KR100408375B1 - Separation method of 4-cyanomethylimidazole - Google Patents
Separation method of 4-cyanomethylimidazole Download PDFInfo
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- KR100408375B1 KR100408375B1 KR10-1998-0033692A KR19980033692A KR100408375B1 KR 100408375 B1 KR100408375 B1 KR 100408375B1 KR 19980033692 A KR19980033692 A KR 19980033692A KR 100408375 B1 KR100408375 B1 KR 100408375B1
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- cyanomethylimidazole
- activated carbon
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/004—Fractional crystallisation; Fractionating or rectifying columns
- B01D9/0045—Washing of crystals, e.g. in wash columns
Abstract
본 발명은 4-시아노메칠이미다졸 수용액에 흡착제를 가하여 4-시아노메칠이미다졸을 흡착하여 분리한 다음, 유기용매로 4-시아노메칠이미다졸을 용출시켜 재결정하는 것을 특징으로 하는 4-시아노메칠이미다졸의 분리방법에 관한 것이다.The present invention is characterized by adsorbing and separating 4-cyanomethylimidazole by adding an adsorbent to an aqueous 4-cyanomethylimidazole solution, and then recrystallizing 4-cyanomethylimidazole with an organic solvent. It relates to a method for separating 4-cyanomethylimidazole.
Description
본 발명은 4-시아노메칠이미다졸의 분리방법에 관한 것으로, 더욱 상세하게는 4-시아노메칠이미다졸 수용액에 흡착제를 가하여 4-시아노메칠이미다졸을 흡착하여 분리한 다음, 유기용매로 4-시아노메칠이미다졸을 용출시켜 재결정하는 것을 특징으로 하는 4-시아노메칠이미다졸의 분리방법에 관한 것이다.The present invention relates to a method for separating 4-cyanomethylimidazole, and more particularly, 4-cyanomethylimidazole is adsorbed and separated by adding an adsorbent to 4-cyanomethylimidazole aqueous solution. The present invention relates to a method for separating 4-cyanomethylimidazole, which is characterized by eluting 4-cyanomethylimidazole with an organic solvent.
4-시아노메칠이미다졸은 항고혈압제, 항암제 및 항히스타민제 등과 같은 의약품의 제조시 중간체로 사용되는 물질로서, 종래에는 L-히스티딘에 클로라민-T 또는 차아염소산나트륨 수용액등의 산화제를 가하여 산화시킨 다음, 탈탄산 과정을 거쳐 합성하고 있으며(J. Appl. Chem., 1969, 19, 83), 이를 반응식으로 표시하면 다음과 같다.4-cyanomethylimidazole is a substance used as an intermediate in the manufacture of medicines such as antihypertensives, anticancers and antihistamines, and is conventionally oxidized by adding oxidizing agents such as chloramine-T or aqueous sodium hypochlorite to L-histidine. Next, it is synthesized through a decarbonation process (J. Appl. Chem., 1969, 19, 83), which is represented by the following reaction scheme.
한편, 상기의 제조방법에 의하여 4-시아노메칠이미다졸을 제조할 지라도, 4-시아노메칠이미다졸을 수용액중에서 추출하기 위한 적절한 유기용매가 공지되어 있지 않기 때문에, 종래에는 4-시아노메칠이미다졸을 분리하기 위하여 (1) 반응완료후 반응용액(수용액)을 농축하여 조상고체로 제조한 다음, (2) 쏙스렛(Soxhlet) 장치등의 특수한 추출장치에서 에틸아세테이트를 이용하여 2일이상 환류시켜 4-시아노메칠이미다졸을 분리하였다.On the other hand, even if 4-cyanomethylimidazole is prepared by the above production method, since an appropriate organic solvent for extracting 4-cyanomethylimidazole in an aqueous solution is not known, 4-cyanomethylimidazole is conventionally used. To separate nomethylimidazole (1) After completion of the reaction, the reaction solution (aqueous solution) is concentrated and prepared as a solid, and (2) Ethyl acetate is used in a special extraction device such as a Soxhlet device. It was refluxed for 2 days or more to separate 4-cyanomethylimidazole.
따라서 종래의 분리방법은 수용액농축 및 쏙스렛추출과정을 반드시 거쳐야하기 때문에 매우 높은 비용이 소모되어 공업적인 이용이 매우 곤란한 문제점이 있다. 즉, L-히스티딘에 산화제로서 차아염소산나트륨 수용액을 반응시켜 4-시아노메칠이미다졸을 제조할 경우 반응용액중 4-시아노메칠이미다졸의 농도가 매우 낮기(1 - 2%) 때문에 과량의 물을 농축하여야 하고 쏙스렛추출과정도 2일이상의 환류가온이 필요하기 때문에 매우 높은 비용이 소모되게 된다.Therefore, the conventional separation method has a problem that it is very difficult to use industrially because the high cost is consumed because it must go through the aqueous solution concentration and choplet extraction process. That is, when 4-cyanomethylimidazole is prepared by reacting L-histidine with an aqueous sodium hypochlorite solution as an oxidizing agent, the concentration of 4-cyanomethylimidazole in the reaction solution is very low (1-2%). Excess water has to be concentrated and the choplet extraction process requires more than two days of reflux heating, which is very expensive.
이에 본 발병자들은 L-히스티딘으로부터 산화-탈탄산 공정을 거쳐 제조한 4-시아노메칠이미다졸을 손쉬운 조작에 의해 낮은 비용으로 분리할 수 있는 방법을 개발하고자 연구를 거듭한 결과, 종래의 방법으로 제조한 4-시아노메칠이미다졸 수용액에 흡착제를 가하여 4-시아노메칠이미다졸을 흡착하여 분리한 다음, 유기용매로 4-시아노메칠이미다졸을 용출시켜 재결정했을 때, 낮은 비용으로 4-시아노메칠이미다졸을 분리할 수 있다는 것을 발견하여 본 발명을 완성하게 되었다.Accordingly, the present inventors have studied to develop a method for separating 4-cyanomethylimidazole prepared from L-histidine through an oxidation-decarbonic acid process at low cost by an easy operation. 4-cyanomethylimidazole was prepared by adding an adsorbent to the aqueous solution of 4-cyanomethylimidazole, and then adsorbing and separating 4-cyanomethylimidazole. The discovery of being able to separate 4-cyanomethylimidazole at cost has led to the completion of the present invention.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 4-시아노메칠이미다졸 수용액에 흡착제를 가하여 4-시아노메칠이미다졸을 흡착하여 분리한 다음, 유기용매로 4-시아노메칠이미다졸을 용출시켜 재결정하는 것을 특징으로 하는 4-시아노메칠이미다졸의 분리방법을 제공하는 것을 목적으로 한다.The present invention is characterized by adsorbing and separating 4-cyanomethylimidazole by adding an adsorbent to an aqueous 4-cyanomethylimidazole solution, and then recrystallizing 4-cyanomethylimidazole with an organic solvent. An object of the present invention is to provide a method for separating 4-cyanomethylimidazole.
이하, 본 발명을 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 분리방법에서 특징적으로 사용하는 흡착제로는 통상적으로 사용되는 흡착제를 사용할 수 있으며 그 예를들면, 분말상 활성탄 또는 Amberlite, XAD-4?(Rohm ＆ Haas, Sigma) 등의 비극성 흡착수지를 사용할 수 있으며, 이중 표면적과 흡착력을 고려할 때 분말상의 활성탄이 더욱 바람직하다.As the adsorbent characteristically used in the separation method of the present invention, a conventionally used adsorbent may be used. For example, powdered activated carbon or Amberlite, XAD-4 ? Non-polar adsorption resins such as (Rohm & Haas, Sigma) can be used, and powdered activated carbon is more preferable in consideration of double surface area and adsorption power.
또한, 본 발명의 분리방법에 있어서, 4-시아노메칠이미다졸 수용액의 pH는 염기성일 경우 불순물을 제거하는데 적절하므로, 탄산수소나트륨등의 알칼리화제를 가하여 4-시아노메칠이미다졸 수용액의 pH를 염기성으로 한 후, 흡착제를 가하는 것이 바람직하다.In addition, in the separation method of the present invention, since the pH of the 4-cyanomethylimidazole aqueous solution is suitable for removing impurities when it is basic, 4-cyanomethylimidazole aqueous solution is added by adding an alkalizing agent such as sodium hydrogen carbonate. It is preferable to make the pH of basic, and to add an adsorbent.
흡착제로부터 4-시아노메칠이미다졸을 용출시키기 위한 유기용매로는 4-시아노메칠이미다졸을 용해시킬 수 있는 공지의 유기용매를 사용할 수 있으며 그 예를들면, 메틸알콜, 에틸알콜, 아세톤 등이 사용가능하다. 또한, 재결정시 사용가능한 용매로는 아세토니트릴 등의 4-시아노메칠이미다졸을 용해시키지 않는 통상의 유기용매를 사용할 수 있다.As the organic solvent for eluting 4-cyanomethylimidazole from the adsorbent, a known organic solvent capable of dissolving 4-cyanomethylimidazole can be used. For example, methyl alcohol, ethyl alcohol, Acetone and the like can be used. Moreover, as a solvent which can be used for recrystallization, the usual organic solvent which does not dissolve 4-cyanomethylimidazole, such as acetonitrile, can be used.
상기와 같은 본 발명에 따라 4-시아노메칠이미다졸을 분리했을 경우, 하기 실시예에서 확인할 수 있는 바와 같이, 간단한 흡착-재결정 공정에 의하여 낮은 비용으로 4-시아노메칠이미다졸을 분리할 수 있으며 또한, 흡착과정에서 미반응물질을 포함한 부반응물질이 제거되어 높은 순도의 4-시아노메칠이미다졸을 손쉽게 분리할 수 있다.When 4-cyanomethylimidazole is separated according to the present invention as described above, 4-cyanomethylimidazole is separated at low cost by a simple adsorption-recrystallization process, as can be seen in the following examples. In addition, the side reactions including the unreacted substances are removed in the adsorption process, so that high-purity 4-cyanomethylimidazole can be easily separated.
이하, 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나 이것이 본 발명의 범위를 제한하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, this does not limit the scope of the present invention.
[실시예 1]Example 1
L-히스티딘(78 g)을 증류수(50 mL)에 현탁한 후, 농염산(1당량)을 용해시킨 다음, 격렬히 교반하면서 5% 소디움하이포클로라이트 수용액 (1540 mL)를 서서히 가한 후, 실온에서 12시간동안 방치하였다. 이 반응액에 분말상의 활성탄 (150 g)을 가하여 10분간 교반한 후, 활성탄을 여과하여 증류수(100 mL)로 세척하였다. 활성탄을 메칠알콜(500 mL)에 현탁하여 10분간 교반한 후, 여과하여 메칠알코올층을 농축하였다. 이때 얻어진 잔사를 아세토니트릴(300 mL)로 재결정하여 4-시아노메칠이미다졸(35 g)을 얻었다.L-histidine (78 g) was suspended in distilled water (50 mL), then dissolved in concentrated hydrochloric acid (1 equiv), then slowly added 5% aqueous sodium hypochlorite solution (1540 mL) with vigorous stirring, followed by room temperature It was left for 12 hours. Powdered activated carbon (150 g) was added to the reaction solution, the mixture was stirred for 10 minutes, and the activated carbon was filtered and washed with distilled water (100 mL). Activated carbon was suspended in methyl alcohol (500 mL), stirred for 10 minutes, and then filtered to concentrate the methyl alcohol layer. The obtained residue was recrystallized from acetonitrile (300 mL) to obtain 4-cyanomethylimidazole (35 g).
융점 ; 135∼138 ℃Melting point; 135 to 138 ° C
1H NMR (DMSO-d6) δ3.9(s,1H), 7.1(s,1H), 7.7(s,1H), 12.2(brs,1H) 1 H NMR (DMSO-d 6 ) δ3.9 (s, 1H), 7.1 (s, 1H), 7.7 (s, 1H), 12.2 (brs, 1H)
[실시예 2]Example 2
L-히스티딘(78 g)을 증류수(50 mL)에 현탁한 후, 농염산(1당량)을 용해시킨 다음, 격렬히 교반하면서 5% 소디움하이포클로라이트 수용액 (1540 mL)를 서서히 가한 후, 실온에서 12시간동안 방치하였다. 이 반응액에 탄산수소나트륨을 가하여 pH를 8로 조정한 후, 분말상의 활성탄 (150 g)을 가하여 10분간 교반한 후, 활성탄을 여과하여 증류수(100 mL)로 세척하였다. 활성탄을 메칠알콜(500 mL)에 현탁하여 10분간 교반한 후, 여과하여 메칠알코올층을 농축하였다. 이때 얻어진 잔사를 아세토니트릴(300 mL)로 재결정하여 4-시아노메칠이미다졸(40 g)을 얻었다.L-histidine (78 g) was suspended in distilled water (50 mL), then dissolved in concentrated hydrochloric acid (1 equiv), then slowly added 5% aqueous sodium hypochlorite solution (1540 mL) with vigorous stirring, followed by room temperature It was left for 12 hours. Sodium hydrogen carbonate was added to the reaction solution to adjust the pH to 8. The powdered activated carbon (150 g) was added thereto, stirred for 10 minutes, and the activated carbon was filtered and washed with distilled water (100 mL). Activated carbon was suspended in methyl alcohol (500 mL), stirred for 10 minutes, and then filtered to concentrate the methyl alcohol layer. The obtained residue was recrystallized from acetonitrile (300 mL) to obtain 4-cyanomethylimidazole (40 g).
[실시예 3]Example 3
L-히스티딘(78 g)을 증류수(50 mL)에 현탁한 후, 농염산(1당량)을 용해시킨 다음, 격렬히 교반하면서 5% 소디움하이포클로라이트 수용액 (1540 mL)를 서서히 가한 후, 실온에서 12시간, -20℃에서 12시간동안 방치한 후, 불용성 물질을 여과하여 제거하였다. 이 반응액에 분말상의 활성탄 (150 g)을 가하여 10분간 교반한 후, 활성탄을 여과하여 증류수(100 mL)로 세척하였다. 활성탄을 메칠알콜(500 mL)에 현탁하여 10분간 교반한 후, 여과하여 메칠알코올층을 농축하였다. 이때 얻어진 잔사를 아세토니트릴(300 mL)로 재결정하여 4-시아노메칠이미다졸(35 g)을 얻었다.L-histidine (78 g) was suspended in distilled water (50 mL), then dissolved in concentrated hydrochloric acid (1 equiv), then slowly added 5% aqueous sodium hypochlorite solution (1540 mL) with vigorous stirring, followed by room temperature After 12 hours of incubation at −20 ° C. for 12 hours, the insoluble material was filtered off. Powdered activated carbon (150 g) was added to the reaction solution, the mixture was stirred for 10 minutes, and the activated carbon was filtered and washed with distilled water (100 mL). Activated carbon was suspended in methyl alcohol (500 mL), stirred for 10 minutes, and then filtered to concentrate the methyl alcohol layer. The obtained residue was recrystallized from acetonitrile (300 mL) to obtain 4-cyanomethylimidazole (35 g).
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| KR19980032014A (en) * | 1995-12-20 | 1998-07-25 | 고사이아키오 | Method for preparing imidazole derivative |
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| KR19980032014A (en) * | 1995-12-20 | 1998-07-25 | 고사이아키오 | Method for preparing imidazole derivative |
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