RU2561272C1 - Method of producing 1-(8-methoxy-4,8-dimethylnonyl)-4-(1-methylethyl)benzene from isoprene (versions) - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to versions of a method of producing 1-(8-methoxy-4,8-dimethylnonyl)-4-(1-methylethyl)benzene, which is an environmentally safe insecticide (juvenoid) used to protect plants. One of the versions includes reacting isoprene with a dialkylamine selected from: dimethylamine, diethylamine, piperidine, morpholine, in the presence of a catalyst, such as butyllithium or lithium, at temperature of 20-60°C; the obtained neryl dialkylamine is methoxylated with methanol while heating in the presence of 1-1.2 equivalents of H₂SO₄ or HClO₄ to form the corresponding N-(7-methoxy-3,7-dimethyl-2Z-octenyl)dialkylamine, which undergoes quaternisation with ethyl- or methyl iodide and the obtained N-(7-methoxy-3,7-dimethyl-2Z-octenyl)trialkylammonium iodide undergoes cross-coupling with an organomagnesium compound, such as para-isopropylbenzylmagnesium chloride, in the presence of a copper catalyst in the form of CuBr or Li₂CuCl₄ at low temperature of (-5°C) - (-10°C) to form 1-(8-methoxy-4,8-dimethylnonen-3-yl-1)-4-(1-methylethyl)benzene, which is hydrogenated with hydrogen in the presence of a Pd/BaSO₄ catalyst and AcOH in ethanol solution at atmospheric pressure and temperature of 20-25°C and the end product is obtained.

EFFECT: versions of the method enable to obtain the end product with high output.

3 cl, 7 ex

Description

The invention relates to the chemistry of terpene compounds, namely to aryl-substituted terpenes, in particular, to a method for producing 1- (8-methoxy-4.8-dimethylnonyl) -4- (1-methylethyl) benzene of formula 1 (also known as Pro-Drone and MV -678) from isoprene (2).

Compound 1 is a widely known drug that is used most effectively in agriculture, as it has growth-regulating activity against various types of insect pests and is an environmentally friendly insecticide (juvenoid) used to protect plants.

Juvenoids are substances that mimic or inhibit the action of the juvenile hormone, which is responsible for the processes of molting and metamorphosis in the body of an insect. As a result, individuals incapable of reproduction are formed. Thus, regulation of the number of insects is achieved, and not the complete destruction of the species. Juvenoids are environmentally friendly insecticides because, as a rule, they do not have an effect on other participants in the biocenosis.

Compound 1 is known to be used to regulate the numbers of such insects, such as cat fleas (LM El-Gazzar, PG Koehler, RS Patterson, J. Milio, J Med. Entomology, 1986, Vol. 23, no. 6, p . 651-4), citrus pest - Florida wax shield (A. Eisa, MA El-Fatah, A. El-Nabawi and AA El-Dash Phytoparasitica 1991, Vol. 19, no., P. 49-55), rice weevil (JN Mkhize, Tropical Pest Management, 1986, Vol. 32, no. 4, p. 324-6; A. Eisa and IMA Ammar, Phytoparasitica ", 1992, Vol. 20, no. 1, p. 7-13 ), pests of wheat flour and grain from the Coleoptera order (LS Mian, MS Mulla, J. Economic Entomology, 1982, Vol. 75, no. 1, p. 80-5; JN Mkhize, Insect Science and Its Application 1993, Vol.14 , no. 3, p. 351-3), meat flies (N. Sukhapanth, C. Ketavan, J Sc i. Soc. of Thailand, 1995, Vol. 21, No. 3, p. 147-60) Juvenile activity of Compound 1 is known for tropical pests such as termites and mosquitoes (WA Banks; LR Miles, DP Harlan , "The effects of insect growth regulators and their potential as control agents for imported fire ants (Hymenoptera: Formicidae)", Florida Entomologist 1983, Vol.66, no. 1, p. 172-81; M.S. Mulla, H.A. Darwazeh, "New insect growth regulators against flood and stagnant water mosquitoes-effects on nontarget organisms." Mosquito News, 1979, Vol. 39, no. 4, p. 746-55).

A known method for producing compound 1 (US patent No. 4002769), which consists of the following five stages (scheme I):

- obtaining para-isopropylbenzyl chloride from para-isopropylbenzyl alcohol by the action of concentrated HCl with extraction of the product with hexane;

- the interaction of para-isopropylbenzyl chloride with triphenylphosphine with the formation of the corresponding phosphonium salt in 90% yield using diethyl ether.

- Wittig reaction of the obtained phosphonium salt with citronellal to form 4,8-dimethyl-1- (n-isopropylphenyl) nona-1,7-diene in the form of a 60:40 mixture of cis and trans isomers (the phosphonium salt is converted by the action of sodium in abs. ethanol phosphorane, to which citronellal is added, and after normal treatment, 4,8-dimethyl-1- (n-isopropylphenyl) nona-1,7-diene is obtained;

- restoration of the vinyl double bond of the obtained diene with sodium in liquid ammonia to form 4,8-dimethyl-1- (n-isopropylphenyl) non-1-ene;

- alkoxymercation-demercuration of 4,8-dimethyl-1- (p-isopropyl-phenyl) non-1-ene (mercury acetate in methanol solution followed by NaBRt in the presence of NaOH), which gives the target product 1, with a total yield of 32% .

The disadvantages of the method include the use of a large amount of concentrated hydrochloric acid, the use of flammable diethyl ether and hexane, explosive metallic sodium, highly toxic liquid ammonia and toxic complexes of mercury.

A known method of obtaining compounds 1 (US patent No. 465943 and 4482751 and application EP 0116370A), consisting of three stages:

(1) obtaining a triphenylphosphonium salt of para-isopropylbenzyl chloride in a methanol solution;

(2) the interaction of the obtained phosphonium salt in a methanol solution with methoxycytronellal in the presence of sodium methoxide, followed by treatment with 30% H ₂ O ₂ and obtaining 8-methoxy-4,8-dimethyl-1- (4-isopropylphenyl) non-1-ena ;

(3) hydrogenation of the double bond of 8-methoxy-4,8-dimethyl-1- (4-isopropylphenyl) non-1-ene with hydrogen, catalyzed by palladium on carbon at a hydrogen pressure of 3-4 atm.

The disadvantages of the method are the need to use commercially available methoxycytronellal, as well as a large amount of toxic methanol, easily decomposable sodium methoxide and explosive 30% hydrogen peroxide, as well as hydrogenation at elevated hydrogen pressure.

A common disadvantage of the two above-mentioned analogues is the need to use equivalent amounts of toxic triphenylphosphine, which in the form of toxic triphenylphosphine oxide is disposed of. In addition, in accordance with modern environmental requirements, it is necessary to completely exclude organophosphorus compounds from industrial practice.

A known method for producing compound 1 (WO 84/02337), in which the main terpene derivative is dihydromyrcene (3,7-dimethylocta-1,6-diene), obtained from alpha or beta-pinene (Scheme 2). This method of the type of chemical reaction is closest to the claimed and adopted as a prototype.

The prototype method includes the following stages (scheme 2):

(1) hydrogenation of alpha or beta-pinene with hydrogen to form pinane (at a hydrogen pressure of 350 atm and a temperature of up to 250 ° C in the presence of a skeletal nickel catalyst);

(2) pinan pyrolysis at 600-620 ° C to form 3,7-dimethylocta-1,6-diene (dihydromyrcene) (two stages yield 22%);

(3) methoxylation of dihydromyrcene in a methanol solution in the presence of acid catalysts to form 7-methoxy-3,7-dimethyloct-1-ene (in the presence of an Amberlyst ion-exchange resin at 50 ° C (58% yield);

(4) metallation of the obtained 7-methoxy-3,7-dimethyloct-1-ene with propyl magnesium chloride in the presence of Cp ₂ TiCl ₂ at 75 ° C, which affords 7-methoxy-3,7-dimethyloctyl magnesium chloride (19 h, 50% conversion) ;

(5) a cross-combination of the obtained alkylmagnesium chloride with cuminyl chloride in the presence of CuCl or Li ₂ CuCl ₄ . The result is the desired product 1 in the form of a mixture with p, p′-diisopropyldibenzyl.

The disadvantages of the prototype are: the need to use high temperatures at the stages of obtaining pinan and dihydromyrcene (250-620 ° C), low and moderate yields of intermediate products (yield of dihydromyrcene 22%) and the target compound (30-38% at the 5th stage and 3% calculated on the starting pinene), the formation of an impurity p, p′-diisopropyl dibenzyl, which can reduce the biological activity of the target compound, as well as the use of propylmagnesium chloride as a metalating agent, since after use, it completely goes to waste ie, it is non-commercial product and its preparation is complicated by the way.

The present invention is to develop a technologically advanced method for producing 1- (8-methoxy-4,8-dimethylnonyl) -4- (1-methylethyl) benzene 1, in high yield from commercially available raw materials.

The technical result of the invention is a new method (options) for the preparation of 1- (8-methoxy-4,8-dimethylnonyl) -4- (1-methylethyl) benzene 1, from industrially available raw materials (isoprene), which provides an increase in the yield of the target product 1, and increasing its purity.

The problem is solved by the proposed method (options I, II and III) for obtaining compound I, including cross-coupling of an organomagnesium compound with a nucleophile, catalyzed by Li ₂ CuCl ₄ (schemes 3-5).

Option I of the proposed method (scheme 3) is that in stage (1) isoprene 2 is reacted with a dialkylamine selected from the group: dimethylamine, diethylamine, piperidine, morpholine, in the presence of a catalyst such as lithium or butyl lithium, when heated;

in step (2), the obtained N- (3,7-dimethylocta-22,6-dien-1-yl) dialkylamine (hereinafter non-aryl dialkylamine) (3a-g) is methoxylated with methanol under heating in the presence of 1-1.2 equivalents of H ₂ SO ₄ or HClO _{4 to} give the corresponding N- (7-methoxy-3,7-dimethyl-2Z-octenyl) dialkylamine (4a-g); which in step (3) is subjected to quaternization with ethyl or methyl iodide;

in step (4), the obtained N- (7-methoxy-3,7-dimethyl-2Z-octenyl) trialkylammonium iodide is cross-coupled with an organomagnesium compound, such as p-isopropylbenzylmagnesium chloride 6, in the presence of a copper catalyst, using CuBr or Li ₂ CuCl ₄ at a temperature of (-5) - (- 10 ° C) and 1- (8-methoxy-4,8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene is obtained in the form mixtures of cis and trans isomers 7a and 7b;

in step (5), the resulting mixture of isomers 7a and 7b is hydrogenated with hydrogen in the presence of a Pd / BaSO ₄ and AcOH catalyst in a solution of ethanol at atmospheric pressure and a temperature of 20-25 ° C and the target product 1 is obtained.

Option II of the inventive method for producing compound 1 is shown in Scheme 4 and includes the following steps: (1) reacting isoprene with a dialkylamine selected from the group: dimethylamine, diethylamine, piperidine, morpholine, in the presence of a catalyst, such as butyl lithium or lithium, when heated; (2) methoxylation of the resulting non -ryldialkylamine (3a-g) with methanol by heating in the presence of 1-1.2 equivalents of H ₂ SO ₄ or HClO _{4 to} give the corresponding N- (7-methoxy-3,7-dimethyl-2Z-octenyl) dialkylamine (4a-d); (3) chlorination of the obtained N- (7-methoxy-3,7-dimethyl-2Z-octenyl) dialkylamine (4a-g) with phosgene or an alkyl (aryl) chlorocarbon ether selected from the group: methyl chlorocarbon ether, ethyl chlorocarbon ether, phenylchlorocarbon ether, with the formation of (Z) -1-chloro-7-methoxy-3,7-dimethyl-2-octene (5 g); (4) the interaction of compound 5 g with para-isopropylbenzylmagnesium chloride 6 in the presence of Li ₂ CuCl ₄ at a temperature of (-20 ° C) - (-3) ° C with the formation of 1- (8-methoxy-4,8-dimethylnonen-3- il-1) -4- (1-methylethyl) benzene as a mixture of cis and trans isomers 7a and 7b;

(5) hydrogenation of a mixture of isomers 7a and 7b with hydrogen in the presence of a Pd / BaSO ₄ and AcOH catalyst in a solution of ethanol at atmospheric pressure and a temperature of 20-25 ° C with the formation of the target product L

Stage (1) and (2) in variants I and II are the same, they are carried out under the same conditions: stage (1) of the interaction of isoprene 2 with dialkylamine is carried out at a temperature of 20-60 ° C, and stage (2) of methoxylation with the formation of the corresponding N- (7-methoxy-3,7-dimethyl-22-octenyl) dialkylamine - at 40-50 ° C.

Option III of the proposed method for producing 1- (8-methoxy-4,8-dimethylnonyl) -4- (1-methylethyl) benzene 1 is shown in scheme 5 and includes the following stages:

(1) взаимодействие изопрена с диалкиламином, выбранным из группы: диметиламин, диэтиламин, пиперидин, морфолин, в присутствии катализатора, такого как Pd(acac)₂-P(OBu)₃-CO₂, при температуре 100-120°C;

(1) the interaction of isoprene with a dialkylamine selected from the group: dimethylamine, diethylamine, piperidine, morpholine, in the presence of a catalyst such as Pd (acac) ₂ -P (OBu) ₃ -CO ₂ , at a temperature of 100-120 ° C;

(2) methoxylation of the obtained N- (3,7-dimethylocta-2E, 6-dien-1-yl) dialkylamine (hereinafter α-geranyl dialkylamine) with 3-d methanol in the presence of 1-1.2 equivalents of H ₂ SO ₄ or HClO ₄ upon heating to form the corresponding N- (7-methoxy-3,7-dimethyl-2E-octenyl) dialkylamine 4e-z;

(3) quaternization of the obtained compound 4e-3 with ethyl or methyl iodide;

(4) a cross-combination of the obtained N- (7-methoxy-3,7-dimethyl-2E-octenyl) trialkylammonium iodide with an organomagnesium compound, such as p-isopropylbenzylmagnesium chloride 6, in the presence of a copper catalyst, which is used CuBr or Li ₂ CuCl ₄ at a temperature of (-5) - (- 10 ° С) with the formation of 1- (8-methoxy-4,8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene in the form of trans- cis isomers 7b and 7a;

(5) hydrogenation of a mixture of isomers 7b and 7a in the presence of a Pd / BaSO ₄ catalyst and AcOH in an ethanol solution at atmospheric pressure and a temperature of 20-25 ° C with the formation of the target product 1.

In the present method does not require the use of high temperatures (250-620 ° C), which are necessary for the implementation of the prototype method. The total yield calculated on the starting material (isoprene) is 29%, and not 3% as in the prototype.

In addition, it is known that a catalytic cross-combination, including alkyl-magnesium components, such as in the prototype, is complicated by the formation of a large number of homogenization products (up to 50%). The cross-coupling product obtained by the claimed method either does not have homocomposition product 8 at all (options I and III), or contains only insignificant amounts of this product (option II), which is due to the use of the benzyl-magnesium component in the cross-combination, and not to the alkyl-magnesium component as in prototype.

The by-product 8 and cross-product isomers that can be formed during the cross-coupling reaction 7a, 7b and 7c are presented below.

As the 2nd component of the cross-coupling reaction in variants I and III of the proposed method, quaternary ammonium salts containing an allyl fragment are used (variants I and III). In this case, the product of homocomposition 8 is not formed. The composition of the ammonium leaving group practically does not affect the yield of the product (61-85%). The isomeric composition of the cross-coupling product varies in the following ranges 7a: 11-48%, 7b: 35-81%, 7c: 2-12%. 7a and 7b are the cis and trans isomers of 1- (8-methoxy-4,8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene; 7c is their skeletal isomer. As a result of hydrogenation, 7a and 7b are converted to the target product 1. In option II, (Z) -1-chloro-7-methoxy-3,7-dimethyl-2-octene (5g) is used as the 2nd component of the cross-coupling reaction ; only in option II, the formation of insignificant amounts of homocomposition product 8 (1-3%) is noted.

The advantage of option III of the method is faster methoxylation of the terminal double bond of α-geranyl dialkylamine (step 2) compared to methoxylation of the internal double bond of non-dialyldialkylamine.

The CuBr or Li ₂ CuCl ₄ catalysts used do not significantly affect the isomeric composition of the product.

The terpene derivative (non-dialyldialkylamines) for the cross-coupling reaction in the present method (options I and II) is obtained under mild conditions (at a temperature of 20-60 ° C), lithium is used in catalytic amounts, which does not require special equipment. Option III requires a higher temperature (100 ° C) and the use of a palladium catalyst. But for the implementation of the prototype method requires very high temperatures (250-620 ° C) and pressure (250 ° C and 350 atm).

In the inventive method, the feedstock isoprene-multi-ton product of petrochemical synthesis. To create the organometallic cross-coupling component 6, cheap and commercially available para-isopropylbenzyl chloride (cuminyl chloride) is used and metallized with magnesium metal, while the prototype uses propylmagnesium chloride, which is not commercially available, which requires an additional step for its preparation, in addition, after the reaction, it is completely goes to waste.

Thus, the claimed method (options I-III) has the following advantages:

- using available raw materials - isoprene, which is a large-tonnage product of petrochemical synthesis;

- the yield of the target product 1, based on the starting isoprene is 29%, whereas in the prototype method, the yield of product 1, based on the starting raw material 3%;

- the yield of the target product in the last stage is 97%, which is higher than in the prototype;

- obtaining a cleaner target product 1 (purity up to 95%), and the impurity (2-5%) is the skeletal isomer of product 1, which does not reduce its biological activity.

- the implementation of the method does not require the use of high temperatures and high pressures;

- in the inventive method, instead of propyl magnesium chloride used in the prototype, cheap and commercially available para-isopropylbenzyl chloride (cuminyl chloride) is used, thus, the stage of producing propyl magnesium chloride is eliminated;

the method does not require the use of toxic reagents, in particular phosphorus-containing compounds;

- alkali metals are used in amounts that do not require the use of explosion-proof equipment;

Thus, the proposed method is more technologically advanced, economical and environmentally friendly than the prototype.

The authors of the present invention investigated the activity of compound 1 in biological trials on a large flour flake Tenebrio Molitor L. - the main pest of grain stocks in the Russian Federation. Compound 1 was tested for the activity of juvenile hormones in the pupae of the large flour flakes (Tene brio molitor L.) of the laboratory wiring of the All-Russian Scientific Research Institute of Plant Protection Chemicals (VNIIKhSZR). It was shown that the compound has high activity (score of 7.6 points, with a maximum possible score of 9 points).

Gas-liquid chromatography (GLC) was performed on an LKhM-8MD chromatograph (5) with a 2000 × 3 mm steel column with 15% SKTFT-50 on an N-AW chromaton, and the carrier gas was helium. ¹ H NMR spectra were recorded on Bruker Avance-200 and Avance-400 instruments (CDCl ₃ , internal TMS standard).

The invention is illustrated by the following examples.

Obtaining compound 1 (option I)

1.1. Interaction of Isoprene with Diethylamine: Preparation of N-Neryl Diethylamine 3b. Finely chopped lithium metal (0.2 g, 28.8 mmol, 28.8 mol%) or butyl lithium (9 ml of a 1.14 N solution of BuLi in benzene, 0.01 mol, 10 mol%) are added to the diethylamine solution ( 14 ml, 0.1 mol) in 50 ml of dry benzene at room temperature with stirring, after 50 minutes isoprene (30 ml, 0.3 mol) was added to the resulting mixture and refluxed under stirring under argon for 18 hours. The reaction mixture was poured into water, extracted with benzene. Dried Na ₂ SO ₄ . Low boiling products are removed at 100 mmHg. Fractional distillation of the residue in vacuo gives the amine 3b - 9.6 g (46%) in the case of lithium or 8.6 g (41%) in the case of butyllithium with so on. 116-120 ° C / 10 mmHg

1.2. Methoxylation of product 3b to form N- (7-methoxy-3,7-dimethyl-2Z-octenyl) diethylamine 4b. N-nonryldiethylamine 3b (40 g, 0.18 mol) was dissolved in 150 ml of MeOH and 24.5 ml (0.36 mol) of 57% HClO _{4 was} added at 0 ° C. It is boiled for 3 days, poured into an aqueous KOH solution (pH 8-8.5), extracted with ether, dried with Na ₂ SO ₄ . Distillation in vacuo gives 25.2 g (58%) of N- (7-methoxy-3,7-dimethyl-2Z-octenyl) diethylamine 46, b.p. 138-142 ° C / 10 mmHg 1 H-NMR spectrum (δ, ppm, J, Hz): 1.03 m (6H, 2 ^N CH ₃ , J = 6.8), 1.3 s (6H, ⁸ CH ₃ , ^7a CH ₃ ), 1.38 m (4H, ⁵ CH ₂ , ⁶ CH ₂ ), 1.78 s (3H, ^3a CH ₃ ), 2.03 m (2H, ⁴ CH ₂ ), 2.43 m (4H, 2 ^N CH ₂ , J = 6.8), 2.96 d (2H, ¹ CH ₂ , J = 7.1), 3.2 s (3H, OCH ₃ ), 5.0 t (1H, ² CH, J = 7, 1 Hz). Found,%: C 74.50; H 12.78; N 5.73. C ₁₅ H ₃₁ NO. Calculated,%: C 74.63, H 12.94, N 5.80.

1.3.1 Quaternization of compound 46 with ethyl iodide. 7 g (28.9 mmol) of amine 4b are mixed with 10 ml of benzene and 9 g (57.8 mmol) of ethyl iodide are added. Leave in the dark at room temperature. After 3 days, the white precipitate was filtered off, washed with pentane. 10.2 g (87%) of N- (7-methoxy-3,7-dimethyl-2Z-octenyl) triethylammonium iodide 5ba are obtained. Found,%: C 51.25; H, 8.97; N, 3.69. C ₁₇ H ₃₆ NOI. Calculated,%: C 51.38; H, 9.13; N, 3.52.

1.3.2. Quaternization of compound 4b with methyl iodide. To 3.0 g (12.9 mmol) of amine 4b was added 0.96 ml of methyl iodide (15.48 mmol) in an argon atmosphere. The mixture was kept at 25 ° C in the dark for 2 days. A brown, viscous oil falls out of solution. The oil is washed with hexane by decantation to remove unreacted amine and excess MeI. Receive: 4.5 g (91%) of N- (7-methoxy-3,7-dimethyl-2Z-octen-1-yl) diethylmethylammonium iodide 5bb in the form of a viscous oil. PMR spectrum (CDCl₃) ppm, J, Hz: 1.10; 1.11 (s, s, 6H,⁸CH₃,^7aCH₃), 1.34-1.46 (m, 10H,^NCH₃, ⁵CH₂,⁶CH₂), 1.85 (s, 3H,^3aCH₃), 2.11 (m, 2H,^fourCH₂), 3.13 (s, 3H, OCH₃), 3.14 (s, 3H,^NCH₃), 3.43-3.63 (m, 4H,^NCH₂4.04 (d, 2H,^oneCH₂, J = 8.33), 5.14 (t, 1H,²CH, J = 8.33).

1.4. The interaction of compound 5ba with para-isopropylbenzyl magnesium chloride 6. From 2.8 g (16.3 mmol) of para-isopropylbenzyl chloride and 0.5 g (20 mmol) of magnesium, Grignard reagent in 20 ml of diethyl ether is obtained. The resulting reagent is added at -20 ° C to a suspension of 4.0 g (10.9 mmol) of salt 5ba and 0.1 ml (0.697 mmol, 8 mol%) of Li ₂ CuCl ₄ in 30 ml of THF, stirred at -7 ÷ -4 ° C for 5 hours and at room temperature for 12 hours. The reaction mixture was poured into a saturated solution of NH ₄ Cl, the product was extracted with a mixture of petroleum ether-diethyl ether, dried with Na ₂ SO ₄ . After distillation in vacuo, 2.7 g (93%) of 1- (8-methoxy-4,8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene are obtained with so on. 123-130 ° C (2 mmHg) in the form of a mixture of isomers: 32% of the cisisomer 7a, 60% of its transisomer 7b, and 8% of the allyl rearrangement product 7c. Homocomposition product 8 was not found. Found,%: C 83.64, H 11.52. C ₂₁ H ₃₄ O. Calculated,%: C 83.38; H, 11.33.

The interaction of N- (7-methoxy-3,7-dimethyl-2Z-octen-1-yl) diethylmethylammonium iodide 5bb (from 1.3.2.) With para-isopropylbenzylmagnesium chloride 6 is carried out similarly.

1.5. Reduction of 1- (8-methoxy-4,8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene. The mixture of isomers (0.8 g, 2.6 mmol) obtained in stage 1.4 in 20 ml of EtOH is hydrogenated with hydrogen gas at atmospheric pressure and room temperature in the presence of 0.1 g of Pd / BaSO ₄ and 1 ml of AcOH. After the usual workup, the expected product, 1- (8-methoxy-4,8-dimethylnonanyl-1) -4- (1-methylethyl) benzene 1, is obtained in 97% yield. ¹ H NMR spectrum, δ ppm, J, Hz: 0.90 d (3H, CH ₃ , J = 6.7), 1.09 s, s (6H, CH ₃ , CH ₃ ) 1.22 d (6H, CH ₃ , CH ₃ , J = 6.5), 1.32 m (6H, CH, ⁵ CH ₂ ), 2.60 t (2H, CH ₂ -Ph, J = 6.7), 2.90 m (1H, CH-Ph), 3.16 s (3H, CH ₃ O), 7.10 m (4H, Ph). Found,%: C 82.91, H 11.82. C ₂₁ H ₃₆ O. Calculated,%: C 82.83, H 11.92.

Example 2

2.1. Interaction of isoprene with dimethylamine: the preparation of N-non-yryldimethylamine 3a is carried out analogously to the preparation of compound 36 (Example 1, p.1.1) using 15.7 g (0.344 mol) of dimethylamine condensed from an ethanol solution. 12.87 g (33%) of amine 3a are obtained with a boiling point. 92-102 ° C / 10 mmHg

2.2. Methoxylation of product 3a to form N- (7-methoxy-3,7-dimethyl-22-octenyl) dimethylamine 4a was carried out analogously to the preparation of compound 4b (Example 1, paragraph 1.2) using 32.5 g (0.18 mol) of N Neryldimethylamine 3a. 22.6 g (59%) of product 4a are obtained, b.p. 110-116 ° C / 10 mmHg Found,%: C 73.09, H 12.61, N 6.64. C ₁₃ H ₂₇ NO. Calculated,%: C 73.18, H 12.76, N 6.56.

2.3. The quaternization of compound 4a is carried out similarly to that described in example 1 (p.1.3.2.) And get the connection 5ab.

2.4. The interaction of compound 5ab with para-isopropylbenzylmagnesium chloride 6 is carried out similarly as described in example 1 (1.4) and get 1- (8-methoxy-4,8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene in as a mixture of isomers: 30% of the cisisomer 7a, 60% of the transisomer 76 and 10% of the product of the allyl rearrangement 7c. Homocomposition product 8 was not found.

2.5. The reduction of 1- (8-methoxy-4,8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene obtained in step 2.4. Is carried out as described in Example 1 (p. 1.5) and get the target compound 1.

Example 3

3.1. N-nergypiperidine 3c was prepared analogously to compound 3b (example 1, p.1.1) using 29.3 g (0.344 mol) of piperidine. Obtain 35.7 g (47%) of amine 3c with so kip. 110-116 ° C / 1 mmHg

3.2. N- (7-methoxy-3,7-dimethyl-2Z-octenyl) piperidine 4b was prepared analogously to compound 4b (example 1, p. 1.2) using 39.8 g (0.18 mol) of N-non-arylpiperidine 3b. Obtain 27.8 g (61%) of amine 4c with so Kip. 124-129 ° C / 10 mmHg Found,%: C 75.67, H 12.18. C ₁₆ H ₃₁ NO. Calculated,%: C 75.83, H 12.33.

3.3. The quaternization of compound 4c is carried out similarly to that described in example 1 (p. 1.3.2.), And compound 5bb is obtained.

3.4. 1- (8-methoxy-4.8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene in the form of a mixture of isomers was obtained from product 5bb according to the procedure described in example 1 (1.4).

3.5. The reduction of 1- (8-methoxy-4,8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene obtained in step 3.4. Is carried out as described in Example 1 (p. 1.5) , and obtain the target compound 1.

Example 4

4.1. Obtaining N-nonrylmorpholine 3g is carried out similarly to that described in example 1 (p.1.1.), Using 30.0 g (0.344 mol) of morpholine. 34.9 g (45%) of the amine 3g are obtained with a bp of 116-128 ° C / 1 mmHg.

4.2. The preparation of N- (7-methoxy-3,7-dimethyl-22-octenyl) morpholine 4g was carried out analogously to that described in Example 1 (1.2.) Using 40.2 g (0.18 mol) of N-non-irylmorpholine 3g. Obtain 29.4 g (64%) of the amine 4 g with so Kip. 141-147 ° C / 1 mmHg Found,%: C 70.76; H 11.36; N, 5.83. C ₁₅ H ₂₉ NO ₂ . Calculated,%: C 70.54; H 11.45; N, 5.48.

4.3. The quaternization of (7-methoxy-3,7-dimethyl-2Z-octenyl) morpholine 4g is carried out as described in example 1, paragraph 1.3.2.)

4.4. 1- (8-methoxy-4,8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene is obtained as a mixture of isomers from the product 5gb according to the procedure similar to that described in example 1 (paragraph 1.4).

4.5. Reduction of 1- (8-methoxy-4,8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene. obtained in stage 4.4., is carried out as described in Example 1 (p. 1.5), and receive the target compound 1.

Obtaining compound 1 (option II)

Example 5

Stage 5.1. and 5.2 to obtain compounds 3b and 4b according to option II, carry out the same way, stages 1 and 2 of option I, described in example 1 (paragraphs 1.1 and 1.2)

5.3.1. Chlorination of compound 4b with phosgene. To a solution of 6.6 g (0.0275 mol) of N- (7-methoxy-3,7-dimethyl-2Z-octenyl) diethylamine 4b in 20 ml of abs. benzene at 0-5 ° C let phosgene pass until 6 g were absorbed (0.06 mol). The benzene is evaporated, pentane is added to the residue, washed with dil. HCl, dried Na ₂ SO ₄ . After distillation, 3.78 g (67%) of (Z) -1-chloro-7-methoxy-3,7-dimethyl-2-octene 5 g are obtained with a boiling point of 90-92 ° C (3 mmHg). ) IR, cm ^-1 (film) 2960, 1660, 1445, 1155, 1030, 980, 835, 660; ¹ H NMR (300 MHz, CDCl ₃ ), δ: 1.12 s (3H, ^7a CH ₃ ), 1, 14 s (3H, ⁸ CH ₃ ), 1.75 (s, 3H, ^3a CH ₃ ), 2.11 m (4H, ⁴ CH ₂ , ⁵ CH ₂ ), 3.18 (s, 3H, OCH ₃ ), 4.01 d (2H, ¹ CH ₂ , J = 8.5 Hz), 5.32 t ( 1H, J = 8.5 Hz, ² CH).

5.3.2. Chlorination of compound 4b with phenyl chloride ether. (Z) -1-chloro-7-methoxy-3,7-dimethyl-2-octene 5g is obtained from 45.1 mmol of N- (7-methoxy-3,7-dimethyl-2E-octen-1-yl) - diethylamine 4b and 45.1 mmol of phenylchlorocarbon ether (added at 7 ° C, then 3 hours at 30 ° C), 5 g of chloride are isolated with so on. 60-63 ° C (1 mmHg). Yield 69%. IR, cm ^-1 (film) 2960, 1660, 1445, 1155, 1030, 980, 660; ¹ H NMR (300 MHz, CDCl ₃ ), δ: 1.12 s (3H, ^7a CH ₃ ), 1, 14 s (3H, ⁸ CH ₃ ), 1.75 (s, 3H, ^3a CH ₃ ), 2.11 m (4 H, ⁴ CH ₂ , ⁵ CH ₂ ), 3.18 (s, 3H, OCH ₃ ), 4.01 d (2 H, ¹ CH ₂ , J = 8.5 Hz), 5.32 t (1H, J = 8.5 Hz, ² CH).

5.4. The reaction of 5 g of compound with para-isopropylbenzylmagnesium chloride 6. From 3.7 g (22 mmol) of para-isopropylbenzyl chloride and 0.8 g (30 mmol) of magnesium, Grignard reagent (6) in 20 ml of diethyl ether is obtained. Over a period of 20 minutes, Grignard reagent is added to a solution of 3.5 g (17 mmol) of chloride 5 g and 1 ml (1.39 mmol, 0.43 mol%) of Li ₂ CuCl ₄ in 20 ml of THF at -20 ° С, stirred at -5 ÷ -7 ° C for 5 h, poured into a saturated solution of NH ₄ Cl, the product is extracted with ether, dried with Na ₂ SO ₄ . After distillation in vacuo, 3.9 g (80%) of 1- (8-methoxy-4,8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene are obtained with so on. 123-130 ° C (2 mm Hg) in the form of a mixture of isomers: 48% - cisisomer 7a, 35% - its transisomer 7b, 12% allylic rearrangement product 7c and homo combination product 8.

5.5. The reduction of 1- (8-methoxy-4,8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene obtained in step 5.4 is carried out as described in Example 1 (paragraph 1.5), and get the target compound 1.

The preparation of compounds 4a, 4c and 4g is carried out in the same way as in stages 1 and 2 of variant I described in example 1 (paragraphs 1.1 and 1.2)

(Z) -1-chloro-7-methoxy-3,7-dimethyl-2-octene 5g is also obtained from compounds 4a, 4c and 4g as described in example 5 (paragraphs 5.3.1 or 5.3.2), as well as during their interaction with methyl and ethyl chloro-ether esters, but the yield of 5 g does not exceed 35%.

Obtaining compound 1 (option III)

Example 6

1.4840, спектр ПМР (CDCl₃; δ, м.д.): 1.42-1.52 м (2Н, ¹¹CH₂, 1.53-1.57 м (2Н, ⁵CH₂, J=7.08), 1.59-1,66 м (4Н, ¹⁰СН₂, ¹²CH₂), 1.67, 1.75 с, с (6Н, ^3aCH₃, ^7aCH₃) 1.98-2.09 м (4Н, ⁴CH₂, ⁶CH₂, J=7.08), 2.34-2.52 м (4Н, ⁹CH₂, ¹³CH₂), 2.97 д (2Н, ¹CH₂, J_1-2=6.6) 4.71, 4.74 с, с (2Н, ⁸CH₂). 5.33 т (1Н, ²CH, J_1-2=6.6). Масс-спектр: m/z (I, %): 221 (M⁺7), 98 (100), 84 (48), 55 (19), 18 (10). Найдено, (%) С 81.09; Н 12.21; N 6.11. C₁₅H₂₇N. Вычислено, (%) С 81.38; Н 12.29; N 6.33. Стадии 6.2-6.5 для получения целевого соединения 1 из α-геранилпиперидина 3ж проводят аналогично описанным в примере 1 (п.п.1.2, 1.3.2, 1.4 и 1.5).6.1 Reaction of isoprene with dialkylamine to produce α-geranylpiperidine 3g. In a steel autoclave in an argon stream, 0.16 g (0.5 mmol) Pd (acac) ₂ , 0.5 g (2 mmol) P (OBu) ₃ , 25 ml of acetonitrile, 19 ml (10 ml) are rapidly mixed at -20 ° C. 0.2 mol) of isoprene, and 4 g (80 mmol) of solid carbon dioxide. The autoclave is heated at 100 ° C for 40 hours. The solvent was evaporated, the residue was distilled in vacuo at 100-109 ° C and a pressure of 2 mm Hg. Obtain 13.1 g (59%) of a mixture of isomers containing 42% α-geranylpiperidine, which is isolated on a laboratory distillation column with a bp. 119-120 ° C / 5 mm Hg, $${\text{n}}_{\text{D}}{}^{\text{21}\text{,5}}$$

1.4840, PMR spectrum (CDCl ₃ ; δ, ppm): 1.42-1.52 m (2Н, ¹¹ CH ₂ , 1.53-1.57 m (2Н, ⁵ CH ₂ , J = 7.08), 1.59-1.66 m ( 4H, ¹⁰ _CH2, ¹² CH _2), 1.67, 1.75, s (6H, ^3a CH _3, ^7a CH _3), 1.98-2.09 m (4H, CH ₂ ^{4, 6} CH _2, J = 7.08), 2.34- 2.52 m (4H, ⁹ CH ₂ , ¹³ CH ₂ ), 2.97 d (2H, ¹ CH ₂ , J _1-2 = 6.6) 4.71, 4.74 s, s (2H, ⁸ CH ₂ ). 5.33 t (1H, ² CH, J _1-2 = 6.6) Mass spectrum: m / z (I,%): 221 (M ⁺ 7), 98 (100), 84 (48), 55 (19), 18 (10). Found, (%) C 81.09; H 12.21; N 6.11. C ₁₅ H ₂₇ N. Calculated, (%) C 81.38; H 12.29; N 6.33. Steps 6.2-6.5 to obtain the target compound 1 from α-geranylpiperidine 3g are carried out similarly described in example 1 (items 1.2, 1.3.2, 1.4 and 1.5).

Example 7

Insecticidal activity was determined by applying pupae to the last abdominal segment 0-6 hours after hatching 4.4 μg of an acetone solution containing 10,000 mg · liter ^{-1 of} compound 1. The compound was tested in two series of 17 animals each. The effect was evaluated during the emergence of adults on the 9-point Schmialeck scale (Schmiaiek P. // Z. Naturforsch 1963. Bd. 18 B. N 7. P. 516). A rating of 0 was attributed to a pupa giving a normal adult, a rating of 9 was attributed to a pupa that did not give an adult and did not differ from the original pupa. Intermediate estimates corresponded to the degree of morphogenetic disturbances in the transformation of pupae into adults.

After studying the morphological changes of each individual, the average score in points (N) was determined by the formula:

The absolute error (AN) was determined by the formula:

Here, 1, 2, 3, ... n is the score in points from 0 to 9,

x ₁ , x ₂ , x ₃ , ... x _n is the number of pupae that received an appropriate estimate,

A is the total number of pupae.

As a result of biological tests for the activity of juvenile hormone, compound (V) in a solution with a concentration of 10 g / L received an estimate of N = 7.6 points (out of 9 possible), absolute measurement error ΔN = 0.38, relative error ΔN / N = 5.1%.

Claims (3)

1. The method of obtaining 1- (8-methoxy-4,8-dimethylnonyl) -4- (1-methylethyl) benzene, comprising a cross-combination of an organomagnesium compound with a nucleophile, catalyzed by Li ₂ CuCl ₄ , characterized in that (1) isoprene subjected to interaction with a dialkylamine selected from the group: dimethylamine, diethylamine, piperidine, morpholine, in the presence of a catalyst, such as butyl lithium or lithium, at a temperature of 20-60 ° C; (2) the resulting non -ryl dialkylamine is methoxylated with methanol when heated in the presence of 1-1.2 equivalents of H ₂ SO ₄ or HClO ₄ to form the corresponding N- (7-methoxy-3,7-dimethyl-2Z-octenyl) dialkylamine, which (3) subjected to quaternization with ethyl or methyl iodide and (4) the resulting N- (7-methoxy-3,7-dimethyl-2Z-octenyl) trialkylammonium iodide is cross-coupled with an organomagnesium compound such as para -isopropylbenzyl magnesium chloride in the presence of a copper catalyst the quality of which is used CuBr or Li ₂ CuCl ₄ at low temperature (-5 ° C) - (-10 ° C) to form 1- (8-methoxy-4,8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene, which (5) is hydrogenated with hydrogen in the presence of a Pd / BaSO catalyst ₄ and AcOH in a solution of ethanol at atmospheric pressure and a temperature of 20-25 ° C and get the target product. 2. A method for producing 1- (8-methoxy-4,8-dimethylnonyl) -4- (1-methylethyl) benzene, comprising cross-coupling an organomagnesium compound with a nucleophile, catalyzed by Li ₂ CuCl ₄ , characterized in that (1) isoprene subjected to interaction with a dialkylamine selected from the group: dimethylamine, diethylamine, piperidine, morpholine, in the presence of a catalyst, such as butyl lithium or lithium, at a temperature of 20-60 ° C; (2) the resulting non -ryl dialkylamine is methoxylated with methanol when heated in the presence of 1-1.2 equivalents of H ₂ SO ₄ or HClO ₄ to form the corresponding N- (7-methoxy-3,7-dimethyl-2Z-octenyl) dialkylamine, which (3) chlorinated with phosgene or alkyl (aryl) chloro ether, selected from the group: methyl chloro ether, ethyl chloro ether, phenyl chloro ether and (2) -1-chloro-7-methoxy-3,7-dimethyl-2-octene, which (4) is reacted with steam in the presence -izopropilbenzilmagniyhloridom Li ₂ CuCl ₄ at a temperature of (-20) - (-3) ° C to form 1- (8-Meto B-4,8-dimethyl-non-3-en-1-yl) -4- (1-methylethyl) benzene, (5) the hydrogenation is hydrogen in the presence of a catalyst Pd / BaSO ₄ and AcOH in ethanol solution at atmospheric pressure and a temperature of 20 -25 ° C gives the target product. 3. A method for producing 1- (8-methoxy-4,8-dimethylnonyl) -4- (1-methylethyl) benzene, comprising a cross-coupling of an organomagnesium compound with a nucleophile, catalyzed by Li ₂ CuCl ₄ , characterized in that (1) isoprene subjected to interaction with a dialkylamine selected from the group: dimethylamine, diethylamine, piperidine, morpholine, in the presence of a catalyst such as Pd (acac) ₂ -P (OBu) ₃ -CO ₂ at a temperature of 100-120 ° C; (2) the resulting alpha-geranyl dialkylamine is methoxylated with methanol in the presence of 1-1.2 equivalents of H ₂ SO ₄ or HClO ₄ when heated to form the corresponding N- (7-methoxy-3,7-dimethyl-2E-octenyl) dialkylamine; which (3) is quaternized with ethyl or methyl iodide; then (4) the resulting N- (7-methoxy-3,7-dimethyl-2E-octenyl) trialkylammonium iodide is cross-coupled with an organomagnesium compound such as para -isopropylbenzylmagnesium chloride in the presence of a copper catalyst, using CuBr or Li ₂ CuCl ₄ at a temperature of (-5) - (-10 ° C); (5) the resulting cross-coupling product of 1- (8-methoxy-4,8-dimethylnonen-3-yl-1) -4- (1-methylethyl) benzene is hydrogenated in the presence of a Pd / BaSO ₄ catalyst and AcOH in an ethanol solution at atmospheric pressure and a temperature of 20-25 ° C with the formation of the target product.