KR940011131B1 - Acid hydrolysis of n-benzyloxycarbonyl-l-aspartyl-l-aspartic acid - Google Patents
Acid hydrolysis of n-benzyloxycarbonyl-l-aspartyl-l-aspartic acid Download PDFInfo
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- KR940011131B1 KR940011131B1 KR1019910021639A KR910021639A KR940011131B1 KR 940011131 B1 KR940011131 B1 KR 940011131B1 KR 1019910021639 A KR1019910021639 A KR 1019910021639A KR 910021639 A KR910021639 A KR 910021639A KR 940011131 B1 KR940011131 B1 KR 940011131B1
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- C—CHEMISTRY; METALLURGY
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본 발명은 인공 감미료인 α-L-아스파틸-L-페닐알라닌 메틸 에스테르의 제조에 있어서, 원료 물질들중의 하나인 N-벤질옥시카보닐-L-아스파트산의 제조 과정중 부생성물로 얻어지는 N-벤질옥시카보닐-L-아스파틸-L-아스파트산을 산가수분해하는 방법에 관한 것으로서, 고순도의 N-벤질옥시카보닐-L-아스파트산을 제조하기 위하여 순도가 낮은 N-벤질옥시카보닐-L-아스파트산의 결정에 함유된 N-벤질옥시카보닐-L-아스파틸-L-아스프트산을 산가수분해방법에 관한 것이다.In the preparation of α-L-aspartyl-L-phenylalanine methyl ester, an artificial sweetener, the present invention is obtained as a by-product during the preparation of N-benzyloxycarbonyl-L-aspartic acid, which is one of the raw materials. A method for acid hydrolysis of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid, wherein N-benzyloxycarbonyl-L-aspartic acid has low purity to prepare N-benzyloxycarbonyl-L-aspartic acid. A method for acid hydrolysis of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid contained in crystals of benzyloxycarbonyl-L-aspartic acid.
종래, N-벤질옥시카보닐-L-아스파트산에 함유되어 있는 N-벤질옥시카보닐-L-아스파틸-L-아스파트산을 가수분해하여 N-벤질옥시카보닐-L-아스파트산의 순도를 향상시키는 방법으로는 유럽 특허 제 0, 072, 015호에 소개된 방법이 있다. 이 방법에 의하면 N-벤질옥시카보닐-L-아스파틸-L-아스파트산을 온도 65~85℃, pH 10.0에서 염기 가수분해하여, N-벤질옥시카보닐-L-아스파틸-L-아스파트산이 0.1~0.2%의 중량퍼센트로 함유된 N-벤질옥시카보닐-L-아스파트산을 제조하였다. 그리고, 미국 특허 제 4, 450, 284호에 의하면 온도 65~90℃, pH 10~`1에서 염기 가수분해하여 N-벤질옥시카보닐-L-아스파틸-L-아스파트산이 0.2%보다 적은 0.1중량% 수준으로 함유된 N-벤질옥시카보닐-L-아스파트산을 제조하였고, 미국 특허 제4, 293, 706호에 의하면 0.17%의 N-벤질옥시카보닐-L-아스파틸-L-아스파트산을 함유한 N-벤질옥시카보닐-L-아스파트산을 얻었다. 이와 같이, 이미 보고된 특허들에 의하면 N-벤질옥시카보닐-L-아스파트산의 결정 순도를 향상시키는 방법으로 N-벤질옥시카보닐-L-아스파틸-L-아스파트산을 염기 가수분해시켰으나, 이 방법으로는 0.1중량% 이하의 N-벤질옥시카보닐-L-아스파틸-L-아스파트산을 함유하는 N-벤질옥시카보닐-L-아스파트산을 제조할 수는 없다.Conventionally, N-benzyloxycarbonyl-L-aspartic acid is hydrolyzed by N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid to N-benzyloxycarbonyl-L-aspartic acid. As a method of improving the purity of the acid, there is a method introduced in EP 0, 072, 015. According to this method, N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid is subjected to base hydrolysis at a temperature of 65 to 85 ° C. and pH 10.0 to thereby N-benzyloxycarbonyl-L-aspartyl-L- N-benzyloxycarbonyl-L-aspartic acid containing 0.1% to 0.2% by weight of aspartic acid was prepared. And, according to U.S. Patent No. 4,450,284, base hydrolysis at a temperature of 65 to 90 ° C. and pH 10 to 1 results in less than 0.2% of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid. N-benzyloxycarbonyl-L-aspartic acid containing 0.1 wt% level was prepared and according to US Patent No. 4, 293, 706, 0.17% of N-benzyloxycarbonyl-L-aspartyl-L N-benzyloxycarbonyl-L-aspartic acid containing aspartic acid was obtained. As such, according to previously reported patents, N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid is used as a base to improve the crystal purity of N-benzyloxycarbonyl-L-aspartic acid. Although decomposed, N-benzyloxycarbonyl-L-aspartic acid containing less than 0.1% by weight of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid cannot be prepared. .
본 발명에서는 N-벤질옥시카보닐-L-아스파틸-L-아스파트산을 염기 가수분해시키는 대신 산가수분해시키므로, 순도가 낮은 N-벤질옥시카보닐-L-아스파트산에 함유된 N-벤질옥시카보닐-L-아스파틸-L-아스파트산을 0.01%까지 줄일 수가 있다. 이에 따라 본 발명은 기존의 염기 가수분해에 의한 N-벤질옥시카보닐-L-아스파트산의 순도 향상 방법과는 달리 N-벤질옥시카보닐-L-아스파틸-L-아스파트산이 기존의 방법들보다 10~20배 적게 함유된 고순도의 N-벤질옥시카보닐-L-아스파트산을 제조하는데 성공하였다.In the present invention, since N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid is hydrolyzed instead of base hydrolysis, N-benzyloxycarbonyl-L-aspartic acid is contained. Benzyloxycarbonyl-L-aspartyl-L-aspartic acid can be reduced by 0.01%. Accordingly, in the present invention, unlike the conventional method for improving the purity of N-benzyloxycarbonyl-L-aspartic acid by base hydrolysis, N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid It was successful to prepare high purity N-benzyloxycarbonyl-L-aspartic acid containing 10-20 times less than the methods.
즉, 본 발명은 N-벤질옥시카보닐-L-아스파틸-L-아스파트산이 함유된 저순도의 N-벤질옥시카보닐-L-아스파트산을 N-벤질옥시카보닐-L-아스파트산 중량의 3배 부피의 물에 녹이고 산을 사용하여 pH를 조정한 후 가열, 교반하에 산가수분해하는 것을 특징으로 하는 N-벤질옥시카보닐-L-아스파틸-L-아스파트산의 산가수분해방법에 관한 것으로, 본 발명의 방법에 따르면 종래의 기술로는 결코 이루어낼 수 없는 고순도의 N-벤질옥시카보닐-L-아스파트산을 제조할 수가 있다.That is, the present invention is a low-purity N-benzyloxycarbonyl-L-aspartic acid containing N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid N-benzyloxycarbonyl-L-as Of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid, which is dissolved in water having a volume of 3 parts by weight of acid and acid-hydrolyzed under heating and stirring after adjusting pH using acid. The present invention relates to an acid hydrolysis method, and according to the method of the present invention, a high-purity N-benzyloxycarbonyl-L-aspartic acid that can be achieved by conventional techniques can be produced.
본 발명의 N-벤질옥시카보닐-L-아스파틸-L-아스파트산의 산 가수분해 방법을 상세히 설명하면 다음과 같다.An acid hydrolysis method of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid of the present invention will be described in detail as follows.
N-벤질옥시카보닐-L-아스파트산과 N-벤질옥시카보닐-L-아스파틸-L-아스파트산, 수분을 함유한 저순도의 N-벤질옥시카보닐-L-아스파트산을 물에 녹이고 염산, 황산 또는 인산을 사용하여 pH를 0.1~0.8까지 내린 후 수용액의 온도를 100℃까지 가열하여 2시간 동안 강력 교반하에 산가수분해시킨다. 반응 종료 후 반응 용액을 45℃까지 내리고 20% NaOH로 pH 1.5를 유지하면서 상온에서 2시간 교반한 후 5℃ 이하에서 1시간 동안 추가 교반하여 생성된 N-벤질옥시카보닐-L-아스파트산을 여과하고, 5℃ 이하의 냉각수로 수세한 다음에 건조하여 N-벤질옥시카보닐-L-아스파트산을 얻는다. 이와 같이 얻은 N-벤질옥시카보닐-L-아스파트산의 중량, 순도, 수율 및 N-벤질옥시카보닐-L-아스파틸-L-아스파트산의 함유량을 HPLC로 분석한다.N-benzyloxycarbonyl-L-aspartic acid and N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid and water containing low purity N-benzyloxycarbonyl-L-aspartic acid Dissolve in water and reduce the pH to 0.1 ~ 0.8 with hydrochloric acid, sulfuric acid or phosphoric acid, and then heat the temperature of the aqueous solution to 100 ℃ and acid hydrolyze under vigorous stirring for 2 hours. After the reaction was completed, the reaction solution was lowered to 45 ° C. and stirred at room temperature for 2 hours while maintaining pH 1.5 with 20% NaOH, and then further stirred for 1 hour at 5 ° C. or lower, thereby producing N-benzyloxycarbonyl-L-aspartic acid. The filtrate was filtered, washed with cool water at 5 DEG C or lower, and dried to obtain N-benzyloxycarbonyl-L-aspartic acid. The weight, purity, yield and content of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid of N-benzyloxycarbonyl-L-aspartic acid thus obtained are analyzed by HPLC.
[실시예 1]Example 1
N-벤질옥시카보닐-L-아스파트산 47.45g(0.357몰)과 N-벤질옥시카보닐-L-아스파틸-L-아스파트산 2.5g(9.363밀리몰), 수분 0.05g을 함유한 저순도의 N-벤질옥시카보닐-L-아스파트산 50g을 물 150㎖에 녹이고 농축 염산을 사용하여 pH 0.5까지 내린 후 100℃에서 2시간 동안 강력 교반하에 산가수분해시켰다. 반응 종료후 반응 용액을 45℃까지 내리고 20% NaOH로 pH 1.5를 유지하면서 상온에서 2시간 교반한 후 5℃ 이하에서 1시간 동안 추가 교반하여 형성된 N-벤질옥시카보닐-L-아스파트산을 여과하고, 5℃ 이하의 냉각수로 수세한 다음 건조하여 N-벤질옥시카보닐-L-아스파트산을 얻었다. 이와 같이 얻은 N-벤질옥시카보닐-L-아스파트산의 중량, 순도, 수율 및 N-벤질옥시카보닐-L-아스파틸-L-아스파트산의 함유량을 HPLC로 분석하였다.Low containing 47.45 g (0.357 mol) of N-benzyloxycarbonyl-L-aspartic acid, 2.5 g (9.363 mmol) of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid, and 0.05 g of water 50 g of N-benzyloxycarbonyl-L-aspartic acid of purity was dissolved in 150 ml of water, lowered to pH 0.5 with concentrated hydrochloric acid, and acid hydrolyzed under vigorous stirring at 100 ° C. for 2 hours. After completion of the reaction, the reaction solution was lowered to 45 ° C. and stirred at room temperature for 2 hours while maintaining pH 1.5 with 20% NaOH, followed by further stirring at 5 ° C. or lower for 1 hour to form N-benzyloxycarbonyl-L-aspartic acid. It filtered, washed with water with 5 degrees C or less cooling water, and dried and obtained N-benzyloxycarbonyl-L-aspartic acid. The weight, purity, yield and content of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid of N-benzyloxycarbonyl-L-aspartic acid thus obtained were analyzed by HPLC.
[HPLC 분석 결과][HPLC Analysis Results]
N-벤질옥시카보닐-L-아스파트산의 중량 : 48.160g(0.362몰)Weight of N-benzyloxycarbonyl-L-aspartic acid: 48.160 g (0.362 mol)
N-벤질옥시카보닐-L-아스파트산의 수율 : 98.90%Yield of N-benzyloxycarbonyl-L-aspartic acid: 98.90%
N-벤질옥시카보닐-L-아스파트산의 순도 : 99.99%Purity of N-benzyloxycarbonyl-L-aspartic acid: 99.99%
N-벤질옥시카보닐-L-아스파틸-L-아스파트산의 함유량 : 0.0101중량%Content of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid: 0.0101% by weight
[실시예 2]Example 2
실시예 1과 동일한 N-벤질옥시카보닐-L-아스파트산 50g을 물 150㎖에 녹이고 농축 염산으로 pH 0.1~2.0까지 내린 후 실시예 1과 동일한 과정으로 N-벤질옥시카보닐-L-아스파트산을 얻고 HPLC로 분석하였다.50 g of the same N-benzyloxycarbonyl-L-aspartic acid as in Example 1 was dissolved in 150 ml of water and lowered to pH 0.1-2.0 with concentrated hydrochloric acid, followed by N-benzyloxycarbonyl-L- as in Example 1. Aspartic acid was obtained and analyzed by HPLC.
[HPLC 분석 결과][HPLC Analysis Results]
N-벤질옥시카보닐-L-아스파트산의 중량 : 48.145g(0.362몰)Weight of N-benzyloxycarbonyl-L-aspartic acid: 48.145 g (0.362 mol)
N-벤질옥시카보닐-L-아스파트산의 수율 : 98.87%Yield of N-benzyloxycarbonyl-L-aspartic acid: 98.87%
N-벤질옥시카보닐-L-아스파트산의 순도 : 99.97%Purity of N-benzyloxycarbonyl-L-aspartic acid: 99.97%
N-벤질옥시카보닐-L-아스파틸-L-아스파트산의 함유량 : 0.0090중량%Content of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid: 0.0090% by weight
[실시예 3]Example 3
실시예 1과 동일한 N-벤질옥시카보닐-L-아스파트산 50g을 물 150㎖에 녹이고 농축 염산으로 pH 0.75까지 내린후 실시예1과 동일한 과정으로 N-벤질옥시카보닐-L-아스파트산을 얻고 HPLC로 분석하였다.50 g of the same N-benzyloxycarbonyl-L-aspartic acid as in Example 1 was dissolved in 150 ml of water and lowered to pH 0.75 with concentrated hydrochloric acid, followed by N-benzyloxycarbonyl-L-aspartic acid in the same manner as in Example 1. Acid was obtained and analyzed by HPLC.
[HPLC 분석 결과][HPLC Analysis Results]
N-벤질옥시카보닐-L-아스파트산의 중량 : 47.620g(0.358몰)Weight of N-benzyloxycarbonyl-L-aspartic acid: 47.620 g (0.358 mol)
N-벤질옥시카보닐-L-아스파트산의 수율 : 97.80%Yield of N-benzyloxycarbonyl-L-aspartic acid: 97.80%
N-벤질옥시카보닐-L-아스파트산의 순도 : 99.87%Purity of N-benzyloxycarbonyl-L-aspartic acid: 99.87%
N-벤질옥시카보닐-L-아스파틸-L-아스파트산의 함유량 : 0.0151중량%Content of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid: 0.0151 wt%
[실시예 4]Example 4
실시예 1과 동일한 N-벤질옥시카보닐-L-아스파트산 50g을 물 150㎖에 녹이고 농축 황산으로 pH 0.1~2.0까지 내린 후 실시예 1과 동일한 과정으로 N-벤질옥시카보닐-L-아스파트산을 얻고 HPLC로 분석하였다.50 g of the same N-benzyloxycarbonyl-L-aspartic acid as in Example 1 was dissolved in 150 ml of water and lowered to pH 0.1-2.0 with concentrated sulfuric acid, followed by N-benzyloxycarbonyl-L- Aspartic acid was obtained and analyzed by HPLC.
[HPLC 분석 결과][HPLC Analysis Results]
N-벤질옥시카보닐-L-아스파트산의 중량 : 48.111g(0.361몰)Weight of N-benzyloxycarbonyl-L-aspartic acid: 48.111 g (0.361 mol)
N-벤질옥시카보닐-L-아스파트산의 수율 : 98.80%Yield of N-benzyloxycarbonyl-L-aspartic acid: 98.80%
N-벤질옥시카보닐-L-아스파트산의 순도 : 99.98%Purity of N-benzyloxycarbonyl-L-aspartic acid: 99.98%
N-벤질옥시카보닐-L-아스파틸-L-아스파트산의 함유량 : 0.010중량%Content of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid: 0.010 wt%
[실시예 5]Example 5
실시예 1과 동일한 N-벤질옥시카보닐-L-아스파트산 50g을 물 150㎖에 녹이고 농축 황산으로 pH 0.8까지 내린 후 실시예 1과 동일한 과정으로 N-벤질옥시카보닐-L-아스파트산을 얻고 HPLC로 분석하였다.50 g of the same N-benzyloxycarbonyl-L-aspartic acid as in Example 1 was dissolved in 150 ml of water and lowered to pH 0.8 with concentrated sulfuric acid, followed by N-benzyloxycarbonyl-L-aspartic acid in the same manner as in Example 1. Acid was obtained and analyzed by HPLC.
[HPLC 분석 결과][HPLC Analysis Results]
N-벤질옥시카보닐-L-아스파트산의 중량 : 47.720g(0.359몰)Weight of N-benzyloxycarbonyl-L-aspartic acid: 47.720 g (0.359 mol)
N-벤질옥시카보닐-L-아스파트산의 수율 : 98.0%Yield of N-benzyloxycarbonyl-L-aspartic acid: 98.0%
N-벤질옥시카보닐-L-아스파트산의 순도 : 99.96%Purity of N-benzyloxycarbonyl-L-aspartic acid: 99.96%
N-벤질옥시카보닐-L-아스파틸-L-아스파트산의 함유량 : 0.0160중량%Content of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid: 0.0160 wt%
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| Application Number | Priority Date | Filing Date | Title |
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| KR1019910021639A KR940011131B1 (en) | 1991-11-29 | 1991-11-29 | Acid hydrolysis of n-benzyloxycarbonyl-l-aspartyl-l-aspartic acid |
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| Application Number | Priority Date | Filing Date | Title |
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| KR1019910021639A KR940011131B1 (en) | 1991-11-29 | 1991-11-29 | Acid hydrolysis of n-benzyloxycarbonyl-l-aspartyl-l-aspartic acid |
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| KR930009985A KR930009985A (en) | 1993-06-21 |
| KR940011131B1 true KR940011131B1 (en) | 1994-11-23 |
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