DE3340348A1 - Process for the preparation of (4-amino-2-chloro-5-alkylphenyl)- alpha -(4-chlorophenyl)-acetonitrile - Google Patents

Abstract

A process is described for the preparation of (4-amino-2-chloro-5-alkylphenyl)- alpha -(4-chlorophenyl)-acetonitrile of the formula: <IMAGE> in which R represents a C1-3-alkyl group, in which a 2-nitro-4-chloroalkylbenzene of the formula: <IMAGE> in which R has the abovementioned meaning, is subjected to a condensation reaction with p-chlorobenzyl cyanide of the formula: <IMAGE> in an alcoholic medium in the presence of an alkali to give the compound 4-chlorophenyl- alpha -(2-chloro-4-hydroxy-imino-5-alkyl-2,5-cyclohexadiene- 1-ylidene)acetonitrile of the formula: <IMAGE> and this compound is reduced in-situ without isolation with an alkali metal sulphide or alkali metal hydrogen sulphide at a temperature up to the reflux point of the solvent.

Description

Process for the production of

(4-Amino-2-chloro-5-alkylphenyl) -α- (4-chlorophenyl) acetonitrile Process for the preparation of (4-amino-2-chloro-5-alkylphenyl) -α- (4-chlorophenyl) acetonitrile The invention relates to a new process for the preparation of (4-amino-2-chloro-5-alkylphenyl) -α- (4-chlorophenyl) acetonitriles of the formula wherein R is a C 1-3 alkyl group.

These anilines are a valuable intermediate, especially in the production of N- {5-chloro-4 - [(4-chlorophenyl) cyanomethyl] -2-methyl} -2-hydroxy-2,5-diiodobenzamide of the formula: represent.

The benzamide of the formula (II) has a strong antelmintic and Estricidal effect, especially against flukes (trematodes) and certain roundworms (Nematodes). In the same way it is against parasitic species in domestic animals Arthropods effective. Finally, it also has broad spectrum anti-parasitic effects with particular activity against the following ecto- and endoparasites in cattle and Sleep.

In cattle: nematodes tHaemonchus sp; Oesophagostomun sp; Bunostomun phlebotumun) Trematodes (Fasciola hepatica), Ioxodideos (Boophilus microplus), Dipteros (Hypoderma sp and Dermatobia hominis); In sheep: nematodes (Haemonchus sp and Oesophagostomun sp), Dipteros (Oestrus ovis) and trematodes (Fasciola hepatica); In horses: nematodes (Parascaris equorum, Strongylus vulgaris and Triodontophorus sp) and Dipteros (Gastrophilus intestinalis).

The benzamide can be administered traditionally or parenterally and works primarily on sheep and cattle, for example. To achieve an antelmintic and estricidal activity in sheep, the dose is 5 mg / kg body weight. To the The dose is also used to produce an antelmintic effect in cattle 5 mg / kg.

The production of such a connection is known (cf. for example DE-PS 26 10 837, AR-PS 285 931 and BE-PS 890119).

One can use one in the relevant process for implementation with the corresponding salicylic acid derivative usable structural homologue to formula (I) produce in two two-step ways: In the event that R stands for a methyl group stands, one way is a condensation of (p-chlosphenyl) acetonitol (III) with 2-nitro-4,5-dichlorotoluene (IV), being in p-position to the nitro group Halogen atom is introduced. Such condensation takes place according to the known one Makosza reaction (cf. "Tetrahedron", Vol. 30, 3723 (1974)) t or by a C-alkylation in the presence of a quaternary ammonium salt, e.g. B. of triethylbenzylammonium chloride (Tebac) in a two-phase system, and in a strongly alkaline environment and an inert solvent, e.g. B. toluene, benzene, etc.

This condensation consists in a substitution of a benzylic one Hydrogen, which because of its to the cyano group in the molecule of the compound (III) neighboring Ob-position is sufficiently acidic, which is an alkyl under the conditions represents the phase transfer reaction catalyzed by quaternary ammonium salts will.

A compound (4-nitro-2-chloro-5-methylphenyl) -CC- (4-chlorophenyl) acetonitrile of the formula (V) is obtained. .01 cl R1C III t Iv. HONs 50% CRN XSBAC CH ° 2> C1 v

In a second stage, the nitro compound is reduced to the corresponding aniline compound (I) with zinc in an acetic acid medium, with sodium dithionite, or in a catalytic manner using hydrogen in the presence of palladium or an Adams catalyst (Pt02.H20).

In its first stage, this process results in a product with very poor quality and low yield. This method is therefore not useful.

The other method where R is hydrogen is by condensation of arylacetonitrile, e.g. B. of phenylacetonitrile (VII) with an aromatic nitro compound, z. B. with nitrobenzene (VI), in which the para position to the nitro group is free.

Such condensation occurs in a methanolic potassium hydroxide solution carried out. The alkaline substance is said to be in a more than threefold molar Ratio, based on the reactants used, are used.

In the first stage, the compound r- (4-hydroxyimino-2,5-cyclohexadien-1-ylidene) phenylacetonitrile is obtained of formula (VIII).

This type of reaction was first described by R. Davis et al in the Journal of American Chemical Society 82, 2913 (1960).

sation During the cords of compounds (VI) and (VII) in In an alcoholic-alkaline environment, the reaction mixture suddenly becomes intense red color and a red precipitate begins in the alkaline reaction medium to form, which takes on a mustard-yellow color when acidified.

In the above article, spectroscopy (infrared spectrum and nuclear magnetic resonance spectrum), based on which one of this kind assigns the structure of a quinone oxime of substances.

However, one takes one to interpret this condensation reaction Mechanism according to which the aromatic nitro compound is in its free para position is subjected to nucleophilic attack by a benzyl cyanide anion, which is due to the highly acidic character of the benzylic hydrogen of this molecule will.

The phenyl-cyanomethylene-quinone oxime (VIII) is the end product that has been isolated by the authors named above.

To produce the aniline homologue of the compound (I), a reduction step is carried out and the compound (XI) is obtained.

The reduction can be carried out with various reducing agents be: (a) zinc powder in the presence of ammonium acetate (J. Jochims, MONTHShefte 94, 677 (1963); (b) iron powder and ammonium chloride (German Patent 2,610,837); (c) Tin chloride in concentrated hydrochloric acid (R. Bixler et col., Journal of Organic Chemistry, 23, 575 (1958)); (d) sodium in methanol and liquid ammonia (Kitano-hoki et col., In Tetrahedron Lett. 1965, 1059); (e) lithium aluminum hydride (J. Smith, Journal of Organic Chemistry, 17, 294 (1952)); (f) "Vitride" (NaAlH2 (OCH2CH20CH3) 2 (M. Cerny et col., Coll. Czech. Chem. Comm. 34, 1033 (1969); (g) catalytic hydrogenation in the presence of a noble metal (palladium and PtO2) (A. Dornow et col., Chem. Ber. 83, 189 (1950)); G. Utzinger et col., Helv. Chim. Acta, 37, 1885 (1954) Each of these Reducing agent has advantages, but also various disadvantages.

Some are inexpensive reagents, e.g. B. iron powder, zinc powder and tin chloride. The quality of the iron powder is essential for the success of the reduction extremely important.

The reaction cakes that you get with these compounds in the treatment the reaction mixture with an alkaline substance receives, hold large proportions End product back. The raw materials are very corrosive and destroy the Investments.

In the other case, when using metallic sodium in methanol, essential precautionary measures are required and appropriate facilities for handling of sodium and the destruction of its remains.

The use of ammonium hydride and lithium, as well as of "Vitride" requires working with a perfectly dry substance or an exhaustive one Isolation and drying of the quinone oxime. The solvents used for this reduction must meet the same requirement. Used with lithium aluminum hydride a very dangerous solvent, namely ethyl ether. In the case of nitrides the medium used is benzene or toluene, which is relatively easy to handle, as far as the solvent is concerned, but also a complete removal of Requires traces of moisture.

Furthermore, the destruction of excess reagent is very dangerous. Apart from this, it must be pointed out that aluminum hydride and lithium are pyrophoric are easy to come into contact with air due to the humidity of the environment and decompose in the presence of oxygen.

The catalytic hydrogenation requires expensive equipment and The techniques are very complicated when considering the manufacture and the recovery of the catalytic converter, as well as the risk of its poisoning and not selective reduction by attacking other groups. Furthermore must be on the increased Costs for a catalyst made from a precious metal should be noted.

It has now surprisingly been found that a reduction of Phenyl-cyanomethylene-quinonoxime carried out easily and without any noticeable disadvantages can be if the reducing agent used is sodium sulfide or sodium hydrogen sulfide used.

The process according to the invention for the preparation of the compound of the formula (I) therefore comprises the condensation of 2-nitro-4-chloro-alkylbenzene of the formula (X): in which R has the meaning given above, with p-chlorobenzyl cyanide of the formula (III) in an alcoholic medium: in the presence of alkali, the compound 4-chlorophenyl-α - (2-chloro-4-hydroxyimino-5-alkyl-2,5-cyclohexadien-1-ylidene) acetonitrile of the formula (IX) being obtained: and in situ reduction without isolation of the product with an alkali metal sulfide or hydrogen sulfide at a temperature up to reflux of the solvent.

An alcohol is preferably used as the solvent for the reaction Methanol, and one works in the presence of alkali, for. B. of potassium hydroxide.

After the first stage of condensation, namely the formation of the quinone oxime IX, the completion of which can be determined by viewing the reaction by thin layer chromatography observed, one finally adds the reducing agent dissolved in methanol-water, in the same reaction vessel.

After refluxing, the reaction is over after about three hours.

An added benefit of the process is that it doesn't it is necessary to isolate or dry the quinone oxime, as is the case with the other processes are the case, and likewise acidification with HCl, filtration, washing and drying are avoided, that is, procedural measures included in the Difficult and costly to develop.

In addition, the quinone oxime is extremely difficult to dry because it retains water even after several days of drying.

Essentially, the method according to the invention is such from Type of a "one-pot process", since the alcoholic and alkaline medium are in the first process stage is retained, and simple in the second stage the Adding reducing agent and increasing the reaction temperature to the reflux temperature, d. H. performs two very specific stages in a single procedural measure.

Another major benefit that the importance of the above unexpected development shows it is that sulfur compounds are not expensive, their handling is very simple and chemical decomposition is not necessary.

The following examples illustrate and illustrate the present invention certain particular considerations, but they should not be considered as limiting the scope of the invention.

Example 1 Preparation of (4-amino-2-chloro-5-methyl-phenyl) -4-chlorophenyl) -acetonitrile (I) 160 ml of methanol and 30.5 g of potassium hydroxide are placed in a one-liter bottle stir until completely dissolved. The temperature is about 50 "C. Cool to 300C and, with continued stirring, adds the following reactants: 2-nitro-4-chlorotoluene: 21.5 grams (0.125 moles) of p-chlorobenzyl cyanide: 20 grams (0.132 moles).

The solution takes on a chestnut-dark purple color. To An extremely viscous paste forms after 5 minutes.

The conditions are maintained and determined for 45 minutes the end of the reaction by thin layer chromatography. If the reaction still doesn't is completed, the same conditions are maintained for an additional 30 minutes.

At the end of the reaction, the 4-chlorophenyl - (2-chloro-4-hydroxyimino-5-methyl-2, 5-cyclohexadiene-1-ylidene) acetonitrile (IX) is formed.

The paste obtained is added immediately with stirring and at room temperature 40 ml of methanol and 14.5 g of sodium hydrogen sulfide, dissolved in 100 ml of water, are added.

The suspension slowly liquefies and clears during the Reaction to, with the formation of a yellow-orange precipitate, which is caused by a Temperature increase is accompanied.

The mixture is refluxed and the conditions are maintained while stirring upright for about 3 hours.

Finally, finish the reaction by thin layer chromatography established.

At the end of the reaction, the mixture is cooled to 100 ° C. and filtered.

For removing mother liquor and residues of sulfur compounds you wash with water.

Finally, it is washed with methanol (2 × 50 ml) and dried. Man receives 23.5 g of the product. Overall yield: 66.3%. Melting point: 148-150 °.

Example 2 The sodium hydrogen sulfide is replaced by an equivalent one Amount of sodium sulfide 9 H2O, and gets a similar result.

It goes without saying that the framework of the ore in accordance with the invention Process also includes the compounds of the formula (I) in which R is C2 - C Is 3-alkyl.

In addition, the invention is not limited to the details given, but various modifications are possible without leaving the scope of the present Invention to leave.

Claims (6)

Claims 1. Process for the preparation of (4-amino-2-chloro-5-alkylphenyl) (4-chlorophenyl) acetonitrile of the formula: wherein R stands for a C 1-3 alkyl group, characterized in that a 2-nitro-4-chloroalkylbenzene of the formula: where R has the meaning given, in an alcoholic medium in the presence of an alkali with p-chlorobenzyl cyanide of the formula: to the compound 4-chlorophenyluC- (2-chloro-4-hydroxyi mino-5-alkyl-2,5-cyclohexadiene-1-ylidene) acetonitrile of the formula: condensed and this reduced at a temperature up to the reflux temperature of the solvent in situ and without isolation with an alkali metal sulfide or hydrogen sulfide. 2. The method according to claim 1, characterized in that as Sodium sulfide or hydrogen sulfide reducing agent is used. 3. The method according to claim 1, characterized in that the Carries out reduction in alkaline methanol. 4. The method according to claim 1, characterized in that the Reduction without isolation of the quinone oxime Formula (IX) through Adding the reducing agent and increasing the reaction temperature to the reflux temperature of the solvent. 5. The method according to claim 1, characterized in that as Alkali potassium hydroxide used. 6. (4-Amino-2-chloro-5-alkylphenyl) - (4-chlorophenyl) acetonitrile.