KR940011148B1 - Process for the preparation of high yield of n-benzyloxy carbonyl-l-aspartic acid - Google Patents

Process for the preparation of high yield of n-benzyloxy carbonyl-l-aspartic acid Download PDF

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KR940011148B1
KR940011148B1 KR1019910021640A KR910021640A KR940011148B1 KR 940011148 B1 KR940011148 B1 KR 940011148B1 KR 1019910021640 A KR1019910021640 A KR 1019910021640A KR 910021640 A KR910021640 A KR 910021640A KR 940011148 B1 KR940011148 B1 KR 940011148B1
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aspartic acid
benzyloxycarbonyl
toluene
reaction
temperature
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KR930009986A (en
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최경석
주대권
한민수
최홍규
황이남
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주식회사 미원
유영학
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups

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Abstract

Title compound is one of the raw materials for preparing an artificial sweetener α-L-aspartyl-L-phenylalanine methylester. L-Aspartic acid dissolved in distilled water is adjusted to pH 11.0 with 45 % NaOH and benzyloxycarbonyl chloride containing toluene 50-90 % and toluene are added to it at 55-80 deg.C. The quantity of used toluene is 1-3 times of L-aspartic acid in weight.

Description

고수율의 N-벤질옥시카보닐-L-아스파트산의 제조방법Process for preparing high yield N-benzyloxycarbonyl-L-aspartic acid

본 발명은 인공 감미료인 α-L-아스파틸-L-페닐알라닌 메틸에스테르의 원료 물질들 중의 하나인 N-벤질옥시카보닐-L-아스파트산을 고수율로 제조하는 방법에 관한 것이다.The present invention relates to a process for producing N-benzyloxycarbonyl-L-aspartic acid, which is one of the raw materials of α-L-aspartyl-L-phenylalanine methyl ester, which is an artificial sweetener.

지금까지 인공 감미료인 1-L-아스파틸-L-페닐알라닌 메틸에스테르를 제조하는데 필요한 공정중의 하난인 L-아스파트산의 아미노기를 보호하기 위하여, 포밀기, 벤질기, 벤조일기, 벤질옥시카보닐기 등 여러종류의 보호기가 사용되어 왔으며, 본 발명은 그 중 하나인 벤질옥시카보닐기를 사용하여 N-벤질옥시카보닐-L-아스파트산을 고수율로 제조함을 그 특징으로 한다.Formyl, benzyl, benzoyl, benzyloxycarbo to protect the amino group of L-aspartic acid, which is a Hanan in the process necessary to prepare artificial sweetener 1-L-aspartyl-L-phenylalanine methyl ester Various kinds of protecting groups such as a silyl group have been used, and the present invention is characterized in that N-benzyloxycarbonyl-L-aspartic acid is produced in high yield using a benzyloxycarbonyl group.

이미 보고된 대한민국 특허 제 84-5195호, 미국 특허 제 4,345,091호, 미국 특허 제 4,293,706호, 미국 특허 제 4,570,015호, 미국 특허 제 4,521,514호, 미국 특허 제 4,450,284호에 의하면, N-벤질옥시카보닐-L-아스파트산의 제조시 반응 온도를 20∼55℃로 하고, 벤질옥시카보닐 클로라이드를 순도 95% 이상의 제품으로 사용함으로써 95% 이하의 N-벤질옥시카보닐-L-아스파트산을 얻을 수 있는 것으로 되어 있다. 그러나, 순도 95% 이상의 벤질옥시카보닐 클로라이드로 N-벤질옥시카보닐-L-아스파트산을 제조할 때 기존의 특허들은 반응 온도 55℃ 이상에서 수행할 경우, 반응 용매가 물이므로 20∼50% NaOH로 pH를 조절하면 벤질옥시카보닐 클로라이드가 분해되어 벤질 알콜을 생성시키고 그에 따라 수율이 감소되는 단점이 있다.According to the already reported Korean Patent Nos. 84-5195, US Patent Nos. 4,345,091, US Patent Nos. 4,293,706, US Patent Nos. 4,570,015, US Patent Nos. 4,521,514 and US Patent No. 4,450,284, N-benzyloxycarbonyl- N-benzyloxycarbonyl-L-aspartic acid of 95% or less can be obtained by using a reaction temperature of 20-55 DEG C in the production of L-aspartic acid and using benzyloxycarbonyl chloride as a product having a purity of 95% or more. It is said to be possible. However, when preparing N-benzyloxycarbonyl-L-aspartic acid with benzyloxycarbonyl chloride with a purity of 95% or more, the existing patents are 20 to 50 because the reaction solvent is water when the reaction temperature is 55 ° C or higher. Adjusting the pH with% NaOH has the disadvantage that benzyloxycarbonyl chloride is decomposed to produce benzyl alcohol and thus the yield is reduced.

본 발명자들은 이런 기존 특허들의 단점을 보완하고 좀 더 높은 수율의 N-벤질옥시카보닐-L-아스파트산을 제조하기 위하여 95% 이상의 벤질옥시카보닐 클로라이드 대신 톨루엔이 함유된 벤질옥시카보닐 클로라이드를 사용하고 톨루엔을 L-아스파트산 중량 대비로 1∼3배 첨가하여 톨루엔과 물이 혼합되지 않는 성질을 이용 이종(異種) 반응을 수행함으로써, 반응 온도 55℃ 이상의 고온에서 N-벤질옥시카보닐-L-아스파트산을 제조할 수 있으며, 기존 특허에 보고된 수율보다 높은 수율의 N-벤질옥시카보닐-L-아스파트산을 제조할수 있음을 밝혀 내고 본 발명을 완성하였다.The inventors have made use of toluene-containing benzyloxycarbonyl chloride instead of 95% or more benzyloxycarbonyl chloride to compensate for the shortcomings of these existing patents and to produce higher yields of N-benzyloxycarbonyl-L-aspartic acid. N-benzyloxycarbo at a high temperature of 55 ° C. or higher by performing a heterogeneous reaction by using toluene and adding 1-3 times of toluene relative to the weight of L-aspartic acid to mix the toluene and water. The present invention has been completed by discovering that it is possible to prepare nile-L-aspartic acid and to produce higher yields of N-benzyloxycarbonyl-L-aspartic acid than the yield reported in the existing patents.

본 발명에서는 톨루엔을 사용함으로써, 벤질옥시카보닐 클로라이드가 고온 반응에서 벤질 알콜로 분해되는 것이 방지되어 L-아스파트산 나트륨염과 반응하게 되고 20∼50% NaOH를 사용하여도 벤질옥시카보닐 클로라이드가 벤질 알콜로 분해되는 경우가 없으므로, 종래 기술의 단점이 보완된 결과를 가져오게 된다.In the present invention, by using toluene, benzyloxycarbonyl chloride is prevented from being decomposed into benzyl alcohol in a high temperature reaction to react with L-aspartic acid sodium salt and benzyloxycarbonyl chloride even when using 20-50% NaOH. Since it is not decomposed into benzyl alcohol, the disadvantages of the prior art are compensated for.

또한, N-벤질옥시카보닐-L-아스파트산 제조시 생성되는 부산물인 N-벤질옥시카보닐-L-아스파틸-L-아스파트산을 염기 가수분해시키는 미국 특허 제 4,450,284호 유럽 특허 제 0 072 015호의 특허가 있는데, 이들 특허에 의하여 염기 가수분해를 pH 10∼12, 온도 65∼90℃에서 수행하는데 반하여, 본 발명에서는 톨루엔의 첨가로 N-벤질옥시카보닐-L-아스파트산을 고온에서 제조할 때 부산물로 생성되는 N-벤질옥시카보닐-L-아스파틸-L-아스파트산을 반응 과정중에 염기 가수분해시키므로, N-벤질옥시카보닐-L-아스파트산의 제조 수율이 향상되어 기존의 N-벤질옥시카보닐-L-아스파트산의 제조방법을 개선하는 결과를 가져온 것이다.In addition, US Patent No. 4,450, 284, which discloses a base hydrolysis of N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid, a by-product produced in the production of N-benzyloxycarbonyl-L-aspartic acid. There is a patent of 0 072 015, whereby the base hydrolysis is performed at pH 10-12, temperature 65-90 DEG C, whereas in the present invention, N-benzyloxycarbonyl-L-aspartic acid is added by addition of toluene. When N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid, which is produced as a by-product at high temperature, is hydrolyzed during the reaction, the preparation of N-benzyloxycarbonyl-L-aspartic acid Yield is improved, resulting in an improvement of the conventional method for preparing N-benzyloxycarbonyl-L-aspartic acid.

즉, 본 발명은 L-아스파트산을 증류수에 녹여 45% NaOH로 pH를 11.0으로 유지하고, 온도를 55℃ 이상으로 올린 다음 톨루엔이 함유된 벤질옥시카보닐 클로라이드와 톨루엔을 첨가한 후 55℃ 이상의 온도에서 교반하에 반응시키는 것을 특징으로 하는 N-벤질옥시카보닐-L-아스파트산의 제조방법에 관한 것이다.That is, in the present invention, L-aspartic acid is dissolved in distilled water to maintain a pH of 11.0 with 45% NaOH, the temperature is raised to 55 ° C. or higher, and toluene-containing benzyloxycarbonyl chloride and toluene are added, followed by 55 ° C. It relates to a method for producing N-benzyloxycarbonyl-L-aspartic acid, which is reacted under stirring at the above temperature.

본 발명에서는 N-벤질옥시카보닐-L-아스파트산의 제조 수율을 최대화하기 위하여, L-아스파트산 증량 대비의 2.5∼3배 부피의 물을 사용하므로써 결정 형성 후 모액으로 유출되는 N-벤질옥시카보닐-L-아스파트산을 최소화하였으며, 톨루엔이 함유된 벤질옥시카보닐 클로라이드를 사용하여 그를 L-아스파트산 나트륨염과 반응시킬 때 톨루엔을 L-아스파트산 중량 대비 1∼3배 부피로 첨가하여 반응 온도 55℃ 이상, pH 11.0±0.1에서 이종(異種)반응을 수행하므로써 벤질옥시카보닐 클로라이드가 벤질 알콜로 분해되는 것을 방지하였다. 또한, 반응중 형성되는 N-벤질옥시카보닐-L-아스파틸-L-아스파트산을 염기 가수분해시켜 N-벤질옥시카보닐-L-아스파트산의 제조 수율을 최대화하고 순도를 향상시켰다.In the present invention, in order to maximize the production yield of N-benzyloxycarbonyl-L-aspartic acid, by using 2.5 to 3 times the volume of water compared to L-aspartic acid increase, N- which flows out into the mother liquor after crystal formation. Benzyloxycarbonyl-L-aspartic acid was minimized, and toluene was 1-3 to the weight of L-aspartic acid when reacting it with L-aspartic acid sodium salt using benzyloxycarbonyl chloride containing toluene. It was added in a double volume to perform a heterogeneous reaction at a reaction temperature of 55 ° C. or higher and pH 11.0 ± 0.1 to prevent the decomposition of benzyloxycarbonyl chloride into benzyl alcohol. In addition, N-benzyloxycarbonyl-L-aspartyl-L-aspartic acid formed during the reaction was subjected to base hydrolysis to maximize the production yield of N-benzyloxycarbonyl-L-aspartic acid and to improve purity. .

이렇게 함으로써 본 발명에 따르면 종래의 방법들보다 제조 수율이 향상된 98% 이상의 N-벤질옥시카보닐-L-아스파트산을 제조할 수 있게 된다.By doing so, according to the present invention, 98% or more of N-benzyloxycarbonyl-L-aspartic acid having an improved production yield can be prepared.

본 발명의 N-벤질옥시카보닐-L-아스파트산의 제조 공정을 상세히 설명하면 다음과 같다.Hereinafter, a process for preparing N-benzyloxycarbonyl-L-aspartic acid of the present invention will be described in detail.

L-아스파트산을 물에 녹이고 45% NaOH로 pH를 11.0으로 맞춘다. 반응 용액의 온도가 55℃ 이상으로 되게 한후 톨루엔을 함유한 벤질옥시카보닐 클로라이드와 톨루엔을 서서히 첨가하면서 45% NaOH로 pH 11.0±0.1을 유지한다. 반응 종료 후 톨루엔 층과 수용액 층을 분리하고 톨루엔 층은 물로 2회 수세한다. 수용액 층을 농축 염산으로 pH 1.0까지 내린 후 수용액 온도를 50℃로 한다. pH 1.0에서 수용액 층을 5℃까지 내리고 강력 교반한 후 형성된 결정을 여과하여 5℃ 이하의 냉각수로 2회 수세한 후 60℃의 진공 건조기에서 건조하여 N-벤질옥시카보닐-L-아스파트산 결정을 얻는다.Dissolve L-aspartic acid in water and adjust the pH to 11.0 with 45% NaOH. After the temperature of the reaction solution is at least 55 ° C., benzyloxycarbonyl chloride and toluene containing toluene are slowly added to maintain pH 11.0 ± 0.1 with 45% NaOH. After completion of the reaction, the toluene layer and the aqueous solution layer were separated and the toluene layer was washed twice with water. The aqueous layer was lowered to pH 1.0 with concentrated hydrochloric acid, and the aqueous solution temperature was 50 ° C. The aqueous layer was lowered to 5 ° C. at pH 1.0, vigorously stirred, and the formed crystals were filtered, washed twice with cooling water of 5 ° C. or lower, and dried in a vacuum dryer at 60 ° C. to N-benzyloxycarbonyl-L-aspartic acid. Get a decision.

상기 본 발명의 제조 공정에서 사용되는 톨루엔을 함유하는 벤질옥시카보닐 클로라이드는 톨루엔을 50∼90%로 함유하는 것을 사용하는 것이 바람직하며, 반응 온도는 55∼80℃가 바람직하다.Benzyloxycarbonyl chloride containing toluene used in the production process of the present invention preferably contains 50 to 90% of toluene, and the reaction temperature is preferably 55 to 80 ° C.

본 발명을 하기의 실시예로써 상세히 설명한다.The invention is illustrated in detail by the following examples.

[실시예 1]Example 1

순도 97%인 L-아스파트산 46g(0.335몰)을 물 120ml에 녹이고 45% NaOH 69ml로 pH를 11.0으로 맞춘다. 반응 용액의 온도가 55∼60℃가 되게 한후 톨루엔을 50% 함유한 벤질옥시카보닐 클로라이드 114ml과 톨루엔 50ml을 10∼20분동안 첨가하면서 45% NaOH로 pH 11.0±0.1을 유지한다. 톨루엔을 50% 함유한 벤질옥시카보닐 클로라이드와 톨루엔이 모두 첨가된 후 반응 용액을 55∼60℃까지 가온하여 60분간 강력 교반하에 반응시키며 이때 pH는 계속 45% NaOH로 11.0±0.1를 유지한다. 반응 종료 후 톨루엔 층과 수용액 층을 분리하고 톨루엔 층은 물 5ml씩 2회 수세한다. 수용액 층을 농축 염산으로 pH 1.0까지 내린후 수용액 온도를 50℃로 한다. pH 1.0에서 수용액 층을 5℃까지 내리고 1시간동안 강력 교반한 후 형성된 걸정을 여과하고 5℃ 이하의 냉각수 40ml로 2회 수세한 후 60℃의 진공건조기에서 5시간 동안 건조하여 N-벤질옥시카보닐-L-아스파트산 결정을 얻는다.46 g (0.335 mol) of L-aspartic acid with a purity of 97% are dissolved in 120 ml of water and the pH is adjusted to 11.0 with 69 ml of 45% NaOH. After the temperature of the reaction solution is 55-60 ° C., 114 ml of benzyloxycarbonyl chloride containing 50% of toluene and 50 ml of toluene are added for 10-20 minutes while maintaining pH 11.0 ± 0.1 with 45% NaOH. After both benzyloxycarbonyl chloride and toluene containing 50% toluene and toluene were added, the reaction solution was heated to 55-60 ° C. and reacted under vigorous stirring for 60 minutes, at which time the pH was maintained at 11.0 ± 0.1 with 45% NaOH. After completion of the reaction, the toluene layer and the aqueous layer were separated, and the toluene layer was washed twice with 5 ml of water. The aqueous layer was lowered to pH 1.0 with concentrated hydrochloric acid, and the aqueous solution temperature was 50 ° C. After lowering the aqueous layer to pH 5 at 5 ° C. and vigorously stirring for 1 hour, the formed gallbladder was filtered, washed twice with 40 ml of cooling water at 5 ° C. or lower, and then dried in a vacuum dryer at 60 ° C. for 5 hours to be N-benzyloxycarbona. Obtain a Ni-L-aspartic acid crystal.

이와 같이 얻어진 N-벤질옥시카보닐-L-아스파트산 결정의 중량은 88.4g(0.327몰)이고 결정 수율은 97.5%이며 결정 순도는 HPLC에서 99.85%이었다.The weight of the N-benzyloxycarbonyl-L-aspartic acid crystal thus obtained was 88.4 g (0.327 mol), the crystal yield was 97.5%, and the crystal purity was 99.85% in HPLC.

[실시예 2]Example 2

톨루엔을 100ml 첨가하고 반응 온도를 60∼65℃까지 가온한 것외에는 실시예 1과 동일한 방법으로 하여 N-벤질옥시카보닐-L-아스파트산 결정을 얻는다.N-benzyloxycarbonyl-L-aspartic acid crystals were obtained in the same manner as in Example 1 except that 100 ml of toluene was added and the reaction temperature was heated to 60 to 65 ° C.

이와 같이 얻어진 N-벤질옥시카보닐-L-아스파트산 결정의 중량은 87.2g(0.327몰)이고 결정 수율은 97.5%이며 결정 순도는 HPLC에서 99.85%이었다.The weight of the N-benzyloxycarbonyl-L-aspartic acid crystal thus obtained was 87.2 g (0.327 mol), the crystal yield was 97.5%, and the crystal purity was 99.85% in HPLC.

[실시예 3]Example 3

톨루엔을 150ml 첨가하고 반응 온도를 70∼75℃까지 가온한 것외에는 실시예 1과 동일한 방법으로 하여 N-벤질옥시카보닐-L-아스파트산 결정을 얻는다.N-benzyloxycarbonyl-L-aspartic acid crystals were obtained in the same manner as in Example 1 except that 150 ml of toluene was added and the reaction temperature was heated to 70 to 75 ° C.

이와 같이 얻어진 N-벤질옥시카보닐-L-아스파트산 결정의 중량은 86.6g(0.324몰)이고 결정 수율은 96.8%이며 결정 순도는 HPLC에서 99.90%이었다.The weight of the N-benzyloxycarbonyl-L-aspartic acid crystal thus obtained was 86.6 g (0.324 mol), the crystal yield was 96.8%, and the crystal purity was 99.90% in HPLC.

Claims (3)

L-아스파트산을 증류수에 녹여 45% NaOH로 pH를 11.0으로 유지하고 온도를 55℃ 이상으로 올린 다음, 톨루엔이 함유된 벤질옥시카보닐 클로라이드와 톨루엔을 첨가한 후 55℃ 이상의 온도에서 교반하에 반응시키는 것을 특징으로 하는 N-벤질옥시카보닐-L-아스파트산의 제조방법.L-aspartic acid was dissolved in distilled water to maintain a pH of 11.0 with 45% NaOH, the temperature was raised to 55 ℃ or more, toluene-containing benzyloxycarbonyl chloride and toluene were added and stirred at a temperature of 55 ℃ or more A method for producing N-benzyloxycarbonyl-L-aspartic acid, characterized in that the reaction. 제 1 항에 있어서, 톨루엔이 50∼90% 함유된 벨질옥시카보닐 클로라이드를 사용하고, 톨루엔을 L-아스파트산 중량 대비 1∼3배 부피로 첨가하는 것을 특징으로 하는 N-벤질옥시카보닐-L-아스파트산의 제조방법.The N-benzyloxycarbonyl according to claim 1, wherein benzyloxycarbonyl chloride containing 50 to 90% of toluene is used, and toluene is added in a volume of 1 to 3 times the weight of L-aspartic acid. Method for preparing -L-aspartic acid. 제 1 항에 있어서, 반응 온도를 55℃∼80℃로 하는 것을 특징으로 하는 N-벤질옥시카보닐-L-아스파트산의 제조방법.The process for producing N-benzyloxycarbonyl-L-aspartic acid according to claim 1, wherein the reaction temperature is 55 ° C to 80 ° C.
KR1019910021640A 1991-11-29 1991-11-29 Process for the preparation of high yield of n-benzyloxy carbonyl-l-aspartic acid KR940011148B1 (en)

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