EP1242613A2 - Procede de separation racemique cinetique d'alcools ou d'esters d'acides carboxyliques - Google Patents

Procede de separation racemique cinetique d'alcools ou d'esters d'acides carboxyliques

Info

Publication number
EP1242613A2
EP1242613A2 EP00990552A EP00990552A EP1242613A2 EP 1242613 A2 EP1242613 A2 EP 1242613A2 EP 00990552 A EP00990552 A EP 00990552A EP 00990552 A EP00990552 A EP 00990552A EP 1242613 A2 EP1242613 A2 EP 1242613A2
Authority
EP
European Patent Office
Prior art keywords
alcohols
organic
fluorinated
carried out
fluorous
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00990552A
Other languages
German (de)
English (en)
Inventor
Fritz Theil
Helmut Sonnenschein
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ASCA GmbH Angewandte Synthesechemie Adlershof
Original Assignee
ASCA GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19963314A external-priority patent/DE19963314A1/de
Priority claimed from DE19963315A external-priority patent/DE19963315A1/de
Priority claimed from DE2000106824 external-priority patent/DE10006824A1/de
Application filed by ASCA GmbH filed Critical ASCA GmbH
Publication of EP1242613A2 publication Critical patent/EP1242613A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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 present invention relates to a process for the kinetic resolution of alcohols or carboxylic acid esters having one or more stereogenic centers.
  • the invention is particularly applicable in the manufacture of active pharmaceutical ingredients or crop protection agents.
  • ester formed is acidic, which can be achieved, for example, by esterification with cyclic carboxylic anhydrides.
  • acidic compounds reduce lipase activity (B. Berger et al. Tetrahedron: Asymmetry 1990, 1, 541-546, UT Bornscheuer, RJ Kazlauskas, Hydrolases in Organic Synthesis, Wiley-VCH, pp. 44-47, Weinheim, 1999) ,
  • Racemic carboxylic acid esters with one or more stereogenic centers in the carboxyl radical of the molecule can be transesterified by Hpase-catalyzed alcoholysis with an alcohol which is different from that already present in the ester molecule.
  • the two resulting enantiomeric carboxylic acid esters can, however, only be separated by means of complex chromatographic methods, which is why this procedure is of no practical importance. Enantiomer separation is usually carried out by Hpase-catalyzed hydrolysis (U. T. Bomscheuer, R. J. Kazlauskas, Hydrolases in Organic Synthesis, Wiley-VCH, Weinheim, 1999).
  • the object is achieved by a process for the kinetic resolution of alcohols or carboxylic acid residues having one or more stereogenic centers, in the reaction of racemic alcohols with fluorinated acylating agents or by esters of racemic carboxylic acids with fluorinated alcohols or of fluorinated carboxylic acid residues racemic alcohols with water fluorophase labeling of the faster or slower reacting enantiomer is achieved.
  • the enantiomers are then separated by extraction between the organic and fluorous phases.
  • Fluorine solvents are understood to be solvents with a high degree of fluorination that are not miscible with conventional organic solvents.
  • R is a perfluorinated alkyl radical such as - (CF 2 ) m -CF 3 , where m can be an integer from 3 to 18 or a perfluorinated aromatic radical such as C 6 F 4 X and X are fluorine or a perfluorinated alkyl radical, R 1 alkyl, is vinyl, aryl, 2-cyanoethyl, 2,2,2-trifluoroethyl or 2,2,2-trichlorethyl and n can be an integer from 1 to 4,
  • racemic carboxylic acid esters having one or more stereogenic centers in the acyl residue of a lipase-catalyzed alcoholysis with a perfluorinated alcohol of the formula II are provided.
  • n is either 0 or an integer from 1 to 4, subjected.
  • X alkyl, alkenyl, alkoxy, aryl, aryloxy or halogen
  • the reactions with a lipase of microbial, vegetable or animal origin are carried out at room temperature or elevated temperatures either in solvents customary for these reactions, such as aliphatic and aromatic hydrocarbons, ethers, tertiary alcohols or also chlorinated hydrocarbons.
  • the perfluorinated enantiomer is then extracted with a perfluorinated solvent which is immiscible with the non-fluorinated organic solvent.
  • the lipase-catalyzed reactions are carried out in a perfluorinated solvent and then extracting the non-fluorinated enantiomer using a non-fluorinated organic solvent.
  • the lipase-catalyzed kinetic resolution can also be carried out in a two-phase system of organic and fluorous solvent which is immiscible at room or lower temperature.
  • the phase homogenization during the chemical reaction is carried out either by heating or controlled, gentle microwave input.
  • the phase and the associated product separation is achieved by cooling the reaction mixture below the phase mixture temperature. In this way, the separation of the enantiomers can be carried out in good yields.
  • racemic alcohols having one or more stereogenic centers with perfluorinated acylating agents are converted into an ester of the formula III,
  • R is a perfluorinated alkyl radical such as - (CF) m -CF 3 , where m can be an integer from 3 to 18, or a perfluorinated aromatic radical such as C 6 F 4 X and X is fluorine or a perfluorinated alkyl radical,
  • R 1 , R 2 are alkyl, alkenyl, aryl or heteroaryl and n can be an integer from 0 to 4, converted and then hydrolyzed enantiomer-selectively in a known manner with ester-cleaving enzymes, preferably lipases.
  • ester-cleaving enzymes preferably lipases.
  • the perfluorinated residue is cleaved from the more rapidly reacting enantiomer, as a result of which this enantiomer is no longer soluble in fluorous solvents.
  • an ester-cleaving enzyme preferably a lipase
  • the perfluorinated residue is cleaved from the more rapidly reacting enantiomer, as a result of which this enantiomer is no longer soluble in fluorous solvents.
  • the free alcohol according to the invention is in the organic phase, the non-cleaved ester in the fluorous and the salt of the carboxylic acid in the aqueous phase.
  • the hydrolysis is carried out with a lipase of microbial, vegetable or animal origin either in a solvent customary for these reactions, such as an aqueous buffer solution, or with the addition of a water-miscible or immiscible solvent in a homogeneous or heterogeneous phase.
  • a solvent customary for these reactions such as an aqueous buffer solution
  • a water-miscible or immiscible solvent in a homogeneous or heterogeneous phase.
  • the pH in the aqueous phase is usually kept constant at values between 6 and 8, preferably at pH 7, by adding suitable bases such as aqueous sodium or potassium hydroxide solution.
  • suitable bases such as aqueous sodium or potassium hydroxide solution.
  • a water-immiscible organic and a fluorous solvent are added to the reaction mixture, which creates a three-phase system.
  • the reaction mixture is extracted with a suitable organic solvent which is immiscible with water and the organic solvent is evaporated off.
  • the resulting residue is divided between suitable organic and fluorous solvents.
  • the alcohol released is isolated from the organic phase and the unreacted carboxylic acid ester from the fluorous phase.
  • the alkali salt of the released carboxylic acid remains in the aqueous Rto_s. In this way, the separation of the enantiomers can be carried out in good yields.
  • a mixture of racemic 1-phenylethanol (0.366 g, 3 mmol) and acetonitrile (10 ml) is mixed with 4,4,5,5,6,6,7,7,8,8,9,9, 10,10, 11, 11, 11-2,2,2-trifluoroethyl heptadecafluorodecanoic acid (2.58 g, 4.5 mmol) and Candida antarctica B lipase (0.1 g) were added and the mixture was stirred at room temperature until 50% of the alcohol had reacted are.
  • the enzyme will filtered off and the filtrate concentrated to dryness in vacuo.
  • the residue is taken up in methanol (10 ml) and the mixture extracted five times with n-perfluorohexane.
  • the organic phase contains (S) -l-phenylethanol with an enantiomeric excess of> 95%.
  • the fluorous phase contains (R) -4,4,5,5,6,6,7,7,8,8,9,9, 10,10,11,11,11 -heptadecafluorundecanoic acid-1-phenylethyl ester an enantiomeric excess of> 95%.
  • the fluorous phase contains (R) -4,4,5, 5,6,6,7,7,8,8,9,9, 10, 10, 11, 11, 11 -heptadecafiuorundecanoic acid 1-phenylethyl ester with an enantiomeric excess of> 95%.
  • the organic phase contains enriched (S) -l-phenylethanol.
  • the fluorous phase contains enriched (R) -4,4,5,5,6,6,7,7,8,8,9,9,10,10, l 1,11,11-heptadecafluorundecanoic acid 1-phenylethyl ester.
  • the fluorous phase contains 2-phenylbutyric acid 3, 3,4,4,5, 5,6,6,7,7, 8, 8, 9,9,10,10,10-heptadecafluorodecyl ester with an enantiomeric excess of> 80% ,
  • the fluorous phase contains 2-phenylbutyric acid e-3,3,4,4,5, 5, 6,6,7,7,8,8,9,9, 10,10,10-heptadecafluorodecyl ester in enantiomerically enriched Shape.
  • the combined organic extracts are evaporated to dryness in vacuo.
  • the residue is taken up in methanol (10 ml) and the resulting mixture extracted five times with n-perfluorohexane.
  • the organic phase contains (R) -l-phenylethanol with an enantiomeric excess of> 95%.
  • the fluorous phase contains (S) -4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadeca- fluoêtcanoic acid-1-phenylethyl ester an enantiomeric excess of> 95%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Analytical Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de séparation racémique cinétique d'alcools ou d'esters d'acides carboxyliques. La transformation catalysée par lipase d'alcools racémiques avec des agents d'acylation fluorés, ou d'esters d'acides carboxyliques racémiques avec des alcools fluorés, ou d'esters fluorés d'acides carboxyliques d'alcools racémiques avec de l'eau, permet d'établir un marquage en phase fluorée de l'énantiomère réagissant plus rapidement ou plus lentement. Les énantiomères sont ensuite séparés de manière extractive par répartition entre phase organique et phase fluorée.
EP00990552A 1999-12-19 2000-12-18 Procede de separation racemique cinetique d'alcools ou d'esters d'acides carboxyliques Withdrawn EP1242613A2 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
DE19963315 1999-12-19
DE19963314A DE19963314A1 (de) 1999-12-19 1999-12-19 Verfahren zur kinetischen Racematspaltung von Alkoholen
DE19963315A DE19963315A1 (de) 1999-12-19 1999-12-19 Verfahren zur kinetischen Racematspaltung von Carbonsäureestern
DE19963314 1999-12-19
DE2000106824 DE10006824A1 (de) 2000-02-08 2000-02-08 Verfahren zur kinetischen Racematspaltung von Carbonsäureestern
DE10006824 2000-02-08
PCT/DE2000/004536 WO2001044492A2 (fr) 1999-12-19 2000-12-18 Procede de separation racemique cinetique d'alcools ou d'esters d'acides carboxyliques

Publications (1)

Publication Number Publication Date
EP1242613A2 true EP1242613A2 (fr) 2002-09-25

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP00990552A Withdrawn EP1242613A2 (fr) 1999-12-19 2000-12-18 Procede de separation racemique cinetique d'alcools ou d'esters d'acides carboxyliques

Country Status (4)

Country Link
US (1) US20030003552A1 (fr)
EP (1) EP1242613A2 (fr)
AU (1) AU3001101A (fr)
WO (1) WO2001044492A2 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7214819B2 (en) * 2001-06-08 2007-05-08 Fluorous Technologies, Inc. Fluorous triphasic reaction and separation processes for the generation of enantioenriched alcohols, amines, carboxylic acids and related compounds
DE10164269A1 (de) * 2001-12-19 2003-07-03 Asca Gmbh Angewandte Synthesec Verfahren zur kinetischen Racematspaltung von Alkoholen mit einem oder mehreren stereogenen Zentren
DE10248166A1 (de) * 2002-10-16 2004-06-17 Bayer Ag Anti-Kazlauskas-Lipasen
EP4139272A1 (fr) * 2020-04-24 2023-03-01 Corteva Agriscience LLC Procédés liés à la formation d'acides arylcyclopropyl-carboxyliques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0144492A2 *

Also Published As

Publication number Publication date
US20030003552A1 (en) 2003-01-02
WO2001044492A2 (fr) 2001-06-21
WO2001044492A3 (fr) 2002-01-31
AU3001101A (en) 2001-06-25

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