CS213703B1 - Biologically activatable iuvenoidogenous substances with the epoxide bond in the molecule and method of preparation the same - Google Patents

Description

The invention relates to biologically activatable epoxy-bonded juvenoid substances in a molecule, a process for their preparation. ..

In MS. author's certificate 199376 and in MS. (P7 783-79) discloses aliphatic-aromatic ethers having an alkoxy (aryloxy) group and a cycloaoetal bond, respectively, in the molecule which, despite their sterically demanding aromatic moiety, exhibited a morphological effect analogous to juvenile hormone when applied to insects.

Jsk has been proven previously (Sláma K., RomaS.uk M., J.Insect Biochem.6, 579 (1976); Sláma K., Kahovcová J., Romanuk M., Pesticide Biocbemistry and Physiology 2, 313 (1976) ), such juvenoidogenic substances are hydrolyzed to a physiologically active component in an insect organism by a biotic (or even a biotic in conjunction with application to a plant organism) effect.

Examples of other juvenoidogenic substances of the same type of linkage of the active ingredient, the ester-type of binding, are those subject of the present invention.

The present invention provides biologically activatable epoxy-bonded juveneidogenic compounds in a molecule of formula (I)

R ^{* 1 * * *} R ² C-CH- (CH 2) a- [c (R ⁵ Z ¹ ) - C (R ⁴ Z ² )] b - CH (R ⁵ ) -0V in which

(AND),

213 703 a denotes 0 or 2, b denotes 0 or 1,

2 R, R is methyl or ethyl, R ³ to R ³ are hydrogen or methyl or ethyl, R ⁶ is straight or branched alkyl of up to 6 carbon atoms or phenyl, Z ¹ , Z ² is hydrogen or together form a double bond or -O-, R ⁷ denotes: hydrogen or - COR ⁸ , where R ⁸ denotes:

a straight or branched substituent of the formula

Z ³ - (CH) i ^c of ⁴ wherein Z ³ and Z ⁴ denote hydrogen or branched alkyl of up to 5 carbon atoms, c denotes an integer ranging from 1 to 20, a substituent of the formula

Z ⁵ - (CH -) - - CH - CH -, <

Z ⁵ Z ⁷ wherein Z ³ denotes hydrogen or a group - COOZ ⁸ ; symbols Z ⁸ and Z ⁷

O is hydrogen or methyl or ethyl or -CH2COOZ;

O denotes an integer ranging from 0 to 2; Z represents a straight or branched alkyl of 1 to 14 carbon atoms, a straight or branched substituent of the formula

Z ⁴ - (CH) -,

Z ⁹ wherein Z ⁴ is as defined above; e is an integer ranging from 0 to 15; the symbol Z ^9, which is represented in Formula maximálnějbřikrét, represents chlorine or bromine or a group - a group of 8 or ¹⁰ 10 or - COOZ; Z represents straight or branched alkyl of up to 6 carbon atoms; Z1 represents hydrogen or chlorine or bromine or a NO2 group or a -COOZ group; Z is as defined above. The process for the preparation of the compounds of the formula I consists in reacting a ketone of the formula II, 6 (II)

COR

R ¹ R ² C = CH- (CH 2) a- [c (R ³ Z ¹ ) - C (R ⁴ Z ² )] b - CH (R ³ ) - 0 - χ gio wherein R to R, Z, Z, a, b have the meaning given above with lithium aluminum hydride in the anhydrous medium of organic solvents inert to the reactants, for example in anhydrous diethyl ether, to form an alcohol of formula III:

R ¹ R ²⁰ = CH / (CH 2) and - (R ¹ R ¹ ) - C (R ⁴ Z ² )] b - CH (R ³ ) - O - (C 1 J CH (OH) R ⁶ , (III) β Σ P wherein R to R, Z, Z, a, b have the meaning given above which longer reacts with compounds of formula IV:

R ⁸ -CO-Y (IV),

213 703 lade symbol Y represents hydroxyl group or chlorine or - OCOR® and R® groups:

Z ⁶ of?

ς * l

Z ⁵ - (OH ₂ ) _d - CH - OH

Z ⁵ - (CH) _c - or Z - '- (OH ₂ ) _d - CH - OH or wherein Z 2 to Z 2, Z 2, c, d, e are as defined above

O or Ϊ and E together form a group and ¹ ·

Z ⁴ - (CH) _f Ό, where symbol. Z ⁴ is as defined above; f represents 2 or 3 or a group

0) - (0¾ - CO,

Z 'h, I z - (CH) _e -, where g denotes 0 or 1 to form an ester of formula V:

A - OCH - (CH _A Cntf) - o - - - - -.

(IN)

Wherein R to R, R, Z, Z, a, b are as defined above, which, like the alcohol of formula III, by reaction with a peracid, preferably monoperphthalic acid, at a temperature of 0 to 20 ° 0 provides the end product Formula I.

The invention is further illustrated by the following examples without being limited thereto.

Example 1

A solution of 934 mg of 4- (3,7-dimethyl-2,6-octadienyloxy) propiophenone in 15 ml of anhydrous diethyl ether was added dropwise at 10-20 ° C with stirring and in the absence of atmospheric humidity to a suspension of 70 mg of LiAlII 4 in 30 ml. ml of anhydrous diethyl ether. The reaction mixture was then heated at reflux for half an hour. After cooling with ice and diluting with diethyl ether, unreacted hydrated ice water and also precipitated aluminum hydroxide were decomposed with a 10-20% aqueous solution of H 2 SO 4 with vigorous stirring. The separated ether layer was washed with saturated NaCl solution, dried over anhydrous MgSO 4 and evaporated under reduced pressure.

The obtained residue was then separated by column chromatography on silica gel with 8 wt% water (eluent: petroleum ether containing up to 50 vol% diethyl ether) to give 720 mg (80%) by chromatography. of pure f (3- (7-dimethyl-2,6-octadienyloxy) phenyl) propanol (b.p. 157 DEG -60 DEG C./0.3 mbar). Elemental analysis for Ο ₁₉ Η ₂ θΟ ₂ ( ₂ 88): calculated 78.42% 0.9,% H found 78.72% 0.9.81% H. IC spectrum (7% in OCl ₄ ): 3623 ( δ OH free), 3465 (γ OH bond), 1670 (γ c = c), 1613, 1585, 1515 cm ^-1 (γ aromatics).

To 700 mg of (3,7-dimethyl-2,6-octadienyloxy) phenyl propanol was added dropwise with stirring at 10-20 ° C a 10 ml solution of monoperphthalic acid in anhydrous diethyl ether (50 mg / ml). After standing at 10-20 ° C for half an hour, everything was shaken between saturated NaHCO 3 solution and diethyl ether. After washing, drying and evaporation under reduced pressure, the obtained residue of the separated ethereal layer was separated by silica gel chromatography (8% by weight).

213 703 water; eluent: petroleum ether containing up to 75% by volume of diethyl ether). 300 mg (40%) of (3,7-dimethyl-6,7-epoxy-2-octenyloxy) phenyl] propanol (boiling point 165-8 ° C / 13.3 Pa) were obtained. Elemental Analysis ^ 9 ^ 8 ^ ^ 04): calculated 74.96% C, 9% 27 74.71% Found Hj 0, 9, 39% H. IR spectrum (4% in CC1 _4): 3623 (^ OH free), 3490 (f OH bond), 1675 (V0 = 0.1613, 1586, 1516 (V aromatics).

The same operating procedure was obtained [(3,7-dimethyl-6,7-epoxyoktyloxy) phenyl propanolj IR spectrum (4% in OC1 _4): Q 3619 free OH), 3480 (T is OH bonded), 1614, 1586, 1522, 1517 cm '(Y aromatics) *

Example 2

To 2.3 g of [(3,7-dimethyl-2,6-octadienyloxy) phenyl] propanol was added 632 mg of anhydrous pyridine and 816 mg of acetic anhydride. After stirring the reaction mixture at 10-20 ° C for half an hour, everything was shaken between diethyl ether and water. Separation of the dried and evaporated ethereal layer on a silica gel column (8% by weight of water as eluent: petroleum ether containing up to 20% diethyl ether) afforded 2.54 g (96%) of ((3,7-diethyl-2,6-octadienyloxy)). phenyl] propyl acetate (boiling point 146-148 ° C / l3,3 Hg). Elemental analysis for ^H 30 ° 21 ° 3 (330): calculated: 76.33% 0, 9, 15% Hj found 76.30% 0.99% H.

To 2.2 g of acetic acid [(3,7-dimethyl-2,6-octadienyloxy) phenyl] propyl ester, 12 ml of a solution of monoperphthalic acid in anhydrous diethyl ether (102 mg / ml) was added dropwise with stirring at 10-20 °. After standing for half an hour at 10-20 ° C, the reaction mixture was partitioned between saturated NaHGO 4 solution and diethyl ether. The separated, washed and dried organic layer, after evaporation of the solvent under reduced pressure, gave a residue which was further separated on a silica gel column (8 wt% water eluent: petroleum ether containing up to 50 vol% diethyl ether). Chromatography yielded 75 [deg.] C. (33%) [(3,7-dimethyl-6,7-epoxy-2-octenyloxy) phenyl] propyl acetate (boiling point 163-165 [deg.] C./13.3 Pa). Elemental analysis for 021 ^Η 30θ4 (346): calculated 72.80% C, 8.72% Hj found 72.63%

C, 8.55%. MS spectrum (70 eV): 346 (M ^& lt ^{; +} & gt ^; ), 303 ([delta] & lt ^; 19 &^gt;). 287 (194

165, (O 2 O 3), 153 (O ₁₀ ^H 17 °), ^χ 35 (C ₆ ^H 6 O), 71 (C 6 O).

Acetic acid phenyl-4- (3,7-dimethyl-6,7-epoxy-2-octenyloxy) phenyl-methyl ester was prepared in the same manner. IR (CC1 4% ₄₎ 1745 (V 0 = 0 ester.), 1671 (Γ 0 = 0), 1615, 1587, 1516 cm - ¹ (/ aromatic).

Example 3

To a solution of 1 g of β (3,7-dimethyl-2,6-octadienyloxy) phenyl] propanol in 10 ml of anhydrous dimethylformamide was added 280 mg of anhydrous pyridine and 1.05 g of stearic acid chloride. The reaction mixture was then shaken between diethyl ether and water, the organic phase after washing and drying was evaporated under reduced pressure. Column chromatography on silica gel (8 wt% water eluting agent: petroleum ether containing up to 20 vol% diethyl ether) afforded 1.16 g (60% [(3,7-dimethyl-2,6-octadienyloxy) phenyl] propyl ester of the acid) elemental analysis for (554): calculated 80.08% C,

213 703

11.26. Found: 79.80% 0.11.05%.

Δδ spectrum (4% in CCl ₄ ): 1758 (δ = 0 ester.), 1675, (δ C = C), 1615, 1587, 1517 cm ^-1 (/ aromatic).

To a solution of 1 g of [(5,7 ^- dimethyl-2,6-octadienyloxy) phenyl] propyl octadecanoate was added dropwise at 10-20 ° C and with stirring, 5.2 ml of a solution of monoperphthalic acid in anhydrous diethyl ether (70 mg / ml). ). After half an hour, the reaction mixture was partitioned between saturated NaHCO 3 solution and diethyl ether. The separated, washed and dried ether layer was evaporated under reduced pressure and the residue was further separated by silica gel column chromatography (8 wt% water; eluent: petroleum ether containing up to 50 vol% diethyl ether). 560 mg (55%) of octadecanoic acid [(5,7-dimethyl-6,7-epoxy-2-octenyloxy) phenyl] propyl ester was obtained. Elemental Analysis for Ηθ ^^ 0 ₂ 0 ₄ (570): Calculated 77.84% 0 10.94% H; found 77.55% 0, 10.70% H.

IR spectrum (4% in CC1 _4): 1757, 1750 (/ 0 = 0 ester.), 1675 (/ C = C), 1614, 1587, 1516 cm ^-1 (aromatic Γ).

Using the same procedure, (5,7-dimethyl-6,7-epoxy-2-octenyloxy) phenyl propyl chloroacetate was prepared. IR spectrum (4% in CC1 _4): 1765, 1742 (/ 0 = 0 ester.), 1672 (/ 0 = 0). 1615, 1587,151? cm ^-1 (aromatics) and 4-chlorobenzoic acid (5,7- (3-methyl-6,7-epoxyoctyloxy) phenyl) propyl ester. iC spektium (4% in CC1 _4): 1724, 1712 (? C = 0 ester.). 1615, 1597, 1522, 1517 cm ^-1 (aromatics).

Example 4

A mixture of 2.88 g of [(5,7-dimethyl-2,6-octadienyioxy) phenyl] propanol, 790 mg of anhydrous pyridine and 1 g of succinic anhydride was heated with stirring at 60-70 ° C for 2 hours. It was then partitioned between diethyl ether and saturated NaHCO 3 solution. The separated, washed, dried and evaporated under reduced pressure organic layer or its residue was finally separated by passing through a silica gel column (8% by weight of water; eluent: petroleum ether containing up to 75% by volume of diethyl ether). The fraction corresponding to 1.5 g of 5-carboxypropionic acid [(5,7-dimethyl-2,6-octadienyloxy) phenyl] propyl ester was reacted at 10-20 ° C with an ethereal solution of diazomethane. After evaporating the excess ethereal diazomethane solution and passing the residue again through a silica gel column (8% by weight of water; eluent: petroleum ether containing up to 50% by volume of diethyl ether), 1.28 g of (5,7-dimethyl-2,6-) was obtained. octadienyloxy) phenyl of 5-methoxypropionic acid propyl ester. Elemental analysis for ^G 24 ^H 54 ° ⁰² ^ ^5): calculated 71.61% C, 8.51% H; found 71.40% C, 8.26% H. IR spectrum (4% in CC1 _4): 1? 44, 1752 (<0 f = 0 ester.), 1671, (C ^- C = C), 1614, 1587, 1517 cm ¹ (/ aromatics).

The reaction mixture obtained by reaction of 1.2 g of 5-methoxypropionic acid (5,7-dimethyl-2,6-octadienyloxy) phenyl] propyl ester with 7.8 ml of a solution of monoperphthalic acid in anhydrous diethyl ether (70 mg / ml) at 10 to 20 ° C After standing for half an hour, it was partitioned between saturated NaHCO 3 solution and diethyl ether. The separated, washed and dried organic layer yielded a residue after evaporation of diethyl ether. further separated on a silica gel column (8 wt% water; eluent: petroleum ether containing up to 50 vol% diethyl ether).

213 703

Chromatography gave 48? mg (38%) of 3-methoxycarbonyl propionic acid [(3,7- <limethyl-6,7-epoxy-2-octenyloxy) phenyl] propyl ester. Elemental analysis for ^H 24 ⁰ 6 34 DEG calculated 68.87% C, 8.18% H; found: 68.82% C, 8.31% H. IR (4% in CCl4):

1744, 1732 (C = O ester), 1673 (VO = C), 1614, 1587, 1517 cm ^-1 (aromatics).

2-Methoxycarbonylbenzoic acid β (3,7-dimethyl-6,7-epoxy-2-octenyloxy) phenyl] propyl ester was prepared in the same manner; IR (4% in CCl3): 1733 (Z = C-ester),

1675 (fC = C), 1613, 1585, 1516 cm @ ¹ (aroma).

The biological activity of the compounds prepared according to the invention was tested on the basis of insect juvenile hormone activity. The substances were applied topically in 1 microliter of acetone at a 1:10, 1: 100 dilution, etc. to freshly stripped pupae of beetles (headed Tenebrionidae) and freshly stripped larvae of last bug instar (headed Pyrrhocoridae and Pentatomidae) and the like. The activities of the test substances were evaluated by inhibition of metamorphosis. Some of the results shown in Table 1 are expressed in standard units, which indicates the amount of the substance in micrograms per insect that under the above experimental conditions gives rise to intermediate forms between pupae and adults (beetles) and between larvae and adults ( for bugs).

Table _1K

Examples of the activities of the compounds prepared according to the invention in ID4 units on insect individuals when topically applied to insects of the family Pyrrhocoridae, Pentatomidae and Tenebriondae

Dyspercus Graphosoma Tenebrio cingulatus italicum molitor (317-diethyl-6,7-epoxy-2-octenyloxy) phenyl 0,05 octadecanoic acid propyl ester (3,7-dimethyl-6,7-epoxy-2-octenyloxy) phenyl acetic acid propyl ester 0,3 (3,7-dimethyl-6,7-epoxy-2-octenyloxy) phenyl propyl monochlorobenzoate 0,1 (3,7-dimethyl-6,7-epoxy-2-octenyloxy) propanol 0,5

Reference substance:

cis-10,11-epoxy-3,7, trimethyl-trans, trans-2,6-tridecadienic acid methyl ester 0,4 (3,7-dimethyl-6,7-epoxyoctyloxy) phenyl propanol 0,1 (3) 7,7-Dimethyl-6,7-epoxy-2-octenyloxy) phenyl propyl ester of 3,7-dimethyl-6,7-epoxy-2-octenyloxy) phenyl propyl ester of monochlorootic acid (3,7-dimethyl-6,7) 4-chloro-benzoic acid propyl-4-chloro-benzoate 0.1

Acetic acid 1-phenyl-1-4- (3,7-dimethyl-6,7-epoxy-2-octenyloxyphenyl methyl ester) 10

0,3 7

0.6

3

10

40

213 703 2-Methoxycarbonylbenzoic acid (3,7-dimethyl-6,7-epoxy-2-octenyloxy) phenyl propyl ester 10 (3,7-dimethyl-6,7-epoxy-2-octenyloxy) phenyl propyl ester 3 -methoxycarbonylpropionic 1 7

Substance

Dyspercus cingulatus

Graphosoma italicum

Tenebrio molitor

Claims (3)

Biologically activated juvenoidogenic substances having an epoxy bond in a molecule of the general formula I - (CH ₂ ) _and -JC (E ³ Z ¹ ) - C (R ⁴ Z ² )] _b - CH (R ⁵ ) -O-yQ 4 -CH (R ⁶ ) - OR ⁷ , Even where a denotes 0 or 2, b denotes 0 or 1, R 2 is R, R is methyl or ethyl, R ³ to R ³ are hydrogen or methyl or ethyl, R ⁶ is straight or branched alkyl of up to 6 carbon atoms or phenyl, 1 2 the symbols Z, Z denote hydrogen or together form a double bond or a -O bond R 'denotes hydrogen or -COR, wherein R represents a straight or branched substituent of the formula Z ^3- (CH) _c -, Z ⁴ wherein Z ³ and Z ⁴ denote hydrogen or straight or branched alkyl of up to 5 carbon atoms, c denotes an integer ranging from 1 to 20, a substituent of the formula Z ⁵ - (CH p). - CH Ifi Wherein C ² represents hydrogen or - COOZ; Z is hydrogen or methyl or ethyl or -CH2COOZ (R); d is an integer ranging from 0 to 2; symbol Q Z represents a straight or branched alkyl having 1 to 14 carbon atoms, a straight or branched substituent of the formula 213 703 Z ⁴ - (CH) _e -, z ⁹ wherein Z ⁴ is as defined above; e is an integer ranging from 0 to 15; the symbol Z ^, which is represented in the formula up to three times, represents chlorine or bromine or the group -ΟΟΖ ^ θ or the group Z Q 1Λ or -COOZ; Z represents 11 straight or branched alkyl of up to 6 carbon atoms; Z ^x denotes hydrogen or a chlorine or bromine group or a -NOg group or a - COOZ group; symbol Z my meaning above. 2. A process according to claim 1, wherein the ketone of formula II (II) is reacted with one another. COR ^c R ^ R ² C - CH - (CH g) a - [θ (R ³ Z ¹ ) - C (R ⁴ Z ² ) J b> CH (R ⁵ ) - 0 - (θ \ Where R to R, Z, Z, a, b are as defined above and lithium aluminum hydride in the anhydrous environment of organic solvents inert to the reactants, for example, in anhydrous diethyl ether, to form an alcohol of formula III R n O = CH - (CH ₂₎ - [^ CIR Z ¹⁾ - C (R ⁴ Z ^2)] _b - CH (R ⁵⁾ - 0 --CH (0H) R ⁶ (III) Wherein R to R, Z, Z, a, b are as defined above, which is further reacted with a compound of formula IV, 8 R ° -CO-Y (IV) Wherein Y is hydroxyl or chlorine or -OCOR and R is Z ⁴ of ⁶ 7? - (CH) _c - or Z ^3- (CH 8) d -CH-CH - or Z - (CH) e -, wherein the symbols Z ³ to Z 2, Z ⁹ , c, d, e are as defined above or Y and R ⁸ together form a group 'Μ'σο · ^ wherein Z ⁴ is as defined above; f denotes 2 or 3 or a group wherein g denotes 0 or 1 to form an ester of formula V: R ¹ R ² -C = CH - ^(0Η24 “[? ( ^R5z1 ) - CH (R ⁵ ) - 0 - (C>) - CH (R ⁶ ) (V) OCOR ⁸ , Wherein R to R, R, Z, Z, a, b have the meanings given above, which, like the alcohol of formula III, by reaction with a peracid at a temperature of 10 to 20 ° C preferably with monoperphthalic acid, gives a final the product of formula I.