JPH09176173A - Production of phosphoric diester and its intermediate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an excellent method for producing tocopherol and ascorbic acid 2-diphosphate. SOLUTION: α-, β-, γ-or δ-Tocopherol is reacted with a halophosphorylating agent to provide a compound, which is then reacted with ascorbic acid having protecting groups at the 3-, 5- and 6-positions. The protecting groups are then eliminated to afford a phosphoric diester represented by the formula (R1 and R2 are each same or different hydrogen atom or methyl group) or its pharmacologically permissible salt in high yield.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a phosphodiester and a novel intermediate thereof. More specifically, the present invention relates to tocopherol, ascorbic acid-2.
-A method for producing a phosphodiester or a pharmaceutically acceptable salt thereof and a novel intermediate thereof.

[0002]

2. Description of the Related Art Tocopherol, ascorbic acid-2-phosphate diester and pharmaceutically acceptable salts thereof, which are the target compounds according to the production method of the present invention, are anticataract agents, agents for preventing and treating menopausal disorders, and beautiful skin. Cosmetics having effects (Japanese Patent Publication No. 2-44478), antioxidants (Japanese Patent Laid-Open No. 63-
139972), an anti-ulcer agent (JP-A-63-27062).
6), anti-inflammatory agent (Japanese Patent Publication No. 1-27044, Japanese Patent Publication No. 5)
No. 23274), ischemic organ injury preventive / therapeutic agent (JP-A-2-111722), and Maillard reaction inhibitor (JP-A-3-161444).

As a method for producing the above phosphoric acid 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 tocopheryl. Then, as phosphorodichloridate,
In the presence of an organic amine such as pyridine or triethylamine in a solvent such as tetrahydrofuran, this is reacted with 5,6-O-isopropylidene ascorbic acid in which the hydroxyl group at the 5 and 6 positions is protected to give a reaction at the 2-position of ascorbic acid. There is known a method of binding to a hydroxyl group and further removing (deacetonizing) this protective group with an acid such as hydrochloric acid (Japanese Patent Publication No. 2-44478 and Japanese Patent Publication No. 5-23274).

[0004]

However, in this production method, the compound obtained by reacting tocopherol with a halophosphoric acid esterifying agent is a compound other than the 2-hydroxy group of 5,6-O-isopropylidene ascorbic acid. Tocopherol, which is the target compound, also binds to the hydroxyl group at the 3-position,
In addition to ascorbic acid-2-phosphoric acid diester, tocopherol and ascorbic acid-3-phosphoric acid diester are by-produced.

Therefore, the present inventors have focused on the hydroxyl group at the 3-position of 5,6-O-isopropylidene ascorbic acid,
As a result of extensive studies on an excellent production method of the phosphoric acid diester having a high yield, the production method of the present invention has been completed.

[0006] The present invention provides an excellent production method of the above-mentioned phosphodiester with high yield and a novel intermediate thereof.

[0007]

Means for Solving the Problems That is, the present invention comprises: (1) a compound obtained by reacting α, β, γ or δ-tocopherol with a halophosphate esterifying agent;
A phosphoric acid diester represented by the formula (I) or a pharmacologically acceptable salt thereof, which comprises reacting ascorbic acid having a protecting group at the 5- and 6-position hydroxyl groups and then removing the protecting group. Salt production method, and

[0008]

Embedded image

[In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a methyl group. ]

Formula (2) (V)

[0011]

Embedded image

[In the formula, R ₁ and R ₂ have the same meanings as described above, and R ₃ represents a benzyl group, a p-methoxybenzyl group or a methoxymethyl group. ] It is related with the phosphodiester represented by these, or its pharmacologically acceptable salt.

The manufacturing method of the present invention will be described in more detail below.

When tocopheryl phosphorodichloridate [formula (II) below] and 5,6-O-isopropylidene ascorbic acid [formula (III) below] having a protecting group at the 3-position hydroxyl group are used The reaction formula of is as follows. The compounds represented by the formulas (IV) and (V) are both novel compounds that have not been published in the literature.

[0015]

Embedded image

[In the formula, R ₁ , R ₂ and R ₃ have the same meanings as described above. ]

A compound obtained by reacting α, β, γ or δ-tocopherol with a halophosphate esterifying agent;
The reaction with ascorbic acid having a protecting group at the 3,5,6 position hydroxyl group is carried out in a non-polar solvent in the presence of an organic amine as a deoxidizing agent. Next, the above protecting group is removed from the compound thus obtained to obtain the target compound represented by the formula (I).

Examples of the nonpolar solvent used in the production method of the present invention include benzene, toluene, chloroform and tetrahydrofuran (THF), but any solvent which does not inhibit the reaction may be used. As the organic amine used as a deoxidizing agent in this reaction, tertiary amines such as pyridine and triethylamine are preferable. This reaction is carried out at about 1 to about 1
It will be finished in about 3 hours.

Examples of the protecting group for the 5- and 6-position hydroxyl groups of ascorbic acid include isopropylidene group, benzylidene group, acyl group such as acetyl group, and the isopropylidene group is common. These protecting groups can be easily removed by acidifying the reaction solution. To make it acidic, for example, hydrochloric acid, phosphoric acid,
An inorganic acid such as sulfuric acid or an organic acid such as acetic acid or citric acid can be used. Further, as a protecting group for the hydroxyl group at the 3-position of ascorbic acid (R ₃ in the formula), a protecting group capable of leaving under mild conditions, such as palladium carbon (Pd-C)
Or a benzyl group or p-methoxybenzyl group which can be easily removed by catalytic reduction with Raney Ni, or 1
A methoxymethyl group which can be easily removed with N hydrochloric acid is particularly preferable. In the removal of the protecting group, it is usual to remove the protecting group at the 5th and 6th positions and then the protecting group at the 3rd position by the above method. However, when the protecting group at the 3rd position is a methoxymethyl group. It is also possible to simultaneously remove the protecting groups at the 3, 5 and 6 positions by using an acid.

The tocopherol derivative, which is the starting material for the production method of the present invention, can be synthesized by the method described in the above-mentioned JP-B-2-44478 and JP-B-5-23274, or in accordance with it. Phosphorus oxychloride and phosphorus oxybromide are preferable as the halophosphoric acid esterifying agent used in the production of the present raw material.

The ascorbic acid derivative which is the other raw material in the production method of the present invention can be appropriately obtained by a known method. For example, 3-O-benzyl-5,6
-O-isopropylidene ascorbic acid and 3-O-
Methoxymethyl-5,6-O-isopropylidene ascorbic acid can be prepared according to known methods, for example, J. Med. Ch
em. 31, 793 (1988).
Alternatively, it can be appropriately synthesized according to this.

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

[0023]

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

[Example 1] Tocopherol, ascorbic acid-2-phosphoric acid diester potassium salt (abbreviation: EPC)
Synthesis of α-tocopherol 4.3 g (0.0
1 mol) and 5 ml of pyridine were added to dissolve and after cooling,
Phosphorus oxychloride (3.0 g) is immediately added, the mixture is stirred for 30 minutes, then returned to room temperature and further stirred for 1 hour. Next, the precipitated pyridine hydrochloride is filtered off, the filtrate is concentrated under reduced pressure at 40 ° C. or lower, and 50 ml of anhydrous benzene is added to the resulting residual oily substance and the mixture is left to cool. 3-O-benzyl-5,6
-O-isopropylidene ascorbic acid 3.4 g (0.
(011 mol) and 3 ml of pyridine dissolved in 30 ml of benzene are gradually added, and the mixture is stirred for 30 minutes, returned to room temperature and further stirred for 2 hours, and then the solvent is distilled off. The residue was crystallized by adding water and recrystallized with ethyl acetate to give crystals with a melting point of 118 to 120 ° C., but the process proceeded to the next step without purification. That is, 40 ml of 1N hydrochloric acid and 70 ml of ethanol were added to this residue, and the mixture was stirred at 60 ° C. for 20 minutes,
Ethanol is distilled off, the residue is extracted with ethyl acetate, washed with water, and ethyl acetate is distilled off. The residue is catalytically reduced with palladium on carbon (Pd-C) in 20 ml of 1N hydrochloric acid and 150 ml of tetrahydrofuran. When the absorption of hydrogen has stopped, palladium carbon is filtered off, and the filtrate is concentrated under reduced pressure. The residual oily substance was further extracted with ethyl acetate, washed with water, the ethyl acetate was distilled off, the residue was dissolved in 100 ml of ethanol, and the pH was adjusted to 6 with potassium hydroxide / ethanol. The precipitated crystals were collected by filtration to give white crude crystals. Then, this was dissolved in water for recrystallization, acidified with hydrochloric acid, extracted with ethyl acetate, washed with water, ethyl acetate was distilled off, the residue was dissolved in ethanol, and potassium hydroxide / ethanol was added thereto again. Was added to adjust the pH to 6, and the precipitated white crystals were collected by filtration, washed with ethanol and dried to obtain 4.8 g of a dipotassium salt of the target compound (EPC-K ₂ ) (yield 6
2.9%). Rf = 0.56 (silica gel; n-
Butanol: water: acetic acid = 4: 1: 1)

Elemental analysis value as C ₃₅ H ₅₅ O ₁₀ PK ₂ · H ₂ O theoretical value (%): C, 55.09; H, 7.53 actual measurement value (%): C, 55.26; H, 7.41

Separately, 4.8 g of the above crystals were dissolved in water, acidified with hydrochloric acid, extracted with ethyl acetate, washed with water, and ethyl acetate was distilled off. The residue was dissolved by adding 70 ml of ethanol and 30 ml of ethyl acetate. Potassium hydroxide /
Ethanol was added to adjust the pH to 2.1, and the precipitated white crystals were collected by filtration, washed with ethanol, and dried to obtain 2.8 g of the objective compound, monopotassium salt (EPC-K ₁ ). 204-206 ° C (decomposition). IR and NMR
Coincided with that of Pharmaceutical Research, 22: 222 (1990).

Example 2 Synthesis of Tocopherol and Ascorbic Acid-2-Phosphoric Acid Diester Dipotassium Salt In the same manner as in Example 1 except that 4.3 g (0.01 mol) of α-tocopherol was used. Ruphosphorodichloridate, and 3-O-methoxymethyl-5,6-O-isopropylidene ascorbic acid 2.9
After reacting with g (0.011 mol) in the same manner, acidified with hydrochloric acid and extracted with ethyl acetate to dissolve the residue in 60 ml of ethanol, add 50 ml of 1N-hydrochloric acid, and heat in nitrogen stream at about 80 ° C for 1 hour. After refluxing, the solvent is distilled off, the residue is extracted with ethyl acetate, washed with a small amount of water, and then ethyl acetate is distilled off. Further, the residue is dissolved in ethanol and neutralized with a potassium hydroxide / ethanol solution, and 4.6 g (yield 60.3%) of the dipotassium salt of the target compound is obtained in the same manner. Rf = 0.56 (silica gel; n-butanol:
Water: acetic acid = 4: 1: 1)

[0028]

According to the conventional method (Example 1 described in Japanese Examined Patent Publication No. 2-44478), the yields of the target compounds, tocopherol and ascorbic acid-2-phosphate diester dipotassium, are 49. In contrast to 1%, according to the manufacturing method of the present invention, 62.9% (Example 1 of the present application)
And the target compound can be obtained in a high yield of 60.3% (Example 2 of the present application).

Claims (4)

[Claims] 1. A compound obtained by reacting α, β, γ or δ-tocopherol with a halophosphate esterifying agent is reacted with ascorbic acid having a protecting group at the 3,5,6 position hydroxyl group, and then reacted. A process for producing a phosphodiester represented by formula (I) or a pharmaceutically acceptable salt thereof, which comprises removing the above protecting group. Embedded image [In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a methyl group. ] 2. The protecting group for the hydroxyl group at the 3-position of ascorbic acid is a group selected from the group consisting of benzyl group, p-methoxybenzyl group and methoxymethyl group, and the protecting group at the 5- and 6-positions is an acyl group. The manufacturing method according to claim 1. 3. The method according to claim 2, wherein the acyl group which is a protective group for the hydroxyl group at the 5- and 6-positions of ascorbic acid is a group selected from the group consisting of an isopropylidene group, a benzylidene group and an acetyl group. 4. Formula (V): [In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a methyl group, and R ₃ represents a benzyl group, a p-methoxybenzyl group or a methoxymethyl group. ] The phosphoric acid diester represented by these or its pharmacologically acceptable salt.