JPH08134086A - Production of dibenzylphosphate-alkali metal salt or alkaline earth metal salt - Google Patents

Abstract

PURPOSE: To efficiently obtain the subject compound useful as an intermediate for medicines, etc., in high purity at a high yield by reacting tribenzylphosphate with an alkali (earth) metal salt in the presence of a water-soluble organic solvent excepting alcohols. CONSTITUTION: Tribenzyl phosphate is dissolved in a water-soluble organic solvent excepting alcohols (e.g. dioxane), an alkali metal compound (e.g. potassium hydroxide) or an alkaline earth metal compound (e.g. calcium hydroxide) is added to the solution and further water is added to the resultant solution, then the solution is reacted by heating at 80 deg.C for 6 hours under stirring. After the reaction, the solvent is distilled away and toluene, etc., is added to the residue, and generated crystals are filtered through a glass filter, etc. The filtered material is dried in a vacuum oven at 80 deg.C for 2 hours to afford the objecting dibenzylphosphate.alkali metal salt or alkaline earth metal salt useful as an intermediate for medicines, etc., in high purity at a high yield.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing dibenzyl phosphate / alkali metal salt or alkaline earth metal salt. In particular, the present invention relates to a method for producing dibenzyl phosphate / alkali metal salt or alkaline earth metal salt useful as a pharmaceutical intermediate with high purity and high yield.

[0002]

2. Description of the Related Art Recently, an alkali metal salt of dibenzyl phosphate has been attracting attention as a compound useful as a raw material of a phosphoric acid ester compound for pharmaceuticals. (See JP-A-6-157594)

Conventionally, as a method for producing dibenzyl phosphate / alkali metal salt, a method is known in which tribenzyl phosphate and sodium iodide are reacted in the presence of an organic solvent such as acetone. [J. A. C.
S. , 77, 5354, (1955)]

Another known method is to react tribenzyl phosphate with an alkali metal salt in the presence of methanol. [J. A. C.
S. , 3, 2183 (1948)]

[0005]

However, in the above method, benzyl iodide produced as a reaction by-product is generated as a tearing gas, which is a problem in work and the price of sodium iodide used as a raw material is high. Has the drawback of being expensive. In addition, the method (1) has a drawback that the solvent methanol reacts with tribenzyl phosphate to generate methyldibenzyl phosphate and dimethylbenzyl phosphate as by-products, which lowers the reaction yield.

In view of the above facts, the inventors of the present invention have conducted earnest research on a method for producing dibenzyl phosphate / alkali metal salt or alkaline earth metal salt, and as a result, tribenzyl phosphate and alkali metal salt or alkaline earth metal salt have been studied. In the method for producing a dibenzyl phosphate / alkali metal salt or alkaline earth metal salt by reacting with a salt, a water-soluble organic solvent (excluding alcohol)
It was found that dibenzyl phosphate / alkali metal salt or alkaline earth metal salt can be obtained with high purity and high yield by carrying out the reaction in the presence of a.

[0007]

That is, the present invention provides a method for producing a dibenzyl phosphate / alkali metal salt by reacting tribenzyl phosphate with an alkali metal salt, wherein a water-soluble organic solvent (provided that the alcohol is The present invention provides a method for producing a dibenzyl phosphate / alkali metal salt, which comprises reacting in the presence of (excluding).

The present invention also provides a method for producing dibenzyl phosphate / alkaline earth metal salt by reacting tribenzyl phosphate with an alkaline earth metal salt, wherein a water-soluble organic solvent (excluding alcohol) is used. The present invention provides a method for producing a dibenzyl phosphate / alkaline earth metal salt, which comprises reacting in the presence of

The present invention will be described in detail below. The present invention comprises reacting tribenzyl phosphate with an alkali metal salt or an alkaline earth metal salt in the presence of a water-soluble organic solvent (excluding alcohol) to give a dibenzyl phosphate / alkali metal salt or dibenzyl salt. This is a method for producing a phosphate / alkaline earth metal salt with high purity and high yield.

The alkali metal salt and alkaline earth metal salt used in the present invention include hydroxides, carbonates, bicarbonates and the like of alkali metals and alkaline earth metals, such as sodium hydroxide and hydroxide. Examples thereof include potassium, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate and the like.

The water-soluble organic solvent used in the present invention may be any one excluding alcohol, for example, dioxane, tetrahydrofuran, 1,2-diethoxyethane, diethylene glycol dimethyl ether, acetone, methyl ethyl ketone, methyl isobutyl ketone, trioxane. , Tetrahydropyran, 1,2-dimethoxyethane, diethylene glycol diethyl ether, and the like, but not limited thereto.

The production method of the present invention may be carried out by adding an alkali metal salt or an alkaline earth metal salt to a solution in which tribenzyl phosphate is dissolved in a water-soluble organic solvent and reacting. For example, when the alkali metal salt is potassium hydroxide, the reaction is represented by the following reaction formula (I).

[0013]

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In the reaction according to the present invention, the amount of tribenzyl phosphate and the water-soluble organic solvent may be 0.5 liter or more per 1 mol of tribenzyl phosphate. If it is less than 0.5 liter, the reaction rate may be slow or the reaction may not proceed at all, which is not preferable. The upper limit is not particularly limited, but it is up to 2 liters for economic reasons.

Further, a water-soluble organic solvent is preferable because the reaction yield and reaction rate are increased by adding water. The amount of water added varies depending on the organic solvent used, but is 40 wt% or less, preferably 1 to 10 wt% with respect to the total amount of the organic solvent and water.

The addition amount of the alkali metal salt or alkaline earth metal salt to tribenzyl phosphate is 0.9 to 1 mol, which is the theoretical addition amount, to 1 mol of the metal salt. When it is less than 0.9 mol, the yield of the obtained dibenzyl phosphate / alkali metal salt or alkaline earth metal salt is lowered, which is not preferable, and when it is more than 1.0 mol, dibenzyl phosphate. Unreacted alkali metal salt or alkaline earth metal salt does not dissolve in the solvent used for crystallization of alkali metal salt or alkaline earth metal salt, for example, toluene solution, and remains in the product to cause a decrease in purity. It is not so preferable.

The reaction temperature is preferably 70 ° C. or higher, and 70
If the temperature is lower than 0 ° C, the reaction rate becomes slow, which is not preferable. Although the reaction time varies depending on the reaction temperature, it is usually 1 hour or more.

After completion of the reaction, the reaction solution is concentrated, the solvent is removed, and then crystallization is carried out by adding an organic solvent which does not dissolve dibenzyl phosphate / alkali metal salt or alkaline earth metal salt such as toluene. Then, after filtering,
The obtained dibenzyl phosphate / alkali metal salt or alkaline earth metal salt is vacuum dried at, for example, 80 ° C. or higher to obtain a product.

[0019]

EXAMPLES The present invention will be described in more detail below with reference to examples.

Example 1 As a reaction vessel, 75.1 g of tribenzyl phosphate was placed in a 1-liter three-necked flask, and 400 m of dioxane was added.
1 was added and dissolved. To this solution were added 21.5 g of a 51.5% aqueous potassium hydroxide solution, 1.77 g of water, and the mixture was heated to 80 ° C. and stirred for 6 hours for reaction.
After the reaction was completed, the solvent was distilled off and 400 ml of toluene was added.
Was added to crystallize and filtered with a centrifugal filter.

The filtrate was dried in a vacuum oven at 80 ° C. for 2 hours to give 59.6 g of potassium salt of dibenzyl phosphate.
I got The reaction yield was 94.9%. The melting point of the obtained product was 215 to 216 ° C. The purity of the product by the absolute calibration curve method of high performance liquid chromatography was 100%.

Example 2 3.76 g of tribenzyl phosphate was placed in a 35 ml round-bottomed flask, and 20 ml of dioxane was added and dissolved. 48% sodium hydroxide solution 0.8 in this solution
After adding 37 g and 10 g of water, the mixture was heated to 90 ° C. and stirred for 10 hours to cause a reaction. After the reaction was completed, the solvent was distilled off, 20 ml of toluene was added thereto, and crystallization was performed, followed by filtration with a glass filter.

The filtrate was dried in a vacuum oven at 80 ° C. for 1 hour to give 2.77 of the sodium salt of dibenzyl phosphate.
g was obtained. The reaction yield was 90.1%. The purity of the product by the absolute calibration curve method of high performance liquid chromatography was 100%.

Example 3 3.76 g of tribenzyl phosphate was placed in a 35 ml round-bottomed flask, and 20 ml of dioxane was added and dissolved. 0.37 g of calcium hydroxide was added to this solution,
After further adding 10 g of water, the mixture was heated to 100 ° C. and stirred for 48 hours for reaction. After the reaction was completed, the solvent was distilled off, 20 ml of toluene was added thereto, and crystallization was performed, followed by filtration with a glass filter.

The filtrate was dried in a vacuum oven at 80 ° C. for 1 hour to give 2.59 calcium salt of dibenzyl phosphate.
g was obtained. The reaction yield was 87.2%. The purity of the product by the absolute calibration curve method of high performance liquid chromatography was 98.32%.

Example 4 3.76 g of tribenzyl phosphate was placed in a 35 ml round-bottomed flask, and 20 ml of dioxane was added and dissolved. To this solution, 1.38 g of potassium carbonate was added, and further 12 g of water was added, followed by heating to 100 ° C. and stirring for 100 hours to cause a reaction. After completion of the reaction, dioxane as a solvent was distilled off, 20 ml of toluene was added thereto, and crystallization was performed, followed by filtration with a glass filter.

The filtrate was dried in a vacuum oven at 80 ° C. for 1 hour to give 2.89 g of potassium salt of dibenzyl phosphate.
I got The reaction yield was 91.6%. The purity of the product by the absolute calibration curve method of high performance liquid chromatography was 97.5%.

Example 5 3.76 g of tribenzyl phosphate was placed in a 35 ml round-bottomed flask, and 20 ml of dioxane was added and dissolved. 1.58 g of barium hydroxide octahydrate was added to this solution, 10 g of water was further added, and the mixture was heated to 100 ° C. to 2
Stir for time to react. After completion of the reaction, the solvent was distilled off,
To this, 20 ml of toluene was added and crystallization was performed, followed by filtration with a glass filter.

The filtrate was dried in a vacuum oven at 80 ° C. for 1 hour to obtain 3.15 g of barium salt of dibenzyl phosphate.
I got The reaction yield was 91.1%. The purity of the product by the absolute calibration curve method of high performance liquid chromatography was 97.12%.

Example 6 3.76 g of tribenzyl phosphate was placed in a 35 ml round-bottomed flask, and 20 ml of dioxane was added and dissolved. A 51.5% aqueous potassium hydroxide solution was added to this solution.
09 g was added, and the mixture was heated to 70 ° C. and stirred for 24 hours to cause a reaction. After the reaction was completed, the solvent was distilled off and toluene 2 was added.
0 ml was added to cause crystallization and the mixture was filtered with a glass filter.

The filtrate was dried in a vacuum oven at 80 ° C. for 1 hour to give 2.86 g of potassium salt of dibenzyl phosphate.
I got The reaction yield was 90.6%. The melting point of this product was 209.7-210.7 ° C. The purity of the product measured by the absolute calibration curve method of high performance liquid chromatography was 99.31%.

Example 7 3.76 g of tribenzyl phosphate was placed in a 35 ml round-bottomed flask, and 20 ml of dioxane was added and dissolved. 48% sodium hydroxide solution 0.8 in this solution
3 g was added and the mixture was heated to 70 ° C. and stirred for 24 hours for reaction. After the reaction was completed, the solvent was distilled off and toluene 20m
1 was added and crystallized and filtered through a glass filter.

The filtrate was dried in a vacuum oven at 80 ° C. for 1 hour to give dibenzyl phosphate sodium salt 2.90.
g was obtained. The reaction yield was 91.8%. The purity of the product by the absolute calibration curve method of high performance liquid chromatography was 99.12%.

Example 8 3.76 g of tribenzyl phosphate was placed in a 35 ml round-bottomed flask, and 20 ml of 1,2-diethoxyethane was added.
And dissolved. To this solution, 1.10 g of 51.5% potassium hydroxide aqueous solution was added, heated to 100 ° C., stirred for 6 hours, and reacted. After the reaction was completed, the solvent was distilled off, 20 ml of toluene was added thereto, and crystallization was performed, followed by filtration with a glass filter.

The filtrate was dried in a vacuum oven at 80 ° C. for 1 hour to give 2.73 g of potassium salt of dibenzyl phosphate.
I got The reaction yield was 85.7%. The purity of the product by the absolute calibration curve method of high performance liquid chromatography was 99.21%. Example 9 3.76 g of tribenzyl phosphate was placed in a 35 ml round-bottomed flask, and 20 ml of diethylene glycol dimethyl ether was added and dissolved. 51.5 in this solution
% Aqueous potassium hydroxide solution (1.10 g) was added, and the mixture was heated to 100 ° C. and stirred for 6 hours for reaction. After the reaction was completed, the solvent was distilled off, 20 ml of toluene was added thereto, and crystallization was performed, followed by filtration with a glass filter.

The filtrate was dried in a vacuum oven at 80 ° C. for 1 hour to give 2.79 g of potassium salt of dibenzyl phosphate.
I got The reaction yield was 87.0%. The purity of the product by the absolute calibration curve method of high performance liquid chromatography was 98.37%.

Comparative Example 1 18.48 g of tribenzyl phosphate was placed in a 200 ml three-necked flask, and 100 ml of methanol was added and dissolved. 85% potassium hydroxide 3.35 g in this solution
Was added and the mixture was heated to 60 ° C. and stirred for 6 hours to cause a reaction. After completion of the reaction, the solvent was distilled off, and 70 ml of toluene was added thereto to crystallize and filtered through a glass filter.

The filtrate was dried in a vacuum oven at 80 ° C. for 1 hour to give 3.68 g of potassium salt of dibenzyl phosphate.
I got The reaction yield was 23.2%. In addition, methyldibenzyl phosphate and dimethylbenzyl phosphate were confirmed as by-products.

Comparative Example 2 3.75 g of tribenzyl phosphate was placed in a 35 ml round-bottomed flask, and 20 ml of toluene was added and dissolved. 51.5% potassium hydroxide aqueous solution 1.1 was added to this solution.
0 g was added and the mixture was heated to 100 ° C. and stirred for 24 hours, but the reaction did not proceed at all and a product was not obtained.

Comparative Example 3 3.75 g of tribenzyl phosphate was placed in a 35 ml eggplant-shaped flask, and 20 ml of n-hexane was added and dissolved. To this solution, 1.10 g of 51.5% potassium hydroxide aqueous solution was added and heated to 100 ° C. and stirred for 24 hours, but the reaction did not proceed at all and a product was not obtained.

[0041]

As described above, according to the production method of the present invention, there is an effect that dibenzyl phosphate / alkali metal salt or alkaline earth metal salt can be obtained with high purity and high yield. Further, the dibenzyl phosphate / alkali metal salt or alkaline earth metal salt produced by the present invention is useful as a pharmaceutical intermediate or the like, and the industrial value of the present invention is extremely high.

Claims (4)

[Claims] 1. A method for producing dibenzyl phosphate / alkali metal salt by reacting tribenzyl phosphate with an alkali metal salt, which comprises reacting in the presence of a water-soluble organic solvent (excluding alcohol). A method for producing a dibenzyl phosphate / alkali metal salt, which is characterized. 2. The method for producing a dibenzyl phosphate / alkali metal salt according to claim 1, wherein the reaction is performed with the water-soluble organic solvent (excluding alcohol) in the presence of water. 3. A method for producing a dibenzyl phosphate / alkaline earth metal salt by reacting tribenzyl phosphate with an alkaline earth metal salt, the method being carried out in the presence of a water-soluble organic solvent (excluding alcohol). A method for producing a dibenzyl phosphate / alkaline earth metal salt, which comprises reacting. 4. The method for producing a dibenzyl phosphate / alkaline earth metal salt according to claim 3, wherein the reaction is carried out in the presence of water with the water-soluble organic solvent (excluding alcohol).