EP0968302A1 - Method for producing esters free of enantiomers - Google Patents

Method for producing esters free of enantiomers

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Publication number
EP0968302A1
EP0968302A1 EP98910636A EP98910636A EP0968302A1 EP 0968302 A1 EP0968302 A1 EP 0968302A1 EP 98910636 A EP98910636 A EP 98910636A EP 98910636 A EP98910636 A EP 98910636A EP 0968302 A1 EP0968302 A1 EP 0968302A1
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EP
European Patent Office
Prior art keywords
formula
alkyl
reaction
substituted
unsubstituted
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EP98910636A
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German (de)
French (fr)
Inventor
Friedhelm Balkenhohl
Stefan Koser
Nicholas John Holman
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BASF SE
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system

Definitions

  • the invention relates to a process for the preparation of enantiomerically pure esters.
  • Optimal racemate resolution should advantageously meet a number of conditions, such as:
  • WO 95/10521 claims 1, 2, 4-triazolo (1, 5-a) pyrimidines their chemical synthesis and their use in pharmaceutical preparations.
  • the object of the present invention was to develop a stereoselective synthesis to give intermediates of 1, 2, 4-triazolo (1, 5-a) pyrimidines, which advantageously provides these compounds with high optical purities and good chemical yields and which is easy Refurbishment of the products enables.
  • R 2 and R 3 independently of one another, water tof or substituted or unsubstituted C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkanoyl- C 1 -C 6 -alkyl thio-, C 1 -C 6 -alkylsulphinyl- or -CC 6 alkylsul - phonyl,
  • R 4 R 5 and, independently of one another, hydrogen or substituted or unsubstituted Ci-C ⁇ -alkyl- or R 4 and R 5 together with the carbon atoms to which they are attached form a substituted or unsubstituted C 3 -Cg-cycloalkylidene,
  • R6 has the meaning given above and R 7 is hydrogen or methyl, converted into compounds of the formula I, dissolved.
  • R 1 in the formulas I and II denotes hydrogen or substituted or unsubstituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy- or Cj . -C 6 -alkanoyl-
  • the radicals mentioned for R 1 have the following meaning, for example:
  • Alkyl branched or unbranched C 1 -C 6 -alkyl chains such as, for example, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2 -methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1st -Methylbutyl, 2 -methylbutyl, 3 -methylbutyl, 1, 1 -dimethylpropyl, 1, 2 -dimethylpropyl, 2, 2 -dimethylpropyl, 1-ethylpropyl, n-hexyl, 1 -methylpentyl, 2 -methylpentyl, 3 -methylpentyl, 4 -Methylpentyl, 1, 1 -dimethylbutyl,
  • Ci-C ⁇ alkoxy chains as mentioned above, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy , 2-methylbutoxy, 3-methylbuboxy, 1, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2, 2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy , 4-methylpentoxy, 1, 1-dimethylbutoxy, 1, 2-dimethylbutoxy, 1, 3-dimethylbutoxy, 2, 2-dimethylbutoxy, 2, 3-dirnethylboxy, 3, 3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1, 1, 2-trimethylpropoxy, 1, 2, 2-trimethylpropoxy, 1-ethyl-l-methylpropoxy or l-ethyl-2-methylprop
  • Alkanoyl branched or unbranched Ci-C ⁇ -alkanoyl chains such as methanoyl, ethanoyl, propanoyl, 1-methylethanoyl, butanoyl, 1-methylpropanoyl, 2-methylpropanoyl, 1, 1-dimethylethanoyl, pentanoyl, 1-methylbutanoyl, 2-methylbutanoyl noyl, 1, 1-dimethylpropanoyl, 1, 2-dimethylpropanoyl, 2, 2-wench - thylpropanoyl, 1-ethylpropanoyl, hexanoyl, 1-methylpentanoy, 1, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, 1, 1- Dimethylbutanoyl, 1, 2-dimethylbutanoyl, 1, 3-dimethylbutanoyl, 2, 2-dimethylbutanoyl, 2, 3-dimethylbutan
  • R 2 and R 3 in formulas I and II independently denote hydrogen or substituted or unsubstituted Ci -C 6 alkyl -, C x -C 6 alkoxy, Ci -C 6 alkanoyl -, -C-C 6 alkylthio -, Ci-C ⁇ - Alkylsulphinyl- or Ci-C ⁇ - Alkylsulphonyl-
  • R 2 and R 3 have, for example, the following meaning:
  • Alkyl branched or unbranched C 1 -C 6 -alkyl chains such as, for example, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2 -methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1st -Methylbutyl, 2 -methylbutyl, 3 -methylbutyl, 1, 1-dimethylpropyl, 1, 2 -dimethylpropyl, 2, 2 -dimethylpropyl, 1 -ethylpropyl, n-hexyl, 1 -methylpentyl, 2 -methylpentyl, 3 -methylpentyl, 4 -Methylpentyl, 1, 1 -dimethylbutyl,
  • Alkanoyl branched or unbranched C 1 -C 6 alkanoyl chains such as methanoyl, ethanoyl, propanoyl, 1-methylethanoyl, butanoyl, 1-methylpropanoyl, 2-methylpropanoyl, 1, 1-dimethylethanoyl, pentanoyl, 1-methylbutanoyl, 2-methylbutanoyl - noyl, 1, 1-dimethylpropanoyl, 1, 2-dimethylpropanoyl, 2,2-dimethylpropanoyl, 1-ethylpropanoyl, hexanoyl, 1-methylpentanoy, 1, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, 1 -Dimethylbutanoyl, 1, 2-Dimethylbutanoyl, 1, 3-Dimethylbutanoyl, 2, 2-Dimethylbutanoyl, 2, 3-Dimethylbutan
  • Alkylsulphinyl branched or unbranched C 1 -C 6 alkylsulphinyl chains such as methylsulphinyl, ethylsulphinyl, n-propylsulphinyl, 1-methylethylsulphinyl, n-butylsulphinyl, 1-methyl-propylsulphinyl, 2-methylpropylsulphinyl, 1, 1-dimethyl, 1, 1-dimethyl Pentylsulphinyl, 1-methylbutylsulphinyl, 2-methylbutylsulphinyl, 3-methylbutylsulphinyl, 1, 1-dimethylpropylsulphinyl, 1, 2-dimethylpropylsulphinyl, 2, 2-dimethylpropylsulphinyl, 1-ethylsulphinyl, 1-ethylsulphinyl, 1-ethylsulphinyl - thylpentylsulphinyl,
  • Alkylsulphonyl branched or unbranched C 1 -C 6 alkylsulphonyl chains such as methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, 1-methylethylsulphonyl, n-butylsulphonyl, 1-methylpro - pylsulphonyl, 2-methylpropylsulphonyl, 1-methylpropylsulphonyl -Pentylsulphonyl, 1-methylbutylsulphonyl, 2-methylbutylsulphonyl, 3-methylbutylsulphonyl, 1, 1-dimethylpropylsulphonyl, 1, 2-dimethylpropylsulphonyl, 2, 2-dimethylpropyl - sulphonyl, 1-ethyl-propyl-1-yl - thylpentylsulphonyl, 2-methylpentylsulphonyl,
  • halogen such as halogen, such as fluorine, chlorine, bromine, cyano ' , nitro, amino, thio, alkyl, alkoxy
  • R 4 and R 5 are not the same and in the formulas I and II independently denote hydrogen or substituted or unsubstituted Ci-C ⁇ -alkyl- or R 4 and R 5 together with the carbon atoms to which they are attached form a substituted or unsubstituted C 3 -C 6 allylid.
  • R 4 and R 5 have the following meaning, for example:
  • Ci -C ß alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl tyl, 1 -methylpropyl, 2 -methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1 -Methylbutyl, 2 -methylbutyl, 3 -methylbutyl, 1, 1-dimethylpropyl, 1, 2 -dimethylpropyl, 2, 2 -dimethylpropyl, 1-ethylpropyl, n-hexyl, 1 -methylpentyl, 2 -methylpentyl, 3 -methylpentyl, 4 -Methylpentyl, 1, 1-dimethylbutyl,
  • Cycloalkylidene branched or unbranched C 3 -C 6 cycloalkylidine chains such as cyclopropylidene, ethylcyclopropylidene, dirne - ethylcyclopropylidene, methylethylcyclopropylidene, cyclobutylidene, ethylcyclobutylidene, dimethylcyclobutylidene, cyclopentylidene or methylcyclopentylidene.
  • substituents such as halogen such as fluorine, chlorine, bromine, cyano, nitro, amino, thio, alkyl, alkoxy or aryl may be used as substituents of the alkyl or cycloalkylidene mentioned for R 4 and R 5 .
  • R 6 in the formulas I and III denotes substituted or unsubstituted aryl-, C 1 -C 2 o -alkyl -, Ci -C 2 o-alkenyl -, -C-C u -alkynyl- or -C-C 2 o- Alkoxy-C 2 o _ lkyl.
  • the radicals mentioned for R 6 have, for example, the following meaning:
  • Aryl simple or condensed aromatic ring systems which may can be substituted with one or more radicals such as halogen such as fluorine, chlorine or bromine, cyano, nitro, amino, thio, alkyl, alkoxy or other saturated or unsaturated non-aromatic rings or ring systems, or optionally with at least one further Ci -Cicj- Alkyl chain can be substituted or via a -C-C ⁇ o alkyl chain to the
  • Ci-C 2 o-alkyl chains such as, for example, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl -, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1 -Methylbutyl, 2 -methylbutyl, 3 -methylbutyl, 2, 2 -dimethylpropyl, 1 -ethylpropyl, n-hexyl, 1, 1 -dimethylpropyl, 1, 2 -dimethylpropyl, 1 -methylpentyl, 2 -methylpentyl, 3 -methylpentyl , 4-methylpentyl, 1, 1-dimethylbutyl,
  • Alkynyl branched or unbranched C 3 -C 20 -alkynyl chains such as, for example, prop-1-in-1-yl, prop-2-in-1-yl, n-but-1-in-1-yl, n-but- l-in-3-yl, n-but-1 - in-4 -yl, n-but -2 - in- 1 -yl, n-pent-1-in-l-yl, n-pent-1 - in-3 -yl, n-pent - 1 - in 4 -yl, n-pent-l-in-5-yl, n-pent-2 -in-l-yl, n- pent -2 - in- 4 -yl, n-pent-2-in-5-yl, 3-methyl-but-1 - in-3 -yl, 3-methyl-but-1 - in-4-yl, n-hex-1 - in- 1 -yl,
  • C ⁇ -alkoxy-C ⁇ -C ⁇ o-alkyl particularly preferably C ⁇ -C 6 alkoxy-Cx-Cs-alkyl very particularly preferably C ⁇ -C 4 alkoxy-C ⁇ -C 4 alkyl.
  • ⁇ - ⁇ -saturated alkoxyalkyl radicals are also preferred.
  • substituents such as halogen such as fluorine, chlorine, bromine, cyano, nitro, amino, thio, alkyl, alkoxy or aryl may be considered as substituents of the alkyl, alkenyl, alkynyl or alkoxyalkyl radicals mentioned for R 6 .
  • lipases or esterases of nomenclature class 3.1 - enzymes which react with ester bonds - are suitable for the process according to the invention.
  • lipases are preferred or esterases of microbial origin or porcine pancreatic lipase.
  • enzymes of microbial origin for example, enzymes from fungi, yeasts or bacteria such as, for example, from Alcaligenes sp., Achromobacter sp., Aspergillus niger, Bacillus subtilis, Candida cylindracea, Candida lypolytica, Candida antarctica, Candida sp. , Chromobacterium viscosum, Chromobacterium sp.
  • Lipases or esterases from Pseudomonas species such as Pseudomonas cepacia or Pseudomonas plantarii, from Candida species such as Candida cylidracea or Candida antarctica such as Novozym ® '"435 or porcine pancreatic lipase are particularly preferred.
  • Pseudomonas plantarii lipase Amano P ® Lipase ( Amano, Japan), NovozymSP523, SP524, SP525, SP526, SP539, SP435 (Novo, Denmark), Chirazyme ® Ll, L2, L3, L4, L5, L6, L7, L8, El (Boehringer Mannheim, Germany) , Swine pancreatic lipase or the lipase from Pseudomonas spec.DSM 8246.
  • the enzymes are used in the reaction directly or as immobilizates on a wide variety of carriers.
  • the amount of enzyme to be added depends on the type of starting material, product, vinyl ester and the activity of the enzyme preparation.
  • the optimal amount of enzyme for the reaction can easily be determined by simple preliminary tests.
  • the enzyme-substrate ratio calculated as the molar ratio between enzyme and substrate, is generally between 1: 1000 to 1: 50000000 or more, preferably 1: 100000 to 1: 5000000, that is, one can use, for example, 10 mg Enzyme 3 kg or more of a substrate with a molecular weight of about 100 to split into its enantiomers.
  • the enzymes can be used directly as free or immobilized enzymes in the reaction or, advantageously, after an activation step in an aqueous medium in the presence of a surface-active substance such as oleic acid, linoleic acid or linolenic acid and subsequent dewatering.
  • a surface-active substance such as oleic acid, linoleic acid or linolenic acid and subsequent dewatering.
  • the enzyme reaction can only be carried out in the presence of the vinyl esters (see formula III) as solvents without the addition of additional solvents or solvent mixtures.
  • further solvents or solvent mixtures are added to the reaction.
  • all apro- table or protic solvents All solvents which are inert in the reaction are suitable, ie they must not take part in the enzyme reaction.
  • primary or secondary alcohols, DMF, DMSO and water are unsuitable because side reactions can occur in the presence of these solvents - they are themselves enzyme substrates or lead to the hydrolysis of the esters - and / or the enzymes tend to stick together and thus the enzyme activity drastically decreases.
  • suitable solvents are pure aliphatic or aromatic hydrocarbons such as hexane, cyclohexane or toluene, halogenated hydrocarbons such as methylene chloride or chloroform, ethers such as MTBE, THF, diethyl ether, diisopropyl ether or dioxane, tertiary alcohols such as tert-butanol, tert. Pentyl alcohol or propylene carbonate, ethylene carbonate or acetonitrile called.
  • solvents or solvent mixtures particularly preferably in the presence of toluene, diethyl ether, diisopropyl ether or tert. Pentyl alcohol.
  • the solvents used should be as anhydrous as possible to prevent unspecific hydrolysis of the esters.
  • Molecular sieves or ammonium salts can advantageously be used to control the water activity in the reaction.
  • vinyl esters are suitable for the reaction, such as, for example, the vinyl esters of longer-chain fatty acids (C 2 to C 20 ) vinyl chloroacetate, vinyl acetate, vinyl propionate or vinyl butyrate, vinyl acetate, vinyl propionate or vinyl butyrate are preferred, vinyl propionate or vinyl butyrate are particularly preferably used.
  • the reaction is advantageously carried out at a temperature between 0 ° C. and 75 ° C., preferably between 10 ° C. and 60 ° C., particularly preferably between 15 ° C. and 50 ° C.
  • reaction times are between 1 and 72 hours. 1 to 3 moles of vinyl ester are added per mole of substrate to be reacted.
  • the course of the reaction can easily be followed using conventional methods, for example by means of gas chromatography.
  • the reaction is usefully terminated at a conversion of 50% of the racemic alcohol - maximum yield with maximum enantiomeric purity in theory -.
  • the reaction can be ended sooner or later, ie before or after reaching a conversion of 50% of the racemate. This is usually done by removing the catalyst from the reaction space, for example by filtering off the enzyme.
  • the ester (Ia) formed in the first reaction is the desired enantiomer, it is separated from the other reaction products (Ila and IV). This can be achieved, for example, by precipitation of the alcohol (Ila) in a non-polar solvent such as toluene and subsequent filtration. The ester remains in the organic phase, which is optionally extracted with water to remove the remaining alcohol.
  • the unwanted alcohol enantiomer can then either be racemized after removal of IV, for example by treatment in the basic and recycled, or else in a ner chemical reaction with inversion of the stereo center such as in a Mitsunobu reaction (see scheme I), or in a reaction with the formation of sulfonic anhydrides with mesylates, tosylates or brosylates and hydrolysis or reaction with carboxylates directly to the esters or in a reaction to form trichloroacetimidates and subsequent reaction with, for example, carboxylic acids or carboxylates, are converted into the desired enantiomer and then esterified.
  • a Mitsunobu reaction see scheme I
  • the ester (Ia) formed in the first reaction is the undesired enantiomer, it is separated from the other reaction products (Ila and IV) as described, for example, above.
  • the ester can then either be cleaved to give the alcohol (IIb) (reaction 2, aminolysis or hydrolysis), racemized and recycled (reaction 3) or cleaved and recycled with racemization (reaction 4) or after cleavage (reaction 2 ) are converted into the desired enantiomer of the alcohol (Ila) in a subsequent chemical reaction in which the stereo center is inverted (reaction 5).
  • the desired enantiomer of the alcohol (Ila) can finally be esterified to the desired ester (reaction 6).
  • the enzymes were weighed into screw-top jars.
  • the reaction was started by adding educt (V) and vinyl propionate (VI) in THF or MTBE / dioxane.
  • the batches were incubated at room temperature (23 ° C.) with stirring (magnetic stirrer, 150 rpm). After 4 h and 24 h, samples were taken for a DC analysis (DC analysis, mobile phase ethyl acetate: methanol, 10: 1, UV analysis).
  • the starting material (V) was introduced together with the vinyl propionate (VI) in THF.
  • the reaction was started by adding the enzyme. After 2, 4, 6, 8, 24, 28 and 96 h incubation at room temperature (23 ° C), samples were taken and the rotation value was determined. The reaction stopped after 96 hours, which means that after 96 hours there was none Shift more between the two enantiomers present in the reaction (ester and alcohol).
  • the mixture was incubated at room temperature (23 ° C.) with shaking (150 rpm).
  • the enantiomeric purity determined by HPLC for the ester was 97.5% ee and for the alcohol 60% ee with 38.1% conversion.
  • the sales and enantiomeric units were determined using further Chirazym® L4 and L6 enzymes.
  • the reaction was carried out under HPLC control and the reaction was stopped exactly at 49.2% conversion.

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Abstract

The invention relates to a method for producing enantiomer-free esters of formula (I) (Ia or Ib), where the substituents represent the following: R<1> is a hydrogen or a substituted or unsubstituted C1-C6-alkyl-, C1-C6-alkoxy-, or C1-C6-alkanoyl; R<2> and R<3> independently of each other are hydrogen or a substituted or unsubstituted C1-C6-alkyl-, C1-C6-alkoxy-, or C1-C6-alkanoyl-, C1-C6-alkylthio-, C1-C6-alkyl sulfinyl or C1-C6-alkyl sulfonyl-; R<4> is not equal to R<5> and independently of each other they are either hydrogen or an substituted or unsubstituted C1-C6-alkyl-, or together with the hydrogen atoms, to which they are bound, form a substituted or unsubstituted C3-C6-cyclo alkylidene; and R<6> is a substituted or unsubstituted aryl-, C1-C20-alkyl-, C3-C20-alkenyl-, C3-C20-alkynyl-, C1-C20-alkoxy-C1-C20-alkyl. The method is characterized in that racemic compounds of the formula (II), in which the substituents R<1> to R<5> have the meanings given above, are reacted with a lipase or esterase in the presence of vinyl esters of formula (III), where R<6> has the meaning given above and R<7> represents hydrogen or methyl, to form compounds of formula (I).

Description

Verfahren zur Herstellung von enantiomerenreinen EsternProcess for the preparation of enantiomerically pure esters
Beschreibungdescription
Die Erfindung betrifft ein Verfahren zur Herstellung von enantiomerenreinen Estern.The invention relates to a process for the preparation of enantiomerically pure esters.
In einer Vielzahl von Publikationen und Patenten werden kineti- sehe Racematspaltungen von Estern mit Lipasen und Esterasen beschrieben. Nur wenige Arbeiten sind zur Racematspaltung von Estern oder Alkoholen erschienen, die einen heteroaromatischen Rest tragen.A large number of publications and patents describe kinetic resolution of esters with lipases and esterases. Only a few papers have been published on the resolution of esters or alcohols bearing a heteroaromatic residue.
So wird beispielsweise von Akita et al. (Tetrahedron Lett.,For example, Akita et al. (Tetrahedron Lett.,
Vol. 27, No. 43, 1986: 5241 - 5244) die enantioselektive Hydrolyse von 3-Acetoxy-3- (2-Furyl) -2-methyl-propansäuremethylestern bzw. 3-Acetoxy-3- (2-Thienyl) -2-methyl-propansäuremethylestern mit einer Aspergillus niger Lipase beschrieben.Vol. 27, No. 43, 1986: 5241-5244) the enantioselective hydrolysis of methyl 3-acetoxy-3- (2-furyl) -2-methyl-propanoate or methyl 3-acetoxy-3- (2-thienyl) -2-methyl-propanoate with one Aspergillus niger lipase.
De Amici et al. beschreibt in J. Org. Chem. 1989, 54, 2646 - 2650 eine enzymatisch katalysierte Transesterifizierung mit Schweine- leberesterase, Candida cylindracea Lipase, Chymotrypsin, Subtili- sin, Schweinepankreaslipase und Lipase P.De Amici et al. in J. Org. Chem. 1989, 54, 2646-2650 describes an enzymatically catalyzed transesterification with porcine liver esterase, Candida cylindracea lipase, chymotrypsin, subtilisin, porcine pancreatic lipase and Lipase P.
Von Tsukamoto et al . (Tetrahedron Asym. , Vol. 2, No. 8, 1991: 759 - 762) wird die Synthese von (R) - und (S) -N, -Diethyl-2 , 2-di fluoro-3- (2-furyl) -3-hydroxypropionamid aus den entsprechenden Estern mit Candida cylindracea Lipase MY und P in Wasser be- schrieben.By Tsukamoto et al. (Tetrahedron Asym., Vol. 2, No. 8, 1991: 759-762) the synthesis of (R) - and (S) -N, -diethyl-2, 2-di fluoro-3- (2-furyl ) -3-hydroxypropionamide from the corresponding esters with Candida cylindracea lipase MY and P in water.
In DE/OS 3743824 und von Schneider et al. (Tetrahedron Asym. Vol. 3, No. 7, 1992: 827 - 830) wird die Herstellung von Pyri- dyl-1-ethanol beschrieben.In DE / OS 3743824 and by Schneider et al. (Tetrahedron Asym. Vol. 3, No. 7, 1992: 827-830) describes the preparation of pyridyl-1-ethanol.
Nachteil dieser Methoden ist die geringe Selektivität der Enzyme, die niedrigen erzielten Enantiomerenreinheiten der Produkte, die geringen chemischen Ausbeuten sowie die großen für die Umsetzung genötigten Enyzmmengen.The disadvantage of these methods is the low selectivity of the enzymes, the low enantiomeric purities of the products, the low chemical yields and the large amounts of enzyme required for the reaction.
Eine optimale Racematspaltung sollte vorteilhafterweise eine Reihe von Bedingungen erfüllen, wie beispielsweise:Optimal racemate resolution should advantageously meet a number of conditions, such as:
1. hohe Enantiomerenreinheit der Antipoden1. high enantiomeric purity of the antipodes
2. hohe chemische Ausbeute 3. hohe Selektivität des Enzyms2. high chemical yield 3. high selectivity of the enzyme
4. geringe Katalysatormengen (Enzymmengen)4. small amounts of catalyst (amounts of enzyme)
5. gute Löslichkeit von Edukt und Produkt unter Reaktionsbedingungen5. good solubility of starting material and product under reaction conditions
6. gute Raum-Zeit-Ausbeute6. good space-time yield
7. leichte Reinigung der Syntheseprodukte7. Easy cleaning of the synthesis products
8. kostengünstige Synthese8. Inexpensive synthesis
In WO 95/10521 werden 1 , 2 , 4-Triazolo (1, 5-a) pyrimidine ihre chemi - sehe Synthese und ihre Verwendung in pharmazeutischen Zubereitungen beansprucht .WO 95/10521 claims 1, 2, 4-triazolo (1, 5-a) pyrimidines their chemical synthesis and their use in pharmaceutical preparations.
Aufgabe der vorliegenden Erfindung war es, eine stereoselektiven Synthese zu Zwischenprodukten von 1, 2 , 4-Triazolo (1 , 5-a)pyrimidi- nen zu entwickeln, die diese Verbindungen vorteilhafterweise mit hohen optischen Reinheiten und guten chemischen Ausbeuten liefert und die eine leichte Aufarbeitung der Produkte ermöglicht.The object of the present invention was to develop a stereoselective synthesis to give intermediates of 1, 2, 4-triazolo (1, 5-a) pyrimidines, which advantageously provides these compounds with high optical purities and good chemical yields and which is easy Refurbishment of the products enables.
Diese Aufgabe wurde durch ein Verfahren zur Herstellung von enan- tiomerenreinen Estern der Formel I (Ia oder Ib)This object was achieved by a process for the preparation of enantiomerically pure esters of the formula I (Ia or Ib)
* = chiral, Ia oder Ib * = chiral, Ia or Ib
in der die Substituenten folgende Bedeutung haben:in which the substituents have the following meaning:
R1 R 1
Wasserstof f oder substituiertes oder unsubstituiertes Cι-C6-Hydrogen f or substituted or unsubstituted Cι-C 6 -
Alkyl- , Ci-Cö-Alkoxy- oder Cχ-C6-Alkanoyl- ,Alkyl, Ci-C ö alkoxy or Cχ-C 6 alkanoyl,
R2 und R3 unabhängig voneinander Wassers tof f oder substi tuiertes oder unsubsti tuiertes Cι-C6-Alkyl- , Cι-C6-Alkoxy- , Cι-C6-Alkanoyl- Cι-C6-Alkyl thio- , Cι-C6-Alkylsulphinyl- oder Cι-C6-Alkylsul - phonyl- ,R 2 and R 3 independently of one another, water tof or substituted or unsubstituted C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkanoyl- C 1 -C 6 -alkyl thio-, C 1 -C 6 -alkylsulphinyl- or -CC 6 alkylsul - phonyl,
R4 und R5 R 4 and R 5
R4 R5 und unabhängig voneinander Wasserstoff oder substituiertes oder unsubstituiertes Ci-Cδ-Alkyl- oder R4 und R5 bilden zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, ein substituiertes oder unsubstituiertes C3-Cg-Cy- cloalkyliden,R 4 R 5 and, independently of one another, hydrogen or substituted or unsubstituted Ci-Cδ-alkyl- or R 4 and R 5 together with the carbon atoms to which they are attached form a substituted or unsubstituted C 3 -Cg-cycloalkylidene,
R6 R 6
substi tuiertes oder unsubstituiertes Aryl- , Cι-C2o-Alkyl- , C3-C2o-Alkenyl- , C3-C20-Alkinyl- , Cι-C20-Alkoxy-Cι-C20-Alkyl-substi tuiertes or unsubstituted aryl, Cι-C 2 o alkyl, C 3 -C 2 o-alkenyl, C 3 -C 20 alkynyl, Cι-C -alkoxy-Cι-C 20 20 alkyl
dadurch gekennzeichnet, daß man racemische Verbindungen der Formel II,characterized in that racemic compounds of the formula II,
in der die Substituenten R1 bis R5 die oben genannten Bedeutungen haben, mit einer Lipase oder Esterase in Gegenwart von Vinylestern der Formel III,in which the substituents R 1 to R 5 have the meanings given above, with a lipase or esterase in the presence of vinyl esters of the formula III,
worin R6 die oben genannte Bedeutung hat und R7 Wasserstoff oder Methyl bedeutet, zu Verbindungen der Formel I umsetzt, gelöst .wherein R6 has the meaning given above and R 7 is hydrogen or methyl, converted into compounds of the formula I, dissolved.
R1 bezeichnet in den Formeln I und II Wasserstoff oder substituiertes oder unsubstituiertes Cι-C6 -Alkyl - , Ci -C6 -Alkoxy- oder Cj.-C6-Alkanoyl- Die für R1 genannten Reste haben beispielsweise folgende Bedeutung:R 1 in the formulas I and II denotes hydrogen or substituted or unsubstituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy- or Cj . -C 6 -alkanoyl- The radicals mentioned for R 1 have the following meaning, for example:
Alkyl verzweigte oder unverzweigte Cι-C6-Alkylketten, wie beispielsweise Methyl, Ethyl, n-Propyl, 1 -Methylethyl , n-Bu- tyl, 1-Methylpropyl, 2 -Methylpropyl , 1 , 1 -Dimethylethyl , n-Pentyl, 1 -Methylbutyl , 2 -Methylbutyl, 3 -Methylbutyl , 1, 1 -Dimethylpropyl, 1 , 2 -Dimethylpropyl , 2 , 2 -Dimethylpropyl , 1-Ethylpropyl, n-Hexyl, 1 -Methylpentyl , 2 -Methylpentyl , 3 -Methylpentyl, 4 -Methylpentyl , 1 , 1 -Dimethylbutyl ,Alkyl branched or unbranched C 1 -C 6 -alkyl chains, such as, for example, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2 -methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1st -Methylbutyl, 2 -methylbutyl, 3 -methylbutyl, 1, 1 -dimethylpropyl, 1, 2 -dimethylpropyl, 2, 2 -dimethylpropyl, 1-ethylpropyl, n-hexyl, 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 -Ethyl - butyl, 1, 1, 2 -Trimethylpropyl, 1, 2 , 2 -Trimethylpropyl , 1- Ethyl- 1-methylpropyl oder 1 -Ethyl - 2 -methylpropyl ,1, 2-dimethylbutyl, 1, 3 -dimethylbutyl, 2, 2 -dimethylbutyl, 2, 3 -dimethylbutyl, 3, 3 -dimethylbutyl, 1 -ethylbutyl, 2 -ethyl-butyl, 1, 1, 2 -trimethylpropyl, 1, 2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl,
Alkoxy verzweigte oder unverzweigte Ci-Cδ-Alkoxyketten wie vorstehend genannt z.B, Methoxy, Ethoxy, Propoxy, 1-Methyle- thoxy, Butoxy, 1-Methylpropoxy, 2-Methylpropoxy, 1,1-Dimethy- lethoxy, Pentoxy, 1-Methylbutoxy, 2-Methylbutoxy, 3-Methylbu- toxy, 1, 1-Dimethylpropoxy, 1 , 2-Dimethylpropoxy, 2 , 2-Dimethyl- propoxy, 1-Ethylpropoxy, Hexoxy, 1-Methylpentoxy, 2-Methyl - pentoxy, 3-Methylpentoxy, 4-Methylpentoxy, 1, 1-Dimethylbu- toxy, 1, 2-Dimethylbutoxy, 1, 3-Dimethylbutoxy, 2 , 2-Dimethylbu- toxy, 2 , 3-Dirnethylb toxy, 3, 3-Dimethylbutoxy, 1-Ethylbutoxy, 2-Ethylbutoxy, 1, 1 , 2-Trimethylpropoxy, 1, 2, 2-Trimethylpro- poxy, 1-Ethyl-l-methylpropoxy oder l-Ethyl-2-methylpropoxy,Alkoxy branched or unbranched Ci-C δ alkoxy chains as mentioned above, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy , 2-methylbutoxy, 3-methylbuboxy, 1, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2, 2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy , 4-methylpentoxy, 1, 1-dimethylbutoxy, 1, 2-dimethylbutoxy, 1, 3-dimethylbutoxy, 2, 2-dimethylbutoxy, 2, 3-dirnethylboxy, 3, 3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1, 1, 2-trimethylpropoxy, 1, 2, 2-trimethylpropoxy, 1-ethyl-l-methylpropoxy or l-ethyl-2-methylpropoxy,
Alkanoyl verzweigte oder unverzweigte Ci-Cβ-Alkanoylketten wie Methanoyl, Ethanoyl, Propanoyl, 1-Methylethanoyl, Butanoyl, 1-Methylpropanoyl, 2-Methylpropanoyl, 1, 1-Dimethylethanoyl, Pentanoyl, 1-Methylbutanoyl, 2-Methylbutanoyl, 3-Methylbuta- noyl, 1, 1-Dimethylpropanoyl, 1, 2-Dimethylpropanoyl , 2, 2-Dirne - thylpropanoyl, 1-Ethylpropanoyl, Hexanoyl , 1-Methylpentanoy, 1, 2-Methylpentanoyl, 3-Methylpentanoyl, 4-Methylpentanoyl, 1, 1-Dimethylbutanoyl, 1, 2-Dimethylbutanoyl, 1, 3-Dimethylbuta- noyl , 2 , 2-Dimethylbutanoyl, 2 , 3-Dimethylbutanoyl, 3,3-Dime- thylbutanoyl, 1-Ethylbutanoyl, 2-Ethylbutanoyl , 1,1,2-Trime- thylpropanoyl, 1 , 2 , 2-Trimethylpropanoyl, 1-Ethyl-l-methylpro- panoyl und l-Ξthyl-2-methylpropanoyl,Alkanoyl branched or unbranched Ci-Cβ-alkanoyl chains such as methanoyl, ethanoyl, propanoyl, 1-methylethanoyl, butanoyl, 1-methylpropanoyl, 2-methylpropanoyl, 1, 1-dimethylethanoyl, pentanoyl, 1-methylbutanoyl, 2-methylbutanoyl noyl, 1, 1-dimethylpropanoyl, 1, 2-dimethylpropanoyl, 2, 2-wench - thylpropanoyl, 1-ethylpropanoyl, hexanoyl, 1-methylpentanoy, 1, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, 1, 1- Dimethylbutanoyl, 1, 2-dimethylbutanoyl, 1, 3-dimethylbutanoyl, 2, 2-dimethylbutanoyl, 2, 3-dimethylbutanoyl, 3,3-dimethylbutanoyl, 1-ethylbutanoyl, 2-ethylbutanoyl, 1,1,2- Trimethylpropanoyl, 1, 2, 2-trimethylpropanoyl, 1-ethyl-l-methylpropanoyl and l-Ξthyl-2-methylpropanoyl,
Als Substituenten der für R1 genannten Reste Alkyl, Alkoxy oder Alkanoyl kommen ggf . ein oder mehrere Substituenten wie Halogen wie Fluor, Chlor, Brom, Cyano, Nitro, A ino, Thio, Alkyl, Alkoxy oder Aryl in Frage. R2 und R3 bezeichnen in den Formeln I und II unabhängig voneinander Wasserstoff oder substituiertes oder unsubstituiertes Ci -C6 -Alkyl - , Cx -C6 -Alkoxy- , Ci -C6 -Alkanoyl - , Cι-C6-Alkylthio-, Ci-Cδ-Alkylsulphinyl- oder Ci-Cδ-Alkylsulphonyl-As substituents of the alkyl, alkoxy or alkanoyl radicals mentioned for R 1 , if appropriate. one or more substituents such as halogen such as fluorine, chlorine, bromine, cyano, nitro, amino, thio, alkyl, alkoxy or aryl in question. R 2 and R 3 in formulas I and II independently denote hydrogen or substituted or unsubstituted Ci -C 6 alkyl -, C x -C 6 alkoxy, Ci -C 6 alkanoyl -, -C-C 6 alkylthio -, Ci-C δ- Alkylsulphinyl- or Ci-C δ- Alkylsulphonyl-
Die für R2 und R3 genannten Reste haben beispielsweise folgende Bedeutung: 'The radicals mentioned for R 2 and R 3 have, for example, the following meaning:
Alkyl verzweigte oder unverzweigte Cι-C6 -Alkylketten, wie beispielsweise Methyl, Ethyl, n-Propyl, 1 -Methylethyl , n-Bu- tyl, 1-Methylpropyl , 2 -Methylpropyl , 1 , 1 -Dimethylethyl , n-Pentyl, 1 -Methylbutyl , 2 -Methylbutyl, 3 -Methylbutyl , 1, 1-Dimethylpropyl, 1 , 2 -Dimethylpropyl , 2 , 2 -Dimethylpropyl , 1 -Ethylpropyl, n-Hexyl, 1 -Methylpentyl , 2 -Methylpentyl , 3 -Methylpentyl , 4 -Methylpentyl , 1 , 1 -Dimethylbutyl ,Alkyl branched or unbranched C 1 -C 6 -alkyl chains, such as, for example, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2 -methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1st -Methylbutyl, 2 -methylbutyl, 3 -methylbutyl, 1, 1-dimethylpropyl, 1, 2 -dimethylpropyl, 2, 2 -dimethylpropyl, 1 -ethylpropyl, n-hexyl, 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 -Ethyl - butyl, 1, 1, 2 -Trimethylpropyl, 1, 2 , 2 -Trimethylpropyl , 1 -Ethyl- 1 -methylpropyl oder 1 -Ethyl - 2 -methylpropyl ,1,2-dimethylbutyl, 1, 3 -dimethylbutyl, 2, 2 -dimethylbutyl, 2, 3 -dimethylbutyl, 3, 3 -dimethylbutyl, 1 -ethylbutyl, 2 -ethyl-butyl, 1, 1, 2 -trimethylpropyl, 1, 2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl,
Alkoxy verzweigte oder unverzweigte Cι-C6-Alkoxyketten wie vorstehend genannt z.B, Methoxy, Ethoxy, Propoxy, 1-Methyle- thoxy, Butoxy, 1-Methylpropoxy, 2-Methylpropoxy, 1, 1-Dimethy- lethoxy, Pentoxy, 1-Methylbutoxy, 2-Methylbutoxy, 3-Methylbu- toxy, 1, 1-Dimethylpropoxy, 1, 2-Dimethylpropoxy, 2 , 2-Dimethyl- propoxy, 1-Ethylpropoxy, Hexoxy, 1-Methylpentoxy, 2-Methyl - pentoxy, 3-Methylpentoxy, 4-Methylpentoxy, 1, 1-Dimethylbu- toxy, 1, 2-Dimethylbutoxy, 1, 3-Dimethylbutoxy, 2 , 2-Dimethylbu- toxy, 2 , 3-Dimethylbutoxy, 3 , 3-Dirnethylbutoxy, 1-Ethylbutoxy, 2-Ethylbutoxy, 1, 1, 2-Trimethylpropoxy, 1, 2, 2-Trimethylpro- poxy, 1-Ethyl-l-methylpropoxy oder l-Ethyl-2-methylpropoxy,Alkoxy branched or unbranched C-C 6 alkoxy chains as mentioned above, for example, methoxy, ethoxy, propoxy, 1-methylthoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1, 1-dimethylethoxy, pentoxy, 1-methylbutoxy , 2-methylbutoxy, 3-methylbuboxy, 1, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2, 2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy , 4-Methylpentoxy, 1, 1-Dimethylbutoxy, 1, 2-Dimethylbutoxy, 1, 3-Dimethylbutoxy, 2, 2-Dimethylbutoxy, 2, 3-Dimethylbutoxy, 3, 3-Dirnethylbutoxy, 1-Ethylbutoxy, 2nd Ethyl butoxy, 1, 1, 2-trimethylpropoxy, 1, 2, 2-trimethylpropoxy, 1-ethyl-1-methylpropoxy or 1-ethyl-2-methylpropoxy,
Alkanoyl verzweigte oder unverzweigte Cι-C6-Alkanoylketten wie Methanoyl, Ethanoyl, Propanoyl, 1-Methylethanoyl, Butanoyl, 1-Methylpropanoyl, 2-Methylpropanoyl, 1, 1-Dimethylethanoyl, Pentanoyl, 1-Methylbutanoyl, 2-Methylbutanoyl, 3-Methylbuta- noyl, 1, 1-Dimethylpropanoyl, 1 , 2-Dimethylpropanoyl , 2,2-Dime- thylpropanoyl, 1-Ethylpropanoyl, Hexanoyl, 1-Methylpentanoy, 1, 2-Methylpentanoyl, 3-Methylpentanoyl , 4-Methylpentanoyl , 1, 1-Dimethylbutanoyl, 1 , 2-Dimethylbutanoyl , 1 , 3-Dimethylbuta- noyl, 2 , 2-Dimethylbutanoyl, 2 , 3-Dimethylbutanoyl, 3, 3-Dirne - thylbutanoyl, 1-Ethylbutanoyl , 2-Ethylbutanoyl , 1, 1, 2-Trime- thylpropanoyl, 1 , 2 , 2-Trimethylpropanoyl, 1-Ethyl-l-methylpro- panoyl und l-Ethyl-2-methylpropanoyl, Alkylthio verzweigte oder unverzweigte Ci-Cβ-Alkylthioketten wie Methylthio, Ethylthio, n-Propylthio, 1-Methylethylthio, n-Butylthio, 1-Methylpropylthio, 2-Methylpropylthio, 1,1-Di- methylethylthio, n-Pentylthio, 1-Methylbutylthio, 2-Methylbu- tylthio, 3-Methylbutylthio, 2 , 2-Dimethylpropylthio, 1-Ethyl- propylthio, n-Hexylthio, 1, 1-Dimethylpropylthio, 1,2-Dime- thylpropylthio, 1-Methylpentylthio, 2-Methylpentylthio, 3-Me- thylpentyl hio, 4-Methylpentylthio, 1, 1-Dimethylbutylthio, 1, 2-Dimethylbutylthio, 1 , 3-Dimethylbutylthio, 2 , 2-Dimethylbu- tylthio, 2 , 3-Dimethylbutylthio, 3 , 3-Dimethylbutylthio,Alkanoyl branched or unbranched C 1 -C 6 alkanoyl chains such as methanoyl, ethanoyl, propanoyl, 1-methylethanoyl, butanoyl, 1-methylpropanoyl, 2-methylpropanoyl, 1, 1-dimethylethanoyl, pentanoyl, 1-methylbutanoyl, 2-methylbutanoyl - noyl, 1, 1-dimethylpropanoyl, 1, 2-dimethylpropanoyl, 2,2-dimethylpropanoyl, 1-ethylpropanoyl, hexanoyl, 1-methylpentanoy, 1, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, 1 -Dimethylbutanoyl, 1, 2-Dimethylbutanoyl, 1, 3-Dimethylbutanoyl, 2, 2-Dimethylbutanoyl, 2, 3-Dimethylbutanoyl, 3, 3-Dirne - thylbutanoyl, 1-ethylbutanoyl, 2-ethylbutanoyl, 1, 1 Trimethylpropanoyl, 1, 2, 2-trimethylpropanoyl, 1-ethyl-l-methylpropanoyl and l-ethyl-2-methylpropanoyl, Alkylthio branched or unbranched Ci-Cβ-alkylthio chains such as methylthio, ethylthio, n-propylthio, 1-methylethylthio, n-butylthio, 1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, n-pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 2, 2-dimethylpropylthio, 1-ethylpropylthio, n-hexylthio, 1, 1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylpentylthio, 2-methylpentylthio, 3- Methylpentyl hio, 4-Methylpentylthio, 1, 1-Dimethylbutylthio, 1, 2-Dimethylbutylthio, 1, 3-Dimethylbutylthio, 2, 2-Dimethylbutylthio, 2, 3-Dimethylbutylthio, 3, 3-Dimethylbutylthio,
1-Ethylbutylthio, 2-Ethylbutylthio, 1 , 1 , 2-Trimethylpropylt - hio, 1 , 2 , 2-Trimethylpropylthio, 1-Ethyl-l-methylpropylthio oder l-Ethyl-2-methylpropylthio,1-ethylbutylthio, 2-ethylbutylthio, 1, 1, 2-trimethylpropylt - hio, 1, 2, 2-trimethylpropylthio, 1-ethyl-l-methylpropylthio or l-ethyl-2-methylpropylthio,
Alkylsulphinyl verzweigte oder unverzweigte Cι-C6-Alkylsulphi- nylketten wie Methylsulphinyl, Ethylsulphinyl, n-Propylsul- phinyl, 1-Methylethylsulphinyl , n-Butylsulphinyl, 1-Methyl - propylsulphinyl, 2-Methylpropylsulphinyl, 1 , 1-Dimethylethyl - sulphinyl, n-Pentylsulphinyl, 1-Methylbutylsulphinyl, 2-Me- thylbutylsulphinyl , 3-Methylbutylsulphinyl , 1 , 1-Dimethylpro - pylsulphinyl , 1 , 2-Dimethylpropylsulphinyl , 2 , 2-Dimethylpro- pylsulphinyl, 1-Ethylpropylsulphinyl , n-Hexylsulphinyl , 1-Me- thylpentylsulphinyl, 2-Methylpentylsulphinyl , 3-Methylpentyl - sulphinyl, 4-Methylpentylsulphinyl , 1 , 1-Dimethylbutylsulphi - nyl, 1 , 2-Dimethylbutylsulphinyl, 1, 3-Dimethylbutylsulphinyl , 2 , 2-Dimethylbutylsulphinyl , 2 , 3-Dimethylbutylsulphinyl , 3 , 3-Dimethylbutylsulphinyl , 1-Ethylbutylsulphinyl , 2-Ethylbu- tylsulphinyl, 1 , 1 , 2-Trimethylpropylsulphinyl, 1,2,2-Trime- thylpropylsulphinyl, 1-Ethyl-l-methylpropylsulphinyl und l-Ethyl-2-methylpropylsulphinyl,Alkylsulphinyl branched or unbranched C 1 -C 6 alkylsulphinyl chains such as methylsulphinyl, ethylsulphinyl, n-propylsulphinyl, 1-methylethylsulphinyl, n-butylsulphinyl, 1-methyl-propylsulphinyl, 2-methylpropylsulphinyl, 1, 1-dimethyl, 1, 1-dimethyl Pentylsulphinyl, 1-methylbutylsulphinyl, 2-methylbutylsulphinyl, 3-methylbutylsulphinyl, 1, 1-dimethylpropylsulphinyl, 1, 2-dimethylpropylsulphinyl, 2, 2-dimethylpropylsulphinyl, 1-ethylsulphinyl, 1-ethylsulphinyl, 1-ethylsulphinyl - thylpentylsulphinyl, 2-methylpentylsulphinyl, 3-methylpentylsulphinyl, 4-methylpentylsulphinyl, 1, 1-dimethylbutylsulphi - nyl, 1, 2-dimethylbutylsulphinyl, 1, 3-dimethylbutylsulphinyl, 2, 2-dimethylbutylsulphinyl, 2, 2-dimethylbutylsulphinyl , 3-dimethylbutylsulphinyl, 1-ethylbutylsulphinyl, 2-ethylbutylsulphinyl, 1, 1, 2-trimethylpropylsulphinyl, 1,2,2-trimethylpropylsulphinyl, 1-ethyl-l-methylpropylsulphinyl and l-ethyl-2-methylpropylsulphinyl
Alkylsulphonyl verzweigte oder unverzweigte Cι-C6-Alkylsulpho- nylketten wie Methylsulphonyl, Ethylsulphonyl, n-Propylsulph- onyl, 1-Methylethylsulphonyl, n-Butylsulphonyl, 1-Methylpro - pylsulphonyl, 2-Methylpropylsulphonyl, 1, 1-Dimethylethylsul - phonyl, n-Pentylsulphonyl , 1-Methylbutylsulphonyl , 2-Methyl- butylsulphonyl, 3-Methylbutylsulphonyl, 1, 1-Dimethylpropyl- sulphonyl, 1, 2-Dimethylpropylsulphonyl, 2 , 2-Dimethylpropyl - sulphonyl, 1-Ethylpropylsulphonyl , n-Hexylsulphonyl, 1-Me- thylpentylsulphonyl, 2-Methylpentylsulphonyl , 3-Methylpentyl - sulphonyl, 4-Methylpentylsulphonyl , 1 , 1-Dimethylbutylsulpho- nyl, 1, 2-Dimethylbutylsulphonyl, 1, 3-Dimethylbutylsulphonyl , 2, 2-Dimethylbutylsulphonyl , 2, 3-Dimethylbutylsulphonyl , 3 , 3-Dimethylbutylsulphonyl, 1-Ethylbutylsulphonyl , 2-Ethylbu- tylsulphonyl, 1 , 1 , 2-Trimethylpropylsulphonyl , 1,2,2-Trime- thylpropylsulphonyl, 1-Ethyl-l-methylpropylsulphonyl und 1-Ethy1-2-methylpropylsulphonyl .Alkylsulphonyl branched or unbranched C 1 -C 6 alkylsulphonyl chains such as methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, 1-methylethylsulphonyl, n-butylsulphonyl, 1-methylpro - pylsulphonyl, 2-methylpropylsulphonyl, 1-methylpropylsulphonyl -Pentylsulphonyl, 1-methylbutylsulphonyl, 2-methylbutylsulphonyl, 3-methylbutylsulphonyl, 1, 1-dimethylpropylsulphonyl, 1, 2-dimethylpropylsulphonyl, 2, 2-dimethylpropyl - sulphonyl, 1-ethyl-propyl-1-yl - thylpentylsulphonyl, 2-methylpentylsulphonyl, 3-methylpentylsulfonyl, 4-methylpentylsulphonyl, 1, 1-dimethylbutylsulphonyl, 1, 2-dimethylbutylsulphonyl, 1, 3-dimethylbutylsulphonyl, 2, 2-dimethylbutyl, 2, 2-dimethylbutylbutyl , 3-dimethylbutylsulphonyl, 1-ethylbutylsulphonyl, 2-ethylbutylsulphonyl, 1, 1, 2-trimethylpropylsulphonyl, 1,2,2-trime- thylpropylsulphonyl, 1-ethyl-l-methylpropylsulphonyl and 1-ethyl-1-2-methylpropylsulphonyl.
Als Substituenten der für R2 und R3 genannten Reste Alkyl, Alkoxy, Alkanoyl, Alkylthio, Alkylsulphinyl oder Alkylsulphonyl kommen ggf. ein oder mehrere Substituenten wie Halogen wie Fluor, Chlor, Brom, Cyano', Nitro, Amino, Thio, Alkyl, Alkoxy oder Aryl in Frage.One or more substituents such as halogen such as halogen, such as fluorine, chlorine, bromine, cyano ' , nitro, amino, thio, alkyl, alkoxy may be used as substituents for the radicals alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl or alkylsulphonyl mentioned for R 2 and R 3 or aryl in question.
R4 und R5 sind ungleich und bezeichnen in den Formeln I und II unabhängig voneinander Wasserstoff oder substituiertes oder unsubstituiertes Ci-Cδ-Alkyl- oder R4 und R5 bilden zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, ein substituiertes oder unsubstitutiertes C3-C6-Alyliden.R 4 and R 5 are not the same and in the formulas I and II independently denote hydrogen or substituted or unsubstituted Ci-C δ -alkyl- or R 4 and R 5 together with the carbon atoms to which they are attached form a substituted or unsubstituted C 3 -C 6 allylid.
Die für R4 und R5 genannten Reste haben beispielsweise folgende Bedeutung :The radicals mentioned for R 4 and R 5 have the following meaning, for example:
Alkyl verzweigte oder unverzweigte Ci -Cß -Alkylketten, wie beispielsweise Methyl, Ethyl, n-Propyl, 1 -Methylethyl , n-Bu- tyl, 1 -Methylpropyl, 2 -Methylpropyl, 1 , 1 -Dimethylethyl , n-Pentyl, 1 -Methylbutyl, 2 -Methylbutyl, 3 -Methylbutyl, 1, 1-Dimethylpropyl, 1, 2 -Dimethylpropyl , 2, 2 -Dimethylpropyl, 1-Ethylpropyl, n-Hexyl, 1 -Methylpentyl, 2 -Methylpentyl, 3 -Methylpentyl, 4 -Methylpentyl, 1, 1-Dimethylbutyl,Alkyl branched or unbranched Ci -C ß alkyl chains, such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl tyl, 1 -methylpropyl, 2 -methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1 -Methylbutyl, 2 -methylbutyl, 3 -methylbutyl, 1, 1-dimethylpropyl, 1, 2 -dimethylpropyl, 2, 2 -dimethylpropyl, 1-ethylpropyl, n-hexyl, 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 -Ethyl - butyl, 1, 1, 2 -Trimethylpropyl, 1, 2 , 2 -Trimethylpropyl , 1 -Ethyl- 1 -methylpropyl oder 1 - Ethyl - 2 -methylpropyl ,1, 2 -dimethylbutyl, 1, 3 -dimethylbutyl, 2, 2 -dimethylbutyl, 2, 3 -dimethylbutyl, 3, 3 -dimethylbutyl, 1 -ethylbutyl, 2 -ethyl-butyl, 1, 1, 2 -trimethylpropyl, 1, 2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl,
Cycloalkyliden verzweigte oder unverzweigte C3-C6-Cycloalkyli- denketten wie Cyclopropyliden, Ethylcyclopropyliden, Dirne - thylcyclopropyliden, Methylethylcyclopropyliden, Cyclobutyli- den, Etyhlcyclobutyliden, Dimethylcyclobutyliden, Cyclopenty- liden oder Methylcyclopentyliden.Cycloalkylidene branched or unbranched C 3 -C 6 cycloalkylidine chains such as cyclopropylidene, ethylcyclopropylidene, dirne - ethylcyclopropylidene, methylethylcyclopropylidene, cyclobutylidene, ethylcyclobutylidene, dimethylcyclobutylidene, cyclopentylidene or methylcyclopentylidene.
Als Substituenten der für R4 und R5 genannten Reste Alkyl oder Cycloalkyliden kommen ggf. ein oder mehrere Substituenten wie Halogen wie Fluor, Chlor, Brom, Cyano, Nitro, Amino, Thio, Alkyl, AI - koxy oder Aryl in Frage.One or more substituents such as halogen such as fluorine, chlorine, bromine, cyano, nitro, amino, thio, alkyl, alkoxy or aryl may be used as substituents of the alkyl or cycloalkylidene mentioned for R 4 and R 5 .
R6 bezeichnet in den Formeln I und III substituiertes oder unsubstituiertes Aryl-, C1-C2o-Alkyl - , Ci -C2o-Alkenyl - , Cι-C u-Al- kinyl - oder Cι-C2o-Alkoxy-Cι-C2o_ lkyl- . ie für R6 genannten Reste haben beispielsweise folgende Bedeutung:R 6 in the formulas I and III denotes substituted or unsubstituted aryl-, C 1 -C 2 o -alkyl -, Ci -C 2 o-alkenyl -, -C-C u -alkynyl- or -C-C 2 o- Alkoxy-C 2 o _ lkyl. The radicals mentioned for R 6 have, for example, the following meaning:
Aryl einfache oder kondensierte aromatische Ringsysteme, die ggf . mit einem oder mehreren Resten wie Halogen wie Fluor, Chlor oder Brom, Cyano, Nitro, Amino, Thio, Alkyl, Alkoxy oder weiteren gesättigten oder ungesättigten nicht aromatischen Ringen oder Ringsystemen substituiert sein können, oder ggf. mit mindestens einer weiteren Ci -Cicj-Alkylkette substi- tuiert sein können oder über eine Cι-Cιo-Alkylkette an dasAryl simple or condensed aromatic ring systems, which may can be substituted with one or more radicals such as halogen such as fluorine, chlorine or bromine, cyano, nitro, amino, thio, alkyl, alkoxy or other saturated or unsaturated non-aromatic rings or ring systems, or optionally with at least one further Ci -Cicj- Alkyl chain can be substituted or via a -C-Cιo alkyl chain to the
Grundgerüst gebunden sind, bevorzugt sind als Arylrest Phenyl und Naphthyl ,Are backbone, phenyl and naphthyl are preferred as aryl radical,
Alkyl verzweigte oder unverzweigte Ci -C2o-Alkylketten, wie beispielsweise Methyl, Ethyl, n-Propyl, 1-Methylethyl, n-Butyl, 1 -Methylpropyl - , 2 -Methylpropyl , 1 , 1 -Dimethylethyl , n-Pentyl, 1 -Methylbutyl , 2 -Methylbutyl, 3 -Methylbutyl , 2, 2 -Dimethylpropyl, 1 -Ethylpropyl , n-Hexyl, 1 , 1 -Dimethyl - propyl , 1 , 2 -Dimethylpropyl , 1 -Methylpentyl, 2 -Methylpentyl , 3 -Methylpentyl, 4 -Methylpentyl , 1 , 1 -Dimethylbutyl ,Alkyl branched or unbranched Ci-C 2 o-alkyl chains, such as, for example, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl -, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1 -Methylbutyl, 2 -methylbutyl, 3 -methylbutyl, 2, 2 -dimethylpropyl, 1 -ethylpropyl, n-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 , n-Heptyl, n-Octyl, n-Nonyl, n-Decyl, n-Undecyl, n-Dodecyl, n-Tetrade- cyl, n-Hexadecyl, n-Octadecyl oder n-Eicosyl, bevorzugt sind Ci-Cs-Alkylketten besonders bevorzugt sind C2-C4-Alkylketten und ganz besonders bevorzugt substituierte C2-C4-Alkylketten (Substituenten siehe unten) wie Chlorethyl oder Methoxyethyl,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-trimethyl propyl, 1-ethyl -1-methyl propyl, 1-ethyl -2-methyl propyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-Hexadecyl, n-octadecyl or n-eicosyl, C 1 -C 4 -alkyl chains are particularly preferred, C 2 -C 4 -alkyl chains are particularly preferred and substituted C 2 -C 4 -alkyl chains are particularly preferred (see below for substituents) such as chloroethyl or methoxyethyl ,
Alkenyl verzweigte oder unverzweigte C3 -C20"Alkenylketten, wie beispielsweise Propenyl, 1-Butenyl, 2-Butenyl, 3-Butenyl, 2 -Methylpropenyl, 1-Pentenyl, 2-Pentenyl, 3-Pentenyl, 4-Pentenyl, 1 -Methyl- 1-butenyl, 2 Methyl-l -butenyl , 3 -Methyl -1 -butenyl, 1 -Methyl - 2 -butenyl, 2 -Methyl -2 -butenyl, 3 -Methyl -2 -butenyl, 1 -Methyl -3 -butenyl, 2 -Methyl -3 -butenyl, 3 -Methyl -3 -butenyl, 1, 1-Dimethyl -2 -propenyl, 1 , 2 -Dimethyl -1 - propenyl, 1, 2 -Dimethyl -2 -propenyl, 1 -Ethyl -1 -propenyl, 1- Ethyl -2 -propenyl, 1-Hexenyl, 2-Hexenyl, 3-Hexenyl, 4-Hexenyl, 5-Hexenyl, 1 -Methyl - 1 -pentenyl , 2-Methyl-l- penteny1 , 3 -Methyl - 1 -pentenyl , 4 -Methyl - 1 -pentenyl , 1 -Methyl -2 -pentenyl, 2 -Methyl -2 -pentenyl , 3 -Methyl -2- pentenyl, 4 -Methyl - 2 -pentenyl , 1 -Methyl - 3 -pentenyl , 2 -Methyl -3 -pentenyl, 3 -Methyl - 3 -pentenyl, 4 -Methyl -3- pentenyl, 1 -Methyl - -pentenyl , 2 -Methyl -4 -pentenyl ,Alkenyl branched or unbranched C 3 -C 20 "alkenyl chains, such as propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylpropenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- Methyl-1-butenyl, 2 methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl -2-butenyl, 3-methyl -2-butenyl, 1-methyl -3 -butenyl, 2 -methyl -3 -butenyl, 3 -methyl -3 -butenyl, 1, 1-dimethyl-2-propenyl, 1, 2 -dimethyl-1-propenyl, 1, 2 -dimethyl-2-propenyl, 1 -Ethyl -1-propenyl, 1-ethyl -2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl1 , 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1 -Methyl -3-pentenyl, 2-methyl -3-pentenyl, 3-methyl-3-pentenyl, 4-methyl -3-pentenyl, 1-methyl-pentenyl, 2-methyl -4-pentenyl,
3 -Methyl -4 -pentenyl, 4 -Methyl -4 -pentenyl, 1, 1 -Dimethyl - 2-butenyl, 1, 1 -Dimethyl - 3 -butenyl , 1 , 2 -Dimethyl - 1 -butenyl , 1, 2 -Dimethyl -2 -butenyl, 1 , 2 -Dimethyl -3 -butenyl , 1, 3 -Dimethyl - 1 -butenyl, 1, 3 -Dimethyl -2 -butenyl , 1, 3 -Dimethyl -3 -butenyl , 2, 2 -Dimethyl -3 -butenyl, 2, 3 -Dimethyl - 1 -butenyl , 2, 3 -Dimethyl - 2 -butenyl, 2 , 3 -Dimethyl -3 -butenyl , 3 , 3 -Dimethyl - 1 -butenyl , 3, 3 -Dimethyl -2 -butenyl, 1 -Ethyl - 1 -butenyl, 1 -Ethyl -2 -butenyl , 1 -Ethyl -3 -butenyl, 2 -Ethyl - 1 -butenyl , 2 -Ethyl -2 -butenyl , 2 -Ethyl -3 -butenyl, 1 , 1 , 2 -Trimethyl - 2 -propenyl , 1-Ethyl - 1- methyl -2 -propenyl, 1 -Ethyl -2 -methyl -1 -propenyl, 1 -Ethyl -2- methyl -2 -propenyl, 1-Heptenyl, 2-Heptenyl, 3-Heptenyl, 4-Heptenyl, 5-Heptenyl, 6-Heptenyl, 1-Octenyl, 2-Octenyl, 3-Octenyl, 4-Octenyl, 5-Octenyl, 6-Octenyl oder 7-Octenyl, bevorzugt sind ungesättigte Alkylketten, die sich von den natürlichen Fettsäuren ableiten lassen wie einfache oder mehrfach ungesättigte Cχ6-, Ci8~ oder C2o-Alkylketten,3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl -2-butenyl, 1,2-dimethyl -3-butenyl, 1,3-dimethyl -1-butenyl, 1,3-dimethyl -2-butenyl, 1,3-dimethyl -3-butenyl, 2,2-dimethyl -3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl -3-butenyl, 3,3-dimethyl-1-butenyl, 3, 3 -dimethyl -2-butenyl, 1-ethyl-1-butenyl, 1-ethyl -2-butenyl, 1-ethyl -3-butenyl, 2-ethyl-1-butenyl, 2-ethyl -2-butenyl, 2-ethyl -3-butenyl, 1, 1, 2-trimethyl - 2-propenyl, 1-ethyl - 1-methyl -2-propenyl, 1-ethyl -2-methyl -1-propenyl, 1-ethyl -2- methyl -2-propenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl or 7-octenyl, preferred are unsaturated alkyl chains which can be derived from natural fatty acids, such as simple or polyunsaturated Cχ 6 -, Ci 8 ~ or C 2 o-alkyl chains,
Alkinyl verzweigte oder unverzweigte C3 -C20 -Alkinylketten, wie beispielsweise Prop-1 - in- 1 -yl, Prop-2 -in- 1-yl , n-But-1-in- 1-yl, n-But-l-in-3-yl, n-But- 1 - in-4 -yl, n-But -2 - in- 1 -yl , n-Pent-1-in-l-yl, n-Pent- 1 - in-3 -yl , n- Pent - 1 - in- 4 -yl , n-Pent-l-in-5-yl, n-Pent-2 -in-l-yl, n- Pent -2 - in- 4 -yl , n-Pent-2-in-5-yl, 3 -Methyl -but- 1 - in-3 -yl, 3 -Methyl -but- 1 - in-4-yl, n-Hex-1 - in- 1 -yl , n-Hex-l-in-3 -yl, n-Hex-1- in-4 -yl, n-Hex-l-in-5-yl, n-Hex- 1 -in-6-yl, n-Hex-2 - in- 1 -yl , n-Hex-2- in-4-yl, n-Hex-2 - in- 5 -yl , n-Hex-2 -in- 6-yl , n-Hex- 3 - in- 1 -yl, n-Hex-3-in-2-yl, 3 -Methyl -pent- 1 - in- 1 -yl, 3 -Methyl -pent- 1 - in-3-yl, 3 -Methyl -pent- 1- in-4 -yl , 3 -Methyl-pent -1 - in- 5 -yl , 4 -Methyl -pent- 1- in- 1 -yl, 4 -Methyl -pent- 2 - in-4 -yl oder 4 -Methyl -pent-2 - in-5-yl, bevorzugt sind C -Cιrj-Alkinylketten besonders bevorzugt C3-C6-Alkinylketten.Alkynyl branched or unbranched C 3 -C 20 -alkynyl chains, such as, for example, prop-1-in-1-yl, prop-2-in-1-yl, n-but-1-in-1-yl, n-but- l-in-3-yl, n-but-1 - in-4 -yl, n-but -2 - in- 1 -yl, n-pent-1-in-l-yl, n-pent-1 - in-3 -yl, n-pent - 1 - in 4 -yl, n-pent-l-in-5-yl, n-pent-2 -in-l-yl, n- pent -2 - in- 4 -yl, n-pent-2-in-5-yl, 3-methyl-but-1 - in-3 -yl, 3-methyl-but-1 - in-4-yl, n-hex-1 - in- 1 -yl, n-hex-l-in-3 -yl, n-hex-1-in-4 -yl, n-hex-l-in-5-yl, n-hex-1 -in- 6-yl, n-Hex-2 - in- 1 -yl, n-Hex-2- in-4-yl, n-Hex-2 - in- 5 -yl, n-Hex-2 -in- 6- yl, n-hex-3 - in- 1 -yl, n-hex-3-in-2-yl, 3-methyl-pent-1 - in- 1 -yl, 3-methyl-pent-1 - in- 3-yl, 3-methyl-pent-1- in-4 -yl, 3-methyl-pent -1 - in 5 -yl, 4-methyl-pent-1-in-1-yl, 4-methyl - pent-2-yn-4-yl or 4-methyl-pent-2-yn-5-yl, preference is given to C -Crj alkynyl chains, particularly preferably C 3 -C 6 alkynyl chains.
Alkoxyalkyl verzweigte oder unverzweigte Cι-C2o-Alkoxy- ci"c 20"Alkylketten wie beispielsweise Methoxymethyl , Methoxye- thyl, Methoxypropyl , Ethoxymethyl, Propoxymethyl, 1-Methyle- thoxymethyl, Butoxymethyl , 1-Methylpropoxymethyl , 2-Methyl - propoxymethyl, 1, 1-Dimethylethoxymethyl , bevorzugt sindAlkoxyalkyl branched or unbranched C 1 -C 2 o-alkoxy c i " c 20 " alkyl chains such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, propoxymethyl, 1-methylthoxymethyl, butoxymethyl, 1-methylpropoxymethyl, 2-methylpropoxymethyl , 1, 1-Dimethylethoxymethyl, are preferred
Cι-Cιo-Alkoxy-Cι-Cιo-Alkyl , besonders bevorzugt Cι-C6-Alkoxy- Cx-Cs-Alkyl ganz besonders bevorzugt Cι-C4-Alkoxy-Cι-C4-Alkyl . Ebenfalls bevorzugt sind α-ß-gesättigte Alkoxyalkylreste.Cι-alkoxy-Cι-Cιo-alkyl, particularly preferably Cι-C 6 alkoxy-Cx-Cs-alkyl very particularly preferably Cι-C 4 alkoxy-Cι-C 4 alkyl. Α-β-saturated alkoxyalkyl radicals are also preferred.
Als Substituenten der für R6 genannten Reste Alkyl, Alkenyl, Alkinyl oder Alkoxyalkyl kommen ggf. ein oder mehrere Substituenten wie Halogen wie Fluor, Chlor, Brom, Cyano, Nitro, Amino, Thio, Alkyl, Alkoxy oder Aryl in Frage.One or more substituents such as halogen such as fluorine, chlorine, bromine, cyano, nitro, amino, thio, alkyl, alkoxy or aryl may be considered as substituents of the alkyl, alkenyl, alkynyl or alkoxyalkyl radicals mentioned for R 6 .
Für das erfindungsgemäße Verfahren sind prinzipiell alle Lipasen oder Esterasen der Nomenklaturklasse 3.1 - Enzyme die mit Esterbindungen reagieren - geeignet. Bevorzugt werden jedoch Lipasen oder Esterasen mikrobiellen Ursprungs oder Schweinepankreasli- pase. Als Enzyme mikrobiellen Ursprungs seinen beispielsweise Enzyme aus Pilzen, Hefen oder Bakterien wie beispielsweise von AI - caligenes sp., Achromobacter sp., Aspergillus niger, Bacillus subtilis, Candida cylindracea, Candida lypolytica, Candida an- tarctica, Candida sp. , Chromobacterium viscosum, Chromobacterium sp . , Geotri'chum candidum, Humicola lanuginosa, Mucor miehei, Pe- nicillium camemberti, Penicillium roqueforti, Phycomyces nitens, Pseudomonas cepacia, Pseudomonas glumae, Pseudomonas fluorescens, Pseudomonas plantarii, Pseudomonas aeruginosa, Pseudomonas sp., Rhizopus arrhizus, Rhizopus delemar, Rhizopus japanicus, Rhizopus niveus, Rhizopus oryzae oder Rhizopus sp . genannt. Besonders bevorzugt werden Lipasen oder Esterasen aus Pseudomonas-Arten wie Pseudomonas cepacia oder Pseudomonas plantarii, aus Candida-Arten wie Candida cylidracea oder Candida antarctica wie Novozym®' "435 oder Schweinepankreaslipase. Ganz besonders bevorzugt werden Pseudomonas plantarii-Lipase, Amano P® Lipase (Firma Amano, Japan) , NovozymSP523, SP524, SP525, SP526, SP539, SP435 (Firma Novo, Dänemark), Chirazyme®Ll , L2, L3 , L4 , L5, L6 , L7 , L8, El (Firma Boehringer Mannheim, Deutschland) , Schweinepankreaslipase oder die Lipase aus Pseudomonas spec. DSM 8246.In principle, all lipases or esterases of nomenclature class 3.1 - enzymes which react with ester bonds - are suitable for the process according to the invention. However, lipases are preferred or esterases of microbial origin or porcine pancreatic lipase. As enzymes of microbial origin, for example, enzymes from fungi, yeasts or bacteria such as, for example, from Alcaligenes sp., Achromobacter sp., Aspergillus niger, Bacillus subtilis, Candida cylindracea, Candida lypolytica, Candida antarctica, Candida sp. , Chromobacterium viscosum, Chromobacterium sp. , Geotri'chum candidum, Humicola lanuginosa, Mucor miehei, Penicillium camemberti, Penicillium roqueforti, Phycomyces nitens, Pseudomonas cepacia, Pseudomonas glumae, Pseudomonas fluorescens, Pseudomonas plantarii, Pseudomonas aerizususizopususopomizususopomizususopomizusopia, pseudomonas aeropus, Pseudomonas aerizususopomizususopia, pseudomonas aeropus, pseudomonas aeropus, pseudomonas aerizususizopomusus, pseudomonas aeropus, pseudomonas aerizususizopus, pseudomonas aeropus, pseudomonas aeropus, pseudomonas aeropus, pseudomonas aerizususizopus, pseudomonas aeropus, pseudomonas aeropus, pseudomonas aeropus, pseudomonas aeropus, pseudomonas aeropus, pseudomonas aeropus, pseudomonas aeropus, pseudomonas aericusus, piz , Rhizopus niveus, Rhizopus oryzae or Rhizopus sp. called. Lipases or esterases from Pseudomonas species such as Pseudomonas cepacia or Pseudomonas plantarii, from Candida species such as Candida cylidracea or Candida antarctica such as Novozym ® '"435 or porcine pancreatic lipase are particularly preferred. Pseudomonas plantarii lipase, Amano P ® Lipase ( Amano, Japan), NovozymSP523, SP524, SP525, SP526, SP539, SP435 (Novo, Denmark), Chirazyme ® Ll, L2, L3, L4, L5, L6, L7, L8, El (Boehringer Mannheim, Germany) , Swine pancreatic lipase or the lipase from Pseudomonas spec.DSM 8246.
Die Enzyme werden in der Reaktion direkt oder als Immobilisate an unterschiedlichsten Trägern eingesetzt. Die zuzusetzende Enzym- menge hängt von der Art des Edukt, Produkts, des Vinylesters und der Akitivität der Enzympräparation ab. Die für die Reaktion optimale Enzymmenge kann leicht durch einfache Vorversuche ermittelt werden. Je nach Enzym liegt das Enzym-Substratverhältnis berechnet als Molverhältnis zwischen Enzym und Substrat in der Re- gel zwischen 1:1000 bis 1:50000000 oder mehr, bevorzugt 1:100000 bis 1:5000000, daß heißt, man kann beispielsweise mit 10 mg eines Enzyms 3 kg oder mehr eines Substrat mit einem Molgewicht von ca. 100 in seine Enantiomeren zu spalten. Die Enantioselektivität (= E) der Enzyme liegt dabei in der Regel vorteilhafterweise zwi- sehen 20 bis 1000.The enzymes are used in the reaction directly or as immobilizates on a wide variety of carriers. The amount of enzyme to be added depends on the type of starting material, product, vinyl ester and the activity of the enzyme preparation. The optimal amount of enzyme for the reaction can easily be determined by simple preliminary tests. Depending on the enzyme, the enzyme-substrate ratio, calculated as the molar ratio between enzyme and substrate, is generally between 1: 1000 to 1: 50000000 or more, preferably 1: 100000 to 1: 5000000, that is, one can use, for example, 10 mg Enzyme 3 kg or more of a substrate with a molecular weight of about 100 to split into its enantiomers. The enantioselectivity (= E) of the enzymes is generally advantageously between 20 and 1000.
Die Enzyme können direkt als freie oder immobilisierte Enzyme in der Reaktion verwendet werden oder aber vorteilhafterweise nach einem Aktivierungsschritt in wäßrigem Medium in Gegenwart einer oberflächenaktiven Substanz wie Ölsäure, Linolsäure oder Linolen- säure und anschließender Entwässerung.The enzymes can be used directly as free or immobilized enzymes in the reaction or, advantageously, after an activation step in an aqueous medium in the presence of a surface-active substance such as oleic acid, linoleic acid or linolenic acid and subsequent dewatering.
Die Enzymreaktion kann ohne Zugabe zusätzlicher Lösungsmittel oder Lösungsmittelgemische nur in Gegenwart der Vinylester (siehe Formel III) als Lösungsmittel durchgeführt werden. Vorteilhafter - weise werden der Reaktion weitere Lösungsmittel oder Lösungsmittelgemische zugesetzt. Prinzipiell eignen sich hierfür alle apro- tischen oder protischen Lösungsmittel. Geeignet sind alle Lösungsmittel, die in der Reaktion inert sind, daß heißt sie dürfen an der Enzymreaktion nicht teilnehmen. Ungeeignet sind beispielsweise primäre oder sekundäre Alkohole, DMF, DMSO sowie Wasser, da in Gegenwart dieser Lösungsmittel Nebenreaktionen auftreten können - sie sind selber Enzymsubstrate oder führen zur Hydrolyse der Ester - und/oder die Enzyme zur Verklebung neigen und so die Enyzmaktivität drastisch abnimmt. DMF und DMSO führen bei längeren Reaktionen zu Schädigungen der Enzyme, vermutlich durch Ent- fernen der Hydrathülle um die Enzyme. Als geeignete Lösungsmittel seien hier beispielsweise reine aliphatische oder aromatische Kohlenwasserstoffe wie Hexan, Cyclohexan oder Toluol, haloge- nierte Kohlenwasserstoffe wie Methylenchlorid oder Chloroform, Ether wie MTBE, THF, Diethylether , Diisopropylether oder Dioxan, tertiäre Alkohole wie tert-Butanol, tert. Pentylalkohol oder Pro - pylencarbonat, Ethylencarbonat oder Acetonitril genannt. Vorteilhafterweise wird in Gegenwart zusätzlicher Lösungsmittel oder Lösungsmittelgemische gearbeitet, besonders bevorzugt in Gegenwart von Toluol, Diethylether, Diisopropylether oder tert. Pentylalko- hol. Die verwendeten Lösungsmittel sollten dabei möglichst wasserfrei sein, um eine unspezifische Hydrolyse der Ester zu verhindern. Zur Kontrolle der Wasseraktivität in der Reaktion können vorteilhafterweise Molsiebe oder Ammoniumsalze verwendet werden.The enzyme reaction can only be carried out in the presence of the vinyl esters (see formula III) as solvents without the addition of additional solvents or solvent mixtures. Advantageously, further solvents or solvent mixtures are added to the reaction. In principle, all apro- table or protic solvents. All solvents which are inert in the reaction are suitable, ie they must not take part in the enzyme reaction. For example, primary or secondary alcohols, DMF, DMSO and water are unsuitable because side reactions can occur in the presence of these solvents - they are themselves enzyme substrates or lead to the hydrolysis of the esters - and / or the enzymes tend to stick together and thus the enzyme activity drastically decreases. In longer reactions, DMF and DMSO lead to damage to the enzymes, presumably by removing the hydration shell around the enzymes. Examples of suitable solvents here are pure aliphatic or aromatic hydrocarbons such as hexane, cyclohexane or toluene, halogenated hydrocarbons such as methylene chloride or chloroform, ethers such as MTBE, THF, diethyl ether, diisopropyl ether or dioxane, tertiary alcohols such as tert-butanol, tert. Pentyl alcohol or propylene carbonate, ethylene carbonate or acetonitrile called. It is advantageous to work in the presence of additional solvents or solvent mixtures, particularly preferably in the presence of toluene, diethyl ether, diisopropyl ether or tert. Pentyl alcohol. The solvents used should be as anhydrous as possible to prevent unspecific hydrolysis of the esters. Molecular sieves or ammonium salts can advantageously be used to control the water activity in the reaction.
Für die Reaktion sind prinzipiell alle Vinylester geeignet wie beispielsweise die Vinylester längerkettiger Fettsäuren (Cι2 bis C20) Chloressigsäurevinylester, Vinylacetat, Vinylpropionat oder Vinylbutyrat , bevorzugt werden Vinylacetat, Vinylpropionat oder Vinylbutyrat , besonders bevorzugt werden Vinylpropionat oder Vi- nylbutyrat verwendet.In principle, all vinyl esters are suitable for the reaction, such as, for example, the vinyl esters of longer-chain fatty acids (C 2 to C 20 ) vinyl chloroacetate, vinyl acetate, vinyl propionate or vinyl butyrate, vinyl acetate, vinyl propionate or vinyl butyrate are preferred, vinyl propionate or vinyl butyrate are particularly preferably used.
Die Reaktion wird vorteilhafterweise bei einer Temperatur zwischen 0 °C und 75 °C durchgeführt, bevorzugt zwischen 10 °C und 60 °C, besonders bevorzugt zwischen 15 °C und 50 °C.The reaction is advantageously carried out at a temperature between 0 ° C. and 75 ° C., preferably between 10 ° C. and 60 ° C., particularly preferably between 15 ° C. and 50 ° C.
Die Reaktionszeiten betragen je nach Substrat, Ester und Enzym zwischen 1 bis 72 Stunden. Pro Mol umzusetzendes Substrat werden 1 bis 3 Mol Vinylester zugesetzt.Depending on the substrate, ester and enzyme, the reaction times are between 1 and 72 hours. 1 to 3 moles of vinyl ester are added per mole of substrate to be reacted.
Der Reaktionsverlauf läßt sich leicht mit üblichen Methoden beispielsweise mittels Gaschromatographie verfolgen. Die Reaktion wird sinnvollerweise bei einem Umsatz von 50% des racemischen Alkohols beendet - maximale Ausbeute bei maximaler Enantiomeren- reinheit in der Theorie -. Zur Erhöhung der Enantiomerenreinheit kann die Reaktion früher oder später, daß heißt vor oder nach dem Erreichen eines Umsatzes von 50% des Racemats, beendet werden. Dies geschieht in der Regel durch Entfernen des Katalysators aus dem Reaktionsraum, beispielsweise durch Abfiltrieren des Enzyms.The course of the reaction can easily be followed using conventional methods, for example by means of gas chromatography. The reaction is usefully terminated at a conversion of 50% of the racemic alcohol - maximum yield with maximum enantiomeric purity in theory -. To increase the enantiomeric purity, the reaction can be ended sooner or later, ie before or after reaching a conversion of 50% of the racemate. This is usually done by removing the catalyst from the reaction space, for example by filtering off the enzyme.
Je nach Enzym wird der R- oder S-Ester (siehe Formel I, An- spruch 1 sowie Formeln Ia und Ib in Schema I, die die einzelnen Enantiomeren darstellen) selktiv gebildet. Das jeweils andere Enantiomer wird nicht umgesetzt und bleibt unverändert auf der Alkoholstufe zurück (siehe Formeln Ha und Ilb in Schema I, die die beiden Enantiomere der Alkohole darstellen) . Schema I zeigt beispielhaft die Synthese für ein Enantiomer des Esters in Reaktion 1. sowie die möglichen weiteren Syntheseverfahren zur Umwandlung des falschen Enantiomeren in das gewünschte Enantiomer in den Reaktionen 2 bis 6. Depending on the enzyme, the R or S ester (see formula I, claim 1 and formulas Ia and Ib in Scheme I, which represent the individual enantiomers) is formed selectively. The other enantiomer is not converted and remains unchanged at the alcohol level (see formulas Ha and Ilb in Scheme I, which represent the two enantiomers of the alcohols). Scheme I shows an example of the synthesis for an enantiomer of the ester in reaction 1 and the possible further synthetic processes for converting the wrong enantiomer into the desired enantiomer in reactions 2 to 6.
Schema I Verfahren zur Herstellung von enantiomerenreinen Estern der Formel I (R-Enantiomer oder S-Enantiomer , Ia oder Ib)Scheme I Process for the preparation of enantiomerically pure esters of the formula I (R-enantiomer or S-enantiomer, Ia or Ib)
:ιib): ιib)
Handelt es sich bei dem in der ersten Reaktion (Schema I) entstehenden Ester (Ia) um das gewünschte Enantiomer, so wird dieser von den weiteren Reaktionsprodukten (Ila und IV) abgetrennt. Dies kann beispielsweise durch Ausfällung des Alkohols (Ila) in einem unpolaren Lösungsmittel wie Toluol und anschließender Filtration erreicht werden. Der Ester bleibt in der organischen Phase, diese wird gegebenenfalls mit Wasser extrahiert, um den restlichen Al- kohol zu entfernen. Das unerwünschte Alkoholenantiomer kann dann entweder nach Entfernen von IV racemisiert beispielsweise durch Behandlung im Basischen und rückgeführt werden, oder aber in ei- ner chemischen Reaktion unter Inversion des Stereozentrums wie beispielsweise in einer Mitsunobu-Reaktion (siehe Schema I) , oder in einer Reaktion unter Bildung von Sulfonsäureanhydriden mit Me- sylaten, Tosylaten oder Brosylaten und Hydrolyse oder Umsetzung mit Carboxylaten direkt zu den Estern umgesetzt werden oder in einer Reaktion unter Bildung von Trichloracetimidaten und anschließender Umsetzung mit beispielsweise Carbonsäuren oder Carboxylaten, in das gewünschte Enantiomer überführt und anschließend verestert werden.If the ester (Ia) formed in the first reaction (Scheme I) is the desired enantiomer, it is separated from the other reaction products (Ila and IV). This can be achieved, for example, by precipitation of the alcohol (Ila) in a non-polar solvent such as toluene and subsequent filtration. The ester remains in the organic phase, which is optionally extracted with water to remove the remaining alcohol. The unwanted alcohol enantiomer can then either be racemized after removal of IV, for example by treatment in the basic and recycled, or else in a ner chemical reaction with inversion of the stereo center such as in a Mitsunobu reaction (see scheme I), or in a reaction with the formation of sulfonic anhydrides with mesylates, tosylates or brosylates and hydrolysis or reaction with carboxylates directly to the esters or in a reaction to form trichloroacetimidates and subsequent reaction with, for example, carboxylic acids or carboxylates, are converted into the desired enantiomer and then esterified.
Handelt es sich bei dem in der ersten Reaktion (Schema I) entstehenden Ester (Ia) um das unerwünschte Enantiomer, so wird dieses wie beispielsweise oben beschrieben von den weiteren Reaktions- produkten (Ila und IV) abgetrennt. Der Ester kann dann entweder unter Erhalt der Stereochemie zum Alkohol (Ilb) gespalten (Reaktion 2, Aminolyse oder Hydrolyse), racemisiert und rückgeführt werden (Reaktion 3) oder unter Racemisierung gespalten und rückgeführt werden (Reaktion 4) oder aber nach Spaltung (Reaktion 2) in einer anschließenden chemischen Reaktion, in der das Stereo - Zentrum invertiert wird, in das gewünschte Enantiomer des Alkohols (Ila) überführt werden (Reaktion 5) . Das erwünschte Enantiomer des Alkohols (Ila) läßt sich schließlich zum gewünschten Ester verestern (Reaktion 6) .If the ester (Ia) formed in the first reaction (Scheme I) is the undesired enantiomer, it is separated from the other reaction products (Ila and IV) as described, for example, above. The ester can then either be cleaved to give the alcohol (IIb) (reaction 2, aminolysis or hydrolysis), racemized and recycled (reaction 3) or cleaved and recycled with racemization (reaction 4) or after cleavage (reaction 2 ) are converted into the desired enantiomer of the alcohol (Ila) in a subsequent chemical reaction in which the stereo center is inverted (reaction 5). The desired enantiomer of the alcohol (Ila) can finally be esterified to the desired ester (reaction 6).
BeispieleExamples
Beispiele 1 bis 10Examples 1 to 10
Die entsprechend dem Schema II verwendeten Enzyme wurden nach folgendem Ansatz getestet:The enzymes used in accordance with Scheme II were tested using the following approach:
0,25 mmol Edukt 2,0 ml THF oder MTBE,Dioxan 0,25 mmol Vinylpropionat 25 mg Enzym0.25 mmol educt 2.0 ml THF or MTBE, dioxane 0.25 mmol vinyl propionate 25 mg enzyme
Schema II Stereoselektive Veresterung mit VinylesternScheme II Stereoselective esterification with vinyl esters
Für die Kurztests wurden die Enzyme in Schraubverschlußgläser eingewogen. Die Reaktion wurde durch Zugabe von Edukt (V) und Vinylpropionat (VI) in THF oder MTBE/Dioxan gestartet. Die Ansätze wurden bei Raumtemperatur (23 °C) unter Rühren (Magnetrührer, 150 rpm) inkubiert. Nach 4 h und 24 h wurden Proben für eine DC-Ana - lytik gezogen (DC-Analytik, Laufmittel Essigester : Methanol, 10:1, UV-Analyse) . Von Ansätzen, die in diesem Schnelltest Umsatz zeigten, wurde der Drehwert bestimmt (Drehwertmessung: [α] 25°C/Na in Ethanol, c = 1) . For the short tests, the enzymes were weighed into screw-top jars. The reaction was started by adding educt (V) and vinyl propionate (VI) in THF or MTBE / dioxane. The batches were incubated at room temperature (23 ° C.) with stirring (magnetic stirrer, 150 rpm). After 4 h and 24 h, samples were taken for a DC analysis (DC analysis, mobile phase ethyl acetate: methanol, 10: 1, UV analysis). The rotation value was determined from batches which showed conversion in this rapid test (rotation value measurement: [α] 25 ° C./Na in ethanol, c = 1).
Tabelle I: Mit verschiedenen Enzymen ermittelte DrehwerteTable I: Rotational values determined with various enzymes
Im Schnelltest (Versuche 1 bis 10) wurden sehr unterschiedliche Aktivitäten der Enzyme im Test mit Vinylpropionat und dem Edukt ermittelt. Beide Enantiomere werden gebildetIn the rapid test (experiments 1 to 10), very different activities of the enzymes were determined in the test with vinyl propionate and the educt. Both enantiomers are formed
Beispiel 11Example 11
Zur Ermittelung der Kinetik der Enantiomerenbildung wurde folgen - der größerer Ansatz mit dem besten Enzym aus den Versuchen 1 bis 10 (Chirazyme® Ll) durchgeführt:To determine the kinetics of enantiomer formation, the following was carried out - the larger batch with the best enzyme from experiments 1 to 10 (Chirazyme ® Ll):
10 mmol Edukt10 mmol educt
80 ml THF80 ml THF
10 mmol Vinylpropionat10 mmol vinyl propionate
410 mg Enzym410 mg enzyme
Das Edukt (V) wurde zusammen mit dem Vinylpropionat (VI) in THF vorgelegt. Die Reaktion wurde durch Zugabe des Enzyms gestartet. Nach 2, 4, 6, 8, 24, 28 und 96 h Inkubation bei Raumtemperatur (23 °C) wurden Proben gezogen und der Drehwert ermittelt. Nach 96 h blieb die Reaktion stehen, daß heißt nach 96 h gibt es keine Verschiebung mehr zwischen den beiden in der Reaktion vorhandenen Enantiomeren (Ester und Alkohol) .The starting material (V) was introduced together with the vinyl propionate (VI) in THF. The reaction was started by adding the enzyme. After 2, 4, 6, 8, 24, 28 and 96 h incubation at room temperature (23 ° C), samples were taken and the rotation value was determined. The reaction stopped after 96 hours, which means that after 96 hours there was none Shift more between the two enantiomers present in the reaction (ester and alcohol).
Tabelle II: Mit Chirazyme® Ll ermittelte DrehwerteTable II: Rotation values determined with Chirazyme ® Ll
Beispiel 12Example 12
Um die Enantiomerenreinheit der einzelnen Komponenten zu ermit- teln wurde ein Ansatz wie unter Beispiel 11 beschrieben durchgeführt und die Enantiomeren (VII und VIII) voneinander getrennt, in dem der Alkohol in Toluol ausgefällt wurde und die organische Phase abgetrennt wurde und mehrmals mit Wasser gewaschen wurde. Die Enantiomerenreinheit des Alkohols sowie des Esters nach Spal ■ tung unter Erhalt des Stereozentrums wurden nach Bildung des Mo- scheresters bestimmt (siehe Schema III) .In order to determine the enantiomeric purity of the individual components, an approach was carried out as described in Example 11 and the enantiomers (VII and VIII) were separated from one another, in which the alcohol was precipitated in toluene and the organic phase was separated off and washed several times with water . The enantiomeric purity of the alcohol and the ester after cleavage to maintain the stereocenter was determined after the formation of the pattern ester (see Scheme III).
PyridinPyridine
Die Enantiomerenreinheit beider Enantiomere wurden außerdem auf einer HPLC-Säule (Chiracel OD 250 x 4 mm, Eluent 900 ml n-Hexan, 100 ml Isopropanol, 1 ml Diethylamin, 10 ml Methanol, Gradient: isokratisch, Fluß: 1,0 ml/min, Druck: 28 bar, UV 254 nm, Laufzeit: 35 min, Probe: 1 mg/5 ml Fliessmittel) bestimmt.The enantiomeric purity of both enantiomers was also determined on an HPLC column (Chiracel OD 250 x 4 mm, eluent 900 ml n-hexane, 100 ml isopropanol, 1 ml diethylamine, 10 ml methanol, gradient: isocratic, flow: 1.0 ml / min , Pressure: 28 bar, UV 254 nm, running time: 35 min, sample: 1 mg / 5 ml eluent).
Die Enantiomerenreinheit des Esters (VIII) wurde mit 99,1 % ee mit der HPLC und mit 85 % ee mit dem Moscherester bestimmt. Die des Alkohols mit 66,1 % ee bei 40 % Umsatz. Die Enantioselektivi tat (E) des Enzyms betrug E = 467. Beispiel 13The enantiomeric purity of the ester (VIII) was determined with 99.1% ee using HPLC and with 85% ee using the Moscher ester. That of alcohol with 66.1% ee and 40% conversion. The enantioselectivity (E) of the enzyme was E = 467. Example 13
Umsetzung des Edukts mit Lipase aus Pseudomonas spec. DSM 8246 in in folgendem Ansatz:Implementation of the educt with lipase from Pseudomonas spec. DSM 8246 in the following approach:
2 , 5 mmol Edukt2.5 mmol educt
20 ml THF oder MTBE/Dioxan20 ml THF or MTBE / dioxane
2,5 mmol Vinylpropionat2.5 mmol vinyl propionate
82 mg Lipase aus P. spec. DSM 824682 mg of lipase from P. spec. DSM 8246
Der Ansatz wurde bei Raumtemperatur (23 °C) unter schütteln (150 rpm) inkubiert. Die mit der HPLC bestimmte Enantiomerenreinheit für den Ester betrug 97,5 % ee und für den Alkohol 60 % ee bei 38,1 % Umsatz .The mixture was incubated at room temperature (23 ° C.) with shaking (150 rpm). The enantiomeric purity determined by HPLC for the ester was 97.5% ee and for the alcohol 60% ee with 38.1% conversion.
Beispiele 14Examples 14
Wie unter Beispiel 12 beschrieben wurden die Umsätze und Enantio- merenreinheiten mit weiteren Enyzmen Chirazym® L4 und L6 be- stimmt. Die Enantiomerenreinheit für L4 betrug 99,5% ee für den Ester und 62,5 % ee für den Alkohol bei 38,6 % Umsatz (E = 652). Um die Enantiomerenreinheiten beider Komponenten exakt bei 50% Umsatz ermitteln zu können wurden die Reaktion unter HPLC-Kon- trolle durchgeführt und die Reaktion exact bei 49,2 % Umsatz ge- stoppt. Die Enantiomerenreinheit für das Enzym L6 betrug unter diesen Bedingungen 99,4 % ee für den Ester und 96,1 % ee für den Alkohol (E = 1417) .As described in Example 12, the sales and enantiomeric units were determined using further Chirazym® L4 and L6 enzymes. The enantiomeric purity for L4 was 99.5% ee for the ester and 62.5% ee for the alcohol at 38.6% conversion (E = 652). In order to be able to determine the enantiomeric purities of both components exactly at 50% conversion, the reaction was carried out under HPLC control and the reaction was stopped exactly at 49.2% conversion. The enantiomeric purity for the enzyme L6 under these conditions was 99.4% ee for the ester and 96.1% ee for the alcohol (E = 1417).
Beispiel 15Example 15
Umsetzung des Edukts mit Lipase aus Pseudomonas spec. DSM 8246 in in größerem Ansatz :Implementation of the educt with lipase from Pseudomonas spec. DSM 8246 in a larger approach:
505 mmol Edukt 2500 ml THF505 mmol starting material 2500 ml THF
505 mmol Vinylpropionat505 mmol vinyl propionate
8,3 g Lipase aus P. spec. DSM 82468.3 g of lipase from P. spec. DSM 8246
Die Reaktion wurde durch Zugabe der Lipase gestartet. Die Versuch wurde wie unter Beispiel 12 beschrieben durchgeführt. Es wurden 99,65 g Produkt nach Aufarbeitung isoliert. Die Enantiomerenreinheiten wurden wie folgt bestimmt: Ester 97 % ee, Alkohol > 98 % ee. The reaction was started by adding the lipase. The test was carried out as described in Example 12. 99.65 g of product were isolated after working up. The enantiomeric purities were determined as follows: ester 97% ee, alcohol> 98% ee.

Claims

Patentansprüche claims
1. Verfahren zur Herstellung von enantiomerenreinen Estern der Formel I (Ia oder Ib)1. Process for the preparation of enantiomerically pure esters of the formula I (Ia or Ib)
chiral, (Ia oder Ib) chiral, (Ia or Ib)
in der die Substituenten folgende Bedeutung haben:in which the substituents have the following meaning:
Ri R i
Wasserstof f oder substituiertes oder unsubstituiertes Cι-C6-Hydrogen f or substituted or unsubstituted Cι-C 6 -
Alkyl- , Cj_-C6-Alkoxy- oder Cι-C6-Alkanoyl- ,Alkyl, Cj_-C 6 alkoxy or -CC 6 alkanoyl,
R2 und R3 R 2 and R 3
unabhängig voneinander Wasserstof f oder substituiertes oder unsubstituiertes Cι-C6-Alkyl- , Cι-C6-Alkoxy- , Cι-C6-Alkanoyl- , Cι-C6-Alkylthio- , Cι-C6-Alkylsulphinyl- oder Cι-C6-Alkylsul - phonyl- ,independently of one another hydrogen f or substituted or unsubstituted -CC 6 -alkyl-, -C-C 6 -alkoxy-, -C-C 6 -alkanoyl-, -Cι-C 6 -alkylthio-, -Cι-C 6 -alkylsulphinyl- or Cι- C 6 alkylsul - phonyl,
R4 und R5 R 4 and R 5
R4 R5 und unabhängig voneinander Wasserstoff oder substituiertes oder unsubstituiertes Cι-C6-Alkyl- oder R4 und R5 bilden zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, ein substituiertes oder unsubstituiertes C3-C6-Cy- cloalkyliden,R 4 R 5 and independently of one another hydrogen or substituted or unsubstituted -CC 6 alkyl or R 4 and R 5 together with the carbon atoms to which they are attached form a substituted or unsubstituted C 3 -C 6 -cycloalkylidene ,
R6 R 6
substituiertes oder unsubstituiertes Aryl- , Cι-C2o-Alkyl- ,substituted or unsubstituted aryl, C 1 -C 2 o -alkyl,
C3-C20-Alkenyl- , C3-C2o-Alkinyl- , Cι-C2o-Alkoxy-Cι-C20-Alkyl-C 3 -C 20 alkenyl, C 3 -C 2 o-alkynyl, -C-C 2 o-alkoxy -CC-C 20 alkyl-
dadurch gekennzeichnet, daß man racemische Verbindungen der Formel II, characterized in that racemic compounds of the formula II,
in der die Substituenten R1 bis R5 die oben genannten Bedeu- tungen haben, mit einer Lipase oder Esterase in Gegenwart von Vinylestern der Formel III,in which the substituents R 1 to R 5 have the meanings given above, with a lipase or esterase in the presence of vinyl esters of the formula III,
worin R6 die oben genannte Bedeutung hat und R7 Wasserstoff oder Methyl bedeutet, zu Verbindungen der Formel I umsetzt.wherein R6 has the meaning given above and R 7 represents hydrogen or methyl, to give compounds of the formula I.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man die Reaktion in Gegenwart mindestens eines inerten Lösungsmittels durchführt.2. The method according to claim 1, characterized in that one carries out the reaction in the presence of at least one inert solvent.
3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß man den in der Reaktion entstehenden Alkohol der Formel II entfernt .3. The method according to claim 1 or 2, characterized in that the alcohol of the formula II formed in the reaction is removed.
4. Verfahren nach einem der Ansprüche 1 bis 3, dadurch gekenn - zeichnet, daß man anschließend die enantiomerenreinen Verbindungen der Formel I unter Erhalt der Stereochemie zu Verbindungen der Formel II spaltet.4. The method according to any one of claims 1 to 3, characterized in that the enantiomerically pure compounds of the formula I are then cleaved to give the compounds of the formula II while maintaining the stereochemistry.
5. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekenn- zeichnet, daß man das jeweils unerwünschte Enantiomer der5. The method according to any one of claims 1 to 4, characterized in that the respective undesirable enantiomer of
Formel II racemisiert und in die Reaktion zurückführt.Formula II racemized and returned to the reaction.
6. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß man die enantiomerenreinen Verbindungen der Formel I unter Racemisierung zu Verbindungen der Formel II spaltet und in die Reaktion zurückführt.6. The method according to any one of claims 1 to 4, characterized in that the enantiomerically pure compounds of the formula I are cleaved under racemization to give compounds of the formula II and returned to the reaction.
7. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß man die jeweils unerwünschte enantiomerenreine Verbindung der Formel II unter Inversion des Stereozentrums in einer chemischen Reaktion in das gewünschte Enantiomer überführt.7. The method according to any one of claims 1 to 4, characterized in that the respectively undesired enantiomerically pure compound of formula II with inversion of the stereo center converted into the desired enantiomer in a chemical reaction.
8. Verfahren nach einem der Ansprüche 3,4 oder 7, dadurch ge- kennzeichnet, daß man die enantiomerenreinen Verbindungen der Formel II unter Erhalt der Stereochemie zu Verbindungen der Formel 'I verestert.8. The method according to any one of claims 3, 4 or 7, characterized in that the enantiomerically pure compounds of the formula II are esterified to give the compounds of the formula ' I while maintaining the stereochemistry.
9. Verfahren nach einem der Ansprüche 1 bis 3, dadurch gekenn- zeichnet, daß man eine Lipase oder Esterase mikrobiellen Ursprungs oder eine Schweinepankreaslipase verwendet. 9. The method according to any one of claims 1 to 3, characterized in that a lipase or esterase of microbial origin or a porcine pancreatic lipase is used.
EP98910636A 1997-02-19 1998-02-09 Method for producing esters free of enantiomers Withdrawn EP0968302A1 (en)

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