CS253350B1 - Insec development regulators on the base of esters and process for preparing thereof - Google Patents

Abstract

Ester derivatives with regulator effect development of insects and the method of their production. Substances have the general formula I wherein the general symbols are as defined above in the definition. I have high values and biological activities environmental stability. When wider use can have substances that are of the present invention, great economic importance.

Description

The present invention relates to ester derivatives having the effect of insect development regulators and processes for their preparation. They are substances imitating the effect of insect juvenile hormone.

A number of such substances, also known under the names of juvenoids, are currently described (K. Sláma et al .: Insect Hormones and Bioanalogues, Springer-Verlag, Wien-New York 1974; or LI Gilbert et al .: The Juvenile Hormones, Plenum) Press, New York 1976). A common feature of the action of juvenoids, chemically otherwise very inferior compounds, is the development of developmental disorders in insects leading, ultimately, to extinction or to a strong suppression of the extent of the pest population. Their advantage is the relatively high specific activity on certain insect species with very low toxicity to vertebrates and a broad spectrum of biological activity, including sterilization and ovicidal effects, undressing disorders and disruption of developmental cycles.

The compounds of the present invention are new structural type lytes derived from a known intermediate (AO 195 530, 206 421 and 243 567). They are characterized by higher activity on some insects, such as wax moth (Galleria melione11a) or house fly (Musea domestica) and higher resistance to environmental influences (temperature, humidity and acidity, etc.).

These facts are essential in both laboratory and field trials in terms of extending the time for which the substances are able to exist in biologically active form, i.e., chemically unchanged, moreover having better absolute values of the measured biological activity.

In real natural conditions, the developmental stage of harmful insects, which is sensitive to the effect of the compounds of the present invention, always occurs over a wider period of time due to the uneven development of the insect population in nature and the active substance needs to act for several weeks.

The economic benefits of the compounds of the present invention are due to their high potency and stability compared to previously prepared compounds.

The invention relates to ester derivatives having the effect of insect development regulators of the general formula I. .

where y is an integer of one or two,

Z is -O- (CH ₂ ) _n -O- wherein n is an integer of two or three,

R is a radical of formula

R ¹ O

Wherein m is an integer of one to three, R is methyl or ethyl and R is alkyl, alkenyl or alkynyl of up to 5 carbon atoms, A is hydrogen, methyl, ethyl, hydroxyl, OCOCH, or a group of formula

X

The present invention also provides a process for the preparation of a juvenoid of formula (I).

In a known process, the cyclic ketone of formula VI is first used

AND

- (CH ₂ ) y (VI) wherein A and y are as defined above, and a nitrogenous base, preferably pyrrolidine, produces an enamine of formula VII (CH ₂ ), (VII) wherein A and y are as defined above. The compound of formula VII is then reacted with a methoxybenzyl halegenide of formula VIII

OCH, (VIII) wherein X is chloro or bromo, provides methoxybenzylcycloalkanone of formula IX

AND

- (CH ₂ ) y

OCH (IX)

O where A and y have the meanings given above and which then provides one of the conventional methods of dealkylation, for example by the action of hydrogen bromide or sodium ethyl mercaptan, to give the free ketophenol of formula II

AND

Wherein A and y have the meanings given above (AO No. 206 421).

The essence of the process according to the invention is that ketophenol of the formula II

A (ch ₂ ) _v

OH (II) o

wherein A and y are as defined above, are reacted with a compound of formula III

R-X (III) wherein R and X are as defined above to form a compound of formula IV

AND

O (IV) wherein R 1, Y and R are as defined above, by reaction with a compound of formula (V)

HO- (CH _{2) n} -OH (V) yields the final product of Formula I.

The following are examples which illustrate the invention without limiting it in any way.

He did

Preparation of (2 Z) -2- (4-) 3-ethoxycarbonyl-2-methyl-2-propen-1-yloxy (benzyl) -1-cyclohexanone ethylene acetal (I, A = H, Z = -O (CH ₂ ) ₂ 0-, y = 2, m = l, ^R1 = CH _3, R ₂ = C ₂ H ₅₎

First, the known intermediate, 2- (4-hydroxybenzyl) -1-cyclohexanone (AO No. 195 530) was prepared.

A mixture of 2- (4-hydroxybenzyl) -1-cyclohexanone (3 g), ethyl 4-bromosuccinate (4.3 g) and anhydrous potash (7.9 g) in 2-butanone (25 ml) was heated to boiling under reflux. The reaction mixture was cooled to 20 ° C, diluted with water (30 mL) and extracted with ether (80 mL). The ethereal solution was dried over sodium sulfate, the ether was evaporated and the crude residue was chromatographed over 50 times silica gel. Elution with petroleum ether with 20% ether separated the two isomers so that 1.9 g of (2Z) -2- (4-) 3-ethoxycarbonyl-2-methyl-2-propenyloxy (benzyl) -1-cyclohexanone and 2, 5 g of the (2E) -isomer; total yield 90.5 4. Constants: (2Z) -isomer: ¹ H-NMR spectrum: 2.02 (dt; 0.6, 0.6, 1.6 Hz), (2E) -isomer: 1 H- NMR Spectrum: 2.12 (dt; 0.7, 0.7, 1.5 Hz).

A solution of (2Z) -2- (4-) 3-ethoxycarbonyl-2-methyl-2-propenyloxy (benzyl) -1-cyclohexanone (0.5 g) in benzene (50 mL) was refluxed in the presence of ethylene glycol 10.5 mL ) and 5 mg of p-toluenesulfonic acid while distilling off the reaction water for 2 h. After cooling to 20 ° C, the reaction mixture was diluted with water and extracted with benzene. After drying over sodium sulfate and evaporation of the solvent, the crude product was purified by silica gel column chromatography eluting with a mixture of petroleum ether and 30% ether. 0.5 g of (954) (2Z) -2- (4-) 3-ethoxycarbonyl-2-methyl-2-propenyloxy (benzyl) -1-cyclohexanone ethylene acetal was obtained (I, A = H, y = 2, Z). = -O (CH 2), O-, m = 1, R ¹ = CH 3

1 z z j

R = C ₂ Hg). Constants: 1 H-NMR spectrum: 5.81 (m; 1.6, 1.6, 1.6, 1.6, 1.6 Hz), 2.02 (dt; 0.6,

0.6, 1.6 Hz), IR spectrum: 1,714, 1,650, 1,611, 1,588, 1,512, 1,240, 1,216, 1,090, 1,042 cm ^-1 .

Example 2

Preparation of (2E) -2- (4-) 3 - ethoxycarbonyl-2-methyl-2-propenyloxy (benzyl) -1-cyklohexanonethylenacetalu (I, AH, y = 2, Z = -0 (CH _{2) 2} 0-, R ¹ = CH 3, R ² = C 2 H _s)

Following the procedure of Example 1, 1.5 g (95 4) of (2E) was obtained from 1.5 g of (2E) -2- (4-) 3-ethoxycarbonyl-2-methyl-2-propenyloxy (benzyl) -1-cyclohexanone. -2- (4-) 3-ethoxycarbonyl-2-methyl-2-propenyloxy (benzyl) -1-cyclohexanone ethylene acetal. Constants: 1 H-NMR spectrum: 6.06 (m; 1.5, 1.5, 1.5, 1.5, 1.5 Hz), 2.18 (dt; 0.7, 0.7, 1.5 Hz), IR spectrum: 1,720, 1674 ^ 1611, 1584,

512, 1 240, 1 229, 1 156, 1 090, 1 046 cm ^-1 . -

Example 3,

Preparation of (2Z) -2- (4-) 3-isopropoxycarbonyl-2-methyl-2-propenyloxy (benzyl) -1-cyclohexanone ethyleneacetal (I, AH, y-2, Z = -O (CH ₂ ) ₂ O-, R ¹ = CH 3, m = 1, R ² -CH (CH 3> ₂ )

Following the procedure of Example 1, isomeric (2z) -2- (4-) 3-isopropoxycarbonyl-2-methyl-2-propenyloxy (benzyl) -1-cyclohexanone was first prepared from 2- (4-hydroxybenzyl) -1-cyclohexanone. and the corresponding (2E) -isomer in a total yield of 90 4. Constants: 1 H-NMR Spectrum: (2Z) -Isomer:

2.02 (dt; 0.6, 0.6, 1.6 Hz), (2E) -isomer: 2.14 (dt; 0.7, 0.7, 1.5 Hz).

Further, as described in Example 1, 0.5 g (90 4) of (2Z) -2- (4-) 3-isopropoxycarbonyl-2-methyl-2-propenyloxy (benzyl) -1-cyclohexanone was obtained from 0.5 g (90 4) ( 2Z) -2- (4-) 3-isopropoxycarbonyl5

-2-methyl-2-propenyloxy (benzyl) -1-cyclohexanone ethylene acetal. Constants: IR spectrum: 1715 ,. 1,650, 1,583, 1,513, 1,242, 1,217, 1,090 cm ^-1 .

Example 4

Preparation of (2E) -2- (4-) 3-isopropoxycarbonyl-2-methyl-2-propenyloxy (benzyl) -1-cyclohexanone ethyleneacetal (I, A = H, y = 2, Z = -O (CH ₂ ) ₂ 0 -, m = L, R ^X = CH 3, R ² = -CH (CH) 2)

Following the procedure of Example 1, 1 g (90%) of (2E) -2- (2E) -2- (4-) 3-isopropoxycarbonyl-2-methyl-2-propenyloxy (benzyl) -1-cyclohexanone was obtained from 1 g. (4-) 3-isopropoxycarbonyl-2-methyl-2-propenyloxy (benzyl) -1-cyclohexanone ethylene acetal. Constants: IR spectrum: 1,719, 1,673, 1612, 1,586) 1,512, 1,242, 1,228, 1,158 cm ^-1 ,

Example 5

Preparation of (2E) -2- (4-) 3-propenyloxycarbonyl-2-ethyl-2-propenyloxy (benzyl) -1-cyclohexanone ethyleneacetal (I, A = H, y = 2, Z = -O (CH ₂ ) ₂ O -, m = 1, R ¹ = C ₂ H ₅ , R ² = -CH 2 = CH ₂

Using the procedure described in Example 1, both (2Z) -2- (4-) 3-propenyloxycarbonyl-2-ethyl-2-propenyloxy (benzyl) -1-cyclohexanone are first prepared from 2- (4-hydroxybenzyl) -1-cyclohexanone and the corresponding (2E) -isomer in an overall yield of 85%. Constants: ^b H-NMR: (2Z) -isomer: 4.12 (t, 0.6, O, 6Hz) (2E) isomer: 4.20 (tf 0.7, 0.7 Hz) .

Further, as described in Example 1, 1 g (6%) of (2E) -2- (4-) 3-propenyloxycarbonyl-2-ethyl-2-propenyloxy (benzyl) -1'-cyclohexanone was obtained (2E). 2- (4-) 3-Propenyloxycarbonyl-2-ethyl-2-propenyloxy (benzyl) -1-cyclohexanone ethylene acetal. Constants: IR spectrum: 1,720,

675, 1612, 1584 cm ^-1 .

Example6

Preparation of (3E) -2- (4-) 4-proparoxycarbonyl-3-methyl-3-buten-1-yloxy (benzyl) -4-acetoxy-1-cyclohexanone ethylene acetal (I, A = -OCOCH ₃ , γ-) 2, Z = -0 (CH ₂ ) ₂ O-, m = 2, R ¹ = CH 3, R ² = -CH ² CECH)

Following the procedure of Example 1, both (3Z) -2- (4-) 4-propargyloxycarbonyl-3-methyl-3-buten-1-yloxy (benzyl) - (2- (4-hydroxybenzyl) -1-cyclohexanone) are first prepared. 4-acetoxy-1-cyclohexanone and the corresponding (3E) -isomer in an overall yield of 85%. Constants: (3Z) -isomer: ^B H-NMR: 2.04 (DTI 0.6, 0.6, 1.6 Hz), (3E) -isomer: ^B H-NMR: 2.16 (dt 0.7, 0.7, 1.5 Hz).

Further, as described in Example 1, 0.5 g of (3E) -2- (4-) 4-propargyloxycarbonyl-3-methyl-3-buten-1-yloxy (benzyl) -4-acetoxy-1-cyclohexanone is obtained. 5 g of (3E) -2- (4-) 4-propargyl-4-carbonyl-3-methyl-3-buten-1-yloxy (benzyl) -4-acetoxy-1-cyclohexanoneethylenaetal. Constants:

IR spectrum: 1720, 1674, 1611, 1240 cm ^-1 .

Example 7

Preparation of (3E) -2- (4-) 4-propargyloxycarbonyl-3-methyl-3-buten-1-yloxy (benzyl) -4-tetrahydropyranyloxy-1-cyclohexanone-1,3-propenylacetal (I, A = 0THP, y = 2, Z = -0 (CH ₂ ) ₃ 0-, m = 2, R ¹ = CH 3, R ² = -CH ² C = CH)

Using the procedure described in Example 1, both (3Z) -2- (4-) 4-propargyloxycarbonyl-3-methyl-3-buten-1-yloxy (benzyl) - (2- (4-hydroxybenzyl) -1-cyclohexanone) are first prepared. 4-tetrahydropyranyloxy-1-cyclohexanone and the corresponding (3E) -isomer in an overall yield of 85%. Constants: (3Z) -isomer: ^B H-NMR: 2.05 (dt, 0.6, 0.6, 1.6 Hz), (3E) -isomer: ^B H-NMR: 2.14 ( dt; 0.7,

0.7, 1.5 Hz).

Further, as described in Example 1, 0.5 g of (3E, -2- (4-) 4-propargyloxycarbonyl-3-methyl-3-buten-1-yloxy (benzyl) -4-tetrahydropyranyloxy-1-cyclohexanone) is obtained. 5 g (90%) <3E) -2- (4-) 4-propargyloxycarbonyl-3-methyl-3-buten-1-yloxy (benzyl) -4-tetrahydropyranyloxy-1-cyclohexanone-1,3-propenyl- acetal. Constants: IR spectrum: 1719, 1680, 1612, 1243 cm ^-1 .

Example 8

Preparation of (2E) -2- (4-) 3-propenyloxycarbonyl-2-ethyl-2-propen-1-yloxy (benzyl) -1-cyclopentanone-1,3-propenylacetal (I, A = H, y = 1, Z = -0 _(CH2) 0- _3, m = l, ^R1 = C2H5, ^R2 = -CH2CH = _CH2)

Following the procedure of Example 1, both (2Z) -2- (4-) 3-propenyloxycarbonyl-2-ethyl-2-propen-1-yloxy (benzyl) - (2- (4-hydroxybenzyl) -1-cyclopentanone) are first prepared. 1-cyclopentanone and the corresponding (2E) -isomer in an overall yield of 87%. Constants: (2Z) -isomer: ¹ H-NMR spectrum:

2.03 (dt; 0.6, 0.6, 1.6 Hz), (2E) -isomer: ¹ H-NMR spectrum: 2.11 (dt; 0.7, 0.7, 1.5 Hz) ).

Further, as described in Example 1, 0.5 g of (2E) -2- (4-) 3-propenyloxycarbonyl-2-ethyl-2-propen-1-yloxy (benzyl) -1-cyclopentanone was obtained from 0.5 g ( 90%) (2E) -2- (4-) 3-propenyloxycarbonyl-2-ethyl-2-propen-1-yloxy (benzyl) -1-cyclopentanone-1,3-propenylacetal. Constants: IR spectrum: 1,720, 1,680, 1,612, 1,245 cm ^-1 .

Example 9 'S ..

Preparation of (2Z) -2- (4-) 3-propenyloxycarbonyl-2-ethyl-2-propen-1-yloxy (benzyl, -1-cyclopentanone-1,3-propenylacetal (I, A = H, y-1, Z = -O (CH ₂ ) ₃ O-, m-1, R ¹ = C ₂ H ₅ , R ² = -CH ₂ CH = CH ₂ )

Using the procedure described in Example 1, from 0.5 g of (2Z) -2- (4-) 3-propenyloxycarbonyl-2-ethyl-2-propen-1-yloxy (benzyl) -1-cyclopentanone prepared in Example 8 0.5 g (90%) of (2Z) -2- (4-) 3-propenyloxycarbonyl-2-ethyl-2-propen-1-yloxy- (benzyl) -1-cyclopentanone-1,3-propenylacetal is obtained. Constants: IR spectrum: 1719, 1675, 1610, 1092 cm ^-1 .

Testing of prepared substances:

The tests used are based on the morphogenetic effect of juvenoids, which is shown to inhibit metamorphosis. Acetone solutions of the studied substances are applied to the body surface by means of a micro-applicator and their effect is evaluated after the subsequent undressing or after an imago trip in control. The measure of efficacy is the proportion of subjects affected and the degree of inhibition of metamorphosis by affecting all subjects in the assay. For comparing different substances, it is most practical to express their efficacy in effective units affecting 50% of the test subjects (ED-50). Doses are reported in µg of pure substance per subject. The following standard tests are used:

1. Dysdercus cingulatus - true bug (Heteroptera, Pyrrhocoridae), which is an important cotton pest in Asia. Last instar larvae are used within 24 hours after stripping, 2 µl of acetone solution is applied. The effect is manifested by the development into transient forms between the larvae and the imago.

2. Galleria mellonella - Lepidoptera (Pyralidae) is a pest in hives and in honeycomb and wax warehouses. Acetone solutions of juvenoids are applied at a dose of 2 [mu] l to the last instar larvae after the end of feeding (days 5-6, total instar length of 8 days). The effect is manifested by the development of intermediate forms between the larvae and the pupae.

3. Musea domestica - house fly (Diptera, Muscidae) is a carrier of some diseases. Juvenoids are administered at a dose of 1 µl per larvae several hours before puparization. The effect is signaled by damping that flies do not hatch and are verified by morphological analysis of puparium individuals. The undeveloped imaginal structures on abdomen characterize the juvenile action and distinguish them from a possible toxic effect. ED-50 is a dose that prevents the passage of flies from puparia in half of the subjects tested.

Table

Biological activity of some of the substances of the present invention compared to the known substance (AO 195 530)

Substance no. Structure DYS GAL MUS 1 and 0 0.05 0,005 0,5 2 o ^z ^ o 1_I 'Q- 0 0.05 0,008 0,5 3 1_1 0.08 0,05 0,8 4 O 0.05 0,1 1 according to AO 195 530 1_1 0 O 0.1 inactive until: 0,3 1

Explanatory notes:

DYS = Dysdercus cingulatus GAL = Galleria mellonella MUS = Musea domestica

Claims (2)

Ester derivatives having the effect of insect development regulators of the general formula I (i) in which y is the whole of Z is three, R is one or two, a group of the formula -O- (CH ₂ ) _n ^- O- wherein n is an integer of two or 2’m R ¹ O OR ^Z Wherein m is an integer of one to three, R is methyl or ethyl and R is alkyl, alkenyl or alkynyl of up to 5 carbon atoms, A is hydrogen, methyl, ethyl, hydroxyl, OCOCH4, or a group of formula and. o ό 2. A process according to claim 1 wherein the ketophenol of formula (II) - (CHjly OH (II) wherein A and y are as defined above, is reacted with a compound of formula III R-X (III) wherein R is as defined above and X is chlorine or bromine, to give a compound of formula IV A. (CH 2) 2 Z 2 -OR (IV) wherein A, y and R are as defined above, by reaction with a compound of Formula V HO- (CH _{2) n} -OH (V) yields the final product of Formula I. Severography, n. P., MOST Price 2,40 Kčs