KR100424845B1 - Method for preparing lactone compounds using polystyrene resin - Google Patents
Method for preparing lactone compounds using polystyrene resin Download PDFInfo
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- KR100424845B1 KR100424845B1 KR1019970046258A KR19970046258A KR100424845B1 KR 100424845 B1 KR100424845 B1 KR 100424845B1 KR 1019970046258 A KR1019970046258 A KR 1019970046258A KR 19970046258 A KR19970046258 A KR 19970046258A KR 100424845 B1 KR100424845 B1 KR 100424845B1
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Description
본 발명은 폴리스티렌 수지를 이용하여 신규한 락톤 화합물을 제조하는 유기합성 방법에 관한 것이다. 더욱 상세하게는, 본 발명은 폴리스티렌 수지를 이용한 고체상에서의 반응을 통하여 용매로는 유기용매와 물의 혼합용매를 이용하며 산 존재하에 시아노겐 브로마이드로 처리하여 신규한 락톤 화합물을 제조하는 방법에 관한 것이다.The present invention relates to an organic synthesis method for producing a novel lactone compound using a polystyrene resin. More specifically, the present invention relates to a method for preparing a novel lactone compound by using a mixed solvent of an organic solvent and water as a solvent through a reaction in a solid phase using a polystyrene resin and treating with cyanogen bromide in the presence of an acid. .
본 발명의 락톤 화합물은 하기 일반식(Ⅰ)로 표시되고, 이것은 하기 일반식(Ⅱ)로 부터 제조된다.The lactone compound of the present invention is represented by the following general formula (I), which is prepared from the following general formula (II).
상기 식에서 R은 화학적으로 치환이 가능한 모든 그룹을 나타내는데, 예를 들어 알킬, 치환된 알킬, 알케닐, 치환된 알케닐, 페닐, 치환된 페닐, 헤테로, 치환된 헤테로 등을 들 수 있다. 상기 식(Ⅱ)에서구조는 아미노메틸 폴리스티렌 수지를 나타낸다.In the formula, R represents all chemically substitutable groups, for example, alkyl, substituted alkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, hetero, substituted hetero and the like. In the formula (II) The structure represents an aminomethyl polystyrene resin.
종래, 수지를 이용한 고체상에서의 유기합성법은 칼럼크로마토그라피와 같은 정제과정이 필요하지 않다는 장점과 컴비네토리얼 라이브러리를 쉽게 구축할 수 있다는 잇점 때문에 최근들어 수많은 연구가 이루어져 왔다(Angew. Chem. Int. Ed. Engl. 1996, 35, 2288~2337: Tetrahedron 1995, 51, 8135~8137). 그러나, 고체상에서 반응시킨후 목적 화합물을 얻기 위하여 수지와 유기화합물 간의 공유결합을 절단하는 과정은 강산, 강염기등의 강한 조건들을 필요로할 뿐만 아니라, 폴리스티렌 수지의 절단과정에서 입체화학구조가 그대로 유지되기 어렵다는 문제점이 있었다.Conventionally, a number of studies have been made in recent years due to the advantage that the organic synthesis method in the solid phase using a resin does not require a purification process such as column chromatography and the advantage that it is easy to build a combinatorial library (Angew. Chem. Int Ed. Engl. 1996, 35, 2288-2337: Tetrahedron 1995, 51, 8135-8137). However, the process of cleaving covalent bonds between the resin and the organic compound in order to obtain the target compound after the reaction in the solid phase not only requires strong conditions such as strong acids and strong bases, but also maintains the stereochemical structure in the process of cutting the polystyrene resin. There was a problem that it is difficult to be.
따라서, 본 발명은 고체상에서의 반응후 목적 화합물을 얻기 위하여 수지와 유기화합물 간의 공유결합을 절단하는 과정에서 필요한 강산, 강염기를 사용하지 않고도 쉽게 수지와 유기화합물 간의 공유결합을 절단하므로써 본 발명을 달성하였다. 본 발명의 또다른 목적은 폴리스티렌 수지의 절단과정에서 입체화학구조가 그대로 유지되는 호모세린락톤을 합성하는 방법을 제공한다.Therefore, the present invention achieves the present invention by easily cutting the covalent bond between the resin and the organic compound without using the strong acid, strong base required in the process of cutting the covalent bond between the resin and the organic compound to obtain the target compound after the reaction in the solid phase. It was. Still another object of the present invention is to provide a method for synthesizing homoserine lactone in which the stereochemical structure is maintained in the process of cutting polystyrene resin.
이하, 본 발명의 구체적 구성과 작용을 상세히 설명한다.Hereinafter, the specific configuration and operation of the present invention will be described in detail.
도 1은 본 발명에 사용된 락톤화합물을 나타낸 것이다.1 shows a lactone compound used in the present invention.
본 발명은 신규의 락톤 화합물의 제조방법으로 아미노메틸 폴리스티렌 수지와 N-Fmoc-L-메치오닌을 축합시킨 화합물(Ⅳ)로부터 그의 보호기를 제거한 다음 적당한 카르복시산과 다시 축합시키는 공정과 상기 축합물(Ⅱ)을 유기용매와 산 존재하에 시아노겐 브로마이드(BrCN)로 처리하는 공정으로 구성된다.The present invention provides a process for preparing a new lactone compound, wherein the protecting group is removed from compound (IV) condensed with aminomethyl polystyrene resin and N-Fmoc-L-methionine and then condensed with a suitable carboxylic acid and the condensate (II) Is treated with cyanogen bromide (BrCN) in the presence of an organic solvent and an acid.
상기의 첫 번째 축합반응은 통상의 방법으로 수행될 수 있으며, 무수 디메틸포아미드 용매하에서 축합시약으로 디이소프로필 카보디이미드, 1-히드록시벤조트리아졸을 사용하는 것이 일반적이다. 목적하는 화합물(Ⅰ)을 제조하기 위해서는 상기 축합 화합물(Ⅱ)을 산 존재하에 시아노겐 브로마이드(BrCN)로 처리한다. 이때 선택되는 산으로는 아세트산, 트리플루오르아세트산, 염산 등을 사용할 수 있고, 유기 용매로는 클로로포름, 디클로로메탄, 디클로로에탄등이며 사용시에는 물과의 혼합용매로 사용하는 것이 바람직하다. 본 발명에 있어서 모든 반응은 실온 또는 그 이하에서 수행된다.The first condensation reaction can be carried out in a conventional manner, it is common to use diisopropyl carbodiimide, 1-hydroxybenzotriazole as the condensation reagent in anhydrous dimethylpoamide solvent. In order to prepare the desired compound (I), the condensation compound (II) is treated with cyanogen bromide (BrCN) in the presence of an acid. At this time, acetic acid, trifluoroacetic acid, hydrochloric acid, etc. may be used as the selected acid, and chloroform, dichloromethane, dichloroethane, etc. may be used as the organic solvent, and it is preferable to use it as a mixed solvent with water. In the present invention all reactions are carried out at or below room temperature.
본 발명 락톤 화합물들의 제조과정을 도식으로 나타내면 다음과 같다.The manufacturing process of the lactone compounds of the present invention is represented as follows.
` `
본 발명에서 사용된 상기의 카르복시산(Ⅵ)의 대표적인 예는 다음과 같다.Representative examples of the carboxylic acid (VI) used in the present invention are as follows.
n-부탄오익에시드(Ⅵ-a)n-butane ooxide (VI-a)
말로닉에시드 모노에틸에스테르(Ⅵ-b)Malonic acid monoethyl ester (VI-b)
(시클로펜틸)아세틱에시드(Ⅵ-c)(Cyclopentyl) acetic acid (VI-c)
N-카보벤질옥시-L-발린(Ⅵ-d)N-carbobenzyloxy-L-valine (VI-d)
N-카보벤질옥시-L-페닐알라닌(Ⅵ-e)N-carbenzyloxy-L-phenylalanine (VI-e)
N-p-톨루엔셜포닐-L-페닐알라닌(Ⅵ-f)N-p-tolucialfonyl-L-phenylalanine (VI-f)
3,4-메틸렌디옥시페닐프로피오닉에시드(Ⅵ-g)3,4-methylenedioxyphenylpropionic acid (VI-g)
p-메톡시페닐아세틱에시드(Ⅵ-h)p-methoxyphenylacetic acid (VI-h)
4-비페닐카복시에시드(Ⅵ-i)4-biphenylcarboxylate (VI-i)
이하, 본 발명의 구체적인 구성과 작용을 실시예를 들어 상세히 설명하면 다음과 같다.Hereinafter, the concrete configuration and operation of the present invention will be described in detail with reference to Examples.
실시예 1. 메치오닌이 결합된 수지(Ⅳ)의 제조Example 1.Preparation of Resin (IV) with Methionine
아미노메틸폴리스티렌 수지 4g(0.9 mmol), N-Fmoc-L-메치오닌 3.36g(9 mmol), 디이소프로필카보디이미드 1.4ml(9 mmol), 1-히드록시벤조트리아졸 1.2g(9 mmol), N-에틸모폴린 1.14ml(9 mmol)을 무수 디메틸포아미드 50ml에 가하여 실온에서 2일간 교반하였다. 수지를 여과한 후 디메틸포아미드(10ml x 2), 메탄올(10ml x 2), 클로로포름(10ml x 2)으로 씻어준 후 메치오닌이 결합된 수지 4.36g을 얻었다.4 g (0.9 mmol) of aminomethylpolystyrene resin, 3.36 g (9 mmol) of N-Fmoc-L-methionine, 1.4 ml (9 mmol) of diisopropylcarbodiimide, 1.2 g (9 mmol) of 1-hydroxybenzotriazole And 1.14 ml (9 mmol) of N-ethyl morpholine were added to 50 ml of anhydrous dimethylpoamide, and the mixture was stirred at room temperature for 2 days. The resin was filtered and washed with dimethylformamide (10 ml x 2), methanol (10 ml x 2) and chloroform (10 ml x 2) to obtain 4.36 g of methionine-bound resin.
이 화합물의 구조식(Ⅳ)은 다음과 같다.Structural formula (IV) of this compound is as follows.
이 화합물을 IR을 이용하여 분석한 결과는 다음과 같다.The compound was analyzed using IR as follows.
IR(KBr) 3403, 3024, 2918, 1718, 1670, 1601㎝-1 IR (KBr) 3403, 3024, 2918, 1718, 1670, 1601 cm -1
실시예 2. 보호기가 제거된 수지(Ⅴ)의 제조Example 2 Preparation of Resin (V) with Protective Group Removed
실시예 1에서 얻은 화합물(Ⅳ) 4.36g을 20% 피페리딘 디메틴포아미드 용액 30ml에 가하여 실온에서 6시간 동안 교반한 후 수지를 여과한 다음, 디메틸포아미드(10ml x 2), 메탄올(10ml x 2), 클로로포름(10ml x 2)으로 씻어준 후 보호기가 제거된 수지 4.24g을 얻었다. 이 화합물의 구조식(Ⅴ)은 하기와 같다.4.36 g of Compound (IV) obtained in Example 1 was added to 30 ml of a 20% piperidine dimethine poamide solution, stirred at room temperature for 6 hours, and then the resin was filtered, and then dimethylpoamide (10 ml x 2) and methanol ( 10 ml x 2) and chloroform (10 ml x 2) were washed to obtain 4.24 g of a resin from which the protecting group was removed. Structural formula (V) of this compound is as follows.
이 화합물을 IR을 이용하여 분석한 결과는 다음과 같다.The compound was analyzed using IR as follows.
IR(KBr) 3382, 2917, 1664, 1600, 1492㎝-1 IR (KBr) 3382, 2917, 1664, 1600, 1492 cm -1
실시예 3. N-(부탄오익)호모세린 락톤(Ⅰ)의 제조Example 3 Preparation of N- (Butane Oy) Homoserine Lactone (I)
실시예 2에서 얻은 수지 302mg(0.27mmol), n-부탄오익에시드(Ⅳ-a) 0.062ml(0.68 mmol), 디이소프로필카보디이미드 0.107ml(0.68 mmol), 1-히드록시벤조트리아졸 92mg(0.68 mmol), N-에틸모폴린 0.086 ml(0.68 mmol)을 무수 디메틸포아미드 5ml에 가하여 실온에서 2일간 교반하였다. 반응액을 여과하여 버린후 생성된 수지화합물(Ⅱ)을 디메틸포아미드(10ml x 2), 메탄올(10ml x 2), 클로로포름(10ml x 2)으로 씻어주었다. 위에서 얻은 수지를 클로로포름 5ml, 물 2ml 용액에 가하고 시아노겐 브로마이드 430mg(4.06 mmol)과 99% 트리플루오르아세트산 2방울을 차례로 가하였다. 실온에서 2일간 교반한 다음 여과하고, 여과액 중 클로로포름액을 취하여 감압농축하여 목적화합물 23mg을 얻었다. 이 화합물의 구조식은 하기와 같다.302 mg (0.27 mmol) of the resin obtained in Example 2, 0.062 ml (0.68 mmol) of n-butanioic acid (IV-a), 0.107 ml (0.68 mmol) of diisopropylcarbodiimide, 92 mg of 1-hydroxybenzotriazole (0.68 mmol) and 0.086 ml (0.68 mmol) of N-ethylmorpholine were added to 5 ml of anhydrous dimethylpoamide and stirred for 2 days at room temperature. The reaction solution was filtered off and the resulting resin compound (II) was washed with dimethylformamide (10ml x 2), methanol (10ml x 2) and chloroform (10ml x 2). The resin obtained above was added to a solution of 5 ml of chloroform and 2 ml of water, followed by 430 mg (4.06 mmol) of cyanogen bromide followed by two drops of 99% trifluoroacetic acid. After stirring for 2 days at room temperature, the mixture was filtered and the chloroform solution was collected in the filtrate, and concentrated under reduced pressure to obtain 23 mg of the target compound. The structural formula of this compound is as follows.
이 화합물을 IR,1H NMR을 이용하여 분석한 결과는 다음과 같다.The compound was analyzed using IR and 1 H NMR. The results are as follows.
IR(KBr) 3310, 2918, 1774, 1647 ㎝-1:1H NMR(CDCl3) δ6.088(br s, 1H), 4.59(ddd, J=11.7, 8.6, 5.8Hz, 1H), 4.50(ddd, J=9.1, 9.1, 1.2Hz, 1H), 4.32(ddd, J=11.4, 9.3, 5.8Hz, 1H), 2.90(dddd, J=12.6, 8.6, 5.9, 1.2Hz, 1H), 2.27(td, J=7.4, 1.6Hz, 2H), 2.16(dddd, J=11.5, 11.5, 12.5, 8.8Hz, 1H), 1.77(sextet, J=7.4Hz, 2H), 1.00(t, J=7.4Hz, 3H)IR (KBr) 3310, 2918, 1774, 1647 cm -1 : 1 H NMR (CDCl 3 ) δ6.088 (br s, 1H), 4.59 (ddd, J = 11.7, 8.6, 5.8 Hz, 1H), 4.50 ( ddd, J = 9.1, 9.1, 1.2 Hz, 1H), 4.32 (ddd, J = 11.4, 9.3, 5.8 Hz, 1H), 2.90 (dddd, J = 12.6, 8.6, 5.9, 1.2 Hz, 1H), 2.27 ( td, J = 7.4, 1.6 Hz, 2H), 2.16 (dddd, J = 11.5, 11.5, 12.5, 8.8 Hz, 1H), 1.77 (sextet, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz , 3H)
실시예 4. N-(말로닉 에틸에스테르)호모세린 락톤(Ⅰ)의 제조Example 4. Preparation of N- (malonic ethyl ester) homoserine lactone (I)
말로닉에시드 모노에틸에스테르(Ⅵ-b) 80mg(0.47 mmol)을 실시예 3과 같이 처리하여 상기 목적화합물 18mg을 얻었다. 이 화합물의 구조식은 하기와 같다.80 mg (0.47 mmol) of malonic acid monoethyl ester (VI-b) was treated in the same manner as in Example 3 to obtain 18 mg of the target compound. The structural formula of this compound is as follows.
이 화합물을 IR,1H NMR을 이용하여 분석한 결과는 다음과 같다.The compound was analyzed using IR and 1 H NMR. The results are as follows.
IR(KBr) 3319, 2922, 1737, 1697 ㎝-1:1H NMR(CDCl3) δ7.75(br s, 1H), 4.60(ddd, J=11.7, 8.8, 6.5Hz, 1H), 4.48(ddd, J=9.0, 9.0, 1.2Hz, 1H), 4.29(ddd, J=11.1, 9.3, 6.0Hz,1H), 4.23(q, J=7.2Hz, 2H), 3.38(s, 2H), 2.81(dddd, J=12.5, 8.7, 6.0, 1.3Hz, 1H), 2.20(dddd, J=11.2, 11.2, 12.5, 8.9Hz, 1H), 1.30(t, J=7.2Hz, 3H)IR (KBr) 3319, 2922, 1737, 1697 cm -1 : 1 H NMR (CDCl 3 ) δ7.75 (br s, 1H), 4.60 (ddd, J = 11.7, 8.8, 6.5 Hz, 1H), 4.48 ( ddd, J = 9.0, 9.0, 1.2 Hz, 1H), 4.29 (ddd, J = 11.1, 9.3, 6.0 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.38 (s, 2H), 2.81 (dddd, J = 12.5, 8.7, 6.0, 1.3 Hz, 1H), 2.20 (dddd, J = 11.2, 11.2, 12.5, 8.9 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H)
실시예 5. N-(시클로펜틸아세틸)효모세린 락톤(Ⅰ)의 제조Example 5 Preparation of N- (Cyclopentylacetyl) Yeastserine Lactone (I)
(시클로펜틸)아세틱에시드(Ⅵ-c) 64mg(0.47 mmol)을 실시예 3과 같이 처리하여 목적화합물 19mg을 얻었다. 이 화합물의 구조식은 하기와 같다.64 mg (0.47 mmol) of (cyclopentyl) acetic acid (VI-c) were treated in the same manner as in Example 3 to obtain 19 mg of the target compound. The structural formula of this compound is as follows.
이 화합물을 IR,1H NMR을 이용하여 분석한 결과는 다음과 같다.The compound was analyzed using IR and 1 H NMR. The results are as follows.
IR(KBr) 3306, 3035, 1777, 1642 ㎝-1:1H NMR(CDCl3) δ5.94(br s, 1H), 4.53(ddd, J=11.8, 8.8, 5.8Hz, 1H), 4.47(ddd, J=9.1, 9.1, 1.1Hz, 1H), 4.28(ddd, J=11.4, 9.4, 5.9Hz, 1H), 2.88(dddd, J=12.7, 8.6, 6.0, 1.3Hz, 1H), 2.26-2.25(m, 2H), 2.12(dddd, J=11.5, 11.5, 12.5, 8.8Hz, 1H), 1.89-1.81(m, 2H), 1.65-1.57(m, 3H), 1.21-1.13(m, 4H)IR (KBr) 3306, 3035, 1777, 1642 cm -1 : 1 H NMR (CDCl 3 ) δ 5.94 (br s, 1H), 4.53 (ddd, J = 11.8, 8.8, 5.8 Hz, 1H), 4.47 ( ddd, J = 9.1, 9.1, 1.1 Hz, 1H), 4.28 (ddd, J = 11.4, 9.4, 5.9 Hz, 1H), 2.88 (dddd, J = 12.7, 8.6, 6.0, 1.3 Hz, 1H), 2.26- 2.25 (m, 2H), 2.12 (dddd, J = 11.5, 11.5, 12.5, 8.8 Hz, 1H), 1.89-1.81 (m, 2H), 1.65-1.57 (m, 3H), 1.21-1.13 (m, 4H )
실시예 6. N-(카보벤질옥시-L-발린)호모세린 락톤(Ⅰ)의 제조Example 6 Preparation of N- (Cabobenzyloxy-L-valine) Homoserine Lactone (I)
N-카보벤질옥시-L-발린(Ⅵ-d) 126mg(0.5mmol)을 실시예 3과 같이 처리하여 목적화합물 29mg을 얻었다. 이 화합물의 구조식은 하기와 같다.126 mg (0.5 mmol) of N-carbobenzyloxy-L-valine (VI-d) was treated in the same manner as in Example 3 to obtain 29 mg of the target compound. The structural formula of this compound is as follows.
이 화합물을 IR,1H NMR을 이용하여 분석한 결과는 다음과 같다.The compound was analyzed using IR and 1 H NMR. The results are as follows.
IR(KBr) 3288, 2922, 1776, 1689 ㎝-1:1H NMR(CDCl3) δ7.38-7.30(m, 5H), 6.80(br d, J=5.4Hz, 1H), 5.46(br d, J=8.3Hz, 1H), 5.13(s, 1H), 4.60-4.54(m, 1H), 4.47(t, J=9.0Hz, 1H), 4.32-4.25(m, 1H), 4.09(m, 1H), 2.78-2.75(m, 1H), 2.22-2.25(m, 2H), 1.84(m, 1H), 1.03, 0.98(2d, J=6.8Hz, 6H)IR (KBr) 3288, 2922, 1776, 1689 cm -1 : 1 H NMR (CDCl 3 ) δ7.38-7.30 (m, 5H), 6.80 (br d, J = 5.4 Hz, 1H), 5.46 (br d , J = 8.3 Hz, 1H, 5.13 (s, 1H), 4.60-4.54 (m, 1H), 4.47 (t, J = 9.0 Hz, 1H), 4.32-4.25 (m, 1H), 4.09 (m, 1H), 2.78-2.75 (m, 1H), 2.22-2.25 (m, 2H), 1.84 (m, 1H), 1.03, 0.98 (2d, J = 6.8 Hz, 6H)
실시예 7. N-(카보벤질옥시-L-페닐알라닌)호모세린 락톤(Ⅰ)의 제조Example 7 Preparation of N- (Carbenzyloxy-L-phenylalanine) Homoserine Lactone (I)
N-카보벤질옥시-L-페닐알라닌(Ⅵ-e) 270mg(0.9mmol)을 실시예 3과 같이 처리하여 목적화합물 44mg을 얻었다. 이 화합물의 구조식은 하기와 같다.270 mg (0.9 mmol) of N-carbobenzyloxy-L-phenylalanine (VI-e) was treated in the same manner as in Example 3 to obtain 44 mg of the target compound. The structural formula of this compound is as follows.
이 화합물을 IR,1H NMR을 이용하여 분석한 결과는 다음과 같다.The compound was analyzed using IR and 1 H NMR. The results are as follows.
IR(KBr) 3297, 2919, 1777, 1691 ㎝-1:1H NMR(CDCl3) δ7.35-7.18(m, 10H), 6.40(br s, 1H), 5.25(br s, 1H), 5.09(s, 3H), 4.43(m, 2H), 4.39(ddd, J=11.3, 8.7, 6.0Hz, 1H), 4.24(ddd, J=10.8, 9.3, 6.0Hz, 1H), 3.11(m, 2H), 2.74(m, 1H), 2.09(m, 1H)IR (KBr) 3297, 2919, 1777, 1691 cm -1 : 1 H NMR (CDCl 3 ) δ7.35-7.18 (m, 10H), 6.40 (br s, 1H), 5.25 (br s, 1H), 5.09 (s, 3H), 4.43 (m, 2H), 4.39 (ddd, J = 11.3, 8.7, 6.0 Hz, 1H), 4.24 (ddd, J = 10.8, 9.3, 6.0 Hz, 1H), 3.11 (m, 2H ), 2.74 (m, 1 H), 2.09 (m, 1 H)
실시예 8. N-(p-톨루엔설포닐-L-페닐알라닌)호모세린 락톤(Ⅰ)의 제조Example 8 Preparation of N- (p-toluenesulfonyl-L-phenylalanine) homoserine lactone (I)
N-p-톨루엔설포닐-L-페닐알라닌(Ⅵ-f) 217mg(0.68mmol)을 실시예 3과 같이 처리하여 목적화합물을 얻었다. 이 화합물의 구조식은 하기와 같다.217 mg (0.68 mmol) of N-p-toluenesulfonyl-L-phenylalanine (VI-f) was treated in the same manner as in Example 3 to obtain the target compound. The structural formula of this compound is as follows.
이 화합물을 IR,1H NMR을 이용하여 분석한 결과는 다음과 같다.The compound was analyzed using IR and 1 H NMR. The results are as follows.
IR(KBr) 3288, 2916, 1773, 1654 ㎝-1:1H NMR(CDCl3) δ7.47(m, 2H), 7.15-7.08(m, 5H), 6.97(br d, J=6.4Hz, 1H), 6.98(m, 2H), 5.00(d, J=7.2Hz, 1H), 4.40(ddd, J=9.3, 9.3, 1.8Hz, 1H), 4.28(ddd, J=11.0, 8.9, 6.3Hz, 1H), 4.19(ddd, J=10.2, 9.2, 6.4Hz, 1H), 3.87(td, J=7.0, 5.8Hz, 1H), 2.95-2.83(m, 2H), 2.59(dddd, J=12.7, 8.7, 6.3, 1.9Hz, 1H), 2.35(s, 3H), 2.13(dddd, J=10.8, 10.8, 12.7, 9.1Hz, 1H)IR (KBr) 3288, 2916, 1773, 1654 cm -1 : 1 H NMR (CDCl 3 ) δ 7.47 (m, 2H), 7.15-7.08 (m, 5H), 6.97 (br d, J = 6.4 Hz, 1H), 6.98 (m, 2H), 5.00 (d, J = 7.2 Hz, 1H), 4.40 (ddd, J = 9.3, 9.3, 1.8 Hz, 1H), 4.28 (ddd, J = 11.0, 8.9, 6.3 Hz , 1H), 4.19 (ddd, J = 10.2, 9.2, 6.4 Hz, 1H), 3.87 (td, J = 7.0, 5.8 Hz, 1H), 2.95-2.83 (m, 2H), 2.59 (dddd, J = 12.7 , 8.7, 6.3, 1.9 Hz, 1H), 2.35 (s, 3H), 2.13 (dddd, J = 10.8, 10.8, 12.7, 9.1 Hz, 1H)
실시예 9. N-(3,4-메틸렌디옥시페닐프로피오닐)호모세린 락톤(Ⅰ)의 제조Example 9 Preparation of N- (3,4-methylenedioxyphenylpropionyl) homoserine lactone (I)
3,4-메틸렌디옥시페닐프로피오닉에시드(Ⅵ-g) 102mg(0.53mmol)을 실시예 3과 같이 처리하여 목적화합물 28mg을 얻었다. 이 화합물의 구조식은 하기와 같다.102 mg (0.53 mmol) of 3,4-methylenedioxyphenylpropionic acid (VI-g) were treated in the same manner as in Example 3 to obtain 28 mg of the target compound. The structural formula of this compound is as follows.
이 화합물을 IR,1H NMR을 이용하여 분석한 결과는 다음과 같다.The compound was analyzed using IR and 1 H NMR. The results are as follows.
IR(KBr) 3308, 2923, 1775, 1637 ㎝-1:1H NMR(CDCl3) δ6.74-6.64(m, 3H), 6.01(br s, 1H), 5.93(s, 2H), 4.52(ddd, J=11.6, 8.5, 5.8Hz, 1H), 4.46(ddd, J=9.1, 9.1, 1.2Hz, 1H), 4.27(ddd, J=11.3, 9.3, 5.8Hz, 1H), 2.90(t, J=7.4Hz, 2H), 2.84(dddd, J=12.5, 8.5, 5.8, 1.2Hz, 1H), 2.51(m, 2H), 2.06(dddd, J=11.5, 11.5, 12.6, 8.9Hz, 1H)IR (KBr) 3308, 2923, 1775, 1637 cm -1 : 1 H NMR (CDCl 3 ) δ6.74-6.64 (m, 3H), 6.01 (br s, 1H), 5.93 (s, 2H), 4.52 ( ddd, J = 11.6, 8.5, 5.8 Hz, 1H), 4.46 (ddd, J = 9.1, 9.1, 1.2 Hz, 1H), 4.27 (ddd, J = 11.3, 9.3, 5.8 Hz, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.84 (dddd, J = 12.5, 8.5, 5.8, 1.2 Hz, 1H), 2.51 (m, 2H), 2.06 (dddd, J = 11.5, 11.5, 12.6, 8.9 Hz, 1H)
실시예 10. N-(4-메톡시페닐아세틸)호모세린 락톤(Ⅰ)의 제조Example 10 Preparation of N- (4-methoxyphenylacetyl) homoserine lactone (I)
p-메톡시페닐아세틱에시드(Ⅵ-h) 113mg(0.68mmol)을 실시예 3과 같이 처리하여 목적화합물 29mg을 얻었다. 이 화합물의 구조식은 하기와 같다.113 mg (0.68 mmol) of p-methoxyphenylacetic acid (VI-h) were treated in the same manner as in Example 3 to obtain 29 mg of the target compound. The structural formula of this compound is as follows.
이 화합물을 IR,1H NMR을 이용하여 분석한 결과는 다음과 같다.The compound was analyzed using IR and 1 H NMR. The results are as follows.
IR(KBr) 3291, 2918, 1773, 1652 ㎝-1:1H NMR(CDCl3) δ7.12(d, J=7.5Hz, 2H), 6.82(d, J=9.4Hz, 2H), 5.87(br s, 1H), 4.44(ddd, J=11.6, 8.7, 6.1Hz, 1H), 4.36(ddd, J=9.0, 9.0, 1.0Hz, 1H), 4.18(ddd, J=11.2, 9.3, 5.9Hz, 1H), 3.74(s, 3H), 3.50(s, 2H), 2.72(dddd, J=12.5, 8.6, 5.9, 1.2Hz, 1H), 2.01(dddd, J=11.3, 11.3, 12.5, 8.9Hz, 1H)IR (KBr) 3291, 2918, 1773, 1652 cm -1 : 1 H NMR (CDCl 3 ) δ7.12 (d, J = 7.5 Hz, 2H), 6.82 (d, J = 9.4 Hz, 2H), 5.87 ( br s, 1H), 4.44 (ddd, J = 11.6, 8.7, 6.1 Hz, 1H), 4.36 (ddd, J = 9.0, 9.0, 1.0 Hz, 1H), 4.18 (ddd, J = 11.2, 9.3, 5.9 Hz , 1H), 3.74 (s, 3H), 3.50 (s, 2H), 2.72 (dddd, J = 12.5, 8.6, 5.9, 1.2Hz, 1H), 2.01 (dddd, J = 11.3, 11.3, 12.5, 8.9Hz , 1H)
실시예 11. N-(4-비페닐카르보닐)호모세린 락톤(Ⅰ)의 제조Example 11 Preparation of N- (4-biphenylcarbonyl) homoserine lactone (I)
4-비페닐카복시에시드(Ⅵ-i) 194mg(0.98mmol)을 실시예 3과 같이 처리하여 목적화합물 58mg을 얻었다. 이 화합물의 구조식은 하기와 같다.194 mg (0.98 mmol) of 4-biphenylcarboxylate (VI-i) was treated in the same manner as in Example 3 to obtain 58 mg of the target compound. The structural formula of this compound is as follows.
이 화합물을 IR,1H NMR을 이용하여 분석한 결과는 다음과 같다.The compound was analyzed using IR and 1 H NMR. The results are as follows.
IR(KBr) 3058, 2917, 1657, 1641 ㎝-1:1H NMR(CDCl3) δ7.89(m, 2H), 7.69-7.61(m, 4H), 7.49-7.38(m, 3H), 6.78(br d, J=4.7Hz, 1H), 4.77(ddd, J=11.6, 8.5, 5.5Hz, 1H), 4.55(ddd, J=9.0, 9.0, 1.0Hz, 1H), 4.38(ddd, J=11.3, 9.3, 5.8Hz, 1H), 3.01(dddd, J=12.5, 8.6, 5.8, 1.2Hz, 1H), 2.29(dddd, J=11.4, 11.4, 12.5, 8.8Hz, 1H)IR (KBr) 3058, 2917, 1657, 1641 cm -1 : 1 H NMR (CDCl 3 ) δ 7.89 (m, 2H), 7.69-7.61 (m, 4H), 7.49-7.38 (m, 3H), 6.78 (br d, J = 4.7 Hz, 1H), 4.77 (ddd, J = 11.6, 8.5, 5.5 Hz, 1H), 4.55 (ddd, J = 9.0, 9.0, 1.0 Hz, 1H), 4.38 (ddd, J = 11.3, 9.3, 5.8 Hz, 1H), 3.01 (dddd, J = 12.5, 8.6, 5.8, 1.2 Hz, 1H), 2.29 (dddd, J = 11.4, 11.4, 12.5, 8.8 Hz, 1H)
이상 실시예를 통하여 설명한 바와 같이 본 발명은 수지와 유기화합물간의 공유결합을 절단하는 과정을 강산, 강염기등의 조건을 사용하지 않으면서 쉽게 절단하고, 폴리스티렌 수지의 절단과정에서 입체화학구조가 그대로 유지되는 호모세린락톤을 제조할 수 있으므로 신규한 유기합성법을 제공하는 효과가 있다. 또한 본 발명의 락톤 화합물은 면역억제제, 항암제등의 의약품으로도 사용할 수 있고 유용한 합성 중간체로도 이용될 수 있으므로 의약산업상 매우 유용한 발명인 것이다.As described above, the present invention can easily cut the process of cleaving covalent bonds between the resin and the organic compound without using conditions such as strong acid and strong base, and maintain the stereochemical structure in the process of cutting the polystyrene resin. Since homoserine lactone can be prepared, there is an effect of providing a novel organic synthesis method. In addition, the lactone compound of the present invention can be used as pharmaceuticals such as immunosuppressants, anticancer agents, and also useful as synthetic intermediates, which is a very useful invention in the pharmaceutical industry.
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US3968233A (en) * | 1973-12-05 | 1976-07-06 | Istituto Chemioterapico Italiano | α-Amino-γ-butyrolactones as sedatives |
JPS5896079A (en) * | 1981-11-30 | 1983-06-07 | Mitsubishi Gas Chem Co Inc | Homoserine lactone derivative |
EP0151964A2 (en) * | 1984-02-02 | 1985-08-21 | Laboratorio Farmaceutico C.T. s.r.l. | New derivatives of alpha-amino-gamma-butyrolactone, method for the preparation thereof and pharmaceutical compositions containing them |
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US3968233A (en) * | 1973-12-05 | 1976-07-06 | Istituto Chemioterapico Italiano | α-Amino-γ-butyrolactones as sedatives |
JPS5896079A (en) * | 1981-11-30 | 1983-06-07 | Mitsubishi Gas Chem Co Inc | Homoserine lactone derivative |
EP0151964A2 (en) * | 1984-02-02 | 1985-08-21 | Laboratorio Farmaceutico C.T. s.r.l. | New derivatives of alpha-amino-gamma-butyrolactone, method for the preparation thereof and pharmaceutical compositions containing them |
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