KR100532573B1 - Process for preparation of Magnesium L-ascorbyl-2-phosphate - Google Patents
Process for preparation of Magnesium L-ascorbyl-2-phosphate Download PDFInfo
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- KR100532573B1 KR100532573B1 KR10-2002-0072649A KR20020072649A KR100532573B1 KR 100532573 B1 KR100532573 B1 KR 100532573B1 KR 20020072649 A KR20020072649 A KR 20020072649A KR 100532573 B1 KR100532573 B1 KR 100532573B1
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- ascorbyl
- phosphate ester
- isopropylidene
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- magnesium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/62—Three oxygen atoms, e.g. ascorbic acid
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
반응 중간체를 결정화하여 불순물과 분리함으로써, 정제 및 제조 공정이 단순한 L-아스코빌-2-인산에스테르마그네슘염의 제조 방법이 개시된다. 이와 같은 L-아스코빌-2-인산에스테르마그네슘염의 제조방법은 수용성 5,6-보호기-L-아스코빌 -2-인산에스테르염을 칼슘염과 반응시켜 결정상의 5,6-보호기-L-아스코빌-2-인산에스테르칼슘을 제조하고 이를 반응액으로부터 분리하는 과정; 상기 결정상의 5,6-보호기-L-아스코빌-2-인산에스테르칼슘을 인산 용액에 용해시킨 후, 상기 5,6-보호기-L-아스코빌-2-인산에스테르칼슘에 결합된 보호기를 제거하는 과정; 및 반응액에 마그네슘염를 첨가하는 과정을 포함한다.By crystallizing the reaction intermediate and separating it from impurities, a method for producing L-ascorbyl-2-phosphate ester magnesium salt having a simple purification and production process is disclosed. Such a method for preparing L-ascorbyl-2-phosphate ester magnesium salt is obtained by reacting a water-soluble 5,6-protecting group-L-ascorbyl-2-phosphate ester salt with a calcium salt to form 5,6-protecting group-L-ascor. Preparing a benzoyl-2-phosphate ester and separating it from the reaction solution; After dissolving the crystalline 5,6-protecting group-L-ascorbyl-2-phosphate ester calcium phosphate solution, the protecting group bound to the 5,6-protecting group-L-ascorbyl-2-phosphate ester calcium was removed. Process of doing; And adding magnesium salt to the reaction solution.
Description
본 발명은 하기 화학식 1의 L-아스코빌-2-인산에스테르마그네슘염의 제조 방법 및 그 중간체에 관한 것으로서, 더욱 상세하게는, 반응 중간체를 결정화하여 불순물과 분리함으로써, 정제 및 제조 공정이 단순한 L-아스코빌-2-인산에스테르마그네슘염의 제조 방법에 관한 것이다.The present invention relates to a process for preparing L-ascorbyl-2-phosphate magnesium salt of formula (1) and to intermediates thereof, and more particularly, to the purification and manufacturing process of L-ascobyl-2-phosphate ester magnesium salts, in which the reaction intermediate is crystallized and separated from impurities. A method for producing ascorbyl-2-phosphate magnesium salt.
아스코빅산(Ascorbic acid)은 노화방지 및 피부미백 효과가 우수하여, 의약품, 식품, 화장품의 원료로 주로 사용되고 있으나, 열, 광원, 산소 등에 의해 쉽게 산화되어 그 활성을 잃을 뿐 만 아니라, 수용액 중에서 분해, 변색되는 단점이 있어서 그 사용에 제한을 받아 왔다. 이와 같은 단점이 없는 다양한 아스코빅산 유도체들이 개발되어 왔으며, 그 중 L-아스코빅산의 2-위치를 인산화시킨 L-아스코빌-2-인산에스테르염은 열, 광원, 산소 등에 불안정한 단점이 없고, 수용액 상에서의 안정성도 우수할 뿐 아니라, 체내에 흡수되면 알칼리 포스파타제에 의해서 인산기가 쉽게 분해되어 아스코빅산과 동등한 효과를 보이는 것으로 알려져 있다.Ascorbic acid has excellent anti-aging and skin whitening effects, and is mainly used as a raw material for medicines, foods, and cosmetics, but it is easily oxidized by heat, light source, and oxygen, and loses its activity. However, there has been a drawback of discoloration due to its disadvantages. Various ascorbic acid derivatives have been developed without such disadvantages, among which L-ascorbyl-2-phosphate ester salts phosphorylated 2-position of L-ascorbic acid do not have unstable disadvantages such as heat, light source, oxygen, etc. In addition to excellent stability in the phase, it is known that when absorbed into the body, phosphate groups are easily decomposed by alkaline phosphatase to have an effect equivalent to ascorbic acid.
이와 같은 L-아스코빌-2-인산에스테르염을 제조하는 다양한 방법들이 알려져 있다. 예를 들면, 미국특허 제4,179,445호는 5,6-이소프로필리덴-L-아스코빅산을 인산화시켜 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르염을 제조하는 방법을 개시하고 있으나, 상기 방법에 의하여 생성된 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르염은 여러 종류의 유기 불순물 및 무기물을 포함한다. 상기 불순물들은 대부분 친수성이고 분자량이 크지 않으므로, 수용액상에서 활성탄으로 흡착, 제거하기 어려우며, 이와 같은 수용액상 정제공정은 생성된 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르염을 변색시키는 원인이 된다.Various methods of preparing such L-ascorbyl-2-phosphate ester salts are known. For example, U.S. Patent No. 4,179,445 discloses a process for preparing 5,6-isopropylidene-L-ascorbyl-2-phosphate ester salts by phosphorylating 5,6-isopropylidene-L-ascorbic acid. However, the 5,6-isopropylidene-L-ascorbyl-2-phosphate ester salt produced by the above method includes various kinds of organic impurities and inorganic substances. Since most of the impurities are hydrophilic and have a low molecular weight, it is difficult to adsorb and remove activated carbon in an aqueous solution. Such an aqueous phase purification process discolors the resulting 5,6-isopropylidene-L-ascorbyl-2-phosphate ester salt. It causes.
미국특허 제4,999,437호는 인산화 반응에서 생성된 불순물인 인산염과 염화칼륨염을 제거하는 공정에서 감압증류를 반복하는 정제방법을 개시하고 있으나, 이와 같은 방법은 공정이 번거롭고, 수율이 저하되는 단점이 있으며, 미국특허 제5,202,445호는 인산화 반응 후, 전기투석법(electrodialysis)을 이용하여 반응액에 존재하는 무기염들을 제거하는 방법을 개시하고 있으나, 이 방법 또한 정제 공정 및 정제 설비가 매우 복잡해지는 단점이 있다.U.S. Patent No. 4,999,437 discloses a purification method of repeating distillation under reduced pressure in the process of removing phosphate and potassium chloride salts, which are impurities generated in the phosphorylation reaction, but such a method is cumbersome and the yield is reduced. U.S. Patent No. 5,202,445 discloses a method for removing inorganic salts present in the reaction solution by electrodialysis after phosphorylation, but this method also has a disadvantage in that the purification process and the purification equipment are very complicated. .
일본 특개소59-106,494호는 인산화 반응으로 생성된 염들을 제거하기 위하여 활성탄, 규조토, 활성백토 등의 흡착제를 사용하는 방법을 개시하고 있으나, 상기 방법은 최종 생성물을 처리하기 때문에 수율 손실이 많고, 고순도의 생성물을 얻기 어려운 단점이 있다. 또한 일본 특개소 59-51,293호는 강유기산이 활성탄에 잘 흡착되는 성질을 이용하여, 산성 조건에서 아스코빌 인산에스테르를 활성탄에 흡착시켜 목적화합물을 수득하는 방법을 개시하고 있으나, 활성탄에 목적화합물을 완전하게 흡착시키는 공정이 쉽지 않고, 탈착 시에도 수율손실이 많아 효과적이지 못하다. 또한, 대한민국 특허 1994-0007419에서도 역시 인산화 반응 후 생성되는 무기염들을 제거하기 위하여, 저급알코올을 첨가하고 감압 농축 및 활성탄을 이용하는 방법을 개시하고 있으나, 상기 방법도 공정이 번거롭고, 수율이 낮으며, 유기불순물이 완전히 제거되지 못하는 단점이 있다. 이외에도 상술한 종래 공정의 공통된 단점 중의 하나는 마그네슘염을 제조하기 전에 양이온 교환수지를 이용하여 중간체를 탈염하는 공정을 거쳐야 한다는 것이다. Japanese Patent Application Laid-Open No. 59-106,494 discloses a method of using an adsorbent such as activated carbon, diatomaceous earth, and activated clay to remove salts generated by phosphorylation reaction, but the method has a high yield loss because it processes the final product, There is a disadvantage that it is difficult to obtain a high purity product. In addition, Japanese Patent Application Laid-Open No. 59-51,293 discloses a method of adsorbing ascorbyl phosphate ester to activated carbon under acidic conditions to obtain a target compound by utilizing the property of fermenting organic acids to activated carbon well. The process of completely adsorption is not easy, and even when desorption, a large yield loss is not effective. In addition, the Republic of Korea Patent 1994-0007419 also discloses a method of adding a lower alcohol, concentrated under reduced pressure and activated carbon in order to remove the inorganic salts generated after the phosphorylation reaction, but also the process is cumbersome, low yield, There is a disadvantage that the organic impurities are not completely removed. In addition, one of the common disadvantages of the above-described conventional process is that before the magnesium salt is prepared, the intermediate salt must be desalted using a cation exchange resin.
따라서 본 발명의 목적은 수용액 상에서 갈변현상 없이 고순도의 목적화합물을 얻을 수 있는 L-아스코빌-2-인산에스테르마그네슘의 제조 방법을 제공하는 것이다. Accordingly, it is an object of the present invention to provide a method for preparing L-ascorbyl-2-phosphate magnesium which can obtain a high purity target compound in aqueous solution without browning.
본 발명의 다른 목적은 이온교환수지를 사용하지 않고 부산물을 쉽게 제거할 수 있을 뿐만 아니라, 제조 공정이 단순한 L-아스코빌-2-인산에스테르마그네슘의 제조 방법을 제공하는 것이다. Another object of the present invention is to provide a method for producing M-ascorbyl-2-phosphate ester, in which the by-products can be easily removed without using an ion exchange resin, and the manufacturing process is simple.
상기 목적을 달성하기 위해, 본 발명은 수용성 5,6-보호기-L-아스코빌-2-인산에스테르염을 칼슘염과 반응시켜 결정상의 5,6-보호기-L-아스코빌-2-인산에스테르칼슘을 제조하고 이를 반응액으로부터 분리하는 과정; 상기 결정상의 5,6-보호기-L-아스코빌-2-인산에스테르칼슘을 인산 용액에 용해시킨 후, 상기 5,6-보호기-L-아스코빌-2-인산에스테르칼슘에 결합된 보호기를 제거하는 과정; 및 반응액에 마그네슘염를 첨가하는 과정을 포함하는 L-아스코빌-2-인산에스테르마그네슘염의 제조방법을 제공한다.In order to achieve the above object, the present invention reacts the water-soluble 5,6-protecting group-L-ascorbyl-2-phosphate ester salt with calcium salt to give 5,6-protecting group-L-ascorbyl-2-phosphate ester in crystalline phase. Preparing calcium and separating it from the reaction solution; After dissolving the crystalline 5,6-protecting group-L-ascorbyl-2-phosphate ester calcium phosphate solution, the protecting group bound to the 5,6-protecting group-L-ascorbyl-2-phosphate ester calcium was removed. Process of doing; And it provides a method for producing L- ascorbyl-2-phosphate ester magnesium salt comprising the step of adding a magnesium salt to the reaction solution.
또한, 본 발명의 방법은 상기 마그네슘염을 첨가한 후, 형성되는 난용성염을 여과·제거하는 과정; 및 여과된 반응액에 유기용매를 첨가하여 L-아스코빌-2-인산에스테르마그네슘염을 결정으로 석출시켜 수득하는 과정을 더욱 포함할 수 있으며, 상기 수용성 5,6-보호기-L-아스코빌-2-인산에스테르염은 수산화칼륨, 수산화나트륨 등의 금속염의 존재 하에서 5,6-보호기-L-아스코빅산과 옥시염화인을 반응시켜 얻어지는 것이 바람직하다. 또한, 본 발명은 하기 화학식 2(여기서, R은 보호기이다.)로 표현되는 L-아스코빌-2-인산에스테르마그네슘염을 제조하기 위한 신규한 고체상의 중간체를 제공한다.In addition, the method of the present invention after the addition of the magnesium salt, the step of filtering and removing the poorly soluble salt formed; And adding an organic solvent to the filtered reaction solution to precipitate L-ascorbyl-2-phosphate magnesium salt as crystals. The water-soluble 5,6-protecting group-L-ascorbyle- The 2-phosphate ester salt is preferably obtained by reacting 5,6-protecting group-L-ascorbic acid with phosphorus oxychloride in the presence of metal salts such as potassium hydroxide and sodium hydroxide. The present invention also provides a novel solid phase intermediate for preparing L-ascorbyl-2-phosphate ester magnesium salt represented by the following formula (2) wherein R is a protecting group.
이하, 본 발명을 더욱 상세히 설명하면 다음과 같다. Hereinafter, the present invention will be described in more detail.
본 발명은 L-아스코르빌-2-인산에스테르 마그네슘염을 제조하는데 있어서, 5,6-이소프로필리덴-L-아스코빌산과 옥시염화인을 반응시킨 후, 무기산 또는 유기산을 이용하여 용액의 pH를 9 내지 10으로 조정하고, 칼슘염를 이용하여 난용성염인 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르 칼슘염을 형성한 다음, 이를 석출시켜 정제하는 과정을 이용하였다. 본 발명에 따른 L-아스코빌-2-인산에스테르마그네슘의 전체 제조 공정의 일예를 하기 반응식 1에 나타내었다. In the present invention, L-ascorbyl-2-phosphate ester magnesium salt is prepared by reacting 5,6-isopropylidene-L-ascorbyl acid with phosphorus oxychloride, and then using the inorganic or organic acid to adjust the pH of the solution. Was adjusted to 9 to 10, using a calcium salt to form a 5,6-isopropylidene-L- ascorbyl-2- phosphate ester calcium salt, a poorly soluble salt, and then used to precipitate and purify. An example of the entire production process of L-ascorbyl-2-phosphate magnesium according to the present invention is shown in Scheme 1 below.
상기 반응식 1에 나타낸 바와 같이, 본 발명에 따라 L-아스코빌-2-인산에스테르마그네슘(Ⅰ)을 제조하기 위해서는, 먼저 5,6-이소프로필리덴-L-아스코빅산(Ⅳ)과 옥시염화인을 반응시키고, 수산화칼륨을 첨가하여 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르 칼륨염(III)을 얻는다. 상기 반응에 사용되는 출발 물질인 5,6-이소프로필리덴-L-아스코빅산(Ⅳ)은 Can. J. Chem., 1969, 47, 2498에 개시된 방법으로 합성할 수 있으며, 상기 5,6-이소프로필리덴-L-아스코빅산(Ⅳ)의 이소프로필리덴기는 아스코빅산을 보호하기 위한 보호기로서, 상기 이소프로필리덴기 외에도 아스코빅산을 보호하기 위한 통상의 보호기가 사용될 수 있다. 상기 반응의 반응 용매로는 물과 피리딘의 혼합 용매를 사용할 수 있으며, 반응 온도는 -5℃ 내지 5℃인 것이 바람직하며, 더욱 바람직하게는 0℃이다. 또한 상기 반응에 사용되는 수산화칼륨은 반응액을 염기성으로 조절하여 수용성 5, 6-이소프로필리덴-L-아스코빌-2-인산에스테르염을 얻기 위한 것으로서, 바람직하게는 50w/v%의 수산화칼륨 수용액의 형태로 반응액에 첨가하여 반응액의 pH를 12 내지 13으로, 바람직하게는 13으로 조절하며, 필요에 따라 수산화칼륨 외에 수산화나트륨 등 다른 금속염을 단독 또는 혼합하여 사용할 수도 있다. 여기서, 상기 반응용액의 pH가 12 미만인 경우, 3위치에 인산화가 일어 날 수 있으며, 반응 온도가 -5℃ 미만이면 반응속도가 느려지며, 5℃를 초과하면 부반응이 발생할 우려가 있다. 또한 인산화 반응에 사용하는 옥시염화인은 5,6-이소프로필리덴-L-아스코빅산(Ⅳ)에 대하여 몰비로 1 내지 1.5배를 사용하는 것이 바람직하며, 만일 상기 인화합물의 사용 몰비가 1배 미만이면 반응 수율이 낮으며, 1.5배를 초과하여도 반응 수율이 더 이상 상승하지 않을 뿐만 아니라, 부산물의 생성량이 증가한다.As shown in Scheme 1, in order to prepare L-ascorbyl-2-phosphate magnesium (I) according to the present invention, 5,6-isopropylidene-L-ascorbic acid (IV) and phosphorus oxychloride Is reacted, and potassium hydroxide is added to obtain 5,6-isopropylidene-L-ascorbyl-2-phosphate ester potassium salt (III). The starting material 5,6-isopropylidene-L-ascorbic acid (IV) used in the reaction was Can. It can be synthesized by the method disclosed in J. Chem., 1969 , 47, 2498, the isopropylidene group of the 5,6-isopropylidene-L- ascorbic acid (IV) as a protecting group for protecting ascorbic acid, In addition to the isopropylidene group, conventional protecting groups for protecting ascorbic acid may be used. As a reaction solvent of the reaction, a mixed solvent of water and pyridine may be used, and the reaction temperature is preferably -5 ° C to 5 ° C, more preferably 0 ° C. In addition, the potassium hydroxide used in the reaction is to obtain a water-soluble 5, 6-isopropylidene-L- ascorbyl-2-phosphate ester salt by adjusting the reaction solution to basic, preferably 50w / v% potassium hydroxide The pH of the reaction solution is adjusted to 12 to 13, preferably 13, in addition to the reaction solution in the form of an aqueous solution, and other metal salts such as sodium hydroxide, in addition to potassium hydroxide, may be used alone or in combination. In this case, when the pH of the reaction solution is less than 12, phosphorylation may occur at the 3-position. If the reaction temperature is less than -5 ° C, the reaction rate is slowed, and if it exceeds 5 ° C, side reactions may occur. In addition, the phosphorus oxychloride used in the phosphorylation reaction is preferably used 1 to 1.5 times in molar ratio with respect to 5,6-isopropylidene-L-ascorbic acid (IV), if the molar ratio of the phosphorus compound is 1 times If less than, the reaction yield is low, and the reaction yield does not increase any more than 1.5 times, as well as the amount of by-products increases.
생성된 화합물은 강염기성의 반응액 중에 있으므로 가온 상황에서의 안정화 및 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르칼슘의 수득량 향상을 위하여, 염산 등의 무기산 또는 초산 등의 유기산을 이용하여 반응액의 pH를 7 내지 10으로 조정하고, 피리딘을 감압 증류한 후, 칼슘클로라이드 이수화물(CaCl2·2H2O) 등의 칼슘염을 첨가하여, 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르(Ⅲ)를 난용성 칼슘염(Ⅱ)으로 변환·침전시키고, 여과하여, 인산화 반응의 부산물로 생성된 인산칼륨 및 염화칼륨을 제거한다. 이때 반응 온도는 20 내지 40℃인 것이 바람직하고, 30 내지 35℃이면 더욱 바람직하며, 만일 반응온도가 20℃ 미만이면 결정 형태에 문제가 발생할 수 있으며, 40℃이상의 온도는 별 의미가 없다. 처음의 반응액의 pH조정은 pH를 7이하로 조정하면 수득율이 떨어지며, 10이상으로 하면 안정성이 떨어지게 되며 바람직하기로는 9.8이 적당하다. 또한 상기 난용성 인산에스테르칼슘염(Ⅱ)을 형성하기 위한 칼슘염의 사용량은 5,6-이소프로필리덴-L-아스코빅산에 대하여 몰비로 1.5 내지 2배인 것이 바람직하며, 만일 상기 칼슘염의 사용량이 1.5배 미만인 경우에는 결정 석출이 완전히 이루어지지 않을 우려가 있고, 2배를 초과하는 경우는 별 의미가 없다. 상기 결정화 반응에서 CaCl2·2H2O대신 마그네슘클로라이드(MgCl2·6H2O) 등을 사용할 경우, 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르 마그네슘염을 결정으로 얻어 낼 수 없으며, 오직 칼슘염 만이 결정으로 얻어진다.The resulting compound is in a strong basic reaction solution, so that it can be stabilized in a warming state and the yield of 5,6-isopropylidene-L-ascorbyl-2-phosphate ester calcium is improved. Inorganic acids such as hydrochloric acid or organic acids such as acetic acid The pH of the reaction solution was adjusted to 7 to 10, the pyridine was distilled under reduced pressure, and calcium salts such as calcium chloride dihydrate (CaCl 2 · 2H 2 O) were added to give 5,6-isopropylidene- L-ascorbyl-2-phosphate ester (III) is converted to precipitated calcium soluble salt (II) and precipitated, and filtered to remove potassium phosphate and potassium chloride produced as by-products of the phosphorylation reaction. In this case, the reaction temperature is preferably 20 to 40 ° C, more preferably 30 to 35 ° C. If the reaction temperature is less than 20 ° C, problems may occur in the crystalline form, and the temperature above 40 ° C has no meaning. The pH of the initial reaction solution is adjusted when the pH is adjusted to 7 or less, the yield is lowered, when set to 10 or more, the stability is lowered, preferably 9.8. In addition, the amount of calcium salt for forming the poorly soluble calcium phosphate salt (II) is preferably 1.5 to 2 times in molar ratio with respect to 5,6-isopropylidene-L-ascorbic acid, and if the amount of the calcium salt is 1.5 In the case of less than 2 times, there is a possibility that crystal precipitation does not occur completely, and in the case of more than 2 times, there is no meaning. In the crystallization reaction, when magnesium chloride (MgCl 2 · 6H 2 O) is used instead of CaCl 2 · 2H 2 O, 5,6-isopropylidene-L-ascorbyl-2-phosphate ester magnesium salt is obtained as crystals. Can not, only calcium salt is obtained as a crystal.
다음으로, 얻어진 순수한 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르 칼슘염(Ⅱ)을 물에 혼탁시킨 후, 인산을 가하여 용액의 pH를 약 1.0 내지 2.0, 바람직하게는 2.0으로 조절하여 칼슘염(Ⅱ)을 용해시킨다. 그 후, 약 50 내지 70℃에서 바람직하게는 60oC의 온도에서 1 내지 3시간 정도, 바람직하게는 2시간 정도 교반하여 탈보호기 반응을 시킨 후, 산화마그네슘(MgO) 또는 수산화마그네슘(Mg(OH)2) 등의 마그네슘염를 가하여 pH를 약 8.5 내지 9.0으로 조정하면, 용액 속에 존재하는 Ca2+은 난용성염인 Ca3(PO4)2으로 석출되고, 과량의 PO4 2-이온은 Mg3(PO4)2의 형태로 석출되므로, 수용액 속에는 순수한 L-아스코빌-2-인산에스테르 마그네슘만 존재하게 된다. 이와 같이 화합물에 존재하는 불필요한 양이온, 음이온들을 난용성 염으로 만들어 단지 침전물을 여과하여 제거하는 조작만으로 이온교환수지를 사용하지 않고도 탈염 및 마그네슘염의 도입을 동시에 수행하여 목적하는 L-아스코빌-2-인산에스테르마그네슘(Ⅰ)을 얻을 수 있다. 고체상의 순수한 L-아스코빌-2-인산에스테르마그네슘(I)은 상기 L-아스코빌-2-인산에스테르마그네슘(Ⅰ)이 용해된 반응물에 메탄올, 에탄올, 프로판올, 이소프로판올 등의 저급 알콜 및 물과 섞이는 기타 유기용매를 첨가하여 L-아스코빌-2-인산에스테르마그네슘(Ⅰ)을 결정으로 석출시켜, 수용액 상에서 갈변현상 없는 목적화합물을 얻을 수 있다.Next, the pure 5,6-isopropylidene-L-ascorbyl-2-phosphate ester calcium salt (II) obtained is turbid in water, and then phosphoric acid is added to adjust the pH of the solution to about 1.0 to 2.0, preferably 2.0. The calcium salt (II) is dissolved by adjusting to. Thereafter, at a temperature of about 50 to 70 ° C., preferably at a temperature of 60 ° C., for 1 to 3 hours, preferably 2 hours, a deprotection group reaction is performed, followed by magnesium oxide (MgO) or magnesium hydroxide (Mg ( When the pH is adjusted to about 8.5 to 9.0 by adding a magnesium salt such as OH) 2 ), Ca 2+ present in the solution precipitates as Ca 3 (PO 4 ) 2 , which is a poorly soluble salt, and excess PO 4 2- ions are Mg. Since it precipitates in the form of 3 (PO 4 ) 2 , only pure M-ascorbyl-2-phosphate magnesium exists in the aqueous solution. In this way, the unnecessary cations and anions present in the compound are made into poorly soluble salts, and the desalination and magnesium salts are simultaneously introduced without the use of ion exchange resins by only filtering and removing the precipitates. Magnesium phosphate ester (I) can be obtained. Pure L-ascorbyl-2-phosphate magnesium (I) in solid form is reacted with lower alcohols such as methanol, ethanol, propanol and isopropanol and water in a reaction product of L-ascorbyl-2-phosphate magnesium (I). L-ascorbyl-2-phosphate magnesium (I) may be precipitated as crystals by adding other organic solvents to be mixed to obtain a target compound without browning in aqueous solution.
대한민국 특허 1994-7418호는 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르 칼륨을 수용액상에서 합성하고, 생성된 무기염들을 석출시켜 제거하기 위하여 물을 거의 감압, 증류하여 제거한 후 유기용매를 사용하였으나(이때 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르 칼륨은 메탄올 용매 중에 용해됨), 본 발명에서는 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르 칼슘의 물에 대한 용해도가 현저히 낮은 것을 발견하고, 수용액상에 존재하는 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르를 칼슘염으로 처리하여, 난용성염인 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르 칼슘을 결정으로 석출시켜, 고순도·고수율로 얻은 다음, 이를 마그네슘염으로 전환하였다. 이는 결국 중간체를 결정화함으로써 인산화 반응 시 생성되는 불순물과 무기염을 동시에 제거할 수 있음을 의미한다. 종래의 방법의 경우, 인산화 반응 후 생성된 염들을 제거한 농축액 속에 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르염 중간체가 존재하므로, 부생성물을 제거하는데 번거로운 공정이 필요한 것에 비하여, 본 발명의 방법은 정제 및 제조 공정이 현저히 간단하고 효과적인 것이다. 또한 본 발명의 방법은 칼슘이온 및 마그네슘 이온이 포스페이트 이온(PO4 3-)과 난용성염을 형성할 수 있으므로 이온교환수지를 사용하지 않고도 탈염 및 마그네슘염을 형성할 수 있다는 장점이 있다.Korean Patent 1994-7418 discloses 5,6-isopropylidene-L-ascorbyl-2-phosphate ester in aqueous solution, and removes water by distillation under reduced pressure and distillation to remove and remove the inorganic salts. An organic solvent was used (at this time 5,6-isopropylidene-L-ascorbyl-2-phosphate potassium potassium was dissolved in methanol solvent), but in the present invention, 5,6-isopropylidene-L-ascorbyle-2 -It was found that the solubility of calcium phosphate in water was significantly lower, and 5,6-isopropylidene-L-ascorbyl-2-phosphate ester present in the aqueous solution was treated with calcium salt to give a poorly soluble salt of 5, 6-isopropylidene-L-ascorbyl-2-phosphate ester calcium was precipitated as crystals, obtained in high purity and high yield, and then converted to magnesium salt. This means that the crystallization of the intermediates can simultaneously remove impurities and inorganic salts generated during the phosphorylation reaction. In the conventional method, since the 5,6-isopropylidene-L-ascorbyl-2-phosphate ester salt intermediate is present in the concentrate from which salts formed after phosphorylation are removed, a cumbersome process is required to remove by-products. In the process of the present invention, the purification and manufacturing process is remarkably simple and effective. In addition, the method of the present invention, since calcium ions and magnesium ions can form poorly soluble salts with phosphate ions (PO 4 3- ) There is an advantage in that desalination and magnesium salts can be formed without using an ion exchange resin.
이하, 실시예를 통하여 본 발명을 더욱 상세하게 설명하나, 하기 실시예는 본 발명을 예시하기 위한 것이며, 본 발명이 하기 실시예에 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to Examples, but the following Examples are for illustrating the present invention, and the present invention is not limited to the following Examples.
[실시예 1] 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르칼슘의 제조 Example 1 Preparation of 5,6-isopropylidene-L-ascorbyl-2-phosphate ester calcium
3L 반응기에 물 1200ml와 피리딘 300ml를 넣고 5,6-이소프로필리덴-L-아스코빅산 216g을 투입하고, 반응액을 0℃로 냉각한 다음, 50% KOH(w/v)를 사용하여 pH를 12 내지 13으로 조절한다. 0℃에서 옥시염화인 143g을 천천히 적가하면서 50% KOH(w/v) 수용액을 이용하여 반응이 진행하는 동안 용액의 pH를 13으로 유지하고, 반응 온도도 0℃로 유지한다. 옥시염화인의 적가가 완료되면, 같은 온도에서 30분간 반응액의 pH를 13으로 유지하면서 교반한 다음, c-HCl을 사용하여 반응액의 pH를 9.8로 조정한 후, 피리딘을 감압 증류하여 제거한다. 반응액의 온도를 30 내지 35℃로 유지하면서, CaCl2·2H2O 220.5g을 25%수용액으로 만들어 천천히 교반하면서 적가한다. 적가가 끝나면 2시간 동안 더 교반한 후, 여과한 다음, 물 400ml로 세척하여 조 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르칼슘 350g을 얻었다.1200 ml of water and 300 ml of pyridine were added to a 3 L reactor, 216 g of 5,6-isopropylidene-L-ascorbic acid was added, the reaction solution was cooled to 0 ° C., and the pH was adjusted using 50% KOH (w / v). Adjust from 12 to 13. While slowly adding dropwise 143 g of phosphorus oxychloride at 0 ° C using a 50% KOH (w / v) aqueous solution, the pH of the solution was maintained at 13 and the reaction temperature was maintained at 0 ° C. When the dropwise addition of phosphorus oxychloride was completed, the mixture was stirred while maintaining the pH of the reaction solution at 13 at the same temperature for 30 minutes, the pH of the reaction solution was adjusted to 9.8 using c-HCl, and then pyridine was distilled off under reduced pressure. do. While maintaining the temperature of the reaction solution at 30 to 35 ° C, 220.5 g of CaCl 2 · 2H 2 O was made 25% aqueous solution and added dropwise with slow stirring. After the addition, the mixture was further stirred for 2 hours, filtered and washed with 400 ml of water to obtain 350 g of crude 5,6-isopropylidene-L-ascorbyl-2-phosphate ester calcium.
[실시예 2] L-아스코빌-2-인산에스테르마그네슘의 제조 Example 2 Preparation of M-ascorbyl-2-Phosphate Magnesium
실시예 1에서 얻은 5,6-이소프로필리덴-L-아스코빌-2-인산에스테르칼슘 350g을 물 1760ml에 혼탁시킨 후, 인산을 가하여 pH를 2.0으로 조정한 후, 35℃에서 약 2시간 교반한다. 탈보호 반응이 완결되면 반응액에 산화마그네슘(MgO)을 천천히 교반하면서 첨가하여, pH가 8.5 내지 9.0이 되도록 한 후, 난용성 마그네슘포스페이트염 및 기타 난용성염들을 20oC 이하에서 여과하여 제거한다. 여액에 활성탄 12g을 가하고 1시간 교반한 후 여과하고, 40 내지 45℃에서 에탄올 1760ml를 천천히 적가하여 L-아스코빌-2-인산에스테르마그네슘 211.1g을 얻었다.350 g of 5,6-isopropylidene-L-ascorbyl-2-phosphate ester calcium obtained in Example 1 was clouded in 1760 ml of water, and then the pH was adjusted to 2.0 by adding phosphoric acid, followed by stirring at 35 ° C. for about 2 hours. do. When the deprotection reaction is completed, magnesium oxide (MgO) is added to the reaction solution with slow stirring to bring the pH to 8.5 to 9.0, and then the poorly soluble magnesium phosphate salt and other poorly soluble salts are filtered off at 20 ° C. or less. . 12 g of activated carbon was added to the filtrate, and the mixture was stirred for 1 hour, filtered, and 1760 ml of ethanol was slowly added dropwise at 40 to 45 ° C to obtain 211.1 g of L-ascorbyl-2-phosphate ester.
이상 상술한 바와 같이, 본 발명에 따른 L-아스코빌-2-인산에스테르마그네슘의 제조방법은 종래의 공정과 비교하여 탈염공정에 이온교환수지를 사용할 필요가 없을 뿐만 아니라, 제조 공정이 단순하고, 부산물을 쉽게 제거할 수 있으며, 목적화합물을 고순도로 얻을 수 있다.As described above, the production method of L-ascorbyl-2-phosphate magnesium according to the present invention does not need to use an ion exchange resin in the desalination process as compared with the conventional process, and the manufacturing process is simple, By-products can be easily removed and the target compound can be obtained in high purity.
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| KR920018060A (en) * | 1991-03-05 | 1992-10-21 | 김만경 | L-ascorbyl-2-phosphate ester salt derivative and preparation method thereof |
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| US6288243B1 (en) * | 1999-06-07 | 2001-09-11 | Roche Vitamins Inc. | Process for purifying L-ascorbyl 2-monophosphate |
| US6388098B1 (en) * | 1999-03-18 | 2002-05-14 | Showa Denko Kabushiki Kaisha | Process for preparing ascorbic acid-2-monophosphate salt |
| KR20030046269A (en) * | 2001-12-05 | 2003-06-12 | 주식회사 엔지켐 | Process for preparation of Magnesium L-ascorbyl-2-phosphate |
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| KR900009676A (en) * | 1988-12-30 | 1990-07-05 | 태평양화학 주식회사 | Method for preparing L-ascorbic acid-2-phosphate ester magnesium salt |
| KR920018060A (en) * | 1991-03-05 | 1992-10-21 | 김만경 | L-ascorbyl-2-phosphate ester salt derivative and preparation method thereof |
| US5420302A (en) * | 1992-08-12 | 1995-05-30 | Basf Aktiengesellschaft | Preparation of calcium L-ascorbate 2-phosphate |
| KR940007419A (en) * | 1992-09-10 | 1994-04-27 | 아더 엠. 킹 | Fiber optic lighting system using conventional headlamp structure |
| US6388098B1 (en) * | 1999-03-18 | 2002-05-14 | Showa Denko Kabushiki Kaisha | Process for preparing ascorbic acid-2-monophosphate salt |
| US6288243B1 (en) * | 1999-06-07 | 2001-09-11 | Roche Vitamins Inc. | Process for purifying L-ascorbyl 2-monophosphate |
| KR20030046269A (en) * | 2001-12-05 | 2003-06-12 | 주식회사 엔지켐 | Process for preparation of Magnesium L-ascorbyl-2-phosphate |
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| CN103113406A (en) * | 2012-11-14 | 2013-05-22 | 江苏江山制药有限公司 | Preparation method of phosphoric acid-2-ascorbic acid ester salt |
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