KR890000194B1 - Process for the preparation of l-phenyl alaine ester - Google Patents
Process for the preparation of l-phenyl alaine ester Download PDFInfo
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- KR890000194B1 KR890000194B1 KR1019850005828A KR850005828A KR890000194B1 KR 890000194 B1 KR890000194 B1 KR 890000194B1 KR 1019850005828 A KR1019850005828 A KR 1019850005828A KR 850005828 A KR850005828 A KR 850005828A KR 890000194 B1 KR890000194 B1 KR 890000194B1
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- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
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Abstract
Description
본 발명은 인공감미료인 아스파람등의 제조에 있어서의 유용한 중간체인 다음 구조식(Ⅰ)의 페닐 알라닌 에스테르의 새로운 제조방법에 관한 것이다.The present invention relates to a novel process for the preparation of phenyl alanine esters of the following structural formula (I), which are useful intermediates in the production of artificial sweeteners, asparam, and the like.
상기식에서 R은 메틸, 에틸기이다.In the above formula, R is methyl or ethyl group.
인공감미료는 1879년 사카린이 발견된 이래 중요한 식품첨가물로서 이용되어 왔으나, 1937년에 합성된 싸이클라메이트가 동물실험에 의해서 암을 유발시킨다고 보고됨에 따라 새로운 비독성 감미료를 찾는 꾸준한 연구가 행해지게 되었으며 그에 따라 현재 많은 새로운 감미료들이 발견되게 되었다. (G.E,Inglett; Food, Tech39(8), 37(1981)).Artificial sweeteners have been used as an important food additive since the discovery of saccharin in 1879.However, since the synthesis of cyclomate synthesized in 1937 has been reported to cause cancer by animal experiments, a steady study has been conducted to find new non-toxic sweeteners. As a result, many new sweeteners have been discovered. (G.E, Inglett; Food, Tech 39 (8), 37 (1981)).
그중에서도 1965년 모어리(Morley)에 의해서 발견된 (J,Chem. Soc.555.1966)아스파람(L-a-아스파틸-L-페닐알라닌 메틸 에스테르)은 설탕에 대해 150-200배의 상대 감미도를 갖는다고 알려져 있다.Among them (J, Chem. Soc. 555.1966) asparam (L- a- aspartyl-L-phenylalanine methyl ester), discovered by Morley in 1965, has a relative sweetness of 150-200 times that of sugar. It is known.
본 발명은 이러한 아스파람의 제조에 유용한 중간물질인 구조식(I)의 L-페닐 알라닌 에스테르의 제조방법에 관한 것으로 이런 아미노산의 저급알콜 에스테르를 제조하는 종래의 방법으로는, 첫째, 티오닐 클로라이드를 이용하는 방법(Schroder, The peptides. Vol.1.1965),The present invention relates to a method for preparing L-phenylalanine ester of structural formula (I), which is a useful intermediate for the preparation of such asparam. As a conventional method for preparing lower alcohol esters of such amino acids, first, thionyl chloride is prepared. Method (Schroder, The peptides.Vol.1.1965),
둘째, 염산(HCl)가스를 이용하는 방법(Sheehan. Organic Chemistry, 1962),Second, using hydrochloric acid (HCl) gas (Sheehan. Organic Chemistry, 1962),
셋째, 아세틸 클로라이드를 이용하는 방법(Waton.J. Chem. Soc.1950)Third, a method using acetyl chloride (Waton. J. Chem. Soc. 1950)
그러나 상기의 세 가지의 제조방법들은 반응이 산존재하에서 진행되게 되므로 가역반응이 일어나 수율이 낮아질 뿐만아니라 그 생성물도 염산염(HC1 Salt)의 형태로 얻어지므로 차기 공정에 투입하기 전에 미리 염기로 중화하여 추출한 다음, 감압농축시켜야 하는등의 조작상의 번거러움이 있었다.However, the above three manufacturing methods, because the reaction proceeds in the presence of acid, not only the reversible reaction occurs, the yield is lowered, the product is also obtained in the form of hydrochloric acid (HC1 Salt), and neutralized with a base before input to the next step After extraction, there was an operational trouble such as concentration under reduced pressure.
또한, 염산가스(HCl gas), 티오닐 클로라이드, 아세틸 클로라이드등이 독성이 강한 화학물질들을 사용하기 때문에 작업상의 애로점이 큰 단점이 있었다.In addition, since hydrochloric acid gas (HCl gas), thionyl chloride, acetyl chloride and the like toxic chemicals are used, there is a major disadvantage in operation.
이에 비해 본 발명에 따르는 에스테르화에서는 염산가스, 디오닐 클로라이드, 아세틸 클로라이드 등을 사용하지 않으므로써 그에 따른 중화 및 추출, 감압농축 등의 추가 조작은 필요없게 되어 공정을 단축시킬수 있으며, 또한 디 싸이클로 헥실 디 카르보 디이미드를 첨가해 주는 것에 의해서 반응이 촉진되는 동시에 가역반응은 억제되게 되어 구조식(I)의 화합물이 극히 좋은 수율로 얻어지고 있다.In contrast, the esterification according to the present invention does not use hydrochloric acid gas, dionyl chloride, acetyl chloride, etc., thereby eliminating the need for additional operations such as neutralization, extraction, and concentration under reduced pressure. By adding dicarbodiimide, the reaction is accelerated and the reversible reaction is suppressed, and the compound of structural formula (I) is obtained in extremely good yield.
본 발명을 상세히 설명하면 다음과 같다.The present invention is described in detail as follows.
저급알콜 즉, 메틸알콜, 에틸알콜등을 반응물 및 용매로하고 여기에 다음 구조식(Ⅱ)의 L-페닐 알라닌을 가해 반응을 진행Lower alcohols, such as methyl alcohol and ethyl alcohol, are used as reactants and solvents, and L-phenyl alanine of the following structural formula (II) is added to proceed with the reaction.
시키면서 디 싸이클로 헥실 카르보 디이미드를 반응촉진 및 가역반응 방지의 목적으로 첨가한 다음, 각기 용매의 환류온도까지 가온하여 반응진행도를 박층 크로마토 그라피법(Silica Gel GF 254사용)으로 확인한 결과 미 반응의 아미노산은 거의 검출되지 않았다.Dicyclohexyl carbodiimide was added for the purpose of promoting the reaction and preventing the reversible reaction. Then, the reaction progress was confirmed by thin layer chromatography (using Silica Gel GF 254) by heating to the reflux temperature of each solvent. The amino acid of was hardly detected.
이를 반응식으로 표시하면 다음과 같다.This is expressed as a reaction scheme as follows.
상기식에서 R는 -CH3또는 -C2H5이다.In which R is -CH 3 or -C 2 H 5 .
알콜의 용량은 아미노산의 중량의 5-13배(용량:중량)가 좋으며 특히 10배용량이 가장 바람직하였다.The dose of alcohol is preferably 5-13 times (volume: weight) of the weight of the amino acid, and particularly preferably 10 times the dose.
디 싸이클로 헥실 카르보 디이미드의 양은 아미노산의 0.9-2.0 당량이 좋으며 1.02 당량이 가장 바람직하였다.The amount of dicycle hexyl carbodiimide was 0.9-2.0 equivalents of amino acid and 1.02 equivalents was most preferred.
반응시간은 대개 1 내지 4시간이면 완결되었다.The reaction time was usually completed in 1 to 4 hours.
다음의 실시예는 본 발명을 더욱 상세히 예시하여 줄 것이나 본 발명의 범위가 이에 제한되는 것은 아니다.The following examples will illustrate the invention in more detail, but the scope of the invention is not limited thereto.
[실시예 1]Example 1
메틸 알콜 100ml에 디 싸이클로 헥실 카르보 디이미드 10.72g(0.052mole)을 실온에서 교반해 주면서 서서히 가한다.To 100 ml of methyl alcohol is added slowly 10.72 g (0.052 mole) of dicyclohexyl carbodiimide while stirring at room temperature.
이 혼합물을 10분간 더 교반한후, L-페닐 알라닌 8.26g(0.05mole)을 약 30분간에 걸쳐서 소량씩 첨가해 준 다음, 수조에서 가온하여 환류시킨다.After the mixture is stirred for 10 more minutes, 8.26 g (0.05 mole) of L-phenyl alanine is added in small portions over about 30 minutes, and then heated and refluxed in a water bath.
반응을 진행시키면서 매 20분마다 샘플을 취하여 L-페닐 알라닌과 L-페닐 알라닌 메틸 에스테르 표준품을 대조로하여 박층 크로마토 그라피법(Silica Gel GF 254사용)으로 반응 완료를 확인한 결과, 1시간 경과후에는 미반응의 L-페닐 알라닌은 검출되지 않았다.Samples were taken every 20 minutes as the reaction proceeded, and the reaction was confirmed by thin layer chromatography (using Silica Gel GF 254) against L-phenylalanine and L-phenylalanine methyl ester standards. Unreacted L-phenylalanine was not detected.
1시간 환류후 감압하에서 용매를 제거하여 백색의 결정 8.8g(수율 97.9%)를 얻었다.After refluxing for 1 hour, the solvent was removed under reduced pressure to obtain 8.8 g of a white crystal (yield 97.9%).
이를 소량의 증류수에 용해시키고 pH를 약 6.0정도로 조정한 다음 에틸렌 디 클로라이드로 재결정하여 L-페닐 알라닌 메틸 에스테르의 백색결정 8.62g(수율 95.99%)을 얻었다.This was dissolved in a small amount of distilled water, the pH was adjusted to about 6.0, and recrystallized with ethylene dichloride to give 8.62 g (yield 95.99%) of white crystals of L-phenylalanine methyl ester.
이를 소량의 증류수에 용해시키고 pH를 약 6.0정도로 조정한 다음 에틸렌 디 클로라이드로 재결정하여 L-페닐 알라닌 메틸 에스테르의 백색결정 8.62g(수율 95.99%)을 얻었다.This was dissolved in a small amount of distilled water, the pH was adjusted to about 6.0, and recrystallized with ethylene dichloride to give 8.62 g (yield 95.99%) of white crystals of L-phenylalanine methyl ester.
이 L-페닐 알라닌 메틸 에스테르 5g(0.028mole)과 L-아스파틸산 염산염 4.26g(0.028mole)을 에틸렌 디클로라이드 용매중에서 반응시켜 아스파람 6.6g을 얻었다.5 g (0.028 mole) of this L-phenylalanine methyl ester and 4.26 g (0.028 mole) of L-aspartic acid hydrochloride were reacted in an ethylene dichloride solvent to obtain 6.6 g of asparam.
[실시예 2]Example 2
실시예 1과 같이 실시하되, 디 싸이클로 헥실 카르보 디 이미드는 5.36g(0.025mole)첨가하였다. 그 결과 L-페닐 알라닌 메틸 에스테르의 백색결정 7.9g(수율 87.9%)을 얻었다.The procedure was carried out as in Example 1, except that 5.36 g (0.025 mole) of dicycle hexyl carbo diimide was added. As a result, 7.9 g (yield 87.9%) of white crystals of L-phenylalanine methyl ester were obtained.
[실시예 3]Example 3
실시예 1과 같이 실시하되, 이 싸이클로 헥실 카르보 디 이미드는 16.09g(0.078mole)첨가하였다. 그 결과 L-페닐 알라닌 메틸 에스테르의 백색 결정 7.1g(수율 79.86%)을 얻었다.The procedure was carried out as in Example 1 except that 16.09 g (0.078 mole) of hexyl carbodiimide was added. As a result, 7.1 g (yield 79.86%) of white crystals of L-phenylalanine methyl ester were obtained.
[실시예 4]Example 4
실시예 1과 같이 실시하되, 메틸 알콜 대신 에틸 알콜 100ml를 사용하였다. 그 결과 L-페닌 알라닌 에틸에스테르 9.47g(수율 97.8%)을 얻었다.100 ml of ethyl alcohol was used in place of methyl alcohol. As a result, 9.47 g (yield 97.8%) of L-phenine alanine ethyl ester was obtained.
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| Application Number | Priority Date | Filing Date | Title |
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| KR1019850005828A KR890000194B1 (en) | 1985-08-13 | 1985-08-13 | Process for the preparation of l-phenyl alaine ester |
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| KR1019850005828A KR890000194B1 (en) | 1985-08-13 | 1985-08-13 | Process for the preparation of l-phenyl alaine ester |
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| KR870002051A KR870002051A (en) | 1987-03-28 |
| KR890000194B1 true KR890000194B1 (en) | 1989-03-10 |
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