KR100835604B1 - Method for preparing unsaturated ketone and their derivatives for anticancer effect - Google Patents
Method for preparing unsaturated ketone and their derivatives for anticancer effect Download PDFInfo
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Abstract
본 발명은 항암 효과를 가지는 하기 화학식 1 의 불포화 케톤 및 그 유도체의 제조 방법에 관한 것이다. The present invention relates to a method for producing an unsaturated ketone of Formula 1 and its derivatives having anticancer effect.
본 발명에 따른 제조 방법은 메틸비닐케톤과 아세트알데히드를 반응시켜 메틸비닐케톤의 알파-카르보닐 위치에 수산화에틸기를 도입하는 베일리스-힐만 반응 시 친수성 용매를 사용함으로써 반응 속도를 가속시킴은 물론 서로 다른 치환기를 선택적이고 높은 수율로 도입할 수 있도록 하며, 또한 화합물들의 대량 합성을 가능하게 한다. 그 결과, 암세포 사멸 유도 활성제, 항암제 등으로 유용하게 사용될 수 있는 화학식 1 의 화합물 및 그의 신규 유도체의 구조 및 활성 상관관계를 포함하여 의약 및 정밀 화학 분야에서 널리 활용될 수 있다.The production method according to the present invention accelerates the reaction rate by using a hydrophilic solvent in the Baileys-Hillman reaction of methyl vinyl ketone and acetaldehyde to introduce ethyl hydroxide at the alpha-carbonyl position of methyl vinyl ketone. It allows the introduction of substituents in selective and high yields, and also enables mass synthesis of compounds. As a result, it can be widely used in the fields of medicine and fine chemistry, including the structure and activity correlation of the compound of formula (1) and its novel derivatives that can be usefully used as cancer cell death inducing activators, anticancer agents and the like.
[화학식 1][Formula 1]
베일리스-힐만 반응, 불포화 케톤, 유도체, 제조방법, 항암 효과 Baileys-Hillman reaction, unsaturated ketones, derivatives, preparation method, anticancer effect
Description
본 발명은 항암 효과를 가지는 불포화 케톤 및 그 유도체의 제조 방법에 관한 것으로, 더욱 상세하게는 토양방선균 BG2-41로부터 분리되어 항암 특성을 나타낸 것으로 확인된 하기의 화학식 1 (국내 특허등록 제10-548743호 참조)로 표시되는 불포화 케톤 화합물 및 그 유도체의 제조 방법에 관한 것이다.The present invention relates to a method for preparing unsaturated ketones and derivatives thereof having an anticancer effect, and more particularly, the following Chemical Formula 1 (Domestic Patent Registration No. 10-548743) isolated from soil actinomycetes BG2-41 and showing anticancer properties To a unsaturated ketone compound and derivatives thereof.
[화학식 1][Formula 1]
불포화 케톤의 불포화 이중결합에 세 개의 서로 다른 치환기를 자리선택성과 입체선택성을 유지하면서 도입시키는 방법은 화학적으로 상당한 어려움이 따르며, 그 결과 여러 비효율적인 경로를 거쳐서 매우 낮은 수율로 얻어지는 것이 일반적이다.The introduction of three different substituents into unsaturated double bonds of unsaturated ketones while maintaining site selectivity and stereoselectivity is a significant chemical challenge, resulting in very low yields through several inefficient pathways.
베일리스-힐만 (Baylis-Hillman) 반응은 촉매로 이용되는 루이스 염기와 알킬 혹은 아릴 알데히드를 이용하여 불포화 케톤의 알파-위치에 새로운 알킬 혹은 아릴기를 도입하는 방법으로, 상기 방법을 이용한 메틸비닐케톤과 아세트알데히드와의 베일리스-힐만 조건 하에서의 축합 반응은 이미 공지되어 있다 (Tetrahedron Lett., 1986, 27, 5007; Tetrahedron Lett., 1986, 27, 4307). 또한, 베일리스-힐만 반응의 산물인 이차 알코올의 아세트산에스테르를 요오드화구리와 페닐그리나드 시약으로 처리하면 1,4-첨가 반응에 의하여 화학식 2 의 화합물이 얻어진다는 것도 이미 알려져 있는 사실이다 (Synth. Comm., 1997, 27, 1157).The Baylis-Hillman reaction is a method of introducing a new alkyl or aryl group to the alpha-position of an unsaturated ketone using a Lewis base and an alkyl or aryl aldehyde used as a catalyst, and methylvinyl ketone and acet using this method. Condensation reactions under Baileys-Hilman conditions with aldehydes are already known ( Tetrahedron Lett ., 1986, 27, 5007; Tetrahedron Lett ., 1986, 27, 4307). It is also known that the compound of formula (2) is obtained by the 1,4-addition reaction when the acetate ester of the secondary alcohol, the product of the Baileys-Hillman reaction, is treated with copper iodide and phenylgrind reagent ( Synth. Comm , 1997, 27, 1157).
[화학식 2][Formula 2]
그러나, 상기의 공지된 사실 (Tetrahedron Lett., 1986, 27, 5007)과 달리 실제로 메틸비닐케톤과 아세트알데히드의 축합반응은 통상적인 베일리스-힐만 조건 하 (용매: THF; 염기: DABCO)에서 매우 낮은 수율로 진행하거나 거의 진행하지 아니하는 문제가 있으며, 특히 반응 물질의 양이 g-단위 이상으로 커지면 반응은 거의 진행하지 않는다. 이는 반응 시간을 늘리거나 (7일 이상), 반응 온도를 상승시켜도 반응 속도와 수율에 별다른 영향을 미치지 않는다.However, in contrast to the above known facts ( Tetrahedron Lett ., 1986, 27, 5007), in fact the condensation reaction of methylvinylketone and acetaldehyde is very low under conventional Baileys-Hilman conditions (solvent: THF; base: DABCO). There is a problem of progressing in yield or hardly progressing, and in particular, the reaction hardly proceeds when the amount of the reactant becomes larger than g-unit. This does not affect reaction rate and yield even if the reaction time is increased (7 days or more) or the reaction temperature is increased.
상기와 같은 베일리스-힐만 반응의 낮은 반응성과 느린 속도에 관한 문제는 여러 문헌에서 관찰되고 있으며, 이러한 문제를 해결하기 위하여 용매를 사용하지 아니하거나 고압 하에서 반응을 시키는 방법 (Tetrahedron Lett., 1986, 27, 4307) 등이 사용되었으나, 상기 방법 모두 대량 합성에는 적합하지 않다는 단점이 있다.Problems related to the low reactivity and slow rate of the Baileys-Hillman reaction have been observed in the literature, and to solve this problem, without using a solvent or reacting under high pressure ( Tetrahedron Lett ., 1986, 27) 4307) is used, but all of the above methods are disadvantageous in that they are not suitable for mass synthesis.
이에 본 발명자들은 뛰어난 항암 효과를 나타내는 상기 화학식 1 의 불포화 케톤 화합물 및 그 유도체를 대량으로 생산하는 방법을 개발하고자 예의 노력한 결과, 메틸비닐케톤과 아세트알데히드를 출발물질로 하고 베일리스-힐만 반응 조건 하에서의 축합 반응을 촉진시킬 수 있는 새로운 반응 조건을 확인함으로써 본 발명을 완성하였다.Accordingly, the present inventors have made diligent efforts to develop a method for producing a large amount of the unsaturated ketone compound of Formula 1 and its derivatives, which exhibits excellent anticancer effect. The present invention has been completed by identifying new reaction conditions that can promote the reaction.
따라서, 본 발명의 목적은 항암 효과를 가지는 하기 화학식 1 로 표현되는 불포화 케톤 화합물을 제조하는 방법을 제공하는데 있다. Accordingly, an object of the present invention is to provide a method for preparing an unsaturated ketone compound represented by the following Chemical Formula 1 having an anticancer effect.
본 발명의 다른 목적은 화학식 1 의 불포화 케톤 화합물의 유도체를 제조하는 방법을 제공하는데 있다. Another object of the present invention to provide a method for preparing a derivative of the unsaturated ketone compound of formula (1).
본 발명의 또 다른 목적은 상기의 방법으로 제조된 화학식 1 의 불포화 케톤 화합물 및 그 신규 유도체들을 제공하는데 있다. Another object of the present invention to provide an unsaturated ketone compound of formula (1) and novel derivatives thereof prepared by the above method.
[화학식 1][Formula 1]
상기의 목적을 달성하기 위하여, 본 발명은 항암 효과를 가지는 화학식 1 으로 표현되는 불포화 케톤 화합물의 제조 방법을 제공한다. In order to achieve the above object, the present invention provides a method for producing an unsaturated ketone compound represented by the formula (1) having an anticancer effect.
구체적으로, 본 발명은 본 발명의 주중간체인 화학식 2 를 제조하는 방법을 제공한다. Specifically, the present invention provides a method for preparing Formula 2, which is the main intermediate of the present invention.
즉, (1) 메틸비닐케톤과 아세트알데히드를 출발물질로 하고 베일리스-힐만 반응을 통해 수산화에틸 메틸비닐케톤 (화학식 3)을 제조하는 단계; 및 That is, (1) preparing ethyl methyl vinyl ketone (Formula 3) by using methyl vinyl ketone and acetaldehyde as a starting material and a Baileys-Hillman reaction; And
[화학식 3][Formula 3]
(2) 상기에서 제조된 베일리스-힐만 반응의 산물인 이차 알코올 (화학식 3)을 아세트산 에스테르 (화학식 4)로 전환시킨 후 요오드화구리 존재 하에서 페닐그리나드 시약의 1,4-첨가 반응에 의해 본 발명의 주중간체인 (E)-3-벤질-3-펜텐-2-온 (화학식 2)을 제조하는 단계;로 이루어진 본 발명의 주중간체인 화학식 2 를 제조하는 방법을 제공한다 (하기 반응식 1 참조).(2) The present invention is obtained by converting the secondary alcohol (Formula 3), which is the product of the Baileys-Hillman reaction, prepared above into acetic acid ester (Formula 4), followed by 1,4-addition reaction of phenylgrind reagent in the presence of copper iodide. ( E ) -3-benzyl-3-penten-2-one (Formula 2) to prepare a main intermediate of the present invention comprising the formula (2) provides a method for preparing a formula (2) ).
[화학식 4][Formula 4]
[반응식 1]Scheme 1
또한, 본 발명은 상기 과정에 더하여, In addition, the present invention, in addition to the above process,
(3) 상기 화학식 2 를 테트라히드로퓨란 (THF) 용매 하에서 LiHMDS (Lithium hexamethyldissilazide) 및 3-t-부틸디메틸실릴옥시-프로판알데히드와 반응시켜 화학식 5 를 제조하는 단계; 및(3) preparing Chemical Formula 5 by reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldissilazide) and 3-t-butyldimethylsilyloxy-propanealdehyde in a tetrahydrofuran (THF) solvent; And
[화학식 5][Formula 5]
단, 상기에서 OTBDMS는 [O(tert-Butyl-dimethylsilyloxy)이다.
However, in the above OTBDMS is [O (tert-Butyl-dimethylsilyloxy).
(4) 상기 화학식 5 를 테트라히드로퓨란 용매 하에서 TBAF (Pyridium p-toluenedisilazide)를 첨가하여 화학식 1 을 제조하는 단계;를 더 포함하는 화학식 1 로 표현되는 불포화 케톤 화합물을 제조하는 방법을 제공한다 (반응식 2 참조).(4) preparing Chemical Formula 1 by adding TBAF (Pyridium p-toluenedisilazide) in tetrahydrofuran solvent to prepare Chemical Formula 1; (4) provides a method of preparing an unsaturated ketone compound represented by Chemical Formula 1 further comprising: 2).
[반응식 2]Scheme 2
본 발명은 항암 효과를 가지는 화학식 1 로 표현되는 불포화 케톤 화합물의 유도체의 제조 방법을 제공한다 (이하, 반응식 3 참조). The present invention provides a method for preparing a derivative of an unsaturated ketone compound represented by the formula (1) having an anticancer effect (hereinafter, see Scheme 3).
구체적으로, 본 발명은 상기 본 발명의 주중간체인 화학식 2 의 제조 방법에 더하여, Specifically, the present invention, in addition to the production method of the formula (2) is the main intermediate of the present invention,
(3) 상기 화학식 2 를 테트라히드로퓨란 용매 하에서 LiHMDS (Lithium hexamethyldissilazide) 및 3-t-부틸디메틸실릴옥시-프로판알데히드와 반응시켜 화학식 5 를 제조하는 단계; 및 (3) preparing Chemical Formula 5 by reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldissilazide) and 3-t-butyldimethylsilyloxy-propanealdehyde in a tetrahydrofuran solvent; And
(4) 상기 화학식 5 를 메탄올 용매 하에서 수소화붕소나트륨 및 세륨클로라이드를 첨가하여 반응시킨 후, 테트라히드로퓨란 용매 하에서 TBAF (pyridium p-toluenesulfonate)를 첨가하여 화학식 6 을 제조하는 단계;를 더 포함하는 하기 화학식 6 으로 표현되는 화학식 1 의 불포화 케톤 화합물의 신규 유도체의 제조 방법을 제공한다. (4) reacting Chemical Formula 5 by adding sodium borohydride and cerium chloride in methanol solvent, and then adding TBAF (pyridium p-toluenesulfonate) in tetrahydrofuran solvent to prepare Chemical Formula 6; It provides a method for producing a novel derivative of the unsaturated ketone compound of formula (1) represented by the formula (6).
[화학식 6][Formula 6]
또한, 본 발명은 상기 본 발명의 주중간체인 화학식 2 의 제조 방법에 더하여, In addition, the present invention is in addition to the production method of the formula (2) which is the main intermediate of the present invention,
(3) 상기 화학식 2 를 테트라히드로퓨란 용매 하에서 LiHMDS (Lithium hexamethyldissilazide) 및 3-t-부틸디메틸실릴옥시-프로판알데히드와 반응시켜 화학식 5 를 제조하는 단계; 및 (3) preparing Chemical Formula 5 by reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldissilazide) and 3-t-butyldimethylsilyloxy-propanealdehyde in a tetrahydrofuran solvent; And
(4) 상기 화학식 5 를 디클로로메탄 용매 하에서 PDC (Pyridinium dichromate)를 첨가하여 반응시킨 후, 테트라히드로퓨란 용매 하에서 TBAF (Pyridium p-toluenedisilazide)를 첨가하여 화학식 7 을 제조하는 단계;를 더 포함하는 화학식 7 로 표현되는 화학식 1 의 불포화 케톤 화합물의 신규 유도체의 제조 방법을 제공한다.(4) reacting Formula 5 with PDC (Pyridinium dichromate) in a dichloromethane solvent, and then adding Pyridium p-toluenedisilazide (TBAF) in tetrahydrofuran solvent to prepare Formula 7; It provides a method for producing a novel derivative of the unsaturated ketone compound of formula (1) represented by 7.
[화학식 7][Formula 7]
또한, 본 발명은 상기 본 발명의 주중간체인 화학식 2 의 제조 방법에 더하여, In addition, the present invention is in addition to the production method of the formula (2) which is the main intermediate of the present invention,
(3) 상기 화학식 2 를 테트라히드로퓨란 용매 하에서 LiHMDS (Lithium hexamethyldissilazide) 및 프로판알데히드와 반응시켜 화학식 8 을 제조하는 단계; 및 (3) preparing Chemical Formula 8 by reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldissilazide) and propanealdehyde in a tetrahydrofuran solvent; And
(4) 상기 화학식 8 을 디클로로메탄 용매 하에서 4Å 분자 여과기 및 PCC (pyridinium chlorochromate)를 첨가하여 화학식 9 를 제조하는 단계;를 더 포함하 는 하기 화학식 9 로 표현되는 화학식 1 의 불포화 케톤 화합물의 신규 유도체의 제조 방법을 제공한다.(4) adding a 4 ′ molecular filter and PCC (pyridinium chlorochromate) to formula (8) in a dichloromethane solvent to prepare formula (9); new derivative of unsaturated ketone compound of formula (1) further comprising formula (9) It provides a method for producing.
[화학식 8][Formula 8]
[화학식 9][Formula 9]
또한, 본 발명은 상기 본 발명의 주중간체인 화학식 2 의 제조 방법에 더하여, In addition, the present invention is in addition to the production method of the formula (2) which is the main intermediate of the present invention,
(3) 상기 화학식 2 를 테트라히드로퓨란 용매 하에서 LiHMDS (Lithium hexamethyldissilazide) 및 4-t-부틸디메틸실릴옥시-부탄알데히드와 반응시킨 후 테트라히드로퓨란에 녹인 TBAF (Pyridium p-toluenedisilazide)를 첨가하여 화학식 10 을 제조하는 단계;를 더 포함하는 하기 화학식 10 으로 표현되는 화학식 1 의 불포화 케톤 화합물의 신규 유도체의 제조 방법을 제공한다. (3) reacting Chemical Formula 2 with LiHMDS (Lithium hexamethyldissilazide) and 4-t-butyldimethylsilyloxy-butanealdehyde in tetrahydrofuran solvent, and then adding TBAF (Pyridium p-toluenedisilazide) dissolved in tetrahydrofuran It provides a method for producing a novel derivative of the unsaturated ketone compound of Formula 1 represented by the following formula (10) further comprising the step of preparing a.
[화학식 10][Formula 10]
또한, 본 발명은 상기의 방법으로 제조된 화학식 1 로 표현되는 불포화 케톤 화합물 및 그의 신규 유도체들 (상기 화학식 3 내지 화학식 10 참조)을 제공한다.In addition, the present invention provides an unsaturated ketone compound represented by the formula (1) and novel derivatives thereof (see Formula 3 to Formula 10) prepared by the above method.
본 발명의 제조 방법에 있어서,In the production method of the present invention,
상기 (1) 단계에서, 본 발명은 친수성 용매, 즉 메탄올, 에탄올 또는 이소프로판올로 이루어진 군에서 적어도 1 종 이상을 사용하는 것이 바람직하고, 더욱 바람직하게는 메탄올을 사용하는 베일리스-힐만 반응을 특징으로 한다.In the step (1), the present invention preferably uses at least one or more of a hydrophilic solvent, that is, methanol, ethanol or isopropanol, more preferably characterized by a Baileys-Hillman reaction using methanol. .
반응 용매는 본 발명에서 가장 중요한 것으로, 종래 베일리스-힐만 반응에서 사용되던 유기용매인 테트라히드로퓨란 (tetrahydrofuran; THF), 에테르 (ethyl ether), 디메틸포름아미드 (dimethyl formamide; DMF), 디메틸술폭사이드(dimethyl sulfoxide, DMSO) 등에서는 반응이 전혀 진행하지 아니하나, 친수성 용매인 메탄올, 에탈올 및 이소프로판올을 용매로 사용하였을 경우, 수 분 내에 반응이 완결될 수 있다. The reaction solvent is most important in the present invention, and organic solvents such as tetrahydrofuran (THF), ether (ethyl ether), dimethyl formamide (DMF), and dimethyl sulfoxide ( In the case of dimethyl sulfoxide, DMSO), the reaction does not proceed at all, but when the hydrophilic solvents methanol, ethanol and isopropanol are used as the solvent, the reaction may be completed within a few minutes.
또한, 상기 (1) 단계에서 베일리스-힐만 반응은, 화학식 3 으로 표시되는 수산화에틸 메틸케톤을 루이스 염기 촉매 존재 하에서 베일리스-힐만 반응을 통해 제조하는 것을 포함할 수 있다.In addition, the Baileys-Hillman reaction in step (1) may include preparing ethyl hydroxide methyl ketone represented by Formula 3 through the Baileys-Hillman reaction in the presence of a Lewis base catalyst.
상기에서 루이스 염기는 디메틸아미노피리딘 (MDAP, N,N-dimethylaminopyridine)이나 다브코 (DABCO, 1,4-diazabicyclo[2,2,2,]octane) 등 을 사용하는 것이 바람직하고, 다브코를 사용하는 것은 더욱 바람직하며, 이때 사용되는 루이스 염기의 양은 출발물질인 수산화에틸 메틸케톤과 아세트알데히드에 대하여 0.1 내지 0.3 당량 사용하는 것이 바람직하다. As the Lewis base, dimethylaminopyridine (MDAP, N, N-dimethylaminopyridine) or dabco (DABCO, 1,4-diazabicyclo [2,2,2,] octane) or the like is preferably used. More preferably, the amount of Lewis base to be used is preferably used in an amount of 0.1 to 0.3 equivalents based on ethyl methyl ketone and acetaldehyde as starting materials.
또한, 본 발명에 있어서 상기 (1) 단계의 베일리스-힐만 반응은 0℃ 내지 상온 (25℃) 범위를 유지하면서 진행하는 것이 바람직하며, 이때 반응 시간은 30분 내지 1 시간이 바람직하다.In addition, in the present invention, the Baileys-Hillman reaction of step (1) is preferably performed while maintaining a range of 0 ° C to room temperature (25 ° C), and the reaction time is preferably 30 minutes to 1 hour.
[반응식 3]Scheme 3
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.
실시예 1. 3-(1-히드록시에틸)-3-부틴-2-온 (화학식 3)의 제조 Example 1. Preparation of 3- (1-hydroxyethyl) -3-butyn-2-one (Formula 3)
출발물질로 메틸비닐케톤 17.4 g (247 mmol)과 아세트알데히드 11.0 g (247 mmol)를 무수 메탄올 30 ㎖에 녹이고, 질소 분위기 하에서 온도를 0℃에 맞춘 다음, 다브코 (DABCO) 4.17 g (37.1 mmol) 를 가하여 1 시간 동안 온도를 유지하면서 교반을 잘 시켜주었다. 17.4 g (247 mmol) of methyl vinyl ketone and 11.0 g (247 mmol) of acetaldehyde were dissolved in 30 mL of anhydrous methanol as a starting material, and the temperature was adjusted to 0 ° C. under a nitrogen atmosphere, followed by 4.17 g (37.1 mmol) of DABCO. ) Was added and the temperature was maintained for 1 hour to ensure good stirring.
TLC 상에서 반응이 완결된 뒤 1 N 염산 용액 10 ㎖를 가하고, 전체 용매 부피의 ⅓이 될 때 까지 감압농축 하였다. After completion of the reaction on TLC, 10 ml of 1 N hydrochloric acid solution was added, and the resultant was concentrated under reduced pressure until the total solvent volume was reached.
아세트산 에틸에스테르 (EtOAc)로 세 번 (3 × 50 ㎖) 추출한 후, 추출한 유기 용매를 모아 포화된 소금물로 씻고, 황산나트륨으로 탈수한 다음 감압 하에서 농축시켜서 실리카겔 컬럼크로마토그래피 (헥산 : 아세트산에틸에스테르 = 4 : 1)로 원하는 생성물 16.7 g (146 mmol, 65%)을 오일 형태로 얻었다: 1H NMR (CDCl3, 400 MHz) d 6.11 (s, 1H), 6.08 (s, 1H), 4.66 (br s, 1H), 3.31 (br s, 1H), 2.36 (s, 3H), 1.32 (d, J = 6.5 Hz, 3H).After extraction three times (3 x 50 ml) with ethyl acetate (EtOAc), the combined organic solvents were collected and washed with saturated brine, dehydrated with sodium sulfate and concentrated under reduced pressure to give silica gel column chromatography (hexane: ethyl acetate = 4). 1) gave 16.7 g (146 mmol, 65%) of the desired product in oil form: 1 H NMR (CDCl 3 , 400 MHz) d 6.11 (s, 1H), 6.08 (s, 1H), 4.66 (br s , 1H), 3.31 (br s, 1H), 2.36 (s, 3H), 1.32 (d, J = 6.5 Hz, 3H).
실시예 2: 아세트산 2-아세틸-1-메틸-알릴 에스테르 (화학식 4, 반응식 1)의 제조Example 2: Preparation of acetic acid 2-acetyl-1-methyl-allyl ester (Formula 4, Scheme 1)
상기 실시예 1 에서 얻은 3-(1-히드록시에틸)-3-부틴-2-온 1.0 g (8.76 mmol)과 아세트산 무수물 1.07 g (10.5 mmol)을 무수 에테르 4 ㎖에 녹인 후, 진한 황산 한 방울을 0℃에서 가하여 3시간 동안 교반하고, 포화된 탄산수소나트륨 수용액을 가해서 얻어진 수용액 층을 아세트산 에틸에스테르로 세 번 (3 × 50 ㎖) 추출하였다.1.0 g (8.76 mmol) of 3- (1-hydroxyethyl) -3-butyn-2-one and 1.07 g (10.5 mmol) of acetic anhydride obtained in Example 1 were dissolved in 4 ml of anhydrous ether, followed by concentrated sulfuric acid. A drop was added at 0 ° C., stirred for 3 hours, and a saturated aqueous solution of sodium hydrogen carbonate was added three times (3 × 50 mL) with ethyl acetate.
모아진 추출액은 포화된 소금물로 씻고, 황산나트륨으로 탈수한 다음 감압 증류하여 얻어진 물질을 실리카겔 컬럼크로마토그래피 (헥산 : 아세트산 에틸에스테르 = 5 : 1)로 목적하는 생성물을 1.11 g (7.09 mmol, 85%) 기름 형태로 수득하였다: 1H NMR (CDCl3, 400 MHz) d 6.11 (s, 1H), 6.00 (s, 1H), 5.73 (q, J = 6.4 Hz, 1H), 2.35 (s, 3H), 2.07 (s, 3H), 1.34 (d, J =6.4 Hz, 3H). The combined extracts were washed with saturated brine, dehydrated with sodium sulfate and distilled under reduced pressure. The obtained product was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 1.11 g (7.09 mmol, 85%) oil of the desired product. Obtained in the form: 1 H NMR (CDCl 3 , 400 MHz) d 6.11 (s, 1H), 6.00 (s, 1H), 5.73 (q, J = 6.4 Hz, 1H), 2.35 (s, 3H), 2.07 (s, 3 H), 1.34 (d, J = 6.4 Hz, 3 H).
실시예 3. (Example 3. EE )-3-벤질-3-펜텐-2-온 (화학식 2, 반응식 1)의 제조) -3-benzyl-3-penten-2-one (Formula 2, Scheme 1)
상기 실시예 2 의 방법으로 제조한 아세트산 2-아세틸-1-메틸-알릴 에스테르 3 g (19.2 mmol)과 요오드화구리 (293 ㎎, 0.08 mmol)를 무수 테트라히드로퓨란 20 ㎖에 섞은 혼합물에 3.0 M 페닐그리나드 에테르 용액 19.2 ㎖ (57.6 mmol)을 영하 78도에서 가하고 3 시간동안 교반하였다. 포화된 염화암모늄 수용액을 첨가하여 반 응을 종결시킨 후, 얻어진 수용액 층을 아세트산 에스테르를 이용하여 세 번 추출하였다 (3 × 50 ㎖).3.0 M phenyl in a mixture of 3 g (19.2 mmol) of acetic acid 2-acetyl-1-methyl-allyl ester prepared by the method of Example 2 and copper iodide (293 mg, 0.08 mmol) in 20 ml of anhydrous tetrahydrofuran 19.2 mL (57.6 mmol) of Grignard ether solution was added at minus 78 ° C. and stirred for 3 h. After completion of the reaction by addition of saturated aqueous ammonium chloride solution, the resulting aqueous layer was extracted three times with acetic acid ester (3 × 50 mL).
모아진 추출액은 포화된 소금물로 씻어 황산나트륨으로 탈수한 다음 감압 농축하여 얻어진 물질을 실리카겔 컬럼크로마토그래피 (헥산 : 아세트산 에틸에스테르 = 7 : 1)로 생성물 3.1 g (17.7 mmol, 92%)을 흰 가루 형태로 얻었다: 1H NMR (CDCl3, 400 MHz) d 7.25-7.22 (m, 2H), 7.16-7.14 (m, 3H), 6.91 (q, J =7.0 Hz, 1H), 3.69 (s, 2H), 2.31 (s, 3H), 1.94 (d, J = 7.0 Hz, 1H) 13C NMR (CDCl3, 100 MHz) d 199.3, 142.5, 140.3, 140.1, 128.7, 128.7, 126.2, 31.1, 26.1, 15.5. The collected extract was washed with saturated brine, dehydrated with sodium sulfate, and concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1), and the product was dried in the form of white powder (3.1 g, 17.7 mmol, 92%). Obtained: 1 H NMR (CDCl 3 , 400 MHz) d 7.25-7.22 (m, 2H), 7.16-7.14 (m, 3H), 6.91 (q, J = 7.0 Hz, 1H), 3.69 (s, 2H), 2.31 (s, 3H), 1.94 (d, J = 7.0 Hz, 1H) 13 C NMR (CDCl 3 , 100 MHz) d 199.3, 142.5, 140.3, 140.1, 128.7, 128.7, 126.2, 31.1, 26.1, 15.5.
실시예 4. (Example 4. EE )-3-벤질-8-t-부틸메틸실릴옥시-6-히드록시-2-옥텐-4-온 (화학식 5, 반응식 2)의 제조) -3-benzyl-8-t-butylmethylsilyloxy-6-hydroxy-2-octen-4-one (Formula 5, Scheme 2)
상기 실시예 3 에서 얻은 (E)-3-벤질-3-펜텐-2-온 817 ㎎ (4.69 mmol)을 무수 테트라히드로퓨란 30 ㎖에 녹인 후 1.0 M LiHMDS (Lithium hexamethyldissilazide) 테트라히드로퓨란 용액 5.6 ㎖ (5.6 mmol)을 영하 78℃에서 적가하고, 30분 동안 교반한 혼합물에 3-t-부틸디메틸실릴옥시-프로판알데히드 1.3 g (7.04 mmol)를 무수 테트라하이드로류란 5 ㎖에 녹인 용액을 한꺼번에 첨가하였다.817 mg (4.69 mmol) of ( E ) -3-benzyl-3-penten-2-one obtained in Example 3 was dissolved in 30 mL of anhydrous tetrahydrofuran, followed by 5.6 mL of 1.0 M LiHMDS (Lithium hexamethyldissilazide) tetrahydrofuran solution. (5.6 mmol) was added dropwise at −78 ° C., and a solution of 1.3 g (7.04 mmol) of 3-t-butyldimethylsilyloxy-propanealdehyde in 5 ml of anhydrous tetrahydrosilane was added all at once to the mixture stirred for 30 minutes. It was.
반응 물질을 영하 78℃에서 3시간 동안 교반한 다음 포화된 염화암모늄 수용액을 넣어 반응을 종결시켰다. 수용액 층을 아세트산 에틸에스테르로 세 번 추출 (3 × 300 ㎖) 한 후, 모인 추출액은 포화된 소금물로 씻고, 황산나트륨으로 탈수하였다.The reaction mass was stirred at minus 78 ° C. for 3 hours and then saturated ammonium chloride aqueous solution was added to terminate the reaction. The aqueous layer was extracted three times (3 x 300 mL) with ethyl acetate, and the combined extracts were washed with saturated brine and dehydrated with sodium sulfate.
탈수된 화합물 용액에서 황산나트륨을 걸러내고, 감압 농축하여 얻어진 물질을 실리카겔 컬럼크로마토그래피법 (헥산 : 아세트산 에틸에스테르 = 10 : 1)에 의해 정제하여 흰 가루 형태의 (E)-3-벤질-8-t-부틸메틸실릴옥시-6-히드록시-2-옥텐-4-온을 1.2 g (3.30 mmol, 70%) 얻었다: 1H NMR (CDCl3, 400 MHz) d 7.19-7.16 (m, 2H), 7.10-7.06 (m, 3H), 6.89 (q, J =7.0 Hz, 1H), 4.23-4.13 (m, 1H), 3.78-3.71 (m, 2H), 3.63 (s, 2H), 3.56 (d, J =2.5 Hz, 1H0, 2.84-2.73 (m, 2H), 1.88 (d, J = 7.0 Hz, 3H), 1.63-1.58 (m, 2H), 0.83 (s, 9H), 0.00 (s, 6H) 13C NMR (CDCl3, 100 MHz) d 201.4, 142.3, 140.4, 140.0, 128.8, 128.6, 126.3, 67.7, 61.6, 44.7, 38.9, 31.2, 26.3, 18.6, 15.6, 0.4, -5.1.Sodium sulfate was filtered off from the dehydrated compound solution, and the resultant was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain ( E ) -3-benzyl-8- in white powder form. 1.2 g (3.30 mmol, 70%) of t-butylmethylsilyloxy-6-hydroxy-2-octen-4-one were obtained: 1 H NMR (CDCl 3 , 400 MHz) d 7.19-7.16 (m, 2H) , 7.10-7.06 (m, 3H), 6.89 (q, J = 7.0 Hz, 1H), 4.23-4.13 (m, 1H), 3.78-3.71 (m, 2H), 3.63 (s, 2H), 3.56 (d , J = 2.5 Hz, 1H0, 2.84-2.73 (m, 2H), 1.88 (d, J = 7.0 Hz, 3H), 1.63-1.58 (m, 2H), 0.83 (s, 9H), 0.00 (s, 6H ) 13 C NMR (CDCl 3 , 100 MHz) d 201.4, 142.3, 140.4, 140.0, 128.8, 128.6, 126.3, 67.7, 61.6, 44.7, 38.9, 31.2, 26.3, 18.6, 15.6, 0.4, -5.1.
실시예 5. (Example 5. EE )-3-벤질-6,8-디히드록시-2-옥텐-4-온 (화학식 1, 반응식 2)의 제조) -3-benzyl-6,8-dihydroxy-2-octen-4-one (Formula 1, Scheme 2)
상기 실시예 4 에서 제조한 (E)-3-벤질-8-t-부틸메틸실릴옥시-6-히드록시-2-옥텐-4-온 115 ㎎ (0.32 mmol)을 무수 테트라히드로퓨란 15 ㎖에 녹이고, 1.0 M TBAF (Pyridium p-toluenedisilazide) 테트라히드로퓨란 용액 0.32 ㎖ (0.32 mmol)을 0℃에서 가한 후, 3시간 동안 교반하였다.115 mg (0.32 mmol) of ( E ) -3-benzyl-8-t-butylmethylsilyloxy-6-hydroxy-2-octen-4-one prepared in Example 4 was added to 15 ml of anhydrous tetrahydrofuran. After dissolving, 0.32 ml (0.32 mmol) of 1.0 M TBAF (Pyridium p-toluenedisilazide) tetrahydrofuran solution was added at 0 ° C., followed by stirring for 3 hours.
반응 혼합물을 감압 농축한 후, 농축된 혼합물은 실리카겔 컬럼크로마토그래피법 (디클로로메탄 : 메탄올 = 10 : 1)에 의해 정제하여 원하는 화합물을 흰 가루 형태로 얻었다 (76 ㎎, 0.31 mmol, 97%): 1H NMR (CD3OD, 400 MHz) d 7.25-7.21 (m, 2H), 7.16-7.07 (m, 3H), 7.10 (q, J = 7.0 Hz, 1H), 4.27-4.21 (m, 1H), 3.72 (s, 2H), 3.70 (t, J = 6.5 Hz, 2H), 3.34 (br s, 1H), 2.96 (dd, J = 16.0, 7.9 Hz, 1H), 2.81 (dd, J = 16.0, 4.6 Hz, 1H), 1.95 (d, J = 7.0 Hz, 3H), 1.71-1.63 (m, 2H) 13C NMR (CD3OD, 100 MHz) d 201.9, 143.2, 142.1, 129.3, 129.3, 126.8, 67.2, 60.7, 46.0, 40.6, 31.5, 15.4.After the reaction mixture was concentrated under reduced pressure, the concentrated mixture was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain the desired compound as a white powder (76 mg, 0.31 mmol, 97%): 1 H NMR (CD 3 OD, 400 MHz) d 7.25-7.21 (m, 2H), 7.16-7.07 (m, 3H), 7.10 (q, J = 7.0 Hz, 1H), 4.27-4.21 (m, 1H) , 3.72 (s, 2H), 3.70 (t, J = 6.5 Hz, 2H), 3.34 (br s, 1H), 2.96 (dd, J = 16.0, 7.9 Hz, 1H), 2.81 (dd, J = 16.0, 4.6 Hz, 1H), 1.95 (d, J = 7.0 Hz, 3H), 1.71-1.63 (m, 2H) 13 C NMR (CD 3 OD, 100 MHz) d 201.9, 143.2, 142.1, 129.3, 129.3, 126.8, 67.2, 60.7, 46.0, 40.6, 31.5, 15.4.
실시예 6. (Example 6. EE )-6-벤질-6-옥텐-1,3,5-트리올 (화학식 6, 반응식 3) 의 제조) -6-benzyl-6-octene-1,3,5-triol (Formula 6, Scheme 3)
상기 실시예 4 에서 제조한 (E)-3-벤질-8-t-부틸메틸실릴옥시-6-히드록시-2-옥텐-4-온 450 ㎎ (1.24 mmol)과 CeCl37H2O 693 ㎎ (1.86 mmol)을 무수 메탄올 20 ㎖와 섞은 혼합물에 수소화붕소나트륨 47 ㎎ (1.24 mmol)을 0℃에서 서서히 넣어주었다. 반응 혼합물은 0℃에서 3시간 동안 혼합하고, 1N 염산 수용액을 적가한 후 혼합물의 부피가 ⅓이 될 때까지 감압 농축하였다. 450 mg (1.24 mmol) of ( E ) -3-benzyl-8-t-butylmethylsilyloxy-6-hydroxy-2-octen-4-one prepared in Example 4 and 693 mg of CeCl 3 7H 2 O 47 mg (1.24 mmol) of sodium borohydride were slowly added to a mixture of (1.86 mmol) and 20 ml of anhydrous methanol at 0 ° C. The reaction mixture was mixed at 0 ° C. for 3 hours, 1N hydrochloric acid aqueous solution was added dropwise and concentrated under reduced pressure until the volume of the mixture became ⅓.
농축된 혼합물을 아세트산 에틸에스테르 50 ㎖로 취하고, 분리된 수용액 층은 아세트산 에틸에스테르로 세 번 추출하였다 (3 × 50 ㎖). 모인 추출액을 포화된 소금물로 씻고, 황산나트륨으로 탈수한 후 감압농축하여 얻어진 물질을 실리카 겔 컬럼크로마토그래피법 (헥산 : 아세트산 에틸에스테르 = 4 : 1) 으로 정제하여 (E)-6-벤질-1-t-부틸디메틸실릴옥시-6-옥텐-3,5-디올 413 ㎎ (1.13 mmol, 91%)을 노란색 시럽 형태로 수득하였다:.The concentrated mixture was taken up with 50 ml of acetic acid ethyl ester, and the separated aqueous layer was extracted three times with acetic acid ethyl ester (3 × 50 ml). The combined extracts were washed with saturated brine, dehydrated with sodium sulfate, and concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain ( E ) -6-benzyl-1-. 413 mg (1.13 mmol, 91%) of t-butyldimethylsilyloxy-6-octene-3,5-diol were obtained in the form of a yellow syrup:
상기 물질 중 97 ㎎을 무수 테트라히드로퓨란 15 ㎖에 녹인 다음, 1.0 M TBAF 테트라히드로퓨란 용액 0.27 ㎖ (0.27 mmol)을 0℃에서 가하여 2시간 동안 교반하였다.97 mg of the material was dissolved in 15 mL of anhydrous tetrahydrofuran, and then 0.27 mL (0.27 mmol) of 1.0 M TBAF tetrahydrofuran solution was added at 0 ° C. and stirred for 2 hours.
반응 혼합물을 감압 농축한 후, 농축된 혼합물을 실라카겔 컬럼크로마토그래피 (디클로로메탄 : 메탄올 = 10 : 1)를 통해 원하는 화합물 56 ㎎을 흰 가루 형태로 얻었다: 1H NMR (CDCl3, 400 MHz) d 7.20-7.07 (m, 5H), 5.80 (q, J = 6.7 Hz, 1H), 4.28 (br s, 1H), 4.04 (br s, 1H), 3.79-3.71 (m, 2H), 3.69-3.65 (m, 2H), 3.47 (d, J = 15.4 Hz, 1H), 3.31 (d, J = 15.6 Hz, 1H), 1.78 (m, 1H), 1.67 (d, J = 6.8 Hz, 3H), 1.67-1.60 (m, 1H), 1.53 (t, J = 5.6 Hz, 2H), 0.83 (s, 9H), 0.00 (s, 6H) 13C NMR (CDCl3, 100 MHz) d 141.0, 140.6, 140.5, 128.7, 126.2, 121.9, 73.0, 70.2, 68.3, 41.9, 38.4, 33.7, 18.5, 14.0, -5.1.After the reaction mixture was concentrated under reduced pressure, the concentrated mixture was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain 56 mg of the desired compound as a white powder: 1 H NMR (CDCl 3 , 400 MHz) d 7.20-7.07 (m, 5H), 5.80 (q, J = 6.7 Hz, 1H), 4.28 (br s, 1H), 4.04 (br s, 1H), 3.79-3.71 (m, 2H), 3.69-3.65 (m, 2H), 3.47 (d, J = 15.4 Hz, 1H), 3.31 (d, J = 15.6 Hz, 1H), 1.78 (m, 1H), 1.67 (d, J = 6.8 Hz, 3H), 1.67 -1.60 (m, 1H), 1.53 (t, J = 5.6 Hz, 2H), 0.83 (s, 9H), 0.00 (s, 6H) 13 C NMR (CDCl 3 , 100 MHz) d 141.0, 140.6, 140.5, 128.7, 126.2, 121.9, 73.0, 70.2, 68.3, 41.9, 38.4, 33.7, 18.5, 14.0, -5.1.
실시예 7. (2Example 7. (2 EE , 5, 5 ZZ )-3-벤질-6,8-디히드록시-2,5-옥타디엔-4-온 (화학식 7, 반응식 3)의 제조) -3-benzyl-6,8-dihydroxy-2,5-octadien-4-one (Formula 7, Scheme 3)
상기 실시예 4 의 제조 방법으로 얻은 (E)-3-벤질-8-t-부틸메틸실릴옥시-6- 히드록시-2-옥텐-4-온 160 ㎎ (0.33 mmol)을 무수 디클로로메탄 12 ㎖에 녹이고, PDC (pyridinium dichromate)를 248 ㎎ (0.66 mmol) 가하여 상온에서 12시간 동안 격렬하게 교반하였다.12 mL of ( E ) -3-benzyl-8-t-butylmethylsilyloxy-6-hydroxy-2-octen-4-one obtained by the preparation method of Example 4 (0.33 mmol) in 12 ml of anhydrous dichloromethane It was dissolved in 248 mg (0.66 mmol) of PDC (pyridinium dichromate), and the mixture was stirred vigorously at room temperature for 12 hours.
반응 혼합물에 에테르를 가하여 얻어진 고체를 짧은 실리카겔 컬럼을 이용하여 디클로로메탄으로 씻으면서 여과한 다음, 여과액을 감압 농축하여 얻어진 물질을 더 이상의 정제 과정 없이 바로 다음 과정에 사용하였다.The solid obtained by adding ether to the reaction mixture was filtered by washing with dichloromethane using a short silica gel column, and the filtrate was concentrated under reduced pressure, and the obtained material was used directly in the next step without further purification.
즉, 상기에서 얻어진 물질은 무수 테트라히드로퓨란 8 ㎖에 용해한 후 1.0 M TBAF 테트라히드로퓨란 용액 0.11 ㎖ (0.11 mmol)을 0℃에서 가하고 2시간 동안 교반하였다. 상기 반응 혼합물을 감압 농축하고, 이때 얻어진 물질은 실리카겔 컬럼크로마토그래피법 (헥산 : 아세트산 에틸에스테르 = 2 : 1)에 의해 정제하여 (2E, 5Z)-3-벤질-6,8-디히드록시-2,5-옥타디엔-4-온을 22 ㎎ (0.09 mmol, 27%: 두 과정 수율)을 흰 가루 형태로 얻었다: 1H NMR (CD3OD, 400 MHz) d 7.28-7.25 (m, 2H), 7.20-7.16 (m, 1H), 7.13-7.12 (m, 2H), 6.76 (q, J = 7.2 Hz, 1H), 5.50 (s, 1H), 4.44 (t, J = 6.7 Hz, 2H), 3.65 (s, 2H), 2.51 (t, J = 6.8 Hz, 2H), 1.90 (d, J = 7.2 Hz, 3H) 13C NMR (CD3OD, 100 MHz) d 193.1, 171.1, 138.5, 133.6, 132.7, 128.6, 127.8, 126.3, 103.3, 67.8, 36.1, 29.7, 22.7.That is, the material obtained above was dissolved in 8 ml of anhydrous tetrahydrofuran, and then 0.11 ml (0.11 mmol) of 1.0 M TBAF tetrahydrofuran solution was added at 0 ° C. and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained material was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give (2E, 5Z) -3-benzyl-6,8-dihydroxy-. 22 mg (0.09 mmol, 27%: two process yield) of 2,5-octadien-4-one was obtained in the form of white powder: 1 H NMR (CD 3 OD, 400 MHz) d 7.28-7.25 (m, 2H ), 7.20-7.16 (m, 1H), 7.13-7.12 (m, 2H), 6.76 (q, J = 7.2 Hz, 1H), 5.50 (s, 1H), 4.44 (t, J = 6.7 Hz, 2H) , 3.65 (s, 2H), 2.51 (t, J = 6.8 Hz, 2H), 1.90 (d, J = 7.2 Hz, 3H) 13 C NMR (CD 3 OD, 100 MHz) d 193.1, 171.1, 138.5, 133.6 , 132.7, 128.6, 127.8, 126.3, 103.3, 67.8, 36.1, 29.7, 22.7.
실시예 8. (Example 8. EE )-3-벤질-6-히드록시-2-옥텐-4-온 (화학식 8, 반응식 3)의 제조) -3-benzyl-6-hydroxy-2-octen-4-one (Formula 8, Scheme 3)
상기 실시예 3 에서 제조한 (E)-3-벤질-3-펜텐-2-온 200 ㎎ (1.15 mmol)을 무수 테트라히드로퓨란 15 ㎖에 녹인 후 1.0 M LiHMDS 테트라히드로퓨란 용액 1.38 ㎖ (1.38 mmol)를 영하 78℃에서 적가하여 30분 동안 교반하였다.200 mg (1.15 mmol) of (E) -3-benzyl-3-penten-2-one prepared in Example 3 was dissolved in 15 ml of anhydrous tetrahydrofuran, followed by 1.38 ml (1.38 mmol) of 1.0 M LiHMDS tetrahydrofuran solution. ) Was added dropwise at -78 ° C and stirred for 30 minutes.
상기 혼합물에 프로판알데히드 0.13 ㎖ (1.72 mmol)를 한꺼번에 가하고, 영하 78℃에서 4시간 동안 교반한 후 포화된 염화암모늄 수용액을 넣어 반응을 종결시켰다. 수용액 층을 아세트산 에틸에스테르를 이용하여 세 번 추출 (3 × 50㎖) 하고, 모인 추출액은 포화된 소금물로 씻어 황산나트륨으로 탈수하였다.0.13 mL (1.72 mmol) of propanealdehyde was added to the mixture at once, and the reaction was terminated by adding a saturated aqueous ammonium chloride solution after stirring for 4 hours at -78 ° C. The aqueous layer was extracted three times (3 x 50 mL) using ethyl acetate, and the combined extracts were washed with saturated brine and dehydrated with sodium sulfate.
탈수된 화합물 용액에서 황산나트륨을 걸러낸 다음 감압 농축하고, 실리카겔 컬럼크로마토그래피법 (헥산 : 아세트 에틸에스테르 = 4 : 1)에 의해 정제하여 원하는 생성물 173 ㎎ (0.75 mmol, 65%)을 노란색 시럽 형태로 얻었다: 1H NMR (CDCl3, 400 MHz) d 7.24-7.20 (m, 2H), 7.14-7.11 (m, 3H), 6.92 (q, J = 6.8 Hz, 1H), 3.97-3.90 (m, 1H), 3.68 (s, 2H), 2.83 (dd, J = 16.8, 4.8 Hz, 1H), 2.70 (dd, J = 16.8, 8.8 Hz, 1H), 1.92 (d, J = 7.2 Hz, 3H), 1.53-1.43 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H) 13C NMR (CDCl3, 100 MHz) d 202.2, 142.2, 140.6, 140.0, 128.8, 128.5, 126.4, 69.7, 43.6, 31.1, 29.7, 15.6, 10.3.Sodium sulfate was filtered off from the dehydrated compound solution, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: acet ethyl ester = 4: 1) to give 173 mg (0.75 mmol, 65%) of the desired product as a yellow syrup. Obtained: 1 H NMR (CDCl 3 , 400 MHz) d 7.24-7.20 (m, 2H), 7.14-7.11 (m, 3H), 6.92 (q, J = 6.8 Hz, 1H), 3.97-3.90 (m, 1H ), 3.68 (s, 2H), 2.83 (dd, J = 16.8, 4.8 Hz, 1H), 2.70 (dd, J = 16.8, 8.8 Hz, 1H), 1.92 (d, J = 7.2 Hz, 3H), 1.53 -1.43 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H) 13 C NMR (CDCl 3 , 100 MHz) d 202.2, 142.2, 140.6, 140.0, 128.8, 128.5, 126.4, 69.7, 43.6, 31.1, 29.7, 15.6, 10.3.
실시예 9. (2Example 9. (2 EE , 5, 5 ZZ )-3-벤질-6-히드록시-2,5-옥타디엔-4-온 (화학식 9, 반응식 3)의 제조) -3-benzyl-6-hydroxy-2,5-octadien-4-one (Formula 9, Scheme 3)
상기 실시예 8 에서 제조한 (E)-3-벤질-6-히드록시-2-옥텐-4-온 95 ㎎ (0.41 mmol)을 무수 디클로로메탄 20 ㎖에 녹인 용액에 4 Å 분자여과기 265 ㎎과 PCC (pyridinium chlorochromate)를 265 ㎎ (0.41 mmol)을 가하고 상온에서 4시간 동안 격렬하게 교반하였다.95 mg (0.41 mmol) of ( E ) -3-benzyl-6-hydroxy-2-octen-4-one prepared in Example 8 was dissolved in 20 ml of anhydrous dichloromethane. 265 mg (0.41 mmol) of PCC (pyridinium chlorochromate) was added thereto, and vigorously stirred at room temperature for 4 hours.
상기 반응 혼합물에 에테르를 가해 얻어진 고체를 짧은 실리카겔 컬럼을 이용하여 디클로로메탄으로 씻으면서 여과하고, 감압 농축하였다. 이때 얻어진 물질을 실리카겔 크로마토그래피법 (헥산 : 아세트산 에틸에스테르 = 5 : 1)에 의해 정제하여 원하는 화합물을 51 ㎎ (0.22 mmol, 54%) 옅은 갈색 시럽의 형태로 얻었다: 1H NMR (CD3OD, 400 MHz) d 15.75 (s, 1H), 7.29-7.15 (m, 5H), 6.94 (q, J = 7.1 Hz, 1H), 5.69 (s, 1H), 3.70 (s, 2H), 2.29 (q, J = 7.5 Hz, 2H), 1.90 (d, J = 7.1 Hz, 3H), 1.09 (t, J = 7.5 Hz, 3H) For the minor compound: 1H NMR (CD3OD, 400 MHz) d 7.29-7.15 (m, 5H), 6.97-6.91 (m, 1H), 3.79 (s, 2H), 3.70 (s, 2H), 2.40 (q, J = 7.5 Hz, 2H), 1.97 (d, J = 7.0 Hz, 1H), 1.00 (t, J = 7.5 Hz, 3H); 13C NMR (CD3OD, 100 MHz) d 205.7, 197.5, 195.0, 184.4, 412.6, 142.1, 139.7, 139.6, 136.4, 136.0, 128.9, 128.8, 128.6, 128.3, 126.5, 126.4, 96.0, 53.5, 32.7, 31.8, 30.7, 30.1, 15.8, 15.2, 10.0, 7.9.The solid obtained by adding ether to the reaction mixture was filtered using a short silica gel column, washing with dichloromethane, and concentrated under reduced pressure. The material thus obtained was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1) to give the desired compound in the form of 51 mg (0.22 mmol, 54%) light brown syrup: 1 H NMR (CD 3 OD , 400 MHz) d 15.75 (s, 1H), 7.29-7.15 (m, 5H), 6.94 (q, J = 7.1 Hz, 1H), 5.69 (s, 1H), 3.70 (s, 2H), 2.29 (q , J = 7.5 Hz, 2H), 1.90 (d, J = 7.1 Hz, 3H), 1.09 (t, J = 7.5 Hz, 3H) For the minor compound: 1 H NMR (CD 3 OD, 400 MHz) d 7.29 -7.15 (m, 5H), 6.97-6.91 (m, 1H), 3.79 (s, 2H), 3.70 (s, 2H), 2.40 (q, J = 7.5 Hz, 2H), 1.97 (d, J = 7.0 Hz, 1H), 1.00 (t, J = 7.5 Hz, 3H); 13 C NMR (CD 3 OD, 100 MHz) d 205.7, 197.5, 195.0, 184.4, 412.6, 142.1, 139.7, 139.6, 136.4, 136.0, 128.9, 128.8, 128.6, 128.3, 126.5, 126.4, 96.0, 53.5, 32.7, 31.8, 30.7, 30.1, 15.8, 15.2, 10.0, 7.9.
실시예 10. (E)-3-벤질-6,9-디히드록시-2-노넨-8-온 (화학식 10, 반응식 3) 의 제조Example 10. Preparation of (E) -3-benzyl-6,9-dihydroxy-2-nonen-8-one (Formula 10, Scheme 3)
상기 실시예 3에서 제조한 (E)-3-벤질-3-펜텐-온 363 ㎎ (2.09 mmol)을 무수 테트라히드로퓨란 15 ㎖에 녹인 후 1.0 M LiHMDS 테트라히드로퓨란 용액 3.1 ㎖ (3.1 mmol)을 영하 78℃에서 적가하고, 30분 동안 교반하였다.363 mg (2.09 mmol) of (E) -3-benzyl-3-penten-one prepared in Example 3 was dissolved in 15 ml of anhydrous tetrahydrofuran, followed by 3.1 ml (3.1 mmol) of 1.0 M LiHMDS tetrahydrofuran solution. It was added dropwise at -78 ° C and stirred for 30 minutes.
상기의 혼합물에 4-t-부틸디메틸실릴옥시-부탄알데히드 422 ㎎ (2.09 mmol)을 무수 테트라히드로퓨란 5 ㎖에 녹여 한꺼번에 가한 다음 영하 78℃에서 3시간을 교반한 다음 포화된 염화암모늄 수용액을 넣어 반응을 종결시켰다.To the mixture was dissolved 422 mg (2.09 mmol) of 4-t-butyldimethylsilyloxy-butanealdehyde in 5 ml of anhydrous tetrahydrofuran, added at once, and stirred for 3 hours at -78 ° C. The reaction was terminated.
수용액 층은 아세트산 에틸에스테르를 이용하여 세 번 추출 (3 × 50 ㎖) 하고, 모인 추출액은 포화된 소금물로 씻어 황산나트륨으로 탈수하였다.The aqueous layer was extracted three times (3 x 50 ml) using ethyl acetate, and the combined extracts were washed with saturated brine and dehydrated with sodium sulfate.
탈수된 화합물 용액에서 황산나트륨을 걸러내고, 감압 농축하여 더 이상 정제하지 아니하고 바로 다음 과정에 이용하였다.Sodium sulfate was filtered from the dehydrated compound solution, concentrated under reduced pressure and used for the next procedure without further purification.
상기에서 얻은 화합물을 무수 테트라히드로퓨란 15 ㎖에 녹이고, 상기 용액에 피리디늄 p-톨루엔설포네이트 5.3 ㎎ (0.02 mmol)을 상온에서 가한 후, 12시간 동안 교반하였다. 반응 혼합물에 트리에틸아민 2 ㎖를 가한 다음 감압 농축하여 얻어진 혼합물을 실리카겔 크로마토그래피법 (헥산 : 아세트산 에틸에스테르 = 1 : 1)에 의해 정제하고 원하는 화합물 228 ㎎ (0.87 mmol, 42%: 두 과정 수율)을 노란색 가루 형태로 수득하였다: 1H NMR (CD3OD, 400 MHz) d 7.26-7.22 (m, 2H), 7.17-7.11 (m, 3H), 6.94 (q, J = 7.0 Hz, 1H), 4.13-4.06 (m, 1H0, 3.68 (s, 2H), 3.65-3.59 (m, 2H), 2.83-2.78 (m, 2H), 1.95 (d, J = 7.0 Hz, 3H), 1.71-1.65 (m, 2H), 1.65-1.53 (m, 2H) 13C NMR (CD3OD, 100 MHz) d 202.0, 142.1, 140.9, 139.9, 128.8, 128.5, 126.4, 68.4, 63.0, 44.1, 33.9, 31.1, 29.5, 14.6.The compound obtained above was dissolved in 15 ml of anhydrous tetrahydrofuran, and 5.3 mg (0.02 mmol) of pyridinium p-toluenesulfonate was added to the solution at room temperature, followed by stirring for 12 hours. 2 ml of triethylamine was added to the reaction mixture, and then the resulting mixture was concentrated under reduced pressure. ) Was obtained in the form of a yellow powder: 1 H NMR (CD 3 OD, 400 MHz) d 7.26-7.22 (m, 2H), 7.17-7.11 (m, 3H), 6.94 (q, J = 7.0 Hz, 1H) , 4.13-4.06 (m, 1H0, 3.68 (s, 2H), 3.65-3.59 (m, 2H), 2.83-2.78 (m, 2H), 1.95 (d, J = 7.0 Hz, 3H), 1.71-1.65 ( m, 2H), 1.65-1.53 (m, 2H) 13 C NMR (CD 3 OD, 100 MHz) d 202.0, 142.1, 140.9, 139.9, 128.8, 128.5, 126.4, 68.4, 63.0, 44.1, 33.9, 31.1, 29.5 , 14.6.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.The specific parts of the present invention have been described in detail above, and it is apparent to those skilled in the art that such specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. something to do. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
상술한 바와 같이, 본 발명은 항암 효과를 가진 화학식 1 로 표시되는 불포화 케톤 화합물 및 그 유도체 및 그 제조 방법을 제공하는 효과가 있다. As described above, the present invention has the effect of providing an unsaturated ketone compound represented by the formula (1) having an anticancer effect, a derivative thereof, and a method for producing the same.
본 발명에 따른 제조 방법은 메틸비닐케톤과 아세트알데히드를 반응시켜 메틸비닐케톤의 알파-카르보닐 위치에 수산화에틸기를 도입하는 베일리스-힐만 반응 시 친수성 용매를 사용함으로써 반응 속도를 가속시킴은 물론 서로 다른 치환기를 선택적이고 높은 수율로 도입할 수 있도록 하며, 또한 화합물들의 대량 합성을 가능하게 한다. 그 결과, 암세포 사멸 유도 활성제, 항암제 등으로 유용하게 사용될 수 있는 화학식 1 의 화합물 및 그의 신규 유도체의 구조 및 활성 상관관계를 포함하여 의약 및 정밀 화학 분야에서 널리 활용될 수 있다.The production method according to the present invention accelerates the reaction rate by using a hydrophilic solvent in the Baileys-Hillman reaction of methyl vinyl ketone and acetaldehyde to introduce ethyl hydroxide at the alpha-carbonyl position of methyl vinyl ketone. It allows the introduction of substituents in selective and high yields, and also enables mass synthesis of compounds. As a result, it can be widely used in the fields of medicine and fine chemistry, including the structure and activity correlation of the compound of formula (1) and its novel derivatives that can be usefully used as cancer cell death inducing activators, anticancer agents and the like.
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