JPH0471918B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a method for synthesizing organic phosphorus compounds, particularly 1-
This invention relates to a method for synthesizing α,β-epoxyphosphine derivatives from alkenylphosphine oxides. (Prior art) Phosphorus α,β-epoxy compounds such as fosfomycin, which is known as a phosphonic acid antibiotic, are themselves important compounds, and furthermore, α,β-epoxy compounds such as fosfomycin are known as phosphonic acid antibiotics.
- Epoxyphosphine derivatives are important synthetic intermediates for the synthesis of various useful compounds. Hitherto, there has been no proposal for epoxide synthesis of 1-alkenylphosphine oxides themselves. As a related compound, a method for synthesizing epoxides of vinylphosphine oxides is based on the addition of a phosphorus compound to α-ketotosylate and the elimination of tosylic acid, that is, p-toluenesulfonic acid, for example, in Synthesis 1985. No. 1, p. 65, and Journal of Organic Chemistry (J.
Org.Chem.) Vol. 26, p. 659 (1961), etc., but even if these are applied to the epoxidation of 1-alkenylphosphine oxides,
The reaction does not proceed satisfactorily. In addition, for the same reason, the commonly used method of adding oxygen to olefin double bonds with peracids such as peracetic acid, perbenzoic acid, and perphthalic acid to synthesize epoxides produces 1-alkenylphosphine oxide. It cannot be applied to other types of epoxidation. Furthermore, there is a method of oxidizing and epoxidizing a phosphonic acid ester derivative such as a 1-alkenephosphonic diester using trifluoroacetic anhydride and high concentration hydrogen peroxide, for example, 90% hydrogen peroxide.
Chem.Ber. Volume 101,
3530 (1968) and Chemical Abstracts (CA) Vol. 103, P. 22654, such methods are extremely dangerous due to the use of a high concentration of peroxide, 90% hydrogen peroxide. In some respects, such highly concentrated hydrogen peroxide is not commercially available and is difficult to obtain; in this epoxide synthesis method, a sodium phosphate buffer must be used; There are drawbacks or problems such as ring-opening reactions proceeding after the epoxidation reaction and the production of side reaction products. There was no way to easily and selectively synthesize it. (Problems to be Solved by the Invention) In view of the problems of the prior art as described above, an object of the present invention is to solve the problems of 1-alkenylphosphine oxide, which cannot be synthesized by the currently widely used epoxide synthesis method. The object of the present invention is to obtain epoxides of the same type safely, easily, and selectively in high yields using readily available reagents. (Means for Solving the Problems) A feature of the method of the present invention for achieving the above object is that trifluoroacetic anhydride is reacted with about 25 to about 35% hydrogen peroxide to produce trifluoroperacetic acid. , the trifluoroperacetic acid is allowed to act on 1-alkenylphosphine in an organic solvent under reflux to epoxidize the compound. The 1-alkenylphosphine oxide to which the method of the present invention is applied is a 1-alkenylphosphonic acid compound such as a 1-alkenylphosphonic acid ester, a 1-alkenylphosphine acid ester, or an olefin diamide at a position other than the α or β-position. A phosphoric acid compound of an alkene having a double bond can be used in combination. The products obtained from the above-mentioned 1-alkenylphosphine oxides by the method of the present invention are α,β-epoxyphosphine oxide derivatives, α,β-epoxyphosphonic acid ester derivatives, α,β-epoxyphosphine oxide derivatives, It is also possible to derive α,β-epoxyphosphine derivatives such as ester derivatives, and phosphine derivatives having epoxy groups at positions other than the α,β-positions. Particularly important among these derivatives is fosfomycin. In the method of the present invention, the action of trifluoroperacetic acid is particularly essential in order to control the oxidation action and add oxygen to the olefin double bond of the alkenyl compound for epoxidation. It can be synthesized from fluoroacetic acid, for example, by the following procedure. That is, under ice cooling, a suitable amount of an organic liquid medium, such as methylene chloride, is mixed with a commercially available solution of about 25 to about 35%, preferably about 30 to about
Add 35% hydrogen peroxide solution, stir at about 0°C, add trifluoroacetic anhydride with stirring, and raise the temperature to room temperature after about 30 minutes to convert trifluoroperacetic acid into methylene chloride liquid medium. efficiently generated inside. The above-mentioned reaction for producing trifluoroperacetic acid is possible at room temperature or at an elevated temperature of about 40°C, but as the temperature rises, an excessive amount of trifluoroacetic anhydride is required and the yield is significantly reduced. Therefore, it is preferable to carry out the above procedure at the lowest possible temperature in the range of 0° C. to room temperature. An organic solvent solution of the substrate 1-alkenylphosphine oxide, for example, a methylene chloride solution of 1-alkenylphosphine oxide, is added dropwise to the thus synthesized trifluoroperacetic acid, and then the boiling point of the organic solvent, CH ₂ Cl ₂ In this case, the epoxidation reaction is carried out by stirring at about 40° C. under reflux for about 8 to 14 hours, preferably about 10 to 12 hours. The organic solvent used here must be a solvent for the substrate, be inert and non-reactive with respect to the solvent itself and the reactants in the system, and have a relatively low boiling point (boiling point of about 100°C or less, preferably about 80°C). C) or below) and be compatible with, preferably the same as, the organic liquid medium used in the synthesis of trifluoroperacetic acid. As applicable,
Examples include methylene chloride, chloroform, ethyl acetate, carbon tetrachloride, diethyl ether, tetrahydrofuran, benzene, dioxane, etc.; Polar solvents with low boiling points, such as ethyl, are preferred, with methylene chloride being most suitable. These solvents may be used alone or in combination. The above-mentioned epoxidation reaction is represented by the following general formula (), and the substrate, that is, the starting material of the epoxidation reaction, diphenyl (1-ethyl-1-propenyl)-phosphine oxide, is epoxidized, An example of obtaining diphenyl-(1,2-epoxy-1-ethylpropyl)-phosphine oxide is as shown in formula (). In the above reaction, regarding the molar ratio of the substrate, trifluoroacetic anhydride, and hydrogen peroxide, hydrogen peroxide needs to be at least equimolar to the substrate;
In addition, since trifluoroacetic anhydride has a low boiling point,
In order to compensate for the amount that evaporates and transfers to the gas phase during the reaction, at least 2 mol, preferably at least 3 mol, is preferably present at the beginning of the reaction. The optimum molar ratio is about 1:3:3. After the reaction mixture in which the epoxidation reaction was completed was cooled, it was transferred to a separating funnel, and the organic layer was mixed with an aqueous solution of potassium bisulfite, an aqueous solution of sodium bicarbonate, and an aqueous solution of sodium bicarbonate.
Furthermore, the epoxide of 1-alkenylphosphine oxides is obtained by washing successively with water, drying, and distilling off the solvent under reduced pressure. Hereinafter, the method of the present invention will be explained with reference to Examples. Example 1 Add 30% hydrogen peroxide solution to 10 ml of methylene chloride on an ice bath.
1.2 ml was added with stirring at about 0° C., and 2.9 g of trifluoroacetic anhydride was gradually added thereto with stirring. After all additions were completed, the mixture was transferred to a hot bath, stirred at 30°C for 30 minutes, and then cooled to room temperature. 1.23 g of the substrate diphenyl-(1-ethyl-1-propenyl)-phosphine oxide was added to the generated trifluoroperacetic acid.
Add 10ml of methylene chloride solution dropwise and keep at 40℃ for 12 hours.
The mixture was stirred under heating under reflux. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, 30 ml of methylene chloride was added, and the mixture was washed successively with an aqueous potassium bisulfite solution, an aqueous sodium bicarbonate solution, and water. After drying over anhydrous sodium sulfate, methylene chloride was distilled off under reduced pressure to obtain 1.24 g of diphenyl-(1,2-epoxy-1-ethylpropyl)-phosphine oxide. The yield in this case was 95%, and the melting point of the obtained compound was 154-156°C. Examples 2 to 5 Four types of 1-alkenyldiphenylphosphine oxides in which R ¹ and R ² of the above formula () were variously changed were used as substrates, and the epoxidation reaction with trifluoroperacetic acid was carried out by the method of Example 1 above. The mixture was reacted for 12 hours under refluxing methylene chloride solvent according to the procedure described in . In this case, the molar ratio of the substrate, trifluoroacetic anhydride used to produce trifluoroperacetic acid, and hydrogen peroxide was 1:3:3. The yield, melting point, and mass spectrometry values of the produced α,β-epoxyphosphine derivative are shown in the following table.

[Table] As is clear from the above examples, according to the method of the present invention, corresponding α,β-epoxyphosphine derivatives can be obtained in extremely high yields from various 1-alkenylphosphine oxides. (Effects of the Invention) The effects of the method of the present invention are listed below. (1) Epoxides of 1-alkenylphosphine oxides, which have been extremely difficult to synthesize by conventional methods, can be synthesized in an extremely safe, simple and high yield by the method of the present invention. (2) It is significantly simpler to operate than the conventional epoxide synthesis of vinylphosphine oxide via α-ketotosylate. (3) Compared to the epoxyphosphonic acid ester synthesis method that uses 90% hydrogen peroxide, the reagents applied to the method of the present invention contain approximately 25 to 35% of the reagents that are easily available on the market.
It is synthesized using hydrogen peroxide (90% hydrogen peroxide solution is not commercially available, but 25-35% hydrogen peroxide solution is commercially available), so it is highly safe and has little risk of explosion. The device and operation are extremely simple. (4) Compared to the above-mentioned method using high concentration hydrogen peroxide, there is no side reaction or secondary reaction, so the selectivity for producing α,β-epoxy derivatives of the target phosphorus compound is high, and the process is highly pure and The target product can be obtained in high yield. (5) The method of the present invention, within the scope of its technical idea,
It is thought that it can be modified and applied not only to α,β-epoxy derivatives but also to the synthesis of various epoxides, and a wide range of applications is expected.

Claims (1)

[Claims] 1. Trifluoroperacetic acid is produced by reacting trifluoroacetic anhydride with about 25 to 35% hydrogen peroxide, and the trifluoroperacetic acid is mixed into 1-alkenylphosphine oxides with organic α, β characterized by being epoxidized by acting under reflux in a solvent.
- A method for producing an epoxyphosphine derivative. 2. The method for producing an α,β-epoxyphosphine derivative according to claim 1, wherein the reaction between the trifluoroacetic anhydride and the hydrogen peroxide solution is carried out in an organic liquid medium. 3. The method for producing an α,β-epoxyphosphine derivative according to claim 2, wherein the organic liquid medium and the organic solvent are compatible with each other. 4. The method for producing an α,β-epoxyphosphine derivative according to any one of the claims, wherein the organic solvent is a polar solvent that is non-reactive in itself and has a low boiling point. 5 α, β according to claim 4, wherein the organic solvent is at least one polar solvent selected from methylene chloride, chloroform, and ethyl acetate.
- A method for producing an epoxyphosphine derivative. 6. The method for producing an α,β-epoxyphosphine derivative according to claim 5, wherein both the organic solvent and the organic liquid medium are methylene chloride. 7. The method for producing an α,β-epoxyphosphine derivative according to any one of the claims, wherein the reaction between the trifluoroacetic anhydride and hydrogen peroxide is carried out at about 0°C to room temperature. 8. Any of the above claims, wherein the 1-alkenylphosphine oxide, trifluoroacetic anhydride, and hydrogen peroxide are present in a molar ratio of about 1:(2 or more):(1 or more) at the initial stage of the reaction. A method for producing an α,β-epoxyphosphine derivative as described in . 9. The method for producing an α,β-epoxyphosphine derivative according to claim 8, wherein the molar ratio is about 1:3:3.