DE19637336A1 - Process for the production of optically active amines - Google Patents

Abstract

The invention relates to a process for the preparation of optically active amines of the formula (I*), in which R and m have the meanings given in the description. In the present process the preparation of said amines is such that (a) in a first stage, racemic amines of the formula (I) are reacted, in the presence of lipases from Candida antarctica and optionally in the presence of a diluent, with esters of the formula (II), in which R<1>, R<2>, X and n have the meanings given in the description; (b) in a second stage the resulting mixture of (S)-amine of the formula (I-S) and acylated (R)-amine of the formula (III) is separated.

Description

The present invention relates to a new process for the production of known, optically active amines, which are used as intermediates for the production of Pharmaceuticals and crop protection products can be used. The Erfin tion also concerns new optically active acylated amines.

From DE-A 43 32 738 it is already known that optically active, primary and have secondary amines prepared by first adding racemic amine to Presence of a hydrolase with an ester in the acid part in the vicinity of the Carbonyl carbon atom has an electron-rich heteroatom, enantio selectively acylated, then the resulting mixture of optically active (S) -amine and separates optically active acylated (R) amine (= amide), thereby obtaining the (S) amine and optionally the other from the acylated (R) amine by amide cleavage Enantiomer wins. Lipases from Pseudomonas come as hydrolases, e.g. B. Amano P, or from Pseudomonas spec. DSM 8246 in question. The optical one The degree of purity of the enantiomers obtained is very high. Disadvantage of this However, the process is that the reaction in the enzymatic acylation is quite long times are required and work is carried out in a very dilute solution. The remaining (S) -enantiomer is only in after relatively long reaction times get sufficiently high optical yield. The achievable space-time Yields therefore leave something to be desired for practical purposes. Is unfavorable also that in relation to the substrate relatively high amounts of enzyme required are. Otherwise, the enzyme has a very high activity, so that a considerable effort for the cleaning, the concentration and the Refurbishment is necessary.

Furthermore, Chimica 48 570 (1994) shows that racemic amines also Ethyl acetate in the presence of lipase from Candida antarctica enantio selective to mixtures of (S) -amine and acetylated (R) -amine (= amide) react from which (S) -amine and acetylated (R) -amine can be isolated, the acetylated (R) amine being released by subsequent amide cleavage can be. A disadvantage of this method is that it takes a long time Response times are required and the yields are not always  are satisfactory. Furthermore, the ratio of enzyme to is also here Substrate so disadvantageous that the process can hardly be used economically is possible.

It has now been found that optically active amines of the formula

in which
R represents aryl optionally monosubstituted to trisubstituted in the same way or differently, but the positions of the aryl group adjacent to the point of attachment do not bear any substituents, or
represents optionally to triple, identical or differently substituted, optionally benzanellated heteroaryl, but the positions of the heteroaryl group adjacent to the point of attachment do not bear any substituents, or
represents alkyl having 1 to 7 carbon atoms, haloalkyl having 1 to 7 carbon atoms and 1 to 5 halogen atoms or alkoxyalkyl having 1 to 7 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the alkoxy part, and
m represents the numbers 0, 1, 2 or 3,
obtained by

• a) in a first stage racemic amines of the formula in which
  R and m have the meanings given above,
  with esters of the formula in which
  R¹ represents alkyl having 1 to 10 carbon atoms or haloalkyl having 1 to 6 carbon atoms and 1 to 5 halogen atoms,
  R² for hydrogen, alkyl with 1 to 10 carbon atoms, haloalkyl with 1 to 6 carbon atoms and 1 to 5 halogen atoms or for optionally single to triple, similar or different by halogen, amino, hydroxy, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, phenyl and / or phenoxy substituted phenyl,
  X represents oxygen, sulfur or an -NR³ group, wherein
  R³ represents alkyl having 1 to 4 carbon atoms,
  and
  n represents the numbers 0, 1, 2 or 3,
  in the presence of lipase from Candida antarctica and optionally in the presence of a diluent,
• b) in a second stage, the mixture of (S) -amine of the formula obtained in which
  R and m have the meanings given above,
  and acylated (R) amine of the formula in which
  R, R², X, m and n have the meanings given above,
  separates and
• c) optionally in a third step from acylated (R) -amine of the formula (III) by treatment with acid or base, optionally in the presence of a diluent (R) -amine of the formula in which
  R and m have the meanings given above,
  releases.

The (R) amines include those optically active compounds of the formula (I) understand the (R) -configura on the asymmetrically substituted carbon atom tion. Correspondingly, among (S) amines, those are optically active To understand compounds of the formula (I) which, at the chirality center, have the (S) - Have configuration. This is asymmetrically substituted in the formulas Carbon atom identified by (*).  

It can be described as extremely surprising that optically active amines Formula (I *) according to the inventive method in high yield and very have good optical purity. Due to the known state of the Technology could not be expected that the special Use of lipase from Candida antarctica a higher enantioselectivity and causes a faster reaction in the reaction between amine and ester than the enzyme systems previously used in corresponding processes.

The method according to the invention has a number of advantages. So enabled it enables the production of a large number of optically active amines in high Yield and excellent optical purity. It is also favorable that at relative high substrate concentration can be worked and the reaction times are short are. This makes it possible to achieve space-time yields that are also practical Purposes are satisfactory. It is also advantageous that the biocatalyst required is available in large quantities and is stable even at elevated temperatures is. The biocatalyst is used in relation to the amount of enzyme Substrate used in a relatively small amount and low enzyme activity. Finally, the implementation of the implementation and the isolation of the desired substances, both the (S) and the (R) amines, no difficulties.

Exposing racemic 1- (4-chlorophenyl) ethylamine in the presence of lipase Candida antarctica with methyl methoxyacetate, separates the resulting Components and treats the (R) -enantiomer of methoxyacetic acid 1- (4- chlorphenyl) ethyl amide with hydrochloric acid, the course of the fiction The following procedure is used to illustrate the process.

The starting materials in carrying out the process according to the invention Formula (I) provides a general definition of the racemic amines required.

R preferably represents optionally substituted phenyl of the formula

wherein

R⁴, R⁵ and R⁶ independently of one another for hydrogen-halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkoxy with 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, cyano, dialkylamino with 1 to 4 carbon atoms in each alkyl group, nitro, phenyl, phenoxy or benzyl, or
R for optionally single to triple, identical or different by halogen, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, alkoxy having 1 to 4 carbon atoms and / or haloalkoxy having 1 to 4 Carbon atoms and 1 to 5 identical or different halogen atoms substituted naphthyl, but the ortho positions to the carbon atom via which the naphthyl radical is bonded are unsubstituted, or
R for optionally benzanellated heteroaryl with 5 or 6 ring members and 1 to 3 heteroatoms, such as nitrogen, oxygen and / or sulfur, in the heterocycle, where these radicals can be monosubstituted to triple, identical or differently substituted by halogen, alkyl having 1 to 4 carbon atoms , Alkoxy having 1 to 4 carbon atoms and / or haloalkyl having 1 to 4 carbon atoms, but the positions adjacent to the linkage of the heteroaryl group do not bear any substituents, or
for straight-chain or branched alkyl with 1 to 7 carbon atoms, haloalkyl with 1 to 5 carbon atoms and 1 to 5 fluorine and / or chlorine atoms or for alkoxyalkyl with 1 to 5 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the alkoxy part.
m also preferably represents the numbers 0, 1, 2 or 3.

Amines of the formula (I) in which
R represents optionally substituted phenyl of the formula

stands in what

R⁴, R⁵ and R⁶ independently of one another for hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec.-butyl, methoxy, ethoxy, methylthio, trichloromethyl, trifluoromethyl, Difluoromethyl, trifluoromethoxy, difluorochloromethoxy, difluoromethoxy, cyano, dimethylamino, diethylamino, nitro, phenyl, phenoxy or benzyl, or
R for optionally single to triple, identical or different by fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, methoxy, ethoxy, trichloromethyl, trifluoromethyl, difluoromethyl , Trifluoromethoxy, difluorochloromethoxy and / or difluoromethoxy substituted naphthyl, but the ortho positions to the carbon atom via which the naphthyl radical is bonded are unsubstituted, or
R represents optionally benzanellated furyl, thienyl, pyridyl or pyrimidine, where these radicals can be substituted once to three times, identically or differently, by fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl , sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, trifluoromethyl and / or trifluoroethyl, but the positions of the heteroaryl group adjacent to the point of attachment do not carry any substituents, or
R represents straight-chain or branched alkyl having 1 to 5 carbon atoms, haloalkyl having 1 to 5 carbon atoms and 1 to 3 fluorine and / or chlorine atoms or alkoxyalkyl having 1 to 3 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the alkoxy part and
m stands for the numbers 0, 1 or 2.

Examples of amines of formula (I) are the compounds of the following Called formulas:

The racemic amines of the formula (I) are known or can be reduced establish known methods.

The in the implementation of the first stage of the method as The esters required for reaction components are general by the formula (II) Are defined.

R¹ preferably represents straight-chain alkyl having 1 to 8 carbon atoms or for straight-chain haloalkyl with 1 to 4 carbon atoms and 1 to 3 Fluorine and / or chlorine atoms.

R² preferably represents hydrogen, straight-chain alkyl having 1 to 8 carbons atoms, straight chain haloalkyl with 1 to 4 carbon atoms and 1 to 3 fluorine, chlorine and / or bromine atoms, or for optionally one times to three times, identical or different due to fluorine, chlorine, bromine, Amino, hydroxy, methyl, ethyl, methoxy, ethoxy, phenyl and / or Phenoxy substituted phenyl.

X preferably represents oxygen or sulfur.

n preferably represents the numbers 0, 1 or 2.

Esters of the formula (II) in which are particularly preferred
R1 represents methyl, ethyl, n-propyl, n-butyl, chloromethyl, 2-chloroethyl, 2-fluoroethyl or 2,2,2-trifluoroethyl,
R² for hydrogen, methyl, ethyl, n-propyl, n-butyl, chloromethyl, trifluoromethyl, 2-chloroethyl or for optionally single or double by fluorine, chlorine, bromine, amino, hydroxy, methyl, ethyl ,, methoxy, phenyl and / or phenoxy substituted phenyl,
X represents oxygen or sulfur and
n stands for the numbers 1 or 2.

Examples of esters of formula (II) are the compounds of the following Called formulas.

The esters of the formula (II) are known or can be prepared by known methods produce.

Serves as a biocatalyst when carrying out the first stage of the invention lipase from Candida antarctica. This is preferably usable Product commercially available under the name Novozym 435®.

The lipase can be either native or in a modified form, e.g. B. microencapsulated or bound to inorganic or organic carrier materials will. As carrier materials come z. B. Celite, Lewatit, Zeolithe, Polysaccharides, polyamides and polystyrene resins come into question.

As a diluent when performing the first stage inventive method all orga usual for such implementations African solvents. Ethers such as methyl can preferably be used tert-butyl ether or tert-amyl methyl ether, furthermore aliphatic or aromatic Hydrocarbons, such as hexane, cyclohexane or toluene, and also nitriles, such as Acetonitrile or butyronitrile, furthermore alcohols, such as tert-butanol or 3-methyl 3-pentanol, and finally also the esters used for acylation.

The temperatures can be in the implementation of the first stage of the Invention according to the method can be varied within a certain range. in the generally one works at temperatures between 0 ° C and 80 ° C, preferably between 10 ° C and 60 ° C.

When performing the first stage of the method according to the invention works generally under atmospheric pressure, optionally under an inert gas, such as Nitrogen or argon.

When carrying out the first stage of the method according to the invention 1 to 1 mol of racemic amine of the formula (I) generally from 0.6 to 10 mol, preferably 1 to 3 mol of ester of the formula (II). The amount of Lipase can also be varied within a certain range. in the  generally 1 to 10% by weight of immobilized lipase, based on racemic amine, which has an activity of 10,000 to 112,000 units of lipase per mole of racemic amine. In detail one travels with the Carrying out the first stage of the method according to the invention in such a way that you put the components together in any order and that resulting mixture until the desired turnover is reached at respective reaction temperature. To end the reaction, go to generally so that the biocatalyst is separated by filtration.

The mixture obtained in the first stage of the process according to the invention becomes worked up in the second stage using customary methods. In general the desired components are isolated by distillation, fractionated Crystallization, acid-base-solvent extraction or otherwise. So can be done, for example, in such a way that the reaction mixture subjected to a fractional distillation. It is also possible to do this that the reaction mixture is concentrated, the remaining residue in one absorbs only little miscible organic solvent with water, the resulting Solution treated with water and mineral acid and the phases separated. By Concentration of the organic phase gives the acylated (R) amine. From the aqueous phase, the (S) -amine can be isolated by first using base treated, then with an organic solvent which is only slightly miscible with water extracted, the combined organic phases dry and concentrated. - Given if further cleaning of the isolated products, e.g. B. by Chromato graphie or distillation.

The acylated (R) amines of the formula

in which
R⁸ represents fluorine, chlorine, bromine, methyl, methoxy or methylthio,
R⁷ and R⁹ stand for hydrogen and
p represents the numbers 0, 1 or 2,
or
R⁸ represents hydrogen,
R⁷ and R⁹ are methyl and
p stands for 2,
are new.

The compounds are examples of acylated (R) amines of the formula (IIIa) of the following formulas:

As acids come in performing the third stage of the invention according to the process, all the usual strong acids into consideration. Preferably ver Mineral acids such as sulfuric acid or hydrochloric acid can be used.

The bases used in carrying out the third stage of the invention All common strong bases are considered. Are preferably usable inorganic bases, such as sodium or potassium hydroxide.

The diluent used in the third stage of the inventions process according to the invention all of the organic processes customary for such reactions Solvents and water into consideration. Water or Mixtures of water and organic solvents, with mixtures of water and toluene may be mentioned as examples.

Temperatures may vary when performing the third stage of the invention Process according to the invention can be varied within a relatively wide range. in the generally one works at temperatures between 20 and 180 ° C, preferably between 30 and 150 ° C.  

When performing the third stage of the method according to the invention works one generally under atmospheric pressure. But it is also possible under to work under increased or reduced pressure.

When performing the third stage of the method according to the invention per 1 mole of acylated (R) -amine of the formula (III), generally 1 to 5 equivalents or a larger excess of acid or base. The Refurbishment is carried out using customary methods. In general, this is how that the reaction mixture after the cleavage and neutralization with an organic solvent which is only slightly miscible with water, which combined organic phases dry and concentrate. The product obtained can, if necessary, by usual methods of any still existing Impurities are freed.

The amines of the formula (I *) which can be prepared by the process according to the invention are valuable intermediates for the manufacture of pharmaceuticals or Active ingredients with insecticidal, fungicidal or herbicidal properties (cf. EP-A 0 519 211, EP-A 0 453 137, EP-A 0 283 879, EP-A 0 264 217 and EP-A 0 341 475). So you get z. B. the fungicidally active compound of the formula

by using the (R) -1- (4-chlorophenyl) ethylamine of the formula

with 2,2-dichloro-1-ethyl-3-methyl-1-cyclopropanecarboxylic acid chloride of the formula

in the presence of an acid binder and in the presence of an inert organic Reacts diluent.

The method according to the invention is carried out by the following Illustrated examples.  

Manufacturing examples example 1 1st stage

A solution of 77.75 g (0.5 mol) of racemic 1- (4-chlorophenyl) ethylamine in 260 g of methyl methoxyacetate is stirred at room temperature with 3.9 g Novozym 435® (= immobilized lipase from Candida antarctica; 7300 U / g), transferred. The mixture is stirred for a further 2.5 hours at room temperature, filtered then the enzyme and washed with 20 g of methyl methoxyacetate.

2nd stage

The filtrate is concentrated under reduced pressure, and the remaining The residue is taken up in 300 ml of methylene chloride. The resulting solution is mixed with 100 ml of ice water and 21 ml of concentrated hydrochloric acid and 0.2 Stirred for hours at room temperature. Then the phases are separated.

The organic phase is dried after drying over magnesium sulfate reduced pressure. This gives 61.9 g of one Product which according to gas chromatographic analysis is 95% from the (R) - Enantiomers of methoxyacetic acid 1- (4-chlorophenyl) ethyl amide exists. Of the ee value is 97.1%.

Then a yield of 51.7% of theory is calculated.

The aqueous phase obtained after the above phase separation is cooled mixed with 35 ml of concentrated aqueous sodium hydroxide solution and then three times with Extracted methylene chloride. The combined organic phases are after Dry concentrated over magnesium sulfate under reduced pressure. You get in this way 37 g of a colorless liquid, which according to gaschromato  graphic analysis to 98.2% from the (S) -enantiomer of 1- (4-chlorophenyl) - ethylamine exists. The ee value is 91.8%.

Then a yield of 46.6% of theory is calculated.

3rd stage

A mixture of 52 g (0.224 mol) of the (R) -enantiomer of Methoxyacetic acid 1- (4-chlorophenyl) ethyl amide, 180 ml water and 67.7 g Concentrated hydrochloric acid is heated under reflux for 10 hours. After this The reaction mixture is initially cooled to room temperature Extracted 100 ml of methylene chloride, then with concentrated aqueous sodium hydroxide solution made alkaline and then three times with 200 ml of methylene chloride extracted. The combined organic phases are over magnesium sulfate dried and then concentrated under reduced pressure. You get on this Assign 33.1 g of a product according to gas chromatographic analysis 99.1% consists of the (R) -enantiomer of 1- (4-chlorophenyl) ethylamine. Of the ee value is 95.1%.

A total yield of 95% of theory is calculated.

Example 2 1st stage

A solution of 3.1 g (0.02 mol) of racemic 1- (4-chlorophenyl) ethylamine in 20 ml of tert-amyl methyl ether is added at room temperature with stirring other with 10.4 g (0.1 mol) of methyl methoxyacetate and 0.6 g of novozyme 435® (= immobilized lipase from Candida antarctica; 7300 U / g) added. Man keeps stirring at 40 ° C and controls the progress of the reaction by samples are examined by gas chromatography. After 1.5 hours there is a turnover reached by 52%. At this point the reaction is stopped by the enzyme is filtered off.  

2nd stage

The filtrate remaining after filtering off the enzyme becomes a fraction subjected to distillation.

In this way, 1.3 g of a colorless liquid are obtained, which according to gas chromatographic analysis of 94% from the (S) -enantiomer of 1- (4- Chlorphenyl) ethylamine exists. The ee value is <98%. Then calculated a yield of 43% of theory.

In addition, 2.1 g of a product are obtained, which according to gas chromatography 99% analysis from the (R) -enantiomer of methoxyacetic acid 1- (4-chloro phenyl) ethyl amide. The ee value is <98%. After that it is calculated a yield of 46.8% of theory.

Example 3 1st stage

A solution of 7.93 g (0.051 mol) of racemic 1- (4-chlorophenyl) - ethylamine in 40 ml of methyl tert-butyl ether is stirred at room temperature successively with 13.2 g (0.1 mol) of methoxyacetic acid n-propyl ester and 0.45 g Novozym 435® (= immobilized lipase from Candida antarctica; 7300 U / g) transferred. The stirring is continued at 40 ° C. and the progression of the Reaction by examining samples by gas chromatography. After 1.5 hours sales of 52% have been achieved. At this point the reaction is stopped break by filtering off the enzyme.

2nd stage

The filtrate remaining after filtering off the enzyme becomes one subjected to fractional distillation.  

This gives 3.5 g (44.3% of theory of the (S) -enantiomer of 1- (4-chlorophenyl) ethylamine. The ee value is 96.4%.

In addition, 5.2 g (45.1% of theory) of the (R) -enantiomer of Methoxyacetic acid 1- (4-chlorophenyl) ethyl amide. The ee value is 99%.

Example 4 1st stage

A solution of 7.8 g (0.05 mol) of racemic 1- (4-chlorophenyl) ethylamine in 35 ml of methyl tert-butyl ether at room temperature with stirring successively with 8.32 g (0.08 mol) of methyl methoxyacetate and 0.39 g Novozym 435® (= immobilized lipase from Candida antarctica; 7300 U / g) transferred. The stirring is continued at room temperature and the progress is monitored the reaction by examining samples by gas chromatography. After 4.5 Hours, sales of 55% are achieved. At this point the reaction stopped by filtering off the enzyme. In the remaining filtrate points the (S) -enantiomer of 1- (4-chlorophenyl) ethylamine has an ee value of 98.1% while the (R) enantiomer of methoxyacetic acid 1- (4-chlorophenyl) - ethylamids with an ee value of 96%.

Example 5 1st stage

A solution of 7.8 g (0.05 mol) of racemic 1- (4-chlorophenyl) ethylamine in 40 ml of methyl tert-butyl ether at room temperature with stirring successively with 13.2 g (0.13 mol) of methyl methoxyacetate and 80 mg Novozym 435® (= immobilized lipase from Candida antarctica; 7300 U / g) transferred. The stirring is continued at 40 ° C. and the progression of the Reaction by examining samples by gas chromatography. After 3 hours sales reached 43.8%. At this point the reaction stopped by filtering off the enzyme. In the remaining filtrate points the (R) -enantiomer of methoxyacetic acid 1- (4-chlorophenyl) ethylamide ee value of 97.7%.

Example 6 1st stage

A solution of 7.8 g (0.05 mol) of racemic 1- (4-chlorophenyl) ethylamine in 40 ml of methyl tert-butyl ether at room temperature with stirring successively with 10.4 g (0.1 mol) of methyl methoxyacetate and 0.45 g Novozym 435® (= immobilized lipase from Candida antarctica; 7300 U / g) transferred. The stirring is continued at 60 ° C. and the progression of the Reaction by examining samples by gas chromatography. After 3 hours sales of 54% achieved. At this point the reaction stopped by filtering off the enzyme. In the remaining filtrate points the (S) -enantiomer of 1- (4-chlorophenyl) ethylamine has an ee value of 98.8% while the (R) enantiomer of methoxyacetic acid 1- (4-chlorophenyl) ethylamids with an ee value of 94.4%.  

Example 7 1st stage

A solution of 16.6 g (0.107 mol) of racemic 1- (4-chlorophenyl) ethyl Amine in 41 g of methyl methoxyacetate is added with stirring Room temperature with 1.2 g Novozym 435® (= immobilized lipase from Candida antarctica; 7300 U / g). You keep stirring at 40 ° C and check that Progress of the reaction by examining samples by gas chromatography. After 2.5 hours, a conversion of 54% is reached. At this point the The reaction was stopped by filtering off the enzyme. In the remaining one The (S) -enantiomer of 1- (4-chlorophenyl) ethylamine has an ee value in filtrate of 95.6%, while the (R) enantiomer of methoxyacetic acid 1- (4- chlorphenyl) ethyl amide with an ee value of 95.3%.

Example 8 1st stage

A solution of 20.06 g (0.129 mol) of racemic 1- (4-chlorophenyl) ethylamine in 20 g (0.19 mol) of methyl methoxyacetate is stirred in Room temperature with 1 g Novozym 435® (= immobilized lipase from Candida antarctica; 7300 U / g). The mixture is stirred for another hour at room temperature and then stops the reaction by filtering off the enzyme. Of the Sales are 43.9%. In the remaining filtrate, the (S) -enantiomer has of 1- (4-chlorophenyl) ethylamine has an ee value of 61%, while the (R) -  Enantiomers of methoxyacetic acid 1- (4-chlorophenyl) ethylamide with one ee value of 98.4% arises.

Example 9 1st stage

A solution of 11.92 g (0.08 mol) of racemic 3-phenyl-1-methyl propylamine in 34 ml of methyl tert-butyl ether at room temperature with 8.32 g (0.08 mol) methyl methoxyacetate and with 0.47 g Novozym 435® (= immobilized lipase from Candida antarctica; 7300 U / g) and then at Stirred 35 to 40 ° C. The progress of the reaction is determined by Samples are taken and examined by gas chromatography. Already after 0.5 hours the turnover is 41%. The reaction is stopped after a total of 3 hours, by filtering off the enzyme. The turnover is 53.8%.

2nd stage

The filtrate remaining after filtering off the enzyme becomes a frak ionized distillation.

5.15 g of the (S) -enantiomer of 3-phenyl-1-methyl are obtained in this way propylamine with an ee of 89.7%. The yield is then calculated to 43.2% of theory.

In addition, 7.88 g of the (R) enantiomer of methoxyacetic acid (3- phenyl-1-methyl-propyl) amide with an ee value of 94%. The yield is then calculated at 46.7% of theory.  

Example 10

A mixture of 17.9 g (0.1 mol) of racemic 1-methyl-3- (4-methoxyphenyl) propylamine, 10.4 g (0.1 mol) methyl methoxyacetate, 0.75 g Novozym 435® (immobilized lipase from Candida antarctica) and 80 ml methyl tert-butyl ether is stirred for 3 hours at 40 ° C. The enzyme is then filtered off. The remaining solution is mixed with 100 ml of 10% aqueous hydrochloric acid and then concentrated under reduced pressure. The residue is cooled to 0 ° C, and the resulting solid is filtered off and dried. This gives 9.95 g of a product which, according to gas chromatogram, consists of 99.2% of the (R) -enantiomer of methoxyacetic acid- [3- (4-methoxyphenyl) -1-methyl] propylamide . The yield is then calculated at 39.6% of theory.
The ee value is 99%.
1 H-NMR spectrum / CDCl₃ / TMS):
δ = 1.1 (d, 3H, CH₃); 1.63-1.71 (m, 2H, CH₂); 2.48-2.58 (m, 2H, CH₂); 3.32 (s, 3H, CH₃); 3.69 (s, 3H, CH₃); 3.78 (d, 2H, CH₂); 4.0 (m, H, CH); 6.3 (d, 1H, NH); 6.7-7.03 (m, 4H, aromatic H) ppm.

Example 11

A mixture of 51.3 g (0.34 mol) of racemic 1- (4-methoxyphenyl) ethylamine, 35.3 g (0.34 mol) methyl methoxyacetate, 2.5 g Novozym 435® ( = immobilized lipase from Candida antarctica) and 80 ml of methyl tert-butyl ether is stirred at 40 ° C. for 5 hours. The enzyme is then filtered off. The remaining solution is mixed with 100 ml of 10% aqueous hydrochloric acid and then concentrated under reduced pressure. The residue is cooled to 0 ° C, and the resulting solid is filtered off and dried. This gives 38.5 g of a product which, according to the gas chromatogram, consists of 96% of the (R) -enantiomer of methoxyacetic acid 1- (4-methoxy-phenyl) -ethylamide. The yield is then calculated at 40.2% of theory.
The ee value is 98.3%.
1 H-NMR spectrum / CDCl₃ / TMS):
δ = 1.49 (d, 3H, CH₃); 3.38 (s, 3H, CH₃); 3.79 (s, 3H, CH₃); 3.87 (d, 2H, CH₂); 5.13 (m, 1H, CH); 6.86 (d, 1H, NH); 6.9-7.28 (m, 4H, aromatic H) ppm.

Claims (7)

1. Process for the preparation of optically active amines of the formula in which
R represents aryl which is monosubstituted to trisubstituted in the same way or differently, but the positions of the aryl group adjacent to the point of attachment do not bear any substituents, or
represents heteroaryl which is optionally monosubstituted to trisubstituted in the same way or differently, optionally benzanellated, but the positions of the heteroaryl group adjacent to the point of attachment bear no substituents,
represents alkyl having 1 to 7 carbon atoms, haloalkyl having 1 to 7 carbon atoms and 1 to 5 halogen atoms or alkoxyalkyl having 1 to 7 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the alkoxy part, and
m represents the numbers 0, 1, 2 or 3,
characterized in that one

• a) in a first stage racemic amines of the formula in which
  R and m have the meanings given above,
  with esters of the formula in which
  R¹ represents alkyl having 1 to 10 carbon atoms or halogen alkyl having 1 to 6 carbon atoms and 1 to 5 halogen atoms,
  R² for hydrogen, alkyl with 1 to 10 carbon atoms, haloalkyl with 1 to 6 carbon atoms and 1 to 5 halogen atoms or for optionally single to triple, identical or different by halogen, amino, hydroxy, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, phenyl and / or phenoxy substituted phenyl,
  X represents oxygen, sulfur or an -NR³ group, in which R³ represents alkyl having 1 to 4 carbon atoms,
  and
  n represents the numbers 0, 1, 2 or 3,
  in the presence of lipase from Candida antarctica and, if appropriate, in the presence of a diluent,
• b) in a second stage, the mixture of (S) -amine of the formula obtained in which
  R and m have the meanings given above,
  and acylated (R) amine of the formula in which
  R, R², X, m and n have the meanings given above,
  separates and
• c) optionally in a third step from acylated (R) -amine of the formula (III) by treatment with acid or base, optionally in the presence of a diluent (R) -amine of the formula in which
  R and m have the meanings given above,
  releases.

2. The method according to claim 1, characterized in that one uses race-mixed amines of the formula (I) in which
R represents optionally substituted phenyl of the formula stands in what
R⁴, R⁵ and R⁶ independently of one another for hydrogen, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, halogenal koxy with 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, cyano, dialkylamino with 1 to 4 carbon atoms in each alkyl group, nitro, phenyl, phenoxy or benzyl, or,
R for optionally single to triple, identical or different by halogen, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, alkoxy having 1 to 4 carbon atoms and / or haloalkoxy having 1 to 4 Carbon atoms and 1 to 5 identical or different halogen atoms substituted naphthyl, but the ortho positions to the carbon atom via which the naphthyl radical is bonded are unsubstituted, or
R is optionally benzanellated heteroaryl with 5 or 6 rings and 1 to 3 heteroatoms in the heterocycle, where these radicals can be monosubstituted to triple, identical or differently substituted by halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms and / or haloalkyl having 1 to 4 carbon atoms, but the positions of the heteroaryl group adjacent to the linking point do not have any substituents, or
represents straight-chain or branched alkyl having 1 to 7 carbon atoms, haloalkyl having 1 to 5 carbon atoms and 1 to 5 fluorine and / or chlorine atoms or for alkoxyalkyl having 1 to 5 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the alkoxy part
and
m stands for the numbers 0, 1, 2 or 3. 3. The method according to claim 1, characterized in that the 1- (4-chlorophenyl) ethylamine of the formula as the racemic amine of the formula (I) starts. 4. The method according to claim 1, characterized in that one uses esters of formula (II) in which
R¹ represents straight-chain alkyl having 1 to 8 carbon atoms or straight-chain haloalkyl having 1 to 4 carbon atoms and 1 to 3 fluorine and / or chlorine atoms,
R² for hydrogen, straight-chain alkyl having 1 to 8 carbon atoms, straight-chain haloalkyl having 1 to 4 carbon atoms and 1 to 3 fluorine, chlorine and / or bromine atoms, or for optionally one to three times, identical or different by fluorine, chlorine, bromine , Amino, hydroxy, methyl, ethyl, methoxy, ethoxy, phenyl and / or phenoxy substituted phenyl,
X represents oxygen or sulfur,
and
n stands for the numbers 0, 1 or 2. 5. The method according to claim 1, characterized in that the methyl methoxyacetate of the formula as the ester of formula (II) starts. 6. The method according to claim 1, characterized in that at Carrying out the first stage at temperatures between 0 ° C and 80 ° C is working. 7. Acylated (R) amines of the formula in which
R⁸ represents fluorine, chlorine, bromine, methyl, methoxy or methylthio,
R⁷ and R⁹ stand for hydrogen and
p represents the numbers 0, 1 or 2,
or
R⁸ represents hydrogen,
R⁷ and R⁹ are methyl and
p stands for 2.