KR101029643B1 - Process for producing N-methyl-3,3-diphenylpropylamine - Google Patents
Process for producing N-methyl-3,3-diphenylpropylamine Download PDFInfo
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Abstract
본 발명은 N,N-디메틸-3,3-디페닐프로필아민을 탈메틸화 반응을 통하여 카바메이트 유도체를 제조하고, 가수분해반응을 거쳐 다음 화학식 (I)의 N-메틸-3,3-디페닐프로필아민을 제조하는 신규의 방법을 제공한다. In the present invention, a carbamate derivative is prepared by demethylation of N, N-dimethyl-3,3-diphenylpropylamine, and then hydrolyzed to N-methyl-3,3-di of formula (I). Provided is a novel process for preparing phenylpropylamine.
본 발명에 따라 제조된 N-메틸-3,3-디페닐프로필아민은 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) 하이드로클로라이드의 제조에 사용할 수 있는 중간체이다. N-methyl-3,3-diphenylpropylamine prepared according to the present invention is methyl 1,1, N-trimethyl- (3,3-diphenylpropyl) -2-aminoethyl-1,4-, an antihypertensive agent. It is an intermediate which can be used for the preparation of dihydro-2,6-dimethyl-4 (3-nitrophenyl) -pyridine-3,5-dicarboxylate (lercanidipine) hydrochloride.
N-메틸-3,3-디페닐프로필아민, 레르카니디핀, N,N-디메틸-3,3-디페닐프로필아민N-methyl-3,3-diphenylpropylamine, lercanidipine, N, N-dimethyl-3,3-diphenylpropylamine
Description
본 발명은 의약품등의 제조에 사용되는 화학식 (I)의 N-메틸-3,3-디페닐프로필아민을 제조하는 신규 방법에 관한 것이다.
The present invention relates to a novel process for producing N-methyl-3,3-diphenylpropylamine of formula (I) for use in the manufacture of pharmaceuticals and the like.
[화학식 1][Formula 1]
상기 화학식 (I)의 화합물은 항고혈압제인 메틸 1,1,N-트리메틸-(3,3-디페닐프로필)-2-아미노에틸-1,4-디하이드로-2,6-디메틸-4(3-니트로페닐)-피리딘-3,5-디 카르복실레이트(레르카니디핀) 하이드로클로라이드의 제조 등에 사용할 수 있는 중간체이다.
The compound of formula (I) is an antihypertensive methyl 1,1, N-trimethyl- (3,3-diphenylpropyl) -2-aminoethyl-1,4-dihydro-2,6-dimethyl-4 ( It is an intermediate which can be used for manufacture of 3-nitrophenyl) -pyridine-3,5-di carboxylate (lercanidipine) hydrochloride, and the like.
상기 화학식 (I) 화합물의 일반적인 제조방법은 독일특허 제 925468호에 기술되어 있는데 반응식은 다음과 같다.
A general method for preparing the compound of formula (I) is described in German Patent No. 925468, where the reaction scheme is as follows.
[반응식 1]Scheme 1
이 반응식에 따르면 아세토페논을 벤질메틸아민, 파라포름알데히드와 반응을 시켜서 β-(메틸벤질아미노)-에틸페닐케톤 하이드로클로라이드 (1)를 만들고, 이것을 페닐마그네슘브로마이드와 반응을 시켜서 1,1-디페닐-3-(메틸벤질아미노)-프로판올-1 (2)을 만든 다음, 여기에 인산을 가하여 130℃에서 1시간 환류 교반한다. 그 다음 반응액을 수산화나트륨 수용액으로 알칼리화하고 에테르로 추출한 후에 감압 농축한다. 얻은 잔류물을 메탄올로 용해하고 농염산을 가하여 중화시킨 다음, 수소화 반응을 통하여 벤질그룹을 제거하여 원하는 최종물질인 N-메틸-3,3-디페닐 프로필아민 (I)을 얻는다.
According to this scheme, acetophenone is reacted with benzylmethylamine and paraformaldehyde to form β- (methylbenzylamino) -ethylphenylketone hydrochloride (1), which is then reacted with phenylmagnesium bromide to produce 1,1-di Phenyl-3- (methylbenzylamino) -propanol-1 (2) is prepared, and phosphoric acid is added thereto, followed by stirring under reflux at 130 ° C for 1 hour. The reaction solution is then alkalized with aqueous sodium hydroxide solution, extracted with ether and concentrated under reduced pressure. The obtained residue is dissolved in methanol, neutralized by addition of concentrated hydrochloric acid, and benzyl group is removed by hydrogenation to obtain N-methyl-3,3-diphenyl propylamine (I) as a desired final substance.
이와 같은 공정은 여러 가지 단점이 있다. 첫 번째로 중간체 (2)를 합성하는 단계에서 먼저 에테르용매에서 페닐마그네슘브로마이드를 만들어야 하는데 이것이 수분에 민감하여 잘 만들어지지 않고 반응 수율이 약 30.6%로 매우 낮으며 순도도 좋지 않다. 두 번째로 최종 단계에서 벤질그룹을 제거하기 위하여 수소와 팔라듐 촉매를 이용한 가압반응이 필요한데 이를 위해서는 가압반응기 설비가 필요하며, 고가의 팔라듐 촉매를 사용해야 하고 수소폭발의 위험성도 있다. 따라서 이 공정은 공업적인 대량생산에서 용이하지 않으며 경제적이지도 못하다.
Such a process has several disadvantages. First, in the step of synthesizing intermediate (2), phenylmagnesium bromide should be first produced in an ether solvent, which is sensitive to moisture and is not well formed. The reaction yield is very low, about 30.6%, and the purity is poor. Second, in order to remove the benzyl group in the final step, a pressurization reaction using hydrogen and a palladium catalyst is required. For this, a pressurization reactor facility is required, an expensive palladium catalyst is used, and there is a risk of hydrogen explosion. This process is therefore not easy and economical in industrial mass production.
또한 N-메틸-3,3-디페닐 프로필아민 (I)의 합성에 이용할 수 있는 제조방법이 미국특허 제 6,071,970에 기술되어 있는데 반응식은 다음과 같다.
Also described in US Pat. No. 6,071,970 is a preparation method which can be used for the synthesis of N-methyl-3,3-diphenyl propylamine (I).
[반응식 2]Scheme 2
이 반응식에 따르면 치환된 3,3-디페닐프로필아민 (3)을 에틸 포르메이트와 반응하여 포름아미드 유도체 (4)를 만든 다음, 테트라히드로퓨란 용매 하에서 환원시약으로 보란-메틸설피드을 사용하고, 염산 처리하여 치환된 N-메틸-3,3-디페닐프로필아민 염산염 (5)을 얻는다.
According to this scheme, substituted 3,3-diphenylpropylamine (3) was reacted with ethyl formate to form formamide derivative (4), and then borane-methylsulfide was used as a reducing reagent in a tetrahydrofuran solvent. Hydrochloric acid treatment gives substituted N-methyl-3,3-diphenylpropylamine hydrochloride (5).
이와 같은 공정은 여러 가지 단점이 있다. 첫 번째로 포름아미드 유도체로부터 목적하는 N-메틸-3,3-디페닐프로필아민을 만드는 단계에서 발화의 위험성이 있으며, 수분에도 민감한 환원시약인 보란-메틸설피드과 폭발의 위험이 있는 테트라히드로퓨란을 용매로 사용하는 등 공업적인 대량생산이 용이하지 않은 문제점이 있다. 두 번째로 고가의 환원시약인 보란-메틸설피드을 사용하면서도 40% 내외의 저조한 반응수율과 그에 따른 다량의 부반응 물질이 생성되며, 목적하는 N-메틸-3,3-디페닐프로필아민 (5)을 수득하기 위해서는 여러 단계의 정제과정이 요구되므로 경제적이지도 않다.
Such a process has several disadvantages. Firstly, borane-methylsulfide, which is a danger of ignition, and water-sensitive reducing reagent, and tetrahydrofuran, which may be explosive, in the step of making the desired N-methyl-3,3-diphenylpropylamine from formamide derivatives. There is a problem that industrial mass production is not easy, such as using a solvent. Secondly, while using borane-methyl sulfide, which is an expensive reducing reagent, yields a low reaction yield of about 40% and a large amount of side reactions. The desired N-methyl-3,3-diphenylpropylamine (5) It is not economical because several steps of purification are required to obtain.
본 발명에서는 목적 화합물을 합성하는데 있어 공지방법의 단점인 낮은 수율과 낮은 순도, 폭발, 그리고 발화성이 강한 환원시약의 사용 및 가압반응설비와 고가의 촉매가 필요한 점 등의 여러 가지 문제점을 해결하고, 온화하고 용이한 반응조건에서 경제적이고 대량생산이 용이한 제조방법으로 목적물을 높은 수율로 제조하는 방법을 제공하는데 그 목적이 있다.
The present invention solves various problems such as low yield, low purity, explosion, and use of reducing reagents having high flammability, pressurization reaction equipment and expensive catalysts, which are disadvantages of known methods in synthesizing a target compound. It is an object of the present invention to provide a method for producing a target product in a high yield as an economical and easy mass production method under mild and easy reaction conditions.
본 발명은 N,N-디메틸-3,3-디페닐프로필아민 (III)을 탈메틸화 반응을 통하여 카바메이트 유도체를 제조하고, 가수분해반응을 거쳐 다음 화학식 (I)의 N-메틸 -3,3-디페닐프로필아민을 제조하는 것을 특징으로 한다.
In the present invention, a carbamate derivative is prepared by demethylation of N, N-dimethyl-3,3-diphenylpropylamine (III), followed by hydrolysis, to form N-methyl-3, It is characterized by preparing 3-diphenylpropylamine.
본 발명의 공정은 다음의 반응식에 의해 설명될 수 있다.
The process of the present invention can be illustrated by the following scheme.
[반응식 3]Scheme 3
본 발명을 보다 구체적으로 설명하면 다음과 같다.
The present invention will be described in more detail as follows.
본 발명은 N,N-디메틸-3,3-디페닐프로필아민 (III)을 에틸 클로로포르메이트 또는 메틸 클로로포르메이트를 사용한 탈메틸화 반응을 통하여 에틸 메틸 3,3-디페닐프로필카바메이트 (II) 혹은 메틸 메틸 3,3-디페닐프로필카바메이트 을 제조한 다음, 초산과 염산 또는 브롬산 혼합액 하에서 가수분해 시켜 목적하는 N-메틸-3,3-디페닐프로필-1-아민 (I)및 그의 염을 제조하는 것으로 구성된다.
The present invention provides ethyl methyl 3,3-diphenylpropylcarbamate (II) by demethylation of N, N-dimethyl-3,3-diphenylpropylamine (III) with ethyl chloroformate or methyl chloroformate. Or methyl methyl 3,3-diphenylpropylcarbamate, and then hydrolyzed under a mixture of acetic acid and hydrochloric acid or bromic acid to give N-methyl-3,3-diphenylpropyl-1-amine (I) and It consists of preparing its salts.
출발물질로 사용되는 N,N-디메틸-3,3-디페닐프로필아민 (III)은 3,3-디페닐프로필아민과 개미산과 포름알데히드 수용액 또는 파라포름알데히드를 사용한 환원성 디메틸화 반응에 의하여 정량적인 수율로 제조할 수 있다.
N, N-dimethyl-3,3-diphenylpropylamine (III) used as a starting material was quantitatively determined by reductive dimethylation using 3,3-diphenylpropylamine, formic acid, aqueous formaldehyde solution or paraformaldehyde. It can be prepared in phosphorus yield.
탈메틸화 반응에서는 에틸 클로로포르메이트 또는 메틸 클로로포르메이트를 사용할 수 있으며, 에틸 클로로포르메이트을 2 내지 5당량을 사용하는 것이 바람직하다. 반응용매로는 벤젠, 톨루엔, 크실렌 등을 사용할 수 있고, 또한 선택적으로 서로 혼합하여 사용할 수 있으며, 톨루엔을 사용하는 것이 바람직하다.
In the demethylation reaction, ethyl chloroformate or methyl chloroformate can be used, preferably 2 to 5 equivalents of ethyl chloroformate. Benzene, toluene, xylene, or the like can be used as the reaction solvent, and can be optionally mixed with each other, and toluene is preferable.
가수분해 반응에서는 수성용매 또는 메탄올, 에탄올, n-프로판올, i-프로판올, n-부탄올, s-부탄올, t-부탄올 등의 양성자성 알코올 용매 및 에틸아세테이트, 메틸 아세테이트, 테트라하이드로퓨란, 디옥산, 디메틸포름아미드, 디메틸 카르보네이트 등의 반 양성자성 용매 또는 개미산, 초산 등의 유기산 용매를 사용하여, 수산화나트륨, 수산화칼륨, 수산화바륨, 탄산수소칼륨, 탄산수소나트륨, 중탄산수소나트륨 등의 알칼리성 무기염류와 염산, 브롬산의 산성 무기산 등을 사용할 수 있고, 바람직하게는 초산과 염산 수용액, 또는 초산과 브롬산 수용액을 사용한다.
Hydrolysis reactions include aqueous solvents or protic alcohol solvents such as methanol, ethanol, n-propanol, i-propanol, n-butanol, s-butanol, t-butanol and ethyl acetate, methyl acetate, tetrahydrofuran, dioxane, Alkali inorganic materials, such as sodium hydroxide, potassium hydroxide, barium hydroxide, potassium hydrogencarbonate, sodium hydrogencarbonate, sodium bicarbonate, using semiprotic solvents, such as dimethylformamide and dimethyl carbonate, or organic acid solvents, such as formic acid and acetic acid Hydrochloric acid, hydrochloric acid, acidic inorganic acid of bromic acid, etc. can be used, Preferably, acetic acid and hydrochloric acid aqueous solution, or acetic acid and bromic acid aqueous solution are used.
본 발명에 따라 준비된 N-메틸-3,3-디페닐 프로필아민 (I)은 알코올성 염화수소, 에틸 아세테이트나 에테르성 염화수소 등을 이용하여 염화 처리하여 염화물로 얻을 수 있고, 에틸 아세테이트, 메틸 아세테이트, 아세톤, 디클로로메탄, 클로로포름, 에테르, 석유에테르 같은 반 양성자성 용매나 메탄올, 에탄올, n-프로판올, i-프로판올, n-부탄올, s-부탄올, t-부탄올 등의 양성자성 용매를 하나 또는 선택적으로 혼합해서 사용하여 재결정화 시킬 수 있다.
N-methyl-3,3-diphenyl propylamine (I) prepared according to the present invention can be obtained by chloride treatment with alcoholic hydrogen chloride, ethyl acetate, ethereal hydrogen chloride, etc., and ethyl acetate, methyl acetate, acetone. Or selectively mix a protic solvent such as dichloromethane, chloroform, ether, petroleum ether or a protic solvent such as methanol, ethanol, n-propanol, i-propanol, n-butanol, s-butanol, t-butanol Can be used to recrystallize.
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.
[참고 실시예 1]Reference Example 1
N,N-디메틸-3,3-디페닐프로필아민
N, N-dimethyl-3,3-diphenylpropylamine
37%의 포름알데히드 수용액과 88%의 개미산 20ml의 혼합액을 10℃이하로 냉각시킨 다음 3,3-디페닐프로필아민 10g을 적가하고, 10분간 저어준 다음, 105℃에서 12시간동안 환류교반하고, 디클로로메탄 50ml로 희석하고, 25% 수산화나트륨 수용액 44ml을 가하고, 격렬히 저어준 다음 유기층을 분리하고, 무수황산마그네슘으로 건조하고, 진공 증발시켜 표제화합물을 11.1g의 오일로 수득한다. 수율 99.97%
A mixture of 37% aqueous formaldehyde solution and 88% formic acid 20 ml was cooled to 10 ° C. or lower, 10 g of 3,3-diphenylpropylamine was added dropwise, stirred for 10 minutes, and stirred under reflux at 105 ° C. for 12 hours. Dilute with 50 ml of dichloromethane, add 44 ml of 25% aqueous sodium hydroxide solution, stir vigorously, separate the organic layer, dry over anhydrous magnesium sulfate, and evaporate in vacuo to afford the title compound as an 11.1 g oil. Yield 99.97%
[실시예 1]Example 1
에틸 메틸 3,3-디페닐프로필카바메이트
Ethyl methyl 3,3-diphenylpropylcarbamate
참고 실시예 1에서 제조된 화합물 11.1g을 120ml 톨루엔에 용해시키고, 13.6ml의 에칠 클로로포르메이트를 가하고 5시간동안 교반한다. 반응액을 여과한 다음, 여액을 진공 하에서 농축시켜서 표제화합물을 13.3g의 오일로 수득한다. 수 율 94.5%
11.1 g of the compound prepared in Reference Example 1 is dissolved in 120 ml toluene, 13.6 ml of ethyl chloroformate is added and stirred for 5 hours. The reaction solution is filtered and the filtrate is concentrated in vacuo to give the title compound as 13.3 g of oil. Yield 94.5%
[실시예 2][Example 2]
N-메틸-3,3-디페닐프로필-1-아민
N-methyl-3,3-diphenylpropyl-1-amine
실시예 1에서 제조된 화합물 7.8g을 50ml의 초산과 50ml의 농염산에 용해시키고, 24시간동안 환류 시킨다. 혼합물을 냉각시킨 다음 여과하고, 20ml의 디클로로메탄과 200ml의 물을 가하고, 격렬히 저어준 다음 유기층을 제거하고, 200ml의 디클로로메탄을 가하고, 저어주면서 50% 수산화나트륨 수용액 100ml을 가하고, 격렬히 저어준 다음 유기층을 분리하고, 무수황산마그네슘으로 건조하고, 진공 증발시켜 표제화합물을 5.6g의 오일로 수득한다. 수율 94.8%
7.8 g of the compound prepared in Example 1 was dissolved in 50 ml of acetic acid and 50 ml of concentrated hydrochloric acid and refluxed for 24 hours. The mixture was cooled and then filtered, 20 ml of dichloromethane and 200 ml of water were added, stirred vigorously and the organic layer was removed, 200 ml of dichloromethane was added, while stirring, 100 ml of 50% aqueous sodium hydroxide solution was added, followed by vigorous stirring. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield the title compound as 5.6 g of oil. Yield 94.8%
[실시예 3]Example 3
N-메틸-3,3-디페닐프로필-1-아민
N-methyl-3,3-diphenylpropyl-1-amine
실시예 1에서 제조된 화합물 5.8g을 50ml의 초산과 15ml의 48% 브롬산수용액에 용해시키고, 5시간동안 환류 시킨다. 혼합물을 냉각시킨 다음 여과하고, 5ml의 디클로로메탄과 100ml의 물을 가하고, 격렬히 저어준 다음 유기층을 제거하고, 150ml의 디클로로메탄을 가하고, 저어주면서 50% 수산화나트륨 수용액 82.5ml을 가하고, 격렬히 저어준 다음 유기층을 분리하고, 무수황산마그네슘으로 건조하고, 진공 증발시켜 표제화합물을 4.1g의 오일로 수득한다. 수율 93.3%
5.8 g of the compound prepared in Example 1 is dissolved in 50 ml of acetic acid and 15 ml of 48% aqueous bromic acid solution and refluxed for 5 hours. The mixture was cooled and then filtered, 5 ml of dichloromethane and 100 ml of water were added, stirred vigorously, the organic layer was removed, 150 ml of dichloromethane was added, 82.5 ml of a 50% aqueous sodium hydroxide solution was stirred and vigorously stirred The organic layer is then separated, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield the title compound as 4.1 g of oil. Yield 93.3%
N,N-디메틸-3,3-디페닐프로필아민을 탈메틸화 반응 및 가수분해반응을 거쳐 레르카니디핀 제조에 사용할 수 있는 중요 중간체인 N-메틸-3,3-디페닐프로필아민을 제조할 수 있으며, 온화한 반응조건과 반응물을 사용하여 고수율 및 고순도로 목적물을 얻을 수 있기 때문에 경제적이며 공업적인 대량생산을 위해 적용이 가능하다.
Demethylation and hydrolysis of N, N-dimethyl-3,3-diphenylpropylamine to prepare N-methyl-3,3-diphenylpropylamine, an important intermediate that can be used to prepare lercanidipine. It can be applied for economic and industrial mass production because the target product can be obtained with high yield and high purity using mild reaction conditions and reactants.
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