The method of obtaining the amides of unsaturated acids

 

(57) Abstract:

The inventive product - amides of unsaturated acids QQ1CR2=CR3CR4=CR5C(X)OTHER1or their salts, where Q-C6H5- pyridyl, naphthyl, degloving, each of which may be substituted by 1 to 3 substituents from the group of C1-C6alkyl, C1-C6alkoxy, CF3, halogen, Q1-1.2-cyclopropene ring, possibly substituted C1-C4-alkyl, R2, R3, R4and R5is the same or different and mean H, C1-C6-alkyl, halo, C1-C4alkyl, where one of the radicals necessarily mean hydrogen, R1-H, C1-C6which may be substituted DIOXOLANYL group, cyclo (C3-C6) alkyl, X = 0. Reagent 1 : carbonyl compound. Reagent 1: reagent Wittig. 5 table.

The invention relates to the field of organic chemistry, and in particular to a method for producing amides of unsaturated acids of the General formula 1

Q Q1CR2= CR3CR4= CR5C(X) OTHER1(1) or their salts, where Q denotes phenyl, pyridyl, naphthyl, degloving, each of which may be substituted by 1-3 substituents selected from the group:1- 1-C4the alkyl, R2, R3, R4and R5denote identical or different groups, including hydrogen, C1-6alkyl group, or C1-6 haloalkyl group; one of the radicals necessarily mean hydrogen, X denotes an oxygen atom, R1denotes hydrogen or C1-6the alkyl may contain as substituents DIOXOLANYL group, cyclo(C3-C6)alkyl having insecticidal activity.

Know the use of amides of the acids as insecticides [1] .

The aim of the invention is to develop affordable method of obtaining compounds of General formula I, having a high insecticidal activity.

This goal is achieved by the described method to obtain compounds I, which is that exercised by the interaction of the carbonyl compounds with the Wittig reagent.

General synthetic methods and techniques.

A variety of compounds were synthesized and characterized in accordance with the following experimental methods.

1H NMR spectra were obtained on a spectrometer Bruker AM-250 for solutions in deuterochloroform TMS, the number of protons, number of peaks, the constants of spin-spin interaction I, Hz.

Over the course of the reaction is also conveniently be monitored using aluminum plates pre-coated with layers of silica gel 0.25 mm thick, containing a fluorescent indicator, shown in a suitable solvent or solvent mixture.

Usually, the treatment of the reaction mixture was carried out as follows.

The reaction mixture was divided between organic solvent and water. The phases were separated from each other, the organic phase is washed at least an equivalent amount of a diluted aqueous solution of the base, and then saturated brine. Then the organic phase is dried over a desiccant, usually over magnesium sulfate, and filtered. Remove volatile solvents, the obtained product was subjected to appropriate treatment before being used in the next stage of the synthesis or analyzed as a final product.

The original aldehyde, cinnamic acid and amine were obtained from Aldrich, BDH, Fluorochem, Fluka, Lancaster Sepethesis, excluding the following source connection, the receipt of which is described below.

a) 4-triftormyetil acid (5 g) (ex Fluorochem in ethanol (100 ml) was treated kontsentrirovaniem processed in the usual way to obtain ethyl-4-cryptomaterial (5 g). NMR1N: 8,90 2H, doublet (d)/, 7,22 (2H, d), 4,37 /2H, Quartet, (K)/, 1,40 3H, triplet(t)/.

The specified ester (5 g) in dichloromethane (40 ml) under nitrogen atmosphere at -20aboutWith treated diisobutylaluminium (43 ml). After 18 h at 25aboutWith added diluted hydrochloric acid, and the mixture was processed in the usual way, getting 4-cryptomaterial alcohol. NMR1N: from 7.24 (2H, d), to 7.15 (2H, d), to 4.52 /2H, singlet (s)/, 3,37 (3H, s).

The specified alcohol was oxidized using conditions Swern'a (oxalicacid, 2,05 ml; dimethylsulfoxide, to 3.33 ml, triethylamine, or 14.8 ml) in dichloromethane, receiving 4-triphtalocyaninine (4 g). NMR1N: 10,04 (2H, s), 7,98 (2H, d), 7,35 (2H, d).

b) 4-bromo-2-vtortola (ex Fluorochem) in glacial acetic acid (88 ml) and acetic anhydride (89,7 g) was cooled to -10aboutC. was added dropwise sulfuric acid (11.7 g), maintaining the reaction temperature below -5aboutC. chromium Trioxide (14,7 g) was added in portions at 0aboutC, the mixture was poured into ice (300 g) and processed in the usual way, getting diacetoacetate-2-fluoro-4-Brabanthal.

The specified diacetate in ethanol (30 ml) and water (30 ml) was treated with concentrated sulfuric acid (3 ml). After a few hours boiling under reflux the solution concentrate,5 /3H, multiplet (m)/.

C) 4-bromo-3-forbindelse was treated in a similar way. To a suspension of 4-chloro-3-triptorelin (ex Fluorochem) (15.9 g) in water (16 ml) was added concentrated hydrochloric acid (18 ml). Added ice (30 g), the mixture was cooled to 0aboutAnd was treated with a solution of sodium nitrite (5.6 g) in water (8 ml). After 15 min the mixture was made neutral to Congo-mouth with a solution of sodium acetate (8 g) in water (10 ml). The solution formaldoxime prepared from the hydrochloride formaldoxime (ex Lancaster) (9,9 g) and sodium acetate (ex BOH) in water (57 ml), with 10aboutC was treated with copper sulfate (2 g) (ex BDH) and sodium sulfite (0.34 g), then a solution of sodium acetate (55 g) in water (60 ml). A previously prepared mixture (containing an aniline derivative) was added dropwise at 10-15aboutC. After 1 h at 15aboutWith added hydrochloric acid (77 ml) and the mixture was processed in the usual way. Purification by distillation (80aboutC, 0.5 mm RT. Art. ) gave 4-chloro-3-triftormetilfosfinov (1.5 g).

(e) naphthoic acid (50 g) (ex Aldrich) in glacial acetic acid at reflux was added a few drops of bromine (ex BDH), and then iodine (0.5 g) (ex BDH). Within 1 h was added dropwise bromine (15 ml). The mixture was cooled to 25aboutWith and premesis the e and treated with concentrated hydrochloric acid. The precipitate was filtered and dried over pjatiokisi phosphorus (ex BDH) to give 5-bromo-2-naphthoic acid (recrystallization from ethanol) (28 g). The melting point of 261 2aboutC. NMR1N: (DMSO, C C3), at 8.60 (1H, s), 8,00 (5H, m), 7,40 (1H, m).

The above acid (34 g) in ethanol (240 ml) was treated with concentrated sulfuric acid (0.5 ml) at reflux for 6 hours Further processing of the reaction mixture is carried out in the usual way, gave ethyl-5-bromo-2-aftout (23 g). Melting point: 52-54aboutC. NMR1N: 8,63 (1H, s), 7,80-8,35 (4H, m), 7,43 /1H, double doublet (DD)/, 4,50 (2N, K) to 1.48 (3H, t).

P R I m e R 1. (+)-(2E, 4E) N-(1,2-dimethylpropyl)-5-/TRANS-2-(4-bromophenyl)cyclopropyl/ Penta-2,4-dienamic (compound I).

(i) 4-bromobenzaldehyde (a 9.25 g) was dissolved in dry dichloromethane (250 ml) at 25aboutC in nitrogen atmosphere. Carbamidomethylation (17,4 g) (ex Lancaster) was added to the solution and the resulting solution was stirred at 25aboutC for 18 hours the Solvent was removed in vacuum. The residue was washed with hexane and was filtered. After removal of the hexane under vacuum was obtained ethyl ester 4-bromcresol acid (12,12 g). NMR 1N: to 7.35 (5H, m), 6,38 (1H, d), 4,1 (2N, K) of 1.35 (3H, t).

(ii) Ethyl -20aboutC. was added dropwise diisobutylaluminium (100 ml of 1M solution in dichloromethane) (ex Aldrich). The solution was allowed to warm to 25aboutWith, then was stirred for 18 h, shared the simple solution between ether and dilute hydrochloric acid. The organic phase was washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated in vacuum, obtaining 3-(4-bromophenyl)propen-2-1-ol in (8.9 g). NMR1N: 7,28 (2H, d), 7,05 (2H, d), of 6.45 (1H, d), and 6.25 (1H, t), 4,25 (2H, d), 2,0 (1H, s).

(iii) the Specified alcohol (1.07 g) suspended in hexane (50 ml) at room temperature and cooled to -20aboutC in nitrogen atmosphere. Diethylzinc (ex Aldrich) (22.7 ml of a 1.1 M solution in hexane) was added dropwise, then added diameter (ex Aldrich) (4,1 ml). Gave the mixture to slowly warm to 25aboutWith, then was stirred for 18 hours was Added a saturated solution of ammonium chloride and was extracted with a mixture of simple ether. The combined ether extracts were washed with saturated sodium thiosulfate solution was dried over magnesium sulfate and removed the solvent in vacuo. Chromatographic purification (silica gel, simple ether/hexane) gave (+)-TRANS-2-(4-bromophenyl)-1-ximetilpropan (0,53 g). NMR1N: 7,38 (2H, d), to 6.95 (2H, d), the 3.65 (2H,ml) and cooled to -70aboutC in nitrogen atmosphere. Was added dropwise a solution of dimethylsulfoxide (ex BDH) (0,36 ml) in dichloromethane (1 ml). After 5 min was added to the specified alcohol (of 0.53 g) in dichloromethane (4 ml) and stirred suspension at -70aboutWith over 30 minutes was Added triethylamine (ex Aldrich) (1.6 ml) and gave the mixture heated for 1 h to 0aboutC. Further processing of the mixture, carried out in the usual way, gave ()-TRANS-/2-(4-bromophenyl)cyclopropyl/-IU-canal, which was used directly. NMR1N: 9,4 (1H, d), 7,33 (2H, d) and 6.9 (2H, d), of 2.54 (1H, m), of 2.20 (1H, m), 1,0-1,9 (2H, m).

(v) Solution diisopropylamide lithium in dry tetrahydrofuran (THF), prepared from n-utility (ex Aldrich) (1.6 ml) and Diisopropylamine (ex Aldrich) (0.4 ml), was treated at -60aboutC in an atmosphere of nitrogen a solution of triethyl-4-phosphonocrotonate (0,58 g) in tetrahydrofuran. After 2 h at -60aboutWith added specified aldehyde (0.52 g). After 18 h at 25aboutThe mixture was divided between the simple ether and water, the ether fraction was processed as described above. Chromatographic purification (silica gel, simple ether/hexane) gave ()-ethyl-5-/TRANS-2-(4-bromophenyl)-cyclopropyl/Penta-2,4-dienoate (0.36 g). NMR1H: 7,4 (2H, d), 7,26 (1H, DD), 6,93 (2H, d), 6,28 (1H, DD), 5,80 (1H, m), USD 5.76 (1H, DD), 4,20 (2N, K) is 2.05 (1H) - Rev.With the complex prepared from trimethylaluminum (ex Aldrich) (0,62 ml of 2M solution in toluene) and 1,2-dimethylpropylene (ex Aldrich) (0.55 g in dry toluene). The resulting mixture was heated under reflux for 3 h, and treated with 2n. hydrochloric acid and separated the organic layer, which was further processed as described above. Chromatographic purification (silica gel, simple ether/hexane) gave compound indicated in the title of example 1, in the amount of 0,096, Thin layer chromatography (silica gel, ethyl acetate: hexane, 3: 7) Rf of 0.25, so pl. 141,9-143,2aboutC.

Connections 2-17, 63, 64, 99 and 100, obtained similarly by using appropriate, the following aldehyde and Wittig reagent and amine, the following: Connection Name connection

2 (a)-(2E, 4E) N-isobutyl-5-/TRANS-2-(4-bromophenyl)cycloprop-

drank/Penta-2,4-dienamic

3 (a)-(2E, 4E) N-(1,2-dimethyldi - saws)-5-/TRANS-2-(3,5-bistri-

formationl) cyclo-

cut/Penta-2,4-dienamic

4 (a)-(2E, 4E) N-(1,2-dimethy-

propyl)-5-/TRANS-2-(2-NAF-

Thiel)cyclopropyl/Penta-2,4-

-dienamic

5 (a)-(2E, 4E) N-neopentyl-5-

-/TRANS-2-(2-naphthyl)cyclo-

cut/Penta-2,4-dienamic

6 (a)-(2E/Z, 4E) N-isobutyl-

-3-methyl-5-/TRANS-2-(2-naphthyl)

qi is dienamic

8 (a)-(2E/Z, 4E) N-isobutyl-

-3-methyl-5-/TRANS-2-(4-bromo-

phenyl)cyclopropyl/Penta-

-2,4-dienamic

9 (a )-(2E/Z, 4E) N-isobutyl-3-methyl-

-5-/TRANS-2-(3,5-bis-trifluoromethyl-

phenyl)cyclopropyl/Penta - 2,4-que-

named

10 (a)-(2E, 4E) N-(1,2-dimethyldi-

drank)-5-/TRANS-2-(4-trifluoromethyl-

phenyl)cyclopropyl/Penta-2,4-

- dienamic

11 (a)-(2E, 4E) N-Isobutyl-5-

-/TRANS-2-(4-triptoreline)

cyclopropyl/-3-methyl-Penta-

-2,4-dienamic

12 (a)-(2E, 4E) N-(1,2-dimethyl-

propyl)-5-/TRANS-2-(4-methoxy-

phenyl)cyclopropyl/Penta-

-2,4-dienamic

13 (a)-(2E, 4E) N-(1,2-dimethyl-

propyl)-5-/TRANS-2-(4-Cryptor-

methoxyphenyl)cyclopropyl/pen

TA - 2,4-dienamic

14 (a)-(2E, 4E) N-(1,2-dimethyl-

propyl)-5-/TRANS-2-(4-bromo-2-

-forfinal)cyclopropyl /pen

TA-2,4-dienamic

15 (a)-(2E, 4E) N-isobutyl-3-me-

Tyl-5-/TRANS-2-(2-fluoro-4-bromo-

phenyl)cyclopropyl/Penta - 2,4-

-dienamic

16 (a)-(2E, 4E) N-(1,2-dimethyldi-

drank)-5-/TRANS-2-(4-bromo-3-fluoro-

phenyl)cyclopropyl/Penta - 2,4-

-dienamic

17 (a)-(2E, 4E) N-isobutyl-3-me-

Tyl-5-/TRANS-2-(4-bromo-3-fluoro-

phenyl)cyclopropyl/Penta-2,4-

- dienamic

63 (a)-(2E, 4E) N-(1,2-dimethyl-

propyl)-5-/TRANS-2-(4-chloro-3-

-tripto the fluorine-

were)cyclopropyl /pen

TA-2,4-dienamic

99 (a)-(2E, 4E) N-isobutyl-3-methyl-

-5-/TRANS-2-(5-bromo-2-naphthyl)

cyclopropyl/Penta-2,4-dienamic

100 (a)-(2E, 4E) N-(2-methylprop-

Neil-2)-3-methyl-5/TRANS-2-(5-bromo-

-2-naphthyl) cyclopropyl/Penta-

-2,4-dienamic

P R I m m e R 2 (+)-(2E, 4E) N-isobutyl-5-TRANS-2-(3-triptoreline)cyclopropyl Penta-2,4-dienamic (compound 18).

(i) a Solution of m-triptoreline acid (10.4 g) in ethanol (120 ml) was heated under reflux in the presence of sulfuric acid (6 ml) within 8 hours After removal of the solvent in vacuo and processing carried out in the usual way, received ethyl ester m-triptoreline acid (12.1 g). NMR1N: 7,58 (4H, m) of 6.4 (1H, d), 4,25 (2N, K) and 1.3 (3H, t).

(ii-vi) This compound was converted into the final product by analogy with the stages (ii)-(vi) of example 1, except that instead of 1,2-dimethylpropylene used isobutylamine.

Connection 19-43 and 95-98 received a similar way, using a derivative of cinnamic acid, the Wittig reagent and amine listed below. Connection connection Name

19 (a)-(2E, 4E) N-(1,2-dimethyldi-

drank)-5-/TRANS-2-(3-trifluoromethyl-

phenyl)cyclopropyl /Penta-2,4-di-

ename

20 (A)-(2E/Z, 4E)2E/Z, 4E) N-(2-methylprop-

Neil-2)-3-methyl-5-/TRANS-2- (3-three

formationl)cycloprop-

drank/Penta-2,4-dienamic

22 (a)-(2E, 4E) N-isobutyl-5-

/TRANS-2-(2-chlorophenyl)-cycloprop-

drank /Penta-2,4-dienamic

23 (a)-(2E, 4E) N-(1,2-dimethyldi-

drank)-5-/TRANS-2-(2-chlorophenyl)

cyclopropyl/Penta-2,4-dienamic

24 (a)-(2E/Z, 4E) N-isobutyl-3-me-

Tyl-5-/TRANS-2-(2-chlorophenyl) cyclo-

cut/Penta-2,4-dienamic

25 (a)-(2E/Z, 4E) N-(2-methylprop-

Neil-2-)-3-methyl-5-/TRANS-2-(2 - chloro-

phenyl)cyclopropyl/Penta-2,4-

-dienamic

26 (a)-(2E, 4E) N-isobutyl-3-methyl-

-5-/TRANS-2-vinylcyclopropyl /

Penta-2,4-dienamic

27 (a)-(2E, 4E) N-(1,2-dimethyldi-

drank)-5-/TRANS-2-vinylcyclopropyl-

drank/Penta-2,4-dienamic

28 (a)-(2E, 4E) N-(1,2-dimethyldi-

drank)-5-/TRANS-2-(3-chlorophenyl)

cyclopropyl/Penta-2,4-dienamic

29 (a)-(2E, 4E) N-isobutyl-3-methyl-

-5-/TRANS-2-(3-chlorophenyl) cyclo-

cut/Penta-2,4-dienamic

30 (a)-(2E, 4E) N-isobutyl-5-/TRANS

-2-(3,4-dichlorophenyl) cycloprop-

drank/Penta-2,4-dienamic

31 (a)-(2E/Z, 4E) N-isobutyl-3-methyl-

5-/TRANS-2-(3,4-dichlorophenyl)cyclo-

cut/Penta - 2,4-dienamic

32 (a)-(2E, 4E) N-(1,2-dimethyldi-

drank)-5-/TRANS-2-(3,4-dichlorophenyl)

cyclopropyl/ Penta-2,4-dienamic

The) N-isobutyl-3-me-

Tyl-5-/TRANS-2-(4-chlorophenyl) cyclo-

cut/2,4-dienamic

35 (a)-(2E/Z, 4E) N-(2-methylprop-

Neil-2)-3-methyl-5-/TRANS-2-(3,4-

-dichlorophenyl) cyclopropyl/

Penta-2,4-dienamic

36 (a)-(2E, 4E) N-cyclopropyl-

Tyl-5-/TRANS-2-(3,4-dichlorophenyl)

cyclopropyl/-3-methyl - Penta-2,4-

-dienamic

37 (a)-(2E, 4E) N-(2,2-dimethyldi-

drank)-3-methyl-5-/TRANS-2-(3,4-di-

chlorophenyl) cyclopropyl/-3-methyl-

-Penta-2,4-dienamic

38 (a)-(2E, 4E) N-(1,1,2-trimethyl-

propyl)-5-/TRANS-2-(3,4-dichloro-

phenyl)cyclopropyl/Penta - 2,4-

-dienamic

39 (a)-(2E, 4E) N-(2-butyl)-5-/TRANS

-2-(3,4-dichlorophenyl)cycloprop-

drank/Penta-2,4 - dienamic

40 (a)-(2E, 4E) N-(2-methoxy-2-methyl-

propyl)-5-/TRANS-2-(3,4-dichloro-

phenyl)cyclopropyl /Penta-2,4-

-dienamic

41 (a)-(2E, 4E) N-(2-methyl-1,3-di-

oxolan-2-ylmethyl)-5-/TRANS

-2- (3,4-dichlorophenyl)cycloprop-

drank/Penta-2,4-dienamic

42 (a)-(2E, 4E) N-(trimethylsilyl-

Teal)-5-/TRANS-2-(3,4-dichlorophenyl)

cyclopropyl /Penta-2,4-dienamic

43 (a)-(2E, 4E) N-cyclopropyl-

Tyl-5-/TRANS-2-(3,4-dichlorophenyl)

cyclopropyl /Penta-2,4-dienamic

95 (a)-(2E, 4E) N-(2,2-dimethyldi-

drank)-5-/TRANS-2-(3,4-dichlorophenyl)

cyclopropyl /Penta-2,4-dienamic

96 (a)-(2E, 4E) N-cyclohex-5-/TRANS-2-(3,4-dichlorophenyl)

cyclopropyl/Penta-2,4-dienamic

98 (a)-(2E, 4E) N-(2-methyl-1,3-di-

oxolan-2-ylmethyl)-3-methyl-5-

-/TRANS-2-(3,4 - dichlorophenyl)cyclo-

cut/Penta-2,4-dienamic

P R I m e R 3. ()-(2E, 4E) N-(1,2-dimethylpropyl)-5-/CIS - /TRANS-2-(2,2-dibromoethenyl)cyclopropyl /Penta-2,4-dienamic (compound 44).

(i) To a solution of CIS/TRANS (3: 1) ethyl-2-formyltetrahydrofolate (1.42 g) (ex Aldrich) in dichloromethane under nitrogen atmosphere was added at room temperature, triphenylphosphine (ex Aldrich) (12 g) and chetyrehhloristy carbon (6.6 g) (ex Aldrich). The solution was stirred at room temperature for 3 h before it is split between a simple ether and water. After the treatment, carried out in the usual way, triphenylphosphine was removed by filtration, and then by chromatographic allocated ethyl-2-(2,2-dibromoethenyl)cyclopropanecarboxylate (2.9 g). NMR 1N: of 5.92 (1H, d), 4,16 (2N, K), 2,44-of 0.95 (4H, m) of 1.26 (3H, t).

(ii) the Specified ester (1.8 g) in dichloromethane was cooled to -20aboutWith and was added dropwise diisobutylaluminium (12 ml, 1M solution in hexane). The solution was heated to 0aboutC and kept at this temperature before adding 2n. hydrochloric acid followed by treatment of the resulting mixture, which was carried out Obie, d), 2,52 (1H, s), 1,8-1,0 (2H, m), 0,8 (2H, m).

(iii) the Specified alcohol (1,58 g) was oxidized using conditions Swern'a (oxalicacid, 0.6 ml; dimethylsulfoxid, 1.0 ml; triethylamine, 4 ml) in dichloromethane to obtain 2-(2,2-dibromoethenyl) cyclopropylmethanol, which is directly used in the next stage. NMR1N: 9,6, 9,43 (1H, d), 5: 80 (1H, d), 2,46 - to 1.82 (2H, m), 1,82-1,0/2N, m).

(iv) a Solution of diisopropylamide lithium obtained from n-utility (2,3 ml of 1.6 M solution in hexane) and Diisopropylamine (0,55 ml), in dry tetrahydrofuran, was treated at -60aboutWith triethylphosphate of 0.85 g) in THF under nitrogen atmosphere. After incubation for 2 h at -60aboutTo the solution was added the indicated aldehyde. After incubation for 18 h at 25aboutC, the mixture was divided between the simple ether and water and processed in the usual way. Chromatographic purification (silica gel, simple ether/hexane) received (+)-(2E, 4E)-ethyl-5-/CIS - /TRANS-2-(2,2-dibromoethenyl)cyclopropyl/cents-2,4-dienoate (1,223 g). NMR1N: 7,24 (1H, DD), 6,28 (1H, DD), by 5.87 (1H, d), 5,80 (1H, d), 5,67 (1H, DD), 4,20 (2N, K) of 1.76 (2H, m) of 1.30 (3H, t), 1,15 (M).

(v) To a solution of specified complex ether (1,233 g) in ethanol (5 ml) and water (2 ml) was added potassium hydroxide (0.25 g). The resulting solution was stirred in techexcel simple ether, was dried over magnesium sulfate and concentrated in vacuum, obtaining ()-(2E, 4E)-5-/CIS - /TRANS-2-(2,2-dibromoethenyl)cyclopropyl/Penta-2,4-diene acid (0.74 g). NMR (C3): 7,30 (1H, DD), of 6.45 (1H, DD), x 6.15 (1H, d), 5,88 (1H, d), 5,00 (1H, s) of 1.92 (2H, m) of 1.28 (2H, m).

(vi) the above acid (0.32 g) was dissolved in dichloromethane (5 ml) was added triethylamine (0,14 ml). Added phenyl-N-phenyl-phosphoramidothioate (ex Lancaster). After 30 minutes of incubation at room temperature was added 1,2-dimethylpropylene (0,087 g) and triethylamine (0,14 ml). The solution was stirred for 18 hours at room temperature before treatment, which was carried out in the usual way. Chromatographic purification (silica gel, simple ether/hexane) received the connection, the name of which is specified in the title of example 3.

P R I m e R 4. ()-(2E, 4E) N-(1,2-dimethylpropyl)-5-(TRANS-2,2-debtor-3-vinylcyclopropyl)Penta-2,4-diene MFA (compound 45).

The esterification of cinnamic acid (7.4 g) was performed in the usual way (ethanol, 120 ml; concentrated sulphuric acid, 6 ml) to give the ethyl ester of cinnamic acid (8.5 g). NMR1N: at 7.55 (1H, d), to 7.15 (5H, m), 6,2 (1H, d), of 4.05 (2H, K) and 1.15 (3H, t). The specified ether (3, 52 g) was treated with diisobutylaluminium (40 ml, 1M solution in hexane) in dichlormid is (C).

The specified alcohol (2,05 g) in pyridine (1.6 ml) was stirred with acetic anhydride (1.8 g) at 25aboutC for 3 h before separation of a mixture between a simple ether and dilute hydrochloric acid. Subsequent processing carried out in the usual way, received 3-phenyl-propenyl-2-acetate. (2.2 g) NMR1N: to 7.15 (5H, m), of 6.52 (1H, d), from 6.22 (1H, t), of 4.57 (2H, d), from 2.00 (3H, s). Specified acetate (1.65 g) was dissolved in diglyme (ex Aldrich) was added chlorodifluoroacetate sodium (ex Fluorochem) (8,4 g) at 25aboutC in nitrogen atmosphere. The solution was heated to 180aboutC and kept at this temperature for half an hour. After cooling to 40aboutWith added the next portion of chlorodifluoroacetate sodium (6.2 g) and then heated the mixture up to 180aboutWith, maintaining at this temperature for another half hour. The mixture was cooled and diluted with hexane. The organic phase is washed with water, dried over magnesium sulfate and the solvent was removed in vacuum. Chromatographic purification (silica gel; simple ether/hexane) received TRANS-2,2-debtor-3-phenylcyclopropane (1.56 g).

NMR1N: 7,30 (5H, m), 4,37 (1H, DD), 4.26 deaths (1H, d), to 2.67 (1H, DD), 2,29 /1H, triple doublet (TD)/ by 2.13 (3H, s). Specified acetate (1.56 g) was stirred for 18 h in aqueous methanol (10 ml) with potassium carbonate (2,94 g). Dal is UP>N: 7,30 (5H, m), of 3.94 (2H, m), 2.63 in (1H, m), 2,24 (1H, m), 1,67 (1H, s). The specified alcohol (0.55 g) was stirred in dichloromethane (6 ml) at 25aboutWith and added pyridinediamine (2 g) (ex Aldrich) and molecular sieves 3 ADot (ex B1 N) (1.5 g). After triasovogo keeping at room temperature the mixture was diluted simple ether and filtered through silica gel, rinsing with simple ether. After removal of the solvent in vacuo was obtained 2,2-debtor-3-phenylcyclopropane (0,255 g). NMR1N: 9,49 (1H, DD), 7,2-the 7.65 (5H, m), 3,61 (1H, TD), 2,955 (1H, TD). The solution diisopropylamide lithium obtained from n-utility (1 ml of 1.6 M solution in hexane) and Diisopropylamine (of 0.24 ml) in dry tetrahydrofuran was treated at -60aboutWith triethylphosphate (0.375 g) in THF under nitrogen atmosphere. After 2 h of incubation at -60aboutWith added specified aldehyde (0,255 g). After 18 h of incubation at 25aboutThe mixture was divided between the simple ether and water and then treated in the usual way. Chromatographic purification (silica gel; simple ether/hexane) gave ()-(2E, 4E)-ethyl-5-/TRANS-2,2-debtor-3-vinylcyclopropyl/Penta-2,4-dienoate, which was converted to the target compound by analogy with the stage (vi) of example 3.

P R I m e R 5. ()-(2E, 4E) N-(1,2-dimethylpropyl-5-/TRANS-2,2-debtor-3-(4-brave-nil)tie acetic anhydride in the usual way with the formation of 3-(4-bromophenyl)propanol-2-acetate (2.25 g), NMR 1N: to 7.35 (2H, d), was 7.08 (2H, d), of 6.52 (1H, d), 6,10 (1H, dt) and 4.65 (2H, d), and 2.1 (3H, s). Specified acetate (2.25 g) were reacted in the usual way with chlorodifluoroacetate sodium with the formation of TRANS-2,2-debtor-3-(4-bromophenyl)cyclopropanemethylamine (2,39 g). NMR1N: of 7.48 (2H, d), and 7.1 (2H, d), 4,30 (2H, m), 2,62 (1H, DD), of 2.23 (2H, m), 2,12 (3H, s).

Specified acetate (2,39 g) were reacted in the usual way with potassium carbonate at 2.36 g with the formation of 2,2-debtor-3-(4-bromophenyl)cyclopropylmethanol (1,93 g). NMR1N: 7,3 (2H, d), a 7.0 (2H, d), 3,8 (2H, m), 3,18 (1H, s) to 2.55 (1H, m), 2,1 (1H, m). The above alcohol (1,93 g) was converted to the target compound by a method similar to that described in stage (iii)-(vi) of example 3.

()-(2E, 4E) N-isobutyl-3-methyl-5-/TRANS-2,2-debtor-3-(4-bromophenyl)cyclo-propyl/Penta-2,4-dienamic (compound 47) was obtained in a similar way, using triethyl-3-methylphosphonochloridate and isobutylamine.

P R I m e R 6. ()-(2E, 4E) N-(1,2-dimethylpropyl)-6-/CIS, TRANS-2, (3-trifluoromethyl - phenyl)cyclopropyl /hexa-2,4-dienamic (compound 48).

(i) buten-4-one (0.31 g) was heated at 60aboutC for one hour with tributyltinhydride (ex Aldrich) (1.6 g) and azobisisobutyronitrile (0.04 g) (ex Aldrich). Cooling and distillation (ugelrohr 150about, 1 mm RT. Art. ) received 4-tributyltin-3-1-ol (1,17 g (2N, m) 0,9-2,0 (N, m).

(ii) Bis-azionitelecomitalia (0.01 g) was dissolved in dry dimethylformamide (10 ml) at 25aboutC in argon atmosphere. Added 3-cryptomaterial (1,03 g (ex Fluorochem) in DMF, and then added the specified alcohol (1,17 g). After incubation for 72 h, the solution was divided between the simple ether and 10% solution of ammonium hydroxide, and then processed in the usual way.

Chromatographic purification (silica gel, simple ether/hexane) was obtained 4-(3-triptoreline)butene-3-1-ol (0,67 g) in a mixture of 1: 1 CIS: TRANS isomers of olefin (I. K. Stille and B. L. Groh, I. Am. Chem. Soc. , 109, 1987, 815). NMR 1H: 7,5 (4H, m), 6,55 (1H, d), 6,32 (1H, dt), of 3.78 (2H, m) to 2.55 (2H, m), 1,50 (1H, s).

(iii-vi) Specified the alcohol was converted to the target compound by analogy with the stages (iii)-(vi) of example 1.

P R I m e R 7. (A)-(e) N-(1,2-dimethylpropyl)-3-/CIS-2 (3-triptoreline)cyclopropyl/propene-2-amide (compound 49).

(i) Ethylpropane (0,98 g) (ex Lancaster) and tributylphosphite (3,01 g) azobisisobutyronitrile (0.01 g) was heated at 60aboutC for 18 hours, Cooled and chromatographic purification (silica gel, simple ether/hexane) was obtained (Z)-ethyl-3-tributylphosphine (1.9 grams) I. K. Stille et al. , I. Amer. Chem. Soc. 109, 1987, 815). NMR1N: 7,14 (1H, d), 6.73 x is cooled to -20aboutC in nitrogen atmosphere. Was added dropwise diisobutylaluminium (4 ml of 1M solution in hexane). After 18 h of incubation at 25aboutWith carefully added diluted hydrochloric acid, then was treated with the mixture in the usual way, getting 3-tributylamine-propen-2-1-ol (0.75 g). NMR1N: 6,72 (1H, dt), 6,10 (1H, d), is 4.15 (2H, DD), 1,40 (N, m), 0,90 (N, m).

(iii-v) Specified alcohol (0.75 g) was transformed into ()-CIS-2-(3-triptoreline)-1-formultimedia (0.2 g) in a manner analogous to stage (ii) of example 6 and the stages (iii) and (iv) of example 1. NMR1N: of 8.95 (1H, d), to 7.50 (4H, m), 1,0-2,5 (4H, m).

(vi) Specified aldehyde (0.2 g) was stirred in dichloromethane (5 ml) with carbethoxymethylthio in nitrogen atmosphere for 18 h at 25aboutAfter concentration in vacuo the residue was washed with hexane, and after removal of the hexane under vacuum received ()-(E)-ethyl-3-/CIS-2-(3-triptoreline)cyclopropane/propene-2-oat (0.18 g). NMR1N: the 7.43 (4H, m), 6,18 (1H, DD), 5,94 (1H, d), 4,06 (2N, K), 2,62 (1H, m), is 2.09 (1H, m) of 1.55 (1H, m) of 1.34 (1H, m) to 1.22 (3H, t).

(vii) the Specified ether was converted to the target compound by analogy with the stage (vi) of example 1.

P R I m e R 8. ()-(2E, 4E) N-(1,2-dimethylpropyl)-5-CIS, TRANS-2 (3-triptoreline)cyclopropyl/Penta-2,4-dienamic (connection methane (3 ml) and cooled to -20aboutC in nitrogen atmosphere. Added diisobutylaluminium (1.3 ml of 1M solution in hexane) and the solution was stirred at 25aboutC for 18 h were Carefully added diluted hydrochloric acid, then was treated with the mixture in the usual way, receiving CIS-2-(3-triptoreline)-2-(3-oxypropane-2-1-yl)cyclopropane (0.15 g). NMR1N: the 7.43 (4H, m), 5,79 (1H, dt), to 4.98 (1H, DD), 3,95 (2H, d), is 2.40 (1H, m), of 1.94 (1H, m) of 1.33 (1H, m), 1,10 (2H, m).

The specified alcohol (1.35 g) was oxidized using the method Swern'a (oxalicacid, 0.54 ml; dimethylsulfoxide, 0,86 ml triethylamine, and 3.8 ml) in dichloromethane, receiving CIS-2-(3-triptoreline)-1-(1-propen-3-allyl)cyclopropane (1.3 g). NMR1N: of 9.21 (4H, d), to 7.50 (4H, m), 6,28 (1H, DD), 5,98 (1H, DD), and 2.79 (1H, m), 2,12 (1H, m), by 1.68 (1H, m) of 1.42 (1H, m).

Specified aldehyde (1.3 g) was reacted with carbethoxymethylthio (1,74 g) by analogy with example 7 (vi) education ()-(2E, 4E)-ethyl-5-/CIS-2, (3-triptoreline)-cyclopropyl/Penta-2,4-dienoate (1.1 g). ASR1N: 7,42 (4H, m), 7,05 (1H, DD), of 6.31 (1H, DD), 5,73 (1H, d), 5,31 (1H, DD), 4,17 (2N, K) of 2.56 (1H, m), 2,03 (1H, m) to 1.48 (1H, m), 1,25 (4H, m). The specified ester was converted to the target compound by analogy with example 1 (vi) forming a mixture consisting of 6: 1 CIS-TRANS cyclopropane isomers.

()-(2E, 4E) N-isobutyl-5-/qi is de mixture of CIS: TRANS cyclopropyl of isomers consisting of 4: 1, using Isopropylamine instead of 1,2-dimethylpropylene.

P R I m e R 9. ()-(2E, 4E) N-(1,2-dimethylpropyl)-5-CIS, TRANS-2, (4-chlorophenyl)-2-methylcyclopropyl/Penta-2,4-dienamic (compound 52).

To a solution of isopropylcyclohexane lithium (from 12.5 ml of 1.6 M solution of n-utility and isopropylcyclohexane (3,3 ml) (ex Aldrich) in THF was added at -60aboutWith ethyltrimethoxysilane (3.6 ml) (ex Fluka). After 30 min of incubation at -60aboutWith added 4-chloracetophenone (ex Aldrich) (1.55 g). After 18 h of incubation at 25aboutThe mixture was divided between the simple ether and water and processed in the usual way. Chromatographic purification (silica gel, simple ether/hexane) was obtained ethyl-3-(4-chlorophenyl)-butene-2-oat (1.22 g) as a mixture of E, Z isomers of olefin composition of 1: 1, NMR1N: to 7.2 (4H, m), the 6.0 and 5.0 (1H, m), of 4.12 (2H, m), of 2.51 and 1,90 (3H, s), 1,25 (3H, m). The specified ester (1.44 g) was dissolved in dichloromethane (13 ml) and cooled to -20aboutC. was added dropwise diisobutylaluminium (12,8 ml of 1M solution in hexane). After incubation for 18 h at 25aboutWith carefully added diluted hydrochloric acid and was treated with the mixture in the usual way, getting 3-(4-chlorophenyl)butene-2-1-ol. NMR1N: 7,18 (4H, s), to 5.85 (1H, t), 4,25 (2H, d), 3,05 (1H, s), is 2.05 (3H, s)

P R I m e R 10. ()-(2E, 4E) N-(1,2-dimethylpropyl)-5-/TRANS-2,2-dimethyl-3-(3-triptoreline)cyclopropa l /Penta-2,4-dienamic (compound 53).

Ethyl ester of 3-triptoreline acid (0,98 g) (example 2) in tetrahydrofuran under nitrogen atmosphere was treated with ridom obtained from isopropyltriphenylphosphonium (2,12 g) and n-utility (2.8 ml). After 20 h of incubation at 80aboutThe mixture was processed in the usual way. Chromatographic purification (silica gel, simple ether/hexane) received ()-n-butyl-/TRANS-3-(3-triptoreline)-2,2-dimethylcyclopropane/format (0,78 g). NMR1N: 7,22 (4H, m), 4,20 (2H, m), of 2.72 (1H, m), from 2.00 (1H, m) of 1.40 (7H, m), 0,89 (6N, m).

The specified ester (0,78 g) was dissolved in dichloromethane (12 ml) under nitrogen atmosphere and cooled to -20aboutC. was added dropwise diisobutylaluminium (7,4 ml) and the stirred solution at 25aboutC for 18 h were Carefully added diluted hydrochloric acid, then was treated with the mixture in the usual way, receiving ()-/TRANS-3-(3-triptoreline)-2,2-dimethylcyclopropane/methanol (0.31 g). NMR1H: 7,5 (4H, m), the 3.65 (2H, d), 2,55 1H, wide (W)), 1,62 (1H, d), to 1.14 (1H, m) and 1.15 (3H, s) of 0.90 (3H, s).

The specified alcohol was converted to the target compound in a manner analogous to the stages (iv)-UNAMID (compound 54) were treated in a similar way, on the basis of the ethyl ester of 3,4-dichloroamino acid.

P R I m e R 11. ()-(2E, 4E) N-(1,2-dimethylpropyl)-5-/TRANS-2-(4-chlorophenyl)-1-methylcyclopropyl/cents - 2,4-dienamic (compound 55).

4-chlorobenzaldehyde (6.8 g) (ex Aldrich) in dichloromethane (250 ml) was reacted with carbethoxymethylthio (17,5 g) (ex Lancaster) at 25aboutC for 18 hours Spent concentrating in vacuo, then abundantly washed the residue with hexane. The collected hexane wash was concentrated, obtaining (E)-ethyl-3-(4-chlorophenyl)-2-methylpropan-2-oat (11.6 g).

NMR1N: to 7.35 (4H, m), 4,25 (2N, K) is 2.05 (3H, s) is 1.31 (3H, t). The specified ester (11.7 g) was dissolved in dichloromethane (100 ml) and cooled to -20aboutC. was added dropwise diisobutylaluminium (100 ml). After 18 h of incubation at 25aboutWith carefully added diluted hydrochloric acid. The resulting mixture was treated in the usual way, obtaining (E)-3-(4-chlorophenyl)-2-methylpropan-2-1-ol (8.6 g). NMR1N: 7,34 (2H, d), 7,22 (2H, d), of 6.49 (1H, s), 4,19 (1H, s), 1,90 (3H, s) of 1.66 (1H, s).

The specified alcohol was treated with diethylzinc (45,5 ml) and diiodomethane (8.1 ml) in hexane in the usual way, receiving ()-/TRANS-2-(4-chlorophenyl)-1-methylcyclopropyl/methanol (1,94 g). NMR1N: to 8.94 (1H, s), 7,30 (2H, d), 7,06 (2H, d), 2,68 (1H, DD), 2,24 (1H, example 3.

P R I m e R 12. (-) N-isobutyl-5-/1S, 2R)-TRANS-2-(3,4-dichlorophenyl)cyclopropyl/Penta-2,4-dienamic (compound 56).

3-(3,4-dichlorophenyl)propen-2-1-ol (1.0 g) obtained by analogy with stage (i) of example 2 and stage (ii) of example 1) was oxidized using the method Swern'a (oxalicacid, 0.5 ml; dimethylsulfoxide, 0.7 ml; triethylamine, 3.4 ml) to give 3-(3,4-dichlorophenyl)-propen-2-al (0.9 g), NMR1N: 9,76 (1H, d), 7,53 (3H, m), 7,41 (1H, d), of 6.68 (2H, DD).

Specified aldehyde (0.66 g) was stirred in ethanol (5 ml) with triethylorthoformate (0.6 ml) (ex Aldrich) and ammonium nitrate (ex Aldrich) (0.01 g) for 3.5 h at 25aboutC. Concentration in vacuo and processing in the usual way received E-1-(3,4-dichlorophenyl)-3,3-diethoxybutane-I (0.97 g). NMR1N: to 7.32 (3H, m), 6,79 (1H, d), to 6.19 (1H, DD), to 5.08 (1H, d), of 3.69 (4H, m), 1,29 (6N, m).

Specified acetal (0,67 g) was dissolved in benzene (25 ml) and treated (+)-L-Diisopropylamine (0.7 g) (ex Aldrich) and p-toluensulfonate (0.01 g) (ex Aldrich). The mixture was heated at 80aboutC for 6 h using the unit Dean-stark. The solution was cooled and treated in the usual way, obtaining (-)-4,5-dicarbonitrile-2-/(E)-2-(3,4-dichlorophenyl)ethynyl/-1,3-dioxolane (0,92 g). NMR1N: to 7.50 (1H, d), 7,40 (1H, d), 7,25 (1H, DD), 6,74 (1H, d), of 6.26 (1H, DD), of 5.81 (1H, d), 5,14 (2H, m), of 4.77 (1H, d), 4,69 (1H, d), 1,33 (N, m).

Specified acetal (0.8 g) was heated at 70aboutC for 12 h in tetrahydrofuran (5 ml) in the presence of dilute hydrochloric acid (3 ml). Processing the mixture in the usual way received (-)-/TRANS-(2R, 3S)-2-(3,4-dichlorophenyl)cyclopropyl/-methanal (0,23 g). NMR1N: 9,39 (1H, d), 7,39 (2H, m) 6,94 (1H, DD), of 2.56 (1H, m), of 1.65 (2H, m).

Diisopropylamide lithium obtained from n-utility (0.6 ml) and Diisopropylamine (0,14 ml), was treated at -60aboutIn the environment of tetrahydrofuran triethyl-4-phosphonocrotonate (0.21 g) in tetrahydrofuran; the treatment was performed in a nitrogen atmosphere. After 2 h of treatment at -60aboutWith added specified aldehyde. After incubation for 18 h at 25aboutWith added water and was treated with the mixture in the usual way. Chromatographic purification (silica gel, hexane/simple ether) was obtained (-)-(2E, 4E)-ethyl-5-/TRANS-(2R, 3S)-2-(3,4-dichlorophenyl)cyclopropyl/Penta-2,4-dienoate (0.16 g). [ ] D - 304,7about(from 0.9, ethanol), NMR1N: 7,28 (3H, m), to 6.88 (1H, DD), 6,18 (1H, DD), of 5.84 (1H, DD), 5,78 (1H, d), 4,10 (2H, K), example 1.

(+)-N-isobutyl-5-/(1R, 2S)-TRANS-2-(3,4-dichlorophenyl)cyclopropyl/Penta-2,4-dienamic (compound 57) was treated in a similar way, using (-)-D-diisopropylate (ex Aldrich).

P R I m e p 13. ()-(2E, 4E) N-isobutyl-5-/TRANS-2-(2,6-dichloro-4-pyridyl)cyclopropyl/-3-methylpentan - 2,4-dienamic (compound 58).

2,6-dichlorophenylamino acid (4.0 g) (prepared according to M. M. Robinson, I, Amer. Chem. Soc. , 80, 5481, 1958) was dissolved in ethanol (20 ml) and concentrated sulfuric acid (1 ml). After 6 h of heating at 80aboutThe solution was cooled, concentrated in vacuo and the residue was treated in the usual way, getting ethyl-2,6-dichloroaniline (3.7 g). NMR1N: to 7.84 (2H, s), 4,48 (2N, K) to 1.48 (3H, t).

The specified ester was dissolved in dichloromethane (60 ml) and cooled to -20aboutC in nitrogen atmosphere. Was added dropwise diisobutylaluminium (38 ml). After incubation for 2 h at 0aboutTo the mixture was added diluted hydrochloric acid, the resulting mixture was then processed in the usual way, getting 2,6-dichloro-4-oxymethylphenyl. 1H NMR: TO 7.64 (2H, s), to 4.98 (2H, s).

The specified alcohol (1.2 g) was oxidized under the conditions Swern'a (oxalicacid, 0.33 ml; dimethylsulfoxide, 0.54 ml); triethylamine, 2.35 ml) to give (2,6-dichloro-4-pyridyl)methanol (1.2 g). NMRaboutThe solution was concentrated in vacuo and the residue was washed with hexane. The collected hexane wash was concentrated in vacuum, obtaining ethyl-3-(2,6-dichloro-4-pyridyl)propanoate (1.2 g). NMR1N: to 7.50 (2H, d), 2,28 (2H, s), of 6.52 (2H, d), 4,29 (2N, K) of 1.32 (3H, t).

The specified ester (0.25 g) was added at 25aboutC in an atmosphere of nitrogen in dimethyl sulfoxide (4 ml) to the ylides derived from trimethylsulfoxonium (0.24 g) and sodium hydride (0,44 g 60% dispersion in mineral oil). After incubation for 18 h at 25aboutto the mixture was carefully added water, the resulting mixture was treated in the usual way. Chromatographic purification (simple ether/hexane, silica gel) received ()-ethyl-/TRANS-2-(2,6-dichloro-4-pyridyl)cyclopropyl/formate (0.12 g). NMR1N: 6,93 (2H, s), 4.16 the (2N, K), 2,42 (1H, TD), 1,99 (1H, dt), was 1.69 (1H, dt), of 1.30 (2H, m), 1,25 (3H, t).

The specified ester (0.34 g) was dissolved in dichloromethane (7 ml) under nitrogen atmosphere and cooled to -20aboutC. was added dropwise diisobutylaluminium (2.8 ml). After 0.5 h was added methanol (0.5 ml) followed by 2M sodium hydroxide (5 ml). The resulting mixture was then processed in the usual way. NMR1N: 6,98 (2H, s) to 3.64 (2H, m), 3,30 (1H, CL), 0,9-2,0 (4H, m). The resulting alcohol (0.21 g) oxide is s-2-(2,6-dichloro-4-pyridyl)cyclopropyl/methanol (0.2 g). NMR1N: 9,44 (1H, d), of 6.96 (2H, s), of 1.0 to 2.6 (4H, m).

The solution diisopropylamide lithium in tetrahydrofuran (2 ml) was obtained from n-utility (0.7 ml) and Diisopropylamine (0.16 ml), was treated at -60aboutWith triethyl-4-phosphono-3-methylcrotonate (0.26 g). After keeping the mixture for 2 h at -60aboutTo it was added the indicated aldehyde (0.2 g). After incubation for 2.5 h at 25aboutTo the mixture was added water, and then were processed in the usual way. Chromatographic purification (silica gel, simple ether/hexane) received ()-(2E, 4E)-ethyl-3-methyl-5-/TRANS-2-(2,6-dichloro-4-pyridyl)cyclopropyl/Penta-2,4-Dien oat (0.18 g). NMR1N: 6,92 (2H, s), from 6.22 (1H, d), of 5.75 (2H, m), 4,14 (2N, K), 2,24 (3H, s), of 1.94 (2H, m) of 1.41 (1H, m) of 1.28 (1H, m) to 1.22 (3H, t).

The specified ester was converted to the target compound by analogy with the stage (vi) of example 1.

P R I m e R 14. ()-(2E, 4E) N-(1,2-dimethylpropyl)-5-/TRANS-2-(3,4-dibromophenyl)cyclopropyl//Penta-2,4 - dienamine (compound 59).

3-nitro-4-bromthymol (54 g) (ex Lancaester) in a mixture of ethanol-water (100 ml, 1: 1) was intensively stirred at 25aboutWith and added iron powder (84 g) (ex BDH). The resulting mixture was heated under reflux to boiling and within 30 minutes was added dropwise Rast was cooled, was podslushivaet 15% solution of potassium hydroxide and filtered through a zeolite, washing with ethanol (g ml). The resulting mixture was diluted with water (1000 ml) and treated in the usual way, getting the 3-amino-4-bromthymol (43,6 g). NMR1N: of 7.25 (1H, d), 6,40 (2H, m), of 3.96 (2H, CP), 2,2 (3H, s).

Specified Minotaur (24 g) was stirred in concentrated Hydrobromic acid (230 ml) at 0aboutC. was Added a solution of sodium nitrite (9,8 g (ex BDH) in water (35 ml), maintaining the reaction temperature between 0 and 5aboutC. the Mixture was poured into a solution of copper bromide (37 g) (ex BDH) in water (230 ml) and Hydrobromic acid at 50aboutC. After incubation for 2 h at 50aboutC and 18 h at 25aboutTo the mixture was added water and the resulting mixture was treated in the usual way. After purification by distillation (100aboutC, 0.5 mm RT. Art. ) received 3,4-dibromsalan (12.7 g). NMR1N: 7,53 (2H, m), to 6.95 (1H, DD), is 2.30 (3H, s). The solution of the specified derivative of toluene (5 g) in Delaney acetic acid (20 ml) (ex BDH) and acetic anhydride (32,6 g) was cooled to -10aboutC. was added dropwise sulfuric acid (7.8 g), maintaining the reaction temperature below -5aboutC. Portions was added chromium trioxide (ex BDH) (6 g), maintaining the reaction temperature between -5 and 0aboutC. After aging in t is ethyl-3,4-dibromobenzyl. NMR1N: 7,53 (2H, m), to 6.95 (1H, DD), 2,30 (6N, C).

The specified diacetate was dissolved in a mixture of water (15 ml) - ethanol (15 ml) was added concentrated sulfuric acid (1.5 ml). After boiling under reflux for 1 h, the solution was processed in the usual way, getting 3,4-dibromosalicylic (2.25 g). NMR1N: 10,04 (1H, s), 7,53 (2H, m), to 6.95 (1H, DD). Specified aldehyde (2.25 g) was dissolved in dichloromethane (25 ml) was added carbethoxymethylthio (2,96 g). After incubation for 18 h at 25aboutThe solution was concentrated in vacuo and the residue was washed with hexane. The collected hexane wash was concentrated in vacuum, obtaining ethyl-3-(3,4-dibromophenyl)propanoate (2.4 g). NMR1N: 7,7 (2H, m) to 7.50 (1H, d), to 7.15 (1H, DD), 6,32 (1H, d), 4.26 deaths (2N, K) of 1.33 (3H, t).

The specified ester (2.4 g) was dissolved in dichloromethane (25 ml) under nitrogen atmosphere and cooled the solution to -20aboutWith, and then was added dropwise diisobutylaluminium (14,5 ml). After incubation for 18 h at 25aboutWith carefully added to a mixture of diluted hydrochloric acid, the mixture was treated in the usual way, getting 3-(3,4-dibromophenyl) propen-2-1-ol. (2,04 g). NMR1N: 7,53 (2H, m), 7,13 (1H, DD), 6,56 (1H, d), of 6.20 (1H, dt), 4,30 (2H, d), to 1.98 (1H, s).

The decree is Rance-2-(3,4-dibromophenyl)cyclopropyl/methanol (1.3 g). NMR1N: 7,40 (1H, d), 7,30 (1H, d), 6,76 (1H, DD), 3,53 (2H, d), 2,30 (1H, s), 1,68 (1H, m) of 1.33 (1H, m), 0,87 (2H, m).

The specified alcohol was converted to the target compound by analogy with the stages (iv)-(vi) of example 1.

(i) (a)-(2E, 4E) N-isobutyl-3-methyl-5-/TRANS-2-(3,4-dibromophenyl)cyclopropyl/Penta-2,4-danami d (compound 60) and (ii) (a)-(2E, 4E) N-(2-methylbutyl-2)-3-methyl-5-/TRANS-2- (3,4-dibromophenyl)cyclopropyl/Penta-2,4-dienamic (compound 93) received a similar way, using triethyl-3-methylphosphonochloridate and (i) isobutylamine and (ii) 2-methylpropenyl-2-amine, respectively.

P R I m e R 15. ()-(2E, 4E) N-1,2-dimethylpropyl)-5-/TRANS-2-(3,5-dichloro-4-bromophenyl)cyclopropyl/Penta - 2,4-dienamic (compound 61).

N-aminobenzonitrile (11,8 g) (Aldrich) in dry chloroform (250 ml) under nitrogen atmosphere was treated with chloride sulfuricum (of 4.05 g), (ex BDH), maintaining the reaction temperature below 35aboutC. After 2 hours boiling under reflux the mixture was poured on ice and podslushivaet 2M solution of sodium hydroxide. Further processing in the usual way received 3,5-dichloro-4-aminobenzonitrile (18.2 g). NMR1N: to 7.35 (2H, s), 4,70 (2H, CL).

The specified aminonitriles (18.7 g) in concentrated Hydrobromic acid (190 ml) was treated at 0aboutWith restaudarores acid (30 ml) at 50aboutC. After 2 h of incubation at 50aboutC and 18 h of incubation at 25aboutThe mixture was diluted with water and then treated in the usual way, getting 3,5-dichloro-4-bromobenzonitrile (9.2 grams). NMR1N: 7,63 (2H, s). Specified nitrile (5 g) in a simple ether (100 ml) under nitrogen atmosphere was treated with diisobutylaluminium (22 ml of a 1M solution in toluene). After incubation for 18 h at 25aboutTo the mixture was added 1,4-dioxane (150 ml) and water (10 ml) and then diluted hydrochloric acid (250 ml). After 30 min of incubation at 25aboutWith the resulting mixture was treated in the usual way, getting 3,5-dichloro-4-bromobenzaldehyde (4.52 g). NMR1N: of 9.89 (1H, s), a 7.85 (2H, s).

The indicated aldehyde was converted to the target compound by analogy with example 1.

()-(2E, 4E) N-isopropyl-3-methyl-5-/TRANS-2-(4-brad-3,5-dichlorophenyl)cyclopropyl/ Penta-2,4-dienamic (compound 62) was treated in a similar way, using triethyl-4-phosphono-3-methylcrotonate and isobutylamine.

P R I m e R 16. ()-(2E, 4E) N-1,2-dimethylpropyl)-5-/TRANS-2-(2,2-dibromoethenyl)phenyl)cyclopropyl/Penta 2,4-dienamic (compound 65). Ethyl-4-formylbenzoate (2,46 g) (ex Lancaster) in dichloromethane (30 ml) was treated under nitrogen atmosphere with triphenylphosphine (15.7 g) and cetarehhloristam carbon (9,9 g) when 01H: 8,0 (2H, d), to 7.50 (2H, d), was 7.45 (1H, s), 3,85 (3H, s).

The specified ester (of 3.32 g) in dichloromethane (10 ml) was treated under nitrogen atmosphere by diisobutylaluminium (21 ml). After incubation for 1 h at 0aboutWith added diluted hydrochloric acid, the mixture was treated in the usual way, getting 4-(2,2-dibromoethenyl) benzyl alcohol (3,18 g). NMR1N: to 7.50 (2H, d), 7,41 (1H, s), 7,20 (2H, d), to 4.33 (2H, s), the 3.65 (1H, s).

The specified alcohol (3,18 g) was oxidized using conditions Swern'a (oxalicacid, of 0.96 ml; dimethyl sulfoxide, and 1.56 ml; triethylamine, 6.9 ml), in the environment of dichloromethane, receiving 4-(2,2-dibromoethenyl)benzaldehyde (2,04 g). NMR1N: 10,94 (1H, s), 7,86 (2H, d), to 7.61 (2H, d), was 7.45 (1H, s).

The indicated aldehyde was transformed in ()-(2E, 4E)-ethyl-5-/TRANS-(4-(2,2-dibromethane)phenyl)cyclopropyl/Penta-2,4-dienoate by analogy with the stages (i) to(v) of example 1. Received slony ether was converted to the target compound by analogy with the stages (v) and (vi) of example 3.

P R I m e R 17. ()-(2E, 4E) N-(1,2-dimethylpropyl)-5-/TRANS-2-(4-ethynylphenyl)cyclopropyl/Penta-2,4 - dienamic (compound (66)

()-TRANS-2-/4-(2,2-dibromoethenyl) phenyl/SUP>With n-butyllithium (8.1 ml). After keeping the mixture for 4 h at 25aboutWith added water, and the resulting mixture was processed in the usual way. Chromatographic purification (silica gel, simple ether/hexane) received ()-TRANS-2-(4-ethynylphenyl)cyclopropanemethanol (0,62 g). NMR1N: 7,41 (2H, d), of 6.90 (2H, d), 3,30 (2H, d), 2,95 (1H, s), 2,59 (1H, s), of 1.85 (1H, m) of 1.34 (1H, m) of 0.90 (2H, m).

The specified alcohol was converted to the target compound by analogy with example 1.

P R I m e R 18. ()-(2E, 4E) N-(1,2-dimethylpropyl)-5-/TRANS-2-(3,4,5-triphenyl)cyclopropyl/Penta-2,4-diene MFA (compound 67) 4-amino-3,5-dichlorobenzonitrile was converted to the target compound by analogy with example 15, using instead of Hydrobromic acid and copper bromide hydrochloric acid and chloride of copper (ex BDH).

()-(2E, 4E) N-isobutyl-3-methyl-5-(TRANS-2-(3,4,5-trichlorophenyl)cyclopropyl/Penta-2,4-diene amide(compound 68) was obtained in a similar way, using triethyl-3-methylphosphonochloridate and isobutylamine.

P R I m e R 19. ()-(2E, 4E) N-(1,2-dimethylpropyl)-4-fluoro-5-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/Penta - 2,4-dienamic (compound 69).

Sodium hydride (0.74 g 60% dispersion in mineral oil) (ex BDH) in THF (30 ml) was treated with ethylformate (2.7 ml) (ex Lan)cyclopropylmethanol (6 g) (example 2) (i) and example 1 (ii)-(iv). After 18 h of incubation at 25aboutTo the mixture was added water, the resulting mixture was processed in the usual way. After chromatographic purification (silica gel, hexane/simple ether) was obtained ()-ethyl-(2Z)-3-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/-2-terpentin-2-oat (4 g). NMR1N: 7,30 (1H, d), to 7.15 (1H, d), of 6.90 (1H, DD), 5,70 (1H, DD), 4,30 (2N, K) of 2.08 (2H, m) of 1.35 (2H, m) of 1.30 (3H, t).

The specified ester (4 g) was dissolved in dichloromethane (30 g) and cooled to -20aboutC in nitrogen atmosphere. Was added dropwise diisobutylaluminium (26 ml). After incubation for 18 h at 25aboutC was added to a mixture of diluted hydrochloric acid, the resulting mixture was processed in the usual way, receiving ()-(2Z)-3-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/-2-forproper-2-1-ol (3.3 grams). NMR1N: to 7.32 (1H, d), 7,17 (1H, d), of 6.90 (1H, DD), 4,10 (2H, DD), 3,60 (1H, t), 1,90 (2H, m), 1,20 (2H, m).

The specified alcohol (3.3 g) was oxidized using conditions Swern'a (oxalicacid, 1,2 ml; dimethyl sulfoxide, 2.0 ml; triethylamine, 8,8 ml), in the environment of dichloromethane, receiving ()-(2Z)-3-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/-2-forproper-2-al (3.25 g). NMR1N: 9,20 (1H, d), 7,39 (1H, d), 7,22 (1H, d), to 6.95 (1H, DD), ceiling of 5.60 (1H, DD), measuring 2.20 (2H, m) of 1.50 (2H, m).

Specified aldehyde (0.5 g) was dissolved in dichloromethane (5 ml) in th at 25aboutC for 18 h, the solution was concentrated in vacuo and the residue was washed with hexane. The collected hexane wash was concentrated in vacuum, obtaining ()-(2E, 4Z)-ethyl-4-fluoro-5-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/Penta-2,4-dienoate (0,58 g). NMR1N: 7,30 (1H, d), to 7.00 (3H, m), equal to 6.05 (1H, d), 5,90 (1H, m), 4,20 (2N, K) a 2.00 (2H, m) of 1.30 (3H, t), of 1.30 (2H, m).

The specified ester was converted to the target compound by analogy with the stage (vi) of example 1.

P R I m e R 20. ()-(2E, 4Z) - N-isobutyl-3-methyl-4-fluoro-5-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/Penta - 2,4-dienamic (compound 70).

()-(2Z)-2-fluoro-3-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/propene-2-al (2,59 g). (Example 19) in the simple ether (10 ml) was treated at 0aboutC in an atmosphere of nitrogen methylmagnesium obtained from magnesium turnings (0.26 g) and methyliodide (0.7 ml) in an environment of simple ether (20 ml). After incubation for 18 h at 25aboutThe mixture was processed in the usual way. Chromatographic purification (silica gel, simple ether/hexane) received ()-(3Z)-4-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/butene-3-2-ol (2.0 g). NMR1N: of 7.23 (1H, d), 7,05 (1H, d), of 6.90 (1H, DD), to 4.52 (1H, m) to 4.23 (1H, m) 3,0 (1H, s), of 1.80 (2H, m) of 1.35 (3H, d), of 1.18 (2H, m).

The above alcohol (2.0 g) was oxidized using conditions Swern'a (oxalicacid, 0.7 ml; d is chlorophil/butene-3,2-he (1.5 g). NMR1N: 7,30 (1H, d), 7,10 (2H, d), to 6.95 (1H, DD), 5,70 (1H, DD), 2,32 (3H, d), 2,10 (2H, m), USD 1.43 (2H, m).

Chlorocatechol (ex Aldrich) (50 g) was added dropwise with stirring to isobutylamino (ex Aldrich) (70 ml) in a simple medium dry ether (250 ml) at 0aboutC. When the mixture was heated to room temperature, it was treated in the usual way, having N-isobutyl-2-chloracetamide. The latter compound (20 g) was heated for 3 h at 120aboutWith triethylphosphite (23 g). The mixture was subjected to vacuum distillation, resulting in N-isobutyl-diphenylphosphonate (22,5 g, temp. the TRC. 140-142,5aboutWith 0.1 mm RT. Art. ).

The solution diisopropylamide lithium in tetrahydrofuran obtained from n-utility (2.3 ml) and Diisopropylamine (0.51 ml) in nitrogen atmosphere at -70aboutWith processed diethyl-N-isobutylphthalate ones (0.46 g) in dry tetrahydrofuran. After 2 h of incubation of the mixture at 25aboutWith it added the specified ketone (0.5 g). After keeping the mixture at 25aboutC for 18 h added water, the mixture was processed in the usual way. After chromatographic purification (silica gel, simple ether/hexane) received target compound (0.24 g). ()-(2Z, 4E) N-(2-methylpropenyl)-3-methyl-4-fluoro-5-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/ Penta-2,4-

P R I m e R 21. ()-(2E, 4E) N-(1,2-dimethylpropyl)-5-/TRANS-2-(3-chloro-4-bromophenyl)cyclopropyl/Penta-2,4 - dienamic (compound 71).

Was obtained in analogy to example 14, using hydrochloric acid and chloride of copper instead of Hydrobromic acid and copper bromide.

()-(2E, 4E) N-isobutyl-3-methyl-5-/TRANS-2-(3-chloro-4-bromophenyl)cyclopropyl/Penta - 2,4-dienamic (compound 72) was treated in a similar way, using triethyl-3-methyl-4-phosphonocrotonate and isobutylamine instead of triethyl-4-phosphonocrotonate and 1,2-dimethylpropylene.

()-(2E, 4E) N-(1,2-dimethylpropyl)-5-/TRANS-2-(3-bromo-4-chlorophenyl)cyclopropyl/Penta-2,4 - dienamic (compound 73) and ()-(2E, 4E) N-isobutyl-3-methyl-5-/TRANS-2-(3-bromo-4-chlorophenyl)cyclopropyl/Penta-2,4 - dienamic (compound 74) was obtained in a similar way, on the basis of 4-chloro-3-nitrotoluene.

P R I m e R 22. ()-(2E, 4E) N-isobutyl-3-methyl-5-/TRANS-2-(4-benzoylphenyl)cyclopropyl/Penta-2,4-dienamic (compound 75).

Powdered zinc (12.5 g (ex BDH) in water (15 ml) at 25aboutC was treated with mercury chloride (1.25 g) (ex Aldrich). Added concentrated hydrochloric acid, the excess decantation. Added 4-benzoylbenzene acid (5 g) (ex Lancaster), then water (15 ml), glacial acetic acid (2 ml) and toluene (15 ml). Added erosively diluted hydrochloric acid. Processing in the usual way got a 4-benzylbenzamide acid (4 g). The above acid (4 g) was dissolved in ethanol (50 ml) and treated with concentrated sulfuric acid (0.5 ml). After 3 hours boiling under reflux the mixture was concentrated in vacuo and the residue was treated in the usual way, getting ethyl-4-benzyl benzoate (4 g). NMR1N: 8,00 (2H, DD), 7,28 (7H, m), 4,39 (2N, K), Android 4.04 (2H, s) of 1.40 (3H, t).

The specified ester (4 g) in dry simple ether was treated at 0aboutC in an atmosphere of nitrogen sociallyengaged (0.9 g). After 1 h of incubation at 0aboutC and 18 h of incubation at 25aboutWith carefully added water and the resulting mixture was treated in the usual way, getting 4-benzylbenzoate alcohol (2,52 g). NMR1N: 7,21 (N, m), a 4.53 (2H, s), of 3.95 (2H, s), 2,10 (1H, CL).

Specified Speer (2,52) was oxidized using conditions (oxalicacid, 1,2 ml; dimethylsulfoxide, 1.8 ml; triethylamine, 8,8 ml), in the environment of dichloromethane, receiving 4-benzylbenzamide (1,33 g). NMR1N: to 9.93 (1H, s), 7,78 (2H, d), 7,33 (2H, d), 7,20 (5H, s), Android 4.04 (2H, s).

The indicated aldehyde was converted to the target compound by analogy with example 15.

()-(2E, 4E) N-(1,2-dimethylpropyl)-5-/TRANS-2-(4-benzoylphenyl)cyclopropyl/Penta-2,4 - dienamic (compound 76) received analogout-2-fluoro-3-methyl-5-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/Penta - 2,4-dienamic (compound 77).

Ethylbromoacetate (Fluorochem) (25 g) and triethylphosphite (ex Aldrich) (29 g) were heated together at 140 5aboutC for 6 h in capacity, equipped with a distillation column. After distillation of the entire ethylbromide person to distil the residue to obtain triethyl-2-fluoro-2-phosphatidate (22g) (temp. the TRC. 98-108aboutWith 0.8 mm RT. Art. ). The last (20 g) was added dropwise to the washed hexane to sodium hydride (3,3 g of 60% dispersion) in dry simple ether (85 ml). After 3 h of incubation at room temperature and 30 min boiling under reflux acetone was added, the resulting mixture was stirred for 4 days at room temperature in a nitrogen atmosphere. After the processing carried out in the usual way, the resulting crude product person to distil, receiving ethyl-2-fluoro-3-methylbutan-2-oat (4 g) (temp. the TRC. 60 2aboutWith 15 mm RT. Art. ) (Macleidt and Wessendorf, ann 674, 1, (1964)). Ethyl-2-fluoro-3-methyl-butene-2-oat (4 g, a 27.4 mmol), N-bromosuccinimide (are 5.36 g, 30 mmol) (ex Aldrich) and benzoyl peroxide (30 mg) was subjected to a joint boiling under reflux in an environment of tetrahydrofuran (60 ml) with simultaneous illumination of a mixture of bright light. After 2 h, solvent was removed, transferred the residue in hexane, filtered through the zeolite and concentrated. Distillation was received with what triethylphosphite (3,82 g, 23,07 mmol) at 140-150aboutC. After 2 h boiling the resulting crude product was purified by distillation, obtaining triethyl-2-fluoro-3-methyl-4-phosphonocrotonate (3.5 g, temp. the TRC. 160-170aboutWith 0.5 mm RT. Art. ). The solution diisopropylamide lithium, prepared from n-utility (6.25 ml) and Diisopropylamine (1.4 ml) in THF (10 ml) at -70aboutC in an atmosphere of nitrogen was treated with the specified phosphonocrotonate (2,82 g). After 2 h of incubation at -70aboutWith the added ()-TRANS-2-(3,4-dichlorophenyl) cyclopropylmethanol (2.15 g). After 18 h of incubation at 25aboutWith added water, the resulting mixture was treated in the usual way. After cleaning chromatographytandem (silica gel, simple ether/hexane) received ()-(2E, 4E)-ethyl-2-fluoro-3-methyl-5-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/Penta - 2,4-dienoate (2.4 g). NMR1N: of 7.23 (1H, d), 7,10 (1H, d), 6,83 (1H, DD), to 6.75 (1H, DD), 5,77 (1H, DD), 4,28 (2N, K), and 2.27 (3H, d), of 1.87 (2H, m) of 1.33 (3H, t) of 1.33 (2H, m).

The specified ester was converted to the target compound by analogy with example 1.

()-(2E, 4E) N-(2-methylpropenyl-2-)-2-fluoro-3-methyl-5-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl l/ Penta-2,4-dienamic (compound 78) was treated in a similar manner, using 2-methylpropanol-2-amine instead of isobutylamine.

P R I m e R 24. ()-(2E, 4E) N-1,2-dimethylpropyl)-5-/r-,4,5-trichlorophenyl)-2-forproper-2-oate - way, similar to the method described in example 23. The specified ester was obtained by processing a suspension of sodium hydride (0.33 g) in tetrahydrofuran (10 ml) diethyloxalate (1,83 g) and ethylformate (1,33 g) in a nitrogen atmosphere. After 4 hours boiling under reflux to the cooled mixture was added 3,4,5-trichlorobenzaldehyde (2,62 g) (prepared as in example 10). After 18 h of incubation at 25aboutWith added water, the resulting mixture was treated in the usual way. Chromatographic purification (silica gel, hexane/simple ether) was obtained (2.5 g). NMR1N: 7,63 (2H, s), 6,77 (1H, d), 4,35 (2N, K) to 1.38 (3H, t).

The following compounds were prepared from aldehyde and Wittig reagent and the amide, the following: Connection Name connection

80 (a)-(2E, 4E) N-isobutyl-3-methyl-

5-/r-1-fluoro-2-(3,4,5-trichloro-

phenyl)cyclopropyl/ Penta-2,4-di-

ename

81 (a)-(2E, 4E) N-(1,2-dimethylpropyl)-

-5/r-1-fluoro-2-(3,4-dichlorophenyl)-

cyclopropyl/ Penta-2,4-dienamic

82 (a)-(2E/Z, 4E) N-(2-methylpropenyl-

-2)-3-methyl-5-/r-1-fluoro-2-(3,4-di-

bromophenyl)cyclopropyl/ Penta-

2,4-dienamic, a mixture of 2E: 2Z some-

ditch composition 5: 4

83 (a)-(2E/Z, 4E) N-isobutyl-3-methyl-

-5-/r-1-fluoro-2-(3,4-dibromophenyl)

cyclopropyl/Penta-2,4-dibromophenyl)

cyclopropyl/Penta-2,4-dienamic

85 (a)-(2E/Z, 4E) N-isobutyl-5-/

r-1-fluoro-2-(3,4-dichlorophenyl)

cyclopropyl/ -3-methylpentan-2,4-

-dienamic, mixture of isomers 2E,

4E: 2Z, 4E composition 4: 1

86 (a)-(2E/Z, 4E) N-(2,2-dimethyl-

propyl)-3-methyl-5-/r-1-fluoro-2-

-(3,4 - dichlorophenyl)cyclopropyl/-

-Penta-2,4-dienamic, a mixture of ISO-

Mer 2E, 4E: 2Z, 4E composition 2: 1

87 (a)-(2E/Z, 4E) N-(2-methylprop-

Neil-2)-3-methyl-5-/r-1-fluoro-2-

-(3,4,5 - trichlorophenyl)cyclo-

cut/Penta-2,4-dienamic

88 (a)-(2Z, 4E) N-isobutyl-3-methyl-

-5-/r-1-fluoro-2-(3,4,5-trichloro-

phenyl) cyclopropyl Penta-

-2,4-dienamic

101 (a) through(2E/Z, 4E) N-isobutyl-3-me-

Tyl-5-/r-1-fluoro-2-(3-chloro-4-

bromophenyl)cyclopropyl/Penta-

-2,4-dienamic, mixture of isomers

2E, 4E: 2Z, 4E composition 1: 1

102 (a)-(2E/Z, 4E) N-(2-methylprop-

Neil-2)-3-methyl-5-/r-1-fluoro-2-(3-

-chloro-4-bromophenyl) cycloprop-

drank/Penta-2,4-dienamic, a mixture of

isomers 2E, 4E: 2Z, 4E composition 2: 1

103 (a)-(2Z, 4E) N-(2-methylprop-

Neil-2)-3-methyl-5-/r-1-fluoro-2-

-(3-chloro-4-bromophenyl) cyclo-

cut/Penta 2,4-dienamic

104 (a)-(2E, 4E) N-isobutyl-2-fluoro-

-3-methyl-5-/r-1-fluoro-2-(3-chloro-

-4-bromophenyl) cyclopropyl/pen

TA-2,4-dienamic

105 (a)-(2E/Z, 4E) N-(2-methylprop-

Neil-2-)-2-peope-

Neil-2)-3-methyl-5-/r-1-fluoro-2-(3,4-

-dichlorophenyl) cyclopropyl/pen

TA-2,4-dienamic

109 (a)-(2E/Z, 4E) N-(2-butyl)-2-fluoro-

-3-methyl-5-/r-1-fluoro-2- (3,4-di-

chlorophenyl)cyclopropyl/pen

TA-2,4-dienamic, mixture of isomers

2 Z: 2E composition 7: 1

110 (a)-(2E/Z, 4E) N-(2-methylprop-

Neil-2)-2-fluoro-3-methyl-5-/r-1-fluoro-

-s-2-(3,4-dichlorophenyl) cyclo-

cut/Penta-2,4-dienamic,

a mixture of 2 isomers: 2E composition of 6: 1

111 (a)-(2E/Z, 4E) N-isobutyl-2-fluoro-

-3-methyl-5-/r-1-fluoro-2-(3,4-di-

chlorophenyl)cyclopropyl/ Penta-

-2,4-dienamic, mixture of isomers

2Z: 2E composition 3: 1

112 (a)-(2E/Z, 4E) N-(2-butyl)-3-methyl

-5-/r-1-fluoro-2-(3,4-dichlorophe-

nil)cyclopropyl/Penta - 2,4-

-dienamic, mixture of isomers

2E: 2Z composition 3: 2

113 (a)-(2Z, 4E) N-(2-butyl)-3-me-

Tyl-5-/r-1-fluoro-2-(3,4-dichlorophe-

nil)cyclopropyl/ Penta-2,4-di-

ename

114 (a)-(2E/Z, 4E) N-(2-butyl)-3-me-

Tyl-5-/r-1-fluoro-2-(3,4 - di-

bromophenyl)cyclopropyl/pen

TA-2,4-dienamic, a mixture of isome-

ditch 2E: 2Z composition of 5: 1

115 (a)-(2E/Z, 4E) N-isobutyl-1-fluoro-

-3-methyl-5-/r-1-fluoro-2 (3,4-di-

bromophenyl)cyclopropyl/Penta-

-2,4-dienamic, mixture of isomers

2Z: 2E composition of 6: 1

116 (a)-(2E/Z, 4E) N-(2-methylprop

- Neil-2-)-2-fluoro-3-methyl-5-/r-1-fluoro-

-s-2-(3,4-yl)-2-fluoro-

-3-methyl-5-/r-1-fluoro-2-(3,4-di-

bromophenyl)cyclopropyl/ Penta-

-2,4-dienamic, mixture of isomers

2Z: 2E composition of 5: 1

118 (a)-(2E, 4E) N-isobutyl-5-/r-1-

-fluorine-2-(3,4-dibromophenyl)

cyclopropyl/Penta-2,4-dienamic

P R I m e R 25. ()-(2E, 4E) N-(1,2-dimethylpropyl)-5/r-1-chloro-2-(3,4-dichlorophenyl)cyclopropyl/Penta-2,4-dienamic (compound 89).

Carbethoxymethylthio (34.8 g) in dichloromethane (100 ml) was treated at -70aboutC in an atmosphere of nitrogen triethylamine carbon (100 ml) for 60 minutes, the Solution was heated to 25aboutWith added water, the resulting mixture was treated in the usual way, getting carboalumination (18,9 g) after recrystallization from a mixture of acetone/hexane. Denney and Ross. , I. Org. Chem. , 1962, 27, 998). Carboalumination (a total of 8.74 g) in dichloromethane (100 ml) was treated under nitrogen atmosphere at 25aboutWith 3,4-dichlorobenzaldehyde. After incubation at 25aboutC for 18 h and removal of the solvent in vacuum were trituration of hexane, and the hexane wash was concentrated in vacuum. Chromatographic purification (silica gel, simple ether/hexane) was obtained ethyl-3-(3,4-dichlorophenyl)-2-chloropropane-2-oat (6.3 g). The specified ester was converted to the target soy is/Penta-2,4-dienamic (compound 90) and ()-(2Z, 4E) N-isobutyl-3-methyl-5-/r-1-chloro-2-(3,4-dichlorophenyl)cyclopropyl/Penta-2,4 - dienamic (compound 91) received similar way, using triethyl-4-phosphono-3-methylcrotonate and isobutylamine instead of triethyl-4-phosphonocrotonate and 1,2-dimethylpropylene.

P R I m e R 26. ()-(2E, 4E) N-isobutyl-5-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/Penta-2,4-ventional (compound 106).

TRANS-2-(3,4-dichlorophenyl)cyclopropanemethanol (3 g) (obtained in example 18) was treated with carbethoxymethylthio (4,85 g) in dichloromethane (30 ml). Concentration in vacuum and filtration, followed by concentration was received)-ethyl-3-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/propene-2-oat (1.8 g).

The processing of the specified complex ester (1.8 g) diisobutylaluminium (12,6 ml of 1M solution in hexane) in dichloromethane was obtained, after treatment of the reaction mixture in the usual way, ()-3-/TRANS-2-(3,4-dichlorophenyl) cyclopropyl/propene-2-1-ol (1,33 g).

The specified alcohol (1,33 g) was oxidized under the conditions Swern'a (oxalicacid, 0.7 ml; dimethylsulfoxide and 1.15 ml, triethylamine, and 3.8 ml) in dichloromethane, receiving ()-3-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/propene-2-1-al, which is directly used in the next stage.

< the, 0.1 mol). After 30 min was added isobutylthiazole (5.8 g, 0.05 mol) in tetrahydrofuran (50 ml). The mixture was left overnight at room temperature, then poured into a mixture of ice-water and was extracted with simple ether. The solution is simple ether was washed with brine, dried and solvent was removed, receiving N-isobutyl-2-(diethoxyphosphoryl)acetamine.

N-isobutyl-2-(diethoxyphosphoryl)acetone (0.7 g) in tetrahydrofuran (5 ml) was added at -70aboutWith diisopropylamide lithium (5.4 mmol) in tetrahydrofuran (15 ml). The mixture was allowed to warm to -20aboutC, then cooled it to -40aboutC.

Previously obtained ()-3-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/propane-2-al in tetrahydrofuran (5 ml) was added to this mixture. The mixture was left overnight at room temperature, and then processed in the usual way. The crude product was purified column chromatography (silica gel, hexane: simple ether 7: 3) to give the target compound.

()-(2E, 4E) N-(1,2-dimethylpropyl)-5-/TRANS-2-(3,4-dichlorophenyl)cyclopropyl/Penta-2,4 - ventional (compound 107) were treated in a similar manner using N-(1,2-dimethylpropyl)-2-(diethoxyphosphoryl)acetone instead of N-isobutyl-2-(diethoxyphosphoryl)acetamide.

()-(2E, 4E) N-(1,2-di the way, using (C-2-(3,4-dichlorophenyl)-r-1-forciblepoppy)methanethiol instead of TRANS-2-(3,4-dichlorophenyl)cyclopropylmethanol, by analogy with example 24.

These NMR1N. and other physico-chemical characteristics of the compounds obtained are given in table. 1 and 2.

In the tables, the following notation:

S - singlet, d - doublet, dd = double doublet, ddd triple doublet, t - triplet, q - Quartet, m - multiplet, b - broad.

BIOLOGICAL DATA

The following examples illustrate, without limiting the scope of the present invention, the pesticidal activity of the compounds of formula I:

Example A - tests with spray.

The activity of the claimed compounds was tested by dissolving the compounds in acetone (5% ) and then diluting this solution with a mixture of water: "Synperonic" (94,5% : 0.5 percent ) to obtain an aqueous emulsion. Then the resulting solution was used for the treatment of the following insects, for which there was activity at the following doses spraying:

Musca domestica

20 females Musca was placed in a cardboard cylinder, both the bottom of which were closed with gauze. The solution containing the compound was sprayed insects and mortality was determined after 48 h at 25aboutC.

The following soybeans is x2">

The following compounds were active at 200 PP or less: 4, 9, 13, 16, 17, 100, 30, 31, 32, 33, 34, 35, 42, 95, 97, 56, 59, 60, 61, 62, 63, 64, 67, 68, 69, 70, 71, 72, 73, 74, 77, 93, 94, 79, 80, 81, 82, 83, 84, 85, 86, 89, 90, 92, 87.

Plutella xylostella

Leaves Chinese cabbage, 8 infected by the larvae of Plutella second age stage, were sprayed with a solution containing the compound. Mortality was determined after 2 days at 25aboutC.

The following compounds were active at 1000 RR or less: 12, 22, 25, 26, 45, 46, 47, 48, 51, 52, 53, 54, 58, 65, 76. The following compounds were active at 200 PP or less: 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 14, 15, 18, 19, 20, 21, 23, 24, 27, 28, 29, 30, 31, 32, 32, 34, 36, 41: 42, 95, 44, 50, 57, 61, 66.

The following compounds were active at 40 PP or less: 8, 10, 16, 17, 33, 35, 37, 38, 39, 40, 97, 55, 56, 59, 60, 62, 63, 64, 67, 68, 69, 70, 71, 72, 73, 74, 77, 78, 93, 79, 80, 81, 90, 92, 87.

Tetranychus urticae

Infected leaves are kidney beans were sprayed with a solution containing the compound. Mortality was determined after 2 days at 25aboutC.

The following compounds were active at 1000 RR or less: 8, 12, 13, 16, 17, 18, 21, 26, 28, 31, 33, 34, 37, 54, 56, 57, 59, 60, 61, 63, 67, 69, 70, 77, 78, 93, 80, 82, 83, 84, 85, 92, 87.

Spodoptera littoralis

Uninfected leaves were sprayed with the test solution containing the compound, and gave the leaves have dried up ewusie connection was active at 1000 RR or less:

1, 5, 6, 7, 13, 14, 15, 100, 18, 20, 21, 29, 34, 36, 37, 38, 40, 41, 42, 95, 44, 46, 49, 50, 51, 53, 55, 63, 65, 66, 67, 91.

The following compounds were active at 200 PP or less:

3, 4, 8, 9, 10, 11, 16, 17, 19, 30, 31, 32, 33, 35, 39, 96, 97, 56, 57, 59, 60, 61, 62, 64, 68, 69, 70, 71, 72, 73, 74, 77, 78, 93, 94, 79, 80, 81, 82, 83, 84, 86, 85, 89, 90, 92, 87.

Myzus persicae

10 adults Myzus was placed on the leaf of Chinese cabbage. After 24 h, the sheet was sprayed with a solution containing the compound. Mortality was determined after 2 days at 25aboutC.

The following compounds were active at 1000 RR or less: 8, 9, 13, 18, 19, 20, 22, 24, 30, 31, 34, 35, 95, 44, 50, 59, 60, 61, 66, 72, 75, 77, 78, 93, 94, 82, 83, 84, 85, 86, 92, 87.

Siabrotica undecimpunctata

Larvae of the second age, and their food was sprayed on filter paper with a solution containing the compound. The activity was determined after 2 days.

The following compounds were active at 1000 RR or less: 3, 6, 9, 11, 12, 13, 14, 17, 28, 29, 30, 31, 32, 33, 35, 37, 39, 95, 96, 97, 44, 54, 55, 56, 59, 61, 62, 67, 69, 71, 72, 74, 77, 78, 94, 80, 81, 82, 83, 86, 92.

The following compounds were active at 200 PP or less: 10, 16, 68, 73, 79, 84, 85, 89.

The example In tests with a local application.

Blatella germanica

Males of B. germanica locally impacted 0,5 µl of a solution of the compound in butanol (with or without piperonyl is less (+ piperonylbutoxide):

10, 11, 13, 15, 16, 17, 30, 35, 36, 37, 39, 40, 41, 42, 55, 56, 57, 59, 60, 61, 63, 64, 67, 68, 69, 70, 71, 72, 73, 74, 77, 78, 94, 79, 80, 81, 82, 83, 84, 85, 86, 92, 87.

The following compounds were active at 10 μg or less (without piperonylbutoxide)

1, 8, 9, 20, 21, 30, 31, 32, 33, 34, 95.

Comparative data.

The connection 31, responsive to the invention, and similar, corresponding European patent application N 0251475 (see below) were compared with testing at Musca domestia. Similarly, the connection 32, responsive to the invention, was compared with analogue, corresponding to the European patent application ER (PL. 3, 4, 5).

1. Local application in respect of the fly room (Musca domestica). Compounds were applied locally only in the form of cellosolve solution or in combination with a synergist (3 or 6 µg of piperonylbutoxide) and the percentage of death for two days is shown in table. 3.

2. Use with directional spray against flies bedroom (Musca domestica). Compounds were sprayed in the form of a mixture of acetone, water and a wetting emulsion, taken in the ratio 5: 94: 5, the percentage of deaths in 2 days is shown in table. 4 and 5. (56) 1. ER N 0251472, class C 07 C 103/58, 1988.

2. ER N 194764, CL 07 103/30, 1987.

The METHOD of OBTAINING Amidaniel, pyridyl, naphthyl, degloving, each of which may be substituted by 1 to 3 substituents selected from the group: C1- C6-alkyl, C1- C6- alkoxy, CF3, halogen;

Q' - 1,2-cyclopropyl ring, possibly substituted C1- C4-alkyl;

R2, R3, R4and R5- same or different, hydrogen, (C1- C6)-alkyl, halo(C1- C4)-alkyl, where one of the radicals necessarily mean hydrogen;

R1is hydrogen, C1- C6-alkyl which may be substituted DIOXOLANYL group, cyclo- (C3- C6)-alkyl;

X = 0,

or their salts,

characterized in that interact corresponding carbonyl compounds with the reagent VI

 

Same patents:

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to (R)-enantiomers of 2-arylpropionamides of the formula (Ia): and their pharmaceutically acceptable salts wherein Aryl represents phenyl group substituted with a group chosen from isopropyl, acetyl, (2'',6''-dichlorophenyl)amino-group, α-hydroxyisopropyl, (R,S)-α-hydroxybenzyl and its individual R-isomers, (R,S)-(α-methylbenzyl) and its individual R-isomer and (R,S)-α-hydroxy-α-methylbenzyl and its individual R-isomer; R represents hydrogen atom (H) or (C1-C4)-alkyl; R' represents the following groups: -amino acid residue consisting of linear or branched (C1-C6)-alkyl substituted with carboxy-group -CO2H; -residue of the formula: -CH2-CH2X-(CH2-CH2O)nR wherein R has abovementioned values; n means a whole number from 0 to 1 while X represents oxygen atom; -heteroaryl chosen from the group consisting of 2-pyrimidinyl or 4-pyrimidinyl. Also, invention proposes a pharmaceutical composition inhibiting of interleukin-8-induced chemotaxis of neutrophiles and comprising as an active components (R)-enantiomers of 2-arylpropionamides of the formula (I) and their pharmaceutically acceptable salts in mixture with a suitable carrier. Also, invention proposes a method for preparing compounds of the formula (Ia). Also, invention proposes (R)-enantiomers of 2-arylpropionic acids of the formula (Va) given in the invention description and their pharmaceutically acceptable salts. Proposed (R)-2-arylpropionamides are useful in prophylaxis and treatment of tissue damage caused by enhanced accumulation of polymorphonuclear neutrophiles in the inflammation sites.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

13 cl, 6 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: method of detecting a compound which is a noncompetitive inhibitor of human immunodeficiency virus (HIV) protease (SEQ ID No:1) involves detection using alanine scanning methods and molecular docking of the compound at least with one atom of an amino acid residue selected from a group consisting of Asn98, Phe99, Asp29, Asp30, Arg8, Gly49, Gly51 and Gly52 SEQ ID NO:1, at a distance of not more than 5 Å.

EFFECT: increased effectiveness of the compounds.

4 cl, 2 dwg, 4 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of (R)-2-arylpropionamides of general formula I, in which Ar is phenyl group, substituted in 3(meta) position by group R1, selected from: linear or branched C1-C8-alkanoyl, C3-C6- cycloalkanoyl, heteroarylcarbonyl, C1-C6-alkylaminocarbonyl, arylaminocarbonyl, C1-C6-alkylamino, C1-C6-acylamino, arylamino, benzoylamino, aryloxy, heteroaryl, C1-C6-alkoxycarbonyl, C6-aryloxycarbonyl, C1-C8-alkansulfonyl, arylsulfonyl, or 3,4-dihydro-1H-quinolyl-2-on; R is selected from: -H, OH; - heteroaryl group is selected from: pyridine, pyrimidine, pyrrole, thiophene, furan, indole, thiazole, oxazole; - α or β carboxyl residue can consist of straight or branched C1-C6-alkyl, C3-C6-cycloalkyl, optionally substituted with other carboxyl (COOH) group; - residue with formula SO2Rd, in which Rd is C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl or pyridyl, on condition that compounds of formula I are not the following compounds: (R)-2-(3-phenoxyphenyl)-propanoyl-phenylglycine; (R)-2-( phenoxyphenyl)-propanoyl-glycine; (R)-2-[(3'-acetyl)phenyl]-R-4''-pyrimidyl)propionamide. Invention also relates to method of obtaining formulaI compound and application of formula I compound for preparation of medications for treatment of diseases including C5a induced hemotaxis of human PMNs.

EFFECT: obtained are novel derivatives of (R)-2-arylpropionamide, possessing useful biological properties.

9 cl, 3 dwg, 2 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining secondary amides. Method is realised by carbonylation of respective tertiary amines by means of carbon monoxide in presence of catalyst, containing less than 750 parts per million (ppm) of palladium, and halogen-containing promoter.

EFFECT: increased catalytic activity of catalyst with reduction of palladium concentration and increase of reaction selectivity.

39 cl, 7 tbl

FIELD: food industry.

SUBSTANCE: present invention relates to food industry, namely to using the compound of formula (I)

in the form of one of its stereoisomers or a mixture of the latter, where n is an integer from 0 to 2, dotted line denotes a single or double carbon-carbon bond. Each separately taken from R1-R4 is a hydrogen atom or denotes R5 or OR5 group. R5 is C1-C5 alkyl group. Optionally, one of the groups R1-R4 is -OH group, and/or R1 and R2, taken together, and/or R3 and R4, combined, represent OCH2O group provided that the said groups, combined, are adjacent substitutes of phenyl group, as an ingredient, imparting, reinforcing, improving or modifying taste of kokumi or umami flavored product. Invention relates to a compound of formula

where R3 denotes a hydrogen atom or C1-3-alkyl group, a R4 denotes C1-3-alkyl group or OR6 group, where R6 is C1-C-3-alkyl group. Invention relates to flavor-modificative composition which contains an ingredient imparting or modifying taste, at least one compound of formula (II), at least one ingredient selected from a group consisting of carrier aroma and flavoring base, and, optionally, at least one aromatic adjuvant.

EFFECT: invention relates to flavored product containing at least one compound of formula (II) and a food base.

13 cl, 21 tbl, 3 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention describes dialkylamide derivatives of pyrethroid acids of the general formula (III): wherein R1 and R2 represent organic radicals and each radical represents ethyl, or they both can be bound and in common with nitrogen atom represent piperidide, hexamethyleneimide, morpholide. Represented compounds are used as chemical agents for control of insect-pests in agriculture, veterinary science and cattle breeding.

EFFECT: valuable properties of compounds.

2 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns chemistry of adamantane derivatives, namely to a new method of obtaining of dialkylamides of 3-brome-1-adamantilalkancarbon acids of the general formula:

R1,R2=H:R3=N(C2H5)2

R1, R2=CH3:R3=N(C2H5)2

which can be of interest as semiproducts in synthesis of some biologically active substances possessing antiviral activity. Method lies in interaction of 1,3-dehydroadamantane with dialkylamides of α-bromalkancarbon acids from the row: diethylamide of α-bromacetic acid, piperidide of α-brompropionic acid, diethylamide of α-bromo-isobutyric acid at mole ratio of reagents peer accordingly 1:3-4, in the environment of the initial dialkylamides of α-bromalkancarbon acids, at temperature of 80-90°C within 4-6 hours.

EFFECT: obtaining of bonds of declared structural formula, excluding reception stage adamantilealkanecarbon acids.

3 ex

Up!