CS262469B1 - 5,9,13-trimethyl-4,6tetradecadien-3,13-diol,3-0-acyl-derivatives thereof and process for preparing them - Google Patents

Abstract

The ee solution addresses substance and high efficiency insect juvenile hormone 5,9,13- -trimethyl-4,6-tetradecadiene-3,13-diol and its 3-O-acyl derivatives of formula (CH 3) 2 COH- (CH 2) 3 -CH (CH 3) -CH 2 -CH-CH-C (CH 1 · · -CHOX-CH 2 CH 1 (I) wherein X-H or COR, wherein R represents a straight or branched chain and 1 to 25 carbon atoms. Preparation of the substance involves the condensation of acetylenic alcohol (CH 3) 2 COH- (CH) -CH (CH) -CH-CBCH from 1,1-dialkoxybutane 3-one CH 3 -CO-CH 2 -CH (O) 2, where lt is methyl or ethyl to form acetal (CH3) 2COH- (CH2> 3-CH (CH3) -CH2-C · ■ C-COH (CH 3 CH 2 -CH (O) 2) so that it is acetylenic the alcohol is converted by two equivalents an alkyl magnesium halide in a solvent to an organomagnesium compound to which it is is treated with 1,1-dialkoxybutan-3-one at temperatures of 0 to 100 ° C and in the obtained acetal and then reducing the triple bond to the double hydrogenation or reduction with complex hydrides, whereupon, under acidic hydrolysis of acetal dehydrates the olefinic acetal (ch3) 2coh- <ch2> 3-ch <ch3> -ch2-ch-ch-coh <ch3) - -CH (OR) 2 to form a dienic aldehyde (CH 3) 2 COH- (CH 2) 3 -CH (CH 3) -CH 2 -CH 3 CH-C 3 CH 3 - -CH-CHO and its action on excess ethnyl magnesium halide in the solvent is formed biologically active diol, with esterification the hydroxyl group at the 3-position with with an alkylating agent to a pyridine solution of the diol while cooling to room temperature.

Description

The subject of the invention is a substance with high efficacy of juvenile insect hormone and a method of its preparation.

Biological methods of combating synanthropic and agricultural pests, which would reduce or replace the problematic use of toxic pesticides, are increasingly at the forefront of basic and applied research. One of these directions is the use of substances with morphoregulatory effects, especially synthetic analogues of the juvenile hormone of insects, or juvenoids, which block developmental and reproductive mechanisms. The main disadvantages of the juvenoids used so far, such as methoprene or hydroprene, are the temporary effect and therefore the necessity of continuous application, low persistence in the insect body and the environment, low selectivity and finally frequent repellency when applied in food.

The described shortcomings are eliminated by the substance according to the invention, 5,9,13-trimethyl-4,6-tetradecadiene-3,13-diol and its 3-O-acyl derivatives, of the general formula (CH ₃ ) ₂ COH-(CH ₂ ) ₃ -CH(CH ₃ )-CH ₂ -CH«CH-C(CH ₃ )» CHOX-CH ₂ CB ₃ (I), where X «· H or COR, with R representing a straight or branched chain with 1 to 25 carbon atoms. The preparation of the substance according to the invention consists in the condensation of acetylenic alcohol (CH ₃ ) ₂ COH-(CH ₂ ) ₃ -CH(CH ₃ )-CH-C«CH sl,l-dialkoxybutan-3-one CH ₃ -CO-CH ₂ -CH(OR) ₂ , where R denotes methyl or ethyl, to form acetal (CHj) ₂ -COH-(CH ₂ > ₃ ~CH(CH ₃ )-CH ₂ -C»C-COH(CH ₃ )-CH ₂ )CH(OÉ) ₂ by converting the acetylenic alcohol with two equivalents of alkylmagnesium halide in a solvent, e.g. in ether or tetrahydrofuran, to an organomagnesium compound, which is treated with 1,1-dialkoxybutan-3-one at temperatures of 0 to 100 °C and in the obtained acetal the triple bond is then reduced to a double bond by hydrogenation or reduction with complex hydrides and at the same time the olefinic acetal (CH ₃ ) ₂ COH-(CH ₂ ) ₃ -CH(CH ₃ )-CH ₂ -CH-COH(CH ₃ )-CH(OIÍ) ₂ is dehydrated during acidic hydrolysis of the acetal groups to form the dienic aldehyde (CH ₃ ) ₂ COH-(CH ₂ ) ₃ -CH(CH ₃ )-CH ₂ -CH=CH-C(CH ₃ )“ “CH-CHO and its action on an excess of ethylmagnesium halide in a suitable solvent, e.g. in ether, the biologically active diol (I) is formed, whereby the esterification of the hydroxyl group at position 3 is carried out by the action of one equivalent of acyl halide on a pyridine solution of diol (I) while cooling to 20 °C.

The substance according to the invention has significantly higher effects on some insect species when applied topically and orally than previously known juvenoids. These effects consist in inducing developmental disorders in preimaginal stages, blocking the transformation into adults, partial to complete sterility of adults and increased mortality of all affected individuals. The result is a restriction of reproduction, gradual extinction and finally complete eradication of the relevant population of the target species. In contrast to previously used juvenoids such as hydroprene or methoprene, the substance according to the invention and their 3-O-acyl derivatives exhibit high persistence in the environment and in the body of insects, in which, depending on the physiological age of the individuals, a prolonged effect occurs to varying degrees. When the substance is ingested by the last larval instar, the effect, manifested by morphological abnormalities during the transformation into imago, is practically immediate. At younger developmental stages, the substance is incorporated into fat reserves upon ingestion and the active ingredient is later released during the mobilization of these reserves, upon completion of metamorphosis. The causes of this mechanism lie, among other things, in high polarity. Substances whose juvenilizing effects are activated by an additional reaction in the insect's body generally belong to the so-called juvenogens.

The importance of using the substance according to the invention lies in the possibilities of simple, health-free and economical application for the control of these pests, against which only poisonous pesticides have been applied so far. The substance is highly active against some species even in small doses and due to the not very demanding production ^- its use is also economically advantageous. The prolonged effect in the pest organism ensures the desired effect even with a single use. Another great advantage of the substance is that its presence in effective doses increases the olfactory and gustatory attractiveness of the bait for some groups of pests, e.g. Blattodea, and thus the percentage of lured and affected individuals increases. Depending on the choice of bait and the method of application, the effect of the substance can be focused exclusively against a single target species. The substance is non-toxic and without any other undesirable effects on warm-blooded organisms. Its use is therefore expedient especially in facilities with high health requirements.

The high biological effectiveness of the substance according to the invention has so far been demonstrated against the following pest species:

Blattodea: Blatta orientalis L., Periplaneta americana (L.) (Blattidae); Blattella germanica (L.) (Blattellidae), Nauphoeta cinerea (oliv.) (Blaberidae);

Orthoptera: Gryllulue domesticus (L.) (Gryllidae);

Hyiuenoptera: Monomorium pharaonis (L.) (Formicidae);

Coleopteras lenebrio molitor L., Tribolium confusum Duv., Tribolium castaneum Herbst (Tenebrionidae);

Lepidoptera Acrolepiopsis assectella (Zeller) (Acrolepiidae).

Among the many biological tests of the effectiveness of the substance according to the invention, we list the following.

A. Biological comparative test on the mealybug (Tenebrio molitor).

The substances being compared were applied topically in 1 µl acetone to the body of freshly formed pupae. The degree of morphological influence is expressed in units of ID ₅₀ and indicates the formation of 50% of adults.

Results table

Substance XD ₅₀ ()ug per individual) X 0.000 7 lauroyl diol 0.004 acetyl diol 0.001 Methoprene 0.01 Hydroprene 10.0

The test has shown that the substance according to the invention (I) is approximately 15 times more effective than Methoprene and 15,000 times more effective than Hydroprene on the tested species when applied topically. Its acetyl lauroyl derivatives are also demonstrably more effective than these substances.

A food mixture containing meat and bone meal, fish meal, wheat germ, soybean meal and dried yeast was impregnated with an acetone solution of the substance according to the invention so that after evaporation of the solvent its content was 1,000 ppm. Each time 30 female larvae of the 7th and 6th instar were reared on this diet for 14 days, after which normal food was given. Adult females were mated with untreated males. Malformations and fertility of these individuals and viability of the F^ generation were evaluated.

Results table

Treated instar % of larvoids % of adultoids % semiimag % image % sterile ^F 1 3rd instar 7. 73.4 26.6 100 0 6. - 6.7 53.3 40.0 83.3 0

Terminology:

larvoid = supernumerary larval instar with wing rudiments adultoid imago with larval genitalia and reduced wings semi-imago «= imago with definitive genitalia and partially deformed wings, sterile.

The test demonstrated that female larvae of the two last instars, exposed to a short-term effect of the substance according to the invention, were not capable of producing viable offspring. Individuals developed from affected 7th instar larvae were mostly morphologically deformed and sterile, some females developed from 6th instar larvae were without malformations and gave rise to the Fj generation, which, however, died out before reaching the 3rd instar.

C. Biological laboratory test on the storage blackthorn (Tribolium confusum).

Larsen's diet, i.e. wheat meal, powdered milk, yeast and oat flakes, was impregnated with an acetone solution of substance (I) or its lauryl ester so that the resulting dose was 0.1, 1, 10 or 100 ppm. 20 freshly hatched adults of the tested species were continuously reared on the treated diet. The ability to create 3 subsequent generations was monitored.

Results table

Substance Dose in ppm Complete generation development

I 100

0.1

Lauryl- 100 ester 10

0.1

Check 0 +

+ + + + + + + + + + + + + + + +

The test showed that the substance according to the invention and its lauryl ester at a dose of 100 ppm blocked the development of the next generation of the warehouse moth. At doses of 10 and 1 ppm, both substances prevented the formation of two more generations. The extremely high biological efficacy was thus proven even in a diet containing 1/10,000% of these substances.

D. Biological laboratory test on the garlic moth (Acrolepiopsis assectella).

An aqueous emulsion of the substance according to the invention and its lauryl ester was added to the food for cultivation of the tested species, consisting of corn meal, wheat germ, dry yeast and vitamins, in doses of 0.1 to 10 ppm. 4 to 50 larvae were reared on 5 ml of the diet thus treated. The degree of morphological influence and the ability of adults to reproduce were evaluated. The residual efficacy after 30 days was also tested.

Results table

Substance Residual time Minimum dose in ppm for 100% in days of sterility malformations

I 0 30 0.5 0.5 0.1 0.1 Lauryl- 0 1.0 0.5 ester 30 10.0 0.5

As the test showed, both substances caused 100% malformations, i.e. the formation of larvoids, at doses of 0.5 and 1 ppm respectively. Complete sterility occurred at doses of 0.1 and 0.5 ppm respectively. The introduction of larvae 30 days after diet treatment demonstrated almost unchanged residual efficacy of both substances.

E. Biological field test on the house fly (Blattella germanica) and the pharaoh ant (Monomorium pharaonis).

The substance according to the invention at a dose of 1,000 ppm in a granular bait mixture was applied to a bakery site with a high incidence of the above-mentioned pest species. The total amount of bait in 5 food chambers was 250 g. For 3 months, the occurrence status and effect of the substance were monitored by weekly trapping in 8 mechanical traps.

a) Blattella germanica.

The following criteria were evaluated:

1. Average of all individuals caught per trap and day.

2. Average images per trap per day.

3. Average of gravid females per trap per day.

4. % of 1st and 2nd instar larvae from the total larval population.

5. % of morphologically deformed females, i.e. larvoids to semiimags.

Results table

Criteria 0 before application Time after application in days 13 20 26 33 40 47 54 61 68 1. 20.5 15.4 13.5 13.3 7.8 10.7 7.2 3.6 3.0 2.5 2. 5.1 3.5 3.5 3.4 2.4 2.4 1.1 0.9 0.6 0.6 3. 2.7 1.2 1.3 0.9 0.6 0.6 0.2 0.2 0.08 0.06 4. 40.0 15.0 15.1 12.3 10.4 8.9 10.0 9.4 8.5 7.1 5. 0 39.9 38.2 41.5 47.3 50.0 47.9 63.6 71.0 76.8

Compared to the long-term average before application, the overall condition 68 days after application of the substance according to the invention decreased more than 8 times, of which the average of adults decreased by 8.5 times and of pregnant females by even 45 times.

The proportion of malformed females reached 76.8%, but the proportion of all sterile females was undoubtedly even higher. After 3 months, the population was reduced to the extent that occurrence outside the traps was not observed at the sites.

b) Monomorium pharaonis.

2 strong colonies were found at the site before application. Average captures before application: 300 to 350 workers, no sexual individual. Average captures 61 to 90 days after application: 3 to 5 workers, 2 to 3 females.

The disappearance of workers and the appearance of individual wandering females signal the collapse of the colony. After 3 months of application, no individual was detected.

The use of the substance according to the invention therefore caused a significant suppression of the originally significant occurrence of both species within 2 to 3 months and demonstrated the high effectiveness of the substance in field conditions.

Example

Preparation of 5,9,13-trimethyl-4,6-tetradecadiene-3,13-diol (I).

A solution of 6-methyl-5-heptene and 29 g of magnesium in 1,000 ml of ether is prepared. This solution is added to a mixture of methoxyallene in an amount of 70 g and 2 g of copper bromide in 200 ml of ether with vigorous stirring and cooling to -5 to +5 °C. The cooling bath is then removed and the mixture is stirred for another 45 min, poured into an ice mixture and, after the precipitate has dissolved, 4 M hydrochloric acid is added until the layers are separated. The organic layer is washed with dilute ammonia and dried. After distilling off the ether through a column, the reaction product is purified by distillation in vacuum. The fraction at 70 °C at 1.6 KPa is collected, yield 120 g, i.e. 80%. 4,8-dimethyl-7-nonen-1-yne (II) is obtained, of the general formula (CHj) ₂ C“CH~(CHj) ₃ ^- CH(ch ₃ )-ch ₂ -c«ch.

A mixture of 120 g of intermediate (II) and 180 g of 99% formic acid is stirred for 20 h at room temperature. The reaction mixture is then poured into 1,000 ml of water and the resulting 4,7-dimethyl-1-nonine formate is extracted with petroleum ether. The extract is washed with dilute ammonia, dried and concentrated. The residue is dissolved in 200 ml of ethanol and 60 g of sodium hydroxide are added to the solution in portions while stirring. The mixture is stirred for another hour and then diluted with 600 ml of water. The hydrolysis product is extracted with petroleum ether, the extract is dried, concentrated and purified by distillation through a column. The resulting intermediate is 4,8-dimethyl-1-nonin-8-ol (III), general formula <CH ₃ > ₂ COH-(CH ₂ ) ₃ -CH(CH ₃ )-CH ₂ -C«CH.

In a flask equipped with a stirrer, reflux condenser and separating funnel, a solution of butylmagnesium chloride in 1,300 ml of ether is prepared from 133 g of butyl chloride and 31 g of magnesium. 107 g of acetylenic alcohol (III) is added dropwise to the butylmagnesium chloride solution while stirring and the mixture is left at room temperature overnight. Then 86 g of 1,1-dimethoxybutan-3-one is added dropwise to the reaction mixture, left at room temperature for 1h and then decomposed by dropping 1,000 ml of saturated ammonium chloride solution. The organic layer is separated, dried and concentrated. 195 g of an evaporator containing 90% of 1,1-dimethoxy-3,7,11-trimethyl-4-dodecyne-3,11-diol (IV), obc. formula (CHj)jCOH-(CHj)jCHICHj)CH ₂ -CC-COH(CHj)-CHj-CH(OCH ₃ ) ₂ .

To a solution of 5 g of nickel acetate in 500 ml of ethanol, 0.8 g of sodium borohydride dissolved in 5 ml of water is added in a hydrogenation apparatus, after 10 min 5 ml of ethylenediamine and then acetal (IV). After the consumption of the theoretical amount, i.e. 14.3 l of hydrogen, the hydrogenation mixture is filtered through diatomaceous earth and concentrated. After adding 500 ml of water, the hydrogenation product 1,1-dimethoxy-3,7,11-trimethyl-4-dodecene-3,11-diol (V) of the general formula (CH ₃ )COH(CH ₂ ) ₃ ~ CH(CH ₃ -CH ₂ -CH»CH-COH(CH ₃ )-CH ₂ CH(OCH ₃ ) ₂ , is extracted from the residue with petroleum ether. The extract is dried and concentrated.

The diacetal (V) from the previous step is added to 400 ml of 60% acetic acid and the mixture is heated for 1 h at 80 °C. The hydrolysis associated with dehydration is monitored by chromatography on Silufol in the toluene-ethyl acetate 8:2 system, detection is carried out with an aqueous solution of potassium permanganate. The starting acetal Rj, 0.30 is converted after hydrolysis and dehydration to an aldehyde Rj, 0.57. After cooling the reaction mixture and diluting with 400 ml of water, the reaction product is extracted with petroleum ether. The extract is washed with an aqueous solution of sodium hydrogen carbonate, dried and concentrated. 136 g of the residue of 3,7,11-trimethyl-2,4-dodecadlen-1-al-11-ol (VI), obc. formula (CH ₃ ) ₂ COH-(CH ₂ ) ₃ ~CH(CH ₃ )-CH ₂ -CH-CH-C(CH ₃ )«CH-CHO.

Aldehyde (VI) in an amount of 136 g is dissolved in 250 ml of ether and the solution is added dropwise with stirring to a 1 M solution of ethylmagnesium bromide in 1,200 ml of ether. After the addition of the aldehyde, the reaction mixture is stirred for another 10 min and then decomposed with 1,000 ml of saturated ammonium chloride solution. The ether layer is separated, dried and concentrated. 152 g of the resulting substance 5,9,13-trimethyl-4,6-tetradecadiene-3,13-diol (I) is obtained, general formula (CHj) ₂ COH-(CH ₂ ) ₃ -CH(CH ₃ )-CH ₂ -CH«CH-C(CH ₃ >= «ch-choh-ch ₂ ch ₃ .

For analysis, the product was purified by chromatography on silica gel in the system toluene-ethyl acetate 7:3 (TLC on Silufol R _f 0.20, detection by spraying 10% HjSO^ and heating to 80 °C; the product develops red-violet). For (268.43) calculated: 76.06 % C, 12.02 % H, found:

76.40% C and 12.10% H.

Example 2

Preparation of 3-0-lauroyl-5,9,13-trimethyl-4,6-tetradecadiene-3,13-diol.

X 20 ml of pyridine are added 2.2 g of lauroyl chloride and after cooling to 20 °C a solution of 2.7 g of 5,9,13-trimethyl-4,6-tetradecadiene-3,13-diol in 5 ml of pyridine is added to the mixture. The mixture is stirred for 12 h at room temperature. Then the solution is poured into water and the product is extracted with ether. The extract is washed with water, dried and concentrated.

For analysis, the product was purified by chromatography on silica gel in the toluene-ethyl acetate system 9:1 (TLC on Silufol Rj 0.30, detection H ₂ SO ₄ >. For C ₂₉ H ₅₄ O ₃ (450.75) calculated: 77.27% C, 12.08% H, found: 77.55% C, 12.30% H.

Example 3

Preparation of 3-O-acetyl-5,9,13-trimethyl-4,6-tetradecadiene-3,13-diol.

To a solution of 2.7 g of 5,9,13-trimethyl-4,6-tetradecadiene-3,13-diol in 25 ml of pyridine, 5 ml of acetic anhydride are added and the mixture is left for 12 h at room temperature. The mixture is then poured into water and the product is extracted with diethyl ether. The extract is washed with water, dried and concentrated.

For analysis, the product was purified by chromatography on silica gel in the toluene-ethyl acetate system 9:1 (TLC on Silufol Rf 0.25, detection H ₂ SO ₄ ). For ^c i9 ^H 34°3 (310.46) calculated: 73.50 6 C, 11.50 « H, found: 73.30 « Ca 11.50 « H.

Claims (2)

OBJECT OF THE INVENTION 1. 5,9,13-trimethyl-4,6-tetradecadiene-3,13-diol and its 3-O-acyl derivatives, of general formula (i) (ch ₃ ) ₂ coh- (ch ₂ ) ₃ -ch (ch ₃ ) -ch ₂ -ch = ch-c (ch ₃ ) -chox-ch ₂ ch ₃ (ch ₃ ) ₂ coh- (ch ₂ ) ₃ -ch (CH ₃ ) -CH ₂ -CH ₂ CH-C ( CH ₃ ) CHCHOX-CH ₂ CH ₃ (I) wherein X H H or COR, where R is a straight or branched chain of 1 to 25 carbon atoms, A process for the preparation of the compound (I) according to claim 1, characterized in that the acetylenic alcohol (CH ₃ ) ₂ COH- (CH ₃ ) ₃ -CH (CH ₃ ) -CH-C ^B CH is condensed with 1,1-dialkoxybutane-3 -on CH ₂ -CO-CH ₃ -CH (CH ₃ ) ₂ , where R is methyl or ethyl, to give (CH ₃ ) ₂ COH- (CH ₂ , ₃ -CH (CH ₃ ) -CH ₂ -C 2C-) acetal acetal COH (CH ₃ ) -CH ₂ -CH (OR *) ₂ by converting the acetylenic alcohol with two equivalents of an alkylmagnesium halide in a solvent to an organomagnesium compound treated with 1,1-dialkoxybutan-3-one at temperatures of 0 to 100 ° C, and in the obtained acetal, the triple bond to the double hydrogenation or reduction with complex hydrides is then reduced, and the olefinic acetal (CH ₃ ) ₃ --CH (CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -CH = is dehydrated upon acid hydrolysis of the acetal groups. CH-COH (CH ₃ ) -CH (Ol ₂ ) ₂ to form the diene-aldehyde (CH ₃ ) ₂ COH- (CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -CH ₂ CH-C (CH ₃ ) = CH -CHO and its action on the excess of ethylmagnesium halide in the solvent produces biologically active diol (I), wherein the esterification of the hydroxyl group in position 3 is optionally carried out with an alkylating agent to a pyridine solution of the diol (I) is added at room temperature.