CS206421B1 - Acetal derivatives of hydroxybenzylcyclohexane-2-on and method of their manufacture - Google Patents

Description

The present invention provides hydroxybenzylcyclohaxan-2-one acetal derivatives and a process for their preparation. Said substances generally have the ability to mimic the effect of insect juvenile hormone and can therefore be used as insecticide adjuvants. A common feature of the action of juvenoids is the development of developmental disorders in insects leading to the disappearance of the insect population. 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 MS. No. 195530, modern insecticides have been described, the active ingredients of which were hydroxybenzylcyclohexanol or hydroxybenzylcyclopentanol derivatives. However, this type of substance has shown very little activity in tests on Acyrtosiphon pisum aphids, which are a significant economic pest. The compounds of the present invention are of particular interest for their high activity against aphids, such as Pea Pygmy (Acyrtosiphon pisum).

These objects are achieved by the present invention, which is based on the hydroxybenzylcyclohexan-2-one acetals derivatives of the general formula I

in which R represents a - group of the general formula

TARGET,

AND

- (ch ₂ ) _w - c - or ² ,

Ri

206,421 wherein m is an integer of one to three, R ¹ is hydrogen or straight or branched alkyl with one; up to three carbons and R ² is hydrogen or straight or branched alkyl of one to four carbons - a group of formula

- (CH ₂ ) _m —CH = C (CH ₃ ) R ¹ , where m and R ^{1 are the} same as in the previous example, or

- a group of the general formula

O / \ '

- (CH ₂ ) _m -C (R ³ ) 4 (CH ₂ ) _b ,

Where m is the same as above, n is an integer of two or three and R ³ is hydrogen, methyl, or ethyl; and

A denotes hydrogen, hydroxyl, O-THP or OCOCH ₃ (THP is the internationally used abbreviation for 3,4,5,6-tetrahydro-2H-pyran-2-yl). These are chemical compounds, which are characterized by the presence of 1,4-dioxaspiro [4,5] dec-6-yl or 1,5-dioxaspiro [5,5] undec-7-yl, n being an integer of 2 or 3.

The present invention also provides a process for the preparation of a novel compound of the formula (I). The process is first to react a cyclic ketone of formula (II) with a nitrogenous base, preferably pyrrolidine, in benzene at boiling point for 4 to 7 hours. to the enamine of formula III

Έ)

(III) which is then reacted with a methoxybenzyl halide of formula IV

-OCH, (IV) zch ₂ 'wherein Z represents chlorine or bromine, in dioxane at 80 to 120 ° C for 5 to 8 hours to give methoxy-

whereupon said intermediate is dealkylated by heating with azeotropic hydrobromic acid in acetic anhydride at 110 to 150 ° C for 1 to 4 hours to the ketophenol VI

0 'Λ,

O (VI)

206,421, which is then converted by reaction with a diol of formula VII

HO- (CH ₂₎ -OH (VII) wherein n is an integer of two or three, carried out in benzene at the reflux temperature of the solvent, to the acetal

wherein n is as defined above, then the intermediate is reacted in 2-butanone in the presence of anhydrous potassium carbonate at 100 to 130 ° C for 4 to 8 hours with a compound of formula IX

RX (IX) wherein R has the same meaning as in Formula I and X is chloro, bromo, -OSO ₂ CH ₃ or -OSO ₂ C ₆ H ₄ CH ₃ , to the final product.

The dealkylation is carried out by a conventional method, for example by the action of hydrogen bromide or ethyl mercaptide. '

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

Example 1

Preparation of 2- [4- (3-methyl-2-butenyloxy) benzyl] -1-cyclohexanone-ethyleneacetal (1, R = -CH ₂ CH = C (Cft ₃ ) ₂ , A = Η, n = 2)

a) A solution of cyclohexanone (73.5 g) and pyrrolidine (85 g) in benzene (350 mL) was heated to boiling for 7 hours while adding 50 mg of p-toluenesulfonic acid 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 (III, A = H, 109 g, 96.5%). Constants: t.v. 113 DEG C. (1.8 kPa).

b) A solution of N- (1-cyclohexenyl) pyrrolidine (13.6 g) and 4-methoxybenzyl chloride (9.1 g) in dioxane (50 mL) was heated at reflux for 5 hours. The reaction mixture was then added dropwise with 15 ml of water and the mixture was heated to boiling for an additional hour, cooled to 20 ° C, the dioxane evaporated and diluted with water (50 ml) and extracted with ether (150 ml). The ether solution was dried over sodium sulfate after shaking with 5% hydrochloric acid and 5% sodium carbonate and water. Evaporation of ether and distillation of the crude residue gave 2- (4-methoxybenzyl) -1-cyclohexanone (V, A = H, 6.63 g, 52.5%).

Constants: mp 165-71 ° C (66 Pa), IR: 1250, 1694, 1710, 2840 cm ^-1 , mass spectrum: M ⁺ = 218.

c) To a solution of 2- (4-methoxybenzyl) -1-cyclohexanone (5.1 g) in acetic anhydride (12 g) 48% hydrobromic acid (12 g) was added dropwise at 20 ° C and the reaction mixture was heated to boiling for two hours. After cooling to 20 ° C, the mixture was poured onto ice (50 g), solid calcium carbonate (23.5 g) was added with stirring, and the mixture was extracted with ether (400 mL). The ether solution was then dried over sodium sulfate, evaporated, and the product purified by chromatography, 30 times silica gel. Elution with a mixture of petroleum ether and 30% ether gave 2.60 g (55%) after evaporation of the eluent.

2- (4-hydroxybenzyl) -1-cyclohexanone (VI, A = H).

Constants: t ° 97 ° C, IR: 838, 1518, 1597, 1615, 1706, 1794, 3605 cm ^-1 , mass spectrum: M ⁺ = 204.

d) 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). The reaction water was then azeotropically distilled off 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 ethylene acetal (VIII, n = 2, A = H) was obtained.

Constants: mp 86-88 ° C, IR: 3400, 3612 cm ^-1 , mass spectrum: M ⁺ = 248.

e) A solution of 2- (4-hydroxybenzyl) -1-cyclohexanone ethylene acetal (1.86 g, 7.5 mmol) and 1-bromo-3-methyl-2-butene (1.8 g, 12 mmol) in 2-butanone (15 mL) was refluxed for 2.5 hours at 100-110 ° C in the presence of anhydrous potassium carbonate (4.2 g, 30 mmol). After cooling, the reaction mixture was diluted with water until complete dissolution of the solid, the organic layer was shaken into ether and dried over sodium sulfate. After evaporation 4

206,421 ether under reduced pressure gave 1.8 g (73.2%) of 2- [4- (3-methyl-2-butenyloxy) benzyl] -1-cyclohexanone-1-ethylene acetal.

Constants: IR: 1019, 1089, 1239, 1680 cm ^-1 , mass spectrum: M ⁺ = 316.

Example ²

Preparation of 2- [4- (3-ethoxy-3-methyl-1-butoxy) benzyl] -1-cyclohexanone ethyleneacetal (I, R = —CH ₂ CH ₂ C (CH ₃ ) ₂ OC ₂ H ₅ , A = Η, n = 2)

To a solution of mercuric trifluoroacetate (1.54 g, 3.6 mmol) in absolute ethanol (7 mL) was stirred at a temperature of 17 to 17 with stirring. A solution of 2- [4- (3-methyl-2-butenyloxy) benzyl] -1-cyclohexanone ethylene acetal (1.03 g, 3.27 mmol), prepared according to Example 1, in absolute ethanol (5 mL) was added dropwise over 10 minutes at 18 ° C. ml) and the reaction mixture was stirred at this temperature for about one hour. It was then cooled to 2-3 ° C and a 3N-potassium hydroxide solution in absolute ethanol (4.3 ml) was slowly added dropwise, followed by a solution of sodium borohydride (0.1 g,

2.5 mmol) in 3N-ethanolic potassium hydroxide solution (4.3 mL). Gradually, metallic mercury was precipitated. Stirring at 2-3 ° C was continued for one hour. The precipitated mercury was then filtered off and the filtrate was concentrated by evaporating the ethanol under reduced pressure. To the residue was added saturated sodium chloride solution (30 mL), the organic layer was washed with ether and dried over sodium sulfate. Column chromatography on a 100-fold silica gel eluting with petroleum ether with 5 to 10% ether afforded 0.42 g (35.5%) of 2- [4- (3-ethoxy-3-methyl-1-butoxy) benzyl] -1-cyclohexanoneethyleneacetyl. .

Constants: IR: 1019, 1089, 1157, 1239 cm ^-1 , mass spectrum: M ⁺ - 362.

Example 3

Preparation of 2- [4- (4,4-ethylenedioxy-1-pentyloxy) benzyl] -1-cyclohexanoriethyleneacetal (I, R = - (CH ₂ ) ₃ C (CH ₃ ) (OCH ₂ ) ₂ , A = Η, n = 2)

To a solution of 2- (4-hydroxybenzyl) -1-cyclohexanone ethylene acetal (1.5 g, 6.05 mmol) prepared according to Example 1 in dimethylsulfoxide (20 mL) was added powdered sodium hydroxide (0.3 g) and the reaction mixture was heated to 100 ° C with stirring for two hours. 5-Chloro-2-pentanone-ethyleneacetyl (1.09 g, 6.65 mmol) was then added and the reaction mixture was heated at 110 ° C for an additional two hours. After cooling to room temperature (20 ° C), the reaction mixture was diluted with water (30 mL) and extracted with ether. After drying the extract over sodium sulfate and evaporating the ether under reduced pressure, 2.1 g (92%) of 2- [4- (4,4-ethylenedioxy-1-pentyloxy) benzyl] -1-cyclohexanone ethylene acetal was obtained.

Constants: t, h. 57-58 ° C, IR: 1052.1065, 1128, 1247 cm ^-1 , Mass Spec .: M ⁺ - 376.

Example 4

Preparation of 4-hydroxy-2- [4- (3-methyl-2-butenyloxy) benzyl] -1-cyclohexanone ethyleneacetal (I, R = -CH ₂ CH = C (CH ₃ ) ₂ , A = OH, n = 2)

In a manner analogous to that described in Example 1, 4-hydroxy-2- (4-hydroxybenzyl) -1-cyclohexanone ethylene acetal (3 g, 11.4 mmol) was first prepared by reaction with 1-bromo-3-methyl-2-butene ( 2.7 g, 18 mmol) gave 3.4 g (90%) of 4-hydroxy-2- [4- (3-methyl-2-butenyloxy) -benzyl] -1-cyclohexanoneethylene acetal.

Constants: IR: 1019, 3615 cm ^-1 , mass: M ⁺ = 332.

Example 5

Preparation of 4-hydroxy-2- [4- (3-methoxy-3-methyl-1-butoxy) -benzyl] -1-cyclohexanone ethyleneacetal (I, R = —CH ₂ CH ₂ C (CH ₃ ) ₂ OCH ₃ , A = OH, n = 2)

Following the procedure described in Example 2, from 4-hydroxy-2- [4- (3-methyl-2-butenyloxy) benzyl] -1-cyclohexanone ethylene acetal (1.5 g, 4.5 mmol) by treatment with mercuric trifluoroacetate (1.97 g) , 4.6 mmol) in absolute ethanol (15 mL) followed by reduction with sodium borohydride (0.2 g, 5 mmol) in an alcoholic medium yielded 0.6 g (36.5%) of 4-hydroxy-2- [4- methoxy-3-methyl-1-butoxy) benzyl] -1-cyclohexanone-ethylene acetal.

Constants: IR Ref .: 1019.1089, 1157.1239, 3615 cm ^-1 , Mass Ref .: M ⁺ = 364.

Example 6

Preparation of 3-hydroxy-2- [4- (4,4-ethylenedioxy-1-pentyloxy) -benzyl] -1-cyclohexanoethylene acetal (I, R = - (CH ₂ ) ₃ C (CH ₃ ) (OCH ₂ ) ₂ , A = OH, n = 2).

.................. ............................ · ............. ~, 206,421

Following a procedure analogous to that described in Example 1, 3-hydroxy-2- (4-hydroxybenzyl) -1-cyclohexanone ethylene acetal (2 g, 7.6 mmol) was first prepared, which was reacted with 5-chloro-2-pentanone ethylene acetal (1.31 g). 8 mmol) described in Example 3 afforded 2.4 g (80%) of 3-hydroxy-2- [4- (4,4-ethylenedioxy-1-pentyloxy) benzyl] -1-cyclohexanone ethylene acetal.

Constants: IR: 1019.1052.1065.1089.1157, 1239.3615 cm ^-1 , mass spec .: M ⁺ = 392.

Example 7

Preparation of 4-acetoxy-2- [4- (4,4-ethylenedioxy-1-pentyloxy) benzyl] -1-cyclohexanone ethyleneacetal (I, R = - (CH ₂ ) ₃ C (CH ₃ ) (OCH ₂ ) ₂ , A = OCOCH ₃ , n = 2)

Following a procedure analogous to that described in Example 1, 4-acetoxy-2- (4-hydroxybenzyl) benzyl) -1-cyclohexanone ethylene acetal (2 g, 6.55 mmol) was first prepared, which was reacted with 5-chloro-2-pentanone ethylene acetal (1). 15 g (7 mmol) described in Example 3 gave 2.2 g (75%) of 4-acetoxy-2- [4- (4,4-ethylenedioxy-1-pentyloxy) benzyl] -1-cyclohexanone ethylene acetal.

Constants: IR Ref .: 1019, 1052, 1239, 1725 cm ^-1 , Mass Spec .: 434.

Example 8

Preparation of 3- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) -2- [4- (3-methyl-2-butenyloxy) benzyl] -1-cyclohexanone ethylenaeetal.

. ^: ~ (I, R = _-CH2 CH = C (CH _{3) 2,} A = O-THP; n = 2)

Procedure analogous to that of Example 1 was first prepared 3- (3,4,5,6-tetrahydro-2H-pyran _and 2-yloxy) -2- (4-hydroxybenzyl) -L-cyklohexanonethylenacetal (3.48 g 10 mmol) which, by treatment with 1-bromo-3-methyl-2-butene (2.7 g, 19 mmol) afforded 3.8 g (88%) of 3- (3,4,5,6-tetrahydro- 2H-pyran-2-yloxy) -2- [4- (3-methyl-2-butenyloxy) benzyl] -1-cyclohexanone ethylene acetal.

Constants: IR: 1019, 1052, 1065, 1239 cm ^-1 , mass: M ⁺ = 416.

Example 9

Preparation of 3- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) -2- [4,3-methoxy-3-methyl-1-butoxy) benzyl] -1-cyclohexanone ethylene acetal.

(I, R = —CH ₂ CH ₂ C (CH ₃ ) ₂ OCH ₃ , A = O — THP, n = 2)

Following the procedure of Example 2, 3- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) -2- [4- (3-methyl-2-butenyloxy) benzyl] -1-cyclohexanone ethylene acetal ( 2.15 g, 5 mmol) by treatment with mercuric trifluoroacetate (2.18 g, 5.1 mmol) in absolute methanol (25 mL) followed by reduction with sodium borohydride (0.22 g, 5.5 mmol) under alkaline conditions to give 0 8 g (34.5%) of 3- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) -2- [4- (3-methoxy-3-methyl-1-butoxy) benzyl 1-cyclohexanone-ethylene acetal.

Constants: IR: 1019, 1089.1239 cm ^-1 , mass: Al ⁺ = 448.

As an example of use, Table 1 shows the results of experiments with aphid pea (Acyrthosiphon pisum). '·

Biological activity of newly prepared substances is evaluated according to morphogenetic effects, eventually according to influence on development and fertility as well as efficacy of juvenile hormones of insects. The test substances are applied in an aqueous emulsion by spraying onto the leaves of the nutrient plant; samples of experimental insects are deposited on the treated leaves [methodology see: Proud I .: Effects of juvenoids on insecticide susceptible and resistant aphids {Myzus persicae, Aphisfabae and Theorioaphis maculata; Homoptera, Aphidida): Acta ent. bohemoslov. 71, 367-381 (1974)]. Effects are evaluated by: cauda shape changes (morphogenetic effect - retention of larvae cauda shape indicates developmental disorder correlated with fertility), viability of 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 the concentration of the test substance, which affects the development and reproductive capacity of approximately 50% of the subjects in the sample. To compare the efficacy of the newly prepared compounds (acetals - see Compound 2 in Table 1), the efficacy data of the commercial juvenoid Methoprene (ZR 512, Altoside-Company Zoecon, CA, USA) are shown. It can be seen from the table that 2- [4- (3-ethoxy-3-methyl-1-butoxy) benzyl] -1-cyclohexanone ethylene acetal is the most effective. 2- [4- (6-methoxy-6-methyl-2-heptyloxy) benzyl] -1-cyclohexanol and (2E) -4- [4- (3-ethoxycarbonyl-2-methyl-2-propenyloxy) benzyl] - 1-cyclohexanol did not act on aphids even when applied at a concentration of 0.1%.

206 421 Table 1. Biological activity of juvenoids on Acyrthosiphon pisum juveňoid ', LC50 (1) methoprene 0.02 (2) 2- [4- (3-ethoxy-3-methyl-1-butoxy) benzyl] -1-cyclohexanone ethylene acetal 0.01 (3) 2- [4- (6-methoxy-6-methyl-2-heptyloxy) benzyl] -1-cyclohexanol néúč. (4) (2E) -2- [4- (3-ethoxycarbonyl-2-methyl-2-propenyloxy) benzyl] -1-cyclohexanol neúč.

SUBJECT OF THE INVENTION

Claims (2)

OBJECT OF THE INVENTION » A hydroxybenzylcyclohexan-2-one acetal derivative of the general formula I (I) in which R represents a group of the general formula CH ₃ AND - / nu i n— I · Ri. wherein m is an integer having the value one to three, R ¹ represents hydrogen or straight or branched alkyl of from one j to three carbons and R ² is hydrogen or straight branched alkyl of from one to four carbons j - group of formula - _{(CH2 m} = CH = C (CH ₃ ) R ¹ , where tn and R ^{1 are the} same as in the previous case, or - a group of the general formula O / \ - (CH ₂ ) _m -C (R ³ ) 4 (CH ₂ ), Where m is the same as above, n is an integer of two or three and R ³ is hydrogen, methyl or ethyl; and A is hydrogen, hydroxyl, O-THP or OCOCH ₃ , n is an integer of 2 or 3. 2. A process according to claim 1, wherein the cyclic ketone of formula II (Π) is first reacted. 208 421 The nitrogenous base is preferably pyrrolidine in benzene at boiling point of benzene for 4 to 7 hours to the enamine of formula III i (III) which is then reacted with methoxybenzyl halide of formula IV ZCH, -4- and ₃ (IV) wherein Z is chlorine or bromine in dioxane at 80 DEG -20 DEG C. for 5-8 hours gives the methoxybenzylcycloalkanone of formula V, whereupon said intermediate is dealkylated by heating with azeotropic hydrobromic acid in acetic anhydride at 110 DEG C. to 150 ° C for 1 to 4 hours to the ketophenol VI, which is then converted by reaction with a diol VII HO - (CH ₂ ) n - OH (VII), wherein n is an integer of two or three, carried out in benzene at the boiling point of the solvent, to the acetal of the compound of formula VI, formula VIII (VIII) then the intermediate is reacted in 2-butanone in the presence of anhydrous potassium carbonate at a temperature of 100 to 130 ° C for 4 to 8 hours with a compound of formula IX RX (IX) wherein R is as defined in 1 and X is chloro, bromo, -OSO ₂ CH ₃ or -OSO ₂ C ₆ H ₄ CH ₃ , to the end product.