SI8410360A8 - Process for preparing new amides of acrylic acid - Google Patents

Description

Process for the preparation of new acrylic acid amides

Technical field of the invention

The invention relates to the field of organic chemical synthesis, specifically to a new process for the preparation of new acrylic acid amides that are useful as biocidal agents.

MK? 3.6172 ^ fot »

A technical problem

M *

There was a need to identify a technologically advanced process for the preparation of novel acrylic acid amides with biocidal properties, in good yields and with a satisfactory purity.

*

The state of the art

The compounds of formula (I) shown below are novel, and the process for their preparation has not yet been described.

Description of solution to a technical problem with implementation examples

The present invention relates to a process for the preparation of novel acrylic acid amides of general formula I

- 2 in which the group stands

(II),

B for the group

Y- (CR ₅ = CR ₆ ) _k (III),

Q for one of the groups

X for 0, S or NH,

Y for C 1 -C 4 -alkyl as well as additionally for C 1 -C 6 -alkyl, Se is k is 1 or 2, or for substituted alkyl, or optionally substituted residue from the group C 1 -C 6 -alkenyl, C C 1 -C 4 -cycloalkyl, C 1 -C 4 -cycloalkenyl, pyridyl, furyl, thienyl, α- and β-naphthyl, or together with the group CB ^ for a 5- to 7-Slenic, preferably saturated, cycloaliphatic residue to which may be a densified benzene ring or a residue

where k is 0, 1 or 2, m is Nos. 1, 2, 3 or 4, n is 0 or 1, hydrogen, C1-C4-alkyl, cyano and, when k is 0, also chlorine, bromine or iodine, < 2 > hydrogen, halogen, nitro, optionally one or more fluorine or chlorine-substituted C1-C4-alkyl or -alkoxy, C1-C4-alkynyloxy, amino, NH (C1-C4-alkyl) ), ItfC 1 -C 4 -alkyl) cyano, phenyl, C 1 -C 8 -cycloalkyl, C 1 -C 4 -alkenyloxy, hydroxyC 1 -C 4 -alkyl), UH COBg,

CO ₂ Sg, CONfi ^ Bg, oxygen interrupted Cg-Cg-alkyl or

CO., LTD

(VII), • O

- 4 ^R 3 ' ^R 4 » ^R 12 and E ₁₃ hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 alkoxy, (G 1 -C 4 -alkyl) -S (O) p (pO) , 1 or 2), hydroxy or (C1-C4-acyl) oxy, R1 / R4 and ^ 12 ^ 13 in each case also methylenedioxy or ethylenedioxy bonded to two adjacent atoms of the phenyl ring,

R 6 and R 6 are hydrogen or C 1 -C 4 -alkyl, R 4 is also taken together with the carbon atom to which it is attached and Y is a 5 to 7 membered, preferably unsaturated, cycloaliphatic residue to which the benzene ring may be fused.

R? and C 1 -C 4 -C 6 -alkyl, C 1 -C 4 -cycloalkyl, phenyl, henzyl, furfuryl, tetrahydrofurfuryl or C 1 -C 4 -alkenyl, and in addition also a C 1 -C 4 -alkylene chain which may be interrupted by 0, ΗΕθ, S (0) ^ where q can be 0, 1 or 2, and Ey is additionally hydrogen, and Ε ^ θ, which occur only when R? and Εθ total represent a chain, represent hydrogen or C _d -C _a alkyl, and optionally the acid addition salts of the compounds defined above, with the proviso that A and B do not both stand for a residue from the group phenyl, monohalogenfenil, mononitrofenil and monoaminofenil .

Within the above definitions, the residues and groups may each be the same or different.

The substituents in the residues listed for T are, in particular, halogen, nitro, amino, optionally one or more halogen substituted with C1-C4-alkyl and -alkoxylOe groups, NH (C1-C4-alkyl) and iCC ^ -C 1 -alkyl ^ as well as phenoxy, phenylthio, -C 1 -alkylthio ·

- 5 Carbon chains in alkyl, alkoxy * alkyl-S (O) p-, mono- or dialkylamino groups contain preferably 1 to 3, especially 1 to 2 carbon atoms · if the chains have more than 2 carbon atoms, but may be unbranched or branched · Halogen stands for fluorine, chlorine, bromine or iodine, and above all for chlorine and bromine.

The residue k is preferably di- or tri-substituted, with two eubstituents, for example, methyl, methoxy, ethyl, ethoxy, fluorine, chlorine, bromine, CF2, CF2, CF3, CH2, CH3 SO, CH ^ SC ^, NH ^, NHCHj, ΝζΟΗ ^) ^, O-CHg-O, 0 ^ 2 ^ -0, are preferably in position 3Λ.

Q is preferably a residue of formula IV, where B? and Βθ together represent in each case an interrupted alkylene chain such that IV represents e.g. groups of the following species:

When A and B are different in Formula I, compounds of Formula I may be cis- / trans-isomers. In this case, Formula I covers both the individual isomers and mixtures of cis and trane-apoyin.

The new compounds are obtained as follows: by the reaction of acrylic acid a formula

COOH • 9 (vin), O

- 6 where A, B and B ^ have the above meaning, or one of its reactions capable of derivatives, optionally made and alto, but a compound of the formula

H - Q (H), where Q is of the above meaning, or with the N-activated derivative of compound IX prepared in a given suitable in situ (then only acid VIII is used).

The process is, therefore, acylation of compound IX with a carboxylic acid of formula VIII in the presence of an acid-activating or withdrawing agent, or with a reactive acid derivative or carboxylic acid metabolism of formula VIII with a compound of formula IX, in the presence of an amino-activating agent, or by reactive amine derivatives. We obtain end products in which X is oxygen.

As the reactive carboxylic acid derivatives of Formula VIII, prepared as appropriate in the reaction mixture, are considered e.g. their alkyl-, aryl-, aralkyl-esters or -thioesters such as methyl-, ethyl-, phenyl- or benzyl ester, their imidazolides, their acid halides as acid chloride or bromide, their anhydrides, their mixed anhydrides with aliphatic or aromatic carboxylic, sulfanic, sulfanic sulfonic acids, sulfonic acids or carbonic acid esters, e.g. with acetic acid, propionic acid, p-toluenesulphonic acid or O-ethylcarbonic acid, or their H-hydroxyimidesters. As reactive derivatives of amine 8 of formula IX, optionally prepared in the reaction mixture, however, suitable e.g.

their phosphoresoders

P 360/84

- 7 -........

The nature of the hydrocarbon residues in the above groups is largely not critical. Alkyl groups generally contain between 1 and 12 carbon atoms, may be straight or branched and interrupted by oxygen or sulfur. The aryl moieties preferably contain 6 or 10 carbon atoms "aralkyl moieties 7 to 12 carbon atoms" wherein the alkyl moiety may contain from 1 to 6 carbon atoms and the aromatic moiety may also be interrupted by C 1 -C 1 -alkyl, but then the aryl moiety the substituted alkyl residue contained correspondingly fewer carbon atoms.

The aromatic rings may also be optionally mixed in each case "e.g. with 1 or more C 1 -C 5 -alkyl groups of C 1 -C 6 alkoxy and / or with one or more halogen atoms.

As acid activators and / or water withdrawals, e.g. Chloromic acid esters such as chloromic acid ethyl ester, phosphorus pentoxide, N, N'dicyclohexylcarbodiimide, 1,1 '-carbonyldiimidazole or N _T N'tionyldiimidazole.

The metabolism is efficiently carried out in a solvent or solvent mixture such as methylene chloride, chloroform, tetrachlorocarbon, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an inorganic base such as sodium carbonate or tertiary alkyl, or tertiary alkyl may be used simultaneously as a solvent, and optionally in the presence of an acid activator, at temperatures between -25 ° C and 150 ° C, and preferably at temperatures between -10 ° C and the boiling point of the reaction mixture.

In this case, it is not necessary to isolate in the reaction mixture of the resultant reaction of a derivative of the compound of general formulas VIII or IX in the reaction, if necessary, the excess of the compound of general formula IX used as solvent.

To prepare such compounds of formula I wherein X stands for sulfur (thioamides), the corresponding amides are reacted in an inert solvent with phosphorus pentasulfide.

Suitable solvents are e.g. toluene, xylene, benzene. The reaction temperature lies between 0 ° C and the boiling point of the reaction mixture, but generally does not exceed 120 ° C.

In accordance with the invention, the resulting cis- / trans-isomeric mixtures can be optionally subsequently separated into the corresponding cis- and trans-isomers by conventional methods.

The separation of the isomers is preferably by fractionation crystallization, e.g. by crystallization from methanol, ethanol, isopropanol, methanol / water or ethanol / petroleum ether.

Compounds of formula I with basic groups can be optionally converted to acid addition salts, preferably in mineral acid salts such as hydrochloric, hydrochloric, sulfuric or phosphoric acids.

The starting materials are known or can be prepared by conventional methods analogous to known compounds. Compounds of formula VIII wherein B represents group III and k represents 1 or 2, e.g. according to the following reaction scheme:

O «J

- 9 a-co-ch ₂ r ₆ (A) (RQ) ₂ PO-CHR j-CO ₂ R * (B) ^R and ^H 2

Y-CO-R

VIII (C) (D) 'Here, A, H, E ·, Ε _ή , Εθ i _n Y have the upper meaning,

E is preferably for the lower alkyl residue, e.g. methyl or ethyl. Preferably, the E 1 is a C 1 -C 4 -alkyl radical. The degree of olefination B in C can be carried out e.g. by Homer's variant of the Vittig reaction.

The compounds of the invention exhibit a potent effect especially against phytopathogenic fungi, in particular against true ash mold, non-ash ash plush (e.g., Plasmopara * and Phytophthora), scabs, gray mold, rust. Due to their very low phyto-toxicity, new compounds can be used in virtually all useful and ornamental crop plants, e.g. in cereals such as maize, wheat, rye, oats, rice, tomatoes, cucumbers, beans, potatoes, turnips, in vineyards and orchards, in roses, carnations and chrysanthemums.

The new compounds show effects on the leaves and a systemic effect. Thus, with many of the compounds of the invention, complete treatment of fungi is achieved in the treatment of Plasmopara leaves with an effective concentration of between 20 and 100 ppm.

In the control of Phytophthora, concentrations of the active substance in general are 100 ppm, in part less, for sufficient effect.

It is particularly advantageous in some cases to combine the compounds of the invention with known fungicidal active substances. In doing so, the effect of the combinations partly clearly outweighs the purely additive effect.

Combination partner Mn-ethylenebisditiocarbamate (Maneb)

Mn-Zn-ethylenebisdithiocarbamate (Mancozeb) Zn-ethylenebisdithiocarbamate (Zineb) N-trichloromethylthio-tetrahydrophthalimide (Captan) N-trichloromethylthiophthalimide (Polpet)

N- (1,1,2,2, -tetrachloroethylthio) tetrahydrophthalimide (Captafol)

2,3-diciano-1,4-dithiaanthraquinone (Ditbianon)

Zn- (N, N'-Propylene-bisdithiocarbamate (Propineb)

Cu-oxychloride *

Na-4-dimethylaminobenzoldiazosulfonate (Phenaminosulf) Triphenyl-Sn-acetate (Pentinacetate)

Triphenyl-Sn hydroxide (Pentinhydroxide) Pe-dimethyldithiocarbamate (Ferbam)

N- (2-furoyl) -N- (2,6-xylyl) -DL-alanine (Furalaxyl)

3- (dimethylamino) propylcarbamate (Propamocarb) N-ethyl-N- (3-dimethylamino) thiocarbamate (Protbiocarb) Tetramethylthiuramdisulfide (Thiram) N-dichlorofluoromethylthio-N, N'-dimethyl-N-p-tolylsulfamide (T-sulfylsulfamide) (t-sulfylsulfamide)

N- (2-methoxyacetyl) -N- (2,6-xylyl) alanine (Metalaxyl) Zn-dimethylthiocarbamate (Ziram)

N-dichlorofluoromethylthio-N ', N' -dimethyl-N-f enylsulfamide (Dichlofluanid)

3-Trichloromethyl-5-ethoxy-4,2,4-thiadiazole (Etridazole)

Three Camin-Zn-ethylenebis (dithiocarbamate) tetrahydro-1,2,4,7-dithiadiazocine-3,8-dition polymer (Metiram)

Al-tris (o-ethylphosphate) (Pbosethyl)

2- cyano-N- (ethylcarbamoyl) -2-methyloxyimino) -acetamide (Cymoxanil)

N- (3-chlorophenyl) -N- (tetrahydrofuran-2-on-3-yl) -cyclopropanecarbonamide (Cyprofuran)

Tetrachloro-isophthalodinitrile (Chlorothalonil)

6-methyl-2-oxo-4,3-dithio E4,5-b1-quinoxaline (Chinomethionate)

4- Cyclododecyl-2,6-dimethylmorpholine (Dodemorph)

1- dodecylguanidinium acetate (Dodin)

Diisopropyl-5-nitroisophthalate (Nitrothal-isopropyl)

2,4-Dichloro-α- (pyrimidin-5-yl) benzhydryl alcohol (Fenarimol)

4- (| 3-Elyloxy-2,4-dichlorophenyl) imidazole (Imazalil)

3- (3,5-Dichlorophenyl) -N-isopropyl-2,4-dioxoimidazolidine4-carboxamide (Iprodione)

Sulfur

2,3-Dihydro-6-methyl-5-phenylcarbamoyl-4,4-oxythiine-4,4 dioxide (Oxycarboxin)

N- (3,5-dichlorophenyl) -4,2-dimethylcyclopropane-4,2 dicarboximide (Procymidon)

6-ethoxycarbonyl-5-netylpyrazolo [4,5-] pyrimidin-2-yl, O-dimethylphosphorioate (Pyrazophos)

2- (thiazol-4-yl) -benzimidazole (Thiabendazole)

1- (4-chlorophenoxy) -3,3-dimethyl-1- (1,2,4-triazol-1-yl) 2-butanone (Triadimephone)

1- (4-Chlorophenoxy) -3-3-dimethyl-1- (1,2,4, -triazol-1-yl) butanol (Triadimenol)

3- (3,5-Dichlorophenyl) -5-methyl-5-vinyloxysolidine-2,4-dione (Vinclozoline)

Methylbenzimidazol-2-ylcarbamate (Carbendazine)

2,4,5-trimethyl-N-phenyl-3-furancarboxamide (Methfuroxam) β- [1,1'-biphenyl-4-yl-oxy) -a- (1,1, -dimethylethyl) -1H-1. 2,4triazole-1-ethanol (Bitertanol)

2- (2-furyl) benzimidazole (Fuberidazole)

5-Butyl-2-ethylamino-6-methylpyrimidin-4-ol (Ethirimol) 2-methyl-3-furanylide (Fenfuram)

Bis- (8-guanidino-octyl) amine (Guazatin)

M *

N-Cyclobexyl-N-methoxy-2,5-dimethylfuran-3-carboxylic acid amide (Furmecyclox)

2-Chloro-4'-fluoro-α- (pyrimidin-5-yl) benzhydryl alcohol (Nuarimol) Methyl-1- (butylcarbamoyl) benzimidazolecarbamate (Benomyl) N, N-diethylphthalimidophosphonothioate (Dithalin)

7-Bromo-5-chloroquinolin-8-yl-acrylate (Halacrimat)

1-C2- (2,4-Dichlorophenyl) -4-propyl-1,3-dioxalan-2-ylmethyl31H-1,2,4-triazole (Propiconazole)

Dimethyl-4,4 '- (o-phenylene) bis (3-thiolophanate) (Tbiophanate-methyl)

1,4-bis (2,2,2-trichloro-1-formamidoethyl) piperazine (Triforine)

2,6-dimethyl-4-tridecylmorpholine (Tridemorph)

4- (3- (4- (1,1-dimethyl-ethyl) phenyl) -2-methyl-propyl-2,6 (cis) -dimethylmorpholine (Fenpropemorph)

1- (2- (2,4-Dichlorophenyl) -4-ethyl-1,3-dioxalan-2-ylmethyl)

1H-1,2,4-triazole (Etaconazole)

1- (1- (2,4-Chlorophenyl) -4,4-dimethyl-3-hydroxy-2-pentyl

1,2,4-Triazole (Diclobutrazole)

2,4-Dichloro-6- (2-chloroanilino) -1,3,5-triazine (Anilazine)

2- j odo-N-phenylbenzamide (Benodanyl)

2-sec-butyl-4,6-dinitroph enyl-3-methylcrotonate (Binapacryl)

5- Butyl-2- (ethylamino) -6-methyl-4-pyrimidinyl dimethylsulfonate (Buprimat)

2,4-dinitro-6-octylphenylcrotinate (Dinocap)

5,6-Dihydro-2-methyl-1,4-oxathine-3-carbanylide (Carboocin) N-propyl-N - ((2,4,6-trichlorophenoxy) -2-ethyl] -imidazole-1 carbonamide (Prochloraz)

For use in plant protection, new compounds are incorporated in the usual manner with excipients and / or carriers into conventional forms of pest control agents, e.g. into solutions, emulsion concentrates, concentrated solutions, suspension powders, powders. If combinations with other active substances are to be used, this may be in the form of co-formulations or e.g. in the form of tank mixes.

Prior to use, the concentrates are diluted with water to give spray sprays with an active substance content of between about 0.001 and 1% by weight. When used as a Low-volume or Ultra-Low-volume preparation, the content of the active substance can also be significantly higher (up to about 20% or about 90% by weight) ·

Examples of the compositions of the invention:

1. Suspension powder by weight. parts of the compound of formula I 20 wt. parts of kaolin wt. parts of sodium sulfate 2 wt. parts of accumulated chalk mass. parts of calcium ligninsulfonate wt. part of diisobutylnaphthalene sodium sulfonate 43% by weight parts of silica chalk.

Grind the ingredients. The agent is suspended in so much water that the concentration of the active substance is about 0.001 to 0.5% by weight.

2. The emulsion concentrate wt. parts of the compound of formula I by weight parts of the triethylamine salt of dodecylbenzenesulfonic acid by weight. parts of dimethylformamide.

The following examples should further explain the preparation process of the invention.

Preparation of output products:

D p * -chloro-4-nitro-benzophenone

A mixture of 100 g (0.54 mol) of 4-nitro-benzoyl chloride,

100 g (0.75 mol) of aluminum chloride and 100 ml = 111 g (0.99 mol) of chlorobenzene are heated to 80 ° C with stirring and exclusion of air humidity, forming a melt. After the hydrogen chloride formation is completed, the temperature is raised to 100 ° C and stirred for half an hour at this temperature. After cooling to about 40 to 5θ ° C, the liquid liquid mixture is poured onto ice and a white precipitate is removed, which is sucked off and washed with ethanol. . Tal. 100 to 102 ° C.

4-amino-4 ¹ -chloro-benzophenone

A hot solution of 15 g (0.05 mol) of 4'-chloro-4-nitro-benzo-phenone in 80 ml of ethanol is added portionwise to a hot solution of 53.5 g (0.24 mol) of tin (II) chloride dihydrate in 5θ ml of concentrated hydrochloric acid under a violent reaction. After the addition is complete, heat for 2 hours in a steam bath and then pour out while stirring in water potassium lye. The precipitate is removed, which is sucked off and dissolved in boiling ethanol. Filter from insoluble and allow to cool. The extracted light yellow crystals were sucked off.

M.p .: 184 to 185 ° C.

4-amino-3,4 *, 5-trichloro-benzophenone

25.2 g (0.1 mol) of 4-amino-4'-chloro-benzophenone were dissolved in 200 ml of tetrabidrofuran. To this solution was added 400 ml of ice, and then, with vigorous stirring and cooling with ice, a quick solution of 14.2 g (0.2 mol) of chlorine in 150 ml of ice. Stirred for 5 minutes and poured into water / A white precipitate is removed which is sucked off and crystallized from ethanol.

M.p .: 165 to 167 ° 0.

4,4 * -diacetamino-diphenylmethane

260 g (2 mol) of aniline hydrochloride dissolved in 600 ml of water were added dropwise while stirring 76 g (1 mol) of methyl. After the addition is complete, heat for 1 hour at 60 ° C, then 3 hours at 90 ° C _? Distilling the resulting methanol. After cooling, a concentrated solution of 40 g of sodium hydroxide was added to the solution while cooling with ice. The oil is removed and crystallized after further stirring. The crystals are filtered off and partitioned between 2 l of chloroform and 10 n of sodium hydroxide solution. The chloroform solution was decided, dried over sodium sulfate and evaporated to dryness in vacuo. Dissolve the residue in 1 L of benzene and continue adding petroleum ether until the oily contaminants are eliminated. After decanting, pour out the remaining benzene-petroleum ether solution with vigorous stirring in about 1 L of petroleum ether, eliminating 4,4'-diamino-diphenyl-methane as oil. This fractionated precipitate is repeated twice more. The oily 4,4'-diamino-diphenyl-methane thus obtained was dissolved in a little ice, preferably with stirring, 205 g (2 mol) of acetic anhydride was added dropwise and then heated to 120 ° C for 1 hour. After cooling, pour into about 3 I of water, suction off the separated crystals and wash with water.

M.p .: 228 to 230 ° C.

4,4'-diamino-benzophenone

Dissolve 100 g of anhydrous chromic acid in 50 ml of water and make up to 240 ml with ice. 97 ml of this solution are added slowly while stirring and cooling to a solution of 77 g of 4,4'-diacet17 amino-diphenylmethane, taking care not to exceed 40 ° C. Then, with continued stirring, it is heated to 90 ° C for 1 hour. Then cool and pour into ice water. An oily product precipitates, which crystallizes on condition. The separated crystals were filtered off with suction, washed with water and then warmed to 92 ml of 66% sulfuric acid for 5 minutes at reflux temperature. After cooling, pour into water and adjust the aqueous solution with 10 n sodium hydroxide solution to alkaline, precipitating the crude 4,4′-diamino-benzophenone.

Tal. 247 to 248 ° C (ethanol).

4,4'-diamino-3,5 ', 5,5'-tetrachloro-benzophenone g (0.12 mol) of 4,4'-diamino-benzophenone was dissolved in a mixture of 25 ml of concentrated hydrochloric acid, 200 ml of water and 500 ml of ice. With vigorous stirring and cooling with ice water, a solution of 33.5 g (0.42 moles) of chlorine in 400 ml of ice was rapidly added to this solution, stirred for a further 2 minutes and poured onto ice. The precipitated precipitate was filtered off with suction and crystallized from ethanol / water. M.p .: 237 to 239 ° C.

-18 Preliminary remark:

An isomer whose C = CH-CO proton in the NMR spectrum is reported at low field strength is referred to as isomer A.

EXAMPLE 1

a) 4-Amino-6- (4-chloro-phenyl) -3,5-dichloro-cinnamic acid styler

A solution of 108 g (0) was slowly added to a suspension of 13.2 g (0.55 mol) of sodium hydride (26.4 g of a 50% suspension in oil) in 50 ml of dry 1,2-dimethoxy-ethane / icing and ice-cooling. , 55 moles) of ethyl ester. of diethylphosphonic acid in 150 ml of dry 1,2-dimethoxyethane, giving a strong foaming effect. After the addition is complete, stir for a further 30 minutes. A suspension of 150 g (0.5 mol) of 4-amino3,4 ', 5-trichloro-benzophenone in 800 ml of dry 1,2-dimethoxyethane was then added and heated to reflux for 1 hour to give a clear solution. The solution was evaporated to dryness in vacuo and the residue partitioned between chloroform and water. The organic phase was dried and evaporated to dryness in vacuo. Crystallization occurs after the addition of 150 ml of ethanol. The crystals were aspirated and washed with ethanol and light petroleum.

Tal. mixtures of isomers A and B: 88 to 110 ° C.

NMR spectrum (CDCl3, 60 MHz):

NMR spectrum (CDCl3, 60 MHz):

»CH-C0- 6.27 ppm singulet (1 proton)

b) 4-amino-g- (4 * -chloro-phenyl) -5,5-dichloro-cinnamic acid, 156 6 (0.568 mol) ethyl ester of 4-amino-3- (4'-chloro-phenyl) 3.5 -Dichloro-cinnamic acid (mixture of isomers k and B) is heated in a mixture of 1000 ml of ethanol and 300 ml of 5 n sodium hydroxide for 1 hour at reflux temperature. · After cooling, dilute with water and acid with 2n hydrochloric acid. The oily product is first extracted and crystallized after a short time. The crystals were aspirated and recrystallized from ethanol. Colorless crystals of pure isomer A are obtained from the ground. 241 to 243 ° C (decomposition).

NMR spectrum (DMSO, 60 MHz):

= CH-C0- 6.37 ppm singulet (1 proton) t

Further evaporation of the mother liquor gave a further crystalline fraction from the ground. 200 to 204 ° C (decomposition) existing from a mixture of A / B isomers "1 / 1.5 ·

NMR spectrum (DMSO, 60 MHz):

= CH-C0- 6.37 ppm singulet] τ (1 proton)

6.29 ppm einguletJ

4-Amino-g- (4-chloro-phenyl) -3,5-dichloro-cinnamic acid morpholide, g (0.058 mol) of 4-amino-5- (4-chlorophenyl) -3,5-dichloro-cinnamic acid (mixture of isomers A and B) in a ratio of * 1: 1.5) 3 dissolved in 700 ml of dry chloroform. Under ice-cooling and stirring, 5.95 g (0.058 mol) of triethylamine was added at 5 ° 0, cooled to -10 ° C, and 6.35 g (0.058 mol) of ethyl ester were added.

- 9:20 hydrochloric acid. After the addition is complete, 25.5 S (0.29 mol) of morpholine is added while further stirring and cooling. The mixture was stirred for a further 4 hours at room temperature, then shaken three times with water, the organic phase dried over sodium sulfate - and evaporated to dryness in vacuo. The residue is chromatographed over a silica gel column. (Quartz Gel: 10: 1 Substance; Elution: Chloroform / Acetester 1: 1). The eluates containing the substance were combined and evaporated to dryness in vacuo. We get colorless crystals from the ground. 140 to 144 ° C, containing a cis- / transisomeric ratio of 5 ^; 2.

NMR spectrum (CDCl3, 80 MHz):

= CH-CO- 6.2 ppm singiylet 1

V (1 proton)

6.14 ppm singuletj

Recrystallization of the resulting mixture of cis / trans isomers from ethanol gives the pure trans isomer from the ground. Mp 168 to 171 ° C. NMR spectrum (CDCl3, 80 MHz):

= CH-CO- 6.2 ppm singulet (1 proton) ·

Steric ratios of the compound of the formula thus prepared

· One explained by H-NMB spectroscopy at 90 MHz. It shows signals

a) H ^ 4-Amino-3,5-dichloro-phenyl ring at 7.09 ppm (singulet)

b) H _A 'and Hg' of the 4-chlorophenyl ring at 7 * 23 ppm (doublet) and at 7.33 ppm (doublet)

c) Hq of olefin at 6.22 ppm (singulet!

(Olefin H isomeric compounds (isomer B) is observed at

6.17 ppm as determined on the spectrum of the isomer mixture).

NOE measurements are performed to clarify the ether ratios of the olefin double bond of the double molecule. (The Nuclear Overhauser Effect, J.H. Noggle, B.E. Schirmer, Academic Press New York and London 1971) ·

NOE measurements were performed using a 90 MHz FT-NMR device (Bruker Models ΗΧ-9Ο / 15) on a 2% solution of the substance in a particularly dried and degassed CDCly η

NOE measurement of homonucleam in the H-NMR spectrum at 90 MHz to give the following results:

irradiated - · observed Intensity change - H-atom signal the H-atom signal t Hc (6.22 ppm) H _a (7.09 ppm) +14 to 15 Hc (6.22 ppm) H _a * (7.23 ppm) + 3 to 5 Hc (6.22 ppm) Hg '(7.33 ppm) + 1 to 3

From these intensity measurements (table), it became apparent that “the spatial distance between Hc and H ^ is significantly smaller than between Hc and H ^”. The compound of the above formula therefore appears in the trans-form shown.

EXAMPLE 2

Trans ^ -amino-P - ^ - chloro-phenyl - ^ - dichloro-cinnamic acid morpholide

Prepared from isomer A of 4-amino-β- (4′-chloro-phenyl) 3,5-dichloro-cinnamic acid with ethyl ester of hydrochloric acid and morpholine.

M.p .: 168 to 171 ° C,

NMR spectrum (CDCl3, 80 MHz):

»CH-CO- 6.2 ppm singulet (1 proton)

EXAMPLE 3.

4-Amino-8- (4-bromo-phenyl) -5,5-dibromo-cinnamic acid morpholide

Prepared from 4-amino-P- (4'-bromo-phenyl) -3,5-chlorobromic acid (mixture of isomers A: B = 1,5 ^ 1), ethyl ester of chloromic acid, triethylamine and morpholine.

Tal. 2.5: 1 mixtures of isomers A and B: 165 to 180 ° C.

NMR spectrum (CDCl3, 80 MHz):

= CH-CO- 6.25 ppm singulet] r (1 proton)

6.20 ppm singuletJ

EXAMPLE 4 4-Amino-E- (4 ¹ -Chloro-phenyl) -3 ·, 5-dibromo-cinnamic acid morpholide

Prepared from 4-amino-3- (4'-chloro-phenyl) -3,5- bromobicyclic acid (mixture of isomers A: B = 5 * -1), chloromic acid ethyl ester, triethylamine and measure 1c).

morpholine analogous to pn-- --.- - - --.- 23 - I

Tal. 6: 1-mixture of isomers o in A and B: 478 to 189 ° C.

NME spectrum (CDCl3, 80 MHz):

»CH-CO- 6.22 ppm singulet]

T (1 proton)

6.18 ppm singuletj

EXAMPLE 5,)

4-Amino-5,5-dibromo-B- (4 * -fluoro-phenyl)-cinnamic acid morpholide

Prepared from 4-amino-3,5-dibromo-P- (4'-fluoro-phenyl) cinnamic acid (isomer ratio A: B «2.5: 1), chloromic acid ethyl ester, triethylamine and morpholine analogous to Example 1c).

Melting point: 4: 1-mixtures of isomers A and B: 186 to 197 ° C.

NME spectrum (CDCl3, 80 MHz):

»CH-CO- 6.21 ppm einguletl f (1 proton)

6.16 ppm singuletj

EXAMPLE 6

4-Amino-3,5-dibromo-3-phenyl-cinnamic acid morpholide

Prepared from 4-amino-3,5-dibromo-E-phenyl-cinnamic acid (isomer ratio A: B »1: 1), chloromic acid ethyl ester, triethylamine and morpholine analogous to Example 1c).

Melting point: 1: 1-mixtures of isomers A and B: 156 to 174 ° C.

NMR sneaker (CDC1-, 400 MHz):

= CH-CC- 6.2 ppm η-ngulet] S) ”and (1 Proton)

6.18 ppm singuletj

- 24 EXAMPLE 7!

4-Amino-8- (4 * -bromo-phenyl) -3,5-dichloro-cinnamic acid morpholide

Prepared from 4-amino-3- (4 * -bromo-phenyl) -3,5-dichloroacetic acid (mixture of isomers A: B 1: 2,5), chloromic acid ethyl ester, triethylamine and morpholine analogous to Example 1C).

Tal. pure isomer'A: 188 to 194 ° C.

NMR spectrum (CDCl3, 60 MHz):

»CH-CO- 6.23 ppm singlet (1 proton).

EXAMPLE 8 4-Amino-5.5-dichloro-3- (4-fluoro-phenyl)-cinnamic acid morpholide

Prepared from 4-amino-3,5-dichloro-f3- (4'-fluoro-phenyl) cinnamic acid (mixture of isomers A: B with 3 ^; 1), chloromic acid ethyl ester, triethylamine and morpholine analogous to Example 1c).

Tal. 3: 1-mixtures of isomers A and B: 160 to 176 ° C.

NMR spectrum (CDCl3, 60 MHz):

= CH-CO- 6.23 ppm singulet!

Γ (1 proton)

6.18 ppm singulet)

EXAMPLE 9 ^With 4-amino-3,5-dichloro-1-phenyl-cinnamic acid morpholide

IZ

Prepared from 4-amino-3,5-dichloro-8-phenyl-cinnamic acid (mixture of isomers A: B »1.5: 1), chloromic acid ethyl ester, triethylamine ^ and morpholine analogous to Example 1c). Melting point: 1: 1 mixtures of isomers A and B: 143 to 160 ° C.

NMR spectrum (CDCl3, 400 MHz):

CH-CO- 6.2 ppm singulet

6.18 ppm singulet

EXAMPLE 10 ^!

a) 3-bromo-4-dimethylaminobenzophenone (1 proton)

CO., LTD

Nr

22.5 g (0.1 mol) of 4-dimethylaminobenzophenone were dissolved in 60 ml of acetic acid. After stirring for 1 hour, a solution of 5.3 ml (0.105 mol) of bromine in 20 ml of acetic acid was added. Stir for another 30 minutes, add water, and add a little sodium bidrogensulfite for discoloration. The resulting lubricated product is shaken with toluene-water, the toluene phase is washed twice more with water, dried and the toluene is distilled off in vacuo.

Yield: 24.4 g (80% theory); tough oil.

b) 3-Bromo-4-dimethylamino-8-phenylcyclic acid

CH

CH

COOH

2.1 g (0.07 mol) of sodium hydride (with 20% paraffin oil) are mixed with 30 ml of absolute 1,2-dimethoxyethane. A solution of 15 "7 g (0.07 mol) of triethylphosphonoacetate in 30 ml of 1,2-dimethoxyethane was added dropwise under ice-water cooling, and after clear dissolution 18.25 g (0.06 mol) of 3-bromo-4-dimethylaminobenzophenone were added. dissolved in 30 ml of 1,2-dimethoxyethane. Boil for 4 hours at reflux and distill off the solvent overnight in vacuo. The residue was shaken with toluene / water, the toluene phase was washed again with water, dried and the toluene was distilled off in vacuo. The residue was boiled with methanolic potassium lye (14 g (0.25 mol) of potassium hydroxide and 250 ml of methanol + 25 ml of water) by reflux for two hours. The solution was evaporated in vacuo and the residue was shaken with toluene-water.

The aqueous solution was adjusted by addition of hydrochloric acid not pH 6.5, whereby the substance was eliminated in solid form. It is soluble in excess hydrochloric acid. After rinsing with water, dry.

Yield: 15.2 g (73% of theory);

M.p .: 147 ° C.

c) 3-Bromo-4-dimethylamino-1-phenylcyclic acid gorfolid

CsCH-CON 0

5.19 g (15 mmol) of 3-bromo-4-dimethylamino-5-phenylcyclic acid were dissolved in 30 ml of absolute tetrahydrofuran and 3.24 g (20 mmol) of N, N-carbonyl__ diimidazole were added in portions. After the solution of carbon dioxide is resolved.1.1.1. And clear dissolution, 1.7 ^ E (20 mmol) of moriolin is added, allowed to stand at room temperature for 10 minutes and then boiled for 30 minutes at reflux. The solution was evaporated in vacuo and the residue was shaken with toluene-water. The toluene phase is washed twice more with water, dried and evaporated in vacuo. The resulting oil crystallizes by scraping with a little methanol.

Yield: 6.25 g (91.5% of theory);

M.p .: 169 ° C.

Rf: 0.55 (toluene-acetone 70: 3θ) ·

According to the above examples, the compounds of the following table may also be obtained according to the invention:

TABLE I r Compounds.formulo ^ CsCRpCO-O • Example ABQ Rj! Fel. ^! ( ⁰ Cj

Rf

No. ^{11 C} 6 ^H 5 / Λ -n; o \ _f H Oil Cl ¹² r »T > 2 ^C and ^H 5 r ~ \ -N 0 · / H Cl ¹³ -O- ° ^H C 1 ^c «« 5 / ~ \ -N. 0 \ -_ / H 174 Cl NH ₂ Cl • 4 Cl ^C « ^H 5 ' / ~ “\ ~ N \ ^ 0 H 136 NH- Br ^C 6 ^H 5 r ~ \ -N 0 \ _t H 75-80 r \ —N 0 \ _ ( H Oil 17 -O- ⁰ '\ cH, r - © ^ - ° ^CH 3 r \ N 0 H

0,51 *

Example 'A

- 2Š R ₁ Tal !. [ ^q Cj Rf ιέ • i

1S

f- \

A_y ° —N ^x 0 \ _y

H 93

H Oil 0,55 *

-N 0 H Oil. 0.57 * ^{21 C} 6 ^H 5

H OQe! 0.49 0.59 *

• yO

- .29 Example

QR _x Tal. ^e C RF

* Rf values: toluene / acetone liquid agent 7: 3 «Use DC plates Poljgram Fa.Macherey-Nagel, (Art. No. 805 021); 25 ° C

EXAMPLE 35 I

3- (3,4-Dimethoxyphenyl) -5-phenyltin-2,4-diene-1-carboxylic acid morpholide

a) 3,4-Dimethoxy-5-methyl-cinnamic acid ethyl ester

with water, a fraction of 24.75 g (625 mmol) of sodium hydride (with 20% paraffin oil) is mixed with 5θθ ml of absolute 1,2-dimethoxyethane and 185 g (825 mmol) of triethyl phosphonoacetate are added dropwise under ice-water cooling. To a clear solution, 135 g (750 mmol) of 5,4-dimethoxyacetophenone are added in one portion and stirred under reflux for 5 hours in a boiling water bath. After standing overnight, 1,2-dimethoxyethane is distilled off in vacuo and the residue is shaken with toluene water. The toluene solution was washed again and dried and the toluene was distilled off in vacuo. The residue was distilled in vacuo.

Yield: 159 g (85% of theory)

Hot. 150 ° C / 0.04 mbar

b) 5- (3,4-Dimethoxyphenyl) -5-phenylpenta-2,4-diene-1-carboxylic acid

32.

5.05 β (45 mmol ον) of potassium tert.butylate was dissolved in 20 ml of absolute dimethylformamide and a solution of 10.0 g (40 mmol) of 3,4-dimethoxy-β-methylcyclic acid ethyl ester and 4.78 g (dropwise) was added dropwise. 45 mmol) of benzaldebide in 10 ml of absolute dimethylformamide. Stirring for another 4 hours>

at room temperature, water is added and acidified with hydrochloric acid. The resulting lubricated product is stirred with hot water and sodium carbonate is added portionwise until dissolved. Shake this aqueous solution twice with toludl. During acidification with hydrochloric acid, the substance is precipitated and recrystallized from toluene after washing with water.

Yield: 9.7 β (78% of theory)

Tal. 164 ° C.

c) ^ SPiSli ^ -lzi ^ i ^ -dimethoxypheny - ^ - phenylpenta-P ^^ - diene-lISSyboxylic acid r ~ \

4.66 g (15 mmol) of 3- (3,4-dimethoxyphenyl) - $ - phenylpenta2,4-diene-1-carboxylic acid is dissolved in 3 ° ml of absolute tetrahydrofuran and 3.24 g (20 mmol) is added in portions 1 , 1'carbonyldiimidazole. After the development of carbon dioxide p 0 is complete, and 1.74 g (20 mmol) of morpholine are added to the clear solution and clear dissolved, allowed to stand at room temperature for 10 minutes and then boiled for 30 minutes at reflux. The solution was evaporated in vacuo and the remaining 15

-52 ^ Shake with toluene-water. The toluene solution was washed twice more with water, dried and evaporated in vacuo.

Yield: 4.9 g (86% of theory), DC pure oil Rf: 0.54 (toluene-acetone 7θ ^: 3Ο)

Analysis: C calc. 72.80%, found 73,12%

H calc. 6.64%, found 6.67%.

N calc. 5.69%, found 5,64%

EXAMPLE 36! .

a) 5x (4-chlorophenyl) -5 ^ (5,4-dimethoxyphenyl) -hexa2,4-diene-1-carboxylic acid

5, θ5 6. Dissolve potassium tert-butylate (45 mmol) in 20 ml of absolute dimethylformamide and dropwise a solution of 10.0 g (40 mmol) of 5,4 dimethoxy-3-methyl-cinnamic acid ethyl ester and 6,96 g in an ice bath. (45 mmol) of 4-chloro acetophenone in 10 ml of absolute dimethylformamide. The mixture was stirred for 4 hours at room temperature, water was added and acidified with hydrochloric acid. The resulting liquid oil is stirred with hot water and sodium carbonate is added portionwise until dissolved. The aqueous solution was washed again with toluene. Acidification with hydrochloric acid eliminates the oil again. It is extracted with toluene, the extract is washed twice with water, dried and the toluene is removed.

distilled in vacuo.

Yield: 11.9 g (83% of theory, oil).

b) (4 ₌ chloro enyl) -3; (4-dimethoxyphenyl) -hexane2,4-diene-1-carboxylic acid

5.38 g (15 mmol) of 5- (4-chlorophenyl) -3- (3,4-dimethoxyphenyl) -hexa-2,4-diene-1-carboxylic acid were dissolved in 3θ ml of absolute tetrahydrofuran and 3 was added in portions. 24 g (20 mmol) of 1,1 '-carbonyldiimidazole. After the development of C0 ₂ is complete, 1.74 g (20 mmol) of morpholine is added, allowed to stand for 10 minutes at room temperature and then boiled for 30 minutes at reflux. The solution was evaporated in vacuo and the residue was shaken with toluene-water. The toluene phase was washed again with water, dried and evaporated in vacuo to about 20 ml. This solution was purified via a chromatographic column filled with 30 g of silica gel mixed with toluene. Elute first with toluene and then with toluene-acetone-90: 10. Fractions with substance Rf 0.47 (toluene-acetane 70:30 on a silica gel plate) were collected and evaporated in vacuo.

Yield: 4.7 g (73% of theory), oil, Analysis: C calc. 67,36% found 67,38% 0 H calc. * ^ 5.12% found 6.22% N calc. 3.27% found 3,13%

♦ EXAMPLE 37 J

a) 3- (3,4-Dimethoxyphenyl) -2-methyl-crotonic acid ethyl ester

3.3 g (110 nunols) of sodium hydride (with 20% paraffin oil) are mixed: with 40 ml of absolute 1,2-dimethoxy-ethane and 26.2 g (110 mmO) of triethyl-2-phosphonpropionate are added dropwise under ice-water cooling. . After clear dissolution is complete, 18 g (100 mmol) of 3,4-dimethoxyacetophenone are added and boiled under reflux for 3 hours. After standing overnight, 1,2-dimethoxy-ethane is distilled off in vacuo and the residue is shaken with toluene-water. The toluene phase was washed again with water, dried and the toluene was distilled off in vacuo. The residue was fractionally distilled in vacuo.

Yield: 19.8 g (81% of theory)

Hot. 145 ° 0 / 0.4 mbar

b) 5- (4-Chlorophenyl) -33 (3, N, N-dimethoxyphenyl) -2-methylpenta-2,4-diene-1-carboxylic acid

Cl

6.17 E (55 mmol) of potassium tert.-butylate was dissolved in 20 ml of absolute dimethylformamide and a solution of 13 "2 g (50 mmol) of ethyl ester 3 (3" 4-dimethoxyphenyl) -2-methylcrotonic acid was added dropwise under stirring. 7 »73 g (55 mmol) of 4-chlorobenzaldehyde in 20 ml of absolute dimethylformamide. The mixture was stirred for 6 hours at room temperature, water was added and acidified with hydrochloric acid. The resulting lubricated product is stirred with hot water and sodium carbonate is added portionwise. Shake this aqueous solution once with toluene. The oil obtained from acidification with hydrochloric acid recrystallizes from toluene-petroleum ether.

Yield: 11 g (61% of theory)

Tal. 164 ° C.

5- (4-Chlorophenyl) -3- (5,4-dimethoxyphenyl) -2-methylpenta-2,4-diene-1-carboxylic acid morpholide

5.38 g (15 mmol) of 5- (4-chlorophenyl) -3- (3 »4-dimethoxyphenyl) -2-methylpenta-2,4-diene-1-carboxylic acid were dissolved in 30 ml of absolute tetrahydrofuran and added in portions 3.24 g (20 mmol) of 1,1tcarbonyldiimidazole. After the development of C0 ₂ is completed, 1.74 g (20 mmol) of morpholine are added, allowed to stand for 10 minutes at room temperature, and then cooked for 2 hours

-3? At reflux. Evaporate the solution in vacuo and shake the residue with toluene-water. The toluene phase was washed again with water, dried and evaporated in vacuo to about 20 ml. Purify this solution via a chromatographic column filled with 30 g of Snow gel quartz mixed with toluene. Elute first with toluene and then with toluene-acetone 90:10. Fractions with substance Rf 0.52 (toluene-acetone 70:30 on a silica gel plate) were collected and evaporated in vacuo.

Yield: 4.95 g (77% of theory); oil Analysis: C calc. 67.36% found 67.61% found 6.10% found 3.36%

H calc. 6.12% N calcd. 3.27%

EXAMPLE 38

5- (4-Chlorophenyl) -3- (3,4-dimethoxyphenyl) - ^, penta-2,4diene-1-carboxylic acid morpholide

a) 3, 4-dimethoxyacetophenone

215.9 g (2.75 mol) of acetyl chloride were added dropwise to 345.5 g (2.5 mol) of Veratrol suspended in 1400 ml of ethylene chloride. Stirred for 3θ minutes at room temperature, cooled with ice / salt and added 366.6 g (2.75 mol) of AlCl 2. Stirred for 3 hours, keeping the temperature below 15 ° 0. After treatment and distillation on a rotary evaporator, 419.1 g (93% of theory) of oil are obtained, boiling. 125 to 127 ° C / 0.5 mbar. From CCl ^ / petroleum ether a substance is obtained from the ground. 48 to 5θ ° C.

·. · '.. f

b) 3,4-Dimethoxy-β-methylcytinetic acid ethyl ester

K 291.7 g (2.6 mol) of potassium tert.butylate, suspended

The mixture was stirred for 7 hours at about 60 ° C .; The solvent was then removed on a rotary evaporator, water was added to the residue, and ether was evaporated. 3,4-Dimethoxy-β-methyl-cinnamic acid ethyl ester was isolated from the ether phase in a yield of 558 g (87% of theory); boil. 137 ° C / 0.17 ”bar.

c) 57 (3,4-dimethoxyphenyl) -5- (4-chlorophenyl) -genta-2,4..di ^is n-1carboxylic acid

28.1 g (0.25 mol) of potassium tert.butylate in 75 ol of dimethylformamide are presented. Upon cooling, 50.7 g (0.22 mol) of 4-chloro-benzaldehyde and 5θ g (0.20 mol) of 3,4-dimethoxy-β-methyl-cinnamic acid ethyl ester in 125 were added over 10 minutes at 10 to 15 ° C. ml of dimethylformamide. The mixture was stirred for 45 minutes without cooling, 350 ml of water was added and 50 ml of 6 N hydrochloric acid was added. The recovered product was aspirated and recrystallized from dioxane.

The yield was 57.6 g (84% of theory);

Tal. 226 to 227 ° C.

2,4-diene-1-carboxylic acid · *)

K 4.52 g (52 mmol) of morpholine in 15 ml of pyridine dock, · <<: Λγ;

'. · - «** !: ·> ζ ·. · ** »S - * * /. * · * · ·

steam while cooling at -5 to O,? C .v; CIO, minutes 2.38 6 (17 »3. ··. · ...,. ··.: -. i: · '·? -. v ?> '-V j' · - »'·. ····.

· · · · · · · · · · ·. ”·· mmoles) of phosphorus trichloride. The reaction was allowed to proceed for half an hour at room temperature and then 12.1 g (35 nmol) of the acid obtained was added at a time, and a further 55 [mu] l of pyridine was added.

»T

Allow to stand for 3 hours at room temperature

V77 for half an hour at 40 jO. Mixtures then _; l ^ d ^ is added and the hydrochloric acid is concentrated ^: until the strongly acidic reMi ^^^ fe ^^^ t ^ / p ^ is precipitated, the reaction product precipitates. Odsesamotga i ^ through water and

-i-. · ··. · · /(>·.* ·. · »- <·». »·» · · - ·· with acetone and recrystallized from / isopropachol / water.

- · ',. 'and'. ''·' ·. * a. · ¹ *** 5 ». · <* '* - · · *:” ·

·. · · · ·. ·; ···. $ £ .. '% · <ΤΛ · · ». ··. ·>». *.,. · TOutput: 12.3 g (85% of theory);

m.p. 125 to 126 ° 0. f S ';

EXAMPLE 39 _Λ · _:, * · ¹ «· - 4 <·.

(-... i .. ... • Li? · .. '·. v- ». ·>.' *? - ·?» v- · · Č-K * J?. * ··. · '·', · ?. '· Λ · J ..- ·· ..'. · '· ··: ·. ·'

3- (5,4-Methylenediocaiphenyl) -5- (4-chlorophenyl) penta-2,4-diene-1-carboxylic acid isopropylamide ^^ ft ^ tv,

- “-: —- / ·· '' v ^v

a) 5 ~ (3,4-methylenedioxyphenyl) -5- (4-chloro-enyl) -peta-2,4diene-1-carboxylic acid and ··· / ·; ·. J ···

35 B (° »25 moles) of potassium tert.butylate • · 71 in 80 ml of dimethylformamide are added over 10 minutes while cooling 29 g (0.26 mol) of 4-chlorobenzaldehyde and 55 g (0.235 mol) of ethyl ester 3,4- methylenedioxy-0-methyl-cinnamic acid in 160 ml of dimethylformamide so that the temperature does not exceed 20 ° C. After stirring for one hour without cooling, water and hydrochloric acid are added (until acidic) and the product is filtered off with suction.

To recrystallize it from a lot of isopropanol.

Yield: 67.8 g (87% of theory);

Tal. 205 to 206 ° C.

4? - jv /:. / 7 <7 / /?/./:?,·- · '·' '' ·· '..' '' · ,. ' _Λ · .. '..

b) J522 £ 22ii25l £ - (3 t ^ -Sgtilgadioxyphenyl) -5- (¾z ^ lorfgnyl) penta-2,4-diene-l-carboxylic acid '' »Υ - '• L

From the 5.9 g (0.10 mol) / isopropylamine in 25 ml of pyridine and 4.6 g (0.034 mol) of the phosphorus trichloride, a phosphoase compound is prepared in the usual way. ' 22.0 g (0.067 moles) after a) of the acid obtained were added, stirred for 4 hours and allowed to stand overnight. After addition of ice and acidification with hydrochloric acid, extra-. shoulder with vinegar, the acetic ester '~ -extract was washed with water and dilute sodium hydroxide,' Hear and evaporate. The residue is recrystallized from benzene / petroleum ether.

Yield: 10.8 g (43.5% of theory);

Tal. 125 to 127 ° C.

•>. ·· '·.

The values of Rf in the following table are determined on the Macherey-Nagel DC plot (Art. No. 805 021). Liquid •.: ·. ·· '· Ί ... · / ·.

agent toluene / acetone 7 ^: 3/22 ° C.

• «f

I

4  - '·· -. - i • In addition, the compounds listed below are also conveniently obtained Tables II Δ • Compounds of Formula B = CH-CO-Q Example Q l · A B Tal / Rf r 40! j i n (ch ₃ ) ₂ / - < ^0CH 3 HQ-och ₃ -CH = CH - ^ 2 ^ - Cl Tal; 0.53 41 ΐ nhch (ch ₃ ) ₂ 1 » II 146 ° C 42 ΐ N (CH _y ) Vj «, n II Tal; 0.71 43 n (c ₂ h ₅ ) ₂ It It Terl 0.63 44 N (CH ₃ ) II w ' Tffl: 0.69 nC ₃ H ₇ 45 -N 0 II * r · -CH = C - ^ - N0 ₂ 46 n II 1 -Q- ^ci CH, ^ 01 47 «T II -CH = CH - ^^ - QCH ₃ Tal 0.59 48 · 1 « II - ^chsch Ό Tal 0.53 49 • lf  ! 1 -CHsCH — j | 1 50 · II II -CH = CH ~ 123 ° C oc ₂ h ₅ 51 j 1 H II -OteCH- ^ 130 ° C i l 1 i ................. i Cl •

Q A B ΛΛ _η -N 0 « OCH, ”And -CH = CH- \ 0 / I OCH, TaL: 0.36 'TaL 0.51 M ! 3 -CH = CH - ^ 0C ₂ H ₅ TeL 0.52 N -otecn — O N0 ₂ 152 ° C n  -CHsCH-Q-C1 Cl Τβϊ: 0.54 n  -CH = CH - (O) - '"^ O -CH, ΛΠυ * 158 ° C n - ^ 2> - ^chsch -O · ^ci 145 ° C tt OCrl « Tal: 0.62 tt -Q> -X ^h , 122 ° C tt QCHj - ^ 2 ^ -och ₃ -ch = ch-c ₆ h ₅ 149 ° C II OCHj • - # Ύ> - (ΚΗ ₃ £ HzCH- <Q> - d? 13CH.J 80 ° C » - “CH

X-

Example Q ' ^A 64 1 • / ~ \ -N 0 and Ό · “ 1 1 65 n 1 i j i 66 • • n '0 —CH, a » 67 -NHCH (CH ₃ ) ₂ II » 68 i Ζ “λ -N 0 \ _t i - / n * O ~ ^CH 3 no ₂ 69 II 70 r \ -NH-N 0 \ _t och ₃ (^ -ocn, 71 -N 'o V_ / i 11 72 n II 73 II II 74 t 1 11 75 i II 9 11 76 It II

B Tal./Rf -CH = CH - \ O / ~ ^C1 181 ° C OCH, -CH = CK — OCH ₃ Tab 0,51 -CH = CH — Cl 102 ° C H 132 ° C -CH = CH - 0CH ₃ Tal <0.62 -ch = ch-c ₆ h ₅ 151 ° C -CH = CH —Cl 138 ° C - (CH = CH) ₂ -C _fi H ₅ 80 ° C CH, and 3 -CH = CH-C- (CH,), - CH, 1 Z Z J Tal ': 0.46 ch ₃ -CH = CH —KZ3 T «l: 0.50 N Toluol / ethanol 8: 2 -CH = CH— 165 ° C -CH = CH - Mp: 0.13 -CH = CH -J J Q • Tal: 0.46

and • · X

44-:

Example Q [ A 1 'B Tal./Rf (. 'j Π -NHCH (CH,) ₂ i och ₃ - <Q-och ₃ -ch = c (ch ₃ ) ₂ 112 ° C 78 ' II -CH = CH-CH (CH ₃ ) ₂ 98 ° C

62 ° C

102 ° C

127 ° C

-NH-CH (CH ₃ ) ₂ / - \ - _ $

H

-NH-CH (CH ₃ ) ₂

It «f

-CH = C (CH ₃ ) ₂

-CH = CH-CH (CH ₃ ) ₂

-CH = C (CH ₃ ) ₂

-C (CH ₃ ) = C (CH ₃ ) ₂

126 ° C

Oil

76 ° C

133 ° C

97 ° C

178 ° C

Oil

Table III e f rtriniil Λ

C = CH-COQ

Rf_ values:

In toluene / acetone 70: 30, CCa .. 22 ° C

Example ^ 2 ^ 3 ^ 4 Rj ^ / Rj ^ / R 13 Q Tal. al 90 3,4- (CH ₃ O) ₂ 4-C1 N (CH ₃ ) C ₄ H _g 0.70 91 II II n (ch ₃ ) ch (ch ₃ ) -C ^ 0.61 / - 92 3-NO- / 4-C1 H N 0 151 ° C 2 V_ / '93 2,3,4- (CH ₃ O) ₃ II II 125 ° C 94 II 4-C1 VI 127 ° C 95 3.4- (0-CH ₂ CH ₂ -0) H tl 0.56 96 II 4-C1 II 75-80 ° C 97 3_CH ₃ /4-CH ₃ 0 H II 137 ° C 98 II 4-C1 tl 151 ° C 99 3.4- (0CH ₂ 0) H II 112 ° C 100 3-F / 4-CH ₃ 0 II IV 138 ° C 101 3-Cl / 4-CH ₃ 0 II A 153 ° C 102 3-Br / 4-CH ₃ 0 • I II 160 ° C 103 IV 4-C1 It 150 ° C 104 2,5- (CH ₃ O) ₂ H II 0.58 105 tl 4-C1 II 124 ° C 106 3-CH ₃ 0/4-C ₂ H ₅ 0 H II 0.63 107 II 4-C1 IV 0.60

Tal. or Rf

Example ^R 11 ^{/ R} 12 ^{/ R} 13

η 3-CH ₃ 0 / 4- (CH ₃ ) ₂ CH 0 il H \ _✓ 117 ° C $ 10 3-CH ₃ 0/4-CH ₂ = CH-CH ₂ 0 II H 143 ° C 110 i 1 4-C1 n 166 ° C I 111 3,5-Cl ₂ /4-NH ₂ H 'I 163 ° C

Analyzes of the oil products of Table II

Example calcd. % C Found. % C calcd. % H found % H calcd. % N Detection «% N 9C 69.64 69.67 6.82 6.73 3,38 3.17 91 69.64 69,96 6.82 6.76 3,38 3.68 95 73.19 73.41 6.14 6.26 3.71 3.41 104 72,80 73.13 6.64 6.77 3.69 3.65 106 73.26 73.33 6.92 6.95 3.56 3.57 107 67.36 67.68 6.12 6.39 3.27 2.96

) • £ ·

Example Q A B Tei./Rf • · i < och ₃ « 77 -NHCH (CH ₃ ) ₂ • -ch = c (ch ₃ ) ₂ 112 ° C 78 II II -CH = CH-CH (CH ₃ ) ₂ 98 ° C 79 (· i i M -CH = cQ 62C p —CH, < -CH = CH Art. · • 80 r ~ \ _r —N 0 l · · \ __ J! 102 ^e C 81 II ' - ^C 6 ^H 5 II 127 ° C

i

-CH = CH No.

-ch = c (ch ₃ ) ₂

-ch = ch-ch (ch ₃ ) ₂

-NH-CH (CH ₃ ) ₂

-ch = c (ch ₃ ) ₂

126 ° C

Oil

76 ° C

133 ° C

-C (CH ₃ ) = C (CH ₃ ) ₂ 97 ° C —N \) \ _J

£ 8:

89 '

OIL

16 ° C

Oil

- 4§ -. L

Tab e 1 a .. IV

Compounds of Formula

Rf values of V. toluene / acetone 70 ϊ 30, ca 22 ° C

Example R ₂ / Rj / R ₄ ^R 11 ^{/ R} 12 ^R 112 4-N (CH ₃ ) ₂ 4-C1 113 2, MCH _3. ) ₂ IV 114 3,4- (CH ₃ ) ₂ It 115 3-NO ₂ /4-CH ₃ 0 H 116 3,4- (CH ₃ O) ₂ 3,4-Cl ₂ 117 3,4- (CH ₃ O) ₂ H 118 It It 119 3-CH ₃ /4-CH ₃ 0 It 120 It II 121 It 11 122 3,4-Cl ₂ It 123 3,4- (CH ₃ O) ₂ 3,4- (CH ₃ 124 3,4- (CH ₃ O) ₂ 4-C1 125 3,5- (CH ₃ ) ₂ /4-CH ₃ 0 H

Tal. or Rf Comments

124 ° C

100 ° C Mixture of isomers Mp 135-137 ° C Z-isomer 106-110 ° C Mixture of isomers 125-127 ° C E-isomer 115-118 ° C Z-isomer 0.5 + 0.56 70 Mp 135-137 ° C * 150 ° C

Example ^ 3 / ^ 3 / ^ 4 ^R U ^{/ R} 12 ^{/ R} 13 Tal. or Eph Comments 126 3,4- (C ₂ H ₅ ) ₂ H 0.58 127 3,4- (CH ₃ O) ₂ 3-C1 resin 128 »1 2-C1 126-129 ° C • 129 3-Br / 4-CH ₃ 0 4-CH 2 O 0.48 Mixture of isomers 130 II 4-CH 2 O 161 ° C Z-isomer 131 3-C ₂ H ₅ /4-CH ₃ Q H 93 ° C 132 3-nC ₃ H ₇ /4-CH ₃ 0 II 0.60 133 3-CH ₂ O / 4-CH ₃ II. 0.53 E-isomer 134 It II 119 ° C E-isomer 135 3-Cl / 4-CH ₃ 0 3-C1, 4-CH 2 O 0.50 136 3-CH ₃ / 4-0H H 0.42 137 3-NH ₂ /4-CH ₃ 0 4-C1 t - f. 138 3,4- (CH ₃ O) ₂ 2-F 118-127 ° C. · ' Ί39 2,3- (CH ₃ ) ₂ /4-CH ₃ 0 H. 171-174 ° C 140 3-CH (CH ₃ ) ₂ /4-CH ₃ 0 II 134-136 ° C 141 3-CH ₃ /4-NO ₂ 4-CH 2 O 0.42 142 3-NH ₂ /4-Cl H 65-67 ° C 143 3-CH 2 / A-CH 2 O 3- CH_ / 4- CHjO 0.47 144 3-NHC0CH, / 4-C1

4-CH.O

- -50Analysis of the oil products of Table-XV

Example. calc. calc. calc.

S C S »C % H 55 H % N 55 N 114 70.87 70.71 6,23 6.10 3.94 4.05 116 59.72 59,87 5.01 5,21 3,32 3.17 120 62.99 63.20 4.73 4.67 3.87 3.70 124 79.05 78.96 7.79 7.78 4.01 3.86 125 65.03 64.74 5.68 5.77 3.61 3.60 127 58.34 58.67 5.13 5,25 3.24 3.22 130 75.59 75.89 7.45 7.69 3.83 3.69 131 '74.75 74.55 6.87 7.01 4:15 4,17 133 59.72 59.91 4.98 5.12 3,32 3.18 134 74.30 74.61 6.50 6.73 4.33 4.01 135 70.98 71.06 6.55 6.68 8.28 8.16 137 75.62 75.61 7.40 7.35 3.84 4.03 139 65.97 65.73 5.76 5.91 7.33 7.19 141 72.42 72.54 7.13 7.26 3.67 3.50

o o

- 51 --- Table V

Compounds of Formula

145 H 3,4- (CH ₃ O) ₂ -C = CH- <iQ> - 'CH ₃ 146 H tt -C = CH-C, H «. , b 5 CH ₃ 147 Nr 3-Br / 4-CH ₃ 0 - @ - ° ^ch 3 Br 148 H 3,4- (CH ₃ O) ₂ 2-: η8ί1; ί1 149 «T tt 1-naphthyl 150 in II 0 151 It II ^CH 2 ^C 6 ^H 5 152 tl II CH (CH ₃ ) ₂ 153 tt H —Νχ-OCHj Oh 154 tl 3,4- (CH ₃ O) ₂ -P 155 CH ₃ tl ^C 6 ^H 5 156 CN tl 0 CJk

Tal. or Rf

127 ° C

145 ° C

93 ° C

Smbla / analysis

0.43

117-120

0.46 + 0.56

Oil

Mp 228-231 ° C

130-132 ° C '0.50 + 0.60

Oh

- 52.-ΐ

Annals it to table y

Example calcd. % Cl Found. % C calcd. % H found % H say. % N found% N 157 74.44 74.69 6.20 6.48 3.47 3.29 158 74.44 74.73 6.20 6.40 3.47 3,32 159 71,93 72.05 6.81 6.92 3.81 3.77 160 67.71 67, 48 7.84 7.79 4.39 4.33 161 71,91 72.20 6.86 • 6.98 3.81 3.74

o O

The best way to make economic use of the invention

a) 4-Amino-6- (4-chloro-phenyl) -5 · ethyl ester. 5-Dichloroacetic acid

A solution of 108 g of a suspension of 13.2 g (0.55 mol) of sodium hydride (26.4 g of a 50% suspension in oil) in 50 ml of dry 1,2-dimethoxy-ethane was added dropwise / stirring and ice-cooling. (0.55 mol) of ethyl ester of diethylphosphonic acid in 150 ml of dry 1,2-dimethoxyethane, giving a strong foaming · After complete addition, stir for a further 30 minutes. Then, a suspension of 15O′g (0.5 mol) of 4-amino3,4 ′, 5-trichloro-henophenone in 800 ml of dry 1,2-dimethoxyethane was added and heated to reflux for 1 hour to give a clear solution. The solution was evaporated to dryness in vacuo and the residue partitioned between chloroform and water. The organic phase was dried and evaporated to dryness in vacuo. Crystallization takes place after the addition of 15θ ml of ethanol. The crystals were aspirated and washed with ethanol and light petroleum.

Tal. mixtures of isomers A and B: 88 to 110 ° C.

NME spectrum (CDCl3, 60.MHz):

.CH-CO- 6.27 ppn singuletl _pro ton)

6.23 ppm singuletj

Recrystallization from ethanol / petroleum ether ₂ twice yields crystals of pure isomer A from m.p. 124 to 125 C.

-52b-NMR spectrum (CDCl3, 60 MHz):

«CH-CO6,27 ppm singulet (1 proton)

b) 4-Amino-3- ⁽⁴ -.klor-phenyl) -3.5-d.iklor-cinnamic acid .136 g (0.368 mol) of ethyl 4-amino-p- (4'-chloro-phenyl) 3, 5-Dichloro-cinnamic acid (a mixture of isomers A and B) is heated in a mixture of 1000 ml of ethanol and 3θ0 ml of sodium hydroxide solution for 1 hour at reflux temperature. After cooling, dilute with water and acid with 2n hydrochloric acid. The oily product is first extracted and crystallized after a short time. The crystals were aspirated and recrystallized from ethanol. Colorless crystals of pure isomer A are obtained from the ground. 241 to 243 ° C (decomposition).

NMR spectrum (DMSO, 60 MHz):

»CH-CO- 6.37 ppm singlet (1 proton)

Further evaporation of the mother liquor gave a further crystalline fraction with fcal. 200 to 204 ° C (decomposition) existing from a mixture of isomers A / B = 1 / 1.5 ·

NMH spectrum (DMSO, 60 MHz):

= CH-C0- 6.37 ppm singulet]

V (1 proton)

6.29 ppm singulet)

c) 4-Amino-P- (4-chloro-phenyl) -3,5-dichloro-cinnamic acid morpholide g (0.058 mol) of 4-amino-P- (4-chlorophenyl) -3,5-dichloro-cinnamic acid (mixture of isomers A and B) dissolved in 700 ml of dry chloroform in a ratio of 1: 1.5. Under ice-cooling and stirring, 5.93 g (0.058 mol) of triethylamine was added at 5 ° θ, cooled to -10 ° C and 6.35 g (0.058 mol) of ethyl ester were added.

- -X ___ Chloromic acid. After completion of the addition, 25.5 g (0.29 mol) of morpholine were added with further stirring and cooling. The mixture was stirred for a further 4 hours at room temperature, then shaken three times with water, the organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue is chromatographed over a silica gel column. (Quartz Gel: 10: 1 Substance; Eluent: Chloroform / Acetester = 1: 1) .. The eluates containing the substance are combined and evaporated to dryness in vacuo. We get colorless crystals from the ground. 140 to 144 ° C containing a cis- / transisome mixture in a ratio of 3: 2.

NMR spectrum (CDCl3, 80 MHz):

= CH-CO- 6.2 ppm singulet)

J- (1 proton)

6.14 ppm singuletj

Recrystallization of the resulting mixture of cis / trans isomers from ethanol gives the pure trans isomer from the ground. Mp 168 to 171 ° C. NMR spectrum (CDCl3, 80 MHz):

»CH-CO- 6.2 ppm singulet (1 proton).

For

CELAMERCK GmbH & Co. KG KG .:

«» * «» *

LJUBLJANA <

Claims (5)

PATENT APPLICATIONS A process for the preparation of novel acrylic acid amides of the general formula Y- ^ R _r -CR ₆ ) _K in which K represents integers 0, 1, or 2, 1 represents integers 0 or 1, R ₁ represents hydrogen, methyl and, if K 0, may also represent bromine, R8 represents hydrogen, halogen, nitro, C1-6alkyl, C1-6alkoxy, amino, dimethylamino, phenyl or C1-6alkenyloxy, R ^ and RJJ independently of one another represent hydrogen, halogen, _C] g-alkyl, methoxy or hydroxy, or R ^ and R ^ together represent a methylenedioxy or ethylenedioxy, linked to two adjacent carbon atoms of the phenyl ring, when K is 0, Y represents C 1-6 alkyl, cyclohexyl, thienyl, N-naphthyl, A-naphthyl optionally substituted by methoxy, or a group "V ₂ "> n (VI) in which when n is O, R p represents hydrogen, halogen, methyl, methoxy or dimethylamino R ₁₂ and R 7 are independently from each other hydrogen, halogen or methoxy and when n is 1, m is 1 and R ₁₂ and R 4 are all hydrogen when K 1, R 4 and R 8 independently of one another hydrogen or methyl, Y represents C ^ _g alkyl, pyridyl or furyl, or together with a group CR ^ represents cyclohexyl, or a group of formula VI, wherein n is 0, R p represents hydrogen, halogen, nitro, C _{1 2} ", alkoxy or dimethylamino, and R ₁₂ and R ^ independently represent hydrogen, halogen, methoxy or hydroxy, or R ^ ₂ and R ^ together represent methylenedioxy bonded to two adjacent carbon atoms of the phenyl ring when K 2, and Rg both represent hydrogen and Y represents a group of formula VI, wherein n is 0, and R p, R ₁₂ and R.J3 each hydrogen, when 1 is 0, R? and R8 independently represent C 1-6 alkyl or benzyl, or R 8? and Rg together represent a C 1-6 alkylene ver igo? interrupted by an oxygen atom, or R_ represents hydrogen and Rg and R _1Q , which are the only ones present when R? and - 55 R _o together represent a chain independently of one another O represent hydrogen or methyl In Z when is 1, R? and Rg together represent C 1-6 alkylene / chain; interrupted by an oxygen atom * and Rg and R ₁₀ both represent hydrogen, with the proviso that when KO Ϊ not be phenylallyl monohalofenil where Rg represents hydrogen, halogen, nitro or amino and R ^ and Rjj both represent hydrogen, characterized in that acrylic acid of the formula COOH (VIII) wherein R _{p is} R 8, R 4, R 4, R 1, R 8, Y and K have the above meanings, or the ethyl ester thereof, if prepared in situ, is reacted with a compound of the formula H— (NH) - (IX) wherein 1, R ?, Rg, Rg and R _1Q have the meanings given above, or with its phosphorous derivative, optionally prepared in situ, in / in the case of a solvent or solvent mixture, / V - 56 - · -:: --- -: - optionally in the presence of a base and, if appropriate, in the presence of an acid activator, at a temperature in the range of -25 ° C to 150 ° C. Process according to claim 1, characterized in that the solvents or solvent mixture, if present, is selected from chloroform, tetrahydrofuran and pyridine. Process according to claim 1 or 2, characterized in that the base, if present, is selected from triethylamine and pyridine. ' Process according to any one of the preceding claims, characterized in that it is an acid activator if it is I present, ethyl chloroformate or 1,1′-carbonyldiimidazole. Process according to any one of the preceding claims, characterized in that the reaction temperature is in the range -10 ° to the boiling point of the reaction mixture.