RU2236414C1 - Method for preparing n-substituted ethyl-(2-dialkoxyphosphoryl-4-cyano)-butaneimidates - Google Patents

Abstract

FIELD: chemistry of organophosphorus compounds, chemical technology.

SUBSTANCE: invention relates to a novel method for preparing N-substituted phosphorylated imidates bearing cyanoethyl-group in structure. Invention describes a method for preparing N-substituted ethyl-(2-dialkoxyphosphoryl-4-cyano)butaneimidates of the formula:

wherein R means (C₃-C₄)-alkyl or isoalkyl; R' means C(O)CH₃, C(O)C₆H₅, Si(CH₃)₃. Method involves interaction of N-substituted ethyl-(2-dialkoxyphosphoryl)ethaneimidates with acrylonitrile in the presence of sodium ethylate as a catalyst in dioxane medium in the mole ratio N-substituted ethyl-(2-dialkoxyphosphoryl)ethaneimidate : acrylonitrile : sodium ethylate = 1:(1.05-1.15):(0.1-0.15), respectively, at temperature 40-60^oC. Invention provides preparing new chemical compounds that are perspective for preparing biologically active compounds used in medicine and agriculture.

EFFECT: improved preparing method.

4 ex

Description

The invention relates to the chemistry of organophosphorus compounds, and in particular to a new method for producing N-substituted phosphorylated imidates having a cyanethyl group in the structure of the general formula

where R = C ₃ -C ₄ is alkyl or isoalkyl;

R '= C (O) CH ₃ , C (O) C ₆ H ₅ , Si (CH ₃ ) ₃ ;

which are new in structure of organophosphorus compounds and can serve as starting materials for the production of biologically active compounds for the needs of medicine and agriculture. The implementation of the proposed method was made possible due to the presence in the starting N-substituted ethyl- (2-dialkoxyphosphoryl) ethanimidates of high C-H acid properties of the activated methylene group.

It is known to attach nitrile of dialkoxyphosphoryl acetic acid to esters of unsaturated carboxylic acids to produce bifunctional compounds of complex structure containing nitrile and ester groups. The reactions were carried out in the presence of alkali metal alcoholates in anhydrous alcohols by heating the reaction mixtures for up to 4 hours in a boiling water bath (A.N. Pudovik, N.M. Lebedeva. ZhOKh, 1955, v.25, p. 1920-1924. A. N. Pudovik, N.M. Lebedeva.JOKH, 1955, v. 25, p. 2225-2240).

The disadvantages of this method are the low yields (less than 17-71%) of the addition products. And also the result is compounds of a different structure than in the present invention.

A known method of attaching an ester of dialkoxyphosphorylacetic acid to acrylonitrile in the presence of sodium ethylate as a catalyst to produce C-cyanethylated esters of dialkoxyphosphorylacetic acid. The processes were carried out in a solution of ethyl alcohol, the total yield of nitriles was 50% of the theoretical (Addition of phosphonoacetic ester and its homologues to unsaturated electrophilic reagents. AN Pudovik, NM Lebedeva. ZhOKh, v.22, No. 12, 1952, p. 228-2132). The disadvantage of this method is the low yield of nitriles.

The above method gives compounds of a completely different structure compared to the invention.

The objective of the invention is to develop a new technologically advanced low-step method for the synthesis of N-substituted ethyl- (2-dialkoxyphosphoryl-4-cyano) butanimidates.

The technical result is the expansion of the arsenal of chemical compounds, the production of new N-substituted ethyl- (2-dialkoxyphosphoryl-4-cyano) butanimidates in high yield (more than 75%) promising for the production of biologically active compounds for the needs of medicine and agriculture.

The specified technical result is achieved by the development of a new method for producing N-substituted ethyl- (2-dialkoxy-phosphoryl-4-cyano) butanimidates of the formula

where R = C ₃ -C ₄ -alkyl or isoalkyl;

R '= C (O) CH ₃ , C (O) C ₆ H ₅ , Si (CH ₃ ) ₃ ;

consisting in the interaction of N-substituted ethyl- (2-dialkoxyphosphoryl) ethanimidates with acrylonitrile in the presence of a sodium ethylate catalyst in dioxane at a molar ratio of N-substituted ethyl- (2-dialkoxyphosphoryl) ethanimidate: acrylonitrile: sodium ethylate (1: 1.05- 1.15: 0.1-0.15), respectively, and a temperature of 40-60 ° C.

The chemical scheme of the proposed method for producing N-substituted ethyl- (2-dialkoxyphosphoryl-4-cyano) butanimidates:

where R = C ₃ -C ₄ is alkyl or isoalkyl;

R '= C (O) CH ₃ , C (O) C ₆ H ₅ , Si (CH ₃ ) ₃ ;

The nucleophilic addition of N-substituted alkyl (dialkoxyphosphoryl) ethanimidates to acrylonitrile occurs at the β-carbon atom. Based on a literature study, the mechanism of interaction of N-substituted ethyl (dialkoxyphosphoryl) ethanimidate with acrylonitrile can be represented as follows:

At the beginning of the reaction, an ambident anion is formed from ethanimidate under the action of an alkoxy anion.

Then, the formed anion nucleophilically attacks the acrylonitrile molecule with the formation of a mesomeric anion.

This mesomeric anion is a strong base and is able to detach the proton from the ethanol molecule.

It is possible that the methylene group of the N-substituted alkyl (dialkoxyphosphoryl) ethanimidate acts as a proton donor.

When choosing a solvent for the reactions of addition to acrylonitrile, we took into account the following requirements for the solvent: the creation of a homogeneous reaction mass, maintaining the required temperature and inertness with respect to the reacting components. Dioxane meets all these requirements, sodium ethoxide and other reagents dissolve in it, it is possible to increase the temperature to 60 ° C or more, and it is absolutely inert with respect to the reagents. The latter requirement excludes the possibility of using ethyl alcohol, since it interacts with acrylonitrile, lowering the yield of the target compound.

At the initial moment of interaction, there is no need for additional heating, since the reaction begins spontaneously even at room temperature. Then, to increase the degree of conversion of the starting reagents and accelerate the reaction, an additional heating of the reaction mass was carried out to 40-60 ° C.

The use of a 5-15% excess of acrylonitrile in this process compared with the stoichiometric amount is necessary due to its interaction with traces of ethyl alcohol introduced into the reaction mass with a catalyst. The proposed method for the preparation of N-substituted ethyl (2-dialkoxyphosphoryl-4-cyano) butanimidates is characterized by the simplicity of the experiment, is carried out under fairly mild conditions, and provides a high (over 75%) yield of the target compounds.

The method is as follows.

For the synthesis of N-substituted ethyl- (2-dialkoxyphosphoryl-4-cyano) butanimidates to a mixture consisting of N-substituted ethyl- (2-dialkoxyphosphoryl) ethanimidate and acrylonitrile, taken in molar amounts of 1: 1.05-1.15 respectively and dissolved in dried dioxane, a catalyst — sodium ethylate — was added in small portions at room temperature and with stirring. The amount of catalyst was 10-15 mol% of the amount of N-substituted imidate. The process proceeds with a slight heating of the reaction mass, and to complete it, it is recommended that the reaction mixture be heated at 50-60 ° C for 2 hours. After that, the reaction mixture was cooled to room temperature, the catalyst was filtered off, and the solvent was distilled off from the filtrate in a vacuum of a water-jet pump. Residues of the solvent were removed by evacuation (P _ost 1-2 hPa) for 1 hour at 50-60 ° C. The yield of N-substituted ethyl- (2-dialkoxyphosphoryl-4-cyano) butanimidates is more than 75%. To obtain chemically pure compounds, additional purification of the obtained compounds was carried out by column adsorption chromatography on silica gel of the μLC 5/40 brand. Identification of synthesized compounds was carried out according to elemental analysis, molecular refraction, determination of molecular weight, IR spectroscopy. For a better understanding of the essence of the proposed technical solution, specific examples of syntheses are given.

Example 1. Ethyl N-acetyl- (2-diisopropoxyphosphoryl-4-cyano) butanimidate,

To a mixture of 4.0 g (0.0136 mol) of ethyl N-acetyl- (2-diisopropoxy-phosphoryl) ethanimidate, 0.8 g (0.0150 mol, 10% gol.) Of acrylonitrile and 16 ml of dry dioxane at a temperature of 20-25 ° C and vigorous stirring in small portions was added a catalyst - sodium ethylate - in an amount of 0.14 g (0.00204 mol, 15% of the amount of the original imidate). Then the reaction mass was heated to 60 ° C and stirred for 2 hours, after which it was cooled, the catalyst was filtered off, and the solvent was distilled off from the filtrate in a vacuum of a water-jet pump. The residue was evacuated for 1 hour at a temperature of 50-60 ° C and 2 hPa. 4.15 g of ethyl N-acetyl- (2-diisopropoxyphosphoryl-4-cyano) butanimidate were obtained. Yield 88%. To obtain a chemically pure substance, it was purified by column adsorption chromatography on silica gel of the grade μLC 5/40, eluent diethyl ether: acetone (1: 1 vol.); R _f 0.68. n $\genfrac{}{}{0ex}{}{\text{20}}{\text{d}}$ 1,4652, d $\genfrac{}{}{0ex}{}{\text{20}}{\text{4}}$ 1.1352. MR _D 84.58, calc. 84.88. Found,%: N 8.61. C ₁₅ H ₂₇ O ₅ PN ₂ . Calculated,%: N 8.09, P 8.96.

IR spectrum, ν, cm ^-1 : 775, 980-1020 (POC); 1124 (SOS); 1248 (P = O); 1660 (C = N); 1720 (NC = O); 2240 (C≡N).

Example 2. Ethyl N-trimethylsilyl- (2-dibutoxyphosphoryl-4-cyano) butanimidate,

To a mixture of 5.0 g (0.0142 mol) of ethyl N-trimethylsilyl- (2-dibutoxyphosphoryl) ethanimidate, 0.85 g (0.0156 mol, 10% mole) of acrylonitrile and 18 ml of dry dioxane at a temperature 20–25 ° C and vigorous stirring in small portions was added the catalyst — sodium ethylate — in an amount of 0.145 g (0.00213 mol, 15% of the amount of the initial imidate). Then the reaction mass was heated to 60 ° C and stirred for 2 hours, after which it was cooled, the catalyst was filtered off, and the solvent was distilled off from the filtrate in a vacuum of a water-jet pump. The residue was evacuated for 1 hour at a temperature of 50-60 ° C and 2 hPa. 4.3 g of ethyl N-trimethylsilyl- (2-dibutoxyphosphoryl-4-cyano) butanimidate are obtained. Yield 75%. To obtain a chemically pure substance, it was purified by column adsorption chromatography on silica gel of the grade μLC 5/40, eluent diethyl ether: acetone (1: 1 vol.); R _f 0.73. n $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ 1.4864, d $\genfrac{}{}{0ex}{}{\text{20}}{\text{4}}$ 1.0017. MR _D 108.97, calc. 109.90. Found,%: N 7.69, P 7.81. C ₁₆ H ₃₇ O ₄ PN ₂ Si Calculated,%: N 7.37, P 8.16.

PC spectrum, ν, cm ^-1 : 760 (Si-N); 775, 980-1010 (POC); 1120 (SOS); 1252 (P = O); 1666 (C = N); 2248 (C≡N).

Example 3. Ethyl N-acetyl- (2-dibutoxyphosphoryl-4-cyano) butanimidate,

To a mixture of 4.5 g (0.0140 mol) of ethyl N-acetyl- (2-dibutoxy-phosphoryl) ethanimidate, 0.9 g (0.0161 mol, 15% mol.) Of acrylonitrile and 16 ml of dry dioxane at a temperature of 20- 25 ° C and vigorous stirring in small portions was added a catalyst - sodium ethylate - in an amount of 0.095 g (0.0014 mol, 10% of the amount of the original imidate). Then the reaction mass was heated to 40 ° C and stirred for 2 hours, after which it was cooled, the catalyst was filtered off, and the solvent was distilled off from the filtrate in a vacuum of a water-jet pump. The residue was evacuated for 1 hour at a temperature of 50-60 ° C and 2 hPa. 4.1 g of ethyl N-acetyl- (2-dibutoxyphosphoryl-4-cyano) butanimidate were obtained. Yield 78%. To obtain a chemically pure substance, it was purified by column adsorption chromatography on silica gel of the grade μLC 5/40, eluent diethyl ether: acetone (1: 1 vol.); R _f 0.70. n $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ 1.4838, d $\genfrac{}{}{0ex}{}{\text{20}}{\text{4}}$ 1,1120. MR _D 95.92, calc. 96.30. Found,%: N 7.64, P 8.20. C ₁₇ H ₃₁ O ₅ PN ₂ Calculated,%: N 7.49, P 8.29.

IR spectrum, ν, cm ^-1 : 775, 990-1104 (POC); 1116 (SOS); 1248 (P = 0); 1656 (C = N); 1720 (NC = 0); 2252 (C≡N).

Example 4. Ethyl N-benzoyl- (2-diisopropoxyphosphoryl-4-cyano) butanimidate,

To a mixture of 6.0 g (0.0169 mol) of ethyl N-benzoyl- (2-diisopropoxyphosphoryl) ethanimidate, 0.96 g (0.0177 mol, 5% mol%) of acrylonitrile and 20 ml of dry dioxane at a temperature of 20-25 ° C and vigorous stirring in small portions was added a catalyst - sodium ethylate - in an amount of 0.116 g (0.0017 mol, 10% of the amount of the original imidate). Then the reaction mass was heated to 50 ° C and stirred for 2 hours, after which it was cooled, the catalyst was filtered off, and the solvent was distilled off from the filtrate in a vacuum of a water-jet pump. The residue was evacuated for 1 hour at a temperature of 50-60 ° C and 2 hPa. 5.5 g of ethyl N-benzoyl- (2-diisopropoxyphosphoryl-4-cyano) butanimidate were obtained. Yield 80%. To obtain a chemically pure substance, it was purified by column adsorption chromatography on silica gel of the grade μLC 5/40, eluent diethyl ether: acetone (1: 1 vol.); R _f 63. n $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ 1,5146, d $\genfrac{}{}{0ex}{}{\text{20}}{\text{4}}$ 1.1271. MR _D 105.34, calc. 106.06. Found,%: N 7.33, P 8.19. C ₁₉ H ₂₇ O ₅ PN ₂ Calculated,%: N 7.11, P 7.87.

Car); 1676 (C=N); 1736 (NC=O); 2250 (C≡N).IR spectrum, ν, cm ^-1 : 775, 980-1104 (POC); 1116 (SOS); 1260 (P = O); 1595 (s

Car); 1676 (C = N); 1736 (NC = O); 2250 (C≡N).

The proposed method allows the synthesis of N-substituted ethyl (2-dialkoxyphosphoryl-4-cyano) butanimidates from the corresponding ethanimidates, which was possible due to the high C-H acid properties of the activated methylene group of the latter.

The method consists in the interaction of N-substituted ethyl- (2-dialkoxyphosphoryl) ethanimidates with acrylonitrile in the presence of sodium ethylate as a catalyst with the formation of N-substituted ethyl- (2-dialkoxyphosphoryl-4-cyano) butanimidates. The advantage of the developed method is the simplicity of the technology and versatility, since it allows one to obtain their cyanoethylated homologues from the corresponding starting ethanimidates.

Claims (1)

The method of obtaining N-substituted ethyl- (2-dialkoxyphosphoryl-4-cyano) butanimidates

where RC _{3 is} C ₄ alkyl or isoalkyl; R'-C (O) CH ₃ , C (O) C ₆ H ₅ , Si (CH ₃ ) ₃ , consisting in the interaction of N-substituted ethyl- (2-dialkoxyphosphoryl) ethanimidates with acrylonitrile in the presence of a sodium ethylate catalyst in dioxane at a molar ratio of N-substituted ethyl- (2-dialkoxyphosphoryl) ethanimidate: acrylonitrile: sodium ethylate (1: 1.05 -1.15: 0.1-0.15), respectively, and a temperature of 40-60 ° C.