KR970002906B1 - Preparation process of alpha-l-aspartyl-l-phenylalanine methylester - Google Patents
Preparation process of alpha-l-aspartyl-l-phenylalanine methylester Download PDFInfo
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Abstract
Description
본 발명은 3-벤질-6-카르복시메틸-2, 5-디케토피페라진과 α-L-아스파틸-L-페닐알라닌으로부터 메탄올중에서 유기산 또는 무기산 촉매하에서 α-L-아스파틸-L-페닐알라닌 메틸에스테르(이하 "α-APM"이라 한다)를 제조하는 방법에 관한 것이다.The present invention relates to 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine and α-L-aspartyl-L-phenylalanine in methanol in an organic or inorganic acid catalyst in α-L-aspartyl-L-phenylalanine methyl ester. (Hereinafter referred to as "α-APM").
3-벤질-6-카르복시메틸-2, 5-디케토피페라진이나 α-L-아스파틸-L-페닐알라닌으로부터 α-APM을 제조하는 방법으로는 한국 공개특허 제86-9039호에 기술되어 있는데, 이 방법에서는 α-L-아스파틸-L-페닐알라닌이나 3-벤질-6-카르복시메틸-2, 5-디케토피페라진을 강산촉매하에 메탄올과 물의 혼합용매를 사용하여 20-80℃에서 일정시간 동안 반응시키며, 메탄올과 물을 00.1-1.0비로 혼합하여 사용하고 있다.A method for preparing α-APM from 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine or α-L-aspartyl-L-phenylalanine is described in Korean Patent Application Publication No. 86-9039. In this method, α-L-aspartyl-L-phenylalanine or 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine is fixed at 20-80 ° C. using a mixed solvent of methanol and water under a strong acid catalyst. The reaction was carried out for a time, and methanol and water were mixed and used at a ratio of 00.1-1.0.
이 방법에 의하여 3-벤질-6-카르복시메틸-2, 5-디케토피페라진이나 α-L-아스파틸-L-페닐알라닌으로부터 α-APM을 제조할 경우, α-APM 수득율이 45% 이하로 저조할 뿐만 아니라 α-APM을 회수할 때 미반응 출발물질인 α-L-아스파틸-L-페닐알라닌이나 3-벤질-6-카르복시메틸-2, 5-디케토피페라진이 상당량 결정으로 혼합되어 얻어지므로 산업적으로 이용가치가 떨어진다.When α-APM is prepared from 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine or α-L-aspartyl-L-phenylalanine by this method, the yield of α-APM is 45% or less. In addition to poor performance, unreacted starting materials α-L-aspartyl-L-phenylalanine, 3-benzyl-6-carboxymethyl-2, and 5-diketopiperazine are obtained by mixing a considerable amount of crystals when recovering α-APM. As a result, the industrial value falls.
본 발명자들은 이러한 종래 기술의 단점을 갖지 않고 3-벤질-6-카르복시메틸-2, 5-디케토피페라진이나 α-L-아스파틸-L-페닐알라닌으로부터 높은 전환율로 α-APM을 제조할 수 있는 방법을 제공하고자 예의 연구한 결과로서 본 발명을 완성하기에 이르렀다.We can produce α-APM with high conversion from 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine or α-L-aspartyl-L-phenylalanine without the disadvantages of this prior art. The present invention has been completed as a result of intensive research to provide a method that can be used.
즉, 본 발명의 목적은 3-벤질-6-카르복시메틸-2, 5-디케토피페라진 또는 α-L-아스파틸-L-페닐알라닌으로부터 α-L-아스파틸-L-페닐알라닌 메틸에스테르를 제조하는 방법에 있어서, 3-벤질-6-카르복시메틸-2, 5-디케토피페라진 또는 α-L-아스파틸-L-페닐알라닌을 메탄올 중에서 유기산 또는 무기산 촉매하에 40-60℃의 본도에서 α-L-아스파틸-L-페닐알라닌 메틸 에스테르로 전환한 뒤 α-L-아스파틸-L-페닐알라닌 메닐에스테르 염산염으로 결정화하는 방법을 제공하는 것이다.That is, it is an object of the present invention to prepare α-L-aspartyl-L-phenylalanine methylester from 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine or α-L-aspartyl-L-phenylalanine. In the process, 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine or α-L-aspartyl-L-phenylalanine in α at 40-60 ° C. under an organic or inorganic acid catalyst in methanol The present invention provides a method for converting into -L-aspartyl-L-phenylalanine methyl ester and crystallizing with α-L-aspartyl-L-phenylalanine menyl ester hydrochloride.
이하 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 방법에 따르면, 메탄올 단독용매를 3-벤질-6-카르복시메틸-2, 5-디케토피페라진이나 α-L-아스파틸-L-페닐알라닌에 일정량 가하고 유기산이나 강산을 촉매로 사용하여 3-벤질-6-카르복시메틸-2, 5-디케토피페라진이나 α-L-아스파틸 -L-페닐알라닌을 40-60℃ 의 온도에서 α-APM으로 전환시킨다.According to the method of the present invention, methanol alone solvent is added to 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine or α-L-aspartyl-L-phenylalanine, and organic or strong acid is used as a catalyst. 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine or α-L-aspartyl-L-phenylalanine is converted to α-APM at a temperature of 40-60 ° C.
본 발명에서는 메탄올을 3-벤질-6-카르복시메닐-2, 5-디케토피페라진이나 α-L-아스파틸-L-페닐알라닌의 사용 무게에 대하여 1-20배 부피 정도의 양으로 사용한다.In the present invention, methanol is used in an amount of about 1-20 times the volume of 3-benzyl-6-carboxymenyl-2, 5-diketopiperazine or α-L-aspartyl-L-phenylalanine.
본 발명의 방법에서 사용되는 유기산의 종류로는 초산과 개미산을 예시할 수 있으며, 강산으로는 염산, 황산 또는 인산 등을 예시할 수 있다. 이들은 3-벤질-6-카르복시메틸-2, 5-디케토피페라진이나 α-L-아스파틸-L-페닐알라닌의 무게에 대하여 1-20%(W/V)의 양으로 사용할 수 있다.Examples of the organic acid used in the method of the present invention may include acetic acid and formic acid, and strong acids may include hydrochloric acid, sulfuric acid or phosphoric acid. They can be used in amounts of 1-20% (W / V) based on the weight of 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine or α-L-aspartyl-L-phenylalanine.
즉, 본 발명에서 사용되는 유기산이나 강산은 전체 용액에서 0.5%(v/v) 이상을 사용할 수 있으며, 바람직하게는 0.5-5%(V/V)의 양으로 사용된다.That is, the organic acid or strong acid used in the present invention may be used in the total solution of 0.5% (v / v) or more, preferably in an amount of 0.5-5% (V / V).
반응온도는 40-60℃ 정도가 적절하고 반응시간은 반응온도에 따라 달라진다The reaction temperature is appropriate about 40-60 ℃ and the reaction time depends on the reaction temperature
본 발명의 방법에서 유기산이나 강산을 10% 이상 사용시에는 3-벤질-6-카르복시메틸-2, 5-디케토피페라진이나 α-L-아스파틸-L-페닐알라닌이 α-APM으로 쉽게 전환이 되는 반면 전환된 α-L-아스파틸-L-페닐알라닌 메틸에스테르가 다시 α-L-아스파틸-β-메틸에스테르-L-페닐알라닌 메틸에스테르(이하 α-MAPM이라 칭함)로 변환될 수 있으므로 바람직하지 않다.When more than 10% of organic or strong acid is used in the method of the present invention, 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine or α-L-aspartyl-L-phenylalanine can be easily converted to α-APM. While converted α-L-aspartyl-L-phenylalanine methylester may be converted back to α-L-aspartyl-β-methylester-L-phenylalanine methylester (hereinafter referred to as α-MAPM). not.
또한, 본 발명에 의하여 제조된 α-L-아스파틸-L-페닐알라닌 메틸에스테르는 메탄올을 진공-저온 농축하여 적절한 농도의 강산 수용액하에서 α-L-아스파틸-L-페닐알라닌 메틸에스테르의 강산염의 형태로 침전시키거나, 메탄올을 일정량 제거한 후 염기성 수용액으로 pH를 4.8-5.2로 조질하여 α-APM을 결정으로 회수할 수 있다.In addition, the α-L-aspartyl-L-phenylalanine methyl ester prepared according to the present invention is a form of the strong acid salt of α-L-aspartyl-L-phenylalanine methyl ester in an aqueous solution of a strong concentration of methanol by vacuum-low temperature concentration. Α-APM can be recovered as crystals by precipitating or by removing a certain amount of methanol and adjusting the pH to 4.8-5.2 with a basic aqueous solution.
본 발명에서는 3-벤질-6-카르복시메틸-2, 5-디케토피페라진이나 α-L-아스파틸-L-페닐알라닌을 α-APM으로 전환시킨 후 농축하여 pH 조절로 α-L-아스파틸-L-페닐알라닌 메틸에스테르를 결정화할 때 3-벤질-6-카르복시메틸-2, 5-디케토피페라진이나 α-L-아스파딜-L-페닐알라닌의 일부가 결정으로 석출되어 α-APM의 순도를 떨어뜨려 제품으로 사용하기에는 다소 어려움이 있는 문제짐이 있었다. 그래서 본 발명에서는 α-APM에 진한 염산을 가하여 α-APM 염산염으로 결정화하고 이어 pH를 4.8로 조정하여 중화하므로써 고순도의 α-APM을 얻을 수 있었다.In the present invention, 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine or α-L-aspartyl-L-phenylalanine is converted to α-APM, and concentrated to adjust α-L-aspartyl When crystallization of -L-phenylalanine methyl ester, a part of 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine or α-L-aspadyl-L-phenylalanine is precipitated as crystals and the purity of α-APM There was a problem burden that is somewhat difficult to use as a product dropped. Thus, in the present invention, high purity α-APM was obtained by adding concentrated hydrochloric acid to α-APM and crystallizing it with α-APM hydrochloride and then adjusting the pH to 4.8 to neutralize it.
따라서 본 발명은 메탄올과 물의 혼합용매를 사용하는 종래의 기슬과는 달리 유기산 또는 강산 촉매하에 메탄올 단독용매를 사용하여 60℃ 이하의 저온 반응으로 3-벤질-6-카르복시메틸-2, 5-디케토피페라진은 80% 이상, α-L-아스파틸-L-페닐알라닌은 50% 이상의 전환율로 α-APM으로 전환시킬 수 있게 한다.Therefore, in the present invention, unlike the conventional gaseum using a mixed solvent of methanol and water, 3-benzyl-6-carboxymethyl-2, 5-dike in a low temperature reaction of 60 ° C. or less using a methanol sole solvent under an organic acid or strong acid catalyst. Topiperazine is at least 80% and α-L-aspartyl-L-phenylalanine is capable of conversion to α-APM at a conversion rate of at least 50%.
이하 실시예를 통하여 본 발명을 보다 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in more detail with reference to the following examples.
(실시예 1)(Example 1)
3-벤질-6-카르복시메틸-2, 5-디케토피페라진 10.0g을 MeOH 50m1에 녹이고 진한 염산 2m1를 가하였다. 혼합물을 55℃-60℃에서 1시간 30분 교반후 HPLC로 분석한 결과 α-L-아스파틸-L-페닐알라닌 메틸에스테르 9.26g(전환율 8.25%)을 확인하였다. 진공농측하에 MeOH 32m1을 제거한 뒤 진한 염산 30ml를 가하고 5℃에서 6시간 교반하여 흡습된 α-L-아스파틸-L-페닐알라닌 메틸에스테르 염산염 결정 16.25g을 얻었으며 결정을 녹여 HPLC로 분석하여 α-APM을 8.76g(회수율 94.6%)를 얻었다.10.0 g of 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine was dissolved in 50 ml of MeOH and 2 ml of concentrated hydrochloric acid was added. The mixture was stirred at 55 ° C.-60 ° C. for 1 hour 30 minutes and analyzed by HPLC. As a result, 9.26 g (conversion rate 8.25%) of α-L-aspartyl-L-phenylalanine methyl ester was confirmed. After removing MeOH 32m1 under vacuum concentration, 30 ml of concentrated hydrochloric acid was added and stirred for 6 hours at 5 ° C. to obtain 16.25 g of crystallized α-L-aspartyl-L-phenylalanine methyl ester hydrochloride crystals. The crystals were dissolved and analyzed by HPLC. 8.76 g (94.6% recovery) of APM was obtained.
(실시예 2)(Example 2)
실시예 1과 동일하게 실시하되, 진한 염산 대신 빙초산 2m1를 사용하였다. 그 결과, α-L-아스파틸-L-페닐알라닌 메틸에스테르 7.98g을 함유한 흡습된 α-L-아스파틸-L-페닐알라닌 메틸에스테르 염산염 결정 1491g을 얻었다(α-L-아스파틸-L-페닐알라닌 메틸에스테르 전환율 83.5%, 회수율 85.1%).It carried out similarly to Example 1, but used glacial acetic acid 2m1 instead of concentrated hydrochloric acid. As a result, 1491 g of a dehydrated α-L-aspartyl-L-phenylalanine methyl ester hydrochloride crystal containing 7.98 g of α-L-aspartyl-L-phenylalanine methyl ester was obtained (α-L-aspartyl-L-phenylalanine Methyl ester conversion 83.5%, recovery 85.1%).
(실시예 3)(Example 3)
실시예 1과 동일하게 실시하되 진한 염산 대신 개미산 2ml를 사용하였다. 그 결과, α-L-아스파틸-L-페닐알라닌 메틸에스테르 7.50g을 함유한 흡습된 α-L-아스파틸-L-페닐알라닌 메틸에스테르 염산염 결정 l432g을 얻었다.(α-L-아스파틸-L-페닐알라닌 메틸에스테르 전환율 84.0%, 회수율 79.6%)2 ml of formic acid was used instead of concentrated hydrochloric acid. As a result, l432 g of a dehydrated α-L-aspartyl-L-phenylalanine methyl ester hydrochloride crystal containing 7.50 g of α-L-aspartyl-L-phenylalanine methyl ester was obtained. (Α-L-aspartyl-L- Phenylalanine methyl ester conversion 84.0%, recovery 79.6%)
(실시예 4)(Example 4)
실시예1과 동일하게 실시하되, 3-벤질-6-카르복시메틸-2, 5-디케토피페라진 대신α-L-아스파틸-L-페닐알라닌을 10g 사용하였다. 그 결파, 흡습된 α-L-아스파틸-L-페닐알라닌 메틸에스테르 9.92g을 얻었고 HPLC 분석 결과, α-APM을 5.301g 함유하고 있었다(55.4% 전환율, 회수율 91.1%).In the same manner as in Example 1, 10 g of α-L-aspartyl-L-phenylalanine was used instead of 3-benzyl-6-carboxymethyl-2 and 5-diketopiperazine. The resulting, hygroscopic α-L-aspartyl-L-phenylalanine methyl ester was obtained 9.92 g, and HPLC analysis showed that 5.301 g of α-APM (55.4% conversion, 91.1% recovery).
(실시예 5)(Example 5)
실시예 1과 동일하게 실시하되, 3-벤질-6-카르복시메틸-2, 5-디케토피페라진 50g와 α-L-아스파틸-L-페닐알라닌 5.0g의 혼합물을 출발물질로, 그리고 진한 염산 대신에 황산 2m1를 사용하였다. 그 결과 얻은 흡습된 α-r-L-아스파틸-L-페닐알라닌 메틸에스테르 염산염 결정 13.40g을 얻었고, 여기에 함유된 α-APM은 7.317g이었다(95.7% 회수율). 3-벤질-6-카르복시메틸-2, 5-디케토피페라진으로부터의 전환율은 83.0% 이고, α-L- 아스파틸 -L-페닐알라닌으로부터 전환율은 57.0%이었다.In the same manner as in Example 1, a mixture of 50 g of 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine and 5.0 g of α-L-aspartyl-L-phenylalanine was used as a starting material, and concentrated hydrochloric acid. 2 ml of sulfuric acid was used instead. As a result, 13.40 g of the hygroscopic α-r-L-aspartyl-L-phenylalanine methyl ester hydrochloride crystal was obtained, and the α-APM contained therein was 7.317 g (95.7% recovery). The conversion from 3-benzyl-6-carboxymethyl-2, 5-diketopiperazine was 83.0%, and the conversion from α-L-aspartyl-L-phenylalanine was 57.0%.
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