KR100607027B1 - New process for activating zinc metal - Google Patents
New process for activating zinc metal Download PDFInfo
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- KR100607027B1 KR100607027B1 KR1020020062392A KR20020062392A KR100607027B1 KR 100607027 B1 KR100607027 B1 KR 100607027B1 KR 1020020062392 A KR1020020062392 A KR 1020020062392A KR 20020062392 A KR20020062392 A KR 20020062392A KR 100607027 B1 KR100607027 B1 KR 100607027B1
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- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22B—PRODUCTION AND REFINING OF METALS; PRETREATMENT OF RAW MATERIALS
- C22B3/00—Extraction of metal compounds from ores or concentrates by wet processes
- C22B3/20—Treatment or purification of solutions, e.g. obtained by leaching
- C22B3/44—Treatment or purification of solutions, e.g. obtained by leaching by chemical processes
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
본 발명은 유기 화합물의 합성에 유용하게 이용되는 아연 금속의 새로운 활성화 방법에 관한 것이다.The present invention relates to a novel method for activating zinc metals usefully used in the synthesis of organic compounds.
Description
본 발명은 리포마트스키(Reformatsky; 참조:Synthesis, 1989, 571) 또는 블레이즈(Blaise; 참조: J. Org. Chem., 1983, 48, 3833) 반응에 유용하게 이용되는 아연 금속의 새로운 활성화 방법에 관한 것이다.The present invention relates to a novel method for activating zinc metals useful for the reaction of Reformatsky (see Synthesis , 1989 , 571 ) or Blaise (see J. Org. Chem ., 1983, 48, 3833). It is about.
상업적으로 판매되는 아연 금속은 반응성이 낮기 때문에 리포마트스키 혹은 블레이즈 반응 등에 사용하기 위해서는 활성화 단계를 거친 다음 사용되어진다. 아연 금속 활성화 방법으로는 아연 금속을 불활성화시키는 산화아연을 화학적 혹은 물리적으로 제거하는 방법 혹은 아연 할라이드를 화학적으로 환원하여 미세 아연 금속을 제조하는 것을 들 수 있다. 전자의 전형적인 방법으로는 아연금속을 산수용액으로 세척한 다음 이를 여과하고 유기용매로 세척한 후 건조하여 사용하거나 (참조: Tetrahedron, Asymmetry, 1998, 9, 805; J. Org. Chem., 1983, 48, 3833) 초음파를 이용해 활성화한 예가 알려져 있다 (참조: Synthesis, 1998, 1713). 후자의 경우는 할로아연 (ZnX2)과 알칼리금속 (리튬, 칼륨 등)을 반응시켜 높은 반응성 을 갖는 리키(Rieke) 아연 금속을 제조하여 반응에 사용한 예가 알려져 있다 (참조: J. Chem. Soc. Chem. Commun., 1986, 775; J. Org. Chem., 1981, 46, 4323; Synthesis, 1975, 452).Since commercially available zinc metals have low reactivity, they are used after an activation step for lipomatsky or blaze reactions. Examples of the zinc metal activation method include chemically or physically removing zinc oxide that inactivates zinc metal, or chemically reducing zinc halide to produce fine zinc metal. A typical method of the former is to wash zinc metal with an aqueous acidic solution, which is then filtered, washed with an organic solvent and then dried (see Tetrahedron, Asymmetry , 1998 , 9 , 805; J. Org. Chem. , 1983 , 48 , 3833) Examples of activation using ultrasound are known ( Synthesis , 1998 , 1713). In the latter case, there is known an example of producing a highly reactive Rike zinc metal by reacting halo zinc (ZnX 2 ) with an alkali metal (lithium, potassium, etc.) (see J. Chem. Soc. Chem. Commun ., 1986 , 775; J. Org.Chem ., 1981 , 46 , 4323; Synthesis , 1975 , 452).
그러나 종래 사용되던 방법들은 별도의 활성화 공정을 거쳐 활성화된 아연금속을 제조한 후 이를 사용하고 있다. 이중에서도 가장 보편적으로 사용될 뿐 아니라 활성화 정도가 본 발명에 따른 방법과 유사한, 산수용액으로 처리하여 활성화시키는 방법은 아연 금속을 산수용액으로 처리한 다음 여과하고 여과된 아연 금속을 유기용매로 세척한 후 건조시키는 복잡한 공정을 거쳐야 하는 단점이 있다.However, the conventional methods are used after producing the zinc metal activated through a separate activation process. Among them, the method of activating by treating with an acid aqueous solution, which is not only the most commonly used but also the degree of activation similar to the method according to the present invention, is performed by treating zinc metal with an acid solution and then filtering and washing the filtered zinc metal with an organic solvent. There is a disadvantage of having to go through a complicated process of drying.
이에 본 발명자들은 여과, 세척, 건조와 같은 복잡한 공정을 생략하면서도 효율적인 새로운 아연 금속의 활성화 방법을 강구하기 위해 집중적인 연구를 수행하였으며, 그 결과 유기산 또는 그의 유도체를 촉매량 사용하는 방법에 의해 이러한 문제점을 해결할 수 있음을 발견하고 본 발명을 완성하게 되었다. 즉, 본 발명의 활성화 방법에 따르면 본 반응에 들어가기 이전에 미리 아연 금속을 활성화시킬 필요가 없이 본 반응과 동일 반응계에서 활성화시키므로 공정이 단순하고 간편할 뿐아니라, 매번 활성화 정도가 일정하게 유지되어 반응 수율의 재현성이 우수하고 활성화도 매우 효과적으로 달성된다. Accordingly, the present inventors have conducted intensive studies to find a new method for activating a new zinc metal while eliminating complicated processes such as filtration, washing, and drying. It has been found that this can be solved and the present invention has been completed. That is, according to the activation method of the present invention, since the activation is performed in the same reaction system as the reaction without the need to activate zinc metal before entering the reaction, the process is simple and simple, and the activation degree is kept constant every time. The reproducibility of the yield is excellent and the activation is achieved very effectively.
따라서, 본 발명은 아연 금속을 활성화시키는 새로운 방법을 제공함을 목적으로 한다.
Accordingly, the present invention aims to provide a new method of activating zinc metal.
본 발명은 반응용매중에서 아연 금속에 촉매량의 유기산 또는 그 유도체를 첨가함을 특징으로 하여 아연 금속을 활성화시키는 새로운 방법에 관한 것이다. The present invention relates to a novel method for activating zinc metal, characterized by adding a catalytic amount of an organic acid or derivative thereof to the zinc metal in the reaction solvent.
예를 들어 활성화된 아연을 사용하여야 하는 블레이즈 반응의 경우 본 발명에 따른 활성화 방법을 도입하면, 테트라하이드로푸란 용매에 아연 금속을 출발물질을 기준으로 하여 2.0 몰배량 가하고 유기산 또는 그 유도체를 촉매량 첨가한 후 환류 교반하여 아연 금속을 활성화시킨다. 이 혼합물에 출발물질로서 벤조니트릴을 가하고, 반응물질로서 에틸브로모아세테이트 1.5 몰배량을 천천히 적가(滴加)한 다음 냉각시키고, 산수용액을 이용하여 가수분해하면 3-옥소-3-페닐프로판산 에틸에스테르를 성공적으로 합성할 수 있다. 이 반응을 하기 반응식 1에 도시하여 나타내었다.For example, in the case of the blaze reaction in which activated zinc should be used, when the activation method according to the present invention is introduced, 2.0 mol of zinc metal is added to a tetrahydrofuran solvent based on the starting material, and a catalytic amount of an organic acid or a derivative thereof is added. After stirring under reflux to activate the zinc metal. Benzonitrile was added to the mixture as a starting material, and 1.5 mole volume of ethyl bromoacetate was slowly added dropwise as a reaction material, followed by cooling, followed by hydrolysis using an aqueous acid solution to form 3-oxo-3-phenylpropanoic acid. Ethyl esters can be successfully synthesized. This reaction is shown in Scheme 1 below.
동일한 반응 조건하에서 유기산 또는 그 유도체로 활성화한 아연 금속을 사용하는 경우와 활성화하지 않은 아연 금속을 사용하는 경우 각각에 대한 블레이즈 반응의 실험결과를 가스 크로마토그래피(GC)로 분석하여 하기 표 1에 나타내었다. 단, 이때 반응조건은 각각 아연 금속 2.0 몰배량, BrCH2CO2Et 1.5 몰배량, CF3SO3H 0.01 몰배량 및 반응온도 80℃이다. Under the same reaction conditions, the results of the blaze reaction for each of using an activated zinc metal and an unactivated zinc metal as an organic acid or a derivative thereof are shown in Table 1 by analyzing by gas chromatography (GC). It was. However, the reaction conditions are 2.0 mol fold of zinc metal, 1.5 mol fold of BrCH 2 CO 2 Et, 0.01 mol fold of CF 3 SO 3 H, and reaction temperature of 80 ° C., respectively.
상기 표 1의 결과로부터 알 수 있듯이, 활성화되지 않은 아연 금속을 사용한 경우 가스 크로마토그래피의 분석결과 출발물질인 벤조니트릴이 50% 잔존하는 것으로 확인되었고, 본 발명에 따라 활성화된 아연 금속을 사용한 경우에는 벤조니트릴이 100% 전환되었다.As can be seen from the results in Table 1, when the zinc metal was not activated, it was confirmed that 50% of benzonitrile, which is a starting material, remained as a result of gas chromatography analysis, and when zinc metal activated according to the present invention was used. Benzonitrile was 100% converted.
한편, 리포마트스키 반응의 경우 본 발명에 따른 활성화 방법을 도입하면, 벤젠 용매에 아연 금속을 출발물질을 기준으로 하여 1.5 몰배량 가하고 유기산 또는 그 유도체를 촉매량 첨가한 후 환류 교반하여 아연 금속을 활성화시킨다. 이 혼합물에 출발물질로서 벤즈알데히드와 반응물질로서 에틸브로모아세테이트 1.3 몰배량을 혼합하여 천천히 적가(滴加)한 다음 냉각시키고, 산수용액을 이용하여 가수분해하면 3-하이드록시-3-페닐프로판산 에틸에스테르를 성공적으로 합성할 수 있다. 이 반응을 하기 반응식 2에 도시하여 나타내었다.On the other hand, in the case of lipomatsky reaction, when the activation method according to the present invention is introduced, 1.5 mol times of zinc metal is added to the benzene solvent based on the starting material, and a catalytic amount of an organic acid or its derivative is added, followed by stirring under reflux to activate the zinc metal. Let's do it. Benzaldehyde as a starting material and 1.3 mole volume of ethyl bromoacetate as a reactant were mixed in this mixture, slowly added dropwise, cooled, and hydrolyzed with an aqueous acid solution to give 3-hydroxy-3-phenylpropanoic acid. Ethyl esters can be successfully synthesized. This reaction is shown in Scheme 2 below.
동일한 반응 조건하에서 유기산 또는 그 유도체로 활성화한 아연 금속을 사용하는 경우와 활성화하지 않은 아연 금속을 사용하는 경우 각각에 대한 리포마 트스키 반응의 실험결과를 가스 크로마토그래피(GC)로 분석하여 하기 표 2에 나타내었다. 단, 이때 반응조건은 각각 아연 금속 1.5 몰배량, BrCH2CO2Et 1.3 몰배량, CF3SO3H 0.01 몰배량 및 반응온도 80 ℃이다. Under the same reaction conditions, the results of lipomatsky reactions for the case of using zinc metal activated with an organic acid or a derivative thereof and the use of non-activated zinc metal were analyzed by gas chromatography (GC). 2 is shown. However, the reaction conditions are 1.5 mol times of zinc metal, 1.3 mol times of BrCH 2 CO 2 Et, 0.01 mol times of CF 3 SO 3 H, and a reaction temperature of 80 ° C., respectively.
상기 표 2의 결과로부터 알 수 있듯이, 활성화되지 않은 아연 금속을 사용한 경우 가스 크로마토그래피의 분석결과 출발물질인 벤즈알데히드가 20% 잔존하는 것으로 확인되었고, 본 발명에 따라 활성화된 아연 금속을 사용한 경우에는 벤즈알데히드가 100% 전환되었다.As can be seen from the results of Table 2, when the zinc metal was not activated, it was confirmed that 20% of benzaldehyde, which is a starting material, remained as a result of gas chromatography analysis, and benzaldehyde was used when the zinc metal activated according to the present invention was used. Was converted to 100%.
본 발명에 따른 아연 금속의 활성화 방법에서 용매로는 테트라하이드로푸란, 벤젠, 톨루엔 및 에테르 중에서 선택된 1종 이상을 사용할 수 있으며, 순도 및 수율 면에서 가장 바람직하게는 벤젠 또는 테트라하이드로푸란을 사용한다. 아연 금속으로는 dust 또는 powder 형태의 아연 금속을 바람직하게 사용하며, 활성화시 바람직한 반응 온도는 20 내지 120 ℃의 범위이다. 아연 금속을 활성화시키기 위하여 첨가하는 유기산 또는 그 유도체로는 RCO2H, RSO3H, RCO2Si(CH3)3, RSO3Si(CH3)3 및 (RSO3)2NH (여기서 R은 수소, 할로겐에 의해 치환되거나 비치환된 탄소수 1 내지 6의 포화 또는 불포화 알킬, 또는 할로겐에 의해 치환되거나 비치환된 탄소수 6 내지 12의 아릴을 나타낸다)로 구성된 그룹에서 선택된 1종 이상을 사용하는 것이 바람직하고, 아연 금속을 기준으로 하여 0.001 내지 0.2 몰배량의 촉매량을 사용하는 것이 바람직하다. In the method for activating the zinc metal according to the present invention, at least one selected from tetrahydrofuran, benzene, toluene and ether may be used, and in terms of purity and yield, benzene or tetrahydrofuran is most preferably used. As the zinc metal, zinc metal in dust or powder form is preferably used, and a preferable reaction temperature upon activation is in the range of 20 to 120 ° C. The organic acid or derivative thereof added to activate the zinc metal includes RCO 2 H, RSO 3 H, RCO 2 Si (CH 3 ) 3 , RSO 3 Si (CH 3 ) 3 and (RSO 3 ) 2 NH, where R is Using at least one selected from the group consisting of hydrogen, saturated or unsaturated alkyl of 1 to 6 carbon atoms unsubstituted or substituted by halogen, or aryl of 6 to 12 carbon atoms unsubstituted or substituted by halogen). It is preferable to use a catalytic amount of 0.001 to 0.2 molar amount based on the zinc metal.
상기 설명한 방법에 따라 활성화한 아연 금속을 리포마트스키 또는 블레이즈 반응과 같이 활성화된 아연 금속을 필요로 하는 방법에 적용한 결과, 반응을 위한 유도기간(Induction period)이 필요 없이 반응물질인 알파-할로에스테르를 적가(滴加)함과 동시에 반응이 진행되었다. 즉, 본 발명에 따라 아연 금속의 안정적인 활성화와 제조공정의 단순화에 따른 생산시간의 감소, 생산성의 향상, 수율 증가 및 원가 절감 등의 개선이 이룩되었다. As a result of applying the zinc metal activated according to the method described above to a method requiring activated zinc metal such as Lipomartsky or Blaze reaction, the reaction material alpha-haloester is not required without the induction period for the reaction. At the same time, the reaction proceeded. That is, according to the present invention has been achieved to reduce the production time, increase the productivity, increase the yield and reduce the cost of the stable activation of the zinc metal and simplify the manufacturing process.
이하, 본 발명을 하기 실시예에 의거하여 보다 구체적으로 설명한다. 그러나 이들 실시예는 본 발명에 대한 이해를 돕기 위한 것일 뿐, 어떤 의미로든 본 발명의 범위가 이들 실시예로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples. However, these examples are only to aid the understanding of the present invention, and the scope of the present invention in any sense is not limited to these examples.
실시예 1: 3-옥소-3-페닐프로판산 에틸에스테르의 제조Example 1: Preparation of 3-oxo-3-phenylpropanoic acid ethyl ester
아연 금속(Zinc dust) 1.23 g에 테트라하이드로푸란 5.0 ㎖와 메탄술폰산 10 mg을 넣고 환류 교반하였다. 환류 교반이 이루어지면 벤조니트릴 1.00 g을 가하고, 에틸브로모아세테이트 2.43 g을 1 시간에 걸쳐 적가(滴加)한 다음, 30 분간 더 환류 교반하고 상온으로 냉각시켰다. 반응용기를 0 내지 5 ℃로 냉각시키고, 6 N 염산 4.5 ㎖를 가하여 서서히 상온으로 승온시킨 다음, 2 시간 교반하여 가수분해 반응을 진행시켰다. 박막크로마토그래피(TLC, thin-layer chromatography)로 반응완결을 확인한 후 에틸아세테이트로 추출한 유기층을 탄산나트륨 수용액으로 세척한 다음 감압 증류하여 용매를 제거하였다. 이렇게 얻어진 혼합물을 실리카겔 칼럼 크로마토그래피(용리액: 에틸아세테이트/노말헥산= 1/10, v/v)로 분리하여 표제화합물을 75% (1.39 g) 수율로 수득하였다. 5.0 ml of tetrahydrofuran and 10 mg of methanesulfonic acid were added to 1.23 g of zinc dust, and the mixture was stirred under reflux. When reflux stirring was performed, 1.00 g of benzonitrile was added, and 2.43 g of ethyl bromoacetate was added dropwise over 1 hour, followed by further reflux stirring for 30 minutes, followed by cooling to room temperature. The reaction vessel was cooled to 0 to 5 ° C., 4.5 ml of 6 N hydrochloric acid was added thereto, and the temperature was gradually raised to room temperature, followed by stirring for 2 hours to proceed with the hydrolysis reaction. After confirming the completion of the reaction by thin-layer chromatography (TLC), the organic layer extracted with ethyl acetate was washed with an aqueous sodium carbonate solution and then distilled under reduced pressure to remove the solvent. The mixture thus obtained was separated by silica gel column chromatography (eluent: ethyl acetate / normal hexane = 1/10, v / v) to give the title compound in 75% (1.39 g) yield.
1H NMR (400MHz, CDCl3) δ 1 H NMR (400 MHz, CDCl 3 ) δ
에놀 형태 (Enol Form) (20%): 12.59 (bs, 1H), 7.97~7.38 (m, 5H), 5.68 (s, 1H), 4.28 (q, J= 7.2Hz, 2H), 1.35 (t, J= 7.2Hz, 3H)Enol Form (20%): 12.59 (bs, 1H), 7.97 ~ 7.38 (m, 5H), 5.68 (s, 1H), 4.28 (q, J = 7.2 Hz , 2H), 1.35 (t, J = 7.2 Hz , 3H)
케토 형태 (Keto Form) (80%): 7.97~7.38 (m, 5H), 4.22 (q, J=7.2Hz, 2H), 4.00 (s, 2H), 1.27 (t, J=7.2Hz, 3H)Keto Form (80%): 7.97 ~ 7.38 (m, 5H), 4.22 (q, J = 7.2Hz , 2H), 4.00 (s, 2H), 1.27 (t, J = 7.2Hz , 3H)
Mass (EI, m/z): 192 (M+), 147 (M-OEt), 105 (M-CH 2 CO 2 Et)Mass (EI, m / z): 192 (M + ), 147 (M- OEt ), 105 (M- CH 2 CO 2 Et )
실시예 2: 3-하이드록시-3-페닐프로판산 에틸에스테르의 제조 (유기산: 메탄술폰산)Example 2: Preparation of 3-hydroxy-3-phenylpropanoic acid ethyl ester (organic acid: methanesulfonic acid)
아연 금속 (Zinc dust) 1.23 g에 벤젠 5.0 ㎖와 메탄술폰산 9 mg을 넣고 환류 교반하였다. 환류 교반이 이루어지면 벤즈알데히드 1.00 g과 에틸브로모아세테이트 2.36 g를 혼합하여 1 시간에 걸쳐 적가(滴加)한 다음, 30 분간 더 환류 교반하고 상온으로 냉각시켰다. 반응용기를 0 내지 5 ℃로 냉각시키고, 6 N 염산 2.5 ㎖를 가하여 서서히 상온으로 승온시킨 다음, 0.5 시간 교반하여 반응을 진행시켰다. 박막크로마토그래피(TLC, thin-layer chromatography)로 반응완결을 확인한 후 에틸아세테이트로 추출한 유기층을 탄산나트륨 수용액으로 세척하고 감압 증류하여 용매를 제거하였다. 이렇게 얻어진 혼합물을 실리카겔 칼럼 크로마토그래피(용리액: 에틸아세테이트/노말헥산=1/10, v/v)로 분리하여 표제화합물을 79% (1.44 g) 수율로 수득하였다. 5.0 ml of benzene and 9 mg of methanesulfonic acid were added to 1.23 g of zinc dust, and the mixture was stirred under reflux. When reflux stirring was performed, 1.00 g of benzaldehyde and 2.36 g of ethyl bromoacetate were mixed and added dropwise over 1 hour, followed by further reflux stirring for 30 minutes and cooling to room temperature. The reaction vessel was cooled to 0 to 5 ° C., 2.5 ml of 6 N hydrochloric acid was added thereto, and gradually warmed to room temperature, followed by stirring for 0.5 hour. After completion of the reaction by thin layer chromatography (TLC), the organic layer extracted with ethyl acetate was washed with aqueous sodium carbonate solution and distilled under reduced pressure to remove the solvent. The mixture thus obtained was separated by silica gel column chromatography (eluent: ethyl acetate / normal hexane = 1/10, v / v) to give the title compound in a yield of 79% (1.44 g).
1H NMR (400MHz, CDCl3) δ 7.33~7.19 (m, 5H), 5.07 (t, J=4.4Hz, 1H), 4.11 (q, J=7.2Hz, 2H), 3.21 (bs, 1H), 2.66 (m, 2H), 1.20 (t, J=7.2Hz, 3H) 1 H NMR (400 MHz, CDCl 3 ) δ 7.33-7.19 (m, 5H), 5.07 (t, J = 4.4 Hz , 1H), 4.11 (q, J = 7.2 Hz , 2H), 3.21 (bs, 1H), 2.66 (m, 2H), 1.20 (t, J = 7.2 Hz , 3H)
Mass (EI, m/z): 194 (M+), 149 (M-OEt), 107 (M-CH 2 CO 2 Et)Mass (EI, m / z): 194 (M + ), 149 (M- OEt ), 107 (M- CH 2 CO 2 Et )
실시예 3: 3-하이드록시-3-페닐프로판산 에틸에스테르의 제조 (유기산: 트리플루오로메탄술폰산)Example 3: Preparation of 3-hydroxy-3-phenylpropanoic acid ethyl ester (organic acid: trifluoromethanesulfonic acid)
아연 금속 (Zinc dust) 1.23g에 벤젠 5.0 ㎖와 트리플루오로메탄술폰산 12 mg을 넣고 환류 교반하였다. 환류 교반이 이루어지면 벤즈알데히드 1.00 g과 에틸브로모아세테이트 2.36 g를 혼합하여 1시간에 걸쳐 적가(滴加)한 다음, 30 분간 더 환류 교반하고 상온으로 냉각시켰다. 반응용기를 0 내지 5 ℃로 냉각시키고, 6 N 염산 2.5 ㎖를 가하여 서서히 상온으로 승온시킨 다음, 0.5 시간 교반하여 반응을 진행시켰다. 박막크로마토그래피(TLC, thin-layer chromatography)로 반응완결을 확인한 후 에틸아세테이트로 추출한 유기층을 탄산나트륨 수용액으로 세척하고 감압 증류하여 용매를 제거하였다. 이렇게 얻어진 혼합물을 실리카겔 칼럼 크로마토그래피(용리액: 에틸아세테이트/노말헥산=1/10, v/v)로 분리하여 표제화합물을 80% (1.46 g) 수율로 수득하였다. 5.0 ml of benzene and 12 mg of trifluoromethanesulfonic acid were added to 1.23 g of zinc dust, and the mixture was stirred under reflux. When reflux stirring was performed, 1.00 g of benzaldehyde and 2.36 g of ethyl bromoacetate were mixed and added dropwise over 1 hour, followed by further reflux stirring for 30 minutes and cooling to room temperature. The reaction vessel was cooled to 0 to 5 ° C., 2.5 ml of 6 N hydrochloric acid was added thereto, and gradually warmed to room temperature, followed by stirring for 0.5 hour. After completion of the reaction by thin layer chromatography (TLC), the organic layer extracted with ethyl acetate was washed with aqueous sodium carbonate solution and distilled under reduced pressure to remove the solvent. The mixture thus obtained was separated by silica gel column chromatography (eluent: ethyl acetate / normal hexane = 1/10, v / v) to give the title compound in 80% (1.46 g) yield.
실시예 4: 3-하이드록시-3-페닐프로판산 에틸에스테르의 제조 (유기산: 트리플루오로메탄술폰이미드)Example 4: Preparation of 3-hydroxy-3-phenylpropanoic acid ethyl ester (organic acid: trifluoromethanesulfonimide)
아연 금속 (Zinc dust) 1.23 g에 벤젠 5.0 ㎖와 트리플루오로메탄술폰이미드 20 mg을 넣고 환류 교반하였다. 환류 교반이 이루어지면 벤즈알데히드 1.00 g과 에틸브로모아세테이트 2.36 g를 혼합하여 1 시간에 걸쳐 적가(滴加)한 다음, 30 분간 더 환류 교반하고 상온으로 냉각시켰다. 반응용기를 0 내지 5 ℃로 냉각시키고, 6 N 염산 2.5 ㎖를 가하여 서서히 상온으로 승온시킨 다음, 0.5 시간 교반하여 반응을 진행시켰다. 박막크로마토그래피(TLC, thin-layer chromatography)로 반응완결을 확인한 후 에틸아세테이트로 추출한 유기층을 탄산나트륨 수용액으로 세척하고 감압 증류하여 용매를 제거하였다. 이렇게 얻어진 혼합물을 실리카겔 칼럼 크로마토그래피(용리액: 에틸아세테이트/노말헥산=1/10, v/v)로 분리하여 표제화합물을 79% (1.45 g) 수율로 수득하였다. 5.0 ml of benzene and 20 mg of trifluoromethanesulfonimide were added to 1.23 g of zinc dust, and the mixture was stirred under reflux. When reflux stirring was performed, 1.00 g of benzaldehyde and 2.36 g of ethyl bromoacetate were mixed and added dropwise over 1 hour, followed by further reflux stirring for 30 minutes and cooling to room temperature. The reaction vessel was cooled to 0 to 5 ° C., 2.5 ml of 6 N hydrochloric acid was added thereto, and gradually warmed to room temperature, followed by stirring for 0.5 hour. After completion of the reaction by thin layer chromatography (TLC), the organic layer extracted with ethyl acetate was washed with aqueous sodium carbonate solution and distilled under reduced pressure to remove the solvent. The resulting mixture was separated by silica gel column chromatography (eluent: ethyl acetate / normal hexane = 1/10, v / v) to give the title compound in 79% (1.45 g) yield.
실시예 5: 3-하이드록시-노난산 에틸에스테르의 제조Example 5: Preparation of 3-hydroxy-nonanoic acid ethyl ester
아연 금속 (Zinc dust) 1.15 g에 벤젠 5.0 ㎖와 트리플루오로메탄술폰산 10 mg을 넣고 환류 교반하였다. 환류 교반이 이루어지면 헵탄알(헵타알데히드) 1.00 g과 에틸브로모아세테이트 2.19 g를 혼합하여 1 시간에 걸쳐 적가(滴加)한 다음, 30 분간 더 환류 교반하고 상온으로 냉각시켰다. 반응용기를 0 내지 5 ℃로 냉각시키고, 6 N 염산 2.0 ㎖를 가하여 서서히 상온으로 승온시킨 다음, 0.5 시간 교반하여 반응을 진행시켰다. 박막크로마토그래피(TLC, thin-layer chromatography)로 반응완결을 확인한 후 에틸아세테이트로 추출한 유기층을 탄산나트륨 수용액으로 세척하고 감압 증류하여 용매를 제거하였다. 이렇게 얻어진 혼합물을 실리카겔 칼럼 크로마토그래피(용리액: 에틸아세테이트/노말헥산= 1/10, v/v)로 분리하여 표제화합물을 78% (1.38 g) 수율로 수득하였다. 5.0 ml of benzene and 10 mg of trifluoromethanesulfonic acid were added to 1.15 g of zinc dust, and the mixture was stirred under reflux. When reflux stirring was performed, 1.00 g of heptane (heptaaldehyde) and 2.19 g of ethyl bromoacetate were mixed and added dropwise over 1 hour, followed by further reflux stirring for 30 minutes, and then cooled to room temperature. The reaction vessel was cooled to 0 to 5 ° C., 2.0 ml of 6 N hydrochloric acid was added thereto, and the temperature was gradually raised to room temperature, followed by stirring for 0.5 hours. After completion of the reaction by thin layer chromatography (TLC), the organic layer extracted with ethyl acetate was washed with aqueous sodium carbonate solution and distilled under reduced pressure to remove the solvent. The mixture thus obtained was separated by silica gel column chromatography (eluent: ethyl acetate / normal hexane = 1/10, v / v) to give the title compound in 78% (1.38 g) yield.
1H NMR (400MHz, CDCl3) δ 4.18 (q, J=7.2Hz, 2H), 4.00 (m, 1H), 2.96 (bs, 1H), 2.51 (dd, J=16.4, 3.2Hz, 1H), 2.40 (dd, J=16.4, 9.2Hz, 1H), 1.42~1.29 (m, 10H), 1.28 (t, J=7.2Hz, 3H), 0.89 (t, J=7.2Hz, 3H) 1 H NMR (400 MHz, CDCl 3 ) δ 4.18 (q, J = 7.2 Hz , 2H), 4.00 (m, 1H), 2.96 (bs, 1H), 2.51 (dd, J = 16.4, 3.2 Hz , 1H), 2.40 (dd, J = 16.4, 9.2Hz , 1H), 1.42 ~ 1.29 (m, 10H), 1.28 (t, J = 7.2Hz , 3H), 0.89 (t, J = 7.2Hz , 3H)
Mass (EI, m/z): 157 (M-OEt), 117 (M+H 2 -CH 2 CO 2 Et)Mass (EI, m / z): 157 (M- OEt ), 117 (M + H 2 -CH 2 CO 2 Et )
앞에서 설명한 바와 같이, 본 발명에 따라 촉매량의 유기산 또는 그 유도 체를 이용하여 아연 금속을 활성화시킴으로써, 활성화된 아연 금속을 이용하는 반응에서 본 반응에 들어가기 이전에 미리 아연 금속을 활성화시킬 필요가 없이 본 반응과 동일 반응계에서 활성화시키므로 공정이 단순하고 간편할 뿐아니라, 매번 활성화 정도가 일정하게 유지되어 반응 수율의 재현성이 우수하고 활성화도 매우 효과적으로 달성되는 개선된 효과를 얻을 수 있다. As described above, according to the present invention, by activating the zinc metal using a catalytic amount of an organic acid or a derivative thereof, in the reaction using the activated zinc metal, there is no need to activate the zinc metal before entering the present reaction. Since it is activated in the same reaction system, the process is not only simple and simple, but also maintains a constant degree of activation every time. Thus, an improved effect of excellent reproducibility of reaction yield and very effective activation can be obtained.
Claims (6)
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| JPS6119707A (en) * | 1984-07-05 | 1986-01-28 | Agency Of Ind Science & Technol | Preparation of highly reactive metal powder |
| US5964919A (en) * | 1992-02-04 | 1999-10-12 | Board Of Regents Of The University Of Nebraska | Method of storing active zero valent zinc metal |
| JP2003112045A (en) * | 2001-10-03 | 2003-04-15 | Sumika Fine Chemicals Co Ltd | Activated zinc, its use, method for preparing the same and method for preparing ethyl 3-hydroxy-3-(2- phenylethyl)hexanoate using the same |
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| JPS6119707A (en) * | 1984-07-05 | 1986-01-28 | Agency Of Ind Science & Technol | Preparation of highly reactive metal powder |
| US5964919A (en) * | 1992-02-04 | 1999-10-12 | Board Of Regents Of The University Of Nebraska | Method of storing active zero valent zinc metal |
| JP2003112045A (en) * | 2001-10-03 | 2003-04-15 | Sumika Fine Chemicals Co Ltd | Activated zinc, its use, method for preparing the same and method for preparing ethyl 3-hydroxy-3-(2- phenylethyl)hexanoate using the same |
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