, ethanol, n-propanol, i-propanol, n-butanol, s-butanol, t-butanol, etc. after crystallization from semiprotic solvents such as ethyl acetate, methyl acetate, acetone It is obtained by mixing and recrystallization using.
나) 아세톤이나 클로로포름과 에테르나 헥산 같은 반 양성자성 용매를 이용한 침전법으로 하이드로클로라이드 헤미하이드레이트 결정(녹는점 : 118~122℃)을 얻은 후에 가) 항과 같은 방법을 다시 반복함으로써 하이드로클로라이드 무수 결정형을 얻는다.B) hydrochloride hemihydrate crystals (melting point: 118 ~ 122 ℃) by precipitation method using acetone or chloroform and semiprotic solvents such as ether or hexane. Get
이러한 방법으로 얻은 무수 결정형들은 184 내지 188℃ 범위에서 녹는다.Anhydrous crystalline forms obtained in this way are soluble in the range of 184-188 ° C.
이하 본 발명을 다음의 실시예에 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]Example 1
1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸 아세토아세테이트1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl acetoacetate
10.0g의 2,N-디메틸-N-(3,3-디페닐프로필)-1-아미노-2-프로판올을 100ml의 1,4-디옥산에 용해시키고, 0.04ml의 트리에틸아민을 가하고 환류하면서 10분에 걸쳐 5.6g의 2,2,6-트리메틸-4H-1,3-디옥신-4-온(디케텐 아세톤 부가물)을 적가한다. 반응 중에 발생하는 아세톤을 대기로 배출시키며 2시간동안 가열한다. 반응액을 25℃로 냉각시킨 후, 혼합물을 진공 증발시켜서 표제화합물을 12.5g의 오일로 수득한다. Dissolve 10.0 g of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol in 100 ml of 1,4-dioxane, add 0.04 ml of triethylamine and reflux 5.6 g of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (diketene acetone adduct) is added dropwise over 10 minutes. Acetone generated during the reaction is discharged to the atmosphere and heated for 2 hours. After cooling the reaction solution to 25 ° C., the mixture is evaporated in vacuo to yield the title compound as 12.5 g of oil.
[실시예 2]Example 2
1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸-3-아미노크로토네이트1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl-3-aminocrotonate
실시예 1에서 제조된 화합물 12.5g을 30ml 에탄올에 용해시키고, 28ml의 암모니아수, 0.3g의 암모늄아세테이트를 가하고 5시간동안 교반한다. 반응액을 190ml 에틸 아세테이트로 희석시키고 100ml의 포화된 염화나트륨 용액으로 3회 세척한다. 유기층을 분리하고, 30분간 무수황산마그네슘으로 건조시키고 여과한 다음에 여액을 진공 하에서 농축시켜서 표제화합물을 12.6g의 오일로 수득한다. 이것은 별도의 정제과정 없이 이후 더 반응시키는데 사용한다.12.5 g of the compound prepared in Example 1 was dissolved in 30 ml ethanol, 28 ml of ammonia water and 0.3 g of ammonium acetate were added and stirred for 5 hours. The reaction solution is diluted with 190 ml ethyl acetate and washed three times with 100 ml of saturated sodium chloride solution. The organic layer is separated, dried over anhydrous magnesium sulfate for 30 minutes, filtered and the filtrate is concentrated in vacuo to yield the title compound as an oil of 12.6 g. This is then used for further reaction without further purification.
[실시예 3]Example 3
메틸 1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸 1,4-디하이드로-2,6-디메틸-4-(3-니트로페닐)피리딘-3,5-디카르복실레이트(레르카니디핀) 하이드로클로라이드Methyl 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3, 5-dicarboxylate (lercanidipine) hydrochloride
실시예 2에서 제조된 화합물 12.6g 및 7.8g의 메틸 α-아세틸-3-니트로신나메이트를 160ml의 에탄올에서 8시간동안 환류시킨다. 혼합물을 냉각시키고 약간 과량의 에탄올성 염화수소를 가한 다음에 혼합물을 진공 하에서 농축시킨다. 잔류물을 에틸 아세테이트에 용해시키고 다시 농축시킨 다음, 잔류물을 120ml의 에틸 아세테이트로 용해시키고 무수의 레르카니디핀 하이드로클로라이드 소량을 가한다. 0~5℃에서 24시간 이상 방치한 후에 생성된 고체를 여과하고 순수한 에탄올과 이소프로필 알콜로 재결정시켜 무수의 레르카니디핀 하이드로클로라이드 14.0g(이론치의 69%)을 수득한다. 융점 185~187℃.12.6 g and 7.8 g of methyl α-acetyl-3-nitrocinnamate prepared in Example 2 are refluxed in 160 ml of ethanol for 8 hours. The mixture is cooled, a slight excess of ethanol hydrogen chloride is added and the mixture is concentrated in vacuo. The residue is dissolved in ethyl acetate and concentrated again, then the residue is dissolved with 120 ml of ethyl acetate and a small amount of anhydrous lercanidipine hydrochloride is added. After standing at 0-5 [deg.] C. for at least 24 hours, the resulting solid is filtered and recrystallized from pure ethanol and isopropyl alcohol to give 14.0 g of anhydrous lercanidipine hydrochloride (69% of theory). Melting point 185-187 degreeC.
[실시예 4]Example 4
메틸 1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸 1,4-디하이드로-2,6-디메틸-4-(3-니트로페닐)피리딘-3,5-디카르복실레이트(레르카니디핀) 하이드로클로라이드 헤미하이드레이트Methyl 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3, 5-dicarboxylate (lercanidipine) hydrochloride hemihydrate
실시예 2와 같은 방법으로 제조된 화합물 6.2g 및 3.8g의 메틸 α-아세틸-3-니트로신나메이트를 80ml의 메탄올에서 8시간동안 환류시킨다. 혼합물을 냉각시키고 약간 과량의 에탄올성 염화수소를 가한 다음에 혼합물을 진공 하에서 농축시킨다. 잔류물을 아세톤에 용해시키고 다시 농축시킨다. 잔류물을 23ml의 아세톤에 용해시키고, 10ml의 아세톤과 440ml의 에테르 혼합액에 서서히 떨어뜨리며 교반한다. 침전물을 여과하여 레르카니디핀 하이드로클로라이드 헤미하이드레이트 7.8g(이론치의 78%)을 수득한다. 융점 118~122℃.6.2 g and 3.8 g of methyl α-acetyl-3-nitrocinnamate prepared in the same manner as in Example 2 were refluxed in 80 ml of methanol for 8 hours. The mixture is cooled, a slight excess of ethanol hydrogen chloride is added and the mixture is concentrated in vacuo. The residue is dissolved in acetone and concentrated again. The residue is dissolved in 23 ml of acetone and stirred dropwise into 10 ml of acetone and 440 ml of ether mixture. The precipitate is filtered to give 7.8 g (78% of theory) of lercanidipine hydrochloride hemihydrate. Melting point 118-122 degreeC.
[실시예 5]Example 5
레르카니디핀 하이드로클로라이드Lercanidipine hydrochloride
실시예 4에서 제조한 레르카니디핀 하이드로클로라이드 헤미하이드레이트 7.8g을 38ml 에틸 아세테이트에 용해시키고 1시간 환류시킨 다음, 실온까지 냉각하고 무수의 레르카니디핀 하이드로클로라이드 소량을 가한다. 0~5℃에서 24시간 이상 방치한 후에 생성된 고체를 여과하고 순수한 에탄올과 이소프로필 알콜로 재결정시켜 무수의 레르카니디핀 하이드로클로라이드 6.6g을 수득한다. 융점 186~188℃.7.8 g of lercanidipine hydrochloride hemihydrate prepared in Example 4 is dissolved in 38 ml ethyl acetate and refluxed for 1 hour, then cooled to room temperature and a small amount of anhydrous lercanidipine hydrochloride is added. After standing at 0-5 ° C. for at least 24 hours, the resulting solid is filtered and recrystallized with pure ethanol and isopropyl alcohol to give 6.6 g of anhydrous lercanidipine hydrochloride. Melting point 186-188 degreeC.
새로운 중간체인 1,1,N-트리메틸-N-(3,3-디페닐프로필)-2-아미노에틸-3-아미노크로토네이트(4)를 통하여 새로운 방법으로 레르카니디핀 하이드로클로라이드를 제조할 수 있으며, 칼럼 크로마토그래피 같은 정제기술이 필요치 않고 일반적인 결정화 또는 재결정화 방법으로 목적 화합물을 비교적 고수율 및 고순도로 얻을 수 있기 때문에 경제적이며 공업적인 대량생산을 위해 적용이 가능하다.Lercanidipine hydrochloride can be prepared by a new method via the new intermediate 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl-3-aminocrotonate (4). It is possible to apply for economical and industrial mass production since purification technology such as column chromatography is not required and the target compound can be obtained in a relatively high yield and purity by a general crystallization or recrystallization method.
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