KR100718166B1 - Process for the preparation of N-sulfonylamidine by Cu-catalyzed three component coupling - Google Patents
Process for the preparation of N-sulfonylamidine by Cu-catalyzed three component coupling Download PDFInfo
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Abstract
본 발명은 구리 촉매 하에서 삼성분 짝지움 반응을 통해 N-술포닐아미딘 화합물을 합성하는 방법에 관한 것으로, 보다 상세하게는 화학식(1)의 아세틸렌 유도체와 화학식(2)의 술포닐 아지드 유도체, 그리고 화학식(3)의 아민 유도체를 구리 촉매에 의해 반응이 촉진되어 세분자 짝지움 반응에 의해 화학식(4)의 N-술포닐아미딘을 얻는 것을 특징으로 한다.The present invention relates to a method for synthesizing an N-sulfonylamidine compound through a ternary mining reaction under a copper catalyst, and more particularly, an acetylene derivative of formula (1) and a sulfonyl azide derivative of formula (2) And the reaction of the amine derivative of formula (3) by a copper catalyst to obtain N-sulfonylamidine of formula (4) by trimolecular pairing reaction.
본 발명의 아미딘 화합물은 많은 천연물의 매우 중요한 구성성분이며 의약품 제조과정에서 주요한 중간체로 자주 사용되고 있는 화합물로서, 본 발명의 다성분 짝지움 방법은 다성분에 대해 매우 넓은 응용범위를 가지고 있으며, 온화한 반응조건에서 생성되며, 해로운 부산물을 최소한으로 줄이는 방법으로 수득율을 아주 극대화하는 경제적인 제조방법을 제공한다.The amidine compound of the present invention is a very important component of many natural products and is frequently used as a major intermediate in the manufacture of pharmaceuticals. The multicomponent matching method of the present invention has a very wide application range for the multicomponent and mild Produced under the reaction conditions, it provides an economical manufacturing method that maximizes yield by minimizing harmful by-products.
Description
본 발명은 구리 촉매 하에서 삼성분 짝지움 반응에 의한 N-술포닐아미딘의 제조방법에 관한 것이다. 보다 상세하게는 화학식(1)의 아세틸렌 유도체와 화학식(2)의 술포닐 아지드 유도체, 그리고 화학식(3)의 아민 유도체를 구리 촉매에 의해 반응이 촉진되어 세분자 짝지움 반응에 의해 화학식(4)의 N-술포닐아미딘 화합물을 제조하는 방법에 관한 것이다.The present invention relates to a process for the preparation of N-sulfonylamidine by a ternary mining reaction under a copper catalyst. More specifically, the reaction between the acetylene derivative of formula (1), the sulfonyl azide derivative of formula (2), and the amine derivative of formula (3) is promoted by a copper catalyst, and the reaction of formula (4) A method for preparing an N-sulfonylamidine compound of
아미딘(amidine) 화합물은 많은 천연물에서 매우 중요한 구성성분이며 의약품 제조과정에서 주요한 중간체로 자주 사용될 뿐만 아니라 금속 촉매의 효율적인 리간드((a) Greenhill, J. V.; Lue, P. Prog. Med. Chem. 1993, 30, 203. (b) Boyd, G. V. In The Chemistry of Amidines and Imidates Patai, S., Rappoport, Z., Eds.; Wiley: New York, 1991; Vol. 2, Chapter 8. (c) Barker, J.; Kilner, M. Coord. Chem. Rev. 1994, 133, 219)로서 많이 사용되고 있다.Amidine compounds are very important constituents in many natural products and are often used as major intermediates in the manufacture of pharmaceuticals, as well as efficient ligands for metal catalysts ((a) Greenhill, JV; Lue, P. Prog. Med. Chem . 1993 , 30, 203. (b) Boyd , GV In The Chemistry of Amidines and Imidates Patai, S., Rappoport, Z., Eds .; Wiley:. New York, 1991; Vol 2, Chapter 8. (c) Barker, J .; Kilner, M. Coord. Chem. Rev. 1994, 133 , 219).
종래 아미딘 화합물을 제조하는 일반적인 방법들은 단순히 기존에 존재하는 기능기를 원하는 아미딘 기능기로 변환하는 것으로 이러한 방법에 사용되는 주된 기능기로는 아미드, 티오아미드, 니트릴, 이소니트릴, 옥심, 알독심 등이 있다. 이러한 기존 방법들은 아미딘으로 변형시키기 위한 전단계의 기능기를 먼저 합성해야 하는 단점((a) Kumagai, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2004, 43, 478. (b) Charette, A. B.; Grenon, M. Tetrahedron Lett. 2000, 41, 1677.(c) Lee, H. K.; Ten, L. N.; Pak, C. S. Bull. Korean. Chem. Soc. 1998, 19, 1148. (d) Xu, F.; Sun, J.; Shen, Q. Tetrahedron Lett. 2002, 43, 1867. (e) Saluste, C. G.; Whitby, R. J.; Furber, M. Angew. Chem. Int. Ed. 2000, 39, 4156. (f) Lange, U. E. W.; Schfer, B.; Baucke, D.; Buschmann, E.; Mack, H. Tetrahedron Lett. 1999, 40, 7067. (g) Takuwa, T.; Minowa, T.; Onishi, J. Y.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2004, 77, 1717. (h) Anbazhagan. M.; Boykin, D. W.; Stephens, C. E. Synthesis 2003, 2467. (i) Katritzky, A. R.; Monteux, D. A.; Tymoshenko, D. O. Org. Lett. 1999, 1, 577.)이 있다.Conventional methods for preparing amidine compounds are simply to convert existing functional groups into desired amidine functional groups. The main functional groups used in these methods are amide, thioamide, nitrile, isonitrile, oxime, aldoxim, etc. have. These existing methods have the disadvantages of first synthesizing the functional groups of the first stage for transformation into amidine ((a) Kumagai, N .; Matsunaga, S .; Shibasaki, M. Angew. Chem., Int. Ed. 2004, 43 , 478. (b) Charette, AB; Grenon, M. Tetrahedron Lett. 2000, 41 , 1677. (c) Lee, HK; Ten, LN; Pak, CS Bull.Korean.Chem. Soc. 1998, 19 , 1148. (d) Xu, F .; Sun, J .; Shen, Q. Tetrahedron Lett. 2002, 43 , 1867. (e) Saluste, CG; Whitby, RJ; Furber, M. Angew. Chem. Int. Ed. 2000 , 39, 4156. (f) Lange , UEW;. Schfer, B .; Baucke, D .; Buschmann, E .; Mack, H. Tetrahedron Lett 1999, 40, 7067. (g) Takuwa, T .; Minowa, T .; Onishi, JY; Mukaiyama, T. Bull. Chem. Soc.Jpn. 2004, 77 , 1717. (h) Anbazhagan.M .; Boykin, DW; Stephens, CE Synthesis 2003, 2467. (i) Katritzky, AR; Monteux, DA; Tymoshenko, DO Org. Lett. 1999, 1 , 577.).
또한 최근에는 다성분 짝지움 반응에 의해 아미딘을 얻을 수 있는 방법도 알려지고 있으나 이는 반응기질의 범위가 넓지 않으며 반응조건에 민감한 작용기에 대해서는 효율적이지 못하다는 단점((a) Keung, W.; Bakir, F.;Patron. A. P.; Rogers, D.;Priest, C. D.; Darmohusodo, V. Tetrahedron Lett. 2004, 45, 733. (b) Xu, Y.; Wang, Y.; Zhu, S. Synthesis 2000, 513.)등이 있다. Also, recently, a method for obtaining amidine by a multicomponent coupling reaction has been known, but this is a disadvantage in that the range of reactor quality is not wide and it is inefficient for functional groups sensitive to reaction conditions ((a) Keung, W .; Bakir, F .; Patron. AP; Rogers, D .; Priest, CD; Darmohusodo, V. Tetrahedron Lett. 2004, 45 , 733. (b) Xu, Y .; Wang, Y .; Zhu, S. Synthesis 2000 , 513.).
본 발명자들은 상기 언급된 바와 같은 여러 가지 문제점을 해결하여 온건한 반응조건에서도 목적하는 N-술포닐아미딘 화합물을 얻을 수 있을 뿐만 아니라 생성되는 해로운 부산물을 최소한으로 줄이는 다성분 짝지움 방법을 이용하여 수득율을 극대화하는 제조방법을 개발하기 위하여 예의 연구한 결과 구리 촉매 존재 하에 아세틸렌, 술포닐 아지드 및 아민을 반응시키면 상기와 같은 목적을 달성할 수 있음을 발견하고 본 발명을 완성하게 되었다. The present inventors have solved various problems as mentioned above to obtain the desired N-sulfonylamidine compound even under moderate reaction conditions, and also by using a multicomponent pairing method which minimizes the harmful by-products generated. As a result of intensive studies to develop a production method for maximizing the yield, it has been found that the above object can be achieved by reacting acetylene, sulfonyl azide and amine in the presence of a copper catalyst.
따라서, 본 발명은 구리 촉매 존재 하에 아세틸렌, 술포닐 아지드, 아민을 반응시켜 N-술포닐아미딘을 제조하는 방법의 제공을 목적으로 한다.Accordingly, an object of the present invention is to provide a method for producing N-sulfonylamidine by reacting acetylene, sulfonyl azide, amine in the presence of a copper catalyst.
본 발명의 N-술포닐아미딘 화합물 제조방법은 하기 화학식(1)의 아세틸렌 유도체와 하기 화학식(2)의 술포닐 아지드 유도체, 그리고 하기 화학식(3)의 아민 유도체를 구리 촉매 하에서 반응시켜 하기 화학식(4)의 N-술포닐아미딘을 얻는 것을 특징으로 한다.The method for preparing N-sulfonylamidine compounds of the present invention is obtained by reacting an acetylene derivative of formula (1), a sulfonyl azide derivative of formula (2), and an amine derivative of formula (3) under a copper catalyst. It is characterized by obtaining N-sulfonylamidine of the formula (4).
상기 화학식(1)에서 R1은 알킬, 시클로알킬, 알케닐, 시클로알케닐, 알키닐, 아릴, 실릴, 또는 질소, 산소 혹은 황 원자를 1개 이상 함유하는 헤테로아릴을 나타낸다. 상기 화학식(2)에서 R2는 알킬, 아릴, 또는 질소를 포함하는 헤테로아릴을 나타낸다. 상기 화학식(3)에서 R3와 R4는 각각 수소, 알킬, 시클로알킬, 알케닐, 시클로알케닐, 아릴, 또는 R3와 R4가 고리형태로 연결된 시클로아민을 나타낸다.R 1 in the formula (1) represents alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, silyl, or heteroaryl containing one or more nitrogen, oxygen or sulfur atoms. R 2 in the formula (2) represents heteroaryl including alkyl, aryl, or nitrogen. In Formula (3), R 3 and R 4 each represent hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, or cycloamine in which R 3 and R 4 are linked in a ring form.
상기 치환체 정의에서 알킬, 알케닐, 또는 알키닐은 바람직하게는 주사슬이 탄소원자 1 내지 10개를 함유하며, 시클로알케닐은 바람직하게는 탄소원자 3내지 7개를 함유하고 환상 이중결합을 1개이상 포함한다. 또한, 아릴은 바람직하게는 페닐 또는 나프틸을 나타내며, 질소, 산소 혹은 황원자를 1개 이상 함유하는 헤테로아릴은 바람직하게는 피리딜, 퓨라닐, 혹은 티에닐을 나타낸다. 또한 시클로아민은 고리에 탄소원자 4 내지는 5을 함유하며 고리 중간에 질소, 산소, 황원자를 1개 이 상 함유하는 화합물도 포함된다. 또한 상기 화학식(1), (2), (3)의 주사슬이나 주고리에 다양한 추가의 기능기가 치환될 수 있다. 이러한 추가 기능기로는 바람직하게는 알코올, 씨올, 알콕시, 에스테르, 플루오로 알킬, 또는 할로겐을 포함한다.Alkyl, alkenyl, or alkynyl in the above substituent definition preferably contains 1 to 10 carbon atoms in the main chain, and cycloalkenyl preferably contains 3 to 7 carbon atoms and 1 cyclic double bond. Contains more than one. In addition, aryl preferably represents phenyl or naphthyl, and heteroaryl containing one or more nitrogen, oxygen or sulfur atoms preferably represents pyridyl, furanyl or thienyl. Cycloamines also include compounds containing 4 to 5 carbon atoms in the ring and at least one nitrogen, oxygen, or sulfur atom in the middle of the ring. In addition, various additional functional groups may be substituted in the main chain or ring of the formulas (1), (2) and (3). Such additional functional groups preferably include alcohols, thiols, alkoxy, esters, fluoroalkyls, or halogens.
본 발명의 다성분 짝지움 반응을 통한 N-술포닐아미딘의 제조방법은 하기 반응식(1)으로 간단히 나타낼 수 있다.Method for producing N-sulfonylamidine through the multicomponent coupling reaction of the present invention can be represented simply by the following scheme (1).
본 발명에서 화학식(1)의 화합물 아세틸렌 100몰％에 대해 화학식(2)의 술포닐 아지드와 화학식(3)의 아민 화합물을 각각 100∼150몰％ 씩 사용할 수 있다. 실험에 의하여 확인한 아민화합물의 사용량에 따른 수율은 100mol％(수득률= 81％), 120mol％(수득률= 95％), 150mol％(수득률= 95％)을 나타내어 110몰％ 이하를 사용하면 반응이 완전히 진행되지 않아 수득율이 낮아지게 되므로 110∼120몰％를 사용하는 것이 바람직함을 알 수 있다.In the present invention, the sulfonyl azide of formula (2) and the amine compound of formula (3) may each be used in an amount of 100 to 150 mol% relative to 100 mol% of the compound acetylene of formula (1). The yield according to the amount of the amine compound confirmed by the experiment was 100 mol% (yield = 81%), 120 mol% (yield = 95%), 150 mol% (yield = 95%). It can be seen that it is preferable to use 110 to 120 mol% because the yield is low because it does not proceed.
본 발명에서 촉매로서 사용하는 구리 금속은 산화수 +1가나 +2가 모두 사용가능하며 화학식 (5)으로 나타낼 수 있다.Copper metal used as a catalyst in the present invention can be used both the oxidation number +1 or +2 can be represented by the formula (5).
CuXn 화학식(5)CuX n Formula (5)
상기 화학식(5)에서 n은 1 또는 2를 나타내며 X는 음이온으로서 할로겐이온이나 황산염, 질산염, 초산염, 또는 그 유도체를 사용할 수 있는데 구리 할로겐염 을 사용하는 것이 반응 속도와 수득율 면에서 보다 바람직하다.In the formula (5), n represents 1 or 2, and X may use halogen ions, sulfates, nitrates, acetates, or derivatives thereof as anions, and copper halide salts are more preferable in terms of reaction rate and yield.
본 발명에서 구리 금속 촉매는 화학식(1)의 아세틸렌 화합물을 기준으로 1∼20몰％ 사용할 수 있는데, 보다 바람직하게는 5∼10몰％ 사용하는 것이 좋다. 실험에 의하여 확인한 촉매사용량에 따른 수득률은 실온에서 1시간 반응시킬 경우, CuI 촉매량 1mol％(수득률= 40％), 2mol％(수득률= 60％), 5mol％(수득률= 96％), 10mol％(수득률= 96 ％)를 나타내는 것을 알 수 있듯이 구리 금속 촉매를 아세틸렌을 기준으로 5몰％ 미만 사용하면 본 발명의 목적물인 N-술포닐아미딘 화합물의 수득률이 감소하는 문제가 있다.In the present invention, the copper metal catalyst may be used in an amount of 1 to 20 mol% based on the acetylene compound of the formula (1), more preferably 5 to 10 mol%. The yield according to the catalyst usage confirmed by the experiment was 1 mol% CuI catalyst (yield = 40%), 2 mol% (yield = 60%), 5 mol% (yield = 96%), 10 mol% (1 hour reaction at room temperature). As can be seen that yield = 96%), when the copper metal catalyst is used less than 5 mol% based on acetylene, there is a problem that the yield of the N-sulfonylamidine compound which is the object of the present invention is reduced.
본 발명의 N-술포닐아미딘 제조시 아세틸렌, 술포닐 아지드, 아민을 용매 중에서 반응시키는 데, 본 발명에서 용매는 반응에 악영향을 주지 않는 모든 유기용매를 사용할 수 있으며 보다 바람직하게는 테트라히드로퓨란이나 아세토니트릴과 같은 극성용매를 사용하는 것이 좋다. 또한 물이나 알코올과 같은 수소결합을 하는 용매가 포함된 유기 용매도 N-술포닐아미딘 제조에 사용될 수 있다. 용매의 양은 화학식(1)의 아세틸렌을 기준으로 1.0∼0.01M 농도로 사용할 수 있는데 용매의 양이 너무 적으면 반응시 교반이 안될 수 있고 너무 많은 경우 반응이 완결되지 않거나 수득율이 낮아지는 문제가 있으므로 0.5∼0.1M 농도가 바람직하다. In preparing the N-sulfonylamidine of the present invention, acetylene, sulfonyl azide, and amine are reacted in a solvent. In the present invention, the solvent may use any organic solvent which does not adversely affect the reaction, and more preferably tetrahydro It is recommended to use a polar solvent such as furan or acetonitrile. In addition, an organic solvent including a solvent capable of hydrogen bonding such as water or alcohol may be used to prepare N-sulfonylamidine. The amount of the solvent may be used in a concentration of 1.0 to 0.01 M based on the acetylene of the formula (1). If the amount of the solvent is too small, the reaction may not be stirred. If the amount is too large, the reaction may not be completed or the yield may be low. 0.5 to 0.1 M concentration is preferred.
친핵성이 떨어지는 아민이나 산과의 염의 형태로 존재하는 암모늄염의 경우 추가로 염기를 사용하는데 화학식(3)의 아민에 대해 110몰％가 더해진다. 친핵성이 떨어지는 아민에는 아닐린과 그 유도체 모르폴린과 그 유도체가 포함되며 암모늄염의 경우는 아미노에스테르와 아미노알코올의 염들이 해당한다. 상기와 같은 아민의 경우 사용되는 염기로는 트리알킬아민, 피리딘과 그 유도체가 포함된다. 실험에 의하여 확인한 아민성분의 유무에 따른 수득률은 아민이 없는 경우는 반응이 진행되지 않았고, 트리에틸아민 첨가시 (수득률 = 91％)를 나타냄을 알 수 있었다.Ammonium salts present in the form of amines with poor nucleophilicity or salts with acids additionally use a base, which adds 110 mol% to the amine of formula (3). Amines with poor nucleophilicity include aniline and its derivatives morpholine and its derivatives, and ammonium salts include aminoesters and aminoalcohol salts. Bases used in the case of such amines include trialkylamines, pyridine and derivatives thereof. The yield according to the presence or absence of the amine component confirmed by the experiment showed that the reaction did not proceed when there was no amine, and the triethylamine was added (a yield = 91%).
화학식(1)의 아세틸렌과 화학식(2)의 술포닐 아지드, 그리고 구리 촉매를 포함하고 있는 불균일 유기 용액에 화학식(3)의 아민을 가하면서 교반하면 질소분자가 생성되면서 균일 용액이 되는데 이때 반응은 0∼50℃에서 30분에서 5시간 동안 진행된다. 반응 후 유기 용액을 포화 염화암모늄 용액으로 닦고 감압하여 유기용매를 제거한 후 남은 반응물을 정제하여 N-술포닐아미딘 화합물을 얻을 수 있다. 상기 반응조건에 있어서, 반응온도가 0℃ 미만에서는 반응시간이 현저히 늘어나 수득율이 떨어지는 문제가 있고, 50℃를 초과하면 반응이 너무 빨리 진행되면서 질소분자가 급격히 생성되므로 폭발의 위험이 있다. 또한 반응시간이 30분 미만에서는 반응이 종결되지 않는 문제가 있어 반응은 0∼50℃에서 30분∼5시간 동안 실시하는 것이 좋다. 실험에 의하여 확인한 반응온도와 시간에 따른 수득률은 요오드화 구리(5mol％)의 경우 -30℃에서 12시간 반응시 수득률(10％), 0℃에서 12시간 반응시 수득률(72％), 25℃에서 30분 반응시 수득률(85％), 50℃에서 30분 반응시 수득률(81％)를 나타냈다.When an amine of formula (3) is added to a heterogeneous organic solution containing acetylene of formula (1), sulfonyl azide of formula (2), and a copper catalyst, the mixture is stirred with a nitrogen solution to form a homogeneous solution. Is carried out for 30 minutes to 5 hours at 0-50 ° C. After the reaction, the organic solution may be washed with a saturated ammonium chloride solution and depressurized to remove the organic solvent, and the remaining reactant may be purified to obtain an N-sulfonylamidine compound. In the above reaction conditions, when the reaction temperature is less than 0 ℃ significantly increases the reaction time, there is a problem that the yield is lowered, if it exceeds 50 ℃ there is a risk of explosion because the reaction proceeds too fast and nitrogen molecules are rapidly generated. In addition, when the reaction time is less than 30 minutes, the reaction is not terminated, the reaction is preferably carried out for 30 minutes to 5 hours at 0 ~ 50 ℃. The yield according to the reaction temperature and time confirmed by the experiment was obtained in the case of copper iodide (5 mol%) for 12 hours at -30 ° C (10%), the yield for 12 hours at 0 ° C (72%), at 25 ° C. Yield (85%) when reacting for 30 minutes, yield (81%) when reacting for 30 minutes at 50 ° C.
이하, 본 발명을 하기 실시예에 의거하여 보다 구체적으로 설명한다. 그러나, 이들 실시 예는 본 발명에 대한 이해를 돕기 위한 것으로서 이들에 의해 본 발명의 권리범위가 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples. However, these examples are intended to help the understanding of the present invention, and the scope of the present invention is not limited thereto.
<실시예1> N1,N1-디이소프로필-N2-(4-메틸벤젠술포닐)-2-페닐아세타미딘 합성Example 1 Synthesis of N 1 , N 1 -diisopropyl-N 2- (4-methylbenzenesulfonyl) -2-phenylacetamidine
10mL의 플라스크에 요오드화구리(9.5mg, 0.05mmol), 페닐아세틸렌(55㎕, 0.5mmol), p-톨루엔술포닐 아지드(120mg, 0.6mmol)을 넣고 유기용매로 테트라히드로퓨란(1mL)을 첨가한 후 잘 교반한다. 디이소프로필아민(85㎕, 0.6mmol)을 넣고 교반하면 질소 분자가 생성된다. 1시간 후 포화 염화암모늄 용액 4mL와 디클로로메탄 4mL를 가한 후 추가로 30분 동안 두 층의 혼합물을 교반한다. 유기층을 취해 황산마그네슘으로 탈수한 후 유기 용매를 감압 건조기로 제거하고 남은 반응 혼합물을 실리카겔 관 크로마토그라피에 의하여 정제하여 흰색 고체의 N-술포닐아미딘을 89％의 수율로 얻었다. Copper iodide (9.5 mg, 0.05 mmol), phenylacetylene (55 μl, 0.5 mmol) and p-toluenesulfonyl azide (120 mg, 0.6 mmol) were added to a 10 mL flask, and tetrahydrofuran (1 mL) was added as an organic solvent. After stirring well. Diisopropylamine (85 µl, 0.6 mmol) is added and stirred to form nitrogen molecules. After 1 hour 4 mL of saturated ammonium chloride solution and 4 mL of dichloromethane are added and the mixture of the two layers is stirred for an additional 30 minutes. The organic layer was taken, dehydrated with magnesium sulfate, the organic solvent was removed with a reduced pressure drier, and the remaining reaction mixture was purified by silica gel column chromatography to obtain N-sulfonylamidine as a white solid in 89% yield.
Rf 0.42 (EtOAc/hexane = 1/2); mp: 147.5-148.5℃ (CH2Cl2/hexane); 1H NMR (400 MHz, CDCl3) d 7.80 (dd, J = 1.7, 6.6 Hz, 2H), 7.30-7.10 (m, 7H), 4.38 (s, 2H), 3.98 (quintet, J = 6.6 Hz, 1H), 3.42 (quintet, J= 6.7 Hz, 1H), 2.36 (s, 3H), 1.36 (d, J = 6.7 Hz, 6H), 0.85 (d, J = 6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 163.4, 141.5, 134.9, 129.0, 128.8, 128.0, 126.7, 126.2, 50.4, 48.0, 38.7, 21.4, 19.8; IR (film) n 2972, 1546, 1447, 1373, 1271, 1139, 1086, 754, 550 cm-1 HRMS (FAB) m/z calcd. for C21H29N2O2S [M+H]+: 373.1950, found: 373.1949.R f 0.42 (EtOAc / hexane = 1/2); mp: 147.5-148.5 ° C. (CH 2 Cl 2 / hexane); 1 H NMR (400 MHz, CDCl 3 ) d 7.80 (dd, J = 1.7, 6.6 Hz, 2H), 7.30-7.10 (m, 7H), 4.38 (s, 2H), 3.98 (quintet, J = 6.6 Hz, 1H), 3.42 (quintet, J = 6.7 Hz, 1H), 2.36 (s, 3H), 1.36 (d, J = 6.7 Hz, 6H), 0.85 (d, J = 6.6 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) d 163.4, 141.5, 134.9, 129.0, 128.8, 128.0, 126.7, 126.2, 50.4, 48.0, 38.7, 21.4, 19.8; IR (film) n 2972, 1546, 1447, 1373, 1271, 1139, 1086, 754, 550 cm -1 HRMS (FAB) m / z calcd. for C 21 H 29 N 2 O 2 S [ M + H ] + : 373.1950, found: 373.1949.
<실시예 2> N1-[(1-메톡시카르보닐)-3-메틸부틸]-N2-(4-메틸벤젠술포닐)-2-페닐아세타미딘 합성Example 2 Synthesis of N 1 -[(1-methoxycarbonyl) -3-methylbutyl] -N 2- (4-methylbenzenesulfonyl) -2-phenylacetamidine
250mL의 플라스크에 요오드화구리(19mg, 0.1mmol), 페닐아세틸렌(1.1mL, 10.0mmol), (R)-페닐알라닌 메틸에스테르 염산염(2.27g, 10.5mmol)을 넣고 테트라히드로퓨란 15mL와 물 5mL을 첨가한 후 잘 교반한다. 트리에틸아민(1.7mL, 12mmol)을 넣고 15분간 교반한다. p-톨루엔술포닐 아지드(2.17g, 11.0mmol)을 테트라히드로퓨란(5 mL)에 용해한 후 이 용액을 천천히 기존의 용액에 더한다. 2시간동안 교반하면서 생성된 질소 분자가 빠져나가게 한다. 포화 염화암모늄 용액 75mL와 디클로로메탄 75mL를 가한 후 추가로 30분 동안 두 층의 혼합물을 교반한다. 유기층을 취해 황산마그네슘으로 탈수한 후 유기 용매를 감압 건조기로 제거하고 남은 반응 혼합물을 실리카겔 관 크로마토그라피에 의하여 정제하여 흰색 고체의 N-술포닐아미딘을 96％의 수율로 얻었다. Copper iodide (19 mg, 0.1 mmol), phenylacetylene (1.1 mL, 10.0 mmol) and (R) -phenylalanine methyl ester hydrochloride (2.27 g, 10.5 mmol) were added to a 250 mL flask, and 15 mL of tetrahydrofuran and 5 mL of water were added. After stirring well. Add triethylamine (1.7 mL, 12 mmol) and stir for 15 minutes. Dissolve p-toluenesulfonyl azide (2.17 g, 11.0 mmol) in tetrahydrofuran (5 mL) and slowly add this solution to the existing solution. The resulting nitrogen molecules are allowed to escape with stirring for 2 hours. 75 mL of saturated ammonium chloride solution and 75 mL of dichloromethane are added and the mixture of the two layers is stirred for an additional 30 minutes. The organic layer was taken, dehydrated with magnesium sulfate, the organic solvent was removed with a reduced pressure drier, and the remaining reaction mixture was purified by silica gel column chromatography to obtain N-sulfonylamidine as a white solid in 96% yield.
Rf 0.30 (EtOAc/hexane = 1/2); [a]D 23 = + 44.5 (c = 2.2 in CHCl3); mp: 125-126℃ (CH2Cl2/hexane); 1H NMR (400 MHz, CDCl3) d 7.81 (d, J = 8.1 Hz, 2H) 7.35-7.20 (m, 5H), 7.20-6.95 (m, 5H), 6.73 (d, J = 7.0 Hz, 2H), 5.63 (d, J = 6.2 Hz, 1H), 4.71 (q, J = 6.4 Hz, 1H), 4.30 (d, J = 17.5 Hz, 1H), 4.15 (d, J = 17.5 Hz, 1H), 3.59 (s, 2H), 3.05 (dd, J = 5.6, 13.9 Hz, 1H), 2.88 (dd, J = 5.6, 13.9 Hz, 1H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) d 170.8, 165.7, 142.6, 140.4, 134.8, 132.4, 130.0, 129.4, 129.2, 128.9, 128.7, 128.2, 127.2, 126.4, 54.9, 52.4, 39.5, 36.5, 21.5 IR (film) n 3312, 2926, 1746, 1549, 1280, 1146, 1092, 698 cm-1; HRMS (FAB) m/z calcd. for C25H27N2O4S [M+H]+: 451.1692, found: 451.1698; Chiralcel OD-H, hexane/i-PrOH (80/20), 0.7 mL/min, 20 ℃, major 20.8 min (R-form), minor 18.0 min (S-form)R f 0.30 (EtOAc / hexane = 1/2); [a] D 23 = +44.5 ( c = 2.2 in CHCl 3 ); mp: 125-126 ° C. (CH 2 Cl 2 / hexane); 1 H NMR (400 MHz, CDCl 3 ) d 7.81 (d, J = 8.1 Hz, 2H) 7.35-7.20 (m, 5H), 7.20-6.95 (m, 5H), 6.73 (d, J = 7.0 Hz, 2H ), 5.63 (d, J = 6.2 Hz, 1H), 4.71 (q, J = 6.4 Hz, 1H), 4.30 (d, J = 17.5 Hz, 1H), 4.15 (d, J = 17.5 Hz, 1H), 3.59 (s, 2H), 3.05 (dd, J = 5.6, 13.9 Hz, 1H), 2.88 (dd, J = 5.6, 13.9 Hz, 1H), 2.41 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) d 170.8, 165.7, 142.6, 140.4, 134.8, 132.4, 130.0, 129.4, 129.2, 128.9, 128.7, 128.2, 127.2, 126.4, 54.9, 52.4, 39.5, 36.5, 21.5 IR ( film) n 3312, 2926, 1746, 1549, 1280, 1146, 1092, 698 cm-1; HRMS (FAB) m / z calcd. for C 25 H 27 N 2 O 4 S [M + H] + : 451.1692, found: 451.1698; Chiralcel OD-H, hexane / i -PrOH (80/20), 0.7 mL / min, 20 ° C, major 20.8 min ( R -form), minor 18.0 min ( S -form)
본 발명의 다성분 짝지움 반응을 이용하여 온화한 반응조건 하에 고수율의 N-술포닐아미딘 화합물을 제조할 수 있다.Using the multicomponent coupling reaction of the present invention, a high yield of N-sulfonylamidine compound can be prepared under mild reaction conditions.
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