RU2366647C1 - Method for preparing 3-substituted-3-(3-phenoxyphenyl)-2-propenenitriles - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to preparation of new intermediate products of -3-substituted-3-(3-phenoxyphenyl)-2-propenenitriles of general formula 1 which can be used in production of biologically active substances, including insecticides, or in production of pharmacologically active compounds. The method for preparing -3-substituted-3-(3-phenoxyphenyl)-2-propenenitriles of general formula 1

where R=H, CH3, consists in reaction of carbonyl compound chosen from 3-phenoxybenzaldehyde or 3-phenoxyphenylmethylketone and acetonitrile with potassium hydroxide added and an end product to be recovered. Preferentially, process is implemented at mole ratio of carbonyl compound, acetonitrile and potassium hydroxide equal to 1:(20-22):1 respectively, in initial acetonitrile medium at boiling temperature 80-82°C. As a rule, the end product is recovered by extraction with diethyl ether. Vacuum distillation is used to distil the extractant and purify the end product.

EFFECT: high-yield and high-purity products.

2 cl, 2 ex

Description

The invention relates to the chemistry of derivatives of nitriles, in particular to a method for producing 3-substituted-3- (3-phenoxyphenyl) -2-propenitrile of the General formula

where R = H, CH ₃

which are new in structure of 3-phenoxyphenyl-containing compounds and may be of interest as intermediates in the synthesis of biologically active substances. Many compounds containing a diphenyl oxide fragment exhibit various types of biological activity. So permethrin [(3-phenoxyphenyl) methyl ester of 3- (2,2-dichloroethenyl) -2,2-dimethylcyclopropanecarboxylic acid; a mixture of cis and trans isomers (3: 1)] and phenotrin [2,2-dimethyl-3- (2-methyl-1-propenyl) cyclopropanecarboxylic acid (3-phenoxyphenyl) methyl ester] are used as antiparasitic drugs , anti-pedicular, insecticidal, ovocidal pharmacological action. There are examples of the use of phenoxyphenylacetylenes based on 1- (2-methyl-4-phenoxyphenyl) ethanone and 1- (3-phenoxyphenyl) ethanone as antithrombotic, anti-inflammatory, antipyretic agents and analgesics [Chemical Encyclopedia: 5 T: T .5. / Ed. Col .: Knunyants I.L. et al. - M.: Big Russian Encycl., 1992. - 639 s].

A known method of producing substituted phenylacrylonitriles containing as substituents atoms of chlorine, hydrogen, nitrile or vinyl groups, which consists in the interaction of styrene with hydrogen cyanide in the presence of oxygen, hydrogen chloride, nitrogen. As the catalysts in this process, various salts of palladium, strontium, rhodium, indium, copper and cobalt were used [Patent US 3524874. C07C 121/70, C07C 121/72. - 1970].

The disadvantages of this method are the low yield of phenylacrylonitriles (7.6-28%), the high toxicity of one of the starting compounds, namely hydrogen cyanide, and the use of a complex catalyst system.

This method does not lead to the production of substances of the claimed structural formula.

There is also a method of producing cinnamonitrile, consisting in the interaction of benzaldehyde with acetonitrile in the presence of potassium hydroxide at a molar ratio of benzaldehyde and potassium hydroxide equal to 1: 1. The final product is isolated by steam distillation, yield 31-45%. By vacuum distillation of the final product, the yield is 22% [Stephen A. DiBiase, James R. Beadle, George W. Gokel. Organic Syntheses, CV 7, 108].

The disadvantage of this method is the rather laborious stage of product isolation, a large overspending of diethyl ether used as an extractant and a low yield of the target product.

This method also does not lead to the production of substances of the claimed structural formula.

The objective of the invention is to develop a technologically advanced low-stage method for the synthesis of 3-substituted-3- (3-phenoxyphenyl) -2-propenitrile in good yield and high purity.

The technical result is the expansion of the range of chemical compounds, in particular the preparation of new 3-substituted-3- (3-phenoxyphenyl) -2-propenitriles in good yield, high purity, and simplification of the isolation of the final product.

The technical result is achieved in a method for producing 3-substituted-3- (3-phenoxyphenyl) -2-propenitrile of the general formula

where R = H, CH ₃

consisting in the interaction of carbonyl compounds, for example 3-phenoxybenzaldehyde or 3-phenoxyphenylmethyl ketone with acetonitrile in the presence of potassium hydroxide, and the selection of the final product by extraction with diethyl ether, followed by distillation of the extractant and purification of the target product by vacuum distillation. The process is carried out at a molar ratio of carbonyl compound, acetonitrile and potassium hydroxide equal to 1: (20-22): 1, respectively, in the medium of the initial acetonitrile at a boiling point of 80-82 ° C.

The essence of the method is the reaction of the addition of acetonitrile to carbonyl compounds, for example 3-phenoxybenzaldehyde or 3-phenoxyphenylmethyl ketone in the presence of potassium hydroxide in acetonitrile

where R = H, CH ₃ .

The method is as follows.

In a reactor equipped with a mechanical stirrer, a reflux condenser with a calcium chloride tube, a thermometer and a dropping funnel, potassium hydroxide is dissolved in acetonitrile by boiling and stirring in a nitrogen atmosphere. Then, a carbonyl compound, for example 3-phenoxybenzaldehyde or 3-phenoxyphenylmethyl ketone in acetonitrile, is added from a dropping funnel. The dropping and synthesis time depends on the reactivity of the carbonyl compound. Next, the hot solution is poured into a glass with crushed ice, after which a two-phase mixture is formed, which is separated using a separatory funnel. The organic layer was separated, and the aqueous was extracted twice with diethyl ether. Combine the organic layer and ether extracts, washed with distilled water. The organic phase is dried over sodium sulfate. The extractant is distilled off, the obtained 3-substituted-3- (3-phenoxyphenyl) -2-propenitrile is purified by vacuum distillation with the addition of hydroquinone.

The yield of these products after isolation is up to 51%.

As the studies showed, the optimal and technological condition for the reaction is its implementation in acetonitrile at a molar ratio carbonyl compound: acetonitrile: potassium hydroxide 1: (20-22): 1. A smaller excess of acetonitrile led to a slight decrease in the yield of the target product due to the incomplete conversion of the carbonyl compound and the incomplete dissolution of potassium hydroxide in acetonitrile. A further increase in the excess of acetonitrile did not affect the yield of 3-substituted- (3-phenoxyphenyl) -2-propenitrile and was impractical.

In the prototype, cinnamonitrile is purified by steam distillation and subsequent distillation of the solvent, which significantly complicates the isolation step, the yield being 31-45%, the degree of purity of the final product is not discussed by the authors. In vacuum distillation, the yield of the final product does not exceed 22%. Our proposed scheme for isolating the target product avoids labor-intensive operations and, most importantly, achieves 48-51% yield after distillation of 3-substituted- (3-phenoxyphenyl) -2-propenitrile on a vacuum pump with a high degree of purity of 98.5%.

The optimum reaction temperature is 80-82 ° C. A decrease in temperature to room temperature leads to a strong increase in the duration of this interaction and a decrease in the yield of the target product, while its increase is limited by the boiling point of acetonitrile.

Example 1. 3- (3-phenoxyphenyl) -2-propenitrile

In a reactor equipped with a mechanical stirrer, a reflux condenser with a calcium chloride tube, a thermometer and a dropping funnel, 3 g (0.05 mol) of potassium hydroxide and 40 ml of acetonitrile are placed. The mixture is boiled under stirring under nitrogen until the potassium hydroxide beads are completely dissolved in acetonitrile. Then, 10 g (0.05 mol) of 3-phenoxybenzaldehyde in 20 ml of acetonitrile are added in a thin stream over a dropping funnel over a period of 1-2 minutes. After adding all 3-phenoxybenzaldehyde, stirring was continued for 10 minutes and the hot solution was poured onto 100 g of crushed ice in a glass. After cooling, a two-phase mixture is formed, which is separated using a separatory funnel. The organic layer was separated, and the aqueous was extracted 2 times with 50 ml of diethyl ether. Combine the organic layer and ether extracts, washed with distilled water. The organic phase is dried over sodium sulfate. After distilling off the solvent (diethyl ether), 3- (3-phenoxyphenyl) -2-propenitrile was distilled in vacuo with the addition of hydroquinone. Yield 5.3 g (0.024 mol, 48%). T.kip. 194-200 ° C / 4 mm Hg Purity - 98.5% (according to GLC). IR spectrum, υ, cm ^-1 : 1600-700 (Ar); 2218 (C≡N); 1696 (C = C); 3064 (C-H). ¹ H NMR, δ, ppm .: 6,84-7,2 m (9H, C ₆ H ₅ OC ₆ H _4); 7.44-7.46 d (1H, Ar-CH); 5.62-5.67 d (1H, CH-CN).

Example 2. 3-methyl-3- (3-phenoxyphenyl) -2-propenitrile

In a reactor equipped with a mechanical stirrer, a reflux condenser with a calcium chloride tube, a thermometer and a dropping funnel, 3 g (0.05 mol) of potassium hydroxide and 40 ml of acetonitrile are placed. Potassium hydroxide should be as fresh as possible. The mixture is boiled under stirring under nitrogen until the potassium hydroxide beads are completely dissolved in acetonitrile. Then, 10 g (0.05 mol) of 3-phenoxyphenylmethylketone in 20 ml of acetonitrile are added dropwise from a dropping funnel over 30-40 minutes. After adding all 3-phenoxyphenylmethyl ketone, stirring was continued for 3 hours, and the hot solution was poured onto 100 g of crushed ice in a glass. After cooling, a two-phase mixture is formed, which is separated using a separatory funnel. The organic layer was separated, and the aqueous was extracted 2 times with diethyl ether. Combine the organic layer and ether extracts, washed with distilled water. The organic phase is dried over sodium sulfate. After distilling off the solvent, 3-methyl-3- (3-phenoxyphenyl) -2-propenitrile was distilled in vacuo with the addition of hydroquinone. Yield 6 g (0.0255 mol, 51%). T.kip. 215-218 ° C / 4 mm Hg Purity - 97.2% (according to GLC). IR spectrum, υ, cm ^-1 : 1600-700 (Ar); 2218 (C≡N); 1672 (C = C); 2926-3034 (CH ₃ ). ¹ H NMR, δ, ppm .: 6,84-7,2 m (9H, C ₆ H ₅ OC ₆ H _4); 1.1-1.3 s

(3H, CH ₃ ); 5.34-5.37 s (1H, CH-CN).

findings

The proposed method allows to obtain 3-substituted-3- (3-phenoxyphenyl) -2-propenitrile, in one step with good yields. Its advantages include preparative simplicity of synthesis and ease of isolation of target products with a high degree of purity. The structure of the synthesized compounds was confirmed by IR, NMR ¹ H-spectroscopy.

Claims (2)

1. The method of obtaining 3-substituted-3- (3-phenoxyphenyl) -2-propenitrile General formula

where R = H, CH ₃ ,
the interaction of a carbonyl compound selected from 3-phenoxybenzaldehyde or 3-phenoxyphenylmethyl ketone with acetonitrile in the presence of potassium hydroxide, followed by isolation of the target product. 2. The method according to claim 1, characterized in that the process is carried out at a molar ratio of carbonyl compound, acetonitrile and potassium hydroxide equal to 1: (20-22): 1, respectively, in the medium of the initial acetonitrile at a boiling point of 80-82 ° C and the selection of the target product is carried out by extraction with diethyl ether, followed by distillation of the extractant and purification of the target product by vacuum distillation.