KR100230653B1 - Water stable L-ascorbic acid derivatives and a method for preparation thereof - Google Patents

Abstract

The present invention relates to a water-stable L-ascorbic acid derivative represented by the following structural formula (I) and a method for preparing the same, wherein 3-amino-1-propanol and phosphorus oxychloride are present in an organic base in an equivalent ratio of 1: 1 to 1.3. 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide and L-ascorbic acid protected by 5,6-hydroxy group formed by reaction under an organic solvent in the presence of organic base After reacting at, it is hydrolyzed and crystallized with a polar organic solvent.

(Ⅰ)

Description

Water stable L-ascorbic acid derivatives and a method for preparation

The present invention relates to a water-stable L-ascorbic acid derivative represented by the following structural formula (I) and a preparation method thereof. More specifically, the water stability is very excellent, and since 3-aminopropanoic acid and L-ascorbic acid are linked in the form of phosphate diester, it is decomposed by enzymes in vivo and 3-aminopropaneic acid and L-ascorbic acid. It relates to a derivative of L-ascorbic acid which can also exhibit the physiological activity of and a preparation method thereof.

(I)

L-ascorbic acid is a bioactive substance with strong antioxidant activity and is used for the treatment of scurvy, and because of various physiological and pharmacological effects such as inhibiting the accumulation of melanin pigment, which causes blemishes and freckles, medicines, cosmetics, food, etc. It is applied to various fields. However, since L-ascorbic acid is easily oxidized and decomposed in an aqueous phase, there are many problems such as color change in color as well as a decrease in the titer in the case of long-term storage or manufacturing process when applied to medicines, cosmetics, and food.

Therefore, many derivatives have been developed to improve the instability of the L-ascorbic acid in the water phase, for example, 2-phosphate magnesium salt, polyphosphate inorganic salt, 2-sulfate inorganic salt, 2 of L-ascorbic acid. -Glucose, etc. Particularly, in the case of L-ascorbic acid-2-phosphate magnesium salt having excellent stabilization of L-ascorbic acid among the above-mentioned derivatives, the production of a whitening cosmetic using the same as an active ingredient is known (Japanese Patent Laid-Open No. 1-283208). , Japanese Patent Application Laid-Open No. 3-227907), but this derivative also causes a number of problems such as discoloration and insoluble crystals generated by itself when applied to an aqueous product. Therefore, purification methods for obtaining high purity compounds for preventing coloration and methods for improving precipitation phenomenon are also known (Japanese Patent Laid-Open No. 62-30791 and Japanese Patent Laid-Open No. 4-275206), but are not effective. .

Accordingly, the present inventors earnestly studied to develop derivatives of water-stable L-ascorbic acid in order to solve the above problems of L-ascorbic acid derivatives. As a result, 3-aminopropane phosphoric acid, which is known to be widely used as an active ingredient of anti-aging cosmetic composition because of its excellent effect on the proliferation and collagen synthesis of fibroblasts and the stability to the skin, was selected from 2- of L-ascorbic acid. When linked to the position in the diester phosphate form, it was found that the above object can be achieved and the present invention has been completed.

Accordingly, an object of the present invention is to provide a derivative of water-stable L-ascorbic acid represented by the following structural formula (I).

(Ⅰ)

Furthermore, another object of the present invention is to provide a method for producing L-ascorbic acid described above.

The above object can be achieved by reacting 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide with L-ascorbic acid in which a 5,6-hydroxy group is protected, more specifically As a method for producing an L-ascorbic acid derivative according to the present invention, first, 3-amino-1-propanol and phosphorus oxychloride are in an organic solvent in the presence of an organic base at an equivalent ratio of 1: 1 to 1.3, at 0 to 5 ° C. The reaction was carried out at a temperature of 1 to 2 hours to prepare 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide, which was then protected by L- with 5,6-hydroxyl group protected in the presence of an organic solvent. It is characterized by reacting with ascorbic acid, hydrolyzing and crystallizing with a polar organic solvent.

Hereinafter, the present invention will be described in more detail.

Method for producing L-ascorbic acid derivatives according to the present invention,

(A) 3-amino-1-propanol and phosphorus oxychloride were reacted for 1 to 2 hours at an temperature of 0 to 5 DEG C in an organic solvent in the presence of an organic base in an equivalent ratio of 1: 1 to 1.3. Producing 2H-1,3,2-oxazaphosphorine P-oxide;

(B) reacting the 5,6-hydroxyl group of L-ascorbic acid with a protective group to produce L-ascorbic acid in which the 5,6-hydroxyl group is protected;

(C) L protected with 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide produced in step (A) and 5,6-hydroxyl group produced in step (B) Reacting ascorbic acid in an organic solvent in the presence of an organic base;

(D) depressurizing and concentrating the filtrate obtained by filtration of the reaction solution, and adding purified water to the obtained residue to react and hydrolyze at a temperature of 5 to 100 ° C. for about 3 hours; And

(E) crystallizing with polar organic solvent;

Characterized in that it comprises a.

The preparation method according to the invention can be represented by the following scheme 1:

(A)

(II)

(B)

＋ 보호기 ------＞

+ Protector ------>

(III)

(C)

＋

-------＞

+

------- ＞

(III) (II) (IV)

(D)

--------＞

-------- ＞

(IV) (I)

As can be seen in Scheme 1, a method for preparing an L-ascorbic acid derivative according to the present invention is described in detail as follows.

(A) 2-chlorotetrahydro- represented by the above formula (II) by stirring 3-amino-1-propanol and phosphorus oxychloride in an organic solvent for 1 to 2 hours at a temperature of 0 to 5 ° C. in the presence of an organic base. Producing 2H-1,3,2-oxazaphosphorin P-oxide; 2-Chlorotetrahydro-2H-1,3,2-oxaza phosphorin P-oxide;

In the above step, 3-amino-1-propanol and phosphorus oxychloride are preferably reacted in an equivalent ratio of 1: 1 to 1.3. If the equivalent ratio is less than 1: 1, the desired product cannot be obtained, and if it is 1: 1.3 or more, an excess of by-products are produced in addition to the desired product. Therefore, when 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide is prepared by the above-described method, an intermediate in which 3-amino-1-propanol and phosphorus oxychloride are 1: 1 bound 95% or more is produced, and by-products in which 2-amino-1-propanol and phosphorus oxychloride are 2: 1 bonded are produced in 1 to 2% or less. However, the by-products can be separated using chromatography, or easily removed by using a difference in solubility in toluene. In particular, two chlorine atoms of the three chlorine atoms in the phosphorus oxychloride molecule are substituted by two functional groups of 3-amino-1-propanol, ie, hydroxyl and amine groups, and cyclized 2-chlorotetrahydro-2H-1,3, The 2-oxaphosphorine P-oxide is produced, and the other chlorine atom is reduced in reactivity at 5 ° C or lower and remains unsubstituted. This is because the chlorine atom of 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorin P-oxide is stable in a low temperature anhydrous inert solvent and is not easily substituted with 3-amino-1-propanol. Therefore, in the preparation method of the present invention, 3-amino-1-propanol and phosphorus oxychloride are reacted at a temperature of 0 to 5 ° C. for 1 to 2 hours at an equivalent ratio of 1: 1.0 to 1.3. Propanol and phosphorus oxychloride can prevent the formation of by-products reacted at 2: 1 or more, and in particular, it is not necessary to introduce ester groups or amide groups in order to protect chlorine atoms of phosphorus oxychloride. There is an advantage to reduce.

As the organic base in step (A) of the production method of the present invention, pyridine, triethylamine, and the like may be used, but triethylamine is preferably used.

In the method (A) of the present invention, an organic solvent may be an inert solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, ethyl ether, etc., but dichloromethane is preferably used.

On the other hand, the reaction temperature is more than 2 equivalents of 3-amino-1-propanol is substituted with phosphorus oxychloride to increase the production of by-products, and the temperature of less than 0 ℃ to reduce the solubility of the reactants difficult to proceed the reaction. In this case, a temperature in the range of 0 to 5 ° C. is preferable because the content of unreacted material is increased to lower the reaction yield.

(B) reacting the 5,6-hydroxyl group of L-ascorbic acid with a protective group to produce L-ascorbic acid in which the 5,6-hydroxyl group is protected;

Benzilidene group, phenylethylidene group, isopropylidene group and the like may be used as the protecting group in the step of producing L-ascorbic acid protected with 5,6-hydroxyl group in the production method of the present invention, isopropylidene group It is preferable to use.

(C) reacting 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide with L-ascorbic acid protected with 5,6-hydroxy group in an organic solvent in the presence of an organic base;

As the organic base in step (C) of the production method of the present invention, pyridine, triethylamine, and the like may be used as described in step (A), but it is preferable to use triethylamine.

In step (C) of the production method of the present invention, an organic solvent may be an inert solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, ethyl ether, etc., but chloroform is preferably used.

(E) concentrating the filtrate obtained by filtration of the reaction solution under reduced pressure, and then adding purified water to the obtained residue to react for about 3 hours at a temperature of about 5 to 100 ° C. for hydrolysis;

Hydrolysis of the residue obtained by concentrating the filtrate obtained by filtration of the reaction solution under reduced pressure in the production method according to the present invention can be hydrolyzed using an acid catalyst such as strong cation exchange resin (Amberlyst 15), hydrochloric acid or sulfuric acid, which are general hydrolysis conditions. However, since the aqueous solution of the compound of formula (IV) shows strong acidity (1% aqueous solution pH = 2), when purified water is added to the residue and then stirred at a temperature of 5 to 100 ° C. for deprotection and PN bonding This can be hydrolyzed. Therefore, it is preferable to add the purified water to the residue obtained by concentrating the filtrate obtained by filtration of the reaction solution, and to react it for about 3 hours at a temperature of about 5 to 100 ° C, preferably 50 ° C for hydrolysis.

(E) gradually dropping a polar organic solvent to crystallize L-ascorbic acid and 3-aminopropanol phosphate diester, which are derivatives of L-ascorbic acid;

Although the polar organic solvent which is a precipitation solvent used by this invention is not specifically limited, For example, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, or dioxane can be used.

Derivatives of L-ascorbic acid provided by the above production method may be used in the form of salts by neutralizing them, and specific examples thereof include alkali metal salts such as sodium and potassium; Alkaline earth metal salts such as calcium and magnesium; Amines such as triethanolamine or salts with ammonia.

Hereinafter, the preparation method of the L-ascorbic acid derivative according to the present invention will be described in more detail. However, the present invention is not limited to these examples.

[Production Example] 2-Chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide (2-Chlorotetrahydro-2H-1,3,2-oxaza phosphorin P-oxide)

34.1 mL (0.36 mol) of phosphorus oxychloride was dissolved in 400 mL of dichloromethane, and the solution was cooled to 0-5 ° C. in an ice water bath. In another vessel, 30 mL (0.39 mol) of 3-amino-1-propanol and 102 mL (0.73 mol) of triethylamine were diluted with 200 mL of dichloromethane, and the reaction solution prepared above was added dropwise for 2 hours. After the addition, the triethylammonium chloride produced was removed. The filtrate was washed with 100 ml purified water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. After concentration, toluene was added to the obtained residue to obtain a crystal. The obtained crystals were dried in vacuo to give 53 g of white solid as a reaction product, 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide.

Melting Point: 79 ~ 82 ℃

IR (CHCl ₃ , cm ⁻¹ ): 3254, 1477, 1274, 1092, 1036, 996

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.7 (m, 1H), 1.1 (m, 1H), 3.3 (m, 2H), 4.4 (m, 2H), 4.9 (br, 1H)

¹³ C-NMR (CDCl ₃ ): δ (ppm) = 25.78, 25.85, 42.05, 42.11, 71.69, 71.81

Example 1 L-ascorbic acid and 3-aminopropanol phosphate diester

10 g (0.046 mol) of 5,6-isopropylidene ascorbic acid, which protected the 5,6-hydroxyl group of L-ascorbic acid using an isopropylidene group, was dissolved in 100 ml of chloroform, and then, 12.9 mL (0.093 mol) of ethylamine was added dropwise. 8.6 g (0.055 mol) of 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide dissolved in 20 ml of chloroform at the same temperature was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature overnight, the organic layer was washed with an aqueous solution of phosphoric acid, dried over anhydrous sodium sulfate and activated carbon, and decolorized. The reaction solution was filtered and the filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in 30 ml of purified water and stirred for 3 hours at 50 ° C in a thermostat. 150 ml of isopropanol was added to the stirred reaction solution to obtain crystals, and the obtained crystals were dried in vacuo to obtain L-ascorbic acid and 3-aminopropanol phosphate diester as 6 g of a white solid.

Melting Point: 176 ~ 180 ℃

IR (KBr, cm ⁻¹ ): 3407, 3322, 3101, 2914, 1747, 1673, 1664, 1533, 1364, 1218, 1072

¹ H-NMR (D ₂ O): δ (ppm) = 1.9 (m, 2H), 3.05 (t, 2H), 3.62 (m, 2H), 3.98 (m, 3H), 4.90 (s, 1H)

¹³ C-NMR (D ₂ O): δ (ppm) = 26.76, 22.86, 32.35, 57.30, 59.77, 59.84, 64.15, 71.55, 71.72, 109.79, 109.88, 156.58, 156.63, 167.32, 167.38

Example 2 L-ascorbic acid and 3-aminopropanol phosphate diester sodium salt

After dissolving 1 g of L-ascorbic acid and 3-aminopropanol phosphate diester obtained in Example 1 in 30 ml of purified water, 5% aqueous sodium carbonate solution was added thereto to pH 7. The solution was lyophilized to give L-ascorbic acid and 3-aminopropanol phosphate diester sodium salt as a white solid.

Example 3 L-ascorbic acid and 3-aminopropanol phosphate diester potassium salt

After dissolving 1 g of L-ascorbic acid and 3-aminopropanol phosphate diester obtained in Example 1 in 30 ml of purified water, 5% aqueous potassium carbonate solution was added thereto to pH 7. The solution was lyophilized to give L-ascorbic acid and 3-aminopropanol phosphate diester potassium salt as a white solid.

Example 4 L-ascorbic acid and 3-aminopropanol phosphate diester calcium salt

After dissolving 1 g of L-ascorbic acid and 3-aminopropanol phosphate diester obtained in Example 1 in 30 ml of purified water, potassium hydroxide was added thereto to pH 7. The solution was lyophilized to give L-ascorbic acid and 3-aminopropanol phosphate diester calcium salt as a white solid.

Example 5 L-ascorbic acid and 3-aminopropanol phosphate diester magnesium salt

After dissolving 1 g of L-ascorbic acid and 3-aminopropanol phosphate diester obtained in Example 1 in 30 ml of purified water, magnesium oxide was added thereto to make pH 7. The solution was lyophilized to give L-ascorbic acid and 3-aminopropanol phosphate diester magnesium salt as a white solid.

Example 6 L-ascorbic acid and 3-aminopropanol phosphate diester triethanolamine salt

After dissolving 1 g of L-ascorbic acid and 3-aminopropanol phosphate diester obtained in Example 1 in 30 ml of purified water, 5% triethanolamine aqueous solution was added thereto to pH 7. The solution was lyophilized to give L-ascorbic acid and 3-aminopropanol phosphate diester triethanolamine salt as a white solid.

[Test Example 1]

3 g of L-ascorbic acid, 3-aminopropanol phosphate diester sodium salt and L-ascorbic acid 2-phosphate magnesium salt, which are the compounds of Example 2, were dissolved in 100 ml of purified water, and then stored in a 50 ° C. thermostat for 30 days. After the change of sedimentation and the presence or absence of coloration was observed according to the following evaluation criteria, the results are shown in Table 1 and Table 2.

Sedimentation One 3 5 7 9 11 13 15 30 Example 2 - - - - - - - - - L-ascorbic acid 2-phosphate magnesium salt - + + ++ ++ ++ +++ +++ +++

<Evaluation Criteria>

－: No sedimentation +: Less sediment formation

++: Sediment generation is large +++: Sediment generation is large

coloring One 3 5 7 9 11 13 15 30 Example 2 - - - - - - - - - L-ascorbic acid 2-phosphate magnesium salt - - - - - - - - +

<Evaluation Criteria>

－: Colorless or light yellow +: coloring pigment

++: during coloring +++: coloring

As can be seen from Tables 1 and 2, since the compound of the present invention is very stable and high purity in the aqueous phase, discoloration does not occur and precipitation does not occur.

[Test Example 2]

L-ascorbic acid, 3-aminopropanol phosphate diester and L-ascorbic acid, which are the compounds of Example 1, were dissolved in hydrion pH 7 buffer solution at a concentration of 50 μM, respectively, and then stored in a constant temperature bath at 50 ° C. for a predetermined time. The sample of Example was measured for UV absorption at 259 nm and L-ascorbic acid at 266 nm. Table 3 shows the sample residual ratio (%) in the sample solution.

0.5 hours 1 hours 3 hours 6 hours 24 hours 6 days 10 days Example 1 100 100 100 100 99.1 95.5 93.5 L-ascorbic acid 17.2 1.0 0 0 0 0 0

In general, the stability of the sample at dilution concentration is greatly reduced. However, as can be seen from Table 3, the compound of Example 1 is present in a stable state in a neutral aqueous solution, but the L-ascorbic acid aqueous solution almost decomposes within 1 hour.

L-ascorbic acid, 3-aminopropanol phosphate diester or a salt thereof, which is a derivative of L-ascorbic acid provided by the method of the present invention, is easy to be applied to a water-based product because it is stable and high-purity in the water phase, L-ascorbic acid with melanin production and human fibroblasts are promoted by the action of enzymes (phosphatase, etc.) in the body, promote the synthesis of collagen fibers (collagen), and furthermore, 3-amino having excellent human skin stability. Since it can be decomposed into propane phosphoric acid, it may be particularly useful as a raw material of the whitening and anti-aging cosmetic composition.

Claims (7)

In the method for preparing a derivative of water-stable L-ascorbic acid, (A) 3-amino-1-propanol and phosphorus oxychloride were reacted for 1 to 2 hours at an temperature of 0 to 5 DEG C in an organic solvent in the presence of an organic base in an equivalent ratio of 1: 1 to 1.3. Producing 2H-1,3,2-oxazaphosphorine P-oxide; (B) reacting the 5,6-hydroxyl group of L-ascorbic acid with a protecting group to produce L-ascorbic acid in which the 5,6-hydroxyl group is protected; (C) L protected with 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide produced in step (A) and 5,6-hydroxyl group produced in step (B) Reacting ascorbic acid in an organic solvent in the presence of an organic base; (D) depressurizing and concentrating the filtrate obtained by filtration of the reaction solution, and adding purified water to the obtained residue to react and hydrolyze at about 5-100 ° C. for about 3 hours; And (E) crystallizing with polar organic solvent; Method for preparing a water-stable L- ascorbic acid derivative, which is represented by Scheme 2, comprising: (A)

(II) (B)

+ Protector ------>

(III) (C)

+

------- ＞

(III) (II) (IV) (D)

-------- ＞

(IV) (I) The method for preparing L-ascorbic acid derivative according to claim 1, wherein the organic solvent used in step (A) or (C) is dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform or ethyl ether. . The method of claim 1, wherein the organic base used in step (A) or (C) is pyridine, triethylamine. The method for preparing an L-ascorbic acid derivative according to claim 1, wherein the protecting group used in step (B) is a benzylidene group, a phenylethylidene group or an isopropylidene group. The method of claim 1, wherein the polar organic solvent used in step (E) is methanol, ethanol, isopropanol, acetone, terahydrofuran, acetonitrile or dioxane. A derivative of L-ascorbic acid represented by the following structural formula (I) and a salt thereof prepared by the method according to claim 1.

(I) The salt of the L- ascorbic acid derivative is an alkali metal salt such as sodium, potassium and the like; Alkaline earth metal salts such as calcium and magnesium; A derivative of L-ascorbic acid, characterized in that it is selected from amines such as triethanolamine or salts with ammonia.