KR850000059B1 - Process of preparing for alpha-l-aspatyl-l-phehylallanine alkylaster - Google Patents
Process of preparing for alpha-l-aspatyl-l-phehylallanine alkylaster Download PDFInfo
- Publication number
- KR850000059B1 KR850000059B1 KR8205909A KR820005909A KR850000059B1 KR 850000059 B1 KR850000059 B1 KR 850000059B1 KR 8205909 A KR8205909 A KR 8205909A KR 820005909 A KR820005909 A KR 820005909A KR 850000059 B1 KR850000059 B1 KR 850000059B1
- Authority
- KR
- South Korea
- Prior art keywords
- group
- aspartic acid
- phenylalanine
- acid
- alkali metal
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biophysics (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
본 발명은 다음 일반식(I)의 저칼로리 인공 감미료인 α-L-아스파틸-L-페닐 알라닌 알킬에스테르의 제조방법에 관한 것이다.The present invention relates to a method for producing α-L-aspartyl-L-phenylalanine alkyl ester which is a low calorie artificial sweetener of the following general formula (I).
여기에서 R2는 탄소수 1-5의 저급알킬기이다. 이제까지 인공감미료는 사카린 나트륨이나 칼슘싸이클라메이트 등이 널리 사용되어 왔으나, 이들 인공감미료는 근년에 들어와 인체의 대사경로에 적합치 않고, 또 불순물로서 혼입되는 아미노화합물에 의한 대사이상으로 인하여 염색체에 이상을 일으킨다고 알려졌다. 그러나, α-L-아스파틸-L-페닐알라닌메틸에스테르(이하 아스파템이라 한다)는 두 아미노산(페닐알라닌과 아스파라긴산)을 축합시켜 합성한 다이펩타이드로서 인체의 대사계에도 적합하고, 설탕과 유사한 맛과 설탕의 약 200배 가량의 감미를 갖고 있는 저칼로리 인공감미료로 주목을 받고 있다.R 2 is a lower alkyl group having 1 to 5 carbon atoms. So far, saccharin sodium and calcium cyclate have been widely used in artificial sweeteners. However, these artificial sweeteners are not suitable for metabolic pathways in human body in recent years, and they have no abnormality in chromosomes due to metabolic abnormalities caused by amino compounds incorporated as impurities. It is known to cause. However, α-L-aspartyl-L-phenylalanine methyl ester (hereinafter referred to as aspartem) is a dipeptide synthesized by condensation of two amino acids (phenylalanine and aspartic acid) and is suitable for the metabolic system of the human body. It is attracting attention as a low-calorie artificial sweetener that has about 200 times the sweetness of sugar.
종래 아스파템의 제법으로는 (i) N-카르보 벤조키시아스파라긴산 무수물과 페닐알라닌메틸에스테르를 축합시키는 방법, (ii) 아스파긴산의 아미노기 및 β-카르복실기를 적당한 보호기로 보호시킨 후 다시 α-카르복실기를 활성에스테르로 하여 페닐알라닌 메틸에스테르와 축합시키는 방법, (iii) 아스파라긴산 무수물의 강산부가염과 페닐알라닌 메틸에스테르를 해리상수 3×10-2이하의 산 존재하에 축합시키는 방법등이 알려져 왔다.Conventionally, aspartame is prepared by (i) condensation of N-carbo benzocythiasparagine anhydride with phenylalanine methyl ester, (ii) protecting the amino and β-carboxyl groups of aspartic acid with a suitable protecting group, and then again forming an α-carboxyl group. A method of condensing with phenylalanine methyl ester as an active ester, (iii) a method of condensing a strong acid addition salt of aspartic anhydride and phenylalanine methyl ester in the presence of an acid having a dissociation constant of 3 × 10 −2 or less.
그러나 이들 방법중 (i), (iii)의 방법에 있어서는 펩타이드 축합시 아스파라긴산의 α-위치 및 β-위치의 카르복실기가 함께 반응에 참여하여 α-와 β-펩타이드가 동시에 생성되므로 인하여 목적물과 부산물의 분리정제 공정이 불가결하게 되어 목적물의 수율 및 순도가 낮아지는 기술적 난점이 있으며, 또 (ii) 의 방법에 있어서는 아스파라긴산의 카르복실기와 아미노기를 각각 보호해야 하고 또 축합후 보호기의 제거가 용이치 않게 때문에 합성 공정이 길고 번잡할 뿐아니라 고가의 보호기를 사용하므로서 제조비용이 높다는 등의 결점을 가지고 있다.However, in the methods of (i) and (iii), the carboxyl groups of the aspartic acid in the α- and β-positions participate in the reaction together to generate the α- and β-peptides simultaneously. As the separation and purification process becomes indispensable, there is a technical difficulty of lowering the yield and purity of the target product, and in the method of (ii), the carboxyl and amino groups of aspartic acid must be protected, respectively, and the removal of the protecting group after condensation is not easy. Not only is the process long and cumbersome, but it also has the drawback that the manufacturing cost is high due to the use of expensive protectors.
따라서, 본 발명자들은 다음과 같은 방법에 의하여 이러한 종래 방법의 기술적·경제적 난점을 해결하고 고수율 및 고순도로 목적물을 얻는 공업적으로 유리한 방법을 얻는데 성공하였다. 즉 본 발명은 우선 아스파라긴산의 β-카르복실기의 수소원자를 1가의 알카리 금속으로 치환한 후 α-아미노기를 쉬프염기로 하여 보호한 다음 N-석시니미딜페닐포스페이트(SDPP) 존재하에 페닐 알라닌 메틸 에스테르와 축합시킨 후 산으로 처리하여 보호기를 제거하여 고순도·고수율의 α-펩타이드를 얻었다.Therefore, the present inventors have succeeded in solving the technical and economic difficulties of the conventional method by the following method and obtaining an industrially advantageous method of obtaining the target product in high yield and high purity. In other words, the present invention first replaces the hydrogen atom of the β-carboxyl group of aspartic acid with a monovalent alkali metal, and then protects the α-amino group with a shift base, and then reacts with phenylalanine methyl ester in the presence of N-succinimidylphenylphosphate (SDPP). After condensation, the acid was treated with acid to remove the protecting group to obtain α-peptide of high purity and high yield.
본 발명은 4단계로 진행되며 반응식으로 표시하면 다음과 같다.The present invention proceeds to step 4 and is represented by the following scheme.
상기 구조식에서 R2는 전술한바와 같으며 M은 K 또는 Na의 알카리 금속이며 R1은 살리실, 5-클로로살리실 및 p-메톡시살리실기이다.Wherein R 2 is the same as described above, M is an alkali metal of K or Na and R 1 is a salicylic, 5-chlorosalicyl and p-methoxysalicyl group.
본 반응을 단계별로 상세히 설명하면 다음과 같다.The reaction is described in detail step by step as follows.
(i) 1단계 : β-카르복실기의 수소대신 알카리 금속치환(i) Step 1: Alkali metal substitution instead of hydrogen of β-carboxyl group
아스파라긴산의 이온화 그룹의 pK´값은 다음과 같다.The pK 'value of the ionized group of aspartic acid is as follows.
따라서 pH7.0에서의 아스파라긴산은 음전하를 띄우며α-아미노기와 α-카르복실기의 전하는 서로 상쇄되어 β-카르복실기의 음이온이 1가의 알카리 금속이온(M+)과 반응하여 -COOM을 만든다.Therefore, aspartic acid at pH 7.0 has a negative charge Charges of the α-amino group and the α-carboxyl group cancel each other so that the anion of the β-carboxyl group reacts with the monovalent alkali metal ion (M + ) to form -COOM.
(ii) 2단계 : α-아미노기의 보호(ii) Step 2: Protection of α-amino Groups
α 위치의 아미노기를 적당한 용매 속에서 쉬프염기로 하여 보호한다. 이때 벤즈 알데하이드의 쉬프 염기는 불완정하여 펩타이드 합성시 아미노기의 보호에는 적합치 못한다. 그러나 살리신 알데하드로, 5-클로로살리실 알데하이드, p-메톡시살리실 알데하이드로부터 만드는 쉬프 염기는 안정되어 아미노기의 보호기로 사용된다. 이때 0-하이드록시 벤질리덴 유도체의 안정성은 질소원자와 하이드록실기 사이의 수소 결합에 기인한다.The amino group at the α position is protected by a Schiffbase as a suitable solvent. At this time, the Schiff base of benzaldehyde is incomplete and is not suitable for protecting amino groups during peptide synthesis. However, with the salicylic aldehyde, the Schiff base made from 5-chlorosalicyl aldehyde, p-methoxysalicyl aldehyde is stable and is used as protecting group of amino group. The stability of the 0-hydroxy benzylidene derivative at this time is due to the hydrogen bond between the nitrogen atom and the hydroxyl group.
이들 쉬프 염기는 산으로 처리하면 쉽게 떨어져 제거된다.These Schiff bases are easily removed and removed by treatment with acid.
(iii) 단계 : α펩타이드 합성(iii) step: α peptide synthesis
아미노기가 쉬프 염기로 보호된 아스파라긴산의 알카리금속염과 페닐알라닌메틸에스테르와의 축합시 새로운 축합제 N-석시니미딜 디페닐포스페이트를 사용하여 반응을 촉진시킨다. 반응은 트리에틸아민, N-메틸몰포린등의 염기중에서 진행하므로 페닐알라닌 메틸에스테르가 아스파라긴산의 α-카르복실기와 반응하여 α-펩타이드만을 만든다. 또, 페닐알라닌메틸에스테르가 아스파라긴산과 당량비로 반응하므로 페닐알라닌메틸에스테르를 과량으로 사용하는 종래 방법보다 훨씬 경제적이다. 축합반응을 반응식으로 나타내면 다음과 같다.When condensation of alkali metal salts of aspartic acid with an amino group protected by a Schiff base with phenylalanine methyl ester, the new condensing agent N-succinimidyl diphenylphosphate is used to promote the reaction. Since the reaction proceeds in a base such as triethylamine or N-methylmorpholine, phenylalanine methyl ester reacts with the α-carboxyl group of aspartic acid to form only the α-peptide. Further, since phenylalanine methyl ester reacts with aspartic acid in an equivalent ratio, it is much more economical than the conventional method using an excessive amount of phenylalanine methyl ester. The condensation reaction is represented by the following equation.
상기 식에서 알 수 있는 바와 같이 N-석시니미딜디페닐포스페이트는 디페닐포스페이트로서 회수된다.As can be seen from the above formula, N-succinimidyldiphenylphosphate is recovered as diphenylphosphate.
(iv) 4단계 : 보호기의 제거(iv) Step 4: Removal of Protectors
아미노기의 보호기인 N-아릴리덴은 메탄올로 희석된 묽은 염산으로 처리하여 제거된다. 반응은 온화하여 실온에서 진행되며 펩타이드 유도체의 라세미화는 일어나지 않는다.N-arylidene, the protecting group of the amino group, is removed by treatment with dilute hydrochloric acid diluted with methanol. The reaction is mild and proceeds at room temperature and no racemization of the peptide derivative occurs.
[실시예 1]Example 1
아스파라긴산 칼륨염의 제조Preparation of Aspartic Acid Potassium Salt
아스파라긴산 13.3g(0.1몰)을 물 100ml에 현탁시키고 50% 탄산칼륨을 가하여 pH6.8로 하면 용해한다.13.3 g (0.1 mole) of aspartic acid is suspended in 100 ml of water, and dissolved by adding 50% potassium carbonate to pH 6.8.
실온에서 30분간 교반한 후 감압농축(10mmHg, 60℃)하여 무색의 점성액 16.9g(수율 : 98.7%)을 얻었다.After stirring for 30 minutes at room temperature, the mixture was concentrated under reduced pressure (10 mmHg, 60 ° C) to obtain 16.9 g of a colorless viscous liquid (yield: 98.7%).
[실시예 2]Example 2
아스파라긴산 나트륨염의 제조Preparation of Aspartic Acid Sodium Salt
아스파라긴산 13.3g(0.1몰)을 물 50ml에 현탁시키고 10% 탄산나트륨을 가하여 pH6.8로 하면 용해한다.13.3 g (0.1 mol) of aspartic acid are suspended in 50 ml of water and dissolved by adding 10% sodium carbonate to pH 6.8.
실온에서 30분간 교반후 감압농축(10mmHg, 60℃)하면 무색 점성액이 남는다. 석유에테르 150ml가하여 결정화시킨 후 침전을 여과 분리하고 진공건조(25℃, 1mmHg)하여 백색분말 15.2g(수율 : 98.4%)을 얻었다.After stirring for 30 minutes at room temperature under reduced pressure (10mmHg, 60 ℃) to leave a colorless viscous liquid. After adding 150 ml of petroleum ether to crystallize, the precipitate was separated by filtration and dried in vacuo (25 ° C., 1 mmHg) to obtain 15.2 g (yield: 98.4%) of white powder.
[실시예 3]Example 3
α-살리실리덴아미노아스파라긴산 칼륨염의 제조Preparation of α-salicylideneaminoaspartic acid potassium salt
아스파라긴산 칼륨염 17.1g(0.1몰)을 메틸렌클로라이드 100ml에 현탁시키고 N,N-디메틸아닐린 18.1g(0.15몰) 살리실알데하이드 13.4g(0.11몰)을 차례로 가한다. 45℃까지 가온하여 1시간 교반한 후 감압농축시켜 유기 용매를 제거하면 미황색의 점성물질이 남는다. n-핵산과 디옥산의 혼합 용매로 세척하여 α-살리실리덴아미노 아스파라긴산 칼륨염 23.0(수율 : 83.5%)을 얻었다.17.1 g (0.1 mol) of aspartic acid potassium salt is suspended in 100 ml of methylene chloride, and 18.1 g (0.15 mol) of N, N-dimethylaniline is added to 13.4 g (0.11 mol) of salicylaldehyde. After heating to 45 ° C. and stirring for 1 hour, the mixture was concentrated under reduced pressure to remove the organic solvent, leaving a pale yellow viscous substance. The mixture was washed with a mixed solvent of n-nucleic acid and dioxane to obtain α-salicylideneamino aspartic acid potassium salt 23.0 (yield: 83.5%).
[실시예 4]Example 4
α-p-메톡시살리실리덴아미노아스파라긴산칼륨염의 제조Preparation of α-p-methoxysalicylideneaminoaspartic acid potassium salt
아스파라긴산칼륨염 17.1g(0.1몰)을 에틸렌클로라이드 120ml에 현탁시키고 N,N-메틸아닐린 18.1g(0.15몰) p-메톡시살리실알데하이드 16.7g(0.11몰)을 차례로 가한다.17.1 g (0.1 mol) of potassium aspartic acid salt is suspended in 120 ml of ethylene chloride, and 18.1 g (0.15 mol) of N, N-methylaniline is added in 16.7 g (0.11 mol) of p-methoxysalicylaldehyde.
실온에서 4-5시간 교반한 후 감압하에 농축시켜 유기 용매를 유거하면 미황색의 점성물질이 남는다. n-핵산과 디옥산의 혼합용매로 세척하여 α-p-메톡시살리실리덴 아미노 아스파라긴산 칼륨염 24.9g(수율 : 81.7%)을 얻었다.After stirring for 4-5 hours at room temperature, concentrated under reduced pressure to distill the organic solvent to leave a slightly yellow viscous substance. Washing with a mixed solvent of n-nucleic acid and dioxane gave 24.9 g (yield: 81.7%) of α-p-methoxysalicylidene amino aspartic acid potassium salt.
[실시예 5]Example 5
α-클로로살리실리덴아미노아스파라긴산 나트륨염의 제조Preparation of α-chlorosalicylideneaminoaspartic acid sodium salt
아스파라긴산 나트륨염 15.5g(0.1몰)을 메틸렌클로라이드 150ml에 현탁시키고 N,N-디메틸아닐린 18.1g(0.15몰) 5-클로로 살리실알데하이드 17.2g(0.11몰)을 차례로 가한다.15.5 g (0.1 mol) of aspartic acid sodium salt are suspended in 150 ml of methylene chloride, and 18.1 g (0.15 mol) of N, N-dimethylaniline and 17.2 g (0.11 mol) of 5-chloro salicylaldehyde are added sequentially.
실온에서 4-5시간 교반한 후 감압하에 농축시켜 유기용매를 증발시키면 황록색의 점성물질이 남는다.After stirring for 4-5 hours at room temperature, the mixture was concentrated under reduced pressure to evaporate the organic solvent, leaving a yellowish green viscous substance.
n-헥산과 디옥산의 혼합 용매로 세척하여 α-5-클로로살리실리덴-아미노아스파라긴산-나트륨염 26.1g(수율 : 84.1%)을 얻었다.Washing with a mixed solvent of n-hexane and dioxane afforded 26.1 g (yield: 84.1%) of α-5-chlorosalicylidene-aminoaspartic acid sodium salt.
[실시예 6]Example 6
아미노로 보호된 아스파템의제조Preparation of amino protected aspartame
α-살리실리덴아미노아스파라긴산 칼륨염 5.5g(0.02몰)과 L-페닐알라닌 메틸에스테르클로라이드 4.8g(0.022몰)을 N,N-디메틸포름아마이드 50ml에 현탁시키고 N-석시니미딜디페닐포스페이트 7.6g을 N,N-디메틸포름아미드 50ml에 용해시켜 가한다. 계속해서 N,N-디메틸포름아미드 50ml에 희석시킨 트리에틸아민 4.4g을 0-5℃에서 5-10분간 가한다. 반응혼합물을 0℃에서 1시간 실온에서 8시간 교반한후 에틸아세테이트 1.5ℓ로 희석하고 5% 염산 500ml씩 2회, 물 500ml씩 2회 세척한다.5.5 g (0.02 mol) of α-salicylideneaminoaspartic acid potassium salt and 4.8 g (0.022 mol) of L-phenylalanine methyl ester chloride were suspended in 50 ml of N, N-dimethylformamide and 7.6 g of N-succinimidyldiphenylphosphate. It is dissolved in 50 ml of N, N-dimethylformamide and added. Subsequently, 4.4 g of triethylamine diluted in 50 ml of N, N-dimethylformamide were added at 0-5 ° C for 5-10 minutes. The reaction mixture was stirred at 0 ° C. for 1 hour at room temperature for 8 hours, diluted with 1.5 L of ethyl acetate, washed twice with 500 ml of 5% hydrochloric acid and twice with 500 ml of water.
에틸아세테이트층을 망초로 건조시킨 후 감압하에 농축하여 아미노기가 보호된 아스파템의 미황색 결정성분발 7.0g(수율 : 87.4%)을 얻었다.The ethyl acetate layer was dried over forget-me-not and concentrated under reduced pressure to obtain 7.0 g (yield: 87.4%) of pale yellow crystalline constituents of the aspartem amino group protected.
[실시예 7]Example 7
α-아스파템의 구조Structure of α-aspartum
메탄올 100ml로 희석한 진한 염산 10ml에 아미노기가 보호된 아스파템 10g을 가하고 30분간 교반한다. 유기용매를 감압하에 농축한 후 잔사에 에테르 250ml가하고 세게 교반한다. 결정을 분리하여 에테르로 세척한 후 진공 건조하여 백색의 결정성 분말 7.1g(수율 : 97.4%)을 얻었다.To 10 ml of concentrated hydrochloric acid diluted with 100 ml of methanol, add 10 g of aspartame protected with an amino group and stir for 30 minutes. The organic solvent is concentrated under reduced pressure, 250 ml of ether is added to the residue, and the mixture is stirred vigorously. The crystals were separated, washed with ether and dried in vacuo to yield 7.1 g of a white crystalline powder (yield: 97.4%).
비선광도-2.3(1N HCl)Non-luminescence -2.3 (1 N HCl)
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR8205909A KR850000059B1 (en) | 1982-12-31 | 1982-12-31 | Process of preparing for alpha-l-aspatyl-l-phehylallanine alkylaster |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR8205909A KR850000059B1 (en) | 1982-12-31 | 1982-12-31 | Process of preparing for alpha-l-aspatyl-l-phehylallanine alkylaster |
Publications (2)
Publication Number | Publication Date |
---|---|
KR840002760A KR840002760A (en) | 1984-07-16 |
KR850000059B1 true KR850000059B1 (en) | 1985-02-15 |
Family
ID=19226405
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR8205909A KR850000059B1 (en) | 1982-12-31 | 1982-12-31 | Process of preparing for alpha-l-aspatyl-l-phehylallanine alkylaster |
Country Status (1)
Country | Link |
---|---|
KR (1) | KR850000059B1 (en) |
-
1982
- 1982-12-31 KR KR8205909A patent/KR850000059B1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
KR840002760A (en) | 1984-07-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0127411B1 (en) | Method of preparing alpha-l-aspartyl-l-phenylalanine methyl ester and its hydrochloride | |
US4521514A (en) | Process for producing an addition compound of a dipeptide ester and an amino acid ester | |
KR920002337B1 (en) | Process for preparing alpha-l-aspartyl-l-phenylalanine methylester of hydrochloride | |
US4760164A (en) | Process for producing α-L-aspartyl-L-phenylalanine methyl ester | |
US4333872A (en) | Method of producing α-L-aspartyl-L-phenylalanine methylester | |
CA1137979A (en) | PROCESS FOR PRODUCING AN .alpha.-L-ASPARTYL- L-PHENYLALANINE LOWER ALKYL ESTER | |
KR850000059B1 (en) | Process of preparing for alpha-l-aspatyl-l-phehylallanine alkylaster | |
US4490386A (en) | Phosphate salts of 1-[2-[(1-alkoxycarbonyl-3-aralkyl)-amino]-1-oxoalkyl]octahydro-1H-indole-2-carboxylic acids, preparation of, and medical compositions thereof | |
EP0285992B1 (en) | Crystalline quinapril and a process for producing the same | |
KR890005064B1 (en) | Process for the preparation of alpha-l-aspartyl-l-phenylalanine methylester | |
SU1342423A3 (en) | Method of producing methyl ether of n-l-alpha-aspartyl-l-phenylalanine | |
EP0058567A1 (en) | Substituted acyl derivatives of octahydro-1H-isoindole-1-carboxylic acids and esters | |
US4048224A (en) | Process for resolving alanine, 3-fluoro and 2-deutero-3-fluoro-DL-alanine | |
JP2507505B2 (en) | New method for producing cephalosporin derivatives | |
JP2662287B2 (en) | Method for separating α-L-aspartyl-L-phenylalanine methyl ester | |
JPH078855B2 (en) | Sulfonium compound | |
KR900000685B1 (en) | Process for the preparation pf alpha-l-aspartyl-phenylalanine alkylester | |
US3933783A (en) | Formation of peptide bonds in the presence of isonitriles | |
KR880002415B1 (en) | Process for the preparation of a-l-aspartyl-l-phenyl alanine alkyl ester | |
US3984417A (en) | Method of producing active amino acid esters | |
CA1298682C (en) | PREPARATION PROCESS OF .alpha.-L-ASPARTYL-L-PHENYL-ALANINE METHYL ESTER OR HYDROHALIDE THEREOF | |
JP2647439B2 (en) | Method for producing N-protected-α-L-aspartyl-L-phenylalanine methyl ester | |
KR920003333B1 (en) | Process for preparing alpha-l-aspartyl-l-phenylalanine beta-low methyl ester | |
KR930007432B1 (en) | Process for preparing alpha-l-aspartyl-l-phenylalanin methyl ester | |
KR890000641B1 (en) | Process for the preparation of n-(4-nitro/cyano phenylthio carbarmoyl)-l-asparthyl-l-phenylalaine methylester |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
G160 | Decision to publish patent application | ||
O035 | Opposition [patent]: request for opposition | ||
O035 | Opposition [patent]: request for opposition | ||
O073 | Decision to grant registration after opposition [patent]: decision to grant registration | ||
GRNT | Written decision to grant | ||
FPAY | Annual fee payment |
Payment date: 19941216 Year of fee payment: 11 |
|
LAPS | Lapse due to unpaid annual fee |