HU181239B - Process for the stereospecific preparation of 3,7,11-trimethyl-2,4-dodecadienic acid derivatives with inhibiting activity against growth of insects - Google Patents

Description

Dr. Lajos Novov Chemical Engineer 25%, dr. Csaba Szántay chemical engineer 25%, dr. János Rohály Chemical Engineer 15%, dr. Attila Kis-Tamás chemical engineer 10%, Ferenc Jurák chemical engineer 10%, István Ujváry chemical engineer 10%, Gábor Baán chemical engineer 5%, Budapest

EGYT Pharmaceutical Chemistry Factory, Budapest

Procedure for the Stereospecific Preparation of 3,7,1-l-trimethyl-2,4-dodecadienoic acid derivatives having insect growth inhibitory activity

2

FIELD OF THE INVENTION The present invention relates to a process for the stereospecific preparation of the insecticide inhibitors of 3,7,11-trimethyl-2,4-dodecadienoic acid of formula (I). In the formula

R ^{1 is} hydrogen or C 1-4 alkoxy,

Z ^{1 is a} hydrogen atom, but R 'and Z ¹ together may represent a double bond,

R ² and R ³ each independently is a linear or branched C 1 -C 5 alkyl group.

The compounds of formula I include i-propyl [11-methoxy-3,7,1-trimethyl-2 (E), 4 (E) -dodecadienoate (methopren) and ethyl [3,7,11] -trimethyl-15 -2 (E), 4 (E) -dodecadienoate (hydropren) is commercially available and has been successfully used in plant protection and in large-scale animal husbandry against insect pests.

Methoprene has been shown to be successful in mosquito species [e.g. yellow fever mosquito (Aedes Aegypti): W. L. Jacob, Mosq. News 32, 592 (1972); W. L. Jacob, J. Econ. Entomol 66, 819 (1973); Henrick C. A. et al., J. Agric. Food Chem. 24, 207 (1976)], flies [e.g. domestic fly (Musca domestica): W. L. Jacob, J. 25 Econ. Entomol. 66, 819 (1973); W. F. Plapp and S.

R. Vinson, Pestic. Bochem. Physiol. 3, 131 (1973);

Henrick C. A. et al., J. Agric. Food Chem., 23, 396 (1975); Morgan P. B. et al., Can. Entomol. 107: 413 (1975); Henrick C. A. et al., J. Agric. Food Chem

24, 207 (1976)], aphids [e.g. flour beetle (Tenebrio molitor); Henrick C. A. et al., J. Agric. Food Chem., 24, 207 (1976), pl. pea beetle (Acyrthosiphon pisum); Henrick C. A. et al., J. Agric. Food 5 Chem., 24, 207 (1976)] and cockroaches [e.g. Nanphoeta cinerea; W. Radwan and F. Sehnal, Experienta 30, 615 (1974)].

Hydroprene has a good result on potato aphids [J. Benskin and J.M. Perron, Can. Entomol. 105, 619 (1973)], flour beetle [R. A. Hamlen, J. Econ. Entomol. 68, 223 (1975); C. A. Henrick et al., Bioorganic Chemistry 7, 235 (1978)] and other grain products for pests [e.g. R. G. Strong and J. Diekman, J. Econ. Entomol. 66, 1167 (1973)].

For the preparation of ethyl [3,7,11-trimethyl-2 (E), 4 (E)] - dodecadienoate compounds, C. A. Henrick et al., J. Med. Org. Chem. 40, 8 (1975)]. In one method, an anion of 6,7-dihydro-citronellated diethyl 2-oxopropylphosphonate gave 2-oxo-6,10-dimethyl-3-undecene which was reacted with the di-lithium salt of acetic acid. The 3-hydroxy-3,7,11-trimethyl-4-undecenoic acid formed in the reaction was converted to the acid chloride with phosphoryl chloride and N ethyldiisopropylamine which was treated with ethyl alcohol to give the 2 (Z) -stereoisomer of hydropren and 3,5-dodecadiene derived from double bond migration. (10%). A major drawback of this process is that esterification can only be achieved with poor yield (50%) and significant amounts of by-products are formed.

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In an improved version of the process, C. A. Henrick et al., Starting from 3,3-dimethylacrylic acid, which formed a dianion with the lithium compound of diisopropylamine, was reacted with 6,7-dihydrocitrone. The resulting 3-hydroxy-2- 5 -isopropenyl-5,9-dimethyl-decanoic acid was converted by thermal reaction to 5-hydroxy-3,7,11-trimethyl-2 (Z) -dodecenoic acid, which was converted to a six-membered lactone in an acidic medium. The lactone was converted with the sodium ethylate to the 2 (Z) stereoisomer of hydropren, which was converted to the 6.5: 3.5 mixture of the hydropren and the 2 (Z) stereoisomers with thiophenol. The process is unfavorable because of the expensive starting material and the low yield of each step.

C. A. Henrick et al., In a new procedure [J. Org. Chem. 40, 8 (1975); J. Agric. Food Chem., 23, 396 (1975)] reacted 6,7-dihydrocitronellate with lithium compound of 1-propin. The resulting 4-hydroxy-6,10-dimethyl-2-undecin was reacted with ethyl ester of orthoacetic acid to give ethyl (3,7,11-trimethyl-3,4-dodeca-dienoate), which was basified with (Z) to a mixture of stereoisomers. The mixture was treated with thiophenol to form the equilibrium mixture of hydropren and 2 (Z) stereoisomers (6.5: 3.5). The effectiveness of the method is impaired by the low production of each of the 25 steps (e.g., the first addition step is 29%).

More recently, the methyl ester analog of hydropren (I;

For the preparation of R * = H, Z '= H, R ² = CH ³ , R ³ = CH ³ ), according to G. Cardillo et al. (JCS Perkin I, 1979, 30, 1729) starting from 3-methyl-3-buten-1-ol. They indicated. The compound was formed with two moles of butyl lithium to form a dianion, which was reacted with 6,7-dihydrocitrone to give 1,5-dihydroxy-3-methylene-7,11-dimethyl dodecane. The compound was acylated and the diacyl 35 was partially hydrolyzed. The resulting 5-acetoxy-3-methylene-7,11-dimethyl dodecan-1-ol was oxidized with Jones reagent, the resulting carboxylic acid was esterified with diazomethane, and the ester was treated with sodium hydride in the presence of crown ethers 2 (E), 4 (E). ) and converted into 2 (Z), 4 (E) 40 stereoisomers. The process is unfavorable because of the expensive starting material and reactants.

The preparation of methoprene by C. A. Henrick et al., J. Org. Chem. 40, 1 (1975)] starting from 7-methoxy-6,7-dihydroxycitronellal and acetyl acetate. The acetic acid ester was dimerized in an acidic medium and treated with sodium alcoholate to give 3-methylglutacone ester. The latter was condensed in the presence of alcoholic potassium hydroxide with 7-methoxy-6,7-dihydro-citronella and the 50 obtained with 1-methoxy-4-carboxy-3.7, 11-trimethyl-2 (Z), 4 (E) - dodecadienoic acid was decarboxylated by heating in the presence of 2,4-dimethylpyridine. The main product obtained from the reaction mixture was 1-methoxy-3,7,1-trimethyl-2 (Z), 4 (E) -dodecadienoic acid, along with unchanged starting material, lactonization product and 10-methoxy-2 from double decarboxylation. 6,10-Trimethyl-1,3 (Z) -undecadiene was isolated. Dodecadienoic acid was isomerized with thiophenol to a mixture of stereoisomers 2 (E), 4 (E) and 2 (Z), 4 (E), and then formed into an ammonium 60 salt, and the stereoisomeric salt of 2 (E), 4 (E) was selected by crystallization. apart. The acid recovered from the ammonium salt was converted to the acid chloride by treatment with thionyl chloride-dimethylformamide and then treated with i-propanol to give methoprene.

The economics and efficiency of the process is impaired by the fact that in principle one mole of methoprene requires at least two moles of acetoxyacetate, the decarboxylation step involves a by-product separation, part of the methoxy group is eliminated by acid chloride formation and i-propyl (3.7). , 11-trimethyl-2 (E), 4 (E) 10-dodecatrienoate) and i-propyl [3,7,11-trimethyl-11-chloro-2 (E), 4 (E) -dodecadienoate ] pollute.

As a result of our previous experiments, it has been possible to develop a more economical process for the synthesis of methoprene and hydroprene-type compounds using fewer reaction steps. Accordingly, 3-oxo-7,11-dimethyl-4 (E) -dodecenoic acid ester is reacted with a dialkylphosphoryl halide to give the 2 (Z), 4 (E) and 2 (E), 4 (E) configurations. enol phosphates are formed in a ratio of 7: 3. These can be reacted with a dialkyl copper lithium compound to give a 7: 3 mixture of dodecadienoic acid stereoisomers of configuration 2 (E), 4 (E) - and 2 (Z), 4 (E). Although the synthesis allows the simple preparation of the target compounds, the unfavorable isomer ratio impairs the efficiency of the reaction.

In our recent research, we have aimed to develop a stereospecific process for the preparation of compounds of formula I having valuable biological activity.

It has now been found that the 3,7,1-trimethyl-2 (E), 4 (E) -dodecadienoic acid derivatives of formula I can be prepared in a simple, stereospecific manner by reacting a compound of formula II. formula: - wherein ^R1, Z, R ² and R ³ are as defined above - 3-oxo-7, l l-dimethyl-4- (E) a -dodecénsav ester III. The i-propenyl ester of formula (I) wherein R1 is C1-5 alkyl, phenyl or phenyl (C1-C4) alkyl is optionally reacted in an aprotic solvent, preferably in the presence of a catalytic amount of acid. alkyl-7,1-dimethyl-3-acyloxy-2 (Z), 4 (E) -dodecadienoate of the formula wherein R, R ¹ , R ³ and Z are as defined above in an aprotic solvent, preferably an inert gas. reaction with a dialkyl copper lithium compound of formula V wherein R ² is as defined above and, if desired, separating the resulting product from the reaction mixture.

For the enol ester formation, aromatic sulfonic acids (such as p-toluenesulfonic acid) or mineral acids (such as hydrochloric acid) are preferably used as acid catalysts. Suitable aprotic solvents are preferably dry aliphatic ethers (especially diethyl ether) or tetrahydrofuran.

The alkylation reaction is carried out at a low temperature [-100 - (-) 10 ° C, preferably -60 - (-) 80 ° C], wherein the 2 (E), 4 (E) -dodecadienoic acid derivative formed in the stereospecific reaction step is The 2 (Z), 4 (E) -configured diastereomer may only contaminate less than 2%.

Further details of our process are given in the accompanying examples, but are not limited to the examples.

Infrared spectra were recorded on a Spectromom 200, ³ H-NMR and ¹³ C-NMR images on a JEOL FX-100. Fluid chromatographic analysis was performed on a Du Pont 830 liquid 2181239 chromatograph (Sil X, 2.1 mm x 0.25 m, eluting with dichloromethane), Ms taken on a JEOL JGC-20K and JMS-01 SG-2 combined GC-Ms ( ionizing energy 75 eV, 108 V, 200 A).

Example I Preparation of i-Propyl [11-methoxy-3,7,1-trimethyl-2 (E), 4 (E) -dodecadienoate] (methopren) (I; R '= CH ₃ O). H, R ² = CH ₃ , R ³ = i-Pr) g (16 mmol) i-propyl [11-methoxy-3-oxo-7,11-dimethyl-4 (E) dodecenoate] (II : R '= CH _{3 ()} , Z = H, R ³ = i-Pr) dissolved in 20 g (200 mmol) of i-propenyl acetate and 0.2 g (1.2 mmol) of anhydrous p-toluenesulfonic acid the mixture was refluxed for six hours. After cooling, ether (50 mL) was added to the reaction mixture, and the ether solution was washed with water (50 mL), brine (50 mL) and dried over magnesium sulfate. After filtering off the desiccant, the solvent was distilled off and the residue (5.1 g of a yellow oil) was filtered through a short column (50 g of Kieselgel 60; benzene-ethyl acetate 3: 2). After distilling off the eluent, 3.5 g (62.5%) of i-propyl [3-acetoxy-1-methoxy-7,1-dimethyl-2 (Z), 4 (E) -dodecadienoate] ( IV: R ^{1 =} CH ₃ O, R = CH ₃ , Z = H, R ³ = i-Pr), Rf = 0.65 (5: 1 hexane-acetone).

The material may contain less than 2% stereoisomer of the 2 (E), 4 (E) configuration according to liquid chromatography analysis.

Retention time: diastereoisomer 2 (E), 4 (E) = 5.3 min 2 diastereoisomers (Z), 4 (E) = 6.6 min

IR (NaCl): 1760, 1710, 1640, 1610, 1450, 1380, 1360, 1245, 1220, 1160, 1130, 1080, 1060, 1000 cm -1.

1 H-NMR (CCl ₄ ): 0.9 (3H, d, J = 6Hz, CH ₃ ), 1-1.9 (19H, m, CH ₃ , CH ₂ , CH), 2.1 (2H, m, CH ₂ ), 2.22 (3H, s, OCCH ₃ ), 3.08 (3H, s, OCH ₃ ). 4.9 (1H, h, J = 5Hz, CHO), 5.2-6.3 (3H, m, CH =).

Ms: M * 354 (2), m / e 340 (4), 322 (6). 280 (15), 264 (7), 262 (5), 237 (8), 220 (10), 197 (15), 136 (20), 124 (12), 95 (12), 81 (16). 73 (100). 69 (12), 43 (55).

To a suspension of 3.6 g (20 mmol) of copper (I) iodide in dry ether (100 ml) was added a solution of 0.83 g (38 mmol) of methyl lithium in 5% ether with stirring and cooling (-30 °). After stirring for another five minutes, the reaction mixture was cooled to -70 ° and 1.7 g (5.6 mmol) of i-propyl- [3-acetoxy-11-methoxy-7,1-dimethyl-2 (Z) was added dropwise. , 4 (E) -dodecadienoate] (IV: R ^{1 ==} CH ₃ OH, R = CH _3. Z = H, R ³ i-Pr) in dry ether (25 mL) at -20 ° After stirring for three hours, the reaction mixture was poured into 100 ml of saturated ammonium chloride solution, the ether layer was separated, the aqueous layer was extracted twice with 100 ml of ether each time, and the combined ethereal extracts were washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated.

Yield: 1.2 g (82%), Rf = 0.9 (hexane-acetone 7: 3), b.p. 140-142 ° (0.05 mm) [b.p. 135-136 ° / 0.06 mm; CA Henrick et al.

J. Org. Chem. 40, 1 (1975)].

According to liquid chromatography analysis, the sample may contain less than 2% of the stereoisomer of configuration 2 (Z), 4 (E).

Retention time: diastereomer 2 (E), 4 (E) 2.33 min 2 (Z), diastereomer 4 (E) 2.83 min.

IR (NaCl): 1710, 1640, 1610, 1470, 1440, 1380, 1360, 1230, 1160, 1100, 1080, 1030, 970 ^cm-first

1 H-NMR (CDCl 3): 0.9 (3H, d, J = 6Hz, CH ₃ ), 1.1-1.8 (19H, m, CH, CH ₂ , CH ₃ ), 2.1 (2H, m, CH ₂ ), 2.3 (3H, d, J = 1.5 Hz, CH ₃ ), 3.2 (3H, s, OCH ₃ ). 5.1 (1H, h, J = 6Hz, CHO), 5.75 (1H, m, CH =), 6.15 (2H, m, CH =).

¹³ C-NMR: 13.8 (q) 19.6 (t), 21.3 (q), 22.0 (q), 25 (q), 33.2 (d), 37.2 (t) , 40.1 (t), 40.6 (t), 49.0 (q). 66.6 (d), 118.2 (d), 128.3 (d), 134.9 (d), 135.7 (d), 152.0 (d). 166.6 (s).

Ms: NT 310 (9), m / e 278 (27), 236 (9), 235 (10). 221 (10), 193 (13), 192 (17), 153 (32), 111 (33), 73 (100), 43 (26).

Example 2

Preparation of ethyl [3,7,11-trimethyl-2 (E), 4 (E) -dodecadienoate] (hydropren) (I: R ¹ = Z = H, R ² = CH ³ , R ³ = CH ³ -CH ₂

5 g (18 mmol) of ethyl [3-oxo-7,11-dimethyl-4 (E) -dodecenoate] (IV ³ = Ζ = Η, R ³ = CH ³ -CH 2 - and 20 g (200 mmol) of p-toluenesulfonic acid (0.2 g, 1.2 mmol) was added to the -propenyl acetate mixture and the mixture was heated under reflux for 6 h. After cooling, the reaction mixture was diluted with ether (50 mL), and the ether solution was saturated with chloride (50 mL), dried over magnesium sulfate, and the solvent was distilled off and the residue (5.4 g of a yellow oil) was filtered through a short column (50 g of Kieselgel 60; benzene-ethyl acetate 3: 2). (87%) ethyl [3-acetoxy-7,11-dimethyl-2 (Z)] - 4 (E) -dodecadienoate] (IV: R ¹ = Z = H, R = CH ³ , R ³ = CH _3). CH _{2 is} obtained, Rf = 0.72 (5: 1 hexane-acetene).

The material may contain less than 2% stereoisomer of the 2 (E), 4 (E) configuration according to liquid chromatography analysis.

Retention time: 2 (E), 4 (E) diastereomer = 2.17 min 2 (Z), 4 (E) diastereomer = 2.35 min.

IR (NaCl): 1760, 1710, 1640, 1600, 1460, 1380, 1360, 1240, 1220, 1150, 1120, 1080, 1020 cm -1.

¹ H-NMR (CCl ₄ ): 0.9 (9H, dm, CH ₃ ), 1-1.8 (11H, m, CH, CH ₂ , CH ₃ ), 2 (2H, m, CH ₂ ), 2.2 (3H, s, OCCH ₃ ), 4 (2H, q, J = 6Hz, 0CH ₂ ), 5.1-6.3 (3H, m, CH =).

Ms: M ⁺ 310 (3), m / e 267 (3), 183 (10), 173 (9), 155 (16), 141 (10), 126 (8), 95 (7), 91 (48 ), 83 (12), 81 (11), 69 (27), 65 (20), 57 (32), 56 (25), 55 (33), 43 (100), 41 (55).

To a suspension of copper (I) copper (I) g (26 mmol) in dry ether (100 mL) cooled to -30 ° C was added methyl lithium ether (1.1 g, 53 mmol) under argon for 5 min. the reaction mixture was cooled to -70 ° and 3.5 g (11 mmol) of ethyl [3-acetoxy-7,11-dimethyl-2 (Z), 4 (E) -dodecadienoate] was added dropwise (IV: R ¹ = Z = H, R = CH ³ , R ³ = CH ₃ -CH _{2 in} dry ether (20 mL) 3

-3181239 solution. The reaction mixture was poured into saturated ammonium chloride solution (100 mL), the organic layer was separated and the aqueous portion was extracted twice with 100 mL of ether. The combined ethereal solutions were washed with brine, dried over magnesium sulfate, and the solvent was distilled off.

Yield: 2.2 g (73%); Rf = 0.92 (7: 3 hexane-acetone), m.p .: 132-135 ° (0.05 mm) [t.p.

137-142 / 0.3 mm; C. A. Henrick et al., J. Org. Chem. 40, 8 (1975)].

The sample may contain less than 2% of the stereoisomer of configuration 2 (Z), 4 (E) according to liquid chromatography.

Retention time: 2 (E), 4 (E) diastereomer - 2.05 2 (Z), 4 (E) diastereomer = 2.35 min.

IR (NaCl): 1710, 1640, 1600, 1460, 1380, 1360, 1220, 1140, 1030, 960 cm -1.

¹ H-NMR (CCl ₄ ): 0.9 (9H, m, CH ₃ ), 1-1.8 (11H, m, CH, CH ₃ , CH ₃ ). 2 (2H, m, CH ₂ ), 2.15 (3H, d, J = 1.5Hz, CH ₃ ), 4 (2H, q, J = 7Hz, OCH ₂ ), 2i 5.75 (1H , tn, CH =), 6.15 (2H, m, CH = CH).

Patent claims:

Claims (4)

Patent claims: A process for the preparation of 3.7,11-trimethyl-2,4-dodecadienoic acid derivatives of the formula (I) R ^{1 is} hydrogen or C ₁₅ alkoxy, Z * is hydrogen, but R and Z ¹ together may represent a double bond, R ² and R ³ are independently linear or branched C 1. _{s is an} alkyl group, characterized in that a 3-oxo-7,11-dimethyl (E) -dodecenoic acid of formula (II) wherein R ¹ , Z, R ² and R ³ are as defined above the ester is reacted with an i-propenyl ester of formula (III) wherein R is C1-C5 alkyl, phenyl or phenyl (C1-C6) alkyl, optionally in an aprotic solvent, preferably in the presence of a catalytic amount of acid; Alkyl-7,11-dimethyl-3-acyloxy-2 (Z), 4 (E) -dodecadienoate of formula (IV) wherein R, R ¹ , R ³ and Z are as defined above in an aprotic solvent, preferably under an inert gas atmosphere, reacting a dialkyl copper lithium compound of formula (V) wherein R ² is as defined above, and isolating the resulting product from the reaction mixture, if desired. 2. A process according to claim 1 wherein the catalyst is aromatic sulfonic acids, preferably hydrochloric acid. 3. The process according to claim 1 or 2, wherein the aprotic solvent is aliphatic ethers, preferably diethyl ether or tetrahydrofuran. 4. Process according to claim 1, characterized in that the reaction of the compounds of formula (IV) and (V) is carried out at a temperature of (-) 100 - (-) 10 ° C, preferably -60 to (-) 80 ° C. 1 drawing Responsible for publishing: Director of Economic and Legal Publishing House 84.4288 - Zrínyi Nyomda, Budapest -4181239 International classification: C 07 C 57/02, A 01 N 27/00