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

SUMMARY OF THE INVENTION The present invention provides a substance having high activity of juvenile insect hormone and a process for its preparation.

Biological methods of combating synanthropic and agricultural pests that 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 application of substances with morforegulatory effects, especially synthetic analogues of juvenile hormone insects or juvenoids, blocking developmental and reproductive mechanisms. The main drawbacks of hitherto applied juvenoids, such as methoprene or hydroprene, are the temporality of action and hence the necessity of continuous application, low persistence in the insect body and environment, low selectivity and, finally, frequent repellency in food application.

The above-mentioned deficiencies are eliminated by the compound 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 ₂ CH-C (CH ₃ ) ₃ CHOX-CH ₂ CB ₃ (I) wherein X 1 · H or COR, wherein R represents a straight or branched chain of 1 to 25 carbon atoms. The preparation of the compound according to the invention consists in condensation of the acetylenic alcohol (CH ₃ ) ₂ COH- (CH ₂ ) ₃ -CH (CH ₃ ) -CH-C 1 CH 1, 1-dialkoxybutan-3-one CH ₃ -CO-CH ₂ - CH (OH) ₂ , where R is methyl or ethyl, to give (CH3) ₂ -COH- (CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -C »C-COH (CH ₃ ) -CH ₂ acetal CH (OE) ₂ by converting the acetylenic alcohol with two equivalents of an alkylmagnesium halide in a solvent such as ether or tetrahydrofuran to an organomagnesium compound that is 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 at the same time the olefinic acetal (CH ₃ ) ₂ COH- (CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -CH is dehydrated in acid hydrolysis of acetal groups -CH-COH (CH ₃ ) -CH (CH ₂ ) ₂ 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 treatment of excess ethylmagnesium halide in the appropriate the solvent, e.g. in ether, forms the biologically active diol (I), wherein the esterification of the hydroxyl group at the 3-position is accomplished by treating one pyridine solution of the diol (I) with one equivalent of acyl halide while cooling to 20 ° C.

The substance of the invention, when administered topically and orally, has significantly higher effects on some insect species than the known juvenoids. These effects consist in inducing developmental disorders in the pre-vaginal stages, blocking adult conversion, partial to complete adult sterility, and increased mortality in all affected individuals. This results in reduced reproduction, gradual extinction and finally complete eradication of the relevant target species population. In contrast to the hitherto applied juvenoids, such as hydroprene or methoprene, the substance according to the invention and its 3-O-acyl derivatives have a high persistence both in the environment and in the insect body, which, depending on the physiological age of the individuals, protahovanému effect. When the substance is ingested by the last larval instar, the effect manifested by morphological abnormalities in the conversion to imago is practically immediate. In the younger developmental stages, upon incorporation, the substance is incorporated into the fat stores, and later release of the active ingredient at the time of mobilization of these stores, upon completion of metamorphesis. The causes of this mechanism are, among others, in high polarity. Substances whose juvenilizing effects are activated by an additional reaction in the insect body are generally among the so-called juvenogens.

The importance of the use of the substance according to the invention lies in the possibilities of simple, health-free and economical application for controlling these pests, to which only toxic pesticides have been applied so far. The substance is highly active with respect to some species even in low doses and due to its not very demanding production ^- its use is also economically advantageous. The protracted effect in the organism of the pest ensures the desired effect even after single use. A further great advantage of the substance is that its presence in effective doses increases the olfactory and gustatoric attractiveness of the bait for some groups of pests, such as Blattodea, thereby increasing the percentage of attracted and affected individuals. Depending on the choice of bait and method of application, the scope of the substance can be targeted exclusively against a single target species. The substance is non-toxic and without any other adverse effects on warm-blooded organisms. Its use is therefore particularly useful in buildings with high health requirements.

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

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

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

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

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

Lepidopteras Acrolepiopsis assectella (Zeller) (Acrolepiidae).

Among the many biological assays of the efficacy of a compound of the invention, the following is disclosed.

A. Biological Comparative Test on Tenebrio molitor.

The compounds to be compared were applied topically in 1 [mu] l 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% ad.ultoids.

Table of results

Substance XD ₅₀ () ug per individual) X 0,000 7 lauroyl diol 0.004 acetyl-diol 0.001 Methopren 0.01 Hydropren 10.0

The test has shown that the compound of the invention (I) is approximately 15 times more potent than Methopren and 15,000 times more potent than Hydropren for topical application to the test species. Its acetyla lauroyl derivatives are also significantly more potent than these substances.

The feed mixture containing meat and bone meal, wheat germ, soy flour and dried yeast was impregnated with an acetone solution of the compound of the invention so that after evaporation of the solvent its content was 1000 ppm. Each of 30 female 7th and 6th instar larvae was kept on this diet for 14 days, after which normal food was given. Adult females were mated with untreated males. Malformations and fertility of these subjects and viability of the F ^ generation were evaluated.

Table of results

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

Terminology:

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

The test showed that female larvae of the two last instars exposed to the short term exposure of the compound of the invention were not capable of producing viable offspring. Individuals developed from affected 7th instar larvae were mostly morphologically deformed and sterile; malformnlch changes and gave birth to the Fj generation, but which died out before reaching the 3rd instar.

C. Biological laboratory test on darkling beetle (Tribolium confusum).

Larsen diet, ie wheat meal, milk powder, yeast and oats. flakes were impregnated with acetone solution of substance (I), respectively. its lauryl ester such that the resulting dose is 0.1, 1, 10 and 10, respectively. 100 ppm. Twenty individuals of newly hatched adults of the test species were kept on a treated diet on a permanent basis. The ability to create 3 successive generations was studied.

Table of results

Substance Dose in ppm Complete development of the generation

I 100

0.1

Lauryl- · 100 ester 10

0.1

Check 0 +

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

The test has shown that the compound of the invention and its lauryl ester at a dose of 100 ppm block the development of a subsequent generation of darkling. At doses of 10 and 1 ppm, both substances prevent the formation of the next two generations. Thus, an extremely high biological activity has been proven in a diet containing 1 / 10,000% of these substances.

D. Biological laboratory test on garlic minor (Acrolepiopsis assectella).

A water emulsion of the compound of the invention and its lauryl ester at doses of 0.1 to 10 ppm was added to the feed for cultivation of the test species, consisting of corn meal, wheat germ, dry yeast and vitamins. Four to fifty larvae were bred per 5 ml of the treated diet. The degree of morphological influence and the ability to reproduce adults were evaluated. Residual efficacy after 30 days was also tested.

Table of results

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

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

As shown by the test, both substances caused 100% malformations, i.e., larvoids, at doses of 0.5; 1 ppm. Complete sterility occurred already at the dose of 0.1 resp. 0.5 ppm. The introduction of larvae 30 days after diet treatment showed almost unchanged residual efficacy of both substances.

E. Biological field test on domestic russia (Blattella germanica) and pharaoh ants (Monomorium pharaonis).

The substance according to the invention at a dose of 1000 ppm in the granular bait mixture was applied at the site of a bakery plant with a high incidence of these pests. The total amount of bait in 5 food chambers was 250 g. For 3 months, the state of occurrence and effect of the substance was monitored by weekly capture into 8 mechanical traps.

(a) Blattella germanica.

The following criteria were evaluated:

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

2. Average imag per trap and day.

3. Average of pregnant females per catcher and day.

4.% of 1st and 2nd instar larvae of total larvae.

5.% of morphologically deformed females, ie larvoids to semiimag.

Table of results

Criterion 0 before application Time after application in days 13 20 May 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 mean before administration, the overall state 68 days after administration of the compound of the invention decreased more than 8x, of which the average of adults 8.5x and pregnant females even 45x.

Malformal females reached 76.8%, but the proportion of all sterile females was undoubtedly even higher. The population was reduced after 3 months to the extent that the occurrence outside the trap was not observed in the habitats.

(b) Monomorium pharaonis.

Two strong colonies were found at the site before application. Mean catches before application: 300 to 350 workers, no sex. Average catches 61 to 90 days after application: 3 to 5 female workers, 2 to 3 females.

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

The application of the substance according to the invention thus caused a significant suppression of the initially significant occurrence of both species within 2 to 3 months and showed a high efficiency of the substance under field conditions.

He did

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

A solution of 6-methyl-5-hepten-2-yl-magnesium bromide was prepared from 189 g of 6-methyl-2-bromo-5-heptene and 29 g of magnesium in 1000 ml of ether. This solution was added to a mixture of 70 g and 2 g of copper (I) bromide in 200 ml of ether, with vigorous stirring and cooling to -5 to +5 ° C. The cooling bath was then removed and the mixture stirred for a further 45 min, poured into ice and, after the precipitate had dissolved, 4 M hydrochloric acid was added until the layers were separated. The organic layer was washed with dilute ammonia and dried. After distilling off the ether through the column, the reaction product was purified by distillation in vacuo. The fraction at 70 ° C was collected at 1.6 KPa, yield 120 g, i.e. 80%. There was obtained 4,8-dimethyl-7-nonen-1-yne (II), municipality. Formula (CH) ₂ C '~ CH (CH) ₃ ^- CH (CH ₃₎ -CH ₂ -C "ch.

A mixture of 120 g of intermediate (II) and 180 g of 99% formic acid was stirred at room temperature for 20 h. The reaction mixture was then poured into 1000 ml of water and the resulting 4,7-dimethyl-1-nonine formate was extracted with petroleum ether. The extract was washed with dilute ammonia, dried and concentrated. The residue is dissolved in 200 ml of ethanol and 60 g of sodium hydroxide are added portionwise with stirring. The mixture was stirred for an additional 1h 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), municipality. of formula <CH ₃ > ₂ COH- (CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -C -CCH.

In a flask equipped with a stirrer, a reflux condenser and a separating funnel, a solution of butyl magnesium chloride in 1,300 ml of ether was prepared from 133 g of butyl chloride and 31 g of magnesium. X of the butylmagnesium chloride solution is added dropwise with stirring to 107 g of acetylenic alcohol (III) and the mixture is left at room temperature overnight. Then 86 g of 1,1-dimethoxybutan-3-one are added dropwise to the reaction mixture, left at room temperature and then quenched by the dropwise addition of 1000 ml of saturated ammonium chloride solution. The organic layer was separated, dried and concentrated. There was obtained 195 g of a residue containing 90% of 1,1-dimethoxy-3,7,11-trimethyl-4-dodecin-3,11-diol (IV), municipality. Formula (CH) jCOH- (CH) jCHICHj) -CO-CH ₂ COH (CH) -CH-CH _{(OCH3) second}

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 the hydrogenation apparatus, after 10 min, 5 ml of ethylenediamine and then acetal (IV). After uptake of the theoretical amount of 14.3 L of hydrogen, the hydrogenation mixture was filtered through diatomaceous earth and concentrated. The hydrogenation product of 1,1-dimethoxy-3,7,11-trimethyl-4-dodecene-3,11-diol (V), municipality, was extracted from the residue after addition of 500 ml of water. of formula (CH ₃ ) COH (CH ₂ ) ₃ -CH (CH ₃ -CH ₂ -CH ₂ CH-COH (CH ₃ ) -CH ₂ CH (OCH ₃ ) ₂ , with petroleum ether, and the extract was dried and concentrated.

Diacetal (V) from the previous step was added to 400 mL of 60% acetic acid and the mixture was heated at 80 ° C for 1 h. The hydrolysis associated with dehydration is monitored by chromatography on Silufol in toluene / ethyl acetate 8: 2, detection is carried out with aqueous potassium permanganate solution. The starting acetal R1, 0.30 is converted to the aldehyde 0.57 after hydrolysis and dehydration. After cooling the reaction mixture and diluting with 400 ml of water, the reaction product is extracted with petroleum ether. The extract was washed with aqueous sodium bicarbonate solution, dried and concentrated. 136 g of a residue of 3,7,11-trimethyl-2,4-dodecadlen-1-al-11-ol (VI), m.p. of formula (CH ₃ ) ₂ COH- (CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -CH-CH-C (CH ₃ ) n CH-CHO.

136 g of aldehyde (VI) are dissolved in 250 ml of ether and the solution is added dropwise with stirring to a 1 M solution of ethylmagnesium bromide in 1200 ml of ether. After addition of the aldehyde, the reaction mixture was stirred for 10 min and then quenched with 1000 mL of saturated ammonium chloride solution. The ether layer was separated, dried and concentrated. 152 g of the residue of the title compound 5,9,13-trimethyl-4,6-tetradecadiene-3,13-diol (I), m.p. of formula (CH ₃ ) ₂ COH- (CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -CH ₂ CH-C (CH ₃ ) = ch-choh-ch ₂ ch ₃ .

For analysis the product was purified by chromatography on silica gel using toluene-ethyl acetate 7: 3 (TLC on Silufol _Rf 0.20 detected by spraying with 10% HjSO ^ and heating to 80 ° C; product develops often purple). Pro (268.43) calculated: 76.06% C, 12.02% H, found:

76.40% C and 12.10% H.

Example 2

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

X 20 ml of pyridine was added with 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 was added to the mixture. . The mixture was stirred at room temperature for 12 h. The solution was poured into water and the product was extracted with ether. The extract was washed with water, dried and concentrated.

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

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 is added 5 ml of acetic anhydride and the mixture is left at room temperature for 12 hours. The mixture was poured into water and the product was extracted with diethyl ether. The extract was washed with water, dried! and thicken.

For analysis, the product was purified by eilica gel chromatography in toluene-ethyl acetate 9: 1 (TLC on Silufol Rf 0.25, detection of H ₂ SO ₄ ). For ^C 19 ^H 34 ° 3 (310.46) calculated: 73.50 6 C, 11.50 H H, found: 73.30 Ca Ca 11.50 H. 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.