RU2496763C1 - 1-alkoxy-2,7-dimethylocta-2,7-dienes, having acaricidal activity, and method for production thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula

, where R is CH₃(CH₃)CHCH₂CH₂-, CH₃CH=CHCH₂-,

, which have acaricidal activity. The invention also relates to a method for production of said compounds, which involves reacting corresponding alcohols with quaternary terpenyl ammonium salts, such as N-(2,7-dimethyl-2,7-octadien-1-yl)allyldiethylammonium bromide, N-(2,7-dimethyl-2,7-octadien-1-yl)allylpiperidinium bromide and N-(2,7-dimethyl-2,7-octadien-1-yl)methyldiethylammonium iodide, in the presence of NaOH.

EFFECT: disclosed compounds can be used as acaricidal preparations in veterinary in case of sarcoptic mange and common scab in pets and farm animals.

2 cl, 2 tbl, 5 ex

Description

The invention relates to the chemistry of terpene compounds, in particular to new compounds of 1-alkoxy-2,7-dimethylocta-2,7-dienes, specifically to 1- (3-methyl-butyloxy) -2,7-dimethylocta-2,7- diene, 1- (but-2-enyloxy) -2,7-dimethylocta-2,7-diene and 1- (3,7-dimethyl-octa-2,6-dienyloxy) -2,7-dimethylocta-2, 7-diene of the general formula

where R = (CH ₃ ) ₂ CHCH ₂ CH ₂ - (1a); R = CH ₃ CH = CHCH ₂ - (1b);

The inventive compounds can most effectively be used in veterinary medicine and agriculture as acaricides. The inventive compounds, their properties and method of preparation are not described in the literature.

Acaricidal preparations are known whose active principle is pyrethroids (fluvalinate, flumetrin, acrinatrin), formamines (amitraz), benzylates (brompropylate), organophosphorus compounds (coumaphos), phenols (thymol), organic acids, essential oils. In Russia, preparations based on fluvalinate (pyrethroid) and amitrase (formamine) are most widely used.

It is known that the listed chemical compounds are toxic to animals and this limits the possibility of their use in veterinary medicine.

Non-toxic compounds of the terpene series are known to have biological activity (insecticidal, fungicidal and antibacterial), which do not cause the appearance of organisms resistant to them.

However, individual compounds of the monoterpene series exhibiting acaricidal activity against ticks parasitizing in animals are still unknown. Extracts of plants containing terpenoids are commonly used against parasitic mites on plants (Here FS, Bianco EM, da Camara CA. Acaricidal and repellent activity of terpenoids from seaweeds Collected in Pemambuco, Brazil. Nat Prod Commun. 2012 Apr; 7 (4) : 463-6.). Complex pentacyclic triterpen, ursolic acid, extracted from plant materials (Annan K, Jackson N, Dickson RA, Sam GH, Komlaga G. Acaricidal effect of an isolate from Hoslundia opposita vahl, is known to exhibit moderate activity against ixodid ticks that parasitize humans). against Amblyomma variegatum (Acari: Ixodidae). Phcog Res 2011; 3: 185-8). However, there are no data on the acaricidal activity of ethers containing monoterpene substituents.

The search for new acaricides among non-toxic compounds of the monoterpene series seems promising.

The closest in structure to the claimed compounds are terpene esters obtained by telomerization of isoprene with allyl and benzyl alcohols in the presence of the catalyst system (π-AllPdCl) ₂ + Ph ₃ P + RONa, as well as with chloroethanol and higher alcohols n-amyl and n-nonyl, which proceeds with low yields (not higher than 38%).

In the case of higher alcohols, an inseparable mixture of isomeric telomeres is formed, the exact composition of which could not be determined (Zakharkin L.I., Guseva V.V., Petrovsky P.V. Simple synthesis of (±) -2,6-dimethyloctan-1-ol formate , a biologically active analogue of the aggregation pheromone of flour flour, from 1-allyloxy and 1-benzyloxy-2, b-dimethyl-2,7-dienes - isoprene telomeres with allyl and benzyl alcohols // Izv. AN Ser. chem. 1995. No. 8. P.1539). The disadvantages of this method of producing terpene esters are the difficulties in isolating individual compounds from mixtures, which greatly reduces the yield of the target products (most of the obtained esters were not isolated in an individual state), as well as the use of an expensive palladium catalyst.

Several methods are described for preparing ethers containing one monoterpene substituent.

For example, linallyl allyl ether was obtained by allylation of linalool with bromide allyl in the presence of NaH in anhydrous DMF (N.V. Ammar, J. Le Notre, M. Salem, M.T. Kaddachi, L. Toupet, J.-L. Renaud , C. Bmneau, P. N. Dixneuf Eur. J. Inorg. Chem. 2003, 4055-4064). The disadvantage of this method is the use of explosive sodium hydride, which requires special equipment, and allyl bromide, which is a lacrimator.

Known methods for producing terpenyl-acyl (C ₁ -C ₄ ), alkenyl (C ₃ -C ₄ ), haloalkyl (C ₃ ), -alkynyl (C ₃ ) esters described in US patent 4173543 (1979): (1 ) esters are obtained in low yields by the reaction of terpene alcohols with lower alkyl, alkenyl, haloalkyl, alkynyl alcohols in the presence of para-toluenesulfonic acid and (2) by reaction of terpene alcohols with sulfates of lower alcohols in the presence of sodium hydride in anhydrous DMF. The disadvantages of these methods are low yields and the use of explosive sodium hydride.

The main disadvantages of the known methods for the preparation of terpene ethers are the need to use palladium catalysts and the formation of isomeric difficultly separable mixtures, the use of hazardous (sodium hydride), toxic (allyl bromide) or expensive (palladium complexes) reagents.

The alkylation of phenolic morphine hydroxyl with quaternary ammonium salts of trialkylanilines (alkyl methyl, ethyl, benzyl) (Rodionow WM Les ethers alcoyliques des acides sulfoaromatiques comme agents d'alcoylation // Bull. Soc. Chim. Fr. 1929. V.45. 4. P.109-121 and Rodionov VM The value of alkyl fragments of aromatic sulfonic acids for the alkylation of organic compounds // Selected Works of the USSR Academy of Sciences. 1958. P.32-48), but there is no alkylation of the allyl alcohol group.

Until now, the use of quaternary ammonium salts for the alkylation of the hydroxyl group of aliphatic alcohols was not known.

Trialkylphenylammonium salts containing a terpene substituent cannot be used for alkylation, since such salts cannot be obtained (decomposed upon receipt) (Zakharkin LI, Petrushkina EA // Izv. AN SSSR. Ser. Chem. 1986 No. 6. P.1344-1347).

An object of the present invention is to provide previously unknown ethers containing a terpene substituent, namely 1- (3-methyl-butyloxy) -2,7-dimethylocta-2,7-diene, 1- (but-2-enyloxy) -2, 7-dimethylocta-2,7-diene and 1- (3,7-dimethyl-octa-2,6-dienyloxy) -2,7-dimethylocta-2,7-diene, which exhibit acaricidal activity and the development of a method for their preparation from commercially available raw materials.

The problem is solved by obtaining new compounds of formula 1

where -R = (CH ₃ ) ₂ CHCH ₂ CH ₂ - (1a);

-R = CH ₃ CH = CHCH ₂ - (1b);

possessing acaricidal activity, and a method for preparing the claimed compounds by reacting the corresponding alcohols with quaternary terpenylammonium salts such as N- (2,7-dimethyl-2,7-octadiene-1-yl) allyldiethylammonium bromide, N- (2,7-dimethyl- 2,7-octadien-1-yl) allyl piperidinium bromide; and N- (2,7-dimethyl-2,7-octadien-1-yl) methyldiethylammonium iodide in the presence of NaOH.

The inventive method is original and is based on a previously unknown non-catalytic reaction of allylation of alcohols with terpenylammonium salts.

Allylation of isoamyl alcohol (2a) with salts, such as N- (2,7-dimethyl-2,7-octadiene-1-yl) allyl piperidinium bromide (3d), N- (2,7-dimethyl-2) , 7-octadien-1-yl) methyldiethylammonium iodide (3e); crotyl alcohol (2b) by the action of N- (2,7-dimethyl-2,7-octadiene-1-yl) allyl piperidinium bromide (3d), as well as the allylation of geraniol (2c) by the action of N- (2,7-dimethyl-2, 7-octadiene-1-yl) allyldiethylammonium bromide (3g) and N- (2,7-dimethyl-2,7-octadiene-1-yl) allyl piperidinium bromide (3d) in the presence of 10 equivalents of NaOH in the corresponding boiling alcohol or at 150 ° C in case of geraniol, ethers of 1- (3-methyl-butyloxy) -2,7-dimethylocta-2,7-diene (1a), 1- (but-2-enyloxy) -2,7-dimethylocta-2 , 7-diene (1b) and 1- (3,7-dimethyl-octa-2,6-dienyloxy) -2,7-dimethylocta-2,7-diene (1c) (MS-GC and NMR) (Scheme 1 ) The allylation of alcohols (2a-b) with salts (3g-3e) takes place in the presence of NaOH and in the absence of a catalyst.

Scheme 1

The effect of the alkyl substituents of the leaving ammonium group on the reaction yield in the case of isoamyl alcohol and geraniol was investigated. Salts (3g, 3d) are the most effective reagents; when they are used, the reaction occurs most selectively without the formation of by-products. Table 1 presents the results of applying the method to obtain the claimed compounds (1A-C) with varying salts and reaction conditions. It turned out that piperidine salt (3d) made it possible to obtain ether (1c) in high yield (97%). An increase in the heating time does not lead to a substantial increase in the yields of esters (1b) and (1c). Salts (3g-e) are prepared by a known two-stage method, including telomerization of isoprene with piperidine or diethylamine in the presence of Pd (acac) ₂ -Ph ₃ P in MeCN solution with the formation of N- (2,7-dimethylocta-2,7-diene-1 -yl) piperidine or diethylamine with a yield of 80-95% and their subsequent quaternization by the action of the corresponding alkyl halide at room temperature for 2-3 days. The target salts (3d) are obtained in 75-90% yield (Petrushkina EA, Zakharkin LI. "Synthesis of new synthetic plant growth regulators - isomeric 1- (dimethyloctyl), 1-alkylpiperidinium and morpholinium halides based on telomerization isoprene with secondary amines "MLC. 2003. T.73. Issue 10. S.1747-1752.).

Table 1 The influence of the reaction conditions and the structure of salts (3d) on the reaction yield Ammonium salt (3d) R ³ OH (ratio (3d) / (2a-c) T ° C, τ h Yield (1a-c),% 3d Isoamyl alcohol (1/25) T. bale., 1 (1a) 40 3rd Isoamyl alcohol (1/25) T. bale., 1 (1a) 8 3rd Isoamyl alcohol (1/25) T. bale., 6.5 (1a) 20 3d Crotyl alcohol (1/42) T. bale., 1 (1b) 10 3G Geraniol (1/2) 150.1 (1c) 57 3d Geraniol (1/2) 150.1 (1c) 97

The proposed method allows to obtain the claimed compounds (1A-C) by direct alkylation of alcohols with salts such as N- (2,7-dimethyl-2,7-octadiene-1-yl) allyldiethylammonium bromide, N- (2,7-dimethyl-2 , 7-octadiene-1-yl) allyl piperidinium bromide; and N- (2,7-dimethyl-2,7-octadiene-1-yl) methyldiethylammonium iodide in the absence of catalysts and solvents. The inventive method of producing simple terpene ethers does not require the use of fire and explosive reagents, toxic substances and expensive catalysts. The inventive method is based on a new, previously not described allylation reaction of alcohols with terpenylammonium salts, discovered by the inventors.

The claimed compounds are 1- (3-methyl-butyloxy) -2,7-dimethylocta-2,7-diene, 1- (but-2-enyloxy) -2,7-dimethylocta-2,7-diene and 1- ( 3,7-dimethyl-octa-2,6-dienyloxy) -2,7-dimethylocta-2,7-diene, of the general formula 1, exhibit high acaricidal activity against Dermanyssus gallinae chicken ticks and Hyalomma scupense cattle ticks.

The invention is illustrated by the following examples.

Example 1

Preparation of 1- (3-methyl-butyloxy) -2,7-dimethylocta-2,7-diene (1a).

0.94 g of N- (2,7-dimethyl-2,7-octadiene-1-yl) allyl piperidinium bromide salt (3d), 1.1 g NaOH and 8 ml of isoamyl alcohol are added to a two-necked flask under reflux, under argon flow. The reaction is carried out with stirring at the boiling point for 1 hour. After heating, the reaction mixture was diluted with water, the product was extracted with ether. The products are separated by silica gel column chromatography. A hexane-ether mixture of increasing polarity is used as an eluent. Ether (1a) was obtained in 40% yield. 1 H-NMR spectrum (600.22 MHz, CDCl ₃ , δ, ppm, J, Hz): 0.91 d (6H, ^3'a CH ₃ , ^3'b CH ₃ , J _3'-3'a = 6.64) ; 1.40-1.52 m (4H, ^{3 '} CH, ⁵ CH ₂ , J _3'-3'a = 6.64, J _3'-2' = 6.87, J _5-4 = 7.78); 1.56-1.70 m (8H, ^2a CH ₃ , ^{2 '} CH ₂ , ^7a CH ₃ , J _2'-3' = 6.87, J _{2'-1 '} = 6.87); 1.91-2.01 m (4H, ⁴ CH ₂ , ⁶ CH ₂ , J _4-3 = 7.56); 3.40 t (2H, ^{1 '} CH ₂ , J _1'-2' = 6.87); 3.85 s (2H, ¹ CH ₂ ); 4.45, 4.47 s, s (2H, ⁸ CH ₂ ); 5.42 t (1H, ³ CH, J _3-4 = 7.56).

¹³ C NMR spectrum (150.93 MHz, CDCl ₃ , δ, ppm): 13.90 ( ^7a C); 22.44 ^{(2 'C);} 22.68 ( ^3'a C, ^3'b C), 25.13 ( ^2a C); 27.30 ( ⁶ C); 27.46 ( ⁵ C); 37.44 ( ⁴ C); 38.65 ( ^{3 '} C); 68.08 ( ^1' C); 76.83 ( ¹ C); 109.83 ( ⁸ C); 127.78 ( ³ C), 132.63 ( ⁷ C), 145.91 ( ² C).

To assign signals in the ¹ H and ¹³ C NMR spectra, two-dimensional homo (H, H) and hetero (H, C) correlation techniques using pulsed field gradients, gs-COZY, gs-HMQC and gs-HMBC, are used.

Mass spectrum (m / z, I,%): M ⁺ 224 (20), 168 (30), 136 (100), 121 (75), 107 (30), 95 (70), 81 (85), 71 (100), 55 (60).

Example 2. Obtaining 1- (but-2-enyloxy) -2,7-dimethylocta-2,7-diene (1b).

Ether (1b) was prepared according to a procedure similar to that described in Example 1, from 0.94 g of N- (2,7-dimethyl-2,7-octadiene-1-yl) allyl piperidinium bromide (3d), 1.1 g of NaOH and 7 ml of crotyl alcohol at boiling point for 1 hour with a yield of 10%.

1 H-NMR spectrum (CDCl ₃ , δ, ppm, J, Hz): 1.50-1.62 m (2H ⁵ CH ₂ ), 1.70 s (6H, ^2a CH ₃ , ^7a CH ₃ ), 1.76 d (3H, ^{4 '} CH ₃ , J _4'-3' = 6.04), 2.03-2.15 m (4H, ⁴ CH ₂ , ⁶ CH ₂ , J _4-3 = 7.20), 3.89 s (2H, ¹ CH ₂ ), 3.91 d (2H, ^{1 '} CH ₂ , J _1'-2' = 5.85), 4.73, 4.76 s, s (2H, ⁸ CH ₂ ), 5.47 t (1H, ³ CH, J _3-4 = 7.20), 5.68 AB a quartet (2H, ^{2 '} CH, ^3' CH, J _{2'-1 '} = 5.85, J _3'-4' = 6.04).

Mass spectrum (m / z, I,%): M ⁺ 208 (1), 153 (1), 136 (20), 121 (10), 107 (5), 95 (100), 81 (25), 69 (23), 55 (75).

Example 3. Obtaining 1- (3,7-dimethyl-octa-2,6-dien-1-yloxy) -2,7-dimethylocta-2,7-diene (1c).

Ether (1c) was prepared according to the procedure described in Example 1 from 0.94 g of N- (2,7-dimethyl-2,7-octadiene-1-yl) allyl piperidinium bromide (3d), 1.1 g of NaOH and 1 ml of geraniol at 150 ° C for 1 hour with a yield of 97%.

1 H-NMR spectrum (CDCl ₃ , δ, ppm, J, Hz): 1.50-1.62 m (2Н ⁵ CH ₂ ), 1.66 s (3Н, ^2a CH ₃ ), 1.71 s (3Н, ^7a CH ₃ ), 1.74 s (3H, ^3'a CH ₃ ), 1.77 s (3H, ^7'a CH ₃ ), 1.81 s (3H, ^{8 '} CH ₃ ), 2.00-2.27 m (8H, ⁴ CH ₂ , ⁶ CH ₂ , ^{5 '} CH ₂ ^2' CH ₂ , J _4-3 = 7.47, J _{5'-6 '} = 6.46), 3.90 s (2H, ¹ CH ₂ ), 3.99 d (2H, ^1' CH ₂ , J _{1'-2 '} = 6.86), 4.72, 4.76 s, s (2H, ⁸ CH ₂ ), 5.16 t (1H, ^6' CH, J _{6'-5 '} = 6.46), 5.41 t (1H, ^2' CH, J _{2 ' -1 '} = 6.86), 5.47 t (1H, ³ CH, J _3-4 = 7.47).

Mass spectrum (m / z, I,%): M ⁺ 153 (10), 136 (10), 123 (30), 109 (5), 95 (40), 81 (50), 69 (100), 55 (20).

Example 4. Tests for the acaricidal activity of compounds (1a-b) were carried out in in vitro experiments on chicken mites Dermanyssus gallinae. Ticks were distributed according to the stages of development into different boxes and stored at a temperature of 20 ° C. During the experiments, aqueous solutions of terpenoids (1a-c) were preliminarily applied to the bottom of the Petri dishes, then larvae, nymphs, and adults of D. Gallinae ticks were placed on the processed bottom of the Petri dishes. The experiments were carried out for 2 days at 20 ° C. The determination of viability and fixation of changes in the morphology of ticks was carried out every 8 hours by viewing Petri dishes under a magnifying glass MBS-1. The results are presented in Table 2. After the death of the objects, the destruction of chitin continued.

table 2 The study of water-alcohol solutions of compounds 1a-c on chicken mites Dermanyssus gallinae in vitro Material results Sample number compound tick developmental stage death color Changing the structure of chitin Morphological changes in internal organs one 1a 10 larvae After 8 hours brown Melting (shortening) of the limbs, melting (deformation) of the chitinous cover, in two cases, complete lysis of the object + 2 1a 10 nymphs After 8 hours brown Melting (shortening) of the limbs, melting (deformation) of the chitinous cover + 3 1a 10 adults After 8 hours Rich brown Melting (shortening) of the limbs, melting (deformation) of the chitinous cover + four 1b 10 larvae After 8 hours tan Melting (shortening) of the limbs, melting (deformation) of the chitinous cover + 5 1b 10 nymphs After 8 hours tan Melting (shortening) of the limbs, melting (deformation) of the chitinous cover + 6 1b 10 adults After 16 hours brown Melting (shortening) of the limbs, melting (deformation) of the chitinous cover + 7 1c 10 larvae After 8 hours normal Melting (shortening) of the limbs, melting (deformation) of the chitinous cover + 8 1c 10 nymphs After 16 hours normal Melting (shortening) of the limbs, melting (deformation) of the chitinous cover + 9 1c 10 adults After 16 hours normal Melting (shortening) of the limbs, melting (deformation) of the chitinous cover +

Example 5. Tests for the acaricidal activity of compounds (1a-c) were carried out in experiments on fed female Hyalomma scupense ixodid ticks. For testing, 0.1% solutions of esters were prepared (16, c) in a 1% aqueous solution of ethanol. For comparison, we used a 1% suspension of diflubenzuron in water as an active juvenoid. 10 copies of well-fed females are placed on fabric napkins, tied with a thread and for 1 min. placed in the test fluid. Then the females are placed in a test tube, closed with a cotton plug and kept in a thermostat in the presence of water. The control is served by the same well-fed females bathed in clean water. Accounting is carried out in the first three days, as well as in the following days, taking into account the effect of acaricide on egg laying and larvae hatching (2-4 weeks). After 27-29 days (the norm of 7-14 days for control), well-fed females treated with experimental preparations began egg laying. After 42 days, females treated with the preparation gave 100% egg laying (1b). Of the five females treated with the preparation (1c), four turned black and died without laying, while of the five females treated with a suspension of diflubenzuron, only three became black and died.

The results of biological tests in vitro showed that the water-alcohol solutions of the claimed compounds (1a-b) have a pronounced acaricidal effect on various stages of development of Dermanyssus gallinae chicken ticks: larva, nymph, and imago, causing tissue changes at different stages of ticks, with the transition of one stage development in another is not noted. The inventive compounds were also tested on Hyalomma scupense ixodid ticks of cattle, it was shown that compounds (1b) and (1c) cause a delay in oviposition. 80% of cases, females die. It was shown that compound (1c) is superior in activity to the commercial juvenoid diflubenzuron.

The technical result of the invention are new compounds: 1- (3-methyl-butyloxy) -2,7-dimethylocta-2,7-diene, 1- (but-2-enyloxy) -2,7-dimethylocta-2,7-diene and 1- (3,7-dimethyl-octa-2,6-dienyloxy) -2,7-dimethylocta-2,7-diene, of the general formula 1, exhibiting high acaricidal activity, and a convenient method for their preparation from available raw materials, which consists in the allylation of the corresponding alcohols with quaternary terpenylammonium salts. The inventive method does not require the use of hazardous reagents, expensive catalysts and makes it easy to isolate the target products with standard techniques.

The inventive compounds in the form of water-alcohol solutions have a pronounced acaricidal effect against chicken ticks Dermanyssus gallinae and ixodid ticks of cattle Hyalomma scupense. The acaricidal activity of the claimed compound (1c) exceeds the activity of the well-known commercially available juvenoid drug diflubenzuron.

Thus, the claimed compounds can be used as acaricidal drugs in veterinary medicine for sarcoptoses and psoroptoses of domestic and farm animals.

Claims (2)

1. Compounds of the general formula

where R = CH ₃ (CH ₃ ) CHCH ₂ CH ₂ -,
R = CH ₃ CH = CHCH ₂ -,

with acaricidal activity. 2. The method of producing compounds according to claim 1, which consists in the interaction of the corresponding alcohols with quaternary terpenylammonium salts, such as N- (2,7-dimethyl-2,7-octadiene-1-yl) allyldiethylammonium bromide, N- (2, 7-dimethyl-2,7-octadien-1-yl) allylpiperidinium bromide and N- (2,7-dimethyl-2,7-octadien-1-yl) methyldiethylammonium iodide, in the presence of NaOH.