The present application is a Continuation Application of PCT/CN2018/1099541, filed on Oct. 9, 2018, which is incorporated by reference for purposes as if fully set forth herein.

TECHNICAL FIELD

The invention relates to the technical field of organic compounds, and particularly, relates to a trifluoromethyl alkenylphosphonate derivative and a preparation method therefor.

BACKGROUND TECHNIQUE

Organic phosphonates have strong biological activity and are widely used as insecticides, renin and protease inhibitors (Reference 1: Shidlovskii A F, Peregudov A S, Averkiev B B, et al, Three-component condensation of trifluoromethyl-substituted cyanovinylphosphonates, arylamines, and ketones and cytotoxic activity of products thus obtained, Russian Chemical Bulletin, 2010, 59, 144. Reference 2: Dellaria Jr J F, Maki R G, Stein H H, et al, New inhibitors of renin that contain novel phosphostatine Leu-Val replacements, Journal of medicinal chemistry, 1990, 33, 534. Reference 3 Wester R T, Chambers R J, Green M D, et al, Preparation of a novel series of phosphonate norstatine renin inhibitors, Bioorganic & Medicinal Chemistry Letters, 1994, 4, 2005. Reference 4 Arai T, Bougauchi M, Sasai H, et al, Catalytic asymmetric synthesis of α-hydroxy phosphonates using the Al—Li-BINOL complex, The Journal of Organic Chemistry, 1996, 61, 2926.). After the introduction of trifluoromethyl into the organic phosphonate molecule, its activity will be further improved. Trifluoromethyl alkenyl phosphonate contains a variety of important functional groups and has various potential physiological activities. In addition, it can be used as an important starting material. It is used in various chemical synthesis, but the existing preparation methods have the problems of rare starting materials, many steps, harsh reaction conditions, and the need to use highly toxic agents, such as thionyl chloride and bromine.

Beneficial Effects

The object of the present invention is to provide a method for preparing a trifluoromethyl alkenyl phosphonate derivative, which has the advantages of short steps, mild reaction conditions, high yield and good universality, and can be synthesized in one step from the starting materials.

Technical Solutions

In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is:

A method for preparing a trifluoromethyl alkenylphosphonate derivative which includes the following steps:

Dissolving an acetylene derivative, an iodine compound and a phosphorus reagent in a solvent and reacting at room temperature to 100° C. to obtain the trifluoromethyl alkenylphosphonate derivative.

The acetylene derivative has the following structure:

[Image Omitted]

R¹is aryl, cyano or ester; R²is hydrogen, cyano or ester;

The iodine compound has the following structure:

[Image Omitted]

The phosphorus reagent has the following general chemical structural formula:

P(OR⁴)₃

R⁴is methyl, ethyl, isopropyl or butyl.

In the present invention, the solvent is selected from the group consisting of acetone, ethyl acetate, toluene, and N, N-dimethylformamide.

In the present invention, the acetylene derivative is selected from the group consisting of phenylacetylene, 4-methylphenylacetylene, 4-methoxyphenylacetylene, 4-fluorophenylacetylene, 4-chlorophenylacetylene, 4-bromophenylacetylene, 4-nitrophenylacetylene, 4-methoxycarbonyl-phenylacetylene, 4-cyano-phenylacetylene, 1-trifluoromethyl-2-cyanoacetylene, 2-ethynylthiophene, 2-bromophenylacetylene, and 3-fluorophenylacetylene; the phosphorus reagent is selected from the group consisting of trimethyl phosphite, triethyl phosphite, and tri-n-butyl phosphate.

In the present invention, the reaction is tracked to completion by a thin layer chromatography (TLC).

In the present invention, a molar ratio of the acetylene derivative:the iodine compound:the phosphorus reagent is 1:1.5:(3 to 7).

In the present invention, the product is subjected to column chromatography separation and purification after the reaction.

The present invention also discloses that an application of an acetylene derivative, an iodine compound and a phosphorus reagent as starting materials to prepare a trifluoromethyl alkenylphosphonate derivative. Preferably, the preparation is performed in a solvent.

In the embodiment, the acetylene derivative, the iodine compound and the phosphorus reagent are dissolved in the solvent and reacted at room temperature to 100° C. to obtain the trifluoromethyl alkenylphosphonate derivative.

The acetylene derivative has the following structure:

[Image Omitted]

R¹is aryl, cyano or ester; R²is hydrogen, cyano or ester.

The iodine compound has the following structure:

[Image Omitted]

The phosphorus reagent has the following general chemical structural formula:

P(OR⁴)₃

R⁴is methyl, ethyl, isopropyl or butyl;

The solvent is selected from the group consisting of acetone, ethyl acetate, toluene, and N, N-dimethylformamide

The reaction of the above technical solution can be expressed as:

[Image Omitted]

Beneficial Effects:

Due to the application of the above technical solutions, the present invention has the following advantages over the prior art:

1. The present invention uses acetylene derivative as starting material, and the starting materials are easily available and there are many types. The products obtained by the method of the present invention have various types, which can be used directly or used in other further reactions.

2. The reaction of the present invention has mild reaction conditions, few steps, simple reaction operation and post-treatment process, high yield, and is suitable for large-scale production, especially no catalyst is needed.

EMBODIMENTS OF THE INVENTION

The following further describes the present invention with reference to the embodiments:

In the embodiments, the iodine compound has the following structure:

[Image Omitted]

Example 1 Synthesis of (1-phenyl-2-trifluoromethyl)vinylphosphonic acid diethyl ester

Taking phenylacetylene as starting material, the reaction steps were as follow:

(1) Phenylacetylene (20.4 mg, 0.2 mmol), the iodine compound (94.8 mg, 0.3 mmol), triethyl phosphite (99.4 mg, 0.6 mmol) were dissolved in 1 mL of acetone in a reaction flask. The reaction mixture was stirred at 60° C.;