KR101374706B1 - Method for preparation of chiral lactone derivatives - Google Patents
Method for preparation of chiral lactone derivatives Download PDFInfo
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- 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
생리활성을 갖고 있는 락톤 유도체의 제조방법이 개시되어 있다. 본 발명은 키랄 팔라듐 촉매 존재하에서, 1,1- 불포화기를 갖고 있는 카르복실산 유도체와 2,4,4,5-테트라브로모-2,5-사이클로헥사다이엔온을 반응시키는 것을 특징으로 하여, 광학 순도와 수율이 높은 키랄 락톤 유도체를 제조할 수 있는 장점이 있다.A method for producing a lactone derivative having physiological activity is disclosed. The present invention is characterized by reacting a carboxylic acid derivative having a 1,1-unsaturated group with 2,4,4,5-tetrabromo-2,5-cyclohexadienone in the presence of a chiral palladium catalyst. In addition, there is an advantage in that a chiral lactone derivative having high optical purity and yield can be prepared.
Description
본 발명은 생리활성을 갖고 있는 락톤 유도체 (lactone derivatives)의 제조방법에 관한 것으로, 특히 키랄 팔라듐 촉매를 이용하여 광학 순도가 높은 광학활성물질을 효율적으로 제조할 수 있는 키랄 락톤 유도체의 제조방법에 관한 것이다.The present invention relates to a method for preparing lactone derivatives having physiological activity, and in particular, to a method for preparing chiral lactone derivatives that can efficiently produce an optically active material having high optical purity using a chiral palladium catalyst. will be.
자연에 존재하는 많은 생리활성분자들은 광학활성을 나타내는 한 가지 이성질체로만 구성된 경우가 많다. 대부분의 생리활성 분자의 경우 한 가지 입체 이성질체만 약리효과를 나타낸다고 알려져 있고, 다른 입체 이성질체는 부작용을 유발할 수 있는 위험성을 지니는 것으로 알려져 있어 키랄 화합물의 효율적인 합성방법에 대한 활발한 연구가 진행되고 있다. 키랄 화합물을 얻는 방법으로 가장 효율적이고 경제적이 방법은 비대칭 촉매를 이용한 방법으로 다양한 키랄 중간체를 제조하는 촉매 비대칭 반응의 개발은 의학화학분야에서 매우 중요하다. 비대칭 반응에 사용되고 있는 대부분의 촉매는 공기 중이나 수분에 불안정하여 무수 반응조건 등 까다로운 반응조건이 필요하여 산업적 활용에 큰 단점으로 지적되고 있다. 따라서 공기나 수분에 안정하고 저렴한 촉매를 이용한 비대칭 반응의 개발은 매우 필요하고 중요하다.Many physiologically active molecules in nature are often composed of only one isomer showing optical activity. In the case of most bioactive molecules, only one stereoisomer is known to have a pharmacological effect, and other stereoisomers are known to have a risk of causing side effects. Therefore, active researches on efficient synthesis methods of chiral compounds are being conducted. The most efficient and economical method for obtaining chiral compounds is the development of catalytic asymmetric reactions for preparing various chiral intermediates by the method using an asymmetric catalyst is very important in the field of medical chemistry. Most catalysts used in asymmetric reactions are unstable in air or moisture and require difficult reaction conditions such as anhydrous reaction conditions. Therefore, the development of an asymmetric reaction using a catalyst which is stable and inexpensive to air or moisture is very necessary and important.
키랄 락톤 유도체들은 생리활성과 관련하여 매우 중용하게 인식되어 이들의 비대칭 합성은 매우 중요하다.Chiral lactone derivatives are recognized as being very important with respect to their biological activity, so their asymmetric synthesis is very important.
본 특허에서는 공기나 수분에 안정하고 취급이 용이한 키랄 팔라듐 촉매를 이용하여 키랄 락톤 유도체들을 합성하였다.In this patent, chiral lactone derivatives are synthesized using a chiral palladium catalyst which is stable to air or moisture and is easy to handle.
본 발명의 목적은 키랄 팔라듐 촉매를 이용하여 광학 순도가 높은 키랄 락톤 유도체의 제조방법을 제공하는 데 있다.An object of the present invention is to provide a method for producing a chiral lactone derivative having high optical purity by using a chiral palladium catalyst.
본 발명의 다른 목적은 공기나 수분에 안정하고 취급이 용이한 키랄 촉매를 이용하여 키랄 락톤 유도체의 제조방법을 제공하는 데 있다.Another object of the present invention is to provide a method for preparing a chiral lactone derivative using a chiral catalyst which is stable to air or moisture and is easy to handle.
상기 목적을 달성하기 위해 본 발명에 다른 키랄 락톤 유도체의 제조방법은, 키랄 팔라듐 촉매 존재하에서, 1,1- 불포화기를 갖고 있는 카르복실산 유도체와 2,4,4,5-테트라브로모-2,5-사이클로헥사다이엔온을 반응시키는 것을 특징으로 한다.In order to achieve the above object, a method for preparing a chiral lactone derivative according to the present invention includes a carboxylic acid derivative having 2,4,4,5-tetrabromo-2 having a 1,1-unsaturated group in the presence of a chiral palladium catalyst. It is characterized by reacting a 5-cyclohexadiene.
상술한 바와 같이, 본 발명에서 공기나 수분에 안정하고 취급이 용이한 키랄 팔라듐 촉매를 이용하여 키랄 락톤 유도체를 효율적으로 제조할 수 있다는 효과가 얻어진다.As described above, in the present invention, an effect of efficiently producing a chiral lactone derivative using a chiral palladium catalyst which is stable to air or moisture and is easy to handle is obtained.
또한, 본 발명에 의하면, 광학 순도와 수율이 높은 키랄 락톤 유도체를 제조할 수 있는 장점이 있다.In addition, according to the present invention, there is an advantage that a chiral lactone derivative having high optical purity and yield can be prepared.
본 발명의 상기 및 그 밖의 목적과 새로운 특징은 본 명세서에 의해서 더욱 명확하게 될 것이다.The above and other objects and novel features of the present invention will become more apparent from the present specification.
먼저, 본 발명에 따른 키랄 락톤 유도체의 제조방법의 특징에 대해 설명한다. First, the characteristic of the manufacturing method of a chiral lactone derivative which concerns on this invention is demonstrated.
본 발명의 일 실시 예에 따른 키랄 락톤 유도체의 제조방법은 키랄 팔라듐 촉매 존재 하에서 1,1-불포화기를 갖고 있는 카르복실산 유도체와 2,4,4,5-테트라브로모-2,5-사이클로헥사다이엔온을 반응시켜 키랄 락톤 유도체를 제조할 수 있다. 상기 제조방법은 키랄 촉매를 이용하여 광학 순도가 높은 광학활성물질을 효율적으로 제조하기 위한 것이다. 위 제조방법에서 사용되는 키랄 팔라듐 촉매는 하기 화학식 1의 화합물이다. A method for preparing a chiral lactone derivative according to an embodiment of the present invention is a carboxylic acid derivative having a 1,1-unsaturated group and 2,4,4,5-tetrabromo-2,5-cyclo in the presence of a chiral palladium catalyst. Chiral lactone derivatives can be prepared by reacting hexadienone. The preparation method is for efficiently preparing an optically active material having high optical purity using a chiral catalyst. The chiral palladium catalyst used in the above production process is a compound of the following formula (1).
[화학식 1][Chemical Formula 1]
상기 화학식 1에서 키랄 촉매의 함량은 반응 물질들의 전체 몰수를 기준으로, 10몰% 이다. 10몰% 사용하면 광학 순도와 수율이 높은 키랄 락톤 유도체를 효율적으로 제조할 수 있다.The content of the chiral catalyst in Chemical Formula 1 is 10 mol% based on the total moles of the reactants. When 10 mol% is used, chiral lactone derivatives having high optical purity and yield can be efficiently produced.
1,1-불포화기를 갖고 있는 카르복실산은 하기의 화학식 2의 구조를 갖는 화합물일 수 있다. The carboxylic acid having a 1,1-unsaturated group may be a compound having the structure of Formula 2 below.
[화학식 2](2)
상기 화학식 2에서 Ar은C6-C14의 아릴이거나 C4-C10의 방향족 헤테로고리 화합물고 상기 아릴기는 C1-C10의 알콕시기, 알킬기, C1-C10알킬 아민기가 치환된 아릴기 또는 할로겐으로 치환될 수 있다. 상기 Ar은 방향족 헤테로고리 화합물인 퓨릴(furyl), 싸이에닐(thienyl) 또는 피리딜(pyridyl)일 수 있다.Ar in Formula 2 is C 6 -C 14 aryl or C 4 -C 10 aromatic heterocyclic compound and the aryl group is an aryl substituted with a C 1 -C 10 alkoxy group, alkyl group, C 1 -C 10 alkyl amine group It may be substituted with a group or a halogen. The Ar may be an aromatic heterocyclic compound such as furyl, thienyl or pyridyl.
상기 2,4,4,5-테트라브로모-2,5-사이클로헥사다이엔온은 하기 화학식 3의 구조를 갖는 화합물일 수 있다.The 2,4,4,5-tetrabromo-2,5-cyclohexadienone may be a compound having a structure of Formula 3 below.
[화학식 3](3)
상기 키랄 락톤 유도체는 화학식 4를 갖는 화합물일 수 있다.The chiral lactone derivative may be a compound having formula (4).
[화학식 4][Chemical Formula 4]
상기 화학식 4에서 Ar은C6-C14의 아릴거나 C4-C10의 방향족 헤테로고리 화합물고 상기 아릴기는 C1-C10의 알콕시기, 알킬기, C1-C10알킬 아민기가 치환된 아릴기 또는 할로겐으로 치환될 수 있다. Ar in Formula 4 is C 6 -C 14 aryl or C 4 -C 10 aromatic heterocyclic compound and the aryl group is an aryl substituted with a C 1 -C 10 alkoxy group, alkyl group, C 1 -C 10 alkyl amine group It may be substituted with a group or a halogen.
상기 Ar은 방향족 헤테로고리 화합물인 퓨릴(furyl), 싸이에닐(thienyl) 또는 피리딜(pyridyl)일 수 있다.Ar may be an aromatic heterocyclic compound, furyl, thienyl, or pyridyl.
또 본 발명의 일 실시 예에서, 1,1-불포화기를 갖고 있는 카르복실산 유도체를 키랄 팔라듐 촉매 존재하에서 2,4,4,5-테트라브로모-2,5-사이클로헥사다이엔온과 반응시켜 키랄 락톤 유도체를 제조할 수 있다. 구체적인 반응식은 하기 반응식 1과 같다.In one embodiment of the present invention, a carboxylic acid derivative having a 1,1-unsaturated group is reacted with 2,4,4,5-tetrabromo-2,5-cyclohexadienone in the presence of a chiral palladium catalyst. The chiral lactone derivative can be prepared. The specific reaction formula is shown in the following Reaction Scheme 1.
[ 반응식 1 ]Scheme 1
상기 반응식 1에서 Ar 은 위에서 정의한 바와 같다.
In the above Reaction Scheme 1, Ar is as defined above.
이하, 하기 실시 예 등에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 다만, 하기 실시 예 등은 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples and the like are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.
입체 선택적인 키랄 락톤 유도체의 합성을 위해 하기 반응식 2, 3 과 같이, 키랄 팔라듐 촉매를 이용한 비대칭 반응을 수행한 결과 높은 수율과 입체선택성을 나타내었다. In order to synthesize a stereoselective chiral lactone derivative, as shown in the following Reaction Schemes 2 and 3, the asymmetric reaction using the chiral palladium catalyst showed high yield and stereoselectivity.
하기 반응식 2와 같이 화학식 1의 촉매를 사용하여 키랄 락톤 유도체를 높은 수율과 입체선택성을 나타내었다.As shown in Scheme 2, the chiral lactone derivative was used to exhibit high yield and stereoselectivity.
[반응식 2][Reaction Scheme 2]
[표 1][Table 1]
a 정제한 수율 a purified yield
b 거울상입체이성질체 비율은 키랄 HPLC를 이용하여 결정하였다
The enantiomeric ratio was determined using chiral HPLC
하기 반응식 3 과 같이, 10 몰%의 촉매량을 사용하여 키랄 락톤 유도체를 합성하였고 그 결과 표 2에 나타내었다.As shown in Scheme 3, a chiral lactone derivative was synthesized using a catalytic amount of 10 mol%, and the results are shown in Table 2.
[반응식 3]Scheme 3
[표 2][Table 2]
a 정제한 수율 a purified yield
b 거울상입체이성질체 비율은 키랄 HPLC를 이용하여 결정하였다.
The enantiomeric ratio was determined using chiral HPLC.
[실시예 1]Example 1
5-(bromomethyl)-5-phenyldihydrofuran-2(3H)-one (4a)5- (bromomethyl) -5-phenyldihydrofuran-2 (3H) -one (4a)
플라스크에 2,4,4,5-테트라브로모-2,5-사이클로헥사다이엔온 0.022 mmol, 트리플로로에탄올(CF3CH2OH) 0.2 mL, 상기 촉매 0.002 mmol을 넣고 상온에서 교반한다. 4-페닐펜텐노이산(4-phenylpent-4-enoic acid) 0.02 mmol 을 넣고 상온에서 2시간 교반한다. 반응 진행이 완료되면 반응 혼합물을 농축 후, 컬럼크로마토크래피로 분리 정제하여 화학식 4를 99% 수율, 75% ee (enantiomeric excess)의 거울상 입체선택성으로 얻는다.2,4,4,5-Tetrabromo-2,5-cyclohexadienone 0.022 mmol, 0.2 mL of trifluoroethanol (CF 3 CH 2 OH) and 0.002 mmol of the catalyst were added to the flask and stirred at room temperature. . Add 0.02 mmol of 4-phenylpentenenoic acid and stir at room temperature for 2 hours. When the reaction proceeds to completion, the reaction mixture is concentrated and separated and purified by column chromatography to obtain Formula 4 in 99% yield and enantiomeric excess of 75% ee (enantiomeric excess).
[α 25 D = +37.5 (c = 1.0, CHCl3); 1H NMR (CDCl3) δ7.43-7.34 (m, 4H), 3.74 (d, J = 11.6 Hz, 1H), 3.69 (d, J = 11.2 Hz, 1H), 2.87-2.76 (m, 2H), 2.60-2.49 (m, 2H); 13C NMR (CDCl3) δ 175.4, 140.7, 128.8, 128.7, 124.9, 86.4, 41.0, 32.4, 29.0; HPLC (85:15, n-hexane : i-PrOH, 214 nm, 0.6 mL/min) Chiralpak IC column, tR = 25.4 min (major), 30.2 min (minor), 75% ee.
나머지 유도체 4b ~ 4e는 실시예 1과 동일한 방법으로 수행하였으며, 거울상 입체 선택성(%)은 표 2에 나타낸 바와 같다. [a 25 D = +37.5 (c = 1.0, CHCl 3 ); 1 H NMR (CDCl 3 ) δ 7.43-7.34 (m, 4H), 3.74 (d, J = 11.6 Hz, 1H), 3.69 (d, J = 11.2 Hz, 1H), 2.87-2.76 (m, 2H) , 2.60-2.49 (m, 2 H); 13 C NMR (CDCl 3 ) δ 175.4, 140.7, 128.8, 128.7, 124.9, 86.4, 41.0, 32.4, 29.0; HPLC (85:15, n-hexane: i -PrOH, 214 nm, 0.6 mL / min) Chiralpak IC column, t R = 25.4 min (major), 30.2 min (minor), 75% ee.
The remaining derivatives 4b to 4e were performed in the same manner as in Example 1, and the enantioselective stereoselectivity (%) is shown in Table 2.
Claims (7)
[화학식 1]
[화학식 2]
상기 화학식 2에서 Ar은C6-C14의 아릴기이거나 C4-C10의 방향족 헤테로고리 화합물이다. 상기 아릴기는 C1-C10의 알콕시기, 알킬기, C1-C10알킬 아민기가 치환된 아릴기 또는 할로겐으로 치환될 수 있다.
[화학식 3]
[화학식 4]
상기 화학식 4에서 Ar은C6-C14의 아릴기이거나 C4-C10의 방향족 헤테로고리 화합물이다. 상기 아릴기는 C1-C10의 알콕시기, 알킬기, C1-C10알킬 아민기가 치환된 아릴기 또는 할로겐으로 치환될 수 있다.
[반응식 1]
상기 반응식에서 Ar은 C6-C14의 아릴기이거나C4-C10의 방향족 헤테로고리 화합물이다. 상기 아릴기는 C1-C10의 알콕시기, 알킬기, C1-C10알킬 아민기가 치환된 아릴기 또는 할로겐으로 치환될 수 있다. In the presence of a compound having the structure of Formula 1 or a chiral palladium catalyst which is an optical isomer thereof, a carboxylic acid derivative having a 1,1-unsaturated group having the structure of Formula 2 and 2,4 having the structure of Formula 3 A method for preparing a chiral lactone derivative having the structure of Chemical Formula 4 by reacting 4,5-tetrabromo-2,5-cyclohexadienone as in Scheme 1 below.
[Chemical Formula 1]
(2)
Ar in Formula 2 is an aryl group of C 6 -C 14 or an aromatic heterocyclic compound of C 4 -C 10 . The aryl group may be substituted with a C 1 -C 10 alkoxy group, an alkyl group, an aryl group substituted with a C 1 -C 10 alkylamine group, or a halogen.
(3)
[Chemical Formula 4]
Ar in Formula 4 is an aryl group of C 6 -C 14 or an aromatic heterocyclic compound of C 4 -C 10 . The aryl group may be substituted with a C 1 -C 10 alkoxy group, an alkyl group, an aryl group substituted with a C 1 -C 10 alkylamine group, or a halogen.
[Reaction Scheme 1]
Ar in the above scheme is a C 6 -C 14 aryl group or C 4 -C 10 aromatic heterocyclic compound. The aryl group may be substituted with a C 1 -C 10 alkoxy group, an alkyl group, an aryl group substituted with a C 1 -C 10 alkylamine group, or a halogen.
상기 키랄 팔라듐 촉매의 함량은, 반응 물질들의 전체 몰수를 기준으로, 10 몰%인 것을 특징으로 하는 키랄 락톤 유도체의 제조방법. The method of claim 1,
The content of the chiral palladium catalyst, based on the total number of moles of the reaction material, characterized in that the manufacturing method of chiral lactone derivatives.
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