DE102005035395A1 - Preparation of optically active 2,3-diarylepoxide compounds comprises epoxidizing diaryl compounds and optionally separating the obtained enantiomeric mixture - Google Patents

Abstract

Preparation of optically active 2,3-diarylepoxide compounds (Ia)-(Id) comprises epoxidizing diaryl compounds (IIa) or (IIb) and optionally separating the obtained enantiomeric mixture. Preparation of optically active 2,3-diarylepoxide compounds of formula (Ia)-(Id) comprises epoxidizing diaryl compounds of formula (IIa) or (IIb) and optionally separating the obtained enantiomeric mixture. R : CH2X, CHO, CH=NR1>, CH=NNR2>, COOH, COOR3>, CONR4>R5> or CN; X : OH, O-SO2R6> or halo; R1>H, OH, 1-8C-alkyl or aryl; R2>H, 1-8C-alkyl or aryl; R3>1-8C-alkyl, 2-8C-hydroxyalkyl or arylalkyl; either R4>, R5>H, 1-8C-alkyl, 2-8C-hydroxyalkyl, aryl or arylalkyl; or R4>R5>N : 5-6 membered (un)saturated ring with 1-3 heteroatoms; and R6>1-8C (halo)alkyl or aryl. Independent claims are included for: (1) new 2,3-diarylepoxide compounds (Ia)-(Id); and (2) preparation of (1,2,4)triazol-1-ylmethyloxirane compounds of formula (IIIa) or (IIIb) comprising either reductive amination of (Ia) or (Ib) (when R is CHO) in the presence of 1H-(1,2,4)triazole or reduction of (Ia) or (Ib) (when R is CONR4>R5> and NR4>R5> form a 1H-(1,2,4)triazole-1-yl ring). Provided that: (a) in (Ia) and (Ib) R is not CH2X or COOH; and (b) R4> and R5> may also be 1-8C hydroxyalkyl. [Image] [Image] [Image].

Description

worin
R für CH₂X, CHO, CH=NR¹, CH=NNR², COOH, COOR³, CONR⁴R⁵ oder CN steht;
X für OH, O-SO₂R⁶ oder Halogen steht;
R¹ für H, OH, C₁-C₈-Alkyl oder Aryl steht;
R² für H, C₁-C₈-Alkyl oder Aryl steht;
R³ für C₁-C₈-Alkyl, C₂-C₈-Hydroxyalkyl oder Arylalkyl steht;
R⁴ und R⁵ unabhängig voneinander für H, C₁-C₈-Alkyl, C₂-C₈-Hydroxyalkyl, Aryl oder Arylalkyl stehen oder gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen gesättigten oder ungesättigten Ring mit 1 bis 3 Heteroatomen bilden; und
R⁶ für C₁-C₈-Alkyl, C₁-C₈-Halogenalkyl oder Aryl steht.The present invention relates to a process for the preparation of substantially enantiomerically pure compounds of the formulas Ia, Ib, Ic and / or Id

wherein
R is CH ₂ X, CHO, CH = NR ¹ , CH = NNR ² , COOH, COOR ³ , CONR ⁴ R ⁵ or CN;
X is OH, O-SO ₂ R ⁶ or halogen;
R ^{1 is} H, OH, C ₁ -C ₈ alkyl or aryl;
R ^{2 is} H, C ₁ -C ₈ alkyl or aryl;
R ^{3 is} C ₁ -C ₈ alkyl, C ₂ -C ₈ hydroxyalkyl or arylalkyl;
R ⁴ and R ⁵ independently of one another are H, C ₁ -C ₈ -alkyl, C ₂ -C ₈ -hydroxyalkyl, aryl or arylalkyl or, together with the nitrogen atom to which they are bonded, a 5- or 6-membered saturated or unsaturated ring having 1 to 3 heteroatoms; and
R ^{6 is} C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl or aryl.

Of Furthermore, the invention relates to certain compounds of the formula Ia and Ib and compounds of the formula Ic and Id. Finally, it concerns the invention a process for the preparation of enantiomerically pure Epoxiconazol using compounds Ia or Ib.

It It is known that in some compounds, one or more Possess asymmetric centers and therefore in different isomeric forms can be present the individual isomers have a different biological effect can have.

So it is known from WO 2005/056548 that the (2S, 3R) -enantiomer of epoxiconazole {(2S, 3R) -1- [3- (2-chlorophenyl) -2- (4-fluorophenyl) oxiranyl] methyl-1H- [1,2,4] triazole} a stronger one has fungicidal activity as its antipode or as the corresponding Racemat, and that the opposite (2R, 3S) enantiomer a more effective growth regulator than the (2S, 3R) enantiomer. The racemate of these compounds is under the common name epoxiconazole known.

Because of the partially different modes of action of individual isomers of a compound having one or more centers of asymmetry, it is therefore generally desirable to be able to produce and provide the individual isomers targeted, thereby achieving the same biological effect with a smaller amount of substance used, but at the same time Risks arising from the presence of the remaining isomers go out, reduce.

The WO 2005/056548 describes a process for preparing the substantially pure enantiomers of Epoxiconazol, in which the racemate of Z-3- (2-chlorophenyl) -2- (4-fluorophenyl) oxiranecarboxylic acid with an optically active salt former is reacted and the two formed diastereomeric salts of a fractional crystallization be subjected. After release of the acid from the separated diastereomers Salts are separated the two essentially enantiomerically pure acids reduced to their corresponding alcohols, which then by reaction with 1H- [1,2,4] triazole be converted into the respective Epoxiconazol enantiomers.

adversely In this process, the complicated separation of the diastereomers Salts that are difficult or impossible to perform on a larger scale.

task It was therefore the object of the present invention to provide a process for the preparation of compounds of the formulas Ia, Ib, Ic and / or Id are available represent that the disadvantages of the methods of the prior art does not have.

worin
R für CH₂X, CHO, CH=NR¹, CH=NNR², COOH, COOR³, CONR⁴R⁵ oder CN steht;
X für OH, O-SO₂R⁶ oder Halogen steht;
R¹ für H, OH, C₁-C₈-Alkyl oder Aryl steht;
R² für H, C₁-C₈-Alkyl oder Aryl steht;
R³ für C₁-C₈-Alkyl, C₂-C₈-Hydroxyalkyl oder Arylalkyl steht;
R⁴ und R⁵ unabhängig voneinander für H, C₁-C₈-Alkyl, C₂-C₈-Hydroxyalkyl, Aryl oder Arylalkyl stehen oder gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen gesättigten oder ungesättigten Ring mit 1 bis 3 Heteroatomen bilden; und
R⁶ für C₁-C₈-Alkyl, C₁-C₈-Halogenalkyl oder Aryl steht;
umfassend die Epoxidierung einer Verbindung der Formel IIa oder einer Verbindung der Formel IIb

worin
R wie vorstehend definiert ist,
und Trennung eines gegebenenfalls entstandenen Enantiomerengemischs.The object has been achieved by a process for the preparation of essentially enantiomerically pure compounds of the formulas Ia, Ib, Ic and / or Id

wherein
R is CH ₂ X, CHO, CH = NR ¹ , CH = NNR ² , COOH, COOR ³ , CONR ⁴ R ⁵ or CN;
X is OH, O-SO ₂ R ⁶ or halogen;
R ^{1 is} H, OH, C ₁ -C ₈ alkyl or aryl;
R ^{2 is} H, C ₁ -C ₈ alkyl or aryl;
R ^{3 is} C ₁ -C ₈ alkyl, C ₂ -C ₈ hydroxyalkyl or arylalkyl;
R ⁴ and R ⁵ independently of one another are H, C ₁ -C ₈ -alkyl, C ₂ -C ₈ -hydroxyalkyl, aryl or arylalkyl or, together with the nitrogen atom to which they are bonded, a 5- or 6-membered saturated or unsaturated ring having 1 to 3 heteroatoms; and
R ^{6 is} C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl or aryl;
comprising the epoxidation of a compound of formula IIa or a compound of formula IIb

wherein
R is as defined above,
and separation of an optionally resulting enantiomeric mixture.

The individual enantiomers or mixtures of enantiomers can then if desired be subjected to a derivatization reaction in which compounds Ia, Ib, Ic and / or Id with different radicals R are obtained.

Another object of the present invention is a process for the separation of enantiomers of mixtures of enantiomers Ia and Ib (mixture A) or mixtures of enantiomers Ic and Id (mixture B). Furthermore, the invention relates to compounds of formulas Ia or Ib, wherein R is CHO, CH = NR ¹ , CH = NNR ² , COOR ³ , CONR ⁴ R ⁵ or CN. Furthermore, the invention relates to compounds of the formulas Ic or Id which are as defined above. Finally, the invention relates to a process for the preparation of compounds of the formulas IIIa or IIIb (epoxiconazole enantiomers) shown below.

The optically active compounds Ia and Ib are valuable intermediates for the Preparation of substantially pure epoxiconazole enantiomers; you can but also as intermediates for other optically active compounds, in particular from the field of plant protection or from the pharmacological field become. The compounds Ic and Id are valuable optically active Intermediates leading to enantiomerically pure pharmacological or agrochemical substances can be further implemented.

Under "essentially enantiomerically pure compounds "(e.g. of the formulas Ia, Ib, Ic and Id, but also IIIa and IIIb and others) It should be understood in the context of the present invention that these in an enantiomeric purity of at least 95% each ee, preferably at least 96% ee and in particular at least 97 ee present

In the context of the present invention, the following definitions apply to generically defined radicals:
C ₁ -C ₄ -alkyl is a linear or branched alkyl radical having 1 to 4 carbon atoms. Examples of these are methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl or tert-butyl. C ₁ -C ₂ alkyl is methyl or ethyl, C ₁ -C ₃ alkyl is also n-propyl or isopropyl.

C ₁ -C ₈ -alkyl is a linear or branched alkyl radical having 1 to 8 carbon atoms. Examples thereof are the above-mentioned C ₁ -C ₄ -alkyl radicals and additionally pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl and their constitutional isomers such as 2-ethylhexyl.

C ₁ -C ₁₂ -alkyl is a linear or branched alkyl radical having 1 to 12 carbon atoms. Examples of these are the abovementioned C ₁ -C ₈ -alkyl radicals and, in addition, nonyl, neononyl, decyl, neodecyl, undecyl and dodecyl and also their constitutional isomers.

C ₂ -C ₈ -hydroxyalkyl is a linear or branched alkyl radical having 2 to 8, in particular 2 to 4, carbon atoms, in which at least one, for example 1, 2, 3 or 4, of the hydrogen atoms is replaced by a hydroxy group are. Examples of these are 2-hydroxy-1-ethyl, 2- and 3-hydroxy-1-propyl, 2-, 3- and 4-hydroxy-1-butyl, 2-, 3-, 4- and 5-hydroxy-1 -pentyl, 2-, 3-, 4-, 5- and 6-hydroxy-1-hexyl, 2-, 3-, 4-, 5-, 6- and 7-hydroxy-1-heptyl, 2-, 3 -, 4-, 5-, 6-, 7- and 8-hydroxy-1-octyl, 2,3-dihydroxy-1-propyl and their constitution isomers.

C ₁ -C ₈ -haloalkyl represents a linear or branched alkyl radical having 1 to 8 C atoms, which is substituted by at least one halogen radical. Examples of these are CH ₂ F, CHF ₂ , CF ₃ , CH ₂ Cl, CHCl ₂ , CCl ₃ , CH ₂ FCH ₂ , CHF ₂ CH ₂ , CF ₃ CH ₂ and the like.

C ₁ -C ₁₂ -haloalkyl represents a linear or branched alkyl radical having 1 to 12 C atoms, which is substituted by at least one halogen radical.

Aryl in the context of the present invention represents optionally substituted phenyl or optionally substituted naphthyl. The aryl radicals may carry 1 to 5 substituents which are selected, for example, from hydroxy, C ₁ -C ₈ -alkyl, C ₁ -C ₈ -haloalkyl, halogen, NO ₂ or phenyl. Examples of aryl are phenyl, naphthyl, biphenyl, tolyl, nitrophenyl, hydroxyphenyl, chlorophenyl, dichlorophenyl and hydroxynaphthyl.

arylalkyl stands for an aryl radical that over an alkylene radical is bonded. Examples of these are benzyl, 2-phenylethyl and the same.

When R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated ring having 1 to 3 heteroatoms, this ring will of course contain at least one nitrogen atom derived from the amide group. In addition, the ring may contain one or two further heteroatoms, which are preferably selected from N, O and S. For example, this ring is pyrrolidine, pyrroline, pyrrole, pyrazolidine, pyrazoline, pyrazole, imidazolidine, imidazoline, imidazole, oxazolidine, oxazoline, Oxazole, isoxazolidine, isoxazoline, isoxazole, thiazolidine, thiazoline, thiazole, triazolidine, triazoline or triazole. The ring is preferably a [1,2,4] triazole ring bonded via the 1-position.

C ₁ -C ₄ alkanols are saturated alcohols having 1 to 4 carbon atoms and one hydroxy group. Examples of these are methanol, ethanol, propanol, isopropanol, n-butanol, butan-2-ol, isobutanol and tert-butanol.

halogen in the context of the present invention is fluorine, chlorine, bromine or iodine.

In compounds Ia, Ib, Ic and Id and in compounds IIa and IIb, R ^{1 is} preferably OH, C ₁ -C ₄ -alkyl, phenyl or tolyl.

Preferably, R ^{2 is} aryl, particularly preferably substituted or unsubstituted phenyl, for example phenyl, nitrophenyl or dinitrophenyl.

R ³ is preferably C ₁ -C ₈ -alkyl or benzyl and more preferably C ₁ -C ₄ -alkyl.

R ⁴ and R ⁵ preferably together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated ring having 1 to 3 heteroatoms. Most preferably, together with the nitrogen atom to which they are attached, they form a [1,2,4] triazol-1-yl ring.

R ⁶ is preferably CF ₃ or p-tolyl.

In the group X is preferably halogen, chlorine, bromine or iodine and especially preferred for chlorine or bromine.

In general, epoxidations are usually stereospecific, ie with retention of the Z / E isomerism. However, under certain conditions, during the epoxidation, rotation occurs at the original double bond, thus inverted the original Z / E isomerism. Whether an inversion takes place under the given epoxidation conditions can easily be ascertained by a person skilled in the art, for example with the aid of preliminary experiments, so that he can select the appropriate starting material IIa or IIb for the preparation of a desired product Ia, Ib, Ic and / or Id. In the process according to the invention, the epoxidation is preferably carried out in such a way that compounds IIa and / or Ib essentially form from compound IIa, while the epoxidation of compound IIb leads essentially to the compounds Ic and / or Id, ie the relative position of the two aryl groups. Groups or Z / E isomerism is essentially retained. "Essentially" means that less than 5%, preferably less than 2% and in particular less than 1% of the compounds IIa or IIb used lead to products I with inverted Z / E configuration.

In principle, all the radicals R mentioned in compounds of the formulas IIa or IIb are stable to epoxidation conditions. However, preference is given to using those compounds IIa or IIb in which R is CH ₂ X, in which X is OH, CHO, COOH, COOR ³ or CONR ⁴ R ⁵ .

The epoxidation can basically take place in two variants:
In a preferred embodiment of the present invention, the epoxidation of compound IIa or IIb is enantioselective (variant A).

In an alternative preferred embodiment of the present invention Invention, the epoxidation is carried out under standard conditions (i.e. H. not especially enantioselective). The enantiomer mixtures formed thereby become subsequently subjected to a separation of enantiomers (variant B). Of course you can in the case, that in the enantioselective epoxidation (variant A) the products are formed in insufficient enantiomeric purity, the Subjected product mixture of the enantiomer separation of variant B. become.

Variant A: Enantioselective epoxidation

enantioselective Epoxidations are usually carried out so that the epoxidized Alkene in the presence of an asymmetric catalyst with one for epoxidations suitable oxidizing agent is reacted.

Usual oxidizing agents for epoxidation are z. As hydrogen peroxide, usually in alkaline medium, molecular oxygen, hydroperoxides, such as tert-butyl hydroperoxide, or cumyl hydroperoxide or trityl hydroperoxide, and peroxyacids, such as perbenzoic acid, meta-chloroperbenzoic acid, 4-nitroperbenzoic acid, monoperphthalic acid, peracetic acid, perpropionic acid, permaleic acid, and monoperbernoic Trifluoroperacetic acid, and also the salts, in particular the alkali or alkaline earth metal salts of these acids or preferably of persulfuric acid, such as potassium peroxomonosulfate, which is available, for example under the trade name Oxone ^® .

Variant A.1: Enantioselective Epoxidation in the presence of a chiral ketone as asymmetric catalyst

In a particularly preferred embodiment is the enantioselective epoxidation of compounds IIa or IIb in the presence of a for enantioselective epoxidations of suitable chiral ketone performed. suitable chiral ketone catalysts are, for example, in R. Curci et al., Acc. Chem. Res. 1989, 22, 205, R.W. Murray, Chem. Rev. 1989, 89, 1187, R. Curci et al., Pure Appl. Chem. 1995, 67, 811 and E.L. Clennan, Trends Organ. Chem.1995, 5, 231, to which reference is hereby made in its entirety.

eingesetzt, worin P für eine Schutzgruppe steht.In particular, the chiral ketone catalyst is the fructose-derived catalyst of the formula A.

used, wherein P is a protective group.

Preferably, P is acetyl (CH ₃ CO) or the two groups P together form a bridging dimethylmethylene group (-C (CH ₃ ) ₂ -), ie the two hydroxy groups are protected by an acetone-derived ketal.

In the event that in compound IIa or IIb R is a group COOH or COOR ³ , preferably a catalyst A is used, in which each P is acetyl.

When using the ketone A as an asymmetric catalyst, it has proved to be advantageous to carry out the epoxidation with potassium peroxomonosulfate as the oxidizing agent. This can be used, for example, in the form of the commercial product ^Oxone® .

In carrying out the epoxidation in the presence of the catalyst A, it is preferred that in the compounds IIa or IIb R is CH ₂ X, where X is halogen or OSO ₂ R ⁶ , CHO, CH = NR ¹ , CH = NNR ² , COOH, COOR ³ , CONR ⁴ R ⁵ or CN. More preferably R is CHO, CH = NR ¹ , CH = NNR ² , COOH, COOR ³ , CONR ⁴ R ⁵ or CN. In particular, R is CHO or COOR ³ .

The enantioselective epoxidation of alkenes in the presence of the above Catalyst A is also known as Shi oxidation and for example in J. Am. Chem. Soc. 2002, 124, 8792, on their designs and references are hereby incorporated by reference.

method for the preparation of the catalyst A are known and, for example in J. Am. Chem. Soc. 2002, 124, 8792, Y. Chi, J. Am. Chem. Soc. 1996, 118, 9806, J. Am. Chem. Soc. 1997, 119, 11224 and Org. Lett. 2001, 3, 715, the contents and references hereby complete Reference is made.

The enantioselective epoxidation in the presence of the ketone A is preferably carried out in a solvent system comprising water and an organic solvent which is at least partially miscible with water. Examples of such organic solvents are protic solvents such as C ₁ -C ₄ alkanols such as methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, isobutanol and tert-butanol, and aprotic polar solvents, for example cyclic ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile and propionitrile, dimethylsulfoxide, dimethylformamide and heterocycles such as N-methylpyrrolidone. Preferably, acetonitrile is used.

In addition, the reaction medium contains preferably catalytic amounts of a phase transfer catalyst. examples for suitable phase transfer catalysts are onium salts, e.g. quaternary ammonium salts and phosphonium salts, furthermore crown ethers and cryptands. Prefers become quaternary Ammonium salts used, e.g. Tetrabutylammonium salts, for example the chloride, bromide, hydroxide, hydrogen sulfate or sulfate of tetrabutylammonium. Specifically, tetrabutylammonium hydrogensulfate is used

Furthermore, the reaction medium preferably contains at least one complexing agent, such as ethylenediamine or ethylenediaminetetraacetic acid, or the corresponding salts, such as Na ₂ (EDTA).

Preferably the epoxidation takes place in the presence of the catalyst A at a pH in basic Area, z. At a pH of 7.1 to 14, preferably from 8 to 10. To set the desired pH If the reaction medium is generally added to a suitable base. Suitable bases are, for example, alkali and alkaline earth hydroxides, such as sodium, potassium, magnesium or calcium hydroxide, alkali and Alkaline earth carbonates, such as sodium, potassium, magnesium or calcium carbonate, and especially alkali and alkaline earth bicarbonates, such as sodium, Potassium, magnesium or calcium bicarbonate.

The execution is preferably carried out so that the epoxidizing substrate (compound IIa or IIb), optionally together with the phase transfer catalyst and / or the complexing agent, is presented and in the presence of Ketone catalyst A with the oxidizing agent and optionally the base added becomes. The addition of the oxidizing agent and the base can both separately as well as together, at once or preferably in portions respectively.

The Reaction temperature is preferably -40 up to + 60 ° C, particularly preferred -10 up to 30 ° C and in particular 0 ° C to room temperature.

The Workup is carried out in a conventional manner, for example extractive and / or chromatographic.

In the enantioselective epoxidation in the presence of the asymmetric ketone A, preferably no inversion of the Z / E isomerism takes place, so that compound IIa preferably reacts essentially to compound Ia or Ib, while compound IIb preferably substantially to compound Ic or Id is implemented. "Substantially" means that less than 5%, preferably less than 2%, and especially less than 1% of the compounds IIa or IIb used lead to products I with inverted Z / E configuration

at the enantioselective epoxidation in the presence of the asymmetric Ketones A, compounds IIa react preferentially to compounds Ia. This means that the compound IIa becomes an epoxidation product leads, the more than 50% Mo compound Ia, based on the total amount obtained compounds Ia and Ib. Preference is given to compound Ia in an enantiomeric purity of at least 70% ee, especially preferably at least 80% ee, stronger preferably at least 90% ee and in particular at least 95% ee received.

links IIb react preferentially in the presence of this epoxidation system to compounds Ic. This means that the compound IIb becomes a Epoxidation product leads, the more than 50% by mole of compound Ic, based on the total amount obtained compounds Ic and Id contains. Preference is given to compound Ic in an enantiomeric purity of at least 40% ee, especially preferably at least 50% ee, stronger preferably at least 70% ee and in particular at least 90% ee, e.g. at least 95% ee, received.

at the enantioselective epoxidation in the presence of the asymmetric Ketones A, compounds IIa are preferably used as substrates, as these tend to epoxidize with higher enantioselectivity compared to compounds IIb become. However, it is quite possible also to epoxidize compounds IIb by this method and if desired the product of enantiomer separation, for example according to the separation method from variant B, subject.

Variant A.2: Enantioselective Epoxidation in the presence of a polyamino acid as an asymmetric catalyst

In an alternative preferred embodiment of the present invention Compound is the enantioselective epoxidation in the presence a polyamino acid.

When polyaminoacids are generally not the natural representatives of this class of polymers (i.e., the polypeptides and proteins), but the synthetic ones Polycondensation products of predominantly α-amino acids. Your Production is generally carried out by polymerization of N-carboxy anhydrides (Leuchs anhydrides). Suitable are both the homopolymers and the copolymers of amino acids. preferred polyaminoacids are the copolymers and especially the homopolymers of natural L-amino acids, e.g. Poly-L-alanine, poly-L-valine, poly-L-leucine and poly-L-isoleucine. Preference is given to using the homo- or copolymers of amino acids which no further functional groups, such as those in Serine, threonine and cysteine occur. Especially preferred the homopolymers of α-L-amino acids are used. In particular, poly-L-alanine and poly-L-leucine used.

The polyaminoacids serve as chiral catalysts that undergo enantioselective epoxidation of alkenes. The chirality induction takes place due to the helical chirality of the polyamino acids.

The polyaminoacids can in both free and supported (immobilized) form be used. Suitable carrier materials as well as immobilized polyamino acids are, for example, in S. Itsuno, M. Sakakura and K. Ito, J. Org. Chem. 1990, 55, 6047 and in the literature cited therein, which is hereby incorporated by reference is fully referenced. To the suitable carrier materials belong for example, clays, clay minerals, silica, alumina, Sodium carbonate, calcium carbonate, cellulose powder, anion exchange materials, synthetic polymers, such as polystyrene, acrylic resins, phenol-formaldehyde resins, Polyurethanes and polyolefins, such as polyethylene and polypropylene. A preferred carrier material is Silica. The use of polyamino acids in immobilized form has the advantage that its separation after the reaction especially easily, for example by simple filtration, succeeds.

The polyamino is not deactivated even after several catalytic cycles, so that they are used again after the isolation as a catalyst can be.

The polyamino may also be in the form of a condensate with a solubilizing polymer, such as polyethylene glycol are used. As a result, the polyamino acid in numerous organic solvents soluble, so that they are then in homogeneous phase with the substrate to be epoxidized is present.

suitable polyaminoacids preferably comprise 5 to 100 fused amino acids and more preferably 5 to 20 fused amino acid units.

When Oxidizing agents are all mentioned above, for epoxidations usually used oxidizing agent suitable. Particularly preferably used However, hydrogen peroxide or a hydrogen peroxide precursor, For example, a urea / hydrogen peroxide adduct (urea-hydrogen peroxides; UHP.).

The Epoxidation, especially when using hydrogen peroxide or a hydrogen peroxide precursor as the oxidizing agent, is preferably carried out in basic medium. Suitable bases are, for example Alkali and alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, Magnesium hydroxide or calcium hydroxide, alkali or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate or calcium carbonate, alkali metal or alkaline earth metal bicarbonates, such as sodium bicarbonate, Potassium bicarbonate or calcium bicarbonate, but also organic, non-nucleophilic bases, for example cyclic amidines, such as DBU (1,8-diazabicyclo [5.4.0] undec-7-ene) or DBN (1,5-diazabicyclo [4.3.0] non-5-ene).

The Epoxidation can take place both in a hydrous and in a water non-aqueous Medium done. Hydrous systems are particularly required when inorganic bases are used. When using organic Bases in organic solvents soluble It is preferred that the epoxidation in a non-aqueous Medium to perform. Suitable organic solvents in in this case are solvents, which are inert in the epoxidation reaction. Examples for suitable organic solvent are alcohols such as methanol, ethanol, propanol, isopropanol and the butanols, cyclic and open-chain ethers, such as tetrahydrofuran, Dioxane, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether and the like, halogenated hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride, aromatic Hydrocarbons, such as benzene, toluene, nitrobenzene, chlorobenzene, Dichlorobenzene and the xylenes, carboxylic acid derivatives such as dimethylformamide and ethyl acetate, nitriles such as acetonitrile and propionitrile, and Dimethyl sulfoxide.

at the implementation in a non-aqueous Reaction medium, the oxidizing agent is preferably in a used in such a form that it is in the organic solvent soluble is. So it is preferable to hydrogen peroxide in the form of in organic solvents soluble Use Precursors UHP.

In In this case, epoxidation is usually in a two-phase system carried out, wherein the substrate to be epoxidized, the oxidizing agent and the Base in dissolved Mold in organic solvent present while the polyamino acid, especially when used in immobilized form, as solid phase is present. However, it is also possible to use epoxidation in organic solvents as a single-phase system, for example, if the polyamino acid by condensation with a solubilizing molecule, such as polyethylene glycol, is soluble in the organic solvent.

at the use of inorganic bases in organic solvents essentially insoluble usually, the epoxidation takes place in a hydrous state System. In a particularly preferred embodiment, it is in the aqueous system, a gel, which in addition to water suitable organic solvent contains. Suitable solvents are for this case, those with neither the substrate nor with the epoxidized Product or react with the other reactants and also capable of gelation are. examples for suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, heptane, Octane, nonane, decane or polyether, cycloaliphatic hydrocarbons, such as cyclopentane, cyclohexane or cyclooctane, aromatic hydrocarbons, such as Benzene, toluene, the xylenes, chlorobenzene, dichlorobenzene and nitrobenzene, as well as the above mentioned ethers.

The Gelation generally takes place in such a way that an aqueous phase, the oxidizing agent, preferably hydrogen peroxide, and a Contains base, with the organic solvent and the polyamino acid over one Period for the gelation is sufficient, mixes. This gel will eventually be the added to epoxidizing substrate.

The Oxidizing agent is preferably at least equimolar and more preferred in excess to be used for epoxidizing substrate. Preferably, the molar ratio of Oxidizer to substrate to be epoxidized 3: 1 to 1: 1 especially preferably from 2: 1 to 1: 1 and in particular from 1.5: 1 to 1.1: 1.

The base is used in such an amount that the reaction medium has a pH of a little at least 7.1, for example 7.1 to 14, preferably at least 8, for example 8 to 14. When using hydrogen peroxide, the base is used in such an amount that the hydrogen peroxide is preferably completely deprotonated (to HOO ^- ).

The weight ratio of polyamino acid to be epoxidized substrate is not very critical, since already sufficient catalytic amounts. It is preferably 10: 1 to 1: 1, more preferably 5: 1 to 1: 1 and especially 3: 1 to 1: 1.

The Reaction temperature is suitably chosen so that the polyamino acid is not gets destroyed. Preferably the reaction temperature -10 up to 40 °, particularly preferably 0 to 30 ° and especially around room temperature.

In the enantioselective epoxidation in the presence of polyamino acids as substrates to be epoxidized preferably those compounds IIa or IIb used in which R is CHO, CH = NR ¹ , CH = NNR ² , COOH, COOR ³ , CONR ⁴ R ⁵ or CN. R particularly preferably represents CHO or COOR ³ and in particular CHO. If hydrogen peroxide is used per se (ie not as a precursor, such as UHP), however, R preferably does not stand for COOH or COOR ³ , since otherwise the Baeyer-Villiger oxidation occurs as a competing reaction. In this case, R is particularly preferably CHO. By contrast, when using hydrogen peroxide precursors, such as UHP, the nature of the R group is not as critical, since hydrogen peroxide is released only slowly, so that the competition reaction does not occur or occurs only weakly. Accordingly, in this case R can also stand for COOH or COOR ³ .

The Work-up is carried out in a manner known per se, e.g. by filtration the polyamino acid and subsequent Extraction and / or chromatography (e.g., column chromatography, preparative TLC or HPLC).

enantioselective Epoxidations of enones and α, β-unsaturated Esters in the presence of polyamino acids as chiral catalysts are basically known and, for example, by S. Juliá et al. in Tetrahedron 1984, 40, 5207, C. Loret and S.M. Roberts in Aldrichchim. Acta. 2002 35 (2), 47 or by S.M. Roberts in J. Chem. Soc., Perkin Trans. 1, 1997, 3501 and in the references cited therein, whereupon is hereby incorporated by reference.

at the enantioselective epoxidation in the presence of polyamic acids, in particular using alkaline hydrogen peroxide or a hydrogen peroxide precursor as oxidizing agent, preferably no inversion of the Z / E isomerism takes place that compound IIa is preferably substantially compound Ia or Ib responds while Compound IIb is preferably substantially compound Ic or Id is implemented. "In the Essential "means that less than 5%, preferably less than 2% and in particular less than 1% of the compounds used IIa or IIb to products I with inverted Z / E configuration

at the enantioselective epoxidation in the presence of polyamic acids, in particular using alkaline hydrogen peroxide or a hydrogen peroxide precursor as the oxidizing agent, compounds IIa in particular react to compounds Ia. This means that the compound IIa becomes an epoxidation product leads, the more than 50% Mo compound Ia, based on the total amount obtained compounds Ia and Ib. Preference is given to compound Ia in an enantiomeric purity of at least 70% ee, especially preferably at least 80% ee, stronger preferably at least 85% ee and in particular at least 90% ee, e.g. at least 95% ee, received.

links IIb react preferentially in the presence of this epoxidation system to compounds Ic. This means that the compound IIb becomes a Epoxidation product leads, the more than 50% by mole of compound Ic, based on the total amount obtained compounds Ic and Id contains. Preference is given to compound Ic in an enantiomeric purity of at least 40% ee, especially preferably at least 50% ee, stronger preferably at least 70% ee and in particular at least 90% ee, e.g. at least 95% ee, received.

Variant B: non-selective Epoxidation and subsequent Enantiomerentrennung

In an alternatively preferred embodiment of the present invention, a compound IIa or IIb is subjected to a customary, ie not specifically enantioselective, epoxidation, and the resulting epoxide is an enantiomeric mixture of the enantiomers Ia and Ib (mixture A) or Ic and Id (mixture B) puts, disconnected. Of course, the enantiomer separation can also be carried out if, in an enantioselective epoxidation according to variant A, the enantioselectivity is not satisfactory, so that enantiomeric mixtures with insufficiently large ee values are obtained.

According to variant B of the method according to the invention The epoxidation can be carried out under conditions as described in the State of the art and, for example, in Jerry March, Advanced Organic Chemistry, Reactions, Mechanisms and Structure; 3rd Edition, 1985, John Wiley & Sons, P. 735 ff., To which reference is hereby made in its entirety is taken.

suitable Oxidizing agents are, for example, hydrogen peroxide, hydrogen peroxide-releasing compounds, such as urea-hydrogen peroxide adduct (UHP), the aforementioned peracids or their salts, the abovementioned persulphates, the above mentioned hydroperoxides and molecular oxygen.

• (a) für den Fall, dass R für CH₂OH steht: (a.1) ein Gemisch A, enthaltend die Enantiomere Ia und Ib, worin R für CH₂OH steht, oder ein Gemisch B, enthaltend die Enantiomere Ic und Id, worin R für CH₂OH steht, mit einem Acylierungsmittel in Gegenwart einer Hydrolase umsetzt, wobei man im Falle des Gemisches A ein Gemisch C erhält, in welchem eines der Enantiomere Ia oder Ib im Wesentlichen in acylierter Form vorliegt und das andere Enantiomer im Wesentlichen in nicht acylierter Form vorliegt, und wobei man im Falle des Gemisches B ein Gemisch D erhält, in welchem eines der Enantiomere Ic oder Id im Wesentlichen in acylierter Form vorliegt und das andere Enantiomer im Wesentlichen in nicht acylierter Form vorliegt; (a.2) aus dem Gemisch C oder aus dem Gemisch D das im Wesentlichen nicht acylierte Enantiomer abtrennt; und (a.3) gewünschtenfalls das in Schritt (a.1) erhaltene im Wesentlichen acylierte Enantiomer zum entsprechenden nicht acylierten Enantiomer hydrolysiert; oder
• (b) für den Fall, dass R für CH₂OH steht: (b.1) ein Gemisch A, enthaltend die Enantiomere Ia und Ib, worin R für CH₂OH steht, oder ein Gemisch B, enthaltend die Enantiomere Ic und Id, worin R für CH₂OH steht, mit einem Acylierungsmittel umsetzt, wobei man im Falle des Gemisches A ein Gemisch E erhält, in welchem beide Enantiomere Ia und Ib im Wesentlichen in acylierter Form vorliegen oder wobei man im Falle des Gemisches B ein Gemisch F erhält, in welchem beide Enantiomere Ic und Id im Wesentlichen in acylierter Form vorliegen; (b.2) das Gemisch E oder das Gemisch F in Gegenwart einer Hydrolase hydrolysiert, wobei man im Falle des Gemischs E ein Gemisch G erhält, in welchem eines der Enantiomere Ia oder Ib im Wesentlichen in acylierter Form vorliegt (d.h. nicht hydrolysiert wird) und das andere Enantiomer im Wesentlichen in nicht acylierter (d.h. zum Alkohol hydrolysierter) Form vorliegt, und wobei man im Falle des Gemisches F ein Gemisch H erhält, in welchem eines der Enantiomere Ic oder Id im Wesentlichen in acylierter Form vorliegt (d.h. nicht hydrolysiert wird) und das andere Enantiomer im Wesentlichen in nicht acylierter (d.h. zum Alkohol hydrolysierter) Form vorliegt; (b.3) aus dem Gemisch G oder aus dem Gemisch H das im Wesentlichen nicht acylierte Enantiomer abtrennt; und (b.4) gewünschtenfalls das in Schritt (b.2) erhaltene im Wesentlichen acylierte Enantiomer zum entsprechenden nicht acylierten Enantiomer hydrolysiert; oder
• (c) für den Fall, dass R für COOH steht: (c.1) ein Gemisch A, enthaltend die Enantiomere Ia und Ib, worin R für COOH steht, oder ein Gemisch B, enthaltend die Enantiomere Ic und Id, worin R für COOH steht, mit einem Alkohol in Gegenwart einer Hydrolase umsetzt, wobei man im Falle des Gemisches A ein Gemisch J erhält, in welchem eines der Enantiomere Ia oder Ib im Wesentlichen in veresterter Form vorliegt und das andere Enantiomer im Wesentlichen in nicht veresterter Form vorliegt, und wobei man im Falle des Gemisches B ein Gemisch K erhält, in welchem eines der Enantiomere Ic oder Id im Wesentlichen in veresterter Form vorliegt und das andere Enantiomer im Wesentlichen in nicht veresterter Form vorliegt; (c.2) aus dem Gemisch J oder aus dem Gemisch K das im Wesentlichen nicht veresterte Enantiomer abtrennt; und (c.3) gewünschtenfalls das in Schritt (c.1) erhaltene im Wesentlichen veresterte Enantiomer zum entsprechenden nicht veresterten Enantiomer hydrolysiert; oder
• (d) für den Fall, dass R für COOR³ oder CONR⁴R⁵ steht: (d.1) ein Gemisch A, enthaltend die Enantiomere Ia und Ib, worin R für COOR³ oder CONR⁴R⁵ steht, oder ein Gemisch B, enthaltend die Enantiomere Ic und Id, worin R für COOR³ oder CONR⁴R⁵ steht, in Gegenwart einer Hydrolase hydrolysiert, wobei man im Falle des Gemisches A ein Gemisch L erhält, in welchem eines der Enantiomere Ia oder Ib im Wesentlichen in veresterter oder amidierter Form vorliegt und das andere Enantiomer im Wesentlichen in nicht veresterter oder nicht amidierter Form vorliegt, und wobei man im Falle des Gemisches B ein Gemisch M erhält, in welchem eines der Enantiomere Ic oder Id im Wesentlichen in veresterter oder amidierter Form vorliegt und das andere Enantiomer im Wesentlichen in nicht veresterter oder in nicht amidierter Form vorliegt; (d.2) aus dem Gemisch L oder aus dem Gemisch M das im Wesentlichen nicht veresterte oder nicht amidierte Enantiomer abtrennt; und (d.3) gewünschtenfalls das in Schritt (d.1) erhaltene im Wesentlichen veresterte oder amidierte Enantiomer zum entsprechenden nicht veresterten oder nicht amidierten Enantiomer hydrolysiert.

In a preferred embodiment, a mixture of enantiomers (hereinafter referred to as enantiomer mixture A) containing the compounds Ia and Ib or a mixture of enantiomers (hereinafter referred to as enantiomer mixture B) containing the compounds Ic and Id, in which

• (a) in the case that R is CH ₂ OH: (a.1) a mixture A containing the enantiomers Ia and Ib, wherein R is CH ₂ OH, or a mixture B, containing the enantiomers Ic and Id , wherein R is CH ₂ OH, with an acylating agent in the presence of a hydrolase, wherein in the case of the mixture A, a mixture C receives, in which one of the enantiomers Ia or Ib is present in substantially acylated form and the other enantiomer substantially is present in non-acylated form, and wherein, in the case of the mixture B, a mixture D is obtained in which one of the enantiomers Ic or Id is present in substantially acylated form and the other enantiomer is present in substantially non-acylated form; (a.2) from the mixture C or from the mixture D separates the substantially non-acylated enantiomer; and (a.3), if desired, hydrolyzing the substantially acylated enantiomer obtained in step (a.1) to the corresponding non-acylated enantiomer; or
• (b) for the case that R is CH ₂ OH: (b.1) a mixture A comprising the enantiomers Ia and Ib wherein R is CH ₂ OH, or a mixture B containing the enantiomers Ic and Id in which R is CH ₂ OH, is reacted with an acylating agent to obtain in the case of the mixture A a mixture E in which both enantiomers Ia and Ib are present in substantially acylated form or wherein in the case of the mixture B a mixture of F in which both enantiomers Ic and Id are present in substantially acylated form; (b.2) the mixture E or the mixture F is hydrolyzed in the presence of a hydrolase, wherein in the case of the mixture E a mixture G is obtained in which one of the enantiomers Ia or Ib is present in substantially acylated form (ie is not hydrolyzed) and the other enantiomer is substantially in non-acylated (ie, alcohol hydrolyzed) form, and in the case of Mixture F, obtaining a mixture H in which one of the enantiomers Ic or Id is substantially acylated (ie, not hydrolyzed) ) and the other enantiomer is substantially in non-acylated (ie, hydrolyzed to alcohol) form; (b.3) from the mixture G or from the mixture H separates the substantially non-acylated enantiomer; and (b.4) if desired, hydrolyzing the substantially acylated enantiomer obtained in step (b.2) to the corresponding non-acylated enantiomer; or
• (c) in the event that R is COOH: (c.1) a mixture A containing the enantiomers Ia and Ib, in which R is COOH, or a mixture B, containing the enantiomers Ic and Id, wherein R represents COOH is reacted with an alcohol in the presence of a hydrolase, wherein, in the case of the mixture A, a mixture J is obtained in which one of the enantiomers Ia or Ib is present substantially in esterified form and the other enantiomer is present substantially in non-esterified form, and wherein, in the case of the mixture B, a mixture K is obtained in which one of the enantiomers Ic or Id is substantially in esterified form and the other enantiomer is substantially unesterified; (c.2) from the mixture J or from the mixture K separates the substantially unesterified enantiomer; and (c.3) if desired, hydrolyzing the substantially esterified enantiomer obtained in step (c.1) to the corresponding unesterified enantiomer; or
• (d) in the event that R is COOR ³ or CONR ⁴ R ⁵ : (d.1) a mixture A containing the enantiomers Ia and Ib, wherein R is COOR ³ or CONR ⁴ R ⁵ , or a mixture B, containing the enantiomers Ic and Id, wherein R is COOR ³ or CONR ⁴ R ⁵ , hydrolyzed in the presence of a hydrolase, wherein in the case of the mixture A, a mixture L is obtained in which one of the enantiomers Ia or Ib substantially in esterified or amidated form is present and the other enantiomer is present in substantially unesterified or unamidated form, and wherein, in the case of the mixture B, a mixture M is obtained in which one of the enantiomers Ic or Id is present substantially in esterified or amidated form, and the other enantiomer is substantially unesterified or un-amidated; (d.2) from the mixture L or from the mixture M separates the substantially unesterified or unamidated enantiomer; and (d.3) if desired, hydrolyzing the substantially esterified or amidated enantiomer obtained in step (d.1) to the corresponding unesterified or unamidated enantiomer.

By "substantially non-acylated enantiomer Ia, Ib, Ic or Id" it is meant that at least 95%, preferably at least 97%, especially at least 98% of this enantiomer is not acylated. "Analogously, the term" substantially acylated enantiomer Ia , Ib, Ic or Id ", that at least 95%, preferably at least 97%, particularly preferably at least 98%, of this enantiomer are acylated. Is acylated while the oxygen of the alcohol group R, that R is in acylated products for a group CH ₂ O (CO) R ^a, wherein R ^a is derived from the acylating agent. By "non-acylated form" is meant that the compound is in the form of its alcohol, ie R is CH ₂ OH.

Under "essentially Unesterified enantiomer Ia, Ib, Ic or Id "should be understood to mean that at least 95%, preferably at least 97%, in particular at least 98% of this Enantiomers are not esterified. Analogously, the expression "substantially esterified enantiomer Ia, Ib, Ic or Id ", that at least 95%, preferably at least 97%, more preferably at least 98%, of this enantiomer esterified. Under "not esterified form "understands that the compound is in the form of its carboxylic acid, i. R stands for COOH.

Under "essentially non-amidated enantiomer Ia, Ib, Ic or Id "should be understood that at least 95%, preferably at least 97%, in particular at least 98% of this Enantiomers are not amidated. Analogously, the expression "substantially amidated enantiomer Ia, Ib, Ic or Id ", that at least 95%, preferably at least 97%, more preferably at least 98% of this enantiomer amidated available. Under "not amidated form "understands that the compound is in the form of its carboxylic acid, i. R stands for COOH.

Separation variant (a)

The hydrolase used in step (a.1) is preferably a lipase. This causes a selective acylation (esterification) of only one of the two enantiomers Ia or Ib (wherein R is CH ₂ OH) in the mixture A or Ic or Id (wherein R is CH ₂ OH) in mixture B. Preferably, it causes the selective acylation of the Ib enantiomer of mixture A or of the Id enantiomer of mixture B. The hydrolase is preferably obtained from a microorganism, more preferably from a bacterium or a yeast. Also suitable are hydrolases obtainable by recombinant methods. The hydrolase can be used in purified or partially purified form or in the form of the microorganism itself or in the form of fermenter extracts. Processes for the recovery and purification of hydrolases from microorganisms are well known to the person skilled in the art, for example from EP-A-11149849 or EP-A-1069183. Preferably, the hydrolase is used in purified form.

The hydrolase can be used freely (ie in native form) or immobilized. An immobilized enzyme is an enzyme which is fixed to an inert carrier. Suitable support materials and the enzymes immobilized thereon are known from EP-A-1149849, EP-A-1 069 183 and DE-OS 100193773 and from the references cited therein. The disclosure of these documents is hereby incorporated by reference in its entirety. Suitable support materials include, for example, clays, clay minerals such as kaolinite, diatomaceous earth, perlite, silica, alumina, sodium carbonate, calcium carbonate, cellulose powders, anion exchange materials, synthetic polymers such as polystyrene, acrylic resins, phenolformaldehyde resins, polyurethanes and polyolefins such as polyethylene and polypropylene. The support materials are usually used to prepare the supported enzymes in a finely divided, particulate form, with porous forms being preferred. The particle size of the carrier material is usually not more than 5 mm; in particular not more than 2 mm (grading curve). Preferred carriers Materials are microporous polymer particles having a void content of preferably 40 to 80 vol .-% and pore sizes of preferably 10 nm to 1 micron, for example, particulate polypropylene, which is commercially available for example under the name Accurel ^® from Akzo.

Prefers Lipases (triacylglycerol acylhydrolases, EC 3.1.1.3) are used. Preferred among these are lipases consisting of bacteria of the genera Burkholderia or Pseudomonas or from yeasts of the genus Candida be won.

Examples for Burkholderia species are Burkholderia ambifaria (eg strains ATCC BAA-244, CCUG 44356, LMG 19182); Burkholderia andropogonis (eg strains ATCC 23061, CCUG 32772, CFBP 2421, CIP 105771, DSM 9511, ICMP 2807, JCM 10487, LMG 2129, NCPPB 934, NRRL B-14296); Burkholderia caledonica (eg, strains W50D, CCUG 42236, CIP 107098, LMG 19076); Burkholderia caribensis (z. B. Strains MWAP 64, CCUG 42847, CIP 106784, DSM 13236, LMG 18531); Burkholderia caryophylls (e.g., strains ATCC 25418, CCUG 20834, CFBP 2429, CFBP 3818, CIP 105770, DSM 50341, HAMBI 2159, ICMP 512, JCM 9310, JCM 10488, LMG 2155, NCPPB 2151); Burkholderia cepacia (eg, strains Ballard 717, 717-ICPB 25, ATCC 25416, CCUG 12691, CCUG 13226, CFBP 2227, CIP 80.24, DSM 7288, HAMBI 1976, ICMP 5796, IFO 14074, JCM 5964, LMG 1222, NCCB 76047, NCPPB 2993, NCTC 10743, NRRL B-14810); Burkholderia cocovenenans (eg strains ATCC 33664, CFBP 4790, DSM 11318, JCM 10561, LMG 11626, NCIMB 9450); Burkholderia fungorum (eg strains Croize P763-2, CCUG 31961, CIP 107096, LMG 16225); Burkholderia gladioli (eg strains ATCC 10248, CCUG 1782, CFBP 2427, CIP 105410, DSM 4285, HAMBI 2157, ICMP 3950, IFO 13700, JCM 9311, LMG 2216, NCCB 38018, NCPPB 1891, NCTC 12378, NRRL B-793); Burkholderia glathei (eg strains ATCC 29195, CFBP 4791, CIP 105421, DSM 50014, JCM 10563, LMG 14190); Burkholderia glumae (e.g., strains ATCC 33617, CCUG 20835, CFBP 4900, CFBP 2430, CIP 106418, DSM 9512, ICMP 3655, LMG 2196, NCPPB 2981, NIAES 1169); Burkholderia graminis (eg strains C4D1M, ATCC 700544, CCUG 42231, CIP 106649, LMG 18924); Burkholderia kururiensis (eg strains KP 23, ATCC 700977, CIP 106643, DSM 13646, JCM 10599, LMG 19447); Burkholderia mallei (eg strains ATCC 23344, NCTC 12938); Burkholderia multivorans (eg strains ATCC BAA-247, CCUG 34080, CIP 105495, DSM 13243, LMG 13010, NCTC 13007); Burkholderia norimbergensis (eg strains R2, ATCC BAA-65, CCUG 39188, CFBP 4792, DSM 11628, CIP 105463, JCM 10565, LMG 18379); Burkholderia phenazinium (eg strains ATCC 33666, CCUG 20836, CFBP 4793, CIP 106502, DSM 10684, JCM 10564, LMG 2247, NCIB 11027); Burkholderia pikettii (eg strains ATCC 27511, CCUG 3318, CFBP 2459, CIP 73.23, DSM 6297, HAMBI 2158, JCM 5969, LMG 5942, NCTC 11149); Burkholderia plantarii (eg strains AZ 8201, ATCC 43733, CCUG 23368, CFBP 3573, CFBP 3997, CIP 105769, DSM 9509, ICMP 9424 JCM 5492, LMG 9035, NCPPB 3590, NIAES 1723); Burkholderia pseudomallei (eg strains WRAIR 286, ATCC 23343, NCTC 12939); Burkholderia pyrrocinia (z. B. strains ATCC 15958, CFBP 4794, CIP 105874, DSM 10685, LMG 14191); Burkholderia sacchari (eg, strains CCT 6771, CIP 107211, IPT 101, LMG 19450); Burkholderia solanacearum (eg strains A. Kelman 60-1, ATCC 11696, CCUG 14272, CFBP 2047, CIP 104762, DSM 9544, ICMP 5712, JCM 10489, LMG 2299, NCAIM B.01459, NCPPB 325, NRRL B-3212); Burkholderia stabilis (eg strains ATCC BAA-67, CCUG 34168, CIP 106845, LMG 14294, NCTC 13011); Burkholderia thailandensis (z. B. strains E 264, ATCC 700388, CIP 106301, DSM 13276); Burkholderia ubonensis (eg strains EY 3383, CIP 107078, NCTC 13147); Burkholderia vandii (eg, strains VA-1316, ATCC 51545, CFBP 4795, DSM 9510, JCM 7957, LMG 16020); Burkholderia vietnamiensis (eg, strains TW 75, ATCC BAA-248, CCUG 34169, CFBP 4796, CIP 105875, DSM 11319, JCM 10562, LMG 10929).

Examples of Pseudomonas species are Pseudomonas aeruginosa (eg strains ATCC 10145, DSM 50071), Pseudomonas agarici (eg strains ATCC 25941, DSM 11810), Pseudomonas alcaligenes (eg strains ATCC 14909, DSM 50342) , Pseudomonas amygdali (e.g., strains ATCC 337614, DSM 7298), Pseudomonas anguiliseptica (e.g., strains ATCC 33660, DSM 12111), Pseudomonas antimicrobica (e.g., strains DSM 8361, NCIB 9898, LMG 18920), Pseudomonas aspleni (e.g., strains ATCC 23835, CCUG 32773), Pseudomonas aurantiaca (e.g., strains ATCC 33663, CIP 106710), Pseudomonas aureofaciens (e.g., strains ATCC 13985, CFBP 2133), Pseudomonas avellanae (e.g. Strains DSM 11809, NCPPB 3487), Pseudomonas azotoformans (e.g., strains CIP 106744, JCM 7733), Pseudomonas balearica (e.g., strains DSM 6083, CIP 105297)), Pseudomonas beijerinsckii (e.g., strains ATCC 19372 , DSM 6083), Pseudomonas beteli (eg strains ATCC 19861, CFBP 4337), Pseudomonas boreopolis (eg strains ATCC 33662, CIP 106717), Pseudomonas carboxyhy drogena (eg strains ATCC 29978, DSM 1083), Pseudomonas caricapapayae (e.g. Strains ATCC 33615, CCUG 32775), Pseudomonas cichorii (e.g., strains ATCC 10857, DSM 50259), Pseudomonas cissicola (e.g., strains ATCC 33616, CCUG 18839), Pseudomonas citronellolis (e.g., strains ATCC 13674 , DSM 50332), Pseudomonas coronafaciens (eg strains DSM 50261, DSM 50262), Pseudomonas corrugata (eg strains ATCC 29736, DSM 7228), Pseudomonas doudoroffii (eg strains ATCC 27123, DSM 7028), Pseudomonas echinoides (eg, strains ATCC 14820, DSM 1805), Pseudomonas elongata (e.g., strains ATCC 10144, DSM 6810), Pseudomonas ficuserectae (e.g., strains ATCC 35104, CCUG 32779), Pseudomonas flavescens (e.g., strains ATCC 51555, DSM 12071), Pseudomonas flectens (e.g. Strains ATCC 12775, CFBB 3281), Pseudomonas fluorescens (e.g., strains ATCC 13525, DSM 50090), Pseudomonas fragi (e.g., strains ATCC 4973, DSM 3456), Pseudomonas fulva (e.g., strains ATCC 31418, CIP 106765), Pseudomonas fuscovaginae (e.g., strains CCUG 32780, DSM 7231), Pseudomonas gelidicola (e.g., strains CIP 106748), Pseudomonas geniculata (e.g., strains ATCC 19374, LMG 2195), Pseudomonas glathei (e.g. B. strains ATCC 29195, DSM 50014), Pseudomonas halophila (e.g., strains ATCC 49241, DSM 3050), Pseudomonas hibiscicola (e.g., strains ATCC 19867, LMG 980), Pseudomonas huttiensis (e.g., strains ATCC 14670, DSM 10281), Pseudomonas iners (e.g., strain CIP 106746), Pseudomonas lancelota (e.g., strains ATCC 14669, CFBP 5587), Pseudomonas lemoignei (e.g., strains ATCC 17989, DSM 7445), Pseudomonas nas lundensis (z. Strains ATCC 19968, DSM 6252), Pseudomonas luteola (e.g., strains ATCC 43273, DSM 6975), Pseudomonas marginalis (e.g., strains ATCC 10844, DSM 13124), Pseudomonas meliae (e.g., strains ATCC 33050 , DSM 6759), Pseudomonas mendocina (eg strains ATCC 25411, DSM 50017), Pseudomonas mucidolens (eg strains ATCC 4685, CCUG 1424), Pseudomonas monteilli (eg strains ATCC 700476, DSM 14164), Pseudomonas nautica (e.g., strains ATCC 27132, DSM 50418), Pseudomonas nitroreducens (e.g., strains ATCC 33634, DSM 14399), Pseudomonas oleovorans (e.g., strains ATCC 8062, DSM 1045), Pseudomonas oryzihabitans (e.g. Strains ATCC 43272, DSM 6835), Pseudomonas pertucinogena (e.g., strains ATCC 190, CCUG 7832), Pseudomonas phenazinium (e.g., strains ATCC 33666, DSM 10684), Pseudomonas pictorum (e.g., strains ATCC 23328 , LMG 981), pseudomonas pseudoalcaligenes (eg strains ATCC 17440, DSM 50188), Pseudomonas putida (eg strains ATCC 12633, DSM 291), Pseudomonas pyrrocinia (eg strains ATCC 1595 8, DSM 10685), Pseudomonas resinovorans (e.g. Strains ATCC 14235, CCUG 2473), Pseudomonas rhodesiae (e.g., strains CCUG 38732, DSM 14020), Pseudomonas saccharophila (e.g., strains ATCC 15946, DSM 654), Pseudomonas savastanoi (e.g., strains ATCC 13522 , CFBP 1670), Pseudomonas spinosa (e.g., strains ATCC 14606), Pseudomonas stanieri (e.g., strains ATCC 27130, DSM 7027), Pseudomonas straminae (e.g., strains ATCC 33636, CIP 106745), Pseudomonas stutzeri (e.g. eg strains ATCC 17588, DSM 5190), Pseudomonas synxantha (eg strains ATCC 9890, CFBP 5591), Pseudomonas syringae (eg strains ATCC 19310, DSM 6693), Pseudomonas syzygii (eg strains ATCC 49543, DSM 7385), Pseudomonas taetrolens (e.g., strains ATCC 4683, CFBP 5592), Pseudomonas tolaasii (e.g., strains ATCC 33618, CCUG 32782), Pseudomonas veronii (e.g., strains ATCC 700272, DSM 11331 ), Pseudomonas viridiflava (eg, strains ATCC 13223, DSM 11124), Pseudomonas vulgaris, Pseudomonas wisconsinensis and Pseudomonas spec. DSM 8246. These are lipases from Burkholderia glumae, Burkholderia plantarii, Burkholderia cepacia, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas fragi, Pseudomonas luteola, Pseudomonas vulgaris, Pseudomonas wisconsinensis and Pseudomonas spec. DSM 8246 preferred. Particularly preferred are lipases from Pseudomonas spec. DSM 8246.

Examples of Candida species are Candida albomarginata (eg strain DSM 70015), Candida antarctica (eg strain DSM 70725), Candida bacarum (eg strain DSM 70854), Candida bogoriensis (eg strain DSM 70872), Candida boidinii (eg strains DSM 70026, 70024, 70033, 70034), Candida bovina (eg strain DSM 70156), Candida brumptii (eg strain DSM 70040), Candida cacaoi (eg strain DSM 2226), Candida cariosilignicola (eg strain DSM 2148), Candida chalmersii (eg strain DSM 70126 ), Candida ciferii (eg strain DSM 70749), Candida cylindracea (eg strain DSM 2031), Candida ernobii (eg strain DSM 70858), Candida famata (eg strain DSM 70590), Candida freyschussii (eg strain DSM 70047), Candida friederichii ( eg strain DSM 70050), Candida glabrata (eg strains DSM 6425, 11226, 70614, 70615), Candida guillermondi (eg strains DSM 11947, 70051, 70052), Candida haemulonii (eg strain DSM 70624), Candida inconspicua (eg strain DSM 70631 ), Candida ingens (eg strains DSM 70068, 70069), Candida intermedia (eg strain DSM 70753), Candida ke fyr (eg strains DSM 70073, 70106), Candida krusei (eg strains DSM 6128, 11956, 70075, 70079, 70086), Candida lactiscondensi (eg strain DSM 70635), Candida lambica (eg strains DSM 70090, 70095), Candida lipolytica ( eg strains DSM 1345, 3286, 8218, 70561 or 70562), Candida lusitaniae (eg strain DSM 70102), Candida macedoniensis (eg strain DSM 70106), Candida magnoliae (eg strains DSM 70638, 70639), Candida membranaefaciens (eg strain DSM 70109 ), Candida multigemnis (eg strain DSM 70862), Candida mycoderma (eg strain DSM 70184), Candida nemodendra (eg strain DSM 70647), Candida nitratophila (eg strain DSM 70649), Candida norvegica (eg strain DSM 70862), Candida parapsilosis ( eg strains DSM 5784, 4237, 11224, 70125, 70126), Candida pelliculosa (eg strain DSM 70130), Candida pini (eg strain DSM 70653), Candida pulcherrima (eg strain DSM 70336), Candida punicea (eg strain DSM 4657), Candida pustula (eg strain DSM 70865), Candida rugosa (eg strain DSM 70761), Candida sake (eg strain DSM 70763), Candida sil vicola (eg strain DSM 70764), Candida solani (eg strain DSM 3315), Candida sp. (eg strain DSM 1247), Candida spandovensis (eg strain DSM 70866), Candida succiphila (eg strain DSM 2149), Candida utilis (eg strains DSM 2361, 70163 or 70167), Candida valida (eg strains DSM 70169, 70178, 70179) , Can dida versatilis (eg strain DSM 6956), Candida vini (eg strain DSM 70184) and Candida zeylanoides (eg strain DSM 70185).

Especially preferred are lipases from Pseudomonas spec. DSM 8246. In preferred embodiments are called lipases enzyme preparations used, which from Pseudomonas spec. DSM 8246 or Burkholderia plantarii by fermentation of the bacterium and drying of the supernatant available are; supported Lipases from Burkholderia cepacia, based on ceramics or diatomite are immobilized and sold by the company Amano Pharmaceutical Co., Tokyo, Japan under the name Amano PS-C I, Amano PS-C II and Amano PS-D are distributed; and enzyme preparations from Burkholderia Glumae. The fermentation of the bacteria, for example, as in EP-A 1 069 183, incorporated herein by reference in its entirety Reference is made.

In the process according to the invention, lipases from yeasts of the genus Candida are particularly preferably used, in particular from Candida antarctica. In a specific embodiment, lipase B from Candida antarctica is used. Preferably, the immobilized form of this lipase, for example, the immobilized on acrylic resin lipase B from Candida antarctica, which is commercially available, for example, under the name "Novozym 435 ^® ".

The The amount of hydrolase to be added depends on the nature and activity of the enzyme preparation. The for The optimal enzyme amount reaction can easily be done by simple preliminary tests be determined. Preferably, 0.1 to 5 wt .-%, especially preferably 1 to 3 wt .-% hydrolase, based on the weight of employed enantiomeric mixture A or the enantiomeric mixture B, used.

The Acylating agents used in step (a.1) are preferred Alkenyl esters of aliphatic mono- or dicarboxylic acids with 2 to 20 carbon atoms or of aromatic carboxylic acids, further the acid anhydrides of aliphatic monocarboxylic acids with 2 to 20 carbon atoms or of aliphatic dicarboxylic acids with 4 to 20 carbon atoms. The alkenyl esters are preferably to the vinyl, propenyl or isopropenyl esters of the above Carboxylic acids, wherein the vinyl esters are particularly preferred. The aliphatic Monocarboxylic acids have 2 to 20 carbon atoms and preferably 2 to 12 carbon atoms on. The aliphatic dicarboxylic acids have 2 to 20 carbon atoms, preferably 3 to 12 carbon atoms and more preferably 4 to 8 carbon atoms. For the acid anhydrides these are those of aliphatic monocarboxylic acids From 2 to 20 carbon atoms, and preferably from 2 to 12 carbon atoms and more preferably having 2 to 8 carbon atoms, or acid anhydrides of aliphatic dicarboxylic acids with 4 to 12 carbon atoms, preferably with 4 to 8 carbon atoms and in particular with 4 or 5 carbon atoms.

Examples for the Vinyl, propenyl or Isopropenylester of aliphatic monocarboxylic acids with 2 to 20 carbon atoms are the vinyl, propenyl or isopropenyl esters of acetic acid, propionic acid, butyric acid, isobutyric, Valeric acid, isovaleric, 2-methyl butyric acid, caproic, 2-methyl valeric acid, 3-methyl valeric acid, 4-methyl valeric acid, 2,2-dimethyl butyric, 3,3-dimethylbutyric acid, 2-ethylhexanoic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid and Arachidonic acid. Among the aforementioned esters, the vinyl esters are preferred.

Examples for the Vinyl, propenyl or Isopropenylester of aliphatic dicarboxylic acids with 2 to 20 carbon atoms are the vinyl, propenyl or isopropenyl esters of oxalic acid, malonic, Succinic acid, Methyl, dimethyl, trimethyl and tetramethyl succinic acid, glutaric acid, 3,3-dimethylglutaric acid, adipic acid, pimelic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid and Sorbic acid. Among the aforementioned esters, the vinyl esters are preferred.

Examples for the Vinyl, propenyl or Isopropenylester of aromatic carboxylic acids are the vinyl, propenyl or Isopropenylester of benzoic acid, phthalic acid and terephthalic acid and preferably benzoic acid. Among the aforementioned esters, the vinyl esters are preferred.

Examples for the anhydrides of aliphatic monocarboxylic acids with 2 to 12 carbon atoms are the acid anhydrides of the above Carboxylic acids, z. B. those of acetic acid, Propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, 2-methylbutyric acid, caproic acid, 2-methylvaleric acid, 3-methylvaleric acid, 4-methylvaleric acid, 2,2-dimethylbutyric acid, 3,3-dimethylbutyric acid, 2-ethylhexanoic acid, enanthic acid and Caprylic acid. Among the above-mentioned anhydrides are those of acetic acid, propionic acid, butyric acid, valeric acid and caproic prefers.

Examples for the anhydrides of aliphatic dicarboxylic acids with 4 to 12 carbon atoms are succinic anhydride, methylsuccinic anhydride, dimethylsuccinic, Trimethylbernsteinsäureanhydrid, Tetramethylbernsteinsäureanhydrid, glutaric and 3,3-dimethylglutaric anhydride. Among them are succinic anhydride and glutaric anhydride prefers.

Among the acylating agents used in step (a.1) are the vinyl esters of aliphatic C ₂ -C ₁₂ monocarboxylic acids, such as acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, 2-ethylhexanoic acid, enanthic acid, caprylic acid and lauric acid; the vinyl esters of aliphatic C ₃ -C ₁₂ dicarboxylic acids, in particular C ₄ -C ₈ dicarboxylic acids, such as succinic acid, adipic acid, pimelic acid, azelaic acid and sebacic acid; benzoate; and the acid anhydrides of aliphatic C ₄ -C ₁₂ dicarboxylic acids, in particular of dicarboxylic acids having 4 or 5 carbon atoms, such as succinic acid and adipic acid, are preferred. Particularly preferred acylating agents are vinyl acetate, vinyl propionate, vinyl 2-ethylhexanoate, vinyl laurate, vinyl benzoate and succinic anhydride. This applies in particular when the enzyme used is a lipase, especially a lipase from a bacterium of the genus Burkholderia or Pseudomonas, or a lipase from a yeast of the genus Candida.

Preferably if, in the reaction in step (a.1), 0.3 to 1 molar equivalents are used, more preferably 0.5 to 0.6 molar equivalents of the acylating agent, based on the enantiomeric mixture A or on the enantiomer mixture B, a. Below molar equivalents should the number of carboxyl groups of the acylating agent in mol be understood that with 1 mol of the selectively to be acylated alcohol Ia or Ib (mixture A) or, in the case of mixture B, with 1 mol of the can selectively react to acylating alcohol Ic or Id. Corresponding one sets in the use of alkenyl esters of aliphatic or aromatic monocarboxylic acids as well as of acid anhydrides of aliphatic mono- or dicarboxylic acids preferably 0.3 to 1 mol, more preferably 0.5 to 0.6 mol of the acylating agent, based on 1 mol of the enantiomeric mixture A or B, while one when using alkenyl esters of aliphatic or aromatic dicarboxylic acids preferably 0.15 to 0.5 mol, more preferably 0.25 to 0.3 mol of acylating agent per mole of enantiomeric mixture A or B is used.

In a preferred embodiment the reaction in step (a.1) is carried out in a non-aqueous reaction medium carried out. Under non-aqueous Reaction media should be understood as reaction media, the less as 1% by weight, preferably less than 0.5% by weight of water, especially preferably less than 0.1% by weight of water and in particular less as 0.05% by weight of water, based on the total weight of the reaction medium, contain. Preferably, the reaction is carried out in an organic solvent carried out. Suitable solvents are for example aliphatic hydrocarbons, preferably with 5 to 8 carbon atoms, such as pentane, cyclopentane, hexane, cyclohexane, Heptane, octane or cyclooctane, or technical alkane or cycloalkane mixtures, halogenated aliphatic hydrocarbons, preferably with 1 or 2 carbon atoms, such as dichloromethane, chloroform, carbon tetrachloride, Dichloroethane or tetrachloroethane, aromatic hydrocarbons, such as benzene, toluene, the xylenes, chlorobenzene or dichlorobenzene, aliphatic acyclic and cyclic ethers, preferably with 4 to 8 carbon atoms, such as diethyl ether, methyl tert-butyl ether, Ethyl tert-butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, Tetrahydrofuran or dioxane, or mixtures of the aforementioned solvents. Particularly preferred are the aforementioned ethers and aromatic Hydrocarbons used. In particular, tetrahydrofuran is used.

In an alternatively preferred embodiment, the reaction takes place in step (a.1) in substance, i. without aqueous or organic solvent. In this case, the acylating agent is preferably selected from the above-mentioned vinyl, propenyl or isopropenyl esters, in particular the vinyl esters.

The Reaction in step (a.1) is usually carried out at a reaction temperature below the deactivation temperature of the hydrolase used and preferably at least -10 ° C. Particularly preferred is in the range from 0 to 100 ° C, in particular from 10 to 60 ° C and especially from 15 to 35 ° C. Particularly preferred is the reaction at the temperature at which the hydrolase its highest activity owns, performed ..

To carry out, for example, the Enantiomerengemisch A or the Enantiomerengemisch B with the hydrolase, the acylating agent and optionally the solvent submit and mix the mixture, for example by stirring or shaking. However, it is also possible to immobilize the hydrolase in a reactor, for example in a column, and to pass through the reactor a mixture containing the mixture of enantiomers and the acylating agent. You can do this by mixing the mixture pass through the reactor until the desired conversion is achieved. The carboxyl groups of the acylating agent are sequentially converted into esters of the enantiomer Ia or Ib of the mixture A or Ic or Id of the mixture B, which is enantioselectively acylated, while the other enantiomer remains substantially unchanged. Preferably, in mixture A, the enantiomer Ib is acylated while the enantiomer Ia remains substantially unchanged. In mixture B, the enantiomer Id is preferably acylated while the enantiomer Ic remains substantially unchanged. As a rule, the acylation is carried out to a conversion of at least 95%, preferably of at least 99% and in particular of at least 99.5%, based on the enantiomer of the mixture A or the mixture B present in the mixture, which is acylated enantioselectively , to lead. The progress of the reaction, ie the sequential ester formation, can be followed by conventional methods such as gas chromatography or HPLC (High Performance Liquid Chromatography).

At the used enantiomeric mixture A or B is in the Rule about the racemate of the alcohols Ia and Ib (R = OH, mixture A) or Ic and Id (R = OH, mixture B); Mixtures in which one of the enantiomers enriched, but are also suitable.

The Working up of the reaction mixture can be carried out in a customary manner, for example by first separating the hydrolase from the reaction mixture, e.g. by filtration or centrifuging, optionally from the filtrate or centrifugate the solvent removed and the residue subsequently subject to a separation operation.

By the enantioselective reaction of the enantiomeric mixture A is formed a mixture C which is essentially an acylated enantiomer (i.e. Ester) and the substantially non-acylated opposite enantiomer contains. Preferably, the enantiomer Ib is substantially acylated Form before, while the enantiomer Ia remains essentially unchanged. This now available Mixture C of alcohol and ester can be mixed with conventional Easily separate methods (step (a.2)). Suitable separation operations For example, extraction, distillation, crystallization or Chromatography, wherein the separation operation depending on used acylating agent. How to separate a reaction mixture in the reaction with vinyl, propenyl or Isopropenylestern of aliphatic dicarboxylic acids is obtained, preferably by distillation, while maintaining a reaction mixture, in which in step (a.1) vinyl, propenyl or isopropenyl ester of aliphatic monocarboxylic acids, anhydrides of aliphatic monocarboxylic acids or acid anhydrides of aliphatic dicarboxylic acids were used as acylating agents, preferably separated by extraction. In the case of the use of acid anhydrides of dicarboxylic acids the separation is preferably carried out extractively with an aqueous Base.

Analogous receives by the enantioselective reaction of the enantiomer mixture B is a mixture D which is essentially an acylated enantiomer (i.e. Ester) and the substantially non-acylated opposite one Enantiomer contains. Preferably, the enantiomer Id is substantially acylated Form before, while the enantiomer IC remains essentially unchanged. This mixture D from alcohol and ester can be slightly separate as described above.

It but it is also possible the entire reaction mixture from step (a.1), optionally under previous separation of the solvent, directly subject to the separation operation, but with the previous separation of the enzyme is preferred.

Of the enantiomeric excess of the separated in step (a.2), non-acylated alcohol can by means of common Be determined method, for example by determining the optical Rotation or by chromatography on a chiral phase, for example by HPLC or gas chromatography over chiral columns.

With the separation variant according to the invention (a) becomes the non-acylated alcohol with an enantiomeric excess (ee value) of preferably at least 90%, more preferably of at least 95% and in particular of at least 98%.

The Enantiomeric purity of the selectively acylated alcohol can with the same procedure. Preferably, the ee value is at least 90%, more preferably at least 95% and in particular at least 98%.

In Step (a.3) can finally the selectively acylated and separated in step (a.2) alcohol if desired be hydrolyzed.

The Hydrolysis of the selectively acylated alcohol in step (a.3) according to common Procedure, for example by reaction with a base. Suitable bases are, for example, alkali metal and alkaline earth metal hydroxides and carbonates, ammonia, amines, such as dimethylamine, diethylamine, Trimethylamine, triethylamine and diisopropylamine. Preferably used for hydrolysis as the base sodium or potassium hydroxide. The hydrolysis can be in water or in a solvent or in a mixture of water and solvent. Suitable solvents are alcohols, preferably having 1 to 3 carbon atoms, such as methanol, Ethanol, propanol or isopropanol, glycols, in particular with 2 to 8 carbon atoms, such as ethylene glycol, di- and triethylene glycol, the mixtures of the abovementioned solvents and mixtures thereof with water.

Separation variant (b)

In the separation variant (b), the enantiomeric mixture A or B is reacted with a customary acylating agent in step (b.1). Examples of suitable acylating agents are the acylating agents mentioned in the statements on step (a.1), the alkyl and alkylaryl esters of the carboxylic acids mentioned there, for example the methyl, isopropyl or benzyl esters of acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid , Isovaleric acid, 2-methylbutyric acid, caproic acid, 2-methylvaleric acid, 3-methylvaleric acid, 4-methylvaleric acid, 2,2-dimethylbutyric acid, 3,3-dimethylbutyric acid, 2-ethylhexanoic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid , Myristic, pentadecanoic, palmitic, margaric, stearic, nonadecanoic, arachidic, oxalic, malonic, succinic, methyl-, dimethyl-trimethyl- and tetramethylsuccinic, glutaric, 3,3-dimethylglutaric, adipic, pimelic, azelaic, sebacic, maleic, fumaric and sorbic acid, benzoic acid, phenyle sacetic acid, phthalic acid and terephthalic acid. Also suitable are the acid halides of the carboxylic acids mentioned there, for example the acid chlorides of acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, 2-methylbutyric acid, caproic acid, 2-methylvaleric acid, 3-methylvaleric acid, 4-methylvaleric acid, 2,2-dimethylbutyric acid, 3,3-dimethylbutyric acid, 2-ethylhexanoic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachidic acid, oxalic acid, malonic acid, succinic acid, methyl-, dimethyl-, Trimethyl- and tetramethylsuccinic acid, glutaric acid, 3,3-dimethylglutaric acid, adipic acid, pimelic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid and sorbic acid, benzoic acid, phenylacetic acid, phthalic acid and terephthalic acid. Finally, suitable acylating agents are the alkyl, alkenyl or alkylaryl esters and also the acid anhydrides or the acid halides of aliphatic halogen-substituted C ₂ -C ₁₂ -carboxylic acids. Examples of such derivatives of halo-substituted C ₂ -C ₁₂ carboxylic acids are the alkyl, alkyl aryl or alkenyl esters of chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid and the like, and also the acid chlorides or acid anhydrides of these acids.

In Step (b.1) preferred acylating agents are selected from the aforementioned esters, acid halides and anhydrides of acetic acid, propionic acid, butyric and phenylacetic acid.

The Acylation in step (b.1) is usually carried out under reaction conditions as known from the prior art for esterification. Suitable conditions are for example in Jerry March, Advanced Organic Chemistry, 3rd Edition, 1985, John Wiley & Sons, page 348 et seq. which is incorporated herein by reference in its entirety.

The acylation in step (b.1) is generally not enantioselective, so that one obtains from the enantiomeric mixture A of the alcohols Ia and Ib (R = CH ₂ OH) a mixture E in which both alcohols Ia and Ib are essentially acylated Form vorlie gene. Analogously, when using a Enantiomerengemisches B of the alcohols Ic and Id (R = CH ₂ OH) as starting material, a mixture F, in which both alcohols Ic and Id are present in substantially acylated form.

At the used enantiomeric mixture A or B is in the Rule about the racemate of the alcohols Ia and Ib (R = OH, mixture A) or Ic and Id (R = OH, mixture B); Mixtures in which one of the enantiomers enriched, but are also suitable.

In Step (b.2) is the acylated enantiomeric mixture E or F in The presence of a hydrolase is selectively hydrolyzed, i. in the enantiomer mixture Essentially, E becomes only one of the acylated alcohols Ia or Ib hydrolyzed while the opposite enantiomer is essentially in the acylated one Form remains. Analogously, in the case of the enantiomeric mixture F essentially only one of the acylated alcohols Ic or Id hydrolyzed, while the opposite enantiomer essentially in the acylated Form remains.

suitable Hydrolases are those in the versions hydrolases mentioned in step (a.1). On the statements made there to preferred hydrolases and their forms of use and to the amount to the enzyme used is hereby fully incorporated by reference.

The Hydrolysis of step (b.2) is preferably carried out in a hydrous System performed. Particularly preferably contains this system besides water an organic solvent. Suitable solvents are the solvents mentioned in the description of step (a.1) as well as mixtures thereof. Depending on the choice of organic solvent the hydrolysis is carried out in a single-phase system, for. B. when using of water-miscible solvents such as dioxane and tetrahydrofuran, or in a two-phase system. Furthermore contains the reaction medium is preferably still a buffer. Suitable buffers are those that buffer in a pH range of 5.5 to 8.5. Such Buffers are known in the art. Examples of suitable buffers are hydrogen phosphate / dihydrogen phosphate, Borax buffer and Tris buffer (Tris (hydroxymethyl) aminomethane)

The Hydrolysis is usually carried out at a reaction temperature below the deactivation temperature of the hydrolase used, and preferably at least -10 ° C. Especially It is preferably in the range of 0 to 100 ° C, especially 10 to 60 ° C and especially from 15 to 35 ° C. Particularly preferred is the reaction at the temperature at which the hydrolase its highest activity owns, performed.

The Hydrolysis in step (b.2) can be done, for example, by that the mixture E of the acylated alcohols Ia and Ib or the Mixture F of the acylated alcohols Ic and Id in an organic solvent submits and then with an aqueous Buffer and the enzyme added. The components are preferably mixed, z. B. by stirring or shaking. But it is also possible the hydrolase in a reactor, for example in a column immobilize, and through the reactor a reaction medium that the acylated mixture obtained in step (b.1) E or F, an organic solvent and water and optionally a buffer. For this purpose, you can the reaction medium in the circulation through the reactor guide until the desired Sales is reached.

at the hydrolysis in step (b.2) selectively becomes the acyl group only an enantiomer Ia or Ib (mixture E) or in the case of the mixture F hydrolytically split off only one enantiomer Ic or Id, while the other enantiomer remains substantially acylated.

In usually one will the hydrolysis up to a conversion of at least 90%, more preferably at least 95% and especially of at least 99%, based on the acylated contained in the mixture Enantiomer which is selectively hydrolysed. The progressive reaction, d. H. the sequential hydrolysis of one enantiomer can be by usual Methods such as gas chromatography or HPLC (High Performance Liquid Chromatography).

Of the Separation step (b.3) and the hydrolysis step (b.4) can be carried out analogously to steps (a.2) and (a.3). On the made there versions is hereby complete Referenced.

Of the enantiomeric excess of the non-acylated (i.e., selectively.) separated in step (b.3) hydrolyzed) alcohol can be determined by common methods, for example, by determining the optical rotation or by Chromatography on a chiral phase, for example by HPLC or gas chromatography over chiral columns.

With the separation variant according to the invention (b) becomes the selectively hydrolyzed alcohol with an enantiomeric excess (ee value) of preferably at least 95%, more preferably of at least 97% and in particular of at least 98%.

The Enantiomeric purity of the acylated residual alcohol (i.e. Esters from step (b.2) and from it in step (b.4) obtained from it Alcohol can be determined by the same method. Preferably is ee value at least 95%, more preferably at least 97% and in particular at least 98%.

Separation variant (c)

These Separation variant is for such enantiomeric mixtures A or B are suitable, in which R in the compounds Ia, Ib, Ic and Id for COOH stands.

In Step (c.1) is due to the presence of a hydrolase in the enantiomeric mixture A of acids Ia and Ib (R = COOH) substantially only one of the enantiomers Ia or Ib esterifies while the opposite enantiomer remains substantially unesterified. Analogously, when using the Enantiomerengemischs B of the acids Ic and Id (R = COOH) substantially only one of the enantiomers Ic or Id esterified while the opposite enantiomer remains substantially unesterified.

At the used enantiomeric mixture A or B is in the Usually the racemate of the acids Ia and Ib (R = COOH, mixture A) or Ic and Id (R = COOH; B); Mixtures in which one of the enantiomers is enriched are but also suitable.

The alcohol used in step (c.1) is preferably selected from such alcohols R'OH, where R 'is C ₁ -C ₈ -alkyl, aryl or aryl-C ₁ -C ₄ -alkyl. Examples of suitable alcohols are methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, isobutanol, tert-butanol, pentanol, neopentanol, hexanol, heptanol, octanol, 2-ethylhexanol, phenol, benzyl alcohol and 2-phenylethanol.

suitable Hydrolases are those in the versions hydrolases mentioned in step (a.1). On the statements made there to preferred hydrolases and their forms of use and to the amount to the enzyme used is hereby fully incorporated by reference.

Preferably in step (c.1) the alcohol is in an amount of 0.6 to 2 mol, particularly preferably 1 to 1.5 mol and in particular 1 to 1.2 mol, based on 1 mol of that enantiomer of the mixture A or from mixture B, which is selectively esterified. alternative is preferably 0.3 to 2 mol, more preferably 0.5 to 1 mol and in particular 0.5 to 0.6 mol of alcohol, based on 1 mol Enantiomer mixture A or mixture of enantiomers B, a.

In usually the esterification in step (c.1) does not take place in one aqueous Reaction medium. Under non-aqueous Reaction media should be understood as reaction media, the less as 1% by weight, preferably less than 0.5% by weight of water, especially preferably less than 0.1% by weight of water and in particular less as 0.05% by weight of water, based on the total weight of the reaction medium, contain. Preferably, the reaction is carried out in an organic solvent carried out. Suitable solvents For example, aliphatic hydrocarbons are preferred with 5 to 8 carbon atoms, such as pentane, cyclopentane, hexane, cyclohexane, Heptane, octane or cyclooctane, or technical alkane or cycloalkane mixtures, halogenated aliphatic hydrocarbons, preferably with 1 or 2 carbon atoms, such as dichloromethane, chloroform, carbon tetrachloride, Dichloroethane or tetrachloroethane, aromatic hydrocarbons, such as benzene, toluene, the xylenes, chlorobenzene or dichlorobenzene, aliphatic acyclic and cyclic ethers, preferably with 4 to 8 carbon atoms, such as diethyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, dipropyl ether, Diisopropyl ether, dibutyl ether, tetrahydrofuran or dioxane, or Mixtures of the aforementioned solvents. Particularly preferred are the aforementioned ethers and aromatic Hydrocarbons used. In particular, tetrahydrofuran is used.

It but it is also possible the esterification step (c.1) in substance, d. H. without additional solvent perform. In this case, the alcohol R'OH is preferably in excess more than previously used and also serves as a solvent.

The Reaction in step (c.1) is usually carried out at a reaction temperature below the deactivation temperature of the hydrolase used and preferably at least -10 ° C. Particularly preferred is in the range from 0 to 100 ° C, in particular from 10 to 60 ° C and especially from 15 to 35 ° C. Particularly preferred is the reaction at the temperature at which the hydrolase its highest activity owns, performed.

to execution For example, it is possible to use the enantiomeric mixture A or the mixture of enantiomers B with the hydrolase, the alcohol and optionally the solvent submit and mix the mixture, z. B. by stirring or Shake. But it is also possible to immobilize the hydrolase in a reactor as described above.

In step (c.1) one of the enantiomeric acids Ia or Ib of the mixture A or Ic or Id of the mixture B is selectively esterified, while the other enantiomer remains essentially unchanged. In general, the esterification will lead to a conversion of at least 95%, particularly preferably of at least 99% and in particular of at least 99.5%, based on the enantiomeric acid contained in the mixture, which is selectively esterified. The progress of the reaction, ie the sequential esterification of the an enantiomer, can be followed by conventional methods such as gas chromatography or HPLC.

The Working up of the reaction mixture can be carried out in a customary manner, for example by first the hydrolase is separated from the reaction mixture, z. B. by filtration or centrifuged, optionally from the filtrate or centrifugate the solvent removed and the residue subsequently subject to a separation operation.

suitable Separation operations (step c.2) are, for example, extraction, distillation, Crystallization or chromatography. The separation operation preferably takes place Extractive, for example, by using the non-esterified acid an aqueous basic solution, z. B. with aqueous Sodium bicarbonate or sodium carbonate, of the ester, advantageously in an organic solvent, which is only partially or not miscible with water, is dissolved, extracted. Suitable organic solvents are known to the person skilled in the art. Examples of this are open-chain ethers, such as diethyl ether, dipropyl ether, or methyl tert-butyl ether, aliphatic Hydrocarbons, such as pentane or hexane, cycloaliphatic hydrocarbons, such as cyclopentane or cyclohexane, aromatic hydrocarbons such as toluene or the xylenes, halogenated hydrocarbons, such as Methylene chloride, chloroform or carbon tetrachloride, or esters, such as ethyl acetate or Propyl acetate.

It but it is also possible the entire reaction mixture from step (c.1), optionally under previous separation of the solvent, directly subject to the separation operation, but with the previous separation of the enzyme is preferred.

Of the enantiomeric excess the non-esterified acid separated in step (c.2) by means of common Be determined method, for example by determining the optical Rotation or by chromatography on a chiral phase, for example by HPLC or gas chromatography over chiral columns.

With the separation variant according to the invention (c) becomes the non-esterified acid with an enantiomeric excess (ee value) of preferably at least 95%, more preferably of at least 97% and in particular of at least 98%.

The Enantiomeric purity of the selectively esterified acid (i.e., the ester) as well as the free acid obtained therefrom in step (c.3) can be purified by the same methods be determined. Preferably, the ee value is at least 95 %, more preferably at least 97% and especially at least 98%.

The Hydrolysis in step (c.3) can be carried out in analogy to step (a.3). On the statements made there is hereby complete Referenced.

Separation variant (d)

In separation variant (d), an enantiomeric mixture A of the enantiomers Ia and Ib or Ic and Id, in which R is COOR ³ or CONR ⁴ R ^5, is hydrolyzed enantioselectively.

The esters or amides used in step (d.1) can be prepared, for example, from their underlying acids (R = COOH) by conventional esterification or amidation techniques. For the esterification suitable alcohols correspond in the statements to step (c.1) listed as suitable alcohols. Suitable for the amidation are both ammonia itself and primary and secondary amines of the formula NHR ⁴ R ⁵ , wherein R ⁴ and R ^{5 are} C ₁ -C ₄ alkyl. Examples of suitable amines are methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, tert-butylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine and dibutylamine.

The Veresterung or the transfer into the acid amide is usually done by known methods, such as in Jerry March, Advance Organic Chemistry, Reactions, Mechanism and Structure, 3rd Edition, 1985, John Wiley & Sons, page 348ff or page 370ff are described, to which reference is hereby made in their entirety becomes.

The enantiomer mixture A or B used is generally the racemate of the esters or amides Ia and Ib (R = COOR ³ or NR ⁴ R ⁵ , mixture A) or Ic and Id (R = COOR ³ or NR ⁴ R ⁵ Mixture B); However, mixtures in which one of the enantiomers is enriched are also suitable.

The hydrolysis in step (d.1) takes place in the presence of a hydrolase. In the case of using esters as starting material (R = COOR ³ ), the hydrolytic enzyme is preferably selected from those hydrolases as described in the comments on step (a.1). The comments made there on suitable and preferred hydrolases and their use forms as well as the amounts to be used are hereby fully incorporated by reference.

In the case of the use of acid amides as starting material (R = CONR ⁴ R ⁵ ) can also be described to step (a.1) hydrolases, eg. As lipases use. However, proteases are preferably used (EC 3.4). Preferred proteases are thermolysin (EC 3.4.24.27), e.g. From Bacillus proteolicus / thermoproteolyticus, the thermolysin-like proteases (TLPs) and subtilisin (EC 3.4.21.62), e.g. B. subtilisin Carlsberg from Bacillus licheniformis or subtilisin from Bacillus subtilis.

Also these enzymes can as described above in pure or crude form, free or carried or also be used as a raw fermenter discharge. Regarding suitable support materials Reference is made to the statements made above.

The Hydrolysis of step (d.1) is preferably carried out in a hydrous System performed. Particularly preferably contains this system besides water an organic solvent. Suitable solvents are the solvents mentioned in the description of step (a.1) as well as mixtures thereof. Depending on the choice of organic solvent the hydrolysis is carried out in a single-phase system, for. B. when using of water-miscible solvents such as dioxane and tetrahydrofuran, or in a two-phase system. Furthermore contains the reaction medium is preferably still a buffer. Suitable buffers are those that buffer in a pH range of 5.5 to 8.5. Such Buffers are known in the art. Examples of suitable buffers are hydrogen phosphate / dihydrogen phosphate, Borax buffer and Tris buffer (Tris (hydroxymethyl) aminomethane)

The Enantioselective hydrolysis in step (d.1) results in the case of the mixture A to a mixture L in which one of the enantiomers Ia or Ib is substantially in hydrolyzed form, d. H. R is COOH, while the other enantiomer essentially in the esterified or amidated Form remains. The same applies analogously when using a mixture B, which contains the enantiomers Ic and Id.

Out the mixture L or from the mixture M is then the one Enantiomer, which is essentially in the form of the free acid, separated (step (d.2)). The separation can be analogous to Step (c.2) take place.

Of the enantiomeric excess the selectively hydrolysed acid separated in step (d.2) by means of common Be determined method, for example by determining the optical Rotation or by chromatography on a chiral phase, for example by HPLC or gas chromatography over chiral columns.

With the separation variant according to the invention (d) becomes the selectively hydrolyzed acid with an enantiomeric excess (ee value) of preferably at least 95%, more preferably of at least 97% and in particular of at least 98%.

The Enantiomeric purity of the unhydrolyzed acid (i.e., the ester or the Amides) and the acid obtained therefrom in step (d.3) be determined by the same methods. Preferably, the ee value is at least 95%, more preferably at least 97% and in particular at least 98%.

The Hydrolysis in step (d.3) of the esterified or amidated enantiomer to the corresponding unesterified or non-amidated enantiomer, d. H. to the enantiomer in the form of the free acid, in analogy to step (a.3).

The enantiomers Ia, Ib, Ic or Id obtained in variant A or variant B can be converted by derivatization of the group R into other enantiomerically pure compounds. Thus, enantiomers Ia to Id in which R is an aldehyde group (R = CHO) can be converted by reduction into the corresponding alcohol (R = CH ₂ OH). By oxidation, they can be converted to the corresponding acids (R = COOH), which in turn can be esterified (R = COOR ³ ) or amidated (R = CONR ⁴ R ⁵ ). The aldehydes (R = CHO) can be converted by reaction with ammonia or suitable amines into the corresponding imines (R = CHNR ¹ ). The reaction of the aldehydes with hydrazines leads to the corresponding Hy drazones (R = C = NNR ² ). Aldehydes can be converted by reaction with hydroxylamine, preferably in the presence of acids in the corresponding nitriles (R = CN). The reaction of aldehydes with hydroxylamine also leads to oximes (R = CH = N-OH) The esters (R = COOR ³ ) can be reductively converted into the corresponding aldehydes (R = CHO).

Such Derivatizations can be carried out according to prior art methods known per se, as described, for example, in Jerry March, Advanced Organic Chemistry, 3rd Edition, 1985, John Wiley & Sons and in the references cited therein, what is hereby incorporated by reference.

• (a) für den Fall, dass R für CH₂OH steht: (a.1) ein Gemisch A, enthaltend die Enantiomere Ia und Ib, worin R für CH₂OH steht, oder ein Gemisch B, enthaltend die Enantiomere Ic und Id, worin R für CH₂OH steht, mit einem Acylierungsmittel in Gegenwart einer Hydrolase umsetzt, wobei man im Falle des Gemisches A ein Gemisch C erhält, in welchem eines der Enantiomere Ia oder Ib im Wesentlichen in acylierter Form vorliegt und das andere Enantiomer im Wesentlichen in nicht acylierter Form vorliegt, und wobei man im Falle des Gemisches B ein Gemisch D erhält, in welchem eines der Enantiomere Ic oder Id im Wesentlichen in acylierter Form vorliegt und das andere Enantiomer im Wesentlichen in nicht acylierter Form vorliegt; (a.2) aus dem Gemisch C oder aus dem Gemisch D das im Wesentlichen nicht acylierte Enantiomer abtrennt; und (a.3) gewünschtenfalls das in Schritt (a.1) erhaltene im Wesentlichen acylierte Enantiomer zum entsprechenden nicht acylierten Enantiomer hydrolysiert; oder
• (b) für den Fall, dass R für CH₂OH steht: (b.1) ein Gemisch A, enthaltend die Enantiomere Ia und Ib, worin R für CH₂OH steht, oder ein Gemisch B, enthaltend die Enantiomere Ic und Id, worin R für CH₂OH steht, mit einem Acylierungsmittel umsetzt, wobei man im Falle des Gemisches A ein Gemisch E erhält, in welchem beide Enantiomere Ia und Ib im Wesentlichen in acylierter Form vorliegen oder wobei man im Falle des Gemisches B ein Gemisch F erhält, in welchem beide Enantiomere Ic und Id im Wesentlichen in acylierter Form vorliegen; (b.2) das Gemisch E oder das Gemisch F in Gegenwart einer Hydrolase hydrolysiert, wobei man im Falle des Gemischs E ein Gemisch G erhält, in welchem eines der Enantiomere Ia oder Ib im Wesentlichen in acylierter Form vorliegt und das andere Enantiomer im Wesentlichen in nicht acylierter (d.h. hydrolysierter) Form vorliegt, und wobei man im Falle des Gemisches F ein Gemisch H erhält, in welchem eines der Enantiomere Ic oder Id im Wesentlichen in acylierter Form vorliegt und das andere Enantiomer im Wesentlichen in nicht acylierter (d.h. hydrolysierter) Form vorliegt; (b.3) aus dem Gemisch G oder aus dem Gemisch H das im Wesentlichen nicht acylierte Enantiomer abtrennt; und (b.4) gewünschtenfalls das in Schritt (b.2) erhaltene im Wesentlichen acylierte Enantiomer zum entsprechenden nicht acylierten Enantiomer hydrolysiert; oder
• (c) für den Fall, dass R für COOH steht: (c.1) ein Gemisch A, enthaltend die Enantiomere Ia und Ib, worin R für COOH steht, oder ein Gemisch B, enthaltend die Enantiomere Ic und Id, worin R für COOH steht, mit einem Alkohol in Gegenwart einer Hydrolase umsetzt, wobei man im Falle des Gemisches A ein Gemisch J erhält, in welchem eines der Enantiomere Ia oder Ib im Wesentlichen in veresterter Form vorliegt und das andere Enantiomer im Wesentlichen in nicht veresterter Form vorliegt, und wobei man im Falle des Gemisches B ein Gemisch K erhält, in welchem eines der Enantiomere Ic oder Id im Wesentlichen in veresterter Form vorliegt und das andere Enantiomer im Wesentlichen in nicht veresterter Form vorliegt; (c.2) aus dem Gemisch J oder aus dem Gemisch K das im Wesentlichen nicht veresterte Enantiomer abtrennt; und (c.3) gewünschtenfalls das in Schritt (c.1) erhaltene im Wesentlichen veresterte Enantiomer zum entsprechenden nicht veresterten Enantiomer hydrolysiert; oder
• (d) für den Fall, dass R für COOR³ oder CONR⁴R⁵ steht: (d.1) ein Gemisch A, enthaltend die Enantiomere Ia und Ib, worin R für COOR³ oder CONR⁴R⁵ steht, oder ein Gemisch B, enthaltend die Enantiomere Ic und Id, worin R für COOR³ oder CONR⁴R⁵ steht, in Gegenwart einer Hydrolase hydrolysiert, wobei man im Falle des Gemisches A ein Gemisch L erhält, in welchem eines der Enantiomere Ia oder Ib im Wesentlichen in veresterter oder amidierter Form vorliegt und das andere Enantiomer im Wesentlichen in nicht veresterter oder in nicht amidierter Form vorliegt, und wobei man im Falle des Gemisches B ein Gemisch M erhält, in welchem eines der Enantiomere Ic oder Id im Wesentlichen in veresterter oder amidierter Form vorliegt und das andere Enantiomer im Wesentlichen in nicht veresterter oder in nicht amidierter Form vorliegt; (d.2) aus dem Gemisch L oder aus dem Gemisch M das im Wesentlichen nicht veresterte oder nicht amidierte Enantiomer abtrennt; und (d.3) gewünschtenfalls das in Schritt (d.1) erhaltene im Wesentlichen veresterte oder amidierte Enantiomer zum entsprechenden nicht veresterten oder nicht amidierten Enantiomer hydrolysiert;

und gewünschtenfalls die Gruppe R derivatisiert.Another object of the present invention is a process for the preparation of substantially enantiomerically pure compounds of formulas Ia, Ib, Ic and / or Id, which are defined as in claim 1, wherein

• (a) in the case that R is CH ₂ OH: (a.1) a mixture A containing the enantiomers Ia and Ib, wherein R is CH ₂ OH, or a mixture B, containing the enantiomers Ic and Id , wherein R is CH ₂ OH, with an acylating agent in the presence of a hydrolase, wherein in the case of the mixture A, a mixture C receives, in which one of the enantiomers Ia or Ib is present in substantially acylated form and the other enantiomer substantially is present in non-acylated form, and wherein, in the case of the mixture B, a mixture D is obtained in which one of the enantiomers Ic or Id is present in substantially acylated form and the other enantiomer is present in substantially non-acylated form; (a.2) from the mixture C or from the mixture D separates the substantially non-acylated enantiomer; and (a.3), if desired, hydrolyzing the substantially acylated enantiomer obtained in step (a.1) to the corresponding non-acylated enantiomer; or
• (b) for the case that R is CH ₂ OH: (b.1) a mixture A comprising the enantiomers Ia and Ib wherein R is CH ₂ OH, or a mixture B containing the enantiomers Ic and Id in which R is CH ₂ OH, is reacted with an acylating agent to obtain in the case of the mixture A a mixture E in which both enantiomers Ia and Ib are present in substantially acylated form or wherein in the case of the mixture B a mixture of F in which both enantiomers Ic and Id are present in substantially acylated form; (b.2) the mixture E or the mixture F is hydrolyzed in the presence of a hydrolase, wherein, in the case of the mixture E, a mixture G is obtained in which one of the enantiomers Ia or Ib is present in substantially acylated form and the other enantiomer substantially in non-acylated (ie hydrolyzed) form, and in the case of Mixture F, obtaining a mixture H in which one of the enantiomers Ic or Id is present in substantially acylated form and the other enantiomer is essentially in non-acylated (ie hydrolyzed) form. Form is present; (b.3) from the mixture G or from the mixture H separates the substantially non-acylated enantiomer; and (b.4) if desired, hydrolyzing the substantially acylated enantiomer obtained in step (b.2) to the corresponding non-acylated enantiomer; or
• (c) in the event that R is COOH: (c.1) a mixture A containing the enantiomers Ia and Ib, in which R is COOH, or a mixture B, containing the enantiomers Ic and Id, wherein R represents COOH is reacted with an alcohol in the presence of a hydrolase, wherein, in the case of the mixture A, a mixture J is obtained in which one of the enantiomers Ia or Ib is present substantially in esterified form and the other enantiomer is present substantially in non-esterified form, and wherein, in the case of the mixture B, a mixture K is obtained in which one of the enantiomers Ic or Id is substantially in esterified form and the other enantiomer is substantially unesterified; (c.2) from the mixture J or from the mixture K separates the substantially unesterified enantiomer; and (c.3) if desired, hydrolyzing the substantially esterified enantiomer obtained in step (c.1) to the corresponding unesterified enantiomer; or
• (d) in the event that R is COOR ³ or CONR ⁴ R ⁵ : (d.1) a mixture A containing the enantiomers Ia and Ib, wherein R is COOR ³ or CONR ⁴ R ⁵ , or a mixture B, containing the enantiomers Ic and Id, wherein R is COOR ³ or CONR ⁴ R ⁵ , hydrolyzed in the presence of a hydrolase, wherein in the case of the mixture A, a mixture L is obtained in which one of the enantiomers Ia or Ib substantially in esterified or amidated form is present and the the enantiomer is present essentially in non-esterified or non-amidated form, and in the case of the mixture B, a mixture M is obtained in which one of the enantiomers Ic or Id is present essentially in esterified or amidated form and the other enantiomer is essentially in is not esterified or in non-amidated form; (d.2) from the mixture L or from the mixture M separates the substantially unesterified or unamidated enantiomer; and (d.3) if desired, hydrolyzing the substantially esterified or amidated enantiomer obtained in step (d.1) to the corresponding unesterified or non-amidated enantiomer;

and, if desired, derivatizing the group R.

The above to the separation variants (a) to (d) apply here accordingly.

worin
R für CHO, CH=NR¹, CH=NNR², COOR³, CONR⁴R⁵ oder CN steht;
R¹ für H, OH, C₁-C₈-Alkyl oder Aryl steht;
R² für H, C₁-C₈-Alkyl oder Aryl steht;
R³ für C₁-C₈-Alkyl, C₂-C₈-Hydroxyalkyl oder Arylalkyl steht, und
R⁴ und R⁵ unabhängig voneinander für H, C₁-C₈-Alkyl, C₁-C₈-Hydroxylkyl, Aryl oder Arylalkyl stehen oder gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen gesättigten oder ungesättigten Ring mit 1 bis 3 Heteroatomen bilden.Another object of the present invention are compounds of the formulas Ia or Ib

wherein
R is CHO, CH = NR ¹ , CH = NNR ² , COOR ³ , CONR ⁴ R ⁵ or CN;
R ^{1 is} H, OH, C ₁ -C ₈ alkyl or aryl;
R ^{2 is} H, C ₁ -C ₈ alkyl or aryl;
R ^{3 is} C ₁ -C ₈ alkyl, C ₂ -C ₈ hydroxyalkyl or arylalkyl, and
R ⁴ and R ⁵ independently of one another are H, C ₁ -C ₈ -alkyl, C ₁ -C ₈ -hydroxylkyl, aryl or arylalkyl or, together with the nitrogen atom to which they are bonded, a 5- or 6-membered saturated or form unsaturated ring with 1 to 3 heteroatoms.

In compounds Ia and Ib, R ^{1 is} preferably OH, C ₁ -C ₄ -alkyl, phenyl or tolyl.

Preferably, R ^{2 is} aryl, more preferably optionally substituted phenyl, eg, phenyl, nitrophenyl or dinitrophenyl.

R ³ is preferably C ₁ -C ₈ -alkyl or benzyl and more preferably C ₁ -C ₄ -alkyl.

R ⁴ and R ⁵ preferably together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated ring having 1 to 3 heteroatoms. Most preferably, together with the nitrogen atom to which they are attached, they form a [1,2,4] triazol-1-yl ring.

R is preferably CHO, COOR ³ or CONR ⁴ R ⁵ .

worin
R für CH₂X, CHO, CH=NR¹, CH=NNR², COOH, COOR³, CONR⁴R⁵ oder CN steht;
X für OH, O-SO₂R⁶ oder Halogen steht;
R¹ für H, OH, C₁-C₈-Alkyl oder Aryl steht;
R² für H, C₁-C₈-Alkyl oder Aryl steht;
R³ für C₁-C₈-Alkyl, C₂-C₈-Hydroxyalkyl oder Arylalkyl steht,
R⁴ und R⁵ unabhängig voneinander für H, C₁-C₈-Alkyl, C₁-C₈-Hydroxylkyl, Aryl oder Arylalkyl stehen oder gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen gesättigten oder ungesättigten Ring mit 1 bis 3 Heteroatomen bilden, und
R⁶ für C₁-C₈-Alkyl, C₁-C₈-Halogenalkyl oder Aryl steht.Another object of the present invention are compounds of the formulas Ic or Id

wherein
R is CH ₂ X, CHO, CH = NR ¹ , CH = NNR ² , COOH, COOR ³ , CONR ⁴ R ⁵ or CN;
X is OH, O-SO ₂ R ⁶ or halogen;
R ^{1 is} H, OH, C ₁ -C ₈ alkyl or aryl;
R ^{2 is} H, C ₁ -C ₈ alkyl or aryl;
R ^{3 is} C ₁ -C ₈ -alkyl, C ₂ -C ₈ -hydroxyalkyl or arylalkyl,
R ⁴ and R ⁵ independently of one another are H, C ₁ -C ₈ -alkyl, C ₁ -C ₈ -hydroxylkyl, aryl or arylalkyl or, together with the nitrogen atom to which they are bonded, a 5- or 6-membered saturated or unsaturated ring having 1 to 3 heteroatoms, and
R ^{6 is} C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl or aryl.

In compounds Ic and Id, R ^{1 is} preferably OH, C ₁ -C ₄ alkyl, phenyl or tolyl.

Preferably, R ^{2 is} aryl, more preferably optionally substituted phenyl, eg, phenyl, nitrophenyl or dinitrophenyl.

R ³ is preferably C ₁ -C ₈ -alkyl or benzyl and more preferably C ₁ -C ₄ -alkyl.

R ⁴ and R ⁵ preferably together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated ring having 1 to 3 heteroatoms. Most preferably, together with the nitrogen atom to which they are attached, they form a [1,2,4] triazol-1-yl ring.

R ⁶ is preferably CF ₃ or p-tolyl.

The compounds Ia and Ib according to the invention and also compounds Ia and Ib in which R is CH ₂ X or COOH are valuable intermediates, for example for the preparation of enantiomerically pure epoxiconazole. Thus, compound Ia or Ib in which R is CHO, can be subjected to a reductive amination in the presence of 1H- [1,2,4] triazole.

bei dem man eine Verbindung Ia gemäß obiger Definition oder eine Verbindung Ib gemäß obiger Definition, worin R für CHO steht, einer reduktiven Aminierung in Gegenwart von 1H-[1,2,4]Triazol unterwirft. Verbindung Ia wird dabei zu Verbindung IIIa umgesetzt, während die reduktive Aminierung der Verbindung Ib die Verbindung IIIb ergibt.Another object of the present invention is accordingly a process for the preparation of compounds of the formulas IIIa or IIIb

in which a compound Ia as defined above or a compound Ib as defined above in which R is CHO is subjected to a reductive amination in the presence of 1H- [1,2,4] triazole. Compound Ia is converted to compound IIIa, while the reductive amination of the compound Ib gives the compound IIIb.

at the reductive amination of compounds Ia or Ib in the presence of 1H- [1,2,4] triazole Essentially no racemization takes place. Essentially means that less than 5%, preferably less than 2% and in particular less than 1% of the compounds Ia reacted lead compound IIIb or that less than 5%, preferably less than 2% and in particular less than 1% of the reacted compounds Ib to the compound IIIa lead.

The Compounds IIIa and IIIb represent the enantiomers of the commercial available Fungicides / growth regulator epoxiconazole. Epoxiconazole it is the racemate of the enantiomers IIIa and IIIb.

The reductive amination is carried out under such reaction conditions that the triazole ring and the phenyl rings are not reduced. Suitable reaction conditions for reductive aminations are For example, Jerry March, Advanced Organic Chemistry, 3rd Ed., John Wiley & Sons, p. 798 et seq., which is incorporated herein by reference in its entirety. The reductive amination is usually carried out in the presence of a hydrogenation catalyst, which may be both homogeneous and heterogeneous. Preferably, the hydrogenation catalyst is selected so that it allows the mildest possible reaction conditions, so that a reduction of the triazole ring and the phenyl rings is avoided.

When Hydrogenation catalysts are all under the above proviso Catalysts of the prior art which are the reductive Catalyze amination of aldehydes to the corresponding amines. Preferably, the hydrogenation catalysts contain at least one Metal of Group VIII.

Especially suitable Group VIII metals are selected from ruthenium, cobalt, Rhodium, nickel, palladium and platinum.

The Metals can also be used as mixtures. In addition, the catalysts can be used alongside Group VIII metals also contain small amounts of other metals, for example, metals of group VIIa, in particular rhenium, or Metals of group Ib, d. H. Copper, silver or gold, included. Particularly preferred Group VIII metals are ruthenium, nickel, Palladium and platinum, in particular ruthenium, nickel and palladium, and stronger prefers ruthenium and nickel. Specifically, the catalyst contains nickel as catalytic active species.

• a) Schwarzkatalysator: Das Metall wird kurz vor der Verwendung als Katalysator aus der Lösung eines seiner Salze reduktiv abgeschieden.
• b) Adams-Katalysator: Die Metalloxide, insbesondere die Oxide von Platin und Palladium, werden in situ durch den zur Hydrierung eingesetzten Wasserstoff reduziert.
• c) Skelett- oder Raney-Katalysator: Der Katalysator wird als "Metallschwamm" aus einer binären Legierung des Metalls (insbesondere Nickel oder Cobalt) mit Aluminium oder Silicium durch Herauslösen eines Partners mit Säure oder Lauge hergestellt. Reste des ursprünglichen Legierungspartners wirken oft synergistisch.
• d) Trägerkatalysator: Schwarzkatalysatoren lassen sich auch auf der Oberfläche einer Trägersubstanz niederschlagen. Geeignete Träger und Trägermaterialien sind nachfolgend beschrieben.

If a heterogeneous catalyst is used, this is suitably present in finely divided form. The finely divided shape is achieved, for example, as follows:

• a) Black catalyst: The metal is deposited reductively shortly before use as a catalyst from the solution of one of its salts.
• b) Adams catalyst: The metal oxides, in particular the oxides of platinum and palladium, are reduced in situ by the hydrogen used for the hydrogenation.
• c) Skeleton or Raney Catalyst: The catalyst is prepared as a "metal sponge" from a binary alloy of the metal (especially nickel or cobalt) with aluminum or silicon by dissolving a partner with acid or alkali. Residues of the original alloying partner often act synergistically.
• d) Supported catalyst: Black catalysts can also be precipitated on the surface of a carrier substance. Suitable carriers and carrier materials are described below.

Such Heterogeneous catalysts are in general form, for example in Organikum, 17th edition, VEB Deutscher Verlag der Wissenschaften, Berlin, 1988, p. 288.

The carrier can of metallic or non-metallic, porous or nonporous material consist.

suitable Metallic materials are, for example, high-alloy stainless steels. suitable non-metallic materials are, for example, mineral materials, e.g. natural and synthetic minerals, glasses or ceramics, plastics, e.g. artificial or natural polymers, or a combination of both.

preferred support materials are coal, especially activated carbon, silica, especially amorphous Silica, alumina, and also the sulfates and carbonates the alkaline earth metals, calcium carbonate, calcium sulfate, magnesium carbonate, Magnesium sulfate, barium carbonate and barium sulfate.

Of the Catalyst can by conventional Procedure on the carrier be applied, e.g. by soaking, wetting or spraying the carrier with a solution, which contains the catalyst or a suitable precursor thereof.

suitable carrier and methods of applying the catalyst thereto are, for example in DE-A-10128242, hereby incorporated by reference Reference is made.

Also homogeneous hydrogenation catalysts can in the process according to the invention be used. Examples are the nickel catalysts, in EP-A-0668257 are described. A disadvantage of using homogeneous catalysts However, their cost of production and also the fact that they are usually are not regenerable.

Therefore be in the process of the invention preferably used heterogeneous hydrogenation catalysts.

Especially Preferably, the metal is in supported form or as a metal sponge used. examples for supported Catalysts are in particular palladium, nickel or ruthenium on charcoal, in particular activated carbon, silicon dioxide, in particular on amorphous silica, barium carbonate, calcium carbonate, magnesium carbonate or alumina, wherein the carriers may be in the forms described above. Preferred carrier forms are the moldings described above.

The metallic catalysts can also in the form of their oxides, in particular palladium oxide, platinum oxide or nickel oxide, which are then under the hydrogenation conditions be reduced to the corresponding metals.

When Metal sponge is used in particular Raney nickel.

specially is used in the process according to the invention Raney nickel as a hydrogenation catalyst.

The depends on the amount of catalyst to be used among others, the respective catalytically active metal and of its use form and can be determined by the expert in each case become.

The reductive amination takes place at a temperature of preferably 20 to 200 ° C, more preferably from 50 to 150 ° C and especially from 70 to 120 ° C.

The Reaction temperature of the reductive amination depends inter alia on the activity and amount of used hydrogenation catalyst from and can in the individual case of Be determined professional. Preferably, it is 20 to 200 ° C, especially preferably from 50 to 150 ° C and in particular from 70 to 120 ° C.

The Reductive amination can be carried out in a suitable solvent. suitable Solvents are for example, aliphatic hydrocarbons, preferably with 5 to 8 carbon atoms, such as pentane, cyclopentane, hexane, cyclohexane, Heptane, octane or cyclooctane, or technical alkane or cycloalkane mixtures, aromatic hydrocarbons, such as benzene, toluene and the xylenes, aliphatic acyclic and cyclic ethers, preferably with 4 to 8 carbon atoms, such as diethyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, Dipropyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran or Dioxane, or mixtures of the aforementioned solvents. Especially preferred be the aforementioned ethers or aromatic hydrocarbons used.

After completion of the reaction, the catalyst is usually removed. The heterogeneous catalyst is preferably separated by filtration or by sedimentation and removal of the upper, product-containing phase. Other separation methods for removing solids from solutions, such as centrifugation, are also suitable for removing the heterogeneous catalysts. The removal of homogeneous catalysts is carried out by conventional methods for the separation of in-phase mixtures, for example by chromatographic methods. Optionally, depending on the type of catalyst, it may be necessary to deactivate it prior to removal. This can be done by conventional methods, for example by washing the reaction solution with protic solvents, for example with water or with C ₁ -C ₃ -alkanols, such as methanol, ethanol, propanol or isopropanol, which are adjusted to basic or acidic if necessary. If a solvent was used in the reaction, this is usually also removed, which can be carried out by conventional methods, for example by distillation, in particular under reduced pressure.

The Reaction product can by conventional Be purified by, for example, distillation, Sublimation, extraction or chromatography.

In a preferred embodiment those used in the synthesis of compounds IIIa or IIIb Compounds Ia or Ib (R = CHO) obtained by adding a Compound IIa or IIb, preferably IIa, the epoxidation process according to the invention, e.g. according to variant A or B, to obtain a compound Ia or Ib subjects and, if necessary, the epoxidation product obtained Ia or Ib derivatized to give a compound Ia or Ib gets in the R for CHO stands. In terms of preferred embodiments of the epoxidation process according to the invention Reference is made to the statements made above.

By the inventive method receives the compounds IIIa or IIIb in an enantiomeric purity preferably at least 95% ee, more preferably at least 97% ee, more preferred of at least 98% ee and in particular of at least 99% ee, e.g. of at least 99.5% ee.

Compounds of the formula Ia or Ib in which R is a group CONR ⁴ R ⁵ , in which R ⁴ and R ^5, together with the nitrogen atom to which they are bonded, form a [1,2,4] triazol-1-yl Ring can be converted into the corresponding enantiomerically pure Epoxiconazole of the formulas IIIa or IIIb by reducing the carbonyl group.

bei dem man eine Verbindung Ia gemäß obiger Definition oder eine Verbindung Ib gemäß obiger Definition, worin R für CONR⁴R⁵ steht und worin R⁴ und R⁵ zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen [1,2,4]Triazol-1-ylring bilden, reduziert. Verbindung Ia wird dabei zu Verbindung IIIa reduziert, während die Reduktion der Verbindung Ib die Verbindung IIIb ergibt.Accordingly, a further subject of the present invention is a process for the preparation of compounds of the formulas IIIa or IIIb

which comprises a compound Ia as defined above or a compound Ib as defined above, wherein R is CONR ⁴ R ⁵ and wherein R ⁴ and R ⁵ together with the nitrogen atom to which they are bonded form a [1,2,4 ] Form triazol-1-yl ring, reduced. Compound Ia is thereby reduced to compound IIIa, while the reduction of the compound Ib gives the compound IIIb.

at The reduction of compounds Ia or Ib essentially takes place no racemization takes place. In essence, that means less than 5%, preferably less than 2% and in particular less than 1% of the reacted compounds Ia lead to the compound IIIb or that less than 5%, preferably less than 2% and in particular less than 1% of the reacted compounds Ib to the compound IIIa lead.

The reduction generally takes place under reaction conditions under which the carbonyl group is reduced to CH ₂ groups, but at the same time the triazolyl ring and the phenyl radicals remain unchanged.

suitable Reaction conditions are, for example, the reduction with amalgamated Zinc and acids, like hydrochloric acid or hydrobromic acid (Clemmensen reduction), the reduction with hydrazine as reducing agent (Wolff-Kishner reduction or Huan-Minlong variant according to Wolff-Kishner)) continue the reduction with complex hydrides, non-complex metal and metalloid hydrides or with trichlorosilane. Also the catalytic described above Hydrogenation under mild reaction conditions can be used in which case hydrogenation using Raney nickel is preferred.

Prefers However, the reduction with the help of complex and non-complex Metal and semi-metal hydrides.

Complex hydrides are generally understood as meaning charged metal complexes containing at least one hydride ligand. Examples thereof are lithium aluminum hydride (LiAlH ₄ ), LiAlH (O-tert-butyl) ₃ , LiAlH (O-methyl) ₃ , NaAlEt ₂ H ₂ , sodium borohydride (NaBH ₄ ) and the like. Examples of non-complex metal and metalloid hydrides are boranes such as BH ₃ , 9-BBN (9-borabicyclo [3.3.1] nonane) and disiamylborane, AlH ₃ , DIBAL-H (AlH (isobutyl) ₂ ) and the like.

Preferred reducing agents are the above-mentioned complex hydrides and non-complex metal and metalloid hydrides. Among these, preferred reducing agents are lithium aluminum hydride and the boranes. In particular, BH _{3 is used} .

The reduction to compounds IIIa or IIIb is preferably in a suitable solvent carried out. Suitable solvents are those which are inert in the reduction process and do not react either with the reactants or with the products. Suitable solvents are in the use of complex hydrides and non-complex metal and metalloid as the reducing agent polar aprotic solvents, for example open-chain and cyclic ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran and dioxane, carboxylic acid derivatives such as ethyl acetate, dimethylformamide and Acetonitrile, dimethylsulfoxide, and halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, dichloroethane and trichloroethane, with the above mentioned ethers being preferred. When hydrogen is used as the reducing agent, the solvents mentioned above for the reductive amination are suitably used. The reduction according to Clemmensen or Wolff-Kishner usually takes place in an aqueous reaction medium.

The reduction with BH ₃ as a reducing agent is preferably carried out at a reaction temperature of -70 to 100 ° C, particularly preferably -10 to 30 ° C.

BH ₃ is used either in gaseous form (as diborane B ₂ H ₆ ) or in solution (eg as etherate).

The compound Ia or Ib and BH ₃ to be reduced are used in a molar ratio of preferably 3: 1 to 1: 2, and more preferably from 2: 1 to 1: 1.

The workup of the reaction mixture from the reduction reaction is carried out in the usual manner, for example by deactivating unreacted reducing agent, for example by adding the reaction mixture with a protic solvent such as water or a C ₁ -C ₃ alcohol, such as methanol, ethanol, propanol or isopropanol , and subsequent purification, for example by extraction, chromatography and the like.

In a preferred embodiment, the compounds Ia or Ib used in the synthesis of the compounds IIIa or IIIb (R = CONR ⁴ R ⁵ , in which R ⁴ and R ^5, together with the nitrogen atom to which they are bonded, form a [1,2] 4] form triazol-1-yl ring) obtained by subjecting a compound IIa or IIb, preferably IIa, the epoxidation process according to the invention, for example according to variant A or B, to obtain a compound Ia or Ib and, if necessary, the resulting epoxidation product Ia or Ib is derivatized to give a compound Ia or Ib in which R is CONR ⁴ R ⁵ , wherein R ⁴ and R ⁵ together with the nitrogen atom to which they are attached, a [1,2,4] triazole-1 -ylring form. This can be done, for example, by amidating a compound Ia or Ib in which R is COOH or COOR ³ , optionally after prior activation, with 1H- [1,2,4] triazole. With regard to preferred embodiments of the epoxidation process according to the invention, reference is made to the statements made above.

By the inventive method receives the compounds IIIa or IIIb in an enantiomeric purity preferably at least 95% ee, more preferably at least 97% ee, more preferred of at least 98% ee and in particular of at least 99% ee, e.g. of at least 99.5% ee.

The enantiomerically pure compounds IIIa and IIIb (epoxiconazole enantiomers) can also be obtained by reacting a compound Ia or Ib in which R is a group CH ₂ X, where X is O-SO ₂ R ⁶ or halogen, with 1H - [1,2,4] triazole in the presence of a base or with a salt of the triazole.

Another object of the invention is therefore a process for the preparation of compounds IIIa or IIIb, in which subjecting a compound IIa or IIb, preferably IIa, the epoxidation process according to the invention, for example according to variant A or B, to obtain a compound Ia or Ib and, if necessary the resulting epoxidation product is derivatized Ia or Ib to give a compound Ia or Ib in which R is CH ₂ X, where X is OSO ₂ R ⁶ or halogen, and this with 1H- [1,2,4] Triazole in the presence of a base or with a salt of the triazole.

Compounds Ia or Ib, wherein R is a group CH ₂ X, wherein X is O-SO ₂ R ⁶ or halogen, are obtainable for example by reacting in compounds Ia or Ib, wherein R is a group CH ₂ OH , the CH ₂ OH group is converted into a suitable leaving group, for example into a group CH ₂ X, wherein X is OSO ₂ R ⁶ or halogen. The conversion of alcohol functions in leaving groups is well known and is, for example, in Organicum, VEB German Publishers of Wissen schaften, 17th edition, Berlin, 1988, page 179 et seq., Which is hereby incorporated by reference in its entirety.

links Ia or Ib, where R is for a group COOH can, can be converted into the corresponding enantiomerically pure Epoxiconazole, by first reduces the carboxyl group to the alcohol and the alcohol as before described converted into the corresponding enantiomerically pure Epoxiconazol. The Reduction of the carboxylic acid to the corresponding alcohol, the transfer of the Alcohol in a suitable leaving group and the implementation of such derivatized compound to the triazole-substituted derivative analogous to conventional Method. These methods are described, for example, in WO 2005/056548 which is incorporated herein by reference in its entirety.

Compounds Ia or Ib, wherein R is a radical COOR ³ , can be converted into the corresponding enantiomerically pure Epoxiconazole, for example, by reducing the ester group to an aldehyde group and the aldehyde group, for example, as described above in a reductive amination. The reduction of the ester group to the corresponding aldehyde group is carried out, for example, using complex hydrides, such as lithium, aluminum hydride or sodium borohydride. Suitable reduction conditions are well known and are described, for example, in Jerry March, Advanced Organic Chemistry, 3rd Edition, 1985, John Wiley and Sons, S 1099 et seq., Which is incorporated by reference in its entirety.

Compounds of the formula Ia or Ib in which R is a radical CH = NR ¹ , CH = NNR ² or CN can also be converted by known processes of the prior art into the corresponding aldehydes or carboxylic acids, which are then as described above , can be converted to the enantiomerically pure Epoxiconazolen.

Claims (24)

Process for the preparation of optically active compounds of the formulas Ia, Ib, Ic and / or Id

wherein R is CH ₂ X, CHO, CH = NR ¹ , CH = NNR ² , COOH, COOR ³ , CONR ⁴ R ⁵ or CN; X is OH, O-SO ₂ R ⁶ or halogen; R ^{1 is} H, OH, C ₁ -C ₈ alkyl or aryl; R ^{2 is} H, C ₁ -C ₈ alkyl or aryl; R ^{3 is} C ₁ -C ₈ alkyl, C ₂ -C ₈ hydroxyalkyl or arylalkyl; R ⁴ and R ⁵ independently of one another are H, C ₁ -C ₈ -alkyl, C ₂ -C ₈ -hydroxyalkyl, aryl or arylalkyl or, together with the nitrogen atom to which they are bonded, a 5- or 6-membered saturated or unsaturated ring having 1 to 3 heteroatoms; and R ^{6 is} C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl or aryl; comprising the epoxidation of a compound of formula IIa or a compound of formula IIb

wherein R is as defined above, and separation of an optionally resulting enantiomeric mixture. Process according to claim 1, wherein the compound IIa or IIb enantioselectively epoxidized. A process as claimed in claim 2, wherein compounds of the formulas IIa or IIb are reacted in the presence of a catalyst of the formula A

wherein P is a protective group, epoxidized with an oxidizing agent. A process according to claim 3, wherein P is acetyl or the two groups P together form a bridging dimethylmethylene group (-C (CH ₃ ) ₂ -). Method according to one of claims 3 or 4, wherein as Oxidizing agent potassium persulfate used. Method according to one of claims 3 to 5, wherein a Epoxidized compound of formula IIa. A process according to any one of claims 3 to 6, wherein in compounds of formula IIa or IIb R is CHO, CH = NR ¹ , CH = NNR ² , COOH, COOR ³ , CONR ⁴ R ⁵ or CN. The method of claim 2, wherein compounds of the formulas IIa or IIb epoxidized in the presence of a polyamino acid. A process according to claim 8 wherein in compounds of formula IIa or IIb R is CHO, CH = NR ¹ , CH = NNR ² , COOH, COOR ³ , CONR ⁴ R ⁵ or CN. Process according to one of claims 8 or 9, wherein the polyamino acid is present under Poly-L-alanine and poly-L-leucine is selected. A process as claimed in claim 1, wherein an enantiomer mixture A comprising the compounds Ia and Ib or a mixture of enantiomers B comprising the compounds Ic and Id is separated by (a) in the case where R is CH ₂ OH: (a.1) a mixture A containing the enantiomers Ia and Ib, wherein R is CH ₂ OH, or a mixture B containing the enantiomers Ic and Id, wherein R is CH ₂ OH, with an acylating agent in the presence of a hydrolase; in the case of the mixture A, a mixture C is obtained in which one of the enans tiomere Ia or Ib is present in substantially acylated form and the other enantiomer is present substantially in non-acylated form, and wherein, in the case of the mixture B, a mixture D is obtained in which one of the enantiomers Ic or Id is present in substantially acylated form, and the other enantiomer is substantially in non-acylated form; (a.2) from the mixture C or from the mixture D separates the substantially non-acylated enantiomer; and (a.3), if desired, hydrolyzing the substantially acylated enantiomer obtained in step (a.1) to the corresponding non-acylated enantiomer; or (b) in the event that R is CH ₂ OH: (b.1) a mixture A containing the enantiomers Ia and Ib, wherein R is CH ₂ OH, or a mixture B containing the enantiomers Ic and Id, in which R is CH ₂ OH, with an acylating agent, wherein in the case of the mixture A, a mixture E is obtained in which both enantiomers Ia and Ib are present in substantially acylated form or wherein in the case of the mixture B is a mixture F in which both enantiomers Ic and Id are present in substantially acylated form; (b.2) the mixture E or the mixture F is hydrolyzed in the presence of a hydrolase, wherein, in the case of the mixture E, a mixture G is obtained in which one of the enantiomers Ia or Ib is present in substantially acylated form and the other enantiomer substantially is present in non-acylated form, and wherein, in the case of the mixture F, a mixture H is obtained in which one of the enantiomers Ic or Id is present in substantially acylated form and the other enantiomer is present in substantially non-acylated form; (b.3) from the mixture G or from the mixture H separates the substantially non-acylated enantiomer; and (b.4) if desired, hydrolyzing the substantially acylated enantiomer obtained in step (b.2) to the corresponding non-acylated enantiomer; or (c) in the event that R is COOH: (c.1) a mixture A containing the enantiomers Ia and Ib, in which R is COOH, or a mixture B, containing the enantiomers Ic and Id, where R is COOH, reacted with an alcohol in the presence of a hydrolase, wherein, in the case of the mixture A, a mixture is obtained in which one of the enantiomers Ia or Ib is present substantially in esterified form and the other enantiomer is present substantially in non-esterified form and in the case of the mixture B, obtaining a mixture K in which one of the enantiomers Ic or Id is substantially esterified and the other enantiomer is substantially unesterified; (c.2) from the mixture J or from the mixture K separates the substantially unesterified enantiomer; and (c.3) if desired, hydrolyzing the substantially esterified enantiomer obtained in step (c.1) to the corresponding unesterified enantiomer; or (d) when R is COOR ³ or CONR ⁴ R ⁵ : (d.1) a mixture A containing the enantiomers Ia and Ib, wherein R is COOR ³ or CONR ⁴ R ⁵ , or Mixture B, containing the enantiomers Ic and Id, wherein R is COOR ³ or CONR ⁴ R ⁵ , hydrolyzed in the presence of a hydrolase, wherein in the case of the mixture A, a mixture L is obtained in which one of the enantiomers Ia or Ib substantially is present in esterified or amidated form and the other enantiomer is present in substantially unesterified or non-amidated form, and wherein, in the case of the mixture B, a mixture M is obtained, in which one of the enantiomers Ic or Id is essentially in esterified or amidated form and the other enantiomer is substantially unesterified or non-amidated; (d.2) from the mixture L or from the mixture M separates the substantially unesterified or unamidated enantiomer; and (d.3) if desired, hydrolyzing the substantially esterified or amidated enantiomer obtained in step (d.1) to the corresponding unesterified or unamidated enantiomer. Process for the preparation of substantially enantiomerically pure compounds of the formulas Ia, Ib, Ic and / or Id, which are as defined in claim 1, wherein (a) in the case where R is CH ₂ OH: (a.1 ) a mixture A containing the enantiomers Ia and Ib, wherein R is CH ₂ OH, or a mixture B, containing the enantiomers Ic and Id, wherein R is CH ₂ OH, with an acylating agent in the presence of a hydrolase, wherein in the case of the mixture A, a mixture C is obtained in which one of the enantiomers Ia or Ib is present in substantially acylated form and the other enantiomer is substantially in non-acylated form, and in the case of the mixture B a mixture D is obtained, in which one of the enantiomers Ic or Id is substantially in acylated form and the other enantiomer is substantially in non-acylated form; (a.2) from the mixture C or from the mixture D separates the substantially non-acylated enantiomer; and (a.3), if desired, hydrolyzing the substantially acylated enantiomer obtained in step (a.1) to the corresponding non-acylated enantiomer; or (b) in the event that R is CH ₂ OH: (b.1) a mixture A containing the enantiomers Ia and Ib, wherein R is CH ₂ OH, or a mixture B containing the enantiomers Ic and Id, in which R is CH ₂ OH, with an acylating agent, wherein, in the case of the mixture A, a mixture E is obtained in which both enantiomers Ia and Ib are present in substantially acylated form or wherein in the case of the mixture B is a mixture F in which both enantiomers Ic and Id are present in substantially acylated form; (b.2) the mixture E or the mixture F is hydrolyzed in the presence of a hydrolase, wherein, in the case of the mixture E, a mixture G is obtained in which one of the enantiomers Ia or Ib is present in substantially acylated form and the other enantiomer substantially is present in non-acylated form, and wherein, in the case of the mixture F, a mixture H is obtained in which one of the enantiomers Ic or Id is present in substantially acylated form and the other enantiomer is present in substantially non-acylated form; (b.3) from the mixture G or from the mixture H separates the substantially non-acylated enantiomer; and (b.4) if desired, hydrolyzing the substantially acylated enantiomer obtained in step (b.2) to the corresponding non-acylated enantiomer; or (c) in the event that R is COOH: (c.1) a mixture A containing the enantiomers Ia and Ib, in which R is COOH, or a mixture B, containing the enantiomers Ic and Id, where R is COOH, reacted with an alcohol in the presence of a hydrolase, wherein, in the case of the mixture A, a mixture is obtained in which one of the enantiomers Ia or Ib is present substantially in esterified form and the other enantiomer is present substantially in non-esterified form and wherein, in the case of the mixture B, a mixture K is obtained in which one of the enantiomers Ic or Id is substantially in esterified form and the other enantiomer is substantially in unrecovered form; (c.2) from the mixture J or from the mixture K separates the substantially unesterified enantiomer; and (c.3) if desired, hydrolyzing the substantially esterified enantiomer obtained in step (c.1) to the corresponding unesterified enantiomer; or (d) when R is COOR ³ or CONR ⁴ R ⁵ : (d.1) a mixture A containing the enantiomers Ia and Ib, wherein R is COOR ³ or CONR ⁴ R ⁵ , or Mixture B, containing the enantiomers Ic and Id, wherein R is COOR ³ or CONR ⁴ R ⁵ , hydrolyzed in the presence of a hydrolase, wherein in the case of the mixture A, a mixture L is obtained in which one of the enantiomers Ia or Ib substantially is present in esterified or amidated form and the other enantiomer is present in substantially unesterified or non-amidated form, and wherein, in the case of the mixture B, a mixture M is obtained, in which one of the enantiomers Ic or Id is essentially in esterified or amidated form and the other enantiomer is substantially unesterified or non-amidated; (d.2) from the mixture L or from the mixture M separates the substantially unesterified or unamidated enantiomer; and (d.3), if desired, hydrolyzing the substantially esterified or amidated enantiomer obtained in step (d.1) to give the corresponding unesterified or non-amidated enantiomer and optionally derivatizing the group R. Method according to one of claims 11 or 12, wherein the Reaction in step (a.1) and (c.1) in a non-aqueous Reaction medium performs. Process according to any one of claims 11 to 13, wherein the acylating agent in step (a.1) is selected among the alkenyl esters of aliphatic mono- and dicarboxylic acids with 2 to 12 carbon atoms or of aromatic carboxylic acids, the anhydrides of monocarboxylic acids with 2 to 12 carbon atoms and the acid anhydrides of aliphatic dicarboxylic acids with 4 to 12 carbon atoms. Method according to one of claims 11 to 14, wherein the hydrolase in step (a.1), (b.2), (c.1) or (d.1) in the case where R is COOR ³ is selected under lipases from bacteria of the genus Burkholderia or Pseudomonas or from yeasts of the genus Candida. Method according to one of claims 11 or 12, wherein the hydrolase in step (d.1) in the case where R stands for CONR ⁴ R ^5, is selected from proteases. Compounds of the formulas Ia or Ib

wherein R is CHO, CH = NR ¹ , CH = NNR ² , COOR ³ , CONR ⁴ R ⁵ or CN; R ^{1 is} H, OH, C ₁ -C ₈ alkyl or aryl; R ^{2 is} H, C ₁ -C ₈ alkyl or aryl; R ^{3 is} C ₁ -C ₈ alkyl, C ₂ -C ₈ hydroxyalkyl or arylalkyl, and R ⁴ and R ^{5 are} independently H, C ₁ -C ₈ alkyl, C ₁ -C ₈ hydroxyalkyl, aryl or arylalkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated ring having 1 to 3 heteroatoms. Compounds of the formulas Ic or Id

wherein R is CH ₂ X, CHO, CH = NR ¹ , CH = NNR ² , COOH, COOR ³ , CONR ⁴ R ⁵ or CN; X is OH, O-SO ₂ R ⁶ or halogen; R ^{1 is} H, OH, C ₁ -C ₈ alkyl or aryl; R ^{2 is} H, C ₁ -C ₈ alkyl or aryl; R ^{3 is} C ₁ -C ₈ alkyl, C ₂ -C ₈ hydroxyalkyl or arylalkyl, R ⁴ and R ⁵ are each independently H, C ₁ -C ₈ alkyl, C ₁ -C ₈ hydroxyalkyl, aryl or Arylalkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated ring having 1 to 3 heteroatoms, and R ^{6 is} C ₁ -C ₈ -alkyl, C ₁ -C ₈ - Haloalkyl or aryl. Process for the preparation of compounds of the formulas IIIa or IIIb

which comprises a compound Ia or a compound Ib as defined in claim 17, wherein R is for CHO is subjected to a reductive amination in the presence of 1H- [1,2,4] triazole, to obtain the compound IIIa in the case of the compound Ia and the compound IIIb in the case of the compound Ib. The method of claim 19, wherein the reductive Amination carried out in the presence of Raney nickel. Method according to one of claims 19 or 20, wherein the compounds Ia or Ib according to the method in one of the claims 1 to 16 are obtained. Process for the preparation of compounds of the formulas IIIa or IIIb

which comprises a compound Ia or a compound Ib as defined in claim 17, wherein R is CONR ⁴ R ⁵ , wherein R ⁴ and R ^{5 taken} together with the nitrogen atom to which they are bonded form a [1,2,4 ] Triazol-1-ylring, to obtain the compound IIIa in the case of the compound Ia and the compound IIIb in the case of the compound Ib. The method of claim 22, wherein borane is used reduced. Method according to one of claims 22 or 23, wherein the compounds Ia or Ib according to the method in one of the claims 1 to 16 are obtained.