CS243567B1 - Carbamate derivatives with insects development regulation effects and method of their production - Google Patents

Description

(54) Carbamate derivatives with effect of insect development regulators and method for their production

The subject of the invention are substances imitating the effect of insect juvenile hormone and a method for their production.

A large number of these substances, also known as juvenoids and insect growth regulators, are currently described. They have been described, for example, by K. Sláma, M. Romaňuk and F. Šorm (Insect Hormones and Bionalogues, Springer-Veriag, Vienna - New York 1974) or by L. I. Gilbert et al. (The Juvenile Hormones, Plenum Press, New York 1976.)

A common feature of the action of juvenoids, otherwise chemically very different compounds, is the development of developmental disorders in insects leading ultimately to the extinction or strong suppression of the extent of the population of harmful insects. Their advantage is the relatively high specific activity on certain insect species with very low toxicity to vertebrates and a wide range of biological activity, including sterilization and ovicidal effects, undressing disorders and disruption of developmental cycles.

In inventions according to the author's certificates No. 195,530 and No. 206,421, modern insecticides have been described, the active ingredient of which were derivatives of hydroxybenzylcyclohexanol and hydroxybenzylcyclopentanol, and derivatives which are characterized by the presence of 1,4-dioxaspiro (4,5) dec-6- yl, respectively. 1,5-dioxa243567 spiro (5,5 -undec-7-yl groups per molecule).

Some of the above-mentioned types of substances have shown very good activity in tests on some insect species of pests (eg Acyrtosiphon pisum aphid) or on certain social insects (eg termites of the families Kalotermitidae or Rhinotermitidae).

The compounds of the present invention exhibit higher environmental stability (e.g., temperature, aqueous, acidity, etc.) compared to the prior art, resulting in increased stability even in laboratory or field trials. where the substances exist in the active form, ie chemically unchanged by the influence of the environment, thus extending their duration of action.

This is particularly important in field trials where, under real natural conditions, the developmental stage of harmful insects that are 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 insect populations in nature and to keep the active substance active for several weeks. In absolute numbers, the value of 243567 of the compounds of the present invention is comparable to that of the previous compounds (AO Nos. 195,530 and 206,421), but their actual efficacy and thus their economic efficiency. benefit is enhanced by their increased stability.

These objects are achieved by the invention which is based on the chemical composition of juvenoid substances, which are characterized by the presence of both a dicyclic group and the presence of an N-alkylcarbamate group, which can be represented by the general formula I in which:

A and y have the meanings given above. The compound of formula VII is then reacted with a methoxybenzyl halide of formula VIII

where

X is chloro or bromo, to give a methoxybenzylcycloalkanone of formula IX wherein y is an integer of one or two,

Z represents a group of the formula --O-- (CH2 --N--) in which n is an integer of two or three, an oxygen atom or a monovalent hydroxyl group, the remaining free valence being then occupied by a hydrogen atom,

R is - (CH 2) _m NHCOOR ¹ wherein m is an integer of one to three, R ¹ is methyl, ethyl, propyl or isopropyl,

A is hydrogen, methyl, ethyl, hydroxyl, OCOCH 3 or a group of formula

where

A and y have the meanings given above and which in turn provides one of the conventional methods of dealkylation, for example by the action of hydrogen bromide or ethylmercaptan sodium, to give the free ketophenol of formula II

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

A process in which the cyclic ketone of formula VI is first reacted

<CH / _y 'f'

I) (vn where

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 general formula II in which

A and y have the meanings given above, and a nitrogenous base, preferably a pyrrolidine, is prepared by enamine of formula VII

in which

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

(Vil)

HO- (CH ₂ ) n -OH (III) wherein n is as defined above to give the ketophenol acetal of formula IV

in which

A, y and n are as defined above, then reacted with a compound of formula V

R = X (V) wherein

R and X are as defined above to give a compound of formula I

where

A, R, y and n are as defined above.

The essence of another process for the preparation of the compounds according to the invention is that ketophenol of the formula II is used

in which

A and y have the meanings given above, reacted with a compound of formula V

R-X (V) where

R and X are as defined above to give a compound of Formula I

where

A, R, and y are as defined above.

The essence of another process for the preparation of the compounds according to the invention is that the keto group of a compound of the formula I is used

A, R and y are as defined above, reduced, preferably with sodium borohydride, to give a compound of formula I

in which

A, R, and y are as defined above.

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

Example 1

Preparation of 2- (4- (2- (ethoxycarbamato / ethoxy) benzyl) -1-cyclohexanone (Formula I, R = —CH 2 CH 2 NHCOOC 2 H 5, Z = O, A = H, y = 2)

a) A solution of cyclohexanone (73.5 g) and pyrrolidine (85 g) in benzene (350 ml) was heated to boiling for 7 hours after addition of p-toluenesulfonic acid (50 mg) while distilling off the reaction water. The reaction mixture was then cooled to ambient temperature (15-20 ° C) and fractionally distilled through a 10 cm puncture distillation column. There was thus obtained N- (1-cyclohexenyl) pyrrolidine (Formula VII, A = H, y = 2.109 g, 96.5%). Constants: b. 113 ° C (1 800 Paj.

b) A solution of N- (1-cyclohexenyl) pyrrolidine (13.6 g) and 4-methoxybenzyl chloride (9.1 g) in dioxane (50 ml) was heated to boiling for 5 hours, then 15 ml of water was added dropwise to the reaction mixture. The mixture was heated to boiling for an additional hour, cooled to 20 ° C, the dioxane evaporated and the mixture diluted with water (50 mL) and extracted with ether (150 mL), after shaking with 5% hydrochloric acid and 5% sodium carbonate and water. Evaporation of the ether and distillation of the crude residue gave 2-4-methoxybenzyl) -1-cyclohexane (Formula IX, A = H, γ = 2.6.63 g, 52.5%) Constants: bv 165-71 ° C.

IR spectrum:

250, 1694, 1710, 2840 cm ^1st

Mass spectrum:

M. + = 218.

cj To a solution of 2- (4-methoxybenzyl) -1-cyclohexanone (5.1 gj in acetic anhydride (12 g) was added dropwise 48% hydrobromic acid (12 g) at 20 ° C and the reaction mixture was heated to boiling for 2 hours. After cooling to 20 ° C, the mixture is poured onto ice (50 g), solid calcium carbonate (23.5 g) is added with stirring, and the mixture is extracted with ether (400 ml). The ether solution is then dried over sodium sulfate, the solvent is evaporated and Elution with a mixture of petroleum ether and 30% ether gave 2.60 g (55%) of 2- (4-hydroxybenzyl) -1-cyclohexanone (Formula II, A = H, y = 2) after evaporation of the eluent.

Constants: mp 97 ° C

IR spectrum:

838, 1,518, 1,597, 1,615, 1,706, 1,795,

605 cm ^1st

Mass spectrum:

M. + = 204.

d) A solution of 2- (4-hydroxybenzyl) -1-cyclohexanone (2 g, 9.8 mmol) and ethyl 2-chloroethylcarbamate (2 g, 13.2 mmol) in dimethylsulfoxide (40 mL) was in the presence of calcined potassium carbonate (3). g (28.3 mmol) was heated with stirring at 110-120 ° C for 3 hours After cooling, the reaction mixture was diluted with water (40 mL) and extracted with ether (3 X 40 mL). The residue was purified by silica gel column chromatography to give 3.05 g (50%) of 2- [4- (2- (ethoxycarbamato / ethoxy) benzyl] -1-cyclohexanone.

Constants:

IR spectrum:

455, 1711, 1612, 1583, 1518, 1250 ^cm-first Mass spectrum:

M. + = 319, 273, 230, 204, 116 (base peak), 107, 88.

Example 2

Preparation of 2- (4- (2- (ethoxycarbamato / ethoxy) benzyl] -1-cyclohexanol (Formula I, R = —CH 2 CH 2 NHCOOC 2 H 5, Z = H, OH, A = H, y = 2))

To a solution of 2- [4- (2- (ethoxycarbamato / ethoxy) benzyl] -1-cyclohexanone (1.4 g, 4.38 mmol) in methanol (40 mL) was added sodium borohydride (0.7 g, 18.48) mmol) in one portion with stirring and cooling to 0 [deg.] C. Reduction was carried out for about 45 minutes, then the methanol was evaporated under reduced pressure, the residue diluted with saturated sodium chloride solution (25 ml), extracted with ether and dried over sodium sulfate. The residue was purified by silica gel column chromatography to obtain the two pure isomers of the desired product: cis-isomer 0.6 g (43%) and trans-isomer 0.6 g (43 percent).

Constants:

cis-isomer:

IR spectrum:

630, 3465, 1729, 1516, 1246, 979 ^cm-first Mass spectrum:

M. + = 321, 275, 258, 257, 232, 206, 188, 116 (base peak), 107.88.

trans-isomer:

IR spectrum:

625, 3,465, 1726, 1,513, 1,243, 1,069,

053 cm ^1st

Mass spectrum:

M. ⁺ = 321,275,258,257,232,206,188

116 (base peak, 107, 88, mp 83-84 ° C).

Example 3

Preparation of 2- [4- (2- (ethoxycarbamato / ethoxy) benzyl] -1-cyclohexanone ethylene acetal (Formula I, R = —CH2CH2NHCOOC2H5, Z = = - OCH2CH2O-, A = H, y = 2)

a) To a solution of 2- (4-hydroxybenzyl) -1-cyclohexanone (2 g, 9.8 mmol) in benzene (50 mL) was added ethylene glycol (2 mL) and p-toluenesulfonic acid (5 mg). Azeotropically distilled off the reaction water for 6 hours After completion of the reaction and evaporation of the benzene under reduced pressure, 2.2 g (90.5%) of 2- (4-hydroxybenzyl) -1-cyclohexanone ethyianacetal (Formula IV, n = 2, y = 2) were obtained. , A = H).

Constants: mp 86-88 ° C.

IR spectrum:

400, 3,612 cm ¹ .

Mass spectrum:

M. + = 248.

b) To a solution of 2- (4-hydroxybenzyl) -1-cyclohexanone ethylene acetal (1.36 g, 5.5 mmol) in dimethylsulfoxide (20 mL) was added triturated sodium hydroxide (0.3 g, 7.5 mmol) and reaction the mixture was stirred at 100 ° C for 2 hours. Then ethyl 2-chloroethylcarbamate (0.9 g, 5.94 mmol) was added dropwise to the reaction mixture in subst. Stirring and heating to 110-120 ° C were continued for 4 hours. After cooling, the reaction mixture was diluted with water (15 mL) and extracted with ether. The extract was dried over sodium sulfate and, after evaporation, the residue was purified by silica gel column chromatography. The yield was 0.45 g, (22.5%).

Constants:

IR spectrum:

455, 1720, 1 521, 1250, 1 158, 1 101,

088, 1056, 927 cm ¹ .

Mass spectrum:

M. + = 362, 320, 317, 274, 248, 141, 116 (base peak), 107, 99, 88, mp 63-64 ° C.

Example 4

Preparation of 2- (4- (3- (methoxycarbamato / propoxy) benzyl) -1-cyclopentanone (Formula I, R = - CH 2 CH 2 CH 2 NHCOOCH 3, Z = O, A = H, y = 1)

The required 2- (4-hydroxybenzyl) -1-cyclopentanone was prepared by a procedure analogous to that described in Example 1a) to (c). A solution of 2- (4-hydroxybenzyl) -1-cyclopentanone (1 g, 5.3 mmol) and methyl 3-chloropropylcarbamate (1 g, 6.6 mmol) in dimethylsulfoxide (20 mL) was in the presence of calcined potassium carbonate (1). (5 g, 14.1 mmol) was heated with stirring at 110-120 ° C for 3 hours. The reaction mixture was worked up as described in Example 1. The yield was 0.81 g (50%) of 2- [4- (3- (methoxycarbamato / propoxy) benzyl] -1-cyclopentanone.

Constants:

IR spectrum:

455, 1705, 1611, 1250 ^cm-first

Example 5

Preparation of 2- (4- (3- (methoxycarbamato / propoxy) benzyl) -1-cyclopentanol (Formula I, R = -CH 2 CH 2 CH 2 NHCOOCH 3, Z = H, OH, A = H, y = 1)

To a solution of 2- [4- (3- (methoxycarbamato / propoxy) benzyl] -1-cyclopentanone (0.7 g, 2.3 mmol) in methanol (20 mL) was added sodium borohydride (0.35 g, 9, 3 mmol) per portion under the same conditions as described in Example 2. The reaction mixture was worked up in a manner analogous to Example 2. The yield was 0.32 g (46%) of the cis-isomer and 0.32 g (46%). of the trans-isomer of 2- (4- (3- (methoxycarbamato / propoxy) benzyl) -1-cyclopentanol).

Constants:

cis-isomer:

IR spectrum:

630, 3465, 1719, 1515, 1245, 979 ^cm-first

trans-isomer:

IR spectrum:

625, 3465, 1718, 1513, 1243, 1054 ^cm-first

Example 6

Preparation of 2- (4- (3- (methoxycarbamato / propoxy) benzyl) -1-cyclopentanone ethylene acetal (Formula I, R = —CH2CH2CH2NHCOOCH3, Z = -OCH2CH2O-, A = H, y = 1))

First, 2- (4-hydroxybenzyl) -1-cyclopentanone ethylene acetal was prepared as described in Example 3a j. Then, to a solution of 2- (4-hydroxybenzyl) -1-cyclopentanone ethyleneate (0.59 g, 2.5 mmol) in dimethylsulfoxide ( 10 ml) of triturated sodium hydroxide (0.15 g, 3.75 mmol) was added and the reaction mixture was heated with stirring at 100 ° C for 2 hours. To the reaction mixture was then added dropwise methyl 3-chloropropylcarbamate (0.42 g, 2.75 mmol) in subst. The reaction and processing were analogous to those described in Example 3b). 0.25 g (29%) of 2- [4- (3- (methoxycarbamato / propoxy) benzyl] -1-cyclopentanone acetal was obtained.

I .243567

Constants:

IR spectrum:

455, 1,719, 1,520, 1,158, 1102, 1089,

057, 928 ^cm-first

Example 7

Preparation of 2- [4- (isopropoxycarbamato / methoxybenzyl) -4-methyl-1-cyclohexanone (Formula I, R = - CH 2 NHCOOCH 2 CH (CH 3) 2, Z = O, A = CH 3, y = 2)

The required 2- (4-hydroxybenzyl) -4-methyl-1-cyclohexanone was prepared by a procedure analogous to Example 1a) to c). A solution of this 2- (4-hydroxybenzyl) -4-methyl-1-cyclohexanone (1 g, 4.6 mmol) and isopropyl chloromethylcarbamate (1 g, 6.6 mmol) in dimethylsulfoxide (20 mL) was in the presence of calcined potassium carbonate (1.5 g, 14.1 mmol) was heated with stirring at 110-120 ° C for 3 hours The reaction mixture was worked up as described in Example 1. 0.7 g (46%) of the product was obtained.

Constants:

IR spectrum:

455, 1720, 1250 ^cm-first

Example 8

Preparation of 2- [4- (isopropoxycarbamato / methoxy) benzyl] -4-methyl-1-cyclohexanone (Formula I, R = -CH 2 NHCOOCH 2 CH (CH 3) 2, Z = O, A = CH 3, y -2)

To a solution of 2- [4- (isopropoxycarbamato / methoxy) benzyl] -4-methyl-1-cyclohexanone (0.8 g, 2.4 mmol) in methanol (20 mL) was added sodium borohydride (0.35 g, 9.3 mmol) per portion under the same conditions as described in Example 2. Treatment of the reaction mixture was the same as in Example 2. 0.38 g, (47%) of the cis -isomer and 0.27 g (46%) were obtained. ° / o) 2- [4- (isopropoxycarbamato / methoxy) benzyl] -4-methyl-1-cyclohexanol trans-isomer.

Constants:

cis-isomer:

IR spectrum:

630, 3,465, 1,720, 1,516, 1,240, 978 cm ⁴ , trans-isomer:

IR spectrum:

625, 3,465, 1,719, 1,514, 1,242, 1,051 cm ^-1 . Example 9

Preparation of 2- [4- (isopropoxycarbamato / methoxy) benzyl] -4-methyl-1-cyclohexanone ethylene acetal (Formula I, R = -CH 2 NHCOOCH 2 CH 2 CH 2, Z = -OCH 2 CH 2 O-, A = CH 3, y = 2)

First, 2- (4-hydroxybenzyl) -4-methyl-1-cyclohexanone ethylene acetal was prepared as described in Example 3a). Then, to a solution of 2- (4-hydroxybenzyl) -4-methyl-1-cyclohexanone ethylene acetal (0.65 g, 2.5 mmol) in dimethylsulfoxide (10 mL) was added triturated sodium hydroxide (0.15 g, 3.75 mmol). ) and the reaction mixture was heated with stirring at 100 ° C for 2 hours, and isopropyl chloromethylcarbamate (0.42 g, 2.75 mmol) was added dropwise to the reaction mixture in subst. in Example 3b) 0.28 g (30%) of 2- [4- (isopropoxycarbamato / methoxy) benzyl] -4-methyl-1-cyclohexanone ethylene acetal was obtained.

Constants:

IR spectrum:

455, 1,719, 1,520, 1,250, 1,159, 1,101,

087, 1057, 927 ^cm-first

Example 10

Preparation of 2- {4- (2- (ethoxycarbamato / ethoxy) benzyl] -4-acetoxy-1-cyclohexanone (Formula I, R = CH 2 CH 2 NHCOOC 2 H 5, Z = O, A = OCOCH 3, y = 2)

First, 2- (4-hydroxybenzyl) -4-acetoxy-1-cyclohexanol was prepared as described in Example 1a) to c). Then to a solution of 2- (4-hydroxybenzyl) -4-acetoxy-1-cyclohexanone (1 g, 3.8 mmol) and ethyl 2-chloroethylcarbamate (1 g, 6.6 mmol) in dimethylsulfoxide (20 mL) Annealed potassium carbonate (1.5 g, 14.1 mmol) was added and the reaction mixture was heated to 110-120 ° C with stirring for 3 hours. The treatment was analogous to that described in Example 1. 0.71 g (50%) of the product was obtained.

Constants:

IR spectrum:

455, 1710, 1695, 1250 ^cm-first

Example 11

Preparation of 2- (4- (2- (ethoxycarbamato / ethoxy) benzyl) -4- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy-1-cyclohexanone) (Formula I, R = - CH2CH2NHCOOC2H5, Z = = O, A = —OTHP, y = 2)

First, 2- (4-hydroxybenzene) -4- (3,4,5,6-tetrahydr o-2H-pyran-2-yloxy) -1-cyclohexanone was prepared according to Example 1a) to (2).

C). Then, to a solution of this material (1.5 g, 4.9 mmol) and ethyl 2-chloroethyl carbamate (1 g, 6.6 mmol) in dimethylsulfoxide (20 mL) was added annealed potassium carbonate (1.5 g, 14.1 mmol) and the reaction the mixture was heated to 110-120 degrees C with stirring for 3 hours. After working up in Example 1, 1.05 g (50%) of the product was obtained.

Constants:

IR spectrum:

455, 1710, 1516, 1250 ^cm-first

Biological activity testing of newly prepared substances:

As an example, the results of experiments with aphid aphid (Acyrtosiphon pisum) are presented. Biological activity of newly prepared substances is evaluated according to morphogenetic effects, event. according to the developmental and fertility effects as well as the efficacy of juvenile insect hormones.

The test substances are applied in an aqueous emulsion by spraying onto the leaves of a live plant; samples of experimental insects are exposed to treated leaves (methodology - see: Proud I .: Acta ent. bohemoslov. 71, 367-381 (1974)). The effects are evaluated according to: cauda shape changes (morphogenetic effect - retention of larvae cauda shape indicates a developmental disorder correlated with fertility), viable progeny and survival of experimental insects throughout the trial period (from first instar to adulthood and onset of reproductive activity) ).

Biological efficacy is expressed by LC-50 values, ie, by the concentration of the test substance, which affects the development and reproductive capacity of about 50% of the subjects in the sample. The observed activity of the compounds of the present invention was higher than that of the commercial juvenoid Methoprene (ZR 515, Altosidj from Zoecon, CA, USA).

However, their duration of action was noticeably longer due to the higher stability of the compounds of the present invention over the commercial preparation of Methoprene and those of our earlier inventions (AO Nos. 195,530 and 206,421) under the conditions of entomological tests, ie in an aqueous emulsion under the influence of atmospheric oxygen, sunlight, temperature, air acidity, etc.

The advantage of the prolonged action of the compounds of the present invention can be particularly appreciated in field trials, i.e. in the case of insect pests in nature, where the developmental stage of the insect pests that is sensitive to juvenoid activity occurs in the period even several weeks, when it is necessary to ensure a longer period of persistence of the active substance under these conditions.

Similar results have been obtained when testing the compounds of the present invention on some social insect species, such as termites of the families Kalotermitidae or Rhinotermitidae.

Table 1 shows the stability of one of the typical representatives of the compounds of the present invention (compound 1j, depending on pH change, in Table 2, the temperature stability of the same substance). of the invention (AO No. 195 530; substance 2).

Table 1

Dependence of substance stability on pH environment

Substance No. Structure pH Amount of substance in% of the weight detected in unchanged form:

h 24 h 48 h 72 h

Table 2

Temperature dependence of substance stability

Substance No. Structure Temperature Amount of substance in% of the weight detected in unchanged form h 24 h 48 h 72 h

OH

Table 3 below compares the biological activity of the compounds of the present invention with that of the two

100.0 99.9 99.7 99.5 100.0 99.7 99.3 99.0 99.9 98.9 97.8 95.9 99.8 98.4 97.0 94.0 acquaintances substances that were already before

praveny.

Table 3

Table of biological activity of prepared compounds compared to the previously synthesized substances (AO Nos. 195 530 and 206 421) on termite colonies of the Kalotermitidae family at a concentration of 0.1% by weight.

° / ³ 'effect

1.

2.

3.

4.

5.

(cis-isomer) (trans-isomer) (cis-isomer) (trans-isomer)

6.

243557

7.

8.

9.

10.

OH (cis-isomer) (trans-isomer) (cis-isomer) (trans-isomer) (AO Nos. 195,530 and 206,421).

^{and |} The percentage effect is the percentage of termite soldiers appearing in the colony. The higher the number, the greater the juvenilizing effect of the substance.

Claims (3)

Subject 1. Carbamate derivatives having the effect of insect development regulators of the formula I y is an integer of one or two; Z represents a group of the formula --O-- (CH2 --N--) in which n is an integer of two or three, an oxygen atom or a monovalent hydroxyl group, the remaining free valence being then occupied by a hydrogen atom, R is - (CH ² ) m NHCOOR ¹ , wherein m is an integer of one to three, R ¹ is methyl, ethyl, propyl or isopropyl, A is hydrogen, methyl, ethyl, hydroxyl, OCOCH 3 or a group of formula VYNALEZU CV 2. A process for the preparation of carbamate derivatives of the formula I in which Z is a group of the formula --O-- (CH2) _n --O-- and the symbols R, A, nay are as defined above, which are active according to claim 1, characterized in that ketophenol of formula II wherein A and y are as defined above, reacted with a diol of formula III HO- (CH 2) n -OH (III) wherein n is as defined above, to give the ketophenol acetal of formula IV wherein: A and y have the meanings given above, reacted with a compound of formula V R = X (V) wherein R and X are as defined above. 4. A process for the preparation of carbamate derivatives of formula (I) wherein Z is OH and H and R, A, and Y are as defined above, as defined in claim 1, wherein the keto group of a compound of formula (I): A, y and n have the meanings given above, which are reacted with a compound of formula V R = X (V) wherein R and X are as defined above. 3. A process for the preparation of carbamate derivatives of formula (I) in which Z is only O, wherein R, A and y are as defined above, as defined in claim 1, wherein the ketophenol of formula (II) is: And in which A, R and y have the meanings given above, reducing, preferably with sodium borohydride.