KR100346672B1 - Method for preparing 3-O-substituted ascorbic acid - Google Patents

Abstract

Provided is a method for producing a water-soluble 3-0-substituted ascorbic acid simply in high yield.

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.

Wherein R is a group selected from the group consisting of lower alkyl groups and lower alkylcarbonyl lower alkyl groups.

Description

Process for preparing 3-0-substituted ascorbic acid

The present invention relates to a process for preparing 3-0-substituted ascorbic acid.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The inventors of the present invention have conducted the study to achieve the above object, and as a result, 3-0-alkyl or

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.

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.

The present invention has been completed based on this remarkable finding, and the following general formula (I)

Wherein R is a group selected from the group consisting of lower alkyl groups and lower alkylcarbonyl lower alkyl groups

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

In which R is as defined in General Formula (I) above.

The manufacturing method of 3-0-substituted ascorbic acid represented by the following is made into the summary.

Hereinafter, the present invention will be described.

In the present invention, the compound used as starting material is represented by the following general formula (I)

In 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

-R ² -CO-R ¹

(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.)

Will be displayed.

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.

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.

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.

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%.

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.

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.

The reaction apparatus is not particularly limited and may be cyclic or batch.

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.

Example

First, the manufacture example of a raw material is demonstrated as a reference example.

Reference Example

(1) [Synthesis of L-5,6-0-isopropylidene ascorbic acid]

180 g of ascorbic acid is stirred in 70 ml of acetone and warmed to 40 ° C.

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) [Synthesis of L-3-0-ethyl-5,6, -0-isopropylidene ascorbic acid]

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.

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.

Example 1

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.

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.

Example 2

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.

Example 3

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.

Comparative Example 1

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.

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.

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%).

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.

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.

Comparative Example 2

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.

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)

In the compound represented by the following general formula (I) by treating 3-0-substituted-5,6-0-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 dioxolane ring is opened to form a vic-glycol group: [Wherein R is a group selected from the group consisting of a lower alkyl group and a lower alkylcarbonyl lower alkyl group.] The process according to claim 1, wherein the non-aqueous solvent is at least one selected from the group consisting of primary alcohols, ethers and halogenated hydrocarbons. The method according to claim 1, wherein the non-aqueous solvent is at least one selected from the group consisting of esters, nitriles, aromatic hydrocarbons, aliphatic hydrocarbons and aprotic organic solvents. The non-aqueous solvent according to claim 1, wherein the non-aqueous solvent is at least one selected from the group consisting of primary alcohols, ethers and halogenated hydrocarbons and esters, nitriles, aromatic hydrocarbons, aliphatic hydrocarbons and aprotic organic solvents. A mixture with one or more selected from the group consisting of: The method according to claim 1, wherein the acidic ion exchange resin has a sulfonic acid group or a carboxylic acid group as an effective functional group.