DE2166184A1 - 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

Fluoroalkylbenzonitriles and their preparation The invention relates to new fluoroalkylbenzonitriles, the intermediates for the production of benzylamines with pharmacological properties are.

The new compounds 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 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 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 and A is a phenyl res t, a cycloaliphatic ring, a heterocyclic aromatic ring with 5 or 6 atoms or a partially or fully reduced heterocyclic ring.

The compounds which can be prepared from the compounds according to the invention are terminally disubstituted perfluoroalkane compounds, one terminal substituent of which is an aromatic ring in which at least one of the hydrogen atoms is substituted by a straight or branched-chain aminoalkyl radical or a heterocyclic amino radical, while the other terminal substituent is a homocyclic or heterocyclic Ring, namely an aryl radical, a substituted aryl radical, a heterocyclic radical or a substituted heterocyclic radical. The compounds according to the invention correspond to the general formula in which n is an integer of 2 or 3, A is a substituted or unsubstituted homocyclic or heterocyclic ring with 5 or 6 atoms, such as an aromatic ring, a heteroaromatic ring or a partially or fully reduced aromatic or heteroaromatic ring, and B is an amino-substituted, means straight or branched aliphatic or heterocyclic side chain having 1 to 8 carbon atoms which is attached to the benzoid ring by one or more carbon-carbon bonds.

The preferred class of compounds that can be prepared are the aminoalkylarylperfluoroalkanes of the general formula 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 are identical to or different from one another, represent hydrogen atoms, alkyl groups (preferably having 1 to 6 carbon atoms), alkenyl or alkynyl groups or form a heterocyclic ring with 5 or 6 atoms, such as imidazolinyl, piperidyl, pyrroldinyl, morpholinyl -, Thiomorpholinyl- or nied.Alkylpiperazinylrestes, can be joined together or to the aromatic ring or one of the methyl substituents which 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 or a partially or fully reduced derivative thereof.

There are also compounds of the compounds according to the invention of the above general formula can be prepared, in which one or more of the heterocyclic Aryl rings or one of the reduced derivatives are further substituted. A preferred one A group of such compounds are derivatives in which one or more hydrogen atoms of the phenyl ring and / or one or more hydrogen atoms of the one represented by A. Ring by substituents from the group of 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, the unsubstituted or substituted phenyl radicals, Acyl groups with up to 4 carbon atoms, perfluoroacyl groups with up to 4 carbon atoms, Amino groups, alkylamino groups with up to 4 carbon atoms, alkylaminoalkyl groups with up to 8 carbon atoms, dialkylamino groups with up to 8 carbon atoms, Dialkylaminoalkyl groups with up to 10 carbon atoms, acylamino groups with up to with 4 carbon atoms, perfluoroacylamino groups with up to 4 carbon atoms, AlkylsulfoKylamino groups with up to 4 carbon atoms, halogen atoms (fluorine, Chlorine, bromine or iodine atoms), hydroxyl groups, alkoxy groups with up to 4 carbon atoms, Perfluoroalkoxy groups with up to 4 carbon atoms, cyano groups, carboxyl groups, Carbamoyl groups, alkylcarbamoyl groups with up to 5 carbon atoms, dialkylcarbamoyl groups with up to 9 carbon atoms, carbalkoxy groups with up to 6 carbon atoms, Mercapto groups, alkyl mercapto groups with up to 4 carbon atoms, perfluoroalkyl mercapto groups with up to 4 carbon atoms, 3 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 and the dialkylsulfamoyl groups with up to 8 carbon atoms are replaced.

Each ring can also have several of these substituents.

A particularly preferred group of compounds which can be prepared from the compounds according to the invention 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 radical) can be joined together.

Examples of compounds that can be prepared are 2- (2-phenyl-1,1, -2,2-tetrafluoroethyl) benzylamine, α-methyl-2- (2-phenyl-1, 1,1,2,2-tetrafluoroethyl) benzylamine, α, α-dimethyl-4- (2-phenyl-1,1,2,2-tetrafluoroethyl) -benzylamine, α-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, as well as the corresponding N, N-disubstituted derivatives, especially the N, N-dialkyl derivatives.

The above-mentioned compounds-exhibit 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 Darren chung 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.

The compounds of the above general formula can be prepared as follows: Flow diagram I. 9 This process stage can include further process stages for the production of the next higher homolog, in that 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, the latter group is converted into OH2k (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 benzene or methyl groups), alkenyl, alkynyl groups or may with each other or with one of the methylene carbon atoms that represent the amine substituent and connects the phenyl ring, or through 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 3rom 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 atoms); and A is an aromatic ring, like the phenyl ring, a cycloaliphatic ring, a heterocyclic aromatic ring with 5 or Ó atoms or a part-way or 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 riketone compound is obtained I mit.Schulfeltetrafluorid to the corresponding. Diaryl perfluoroalkyl compound, such as 2-bromo-α, α, α ', α'-tetrafluorobibenzyl 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 riketone with excess sulfur tetrafluoride and catalytic amounts of one.

Lewis acid such as hydrogen fluoride, boron trifluoride or the like.

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 fluorine 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 phenylperfluoroalkylbromobenzene thus obtained 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 0. The product can be easily processed in a conventional manner by removing the metal salts that precipitate from the reaction mixture, nitrating, Evaporation of the solvent and possibly recrystallization gain.

The phenyl perfluoroalkylbenzonitrile then becomes the corresponding Benzylamine, e.g. 2- (2-phonyl-1,1,2,2-testrafluoroethyl) 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, like tetrahydrofuran, ether or other, usually together with lithium aluminum hydride solvent used. This reduction is preferably carried out in the presence of aluminum chloride and an ether compatible with aluminum chloride as a solvent. The temperature at which the reduction is carried out is not particularly critical; however, it is preferred to operate at room temperature and a temperature range of 0 to 500 C is satisfactory. the benzylamine compound thus obtained can be easily obtained by conventional methods.

To produce higher homologues of the benzylamine compound, the Phenylperfluoroalk'ylarylnitrile obtained as an intermediate by known methods converted into the desired compounds. For example, you can use the intermediate product 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 Bebzibutruke used as the starting material in the next higher homolog, namely da Ogebtkoerfkyirakkjtk-phenylaceto nitrile.

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 aralkyla.mine, e.g., the benzylamine compound (IV), among known 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 IT, N-dimethylamine (VI)> in which the radicals R2 and R3 Methyl groups can be easily obtained by reacting the primary amine compound (V) with sormaldehyde and formic acid according to the well-known Eschweiler-Clarke modification the Leuckart reaction. The N, N-dimethylamine is obtained in a familiar way. The N-methyl aralkylamine, e.g., the N-methylbenzylamine, of the formula (VIII), wherein Alk is the methyl group, can either by reducing the corresponding N- (Phenylperfluoroalkylbenzyl) -formamide (V) or by monoentalkylation of the corresponding N, N-dimethylamine (VI)> where R2 and R3 are methyl groups, getting produced. The formamido-methyl derivative is reduced with lithium aluminum hydride among those described above for the reduction of the corresponding benzonitrile (III) Conditions. Likewise, the dealkylation of N, N-dimethylamine (VI) can be carried out in a known manner Way by treating with cyanogen bromide and subsequent hydrolysis of the intermediate product resulting cyanamide or by reaction with a haloformic acid ester and Carry out hydrolysis of the intermediate urethane. In both cases the desired connection can be obtained in a known manner.

The lower N-alkylamines and the lower N, N-dialkylamines, the Compounds (VII) and (VI) are also derived 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, e.g. 3. with acetyl chloride, acetic anhydride, propionic acid chloride, Butyric acid chloride or valeric acid chloride, to that of the formula (v) corresponding N-alkanoylamide, e.g. the N-acetyl-, N-propionyl-, N-butyryl- or N-valerylamide, around. The amide thus obtained is as above for the corresponding benzonitrile compound (III) described, with lithium aluminum hydride, to the corresponding lower wJ-all-ylbenzylamine compound (VI) reduced.

The secondary amine compounds (VII) prepared in this way are the lower N-alkyl derivatives of 2- (phenylperfluoroalkyl) -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 produced, inden that used to produce 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-dipropyl-, N, M-dibutyl or N, N-diamyl derivatives of substituted or unsubstituted phenylperfluoroalkylbenzylamine.

According to another process for the preparation of the compounds of general formula (VI), wherein the 1-pyrrolidinyl, 1-piperidyl, 4-morpholinyl, 4-thiomorpholinyl or 1-lower. Means alkyl-4-piperazinylnest, the primary amine (IV) with an o ', oc-dihalo compound, such as tetremethylene 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 by the following procedure.

Flowchart 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 D2arylperfluoroalkyl compound (II) under anhydrous conditions with magnesium to give Grignard's reagent (IIA) unset, which in turn is caused by the addition 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 benzyl 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 Amine nitrogen atom part of a heterocyclic ring, such as the piperidyl, Pyrrolidinyl, norpholinyl, thiomorpholinyl or 1-lower alkyl-4-piperazinyl ring, forms.

Another method can be used to remove the benzyl halide (IID) alkylated tetrafluorobibenzyl compounds, e.g. from 2,3-dimethyl-α, α, α ', '-tetrafluorobibenzyl, by adding the alkyl substituent to the corresponding molar amount of an N-bromimide, such as N-bromobernotoinoimide, selectively brominated. The aromatic ring may have one or more alkyl substituents, and if one chooses the correct molar amount of N-3romamid, becomes one or more Alkyl substituents by bromine. substituted, and the desired benzyl bromide compound is formed. The Br oin becomes sub 5 tituent 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 one 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- (a, a, ß, ß-tetrafluorophenethyl) -benzonitrile reacts with methyl magnesium bromide to a ketimine and this with lithium aluminum hydride reduced, a-l-ethyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine is obtained. If the benzonitrile used as the starting material is replaced by the homologous α, ß, ß-Tetrafluorophenethyl) -phenylacetonitrile, are those after the formation of the ketimine with the corresponding Grignard's reagent and reduction with lithium aluminum hydride products obtained the «-methyl-,« -ethyl- and α-propyl derivatives of 2- (α, α, ß, ß-tetrafluorophenethyl) phenethylamine.

According to another method for the preparation of such cc-alkyl-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 '- (α, α, ß, ß-tetrafuophenethyl) acetophenone compound converted will. The acetophenone compound is then converted into the corresponding in a conventional manner Oxime transferred, which. the latter into the desired one by catalytic hydrogenation α-alkyl substituted benzylamine compound is converted.

In addition to the α-alkyl-2- (α, α, ß, ß-tetrafluorophenethyl) -phenethylamine compounds, the corresponding α, α-disubstituted, ie dialkyl compounds from a bromine- or iodine-substituted diarylperfluoroalkyl compound of the above general formula II, in the Hal bromine or Iodine means to be made. The compounds prepared by the following process are, for example, 0 ', -dimethyl-, α, α-diethyl, α, α-dipropyl, α-methyl-α-ethyl, α-methyl-α-propyl, α-ethyl -α-propyl-, -Methyl-butyl- and -Methyl-α-isopropyl- (α,, ß, ß-tetrafluorophenethyl) -benzylamine. The corresponding N-alkyl or N, N-dialkyl derivatives, for example the N-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-propylderivate, are prepared by the same methods that on the previous pages for the conversion of the benzylamine into the corresponding N-alkyl or N, N-dialkyl derivatives have been described.

In the process described below for the preparation of the cc α, α-Dialkyl-substituted benzylamine compounds becomes one in the position No. 3 or 4 bromo substituted diaryl perfluoroalkyl compound among anhydrous Conditions with Magnesium converted into Grignard's reagent IIAi> then 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, Ethyl propyl ketone or methyl isopropyl ketone, converted into the corresponding by hydrolysis Benzyl alcohol IIA2 is converted, with the alkyl substituent on the carbinol carbon atom of benzyl alcohol are bound. Another method is to use the 3'- or 4'-perfluoroalkylphenyl-substituted acetophenone with a lower alkyl Grignardian Reagent reacted, and after hydrolysis is then obtained the o ', c'-dialkylbenzyl alcohol. The Grignard reagent IIA1 can also be reacted with carbon dioxide and the product hydrolyze to the corresponding benzoic acid. This acid is esterified and reacted with a Grignard lower alkyl reagent, after hydrolysis the α, α-dialkylbenzyl alcohol is obtained. This tertiary alcohol then becomes according to Ritter's reaction with alkali metal cyanide in sulfuric acid or methanesulfonic acid in the corresponding benzylformamide compound IIA3 Hub he led to the acidic Hydrolysis provides the desired c ', o'-dialkyl substituted benzylamine compound.

The di- and used as starting materials in the above process 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 Reacts heterocyclic bromophenyl ketimine and this under acidic conditions hydrolyzed to the phenylacetophenone or the heterocyclic phenacyl compound. As already mentioned, the heterocyclic part of the Mole is a heterocyclic part aromatic ring with 5 or 6 atoms, namely a pyrimidine, thiazole, thiophene, 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, a correspondingly substituted benzaldehyde is used a bromine or iodine substituted acetophenone in the presence of an acidic or alkaline one Condensing agent condensed, with a substituted as the first intermediate product Benzalacetophenone (A) is formed, which is isolated by conventional methods and converted into 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 an excess of alkali metal 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 dibenzoylmethane compound is with at least 2 molar equivalents of bromine to the corresponding dibenzoyldibromometalane compound (E) implemented. The dibromo compound one leaves with sodium acetate and glacial acetic acid react to convert the -Erom substituents through acetoxy substituents replace, and the compound so obtained is mixed with water to give the desired diarylpropane trione monohydrate compound (y) hydrolyzed, in turn by heating in vacuo with elimination of water is converted into the desired propanetrione that is used in the preparation of the perfluoroalkyl compounds (I) according to the invention is used as a starting material.

When the starting material-serving benzaldehyde compound by a heterocyclic aldehyde, such as thiophene-2-aldehyde, is obtained as Product a 1-aryl-3-heterooycl. propanetrione compound The used as starting materials 2-, 3- or 4-bromobenzonitriles or heterocyclic nitriles that have 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 Benzyl magnesium halide can also be easily synthesized using known synthetic methods make from the corresponding benzyl halide ago.

Example 1 2'-Bromo-2-phenylacetophenone A solution of 12.0 g (0.066 Mol) 2-bromobenzonitrile in 80 ml of absolute ether is stirred and under nitrogen added dropwise to a solution of benzyl magnesium chloride, which consists of 0.42 g (0.264 g-atom) Magnesium turnings and 33.42 g (0.264 diol) benzyl chloride in 140 ml absolute ether has been made.

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 the ice bath and rivet 15 percent ethanol in ether and then washed with absolute ether. After brief air drying, the salt becomes a cold mixture of methanol and ether recrystallized; F = 176-181 ° C.

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; Nd25.5 ° = 1.6050.

Analysis calculated for 014H11Br0: C = 61.11%; H = 4.03; Br = 29.04 %; found: C = 61.17; H = 3.97%; Br = 28.99%.

Example 2 2-bromobenzil 5.2 g (0.0189 mol) of 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 marked. 0.58 g (0.002 mole) 2-bromobenzil and 0.24 g (0.0022 mole) o-phenylenediamine are heated to reflux temperature in 10 ml of absolute ethanol for 3 hours. To 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 smilat 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 Vo; H = 3.55; N = 7.63%.

Example 3 2-Bromo-alpha;, alpha;, alpha; ', alpha;' - 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 rustproof autoclave 30 Minutes at room temperature, 2 hours at 1000 a, 2 hours at 1200 C and 6 hours shaken at 1400 a. 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 sample for analysis is made sublimated again.

Analysis calculated for C14HgBrF4: a = 50.49%; H = 2.72 -; Br = 24.00 %; found: C = 50.87; H = 2.94%; Br = 23; 33%.

B e i s p i e l 4 2- (alpha ;, alpha ;, ß, ß-tetrafluorophenethyl) benzonitrile A mixture of 3.33 g (0.01 mol) of 2-bromo-alpha;, alpha;, alpha; ', alpha;' - 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 evaporation of the solvent from the filtrate remains under reduced pressure the product is an oily brown solid. The purification is carried out by column chromatography of 150 g of silica, and the product is with a mixture of 3 parts of benzene and 1 part of hexane eluted. Those fractions found in thin layer chromatography on silica will give a spot with Rf = 0.7 when developed with benzene united. After evaporation of the solvents remain behind under reduced pressure white crystals; F = 84-86 ° C. An analytical sample sublimed at 550 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: a = 65.50 0%; H = 3.04 c%; N = 4.52%.

Example 5 2- (alpha ;, alpha ;, β, β-tetrafluorophenethyl) benzylamine 250 mg (0.0066 liol) lithium aluminum hydride are weighed out under nitrogen, in transferred to a dry, nitrogen purged reaction flask and poured into 15 ml suspended in absolute ether. A solution of 880 mg (0.0066 mol) of aluminum chloride is used for this added dropwise in 15 ml of absolute ether. The mixture that made a white precipitate contains, is stirred for 5 minutes at room temperature and then dropwise with a Solution of 0.942 g (0.00338 ilol) 2 - («,, ß, ß-detrafluorophenethyl) benzonitrile in 30 ml of absolute ether added. The mixture will take 18 hours Stirred 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 Ether becomes the precipitate in 20 ml of 40 percent aqueous sodium hydroxide solution and 200 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 submitted for analysis by sublimation purified at 470 a and 0.05 mm Hg; F = 55-57 ° C.

Analysis calculated for C15H13F4N: a = 63.57%; H = 4.62%; N = 4.94 ; found: C = 63.93%; H = 4w54; N = 4.94%.

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 0; found: C = 56.53%; H = 4.15%; N = 4.45.

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

When diluted with ether, the lactate precipitates; F = 144-146 ° C.

When recrystallizing from a mixture of isopropyl alcohol and Ether, the melting point remains unchanged.

Analysis Calculated for C15H13F4N-C3H603: C = 57.90%; H = 5.13%; found: C = 58.06%; H = 4.88%.

Example 6 N-Methyl-2- (alpha ;, alpha ;, β, β-tetrafluorophenethyl) benzylamine 1.4 g (0.005 mol) 2- (alpha;, alpha;, ß, ß-tetrafluorophenethyl) -benzylaamine are in 100 ml of ethyl formate were stirred at reflux temperature for 20 hours. By Evaporate the solution to dryness and stir the solid residue with something Petroleum ether is obtained N- [2- (alpha ;, alpha ;, ß-ß-tetrafluorophenethyl) - = benzyl] formanide ; F - = 61-75 ° C.

290 mg (0.0077 mol) of lithium aluminum hydride are added 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-g - (a, «, B, B-etrafluorophenethyl) -benzy g-formamide in 25 ml of absolute ether and the mixture is stirred for 18 hours at reflux temperature. After adding absolute ether, the mixture is cooled 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 washed.

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; F = 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 Xo; found: C = 57.86%; H = £ 4.68% o; N = 4.41 .

Example 7 N, β, β-tetrafluorophenethyl) benzylamine A solution of 2.2 g (0.006 mol) 2- (alpha ;, alpha;, ß, ß-tetrafluorophenethyl) benzyiamine (+) lactate in 3 ml of 88 percent formic acid is mixed with 1 g (0.013 mol) of 37 percent Pormaldehyde is added and the mixture is 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.HC1: C = 58.71%; H = 5.22%; N = $ 4.03%; Cl = 10.19%; found: C = 59.12%; H = 5.22; N = 3.83; al = 10.10 %.

B e i s p i e 1 e 8 to 66 B, N-dialkyl-2- [2- (phenyl-1,1,2,2-5tetrafluoro) ethyl] 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 n lt "H fluorine 10" "" H methyl 11 "" "H tert-butyl 12" lt u 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 H tert-butyl 26" lt lt H Methoxy 27 "" "H Ethoxy 28 n lt" H Trifluoromethyl 29 n lt lt H Methylsulfonyl 30 "" "H Methylmercapto 31 "" "H Dimethylsulfamoyl 32" "" Methyl Methyl 33 "" according to Chlorine Methyl 34 "" "Chlorine Dimethylsulfamoyl 35" "" Chlorine Chlorine 36 III "" H Chlorine 37 "" "H Fluor 38 lt lt lt H Methyl 39" lt lt H tert-butyl Pliess-Bei- diagram, game Formula A n X X '40 III Phenyl 2 H Mothoxy 41 "" "H Ethoxy 42" n lt H Trifluoromethyl 43 lt lt lt H Methylsulfonyl 44 n "lt II Methylmercapto 45 lt n lt H dimethylsulfamoyl 46 "" "methyl methyl 47" "" chlorine methyl 48 n lt lt chlorine dimethylsulfamoyl 49 lt lt "chlorine chlorine 50 IV:" lt chlorine 51 lt "lt H Fluorine 52 lt lt lt E methyl 53 "lt lt H tert-butyl 54" lt II methoxy 55 "" "H Ethoxy 56 lt lt lt H Trifluoromethyl 57 lt lt lt Methylsulfonyl 58 lt lt lt H Methylmercapto 59 "" "H Dimethylaulfamoyl 60" "" Methyl Methyl 61 "" "Chloromethyl 62 lt "lt Chlor Dimethylsulfamoyl 63" "" Chlot Chlor 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, 3utyl or amyl group.

Flow example diagram, play formula A n X 66 IIE Phenyl 2 derivatives 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 alkyl-4-piperazinylreat and Alk is a methyl, Mean ethyl, propyl, butyl or amyl radical.

B e i 5 p 1 e 1 67 N, N-dialkyl-2- [2- (hetercoyclic-1,1,2,2-tetrafluoro) -ethyl] benzylamines Following the procedures of Examples 8 through 66 with appropriate amounts of the corresponding starting materials, but the substituent A is pyridine, Is pyrimidine, thiazole, thiophene, imidazole or oxazole, the corresponding ones are obtained Products.

B e i 5 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 of tetrahydrofuran, in which there is an iodine crystal, suspended. A solution of 0.5 g (0.0015 moles) of 2-Hrem-α, α, α ', α'-tetrafluorobibenzyl 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 startsO Then the mixture heated under reflux and the remaining solution of the 2-Drom-α, α, α ', α'-tetrafluorobibenzyla added. The mixture is heated further in the reflux condenser until the magnesium is consumed. The mixture is then cooled in ice and diluted with 3 ml of detrahydrofuran. Carbon dioxide is initially about 1 hour passed the surface while that Mixture is stirred; vv.

and then passed through the solution for 3 minutes. After another The mixture is left in the cold for 16 hours at room temperature.

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 diluent 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 1N 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 of the solid residue from hexane gives white crystals; F = 130132 ° C. An analytical sample melts after recrystallization from cyclohexane and subliming at 1000 C and 0.2 mm Hg at 131-132 ° C.

Analysis Calculated for C15H10F402: C = 60.36%; H = 3.38%; found: C = 60.45; H = 3.48%.

B e i s p i e l 69 α, ß, ß, γ, γ-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 IIol) 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.

B. 103.8 g (0.37 mol) of 2-bromobenzalacetophenone 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 of concentrated hydrochloric acid made and diluted with 65 ml 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-bromophenyl) -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 methanol is on a rotating evaporator evaporated at 600 a. 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. Bin with dropping funnel, thermometer, stirrer, gas inlet tube The round bottom flask equipped with a gas outlet tube is charged with 15.35 g (0.0615 mol) of (2-bromobenzoXrl) -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 was added dropwise. This creates a stream of air over the surface of the solution . 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 over magnesium sulfate. After evaporation of the ether you get one bright orange, viscous syrup that is below 0.5 mm Eg at 170-195 ° C distilled. This distillate becomes 1- (2-bromophenyl) -3-phenylpropane-1,2,3-trione by redistillation won; Yield 8.31 g; Kp0.3 mm = 174-177 ° C.

Analysis Calculated for C15H9Br03: C = 56.81%; H = 2w86; found: C = 56.63; H = 3.02 fo.

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 silver and 10 ml of hydrogen fluoride are used in a stainless steel bomb 2 hours at 1000 C, 2 hours at 1200 C and Heated to 1400 C for 6 hours. After cooling, the contents of the bomb are dissolved in hexane and the solution filtered. To the evaporation of the hexane from the Filtrate is obtained. you get a yeast-brown oil. The fractional distillation of the oil yields 4.64 g of 2- (α, α, ß, ß, γ, γ-hexafluorophonylpropyl) bromobenzene ; Kp0> 05 mm = 83-87 ° C.

Analysis calculated for C15H9BrF6: C = 47.02%; H = 2.37% F = 29.75 %; found: C = 46.94; H = 2.67%; F = 29.52 fo.

G. A mixture of 4.64 g (0.0121 mol) 2- (α, α, ß, ß, γγ-hexafluorophenylpropyl) bromobenzene, 1.19 g (0.0133 mol) of copper (I) cyanide, 46 ml of quinoline and 4.6 ml of dimethylformamide is stirred with the magnetic stirrer and kept at reflux temperature for 24 hours. The dark reaction mixture is diluted with ether and 6N hydrochloric acid and the whole Mixture filtered through a plug of diatomaceous earth. The ether phase is withdrawn, washed with 3N hydrochloric acid and water and dried over magnesium sulfate. To evaporation of the ether gives 4.06 g of oil, which is below 1.0 mm Hg at 137-140 ° C distilled. This distillate crystallizes out immediately and is recrystallized from hexane. 2.37 g of sparkling white plates are obtained; X = 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 2- (α, α, β, β, γγ-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. 2- (α, α, ß, ß, γγ-hexafluorophenylpropyl) benzylamine hydrochloride is obtained ; F = 162-163.5 ° C.

Analysis Calculated for C16H13F6N.HCl: C = 52.12; H = 3.55; Cl = 9.6t Vo; F = 30.92 Vo; found: C = 52.42 50; H = 3.77%; Cl = 9.53%; F = 30.70 ? ia.

3 e i 5 p i e 1 70 4-fluoro-2 - («,, 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 are 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 550 ° C. and 0.05 mm Hg; F = 75-76.5 ° C. A sample from a previous experiment is used again for analysis sublimed: P = 77-78 ° C.

Analysis Calculated for C7H3BrFN: C = 42.00%; H = 1.50%; N = 7.00 ; found: C = 41.41%; H = 1.68 C / a; 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 The combined organic layers are extracted with 45 ml of ice-cold 6n Hydrochloric acid extracted in several portions and the combined acidic extracts 45 Minutes on.

heated in the steam bath. The product separates out as an oil and becomes extracted with benzene. 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-erom-4-fluorobenzil.

The yellow crystalline product (? = 62-76 ° C) is from 95 percent Recrystallized 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 μm Hg from 67.5-69 ° C.

Analysis Calculated for C14H8BrPO2: C = 54.72; H = 2.61 fo; Br = 26.06 %; found: C = 55.08 C / o; H = 2.84%; Br = 25.75.

D. 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'-pentafluorobibenzyl convicted. By sublimating the raw brown solid material at 500 C and 0.1 mm Hg gives white crystals; P = 47-48 C. A sample is used for analysis sublimated again.

Analysis Calculated for C14H8BrF5: C = 47.89%; H = 2.30? A; Br = 22.76 %.

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

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. Those Fractions produced by thin layer chromatography on a fluorescent silica layer contain a main component with an Rf value of 0.65 when developing with benzene, are united. After evaporating the solvents under reduced pressure A solid substance remains which is sublimed at 600 ° C. and 0.1 mm Hg; F = 68700 C.

A sample is sublimed again for analysis.

Analysis Calculated for C15H8F5N: C = 60.62; 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 According to the process described in Example 5, 4-fluorine-α, ß, ß-tetrafluorophenethyl) benzonitrile is obtained reduced to 4-fluoro-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine. By Sublimation of the crude product is obtained at 700 a and 0.05 mm Eg man white crystals; F = 52.5-54 ° C. A sample sublimed again for analysis melts at 53-54.50 C.

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

For example 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'-3rom-2- (fluorophenyl) -acetophenone from 2-bromobenzonitrile and p-fluorobenzylmagnesium chloride. Distillation of the yellow crystals yields almost colorless crystals; KP0.1 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%; Br = 26.83%.

B. 2-Bromo-4'-fluorobenzil Following the procedure of Example 2, 2'-bromo-2- (p-fluorophenyl) acetophenone is obtained oxidized to 2-bromo-2'-fluorobenzil. The yellow crystalline product (? = 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 = 79-90 ° C.

Analysis Calculated for C14H8BrFO2: C = 54.72%; H = 2.61%; Br = 26.06 / o; found: C = 55.07.00; H = 2.67; Br = 25.93 fo.

C. 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 60-70 ° C and 0.1 mm Hg gives white crystals; F = 52-53.5 ° C.

Analysis Calculated for C14H8BrF5: C = 47.89; H = 2.30%; Br = 22.76 %; found: C = 48.21%; H = 2.37%; Br = 23.04%.

D. 2- (4, α, α, ß, ß-Pentafluorophenethyl) -benzonitrile A mixture from 8.5 g (0.024 MOl) 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 54 hours. The precipitation is filtered off after cooling the mixture and with a mixture of benzene and ether washed. The solvents are reduced by the piltrate Pressure evaporated, leaving an oily black solid. 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 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. Remain on evaporation of the solvent 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? Jo; N = 4.57%.

E. 2- (4-α, α, ß, ß-Pentafluorophenethyl) -benzylamine After the In the procedure of Example 5, 2- (4 ,,, β, β-pentafluorophenothyl) -benzonitrile is given to 2- (4, α, α, β, β-pentafluorophenethyl) -benzylamine reduced. The crude product (7 = 6466O C) is sublimed at 600 C and 0.05 mm Hg, white crystals are obtained; F = 64-65.5 ° C.

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

For example, 1 72 2- [2- (α, α, β, β-tetrafluorophenethyl) phenyl] imidazoline 2.06 g (0.0074 mol) of 2- (α, α, ß, ß-tetrafluorophenethyl) benzonitrile 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 resin 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 2580 ° C. By recrystallization a purified sample is obtained from acetone; F = 266-267 ° C.

Analysis Calculated for C17H14F4H2.HCl: C = 56.90%; H = 4.21%; N = 7.81; found: C = 56.94; H = 4.03%; N = 7.60%., B e i 5 p i e '1 73 2- (α, α, β, β-tetrafluorophenothyl) phenethylamine A. 2- (α, α, ß, ß-Tetraflurophenethyl) -benzyl alcohol 530 mg (0.0139 liol) 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 ilol) 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 C5H12F40: C = 63.37%; H = 4.26%; F = 26.74 %; found: C = 63.78%; H = 4.27; F = 26.38.

B. 2- (α, α, ß, ß-Tetrafluorophenethyl) -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 gel-ost 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; P = 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 practices 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 (S = 78 to 820 C) is sublimated at 60o C and 0.05 mm Hg. The product melts at 80.5-82 ° C.

Analysis Calculated for C15H11BrF4: C = 51.89%; H = 3.20? Jo; Br = 23.02 C / o; found: C = 52.18%; H = 3.32%; Br = 22.89.

C. 2- (a, a, ß, ß-Tetrafluornhenethy henylacetonitril 3.5 g (0.01 mol) 2- (α, α, ß, ß-tetrafluorophenethyl) benzyl bromide and 2.0 g (0.0308 mol) Potassium cyanide is dissolved in 35 ml of acetone and 5 ml of water and the solution becomes 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) phenylacetonitrl reduced to 2- (α, α, ß, ß-tetrafluorophenethyl) -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 cleaned sample is obtained; F = 188.5-190 ° C.

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

For example, 1 75 "-Methyl 2- (", a, B, ß-tetrafluorophenethyl) benzylamine A. E-Ethy1-2 - («,«, ß, ß-tetrafluorophenethyl) -phenylketimin A solution of 19.3% (0.0685 mol) 2- (α, α, ß, ß-tetrafluorophenethyl) benzonitrile in 150 ml of absolute Ether is added dropwise with stirring to a solution of methylmagnesium bromide, which under nitrogen from 4.8 g (0.2 g atom) of magnesium turnings and 25 g (0.26 mol) of methyl bromide in 150 ml of absolute ether. The mixture is 16 hours at Stirred at reflux temperature. After cooling in an ice bath, the adduct is added dropwise hydrolyzed by 20 ml of water. The organic phase is decanted and the gelatinous Precipitate washed thoroughly with ether. The combined ether extracts are in several portions with 45 ml ice-cold 6n Hydrochloric acid extracted. After the combined acidic extracts have been cooled further, that which has precipitated out as a precipitate is obtained The hydrochloride of the product was collected and washed with ether. After prolonged drying in vacuo, the crystalline hydrochloride melts at 144-146 ° after previous sintering C. By repeated recrystallization from a mixture of isopropyl alcohol and an analytical sample is obtained with absolute ether; F = 147-148.5 ° C.

Analysis Calculated for C16H13F4N.HCl: C = 57.94%; H = 4.25? / 0; N = 4.22%; found: C = 58.08 Xo; H = 4.18 ro; N = 4.39%.

B. α-methyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine 1.05 g (0.0276 mole) lithium aluminum hydride is weighed out under nitrogen, in transferred to a dry, nitrogen-purged reaction flask and placed in 25 ml of dry, peroxide-free tetrahydrofuran suspended. The mixture is under Stirring cooled in an ice bath, a solution of 4.3 g (0.013 mol) of methyl-2- (α, α, ß, ß-tetrafluorophenethyl) phenylket imine hydrochloride is added dropwise in 70 ml of tetrahydrofuran. The mixture is at room temperature Stirred for 18 hours under nitrogen. After cooling in an ice bath, hydrolysis takes place by 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. After evaporation of the dried ether filtrate remains under reduced pressure the product is a red oily residue.

The base can be converted into the hydrogen maleate by a solution of the same 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 material is obtained; F = 157-158 ° C (decomp.).

Analysis Calculated for C16H15F4N.C4H404: C = 58.11%; H = 4.63?; found: C = 58.11%; H = 4.64? B.

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 the 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 keep the heartbeat to slow down, and 10 minutes later it will affect its anti-arrhythmic effects compound to be tested administered intravenously.

10 minutes after application of the test compound are in the wreath-shaped Artery 0.0035 ml / kg tetrafluorohexachlorobutane (TFHCB), a sclerosing agent, which causes myocardial infarction and arrhythmia in dogs (see Ascanio and colleagues, "J. Am. Physiol.", Vol. 209, 9165, pp. 1081-1088). In control animals this dose of TFHCB produces ventricular arrhythmias in 100% of the animals examined and leads to death as a result of ventricular pibrillation in 33% of the animals examined.

After the injection of the sclerosing agent it will last for an 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 the test compounds received Values are plotted on a graph and the animal protective dose becomes graphically estimated (ED80mg / kg). This number indicates that 80 lbs / o of all electrical (EKG) complexes are normal.

The compound 2- (α, α, ß, ß-tetrafluorophenethyl) -benzlamine 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- (α, α, ß, ß-tetrafluorophenethyl) benzylamine hydrochloride 5 mg lactose 430 mg magnesia stearate 5 mg 3 e i s p i e 1 -78 solutions for parenteral use Administration A solution for injection is prepared by taking the active ingredient with dextrose, methyl paraben, propyl paraben and distilled water in the below mixes specified proportions and then sterilized.

per ml of 2 - («,«, ß, B-tetrafluorophenethyl) benzylamine hydrochloride 5 mg Dextrose 44 mg methyl paraben. 1.5 mg propyl paraben. . 0.2 mg water for injection Remainder 3 e i s 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: 2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine hydrochloride per tablet 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-tetraflurophenethyl) benzylamine 1.06 g (0.00357 ol) 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 one obtains N- [α-methyl-2- (α, α, ß, ß-tetrafluorophenethyl-benzyl] -formamide ; F = 94.5-99 ° C. By recrystallizing 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, -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 crystals; F = 175-176 ° a. With further recrystallization from acetone, the melting point remains unchanged.

Analysis Calculated for C17H17F4N.C4H404: C = 59.01%; H = 4.95 5t 28%; found: C - = 58.84%; H = 5.09; N = 3.28 ch.

The hydrochloride is obtained 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 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%; m = 4.05 p; found: C = 58.47%; H = 5.40%; N = 4.08 do.

For example, 81 (+) = α, N-dimethyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine 9.5 g (0.0305 mol) of racemic α, N-dimethyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine in 25 ml-boiling absolute ethanol with a solution of 2.3 g (0.0153 mol) (-) - Tartaric acid added to 20 ml of absolute ethanol. The crystallization is through Inoculation triggered and the solution left to stand at room temperature until no further precipitate forms. After collecting the (-) - tartrate, the ethanol Mother liquor evaporated to dryness under reduced pressure and the residue in Suspended in water. The mixture becomes alkaline with saturated sodium carbonate solution made and the oily base extracted with hexane. After evaporation of the washed and dried hexane extract under reduced pressure, 1.35 g of (+) - base remain.

The (+) - base is dissolved in 4 ml of absolute ethanol and the solution with a solution of 326 mg (0.00217 mol) (+) - tartaric acid in 3 ml of absolute ethanol offset. The (+) - tartrate separates out in the form of white crystals; F = 183-186 ° C; Yield 1.3g. Obtained after five recrystallization from absolute ethanol a product with a constant specific rotation: [α] 24 D = + 18.75 °.

The (+) - tartrate is suspended in water and the mixture with saturated Sodium carbonate solution made alkaline. The oily base is extracted with hexane. After evaporation of the washed and dried hexane extract remains the (+) base as a pale yellow oil; [α] 24 D = + 31.76 °.

For example 82 (-) - α, N-dimethyl-2- (α, α, ß, ß-tetrafluorophenethyl) benzylamine 9.6 g (0.0249 mol) of the α, N-dimethyl-α, ß, ß-tetrafluorophenethyl) benzylamine - (-) - tartrate obtained in Example 81 are suspended in water, and the mixture is washed with saturated sodium carbonate solution made alkaline. The oily base is extracted with hexane. After evaporation of the washed and dried hexane extract, 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 the Solution with a solution of 1.85 g (0.0123 mol) (+) - tartaric acid in 20 ml absolute Ethanol added. The crystallization is triggered by inoculation and the solution left to stand at room temperature until no further precipitate forms. After the (+) - tartrate has been collected, the ethanolic mother liquor is reduced under reduced pressure Pressure evaporated to dryness and the solid residue suspended in water. That The mixture is made alkaline with saturated sodium carbonate solution and the oily Base extracted with hexane. After evaporation of the washed and dried Hexane extract under reduced pressure remains behind the (-) - base in an amount of, 1.09 g.

The (-) - base is dissolved in 4 ml of absolute ethanol and the solution with a solution of 262 mg (0.00175 mol) (-) - tartaric acid in 2 ml of absolute ethanol offset. The (-) - tartrate separates out in the form of white crystals; F = 184-187 ° C; Yield 1.1g. Obtained by recrystallizing three times from absolute ethanol a product of constant specific rotation: [α] 23.5 ° D = -21.82 ° ; F = 190-192 ° C.

Analysis Calculated for C17H17F4H.1 / 2 C4H406: C = 59.05 {t "o '; H = 5.22 %; IvJ = 3.62% o; found: C = 59.25%; H = 5.30%; N = 3.49%.

The (-) - tartrate is suspended in water and the mixture with saturated Sodium carbonate solution made alkaline. The oily base is extracted with hexane. After evaporation of the washed and dried hexane extract remains the (-) - base as a pale yellow oil; [α] 24 D = -21.17 °.

B e i s p i e l 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 together with 41 g of sulfur tetrafluoride, 1.3 g of mercury, 1 g of hydrogen fluoride and 40 ml of benzene in a stainless steel autoclave 10 Heated to 800 C for hours. After cooling and opening the vessel to the atmosphere the mixture is then separated from the mercury and filtered. After evaporation of the benzene from the filtrate under reduced pressure leaves a brown residue, which is stirred with hot cyclohexane and filtered. After the cyclohexane has evaporated a brown solid remains as the product from the filtrate under reduced pressure Material. White crystals are obtained by sublimation at 1050 ° C. and 0.05 mm Hg; F = 71.5-73.5 ° C. An analytical sample obtained by recrystallization from hexane melts at 73-75 ° a.

Analysis Calculated for ° 16H1424 C = 68.08%; H = 5.00 do; found: C = 67.76 C / o; H = 5.00%.

B. α, α, α ', α'-tetrafluoroethylene-2,2'-bis- (benzyl bromide) A mixture of 1.41 g (0.005-01) 2,2'-dimethyl-α, α, α ', α'-tetrafluorobibenzyl, 1.78 g (0.01 mol) sT-bromosuccinimide, a trace of benzoyl peroxide and 60 ml carbon tetrachloride is stirred for 7 hours at reflux temperature. After cooling down, 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 sample 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%.

C. α, α, α ', α'-tetrafluoroethylene-2,2'-bis (benzylhexaminium bromide 6.44 g (0.046 mol) of hexamine are dissolved in 75 ml of boiling chloroform. One sets 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 it will the precipitate collected, washed with absolute ether and dried. You get a white, crystalline solid substance; F = 186-190 ° C (decomp.).

D. α, α, α ', α'-tetrafluoroethylene-2,2'-bis (benzylamine A mixture of 17.2 g (0.0239 mol) o:, o:, cc1, cc'-tetrafluoroethylene-2,2'-bis- (benzlhexaminium 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 C / o; 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 small excess of 85 to 90 percent (~) lactic acid offset. The (~) -dilactate precipitates in the form of white crystals; F = 180.5-181.5 ° C. By repeated recrystallization from mixtures of absolute ethanol and absolute Methanol gives a cleaned 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%.

For example, 84 N, N-dimethyl-3- (α, α, ß, ß-tetrafluorophenethyl) -o-xylene-α, α, -diamine A. 2 ', 3'-Dimethyl-2-phenylacetophonon Following the procedure of Example 1, 2,3-dimethylbenzonitrile is obtained 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 prom white crystals; F = 228.5 to 229.5 ° C.

Analysis Calculated for C16H17N.HCl: C = 73.97%; H = 6.98?, O '; N = 5.39%; found: 'c = 73> 49%; H = 6.89%; 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; F = 52-53 ° C.

B. 2,3-Dimethylbenzil 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 95 ° 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 fo; .F = 26.92 %; found: C = 68.16%; H = 5.16%; F = 26.63%.

D. 3- (α, α, ß, ß-Tetrafluorophenethyl) -o-xylene-α, α, -dibromide A mixture of 6.13 g (0.022 mol) 2,3-dimethyl-α, α, α ', α'-tetrafluorobibenzyl, 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 P-material is obtained from petroleum ether; F = 88-92 ° C. An analysis sample is made by sublimation at 850 C and 0.02 mm Hg; F = 90-92 ° C.

Analysis Calculated for C16H12Br2F4: C = t), 66; H = 2.75%; found: C = 43.78%; H = 2.74.

E. N, N-Dimethyl-3 (α, α, β, β-tetrafluorophenethyl) -o-xylene-α, α, -diamine 2.0 g (0.0045 moles) of 3- (α, α, β, β-tetrafluorophenethyl) -oxylene-α, α'-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 material becomes with. Benzene stirred 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 C18H20F4N2.2HBr: C = 43.04; H = 4.41%; N = 5.58%; Br = 31.83 fo; found: C = 43.21%; H = 4.39; N = 5.60; Br = 31.64 %.

3 e i 5 p i e 1 85 N, N-dibenzyl-3- (α, α, ß, ß-tetrafluorophenethyl) -oxylene 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 mol of benzylamine in 50 ml of dry benzene is added for 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 evaporation of the benzene filtrate, a viscous one remains yellow oil mixed with boiling absolute ether. The insoluble hydrobromide the product is collected and made from a mixture of benzene, absolute ethanol and absolute ether recrystallized, whereby one detects white solid crystals; F = 172-174 ° C. An analytical sample is obtained by recrystallization from acetone; F = 176-177.5 O.

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

For example 86 4- (α, α, ß, ß-tetrafluorophenethyl) -isoindoline A. N-Benzy1-4- (α ,, ß2ß-tetrafluorophenethyl) -isoindoline After collecting the N, N-dibenzyl-3- (α, α, ß, ß-tetrafluorophenethyl) -o-xylene-α, α , '- diamine hydrobromides remaining ethereal filtrate according to Example 85 becomes dry in vacuum evaporated, the viscous, oily yellow base remaining as cream 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 ° a.

Analysis Calculated for C23H19F4N.HBr; 0 = 59.24%; H = 4.32%; NT = 3.00%; found: C = 58.84%; H = 4.30%; N = 3.05%.

B. 4- (α, α, ß, ß-Tetrafluorophenethyl) -isoindoline A solution of 1.63 g (0.0035 mol) of N-benzyl-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 Hydrobromide of the product (F = 191-192 ° C) as a 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 C16H1324NHBr: C - 51.09%; H = 3.75 Sg; N = 3.72%; found: C = .50.94 fo; H = 3.78%; N = 3.83%.

Eg 1 87 2-methyl-3- (α, α, ß, ß-tetrafluorophenethyl) benzylamine A. 2-Methyls, ß, ß-tetrafluoroshenethyl) benzyl bromide A mixture of 4.0 g (0.0142 Mol) 2,3-dimethyl-α, α-tetrafluorobibenzyl, 2.52 g (0.0142 mol) N-bromosuccinimide, 50 mg of benzoyl peroxide and 100 ml of carbon tetrachloride is added for 2 1/2 hours at reflux temperature touched. After cooling, the succinimide precipitate is filtered off and that The filtrate was evaporated to dryness under reduced pressure. The solid residue will recrystallized from petroleum ether, white crystals being obtained; F = 67-71 ° C. Repeated recrystallization from petroleum ether gives an analytical one Sample; F = 69-71 ° C.

Analysis calculated for C16H13BrF4: o = 53.21%; H = 3.63%; Br = 22.12%.

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

B. N- [2-methyl-3- (α, α, β, β-tetrafluorophenethyl) benzyl] phthalimide A mixture of 8.02 g (0.022 riol) 2-methyl-3- (α, α, ß, ßetafluorophenethyl) 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 = t35 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) -benzy27-phthalimide are dissolved in 100 ml of boiling 95 percent ethanol. After adding 0.87 ml 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 is obtained a further precipitate of phthalhydrazide, the is also filtered off. The filtrate is cooled in an ice bath, concentrated with 1.5 ml Hydrochloric acid acidified to a pH-Vert 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 low impact of Phthalhydrazide, which is filtered off. After concentrating 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 one cleaned that Hydrochloride; F = 209-211.5 ° C.

Analysis Calculated for C16H15F4N.HCl: C = 57.58 O / F; H 4.83, N = 4.20 Y; found: C = 57.28%; H = 4.83; N = 4.12%; 3 B e i s p i e 1 88 α, α, -Dimethyl-3- (α, α, ß, ß-tetrafluorophenethyl) -benzylamine A. 3 '-Bromo-2-phenylacetophenone Following the procedures of Example 1, 3-bromobenzonitrile is obtained 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 at 0.1 mm Hg at 143-155 ° C. The one boiling at 0.1 mm Hg at 150-155 ° C Fraction is recrystallized from hexane and an analytical sample is obtained in the form of white crystals; F = 62-64 ° C.

Analysis Calculated for C14H11Br0: C = 61.11%; H = 4.03%; found: C = 61.25%; H = 4.00%.

3. 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 (F = 78-82 ° C), and an analysis sample is obtained by recrystallization from hexane; F = 81 up to 82.5 ° C.

Analysis Calculated for C14H9Bro 2: C = 58.15%; H = 3.13%; found: C = 57.81%; H = 3.05.

C. 3-Bromo-α, α, α ', α'-totrafluorobibonzyl According to Example 83 is 3-erombenzil in 3-bromo-α, α, α ', α'-tetrafluorobibenzyl 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 (B- = 74-76 ° C) receives by recrystallization from petroleum ether.

Analysis Calculated for C14H9BrF4: C = 50.47%; 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 mol) of 3-bromo-a, a, ', a'-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 stir for several hours at reflux temperature, -after the 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 5 g (0.06 mol) of acetone in 5 ml of absolute ether is added dropwise.

After 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 cleaning 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 analyson sample is recrystallized from hexane; F = 76-78 ° C.

Analysis Calculated for C17H16F40: C = 65.37%; H = 5.16%; found: C = 65.54%; H = 5.15%.

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 portions, whereby 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 holds at 10-200 C. After stirring for 10 minutes, the ice bath is removed and a Solution of 5.58 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 4 sodium carbonate. The oily product is extracted with ether. After evaporating the washed and dried ether extracts, an oily solid substance remains as the product. The purification is carried out by column chromatography on 200 g silicon dioxide gel, whereby the product is eluted with chloroform. Those fractions found 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, the purified hydrochloride is obtained; 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%; N = 4.02%; found: C = 58.93 fo; H = 5.58; N = 3.85.

Example 89 4- (α, α, β, β-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 sublimated at 70-75 ° a and 0.02 mm Hg purified; F = 80-82 ° C. An analytical sample (F = 82-83.5 ° C) is through repeated-s sublimation won.

Analysis Calculated for C14H9BrF4: C = 50.49%; H = 2.72; Br =? 4.00 %; found: C = 50.51 db; H = 2.81%; Br = 23.78%.

B. 4- (α, α, ß, ß-tetrafluorohenethyl) -bezonitrile After The procedure of Example 4 is 4-bromo-α, α, α ', α'-tetrafluorobibenzyl converted into 4- (α, α, ß, ß-tetrafluorophenethyl) benzonitrile. The raw one crystalline product is purified by sublimation at 85 ° C and 0.02 mm Hg; F. = 118-123 ° C. By sublimating again one obtains an almost white solid Material; F = 120.5-123 ° C. An analytically pure sample is made by recrystallization Hexane and sublimation again obtained: F = 123.5-125.5 ° C.

Analysis Calculated for C15H9F4N: C = 64.52%; H = 3.25%; N = 5.02 %; 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-tetrafluorophonethyl) -benzylamine reduced. The white crystalline product (S = 99.5-102 ° C) is sublimated cleaned at 900 C and 0.01 mm Hg; F = 101-103 ° C.

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

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: a = 56.35%; H = 4.41%; N = 4.38%; found: C = 56.37%; H = 4.48%; N = 4.35%.

For example, 1 90 a-lethyl-4- (a, a, ß, ß-tetrafluorophenetha benzylamine A. 4 '- (α, α, ß, ß-Tetrafluorophenethyl) -acetophenone 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 Hg gives white crystals; F = 128-133 ° C. An analytically pure sample (F = 134-135.5 ° C) is obtained by repeated recrystallization from hexane and repeated Sublimation made.

Analysis Calculated for C16H12F40: C = 64.86%; H = 4.08%; F = 25.65% ; found: C = 65.09%; H H = 4.31%; F = 25.23? / B.

B. 4 '- («,«, ß, ß-Detrafluorophenethyl) -acetophenonoxim A solution of 1.1 g (0.00372 moles) of 4 '- (α, α, β, β-tetrafluorophenethyl) acetophenone, 0.7 g (0.0071 mol) of hydroxylamine hydrochloride, 8.5 ml of absolute ethanol and 1.5 ml of dry Pyridine is heated to reflux temperature for 6 hours. The solvents are evaporated under reduced pressure and the solid residue is stirred with water. The crystalline product (temperature = 137-139 ° C) is collected and made of hexene uncrystallized 0010 lized. White needles are obtained; B = 139-141 C. By recrystallization from hexane an analytical sample is obtained; F = 140-141 ° C.

Analysis Calculated for C16H13F4NO: C = 6.173%; 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 270 ° C. until hydrogen absorption has ended. 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 benzoin extract leaves the product in the form of a white crystalline solid substance; F = 63.5-66 ° C.

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

Analysis Calculated for C16H15F4N: C = 64.65%; H = 5.09%; N = 4.71 7s; found: C = 64.557 ;; H = 5.07%; N = 4.72 00.

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. Avg Recrystallization from a mixture of methanol and ether gives an analytically pure Sample; F = 218-219 ° C.

Analysis calculated for C16H15F4N. HCl: C = 57.58%; H = 4.83%; N = 4.20%; found: C = 57.22%; H = 4.7.5 A; N = 4.15? O.

B e i 5 p i e 1 91 α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) -benzylamine A. 2- [4- (α, α, ß, ß-Tetrafluorophenethyl) -phenyl] -propanol-2 According to the example 88 becomes 4- (α, α, ß, ß-tetrafluorophenethyl) -phenylmagnesium bromide from 4-bromo-α, α, α ', α'-tetraflurobiben -zyl and with acetone to 2- [4- (α, α, ß, ß-tetrafluorophenethyl) -phenyA7-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 C17H16F4O: C = 65.37%; H = 5.16%; F = 24.33 %; found: C = 65.46%; H = 5.19%; F = 24.52 fo.

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 ether becomes 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 off, washed with water and dried over anhydrous magnesium sulfate. After the solvent has evaporated under reduced pressure, the crystalline product as residue. Obtained by sublimation at 67 ° C and 0.02 mm Hg one a purified material; F = 54-60 ° C.

C. N- [α, α, -Dmethyl-4- (α, α, β, β-tetrafluorophenethyl) benzyl] formamide According to Example 88, 2- [4- (α, α, β, β-tetrafluorophenethyl) -phenyl] -propanol-2 by the Ritter reaction in N- [α, α-dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl-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 C18H17F4NO: C = 63.71; H = 5.05%; N = 4.13 %; found: C = 63.96 G + o; H = 4.83%; N = 4.01 fo.

D. 2- [4-α, α, ß, ß-tetrafluorophenethyl) phenyl] propene If the crude, oily, solid mixture produced by the Ritter reaction from 2-S- ( «, A, B, ß-T (tetrafluorophenethyl) -phenygpropanol-2 obtained according to Example 91-C is subjected to column chromatography on silica gel to give 2- [4- (α, α, ß, ß-tetrafluorophenethyl) phenyl] propene as a second component. Those fractions that are a main 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 C17H14F4: C = 69.58%; H = 4.79 C / o; found: C = 69.58; H = 4.83%.

E. N- [α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) -benzl] formamide According to Example 88, 2- [4- (α, α, ß, ß-tetrafluorophenethyl) phenyl] propene is used by the Ritter reaction in N- [α, α-dimethyl-4- (α, α, ß, ß-tetrafluorophenetnyl) -benzyl] -formamide convicted. The purified product (S = 115-119 ° C) is obtained by column chromatography of the crude silica gel as described in Example 91-C.

F. α, α, k-Dimethyl-4- (α, α, ß, ß-tetraflurophenethyl) benzylamine According to Example 88, N- [α, α-dimethyl-4- (α, α, β, β-tetrafluorophenethyl) benzyl] formamide is used to, αα-dimethyl-4- (α, α, ß, ß-tetrafluorophenothyl) -benzylamine hydrolyzed. The hydrochloride of the product (? = 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%; found: C = 58.55%; H = 5.26%; N = 4.09%.

B e i 5 p i e 1 92 4- (α, α, β, β-tetrafluorophenethyl) -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 diluting with absolute. ether the dihydrogen citrate precipitates in the form of white crystals; F = 169-170 ° C (decomp.). By recrystallization from a mixture of absolute ethanol and absolute methanol a purified sample is obtained; F - 166-168 ° C.

Analysis Calculated for C18H19F4N.C6H8O7: C = 55.70; H = 5.26; N = 2.71%; found: C = 55.82 fo; H = 5.23%; N = 2.53 fo.

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 one. Solution of the same in absolute ether with a slight overshoot of an 8.2 normal Hydrogen chloride solution is added to ethanol. The hydrochloride falls (F = 203-205 ° C) 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%; found: C = 59.92%; H = 5.55%; N = 3.68%.

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 950 C in an oil bath. After adding 5 ml of concentrated hydrochloric acid to the cooled mixture, the solution is reduced under reduced pressure Pressure evaporated to the rock. 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 is obtained in the form of white crystals; F = 171-173.5 ° C.

The analytically pure is obtained by recrystallization from isopropyl alcohol Sample; F = 174-175.5 ° C.

Analysis Calculated for C19H21F4N.HC1: C = 60.72; H = 5.90; N = 3.72 O'; found: C = 60.90%; H = 5.75%; N = 3.84 V.

B e i -s p i e 1 94 4- (p-methyl-α, α, ß, ß-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 combine, washed and dried organic extracts 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%; H = 4.27 do B. 4-Bromo-41-methylbenzil 90 g (0.36 mol) copper (II) sulfate are heated while stirring on the steam bath with 110 ml of pyridine and 45 ml of water, until complete solution has occurred. 55 g (0.18 mol) of 4-bromo-4'-methylbenzoin are used and the mixture is heated on the steam bath for 3 hours while stirring. This separates the yellow crystalline product separates. After cooling and diluting with water the product is collected, washed with water, 1N 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%; n = 3.66; found: C = 59.49 Ya; H = 3.59.

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 900 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%; H = 3> 18%; Br = 23.14.

D. 2- [4- (p-methyl-α, α, ß, ß-tetrafluorophenethyl) phenyl] 2-propanol Following the procedure of Example 88 gives 4- (p-methyl-α, α, ß, ß-tetrafluorophenethyl) -phenylmagnesium bromide made from 4-bromo-4'-methyl-α, α, α ', α'-tetrafluorobibenzyl and with acetone to form 2-S- (p-methyl-o:, ß, ß-tetrafluorophenethyl) -phenyA7-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 = 83-88 ° E.

By subliming at 800 C and 0.05 mm Eg and recrystallizing an analytically pure sample in the form of white crystals is obtained from petroleum ether; F. = 88-90 ° o.

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

E. N- [α, α-Dimethyl-4- (p-methyl-α, α, β, β-tetrafluorophenethyl) benzyl] formmide 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, ß, 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 ° C. 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 =)., 96 0 /; found: C = 64.34%; H = 5.35; N = 3.76% o.

F. 4- (p-methyl-α, α, ß, ß-tetrafluorophenethyl) -α, α, K-trimethylbenzylamine by the method of example 6 becomes N- [α, α, -dimethyl-4- (p-methyl-α, α, ß, ß-tetrafluorophenethyl) -benzyl] -formamide to 4- (p-methyl-α, α, ß, ß-tetrafluorophenethyl) -α, α, N-trimethylben zylamine reduced. The crude oily base is converted into the hydrochloride by a solution of the same in ethanol with a slight excess of 8 normal Hydrogen chloride is added to ethanol. When diluting with absolute ether, this falls white crystalline hydrochloride from; F = 189-190 °. When recrystallizing from a mixture from isopropyl alcohol and ether, the melting point remains unchanged.

Analysis Calculated for C19H21F4N.HCl: C = 60.72%; H = 5.90; N = 3.73%; found:% C = 61.12 c / a; H = 5.81 0 / o; N = 3.61%.

3 e i s p i e 1 95 α, α, -Dimethyl-4- (p-methyl-α, α, ß, ß-tetrafluorophenethyl) -benzylamine Following the procedure of Example 88 gives N- [α, α-dimethyl-4- (p-methyl-α, α, β, β-tetrafluorophenethyl) benzyl] formamide to α, α, -Dimethyl-4- (p-methyl-α, α, ß, ß-tetrafluorophenethyl) -benzylamine hydrolyzed. The hydrochloride of the product (S = 254.5-2456.5 ° 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 Vo; H = 5.57%; N = 3.87%; found: C = 59.70%; H = 5.59%; N = 3.90%.

3 e i 5 p i e 1 96 2-Amino-4-methyl-N- [1- (α, α, β, β-tetrafluorophenethyl) benzyl] valeric acid amide 3.7 g (0.0146 mol) of Woodward's reagent K are in 25 ml of freshly distilled dry Acotonitrile is stirred and the mixture is cooled to -5 ° 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 mol) of triethylamine in 40 ml of aoetonitrile at such a rate that the temperature stays at -5 to 0 ° C. The mixture is 55 minutes below 0 ° C and then stirred for 1 hour at room temperature. After cooling the solution again 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 which remains 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 1N hydrochloric acid and again with water and over anhydrous sodium sulfate dried. Remains after evaporation of the solvent under reduced pressure the N-carbobenzoxy 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-N- [2- (α, α, ß, ßtetrafluorophenethyl) benzyl] valeric acid amide hydrogenfuma rat in the form of white crystals; 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.

decomposed ..>.

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

B e i s p i e l 97 salts of α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) benzylamine A. asa-Dimethyl-4- («, a, ß, B-tetrafluorophenethyl) benzylamine isethionate 15 g (0.1 mol) of sodium isethionate are dissolved in 50 ml of water, and the solution is poured into a thoroughly washed column containing 160 g of an organic, contains strongly acidic cation exchanger in the hydrogen ion form ("Rexyn 101 H"). 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 isethionic acid in the solution by potentiometric titration determined to be 3.8 molar.

4.1 g (0.0132 mol) 1,1-dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) -benzylamine 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 te 5.8 g; F = 134.5-136 ° C. By recrystallizing from 50 ml of 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 5; s = 7.51%; found: C = 52.33 c -; H = 5.31%; N = 3.10 ??; S = 7.41%.

For the α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) -benzylamine-isethionate the following physical parameters were determined: Water solubility :> 400 mg / ml pn of a 1 percent aqueous solution: 4.7 B. α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) -benzylamine- (t) -lactate 6.0 g (0.0172 mol) of α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) -benzylamine hydrochloride are in saturated Na-.

Triumoarbonatlösung suspended, and the base is extracted with hexane. The combined hexane extracts are washed thoroughly with water and dried over anhydrous Dried magnesium sulfate. By evaporating the solvent under reduced 5.3 g of white crystalline base are obtained under pressure; 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), 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 0 ° C, the product is collected; Yield 6.5 g (95? Yes); 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.C3H6O3: 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) -benzylamine 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 are salts produced 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 α, α-dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) benzylamine dihydrogen citrate C. "Tartaric acid α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl ) -benzylamine (+) -hydrogen tartrate D. "Phosphoric acid α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) benzylamine dihydrogen phosphate hydrate E. "Sulfuric acid α, α, -Dimethyl-4- (α, α, ß, ß-tetrafluorophenethyl) benzylamine sulfate trihydrate F. "Methanesulfone-α, α, -Dimethyl-4- (α, α, β, β-totrafluorophenethyl) -benzylamine methanesulfonate.

Analysis C H N be ge be bewerecn- @un recn fun- recn- fun melting point, ° C net 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 3.52 P. 206.5-211.5 53, Q6 53.22 5.20 5.32 3.44 3.32

Claims (5)

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 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 and A is a phenylres t, a cycloaliphatic ring, a heterocyclic aromatic ring with 5 or 6 atoms or a partially or fully reduced heterocyclic ring. 2. Compounds according to claim 1, characterized by the general formula 3. Compounds according to claim l, characterized by the formula II. Process for the preparation of 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 groups, acyl groups with up to 4 carbon atoms, perfluoroacyl groups with up to 4 carbon atoms, amino groups, Alkylamino groups with up to 4 carbon atoms, dialkylamino groups with up to 8 carbon atoms, acylamino groups with up to 4 carbon atoms, perfluoroacylamino groups with up to 4 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, cyano, carboxyl, carbamoyl groups, alkylcarbamoyl groups with up to 5 carbon atoms, dialkylcarbamoyl groups with up to 9 carbon atoms, carbalkoxy groups with up to 6 carbon atoms, mercapto groups, alkyl mercapto groups mi t 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, Hal is a bromine or iodine atom, n is 2 or 3 and A is a phenyl radical, a cycloaliphatic ring, a heterocyclic aromatic ring with 5 or 6 atoms or a partially or fully reduced one Heterocyclic ring means, characterized in that one is a compound of the general formula with a metal cyanide. 5. The method according to claim 4, characterized in that A is a means unsubstituted or substituted phenyl radical.