KR20020042085A - Process for preparing (S)-1-acetyl-2-pyrrolidinecarboxamide - Google Patents
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Abstract
Description
하기 화학식 1의 (S)-1-아세틸-2-피롤리딘카복스아미드는 거울상이성체로서 순수한 (S)-이성체를 얻기 위해 크게 두가지 방법이 이용되어 왔다:(S) -1-acetyl-2-pyrrolidinecarboxamide of the following formula (1) has been largely used to obtain pure (S) -isomer as enantiomer:
[화학식 1][Formula 1]
하나는 아민 라세미체를 얻은 후 마지막 단계에서 이를 분할하는 것이고, 다른 하나는 처음부터 (S)-입체배열을 갖는 출발물질로부터 시작하여 입체특이적인 방법으로 합성하는 것이다.One is to obtain the amine racemate and then split it in the last step, and the other is to synthesize from the starting material with the (S) -stereoconfiguration from the beginning and synthesize it by stereospecific methods.
이중 분할방법은 GB 1,207,752호 및 AU 526,007호에 기재되어 있으나, 이 방법에 의해 분할할 경우 출발물질의 상당량이 손실되며 고가의 분할용 시약이 필요하다는 문제점이 있다. 한편, 입체특이적 합성법은 신테라보(Synthelabo)에 의한GB 1,555,890호와 라비자(Ravizza)에 의한 GB 2,014,990호, 그리고 아스트라(Astra)에 의한 US 5,300,660호에 공지되어 있다. 이들 문헌에 공지된 입체특이적 합성법에 대해 간단히 살펴보면 다음과 같다.The double dividing method is described in GB 1,207,752 and AU 526,007, but the dividing by this method has a problem that a considerable amount of starting material is lost and expensive dividing reagents are required. Stereospecific synthesis, on the other hand, is known from GB 1,555,890 by Synthelabo, GB 2,014,990 by Ravizza and US 5,300,660 by Astra. A brief review of stereospecific synthesis methods known in these documents is as follows.
GB 1,555,890호에서는, 하기 반응식 1에 나타낸 바와 같이, (S)-프롤린의 카복실기를 먼저 에스테르화시키고 이를 아미드로 전환시킨 후 1번 위치의 아민에 아세틸기를 도입하여 목적하는 화학식 1의 화합물을 합성한다.In GB 1,555,890, as shown in Scheme 1, the carboxyl group of (S) -proline is first esterified and converted to an amide, followed by the introduction of an acetyl group to the amine at position 1 to synthesize the desired compound of formula (I). .
그러나, 상기 방법은 에스테르 화합물에서 아미드 화합물로 전환시키는 과정에서 사용하는 SOCl2촉매의 맹독성으로인하여 바람직하지 않으며 촉매의 맹독성을 피하기 위하여 아예 사용하지 않는 경우 반응시간이 100시간이상으로 길어지는 단점이 있다.However, this method is not preferable due to the toxicity of SOCl 2 catalyst used in the process of conversion from ester compound to amide compound, and the reaction time is longer than 100 hours when not used at all to avoid the toxicity of catalyst. .
GB 2,014,990호에서는, 하기 반응식 2에 나타낸 바와 같이, 아세틸화, 환원, 염소화 및 아민화를 포함하는 4단계 반응을 거쳐 (S)-2-아미노메틸-1-에틸-피롤리딘을 제조한다.In GB 2,014,990, (S) -2-aminomethyl-1-ethyl-pyrrolidine is prepared through a four step reaction involving acetylation, reduction, chlorination and amination, as shown in Scheme 2 below.
상기 방법에서는 피롤리딘의 1번 위치에 아세트산 무수물을 사용하여 용이하면서도 고수율로 아세틸기를 도입시키고 있는 장점에도 불구하고, 다단계의 반응으로 인하여 총 29%의 낮은 수율로 목적화합물을 제조하고 있는 단점이 있다. 또한, 최종적으로 제조되는 화합물의 구조가 본원 발명에 따른 화학식 1의 화합물과는 전혀 상이하므로 사실상 목적이 상이하다.In the above method, despite the advantage of easily introducing acetyl groups in a high yield using acetic anhydride at position 1 of pyrrolidine, the target compound is prepared in a low yield of 29% due to the multi-step reaction. There is this. In addition, since the structure of the finally prepared compound is completely different from the compound of the formula (1) according to the present invention, the purpose is substantially different.
US 5,300,660호에서는, 하기 반응식 3에 나타낸 바와 같이, (S)-프롤린의 1번 위치 아민에 에틸기를 도입하는 방법으로서 4가지 가능한 경로를 모색하고 있다.In US Pat. No. 5,300,660, as shown in Scheme 3 below, four possible routes are sought as a method of introducing an ethyl group into the amine at position 1 of (S) -proline.
상기 반응식 3의 방법중에서 가장 바람직하다고 기술된 경로 B의 방법은 GB 1,555,890호에 개시된 방법과 유사하나 1번 위치의 아민에 아세틸기가 아닌 에틸기를 도입한다는 차이점이 있다. 그러나, 경로 B의 경우에도 역시 1차 중간체인 에스테르 화합물을 아미드로 전환시키는 과정에 GB 1,555,890호의 기술과 마찬가지의 한계점을 가지고 있다. 또한, 경로 B에서는 중간체로 생성된 (S)-프롤린아미드의1번 위치 아민에 아실할라이드에 비해 반응성이 적은 알킬할라이드를 도입시켜야 하므로 30℃ 이상의 온도에서 20시간이상 반응시켜야 한다는 단점이 있고, 이에 따라 수율이 65% 정도로 저하되며, 에스테르화 반응 후 잔류하는 디클로로메탄에 의해 하기 반응식 4에 도시한 바와 같은 부반응이 있을 수 있다는 추가의 문제점이 있다 (참조: J. Org. Chem. 2254, 1994)The method of route B described as most preferred in the scheme 3 is similar to that disclosed in GB 1,555,890, except that an ethyl group other than an acetyl group is introduced into the amine at position 1. However, route B also has the same limitations as the GB 1,555,890 technique for the conversion of ester compounds, also primary intermediates, to amides. In addition, the route B has a disadvantage in that it must be reacted for more than 20 hours at a temperature of 30 ° C. or higher because an alkyl halide having less reactivity than acyl halide should be introduced into the (S) -prolineamide 1-position amine produced as an intermediate. As a result, the yield is reduced to about 65%, and there is an additional problem that there may be a side reaction as shown in Scheme 4 by the dichloromethane remaining after the esterification reaction (see J. Org. Chem. 2254, 1994).
상기한 바와 같은 기술적 배경하에, 본원 발명자들은 화학식 1의 (S)-1-아세틸-2-피롤리딘카복스아미드를 간편하면서도 효율적으로 합성할 수 있는 방법을 개발하기위해 집중적인 연구를 수행하였으며, 그 결과 하기 설명하는 바와 방법을 이용하면 이러한 목적을 달성할 수 있음을 확인하고 본 발명을 완성하게 되었다.Under the technical background as described above, the inventors of the present invention conducted intensive research to develop a method capable of easily and efficiently synthesizing (S) -1-acetyl-2-pyrrolidinecarboxamide of Formula 1, As a result, it was confirmed that this object can be achieved by using the method described below and the present invention was completed.
따라서, 본 발명은 화학식 1의 (S)-1-아세틸-2-피롤리딘카복스아미드를 제조하는 새로운 제조방법을 제공한다.Accordingly, the present invention provides a novel process for preparing (S) -1-acetyl-2-pyrrolidinecarboxamide of formula (1).
본 발명에 따르면, 화학식 1의 화합물은 하기 화학식 2의 (S)-프롤린을 (a) 아세트산 무수물과 반응시키거나, (b) 아세트산 무수물과 반응시킨 후 하기 화학식3의 아실할라이드와 반응시켜 하기 화학식 4의 화합물을 형성하고, 생성된 화학식 4의 화합물을 알콜성 암모니아와 반응시킴을 특징으로 하여 제조할 수 있다.According to the present invention, the compound of formula 1 is reacted with (a) acetic anhydride of (a) acetic anhydride or (b) acetic anhydride and then with acyl halide of formula (3) It can be prepared by forming a compound of 4 and reacting the resulting compound of formula 4 with alcoholic ammonia.
상기식에서In the above formula
X 는 할로겐을 나타내고,X represents a halogen,
R 은 메틸, 에톡시 또는 t-부틸을 나타낸다.R represents methyl, ethoxy or t-butyl.
본 발명에 따른 제조방법을 도시하면 하기 반응식 5와 같다.The preparation method according to the invention is shown in Scheme 5 below.
본 발명에 따른 방법에서 아세트산 무수물은 화학식 2의 화합물을 기준으로하여 바람직하게는 1 내지 5 몰배량, 특히 바람직하게는 1.0 내지 2.5 몰배량으로 사용하며 화학식 3의 아실할라이드는 역시 화학식 2의 화합물을 기준으로 하여 1.0 내지 1.5 몰배량으로 사용하는 것이 바람직하다. 또한, 화학식 2의 화합물에서 카복실기에 아실기를 도입하는 단계는 염기의 존재하에 수행하는 것이 바람직하다. 즉, 아세트산 무수물과만 반응시키는 방법 (a)에서는 처음부터 염기를 가하여 반응시키며, 화학식 3의 아실할라이드와 반응시키는 공정이 추가되는 방법 (b)에서는 아실할라이드와 반응시키는 단계를 염기 존재하에 진행시킨다. 이때 사용하기에 바람직한 염기로는 트리에틸아민, 피리딘 및 디에틸아민 중에서 선택된 1종 이상을 언급할 수 있으며 화학식 2의 화합물을 기준으로 하여 바람직하게 1 내지 3 몰배량 사용한다.Acetic anhydride in the process according to the invention is preferably used in an amount of 1 to 5 molar times, particularly preferably 1.0 to 2.5 molar times, based on the compound of the formula (2) and the acyl halide of the formula (3) It is preferable to use 1.0-1.5 molar volume as a reference. In addition, the step of introducing the acyl group to the carboxyl group in the compound of Formula 2 is preferably carried out in the presence of a base. That is, in the method (a) of reacting only with acetic anhydride, the reaction is carried out by adding a base from the beginning. . Preferred bases for use may include one or more selected from triethylamine, pyridine and diethylamine, and preferably 1-3 molar doses based on the compound of formula (2).
수득된 화학식 4의 화합물을 알콜성 암모니아와 반응시키면 목적하는 화학식 1의 화합물이 형성된다. 알콜성 암모니아로는 암모니아-메탄올 용액 또는 암모니아-에탄올 용액 등을 사용하며 암모니아의 농도는 2 내지 7N 인 것이 바람직하다. 또한, 알콜성 암모니아는 화학식 2의 화합물에 대해 암모니아가 1몰배량 이상이 되도록 하는 양으로 사용한다.Reaction of the obtained compound of formula 4 with alcoholic ammonia forms the desired compound of formula 1. As the alcoholic ammonia, ammonia-methanol solution or ammonia-ethanol solution is used, and the concentration of ammonia is preferably 2 to 7N. In addition, alcoholic ammonia is used in an amount such that ammonia is at least one molar amount relative to the compound of the formula (2).
또한, 본 발명에 따른 반응은 임의로 용매중에서 진행시키며 바람직한 용매로는 에틸아세테이트, 디클로로메탄, 벤젠, 톨루엔, 테트라하이드로푸란, 디메틸아세타미드 및 디메틸설폭사이드 중에서 선택된 1종 이상을 들 수 있다. 반응은 실온 내지 냉각하에서, 바람직하게는 실온 내지 -20℃에서 통상 5시간 이하의 반응시간 동안 진행된다.In addition, the reaction according to the present invention optionally proceeds in a solvent, and preferred solvents include one or more selected from ethyl acetate, dichloromethane, benzene, toluene, tetrahydrofuran, dimethylacetamide and dimethyl sulfoxide. The reaction proceeds at room temperature to cooling, preferably at room temperature to −20 ° C. for a reaction time of usually up to 5 hours.
본 발명에 따른 방법에서 반응 중간체로서 형성되는 화학식 4의 화합물은 분리될 필요가 없으므로 본 발명에 따른 방법은 단일용기반응(one pot reaction)이며, 선행기술에 비하여 매우 빠른 시간내에 반응이 완결된다. 따라서, 본 발명에 따르면 화학식 1의 화합물을 고수율로 형성하게 되므로 경제적일 뿐아니라, 산업적으로 적용함에 있어서도 매우 큰 잇점을 제공하고 있다. 특히, 본원 발명에 따른 방법에서는 피롤리딘의 1번 위치 아민에 미리 아세틸기를 도입시켜 보호기로서의 역할을 수행하게 하므로 디클로로메탄과 같은 용매를 사용하여도 상기 반응식 4에 도시한 바와 같은 부반응의 염려가 전혀 없다.Since the compound of formula 4 formed as a reaction intermediate in the process according to the invention does not need to be separated, the process according to the invention is a one pot reaction and the reaction is completed in a very quick time compared to the prior art. Therefore, according to the present invention, since the compound of Formula 1 is formed in high yield, the compound of Formula 1 is economical and also provides a very large advantage in industrial applications. In particular, in the method according to the present invention, since the acetyl group is introduced into the amine of position 1 of pyrrolidine in advance to act as a protecting group, there is a risk of side reactions as shown in Scheme 4 even when a solvent such as dichloromethane is used. Not at all.
또한, 본 발명의 방법에 따라 제조된 화학식 1의 화합물은 칼럼 크로마토그래피 또는 재결정 등의 방법에 의해 추가로 정제될 수 있다.In addition, the compound of formula 1 prepared according to the method of the present invention may be further purified by methods such as column chromatography or recrystallization.
이하, 본 발명을 하기 실시예에 의거하여 보다 구체적으로 설명한다. 그러나, 이들 실시예는 본 발명에 대한 이해를 돕기위한 것일 뿐, 어떤 의미로도 본 발명의 범위가 이들 실시예로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention is not limited to these examples in any sense.
실시예 1Example 1
무수 에틸아세테이트 150㎖중의 (S)-프롤린 57.5g(0.5몰)의 현탁용액에 트리에틸아민 153.1㎖(1.1몰)을 가한 다음, 아세트산 무수물 104.2㎖(1.1몰)을 실온에서 2시간 동안 적가하였다. 반응용액을 -20℃로 냉각한 후 7N-암모니아-메탄올 용액 236.8㎖를 -20℃에서 20분 동안 적가하였다. 반응물을 -10℃에서 1시간 동안 교반한 후 여과하여 표제화합물 63.3g (수율 81.2%)을 수득하였다.153.1 ml (1.1 mol) of triethylamine was added to a suspension of 57.5 g (0.5 mol) of (S) -proline in 150 ml of anhydrous ethyl acetate, and then 104.2 ml (1.1 mol) of acetic anhydride was added dropwise at room temperature for 2 hours. . After cooling the reaction solution to −20 ° C., 236.8 mL of 7N-ammonia-methanol solution was added dropwise at −20 ° C. for 20 minutes. The reaction was stirred at −10 ° C. for 1 hour and then filtered to yield 63.3 g (81.2% yield) of the title compound.
실시예 2Example 2
무수 에틸아세테이트 150㎖중의 (S)-프롤린 57.5g(0.5몰)의 현탁용액에 아세트산 무수물 104.2㎖(1.1몰)을 실온에서 2시간 동안 적가하였다. 실온에서 1시간 동안 교반한 후 0℃로 냉각시켰다. 트리에틸아민 153.1㎖(1.1몰)을 가한 후 에틸클로로포메이트 48.2㎖(0.55몰)을 -10℃에서 30분 동안 적가하였다. -10℃에서 30분간 교반한 다음 반응중 생성된 염류를 물로 추출하여 제거하였다. 반응용액을 -20℃로 냉각시킨 후 7N-암모니아-메탄올 용액 236.8㎖를 -20℃에서 20분 동안 적가하였다. 반응물을 -10℃에서 1시간 동안 교반하고 여과하여 표제화합물 61.8g(수율 79.3%)을 수득하였다.To a suspension of 57.5 g (0.5 mol) of (S) -proline in 150 ml of anhydrous ethyl acetate, 104.2 ml (1.1 mol) of acetic anhydride were added dropwise at room temperature for 2 hours. After stirring for 1 hour at room temperature it was cooled to 0 ° C. 153.1 mL (1.1 mole) of triethylamine was added, followed by dropwise addition of 48.2 mL (0.55 mole) of ethylchloroformate at −10 ° C. for 30 minutes. After stirring at −10 ° C. for 30 minutes, the salts generated during the reaction were extracted and removed with water. After cooling the reaction solution to −20 ° C., 236.8 mL of 7N-ammonia-methanol solution was added dropwise at −20 ° C. for 20 minutes. The reaction was stirred at −10 ° C. for 1 hour and filtered to give 61.8 g (79.3% yield) of the title compound.
실시예 3Example 3
무수 에틸아세테이트 300㎖중의 (S)-프롤린 115.1g(1.0몰)의 현탁용액에 아세트산 무수물 104.2㎖(1.1몰)을 실온에서 2시간 동안 적가하였다. 실온에서 1시간 동안 교반한 후 0℃로 냉각시켰다. 트리에틸아민 306.2㎖(2.2몰)을 가한 후 트리메틸아세틸클로라이드 135.5㎖(1.1몰)을 1시간 동안 적가하였다. -10℃에서 1시간 교반한 다음 반응중 생성된 염류를 물로 추출하여 제거하였다. 반응용액을 -20℃로 냉각시킨 후 7N-암모니아-메탄올 용액 473.6㎖를 -20℃에서 20분 동안 적가하였다. 반응물을 -10℃에서 1시간 동안 교반하고 여과하여 표제화합물 126.5g(수율 81.1%)을 수득하였다.To a suspension of 115.1 g (1.0 mol) of (S) -proline in 300 ml of anhydrous ethyl acetate, 104.2 ml (1.1 mol) of acetic anhydride were added dropwise at room temperature for 2 hours. After stirring for 1 hour at room temperature it was cooled to 0 ° C. 306.2 mL (2.2 mol) of triethylamine was added, followed by dropwise addition of 135.5 mL (1.1 mol) of trimethylacetyl chloride for 1 hour. After stirring at −10 ° C. for 1 hour, the salts generated during the reaction were extracted and removed with water. After cooling the reaction solution to −20 ° C., 473.6 mL of 7N-ammonia-methanol solution was added dropwise at −20 ° C. for 20 minutes. The reaction was stirred at −10 ° C. for 1 h and filtered to give 126.5 g (81.1% yield) of the title compound.
실시예 4Example 4
무수 디클로로메탄 250㎖중의 (S)-프롤린 115.1g(1.0몰)의 현탁용액에 아세트산 무수물 104.2㎖(1.1몰)을 실온에서 2시간 동안 적가하였다. 실온에서 1시간 동안 교반한 후 -10℃로 냉각시켰다. 트리에틸아민 306.2㎖(2.2몰)을 가한 후 아세틸클로라이드 71.1㎖(1.1몰)을 -20℃에서 1시간 동안 적가하였다. -20℃에서 1시간 교반한 다음 반응중 생성된 염류를 물로 추출하여 제거하였다. 반응용액을 -20℃로 냉각시킨 다음 7N-암모니아-메탄올 용액 473.6㎖를 -20℃에서 20분 동안 적가하였다. 반응물을 -10℃에서 1시간 동안 교반하고 여과하여 표제화합물 119.6g(수율 76.7%)을 수득하였다.To a suspension of 115.1 g (1.0 mole) of (S) -proline in 250 mL of anhydrous dichloromethane, 104.2 mL (1.1 mole) of acetic anhydride were added dropwise at room temperature for 2 hours. Stirred at room temperature for 1 hour and then cooled to -10 ° C. After adding 306.2 mL (2.2 mol) of triethylamine, 71.1 mL (1.1 mol) of acetyl chloride was added dropwise at −20 ° C. for 1 hour. After stirring at −20 ° C. for 1 hour, the salts generated during the reaction were extracted and removed with water. The reaction solution was cooled to −20 ° C., and 473.6 mL of 7N-ammonia-methanol solution was added dropwise at −20 ° C. for 20 minutes. The reaction was stirred at −10 ° C. for 1 hour and filtered to give 119.6 g (76.7% yield) of the title compound.
실시예 5Example 5
아세틸 클로라이드 대신 아세틸 브로마이드를 사용하는 점을 제외하고는 실시예 4에서와 동일한 방법으로 반응시켜 표제화합물 120.9g(수율 77.5%)을 수득하였다.The reaction was carried out in the same manner as in Example 4, except that acetyl bromide was used instead of acetyl chloride, to obtain 120.9 g (yield 77.5%) of the title compound.
본 발명의 방법에 따르면, 화학식 1의 (S)-1-아세틸-2-피롤리딘카복스아미드를 선행기술에 비하여 간편하면서도 고수율로 제조할 수 있다.According to the method of the present invention, (S) -1-acetyl-2-pyrrolidinecarboxamide of formula (1) can be prepared in a simple and high yield compared to the prior art.
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