WO1998037081A1 - Procede de production d'alcools heteroaromatiques exempts d'enantiomeres - Google Patents

Procede de production d'alcools heteroaromatiques exempts d'enantiomeres Download PDF

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Publication number
WO1998037081A1
WO1998037081A1 PCT/EP1998/000707 EP9800707W WO9837081A1 WO 1998037081 A1 WO1998037081 A1 WO 1998037081A1 EP 9800707 W EP9800707 W EP 9800707W WO 9837081 A1 WO9837081 A1 WO 9837081A1
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alkyl
formula
substituted
unsubstituted
reaction
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PCT/EP1998/000707
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German (de)
English (en)
Inventor
Friedhelm Balkenhohl
Stefan Koser
Nicholas John Holman
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Basf Aktiengesellschaft
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Priority to CA002280833A priority Critical patent/CA2280833A1/fr
Priority to EP98909425A priority patent/EP0966469A1/fr
Priority to JP53621198A priority patent/JP2001512468A/ja
Publication of WO1998037081A1 publication Critical patent/WO1998037081A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/18—Carboxylic ester hydrolases (3.1.1)
    • C12N9/20—Triglyceride splitting, e.g. by means of lipase
    • 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
    • C12P17/188—Heterocyclic compound containing in the condensed system at least one hetero ring having nitrogen atoms and oxygen atoms as the only ring heteroatoms
    • 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

Definitions

  • the invention relates to a process for the production of enantiomerically pure alcohols.
  • Optimal racemate resolution should advantageously meet a number of conditions, such as:
  • WO 95/10521 claims 1, 2, -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 for the synthesis of 1,2,4-triazolo (1, 5-a) pyrimidines, which advantageously provides these compounds with high optical purities and good chemical yields and which enables easy processing of the products.
  • Ci-C ⁇ -alkyl independently of one another hydrogen or substituted or unsubstituted Ci-C ⁇ -alkyl, Ci-C ⁇ alkoxy, Ci-C ⁇ alkanoyl, -C-C 6 alkylthio-, Ci-C ⁇ -alkylsulphinyl or C ⁇ -C 6 -Alkylsul - phonyl-,
  • R 4 R 5 and independently of one another hydrogen or substituted or unsubstituted C 1 -C 6 -alkyl- or R 4 and R 5 together with the carbon atoms to which they are attached form a substituted or unsubstituted C 6 -C 6 -cycloalkylidene,
  • R 1 to R 5 have the meanings given above and R6 is substituted or unsubstituted aryl, C 1 -C 20 -alkyl, C 3 -C 2 _-alkenyl, C 3 -C 20 -alkynyl, C 1 -C -C 20 - Alkoxy -CC 20 alkyl- means, with a lipase or esterase in the presence of an alcohol R 7 OH (III), in which R 7 is substituted or unsubstituted -CC-alkyl-, is reacted, dissolved.
  • R 7 OH III
  • R 1 in the formulas I and II denotes hydrogen or substituted or unsubstituted Ci-C ⁇ - alkyl-, -C-C 6 -alkoxy- or C ⁇ -C 6 -alkanoyl-
  • Ci-C ⁇ -alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1- Methyl butyl, 2-methyl butyl, 3-methyl butyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 2, 2-dimethyl propyl, 1-ethyl propyl, n-hexyl, 1-methyl pentyl, 2-methyl pentyl, 3-methyl pentyl, 4 - Methylpentyl, 1, 1 -dimethylbutyl, 1, 2-Dimethylbutyl, 1, 3 -Dirnethylbutyl, 2, 2 -Dimethylbutyl, 2, 3-Dimethylbutyl, 3, 3 -Dimethylbutyl, 1 -Ethylbuty
  • 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, 1st -Methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2, 2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3 -Methylpentoxy, 4-Methylpentoxy, 1, 1-Dimethylbu-toxy, 1, 2-Dirnethylbutoxy, 1, 3-Dimethylbutoxy, 2, 2-Dimethylbutoxy, 2, 3-Dimethylbutoxy, 3, 3-Dimethylbutoxy, 1-Ethylbutoxy , 2-ethylbutoxy, 1, 1, 2-trimethylpropoxy, 1, 2, 2-trimethylpropoxy, 1-ethyl-
  • Alkanoyl branched or unbranched C] - C 6 alkanoyl chains such as methanoyl, ethanoyl, propanoyl, 1-methylethanoyl, butanoyl, 1-methylpropanoyl, 2-methylpropanoyl, 1, 1-dimethylethanoyl, pentanoyl, 1-methylbutanoyl, 2-methylbutanoyl -Methylbuta- noyl, 1, 1-dimethylpropanoyl, 1, 2-dimethylpropanoyl, 2,2-dimethylpropanoyl, 1-ethylpropanoyl, hexanoyl, 1-methylpentanoyl, 1, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, 1 , 1-Dimethylbutanoyl, 1, 2-Dimethylbutanoyl, 1, 3-Dimethylbutanoyl, 2, 2-Dimethylbutanoy
  • 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, alkoxy or alkanoyl radicals mentioned for R 1 .
  • R 2 and R 3 in the formulas I and II independently of one another denote hydrogen or substituted or unsubstituted C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, C 1 -C 6 -alkanoyl -, C 1 -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 6 -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 -di
  • Ci-C ⁇ -alkanoyl chains such as
  • Alkylthio branched or unbranched C ⁇ -C6-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- Methylpentylthio, 4-Methylpentylthio, 1, 1-Dimethylbutylthio, 1, 2-Dimethylbutylthio, 1, 3-Dimethylbuty
  • Alkylsulphonyl branched or unbranched Ci-C ß- 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-dimethylpropylsulphonyl, 1-ethylylpylyl - thylpentylsulphonyl, 2-methylpentylsulphonyl, 3-methylpentyl
  • halogen such as halogen, such as fluorine, chlorine, bromine, cyano, nitro, amino, thio, alkyl, or alkoxy
  • R 4 and R 5 are not the same and denote in the formulas I and II independently of one another hydrogen or substituted or unsubstituted C 1 -C 6 -alkyl- or R 4 and R 5 together with the carbon atoms to which they are attached form a substituted tes or unsubstituted C 3 -C 6 allyl.
  • the radicals mentioned for R 4 and R 5 have the following meaning, for example:
  • Ci-C ö alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1 -Methylbutyl, 2 -Methylbutyl, 3 -Methylbutyl, 1, 1-Dimethylpropyl, 1, 2 -Dirnethylpropyl, 2, 2 -Dirnethylpropyl, 1-Ethylpropyl, n-Hexyl, 1-Methylpentyl, 2-Methylpentyl, 3-Methylpentyl, 4 -Methylpentyl, 1, 1 -dimethylbutyl,
  • Cycloalkylidene branched or unbranched C 3 -C_-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 II and IV denotes substituted or unsubstituted aryl, C 1 -C 0 -alkyl, C 1 -C 20 -alkenyl, C 1 -C 2 o -alkynyl- or C 1 -C 0 -alkoxy-C 1 -C 20 alkyl.
  • Aryl simple or condensed aromatic ring systems which can optionally 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 can optionally be substituted with at least one further C 1 -C 0 -alkyl chain or via a Ci-Ci .
  • Alkyl chain to that
  • Alkyl branched or unbranched C 1 -C 4 -alkyl chains such as, for example, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl -, 2-methylpropyl, 1, 1 -dimethylethyl, n-pentyl, 1 - Methyl butyl, 2-methyl butyl, 3-methyl butyl, 2, 2 -dirnethylpropyl, 1 -ethylpropyl, n-hexyl, 1, 1 -dimethylpropyl, 1, 2 -dirnethylpropyl, 1 -methylpentyl, 2 -methylpentyl, 3 -methylpentyl, 4 -methylpentyl, 1, 1 -dimethylbutyl, 1,2-dimethylbutyl, 1, 3 -dimethylbutyl, 2, 2 -dimethylbutyl, 2, 3 -d
  • Alkoxyalkyl branched or unbranched C ⁇ -C_o ⁇ alkoxy-C ⁇ -C 2 o-alkyl chains such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, propoxymethyl, 1-methylthoxymethyl, butoxymethyl, 1-methylpropoxymethyl, 2-methyl - propoxymethyl, 1st , 1-Dimethylethoxymethyl, are preferred
  • Ci-C ⁇ -alkoxy-Ci-C ⁇ -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 .
  • R 7 in the formulas III and IV denotes substituted or unsubstituted Cx -C ⁇ 0 alkyl -.
  • Alkyl branched or unbranched C ⁇ -C ⁇ _ alkyl chains such as 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 -Dirnethylpropyl, 1 -Ethylpropyl, n-Hexyl, 1, 1 -Dimethyl-propyl, 1, 2 -Dirnethylpropyl, 1-Methylpentyl, 2-Methylpentyl, 3-Methylpentyl, 4 -Methylpentyl, 1, 1 -dimethylbutyl, 1, 2 -dimethylbutyl, 1, 3 -dimethylbutyl, 2, 2 -dimethylbuty
  • 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, alkenyl, alkynyl or alkoxyalkyl radicals mentioned for R 7 .
  • lipases or esterases of nomenclature class 3.1 - enzymes which react with ester bonds - are suitable for the process according to the invention.
  • lipases or esterases of microbial origin or porcine pancreatic lipase are preferred.
  • enzymes of microbial origin for example, enzymes from fungi, yeasts or bacteria such as, for example, Alcaligenes sp., Achromobacter sp., Aspergillus niger, Bacillus subtilis, Candida cylindracea, Candida lypolytica, Candida antarctica, Candida sp., Chromobacterium viscosum, Chromobacterium sp., Geotrichum candidum, Humicola lanuginosa, Mucor miehei, Penicillium camemberti, Penicillium roqueforti, Phycomyces nitens, Pseudomonas cepacia, Pseudomonas Rhumae, Pseudomonas fluorescens, Pseudomonas plantarii, Pseudomonas aeropinizizopus, Pseudomonas aeropinizizopus japanicus, Rhizopus niveus,
  • 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), Novozym SP523, SP524, SP525, SP526, SP539, SP435 (Novo, Denmark), Chirazyme ® Ll, L2, L3, L4, L5, are very particularly preferred.
  • L6, L7, L8, El Boehringer Mannheim, Germany
  • 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 to say that 10 mg of an enzyme 3 can be used, for example to split kg or more of a substrate with a molecular weight of about 100 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. Immobilized and / or activated enzymes are preferably used.
  • the enzyme reaction can only be carried out in the presence of the alcohols (see formula III) as solvent without the addition of additional solvents or solvent mixtures. Further solvents or solvent mixtures are advantageously added to the reaction.
  • all aprotic or protic solvents are suitable for this. All solvents which are inert in the reaction are suitable, ie they must not take part in the enzyme reaction.
  • other primary or secondary alcohols, DMF, DMSO and water in unsuitable amounts are unsuitable, since side reactions can occur in the presence of these solvents and / or the enzymes tend to stick together, thus drastically reducing the enzyme activity.
  • DMF and DMSO lead to damage to the enzymes, presumably by removing the hydration shell around the enzymes.
  • 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. Called pentyl alcohol or propylene carbonate, ethylene carbonate or acetonitrile. 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.
  • hydrolysis of the esters (formula II) to the corresponding alcohols (formula I) is also possible in water or in an aqueous medium in the presence of organic solvents, for example in buffer / solvent mixtures with sufficient amounts of water for the hydrolysis.
  • organic solvents for example in buffer / solvent mixtures with sufficient amounts of water for the hydrolysis.
  • the reaction with most enzymes under these conditions is not sufficiently selective so that only insufficient enantiomeric purities are achieved.
  • all substituted or unsubstituted alcohols of the formula III are suitable for the reaction, such as the saturated or unsaturated primary fatty alcohols (C 6 to C 2 ) such as 1-hexanol, 1-heptanol, 1-octanol, 1-nonanol, 1- Decanol, 1-undecanol, 1-dodecanol, 1-tridecanol, 1-tetradecanol, 1-pentadecanol, 1-hexadecanol, 1-heptadecanol, stearyl alcohol, oleyl alcohol, erucy alcohol, " ricinol alcohol, linoleyl alcohol, linolenyl alcohol, arachidyl alcohol , Gadoley alcohol, 1-heneicosanol or 1-docosanol, ethanol, propanol, butanol, pentanol or hexanol, which may optionally be preferably substituted with alkoxy groups
  • 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 10 moles of alcohol 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 ester - 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 alcohol (Ia) formed in the first reaction is the desired enantiomer, it is separated from the other reaction products (Ha 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 undesired ester enantiomer can then either be recycled after removal of IV with cleavage racemized, for example by treatment in the basic and after renewed esterification (reaction 4), or else cleaved to maintain the stereocenter (reaction 2) and then racemized (reaction 3), esterified (Reaction 4) and recycled.
  • the alcohol obtained by cleavage to maintain the stereocenter is converted in a chemical reaction inversely by the stereocenter, such as in a Mitsu nobu reaction (see Scheme I, reaction 5), or in a reaction with the corresponding sulfonic anhydrides to form mesylates ,
  • a chemical reaction inversely by the stereocenter such as in a Mitsu nobu reaction (see Scheme I, reaction 5), or in a reaction with the corresponding sulfonic anhydrides to form mesylates
  • Tosylates or brosylates and hydrolysis or reaction with carboxylates can be reacted directly to the esters or in a reaction to form trichloroacetimidates and subsequent reaction with, for example, carboxylic acids or carboxylates, converted into the desired enantiomer.
  • the alcohol (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 alcohol can then either be racemized, esterified and recycled or, in a subsequent chemical reaction in which the stereo center is inverted, converted into the desired enantiomer of the alcohol (Ib) (reaction 5).
  • the concentration of the starting material and product was determined by HPLC.
  • 250 ⁇ l of the reaction broth was diluted as a sample with 750 ⁇ l of methanol and analyzed in the HPLC (HPLC columns: Chiracel OD, 250 x 4 mm or YMC-Pack ODS-AQ S-5 ⁇ m 120 A, 250 x 4.6 mm, eluent: 880 ml n-hexane, 60 ml isopropanol, 60 ml ethyl acetate or (A) acetonitrile, (B) 1.36 g KH 2 P0 4 to 11 H 2 0, pH 2.5 with H 3 P0 4 and gradient 0 min 10% (A) + 90% (B) 75 min 40% (A) + 60% (B), injection volume: 50 or 10 ⁇ l, detection: UV 270 or 210 nm, flow rate: 1, 0 or 0.8 ml / min, retention times: esters: 13.4 min or 33.9 min, alcohol

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Abstract

Procédé de production d'alcools exempts d'énantiomères de formule (I) dans laquelle les substituants ont la signification suivante: R1 est hydrogène ou C¿1?-C6-alkyl-, C1-C6-alcoxy-, ou C1-C6-alcanoyl- substitués ou non substitués; R?2 et R3¿ sont indépendamment l'un de l'autre hydrogène ou C¿1?-C6-alkyl-, C1-C6-alcoxy-, C1-C6-alcanoyl-, C1-C6-alkylthio-, C1-C6-alkylsulfinyl- ou C1-C6-alkylsulfonyl- substitués ou non substitués; R?4 et R5¿ ne sont pas identiques et sont indépendamment l'un de l'autre hydrogène ou C¿1?-C6-alkyl- substitué ou non substitué, ou bien R?4 et R5¿ forment ensemble, avec les atomes de carbone auxquels ils sont liés, un C¿3?-C6-cycloalkylidène substitué ou non substitué. Ledit procédé est caractérisé en ce que des mélanges racémiques de formule (II) dans laquelle les substituants R?1 à R5¿ ont la signification susmentionnée et R6 est aryl-, C¿1?-C20-alkyl-, C3-C20-alcényl- ou C3-C20-alcinyl- substitués ou non substitués, sont mis en réaction avec une lipase ou estérase en présence d'un alcool de formule R?7¿OH (III) dans laquelle R7 est C¿1?-C10-alkyl- substitué ou non substitué.
PCT/EP1998/000707 1997-02-19 1998-02-09 Procede de production d'alcools heteroaromatiques exempts d'enantiomeres WO1998037081A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002280833A CA2280833A1 (fr) 1997-02-19 1998-02-09 Procede de production d'alcools heteroaromatiques exempts d'enantiomeres
EP98909425A EP0966469A1 (fr) 1997-02-19 1998-02-09 Procede de production d'alcools heteroaromatiques exempts d'enantiomeres
JP53621198A JP2001512468A (ja) 1997-02-19 1998-02-09 エナンチオマー的に純粋なヘテロ芳香族アルコールの製造方法

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DE19706336A DE19706336A1 (de) 1997-02-19 1997-02-19 Verfahren zur Herstellung von enantiomerenreinen Alkoholen
DE19706336.5 1997-02-19

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WO (1) WO1998037081A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000106896A (ja) * 1998-09-30 2000-04-18 Basf Ag アリ―ルアルキルカルボン酸エステルのラセミ化合物分割法
US11814734B2 (en) 2019-05-13 2023-11-14 Ecolab Usa Inc. 1,2,4-triazolo[1,5-a] pyrimidine derivative as copper corrosion inhibitor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63173597A (ja) * 1987-01-14 1988-07-18 Lion Corp 酵素によるエステル交換反応
WO1995010521A1 (fr) * 1993-10-13 1995-04-20 Knoll Ag Agents therapeutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
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US11814734B2 (en) 2019-05-13 2023-11-14 Ecolab Usa Inc. 1,2,4-triazolo[1,5-a] pyrimidine derivative as copper corrosion inhibitor

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CN1248258A (zh) 2000-03-22
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CA2280833A1 (fr) 1998-08-27
EP0966469A1 (fr) 1999-12-29

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