JP2001002690A - Production of phosphoric diester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an excellent method for producing an ascorbic-2-phosphoric diester using tocopherol. SOLUTION: This method for producing a phosphoric diester of the formula (R1 and R2 are each H or methyl) or a pharmacologically acceptable salt thereof comprises the following process: ascorbic acid or that with the hydroxyl groups at 5- and 6-positions protected is reacted with a compound formed by reaction of α-, β-, γ- or δ-tocopherol with a halophosphoric esterifying agent; wherein the reaction is carried out in an organic solvent with high affinity for water using, as deacidifier, an alkali metal hydroxide or carbonate or a tertiary amine in the three equivalent ratio or greater; subsequently to the above reaction, in the case of the ascorbic acid with the hydroxyl groups at 5- and 6-positions protected, the protective groups are eliminated.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a phosphoric diester. More specifically, the present invention relates to a method for producing tocopherol, ascorbic acid-2-phosphate diester or a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art Tocopherol, ascorbic acid-2-phosphate diester and pharmacologically acceptable salts thereof, which are the target compounds according to the production method of the present invention, are used as anti-cataract agents, agents for preventing and treating climacteric disorders, and for beautiful skin. Cosmetics with action (Japanese Patent Publication No. 2-44478), antioxidants (Patent No. 2052513),
Anti-ulcer agent (patent No. 2526059), anti-inflammatory agent (Japanese Patent Publication No. 1-270)
No. 44, Japanese Patent Publication No. 5-23274), various uses such as a prophylactic / therapeutic agent for ischemic organ damage (Patent No. 2714678) and a Maillard reaction inhibitor (Patent No. 2846331) are already known.

[0003] As a method for producing the above phosphoric diester,
Conventionally, α, β, γ or δ-tocopherol is phosphorylated with a halophosphate esterifying agent such as phosphorus oxychloride in a solvent such as benzene or toluene in the presence of an organic amine such as pyridine or triethylamine to phosphorylate tocopheryl. As phosphorodichloridate, etc.
This is reacted with 5,6-O-isopropylidene ascorbic acid in which the hydroxyl group at the 5,6-position is protected in the presence of an organic amine such as pyridine or triethylamine in a solvent such as tetrahydrofuran to give the 2-position of ascorbic acid. A method is known in which the protecting group is eliminated (deacetonized) with an acid such as hydrochloric acid by bonding to a hydroxyl group (Japanese Patent Publication No. 2-44478, Japanese Patent Publication No. 5-23274).

However, in this production method, the compound obtained by reacting a tocopherol with a halophosphate esterifying agent is not only capable of reacting with a hydroxyl group at the 3-position but also a hydroxyl group at the 2-position of 5,6-O-isopropylidene ascorbic acid. Combine
Target compound tocopherol, ascorbic acid-2
In addition to the phosphoric acid diester, there is a disadvantage that tocopherol and ascorbic acid-3-phosphate diester are by-produced.

Therefore, the present inventors focused on the hydroxyl group at the 3-position of 5,6-O-isopropylidene ascorbic acid,
As a result of intensive studies on an excellent production method with a high yield of the above-mentioned phosphoric diester, a compound obtained by reacting an α, β, γ or δ-tocopherol with a halophosphoric acid esterifying agent and a 3,5,6-position A method for producing the above-mentioned phosphoric diester or a pharmacologically acceptable salt thereof, characterized by reacting ascorbic acid having a protecting group with a hydroxyl group of the above, and then removing the above-mentioned protecting group (particularly, Kaihei 9-17
No. 6173).

However, this production method has a drawback that the reaction step is long, though the yield is better than the above-mentioned method.

Further, JP-A-8-157488 discloses that an aprotic polar solvent (such as dimethyl sulfoxide or tetrahydrofuran) is used as a solvent by using a tocopherol halophosphate ester and ascorbic acid in which the hydroxyl groups at positions 5 and 6 are not protected. Wherein the reaction is carried out in the presence of a dehydrohalogenating reagent (such as potassium carbonate or lithium carbonate), wherein tocopherol, ascorbic acid-2-phosphate diester or tocopherol, ascorbic acid-
A method for producing a 3-phosphate diester is disclosed.

However, this production method aims to produce not only tocopherol and ascorbic acid-2-phosphate diester, but also tocopherol and ascorbic acid-3-phosphate diester, and tocopherol and ascorbic acid-2-phosphate. It is not yet satisfactory from the viewpoint of efficiently producing only phosphoric diester.

[0009]

Therefore, the present inventor has proposed:
Furthermore, the present inventors have conducted intensive studies on a method for producing the above-mentioned tocopherol and ascorbic acid-2-phosphate diester which is simple and high in yield.

As a result, the present inventor has found that ascorbic acid 3
Paying attention to the fact that the hydroxyl group at the position is an acidic group, in an organic solvent having a high affinity for water, a hydroxide or carbonate of an alkali metal in a ratio of 3 equivalents or more or a tertiary amine in a ratio of 3 equivalents or more ( Base, deoxidizing agent) in excess to add ascorbic acid or ascorbic acid in which the hydroxyl group at the 5- or 6-position is protected (eg:
When 5,6-O-isopropylidene ascorbic acid) is reacted with tocopheryl phosphorodihalolidate (eg, tocopheryl phosphorodichloridate), it reacts almost selectively with the hydroxyl group at the 2-position of ascorbic acid. I found to do. Furthermore, it has been found that if water is added to these organic solvents in advance, they are not colored and have few impurities, and it is extremely easy to purify the target compound.
The present invention has been completed based on these new findings.

The present invention provides a simple and high-yield production method of the above-mentioned tocopherol and ascorbic acid-2-phosphate diester.

[0012]

The present invention provides (1) α, β,
When reacting a compound obtained by reacting a halophosphate esterifying agent with γ or δ-tocopherol with ascorbic acid or ascorbic acid having a protecting group at the hydroxyl group at the 5,6-position, 3 or the like as a deoxidizing agent Using an alkali metal hydroxide or carbonate or a tertiary amine in a quantitative ratio or more, the reaction is carried out in an organic solvent having a high affinity for water. Then, ascorbic acid having a protecting group at the hydroxyl group at the 5th or 6th position is reacted. In this case, a method for producing a phosphoric diester represented by the following formula (I) or a pharmaceutically acceptable salt thereof, wherein the protecting group is eliminated:

[0013]

Embedded image

Wherein R ₁ and R ₂ are the same or different and each represent a hydrogen atom or a methyl group. (2) wherein the alkali metal hydroxide or carbonate is a basic compound selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. The production method according to (3), wherein the tertiary amine is an amine selected from the group consisting of trimethylamine, triethylamine and tributylamine, (4) the production method according to (1), wherein the organic solvent is dimethylformamide, dimethylsulfoxide, pyridine, The production method according to the above (1), which is a solvent selected from the group consisting of acetonitrile and dioxane, (5) the production method according to the above (1), wherein water is added to an organic solvent, (6) ascorbin. The production method according to the above (1), wherein the protecting group for the hydroxyl group at the 5- or 6-position of the acid is an acyl group, and (7) the acyl group is an isopropylidene group, a benzylidene group or the like. And a group selected from the group consisting of acetyl groups.

The starting materials for the production method of the present invention, 5, 6
The ascorbic acid having a protecting group at the hydroxyl group at the 2-position can be synthesized, for example, by the method described in JP-B-2-44478 and JP-B-5-23274, or according to the method. Examples of the protecting group for the hydroxyl group at the 5-position and the 6-position of ascorbic acid include acyl groups such as an isopropylidene group, a benzylidene group, and an acetyl group, and an isopropylidene group is generally used. These protecting groups can be easily removed by making the reaction solution acidic. For the acidification, an inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid or the like, or an organic acid such as acetic acid or citric acid can be used.

The tocopherol derivative (tocopheryl phosphorodihalolidate), which is the other starting material in the production method of the present invention, is prepared, for example, by the method described in the above-mentioned JP-B-2-44478 and JP-B-5-23274. Or according to this. As the halophosphate esterifying agent used in the production of the raw material, phosphorus oxychloride and phosphorus oxybromide are preferable.

In the production method of the present invention, a hydroxide or carbonate of an alkali metal or a tertiary amine is used as a deoxidizing agent.

The alkali metal hydroxide or carbonate used as a deoxidizing agent in the production method of the present invention includes sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate as described above. , Potassium bicarbonate and the like. In the production method of the present invention, these basic compounds are used in a ratio of 3 equivalents or more. As described above, JP-A-8-157488 discloses a dehydrohalogenating reagent such as potassium carbonate or lithium carbonate as a deoxidizing agent. No excellent effect (ie high yield and very easy purification) is disclosed.

The tertiary amine used as a deoxidizing agent in the production method of the present invention is used in a ratio of 3 equivalents or more, but trimethylamine, triethylamine and tributylamine are preferable, and triethylamine is particularly preferable.
On the other hand, pyridine, which is a tertiary amine, is not preferred in that the yield of the target compound is lower than those amines. The tertiary amine used as a deoxidizing agent in the production method of the present invention is disclosed in Japanese Patent Publication No. 2-44478 and Japanese Patent Publication No. 5-23274, and pyridine and triethylamine are disclosed.
Specifically, in the Examples, pyridine is used in a ratio of 2 equivalents, but there is no disclosure of the excellent effect when a tertiary amine such as triethylamine is used in a ratio of 3 equivalents or more.

The organic solvent having high affinity for water used in the production method of the present invention includes dimethylformamide (DMF),
Dimethyl sulfoxide (DMSO), pyridine, acetonitrile, dioxane, and the like are preferable, but any other organic solvent having high affinity for water that does not inhibit the reaction can be used.

A compound obtained by adding water to an organic solvent having a high affinity for water used as a reaction solvent of the present invention and reacting α, β, γ or δ-tocopherol with a halophosphate esterifying agent. , Ascorbic acid or 5,6
When ascorbic acid having a protecting group at the hydroxyl group is reacted, the purification of the target compounds tocopherol and ascorbic acid-2-phosphate diester is very easy. The amount of water used for the purpose of facilitating purification of the target compound and added to the organic solvent varies depending on the type of the organic solvent used and the amount used.
About 0.5 for F, DMSO, pyridine, acetonitrile, etc.
% To 2% is preferred. Water is preferably added to the organic solvent used for dissolving ascorbic acid or ascorbic acid in which the hydroxyl group at the 5,6-position is protected before this reaction.

This reaction may be carried out at room temperature, but is preferably carried out under cooling since it is an exothermic reaction.
It takes about 3 hours.

The free acid of the phosphoric diester represented by the formula (I) obtained as described above can be converted into an alkali metal salt such as a sodium salt or a potassium salt by a conventional method using, for example, an alkali hydroxide. And alkaline earth metal salts such as calcium salts and magnesium salts. The free acid of the phosphoric diester has two acid residues, and forms a mono- or di-salt depending on the neutralization amount of the alkali hydroxide.

[0024]

The present invention will be described in more detail with reference to the following examples.

Example 1 Synthesis of Tocopherol and Ascorbic Acid-2-Phosphate Diester Potassium Salt 4.3 g (0.01 mol) of dl-α-tocopherol and 5 ml of pyridine were dissolved in 40 ml of benzene, and phosphorus oxychloride was added thereto. .
After stirring for about 1.5 hours, the precipitated pyridine hydrochloride was filtered off, and the filtrate was concentrated. The residue oil obtained is dissolved in 15 ml of chloroform and placed.

On the other hand, 40 ml of DMF was added to 3.0 g of 5,6-isopropylidene ascorbic acid and 4.5 g of anhydrous potassium carbonate, and the above-mentioned chloroform solution was gradually added dropwise with cooling and stirring. After the addition was completed, the mixture was further stirred for 30 minutes. Return to room temperature
After stirring for 1 hour, chloroform is distilled off, and about 60 ml of water is further added.
And acidified with hydrochloric acid, extracted with ethyl acetate, and the ethyl acetate was distilled off. Ethanol (60 ml) and 1N-hydrochloric acid (40 ml) are added to the residual oil, and the mixture is stirred at 60 ° C. for 15 minutes. The ethanol is distilled off. The residue is extracted with ethyl acetate, washed with water, and then ethyl acetate is distilled off. The resulting semi-solid was dissolved in 70 ml of ethanol, and a potassium hydroxide / ethanol solution was gradually added thereto to adjust the pH to 7, and the precipitated white crystals were collected by filtration.The crystals were dissolved in water and acidified with hydrochloric acid to recrystallize them. After extraction with ethyl acetate, washing with water, the ethyl acetate was distilled off, the residue was dissolved in ethanol, and potassium hydroxide / ethanol was gradually added again to adjust the pH to about 6.5, and the precipitated white crystals were collected by filtration and washed with ethanol. After washing and drying, 5.2 g (yield: 68.2.%) Of the diester salt of the target compound is obtained. TLCRf = 0.56 (n-butanol:
Acetic acid: water = 4: 1: 1).

Elemental analysis value C ₃₅ H ₅₅ O ₁₀ PK ₂ · H ₂ O
Theoretical value (%): C, 55.09; H, 7.53 Actual value (%): C, 55.33; H, 7.61

[Example 2] Synthesis of tocopherol and dipotassium dipotassium ascorbic acid-2-phosphate Example was prepared using 4.3 g (0.01 mol) of dl-α-tocopherol.
The reaction was conducted in the same manner as in Example 1 except that 40 ml of DMSO and 0.5 ml of water were used instead of 40 ml of DMF to obtain 5.3 g (69.5%) of the dipotassium salt of the target compound.

Example 3 Synthesis of Tocopherol and Dipotassium Ascorbic Acid-2-Phosphate Dipotassium Salt Example was prepared using 4.3 g (0.01 mol) of dl-α-tocopherol.
The reaction was carried out in the same manner as in Example 1 except that 6 ml of triethylamine, 40 ml of pyridine and 0.5 ml of water were used instead of 40 ml of potassium carbonate and DMF. After the reaction, the solvent was distilled off, and the residue was added with 30 ml of water. The mixture was acidified with hydrochloric acid, extracted with ethyl acetate, and treated in the same manner to obtain 5.5 g (72.1%) of the dipotassium salt of the target compound.

Example 4 Synthesis of Tocopherol, Ascorbic Acid-2-phosphate Dipotassium Dipotassium Salt dl-α-tocopherol 4.3 g (0.01 mol), pyridine 5 ml,
Α-Tocopherol phosphodichloridate was prepared in the same manner as in Example 1 using 40 ml of benzene, and dissolved in 15 ml of chloroform. On the other hand, 2.5 g of L-ascorbic acid,
To 4.5 g of anhydrous potassium carbonate, 40 ml of DMF and 0.5 ml of water were added, and the mixture was cooled.The chloroform solution was gradually added dropwise thereto.After stirring for 30 minutes, the mixture was returned to room temperature and stirred for 1 hour.
50 ml of water is added thereto, and chloroform is distilled off. To this was added 50 ml of water, further acidified with hydrochloric acid, extracted with ethyl acetate, washed with a small amount of water, and evaporated to remove ethyl acetate.The residual oil was dissolved by adding 70 ml of ethanol, and the pH was adjusted to 7 with potassium hydroxide / ethanol. And the precipitated white crystals are collected by filtration.
Recrystallization is performed in the same manner as in Example 1 to obtain 5.2 g (68.2%) of the dipotassium salt of the target compound.

Example 5 Synthesis of Tocopherol, Ascorbic Acid-2-phosphate Dipotassium Dipotassium Salt Example 1 was prepared using 4.3 g (0.01 mol) of dl-α-tocopherol.
The reaction was carried out in the same manner as in Example 4 except that 6 ml of triethylamine was used instead of anhydrous potassium carbonate in 4, to obtain 5.3 g (69.5%) of the dipotassium salt of the target compound.

Example 6 Synthesis of Tocopherol and Ascorbic Acid-2-Phosphate Diester Dipotassium Salt Example 4 was prepared using dl-α-tocopherol 4.3 g (0.01 mol).
Except that anhydrous potassium carbonate and DMF in Example 4 were replaced with 6 ml of triethylamine and 40 ml of pyridine, respectively, the reaction was carried out in the same manner as in Example 4 to obtain 5.6 g of dipotassium salt of the target compound (73.
4%).

Example 7 Synthesis of Tocopherol and Ascorbic Acid-2-phosphate Dipotassium Dipotassium Salt Example was prepared by using 4.3 g (0.01 mol) of dl-α-tocopherol.
Except that anhydrous potassium carbonate and DMF of 4 were replaced with 6 ml of triethylamine and 60 ml of acetonitrile, respectively, the reaction treatment was carried out in the same manner as in Example 4 to obtain the dipotassium salt of the target compound.
5.2g (68.2%) is obtained.

Example 8 Synthesis of Tocopherol and Dipotassium Ascorbic Acid-2-Phosphate Dipotassium Salt Example was prepared using 4.3 g (0.01 mol) of dl-α-tocopherol.
The reaction was carried out in the same manner as in Example 4 except that anhydrous potassium carbonate and DMF in Example 4 were replaced with 5 ml of triethylamine, 40 ml of acetonitrile and 5 ml of pyridine, respectively, to obtain 5.4 g (70.8%) of the dipotassium salt of the target compound.

[0035]

The production method of the present invention, compared with the conventional method,
The feature is that the process is short and the yield is high.

That is, according to Example 1 described in Japanese Patent Publication No. 2-44478, the yield of the target compound tocopherol and dipotassium ascorbic acid-2-phosphate dipotassium was 49.1% of the theoretical value. According to the method described in JP-157488, the yield was about 28% (Example 1), whereas the production method of the present invention provided a high yield of 73.4% (Example 6 of the present application). There is an advantage that can be. Further, the yield of the production method of the present invention is higher than 62.9% (Example 1) and 60.3% (Example 2) according to the method described in JP-A-9-176173. The manufacturing method is superior to this method in that the manufacturing process is shorter.

Further, water is added to an organic solvent having a high affinity for water to be used as the reaction solvent of the present invention, so that α, β,
When a compound obtained by reacting γ or δ-tocopherol with a halophosphate esterifying agent is reacted with ascorbic acid or ascorbic acid having a protecting group at the hydroxyl group at the 5,6-position, the target compound tocopherol, ascorbic acid- There is an advantage that purification of 2-phosphate diester is extremely easy.

Claims (7)

[Claims] (1) a compound obtained by reacting α, β, γ or δ-tocopherol with a halophosphate esterifying agent;
When reacting ascorbic acid or ascorbic acid having a protecting group at the hydroxyl group at the 5,6-position, as a deoxidizing agent,
Using an alkali metal hydroxide or carbonate or a tertiary amine in an equivalence ratio of at least 3 in an organic solvent having a high affinity for water, then ascorbin having a protecting group at the hydroxyl group at the 5- or 6-position In the case of an acid, a method for producing a phosphoric diester represented by the following formula (I) or a pharmacologically acceptable salt thereof, wherein the protecting group is eliminated. Embedded image [Wherein, R ₁ and R ₂ are the same or different and each represent a hydrogen atom or a methyl group. ] 2. The hydroxide or carbonate of an alkali metal is a basic compound selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. Manufacturing method. 3. The method according to claim 1, wherein the tertiary amine is an amine selected from the group consisting of trimethylamine, triethylamine and tributylamine. 4. The method according to claim 1, wherein the organic solvent is a solvent selected from the group consisting of dimethylformamide, dimethylsulfoxide, pyridine, acetonitrile and dioxane. 5. The method according to claim 1, wherein water is added to the organic solvent. 6. The method according to claim 1, wherein the protecting group for the hydroxyl group at the 5- and 6-positions of ascorbic acid is an acyl group. 7. The method according to claim 6, wherein the acyl group is a group selected from the group consisting of an isopropylidene group, a benzylidene group and an acetyl group.