KR100346672B1 - Method for preparing 3-O-substituted ascorbic acid - Google Patents
Method for preparing 3-O-substituted ascorbic acid Download PDFInfo
- Publication number
- KR100346672B1 KR100346672B1 KR1019950002257A KR19950002257A KR100346672B1 KR 100346672 B1 KR100346672 B1 KR 100346672B1 KR 1019950002257 A KR1019950002257 A KR 1019950002257A KR 19950002257 A KR19950002257 A KR 19950002257A KR 100346672 B1 KR100346672 B1 KR 100346672B1
- Authority
- KR
- South Korea
- Prior art keywords
- group
- ascorbic acid
- general formula
- substituted
- aqueous solvent
- Prior art date
Links
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
수용성의 3-0-치환 아스코르브산을 간편하게 고수율로 제조하는 방법을 제공한다.Provided is a method for producing a water-soluble 3-0-substituted ascorbic acid simply in high yield.
하기 일반식 (I) 로 표시되는 3-0-치환-5,6-이소프로필리덴 아스코르브산을 비수성 용매 중, 산성 이온 교환 수지로 처리하여 하기 일반식 (I) 로 표시되는 화합물 중의 디옥소란 고리를 개환하고, vic-글리콜기를 형성하는 것을 특징으로 하는 하기 일반식 (II) 로 표시되는 3-0-치환 아스코르브산의 제조방법.Dioxo in the compound represented by the following general formula (I) by treating 3-0-substituted-5,6-isopropylidene ascorbic acid represented by the following general formula (I) with an acidic ion exchange resin in a non-aqueous solvent. A method for producing 3-0-substituted ascorbic acid represented by the following general formula (II), wherein the column ring is opened to form a vic-glycol group.
(식 중, R 은 저급알킬기 및 저급알킬카르보닐 저급알킬기로 이루어진 군으로부터 선택된 기이다).Wherein R is a group selected from the group consisting of lower alkyl groups and lower alkylcarbonyl lower alkyl groups.
Description
본 발명은 3-0-치환 아스코르브산의 제조방법에 관한 것이다.The present invention relates to a process for preparing 3-0-substituted ascorbic acid.
3-위치의 수산기를 저급 알킬기나 저급 알킬카르보닐 지급알킬기 등의 알킬기로 치환한 3-0-치환 아스코르브산 유도체는 아스코르브산보다 안정적이며, 또한 항산화 작용을 나타내고, 식품 및 화장품의 품질 열화 방지에 유용한 것 외에, 라디칼 소거 작용에 의거하여 의약품으로서도 유용하다. 또 이외에 3-0-알킬 아스코르브산 유도체에는 암전이 방지 작용 등의 의약으로서의 유용성도 발견되고 있다.3-0-substituted ascorbic acid derivatives in which a 3-position hydroxyl group is substituted with an alkyl group such as a lower alkyl group or a lower alkylcarbonyl-supply alkyl group are more stable than ascorbic acid and exhibit antioxidant activity and are used to prevent deterioration of quality of food and cosmetics. In addition to being useful, it is also useful as a medicine based on radical scavenging action. In addition, the utility of the 3-0-alkyl ascorbic acid derivative has been found to be useful as a medicament such as anticancer activity.
이것들의 3-0-치환 아스코르브산 유도체의 제조방법으로서는 아스코르브산 나트륨염을 디메틸 술폭시드 (DMSO) 또는 디메틸 포름아미드 (DMF) 중에서 할로겐화 알킬에 의해 알킬화하는 방법 [K.G.A.Jackson 등 Can. J. Chem., 43, 450(1965), K.KaTo 등 J. Med. Chem., 31, 793 (1988)] 및 아스코르브산을 DMSO 중에서 나트륨 메톡시드 존재 하에 할로겐화 알킬에 의해 알킬화하는 방법이 알려져 있다. 그러나 이것들의 방법으로는 3-위치의 수산기에 도입할 수 있는 알킬기에 제한이 있고, 부생성물도 많다. 또 용매로 사용하는 DMSO와 DMF의 비점이 높으며 또한 생성물의 3-0치환 아스코르브산 유도체가 이들 극성 용매에 잘 용해하기 때문에 정제가 어렵고, 많은 경우, 컬럼 크로마토그래피 등의 처리를 필요로 하고 그 수율도 낮은 등의 문제가 있었다.As a method for producing these 3-0-substituted ascorbic acid derivatives, a method for alkylating sodium ascorbic acid salt with halogenated alkyl in dimethyl sulfoxide (DMSO) or dimethyl formamide (DMF) [K.G.A.Jackson et al. J. Chem., 43, 450 (1965), K. KaTo et al. J. Med. Chem., 31, 793 (1988)] and ascorbic acid are known to alkylate with halogenated alkyl in the presence of sodium methoxide in DMSO. However, these methods have limitations on the alkyl groups that can be introduced into the 3-position hydroxyl group, and many by-products. Moreover, since the boiling point of DMSO and DMF used as a solvent is high, and the 3-0 substituted ascorbic acid derivative of the product dissolves in these polar solvents well, purification is difficult, and in many cases, it is necessary to process by column chromatography and the yield There was also a problem such as low.
한편, 일본국 특개평 1-228977 호 공보에는 제 1 의 공정에서, 아스코르브산의 5 위치 및 6 위치의 vic-글리콜기를 이소프로필리덴기로 보호하여, 5,6-0-이소프로필리덴 아스코르브산을 수득하고, 다음에 제 2 의 공정에서, 상기 5,6-0-이소프로필리덴 아스코르브산을 할로겐화 알킬과 반응시켜서 3-0-알킬-5,6-이소프로필리덴 아스코르브산을 수득하고, 최후로 제 3 의 공정에서, 상기 3-0-알킬-5,6-0-이소프로필리덴 아스코르브산을 유기 용매애 용해시킨 후, 산 수용액으로 처리하며, 디옥소란 고리를 개환하여 다시 vic-글리콜을 형성함으로써 목적의 3-0-알킬 아스코르브산을 수득하는 방법이 개시되어 있다.On the other hand, Japanese Unexamined Patent Application Publication No. 1-228977 discloses 5,6-0-isopropylidene ascorbic acid in the first step by protecting vic-glycol groups of 5 and 6 positions of ascorbic acid with an isopropylidene group. And then, in the second step, the 5,6-0-isopropylidene ascorbic acid is reacted with halogenated alkyl to give 3-0-alkyl-5,6-isopropylidene ascorbic acid, and finally In the third step, the 3-0-alkyl-5,6-0-isopropylidene ascorbic acid is dissolved in an organic solvent, treated with an aqueous acid solution, and the dioxolane ring is opened again to form vic-glycol. A method of obtaining the desired 3-0-alkyl ascorbic acid by forming is disclosed.
이 방법의 제 1 의 공정에서 아스코르브산의 vic-글리콜기를 보호하기 위하여 형성된 디옥소란 고리는 하기식에 표시한 바와 같이 산성 조건 하에서 생성하는카르보늄 이온을 형성하고, 이것이 공명에 의해 안정화된다.The dioxolane ring formed to protect the vic-glycol group of ascorbic acid in the first step of this method forms carbonium ions to be produced under acidic conditions as shown in the following formula, which is stabilized by resonance.
이 때문에 디옥소란 고리는 제 2 공정에서 형성된 3-0-알킬에테르 결합에 비하여, 산에 대한 반응성이 풍부하므로 제 3 공정에 있어서 용이하게 개환하여 다시 vic-글리콜로 되고 목적으로 하는 3-0-알킬 아스코르브산이 형성된다.For this reason, since the dioxolane ring is rich in reactivity with an acid compared with the 3-0-alkylether bond formed in the 2nd process, it is easily ring-opened in a 3rd process, and becomes vic-glycol again, and becomes the target 3-0. Alkyl ascorbic acid is formed.
이 탈이소프로필리덴 반응에 사용되는 산의 수용액으로서 상기 특개평 1-228977 호 공보에는 염산, 아세트산, 황산, p-톨루엔술폰산, 메탄술폰산, 캠퍼술폰산 등의 산의 수용액이 개시되어 있다.As an aqueous solution of an acid used for this deisopropylidene reaction, the above-mentioned Japanese Patent Application Laid-Open No. 1-228977 discloses an aqueous solution of an acid such as hydrochloric acid, acetic acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, and the like.
그러나 이 특개평 1-228977 호 공보에 기재된 방법은 3-0-저급알킬-5,6-0-이소프로필리덴 아스코르브산을 산 처리하여, 수용성이 풍부한 3-0-저급알킬 아스코르브산을 수득하는 공정에 있어서, 유기 용매와 함께 산 수용액을 이용하기 때문에, 반응 후 물을 함유하는 반응 용액을 농축하는 것만으로는 3-0-저급알킬 아스코르브산을 수득하는 것이 어렵고, 용매를 완전히 증류제거하여 잔류물을 충분히 건조시킴으로써, 비로서 목적하는 3-0-저급알킬 아스코르브산이 수득된다는 폐단이있었다.However, the method described in Japanese Patent Application Laid-Open No. 1-228977 discloses an acid treatment of 3-0-lower alkyl-5,6-0-isopropylidene ascorbic acid to obtain water-soluble 3-0-lower alkyl ascorbic acid. In the process, since an aqueous acid solution is used together with an organic solvent, it is difficult to obtain 3-0-lower alkyl ascorbic acid only by concentrating the reaction solution containing water after the reaction, and the solvent is distilled off completely to remain. By drying the water sufficiently, there was a closure that the desired 3-0-lower alkyl ascorbic acid was obtained as a ratio.
또 건조 조건을 간소화할 목적으로 비점이 낮은 유기 용매 (에틸 아세테이트 등) 로 추출하였다고 하더라도, 목적물의 유기 용매에 대한 분배율이 나쁘기 때문에 대량의 용매를 필요로 하고, 또 추출효율의 개선을 목적으로 추출조제를 사용하는 등의 필요가 있고, 수율에 있어서도 개선하는 것이 요망되고 있었다.In addition, even if extracted with an organic solvent having a low boiling point (such as ethyl acetate) for the purpose of simplifying the drying conditions, a large amount of solvent is required because of poor distribution of the target organic solvent, and for the purpose of improving the extraction efficiency. It is necessary to use a preparation etc. and to improve also in yield.
따라서, 본 발명의 목적은 수용성의 3-0-치환 아스코르브산을 간편하게 고수율로 제조하는 방법을 제공하는데 있다.Accordingly, it is an object of the present invention to provide a method for producing a water-soluble 3-0-substituted ascorbic acid simply in high yield.
본 발명자들은, 상기 목적 달성을 위하여 검토를 가한 결과, 3-0-알킬 또는The inventors of the present invention have conducted the study to achieve the above object, and as a result, 3-0-alkyl or
3-0-알킬 카르보닐 알킬-5,6,0-이소프로필리덴 아스코르브산 (3-0-알킬 또는 3-0-알킬 카르보닐 알킬 아스코르브산 아세트니드)의 산 처리에 있어서, 상기 특개평 1-228977 호 공보 기재의 유기 용매-산 수용액으로 이루어진 반응계 대신에, 비수성 용매-산성 이온 교환 수지로 이루어지는 물을 함유하지 않는 반응계를 사용하더라도, 디옥소란 고리의 개환 (이소프로필리덴기의 탈리) 에 의한 vic-글리콜 형성 반응이 부반응을 일으키는 일이 없이 원활하고 또한 신속하게 진행하고, 반응 후, 산성 이온 교환 수지를 제거하고, 반응액을 농축시키는 것만으로 3-0-알킬 또는 3-0-알킬 카르보닐 알킬 아스코르브산이 정량적으로 수득된다는 것을 발견하였다.In the acid treatment of 3-0-alkyl carbonyl alkyl-5,6,0-isopropylidene ascorbic acid (3-0-alkyl or 3-0-alkyl carbonyl alkyl ascorbic acid acetide), Ring opening of the dioxolane ring (desorption of isopropylidene group) even when a reaction system containing no water of a non-aqueous solvent-acidic ion exchange resin is used instead of the reaction system composed of an organic solvent-acid aqueous solution described in Japanese Patent No. 228977. ) Vic-glycol formation reaction proceeds smoothly and quickly without causing side reactions, and after the reaction, the acidic ion exchange resin is removed and the reaction solution is concentrated to form 3-0-alkyl or 3-0. It has been found that -alkyl carbonyl alkyl ascorbic acid is obtained quantitatively.
이 디옥소란 고리의 개환 (이소프로필리덴기의 탈리) 에 의한 vic-글리콜의 형성 반응은 종래 물이 관여하는 가수분해 반응이라고 생각되고, 따라서 상기 특개평 1-228977 호 공보에 기재된 방법에서도 유기 용매-산 수용액으로 이루어진 함수반응계를 사용하고 있는 것이지만 본 발명자들이 상기 디옥소란 고리의 개환에 의한 vic-글리콜의 형성 반응을 물을 함유하지 않는 비수성 용매-산성 이온 교환 수지로 이루어진 반응계에서 달성할 수 있었다는 것은 놀랄만한 일이다.The formation reaction of vic-glycol by ring-opening of this dioxolane ring (desorption of isopropylidene group) is considered to be a hydrolysis reaction involving water in the related art, and therefore, the method described in Japanese Patent Application Laid-Open No. 1-228977 is also organic. Although a water-containing reaction system composed of a solvent-acid aqueous solution is used, the inventors have achieved a reaction of forming vic-glycol by ring-opening of the dioxolane ring in a reaction system composed of a non-aqueous solvent-acidic ion exchange resin containing no water. It is surprising that we could do it.
본 발명은 이 놀랄만한 지견에 의거하여 완성된 것이며, 하기 일반식 (I)The present invention has been completed based on this remarkable finding, and the following general formula (I)
(식 중 R 은 저급알킬기 및 저급알킬카르보닐 저급알킬기로 이루어진 군으로부터 선택되는 기이다)Wherein R is a group selected from the group consisting of lower alkyl groups and lower alkylcarbonyl lower alkyl groups
로 표시되는 3-0-치환-5,6,0-이소프로필리덴 아스코르브산을 비수성 용매 중 산성 이온 교환 수지로 처리하며 상기 일반식 (I) 로 표시되는 화합물 중의 디옥소란 고리를 개환하고, vic-글리콜기를 형성하는 것을 특정으로 하는 하기 일반식 (II)The 3-0-substituted-5,6,0-isopropylidene ascorbic acid represented by the above is treated with an acidic ion exchange resin in a non-aqueous solvent, and the dioxolane ring in the compound represented by the above general formula (I) is opened. , the following general formula (II) specifying the formation of a vic-glycol group
(식 중 R 은 상기 일반식 (I) 에서 정의한 바와 같다)In which R is as defined in General Formula (I) above.
로 표시되는 3-0-치환 아스코르브산의 제조방법을 요지로 한다.The manufacturing method of 3-0-substituted ascorbic acid represented by the following is made into the summary.
이하, 본 발명을 설명한다.Hereinafter, the present invention will be described.
본 발명에 있어서, 출발물질로서 사용되는 화합물은 하기 일반식 (I)In the present invention, the compound used as starting material is represented by the following general formula (I)
로 표시되는 3-0-치환-5,6-0-이소프로필리덴 아스코르브산에 있어서, R 은 저급알킬기 및 저급알킬 카르보닐 저급알킬기이다. R 로서의 저급알킬기로서는, 메틸기, 에틸기, 프로필기, 부틸기를 들 수 있다. 또 R 로서의 저급알킬 카르보닐 저급알킬기는, 식In the 3-0-substituted-5,6-0-isopropylidene ascorbic acid represented by: R is a lower alkyl group and a lower alkyl carbonyl lower alkyl group. As a lower alkyl group as R, a methyl group, an ethyl group, a propyl group, and a butyl group are mentioned. And the lower alkyl carbonyl lower alkyl group as R is
-R2-CO-R1 -R 2 -CO-R 1
(식 중, R1은 메틸기, 에틸기, 프로필기, 부틸기이며, R2는 메틸렌기, 에틸렌기, 프로필렌기, 부틸렌기이다)(In formula, R <1> is a methyl group, an ethyl group, a propyl group, and a butyl group, and R <2> is a methylene group, ethylene group, a propylene group, butylene group.)
로 표시되는 것이다.Will be displayed.
본 발명에 있어서는 상기 일반식 (I) 로 표시되는 3-0-알킬-5,6-0-이소프로필리덴 아스코르브산을 비수성 용매 중, 산성 이온 교환 수지로 처리한다.In the present invention, 3-0-alkyl-5,6-0-isopropylidene ascorbic acid represented by the general formula (I) is treated with an acidic ion exchange resin in a non-aqueous solvent.
비수성 용매로서는 vic-글리콜기와 산성 조건 하에 반응시키는 케톤류를 제외하면 각종 용해를 사용할 수가 있으나, 메탄올, 에탄올, n-프로판올, n-부탄올 등의 제 1 급 저급알콜을 함유하는 제 1 급 알콜류; 디에틸 에테르, 테트라히드로푸란 들의 직쇄 또는 환상 에테르를 함유하는 에테르류; 몇 메틸렌 디클로라이드, 클로로포름, 에틸렌 디클로라이드 등의 할로겐화 탄화수소류를 사용하는 것이 바람직하다. 그 이유는 이것들을 사용하면 반응이 신속히 진행되고, 또한 부생성물의 생성을 억제하여 목적물이 정량적으로 수득되기 때문이다.As the non-aqueous solvent, various dissolutions can be used except for vic-glycol groups and ketones reacted under acidic conditions, but primary alcohols containing primary lower alcohols such as methanol, ethanol, n-propanol and n-butanol; Ethers containing diethyl ether, linear or cyclic ethers of tetrahydrofurans; It is preferable to use halogenated hydrocarbons such as some methylene dichloride, chloroform and ethylene dichloride. The reason for this is that the reaction proceeds rapidly when these are used, and the production of the by-products is suppressed to obtain the target product quantitatively.
또 메틸아세테이트, 에틸아세테이트, 부틸아세테이트 들의 에스테르류; 아세토니트릴 등의 니트릴류; 벤젠 등의 방향족 탄화수소류; 펜탄 등의 지방족 탄화수소류; 디메틸포름아미드 (DMF), 디메틸술폭시드 (DMSO), 1,3-디메틸-2-이미다졸리디논 (DMI) 등의 비프로톤성 유기 용매를 단독으로 사용할 수도 있으나, 이것들의 용매는 상기 제 1 급 알콜류, 에테르류, 할로겐화 탄화수소류 중의 적어도 1 종과 혼합하여 사용하는 것이 바람직하다.Methyl acetate, ethyl acetate, butyl acetate esters; Nitriles such as acetonitrile; Aromatic hydrocarbons such as benzene; Aliphatic hydrocarbons such as pentane; Although aprotic organic solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and 1,3-dimethyl-2-imidazolidinone (DMI) may be used alone, these solvents may be used as the first solvent. It is preferable to use it in mixture with at least 1 sort (s) of class alcohols, ethers, and halogenated hydrocarbons.
상기 용매에 용해되는 일반식 (I) 의 3-0-치환-5,6-0-이소프로필리덴 아스코르브산의 농도는 용매의 종류에 따라서 상이하나, 일반적으로 0.01∼80.0w/v%이다.The concentration of 3-0-substituted-5,6-0-isopropylidene ascorbic acid of the general formula (I) dissolved in the solvent is different depending on the type of solvent, but is generally 0.01 to 80.0 w / v%.
본 발명의 방법에서 사용하는 산성 이온 교환 수지로서는 이온 교환에 필요한 관능기가 수소 이온과 쌍을 이루고, 또한 반응 용매애 대하여 안정적인 것이면 그 종류, 용량, 수지의 형태 (형상, 크기) 등에서는 특별히 한정되지 않는다. 바람직하게는 강산성의 이온 교환 수지가 반응 시간의 단축의 의미에서 유리하다.The acidic ion exchange resin used in the method of the present invention is not particularly limited in kind, capacity, form (shape, size) of the resin as long as the functional group necessary for ion exchange is paired with hydrogen ions and stable to the reaction solvent. Do not. Preferably, a strongly acidic ion exchange resin is advantageous in the sense of shortening the reaction time.
특히 유효 관능기가 술폰산계의 깃이 값싸게 입수하기 쉬우므로 바람직하나, 카르복실산계의 것을 사용할 수도 있다. 또 사용하는 이온 교환 수지의 양은 특별히 제한되지 않으나, 바람직하게는 원료 1 중량부에 대하여 1/100 ~ 10000 중량부 정도가 반응시간의 단축 및 경제성의 면에서 적절하다.In particular, an effective functional group is preferable because a sulfonic acid-based feather is easy to obtain inexpensively, but a carboxylic acid-based one can also be used. The amount of the ion exchange resin to be used is not particularly limited, but preferably about 1/100 to 10000 parts by weight based on 1 part by weight of the raw material is appropriate in terms of shortening of reaction time and economical efficiency.
반응 장치는 특별히 한정되지 않고, 순환식이거나 배치식이어도 좋다.The reaction apparatus is not particularly limited and may be cyclic or batch.
또 반응 온도는 특별히 한정되지 않으나, 가열하는 것이 바람직하고, 반응 용매를 환류시킬때까지 건가열함으로써 반응 시간이 단축된다.Moreover, although reaction temperature is not specifically limited, It is preferable to heat, and reaction time is shortened by dry heating until reflux of a reaction solvent is carried out.
실시예Example
먼저 원료의 제조예를 참고예로서 설명한다.First, the manufacture example of a raw material is demonstrated as a reference example.
참고예Reference Example
(1) [L-5,6-0-이소프로필리덴 아스코르브산의 합성](1) [Synthesis of L-5,6-0-isopropylidene ascorbic acid]
아스코르브산 180 g을 아세톤 70 ㎖중에서 교반하고, 40℃ 로 가온한다.180 g of ascorbic acid is stirred in 70 ml of acetone and warmed to 40 ° C.
염화 아세틸 20㎖ 을 가하고, 교반을 계속하여 슬러리층을 형성시켰다. 3시간 후 빙냉하여 석출한 침전을 여취하였다. 침전을 냉 아세톤-헥산 혼액 (1:3)으로 세정한 후, 감압 건조시켰다. 아세톤으로부터 재결정하고, L-5,6,0-이소프로필리덴 아스코르브산 190 g(mp 206-208℃)을 수득하였다.20 ml of acetyl chloride was added, and stirring was continued to form a slurry layer. After 3 hours, the precipitate was precipitated by ice cooling. The precipitate was washed with cold acetone-hexane mixture (1: 3) and then dried under reduced pressure. Recrystallization from acetone gave 190 g (mp 206-208 ° C) of L-5,6,0-isopropylidene ascorbic acid.
(2) [L-3-0-에틸-5,6,-0-이소프로필리덴 아스코르브산의 합성](2) [Synthesis of L-3-0-ethyl-5,6, -0-isopropylidene ascorbic acid]
(1) 에서 수득된 L-5,6-0-이소프로필리덴 아스코르브산 4.32 g 을 DMSO 30 ㎖ 에 용해하고 NaHCO31.78 g 을 가하여 실온에서 30 분간 교반하였다. 브롬화 에틸 3.24 g 을 가하여 40 ℃ 로 가온하여, 7 시간 교반하였다. 냉각 후 H2O 100㎖ 와 에틸 아세테이트 (100 ㎖ × 2) 를 가하여 진탕하였다. 유기층를 합쳐서 물, 포화식염수로 세정하여, 황산 나트륨으로 건조시켜 감압 하에 농축시켰다. 수득된 잔류물을 진공으로 건조시켜 고화시키고, 벤젠, 헥산 혼액 (3:1)으로 재결정하고, L-3-0-에틸-5,6-0-이소프로필리덴 아스코르브산 4.20 g (mp 104 ~ 105 ℃) 를 수득하였다.4.32 g of L-5,6-0-isopropylidene ascorbic acid obtained in (1) was dissolved in 30 ml of DMSO, 1.78 g of NaHCO 3 was added, and the mixture was stirred at room temperature for 30 minutes. Ethyl bromide 3.24 g was added, it heated to 40 degreeC, and it stirred for 7 hours. After cooling, 100 ml of H 2 O and ethyl acetate (100 ml × 2) were added and shaken. The organic layers were combined, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was dried in vacuo to solidify, recrystallized from a mixture of benzene and hexane (3: 1), and 4.20 g of L-3-0-ethyl-5,6-0-isopropylidene ascorbic acid (mp104- 105 ° C.) was obtained.
동일하게 조작하여, L-3-0-아세토닐-5,6-0-이소프로필리덴 아스코르브산 및 L-3-0-옥틸-5,6-0-이소프로필리덴 아스코르브산을 수득하였다.In the same manner, L-3-0-acetonyl-5,6-0-isopropylidene ascorbic acid and L-3-0-octyl-5,6-0-isopropylidene ascorbic acid were obtained.
실시예 1Example 1
참고예에서 수득한 L-3-0-에틸-5,6-0-이소프로필리덴 아스코르브산 0.5 g 을 표 1 에 표시한 각종 용매 5 ㎖ 에 용해하고, 유효 관능기가 술폰산기인 산성 이온교환 수지 앰버라이트 (Amberlite) IR-120 (H+) 약 0.05 g 을 가하여 가열하고 환류시켰다. 반응의 진행은 박층 크로마토그래피 (Si 60; 에틸 아세테이트:벤젠2:1; I2발색) 로 확인하였다. 표 1 에 원료의 소실에 요한 시간과 부생성물의 유무를 용매마다 표시하였다.0.5 g of L-3-0-ethyl-5,6-0-isopropylidene ascorbic acid obtained in the reference example was dissolved in 5 ml of various solvents shown in Table 1, and the acidic ion exchange resin amber whose effective functional group was a sulfonic acid group. About 0.05 g of Amberlite IR-120 (H + ) was added, heated and refluxed. The progress of the reaction was confirmed by thin layer chromatography (Si 60; ethyl acetate: benzene 2: 1; I 2 color development). Table 1 shows the time required for the disappearance of the raw materials and the presence or absence of by-products for each solvent.
부생성물을 인정할 수 없었던 알콜계, 할로겐계 및 에테르계의 시험예에 관해서는 반응액을 여과하여 촉매의 이온 교환 수지를 제거한 후, 감압 하 농축시켜 진공에서 건조시키고, 거의 정량적으로 3-0-에틸 아스코르브산의 결정 0.40 ~ 0.41 g (mp 101 - 104 ℃) 를 수득하였다.In the case of the alcohol, halogen and ether test examples in which the by-product could not be recognized, the reaction solution was filtered to remove the ion exchange resin of the catalyst, concentrated under reduced pressure, dried in vacuo, and almost quantitatively 3-0-. 0.40 to 0.41 g (mp 101-104 DEG C) of ethyl ascorbic acid were obtained.
실시예 2Example 2
참고예에서 수득한 L-3-0-에틸-5,6-0-이소프로필리덴 아스코르브산 0.5 g 을 MeOH 5 ㎖ 에 용해시켜, 유효 관능기가 카르복실산기인 산성 이온 교환 수지 앰버라이트 (Amberlite) IR-50 (H+) 약 0.05 g 을 가하여 가열하고 환류시켰다. 반응의 진행은 박층 크로마토그래피 (Si 60; 에틸 아세테이트:벤잰 2:1; I2발색) 로 확인하였다. 원료의 소실에는 10 ~ 16 시간을 요하였으나, 부생성물의 생성은 인정되지 않았으며, 여과 이온 교환 수지를 제거하여 잔류물을 에틸 아세테이트:핵산으로부터 재결정화하여 3-0-에틸 아스코르브산 (mp 140 ℃) 을 수득하였다. 반응은 정량적이었다.0.5 g of L-3-0-ethyl-5,6-0-isopropylidene ascorbic acid obtained in the reference example was dissolved in 5 ml of MeOH, and the acidic ion exchange resin Amberlite having an effective functional group was a carboxylic acid group. About 0.05 g of IR-50 (H + ) was added and heated to reflux. Progress of the reaction was confirmed by thin layer chromatography (Si 60; ethyl acetate: benzane 2: 1; I 2 color development). The loss of raw materials required 10 to 16 hours, but the formation of by-products was not recognized and the residue was recrystallized from ethyl acetate: nucleic acid by removing the filtration ion exchange resin (mp 140). C) was obtained. The reaction was quantitative.
실시예 3Example 3
참고예에서 수득한 L-3-0-아세토닐-5,6-0-이소프로필리덴 아스코르브산 1.0 g 을 MeOH에 5 ㎖ 에 용해하여 유효 관능기가 카르복실산기인 산성 이온 교환 수지 앰버라이트 (Amberlite) IR-120 (H+) 약 0.1 g 을 가하여 가열하여 3 시간 환류시켰다. 냉각 후, 반응액을 여과하여 수지를 제거하고, 감압 하에 건조시켜 잔류물의 고형물을 에틸 아세테이트:헥산으로 재결정하여 L-3-0-아세토닐 아스코르브산(mp 142 ~ 143 ℃) 0.80 g (94 %) 을 수득하였다.1.0 g of L-3-0-acetonyl-5,6-0-isopropylidene ascorbic acid obtained in the reference example was dissolved in 5 ml of MeOH to form an acidic ion exchange resin Amberlite having an effective functional group as a carboxylic acid group. ) 0.1 g of IR-120 (H + ) was added and heated to reflux for 3 hours. After cooling, the reaction solution was filtered to remove the resin, dried under reduced pressure, and the residue solid was recrystallized from ethyl acetate: hexane to give 0.80 g (94% of L-3-0-acetonyl ascorbic acid (mp 142-143 ° C)). ) Was obtained.
비교예 1Comparative Example 1
참고예에서 수득한 L-3-0-에틸-5,6-0-이소프로필리덴 아스코르브산 1.0 g 및 3-0-옥틸-5,6-0-이소프로필리덴 아스코르브산 1.0g 을테트라히드로푸란-메탄올(3:1) 혼액 10 ㎖ 에 용해하여, 2N 염산 2 ㎖ 을 가하여 70 ℃ 로 가온하고 3 시간 교반하였다. 반응액을 감압 하에 회전 증발기로 농축시켰다. 3-0-옥틸-5,6-0-이소프로필리덴 아스코르브산으로 농축을 시작하고부터 3-0-옥틸 아스코르브산이 석출되는 시점에서 농축을 멈추고 냉각시켰다. 석출된 화합물을 여취하여 물로 세정한 후 감압 건조시켜 염화 메틸렌:헥산으로 재결정하여 3-0-옥틸 아스코르브산 0.80 g (수율 90 %) 을 수득하였다.1.0 g of L-3-0-ethyl-5,6-0-isopropylidene ascorbic acid and 1.0 g of 3-0-octyl-5,6-0-isopropylidene ascorbic acid obtained in the reference example were tetrahydrofuran. It was dissolved in 10 ml of a methanol (3: 1) mixture, 2 ml of 2N hydrochloric acid was added thereto, warmed to 70 ° C, and stirred for 3 hours. The reaction solution was concentrated on a rotary evaporator under reduced pressure. Concentration was stopped and cooled after 3-0-octyl-5,6-0-isopropylidene ascorbic acid was started, and at the time when 3-0-octyl ascorbic acid precipitated. The precipitated compound was filtered, washed with water and dried under reduced pressure, and recrystallized with methylene chloride: hexane to give 0.80 g (yield 90%) of 3-0-octyl ascorbic acid.
동시에 생성된 3-0-에틸 아스코르브산에 있어서는 용매를 완전히 증류 제거하여, 수득되는 오일상의 잔류물에 메탄올을 가하여 다시 용매를 증류 제거하였다.In the 3-0-ethyl ascorbic acid produced at the same time, the solvent was distilled off completely, methanol was added to the oily residue obtained, and the solvent was distilled off again.
이 잔류물비 고화할 때까지 진공 펌프로 건조시키고, 에틸 아세테이트:석유에테르로 재결정하여 3-0-에틸 아스코르브산 0.71 g (수율 85%) 을 수득하였다.The residue was dried with a vacuum pump until it solidified, and recrystallized with ethyl acetate: petroleum ether to obtain 0.71 g of 3-0-ethyl ascorbic acid (yield 85%).
이와 같이 물에 거의 용해되지 않는 3-0-옥틸 아스코르브산으로는 사용한 유기 용매를 증류 제거하는 것만으로 목적 화합물이 침강하여 이것을 여취함으로써 고형물로서 반응액으로부터 꺼낼 수가 있었다.In this way, 3-0-octyl ascorbic acid, which is hardly soluble in water, precipitated the desired compound by filtering off the organic solvent used, and was extracted from the reaction solution as a solid by filtration.
한편, 3-0-에틸 아스코르브산과 같이 물에 대한 용해도가 100 mg/㎖ 로 극히 물에 잘 용해하는 저급알킬 아스코르브산으로는 반응생성물을 고화시키는데 용매의 증류 제거를 충분히 실시할 필요가 있으며, 염산 중에 함유하는 수분의 증류 제거는 용이하지 않았다. 이것은 제조량이 증가함에 따라 농축은 어렵게 되고, 10kg 이상의 제조에 있어서는 좀처럼 고형물을 수득할 수 없고 수율 50 % 이하로 되는 것을 의미한다.On the other hand, lower alkyl ascorbic acid, which is very soluble in water, such as 3-0-ethyl ascorbic acid, which is very soluble in water at 100 mg / ml, needs to be sufficiently distilled off to solidify the reaction product. Distillation of the water contained in it was not easy. This means that the concentration becomes difficult as the production amount increases, and in the case of production of 10 kg or more, a solid is hardly obtained and the yield is 50% or less.
비교예 2Comparative Example 2
참고예에서 수득한 L-3-0-에틸-5,6-0-이소프로필리덴 아스코르브산 1.0 g 을 MeOH 5㎖ 에 용해하고, p-톨루엔 술폰산 0.03 g 을 가하여 가열하고, 1 시간 환류시켰다. 냉각 후 반응액을 농축시키고, 잔류물을 에틸 아세테이트:이소프로판올 (10:1) 혼액을 가하여 용해시켰다. 이 용액을 5 % NaHCO3및 포화 식염수로 세정하여 황산 나트륨으로 건조시키고, 용매를 증류 제거하여 고형물이 수득될 때까지 진공으로 건조시켰다. 수득된 고형물을 에틸 아세테이트:헥산으로 재결정하여 L-3-0-에틸 아스코르브산 0.68 g (수율 80 %) 을 수득하였다. 이 경우, 비수성 용매 중의 반응인데도 불구하고, 촉매의 p-톨루엔 술폰산을 제거하는 조작이 번잡하고, 수율도 실시예보다도 현저하게 떨어지고, 비교예 1 과 거의 동일하였다.1.0 g of L-3-0-ethyl-5,6-0-isopropylidene ascorbic acid obtained in the reference example was dissolved in 5 ml of MeOH, 0.03 g of p-toluene sulfonic acid was added and heated to reflux for 1 hour. After cooling, the reaction solution was concentrated and the residue was dissolved by adding an ethyl acetate: isopropanol (10: 1) mixture. The solution was washed with 5% NaHCO 3 and saturated brine, dried over sodium sulfate, and the solvent was dried in vacuo until a solid was obtained by distillation. The obtained solid was recrystallized from ethyl acetate: hexane to give 0.68 g (80% yield) of L-3-0-ethyl ascorbic acid. In this case, despite the reaction in the non-aqueous solvent, the operation of removing p-toluene sulfonic acid of the catalyst was complicated, and the yield was also significantly lower than that of the example, and was almost the same as in Comparative Example 1.
상술한 바와 같이 본 발명에 의하면 L-3-0-치환-5,6-0-이소프로필리덴 아스코르브산을 비수성 용매 중, 산성 이온 교환 수지로 처리함으로써, 디옥소란 고리의 개환 반응은 신속히 진행하고, 고수율로 L-3-0-알킬 아스코르브산이 수득된다.As described above, according to the present invention, the ring-opening reaction of the dioxolane ring is rapidly carried out by treating L-3-0-substituted-5,6-0-isopropylidene ascorbic acid with an acidic ion exchange resin in a non-aqueous solvent. Proceed and L-3-0-alkyl ascorbic acid is obtained in high yield.
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP94-273527 | 1994-11-08 | ||
| JP6273527A JPH08134055A (en) | 1994-11-08 | 1994-11-08 | Production of 3-o-substituted-ascorbic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR960017654A KR960017654A (en) | 1996-06-17 |
| KR100346672B1 true KR100346672B1 (en) | 2002-11-23 |
Family
ID=17529098
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019950002257A KR100346672B1 (en) | 1994-11-08 | 1995-02-08 | Method for preparing 3-O-substituted ascorbic acid |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPH08134055A (en) |
| KR (1) | KR100346672B1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100459679B1 (en) * | 2003-04-30 | 2004-12-03 | 주식회사 펩트론 | Vitamin C derivatives with peptide, preparation method thereof and composition comprising the same |
| KR100500503B1 (en) * | 2001-05-30 | 2005-07-14 | (주)코스몰 | Process for preparing a crystal 3-0-alkyl ascorbic acid |
| KR101350540B1 (en) | 2012-02-01 | 2014-01-14 | 주식회사 카이로켐 | Process for the preparation of L-3-O-Alkyl ascorbic acid |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002284625A (en) * | 2001-03-23 | 2002-10-03 | Nippon Hypox Lab Inc | Cosmetics |
| JP2002284626A (en) * | 2001-03-23 | 2002-10-03 | Nippon Hypox Lab Inc | External skin preparation |
| JP2002284665A (en) * | 2001-03-23 | 2002-10-03 | Nippon Hypox Lab Inc | Cosmetics |
| US6861050B2 (en) | 2001-06-08 | 2005-03-01 | Shiseido Company, Ltd. | Method of preventing darkening of skin or inhibiting melanization of melenin monomer and polymerization inhibitor of biological dihydroxyindole compound |
| KR100761959B1 (en) * | 2006-10-12 | 2007-10-04 | (주)코스몰 | Method for preparating crystalline 3-o-alkyl-ascorbic acid |
| CN105367524A (en) * | 2015-06-19 | 2016-03-02 | 上海珈叶实业有限公司 | Preparation method of 3-O-alkyl ascorbic acid |
| CN110642816A (en) * | 2019-09-25 | 2020-01-03 | 旖肽(上海)生物科技有限公司 | Crystalline 3-O-ethyl vitamin C and preparation method and application thereof |
| WO2022059776A1 (en) | 2020-09-17 | 2022-03-24 | 昭和電工株式会社 | Autophagy activator |
| WO2022059775A1 (en) | 2020-09-17 | 2022-03-24 | 昭和電工株式会社 | Autophagy activator |
| WO2023200186A1 (en) * | 2022-04-11 | 2023-10-19 | 한국과학기술원 | Method for producing chemically recyclable poly(vinyl alcohol) copolymer through ring-opening metathesis polymerization of cyclohexene derivatives |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6377890A (en) * | 1986-09-19 | 1988-04-08 | Nippon Saafuakutanto Kogyo Kk | Purifying method for l-ascorbic acid-2-phosphate |
| JPH02275874A (en) * | 1989-01-21 | 1990-11-09 | Takeda Chem Ind Ltd | Preparation of ascorbic acid derivative |
| US5143648A (en) * | 1989-07-20 | 1992-09-01 | Nippon Hypox Laboratories Incorporated | Ascorbic acid derivative and use as antioxidant |
| JPH06263790A (en) * | 1993-03-12 | 1994-09-20 | Unitika Ltd | 2-o-beta-d-galactopyranosyl-l-ascorbic acid or its salt, its production and use thereof |
-
1994
- 1994-11-08 JP JP6273527A patent/JPH08134055A/en active Pending
-
1995
- 1995-02-08 KR KR1019950002257A patent/KR100346672B1/en not_active IP Right Cessation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6377890A (en) * | 1986-09-19 | 1988-04-08 | Nippon Saafuakutanto Kogyo Kk | Purifying method for l-ascorbic acid-2-phosphate |
| JPH02275874A (en) * | 1989-01-21 | 1990-11-09 | Takeda Chem Ind Ltd | Preparation of ascorbic acid derivative |
| US5143648A (en) * | 1989-07-20 | 1992-09-01 | Nippon Hypox Laboratories Incorporated | Ascorbic acid derivative and use as antioxidant |
| JPH06263790A (en) * | 1993-03-12 | 1994-09-20 | Unitika Ltd | 2-o-beta-d-galactopyranosyl-l-ascorbic acid or its salt, its production and use thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100500503B1 (en) * | 2001-05-30 | 2005-07-14 | (주)코스몰 | Process for preparing a crystal 3-0-alkyl ascorbic acid |
| KR100459679B1 (en) * | 2003-04-30 | 2004-12-03 | 주식회사 펩트론 | Vitamin C derivatives with peptide, preparation method thereof and composition comprising the same |
| KR101350540B1 (en) | 2012-02-01 | 2014-01-14 | 주식회사 카이로켐 | Process for the preparation of L-3-O-Alkyl ascorbic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| KR960017654A (en) | 1996-06-17 |
| JPH08134055A (en) | 1996-05-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100346672B1 (en) | Method for preparing 3-O-substituted ascorbic acid | |
| SU1223842A3 (en) | Method of producing derivatives of benzophenonhydrazones | |
| CN116171270A (en) | Preparation method of (S) -4-chloro-2-aminobutyric acid hydrochloride and (S) -4-chloro-2-aminobutyric acid ester | |
| KR20100120973A (en) | Method for preparating ascorbic acid derivatives | |
| Jensen et al. | Benzylation of aldonolactones with benzyl trichloroacetimidate | |
| US5401858A (en) | Preparation of quinic acid derivatives | |
| US3349095A (en) | 1-(5'-nitrofuryl)-1, 3-diketopropane derivatives and their preparation | |
| EP0252353B1 (en) | 4-benzyloxy-3-pyrrolin-2-one-1-yl-acetamide, preparation and use | |
| JP4097291B2 (en) | Method for producing substituted valinamide derivative | |
| CN111995605B (en) | Chrysin cinnamate or its derivative and its preparation method | |
| AU2018374838B2 (en) | Process for preparing acylated amphetamine derivatives | |
| KR100365020B1 (en) | Preparation method of arbutin intermediats | |
| US4264500A (en) | Process of making 6-chloro-α-methyl-carbazole-2-acetic acid | |
| CN101654426B (en) | Method for preparing ilomastat | |
| SU607549A3 (en) | Method of obtaining carbalcoxythioureidebenzol derivatives | |
| CN110669031B (en) | Total synthesis method of natural product isoperidone J | |
| KR0157422B1 (en) | Process for production of 6-(3-dimethylamino-propionyl)forskolin | |
| EP4083045B1 (en) | Novel method for synthesizing decursin derivative | |
| CN112552258B (en) | Thiazole amide isomagnanide derivative and preparation method and application thereof | |
| Budak et al. | Preparation of diethyl malonate adducts from chalcone analogs containing a thienyl ring | |
| SU1698253A1 (en) | Process for preparing hexahydro-5-hydroxy-4-hydroxymethyl-2h-cyclopentafuran-2-one derivatives | |
| KR20010070672A (en) | Process for preparing a crystal 3-0-alkyl ascorbic acid | |
| RU2632668C2 (en) | Method of producing 2,3,5,6,8-pentaghydroxy-1,4-naphthoquinone (spinochrome d) and intermediate compounds used in this method | |
| FI74949C (en) | FRAMSTAELLNINGSFOERFARANDE FOER 6-CHLORO-METHYL-CARBAZOLE-2-AETXYXRA. ADDITIONAL TO PATENT 71130 - TILLAEGG TILL PATENT 71130 | |
| CN116444505A (en) | Silybin sulfonamide derivative with anti-tumor activity and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| FPAY | Annual fee payment |
Payment date: 20120611 Year of fee payment: 11 |
|
| FPAY | Annual fee payment |
Payment date: 20130520 Year of fee payment: 12 |
|
| LAPS | Lapse due to unpaid annual fee |