CS268295B1

CS268295B1 - Oxime ether derivatives having insect development regulators and a process for their production

Info

Publication number: CS268295B1
Application number: CS876005A
Authority: CS
Inventors: Zdenek Ing Csc Wimmer; Miroslav Ing Drsc Romanuk; Frantisek Rndr Csc Sehnal; Jelena Prom Biol Kuldova; Ivan Doc Rndr Drsc Hrdy
Original assignee: Zdenek Ing Csc Wimmer; Romanuk Miroslav; Frantisek Rndr Csc Sehnal; Jelena Prom Biol Kuldova; Ivan Doc Rndr Drsc Hrdy
Priority date: 1987-08-14
Filing date: 1987-08-14
Publication date: 1990-03-14
Also published as: CS600587A1

Abstract

Nová látky, která jsou předmčtem tohoto řeíení mají obecný vzorec I, ve kterám y je celá číslo v hodnot? jedna nebo dvá, Z znamená kyslík, hydroxylovou skupinu, přičemž druhá vazba nese vodík nebo skupinu obecnáho vzorce -0-/01^/ -0-, ve kterám n je celá číslo v hodnotí dvč nebo tři, R znamená skupinu obecnáho vzorce -/CH,/m-O-N=CH R^, ve kterám m je celá číslo v hodnot? jedna až tři a Rj značí alkyl s počtem uhlíků jedna až p?t, 2-pyridyl, fenyl, 2-chinolyl nebo 1-isochinolyl, A značí vodík, methyl, ethyl hydroxylovou skupinu, skupinu OCOCHj nebo tetrahydropyrenyloxy skupinu. Jsou užitečná jako juvenogeny proti hmyzu, například proti zavíječi voskovámu-Galleria raellonella.The new substances which are the subject of this solution have the general formula I, in which y is an integer of one or two, Z represents oxygen, a hydroxyl group, the second bond carrying hydrogen or a group of the general formula -O-/O1^/ -O-, in which n is an integer of two or three, R represents a group of the general formula -/CH,/m-O-N=CH R^, in which m is an integer of one to three and Rj represents an alkyl with a number of carbons one to five, 2-pyridyl, phenyl, 2-quinolyl or 1-isoquinolyl, A represents hydrogen, methyl, ethyl hydroxyl group, OCOCHj group or tetrahydropyrenyloxy group. They are useful as juvenogens against insects, for example against the wax moth -Galleria raellonella.

Description

Preferred embodiments of the present invention are oxime ether derivatives having insect development regulators and a process for their production. These are substances that mimic the effect of insect juvenile hormone. At present, a large number of such substances are known, also known as juenoids / K. Sláma et al .: Insect Hormones and Bioanalogues, Springer Verlag, Vien - Nev York1974; or LI Gilbert et al: The Juvenile Hormones, Plenum Press, Nev York 1976 /. A common feature of the action of juvenoids, by chemical means of otherwise very different compounds, is the emergence of developmental disorders in insects, leading ultimately to extinction or to strong suppression of the population of harmful insects. Their advantage is the relative high specificity of activity on some insect species at very low vertebrate toxicity and broad spectrumbiological activity, which includes sierilizing and ovicidal effects, lagging disorders of developmental cycles. The substances of the present invention are of the new structural type, referred to by the known intermediate (AO 195530, 206421 and 243567 and PV 5546-86). These substances broaden the structural spectrum of substances with the effect of insect development regulators on another type of previously unknown derivatives. They are characterized by higher activity compared to commercially available American hydropren / ZR 512 / and methoprene / ZR 515 / preparations for certain insect species at a higher selectivity, including their potential economic benefit. The object of the invention are oxime ether derivatives having the effect of controlling the development of insects of the general formula I,

wherein y is an integer of one or two, Z is an oxygen, a hydroxyl group, the remaining bond being attached to a hydrogen atom or a group of formula -0- / 01 ^ / η-θ-, wherein n is an integer in two or three, R is a group of the formula - (CH 2 -O-NmCH-R p) in which m is an integer of one to three and R 4 is an alkyl having one carbon atom, 2-pyridyl, phenyl, 2-quinolyl or 1-isoquinolyl, A represents hydrogen, methyl, ethyl, hydroxyl, OCOCH3 or a group of formula.

In a known process, the starting intermediate II / AO No. 206421 is first prepared. The principle of the present invention is that the ketophenol of the formula II

(11) wherein A and Y are as defined above are reacted

with a compound of formula III

X- / CH24-X

wherein m is as defined above and X is bromo, compounds of formula IV

chlorine or (V) (111) p-toluenesulfonyloxy group to give (IV) wherein A, y, m and X are as defined above, which reaction with a compound of formula VHO-N = CH-R 1 / V / wherein R 1 is meaningful The above gives the final product of formula I. The following are examples which illustrate the invention without limiting it in any way. Example 1 Preparation of 2- [4- (2-O-ethylpropanaldoxime) oxybenzyl-1-cyclohexanone] (1, A = II, Z = 0, y = 2, m = 2, ii1 = ch2cii3) a) To a mixture of 2- (4-hydroxybenzyl) -1-cyclohexanone (3 g), water (20 ml) and 1,2-dibromoethane (3.32 g) was added a solution of 0.56 g of sodium hydroxide in water (3 g). 8 ml) and the reaction mixture was heated to the boiling point of the solvent for 6 hours. After cooling, the product was extracted into ether (3 X 40 mL) and the crude residue was purified by column chromatography to dry and evaporate the solvent. The yields were 1.25 g (33%) of 2- (4- (2-bromoethoxy) benzyl) -1-cyclohexanone, IR: 1712, 1243 cm -1, mp 68-71 ° C. b / To a solution of propanaldoxime (0.14 g / in DMFA / 5 mL) was added sodium hydride / 0.1 g of a 50% dispersion in oil with stirring and cooling to 0 ° C. At this temperature, the reaction mixture was stirred for 1 h and then a solution of 2- (4- (2-bromoethoxy) benzyl) -1-cyclohexanone (0.5 g) in DMFA (5 mL) was added. The reaction mixture was cooled to 0 ° C, diluted with ethyl acetate (20 mL) and washed with water (5 mL), 5% hydrochloric acid (5 mL) and water until neutral. Column chromatography of the crude residue resulted in separation of the two syn and anti-isomers of oxime ether to give 154 mg / 32 / / syn-a of 136.7 mg / 28 / / anti-2- / 4- (2-O-ethylpropanaldoxime). mp 47-50 ° C, Syn-isomer: 1732, 1713, 1251, 958 cm -1, n-isomer: 1714, 1634, 1249, 948 cm -1. Example 2 Preparation of syn-2- / 4- (2-O-ethylpropanaldoxime) oxybenzyl-1-cyclohexanol / 1, A = H, Z = OH, II y = 2, m = 2, U 1 = CH 2 CH 3 / 2- (4- (2-O-ethylpropanaldoxime) oxybenzyl) -1-cyclohexanone (0.42 g) in methanol (20 mL) was added sodium borohydride (0.23 g) in one portion and the reaction mixture was stirred at 0 ° C. After 1 h, the methanol was evaporated under reduced pressure, the residue was diluted with saturated brine (20 ml) and extracted into ether. After drying and evaporation of the solvent, the residue was chromatographed on silica gel. 201.6 mg (48) of cis-syn- and 167.5 mg of trans-syn-2- (4- (2-O-ethylpropanaldoxime) oxybenzyl) -1-cyclohexanol were obtained. Cis-syn isomer: IR spectrum: 3628, 1248, 1081,958, 889 cm @ -1 trans-syn-isomer: IR spectrum: 3625, 1249, 1070, 958, 889 cm @ -1. . Example 3 Preparation of 2- [4- (2-O-ethylpropnano-oxime) oxybenzyl] -1-cyclohexanone ethylene acetal (1), A = H, Z = -OCl 2 CH 2 O-, y = 2, m = 2, R 1 = CH, CH 2 / a) To a mixture of 2- (4-hydroxybenzyl) -1-cyclohexanone ethylene acetal (1.5 g), water (8 ml) and 1,2-dibromomethane (1.35 g) was added sodium hydroxide solution (0.23). g / v (1.6 ml). The reaction mixture was heated to boiling solvent with stirring for 4 h. After cooling, the product was extracted into ether (3 x 40 mL). After drying and evaporating the solvent, the residue was purified by column chromatography to give 0.54 g (26) of 5 '[2- (4- (2-O-bromoethoxy) -benzyl] -1-cyclohexanone-ethylene-acetal. IR: 1242, 1158, 1100, 1089, 926 cm @ -1; mp 88-88.5 DEG C .; b) To a solution of propanaldoxime (0.098 g) in DMFA (4 mL) was added sodium hydride (0.07 g of 50% disodium in oil) with stirring and cooling to 0 ° C. At this temperature, the reaction mixture was stirred for 1 h. A solution of 2- (4- (2-O-bromoethoxy) benzyl) -1-cyclohexanone-ethylene acetal (0.4 g) in DMFA (4 mL) was then added and the reaction mixture was stirred at rt. After cooling to 0 ° C, the reaction mixture was diluted with ethyl acetate (20 mL) and washed sequentially with water (4 mL), 5 mL of hydrochloric acid (4 mL) and water until neutral. After drying and evaporation of the solvent, the two syn- and natioisomers formed were separated by column chromatography. 104.6 mg / 27 / / syn- and 73.3 mg / 19 / / anti-2- / 4- (2-O-ethylpropanaldoxime / oxybenzyl) -1-cyclohexane-268,295 B1-was obtained.

In the method described in Example 1, from 0.5 g of 2- / 4- (2-bromoethoxybenzyl) -1-cyclohexanone was obtained 335 mg / 60% of syn-2- [4- (2-O-ethyl) pyridine-2]. carboxaldehyde oxime oxycarbonyl} -1-cyclohexanone. IR: 1713, 1613, 1587, 1569, 1515, 1514, 1251 cm -1 53-55 ° C, Example 5 Preparation of syn-2- [4- (2-O-ethyl-pyridine-2-carboxalohydroxime) oxybenzy] 1j-1-cyclohexanol / 1, A = H, Z = 0, 1, Y = 2, m = 2, R 1 = /

473 mg / 36 ¢ / cis-syn was obtained from 1.3 g of syn-2- | 4- (2-O-ethyl) pyridine-2-carboxaldehyde oxime oxybenzyl-1-cyclohexanone as described in Example 2 and 331.5 mg (25%) of trans-syn-2- [4- (2-O-ethyl) pyridine-2-carboxaldehyde oxime] oxybenzyl-1-cyclohexanol. C 18 -isomer: IR: 3630, 1080, 977, 951, 862 trans-isomer: IR: 3625, 1035, 951, 86: cm -1, mp 89-91 ° C.

Acetyl-4- (2-O-ethyl) -pyridine-2-carboxaldehyde oxime oxybenzyl-1-cyclohexanone-ethylene acetal, 190 mg / 34 cm @ 3 / w / w, IR spectrum: 949, 850 cm @ -1 106 ° C. ' EXAMPLE 7 Preparation of 4-acetoxy-2- [4- (O-methylbutanaldoxime) oxybenzyl] -1-cyclohexanone (1), A = OCOC10, Z = 0, y = 2, m = 1, RJ = - (CH 2 CH 2). j /

By the method described in Example 1, from 0.5 g of 4-acetoxy-2- [4- (O-bromomethoxy) benzyl] -1-cyclohexanone, 200 mg / 40% / syn- and 190 mg / 35 µg / anti were obtained. Example 4-Acetoxy-2- [4- (O-methylbutanal-doxime) -oxybenzyl] -1-cyclohexanone, Syn-isomer: IR Spectrum: 958 cm -1 8 Preparation of syn-4-tetrahydropyranloxy-2- [4- (3-propylbenzaldehyde oxime) oxybenzyl] -1-cyclopentane / 1, A = THP-O-, Z = 0, y = 1, m = 3, R i = C ^ /

In the method described in Example 1, from 0.5 g was 4-tetrahydropyranyloxy-2- (4- [3-O-bromo-propoxy] -bromo)

/ 1, A = CH 3, Z = 0, y = 1, m = 2, R 4 = C 1 - N /

180 mg / 35 µl / son of lopentanone was obtained by the method described in Example 1 from 0.5 g of 4-methyl-2- (4- (2-O-bromoethoxy) benzyl-1-cyclopropyl-4,268,295 B1) -4-methyl-2- [4- (2-O-ethyl) quinoline-2-carboxaldehyde-oxa-oxybenzyl] -1-cyclopentanone. IR spectrum: 1715, 1589, 1249, 861 cm Example 10 Preparation of syn-4-hydroxy-2- [4- (2-O-ethyl-1-isoquinoline-1-carboxaldehyde oxime) oxybenzyl] -1-cyclopentanone / 1, A = OH, Z = O, y = 1, m = 2, R ^ Cglt ^ N- /

120 mg / 25 µl / syn-4-hydroxy-2- was obtained as described in Example 1 from 0.5 g of 4-hydroxy-2- (4- (2-O-bromoethoxy) benzyl) -1-cyclopentanone. β- (2-O-ethyl) isoquinoline-1-carboxaldehyde oxime oxybenzyl-1-cyclopentanone. IR spectrum: 1716, 1614, 1250, 862 cm @ -1.

Method of testing prepared substances

The tests are based on the n-morphogenetic of juvenoids, which manifests itself as an inhibition of metamorphosis. Acetone solutions of the substances to be examined are deposited on the surface of the rubble by means of a microapplier and their ears are evaluated after the subsequent lashing, possibly after an iraag trip in control. The measure of effectiveness is the proportion of affected individuals and the degree of metamorphosis inhibition affects all individuals in the test. For comparison of the different substances, the expression of their efficacy in effective units affecting 50 µl of the test subjects (ED-50) is the most practical. Doses are given in µg of pure substance per subject.

The following standard tests are used: 1. Dysdercus cingulatus - Heteroptera, Pyrrhocoridae /, which is an important pseudopod in Asia. The last immature larvae are used for the test within 24 hours after stripping, applied with 2 µl of acetone solution. The effect manifests itself in the development into intermediate forms of the intermediate and imagery. 2. Galleria mellonella - Wax moth / Lepidoptera, Pyralidae / is a pest in hives and honeycomb and wax pits. Acetone solutions of juvenoids are applied at a dose of 2 µl to larva-last instar after the end of the gland / 5. - 6th day, total instar distance 8 days /. The effect develops through the development of transitional forms between the larva and the pupa. 3. Musea domestica - House Fly / Diptera, Muscidae / is a carrier of some diseases. Juve-noids are applied at a dose of 1 µl per larva a few hours before puparization. the effect is signaled by the non-hatching of flies and is verified by morphological analysis of pupar-treated individuals. Undeveloped imaginary structures on the abdomen characterize juvenile adaptation and distinguish them from potential toxic effects. The ED-50 is a dose that prevents the flies from the umbilical flies from flying half of the individuals tested.

Table

The biological activity of some of the compounds of the present invention compared to commercially available hydropren / ZR 512 / and methoprene / ZR 515 /

Structure

DYS GAL MUS PHO 2.0 0.002 0.8 0.01 1.0 0.005 0.2 0.008 4.0 0.008 0.2 0.02 CS 268 295 Dl 5-

ZR 512 ZR 515 Nakt. 0.008 0.8 0.01 0.4 0.8 inact. 0.02 1.0 10 inact 0.05 0.8 0.008 1.0 0.1 0.02 1.0 0.008 5.0

Explanations: DYS = Dysdercus cingulatusGAL = Galleria mellonellaMUS «Musea domesticainakt. »InaktlvníPHO Phorodon humuli

Activity values on the PHO / Phorodon humuli / aphids are given by the so-called effective concentration of EC-5O. The method of testing substances for aphid species is standardly used and described in publications such as Proud I, Acta ent. bohemoslov. 71, 367 (1974) or Proud I., Kuldova J.:IOBC/VPRS Bull. 4, 21 (1981). The following is Table 2 of the biological activities of some other derivatives of the present invention.

Table 2

DYS GAL MUS PHO 2.0 0.003 0.8 0.05 3.0 0.008 0.8 0.05 0.5 0.002 0.3 0.03 1.0 0.005 0.4 0.05

Explanations: DYS = Dysdercus cingulatusGAL = Galleria mellonellaMUS = Musea domesticaPHO = Phorodon humuli

Claims

- (, - CS 268 295 D1 SUBJECT MATTER)

1. Oxim-βther derivatives with regulators effect! the development of insects of formula (I) wherein y is an integer of one or two, Z is oxygen, the hydroxyl group wherein the remaining bond is attached to a hydrogen atom, or a group of formula -O- / CH 2 / n-O-, in which is an integer v evaluating two or three; R is a group of the formula - (CH-) -OK = CH-R; one to three and denotes alkyl of one to phenyl, 2-quinolyl or 1-isoquinolyl, methyl, ethyl, hydroxyl, OCOCH3 or 2-pyridyl;

2. A process for producing oxime ether derivatives according to claim 1, wherein the ketophenol of the general formula is

Wherein A and Y are as defined above, are reacted with a compound of formula III X- / CH, / -X / 111 / 2fn wherein m is as defined above η X denotes bromo, chloro or p-toluenesulfonyloxy group at forming a compound of formula IV

(IV) wherein A, y, m and X are as defined above, which reacts with N = CH-R 1 where R 1 is as defined above to give the final product with a compound of formula V / V / formula I.