DE2166185A1 - Cardio-active fluoro-substd benzylamines - Google Patents

Abstract

Cardio-active fluoro-substd. benzylamines. Cpds. for the treatment or prophylaxis of cardiac arrhythmia are of general formula (I) where n is 2-4; A is a 5-6 atom homocyclic or heterocyclic nucleus, opt. substd.; B is a 1-8C aliphatic or heterocyclic side chain, amino-substd. and linked to the benzene nucleus by 1 or more C atoms. Prefd. cpds. are of formula (II), where X and X' are H, alkyl, alkenyl, perfluoroalkyl, Ph, substd. phenyl, amino, alkylamino, dialkylamino, alkylsulphonamido, halogen, OH, alkoxy, alkylthio, SH, perfluoroalkylthio, alkylsulphonyl, perfluoroalkylsulphonyl, sulphamoyl, alkylsulphamoyl, dialkylsulphamoyl, n is 2 or 3; R2 and R3 are H, alkyl, alkenyl, aralkyl, alkynyl and may be linked together by an atom of N, O or S to form a 5 or 6 atom heterocycle; m is 1-4; A is Ph, a cycloaliphatic ring or a 5-6 atom heterocyclic ring or a heterocyclic ring partially or completely reduced.

Description

N-acylated fluoroalkylarylalkylamines and their preparation. The invention relates to N-acylated fluoroalkylarylalkylamines, which also have a homocyclic or heterocyclic ring. These compounds are pharmacologically active and can be used to treat and prevent cardiac arrhythmias. They are also Intermediates for the production of pharmacologically active arylalkylamines.

The compounds according to the invention have the general formula in which X and X 'are hydrogen atoms, alkyl groups with up to 6 carbon atoms, alkenyl groups with up to 6 carbon atoms, perfluoroalkyl groups with up to 4 carbon atoms, unsubstituted or substituted phenyl radicals, amino groups, alkylamino groups with up to LI carbon atoms, dialkylamino groups with up to 8 carbon atoms, Alkylsulfonylamino groups with up to 4 carbon atoms, halogen atoms (fluorine, chlorine, bromine or iodine), hydroxyl groups, alkoxy groups with up to 4 carbon atoms, perfluoroalkoxy groups with up to 4 carbon atoms, mercapto groups, alkyl mercapto groups with up to 4 carbon atoms, perfluoroalkyl mercapto groups with up to 4 carbon atoms, Alkylsulfonyl groups with up to 4 carbon atoms, perfluoroalkylsulfonyl groups with up to 4 carbon atoms, sulfamoyl groups, alkylsulfamoyl groups with up to 4 carbon atoms or dialkylsulfamoyl groups with up to 8 carbon atoms, n has the value 2 or 3, R1 is hydrogena tom or a lower alkyl group, m is an integer from 1 to 4 inclusive and A is a phenyl radical, a cycloaliphatic ring, a heterocyclic aromatic ring with 5 or 6 atoms or a partially or fully reduced heterocyclic ring.

Aminoalkylarylperfluoroalkanes of the general formula can be obtained from the compounds according to the invention produce in which n is an integer from 2 or 3, m is an integer from 1 to 4 inclusive, one or more of the methylene (CH2) hydrogen atoms can be substituted by a lower alkyl group with 1 to 4 carbon atoms, R2 and R3, which can be the same or different from one another, denote hydrogen atoms, alkyl groups (preferably with 1 to 6 carbon atoms), alkenyl or alkynyl groups or with the formation of a heterocyclic ring with 5 or 6 atoms, such as the imidazolinyl, piperidyl) pyrrolidinyl , Morpholinylw, thiomorpholinyl or lower alkylpiperazinyl radicals, grouped together or bonded to the aromatic ring or one of the methylene substituents that bind the aromatic ring to the amine radical, while A is an aryl radical, in particular a phenyl or substituted phenyl radical, a heterocyclic aromatic radical Means a remainder or a partially or completely reduced derivative thereof.

A particularly preferred group of compounds that can be prepared corresponds to the general formula or derivatives of these compounds in which one or more of the methylene (CH2) hydrogen atoms are substituted by a lower alkyl group having 1 to 4 carbon atoms, where R2 and R3 are hydrogen atoms, alkyl groups (preferably having 1 to 6 carbon atoms), alkenyl or alkynyl groups mean, but also via a nitrogen, oxygen or sulfur atom to a heterocyclic ring with 5 or 6 atoms (such as 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-thiomorpholinyl or 1-lower alkyl -4-piperazinyl residue) can be ammenlossen.

Examples of such compounds are 2- (2-phenyl-1,1,2,2-tetrafluoroethyl) benzylamine, cC-methyl-2- (2-phenyl-1,1,2,2-tetrafluoroethyl) -benzylamine,, oCDimethyl-4- (2-phenyl-1,1,2,2 tetrafluoroethyl) benzylamine, cC-methyl-4- (2-phenyl-1,1,2,2-tetrafluoroethyl) benzylamine, the corresponding secondary amines, such as the N-methyl-, N-ethyl-, N-propyl, N-allyl, N-propargyl, N-isopropyl, N-butyl, N-tert-butyl, N-amyl and N-acyl derivatives, and the corresponding N, N-disubstituted derivatives, in particular the N, N-dialkyl derivatives.

The above compounds have in the form of the free bases or their salts have valuable pharmacological properties. In particular, it was found that they have anti-arrhythmic activity. It was found that the dosage of the compounds according to the invention represented by the above general formula has a preventive effect against arrhythmia in animals in conditions under which animals usually develop arrhythmia 100% of the time.

It was also found that by administering the compounds according to the invention, an arrhythmia already present in the treated animal can be brought to a standstill and the heart returns to its normal rhythm. As anti-arrhythmic agents, these compounds can be used orally or parenterally presented will. The mixtures for administration can be used in a conventional manner the usual pharmaceutical carriers and vehicles as components non-toxic ones which can be used in the pharmaceutical preparations according to the invention Acid addition salts are salts that are formed by reacting an equivalent amount an amine compound of the above formula with one in the intended Form dose of pharmaceutically acceptable acid. Salts of the above compounds, the are suitable for the stated purpose, are the salts of the amines in question with Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, Isethionic acid, fumaric acid, acetic acid, propionic acid, lactic acid, gluconic acid, maleic acid, Succinic acid, tartaric acid etc. The salts of the compounds according to the invention are expediently generated in the manufacture of pharmaceutical preparations. The pharmacological Effect of the salts is considered to be the same as that of the chemically equivalent amount of the bases concerned.

The daily doses are based on the total body weight of the test animal and vary between 1.00 and 100.00 mg / kg. So is a unit dose for four times administration per day in dogs between 2.5 and 250 mg / 10 kg, and the total daily dose for the dog varies between about 10 and 1000 mg / 10 kg. For larger animals, appropriate doses based on body weight, applied. Suitable dosage forms for the administration of the compounds are tablets, Capsules (which can be composed for immediate release or long-term release), Syrups, elixirs, solutions intended for parenteral application and the like. The dosage forms preferably contain a multiple or more per unit Multiples of the desired dose unit in combination with the pharmaceutically acceptable, diluents or carriers necessary for the preparation of the unit dose.

The compounds of the above general formula can be prepared as follows: Flow diagram I. * This process stage can include further process stages for the production of the next higher homologue, in which the cyan substituent is hydrolyzed in the usual way to the corresponding carboxyl derivative, this is reduced with lithium aluminum hydride to the CH2OH derivative, and the latter group is completely converted into CH2X (X = halogen or sulfonyloxy) and this compound is then treated with cyanions.

In the above scheme, the symbols have the following meanings: R1 is a hydrogen atom, a lower alkyl group (preferably with 1 to 5 carbon atoms) or an amino-substituted lower alkyl group; R2 and R3 can be the same or different be and mean hydrogen atoms, alkyl groups (preferably with 1 to 6 carbon atoms), Aralkyl groups (preferably benzyl or phenethyl groups), alkenyl, alkynyl groups or can be with each other or with one of the methylene carbon atoms that make up the amine substituents and connects the phenyl ring, or by a nitrogen, oxygen or sulfur atom to a heterocyclic ring with 5 or 6 atoms (like the imidazolinyl, Piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl or lower alkylpiperazinyl radical) be connected; X and X 'are hydrogen, halogen atoms (chlorine or fluorine), alkyl radicals (preferably with 1 to 6 carbon atoms), alkoxy radicals (preferably with 1 to 5 carbon atoms), perfluoroalkyl radicals (e.g. the trifluoromethyl radical), alkyl mercapto radicals (preferably with 1 to 6 carbon atoms), alkylsulfonyl radicals (preferably with 1 to 6 carbon atoms) or dialkylsulfamoyl radicals (preferably with 2 to 8 Carbon atoms); Hal means a bromine or iodine atom; n is 2 or 3; m is an integer from 1 to 4 inclusive; Alk means an alkyl group (preferably-a lower alkyl group having 1 to 6 carbon atoms3; and A is an aromatic ring, like the phenyl ring, a cycloaliphatic ring, a heterocyclic aromatic ring with 5 or 6 atoms or a partial completely reduced heterocyclic ring, e.g. a pyridine, pyrimidine, thiazole, Thiophene, imidazole, oxazole ring or a partially or fully hydrogenated one Derivative of such a ring.

According to the method according to the invention, a di- or triketone compound is obtained I mit.Schulfeltetrafluorid to the corresponding diarylperfluoroalkyl compound, such as 2-bromo-α, α, α ', α'-tetrafluorhibonzyl or 1- (2-bromophenyl) -1,1,2,2, -3,3-hexafluoro-3-phenylpropane' implemented. This conversion to the perfluoro compound is preferably carried out at elevated levels Temperatures by mixing the di- or triketone with excess sulfur tetrafluoride and catalytic amounts of a Lewis acid such as hydrogen fluoride, boron trifluoride or similar.

The sulfur tetrafluoride used for the reaction is either before adding to the reaction mixture by shaking with a little mercury or by Purified addition of mercury immediately to the reaction mixture.

The amount of mercury used for this is not critical; preferably However, at least about 1 g of mercury is used per 100 g of sulfur tetrafluoride, in order to remove undesirable impurities such as sulfur chloride from the latter.

The sulfur tetrafluoride is preferably treated in the reaction mixture even by adding the mercury directly to the the sulfur tetrafluoride and the Di- or triketone-containing reaction mixture is added.

The temperature of the reaction mixture is not particularly important but is preferably kept between 50 and 2000 ° C. The perfluoro compound leaves easily from the reaction mixture by extracting with solvents such as benzene, Toluene, methylene chloride, chloroform or the like, and evaporating the solvent win in solid form.

The thus obtained. Phenylperfluoralkylbrombenzoi is made by reaction with a metal cyanide, such as copper (I) cyanide, and suitable anhydrous and hydroxyl group-free Solvents such as acetonitrile, dimethylformamide, quinoline or pyridine appropriately substituted benzonitrile converted. Preferably used as Quinoline solvent with a small amount of dimethylformamide. The temperature, in which this reaction is carried out is not critical, but is preferred in the range from 100 to 2000 C. The product can be easily processed in a conventional manner by removing the metal salts that precipitate from the reaction mixture, filtering, Evaporation of the solvent and possibly recrystallization gain.

The phenyl perfluoroalkylbenonitrile then becomes the corresponding Benzylamine, e.g. 2- (2-phenyl-1,1,2,2-tetrafluoroethyl) -or 4- (3-phenyl-1,1,2,2,3,3-hexafluoropropyl) -benzylamine, reduced. The reduction is readily accomplished by treating the benzonitrile compound with lithium aluminum hydride in the presence of an inert organic solvent, such as tetrahydrofuran, ether or others, usually together with lithium aluminum hydride solvent used. This reduction is preferably in the opposite of Aluminum chloride and an ether compatible with aluminum chloride as a solvent carried out. The temperature at which the reduction is carried out is not particularly crucial; however, it is preferable to work at room temperature, and a temperature range of 0 to 500 ° C is satisfactory. the so obtained benzylamine compound can be easily obtained by conventional methods.

To produce higher homologues of the benzylamine compound, the Phenylperfluoroalkylarylnitrile obtained as an intermediate by known methods converted into the desired compounds, for example, the intermediate Hydrolyze phenyl perfluoroalkylbenzonitrile to the corresponding benzoic acid. The acid is then converted to the corresponding benzyl alcohol with lithium aluminum hydride reduced, which is obtained by conventional methods and with hydrogen halide, such as aqueous hydrobromic acid, converted to the corresponding benzyl halide will. The product obtained in this way is cleaned by conventional methods and with Potassium cyanide implemented; this is the final stage of the conversion process Benzonitrile used as the starting material in the next higher homolog, namely the phenylperfluoroalkyl-phenylacetonitrile.

The corresponding N- (phenylperfluoroalkylbenzyl) -formamide (V) or a higher homologue of the same, in which R1 is a hydrogen atom, is indicated by Formylating the aralkylamine, e.g., the benzylamine compound (IV), among known ones Process conditions and using known reactants such as formic acid or their esters. This formamide derivative can then be used in conventional Way to be won. The N, N-dimethylamine (VI), in which the residues R2 and R3 are methyl groups can be easily obtained by reacting the primary amine compound (V) with formaldehyde and formic acid according to the well-known Eschweiler-Clarke modification of Leuckartschen Produce reaction. The N, N-dimethylamine is obtained in a known manner, The N-methylaraltylamine, e.g., N-methylbenzylamine, of formula (VII) wherein Alk denotes the methyl group, can either by reduction of the corresponding N- (ihenylperfluoroalkylbenzyl ) -formamids (V) or by monoentalkylation of the corresponding N, N-dimethylamine (VI), where R2 and R3 are methyl groups. The reduction of the jamamido methyl derivative takes place with lithium aluminum hydride among the above for the reduction of the corresponding Benzonitrile (III) described conditions. The dealkylation can also be used of the N, N-Di methylamine (VI) in a known manner by treatment with cyanogen bromide and subsequent hydrolysis of the intermediate cyanamide or by Reaction with a haloformic acid ester and hydrolysis of the intermediate product Perform resulting urethane. In both cases, the desired connection can be made win in a familiar way.

The lower N-alkylamines and the lower N, N-dialkylamines, the Compounds (VII) and (vi) correspond, are also from the corresponding primary amine (IV) prepared by analogous reactions. For example, this is how you set the primary Amine (IV) with a lower aliphatic acid halide or anhydride with 2 to 5 carbon atoms, see B. with acetyl chloride, acetic anhydride, propionic acid chloride, Butyric acid chloride or valeric acid chloride, to that of the formula (v) | corresponding N-alkanoyl amide, e.g. N-acetyl, N-propionyl, N-butyryl or N-valeryl amide, around. The amide thus obtained is as above for the corresponding benzonitrile compound (III), with lithium aluminum hydride, to the corresponding lower N-alkylbenzylamine precursor (VI) reduced.

The secondary amine compounds (VIII) prepared in this way are the lower N-alkyl derivatives of 2- (phenylperfluoroaltyl) -benzylamines, such as e.g. the N-ethyl, N-propyl, N-butyl or N-amyl derivatives. The corresponding tertiary Amines (VI), namely the lower N, N-dialkyl derivatives, are derived from the secondary Amines made by using that used to make the secondary amines Procedure repeated.

For example, the amides of the secondary amines are produced and reduced they with lithium aluminum hydride to the corresponding tertiary amines, e.g. the corresponding N, N-diethyl, N-ethyl-N-methyl-, N, N-lipropyl-, N, N-dibutyl or N, -diamyl derivatives of substituted or unsubstituted phenylperfluoroalkylbenzylamine.

According to another process for the preparation of the compounds of general formula (VI), wherein denotes the 1-pyrrolidinyul-, 1-piperidyl-, 4-lorpholinyl-, 4-thiomorcholinyl or 1-lower alkyl-4-piperazinyl radical, the primary amine (IV-) is treated with an α, α-dihalo compound, such as T. etramethylene bromide, pentamethylene bromide, ß, ß'-dichlorodiethyl ether, ß, ß'-dichlorodiethyl sulfide or an N-alkyl-ß, ß'-dichlorodiethylamine, condensed.

According to another method for producing the primary, secondary and tertiary benzylamine products according to the invention is a bromine or iodine substituted one Diaryl perfluoroalkyl compound (II) is converted according to the following procedure.

Flow diagram II Another process for the production of primary, secondary or tertiary benzylamine products of the general formulas (IV), (VI) or (VII) In the above formulas, Hal, n, R2, R3, X and X 'have the meanings given earlier.

In this sense, the bromine or iodine substituted liaryl perfluoroalkyl compound (ii) under anhydrous conditions with magnesium to give the Grignard's reagent (IIA) unset, which in turn is caused by the accumulation of carbon dioxide and subsequent acid hydrolysis is converted into the corresponding carboxylic acid (IIB) by the Bromine or iodine substituent is replaced by a carboxyl group. This acid will then reduced with lithium aluminum hydride to the corresponding bensyl alcohol (IIC), which is obtained in a conventional way and by reaction with an acid halide, such as thionyl chloride, thionyl bromide or the like, into the corresponding benzyl halide compound (IID) is transferred, the corresponding in the reaction with ammonia or an amine primary, secondary or tertiary amine (IIE) provides, which in a conventional manner is won. In this way, in addition to the N-alkyl- and N, N-dialkyl derivatives of substituted and unsubstituted phenyl perfluoroalkylbenzylamines or higher homologues of the same the corresponding compounds in which the Amino nitrogen atom part of a heterocyclic ring, such as the piperidyl, Pyrrolidinyl, morpholinyl, thiomorpholinyl or 1-nn ed.alkyl-4-piperazinyl ring, forms.

Another method is to omit the benzyl halide (IID) alkylated tetrafluorobibenzyl compounds, e.g. from 2,3-dimethyl-α, α, α ', α'-tetrafluorobibenzyl, by adding the alkyl substituent in the appropriate molar amount an N-bromimide such as N-bromosuccinic acid imide, selectively brominated. The aromatic one Ring can have one or more alkyl substituents, and if you have the right one molar amount of IT-bromamide will be one or more alkyl substituents substituted by bromine, and the desired benzyl bromide compound is formed. The bromine substituent becomes then by the desired amine function and this can be done by various known methods of converting Benzyl bromides into the corresponding benzylamines or substituted benzylamines take place. For example, the benzyl bromide compound is mixed with hexamethylenetetramine to the corresponding Hexaminiumbromidverbindungen, which in turn in the implementation converts into the desired benzylamine with concentrated hydrochloric acid, but you can the benzyl bromide compound also with potassium phthalimide into the corresponding phthalimide derivative transfer, which then by acid hydrolysis or reaction with hydrazine in the corresponding benzylamine passes.

The perfluoroalkylaralkylamines in which the amino nitrogen atom is attached a branched aliphatic side chain is attached, can easily be passed through Implementation of the appropriately substituted nitrile III with a lower alkyl magnesium halide, like methylmagnesium bromide, to an imine as an intermediate and reduction of the imine with lithium aluminum hydride to the corresponding branched chain primary amine produce in which the alkyl substituent is directly attached to the amino substituent adjacent carbon atom is bonded. If, for example, 2- (α, α, ß, ß-tetrafluorophenethyl) -benzoitriln with methylmagnesium bromide to form a ketimine and this with lithium aluminum hydride reduced, a-methyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine is obtained. If the benzonitrile used as the starting material is replaced by the homologous 2- (α, α, ß, ß-tetrafluorophenethyl) phenylacetonitrile, are those after the formation of the ketimine with the corresponding Grignard's reagent and the reduction with lithium aluminum hydride products obtained the o: -Methyl-, α-ethyl and α-propyl derivatives of 2- (α, α, ß, ß-tetrafluorophenethyl) -phenethylamine.

Another method for the preparation of such cc-alkylsub substituted Benzylamine becomes the benzonitrile III by reaction with a lower alkyl Grignar's reagent, such as methyl, ethyl, propyl or butyl magnesium bromide, converted into the Grignard adduct, which is then converted into the 4 '- (K, «, B, β-tetrafluorophenethyl) acetophenone compound is converted. The acetophenone compound is then converted into the corresponding oxime in a conventional manner, which the latter by catalytic hydrogenation into the desired cc-alkyl-substituted benzylamine compound is converted.

In addition to the α-alkyl-2- (α, α, ß, ß-tetrafluorophenethyl) -penenthylamine compounds, the corresponding α, α, -disubstituted, ie dialkyl compounds from a bromo- or iodo-substituted diarylperfluoroalkyl compound of the above general formula II, in the Hal bromine or iodine means to be produced. The compounds prepared by the following processes are, for example, α, α-dimethyl, α, α-diethyl, α, α-dipropyl, α-methyl-α-ethyl, α-methyl-α-propyl, α- Ethyl-α-propyl-, cc-methyl-cc-butyl- and α-methyl-α-isopropyl- (α, α, ß, ß-tetrafluorophenethyl) benzylamine. The corresponding N-alkyl or N, N-dialkyl derivatives, for example the methyl, N-ethyl, N-propyl, N-butyl, N, N-dimethyl, N, N-diethyl, N, N- Dipropyl, N-methyl-N-ethyl, N-methyl-N-propyl, N-methyl-N-butyl or N-ethyl-N-propyl derivatives are prepared using the same methods as those on the previous pages for the conversion of the benzylamine into the corresponding M-alkyl or N, N-dialkyl derivatives have been described.

In the process described below for the preparation of the α, α, -dialkyl-substituted Benzylamine compounds become one in the No. 3 or 4 position bromo-substituted Diaryl perfluoroalkyl compound under anhydrous conditions with magnesium converted into Grignard's reagent IIA1, which is then mixed with an aliphatic ketone, such as acetone, diethyl ketone, di-n-propyl ketone, or a mixed ketone such as methyl ethyl ketone, Methyl propyl ketone, methyl butyl ketone, methyl propyl ketone or methyl isopropyl ketone, implemented and converted into the corresponding benzyl alcohol IIA2 by hydrolysis is, with the alkyl substituent on the Oarbinolkohienstoffatom of the benzyl alcohol are bound. -A different method is used to make the 3'- or 4'-perfluoroalkylphenyl-substituted Acetophenone reacted with a lower alkyl Grignard reagent, and after Hydrolysis then gives a, «- dialkylbenzyl alcohol. One can also use the -Grignardian Reagent IIA1 with carbon dioxide and the product to the corresponding benzoic acid hydrolyze. This acid is esterified and combined with a Grignard lower alkyl reagent implemented, whereby the cc, cc-dialkylbenzyl alcohol is obtained after the hydrolysis. This tertiary alcohol is then after the Ritter's reaction with alkali metal cyanide in sulfuric acid or nethanesulfonic acid converted into the corresponding benzylformamide compound IIA3, which is the desired α, α-dialkyl-substituted in acid hydrolysis Benzylamine compound supplies.

The di- and used as starting materials in the above processes Triketones can be easily made from known substances. This is how you get the Diaryldiketo compounds easily by first substituting the appropriately Bromobenzonitrile with a benzylmagnesium halide to give the corresponding bromophenylbenzylketimine converts and this under acidic conditions to the bromine-substituted acetophenone compound hydrolyzed.

The diaryldiketo compounds can also be prepared by one first the appropriately substituted benzonitrile or a nitrile one accordingly substituted heterocyclic compound with a benzyl magnesium halide which an additional bromine substituent on the phenyl ring des Benzyl magnesium halide is bound to the corresponding bromophenylbenzyl ketimine or the corresponding Heterocyclic Broniphenylketimin converts and this under acidic conditions hydrolyzed to the phenylacetophenone or the heterocyclic phenacyl compound. As already mentioned, the heterocyclic part of the Mole'ruls has a heterocyclic one aromatic ring with 5 or 6 atoms, namely a pyrimidine, thiazole, shiophene, Imidazole or oxazole ring.

The bromophenylacetophenone or heterocyclic bromophenacyl compound thus obtained then becomes bromine-substituted with a mild oxidizing agent such as selenous acid Benzil compound implemented. The oxidation is carried out in an aqueous medium, which contains a solvent for the bromophenylacetophenone. Preferably this is Solvent at least partially miscible with water. Typical examples of such Solvents are dioxane, acetic acid and the lower aliphatic alcohols. the The temperature at which this reaction is carried out is not critical; preferably one works, however, at elevated temperatures in the range of about 50 to 1500 C. The desired product can be easily obtained by known methods such as extraction with liquids immiscible with water. Solvents such as benzene, Xylene, toluene and the like are preferred.

The conversion described above is in the Pliess diagram below shown.

Flow diagram III Production of the initial diketones In the above formulas, Hal, X and X 'have the meanings given earlier.

The corresponding diarylpropane triones likewise encompassed by the general formula (I) of flow diagram I are produced according to the invention according to the following flow diagram: Flow diagram IV Production of the starting triketones Flowchart IV (continued) Preparation of the starting triketones Herein the symbols Hal, Alk, X and X 'have the above meanings.

In this sense, an appropriately substituted benzene becomes aldehyde with a bromo- or iodine-substituted acetophenone in the presence of an acidic or alkaline condensing agent condensed, with a first intermediate product substituted benzalacetophenone (A) is formed, which is isolated by conventional methods and in a suitable solvent with an equimolar amount of bromine to the corresponding one Benzalacetophenone dibromide (B) is reacted, which is isolated in a known manner will. The dibromide is then mixed with a dash of alkali alcoholate, such as sodium methylate, in a lower alkylenol ether of the corresponding dibenzoylmethane compound (C) convicted. The enol ether then becomes the corresponding one under acidic conditions Hydrolyzed dibenzoylmethane compound (D). The dibenzoyimethane compound is with at least 2 molar equivalents of bromine to the corresponding dibenzoyldibroinethane compound (E) implemented. The dibromo compound one leaves with sodium acetate and glacial acetic acid react to replace the bromine substituents with acetoxy substituents, and the compound thus obtained becomes the desired diarylpropantrione monohydrate compound with water (P) hydrolyzed, which in turn by heating in a vacuum with elimination of water is converted into the desired propanetrione, which is used in the preparation of the perfluoroalkyl compounds (I) according to the invention is used as a starting material.

If the starting material used benzaldehyde compound by a heterocyclic aldehyde, such as thiophene-2-aldehyde, is replaced, is obtained as the product a 1-aryl-3-heterocycl. propanetrione compound The used as starting materials 2-, - or 4-bromobenzonitriles or heterocyclic nitriles, the additional substituents X in the aromatic or heteroaromatic ring are either known Compounds or can be made from the corresponding benzoic acids or heterocyclic acids Carboxylic acids by converting the acid into the corresponding amide and splitting off water can be prepared from the amide to form the desired nitrile. The substituted one Benzylmag neutrium halide can also be easily prepared by known synthetic methods from the corresponding benzyl halide.

B e i s p i e-) 1 2'-bromo-2-henvlacetonhenone A solution of 12.0 g (0.066 mol) of 2-bromobenzonitrile in 80 ml of absolute ether is stirred and under Nitrogen was added dropwise to a solution of benzyl magnesium chloride, which consists of 0.42 g (0.264 g atom) of magnesium turnings and 33.42 g (0.264 mol) of benzyl chloride in 140 ml of absolute Ether has been produced.

The mixture is stirred at room temperature for 7 hours and overnight ditched. After cooling in an ice bath, the adduct is made by adding dropwise 100 ml of 0.5 molar citric acid hydrolyzed. The organic phase is separated off and the aqueous phase extracted several times with cold benzene. the Combined organic layers are ice cold in several portions with 100 ml Extracted 6N hydrochloric acid. After cooling the combined acidic extracts for several hours The precipitate of 2-bromophenylbenzylketimine hydrochloride is collected in an ice bath and washed with 15 percent ethanol in ether and then with absolute ether. After brief air drying, the salt becomes a cold mixture of methanol and ether recrystallized; F = 176-181 ° E.

The ketimine hydrochloride is suspended in 25 ml of 3N hydrochloric acid Heated for 1 1/2 hours on the steam bath. The product separates out as an oil and is extracted with benzene. After evaporating the washed and dried Benzene extract leaves a yellow oil; o = = nD analysis Calculated for 014H113r0: C = 61.11%; H = 4.03%; Br = 29.04 fa; found: o = 61.17; H = 3.97%; Br = 28.99%.

Example 2 2-erombenzil 5.2 g (0.0189 mol) 2'-bromo-2-phenylacetophenone, 2.68 g (0.0208 mol) of selenious acid, 15 ml of p-dioxane and 3.6 ml of water are used for 18 hours stirred at reflux temperature. The supernatant two-phase solution is drawn off and the remaining selenium precipitate washed with benzene. The one with the washing liquids combined solution is concentrated to a small volume under reduced pressure and the residue is divided between benzene and water. After the washed and dried benzene extract remains under reduced pressure a yellow oily product.

A sample is converted into the crystalline derivative 2-phenyl-3- (2-bromophenyl ) -quinoxaline. 0.58 g (0.002 mol) 2-bromobenzil and 0.24 g (0.0022 ol) o-Phenylenediamine is refluxed in 10 ml of absolute ethanol for 3 hours heated. After evaporation of the solvent under reduced pressure and recrystallization the residue from 95 percent ethanol gives a crystalline product; F = 131-132.5 ° C. An analysis sample melts after repeated recrystallization from 95 percent ethanol at 133-134.5 ° C.

Analysis calculated for C20H13BrN2: C = 66.51%; H = 3.63%; N = 7.76%; found: C = 66.45%, H = 3.55%, N = 7.63%.

Example 3 2-Bromo-α, α, α ', α'-tetrafluorobibenzyl 2.6 g (0.009 mol) of 2-bromobenzil together with 33 g of sulfur tetrafluoride, 2 g of mercury and a trace of hydrogen fluoride in a stainless autoclave 30 Minutes at room temperature, 2 hours at 100 ° C, 2 hours at 120 ° C and 6 hours shaken at 140 ° C. After cooling and opening the autoclave to the atmosphere the mixture is then dissolved in benzene, separated from the mercury and replaced with diatomaceous earth filtered. After evaporating the benzene from the filtrate under reduced pressure What remains is a brown solid substance as the product. By sublimation at 85-95 ° C and 0.1 mm Hg white crystals are obtained; F = 54-55 ° C. A test sample is made sublimated again.

Analysis Calculated for C14H9BrF4: C = 50.49%; H = 2.72%; Br = 24.00%; found: a = 50.87; H = 2.94%; Br = 23; 33.

Example 4 2- (α, α, β, β-tetrafluorophenethyl) benzonitrile A mixture of 3.33 g (0.01 mol) of 2-bromo-α, α, α ', α'-tetrafluorobibenzyl, 2.70 g of copper (i) cyanide, 30 ml of dry quinoline and 3 ml of dry dimethylformamide is stirred for 30 hours. Maintained reflux temperature. After cooling and diluting with ether, the precipitate is filtered off and washed with ether. After the solvents have evaporated from the filtrate, it is left behind under reduced pressure the product is an oily brown solid. The purification is carried out by column chromatography of 150 g of silicon dioxide, and the product 'is with a mixture of 3 parts of benzene and 1 part of hexane eluted. Those factions. those in thin layer chromatography on silica will give a spot with Rf = 0.7 when developed with benzene united1 After evaporation of the solvents remain behind under reduced pressure white crystals; F = 84-86 ° C. An analytical sample sublimed at 55 ° C and 0.05 mm Hg has a melting point of 85-86 ° C.

Analysis Calculated for C15H9F4N: C = 64.52%; H = 3.25%; N = 5.02 %; found: C = 65.50%; H = 3.04%; N = 4.52%.

Example 5 α, ß, ß-Tetrafluorophenethyl) benzylamine 250 mg (0.0066 Moles) lithium aluminum hydride are weighed out under nitrogen, in a dry, Transferred the reaction flask flushed with nitrogen and immersed in 15 ml of absolute ether suspended. For this purpose, a solution of 880 mg (0.0066 Nol) aluminum chloride in 15 ml of absolute ether were added dropwise. The mixture, which contains a white precipitate, is stirred for 5 minutes at room temperature and then with a solution dropwise of 0.942 g (0.00338 Ilol) 2- (α, α, ß, ß-tetrafluorophenethyl) benzonitrile added to 30 ml of absolute ether. The mixture will be 18 hours stirred under nitrogen at room temperature.

The hydrolysis is carried out by adding 4 ml of water dropwise. After decanting the ether layer and washing the gelatinous precipitate twice with boiling The precipitate is dissolved in 20 ml of 40 percent aqueous sodium hydroxide solution and 200 ether ml of water suspended. The mixture is repeated several times with a mixture of the same Part of benzene and ether extracted.

After evaporation of the solvent under reduced pressure the washed and dried organic extract leaves the product as solid residue; F = 54-56 ° C. A sample is used for analysis by sublimation purified at 47 ° C and 0.05 mm Hg; F = 55-57 ° C.

Analysis calculated for 015H13F4N: C = 63.57%; H = 4.62; N = 4.94 %; found: C = 63.93%; R = 4.54%; N = 4.94 0.

The base can be converted into the hydrochloride by adding a Solution in ethanol with a small excess of ethanolic hydrogen chloride offset. When diluted with ether, the hydrochloride precipitates; F = 244-247 ° C. Avg repeated recrystallization from mixtures of ethanol and ether and from isopropyl alcohol a purified material is obtained; F = 253-254 ° C.

Analysis Calculated for C15H13F4N.HCl: C = 56.35%; H = 4.41%; N = 4.38%; found: C = 56.53; II = 4.15%; N = 4.45.

The lactate is obtained by adding a solution of 2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine in ethanol with a small excess of 85 to 90 percent lactic acid.

When diluted with ether, the lactate precipitates; F = 144-146 ° .C at Recrystallization from a mixture of isopropyl alcohol and ether remains the melting point unchanged.

Analysis Calculated for C15H13F4N.C3H6O3: C = 57.90%; H = 5.13% ; found: C = 58.06%; H = 4.88%.

B e i 5 p i e 1 6 N-methyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine 1.4 g (0.005 Mö1) 2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine become stirred in 100 ml of ethyl formate for 20 hours at reflux temperature. By Evaporate the solution to dryness and stir the solid residue with something Petroleum ether is obtained N- [2- (α, α, ß, ß-tetrafluorophenethnyl) benzyl] formamide; P = 61-75 ° C.

290 mg (0.0077 mol) of lithium aluminum hydride are under nitrogen weighed, transferred to a dry, nitrogen purged reaction flask and suspended in 10 ml of absolute ether. A solution of 1.2 g (0.00386 Mol) N- [2- (α, α, ß, ß-tetrafluorophenethyl) benzyl] formamide in 25 ml of absolute Ether and the mixture is stirred for 18 hours at reflux temperature. After the addition the mixture is cooled by absolute ether in an ice bath, and the hydrolysis by successive Add dropwise 0.3 ml of water, 0.2 ml of 20 percent aqueous sodium hydroxide solution and 0.6 ml of water carried out. The granular precipitate is filtered off and washed with ether.

Remains on evaporation of the ether filtrate under reduced pressure the oily base as a residue. The base is made by adding a small excess Ethanolic hydrogen chloride converted into a solution in ethanol in the hydrochloride. The hydrochloride precipitates and becomes after recrystallization from absolute ethanol Obtained in the form of white crystals; 1? = 251-253 ° C. One by recrystallization Analysis sample obtained from absolute ethanol and from a mixture of methanol and ether melts at 252-253 ° C.

Analysis Calculated for C16H15N.HCl: C = 57.58%; H = 4.83%; N = 4.20%; found: a = 57.86%; H = 4.68%; N = 4.41 74.

Example 7 N, N-Dimethyl-2- (α, α, β, β-tetrafluorophenethyl) benzylamine A solution of 2.2 g of (0.006 Itol) 2- (α, α, ß, ß-tetrafluorophenethyl) benzyiamine (+) -lactate in 3 ml of 88 percent formic acid is mixed with 1 g (0.013 mol) of 37 percent Formaldehyde was added and the mixture was heated on the steam bath for 18 hours while stirring. After adding 1 ml of concentrated hydrochloric acid, the solution is reduced under reduced pressure Pressure evaporated to dryness. The remaining syrup is dissolved in 25 ml of water and made the solution strongly alkaline with 40 percent aqueous sodium hydroxide solution. The base is extracted with benzene. When evaporating the washed and dried Benzene extract under reduced pressure, the product remains as an oily residue. The base is converted into the hydrochloride by adding a solution of the same in Isopropyl alcohol with a slight excess of 8.2 normal hydrogen chloride in Ethanol added. The hydrochloride precipitates in the form of white crystals; F = 190 = 192 ° c. When recrystallizing from isopropyl alcohol, the melting point remains unchanged.

Analysis Calculated for C17H17F4N.HCl: C = 58.71%; H = 5.22%; N = 4.03%; Cl = 10.19%; found: C = 59.12 7'o; H = 5.22 5§; N = 3.83; Cl = 10.10 %.

3 e i s p i e 1 e 8 to 66 X dialkyl-2-g- (pnenyl-t, 1,2,2-tetrafluoro) -äthyz7-benzylamine The following products are made using the appropriate starting materials manufactured: Flow example diagram, play formula A n X X '8 I Phenyl 2 H chlorine 9 "" "H fluorine 10 lt u u H methyl 11" "" H tert-butyl 12 "" "H methoxy 13 "" "H Ethoxy 14" "" H Trifluoromethyl 15 "" "H Methylsulfonyl 16" "" H Methylmercapto 17 "" "H Dimethylsulfamoyl 18" lt lt methyl methyl 19 "" "chlorine Methyl 20 "" "Chlorine Dimethylsulfamoyl 21" "" Chlorine Chlorine 22 II "" H Chlorine 23 "" "H Fluor 24" "" H Methyl 25 "lt lt tert-butyl 26" "" H Methoxy 27 "" "H Ethoxy 28 lt lt lt H Trifluoromethyl 29" "" H Methylsulfonyl 30 "" "H Methylmercapto 31 "" "H Dimethylsulfamoyl 32 lt lt lt methyl methyl 33" "" chlorine methyl 34 "lt lt chlorine dimethylsulfamoyl 35" "" chlorine chlorine 36 III "" H chlorine 37 u lt lt H fluorine 38 "lt lt H methyl 39" "" H tert-butyl Flowing diagram, game Formula A n X X '40 III Phenyl 2 H Methoxy 41 "" "H Ethoxy 42 n "" H Trifluoromethyl 43 "" "H Methylsulfonyl 44" "" H Methylmercapto 45 "" "H dimethylsulfamoyl 46" "" methyl methyl 47 n "lt chlorine methyl 48" n lt chlorine Dimethylsulfamoyl 49 "" "Chlorine Chlorine 50 IV" "H Chlorine 51 n n lt H Fluorine 52 n n lt E methyl 53 "" "H tert-butyl 54" "" H methoxy 55 "" "H ethoxy 56" " "H Trifluoromethyl 57" "" H Methylsulfonyl 58 "" "H Methylmercapto 59" "" H dimethylsulfamoyl 60 n "lt methyl methyl 61 1 lt n" chlorine methyl 62 "" "chlorine Dimethylsulfamoyl 63 n n lt chlorine chlorine 64 VI "" derivatives of all compounds of the general formula IV, in which R2 and R3 are methyl, ethyl, propyl, butyl or Are amyl residues.

65 VII Phenyl 2 derivatives of the compounds of the general formula IV, in which Alk is a methyl, ethyl, propyl, butyl or amyl group.

Flow example diagram, play formula A n X X '66 IIE Phenyl 2 derivatives of the compounds of the general formula IV in which N R2 denotes the 1-piperi-R3 dyl-, 1-pyrrolidinyl-.

4-thiomorpholinyl, 4-morpholinyl or a 1-lower alky1-4-piperazinyl radical and Alk is a methyl, ethyl, propyl, butyl or amyl radical.

3 e i 5 p i e 1 67 N, N-Dialkyl-2- [2- (heterocyclic-1,1,2,2-tetrafluoro) -ethyl] -benzylamines Following the procedures of Examples 8 to 66 with appropriate amounts of the appropriate Carries out starting materials, but the substituent A pyridine, pyrimidine, thiazole, Is thiophene, imidazole or oxazole, the corresponding products are obtained.

3 e i 8 p i e 1 68 α, ß, ß-tetrafluorophenethyl) benzoic acid In a dry device kept under nitrogen gives 40 mg (0.00165 g-atom) Magnesium shavings in 0.5 ml tetrahydrofuran, in which there is an iodine crystal, suspended. A solution of 0.5 g (0.0015 mol) of 2-bromo = α, α, α ', α'-Te'-trafluorobibenzyl in 1.5 ml of tetrahydrofuran and a solution of 0.3 g of ethylene bromide in 4 drops of tetrahydrofuran are alternately added dropwise until the reaction starts. Then the mixture heated under reflux and the remaining solution of the 2-bromo-α, α, α ', α'-tetrafluorobibenzyl added. The reflux cooler is heated further until the magnesium is consumed. The mixture is then cooled in ice and diluted with 3 ml of tetrahydrofuran. Carbon dioxide is initially about 1 hour passed the surface while that Mixture is stirred, and then passed through the solution for 3 minutes. After a The mixture is left in the cold for a further hour for 16 hours at room temperature stand.

Most of the solvent is reduced under reduced pressure 460 C evaporated and the residue dissolved in benzene. The ice-cold solution is added with water and dilute hydrochloric acid, the organic phase is separated off and washed with water and evaporate them to dryness under reduced pressure. The oily residue is stirred with sodium hydroxide solution and the mixture is centrifuged. The clear protruding alkaline solution is decanted, acidified with 6N hydrochloric acid and the solid product extracted with benzene. After evaporation of the washed benzene extract and recrystallization the solid residue from hexane gives white crystals; P = 130132 ° C. A analytical sample melts after recrystallization from cyclohexane and sublimation at 1000 C and 0.2 mm Hg at 131-132 ° C.

Analysis Calculated for C15H10F4O2: C = 60.36 7'o; H = 3.38% o; found: C = 60.45; H = 3.48%.

B e i s p i e 1 69 α, ß, ß, γγ-hexafluorophenylpropyl) benzylamine A. A round bottom flask fitted with a paddle stirrer is charged with 19.3 g (0.482 mol) sodium hydroxide, 134.5 grams of water, 68.8 grams of 95 percent ethanol, and 45.4 grams (0.38 moles) of acetophenone loaded. The solution is stirred vigorously and cooled to temperatures in an ice bath held between 15 and 300 C. Then 69.89 g (0.378 mol) are used in one shot 2-bromobenzaldehyde and the mixture is stirred vigorously for several hours. After standing overnight at room temperature, the mixture is diluted with 300 ml of ether. The ether phase is separated and washed with water until the wash water against litmus paper neutral reacted. After drying the ethereal solution over magnesium sulfate and evaporation of the In ether, 103.8 g of 2-bromobenzalacetophenone are obtained as a yellow oil.

3. 103.8 g (0.37 mol) of 2-bromobenzalacctophenes are dissolved in 226 ml of carbon tetrachloride solved. The solution is cooled in an ice bath while stirring. Over the course of 0.5 hours 60.50 g (Q, 38 mol) of bromine are added dropwise and the mixture is then stirred a further half a hour. The crystalline product is filtered off with hot absolute ethanol washed and dried. 87.7 g of 2-bromobenzalacetophenone dibromide are obtained.

C. 87.7 g (0.196 moles) of 2-bromobenzalacetophenone dibromide are in a with stirrer, dropping funnel and with a drying tube equipped with a calcium chloride Reflux condenser equipped round bottom flask with stirring with 100 ml dry methanol offset. A solution of 9.01 g (0.392 mol) of sodium in 95 is then quickly added ml of absolute methanol and the mixture is heated to reflux temperature for 1 hour. After cooling, the mixture becomes neutral with about 0.5 ml. Concentrated hydrochloric acid made and diluted with 65 mm of water. Crystallization occurs when the mixture is stirred instead of. The product is filtered off, washed with water and absolute methanol and finally recrystallized from methanol. 35.90 g of 3- (2-bromophenyl) -3-methoxy-1-phenylpropen-1-one are obtained.

D. A mixture of 19.34 g of 3- (2-: 3romophenyl) -3-methoxy-1-phenylpropen-1-one, 200 ml of absolute methanol and 20 ml of 6N hydrochloric acid are refluxed for 1.5 hours touched.

Then the bulk of the ethanol is put on a rotating evaporator evaporated at 600 C. The residue is diluted with 500 ml of water and twice extracted with 200 ml of benzene each time.

The benzene extracts are combined, with water, with saturated sodium bicarbonate solution and then washed again with water and dried over magnesium sulfate. By Filtration and evaporation of the benzene gives 19.19 g of (2-bromobenzoyl) benzoylmethane.

E. One with dropping funnel, thermometer, stirrer, gas inlet tube The round bottom flask equipped with a gas outlet tube is filled with 15.35 g (0.0615 mol) of (2-bromobenzoyl) benzoylmethane and charged 5 ml of chloroform. The solution is cooled to 0 to 150 C in an ice bath, and in the course of 30 minutes a solution of 21.7 g (0.135 mol) of bromine in 55 ml of chloroform added. This creates a stream of air over the surface of the solution passed to drive off the hydrogen bromide formed as a by-product. To When the addition is complete, the solution is stirred for a further 15 minutes, and then the chloroform evaporated on a rotating evaporator at temperatures of 25 to 400 C.

The oily residue is treated with a hot solution of 11.2 g (0.136 Mol) freshly melted sodium acetate in 55 ml of glacial acetic acid. The solution will be stirred with the magnetic stirrer and kept at reflux temperature for 2 hours. then most of the acetic acid is evaporated in the rotating evaporator. The residue is dissolved in ether and the ether phase washed five times with 250 ml of water and dried a magnesium sulfate. After evaporation of the ether one receives one bright orange, viscous syrup that is below 0.5 mm Hg at 170-195 ° C distilled. This distillate becomes 1- (2-bromophenyl) -3-phenylpropane-1,2,3-trione by redistillation won; Yield 8.31 g; KP0.3mm x 174-177 ° C.

Analysis Calculated for C15H9Br03: C = 56.81%; H = 2.86 74; found: C = 56.63%; H = 3.02%.

F. A mixture of 8.31 g (0.0262 moles) 1- (2-bromophenyl) -3-phenylpropane-1,2,3-trione, 112 g of sulfur tetrafluoride, 1 g of mercury and 10 ml of hydrogen fluoride is in one Stainless steel bomb 2 hours at 100 ° C, 2 hours at 120 ° C and 6 hours heated to 140 ° C. After cooling, the contents of the bomb are dissolved in hexane and the Solution filtered. To evaporation of the hexane from the filtrate a light brown oil is obtained. The fractional distillation of the oil gives 4.64 g of 2- (α, α, ß, ß, γ, γ-hexafluorophenylpropyl) bromobenzene ; KP0.05 mm = 83-87 ° C.

Analjrs e Calculated for C15H9BrF6: C = 47.02%; H = 2.37 5s; F = 29.75 %; Found: 0'- 46.94 H H = 2.67 C%; F = 29.52%.

G. A mixture of 4.64 g (0.0121 mol) 2- (α, α, ß, ß γ, γ-hexafluorophenylpropyl) bromobenzene, 1.19 g 0.0133 mol) copper (I) cyanide, 46 ml of quinoline and 4.6 ml of dimethylformamide are stirred with the magnetic stirrer and Maintained at reflux temperature for 24 hours. The dark reaction mixture is with Diluted ether and 6N hydrochloric acid and the whole mixture through a plug of diatomaceous earth filtered. The ether phase is drawn off and washed with 3N hydrochloric acid and water and dried over magnesium sulfate. After evaporation of the ether, 4.06 is obtained g of oil distilling below 1.0 mm Hg at 137-140 ° C. This distillate crystallizes immediately and is recrystallized from hexane. 2.37 g of sparkling white are obtained Plates ; F = 72 = 73 ° C.

H. To a solution of 0.46 g (0.012 mol) of lithium aluminum hydride in 20 ml of dry ether become a solution of 1.6 g (0.012 Mol) aluminum chloride in 25 ml of ether was added dropwise. The solution is stirred for 15 minutes, and then a solution of 2.00 g (0.00608 mol) of α, β, β, γ, γ-hexafluorophenylpropyl) benzonitrile in 25 ml of dry ether added dropwise over the course of 15 to 20 minutes.

The mixture is stirred overnight at room temperature.

The excess lithium aluminum hydride is added dropwise by 5N sodium hydroxide solution, until a clear ether phase has formed, decomposes. The ether is decanted and the remaining gelatinous residue three times with 100 ml of ether extracted. The ether phases are united and over Dried magnesium sulfate. After evaporation of the ether, 1.98 g of one are obtained clear, colorless oil. This oil is dissolved in ether and the solution makes it drier gaseous hydrogen chloride passed. The white crystalline precipitate is filtered off and recrystallized from ethyl acetate. One obtains 2- (α, α, ß, ß, γ, γ-hexafluorophenylpropyl) benzylamine hydrochloride; F = 162-163.5 ° C.

Analysis Calculated for C16H13F6N.HCl: C = 52.12%; H = 3.55; Cl = 9.61; P = 30.92; Found: C = 52.42.7 "; H = 3.77%; Cl = 9.53; P = 30.70 do.

3 e i 5 p i e 1 70 4-fluoro-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine A. 2-Bromo-4-fluorobenzonitrile A solution of 10.9 grams (0.05 moles) of 2-bromo-4-fluorobenzamide in 50 ml of dry pyridine is added dropwise with stirring and cooling in an ice bath 11.2 g (0.0525 mol) of trifluoroacetic anhydride were added. After standing for 2 hours at room temperature, most of the solvent is reduced under reduced pressure driven off and the residue dissolved in ether. After evaporation of the washed and dried ether extract under reduced pressure remains as a product a solid substance. White crystals are obtained by sublimation at 55 ° C. and 0.05 mm Hg; F = 75-76.5 C. A sample from a previous experiment is used again for analysis sublimed: F = 77-78 ° C.

Analysis calculated for C7H3BrFN: C = 42.00%; H = 1.50%; N = 7.00 %; found: C = 41y41; H = 1.68%; N = 6.92%.

B. 2'-Bromo-4'-fluoro-2-phenylacetophenone A solution of 6.0 g (0.03 Mol) 2-bromo-4-fluorobenzonitrile in 35 ml of absolute ether becomes one with stirring Solution of benzyl magnesium chloride was added dropwise, which under nitrogen from 2.9 g (0.12 g atom) magnesium turnings and 15.2 g (0.12 mol) benzyl chloride in 65 ml absolute ether has been made.

The mixture is stirred at room temperature for 18 hours. After cooling The adduct is hydrolyzed in an ice bath by adding dropwise 100 ml of 0.5 molar citric acid. The organic phase is separated off and the aqueous phase repeatedly with benzene extracted. The combined organic layers are washed with 45 ml of ice-cold 6n Hydrochloric acid extracted in several portions and the combined acidic extracts 45 Heated for minutes on the steam bath. The product separates out as an oil and becomes with Benzene extracted. After evaporating the washed and dried benzene extract a yellow oil remains, which is purified by distillation; KP0.05 mm 112-115 ° C.

C. 2-Bromo-4-fluorobenzil. Following the procedure described in Example 2 2'-bromo-4'-fluoro-2-phenylacetophenone is oxidized to 2-bromo-4-fluorobenzil.

The yellow crystalline product (? = 62-66 ° C) is from 95 percent Recrystallized from ethanol to a material with a: melting point of 67-68.5 ° C. An analysis sample shows a melting point after sublimation at 60 ° C. and 0.1 mm Hg from 67.5-69 ° C.

Analysis Calculated for C14H8BrSO2: C = 54.72 C / o; H = 2.61%; Br = 26.06%; found: C = 55.08%; H = 2.84; Br = 25.75 db.

D. 2-Bromo-4, α, α, α ', α'-pentafluorobibenzyl Following the procedure of Example 3, 2-bromo-4-fluorobenzyl is converted into 2-bromo-4, α, α, α ', α'-pentafluorobibenzyl convicted. By sublimating the raw brown solid material at 500 C and 0.1 mm Hg white crystals are obtained; F = 47-48 ° C. A sample is used for analysis sublimated again.

Analysis Calculated for C14H8BrF5: C = 47.89 7'o; H = 2.30%; Br = 22.76 %.

found: C = 48.44; H = 2.53%; Br = 22.47 do.

E. 4-Fluoro-2- (α, α, β, β-tetrafluorophenethyl) benzonitrile A mixture of 4.9 g (0.0139 mol) of 2-bromo-4, α, α, α'α'-pentafluorobibenzyl, 3.70 g of copper (I) cyanide, 60 ml of dry quinoline and 6 ml of dry dimethylformamide is stirred for 18 hours at reflux temperature. After cooling in an ice bath it will be the precipitate is filtered off and washed with a mixture of benzene and ether. The solvents are evaporated from the filtrate under reduced pressure, whereby the crude product remains as an oily black solid substance. The cleaning takes place by column chromatography on 300 g of silica, the product with a Mixture of two parts of benzene and 1 part of carbon tetrachloride is eluted. The few Fractions obtained in thin layer chromatography on a fluorescent silica When developing with benzene, it is not a major component with an Rf value of 0.65 -contained are united. After evaporation of the solvents under reduced A solid substance remains under pressure, which is sublimed at 600 ° C. and 0.1 mm Hg; F = 68-70 ° C.

A sample is sublimed again for analysis.

Analysis Calculated for C15H8F5N: C = 60.62 O; H = 2.71%; N = 4.71 %; found: C = 61.33; H = 2.76%; N = 4.70.

F. 4-Fluoro-2- (α, α, β, β-tetrafluorophenethyl) benzylamine Following the process described in Example 5, 4-fluoro-α, ß, ß-tetrafluorophenethyl) benzonitrile is obtained reduced to 4-fluoro-2- (α, α, ß, ß-tetrafluorophenethyl) -benzlamine. By Sublimation of the crude product is obtained at 700 C and 0.05 mm Eg man white crystals; F = 52.5-54 ° C. A sample sublimed again for analysis melts at 53-54.5 ° C.

Analysis Calculated for C15H12F5N: C = 59.80%; H = 4.02; N = 4.65 %; Found: C = 60.11%; H = 4.07%; N = 4.61%.

B e i s p i e l 71 2- (4, α, α, ß, ß-pentafluorophenethyl) benzylamine A. 2'-Bromo-2- (p-fluorophenyl) acetophenone Following the procedure of Example 1 is obtained 2'-erom-2- (fluorophenyl) -acetophenone from 2r-bromobenzonitrile and p-fluorobenzylmagnesium chloride. Distillation of the yellow crystals yields almost colorless crystals; KP 0.1 mm = 130-132 ° C; F = 44-46 ° C.

Analysis calculated for C14H10BrFO: C = 57.37%; H = 3.44%; Br = 27.27%; found: C = 58.04%; - H = 3.59 0 / a; Br = 26.85%.

B. 2-Bromo-4'-fluorobenzil Following the procedure of Example 2, 2'-bromo-2- (p-fluorophenyl) acetophenone is obtained oxidized to 2-bromo-4'-fluorobenzil. The yellow crystalline product (F = 72-78 ° C) is recrystallized from 95 percent ethanol: F = 76.5-78.5 ° C. By repeated Recrystallization from 95 percent ethanol gives an analytically pure sample ; F = 79-80 ° C.

Analysis Calculated for C14H8BrFo2: C = 54.72%; H = 2.61%; Br = 26.06%; found: C = 55.07%; H = 2.67%; Br = 25.95 p.

C. 2-Bromo-4'α, α, α ', α'-pentafluorobibenzyl According to Following the procedure of Example 3, 2-bromo-4'-fluorobenzyl is converted into 2-bromo-4 ', α, α, α', α'-pentafluorobibenmzyl convicted. By sublimating the raw brown solid material at 60-70 ° C and 0.1 mm Hg gives white crystals; F = 52-53.5 ° C.

Analysis calculated for C1 to BrF5: C = 47.89 f; H = 2.30%; Br = 22.76 g / o; found: C = 48.21; H = 2.37%; Br = 23.04%.

D. 2- (4, α, α, ß, ß-Pontafluorophenethyl) -benzonitrile A mixture from 8.5 g (0.024 eIol) 2-bromo-4, α, α, α ', α'-pentafluorobibenzyl, 6.4 g copper (I) cyanide, 75 ml dry quinoline and 7.5 ml dry dimethylformamide is kept at reflux temperature with stirring for 34 hours. The precipitation is filtered off after cooling the mixture and with a mixture of benzene and ether washed. The solvents are reduced from the filtrate Pressure evaporated 'leaving an oily black solid substance. By sublimation at 80 ° C. and 0.05 mm Hg, a light brown solid material is obtained; F = 90-93 ° C. The purification is carried out by column chromatography on 300 g of silicon dioxide, with the product is eluted with a mixture of equal parts of benzene and hexane. The fractions obtained by thin layer chromatography on fluorescent silica show an Rf value of 0.85 when developed with benzene united. Left behind when the solvent evaporates under reduced pressure white crystals; F = 96.5 to 97.5 ° C. A sample is sublimed for analysis.

Analysis calculated for C15H8F5N: C = 60.62%; H = 2.71%; N = 4.71 %; found: C = 60.81%; H = 2.57%; N = 4.57 7'o.

E. 2- (4, α, α, ß, ß-Pentafluorophenethyl) -benzylamine After the The procedure of Example 5 is 2- (4, α, α, β, β-pentafluorophenethyl) benzonitrile reduced to 2- (4, α, α, ß, ß-pentafluorophenethyl) benzylamine. The raw product (= @@@@@ is sublimated at 600 C and 0.05 mm Hg, giving white crystals; F = 64-65.5 ° 0.

Analysis Calculated for C15H12F5N: C = 59.80%; H = 4.02? Jo; N = 4.65 %; found: C = 59.80%; H = 3.93%; N = 4.67 / o.

For example, 72 2- [2- (α, α, β, β-tetrafluorophenethyl) phenyl] imidazoline 2.06 g (0.0074 mol) of 2- (α, α, ß, ß-tetrafluorophenethyl) benzonitrile become together with 1.2 g (0.02 mol) of ethylenediamine and 3 drops of carbon disulfide 18 Heated to 160-165 ° C for hours in the sealed tube. After cooling in an ice bath the tube is opened and the contents poured into water. The separating orange barz is washed by decantation with water and then in ethyl acetate solved. The ethyl acetate solution is extracted with 3N hydrochloric acid. The United, Ice-cold, acidic extracts become strong with 40 percent aqueous sodium hydroxide solution made alkaline and the oily base extracted with ethyl acetate. The washed ones and dried ethyl acetate extracts are concentrated to 25 ml under reduced pressure and 0.6 ml of 8 normal ethanolic hydrogen chloride was added. When diluting the white crystalline hydrochloride falls with an equal volume of absolute ether of the product; F = 263-266 ° C. The product sinters at 258 ° C. By recrystallization a purified sample is obtained from acetone; F = 266-267 ° C.

Analysis Calculated for C17H14F4N2.HCl: C = 56.90%; H = 4.21%; N = 7.81%; found: C = 56.94%; H = 4.03; N = 7.60%.

For example 73 2- (α, α, ß, ß-tetrafluorophenethyl) phenethylamine A. 2- (α, α, ß, ß-Tetrafluorophenethyl) benzyl alcohol 530 mg (0.0139 mol) Lithium aluminum hydride are weighed out under nitrogen, into one with dry Purged with nitrogen Reaction flask transferred and in 15 ml absolute Ether suspended. A solution of 4.15 g (0.0139 mol) of 2- (α, α, ß, ß-tetrafluorophenethyl) benzoic acid is used for this added dropwise in 35 ml of absolute ether. The mixture is 30 minutes at room temperature stirred and then left to stand overnight under nitrogen. The hydrolysis takes place by adding 1 ml of water dropwise. The precipitate is filtered off and washed with ether washed. After evaporating the dried ether filtrate under reduced The product remains under pressure as a solid white substance; F = 80-81 ° C. For analysis a sample is sublimed at 700 ° C and 0.1 mm Hg.

Analysis Calculated for C15H12F40: C = 63.37%; H = 4.26 i0; F = 26.74 O; found: C = 63.78; H = 4.27%; p = 26.38 00.

B. 2- (α, α, ß, ß-Tetrafluorophenothyl) -benzyl bromide A suspension of 3.3 g (0.0116 moles) of 2- (α, α, ß, ß-tetrafluorophenethyl) benzyl alcohol in 15 ml of 48 percent hydrobromic acid is stirred for 3 hours on the Steam bath heated. The product crystallized from the cooled mixture becomes collected and dissolved in benzene. After evaporation of the washed and dried Benzene extract under reduced pressure and subliming the solid residue 600 C and 0.05 mm Hg, white crystals are obtained; F = 70-77 ° C.

A sample from a previous experiment is used for analysis by column chromatography on silica eluting with a mixture 2 parts benzene and 1 part carbon tetrachloride purified. Those factions those in thin-layer chromatography on fluorescent silica during development with benzene showing an Rf value of 0.85 are combined and the solvent is evaporated under reduced pressure. The solid residue (p = 78 to 820 C) is sublimed at 6t ° C and 0.05 mm Hg. The product melts at 80.5-82 ° C.

Analysis Calculated for Cd15H11BrF4: C = 51.89%; H = 3.20%; Br = 23.2%; found: C = 52.18; H = 3.32? ,,; Br = 22.89.

C. 2- (α, α, β, β-tetrafluorophenethyl) phenylacetonitrile 3.5 g (0.01 mol) 2- (α, α, ß, ß-tetrafluorophenethylbenyl bromide and 2.0 g (0.0308 Mol) potassium cyanide are dissolved in 35 ml of acetone and 5 ml of water, and the solution is heated to reflux temperature for 18 hours. The organic phase is separated the acetone is distilled off under reduced pressure and the oily residue in benzene solved. After evaporating the washed and dried benzene extract under A brown oil remains as the product under reduced pressure.

D. 2- (α, α, ß, ß-Tetrafluorophenethyl) -phenethylamine According to Following the procedure of Example 5, 2- (α, α, β, β-tetrafluorophenethyl) phenylacetonitrile reduced to 2- (α, α, ß, ß-tetraflurophenethyl) -phenethylamine. The product, a yellow oil, is converted into the hydrochloride by adding an ethanolic solution the same with a slight excess of 8.2 normal ethanolic hydrogen chloride is moved. When diluted with absolute ether, the product falls in the form of a whiter Crystals from; F = 212-214 ° C. By recrystallization from a mixture of absolute Ethanol and absolute ether give a purified sample; F = 213.5-215.5 ° C.

Analysis Calculated for C16H15F4N.HCl: C = 57.58%; H = 4.83%; N = 4.20%; found: C = 57.88%; H = 4.78%; N = 4.25%.

For example, 74 N-Benzyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine A mixture of 3.9 g (0.0138 mol) 2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine, 1.77 g (0.014 mole) benzyl chloride, 2.5 g anhydrous potassium carbonate and 25 ml benzene is stirred for 40 hours at reflux temperature. After filtering will the solvent is evaporated off under reduced pressure and it remains as a product an oil. The purification is carried out by column chromatography on 250 g of silicon dioxide, the product being eluted with 1 percent methanol in chloroform. Those Fractions produced by thin layer chromatography on fluorescent silica when developed with 5 percent methanol in chloroform, a spot with a Show Rf value of 0.5 are combined with each other.

Remains after evaporation of the solvent under reduced pressure an oil. The base is converted into the hydrochloride by making a solution of the same in ethanol with a slight excess of an 8 normal hydrogen chloride solution is added to ethanol. When diluted with absolute ether, the hydrochloride falls in the form of white crystals; F = 188-189.5 ° C. By recrystallization from acetone a purified sample is obtained; F = 188.5-190 ° C.

Analysis calculated for C22H19F4N.HCl; C = 64.48; H = 4.92%; Cl = 8.65%; found: C = 64.75 7 "; H = 4.89 Vo; al = 8.64%.

For example, 75 α-methyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine A. Methyl 2- (1,1, ß, ß-tetrafluorophenethyl) -phenylkeitimin A solution of 19.3 g (0.0685: ol) 2- (α, α, ß, ß- = tetrafluorophenethyl) benzonitrile in 150 ml absolute ether is added dropwise with stirring to a solution of methylmagnesium bromide, which under nitrogen from 4.8 g (0.2 g atom) magnesium shavings and 25 g 20.26 mol) Methyl bromide has been prepared in 150 ml of absolute ether. The mixture will Stirred for 16 hours at reflux temperature. After cooling in an ice bath, the adduct becomes hydrolyzed by the dropwise addition of 20 ml of water. The organic phase is decanted and the gelatinous blow again thoroughly washed with ether. The United Ether extracts are mixed with 45 ml ice-cold 6n hydrochloric acid extracted. After further cooling the combined acidic extracts this becomes a precipitate the precipitated hydrochloride of the product was collected and washed with ether. After a long time Drying in vacuo melts the crystalline hydrochloride after previous sintering at 144-146 ° C. By repeated recrystallization from a mixture of isopropyl alcohol and absolute ether an analytical sample is obtained; 6 -F = 147-148.5 C. Analysis Calculated for C16H13F4N.HCl: C = 57.94 7'o; H = 4.25%; N = 4.22 dp; found: C = 58.08%; H = 4.18%; N = 4.39%.

B. «-Methvl-2- (α,«, β, β-tetrafluorophenethyl) -benzzlamine 1.05 g (0.0276 Moles) lithium aluminum hydride are weighed out under nitrogen, in a dry, Transferred reaction tubes flushed with nitrogen and poured into 25 ml dry, peroxide-free Suspended tetrahydrofuran. The mixture is cooled with stirring in an ice bath, whereby a solution of 43 g (0.013 mol) of methyl 2- (α, α, ß, ß-tetrafluorophenethyl) phenylketimine hydrochloride added dropwise in 70 ml of tetrahydrofuran. The mixture is at room temperature for 18 hours stirred under nitrogen. After cooling in an ice bath, hydrolysis takes place successive dropwise addition of 1 ml of water, 1 ml of 20 percent aqueous sodium hydroxide solution and 3 ml of water. The precipitate is filtered off and washed with ether. To the evaporation of the dried ether filtrate remains behind under reduced pressure als'Produkt a red oily residue.

The base can be converted into the hydrogem \ nmaleate by a solution of them in isopropyl alcohol with a slight excess of a solution heated by maleic acid in isopropyl alcohol. When diluting with absolute ether the hydrogen maleate precipitates in the form of white crystals; F = 153-154 ° C (decomp.). By repeated recrystallization from mixtures of isopropyl alcohol and ether a purified 1-aterial is obtained; F = 157-158 ° C (decomp.).

Analysis Calculated for C16H15F4N.C4H4O4: C = 58.11; H = 4.63,000; found: C = 58.11%; H = 4.64%.

EXAMPLE 76 Prevention or modification of the ventricular Arhythmia Parforce dogs of both sexes weighing 6 to 10 kg are used Vinbarbital anesthetized using a dose of 50 mg / kg body weight, and mean arterial pressure - as well as the electrocardiogram (lead II) are recorded. The animals are artificially ventilated, and the chest is on fourth or fifth space opened. The pericardium is opened and a Part of the anterior descending annular artery immediately distal to hers Origin freed from the surrounding tissue. Then mecamylamine is given to the Heartbeat slow down, and 10 minutes later it will turn on your anti-arrhythmic Effect of the compound to be tested administered intravenously.

10 minutes after application of the test compound are in the wreath-shaped Artery 0.0035 ml / kg detrafluorohexachlorobutane (TFHCB), a sclerosing agent, which causes myocardial infarction and arrhythmia in dogs (see Ascanio and colleagues, "J. Am. Physiol.", Vol. 209, 1965, pp. 1081-1088). In control animals this dose of TFHCB produces ventricular arrhythmia in 100,000 of the animals examined and leads to death as a result of ventricular fibrillation in 33% of the animals examined.

After the injection of the sclerosing iibble it will take one hour an electrocardiogram was taken at intervals of 2 minutes and the mean one Number of electrical (EKG) complexes per minute as well as the percentage of normal Complex calculated. Those with different doses of vest joints received Values are plotted on a graph and the animal protective dose becomes graphically estimated (3D80mg / kg). This number indicates that 80% of all electrical (EKG) complexes are normal.

The compound 2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine is studied at doses of 0.02 to 2.5 mg / kg. The calculated mean percentage the normal complexes is 20 to 97.

So the estimated ED80 value is equal to 0.16 mg / kg compared to Quinidine sulfate, which when taken under similar conditions in doses of 2.5, 5.0 or 10.0 mg / kg is tested, a mean percentage of the normal values of 25, 51 and 90, respectively, from which an estimated ED80 value of 8.8 mg / kg follows.

Example 1 77 capsules Capsules for oral administration are manufactured by dispersing the active ingredient in lactose and magnesium stearate and the mixture in normal soft gelatin capsules, making each capsule the following Composition has: per capsule 2 ",", B, ß-detrafluorophenethyl) benzylamine hydrochloride 5 mg lactose 430 mg magnesium stearate 5 mg B e i s p i e 1 -78 solutions for parenteral Administration A solution for injection is prepared by taking the active ingredient with dextrose, methylparaben, propylparaben and distilled water in the below the specified proportions and then sterilized.

per ml of α, α, ß, ß-tetrafluorophenethyl) benzylamine hydrochloride: 5 mg dextrose 44 mg methyl paraben 1.5 mg propyl paraben. 0.2 mg water for injection Remainder B e i 5 p i e 1 79 tablets Tablets for oral administration are produced, by mixing the active ingredient with suitable amounts of vehicles and binders, the mixture is shaped into tablets in the tablet machine and each tablet with provides a coating.

The composition is as follows: per tablet 2 - («,«, ß, ~ ß-tetrafluorophenethyl) benzylamine hydrochloride 10 mg cellulose as filter aid 11 mg lactose 9 mg dibasic calcium phosphate - 143 mg guar resin 6.1 mg corn starch 4 mg magnesium stearate 0.9 mg more opaque yellow film coating 3 mg Following Examples 77, 78 and 79 are agents for treatment or prevention of the arrhythmia produced by taking the tetrafluorophenethylbenzylamine replaced by one of the other active ingredients.

For example 80 α, N-dimethyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine 1.06 g (0.00357 moles) of α-methyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine are stirred in 50 ml of ethyl formate at reflux temperature for 21 hours held. After evaporating the solution to dryness and stirring the residue with hexane, N- [α-methyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzyl] formamide is obtained ; F = 94.5-99 ° C. Avg. Uncrystallized from mixtures of ether and petroleum ether and a purified sample is obtained from isopropyl alcohol and water; F = 103 to 1050 C.

Following the procedures of Example 6, the N- [α-methyl-2- (α, α, β, β-tetrafluorophenethyl) benzyl] formamide is obtained reduced to α, N-dimethyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine.

The product, a yellow oil, is converted into the hydrogen fumarate, by mixing an ethereal solution of the same with a solution of a slight excess added to fumaric acid in absolute ethanol. The hydrogen fumarate precipitates and falls after recrystallization from acetone in the form of white crystalline crystals; F - 175 - 176 ° C. With further recrystallization from acetone, the melting point remains unchanged.

Analysis Calculated for C17H17F4N.C4H4O3: C = 59.01%; H = 4.95 to 9 = 3.28%; found: C - = 58.84%; H = 5.09?; N = 3.28, ó.

The hydrochloride is by adding a solution of the base in absolute Ethanol made with a small excess of ethanolic hydrogen chloride. When diluted with absolute ether, the hydrochloride precipitates; an analytical one The sample is obtained by recrystallization from a mixture of acetone and absolute ether; F = 190-192 ° C.

Analysis Calculated for C17H17F4N.HCl: C = 58.71%; H - 5.22%; N = 4.05%; found: C = 58.47%; H = 5.40%; N = 4, C8%.

B e i s n i e 1 81 (+) - α, N-dimethyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine 9.5 g (0.0305 mol) of racemic, N-Drmethyl-2 - (, α, ß, ß-tetrafluorophenethyl) benzylamine in 25 ml of boiling absolute ethanol with. a solution of 2.3 g (0.0153 Mol) (-) - tartaric acid added in 20 ml of absolute ethanol. The crystallization will triggered by inoculation and the solution left at room temperature until no further precipitate forms. After collecting the (-) - tartrate, the Ethanolic mother liquor evaporated to dryness under reduced pressure and the Suspended residue in water. The mixture is made with saturated sodium carbonate solution made alkaline and extracted the oily base with hexane. After steaming of the washed and dried hexane extract remain under reduced pressure 1.35 g (+) - base.

The (+) - base is dissolved in 4 ml of absolute ethanol and a solution of 326 mg (0.00217 mol) of (+) - tartaric acid in 3 ml of absolute ethanol is added to the solution. The (+) - tartrate separates out in the form of white crystals; F = 183-186 ° C; Yield 1.3g. After five recrystallization from absolute ethanol, a product with a constant specific rotation is obtained: The (+) - tartrate is suspended in water and the mixture is made alkaline with saturated sodium carbonate solution. The oily base is extracted with hexane. After the washed and dried hexane extract has been evaporated, the (+) - base remains as a pale yellow oil; B ei 5 pie 1 82 (-) - α, N-dimethyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine 9.6 g (0.0249 mol) of the α, N- obtained in Example 81 Dimethyl-α, ß, ß-tetrafluorophenethyl) -benzylamine - (-) - tartrates are suspended in water, and the mixture is made alkaline with saturated sodium carbonate solution. The oily base is extracted with hexane. After the washed and dried, en'Hexanextrakts have been evaporated, the base remains as a pale yellow oil. The base, 7.65 g (0.0246 mol), is dissolved in 20 ml of absolute ethanol and a solution of 1.85 g (0.0123 mol) of (+) - tartaric acid in 20 ml of absolute ethanol is added to the solution. Crystallization is initiated by seeding and the solution is left to stand at room temperature until no further precipitate forms. After collecting the (+) - tartrate, the ethanolic mother liquor is evaporated to dryness under reduced pressure and the solid residue is suspended in water. The mixture is made alkaline with saturated sodium carbonate solution and the oily base is extracted with hexane. After the washed and dried hexane extract has been evaporated under reduced pressure, the (-) - base remains in an amount of 1.09 g.

The (-) - base is dissolved in 4 ml of absolute ethanol and a solution of 262 mg (0.00175 mol) of (-) - isic acid in 2 ml of absolute ethanol is added to the solution. The (-) - tartrate separates in the form of white crystals; F = 184-187 ° C; Yield 1.1g. By recrystallizing three times from absolute ethanol, a product of constant specific rotation is obtained: F = 190-192 ° C.

Analysis Calculated for C17H17F4N.1 / 2 C4H406: C = 59.05%; H = 5.22 /O; N = 3.62 cp; found: C = 59.25%; H = 5.30%; IN = 3.49.

The (-) - tartrate is suspended in water and the mixture is made alkaline with saturated sodium carbonate solution. The oily base is extracted with hexane. After the washed and dried hexane extract has been evaporated, the (-) - base remains as a pale yellow oil; Example 83 α, α, α ', α'-Tetrafluoroethylene-2,2'-bis (benzylamine) A. 2,2'-Dimethyl-α, α, α', α'-Tetrafluorobibenzyl 4.76 g ( 0.02 mol) o-tolil are heated to 800 ° C. for 10 hours in a stainless steel autoclave together with 41 g of sulfur tetrafluoride, 1.3 g of mercury, 1 g of hydrogen fluoride and 40 ml of benzene. After cooling and opening the vessel to the atmosphere, the mixture is separated from the mercury and filtered. After evaporation of the benzene from the piltrate under reduced pressure, a brown residue remains, which is stirred with hot cyclohexane and filtered. After the cyclohexane has evaporated from the filtrate under reduced pressure, the product remains a brown solid. White crystals are obtained by sublimation at 105 ° C. and 0.05 mm Hg; F = 71.5-73.5 ° C. An analysis sample obtained by recrystallization from hexane melts at 75-75 ° C.

Analysis calculated for 016H14F4: C = 68.08%; H = 5.00%; found: C = 67.76%; H = 5.00%.

B. α, α, α ', α'-tetrafluoroethylene-2,2'-bis- (benzyl bromide) A mixture of 1.41 g (0.005 ol) 2,2'-dimethyl-α, α, α ', α'-tetrafluorobibenzyl, 1.78 g (0.01 mol) of N-bromosuccinimide, a trace of benzoyl peroxide and 60 ml of carbon tetrachloride is stirred for 7 hours at reflux temperature. After iCuiling, the precipitation, a mixture of the product and succinimide, collected, dried and stirred with 5 percent aqueous sodium hydroxide solution. The insoluble product becomes collected, washed with water, dried and recrystallized from benzene.

White crystals are obtained; F = 178-183 ° C. By repeated recrystallization an analytical temperature is obtained from benzene: F = 184-186 ° C.

Analysis Calculated for C16H12Br2F4: C = 43.67%; H = 2.75; found: C = 43.94%; H = 2.77 7'o.

c. α, α, α ', α'-Tetrafluoroethylene-2,2'-bis- (benzylhexaminium-6,44 g (0.046 mol) hexamine are dissolved in 75 ml boiling chlorine form. Place 10.1 g (0.023 mol) α, α, α ', α'-tetrafluoroethylene-2,2'-bis- (benzyl bromide) and the mixture is heated to reflux temperature for 8 hours. After cooling the precipitate collected, washed with absolute ether and dried. You get a white, sweet, crystalline solid; F = 186-190 ° C (decomp.).

D. α, α, α ', α'-tetrafluoroethylene-2,2'-bis- (benzylamine) A mixture of 17.2 g (0.0239 mol) of α, α, α ', α'-tetrafluoroethylene-2,2'-bis (benzylhexaminium bromide), 25.6 ml of concentrated hydrochloric acid and 135 ml of absolute ethanol is 9 hours on Heated to reflux temperature. After cooling, the white precipitate is filtered off and the filtrate was evaporated under reduced pressure. The residue and the precipitate are combined, dissolved in water and the cooled solution with 40 percent aqueous Caustic soda made strongly alkaline. The white solid product separates out and is collected, washed with water and ether, and evaporated from a solution the same dried in benzene; F = 96-97 ° C.

Another amount of product is obtained from the essential washing liquids; F = 93-95 ° C. An analytical sample melts in a vacuum after sublimation 98.5-100 ° C.

Analysis Calculated for C16H16F4N2: C = 61.53%; H = 5.16%; N = 8.98 %; found: C = 61.15%; H = 5.09%; N = 8.83%.

The (~) -dilactate is prepared by adding a solution of α, α, α ', α'-tetrafluoroethylene-2,2'-bis- (benzylamine) in isopropyl alcohol with a slight excess of 85 to 90 percent (~) lactic acid offset. The (+) - dilactate precipitates in the form of white crystals; F = 180.5-α8α, 5 ° C. By repeated recrystallization from mixtures of absolute ethanol and absolutom Methanol gives a purified sample; F = 186 to 187.5 ° C.

Analysis Calculated for C16H16F4N2.2C3H6O3: C = 53.66%; H = 5.73 %; N = 5.69%; found: C = 53.92%; H = 5.91%; N = 5.69 7'o.

3 e i 5 p i e 1 84 N, N-dimethyl-3- («, B, B-tetrafluorophenethyl) -o-xylene-α, α, -diamine A. 2 ', 3'-Dimethyl-2-phenylacetophenone Following the procedure of Example 1 gives 2,3-dimethylbenzonitrile reacted with benzylmagnesium chloride to 2,3-dimethylphenylbenzylketimine hydrochloride. After recrystallization from a mixture of absolute ethanol and absolute Ether, the product is obtained in the form of white crystals; F = 228.5 to 229.5 ° C.

Analysis Calculated for C16H17N.HCl: C = 73.97%; H = 6.98%; N = 5.39%; found: C = 73.49 c / o; H = 6.89%; N, N = 5.29.

By hydrolysing the ketimine hydrochloride according to the method of the example 1 gives 2 ', 3'-dimethyl-2-phenylacetophenone.

After recrystallization from isopropyl alcohol and from methanol precipitates the purified product in the form of white crystals at; P = 52-53 ° C.

B. 2,3-Dmethylbenzil Following the procedure of Example 2 is 2 ', 3'-dimethyl-2-phenylacetophenone oxidized to 2,3-dimethylbenzil. The crystalline product is recrystallized several times purified from absolute methanol; F = 61.5-62.5 ° a.

C. 2,3-Dimethyl-α, α, α ', α'-tetrafluorobibenzyl Following the procedure of Example 83 is 2,3-dimethylbenzil in 2,3-dimethyl-α, α, α ', α'-tetrafluorobibenzyl converted. The crude crystalline product is made by subliming at 950 C and 0.05 mm Hg purified; F = 110-111.5 ° C. An analytical sample (F = 110-111 ° C) is obtained by recrystallization from hexane.

Analysis Calculated for C16H14F4: C = 68.08%; H = 5.00%; F = 26.92 %; found: C = 68.16%; H = 5.16; F = 26.63.

D. 3- (α, α, β, β-tetrafluorophenetyl) -o-xylene-α, α'-dibromide A mixture of 6.13 g (0.022 mol) 2,3-Dmethyl-α, α, α ', α'-te-trafluorobibenzyl, 7.85 g (0.044 mol) of N-bromosuccinimide, a catalytic amount of benzoyl peroxide and 175 ml of carbon tetrachloride is stirred for 6 hours at reflux temperature. To After cooling, the succinimide precipitate is filtered off and washed with carbon tetrachloride washed. After evaporation of the filtrate remains under reduced pressure as a product, a somewhat oily solid substance; F = 71-83 ° C. By recrystallization a purified material is obtained from petroleum ether; F = 88-92 ° C. An analysis sample is made by sublimation at 85 ° C and 0.02 mm Hg; F = 90-92 ° C.

Analysis Calculated for C16H12Br2F4: C = .43.66 Vo; H = 2.75 7'a; found: C = 43.78 H = 2.74.

E. N, N-dimethyl-3- (α, α, β, β-tetrafluorophenethyl) -oxylene «,« '- diamine 2.0 g (0.0045 mol) 3- (α, α, ß, ß-tetrafluorophenethyl) -o-xylene - «,« - dibromide are added to 15 to 25 ml of liquid methylamine, while the latter in one Mixture of solid carbon dioxide and chloroform is cooled. The solid material goes after 10 minutes in solution, remove the cooling bath and allow the solution to evaporate. The remaining solid is stirred with benzene and the insoluble methylamine hydrobromide filtered off. Obtained by evaporating the benzene filtrate under reduced pressure the residue is a resinous solid.

The base is converted into the dihydrobromide by converting into its Ethanolic solution introduces gaseous hydrogen bromide. When diluting with absolute Ether precipitates the dihydrobromide and is made from a mixture of absolute ethanol and absolute ether recrystallized. The cleaned material melts at 254-256 ° C. An analytical sample is prepared by recrystallization from absolute ethanol; F = 251-253 ° C.

Analysis Calculated for C1aH20F4N2.2HBr: C = 43.04%; H = 4.41%; N = 5.58 5; Br = 31.83%; found: C = 43.21 5s; H = 4.39%; N = 5.60%; Br = 31.64 %.

For example 1 85 N, N-dibenzyl-3- (α, α, ß, ß-tetrafluorophenethyl) -o-xylene-α, α, -diamine A solution of 2.2 g (0.005 mol) of 3- (α, α, ß, ß-tetrafluorophenethyl) -o-xylene-α, α, -dibromide and 1.7 g (0.016 col) benzylamine in 50 ml dry benzene is 15 minutes at room temperature touched. Here, the separation of a white precipitate begins. The mixture is heated to reflux temperature for 18 hours. After cooling, the precipitate becomes the end Benzylamine hydrobromide collected and washed with benzene.

After the evaporation of the benzene filtrate, a viscous one remains behind yellow oil mixed with boiling absolute ether. The insoluble hydrobromide the product is collected and made from a mixture of benzene and absolute ethanol and absolute ether recrystallized to give white solid crystals; F - 172-174 ° C. An analytical sample is obtained by recrystallization from acetone; F = 176-177.5 ° 0.

Analysis Calculated for C30H28F4N2.HBr: C = 62.81%; H = 5.10 Vc; N = 4.89 c '; found: C = 62.64%; H = 5.10%; N = 5.22%.

B e i 5 p i e 1 86 4- (α, α, ß, ß-tetrafluorophenethyl) -isoindoline A. N-Benzyl-4- (α, α, ß, ß-tetrafluorophenethyl) -isoindoline The after the Collect the N, N-dibenzyl-3- (α, α, ß, ß-tetrafluorophenethyl) -o-xylene-α, α, '- diamine hydrobromide remaining ethereal filtrate according to Example 85 becomes dry in vacuo evaporated, the viscous, oily yellow base remaining as the crude product. The hydrobromide is prepared by making a solution of the base in methanol with an equivalent Amount of 48 percent aqueous hydrobromic acid added. When diluting with the hydrobromide precipitates with absolute ether; F = 228-231 ° C. A sample for analysis is made by repeated recrystallization from a mixture of absolute methanol and obtained with absolute ether and treatment with decolorizing charcoal in the form of white crystals; F = 236.5-238.5 ° C.

Analysis Calculated for C23H19F4N.HBr: C = 59.24? Io '; H = 4.32%; N = 3.00%; found: C = 58.84%; H = 4.30 cg; N = 3.05%.

B. 4- (α, α, ß, ß-Tetrafluorophenethyl) -isoindoline A solution of 1.63 g (0.0055 mol) of N-benzl-4- (α, α, ß, ß-tetrafluorophenethyl) -isoindoline hydrobromide in 160 ml absolute Ethanol and 14 ml of absolute methanol with 320 mg of 5 percent palladium on carbon under hydrogen at atmospheric pressure stirred until hydrogen absorption ceases. The catalyst is filtered off, and after evaporation of the filtrate under reduced pressure, the crystalline remains Hydr.oEromid of the product (? = 191-192 ° C) as residue. By recrystallization from mixtures of absolute ethanol and absolute ether and treatment with decolorizing charcoal an analytical sample is obtained by recrystallization from isopropyl alcohol; F = 192-194 ° C.

Analysis Calculated for C16H13F4N.HBr: C = 51.09%; H = 3.75%; N = 3.72%; found: C, 50.94%; H = 3.78; N = 3.83 q.

B e i s p i e 1 87 2-methyl-3- (α, α, ß, ß-tetrafluorohenethyl) benzylamine A. 2-Methyl-3- (α, α, -ß, ß-tetraflurophenethl) -benzyl bromide A mixture from 4.0 g (0.0142 mol) 2,3-dimethyl-α, α, α'α'-tetrafluorobibenzyl, 2.52 g (0.0142 mole) of N-bromosuccinimide, 50 mg of benzoyl peroxide and 100 ml of carbon tetrachloride is stirred for 2 1/2 hours at reflux temperature. After cooling, the precipitate becomes filtered off from succinimide and the filtrate to dryness under reduced pressure evaporated. The solid residue is recrystallized from petroleum ether, whereby one receives white crystals; F = 67-71 ° C. By repeated recrystallization from petroleum ether an analytical sample is obtained; F = 69-71 ° C.

Analysis Calculated for C16H13BrF4: C = 53.21%; H = 3.63%; Br = 22.12%.

found: C = 54.21%; H = 3.84 Czio; Br = 21.38%.

one the purified hydrochloride; F = 209-211.5 ° C.

Analysis calculated for C16H15F4N.HCl: C = 57.58 salt H = 4.83%; N = 4.20%; found: C = 57.28%; H = 4.83%; N = 4.12%.

For example, 88 α, α, = dimethyl-3- (α, α, ß, ß-tetrafluorophenethyl) benzylamine A. 3'-Bromo-2-phenylacetophenone Following the procedures of Example 1 gives 3-bromobenzonitrile reacted with benzyl magnesium chloride to give 3-bromophenylbenzyl ketimine hydrochloride. This salt, which accrues as an oily solid substance, is used directly without cleaning Example 1 hydrolyzed. The crude 3'-bromo-2-phenylacetophenone, an oily solid Substance, is distilled in vacuo, collecting the pale yellow solid product, which passes over at Oj1 mm Hg at 143-155 ° C. The one boiling at 0.1 mm Hg at 150-155 ° C Praction is recrystallized from hexane to give an analytical sample in the form of white crystals; F = 62-64 ° C.

Analysis ~ Calculated for C14H11BrO: C = 61.11%; H = 4.03 ap; found: C = 61.25%; H = 4.00%.

B. 3-bromobenzil According to Example 2, 3'-bromo-2-phenylacetophenone is used oxidized to 3-bromobenzil. The oily product is purified by vacuum distillation; Kp0.05 mm = 148-155 ° C. The distillate solidifies to yellow crystals (? = 78-82 ° C), and an analytical sample is obtained by recrystallization from hexane; F = 81 up to 82.50 C.

Analysis calculated for C14H9BrO2: C = 58.15%; H = 3.13%; found: C = 57.81; H - 3.05%.

C. 3-Bromo-α, α, α ', α'-tetrafluorobibenzyl According to Example 83 is 3-bromobenzyl in 3-bromo-α, α, α ', α'-tatrafluorobibenzyl convicted. The crude crystalline product is made by subliming at 65 ° C and 0.02 mm Hg purified; F = 72-75 ° C. The analytical sample (F = 74-76 ° C) is obtained by Recrystallize from petroleum ether.

Analysis Calculated for C14H9BrF4: C = 50.47 Xo; H = 2.72; found: C = 50.51%; H = 2.57.

D. 2- [3 (α, α, β, β-tetrafluorophenethyl) phenyl] propanol-2 The Grignard's reagent 3- (α, α, ß, ß-tetrafluorophenethyl) -phenylmagnesium bromide is prepared as follows: In a nitrogen atmosphere, 0.72 g (0.0297 g-atom) magnesium shavings covered with 6 ml of absolute ether. First you put one Iodine crystal and then a few milliliters of a solution of 8.97 g (0.027 M-ol) 3-bromo-α, α, α ', α'-tetrafluorobibenzyl in 30 ml of absolute ether. The mixture is brought to reflux temperature with stirring heated and with a few drops of a solution of 0.2 g of ethylene bromide in 1 ml of absolute Ether shifted. Then one begins with the dropwise addition of the remaining solution of the bromide and continue stirring at reflux temperature for several hours after formation of the Grignardian adduct has begun. During this period there will be a total of 0.1 g freshly cut magnesium pieces and the remainder of the ethylene bromide solution added in several proportions.

The solution of Grignard's reagent is cooled in an ice bath, and it a solution of 3.5 g (0.06 mol) of acetone in 5 ml of absolute ether is added dropwise.

After stirring overnight at room temperature under nitrogen the mixture is cooled in an ice bath and hydrolyzed by dropping them of 2 ml of water. The ether solution is decanted from the gelatinous precipitate and the precipitate was extracted several times with ether. After evaporation of the combined, washed and dried ether extracts under reduced pressure what remains is the crude product as a solid substance. The purification is carried out by column chromatography on 200 g of silica gel, the product being eluted with benzene. Those 'factions that of thin-layer chromatography on silica when developing with chloroform show a spot with an Rf value of 0.2 are pooled. After evaporation of the solvent under reduced pressure, the white crystalline remains Product. An analysis sample is recrystallized from hexane; F = 76-78 ° C.

Analysis Calculated for C17H16F4O C = 65.37; H = 5.16; found: C. = 65.54%; H = 5.15? / O.

E. N- [α, α, -Dimethyl-3- (α, α, ß, ß-tetrafluorophenethyl) -benzyl] formamide 6 ml of glacial acetic acid are cooled in an ice bath while stirring until the substance is semi-solid has become. 1.08 g (0.022 mol) of sodium cyanide are added in proportions, with the temperature is kept at 15-20 ° C. Then you slowly add an ice-cold solution of 5.4 g of concentrated sulfuric acid in 2.8 ml of glacial acetic acid, while the temperature keeps at 10-20 ° C. After stirring for 10 minutes, the ice bath is removed and a Solution of 558 g (0.01785 mol) of 2- [3- (α, α, ß, ß-tetrafluorophenethyl) -phenyl] -propanol-2 added in 3 ml of glacial acetic acid. The mixture is stirred for a further 9 hours at 250 ° C. Then it is poured the reaction mixture in 80 ml of ice and water and neutralized with solid sodium carbonate. The oily product is extracted with ether. After evaporating the washed and dried extracts of ether, an oily solid substance remains as the product. The purification is carried out by column chromatography on 200 g of silicon dioxide B. N- [2-methyl-3- (α, α, ß, ß-tetrafluorophenethyl) benzyl] phthalimide A mixture from 8.02 g (0.022 mol) 2methyl-3- (α, α, ß, ßtetrafluorophenethyl) -benzyl bromide, 4.10 g (0.022 mol) of potassium phthalimide and 40 ml of dimethylformamide is added for 30 minutes Room temperature, stirred for 4 hours at 950 C and 3 hours at reflux temperature. After cooling, the mixture is diluted with 100 ml of chloroform and with 150 ml Water washed. After extracting the aqueous layer with chloroform the combined organic extracts washed with 0.1N sodium hydroxide solution and with water, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo.

By recrystallizing the solid residue from isopropyl alcohol the white crystalline product is obtained; F = 135 to 1370 C.

C. 2-methyl-3- (α, α, ß, ß-tetrafluorophenethyl) benzylamine 3.74 g (0.00876 moles) of N- [2-methyl-3- (α, α, β, β-tetrafluorophenethyl) benzy g-phthalimide are dissolved in 100 ml of boiling 95 percent ethanol. After addition of 0.87 ml of 100 percent hydrazine hydrate, the mixture is refluxed for 7 hours heated. After cooling and standing, the voluminous white precipitate becomes filtered off from phthalhydrazide. After evaporation of the ethanol filtrate to about half the volume, a further precipitate of phthalhydrazide is obtained is also filtered off. The filtrate is cooled in an ice bath, concentrated with 1.5 ml Hydrochloric acid acidified to a pH of 2 and under reduced pressure to dryness evaporated. The solid residue is dissolved in 25 ml of absolute ethanol. By diluting the solution with 15 ml of absolute ether gives a further precipitate of Phthalhydrazide, which is filtered off. After reducing the filtrate to 15 ml and Dilute with 25 ml of absolute ether, the hydrochloride falls in the form of shiny white Panels made of; F = 199.5-201 ° C. By repeated recrystallization from mixtures obtained from absolute ethanol and absolute ether oxide gel, where the product is eluted with chloroform. The respective fractions that occur in thin-layer chromatography on silica on development with chloroform, a spot with an Rf value of 0.1 show are combined. After evaporation of the solvent under reduced The white crystalline product remains under pressure; F = 90-95 ° C.

F. α, α, -Dimethyl-3- (α, α, ß, ß-tetrafluorophenethyl) -benzylamine A solution of 2.62 g (0.0077 mol) N- [α, α, -Dimethyl-3- (α, α, ß, ß-tetrafluorophenethyl) -benzyl] -formamide in 56 ml of glacial acetic acid, 35 ml of water. and 5.6 ml of concentrated hydrochloric acid is stirred for 6 hours at reflux temperature. To the evaporation of the solvent under reduced pressure leaves the hydrochloride of the product as a white crystalline residue.

By recrystallization from mixtures of absolute methanol and absolute Ether gives the purified hydrochloride; F = 179-180 ° C. When recrystallizing from a mixture of absolute methanol and absolute ether, the melting point remains unchanged.

Analysis Calculated for C17H17F4N.HCl: C = 58.71%; H = 5.22 fo; N = 4.02%; found: C = 58.93 fo; H = 5.58%; N = 3.85 dO.

For example 89 4- (α, α, ß, ß-tetrafluorophenethyl) benzylamine A. 4-Bromo-α, α, α ', α'-tetrafluorobibenzyl According to Example 3 4-bromobenzyl becomes 4-bromo-α, α, α ', α'-tetrafluorobibenzyl convicted. The crude crystalline product is made by sublimation at 70-75 ° C and 0.02 mm Hg purified; F = 80-82 ° C. An analytical sample (S = 82-83.5 ° C) to) is obtained by sublimating again.

Analysis Calculated for C14H9BrF4: C = 50.49 p; H = 2.72%; Br = 24.00 %; found: C = 50.51; H = 2.81%; Br = 23.78%.

B. 4- (α, α, ß, ß-tetrafluorothoenethyl) -benzonitrile After The procedure of Example 4 is 4-bromo-α, α, α ', α'-tetrafluorobibenzyl converted into 4- (α, α, ß, ß-tetrafluorophenethyl) benzonitol. The raw one crystalline product is purified by sublimation at 850 C and 0.02 mm Hg; F. = 118-123 ° C. By subliming again you get a nearly white solid one Material ; F - = 120.5-123 ° C. An analytically pure sample is obtained by recrystallization obtained from hexane and repeated sublimation; F = 123.5-125.5 ° C.

Analysis Calculated for C15H9F4N: C = 64.52%; H = 3.25%; g = 5.02 7'c; found: C = 64.76; H = 3.37%; N = 4.80%.

C. 4- (α, α, ß, ß-Tetrafluorophenethyl) -benzylamine According to the example 5 becomes 4- (α, α, ß, ß-tetrafluorophenethyl) -benzonitrile to 4- (α, α, ß, ß-tetrafluorophenethyl) -benzylamine reduced. The white crystalline product (F = 99.5-102 ° C) is sublimated cleaned at 90 ° C and 0.01 mm Hg; B = 101-103 ° a.

Analysis Calculated for C15H13F4N: C = 63.57%; H = 4.62%; N = 4.94 %; found: C = 63.66%; H. = 4.80%; N = 4.97.

The base can be converted into the hydrochloride by adding a Solution of the same in ethanol with a small excess of ethanolic hydrogen chloride offset. The hydrochloride separates out in the form of white flakes; F = 252-253 ° C.

When recrystallizing further from ethanol, the melting point remains unchanged.

Analysis Calculated for C15H13F4N.HCl: C = 56.35%; H = 4.41%; N = 4.38%; found: C = 56.37 d -; H = 4.48%; N = 4.35%.

B e 1 5 p 1 e 1 90 "-Methyl-4 - (=,", ß, ß-tetrafluoroshenethybenz / ramine A. 4 '- (α, α, ß, ß-Tetrafluorophenethyl) -acetochenone A solution of 3.3 g (0.0118 mol) 4- (α, α, ß, ß-tetrafluorophenethyl) benzonitrile in 25 ml dry, peroxide-free tetrahydrofuran is stirred to a solution of 0.03 Moles of methyl magnesium bromide in 25 ml of absolute ether were added dropwise under nitrogen. The mixture is stirred at reflux temperature for 26 hours. After cooling in the Ice bath, the adduct is hydrolyzed by adding dropwise 5 ml of water and the mixture diluted with 50 ml of ether. The organic phase is decanted and the gelatinous Precipitate washed thoroughly with ether. The combined ether extracts become Washed once with water, in several portions with 15 ml of ice-cold 6N hydrochloric acid extracted, then washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, remains as Product an oily solid residue. By subliming at 95 to 1000 C and 0.02 mm mg gives white crystals; F = 128-133 ° C. An analytically pure sample (F = 134-135.5 ° is obtained by repeated recrystallization from hexane and repeated sublimation manufactured.

Analysis Calculated for C16H12F4O: C = 64.86%; H = 4.08%; F = 25.65 %; found: C = 65.09%; H = 4.31%; F = 25.23%.

B. 4 '- (α, α, ß, ß-Tetrafluorophenethyl) -acetophenone oxime One Solution of 1.1 g (0.00372 mol) 4 '- (α, α, ß, ß-tetrafluorophenethyl) acetophenone, 0.7 g (0.0071 mol) of hydroxylamine hydrochloride, 8.5 ml of absolute ethanol and 1.5 ml dry pyridine is heated to reflux temperature for 6 hours. The solvents are evaporated under reduced pressure and the solid residue is washed with water stirred. The crystalline product (m.p. 137-139 ° C) is collected and made from hexane recrystallized. White needles are obtained; F = 139-141 ° C. Avg Recrystallization from hexane gives an analytical sample; F = 140-141 ° C.

Analysis Calculated for C16H13F4N0: C = 61.73%; H = 4.21; N = 4.50 %; found: - C = 61.90%; H = 4.20%; N = 4.50%.

C. α-Methyl-4- (α, α, ß, ß-tetrafluorophenethyl) benzylamine A solution of 2.45 g (0.00787 mol) of 4 '- (α, α, ß, ß-tetrafluorophenethyl) acetophenone oxime in 47 ml of absolute ethanol and 3 ml of an 8 normal hydrogen chloride solution in ethanol is with 1.0 g of 5 percent palladium on carbon under hydrogen at atmospheric pressure and stirred at 27 ° C until hydrogen absorption is complete. The catalyst will filtered off, and remains after evaporation of the filtrate under reduced pressure a solid residue which is stirred with benzene and ether. The insoluble hydrochloride the product is collected; F = 210-213 ° C. By repeated recrystallization from a mixture of ethanol and ether, from acetone and from a cold mixture the purified hydrochloride is obtained from methanol and ether; F = 216-217 ° C. That Salt is suspended in water and the ice-cold mixture with 5 percent aqueous Sodium hydroxide solution made strongly alkaline and the base extracted with benzene. After this Evaporation of the washed and dried benzene extract leaves the product in the form of a white crystalline solid substance; F = 63.5-66 ° C.

An analytically pure sample is obtained by subliming at 600 a and 0.05 mm Hg manufactured; .F = 64.5-66 ° C.

Analysis -Calculated for C16H14F4N: C = 64.65%; H = 5.09%; N = 4.71 %; found: C = 64.55%; H = 5.07?, A '; N = 4.72%.

The base can be converted back into the hydrochloride, by making a solution of the same in methanol with a slight excess an 8 normal hydrogen chloride solution in ethanol. When diluting with The white crystalline hydrochloride precipitates with absolute ether; F = 215-217 ° C. By Recrystallization from a mixture of methanol and ether gives an analytically pure Sample; F = 218-219 ° C.

Analysis calculated for C16H15F4NeHCl: @ a = 57.58%; H = 4.83%; N = 4.20%; found: C = 57.22%; H = 4.7-5 f; N = 4.15%.

B e i 8 p i e l 91 a «-dimethyl-4- (a, a, ß, ß-tetrafluorophenethybenzylamine A. 2- [4- (α, α, ß, ß-Tatrafluorophenethyl) -phenyl] -propanol-2 According to the example 88 becomes 4- (α, α, ß, ß-tetrafluorophenethyl) -phenylmagnosium bromide from 4-bromo-α, α, α ', α'-tetrafluorobibenzyl prepared and with acetone to 2- [4- (α, α, ß, ß-tetrafluorophenethyl) -phenyl] -propanol-2 implemented. The crude, oily, solid product is purified by column chromatography on silica gel, the product being eluted with chloroform. Those Fractions produced by thin layer chromatography on silica gel and development with chloroform show a stain with an Rf value of 0.25, with each other united. Evaporation of the solvent under reduced pressure gives the residue is the white crystalline product; F = 60-62 ° C. An analytically pure sample is made by subliming at 60 ° C and 0.02 mm Hg; F = 62-63.5 ° C.

Analysis calculated for 017H16F40: c = 65.37%; H = 5.16%; F = 24.33 %; found: C = 65.46%; H = 5.19%; F = 24.52%.

B. 2- [4- (α, α, ß, ß-tetrafluorophenethyl) phenyl] propanol-2 A solution of 500 mg (0.00169 mol) of 4 '- (α, α, ß, ß-tetrafluorophenethyl) acetophenone in 18 ml of absolute ather is under Stir at room temperature under Nitrogen to a solution of 0.00189 moles of methyl magnesium bromide in 5 ml of absolute Ether added dropwise. After heating at reflux temperature for 4 hours and allowing to stand overnight at room temperature, the mixture is cooled in an ice bath and added dropwise hydrolyzed by 4 ml of water. After filtering, the ether layer is removed from the The filtrate was separated, washed with water and dried over anhydrous magnesium sulfate. After the solvent has evaporated off under reduced pressure, the crystalline product as residue. Obtained by subliming at 670 C and 0.02 mm Hg one purified material; F = 54-60 ° a.

C. N- [α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) -benzyl] formamide According to Example 88, 2- [4- (α, α, ß, ß-tetrafluorophenethyl) -phenyl] -propanol-2 by the Ritter reaction in N- [α, α, -Dimethyl-4- (α, α, ß, ß-tetraflurophenethyl) -benzyl] -formamide convicted. The crude, oily, solid mixture is analyzed by column chromatography Silica gel and decomposed the product with chloroform, and with 2 percent Eluted methanol in chloroform. Those fractions found in thin layer chromatography on fluorescent silica when developed with chloroform showing an Rf value of 0.17 are combined with each other. After evaporation of the solvent under reduced pressure, the white crystalline remains Product; F = 115.5-117 ° C. By recrystallization from a mixture of absolute Ether and petroleum ether give an analytically pure sample; F = 116.5-118 ° C.

Analysis Calculated for C18H17F4N0: C = 63.71%; H = 5.05 do; N = 4.13 ??; found: C = 63.96%; H = 4.83%; N = 4.01%.

D. 2- [4- (α, α, ß, ß-tetrafluorophenethyl) phenyl] propene If one the crude, oily, solid mixture, which by the Ritter reaction from 2- [4- (α, α, ß, ß-tetrafluorophenethyl) -phenyl] -propanol-2 is obtained according to Example 91-C, column chromatography on silica gel Subjected, one obtains 2- [4- (α, α, ß, ß-tetrafluorophenethyl ~ -phenyl] -propene as a second component. Those fractions that are a major component on the solvent front in thin layer chromatography on fluorescent silica and developing show with chloroform are combined. After evaporation of the solvent under The white crystalline product remains under reduced pressure; F = 97-104 ° C. Avg Sublimation at 800 ° C. and 0.02 mm Hg gives a purified sample; F = 106.5-111 ° C.

Analysis Calculated for C17H144: C = 69.38%; H = 4.79 7'a; found: C = 69.58 io; H = 4.83? E. N- [α, α-Dimethyl-4- (α, α, β, β-tetrafluorophenethyl) benzyl] formamide According to Example 88, 2- [4- (α, α, β, β-tetrafluorophenethyl) phenyl] propene is used by the Ritter reaction in N-C «,« - dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) -benzyl] -formamide convicted. The purified product (melting point 115-119 ° C.) is obtained by column chromatography of the crude silica gel as described in Example 91-C.

F. α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) -benzylamine According to Example 88, N- [α, α-dimethyl-4- (α, α, β, β-tetrafluorophenethyl) benzyl] formamide is used to α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluoropkenethyl) -benzylamine hydrolyzed. The hydrochloride of the product (1, = 271.5-272.5 ° C.) is isolated. By repeated recrystallization from mixtures of absolute ethanol and absolute ether gives the purified hydrochloride; F = 274-275 ° C.

Analysis Calculated for C17H17F4N.HCl: C = 58.71%; H = 5.22%; N = 4.02 i0; found: C = 58.55%; H = 5.26%; N = 4.09.

B e i s p i e l 92 α, ß, ß-Tefrafluorophenethyl) -α, α, N-trimethylbenzylamine Following the procedure of Example 6, N- [α, α, -Dimethyl-4- (α, α, β, β-tetrafluorophenethyl) benzyl] formamide is obtained to 4- (α, α, ß, ß-tetrafluorophenethyl) -α, α, N-trimethylbenzylamine reduced. The crude base is converted to the dihydrogen citrate by adding a Solution of the same in isopropyl alcohol with a solution of a molar equivalent Citric acid added to isopropyl alcohol. When diluted with absolute ether it falls the dihydrogen citrate in the form of white crystals; F = 169-170 ° C (decomp.). By Recrystallize from a mixture of absolute ethanol and absolute methanol a purified sample is obtained; F = 166-168 ° C.

Analysis Calculated for C18H19F4N.C6H807: C = 55.70%; H = 5.26; - N = 2.71%; found: C = 55.82,000; H = 5.23%; N = 2.53%.

The base can be purified by sublimation at 800 C and 0.02 mm Hg white crystals are obtained; F = 65-800C.

The purified base is converted into the hydrochloride by a solution of them in absolute ether with a slight excess of an 8.2 normal Hydrogen chloride solution is added to ethanol. The hydrochloride falls (F = 203-2050C) the end. An analytically pure sample (temperature = 206-208 ° C) is obtained by repeated recrystallization from ethanol.

Analysis Calculated for C18H19F4N.HCl: C = 59.76%; H = 5.57%; N = 3.87 sp; found: C = 59.92%; H = 5.55%; N = 3.68 ço.

For example 93 4- (α, α, ß, ß-tetrafluorophenethyl) -α, α, N, N-tetramethylbenzylamine A solution of 5.8 g (0.0167 mol) of α, α, -dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) -benzylamine hydrochloride in 8 ml of 88 percent formic acid is mixed with 3 g (0.1 mol) of 37 percent formaldehyde added and the mixture was stirred overnight at 95 ° C. in an oil bath ml of concentrated hydrochloric acid to the cooled mixture, the solution is reduced under reduced pressure Pressure evaporated to dryness. The remaining syrup is dissolved in 120 ml of water and made the solution strongly alkaline with 40 percent aqueous sodium hydroxide solution. The base is extracted with benzene. After evaporation of the washed and dried Benzene extract under reduced pressure leaves the product in the form of an oil; Yield 6.7g. According to a comparison with an authentic one, this product contains Sample unreacted starting material by thin layer chromatography. The base is converted into the mixed hydrochloride by adding a solution of the same in Isopropyl alcohol with a slight excess of an 8.2 normal hydrogen chloride solution is added to ethanol. When diluted with ether, the mixture of hydrochlorides falls the end; F = 182-190 ° C. This material is made with a similar blend of a previous experiment combined, and a solution of 7.75 g of this material in 13.3 5.3 g of 37 percent formaldehyde are added to ml of 88 percent formic acid.

The mixture is heated to 950 ° C. in an oil bath for 2 1/2 days while stirring. By working up according to the method described above, the oily base is obtained which is then converted into the hydrochloride by the process described above, which occurs in the form of white crystals; F = 171-173.5 ° C.

The analytically pure is obtained by recrystallization from isopropyl alcohol Sample; F = 174i75.5O C.

Analysis Calculated for C19H21F4N.HCl: C = 60.72%; H = 5.90%; N = = 3.72 o; found: C = 60.90%; H. = 5.75?, O; N = 3.84?, G.

B e i 5 p i e 1 94 4- (p-methyl-α, αβ, β-tetrafluorophenethyl) -α, α, N-trimethylbenzylamine A. 4-Bromo-4'-methylbenzoin A solution of 67 grams (0.314 moles) of p-bromophenylglyoxal in 300 ml of dry toluene is in the course of 1 1/2 hours with stirring to a suspension of 84 g (0.6 mol) of anhydrous aluminum chloride cooled in an ice bath added dropwise in 1.25 1 dry toluene. The mixture is stirred in the cold for a further 5 hours and keep the mixture overnight at 5 to 100 C. The mixture is in 2 1 ice and Poured 6N hydrochloric acid. The aqueous phase is separated and three times with benzene extracted. The combined, washed and dried organic extracts are concentrated to 200 ml under reduced pressure. When diluting with 150 ml of petroleum ether the white crystalline product precipitates; F = 80-82 ° C. By recrystallizing several times an analytically pure sample is obtained from 60 percent ethanol; F = 82-83.5 ° C.

Analysis Calculated for C15H13BrO2: C = 59.02%; H = 4.29; found: C = 59.18 C%; H = 4.27 fo.

B. 4-Bromo-4'-methylbenzil 90 g (0.36 mol) of copper (II) sulfate heated with stirring on the steam bath with 110 ml pyridine and 45 ml water until complete Solution has occurred. 55 g (0.18 mol) of 4-bromo-4'-methylbenzoin are added and heat the mixture on the steam bath with stirring for 3 hours. This separates the yellow crystalline product. After cooling and diluting with water it becomes the product collected, washed with water, in hydrochloric acid and again with water and dried; F = 132-135 ° C.

Obtained by repeated recrystallization from 95 percent ethanol an analytically pure sample in the form of yellow needles; F = 136-137 ° C.

Analysis Calculated for C15H11BrO2: C = 59.41%; H = 3.66%; found: C = 59.49%; H = 3.59 0.

C. 4-Bromo-4'-methyl-α, α, α ', α'-tetrafluorobibenzyl Following the procedure of Example 83, the 4-bromo-4'-methylbenzil is converted into 4-bromo-4'-methyl-α, α, α ', α'-tetrafluorobibenzyl converted. The crystalline crude product is sublimated at 90 ° C and 0.05 mm Hg purified. The white crystals melt at 103.5-105.5 ° C. By doing it again Sublimation gives an analytically pure sample.

Analysis Calculated for C15H11BRF4: C = 51.88%, H = 3.19%; Br = 23.01 %; found: C = 51.87 7'o; H = 3.18%; Br = 23.14%.

D. 2- [4- (p-Methyl-α, α, β, β-tetrafluorophenethyl) phenyl] propanol-2 Following the procedure of Example 88, 4- (p-methyl-α, α, ß, ß-tetrafluorophenethyl ) -phenylmagnesium bromide from 4-bromo-4'-methyl-α, α, α ', -'-tetrafluorobibenzyl prepared and with acetone to 2- [4- [p-methyl-α, α, ß, ß-tetrafluorophenethyl) -phenyl] -propanol-2 implemented. The oily solid crude product is purified by column chromatography on silica gel, the product being eluted with chloroform. The parliamentary groups those in thin-layer chromatography on fluorescent silica during development showing a spot with an Rf value of 0.25 with chloroform are combined.

Remains after evaporation of the solvent under reduced pressure the pale yellow solid product; F = 83-8 ° C.

By subliming at 800 C and 0.05 mm Hg and recrystallizing Petroleum ether gives an analytically pure sample in the form of white crystals; F, = 88-90 ° C.

Analysis Calculated for C18H18F40: C = 66.25%; H = 5.56? Jo; F = 23.29% ; found: C = 66.18%; H = 5.50%; F = 23.33%.

E. N- [α, α-Dimethyl-4- (p-methyl-α, α, β, β-tetrafluorophenethyl) benzyl] formamide Following the procedure of Example 88, 2- [4- (p-methyl-α, α, β, β-tetrafluorophenethyl) phenyl] propanol-2 by the Ritter reaction in N- [α, α-dimethyl-4- (p-methyl-α, α, kβ, ß-tetrafluorophenethyl) benzyl] formamide convicted. The crude solid mixture is purified by column chromatography on silica gel decomposed and the product with chloroform and with 2 percent methanol in chloroform eluted. Those fractions which are fluorescent in thin layer chromatography Silica had a major spot with an Rf value when developed with chloroform of 0.15 are pooled.

Remains after evaporation of the solvent under reduced pressure the pale yellow crystalline product; F = 109-119 ° 0. By repeated recrystallization from mixtures of ethanol and water as well as from ether and petroleum ether one obtains an analytically pure sample; F = 121-122.5 ° C.

Analysis Calculated for C19H19F4NO: C = 64.58%; H = 5.42%; N = 3.96 ° / f; found: C = 64.34%; H = 5.35 7 '; N = 3.76.

F. 4- (p-Methyl-α, α, β, β-tetrafluorophenethyl) -α, α, N-trimethylbenzylamine Following the procedures of Example 6, N- [α, α, -Dimethyl-4 (p-methyl-α, α, β, β-tetrafluorophenethyl) -benzyl] -formamide to 4- (p-methyl-α, α, ß, ß-tetrafluorophenethyl-α, α, N-trimethylbenzylamine reduced. The crude oily 3ase is converted into the hydrochloride by one Solution of the same in ethanol with a slight excess of 8 normal hydrogen chloride added to ethanol. When diluting with absolute ether, this falls white crystalline hydrochloride from; F = 189-190 ° C. When recrystallizing from a mixture from isopropyl alcohol and ether, the melting point remains unchanged.

Analysis Calculated for C19H21F4NHCl: C = 60.72%; H = 5.90%; N = 3.73 7'o; found: C = 61.12%; H = 5.81% N = 3.61%.

For example 1 95 α, α, -Dimethyl-4- (p-methyl-α, α, ß, ß-tetrafluorophenethyl) -benzylamine Following the procedure of Example 88, N - «,« - dimethyl-4 (p-methyl - «,«, ß, ß-tetrafluorophenethyl) benzy see below α, α-dimethyl-4- (p-methyl-α, α, ß, ß-tetrafluorophenothyl) benzylamine hydrolyzed. The hydrochloride of the product (F = 254.5-256.5 ° C) is isolated. A purified sample is obtained by recrystallization from absolute ethanol; F = 256-258 ° C.

Analysis Calculated for C18H19F4N.HCl: C = 59.75%; H = 5.57 Ω; N = 3.87%; found: C = 59.70%; H = 5.59; N = 3.90.

For example 1 96 2-Amino-4-methyl-N- [2- (α, α, ß, ß-tetrafluorophenethyl) benzyl] valeric acid amide 3.7 g (0.0146 mol) of Woodward's reagent K are in 25 ml of freshly distilled dry Stirred acetonitrile, and the mixture is cooled to -50 ° C. in an ice-salt bath. A solution of 3.9 g (0.0146 mol) of N-carbobenzoxy-L-leucine and 1.5 is then added dropwise g (0.0146 IIol) of triethylamine in 40 ml of acetonitrile at such a rate that the temperature remains at -5 to 0 ° C. The mixture is 55 minutes below 0 ° C and then stirred for 1 hour at room temperature. After another cooling of the solution to -5 ° C is a solution of 2.75 g (0.0097 mol) of 2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine in 12 ml of acetonitrile were added dropwise. The mixture is 1 hour below 0 ° C and stirred for 3 hours at room temperature and then stand at room temperature calmly.

After evaporation of the solvent at room temperature under reduced The viscous yellow oil that remains behind as residue is under pressure between methylene chloride and water, which is weak with a few drops of 40 percent aqueous sodium hydroxide solution has been made alkaline. The methylene chloride extract is mixed with water, washed with in hydrochloric acid and again with water and over anhydrous sodium sulfate dried. Remains after evaporation of the solvent under reduced pressure the N-carbobenzosyl derivative of the product as a yellow oil.

A solution of 6.6 g of the oily N-carbobenzoxy derivative in 60 ml of absolute Ethanol is at atmospheric pressure and room temperature over 2 g of 5 percent palladium Shaken on charcoal with hydrogen until hydrogen absorption ceases is. The catalyst is filtered off, and after evaporation of the solvent under reduced pressure, the product remains as a pale yellow oil. The base will converted into hydrogen fumarate by dissolving it in absolute ether mixed with a solution of an excess of fumaric acid in absolute ethanol will. Upon further dilution with ether, the 2-amino-4-methyl-g- g - («,«; ß, ßtetrafluorophenethyl) benzyl] valeric acid amide hydrogen fumarate in the form of white tristaIIe; F = 137-140 ° C (decomp.).

By repeated recrystallization from mixtures of methanol and Ether, a purified sample is obtained (F = 140.5-141.5 ° C, decomp.).

Analysis Calculated for C21H24F4N2O-C4H4O4: C = 58.59 p; H = 5.51% ; N = 5.47%; found: C = 58.74%; H = 5.50%; N = 5.50 7o.

B B e i s p i e 1 97 salts of α, α, -dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) benzylamine h. Dimethyl 4- (α, ß, B-tetræfluorophenethyl) benzyl aminate 15 g (0.1 mol) sodium isethionate are dissolved in 50 ml of water, and the solution is in poured a thoroughly washed column that. 160 g of an organic, strong acidic cation exchanger in the hydrogen ion form ("Rexyn 101 X"). The column is eluted with water until the drain, the total amount of which is 400 ml, has a pH of 5.5. The effluent is concentrated to 50 ml in vacuo and the concentration of isathionic acid in the solution by potentiometric titration determined to be 3.8 molar.

4.1 g (0.0132 moles) of α, α, -dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) benzylate are dissolved in 20 ml of isopropyl alcohol, and the solution is 3.7 ml of the 3.8 molar Isäthionsäurelösung added. After diluting with 400 ml of absolute ether begins the crystallization of the isethionate. After standing for several hours at room temperature the product is collected, washed with absolute ether and dissolved in 300 ml of benzene. The water is driven off by azeotropic distillation with 200 ml of benzene. the end the remaining solution becomes the product by diluting it with 200 ml of absolute ether failed; Yield 5.8 g; F = 134.51360 C. By recrystallization from 50 ml isopropyl alcohol and 200 ml of absolute ether, the melting point rises to 135-136.5 ° C.

Analysis -Calculated for C17H17F4n.C2H6O4S: C = 52.17%; H = 5.30 %; N = 3.20%; S = 7.51%; found: C = 52.33%; H = 5.31 Ω; N = 3.10?; S. = 7.41, -.

For the asa-dimethyl-4- (a, «, ß, ß-tetrafluorophenetnyl) -benzylamine-isethionate the following physical characteristics were determined: Water solubility: > 400 mg / ml pH of a 1 percent aqueous solution: 4.7 B. α, α-dimethyl-4- (α, α, ß, ß-tetrafluprphenethyl) -benzylamine - (+ -) - lactate 6.0 g (0.0172 mol) of α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) -benzylamine hydrochloride are suspended in saturated sodium carbonate solution, and the base is made with hexane extracted. The combined hexane extracts are washed thoroughly with water and over anhydrous magnesium sulfate; getroclmet. By evaporating the solvent under min-.

This pressure gives 5.3 g of white crystalline base; F = 82-84 ° C.

A solution of 0.017 mol of the base in 25 ml of acetone is with a Solution of 1.85 g (0.0175 mol) of 85 to 90 percent (+ -) lactic acid in 5 ml of acetone offset. After diluting with 125 ml of absolute ether, the lactate begins to slowly begin crystallize out. After standing for 5 hours at room temperature and 16 hours Cooling to 00 C. the product collected; Yield 6.5 g (95); F = 146-148 ° C. Recrystallization from 30 ml of acetone and 125 ml of absolute ether gives an initial yield of 4.75 g; F = 146-148 ° C.

Analysis Calculated for C17H17F4N.03H603: C = 59.84%; H = 5.78%; N = 3.49%; found: c = 59.78%; H = 5.75%; N = 3.36.

C. Other salts of α, α-dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) benzylamine A solution of the base α, α-dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) -benzylatin in isopropyl alcohol is titrated with an equivalent amount of the respective acid, whereby the corresponding salt is formed, which when an equal volume is added Ether completely precipitates out of solution. The precipitated salt is then used by the solution filtered off and dried. In the following table Salts prepared in this way are given with their physical constants.

Reagents and salts Free base Acid reagent Salt A. α, α-Dimethyl-4- Maleic acid α, α, -Dimethyl-4- (α, α, (α, α, ß, ß-tetra- ß, ß-tetrafluorophenefluorophenethyl) -thyl) -benzylaminebenzylamine hydrogen maleate B. Citric acid «,« - dimethyl-4- («,«, ß, ß-tetrafluorophenethyl) benzylamine dihydrogen citrate C. 1 'Tartaric acid α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl ) -benzylamine (+) - hydrogen tartrate D. "Phosphoric acid α, α-dimethyl4- (α, α, ß, ß-tetrafluorophenethyl) -benzylamine-dihydrogenpho 5 phathydrate E. "Sulfuric acid α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) benzylamine sulfate trihydrate F. "Methanesulfone-α, α, -Dimethyl-4- (α, α, acid β, β-tetrafluorophenethyl) -benzylamine methanesulfonate.

Analysis o H N Melting point, ° C de- fun- rech- funnet den net den net den A. 160-161 59.01 59.43 4.95 5.10 3.28 3.20 B. 165-166 54.87- 54.87 5.01 5.15 2.78 2.58 C. 185-187 (dec.) 54.66 54.60 5.02 5.46 3.04 2.76 D. 251-253 53.96 53.51 5.46 5.21 3.70 3.71 E. 209.5-211.5 52.70 52.51 5.46 5.00 3.62, 52 F. 206.5-211.5 53.06 53.22 5.20 5.32 3.44 3.32

Claims (6)

Claims 1. Compounds of the general formula in which X and X 'are hydrogen atoms, alkyl groups with up to 6 carbon atoms, alkenyl groups with up to 6 carbon atoms, perfluoroalkyl groups with up to 4 carbon atoms, unsubstituted or substituted phenyl radicals, amino groups, alkylamino groups with up to 4 carbon atoms, dialkylamino groups with up to 8 carbon atoms, Alkylsulfonylamino groups with up to 4 carbon atoms, halogen atoms (fluorine, chlorine, bromine or iodine), hydroxyl groups, alkoxy groups with up to 1 carbon atoms, perfluoroalkoxy groups with up to 4 carbon atoms, mercapto groups, alkyl mercapto groups with up to 4 carbon atoms, perfluoroalkyl mercapto groups with up to 4 carbon atoms, Alkylsulfonyl groups with up to 4 carbon atoms, perfluoroalkylsulfonyl groups with up to. to 4 carbon atoms, sulfamoyl groups, alkylsulfamoyl groups with up to 4 carbon atoms or dialkylsulfamoyl groups with up to 8 carbon atoms, n can be 2 or 3, Rl is a hydrogen atom or a lower alkyl group, m is an integer from 1 to 4 inclusive and A is a phenyl radical , a cycloaliphatic ring, a heterocyclic aromatic ring having 5 or 6 atoms, or a partially or fully reduced heterocyclic ring. 2. Compounds according to claim 1, characterized by the general formula 3. Compound according to claim 1, characterized by the structural formula 4. A compound according to claim 1, characterized by the structural formula 5. Process for the preparation of compounds of the general formula in which X and X 'have the meanings according to claim 1, n is 2 or 3, R1 is a hydrogen atom or a lower alkyl radical and A is a phenyl radical, a cycloaliphatic ring, a heterocyclic aromatic ring with 5 or 6 atoms or partially or completely reduced heterocyclic ring, characterized in that the corresponding compound of the general formula with an acylating agent from the group of halides of lower aliphatic carboxylic acids, which converts anhydrides of lower aliphatic carboxylic acids and the lower alkyl formates. 6. The method according to claim 5, characterized in that A is a means unsubstituted or substituted phenyl radical.