KR20040049158A - Method of selective bromination of asymmetric ketones - Google Patents
Method of selective bromination of asymmetric ketones Download PDFInfo
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- KR20040049158A KR20040049158A KR1020020077008A KR20020077008A KR20040049158A KR 20040049158 A KR20040049158 A KR 20040049158A KR 1020020077008 A KR1020020077008 A KR 1020020077008A KR 20020077008 A KR20020077008 A KR 20020077008A KR 20040049158 A KR20040049158 A KR 20040049158A
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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Abstract
Description
본 발명은 비대칭 케톤 유도체의 비활성화된 알파위치에 선택적으로 브롬화시키는 신규 방법에 관한 것이다.The present invention relates to a novel method for selectively brominating at an inactivated alpha position of an asymmetric ketone derivative.
구체적으로, 본 발명은 비대칭 케톤 유도체와 브롬화 시약에 의한 반응으로부터 비대칭 케톤 유도체를 비선택적 브롬화시킨 후, 브롬제거제를 사용하여 선택적 탈브롬화시켜 하기 화학식 1 로 표시되는 화합물을 제조하는 방법이다.Specifically, the present invention is a method for preparing a compound represented by the following Chemical Formula 1 by non-selective bromination of an asymmetric ketone derivative from a reaction with an asymmetric ketone derivative and a bromination reagent, followed by selective debromination using a brominating agent.
[화학식 1][Formula 1]
(식중 R1과 R2는 서로 독립적이며 수소원소, 시아노기, 니트로기, C1~ C24의 알킬기, 치환되어 있지 않거나 할로겐 원자, C1~ C6의 알킬기, C1~ C8의 알콕시기로 이루어진 군에서 선택되는 1 이상의 치환기가 동일하거나 상이하게 치환되어 있는 아릴기; 알킬기 또는 아릴기로 치환되어 있는 카르보닐기; 카르복실기; 알킬기 또는 아릴기로 치환되어져 있는 카르복실산 에스테르기로 구성된 군이고, R3는 할로겐 원자, 수소원자, C1~ C24의 알킬기로 구성된 군으로부터 선택됨)(Wherein R 1 and R 2 are each independently a hydrogen atom, a cyano group, a nitro group, C 1 ~ C 24 alkyl group, not substituted, or a halogen atom, C 1 ~ C 6 alkyl, C alkoxy of 1 ~ C 8 An aryl group wherein one or more substituents selected from the group consisting of groups are the same or differently substituted; a carbonyl group substituted with an alkyl group or an aryl group; a carboxyl group; a carboxylic ester group substituted with an alkyl group or an aryl group, and R 3 is Selected from the group consisting of halogen atoms, hydrogen atoms, alkyl groups of C 1 to C 24 )
알파 브로모케톤들은 다양한 선형 또는 고리 화합물, 특히 헤테로 고리 화합물들의 제조를 위한 중요한 중간체로 사용되는 물질이다. 비대칭 케톤의 브롬치환된 위치에 따라서 생성물에서의 치환기의 위치가 달라지므로, 비활성화된 알파위치에 브롬치환된 화합물들은 다양한 화합물의 제조에 있어서 매우 중요한 중간체들로 사용되고 있으며, 그 제조방법에 대해서 오랫동안 연구되어 왔다. 이 방법들은 첫째, 브롬이 치환될 위치를 지정해주는 작용기를 가진 반응물로부터 위치선택적 브롬화 반응을 진행시키거나, 둘째, 열역학적 평형 반응을 이용하여 위치선택적 브롬화 반응을 진행시키는, 두가지 방법으로 크게 분류할 수 있다.Alpha bromoketones are materials used as important intermediates for the preparation of various linear or ring compounds, especially heterocyclic compounds. Since the position of the substituent in the product varies according to the brominated substituted position of the asymmetric ketone, the brominated substituted compounds at the inactivated alpha position are used as intermediates which are very important in the preparation of various compounds, and have been studied for a long time. Has been. These methods can be broadly classified into two methods: firstly, a regioselective bromination reaction from a reactant having a functional group which specifies a position to be substituted for bromine, or secondly, a regioselective bromination reaction using a thermodynamic equilibrium reaction. have.
첫째, 브롬이 치환될 위치를 지정해주는 작용기를 가진 반응물로부터 위치선택적 브롬화 반응을 진행하는 예로는, Acta Chemica Scandinavica,1986,B(40), 700 에는 (트리메틸실릴)메틸 케톤으로부터 브롬분자에의한 브롬치환반응을 이용하여 브롬화하는 방법이 개시되어 있고, Arch. Pharmaz.,1975,38, 755 및 Liebigs Ann Chem.,1986, 177 에는 디아조메틸케톤으로부터 브롬산에의한 브롬치환반응을 이용하여 브롬화하는 방법이 개시되어 있고, Chem. Lett.1983, 1841 및 J. Org. Chem.1973, 38, 185 에는 각각 NaBrO2, CrO2Cl2에 의한 올레핀의 산화반응을 이용한 방법이 개시되어 있으며, Synthesis.1990, 595 에는 위치지정 치환기로써 에스테르기로 보호하고 브롬치환 반응후 에스테르 제거반응에 의해, 비활성화된 알파위치에 브롬치환된 화합물들을 제조하는 방법들이 개시되어 있다.First, examples of the regioselective bromination reaction from a reactant having a functional group which designates the position of bromine substitution are Acta Chemica Scandinavica, 1986 , B (40) , 700 to (trimethylsilyl) methyl ketone from bromine molecules. A bromination method using a bromine substitution reaction is disclosed, and Arch. Pharmaz., 1975 , 38 , 755 and Liebigs Ann Chem., 1986 , 177 disclose a process for bromination from diazommethyl ketones using a bromine substitution reaction with bromic acid, and Chem. Lett. 1983 , 1841 and J. Org. Chem. 1973, 38, 185 has each of NaBrO method is disclosed using an oxidation reaction of olefins by 2, CrO 2 Cl 2, Synthesis . 1990 , 595 discloses methods for preparing brominated substituted compounds at inactivated alpha positions by protecting with ester groups with positional substituents and by ester removal after bromination.
그러나, 상기의 종래 기술들은 비활성화된 알파위치에 브롬치환된 케톤들을 매우 순수하게 얻을 수 있는 방법이지만, 그 반응물들이 매우 고가이어서 공업적 규모의 합성에 이용하기 어려운 문제점이 있다.However, the above prior arts are a method of obtaining purely brominated ketones in an inactivated alpha position, but the reactants are very expensive and thus difficult to use for industrial scale synthesis.
둘째, 반응 속도론적으로는 덜 활성화되어 있지만, 열역학적으로는 더 안정한 알파위치에의 브롬을 도입하기 위해서 열역학적 평형을 이용하는 방법의 예로는, Helvetica Chimica Acta,1983,66, 1475 에는 반응물로써 비대칭 케톤을 디클로로메탄에 용해시키고, 브롬 1 당량을 -10 ℃ 에서 90 분 동안 가하고 3 시간 동안 상온에서 방치후 감압증류하여 생성물을 얻는 방법이 개시되어 있고, J. Org. Chem.,1947,12, 342 에는 반응물로써 비대칭 케톤을 에테르에 용해시키고, 브롬 1 당량을 0 ℃ 에서 90 분 동안 가하고 24 시간 동안 상온에서 방치후, 알칼리용액으로 세척한 후, 감압증류하여 생성물을 얻는 방법이 개시되어 있고, 일본 공개특허공보 제2000-336064호에는 반응물로써 비대칭 케톤을 n-클로로부탄에 용해시키고, 브롬 1 당량을 -10 ℃ 에서 2 시간동안 가하고 16 시간 동안 보온하여 방치후, 감압증류하여 생성물을 얻는 방법들이 제시되어 있다. 그러나 상기의 열역학적 평형을 이용한 종래의 기술들은, 비활성화된 알파위치에의 브롬치환된 케톤들을 매우 경제적으로 얻을 수 있는 방법이 개시되어 있지만, 긴 반응시간에 의한 수득률의 저하와 열역학적 평형의 한계 때문에 발생되는 생성물의 순도가 낮다는 문제점이 있다.Second, an example of using thermodynamic equilibrium to introduce bromine to a less reactive kinetics, but thermodynamically more stable, is Helvetica Chimica Acta, 1983 , 66 , 1475 which uses asymmetric ketones as reactants. A method of dissolving in dichloromethane, adding 1 equivalent of bromine at −10 ° C. for 90 minutes, and leaving the product at room temperature for 3 hours, followed by distillation under reduced pressure, discloses a method of J. Org. Chem., 1947 , 12 , 342, asymmetric ketones were dissolved in ether as a reactant, 1 equivalent of bromine was added at 0 ° C. for 90 minutes, left at room temperature for 24 hours, washed with alkaline solution, and distilled under reduced pressure. Japanese Unexamined Patent Publication No. 2000-336064 discloses a method of dissolving asymmetric ketones in n-chlorobutane as a reactant, adding 1 equivalent of bromine at -10 DEG C for 2 hours, and incubating for 16 hours. Methods for obtaining the product by distillation under reduced pressure are presented. However, the conventional techniques using the thermodynamic equilibrium described above are very economically obtainable brominated substituted ketones to the inactivated alpha position, but occur due to the decrease in yield and the limitation of thermodynamic equilibrium due to long reaction time. There is a problem that the purity of the product is low.
위에서 살펴본 바와 같이 현재까지 알려진 비대칭 케톤 유도체의 선택적 치환반응들은 반응물이 고가이거나, 생성물의 수율이 낮거나, 순도가 낮다는 문제점들을 가지고 있었다.As described above, the selective substitution reactions of the asymmetric ketone derivatives known to date have problems that the reactants are expensive, the yield of the product is low, or the purity is low.
따라서, 당 기술의 분야에서 비활성화된 알파위치에 브롬치환된 비대칭 케톤유도체를 경제적이며, 고순도로 제조하기 위한 신규의 공업적 방법들이 요구되고 있다.Therefore, there is a need in the art for new industrial methods for the production of economically and highly purified brominated substituted asymmetric ketone derivatives at inactivated alpha positions.
이에 따라, 본 발명의 목적은 디브롬치환 반응 후 선택적 탈브롬화 반응에 의한 비활성화된 알파위치에 브롬치환된 비대칭 케톤 유도체를 제조하는 방법으로서, 경제적이고, 고순도의 브롬치환된 비대칭 케톤 유도체를 제조하는 방법을 제공하는데 있다.Accordingly, an object of the present invention is a method for producing a brominated substituted asymmetric ketone derivative in the deactivated alpha position by a selective debromination reaction after the dibromination, to produce an economical, high purity brominated substituted asymmetric ketone derivative To provide a method.
본 발명은 다양한 화합물들의 제조를 위한 중간체로 매우 많이 사용되는, 비 활성화된 알파위치에 브롬치환된 비대칭 케톤 유도체를 경제적이며, 고순도로 제조하는 방법에 관한 것이다.The present invention relates to a process for the economic and high purity production of asymmetric ketone derivatives brominated at inactivated alpha positions which are very widely used as intermediates for the preparation of various compounds.
비대칭 케톤 유도체와 브롬화 시약에 의한 반응으로부터 비대칭 케톤 유도체를 비선택적 브롬화시킨 후, 브롬제거제를 사용하여 선택적 탈브롬화시켜 하기 화학식 1 로 표시되는 화합물을 제조하는 방법이고, 상기 비대칭 케톤에 대한 브롬화 시약의 몰비가 1 내지 2.5 이고, 비대칭 케톤에 대한 브롬제거제의 몰비가 0.5 내지 10 인 것을 특징으로 하는 비대칭 케톤의 선택적 브롬화 방법.Non-selective bromination of the asymmetric ketone derivative from the reaction with the asymmetric ketone derivative and the bromination reagent, followed by selective debromination using a bromination agent to prepare a compound represented by the following formula (1), A method of selective bromination of asymmetric ketones, characterized in that the molar ratio is 1 to 2.5, and the molar ratio of the bromate to the asymmetric ketone is 0.5 to 10.
[화학식 1][Formula 1]
(식중 R1과 R2는 서로 독립적이며 수소원소, 시아노기, 니트로기, C1~ C24의 알킬기, 치환되어 있지 않거나 할로겐 원자, C1~ C6의 알킬기, C1~ C8의 알콕시기로 이루어진 군에서 선택되는 1 이상의 치환기가 동일하거나 상이하게 치환되어 있는 아릴기; 알킬기 또는 아릴기로 치환되어 있는 카르보닐기; 카르복실기; 알킬기 또는 아릴기로 치환되어져 있는 카르복실산 에스테르기로 구성된 군이고, R3는 할로겐 원자, 수소원자, C1~ C24의 알킬기로 구성된 군으로부터 선택됨)(Wherein R 1 and R 2 are each independently a hydrogen atom, a cyano group, a nitro group, C 1 ~ C 24 alkyl group, not substituted, or a halogen atom, C 1 ~ C 6 alkyl, C alkoxy of 1 ~ C 8 An aryl group wherein one or more substituents selected from the group consisting of groups are the same or differently substituted; a carbonyl group substituted with an alkyl group or an aryl group; a carboxyl group; a carboxylic ester group substituted with an alkyl group or an aryl group, and R 3 is Selected from the group consisting of halogen atoms, hydrogen atoms, alkyl groups of C 1 to C 24 )
본 발명자들은 비활성화된 알파위치에 브롬치환된 비대칭 케톤 유도체를 제조하는 방법으로 출발물질을 비대칭 케톤 유도체로 하고, 브롬화 시약으로 브롬분자, 하이포아브롬산, 아브롬산과 브롬화 수소, 브롬산과 브롬화 수소, 및 산화제와 Br-와 같이 작용 할 수 있는 반응물질로 하며, 브롬 제거제는 무기 환원제로 아황산 또는 황 화합물로 황, 황화수소, 아황산나트륨 또는 아황산수소나트륨; 수소를 포함하고 산과 반응하여 수소를 발생할 수 있는 금속류로는 철, 아연, 마그네슘, 알루미늄 또는 주석; 수소화 금속으로 수소화알루미늄, 수소화보론 또는 수소화나트륨; 유기 브롬제거제로는 이차알코올류로 이소프로판올 또는 이소부탄올; 알파수소를 가진 카르보닐류로 아세톤, 포름알데히드 또는 아세트알데히드; 니트로기에 의해 활성화된 니트로 알칸류로 니트로메탄; 활성화된 올레핀류로 에틸렌, 프로필렌 또는 부틸렌; 활성화된 방향족 화합물로 페놀, 아닐린, 아니졸, 푸란, 피롤, 티오펜 또는 디히드로벤조퀴논에서 선택하여 사용한 제거반응시,The present inventors use the starting material as an asymmetric ketone derivative in a method of preparing a brominated substituted asymmetric ketone derivative at an inactivated alpha position, and as a bromination reagent, bromine molecule, hypobromic acid, abromic acid and hydrogen bromide, bromic acid and hydrogen bromide, And an oxidizing agent and a reactant capable of acting as Br − , a bromine remover as an inorganic reducing agent, sulfur, hydrogen sulfide, sodium sulfite or sodium hydrogen sulfite as sulfurous acid or a sulfur compound; Metals that include hydrogen and can react with acids to generate hydrogen include iron, zinc, magnesium, aluminum or tin; Aluminum hydride, boron hydride or sodium hydride as the metal hydride; Organic bromine removers include secondary alcohols such as isopropanol or isobutanol; Carbonyls with alpha hydrogen include acetone, formaldehyde or acetaldehyde; Nitromethane with nitro alkanes activated by nitro groups; Activated olefins include ethylene, propylene or butylene; When the removal reaction is selected from phenol, aniline, anisol, furan, pyrrole, thiophene or dihydrobenzoquinone as an activated aromatic compound,
i) 적하되는 브롬의 양을 최적화함으로써, 생성되는 브롬화수소의 양과 적하해야 하는 브롬제거제의 양을 최소화 할 수 있고,i) By optimizing the amount of bromine to be loaded, the amount of hydrogen bromide produced and the amount of bromate remover to be loaded can be minimized,
ii) 비대칭 케톤에 따라 용해도를 고려하여, 특정 용매를 선택하여 반응에 필요한 용매의 양을 최소화하며, 적하되는 특정 브롬제거제를 선택하여, 생성된 브로모케톤의 정제공정을 단순화 할 수 있었다.ii) In consideration of the solubility according to the asymmetric ketone, by selecting a specific solvent to minimize the amount of solvent required for the reaction, by selecting a specific bromine remover dropping, it was possible to simplify the purification process of the resulting bromoketone.
본원 발명에 따른, 비활성화된 알파위치에 브롬치환된 비대칭 케톤 유도체의 제조반응식은 하기 반응식 1 과 같다.According to the present invention, the reaction scheme for preparing an asymmetric ketone derivative brominated at an inactivated alpha position is shown in Scheme 1 below.
즉, 비대칭 케톤을 브롬화 반응과 탈브롬화 반응의 가역적 평형반응에 의해서, 활성화된 알파 위치와 비활성화된 알파 위치 모두 브롬치환시키는, 디브롬화 반응후, 브롬제거제의 도입에 의해 반응계가 비가역 조건으로 변하여, 생성된 브롬화수소 의한 활성화된 알파 위치에 도입된 브롬만 선택적으로 제거함으로써, 비활성화된 알파위치에만 브롬이 치환된 비대칭 케톤 유도체를 제조하게 된다.That is, after the dibromination reaction in which the asymmetric ketone is brominated with both the activated and deactivated alpha positions by the reversible equilibrium reaction between the bromination and debromination reactions, the reaction system is changed to irreversible conditions by the introduction of the bromine remover. By selectively removing only bromine introduced at the activated alpha position by the generated hydrogen bromide, an asymmetric ketone derivative in which bromine is substituted only at the inactivated alpha position is prepared.
본원 발명의 바람직한 구현예는 대기압하에서 특정 용매중 용해된 비대칭 케톤에, 브롬화 시약을 특정용매에 용해하여 적하하며, 일정 시간후 브롬제거제를 적하하는 것을 특징으로 한다.A preferred embodiment of the present invention is characterized by dropping a bromination reagent in a specific solvent and dropping the asymmetric ketone dissolved in a specific solvent under atmospheric pressure, and then adding a bromine remover after a certain time.
본 발명의 비활성화된 알파위치에 브롬치환된 비대칭 케톤 유도체를 제조하는 방법을 보다 상세히 설명하면 다음과 같다.Hereinafter, a method for preparing a brominated substituted asymmetric ketone derivative at an inactivated alpha position will be described in detail.
화학식 1 로 표시되는 비대칭 케톤의 브롬화 반응은, 먼저 활성화된 곳에 브롬이 치환되고, 다음에 비활성화된 곳에 브롬이 치환되는데, 그 반응 메커니즘은 하기의 반응식 2 와 같다.In the bromination reaction of the asymmetric ketone represented by the formula (1), bromine is substituted first in the activated place, and then bromine is substituted in the inactive place, and the reaction mechanism is shown in Scheme 2 below.
브롬화 반응은 활성화된 곳, 즉 엔올과 같이 안정화되는 곳에서 더욱 진행된다. 그리고 반응식 2 에 나타낸 바와 같이, 그 역반응인 탈브롬화 반응도 브롬화 반응과 똑같은 반응 중간체를 거쳐서 진행되므로, 엔올이 더 안정화되는, 즉 보다 활성화된 곳에서 더욱 진행된다.The bromination reaction proceeds further where it is activated, i.e. where it is stabilized, such as enol. And as shown in Scheme 2, the reverse bromination reaction proceeds through the same reaction intermediate as the bromination reaction, so that the enol is further stabilized, that is, further activated.
결론적으로, 먼저 브롬화된 곳이 먼저 탈브롬화 된다는 사실을 이용하여 비대칭 케톤의 활성화된 곳과 비활성화된 곳, 모두를 브롬으로 치환시킨 후, 활성화된 곳의 브롬을 선택적으로 제거함으로써, 비대칭 케톤의 비활성화된 알파 위치에 브롬이 선택적으로 치환된 화합물을 제조한다는 것이 본 발명의 특징이다.In conclusion, using the fact that first brominated sites are first debrominated, the activated and inactivated sites of the asymmetric ketones are replaced with bromine, and then the bromines of the activated sites are selectively removed to deactivate the asymmetric ketones. It is a feature of the present invention that a compound is optionally substituted with bromine at the alpha position.
본 발명의 발명자들은 바람직한 용매의 선택을 위해서, 브롬과의 반응성이없는 다양한 용매들을 사용하여 시험하였고, 또한 바람직한 브롬제거제를 선택하기 위해서, 다양한 브롬제거제를 시험하였으며, 이 발명의 보편적인 응용을 위해서 다양한 비대칭 케톤 유도체를 반응물로써 시험하였고 그 결과는 하기의 표 1 에 나타내었다.The inventors of the present invention tested various solvents that were not reactive with bromine for the selection of preferred solvents, and also tested various bromate removers to select preferred bromates, and for universal applications of this invention. Various asymmetric ketone derivatives were tested as reactants and the results are shown in Table 1 below.
[표 1]TABLE 1
주) 반응물: Note) Reactants:
상기의 표 1 에서, 상술한 바와 같이 비대칭케톤의 비활성화된 알파 위치에 브롬을 도입하기 위한 반응에서, 본 발명자들은 용매, 브롬화시약, 브롬제거제 그리고 반응물들에 대한 다양한 연구를 수행하였다.In Table 1 above, in the reaction for introducing bromine to the deactivated alpha position of the asymmetric ketone as described above, the inventors conducted various studies on the solvent, bromination reagent, bromine remover and reactants.
첫째, 용매로써, 브롬화시약과의 반응성이 없는 유기용매는 할로겐기가 치환된 C1~4지방족 화합물 또는 C1~4지방산이 바람직하고, 특히 바람직한 것은 아세트산, 디클로로메탄, 클로로포름, 또는 테트라클로로메탄 등을 들 수 있다. 상기의 표 1 에서 나타나 있는 바와 같이 아세트산이 더 짧은 시간에 더 높은 수율을 나타내는 것을 볼 수 있다. 하지만 공업적인 면에서 생성물이 단순하고 경제적인 정제를 위해서는 디클로로메탄과 같은 끓는점이 낮은 용매가 더 유리하리라고 기대된다.First, as a solvent, an organic solvent which is not reactive with a bromination reagent is preferably a C 1-4 aliphatic compound substituted with a halogen group or a C 1-4 fatty acid, particularly preferably acetic acid, dichloromethane, chloroform, or tetrachloromethane. Can be mentioned. As shown in Table 1 above, it can be seen that acetic acid shows higher yields in a shorter time. However, industrially, low boiling solvents such as dichloromethane are expected to be more advantageous for simple and economical purification of the product.
둘째, 브롬제거제로써, 브롬과의 반응성이 있는 모든 화합물들이 가능하지만, 무기 환원제로써 아황산나트륨이 사용되고, 알파수소를 가진 케톤으로써 아세톤이 사용되고, 활성화된 방향족 화합물로써 디하이드로퀴논이 사용되고 있으나, 이들은 각각의 장단점을 가지고 있어서, 경우에 따라서 선택하여 사용하여야 한다.Secondly, as bromine remover, all compounds reactive with bromine are possible, but sodium sulfite is used as inorganic reducing agent, acetone is used as ketone with alpha hydrogen, and dihydroquinone is used as activated aromatic compound. It has advantages and disadvantages and should be selected and used in some cases.
셋째, 브롬화시약으로써, 브롬반응을 위한 다양한 시약들도 가능 하지만, 본 발명에서는, 브롬 그리고 브롬산과 브롬화수소산을 이용하였다.Third, as the bromination reagent, various reagents for the bromination reaction are possible, but in the present invention, bromine and bromic acid and hydrobromic acid were used.
넷째, 반응물로써, 비대칭 케톤으로 표시되는 모든 반응물 중에서 화합물 1 ~ 5 가 시험되어졌는데, 각 반응물마다 반응시간과 적하되는 브롬의 양 그리고 그에 따른 브롬제거제의 양이 다르게 결정되어 지는데, 특히 비대칭 케톤으로 표시되는 반응물 중에서, R1이 페닐기인 1 과 5 는 R1의 작은 활성화 능력 때문에 2.2 당량의 브롬을 적하해야 한다.Fourth, as a reactant, compounds 1 to 5 were tested among all reactants represented by asymmetric ketones. For each reactant, the reaction time, the amount of bromine dropped and the amount of bromine remover were determined differently. Of the reactants represented, 1 and 5, in which R 1 is a phenyl group, must drop 2.2 equivalents of bromine due to the small activation capacity of R 1 .
상술 한 바와 같이, 본 발명의 방법은 반응물의 종류에 따라 브롬의 적하량, 용매의 종류와 양에 따른 pH, 브롬제거제의 종류와 양, 반응시간과 온도 등 여러 가지 조건를 고려하여 수행되어야 하는 것이어서, 각 경우마다 실제로는 HPLC (high pressure liquid chromatography) 를 통해 반응의 진행상황을 확인하여 수행시키는 것이 필요하다.As described above, the method of the present invention is to be carried out in consideration of various conditions such as the dropping amount of bromine, the pH according to the type and amount of the solvent, the type and amount of the bromine remover, the reaction time and temperature according to the kind of reactant In each case, it is necessary to confirm the progress of the reaction through HPLC (high pressure liquid chromatography).
이하에서, 본 발명을 실시예에 의거하여 더욱 상세히 설명하지만, 이러한 실시예에 의해 본 발명이 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
[실시예]EXAMPLE
하기의 실시예에 사용된 모든 용매 및 시약은 시판품이어서 특별한 정제 없이 사용하였다.All solvents and reagents used in the examples below were commercially available and used without special purification.
실시예 1Example 1
100 ㎖ 둥근 바닥 플라스크에 1-페닐-2-프로판온 (4.0 g, 29.85 mmol) 과 아세트산 (10 ㎖) 그리고 48 % 브롬화수소산 (5 ㎖) 을 넣고, 아세트산 (15 ㎖) 에 녹인, 브롬 (10.5 g, 65.6 mmol, 2.2 당량) 을 1 분 동안 적하하였다. 그 후, 상온에서 6 시간 동안 방치한 후, 아세톤 (22 ㎖, 17.34 g, 10 당량) 를 반응혼합물에 적하하였고, 또 다시 상온에서 30 시간 방치 한 후, 감압하에서 10 시간 동안 잔여 아세톤과 브로모아세톤을 제거하고, 그 반응혼합물은 물 200 ㎖ 가 들어 있는 500 ㎖ 비이커로 옮긴 뒤 디클로로메탄 (100 ㎖) 으로 추출하였고, 무수황산나트륨으로 탈수 한 후, 짧은 실리카 컬럼을 통과시켜 무기물을 제거하여, 1-페닐-2-프로판온 (1.52 mmol, 5 %), 1-브로모-1-페닐 -2-프로판온 (1.01 mmol, 3 %), 1-브로모-3-페닐-2-프로판온 (25.25 mmol, 85 %), 1,3-디브로모-1-페닐-2-프로판온 (1.01 mmol, 3 %) 를 포함하는 혼합물 (6.09 g)을 얻었다.Into a 100 mL round bottom flask was placed 1-phenyl-2-propanone (4.0 g, 29.85 mmol), acetic acid (10 mL) and 48% hydrobromic acid (5 mL) and dissolved in acetic acid (15 mL), bromine (10.5). g, 65.6 mmol, 2.2 equiv) was added dropwise for 1 minute. Thereafter, after standing at room temperature for 6 hours, acetone (22 ml, 17.34 g, 10 equivalents) was added dropwise to the reaction mixture, and again left at room temperature for 30 hours, and then remaining acetone and bromo for 10 hours under reduced pressure. Acetone was removed, and the reaction mixture was transferred to a 500 ml beaker containing 200 ml of water, extracted with dichloromethane (100 ml), dehydrated with anhydrous sodium sulfate, and passed through a short silica column to remove inorganics. -Phenyl-2-propanone (1.52 mmol, 5%), 1-bromo-1-phenyl-2-propanone (1.01 mmol, 3%), 1-bromo-3-phenyl-2-propanone ( 25.25 mmol, 85%), 1,3-dibromo-1-phenyl-2-propanone (1.01 mmol, 3%) was obtained (6.09 g).
1-페닐-2-프로판온 (keto form)1-phenyl-2-propanone (keto form)
1H NMR (200 MHz, CDCl3) δ 7.15-7.40 (m, 5H), 3.68 (s, 2H), 2.14 (s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.15-7.40 (m, 5H), 3.68 (s, 2H), 2.14 (s, 3H).
13C NMR (50 MHz, CDCl3) δ 206.1, 134.0, 129.1, 128.4, 126.7, 50.6, 28.9. 13 C NMR (50 MHz, CDCl 3 ) δ 206.1, 134.0, 129.1, 128.4, 126.7, 50.6, 28.9.
1-브로모-1-페닐-2-프로판온 (keto form)1-bromo-1-phenyl-2-propanone (keto form)
1H NMR (200 MHz, CDCl3) δ 7.34-7.44 (m, 5H), 5.44 (s, 1H), 2.29 (s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.34-7.44 (m, 5H), 5.44 (s, 1H), 2.29 (s, 3H).
13C NMR (50 MHz, CDCl3) δ 199.0, 135.1, 129.1, 129.0, 128.7, 56.2, 26.1. 13 C NMR (50 MHz, CDCl 3 ) δ 199.0, 135.1, 129.1, 129.0, 128.7, 56.2, 26.1.
MS (CI) 215 (M++1), 213 (M++1), 175, 173, 163, 161, 135, 133 (100), 117, 105,MS (CI) 215 (M + +1), 213 (M + +1), 175, 173, 163, 161, 135, 133 (100), 117, 105,
91, 57, 43.91, 57, 43.
1-브로모-3-페닐-2-프로판온 (keto form)1-bromo-3-phenyl-2-propanone (keto form)
1H NMR (200 MHz, CDCl3) δ 7.20-7.35 (m, 5H), 3.94 (s, 2H), 3.91 (s, 2H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.20-7.35 (m, 5H), 3.94 (s, 2H), 3.91 (s, 2H).
13C NMR (50 MHz, CDCl3) δ 199.2, 133.2, 129.4, 128.9, 127.5, 46.8, 33.3. 13 C NMR (50 MHz, CDCl 3 ) δ 199.2, 133.2, 129.4, 128.9, 127.5, 46.8, 33.3.
MS (CI) 215 (M++1), 213 (M++1), 175, 173, 163, 161, 145, 143, 135 (100), 133,MS (CI) 215 (M + +1), 213 (M + +1), 175, 173, 163, 161, 145, 143, 135 (100), 133,
119, 105, 91.119, 105, 91.
1, 3-디브로모-1-페닐-2-프로판온 (keto form)1, 3-dibromo-1-phenyl-2-propanone (keto form)
1H NMR (200 MHz, CDCl3) δ 7.30-7.50 (m, 5H), 5.84 (s, 1H), 4.23 (d,J= 12.8 1 H NMR (200 MHz, CDCl 3 ) δ 7.30-7.50 (m, 5H), 5.84 (s, 1H), 4.23 (d, J = 12.8
Hz, 1H), 4.04 (d,J= 12.8 Hz, 1H).Hz, 1H), 4.04 (d, J = 12.8 Hz, 1H).
13C NMR (50 MHz, CDCl3) δ 192.8, 134.2, 129.5, 129.1, 128.9, 51.3, 30.8. 13 C NMR (50 MHz, CDCl 3 ) δ 192.8, 134.2, 129.5, 129.1, 128.9, 51.3, 30.8.
MS (CI) 295 (M++1), 293 (M++1), 291 (M++1), 213, 211, 133 (100), 131, 104, 91.MS (CI) 295 (M + +1), 293 (M + +1), 291 (M + +1), 213, 211, 133 (100), 131, 104, 91.
실시예 2Example 2
100 ㎖ 둥근 바닥 플라스크에 1-페닐-1,3-부탄디온 (2.30 g, 14.13 mmol) 과 아세트산 (10 ㎖) 을 넣고, 아세트산 (7 ㎖) 에 녹인, 브롬 (2.94 g, 65.6 mmol, 1.3 당량) 을 1 분 동안 적하하였다. 그 후, 상온에서 2 시간 동안 방치한 후, 디히드로벤조퀴논 (1.0 g, 9.1 mmol, 0.64 당량) 을 반응혼합물에 적하 하였고, 또 다시 상온에서 30 시간 방치 한 후, 물 200 ㎖ 가 들어 있는 500 ㎖ 비이커로 옮긴 뒤 디클로로메탄 (100 ㎖) 으로 추출하였고, 무수황산나트륨으로 탈수 한 후, 짧은 실리카 컬럼을 통과시켜 무기물을 제거하여, 1-페닐-1,3-부탄디온 (2.04 mmol, 11.1 %), 1-브로모-4-페닐-1,3-부탄디온 (15.7 mmol, 85.2 %), 1-디브로모-4-페닐-1,3-부탄디온 (0.16 mmol, 1 %) 을 포함하는 혼합물(3.78 g) 을 얻었다.1-phenyl-1,3-butanedione (2.30 g, 14.13 mmol) and acetic acid (10 mL) were placed in a 100 mL round bottom flask, and bromine (2.94 g, 65.6 mmol, 1.3 equivalents) was dissolved in acetic acid (7 mL). ) Was added dropwise for 1 minute. Then, after standing at room temperature for 2 hours, dihydrobenzoquinone (1.0 g, 9.1 mmol, 0.64 equiv) was added dropwise to the reaction mixture, and again left at room temperature for 30 hours, followed by 500 containing 200 ml of water. Transfer to a beaker, extracted with dichloromethane (100 mL), dehydrated with anhydrous sodium sulfate, and then pass through a short silica column to remove inorganics. 1-phenyl-1,3-butanedione (2.04 mmol, 11.1%) , 1-bromo-4-phenyl-1,3-butanedione (15.7 mmol, 85.2%), 1-dibromo-4-phenyl-1,3-butanedione (0.16 mmol, 1%) A mixture (3.78 g) was obtained.
1-페닐-1, 3-부탄디온 (keto form:enol form = 0.09:1.0) (enol form)1-phenyl-1, 3-butanedione (keto form: enol form = 0.09: 1.0) (enol form)
1H NMR (200 MHz, CDCl3) δ 16.19 (bs, 1H), 7.80-7.90 (m, 2H), 7.30-7.60 (m, 1 H NMR (200 MHz, CDCl 3 ) δ 16.19 (bs, 1H), 7.80-7.90 (m, 2H), 7.30-7.60 (m,
3H), 6.17 (s, 1H), 2.19 (s, 3H).3H), 6.17 (s, 1 H), 2.19 (s, 3 H).
13C NMR (50 MHz, CDCl3) δ 193.7, 183.3, 134.8, 132.2, 128.5, 126.9, 96.6, 13 C NMR (50 MHz, CDCl 3 ) δ 193.7, 183.3, 134.8, 132.2, 128.5, 126.9, 96.6,
25.7.25.7.
(keto form)(keto form)
1 H NMR (200 MHz, CDCl3) δ 4.09 (s, 2H), 2.29 (s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 4.09 (s, 2H), 2.29 (s, 3H).
13C NMR (50 MHz, CDCl3) δ 128.7. 13 C NMR (50 MHz, CDCl 3 ) δ 128.7.
2-브로모-1-페닐-1, 3-부탄디온 (keto form)2-bromo-1-phenyl-1, 3-butanedione (keto form)
1H NMR (200 MHz, CDCl3) δ 7.90-8.00 (m, 2H), 7.60-7.70 (m, 1H), 7.40-7.60 (m, 1 H NMR (200 MHz, CDCl 3 ) δ 7.90-8.00 (m, 2H), 7.60-7.70 (m, 1H), 7.40-7.60 (m,
2H), 5.65 (s, 1H), 2.46 (s, 3H).2H), 5.65 (s, 1H), 2.46 (s, 3H).
13C NMR (50 MHz, CDCl3) δ 198.2, 189.9, 134.5, 133.6, 129.2, 129.0, 52.9, 13 C NMR (50 MHz, CDCl 3 ) δ 198.2, 189.9, 134.5, 133.6, 129.2, 129.0, 52.9,
27.1.27.1.
4-브로모-1-페닐-1, 3-부탄디온 (enol form)4-bromo-1-phenyl-1, 3-butanedione (enol form)
1H NMR (200 MHz, CDCl3) δ 15.63 (bs, 1H), 7.87-7.92 (m, 2H), 7.40-7.60 (m, 1 H NMR (200 MHz, CDCl 3 ) δ 15.63 (bs, 1H), 7.87-7.92 (m, 2H), 7.40-7.60 (m,
3H), 6.45 (s, 1H), 3.97 (s, 2H).3H), 6.45 (s, 1 H), 3.97 (s, 2 H).
13C NMR (50 MHz, CDCl3) δ 188.4, 184.0, 133.9, 132.9, 128.7, 127.1, 95.4, 13 C NMR (50 MHz, CDCl 3 ) δ 188.4, 184.0, 133.9, 132.9, 128.7, 127.1, 95.4,
31.2.31.2.
2, 4-디브로모-1-페닐-1, 3-부탄디온 (keto form)2, 4-dibromo-1-phenyl-1, 3-butanedione (keto form)
1H NMR (200 MHz, CDCl3) δ 8.00 (dd,J= 7.0, 1.4 Hz, 2H), 7.67 (t,J= 7.3 1 H NMR (200 MHz, CDCl 3 ) δ 8.00 (dd, J = 7.0, 1.4 Hz, 2H), 7.67 (t, J = 7.3
Hz, 1H), 7.47-7.57 (m, 2H), 6.12 (s, 1H), 4.43 (d,Hz, 1H), 7.47-7.57 (m, 2H), 6.12 (s, 1H), 4.43 (d,
J= 13.8 Hz, 1H), 4.30 (d,J= 13.8 Hz, 1H). J = 13.8 Hz, 1H), 4.30 (d, J = 13.8 Hz, 1H).
13C NMR (50 MHz, CDCl3) δ 192.0, 189.7, 134.7, 133.2, 129.2, 129.0, 49.4, 13 C NMR (50 MHz, CDCl 3 ) δ 192.0, 189.7, 134.7, 133.2, 129.2, 129.0, 49.4,
32.0.32.0.
4, 4-디부로모-1-페닐-1, 3-부탄디온. (enol form)4, 4-dibumomo-1-phenyl-1, 3-butanedione. (enol form)
1H NMR (200 MHz, CDCl3) δ 14.89 (bs, 1H), 7.93 (d,J= 8.0 Hz, 1H), 7.46-7.64 1 H NMR (200 MHz, CDCl 3 ) δ 14.89 (bs, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.46-7.64
(m, 3H), 6.66 (s, 1H), 5.95 (s, 1H).(m, 3 H), 6.66 (s, 1 H), 5.95 (s, 1 H).
13C NMR (50 MHz, CDCl3) δ 188.8, 181.9, 133.1, 132.9, 128.8, 127.1, 92.0, 13 C NMR (50 MHz, CDCl 3 ) δ 188.8, 181.9, 133.1, 132.9, 128.8, 127.1, 92.0,
39.6.39.6.
실시예 3Example 3
25 ㎖ 둥근 바닥 플라스크에 2-아세틸알파테트랄온 (79 mg, 0.422 mmol) 과 아세트산 (2 ㎖) 을 넣고, 아세트산 (2 ㎖) 에 녹인, 브롬 (135 mg, 0.84 mmol, 2.0 당량) 을 1 분 동안 적하하였다. 그 후, 상온에서 3 시간 동안 방치한 후, 아세톤 (0.3 ㎖, 4.22 mmole, 10 당량) 을 반응혼합물에 적하 하였고, 또 다시 상온에서 30 분 방치 한 후, 물 100 ㎖ 가 들어 있는 250 ㎖ 비이커로 옮긴 뒤 디클로로메탄 (50 ㎖) 으로 추출하였고, 무수황산나트륨으로 탈수 한 후, 짧은 실리카 컬럼을 통과 시켜 무기물을 제거하여, 2-브로모아세틸알파테트랄온 (107 mg, 0.401 mmol, 95.0 %) 을 얻었다.2-acetylalphatetralone (79 mg, 0.422 mmol) and acetic acid (2 mL) were added to a 25 mL round bottom flask, and bromine (135 mg, 0.84 mmol, 2.0 equiv) dissolved in acetic acid (2 mL) was added 1 It was dripped for minutes. Then, after standing at room temperature for 3 hours, acetone (0.3 mL, 4.22 mmole, 10 equivalents) was added dropwise to the reaction mixture, and again left at room temperature for 30 minutes, followed by a 250 mL beaker containing 100 mL of water. After transferring, the mixture was extracted with dichloromethane (50 mL), dehydrated with anhydrous sodium sulfate, and passed through a short silica column to remove inorganics, thereby obtaining 2-bromoacetylalphatetralone (107 mg, 0.401 mmol, 95.0%). Got it.
2-아세틸알파테트랄온 (enol form)2-acetylalphatetralone (enol form)
1H NMR (200 MHz, CDCl3) δ 16.36 (bs, 1H), 7.94 (dd,J= 7.2, 1.6 Hz, 1H), 1 H NMR (200 MHz, CDCl 3 ) δ 16.36 (bs, 1H), 7.94 (dd, J = 7.2, 1.6 Hz, 1H),
7.27-7.45 (m, 2H), 7.20 (dd,J= 6.8, 1.0 Hz, 1H),7.27-7.45 (m, 2H), 7.20 (dd, J = 6.8, 1.0 Hz, 1H),
2.88 (t,J= 8.0 Hz, 2H), 2.62 (t,J= 7.8 Hz, 2H),2.88 (t, J = 8.0 Hz, 2H), 2.62 (t, J = 7.8 Hz, 2H),
2.24 (s, 3H).2.24 (s, 3 H).
13C NMR (50 MHz, CDCl3) δ 193.8, 176.8, 140.7, 131.8, 131.0, 127.5, 126.7, 13 C NMR (50 MHz, CDCl 3 ) δ 193.8, 176.8, 140.7, 131.8, 131.0, 127.5, 126.7,
125.7, 105.9, 28.1, 23.8, 22.6.125.7, 105.9, 28.1, 23.8, 22.6.
2-브로모아세틸알파테트랄온 (enol form)2-bromoacetylalphatetralone (enol form)
1H NMR (200 MHz, CDCl3) δ 15.82 (bs, 1H), 7.91 (d,J= 7.2 Hz, 1H), 7.20-7.45 1 H NMR (200 MHz, CDCl 3 ) δ 15.82 (bs, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.20-7.45
(m, 2H), 7.18 (d,J= 7.2 Hz, 1H), 4.03 (s, 3H),(m, 2H), 7.18 (d, J = 7.2 Hz, 1H), 4.03 (s, 3H),
2.87 (t,J= 7.8 Hz, 2H), 2.63 (t,J= 7.6 Hz, 2H).2.87 (t, J = 7.8 Hz, 2H), 2.63 (t, J = 7.6 Hz, 2H).
13C NMR (50 MHz, CDCl3) δ 184.0, 181.2, 141.3, 132.6, 130.8, 127.7, 126.8, 13 C NMR (50 MHz, CDCl 3 ) δ 184.0, 181.2, 141.3, 132.6, 130.8, 127.7, 126.8,
126.1, 105.6, 28.5, 27.8, 22.5.126.1, 105.6, 28.5, 27.8, 22.5.
실시예 4Example 4
50 ㎖ 둥근 바닥 플라스크에 아세토아세트산에틸에스테르 (894 mg, 14.13 mmol) 과 아세트산 (4 ㎖) 을 넣고, 아세트산 (2 ㎖) 에 녹인, 브롬 (1.65 g, 10.3 mmol, 1.5 당량) 을 1 분 동안 적하하였다. 그 후, 상온에서 30 분 동안 방치한후, 디히드로벤조퀴논 (1.0 g, 9.1 mmol, 1,3 당량) 을 반응혼합물에 적하 하였고, 또 다시 상온에서 1 시간 방치 한 후, 물 100 ㎖ 가 들어 있는 250 ㎖ 비이커로 옮긴 뒤 디클로로메탄 (50 ㎖) 으로 추출하였고, 무수황산나트륨으로 탈수 한 후, 짧은 실리카 컬럼을 통과시켜 무기물을 제거하여, 아세토아세트산에틸에스테르 (0.223 mmol, 3.2 %), 4-브로모아세토아세트산에틸에스테르 (6.204 mmol, 90.2 %), 4,4-디브로모아세토아세트산 에틸에스테르 (0.223 mmol, 3.2 %) 을 포함하는 혼합물 (1.390 g) 을 얻었다.Acetoacetic acid ethyl ester (894 mg, 14.13 mmol) and acetic acid (4 mL) were added to a 50 mL round bottom flask, and bromine (1.65 g, 10.3 mmol, 1.5 equiv) dissolved in acetic acid (2 mL) was added dropwise for 1 minute. It was. Thereafter, after standing at room temperature for 30 minutes, dihydrobenzoquinone (1.0 g, 9.1 mmol, 1,3 equiv) was added dropwise to the reaction mixture, and further left at room temperature for 1 hour, followed by 100 ml of water. Transfer to a 250 mL beaker, extract with dichloromethane (50 mL), dehydrate with anhydrous sodium sulfate, and pass through a short silica column to remove inorganics. A mixture (1.390 g) containing acetoacetic acid ethyl ester (6.204 mmol, 90.2%) and 4,4-dibromoacetoacetic acid ethyl ester (0.223 mmol, 3.2%) were obtained.
아세토아세트산에틸에스테르 (keto form:enol form = 1.0:0.1)(keto form)Acetoacetic acid ethyl ester (keto form: enol form = 1.0: 0.1)
1H NMR (200 MHz, CDCl3) δ 4.21 (q,J= 7.2 Hz, 2H), 3.46 (s, 2H), 2.28 (s, 1 H NMR (200 MHz, CDCl 3 ) δ 4.21 (q, J = 7.2 Hz, 2H), 3.46 (s, 2H), 2.28 (s,
3H), 1.29 (t,J= 7.3 Hz, 3H).3H), 1.29 (t, J = 7.3 Hz, 3H).
13C NMR (50 MHz, CDCl3) δ 200.4, 166.9, 61.0, 49.8, 29.8, 13.8. 13 C NMR (50 MHz, CDCl 3 ) δ 200.4, 166.9, 61.0, 49.8, 29.8, 13.8.
(enol form)(enol form)
1H NMR (200 MHz, CDCl3) δ 12.12 (bs, 1H), 4.98 (s, 1H), 1.96 (s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 12.12 (bs, 1H), 4.98 (s, 1H), 1.96 (s, 3H).
13C NMR (50 MHz, CDCl3) δ 175.2, 89.5, 59.6, 20.8, 14.0. 13 C NMR (50 MHz, CDCl 3 ) δ 175.2, 89.5, 59.6, 20.8, 14.0.
2-브로모아세토아세트산에틸에스테르 (keto form)2-bromoacetoacetic acid ethyl ester (keto form)
1H NMR (200 MHz, CDCl3) δ 4.77 (s, 1H), 4.29 (q,J= 7.2 Hz, 2H), 2.45 (s, 1 H NMR (200 MHz, CDCl 3 ) δ 4.77 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 2.45 (s,
3H), 1.32 (t,J= 7.1 Hz, 3H).3H), 1.32 (t, J = 7.1 Hz, 3H).
13C NMR (50 MHz, CDCl3) δ 196.3, 165.1, 63.1, 49.1, 26.4, 13.8. 13 C NMR (50 MHz, CDCl 3 ) δ 196.3, 165.1, 63.1, 49.1, 26.4, 13.8.
MS (CI) 211 (M++1), 209 (M++1), 183, 181, 131 (100), 103, 85.MS (CI) 211 (M + +1), 209 (M + +1), 183, 181, 131 (100), 103, 85.
4-브로모아세토아세트산에틸에스테르 (keto form:enol form = 1.0:0.21) (keto form)4-bromoacetoacetic acid ethyl ester (keto form: enol form = 1.0: 0.21) (keto form)
1H NMR (200 MHz, CDCl3) δ 4.21 (q,J= 7.2 Hz, 2H), 4.08 (s, 2H), 3.71 (s, 1 H NMR (200 MHz, CDCl 3 ) δ 4.21 (q, J = 7.2 Hz, 2H), 4.08 (s, 2H), 3.71 (s,
2H), 1.29 (t,J= 7.1 Hz, 3H).2H), 1.29 (t, J = 7.1 Hz, 3H).
13C NMR (50 MHz, CDCl3) δ 194.3, 166.4, 61.6, 46.0, 33.8, 13.9. 13 C NMR (50 MHz, CDCl 3 ) δ 194.3, 166.4, 61.6, 46.0, 33.8, 13.9.
(enol form)(enol form)
1H NMR (200 MHz, CDCl3) δ 11.99 (s, 1H), 5.29 (s, 1H), 4.23 (q,J= 7.0 Hz, 1 H NMR (200 MHz, CDCl 3 ) δ 11.99 (s, 1H), 5.29 (s, 1H), 4.23 (q, J = 7.0 Hz,
2H), 3.87 (s, 2H), 1.30 (t,J= 7.0 Hz, 3H).2H), 3.87 (s, 2H), 1.30 (t, J = 7.0 Hz, 3H).
MS (CI) 211 (M++1), 209 (M++1, 100), 165, 163, 131, 129, 101, 85, 47.MS (CI) 211 (M + +1), 209 (M + +1, 100), 165, 163, 131, 129, 101, 85, 47.
2,2-디브로모아세토아세트산에틸에스테르 (keto form)2,2-dibromoacetoacetic acid ethyl ester (keto form)
1H NMR (200 MHz, CDCl3) δ 4.36 (q,J= 7.1 Hz, 2H), 2.58 (s, 3H), 1.33 (t,J 1 H NMR (200 MHz, CDCl 3 ) δ 4.36 (q, J = 7.1 Hz, 2H), 2.58 (s, 3H), 1.33 (t, J
= 7.2 Hz, 3H).= 7.2 Hz, 3H).
13C NMR (50 MHz, CDCl3) δ 190.9, 163.6, 64.7, 59.8, 23.5, 13.7. 13 C NMR (50 MHz, CDCl 3 ) δ 190.9, 163.6, 64.7, 59.8, 23.5, 13.7.
MS (CI) 291 (M++1), 289 (M++1), 287 (M++1), 263, 261, 256, 245, 243, 241, 211,MS (CI) 291 (M + +1), 289 (M + +1), 287 (M + +1), 263, 261, 256, 245, 243, 241, 211,
209, 207, 131 (100), 105, 85, 47.209, 207, 131 (100), 105, 85, 47.
4,4-디브로모아세토아세트산에틸에스테르 (keto form : enol form = 1.0 : 0.25) (keto form)4,4-dibromoacetoacetic acid ethyl ester (keto form: enol form = 1.0: 0.25) (keto form)
1H NMR (200 MHz, CDCl3) δ 6.02 (s, 1H), 4.24 (q,J= 7.0 Hz, 2H), 3.96 (s, 1 H NMR (200 MHz, CDCl 3 ) δ 6.02 (s, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.96 (s,
2H), 1.30 (t,J= 6.8 Hz, 3H).2H), 1.30 (t, J = 6.8 Hz, 3H).
13C NMR (50 MHz, CDCl3) δ 188.7, 166.1, 61.9, 42.0, 41.8, 14.0. 13 C NMR (50 MHz, CDCl 3 ) δ 188.7, 166.1, 61.9, 42.0, 41.8, 14.0.
(enol form)(enol form)
1H NMR (200 MHz, CDCl3) δ 12.10 (bs, 1H), 5.92 (s, 1H), 5.42 (s, 1H), 4.26 1 H NMR (200 MHz, CDCl 3 ) δ 12.10 (bs, 1H), 5.92 (s, 1H), 5.42 (s, 1H), 4.26
(q,J= 6.8 Hz, 2H), 1.32 (t,J= 7.0 Hz, 3H).(q, J = 6.8 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H).
실시예 5Example 5
100 ㎖ 둥근 바닥 플라스크에 1-페닐-2-부탄온 (2.0 g, 13.5 mmol) 과 아세트산 (10 ㎖) 그리고 48 % 브롬화수소산 (2 ㎖) 을 넣고, 아세트산 (5 ㎖) 에 녹인, 브롬 (4.32 g, 27.0 mmol, 2.0 당량) 을 1 분 동안 적하하였다. 그 후, 상온에서 6 시간 동안 방치한 후, 아황산 나트륨 (3.4 g, 2 당량) 를 반응혼합물에 적하하였고, 또 다시 상온에서 30 시간 방치 한 후, 그 반응혼합물은 물 200 ㎖가 들어 있는 500 ㎖ 비이커로 옮긴 뒤 디클로로메탄 (100 ㎖) 으로 추출하였고, 무수황산나트륨으로 탈수 한 후, 짧은 실리카 컬럼을 통과 시켜 무기물을 제거하여, 1-페닐-2-부탄온 (0.41 mmol, 3 %), 1-브로모-3-페닐-2-부탄온 (11.5 mmol, 85 %), 1,3-디브로모-1-페닐-2-부탄온 (0.41 mmol, 3 %) 를 포함하는 혼합물 (2.80 g)을 얻었다.Into a 100 mL round bottom flask was placed 1-phenyl-2-butanone (2.0 g, 13.5 mmol), acetic acid (10 mL) and 48% hydrobromic acid (2 mL), and bromine (4.32) dissolved in acetic acid (5 mL). g, 27.0 mmol, 2.0 equiv) was added dropwise for 1 minute. Thereafter, after standing at room temperature for 6 hours, sodium sulfite (3.4 g, 2 equivalents) was added dropwise to the reaction mixture, and again left at room temperature for 30 hours, the reaction mixture was 500 ml containing 200 ml of water. Transferred to a beaker, extracted with dichloromethane (100 mL), dehydrated with anhydrous sodium sulfate, and passed through a short silica column to remove inorganics. 1-phenyl-2-butanone (0.41 mmol, 3%), 1- Mixture comprising bromo-3-phenyl-2-butanone (11.5 mmol, 85%), 1,3-dibromo-1-phenyl-2-butanone (0.41 mmol, 3%) (2.80 g) Got.
1-페닐-2-부탄온 (keto form)1-phenyl-2-butanone (keto form)
1H NMR (200 MHz, CDCl3) δ 7.15-7.40 (m, 5H), 3.68 (s, 2H), 2.40 (q,J= 7.2 1 H NMR (200 MHz, CDCl 3 ) δ 7.15-7.40 (m, 5H), 3.68 (s, 2H), 2.40 (q, J = 7.2
Hz, 2H), 1.05 (t,J= 7.3 Hz, 3H).Hz, 2H), 1.05 (t, J = 7.3 Hz, 3H).
1-브로모-1-페닐-2-부탄온 (keto form)1-bromo-1-phenyl-2-butanone (keto form)
1H NMR (200 MHz, CDCl3) δ 7.34-7.44 (m, 5H), 5.44 (s, 1H), 2.42 (q,J= 7.2 1 H NMR (200 MHz, CDCl 3 ) δ 7.34-7.44 (m, 5H), 5.44 (s, 1H), 2.42 (q, J = 7.2
Hz, 2H), 1.05 (t,J= 7.3 Hz, 3H).Hz, 2H), 1.05 (t, J = 7.3 Hz, 3H).
1-브로모-3-페닐-2-부탄온 (keto form)1-bromo-3-phenyl-2-butanone (keto form)
1H NMR (200 MHz, CDCl3) δ 7.20-7.35 (m, 5H), 4.11 (q,J= 7.2 Hz, 1H), 3.91 1 H NMR (200 MHz, CDCl 3 ) δ 7.20-7.35 (m, 5H), 4.11 (q, J = 7.2 Hz, 1H), 3.91
(s, 2H), 1.65 (d,J= 7.2 Hz, 3H).(s, 2H), 1.65 (d, J = 7.2 Hz, 3H).
실시예 6Example 6
100 ㎖ 둥근 바닥 플라스크에 1-페닐-2-프로판온 (4.0 g, 29.85 mmol) 과 디클로로메탄 (20 ㎖) 그리고 48 % 브롬화수소산 (2 ㎖) 을 넣고, 디클로로메탄 (15 ㎖) 에 녹인, 브롬 (9.55 g, 59.7 mmol, 2.0 당량) 을 1 분 동안 적하하였다. 그후, 상온에서 24 시간 동안 방치한 후, 아세톤 (22 ㎖, 17.34 g, 10 당량) 을 반응혼합물에 적하하였고, 또 다시 상온에서 30 시간 방치 한 후, 그 반응혼합물은 물 (200 ㎖) 가 들어 있는 500 ㎖ 비이커로 옮긴 뒤 디클로로메탄 (100 ㎖) 를 추가로 첨가하여 추출하였고, 무수황산나트륨으로 탈수 한 후, 짧은 실리카 컬럼을 통과 시켜 무기물을 제거하여, 1-페닐-2-프로판온 (1.22 mmol, 4 %), 1-브로모-1-페닐-2-프로판온 (1.22 mmol, 4 %), 1-브로모-3-페닐-2-프로판온 (23.76 mmol, 80 %)을 포함하는 혼합물 (5.37 g) 을 얻었다.1-phenyl-2-propanone (4.0 g, 29.85 mmol), dichloromethane (20 mL) and 48% hydrobromic acid (2 mL) were added to a 100 mL round bottom flask, and bromine dissolved in dichloromethane (15 mL). (9.55 g, 59.7 mmol, 2.0 equiv) was added dropwise for 1 minute. Then, after standing at room temperature for 24 hours, acetone (22 mL, 17.34 g, 10 equivalents) was added dropwise to the reaction mixture, and again left at room temperature for 30 hours, after which the reaction mixture contained water (200 mL). The resulting mixture was transferred to a 500 ml beaker, followed by extraction with additional dichloromethane (100 ml), dehydrated with anhydrous sodium sulfate, and passed through a short silica column to remove inorganics. 1-phenyl-2-propanone (1.22 mmol , 4%), 1-bromo-1-phenyl-2-propanone (1.22 mmol, 4%), 1-bromo-3-phenyl-2-propanone (23.76 mmol, 80%) (5.37 g) was obtained.
실시예 7Example 7
100 ㎖ 둥근 바닥 플라스크에 1-페닐-2-프로판온 (4.0 g, 29.85 mmol) 과 아세트산 (20 ㎖) 그리고 브롬산 (3.60 g, 23.9 mmol, 0.8 당량) 을 넣고, 48 % 브롬화수소산 (5 ㎖) 을 적하하였다. 그 후, 상온에서 4 시간 동안 방치한 후, 아황산 나트륨 (7.52 g, 59.7 mmol, 2 당량) 을 반응혼합물에 적하 하였고, 또 다시 상온에서 30 시간 방치 한 후, 그 반응혼합물은 물 200 ㎖ 가 들어 있는 500 ㎖ 비이커로 옮긴 후 디클로로메탄 (100 ㎖) 으로 추출하였고, 무수황산나트륨으로 탈수 한 후, 짧은 실리카 컬럼을 통과시켜 무기물을 제거하여, 1-페닐-2-프로판온 (0.90 mmol, 3 %), 1-브로모-1-페닐-2-프로판온 (0.60 mmol, 2 %), 1-브로모-3-페닐-2-프로판온 (24.48 mmol, 82 %), 1,3-디브로모-1-페닐-2- 프로판온 (0.90 mmol, 3 %) 을 포함하는 혼합물 (5.73 g) 을 얻었다.1-phenyl-2-propanone (4.0 g, 29.85 mmol), acetic acid (20 mL) and bromic acid (3.60 g, 23.9 mmol, 0.8 equiv) were added to a 100 mL round bottom flask, and 48% hydrobromic acid (5 mL) was added. ) Was added dropwise. Thereafter, after standing at room temperature for 4 hours, sodium sulfite (7.52 g, 59.7 mmol, 2 equivalents) was added dropwise to the reaction mixture, and again left at room temperature for 30 hours, the reaction mixture contained 200 ml of water. After transferring to a 500 mL beaker, extracted with dichloromethane (100 mL), dehydrated with anhydrous sodium sulfate, and passed through a short silica column to remove inorganics, 1-phenyl-2-propanone (0.90 mmol, 3%) , 1-bromo-1-phenyl-2-propanone (0.60 mmol, 2%), 1-bromo-3-phenyl-2-propanone (24.48 mmol, 82%), 1,3-dibromo A mixture (5.73 g) containing -1-phenyl-2-propanone (0.90 mmol, 3%) was obtained.
본 발명은 다양한 화합물들의 제조를 위한 중간체로 많이 사용되고 있는, 비대칭 케톤의 비활성화된 알파위치에 선택적으로 브롬치환된 비대칭 케톤들을 경제적이며, 고순도로서 제조할 수 있는 신규의 공업적 방법에 사용할 수 있다.The present invention can be used in a novel industrial process that can be produced economically and with high purity of asymmetric ketones selectively brominated at an inactivated alpha position of an asymmetric ketone, which is widely used as an intermediate for the preparation of various compounds.
Claims (4)
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