EP2086952A2 - Procédé de synthèse stéréosélective d'époxydes chiraux par réduction adh de cétones substituées avec des groupes partants alpha, et cyclisation - Google Patents

Procédé de synthèse stéréosélective d'époxydes chiraux par réduction adh de cétones substituées avec des groupes partants alpha, et cyclisation

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Publication number
EP2086952A2
EP2086952A2 EP07846734A EP07846734A EP2086952A2 EP 2086952 A2 EP2086952 A2 EP 2086952A2 EP 07846734 A EP07846734 A EP 07846734A EP 07846734 A EP07846734 A EP 07846734A EP 2086952 A2 EP2086952 A2 EP 2086952A2
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EP
European Patent Office
Prior art keywords
optionally substituted
chiral
radical
reduction
alcohol
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Withdrawn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
EP07846734A
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German (de)
English (en)
Inventor
Andreas Meudt
Richard A. Wisdom
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.)
Euticals GmbH
Original Assignee
Archimica GmbH
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Publication date
Application filed by Archimica GmbH filed Critical Archimica GmbH
Publication of EP2086952A2 publication Critical patent/EP2086952A2/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals

Definitions

  • the invention relates to a process for the stereoselective synthesis of chiral epoxides by (R) - or (S) -alkanol dehydrogenase reduction of ⁇ -leaving group-substituted ketones to the corresponding chiral alcohols and subsequent base-induced cyclization to the corresponding epoxides (EQUATION 1 ).
  • Catalytic enantioselective standard chemical processes for the enantioselective reduction of ketones include asymmetric hydrogenation with homogeneous noble metal catalysts, reduction by organoboranes [H. C. Brown, G.G. Pai, J. Org. Chem. 1983, 48, 1784], which consist of borohydrides and chiral diols or aminoalcohols [K. Soai, T. Yamanoi, H. Hikima, J. Organomet. Chem. 1985, 290; H.C. Brown, B.T. Cho, W.S. Park, J. Org. Chem. 1987, 52, 4020], the reduction by reagents prepared from borane and aminoalcohols [S.
  • the catalytic-enantioselective standard biochemical processes for the production of chiral epoxides use fermentatively baker's yeast (Saccharomyces cerevisiae) [M. de Carvalho, MT Okamoto, PJS Moran, JAR Rodrigues, Tetrahedron 1991, 47, 2073] or other microorganisms [EP 0 198 440 B1] in the so-called "whole cell method", Cryptococcus macerans [M.Imuta, KI Kawai, H. Par., J. Org. Chem. 1980, 45, 3352].
  • ⁇ -halo ketones are enzymatically reduced with the aid of whole cells, eg of Escherichia coli, or cell suspensions.
  • the keto group is stereoselectively reduced to a secondary hydroxy group.
  • ⁇ -halogen ketones are used with Carbamin Textreester- groups already having a center of chirality. From these, by enzymatic reduction, connection with two adjacent chiral centers are obtained.
  • DE 101 05 866 A1 discloses a process for the preparation of chiral, propargylic, terminal epoxides. These are prepared from ⁇ -halo-substituted propargylic ketones which are first enzymatically reacted under the action of an alcohol dehydrogenase and a system for cofactor regeneration to chiral, ⁇ -halo-substituted propargylic alcohols.
  • concentration of the starting ketone is generally 10 mM.
  • the ⁇ -halo-substituted propargylic alcohols are treated with a base.
  • the mentioned chiral, propargylic epoxides are formed.
  • the chiral alcohols are extracted with an organic solvent and then purified by column chromatography. Then they are converted to the epoxides.
  • the present process accordingly relates to a process for the preparation of chiral epoxides by reduction of ⁇ -leaving group-substituted ketones with a cell-free [R] or (S) -selective alcohol dehydrogenase (ADH) in the presence of a cofactor to the corresponding chiral alcohols and subsequent, base-induced cyclization to the corresponding chiral epoxides (EQUATION 1),
  • LG is F, Cl, Br, I 1 OSO 2 Ar, OSO 2 R 4 or OP (O) OR 4 OR 5 , and
  • Ri, R 2 and R 3 independently of one another represent hydrogen, a branched or unbranched, optionally substituted C 1 -C 20 -alkyl radical, an optionally substituted C 3 -C 10 -cycloalkyl , alkenyl radical or an optionally substituted carbo- or heterocyclic aryl radical or a radical from the group CO 2 R 4 , CONR 4 R 5 , COSR 4 , CS 2 R 4 , C (NH) NR 4 R 5 , CN, CHal 31 OAr, SAr, OR 4 , SR 4 , CHO, OH, NR 4 R 5 , Cl 1 represents F, Br, I or SiR 4 R 5 R 6 , wherein
  • R 4 , R 5 and Re independently of one another are hydrogen, a branched or unbranched, optionally substituted C 1 -C 20 alkyl radical, an optionally substituted C 3 -C 10 -cycloalkyl, alkenyl radical or an optionally substituted carbo- or heterocyclic aryl radical symbolizes characterized in that the intermediately formed alcohol II is reacted without isolation with the aid of the base to the epoxide.
  • R 1 represents phenyl which is optionally substituted with one or more halogen atoms and R 2 and R 3 are hydrogen atoms.
  • Ar is, as usual, a mononuclear or polynuclear, carbocyclic or heterocyclic aromatic radical, preferably phenyl, naphthyl, anthracenyl, furanyl, thiophenyl, benzimidazolyl, etc.
  • carbocyclic aromatic radicals contain from 6 to 20 carbon atoms as ring members the heterocyclic aromatic radicals may also be less than 6 carbon atoms.
  • the heteroatom (s) in the heterocyclic aromatic radicals are preferably one or more nitrogen, oxygen and / or sulfur (s).
  • alkyl, cycloalkyl, alkenyl, aryl or heteroaryl radicals may be further substituted, as long as the substituents do not affect the reaction.
  • substituents include halogen atoms (F, Cl, Br, I), alkyl groups (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, te / t-butyl, etc.) or alkoxy groups (methoxy, ethoxy, propoxy, Isopropoxy, butoxy, isobutoxy, sec-butoxy, te / t-butoxy, etc.).
  • Hal is a halogen atom, in particular fluorine, chlorine, bromine or iodine.
  • Suitable ADH enzymes are (R) - or (S) -alcohol dehydrogenases.
  • Suitable ADH enzymes are available, for example, from Biocatalytics Ine, Juelich Chiral Solutions GmbH or X-zyme GmbH, or Sigma-Aldrich Inc. Alternatively, they can also be obtained from natural sources. Methods for identifying, characterizing, cloning and expressing such enzymes from cell material are well described and known to those skilled in the art. Also known are a number of methods that can be used to improve the properties of the enzymes, in particular as regards their activity, stability and selectivity. The method of the invention is not limited to the use of ADH enzymes from particular sources.
  • Suitable cofactors are NADPH 2 , NADH 2 , NAD or NADP, or salts thereof, more preferably NAD or NADP are used.
  • Preferred is a Loading with 0.02 to 100 mmol of cofactor per 10 mol of substrate, more preferably 0.02 to 10 mmol of cofactor per 10 mol of substrate.
  • the process according to the invention is carried out in such a way that, in the presence of a suitable system, the regeneration of the oxidizing cofactor is carried out and this is continuously reduced again during the process.
  • reactivating the oxidized cofactors typically enzymatic or other methods known to those skilled in the art are used.
  • the cofactor is recycled continuously and can thus be used in several oxidation / reduction cycles.
  • Another common method is the use of a second enzyme system in the reactor.
  • Two methods described in detail include the use of formate dehydrogenase for the oxidation of formic acid to carbon dioxide, or the use of glucose dehydrogenase for the oxidation of glucose, to name only a few.
  • the reaction is carried out in a solvent.
  • suitable solvents for the ADH reduction are those which give no side reactions, these are organic solvents such as methanol, ethanol, isopropanol, linear and branched alcohols, ligroin, butane, pentane, hexane, heptane, octane, cyclopentane, cyclohexane, cycloheptane, Cyclooctane, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, 1, 1, 2,2-tetrachloroethane, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, dimethylformamide, diethylformamide, dimethylacetamide, diethylacetamide, diethyl ether, diisopropyl ether, tert-butyl methyl ether , THF
  • linear or branched alcohols or linear, branched or cyclic ethers such as methanol, ethanol, isopropanol, diisopropyl ether, tert-butyl methyl ether, toluene, xylene, tetrahydrofuran (THF), dioxane, or mixtures thereof
  • very particularly preferred are ethanol, isopropanol, linear and branched alcohols, diethyl ether, diisopropyl ether, tert-butyl methyl ether, toluene, xylene, THF, dioxane, or mixtures of these.
  • the process can also be carried out without addition of solvent.
  • the organic phase After completion of epoxidation, the organic phase can be easily separated from the aqueous phase.
  • the phase separation can be done by simple
  • Solvents similar to those mentioned above, are added.
  • the aqueous phase can be additionally extracted with organic solvents to further increase the yield.
  • the epoxide may be further purified, for example by distillation or, as far as it is concerned
  • a buffer to the reaction solution in order to stabilize the pH and to ensure that the enzyme can react in the optimum pH range for its action.
  • the optimal pH range varies from enzyme to enzyme. It is usually in the range of pH 3 to 11. Suitable buffer systems are known to the person skilled in the art, so that it is not necessary to discuss this further here.
  • the reduction to the alcohols (IIa) or (IIb) can generally be carried out at temperatures in the range of 0 to +90 0 C, more preferably temperatures in the range of 0 to + 60 0 C, wherein lower temperatures generally higher Selectivities are correlated.
  • the reaction time depends on the temperature used and is generally 1 to 72 hours, especially 4 to 45 hours.
  • the reaction expediently proceeds in a 2-phase system. In this case, sufficient mixing is necessary to ensure adequate mass transfer at the phase boundary in the enzymatic reduction to the alcohol as well as in the reaction of the alcohol with a base to the epoxide.
  • stirrer speed is best suited to achieve a sufficient reaction rate.
  • the ee values of the intermediately produced alcohols are well> 95%, in most cases> 99%, with simultaneously very high tolerance to functional groups in the substrate.
  • the cyclization of the alcohols (IIa) or (IIb) to the epoxides can be carried out generally at temperatures in the range of -100 to +120 0 C, more preferably temperatures in the range of 0 to + 60 0 C.
  • the reaction time is dependent from the applied temperature and is generally 1 to 72 hours, especially 24 to 60 hours. Sufficient conversion can be ensured here, for example, by GC or HPLC reaction control.
  • the reaction solution is heated to the reaction temperature before addition of the ADH enzyme.
  • bases are suitable for the cyclization. Preference is given to amine bases, carbonates, bicarbonates, hydroxides, hydrides, alcoholates, phosphates, hydrogen phosphates, particularly preferably tertiary amines, very particularly preferably sodium hydroxide, potassium hydroxide, triethylamine or pyridine.
  • the base is preferably used stoichiometrically or superstoichiometrically with respect to the compound (IIa) or (IIb).
  • the isolation of the products is preferably carried out either by distillation or by crystallization.
  • the ee values are significantly greater than 99%, which means that no further purification is necessary.
  • the substrate breadth of this new technology is very high. It is possible to use ⁇ -leaving group-substituted ketones with aryl radicals of different substitution pattern as well as aliphatic halomethyl ketones. Chloroacetyl ketones react in particularly good yields and high ee values.
  • the new process yields a wide range of chiral epoxides in very high yields of> 85%, mostly> 90%, and very high ee values, and depending on the enzyme used, both enantiomers can be obtained.
  • the process according to the invention shall be illustrated by the following examples, without limiting the invention thereto:
  • a mixture of 2 g of 2-chloro-4'-bromo-acetophenone and 10.3 g of toluene was prepared and heated to 45 0 C. 1 ml of this substrate mixture (corresponding to about 160 mg 2-chloro-4'-bromo-acetophenone) was then added to a mixture of 2.1 ml Tris.HCl buffer (0.1 M, pH 7.1), 0 , 2 mg magnesium sulfate, 600 ⁇ L isopropanol, 1 mg NADP sodium salt and 19 U Thermoanaerobium sp. Alcoholdehydrogenase (Juelich Chiral Solutions GmbH). The suspension was shaken at 45 ° C. for 190 minutes.
  • a mixture of 5 g of 2-chloro-4'-iodo-acetophenone and 20 ml of toluene was prepared and heated to 45 0 C. 2 ml of this substrate mixture (corresponding to about 400 mg 2-chloro-4'-iodo-acetophenone) was then mixed with a mixture of 3.1 ml Tris.HCl buffer (0.1 M, pH 7.0), 1 mg of magnesium sulfate, 1 ml of isopropanol, 2 mg of NADP sodium salt and 83 U of Lactobacillus brevis alcohol dehydrogenase. The solution was shaken at 45 ° C. for 64 hours. The ketone was then converted to 89% to the alcohol, as could be determined on a sample. After adding 0.2 M NaOH and MMO further shaking at 40 0 C of the alcohol was converted into the epoxide. This had an ee> 99% (Chiral HPLC with a Chiralpak AD-RH column).
  • Lactobacillus brevis alcohol dehydrogenase for the biological reduction of 2-chloro-1-pyridin-3-yl-ethanone was used. After 17 hours at 40 0 C, a conversion of 99% was reached. Treatment with alkali resulted in complete conversion of the alcohol to Oxirane. This had an ee value of 98.4% (determined by chiral GC 1 cyclodextrin gamma modified with trifluoroacetic acid (TFA)).
  • Example 6 2-Thiophen-3-yl-oxirane. 292 mg of 2-chloro-1-thiophen-3-yl-ethanone was dissolved in 4 ml of toluene and distributed over 2 reaction flasks. To each flask was then added 0.3 ml of isopropanol, 1.5 ml of 0.05 M sodium phosphate buffer, pH 7.1, 2 mg of NADP sodium salt and 2 mg of magnesium sulfate. The first reaction mixture was 110 U Thermoanaerobium sp. Added alcohol dehydrogenase, the second 120 U Lactobacillus brevis alcohol dehydrogenase. After shaking at 40 ° C.
  • Example 7 (R) -2- (4-Chloro-phenyl) -oxirane
  • Treatment with 0.2 ml of 10 M NaOH and a further 30 min shaking resulted in complete conversion to the epoxide with ee> 99.5% (determined by chiral HPLC using a Chiralpak AD-RH column).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Epoxy Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'époxydes chiraux par réduction de cétones substituées avec des groupes partants α avec des alcool déshydrogénases (R)- ou (S)-sélectives sans cellule en la présence d'un cofacteur et éventuellement d'un système approprié de régénération du cofacteur oxydé en alcools chiraux, puis cyclisation induite par une base en époxydes chiraux (équation 1 dans laquelle LG peut représenter F, Cl, Br, I, OSO2Ar, OSO2R4 ou OP(O)OR4R5 et R1, R2 et R3 sont indépendamment l'un de l'autre hydrogène, un radical alkyle en C1-C20 ramifié ou non, éventuellement substitué, un radical cycloalkyle ou alcényle en C3-C10 éventuellement substitué ou un radical aryle carbocylique ou hétérocyclique éventuellement substitué ou un radical compris dans le groupe CO2R4, CONR4R5, COSR4, CS2R4, C(NH)NR4R5, CN, CHaI3, OAr, SAr, OR4, SR4, CHO, OH, NR4R5, Cl, F, Br, I ou SiR4R5R6, où R4, R5 et R6 sont indépendamment l'un de l'autre un hydrogène, un radical alkyle en C1-C20 ramifié ou non, éventuellement substitué, un radical cycloalkyle ou alcényle en C3-C10 éventuellement substitué ou un radical aryle carbocyclique ou hétérocyclique substitué), l'alcool chiral II formé de façon intermédiaire n'étant pas isolé.
EP07846734A 2006-11-30 2007-11-22 Procédé de synthèse stéréosélective d'époxydes chiraux par réduction adh de cétones substituées avec des groupes partants alpha, et cyclisation Withdrawn EP2086952A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE200610056526 DE102006056526A1 (de) 2006-11-30 2006-11-30 Verfahren zur stereoselektiven Synthese von chiralen Epoxiden durch ADH-Reduktion von alpha-Abgangsgruppen-substituierten Ketonen und Cyclisierung
PCT/EP2007/010125 WO2008064817A2 (fr) 2006-11-30 2007-11-22 Procédé de synthèse stéréosélective d'époxydes chiraux par réduction adh de cétones substituées avec des groupes partants alpha, et cyclisation

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EP2086952A2 true EP2086952A2 (fr) 2009-08-12

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DK2195293T3 (da) 2007-08-22 2014-02-03 Astrazeneca Ab Cyclopropylamidderivater
TW201039825A (en) 2009-02-20 2010-11-16 Astrazeneca Ab Cyclopropyl amide derivatives 983
PL2445890T3 (pl) 2009-06-22 2016-02-29 Sk Biopharmaceuticals Co Ltd Sposób wytwarzania estru (R)-1-arylo-2-tetrazoliloetylowego kwasu karbaminowego
US8404461B2 (en) 2009-10-15 2013-03-26 SK Biopharmaceutical Co. Ltd. Method for preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester
NZ600509A (en) 2009-12-29 2014-08-29 Butamax Tm Advanced Biofuels Alcohol dehydrogenases (adh) useful for fermentive production of lower alkyl alcohols
BR112012020629A2 (pt) 2010-02-18 2018-06-19 Astrazeneca Ab forma cristalina, e, método para a terapia de um distúrbio
EP2643467A1 (fr) * 2010-11-24 2013-10-02 Basf Se Procédé de fabrication d'alcools optiquement actifs n-hétérocycliques
US20130273619A1 (en) 2012-04-16 2013-10-17 Basf Se Process for the Preparation of (3E, 7E)-Homofarnesol
CN113831218B (zh) * 2020-06-23 2023-11-28 利尔化学股份有限公司 一种制备4-氟苯基环氧乙烷的方法

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* Cited by examiner, † Cited by third party
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DE69131685T2 (de) * 1990-07-24 2000-04-27 Kanegafuchi Kagaku Kogyo K.K., Osaka Verfahren zur herstellung optisch aktiven (-)-2-halo-1-(substituiertes phenyl)ethanols
DE10105866A1 (de) * 2001-02-09 2002-08-29 Forschungszentrum Juelich Gmbh Verfahren zur Herstellung von optisch aktiven, propargylischen, terminalen Epoxiden
DE102004007029A1 (de) * 2004-02-12 2005-09-08 Consortium für elektrochemische Industrie GmbH Verfahren zur enantioselektiven Reduktion von Ketoverbindungen durch Enzyme
DE102005028312B4 (de) * 2005-06-18 2008-05-08 Archimica Gmbh Verfahren zur Herstellung von enantiomerenreinen Epoxiden durch ADH-Reduktion von α-Abgangsgruppen-substituierten Ketonen und Cyclisierung

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008064817A3 *

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WO2008064817A3 (fr) 2008-07-17
WO2008064817A2 (fr) 2008-06-05

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