MXPA97006609A - Procedure for the obtaining of aminas optically active - Google Patents

Abstract

The present invention relates to a novel process that can be obtained (R) -amines of the formula (I) in which R1, R2 and n have the meanings indicated in the description, by reaction of racemic N-acyl amines of the formula ( II) in which R1, R2, R3 and n have the meanings indicated in the description, with lipases, which are suitable for the dissociation of the (R) -enantiomers of the N-acyl amines of the formula (I), in Presence of water as well, if appropriate, in the presence of an organic diluent, at a pH value between 3.0 and 10.0 at temperatures between 0 ° C and 80 ° C.

Description

PROCEDURE FOR THE OBTAINING OF OPTICALLY ACTIVE AMINES. Description of the invention The present invention relates to a new process for the preparation of (R) -amines by enzymatic hydrolysis of N-acylamine racemates. It has already been known to obtain optically active Np-ami-n-phenyl-acetylamino-derivatives by enzymatic cleavage of the corresponding racemates with benzyl-penicillin-acylase as a biocatalyst (cf. J. Org. Chem. 44., 2222-2225 (cf. However, in this procedure, the fact that the optical yields are, in part, very low is advantageous, and in this method the (S) -enantiomer of the starting racemate is hydrolyzed in this way. example, from the corresponding racemate the (R) -enantiomer of Np-amino-1-phenylacetyl-1-phenetmine and free (S) -amine Another disadvantage is that the biocatalyst reacts in a very specific way with respect to to the substrate and only those compounds containing a phenylacetyl group can be used It is further known that (S) -amines and (R) -enantiomers of N-acylated 1-met1-phenyl-alkylamines can be obtained by reaction of the N-racemate. -aci l-1-metl-phenyl-alkyl amines with the aid of certain biocatalysts (see EP-A 0 399 589). This process has the drawback that only the corresponding (R) -REF: 25359 amines can be obtained when the (R) -enantiomers of the N-acyl-1-met1-phenyl-alkylamines are deacylated in a reaction step. additional. It has now been found that (R) -amines of the formula are obtained NH, * CH (I), (CH2) n- wherein R 1 signifies alkyl, optionally substituted, R 2 means optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heterocyclyl, where, however, R1 and R2 are not identical, and n means the numbers 0, 1, 2 or 3, if racemic N-acylamines of the formula are reacted C HN R (II), CH R1 (CH2) n-R ' wherein R 1, R 2 and n have the meanings given above and R 3 signifies hydrogen, amino, dialkylamino, alkylthio, means optionally substituted alkyl or optionally substituted alkoxy, the carbonaceous chains may be interengaged in those residues which contain more than one carbon atom, by heteroatoms or by groups of heteroatoms, or R3 means optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally optionally substituted aryl or optionally substituted heterocyclyl, with lipases, which are suitable for the dissociation of the (R) -enantiomers of the N-acyl amines of the formula (II), in the presence of water as well as, if appropriate, in the presence of an organic diluent, at a pH value comprised between 3.0 and 10.0 at temperatures between 0 ° C and 80 ° C. By (R) -amines is meant those optically active compounds of the formula (I) which have the (R) -configuration asymmetrically substituted on the carbon atom. In formula (I) the asymmetrically substituted carbon atom has been characterized by means of (*). It should be considered as extremely surprising that (R) -amines can be obtained according to the process of the invention, since it was only known from the prior art that (S) -amines were accessible with the aid of biocatalysts from racemates of N-acylamines. The process according to the invention is characterized by a series of advantages. In this way, it is possible to obtain (R) -amines of the formula (I) with optically extremely high purity. It is also favorable that the N-acylamines required as starting materials can be obtained in a simple manner and that the acyl residue can vary widely. Finally, the performance of the reaction and the isolation of the desired substances do not present any kind of difficulties either. In the present case alkyl means, insofar as it is not defined otherwise, saturated aliphatic hydrocarbon radicals, which may be straight chain or branched chain. In the present case, cycloalkyl means, insofar as it is not otherwise defined, saturated carbocyclic radicals, which can optionally form a bicyclic or polycyclic ring system with other condensed or bridged rings. In the present case, cycloalkenyl means, insofar as it is not otherwise defined, unsaturated carbocyclic moieties, which can form a bicyclic or polycyclic ring system, if appropriate, with other fused or bridged rings. In the present case aryl means, insofar as it is not otherwise defined, aromatic, mono-, di- or polycyclic hydrocarbon radicals, such as for example phenyl, naphthyl, anthranil, phenanthryl, preferably phenyl or naphthyl, especially phenyl. In the present case heterocyclyl means, insofar as it is not otherwise defined, saturated or unsaturated ring residues, in which at least one member of the ring is a heteroatom, ie it is a non-carbon atom. If the ring contains several heteroatoms, these may be the same or different. Preferred heteroatoms are oxygen, nitrogen or sulfur. If necessary, the ring residues form a bicyclic or polycyclic ring system together with other carbocyclic or heterocyclic rings, condensed or bridged. Monocyclic or bicyclic ring systems are preferred, especially monocyclic or bicyclic ring systems with aromatic character. In the present case halogen means, insofar as it is not defined otherwise, fluorine, chlorine, bromine or iodine, preferably means fluorine, chlorine or bromine, especially fluorine or chlorine. If the racemic N- [l- (4-chlorophenyl) ethyl] acetamide is used as a starting substance and lipase from Candida Antarctica as a biocatalyst, the development of the process according to the invention can be represented by the scheme of formulas below.

(Racemato) Lipase from Candida + H2O CH3-COOH Antarctic (R) -amine (S) -acyl-amine The racemic N-acylamines, which are necessary as starting materials for carrying out the process according to the invention, are generally defined by the formula (II). Preferably, it means straight-chain or branched-chain alkyl with 1 to 8 carbon atoms, the alkyl radicals being able to be substituted once or several times, in the same or different ways by halogen, cyano, amino, hydroxy, formyl, carboxy, carbamoyl, alkoxy or alkylthio, respectively straight-chain or branched chain, with respectively 6 carbon atoms; halogenoalkoxy or halogenoalkylthio respectively straight-chain or branched chain with respectively 1 to 6 carbon atoms and 1 to 13 identical or different halogen atoms; alkylamino, dialkylamino, alkylcarbonyl, alkylcarbyloxy, alkoxycarbonyl, alkylsulfonyloxy, hydroxyalkylalkyl or alkoxyiminoalkyl respectively straight-chain or branched chain with 1 to 6 carbon atoms respectively in the individual alkyl portions; or by alkylene double-bonded with 1 to 6 carbon atoms or by dioxyalkylene double-bonded with 1 to 4 carbon atoms, the two mentioned radicals can be substituted last, in turn, once or several times, in the same way or different forms by halogen, by straight-chain alkyl or branched chain with 1 to 4 carbon atoms and / or by halogenoalkyl straight chain or branched chain with 1 to 4 carbon atoms and 9 halogen atoms equal or different Preferably, R2 means cycloalkyl with 3 to 7 carbon atoms, these residues can be substituted one to four times, in the same or different ways by halogen and / or by alkyl with 1 to 4 carbon atoms, or R2 means cycloalkenyl with 3 to 7 carbon atoms, these residues may be substituted one to four times, in the same or in different ways, by halogen and / or by alkyl with 1 to 4 carbon atoms, or R2 denotes saturated or unsaturated heterocyclyl, optionally benzo-condensed, with 3 to 7 ring members in the heterocycle, of which 1 to 3 heteroatoms may be the same or different, such as oxygen, nitrogen or sulfur, the radicals of one to three may be substituted. sometimes in the same or different manner by halogen, by alkyl with 1 to 4 carbon atoms, by alkoxy with 1 to 4 carbon atoms, and / or by halogenalkyl with 1 to 4 carbon atoms and 1 to 5 halogen atoms igua or different, or Preferably R2 means aryl with 6 to 10 carbon atoms, each of these residues can be substituted from one to five times, in the same or different ways by halogen, cyano, nitro, amino, hydroxy, formyl , carboxy, carbamoyl, thiocarbamoyl; alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulphonyl respectively straight-chain or branched chain with respectively 1 to 6 carbon atoms; alkenyl or alkenyloxy respectively straight-chain or branched chain with respectively 2 to 6 carbon atoms; halogenoalkyl, halogenoalkoxy, halogenoalkylthio, ha-loloalkylsulfinyl or halogenoalkylsulfonyl respectively straight-chain or branched chain with respectively 1 to 6 carbon atoms and 1 to 13 same or different halogen atoms; halogenoalkenyl or halogenoalkynyloxy respectively straight-chain or branched chain with respectively 2 to 6 carbon atoms and 1 to 13 halogen atoms not identical or different; alkylamino, dialkylamino, alkylcarbonyl, alkylcarbyloxy, alkoxycarbonyl, alkylsulfonyloxy, hydroxii-minoalkyl or alkoxyiminoalkyl respectively straight-chain or branched chain with respectively 1 to 6 carbon atoms in the individual alkyl portions; phenyl, phenoxy, phenylthio, benzyloxy, benzylthio or phenylethyloxy, or by alkylene double-bonded with 3 or 4 carbon atoms or by dioxyalkylene double-bonded with 1 or 2 carbon atoms, these two radicals can be substituted last, in turn, one or several times, in a same or differently by halogen, by straight chain or branched chain alkyl with 4 carbon atoms and / or by straight chain or branched chain haloalkyl with 1 to 4 carbon atoms and 1 to 9 carbon atoms halogen the same or different. Preferably, n also means the numbers 0, 1, 2 or 3. Preferably, R 3 is hydrogen, amino, dialkylamino having 1 to 6 carbon atoms in each alkyl part, alkylthio having 1 to 6 carbon atoms, straight-chain alkyl or branched chain with 1 to 10 carbon atoms or straight chain or branched chain alkoxy with 1 to 6 carbon atoms, it being possible for the alkyl radicals or the alkoxy radicals to be replaced one or more times, in the same or in different ways by halogen, by cyano, by nitro, by amino, by hydroxy, by formyl, by carboxy, by carbamoyl; alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl respectively straight-chain or branched chain with 1 to 6 carbon atoms respectively; alkenyl or alkenyloxy respectively straight-chain or branched chain with respectively 2 to 6 carbon atoms; halogenoalkoxy, halogenoalkylthio, halogenoalkylsulfinyl or halogenoalkylsulfonyl, respectively of straight chain or branched chain with respectively 1 to 6 carbon atoms and 1 to 13 same or different halogen atoms; alkylamino, dialkylamino, alkylcarbonyl, alkylcarbyloxy, alkoxycarbonyl, alkylsulfonyloxy, hydroxyl i-noalkyl or alkoxyiminoalkyl respectively straight-chain or branched chain with respectively 1 to 6 carbon atoms in the individual alkyl portions; or by alkylene double-bonded with 1 to 6 carbon atoms or by dioxyalkylene double-bonded with 1 to 4 carbon atoms, the two mentioned radicals can be substituted last, in turn, once or several times, in the same way or different forms by halogen, by straight-chain or branched-chain alkyl with 1 to 4 carbon atoms and / or by straight-chain or branched-chain haloalkyl with 1 to 4 carbon atoms and 1 to 9 identical halogen atoms or different, or by phenyl, or Preferably, R3 means cycloalkyl with 3 to 7 carbon atoms, these residues may be substituted one to four times, in the same or different ways by halogen and / or by alkyl with 1 to 4 carbon atoms. to 4 carbon atoms, or R3 means cycloalkenyl with 3 to 7 carbon atoms, these residues may be substituted one to four times, in the same or different ways by halogen and / or by alkyl with 1 to 4 atoms Carbon, or Pre R3 means saturated or unsaturated heterocyclyl with 3 to 7 members in the ring, 1 to 3 being the same or different heteroatoms, such as oxygen, nitrogen or sulfur, the radicals being able to be substituted one to three times, the same or different forms by halogen, by alkyl with 1 to 4 carbon atoms, by alkoxy with 1 to 4 carbon atoms and / or by halogen-alkyl with 1 to 4 carbon atoms and 1 to 5 carbon atoms; Halogen equal or different, or Preferably, R3 means aryl having 6 to 10 carbon atoms, each of these residues can be substituted from one to five times, in the same or different ways, by halogen, by cyano, by alkyl of straight chain or branched chain with 1 to 4 carbon atoms, halogenoalkyl straight chain or branched chain with 1 to 4 carbon atoms and 1 to 9 same or different halogen atoms, straight chain or straight chain alkoxy or alkylthio mime with 1 to 4 carbon atoms, halogenoalkoxy or straight chain or branched chain halogen alkylthio with 1 to 4 carbon atoms and 1 to 9 same or different halogen atoms, phenyl, phenoxy, phenylthio, benzyloxy, benzylthio or phenylethyloxy , or by alkylene double-bonded with 3 or 4 carbon atoms or by dioxyalkylene double-bonded with 1 or 2 carbon atoms, the two mentioned radicals can be substituted lastly, in turn, once or several times, in the same or in different forms by halogen, by straight-chain or branched-chain alkyl with 1 to 4 carbon atoms and / or by straight-chain or branched-chain halogen-alkyl with 1 to 4 carbon atoms and 1 to 9 carbon atoms; halogen the same or different. R 1 is particularly preferably methyl, ethyl or n-propyl. Particularly preferably, R 2 means cyclohexyl, norbornyl, or cyclohexenyl, these radicals being able to be substituted one to four times, in the same or in different ways by fluorine, by chlorine, by methyl and / or ethyl, or by furyl, pyridyl, thienyl, benzofuryl, quinolyl or benzothienyl, which may be substituted one to three times, in the same or in different ways by fluorine, by chlorine, by bromine, by methyl, by ethyl, by n-propyl, by i-propyl, by n-butyl, by i-butyl, by s-butyl, by t-butyl, by methoxy, by ethoxy, by n-propoxy, by i-propoxy, by trifluoromethyl and / or by trifluoroethyl, or particularly preferably, R2 means phenyl or naphthyl, each of these residues can be substituted from one to five times, in the same or in different ways fluorine, chlorine, bromine, cyano, nitro, amino, hydrix, formyl, carboxy, carbamoyl, thiocarba oyl, methyl, ethyl, n- or i-propyl, n-, i-, s- or t-butyl, by methoxy, by ethoxy, by n- or i-propoxy, by methylthio, by ethylthio, by n- or i-propylthio, by methylsulfinyl, by ethylsulfinyl, by Methylsulfonyl or Ethylsulphonyl, Trifluoromethyl, Trifluoroyl, Difluoromethoxy, Trifluoromethoxy, Difluorochloromethoxy, Trifluoroethoxy, Difluoromethylthio, Difluorochloromethylthio, Trifluoromethylthio tri- fluomomethyl sulphonyl or trifluoromethylsulphonyl, methylamino, ethylamino, n- or i-propylamino, dimethylamino, diethylamino, methoxycarbonyl, ethoxycarbonyl, phenyl, phenoxy, phenylthio, benzyloxy, benzylthio or phenylethyloxy, or trimethylene. (propane-1, 3-diyl) methylenedioxy or ethylenedioxy, respectively double-bonded, each optionally substituted one or more times, in the same or different manner by fluorine, by chlorine, by methyl, by trifluoromethyl, by ethyl, by n- or i-propyl. Particularly preferably n also denotes the numbers 0, 1, 2 or 3. R 3 is particularly preferably hydrogen, amino, dimethylamino, methylthio, methyl, ethyl, n- or i-propyl, n-, i-, s -butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, methoxymethyl, hydroxymethyl, 1-hydroxy-1-ethyl, 2-hydroxycarbonyl-1-hydroxy-1-ethyl, 2-hydroxycarbonyl-1-ethyl, 3-hydroxy - carbonyl-1-propyl and benzyl. The racemic N-acylamines of the formula (II) are known or can be obtained according to the known methods for the acylation of amines. In this way, the N-acylamines of the formula (II) are obtained, for example, by reaction of racemic amines with acyl chlorides or with acid anhydrides. Suitable biocatalysts for carrying out the process according to the invention are all those lipases which are suitable for the selective dissociation of the (N) -enantiomers of N-acylamines of the formula (II). Examples which may be mentioned include Lipase from Candida Antarctica, Newlasa F, Lipase from Pseudomonas Sp. And Lipase M. Lipases which can be used as biocatalysts are known. The lipases can be used in carrying out the process according to the invention either in the native state or in a modified form, for example microencapsulated or bound on inorganic or organic support materials. Suitable support materials include, for example, celites, zeolites, polysaccharides, polyamides and polystyrene resins.

Suitable organic diluents which can be used in carrying out the process according to the invention are all the solvents customary for this type of reaction. Preference is given to using alcohols, such as methanol, ethanol, n-butanol, benzyl alcohol and phenethyl alcohol, as well as ethers, such as tetrahydrofuran and dioxane, in addition hydrocarbons, such as pentane and hexane, as well as amides, such as dimethylformamide. , or also strong polar solvents such as dintethylsulfoxide. Finally, organic diluents also include emulsifiers and surface-active substances which can act as phase transfer catalysts. Preference is given to alkylaryl polyglycol ethers, polyethylene oxide fatty acid esters, polyethylene oxide ethers of fatty alcohols and ethoxylates of 4- (1,1,1,3-tetramethylbutyl) -phenol. In order to adjust the desired pH value, all common buffer systems are used in the process according to the invention. Preference is given to using mixtures of sodium dihydrogen phosphate / disodium hydrogen phosphate, citrate buffer, glycine buffer or other mixtures of suitable acids and bases. The pH value can be varied within a certain range in the performance of the process according to the invention. In general, the pH values are between 3.09 and 10.0, preferably between 4.0 and 9.0.

The reaction temperatures in carrying out the process according to the invention can vary within a certain range. In general, work is carried out at temperatures between 0 ° C and 80 ° C, preferably between 20 ° C and 70 ° C. The concentrations in racemic N-acyl amines of the formula (II) can vary within a certain range in carrying out the process according to the invention. In general, racemic mixtures are used, in which the concentration in racemic N-acylamine of the formula (II) is between 1 and 200 g / liter, preferably between 2 and 100 g / liter. In carrying out the process according to the invention, 1 g of racemic N-acyl amine of the formula (II) is used, generally 0.01 to 200 g, preferably 0.05 to 100 g of biocatalyst. Working up is carried out by customary methods. In general, the process is carried out in such a way that the biocatalyst is separated and the desired components are isolated from the reaction mixture remaining by distillation, fractional crystallization, extraction with acid-base solvents or by another route. In this case the (R) -amines of the formula (I) are obtained either in free state or in the form of salts, from which the (R) -amines can be liberated by treatment with bases. In addition, the (S) -enantiomers of the N-acyl amines of the formula (II) can also be separated from the reaction mixture. The latter can be transformed into another chemical reaction stage, for example by acid or basic saponification, or enzymatically, in the free (S) -amines or in their acid addition salts. The (R) -amines obtainable according to the process of the invention of the formula (I) are valuable intermediates for the preparation of pharmaceutical products or active products with insecticidal, fungicidal or herbicidal properties (cf. EP-A 0 519211, EP -A 0453 137, EP-A 0283 879, EP-A 0 264 217 and EP-A 0 341 475). In this way, for example, the product with fungicidal activity of the formula is obtained by reaction of the (R) -l- (4-chloro-phenyl) -ethylamine of the formula with 2,2-dichloro-l-ethyl-3-methyl-l-cyclopropanecarbonyl chloride of the formula Cl in the presence of an acid accepting agent and in the presence of an inert organic diluent. The implementation of the method according to the invention is explained by means of the following examples. Examples of obtaining. Example 1.

A mixture consisting of 50 mg of racemic N- [1- (4-chloro-phenyl) -ethyl] -acetamide and 100 mg of lipase from Candida antarctica (Novozym 435 *) was completed., E.C. Nr. 3.1.1.3) with a 50 mM aqueous solution of a sodium dihydrogen phosphate / hydrodiophosphate disodium phosphate buffer to a volume of 10 ml. The reaction mixture, which had a pH value of 8, was shaken for 168 hours at 50 ° C. It was then centrifuged for 5 minutes and then the liquid phase was analyzed. For this, a defined part was taken from the load, which was frozen at -60 ° C for 1 hour and then dried by lyophilisate. The dried sample was extracted with methanol under the addition of molecular sieve for one hour under intense repeated treatment with a Vortex vibrator. The ethanolic phase, anhi-dra, obtained after centrifugation, was analyzed by gas chromatography. For the determination of the concentrations in racemic amine and in racemic N-acetylamine in the determination of the conversion, a conventional reverse phase RP 18 column was used in the HPLC analysis. A mixture of acetonitrile / 20 mM phosphate buffer, pH 2.0, 80:20 (v / v) is used as the eluent. For UV detection, a wavelength of 220 nm was used. A calibration according to the external standard method was carried out both for the racemic amine and also for the N-acetylamine. For the chiral analytical capillary gas chromatography was used. As a column, a capillary glass column with a length of 20 meters served. A chiral mixed phase was used as the separating material; as carrier gas, H2 was used with a carrier gas pressure of 0.4 bar. A temperature gradient of 80 ° C // 1 minute iso // 2.5 ° C / minute // 150 ° C // 10 ° C / minute // 200 ° C was used. For the evaluation of the enantioselectivity of the reaction, the excess of enantiomers (ee value) was used, which is calculated as follows: (R - S) ee = X 100% (R + S) In this case R and S designate the concentration of the individual enantiomers of the amine formed. In this way it was observed that the (R) -l- (4-chloro-phenyl) -ethylamine had been formed in a yield of 43% with an ee value of > 99% Example 2 A mixture consisting of 3 mg of racemic N- [1- (4-chloro-phenyl) ethyl] acetamide and 0.75 mg of purified, free lipase B, derived from Candida antarctica, was completed with a 50 mM aqueous solution of a sodium dihydrogen phosphate / disodium hydrogen phosphate buffer to a volume of 1.5 ml. The reaction mixture, which showed a pH value, was shaken for 360 hours at 30 ° C. It was then elaborated and analyzed in the manner indicated in example l. From this it follows that the (R) -l- (4-chlorophenyl) -ethylamine has been formed in a yield of 25% and with an ee value of > 99% Example 3 A mixture consisting of 1.3 mg of racemic N- [1- (4-methylphenyl) -ethyl] -acetamide and 15 mg of lipase from Candida antarctica (Novozym 435 *, EC Nr. 3.1.1.3) with a 50 mM aqueous solution of a sodium dihydrogen phosphate / hydrogen phosphate disodium phosphate buffer to a volume of 1.5 ml. The reaction mixture, which had a pH value of 8, was shaken for 400 hours at 50 ° C. It was then worked out and analyzed in the manner indicated in Example 1. It follows that (R) -l- (4-methylphenyl) -ethyl-amine had been formed with a 32% yield and with an ee value of > 90% Example 4 » A mixture consisting of 1.2 mg of N- (1-phenyl-ethyl) -acetamide racemic and 15 mg of lipase from Candida antarctica (Nov ryro 435 *, E.C.Nr. 3. 1.1.3) with a 50 mM aqueous solution of a sodium dihydrogen phosphate / disodium hydrogen phosphate buffer to a volume of 1.5 ml. The reaction mixture, which had a pH value of 8, was shaken for 400 hours at 50 ° C. It was then elaborated and analyzed in the manner indicated in example l. It follows from this that the (R) -1-phenyl-ethylamine had been formed with a yield of 7.6% with an ee value of > 90% Example 5 NH2 A mixture consisting of 200 mg was completed (0.88 mmol) of N- [1- (4-chloro-phenyl) -ethyl] -methioacetamide racemic and 50 U of lipase from Candida Antarctic (Novozym 435 *) with a 50 mM aqueous solution of a buffer mixture. of sodium dihydrogen phosphate / disodium hydrogen phosphate up to a volume of 7 ml. The reaction mixture, which had a pH value of 8, was stirred for 48 hours at 40 ° C. The reaction mixture was then extracted three times with diisopropyl ether. The combined organic phases were concentrated by evaporation under reduced pressure. The remaining residue was tested by gas chromatography with the aid of a chiral column. In this way it was deduced that the reaction had passed with a conversion of 48%. The (R) -l- (4-chlorophenyl) -ethylamine obtained has an ee value of 99%. For the (S) -N- [1- (4-chloro-phenyl) -ethyl] -methoxyacetamide an ee value of 92% was deduced. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property:

Claims (6)

1. CLAIMS 1.- Procedure for obtaining (R) -amines of the formula
2. NH, • CH (i), (CH2) n-R wherein R 1 signifies alkyl, optionally substituted, R 2 means optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heterocyclyl, where, however, R1 and R2 are not identical, and n means the numbers 0, 1, 2 or 3, characterized in that racemic N-acylamines of the formula are reacted
3. C HN (II). CH R1 (CH2) -R2 wherein R1, R2 and n have the meanings indicated above and R3 signifies hydrogen, amino, dialkylamino, alkylthio, means optionally substituted alkyl or means optionally substituted alkoxy, the carbonaceous chains may be interengaged in those residues containing more than one carbon atom, heteroatoms or groups of heteroatoms, or R3 means optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally optionally substituted aryl or optionally substituted heterocyclyl, with lipases, which are suitable for the dissociation of the (R) -enantiomers of the N-acyl amines of the formula (II), in the presence of water and, if appropriate, in the presence of an organic diluent, at a pH value between 3.0 and 10.0 at temperatures between 0 ° C and 80 ° C. 2. Process according to claim 1, characterized in that racemic N-acylamines of the formula (II) are used, in which R1 means straight-chain or branched-chain alkyl with 1 to 8 carbon atoms, the residues being able to be substituted. alkyls one or several times, likewise or differently by halogen, cyano, amino, hydroxy, formyl, carboxy, carbamoyl, alkoxy or alkylthio, respectively straight-chain or branched chain, with respectively 6 atoms of carbon; halogenoalkoxy or halogenoalkylthio respectively straight-chain or branched chain with respectively 1 to 6 carbon atoms and 1 to 13 identical or different halogen atoms; alkylamino, dialkylamino, alkylcarbonyl, alkylcarbyloxy, alkoxycarbonyl, alkylsulfonyloxy, hydroxy-iminoalkyl or alkoxyiminoalkyl, respectively of straight chain or branched chain with respectively 1 to 6 carbon atoms in the individual alkyl portions; or by alkylene double-bonded with 1 to 6 carbon atoms or by dioxyalkylene double-bonded with 1 to 4 carbon atoms, the two mentioned radicals can be substituted last, in turn, once or several times, in the same way or different forms by halogen, by straight-chain or branched-chain alkyl with 1 to 4 carbon atoms and / or by straight-chain or branched chain halogen with 1 to 4 carbon atoms and 1 to 9 identical halogen atoms or different, it means cycloalkyl with 3 to 7 carbon atoms, these residues may be substituted one to four times, in the same or different ways by halogen and / or by alkyl with 1 to 4 carbon atoms, or R2 means cycloalkenyl with 3 to 7 carbon atoms, these residues may be substituted one to four times, in the same or different ways, by halogen and / or by alkyl with 1 to 4 carbon atoms, or R2 means saturated heterocyclyl or unsaturated benzocondensate, with 3 to 7 members in the ring in the heterocycle, of which 1 to 3 heteroatoms may be the same or different, such as oxygen, nitrogen or sulfur, the residues of one to three may be substituted. sometimes equally or in different forms by halogen, by alkyl with 1 to 4 carbon atoms, by alkoxy with 1 to 4 carbon atoms, and / or by halogenalkyl with 1 to 4 carbon atoms and 1 to 5 halogen atoms same or different, or R2 means aryl with 6 to 10 carbon atoms, each of these residues may be substituted from one to five times, in the same or different ways by halogen, cyano, nitro, amino, hydroxy, for ilo , carboxy, carbamoyl, thiocarbamoyl; alkyl, alkoxy, alkylthio, alkylsulfinyl alkylsulfonyl respectively straight-chain or branched chain with 1 to 6 carbon atoms respectively; alkenyl or alkenyloxy respectively straight-chain or branched chain with respectively 2 to 6 carbon atoms; halogenoalkyl, halogenoalkoxy, halogenoalkylthio, haloalkyl sulfinyl or halogenoalkylsulfonyl, respectively straight-chain or branched chain with 1 to 6 carbon atoms and 1 to 13 identical or different halogen atoms; halogenoalkenyl or halogenoalkynyloxy respectively straight-chain or branched chain with respectively 2 to 6 carbon atoms and 1 to 13 different same halogen atoms; alkylamino, dialkylamino, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkylsulfonyloxy, hydroxylaminoalkyl or alkoxyiminoalkyl respectively straight-chain or branched chain with respectively 1 to 6 carbon atoms in the individual alkyl portions; phenyl, phenoxy, phenylthio, benzyloxy, benzylthio or phenylethyloxy, or by alkylene double-bonded with 3 or 4 carbon atoms or by dioxyalkylene double-bonded with 1 or 2 carbon atoms, these two radicals can be substituted last, in turn, one or more times, in the same or in different ways by halogen, by straight-chain or branched-chain alkyl with 1 to 4 carbon atoms and / or by straight-chain or branched-chain halogenoalkyl. 1 to 4 carbon atoms and 1 to 9 identical or different halogen atoms, n also means numbers 0, 1, 2 or 3, and ignites hydrogen, amino, dialkylamino with 1 to 6 carbon atoms in each alkyl part, alkylthio with 1 to 6 carbon atoms, straight-chain or branched-chain alkyl with 1 to 10 carbon atoms or straight-chain or branched-chain alkoxy with 1 to 6 carbon atoms, the alkyl radicals or alkoxy radicals may be substituted. one or one several times, in the same or different ways by halogen, by cyano, by nitro, by amino, by hydroxy, by formyl, by carboxy, by carbayl; alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl respectively straight-chain or branched chain with 1 to 6 carbon atoms respectively; alkenyl or alkenyloxy respectively straight-chain or branched chain with respectively 2 to 6 carbon atoms; halogenalkoxy, halogenoalkylthio, halogenoalkylsulfonynyl or haldgenoalkylsulphonyl respectively straight-chain or branched chain with respectively 1 to 6 carbon atoms and 1 to 13 identical or different halogen atoms; alkylamino, dialkylamino, alkylcarbonyl, alkylcar- nyloxy, alkoxycarbonyl, alkylsulfonyloxy, hydroxyiminoalkyl or alkoxyiminoalkyl respectively of straight chain or branched chain with 1 to 6 carbon atoms respectively in the individual alkyl moieties; 0 by alkylene double-bonded with 1 to 6 carbon atoms or by dioxyalkylene double-bonded to 1 to 4 carbon atoms, the two radicals mentioned may be substituted lastly, in turn, one or more times, in the same or in different forms by halogen, by straight-chain or branched-chain alkyl with 1 to 4 carbon atoms. to 4 carbon atoms and / or straight chain or branched chain halogen alkyl with 1 to 4 carbon atoms and 1 to 9 same or different halogen atoms, or for phenyl, or R3 means cycloalkyl with 3 to 7 carbon atoms , these residues can be substituted one to four times, in the same or in different ways by halogen and / or by alkyl with 1 to 4 carbon atoms, or R3 means cycloalkenyl with 3 to 7 carbon atoms, and can be these residues are substituted one to four times, in the same or in different ways by halogen and / or by alkyl with 1 to 4 carbon atoms, or R3 means saturated or unsaturated heterocyclyl with 3 to 7 members in the ring, respectively being 1 to 3 of the same hetero equal or different atoms, such as oxygen, nitrogen or sulfur, the radicals being able to be substituted one to three times, in the same or in different forms by halogen, by alkyl with 1 to 4 carbon atoms, by alkoxy with 1 to 4 carbon atoms and / or by halogen-alkyl having 1 to 4 carbon atoms and 1 to 5 same or different halogen atoms, or aryl means with 6 to 10 carbon atoms, each of these residues may be substituted one to five times, in the same or in different ways, by halogen, by cyano, by straight-chain or branched-chain alkyl with 1 to 4 carbon atoms, straight-chain or branched-chain halogen with 1 to 4 carbon atoms and 1 to 9 identical or different halogen atoms, straight chain or branched chain alkoxy or alkylthio having 1 to 4 carbon atoms, halogenoalkoxy or straight chain or branched chain halogenalkylthio having 4 carbon atoms and 1 carbon atom; to 9 halogen atoms The same or different atoms, phenyl, phenoxy, phenylthio, benzyloxy, benzylthio or phenylethyloxy, or by alkylene double-bonded with 3 or 4 carbon atoms or by dioxyalkylene or double-bonded with 1 or 2 parts of carbon, may be substituted the two re. cited at the same time, in turn, once or several times, in an ig-al form or in different ways by halogen, by straight-chain or branched-chain alkyl with 1 to 4 carbon atoms and / or by haloalkyl chain linear or branched chain with 1 to 4 carbon atoms and 9 equal or different halogen atoms. 3. Method according to claim 1, characterized in that the compound of the formula is used as racemic N-acylamine
4. 4. - Process according to claim 1, characterized in that Lipase from Antarctic Candida, Newlasa F. Lipase from Pseudo onas Sp or Lipase M is used as the biocatalyst. Process according to claim 1, characterized in that a pH value is used. between 4.0 and 9.0. 6. Method according to claim 1, characterized in that the work is carried out at temperatures between 20 ° C and 70 ° c.