WO2005014509A1 - Procede d'elaboration d'esters et d'alcools a enrichissement enantiomere - Google Patents

Procede d'elaboration d'esters et d'alcools a enrichissement enantiomere Download PDF

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WO2005014509A1
WO2005014509A1 PCT/EP2004/007481 EP2004007481W WO2005014509A1 WO 2005014509 A1 WO2005014509 A1 WO 2005014509A1 EP 2004007481 W EP2004007481 W EP 2004007481W WO 2005014509 A1 WO2005014509 A1 WO 2005014509A1
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process according
alcohol
acyl donor
catalyst
secondary alcohol
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PCT/EP2004/007481
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English (en)
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Gerardus Karel Maria Verzijl
Quirinus Bernardus Broxterman
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Dsm Ip Assets B.V.
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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
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/56—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by isomerisation

Definitions

  • the invention relates to a process for the preparation of an enantiomerically enriched ester, in which a mixture of the enantiomers of the corresponding chiral secondary alcohol in the presence of a racemisation catalyst for the substrate is subjected to an enantioselective acylation with the aid of an acyl donor and a stereoselective acylation catalyst upon which the enantiomerically enriched ester and an acyl donor residue are formed.
  • DKR Dynamic Kinetic Resolution
  • transition metal (Ru) based transfer hydrogenation catalysts are used as the racemisation catalyst.
  • hydridic route using catalysts based on transition metals like Ru, Ir and Rh
  • the superior transfer hydrogenation mechanism is the mechanism that also operates in the transition metal based racemisation catalysis.
  • Meerwein, Ponndorf, Verley (MPV) catalysts based on for instance aluminium.
  • a disadvantage of the hydridic method is that the racemisation catalyst, particularly the metal (e.g. Ru) in the catalyst is expensive.
  • the invention now provides a process for the preparation of enantiomerically enriched esters in a DKR process wherein racemisation of the substrate is achieved via a direct hydrogen transfer mechanism wherein a catalyst based on a cheap metal, for instance Al, can be used.
  • a catalyst based on a cheap metal, for instance Al can be used.
  • the MPV catalyst has no or only low activity as a not stereoselective esterification catalyst under the reaction conditions.
  • catalytic amounts of this racemisation catalyst can be used.
  • a direct hydrogen transfer mechanism based catalyst is present as the racemisation catalyst for the substrate, and wherein a carbonyl compound is present. It is expected that the racemisation proceeds via a direct hydrogen transfer mechanism, whereas in the transition metal catalyst based conversion described by Backvall et al. in Journal of Organometallic Chemistry 652 (2002) 105-111 the racemisation proceeds via the hydridic route.
  • the direct hydrogen transfer mechanism essentially does not proceed through a metal hydride bond but rather via a cyclic mechanism as illustrated in Fig. 1 for a specific embodiment.
  • the choice of the secondary alcohol is determined by the desired product. Also, mixtures of different secondary alcohols may be used.
  • a secondary alcohol can, for instance, be represented by the following formula (1),
  • R 1 ⁇ R 2 and R 1 and R 2 each independently represent an alkyl group with for instance 1-20 C-atoms, preferably 1-6 C-atoms, an alkenyl group with for instance 2-20 C-atoms, preferably 2-6 C-atoms, an alkynyl group with for instance 2-20 C-atoms preferably 2-6 C-atoms or an (hetero)aryl group optionally containing for instance one or more O, S or N atoms, with for instance 4-20 C-atoms, preferably 5-10 C-atoms; or wherein R 1 and R 2 together form an (un)saturated ring with for instance 3-20 C-atoms which ring may contain one or more hetero atoms, for instance O, S or N.
  • the alkyl, alkenyl, and (hetero) aryl groups of R 1 and R 2 and the ring may include any substituents that are inert in the reaction system.
  • Suitable substituents are, for example, alkyl groups, (hetero) aryl groups, alkoxy groups, alkenyl groups, (substituted) amine groups which are unreactive in the acylation reaction, halogens, nitrile, nitro, acyl, carboxyl, carbamoyl or sulphonate groups; the substituents may contain for instance 0-19 C-atoms, particularly 0-10 C-atoms.
  • a particular class of secondary alcohols is the class of secondary alcohols with a double or triple bond at the ⁇ , ⁇ -position ((2,3)-position) with respect to the (chiral) alcohol carbon (1 -position), for instance compounds with formula (1), wherein R 1 and/or R 2 represent an alkenyl or alkynyl group and wherein the alkenyl or alkynyl bond in R 1 and/or R 2 is located at the ⁇ , ⁇ -position with respect to the (chiral) alcohol carbon.
  • catalysts acting by the hydride mechanism deactivate by irreversible Michael- addition of the transition-metal-hydride complex to the double bond of ( ⁇ , ⁇ )- unsaturated substrates (J. Am. Chem. Soc.
  • MPV-catalyst A special feature of the MPV-catalyst is the ability of ( ⁇ . ⁇ )-ketone reduction without significant deactivation of the MPV-catalyst. Therefore MPV-catalysts have addional advantage that negligible deactivation will occur during racemisation of ( ⁇ , ⁇ )-unsaturated secondary alcohols in the presence of ( ⁇ , ⁇ )-unsaturated carboxy-com pounds (Michael-acceptors).
  • the carbonyl compound is, for instance, an aldehyde or a ketone, preferably a ketone.
  • the carbonyl compound may be represented by the formula R 3 -C(O)-R 4 , wherein R 3 and R 4 each independently for instance represent H, an alkylgroup with for instance 1-20 C-atoms, or an (hetero) arylgroup with for instance 3-25 C-atoms and for instance containing a 3-10, preferably a 5-8 membered aromatic ring with 0-4 hetero atoms, for example O, S or N or wherein R 3 and R 4 together form an (un)saturated ring with for instance 3-20 C-atoms which ring may contain one or more hetero atoms, for instance O, S or N; with the proviso that not both R 3 and R 4 are H.
  • the alkyl and (hetero) aryl groups and the ring may include one or more substituents that are inert in the reaction system, for instance alkyl, alkenyl, alkynyl, alkoxy, amino, acyl, aryl, aralkyl, alkaryl, carboxamide, acylamino, or heteroaryl groups with, for instance, 1-20 C-atoms, or halogens, cyano or nitro groups.
  • the carbonyl compound is a ketone, it preferably corresponds to the substrate alcohol.
  • the carbonyl compound may be added as such or prepared in situ.
  • the result of the process according to the invention is an enantiomeric balance (e.b.) higher than 0.
  • the enantiomeric balance is defined by the following formula wherein (R) and (S)-substrate and (R) and (S)-product are expressed in moles:
  • the racemisation catalyst according to the invention is represented by the formula L m M n p X q S r wherein: Each L independently represents a complex bound ligand being a ketone or an alcohol; during at least part of the reaction at least one of them being the substrate alcohol or the corresponding ketone.
  • the integer m may have any value, for instance a value up to 100, or even higher,
  • Each M independently represents a metal of group lll a , lll or IV b of the periodic system in oxidation state n;
  • Each X independently represents a covalently bound ligand; at least one X being an alkoxide;
  • Each S independently represents a neutral ligand that may be present in the catalyst and does not participate in the reaction mechanism; m is an integer > 0; n represents the oxidation state of the metal and is > 1 ; p represent the number of metal atoms in the catalyst and is > 1 ; q is equal to n x p; r is > 0.
  • steps 1-4 represent an illustration of the preparation of an active species, which preparation can be performed separately or in situ using methods known per se.
  • Steps 5-8 represent the formation of racemic alcohol (alcohol B in the example of Fig. 1) and steps 9- 11 represent the propagation step with alcohol exchange/liberation of alcohol B and capture of a new molecule (C in the example of Fig. 1 , which equals A).
  • Each metal M is independently chosen from group lll a , group lll b or group IV b of the periodic system, and for instance represents B, Al, Ga, In, Tl, Sc, Y, Ti, Zr, Hf, a lanthanide, or an actinide.
  • M represents Al.
  • the integer n represents the oxidation state of the metal and is > 1 , for instance 1 ,2,3
  • Each X independently represents a covalently bound ligand of which at least one is an alkoxide.
  • Suitable examples are halides, in particular Cl “ or Br " ; alkyl groups with e.g. 1-12 C-atoms, for example methyl, ethyl, n-propyl ( ⁇ Pr) or i-butyl ('Bu) groups, alkoxy groups with e.g.
  • n- pentoxy, i-propoxy, t-butoxy groups preferably the alkoxy groups derived from a secondary alcohol; anions derived from amides, amino alcohols or amines; a CN " group; anionic aromatic ligands, in particular cyclopentadienyl (Cp), pentamethyl cyclopentadienyl (Cp*) or indenyl.
  • the integer q is equal to n x p and may have any value larger than or equal to 1 , for instance between 1 and 100. However, q may also represent higher values.
  • Each S independently represents an easily exchangeable neutral ligand, for example a phosphine in particular PPh 3 or PCy 3 , a nitrile or a coordinating solvent molecule, especially tetrahydrofuran (THF), acetonitrile, dimethylfomamide, an alcohol, an amine, in particular a tertiary amine, for example Et 3 N.
  • the integer r may represent any value larger than or equal to 0, up to 100 or even higher.
  • the integer p represents the number of metal atoms in the catalyst and may range from 1 to any value. If p>1 the catalyst is in the form of a cluster. Such clusters may contain many metal atoms, for instance up to 100; in practice often 1-10.
  • Clusters of aluminium alkoxide catalysts are for instance described in "Catalytic applications of aluminum isopropoxide in organic synthesis” by Jerome et al. Chattem Chemicals, Inc., Chattenooga, TN, USA. Chemical Industries (Dekker) (2003), 89 (Catalysis of Organic Reactions), 97-114, and references cited therein.
  • the active species of the racemisation catalyst can be prepared according to methods known in the art for instance as described for MPV catalysts; for instance as described in (a) Yamamoto, H.; O ganometallics in Synthesis, A Manual, Second edition (Manfred Schlosser (Editor), 2002, 535-577 John & Wiley & Sons Ltd.
  • the activation may be performed separately or in situ.
  • the racemisation catalyst may be as well in the form of a heterogeneous catalyst as in the form of a homogeneous catalyst.
  • Acyl donors that can be used in the process of the present invention are the well known acyl donors as for instance described in Enzyme Catalysis in Organic Synthesis. A comprehensive Handbook, Second, Completely Revised and Enlarged Edition. (Editors: K. Drauz and H. Waldmann), Vol II, 2002, 472, 544, Wiley-VHS, and references cited herein and by U.T. Bornscheuer and R.J.
  • acyl donors are esters of CrC 20 carboxylic acids, preferably isopropyl acetate, isopropenyl acetate, isobutyl acetate, vinyl acetate, ethyl acetate, isopropyl laureate, isopropenyl laureate or other esters of carboxylic acids and C- ⁇ -C 7 alcohols.
  • carboxylic acid esters are used, in particular esters of saturated alcohols, preferably secondary alcohols, for instance isopropanol.
  • the esters preferably are derived from a carboxylic acid with 3-20 C- atoms, particularly a carboxylic acid with 4-20 C-atoms, preferably from butyric acid.
  • a particularly preferred ester to be used as acylating agent is isopropyl butyric acid ester.
  • an acyldonor is chosen such that the acyldonor itself is (relatively) not volatile under the reaction conditions while its acyl donor residue is volatile, and oxidation of the substrate is prevented as much as possible under the reaction conditions.
  • acyldonors are carboxylic acid esters of an alcohol with 1-4 C-atoms and a carboxylic acid with 3-20 C-atoms, particularly a carboxylic acid with 4-20 C- atoms, for instance isopropyl butyric acid ester.
  • the acyl donor residue is removed from the reaction mixture, more preferably it is removed on a continuous basis, for example by preferentially transferring the acyl donor residue to another phase relative to the acyl donor and the other reaction components. This can be achieved by physical and by chemical methods, or by a combination thereof.
  • Examples of physical methods by which the acyl donor residue can irreversibly be removed from the phase in which the stereoselective acylation reaction occurs are selective crystallisation, extraction, complexing to an insoluble complex, absorption or adsorption; or by such a choice of the acyl donor that the acyl donor residue is sufficiently volatile relative to the reaction mixture, or is converted in situ into another compound that is sufficiently volatile relative to the reaction mixture to remove the acyl donor residue irreversibly e.g.
  • acyl donor residue in order to remove the acyl donor residue use can be made of a reduced pressure, depending on the boiling point of the reaction mixture.
  • the pressure (at a given temperature) is preferably chosen in such a way that the mixture refluxes or is close to refluxing.
  • the boiling point of a mixture can be lowered by making an azeotropic composition of the mixture.
  • the concentration at which the reaction is carried out is not particularly critical.
  • the reaction can be carried out without a solvent.
  • a solvent may be used.
  • the reaction can suitably be carried out at higher concentrations, for example at a substrate concentration higher than 0.5 M, in particular higher than 1M.
  • the enantioselective conversion of the secondary alcohol in the ester can be carried out with the known R- or S-selective asymmetric acylation catalysts, for example as described by Christine E Garrett et al., J.Am.Chem. Soc.
  • Suitable enzymes that can be used in the method according to the invention are for example the known enzymes with hydrolytic activity and a high enantioselectivity in such reactions that are also active in an organic environment, for example enzymes with lipase or esterase activity or, when an amide is used as acyl donor, enzymes with amidase activity and esterase or lipase activity, for example originating from Pseudomonas, in particular Pseudomonas fluorescens, Pseudomonas fragi; Burkholderia, for example Burkholderia cepacia; Chromobacterium, in particular Chromobacte um viscosum; Bacillus, in particular Bacillus thermocatenulatus, Bacillus
  • an enzyme originating from Pseudomonas cepacia, Pseudomonas sp., Burkholderia cepacia, Porcine pancreas, Rhizomucor miehei, Humicola lanuginosa, Candida rugose or Candida antarctica or subtilisin is used.
  • an R-selective enzyme for example from Candida antarctica, the R-ester is obtained as product.
  • the S-ester is the desired product, acylation will be performed with an S-selective enzyme.
  • Such enzymes can be obtained via generally known technologies. Many enzymes are produced on a technical scale and are commercially available.
  • the enzyme preparation as used in the present invention is not limited by purity etc. and can be both a crude enzyme solution and a purified enzyme, but it can also consist of (permeabilised and/or immobilised) cells that have the desired activity, or of a homogenate of cells with such an activity.
  • the enzyme can also be used in an immobilised form or in a chemically modified form.
  • the invention is in no way limited by the form in which the enzyme is used for the present invention. Within the framework of the invention it is of course also possible to use an enzyme originating from a genetically modified microorganism.
  • the quantities of racemisation catalyst to be used are not particularly critical.
  • the racemisation catalyst is used in an amount of less than 50, preferably less than 20, more preferably less than 15 mol%, calculated relative to the substrate.
  • the optimum quantities of both catalysts are linked to each other; the quantity of acylation catalyst is preferably adapted so that the overall reaction continues to proceed efficiently, that is to say, that the racemisation reaction does not proceed much slower than the acylation reaction and thus the e.e. of the remaining substrate does not become too high.
  • the optimum balance between racemisation catalyst and acylation catalyst for a given reaction/catalyst system can simply be established by experimental means.
  • the secondary alcohol that is used as substrate can if desired be formed on beforehand from the corresponding ketone in a separate step (that principally does not need to be stereoselective at all) with the aid of a reducing ancillary reagent, the reduction preferably being catalysed by the racemisation catalyst, and a cheap and preferably volatile alcohol being used as reducing ancillary reagent (non stereoselective transfer hydrogenation).
  • the substrate alcohol can optionally be formed in situ from the corresponding ketone with the aid of a reducing ancillary reagent. This gives the freedom of choice to employ substrate ketone or substrate alcohol or mixtures of both as substrate. The choice will depend on the availability and the simplicity of the synthesis.
  • a hydrogen donor is also added as ancillary reagent.
  • ancillary reagent preferably a secondary alcohol is added to the reaction mixture that promotes the conversion of the ketone to the substrate alcohol and is not converted by the acylation catalyst.
  • the ancillary reagent is preferably chosen in such a way that it is not also removed from the reaction mixture by the same irreversible removal method by which the acyl donor residue is removed, that this ancillary reagent is not acylated by the acylation catalyst, and has sufficient reduction potential, relative to the substrate ketone, for the creation of a redox equilibrium. Reducing agents other than alcohols can of course also be used as ancillary reagents.
  • the product ester obtained may subsequently be isolated from the mother liquor using common practice isolation techniques, depending on the nature of the ester, for instance by extraction, distillation, chromatography or crystallization. If the product is isolated by crystallization further enantiomeric enrichment may be obtained. If desired, the mother liquor (which may contain the alcohol, ester and/or ketone involved in the reaction) may be recycled to the non stereoselective reduction, for instance (transfer)hydrogenation, or to the conversion of the mixture of the enantiomers of the alcohol to the enantiomerically enriched ester.
  • the ester in the mother liquor will first be saponified. This is especially desirable if saponification of the ester under the reaction conditions of the non stereoselective reduction by means of (transfer) hydrogenation respectively the conversion of the mixture of the enantiomers of the alcohol to the enantiomerically enriched ester, is rather slow.
  • an enantiomerically enriched ester can be obtained with enantiomeric excess (e.e.) larger than 80%, preferably larger than 90%, more preferably larger than 95%, most preferably larger than 98%, in particular larger than 99%, optionally after (re)crystallization.
  • the enantiomerically enriched ester obtained can subsequently be used as such.
  • the alcohol is the desired product, the enantiomerically enriched ester is subsequently converted by a known procedure into the corresponding enantiomerically enriched alcohol. This can for example be effected by means of a conversion catalysed by an acid, base or enzyme.
  • the enantiomeric excess of the product alcohol can be increased.
  • the enantioselective esterification according to the invention has been carried out with the aid of an enzyme, the same enzyme can very suitably be used for the conversion of the enantiomerically enriched ester into the enantiomerically enriched alcohol.
  • the acyl donor can be freely chosen in such a way that the physical or chemical properties of the acyl donor and the acyl donor residue are optimal for the irreversible removal of the acyl donor residue and the treatment of the reaction mixture.
  • enantiomerically enriched alcohols with an enantiomeric excess (e.e.) larger than 95%, preferably larger than 98%, more preferably larger than 99% can be obtained, optionally after recrystallization and/or hydrolysis with the aid of an enantioselective enzyme.
  • the alcohols thus obtained form commonly used building blocks in the preparation of for example liquid crystals, agrochemicals, food additives, fragrance material and pharmaceuticals, for example of secondary aliphatic alcohols or aryl alcohols, for example of 1-aryl-ethanols, -propanols, -butanols or - pentanols.
  • enantiomeric excess e.e.
  • 1-naphthalene-1 -ethanol in the separation of enantiomers via HPLC with chiral stationary phase on the basis of polysaccharides (WO-A-9627615); 1-naphthalene-1-propanol as an example of a product in the asymmetrically catalysed dialkyl zinc addition to aldehydes (Chem. Lett. (1983), (6), 841-2); 1-(1 ,3-benzodioxol-5-yl)-1-butanol in the preparation of a proteinase 3 inhibitor in the treatment of leukemia (US-A-8508056).
  • the invention also relates to the preparation of an enantiomerically enriched alcohol from the enantiomerically enriched ester obtained.
  • Example I A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (915 mg, 7.5 mmol), acetophenone (3) (900 mg, 7.5 mmol), isopropyl butyrate (1.95 g, 15 mmol) and o-xylene (20 mL). To the well-stirred reaction mixture was added Novozym ® 435 (150 mg). The reaction mixture was heated to 70°C and pressure was slowly decreased to 65-70 mbar in order to get distillation conditions.
  • (RS)-1- phenylethanol (1) 915 mg, 7.5 mmol
  • acetophenone (3) 900 mg, 7.5 mmol
  • isopropyl butyrate 1.95 g, 15 mmol
  • o-xylene 20 mL
  • Example II A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with acetophenone (3) (288 mg, 2.4 mmol), o-xylene (20 mL) and aluminum isopropoxide (163.4 mg, 0.8 mmol). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. The reaction mixture was heated to 70°C and pressure was slowly decreased to 65-70 mbar in order to get distillation conditions. Reaction was conducted for 1 hour without notible reduction of 3.
  • Example A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (1.22 g, 10 mmol), acetophenone (3) (360 mg, 3 mmol), acyl donor (20 mmol) and toluene (20 mL).
  • Novozym ® 435 see table.
  • the reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. Then, solid aluminum isopropoxide (204.3 mg, 1 mmol) was introduced into the reaction mixture. After degassing by dry nitrogen, AI(0'Pr) 3 was dissolved at 70°C.
  • Example IV To a 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (915 mg, 7.5 mmol), acetophenone (900 mg, 7.5 mmol), isopropyl butyrate (1.95 g, 15 mmol) and o-xylene (20 mL). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. To the well-stirred reaction mixture was added Novozym ® 435 (150 mg) and solid aluminum isopropoxide (245.1 mg, 1.2 mmol). The reaction mixture was heated to 70°C and pressure was slowly decreased to 90 mbar in first hour to 65 mbar in second hour.
  • (RS)-1- phenylethanol (1) 915 mg, 7.5 mmol
  • acetophenone 900 mg, 7.5 mmol
  • isopropyl butyrate 1.95 g, 15 mmol
  • the reaction was performed without ketone for 2 hours (step 1).
  • Next step was initiated by the addition of benzophenone (291.5 mg, 1.6 mmol).
  • the reaction was continued for 1 hour under ditillation conditions at 200 mbar (step 2).
  • the observations are listed in table 1.
  • Example VI A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (976 mg, 8 mmol), isopropyl butyrate (2.08 g, 16 mmol), benzophenone (728.9, 4 mmol), o-xylene (20 mL) and solid aluminum isopropoxide (163.4 mg, 0.8 mmol). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. To the well-stirred reaction mixture was added Novozym ® 435 (150 mg). The reaction mixture was heated to 70°C and pressure in the reaction vessel was slowly decreased to 70 mbar in order to get distillation conditions. The isopropanol generated by enzymatic transesterification, together with small amounts of isopropyl butyrate and o-xylene, were slowly distilled under given conditions. The dynamic kinetic resolution was continued during 1 night (Table 2).
  • the reaction mixture was degassed by 5 cycles of vacuum and pre-dried nitrogen purge.
  • a 2 M solution of trimethyialuminum in toluene (0.4 ml, (0.8 mmol) was added. Trimethyialuminum was allowed to react with isopropanol at 70°C for 15 minutes.
  • Experiment was continued by subsequent addition of isopropyl butyrate (2.08 g, 16 mmol), (RS)-1 -phenylethanol (1) (976 mg, 8 mmol) benzophenone (728.9, 4 mmol) and Novozym ® 435 (150 mg).
  • the pressure was slowly decreased to 190 mbar over a period of 1 hour.
  • the dynamic kinetic resolution was continued for 6 hours (Table 4).
  • Racemisation catalyst prepared from 1 ,1 '-bi-2-naphthol and AI(CH 3 ) 3
  • Example VIII Racemisation catalyst prepared from 1 ,1 '-bi-2-naphthol and AI(CH 3 ) 3
  • the acyl donor residue (isopropanol), was distilled at a continuous base at 70°C and 190 mbar for 22 h giving 2b in 94 % yield and 98 % e.e.. Yield calculation of 2b is based on the total amount of 1 and 3 introduced at the beginning of the experiment.
  • a stock solution of catalyst was prepared from AI(CH 3 ) 3 and 1 ,1'- bi-2-naphtol in toluene under a dry atmosphere of nitrogen:
  • a 50-mL Schlenk equipped with a magnetic stirring bar was charged with freshly degassed toluene (9.5 mL) and a 2 M toluene solution of AI(CH 3 ) 3 (0.5 ml, 1 mmol).
  • To the AI(CH 3 ) 3 -solution was added dropwise at r.t., a warm solution of ,1'-bi-2-naphtol (286.3, 1mmol) in toluene (10 mL).
  • (RS)-l-phenylethanol (1) (122 mg, 1 mmol) was then added to the Al-complex solution and the resulting mixture was stirred for 15 minutes at 70°C and cooled to r.t..
  • the catalyst solution was used as such in DKR.
  • the temperature was increased to 70°C and the acyl donor residue (isopropanol) was distilled during the course of the DKR by smooth decrease of the pressure to190 mbar.
  • An additional amount of catalyst solution (1 ml) was added after 1 hour and 17 hours respectively (total catalyst amount is 3 mol %).
  • the reaction was continued for 18 hours by contineous distillation of isopropanol giving 2b in 95 % yield and 99 % e.e.. Yield calculation of 2b is based on the total amount of 1 introduced at the beginning of the experiment.
  • the Oppenauer-oxidation was carried out at 70°C and atmospheric pressure for 1 hour, and then the pressure was decreased to 210 mbar smoothly in order to get distillation of the liberating isopropanol and the remaining acetone.
  • the DKR was continued for 1 night at 70°C and 210 mbar giving 2b in 83 % yield and 95 % e.e..
  • Example XI A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with acetophenone (3) (960 mg, 8 mmol), isopropyl butyrate (2.08 g, 16 mmol), benzhydrol (1.77 g, 9.6 mmol) and toluene (20 mL). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. Solid aluminum isopropoxide (163.4 mg, 0.8 mmol) and Novozym ® 435 (150 mg) was added to the well-stirred reaction mixture. The mixture was degassed once more by 5 cycles of vacuum and dry nitrogen purges.
  • the Meerwein-Ponndorf-Verley reduction/dynamic kinetic resolution was started by heating the reaction mixture to 70°C and by smooth distillation of the generated isopropanol at approximately 190 mbar from the reaction mixture. Removal of isopropanol was accompanied by distillation of small amounts of isopropyl butyrate and toluene. The MPV/DKR was continued for 1 night (table 6). Table 6
  • Example XII A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with cyclohexylmethyl ketone (6) (1.01 g, 8 mmol), benzhydrol (1.77 g, 9.6 mmol) isopropyl butyrate (2.08 g, 16 mmol), toluene (20 mL) and Novozym ® 435 (150 mg). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. Solid aluminum isopropoxide (245 mg, 1.2 mmol) was added to the well- stirred reaction mixture and dissolved at 70°C. The mixture was degassed once more by 5 cycles of vacuum and dry nitrogen purge.
  • the MPV-reduction of 6 was initially performed at atmospheric pressure for 2 hours. Then, the Meerwein- Ponndorf-Verley reduction/dynamic kinetic resolution (MPV-DKR) was conducted by smooth distillation of the generated isopropanol at approximately 210 mbar. Removal of isopropanol was accompanied by distillation of small amounts of isopropyl butyrate and toluene. The MPV/DKR was continued for 24 hours giving 7b in 83 % yield and 99 % e.e..
  • Example XIII Illustration of DKR at high concentration Example XIII A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (6.1 g, 50 mmol), acetophenone (3) (1.8 g, 15 mmol), isopropyl butyrate (13 g, 100 mmol) and toluene (50 mL). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. To the well-stirred reaction mixture was added solid aluminum isopropoxide (1.02 g, 5 mmol) and Novozym ® 435 (930 mg) respectively. The mixture was degassed once more by 5 cycles of vacuum and dry nitrogen purges.
  • (RS)-1- phenylethanol (1) 6.1 g, 50 mmol
  • acetophenone (3) 1.8 g, 15 mmol
  • isopropyl butyrate 13 g, 100 mmol
  • the reaction was started by heating to 70°C and by slow adjustment of the pressure to approximately 190 mbar to get distillative removal of isopropanol. In first 3 hours of the reaction, a significant volume of isopropanol, together with small amounts of acetone, isopropyl butyrate and toluene was collected. The reaction was terminated after 23 hours by cooling to room temperature. Filtration of Novozym ® 435 and solid side products through a glass filter followed by evaporation under reduced pressure of residual isopropyl butyrate and toluene gave a glacial colorless liquid of product. The crude product was hydrolysed in a mixture of methanol (25 mL) and 5 N KOH (12 mL) for 30 minutes at room temperature.
  • Example XIV A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)- ⁇ - vinylbenzylalcohol (4) (13.42 g, 10 mmol), benzophenone (546 mg, 3 mmol), toluene (10 mL), isopropyl butyrate (2.6 g, 20 mmol) and Novozym ® 435 (100 mg). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. To the well-stirred reaction mixture was added solid aluminum isopropoxide (204.25 mg, 1 mmol). The mixture was degassed once again by dry nitrogen.
  • (RS)- ⁇ - vinylbenzylalcohol (4) 13.42 g, 10 mmol
  • benzophenone 546 mg, 3 mmol
  • toluene 10 mL
  • isopropyl butyrate 2.6 g, 20 mmol
  • Novozym ® 435 100
  • the reaction was started by heating the reaction mixture to 70°C and distillation of isopropanol at approximately 190 mbar. Distillation of isopropanol is accompanied by distillation of acetone, isopropyl butyrate. Distillation was continued for 24 hours giving 5b in 87 % yield and 96 % e.e..
  • a stock reaction mixture of 1 was prepared seperately under a dry atmosphere of nitrogen:

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Abstract

L'invention concerne un procédé d'élaboration d'ester à enrichissement énantiomère : on soumet un mélange d'énantiomères de l'alcool secondaire chiral correspondant, en présence d'un catalyseur de racémisation pour le substrat, à une acylation énantiosélective au moyen d'un donneur acyle et d'un catalyseur d'acylation stéréosélectif, donnant l'ester à enrichissement énantiomère et un résidu de donneur acyle, en présence d'un composé carbonyle. Le catalyseur comprend au moins un ligand et un métal M pouvant appartenir au groupe IIIa, IIIb, IVb du système périodique, de préférence Al.
PCT/EP2004/007481 2003-07-15 2004-07-06 Procede d'elaboration d'esters et d'alcools a enrichissement enantiomere WO2005014509A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1710221A1 (fr) * 2005-04-07 2006-10-11 DSM IP Assets B.V. Procédé de préparation d'un ester optiquement active
WO2009144906A1 (fr) * 2008-05-26 2009-12-03 高砂香料工業株式会社 Complexe de l'aluminium et ses utilisations
CN104151169A (zh) * 2014-08-14 2014-11-19 陈永军 一种拆分制备光学纯s-1-苯乙胺的方法
CN104263799A (zh) * 2014-09-17 2015-01-07 王际宽 一种s-2-四氢萘胺的制备方法
CN108906124A (zh) * 2017-03-17 2018-11-30 苏州大学 三茂稀土金属配合物作为催化剂在催化酮和频哪醇硼烷合成反应中的应用
CN113816855A (zh) * 2021-08-19 2021-12-21 常州大学 合成手性烯丙基羧酸酯的方法

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1710221A1 (fr) * 2005-04-07 2006-10-11 DSM IP Assets B.V. Procédé de préparation d'un ester optiquement active
WO2006105996A2 (fr) * 2005-04-07 2006-10-12 Dsm Ip Assets B.V. Procede de preparation d'un compose optiquement actif
WO2006105996A3 (fr) * 2005-04-07 2006-12-21 Dsm Ip Assets Bv Procede de preparation d'un compose optiquement actif
JP5432895B2 (ja) * 2008-05-26 2014-03-05 高砂香料工業株式会社 アルミニウム錯体とその使用
CN102046572A (zh) * 2008-05-26 2011-05-04 高砂香料工业株式会社 铝络合物及其应用
US8329930B2 (en) 2008-05-26 2012-12-11 Takasago International Corporation Aluminum complex and use thereof
WO2009144906A1 (fr) * 2008-05-26 2009-12-03 高砂香料工業株式会社 Complexe de l'aluminium et ses utilisations
CN104151169A (zh) * 2014-08-14 2014-11-19 陈永军 一种拆分制备光学纯s-1-苯乙胺的方法
CN104151169B (zh) * 2014-08-14 2016-08-24 六安佳诺生化科技有限公司 一种拆分制备光学纯s-1-苯乙胺的方法
CN104263799A (zh) * 2014-09-17 2015-01-07 王际宽 一种s-2-四氢萘胺的制备方法
CN104263799B (zh) * 2014-09-17 2018-08-28 王际宽 一种s-2-四氢萘胺的制备方法
CN108906124A (zh) * 2017-03-17 2018-11-30 苏州大学 三茂稀土金属配合物作为催化剂在催化酮和频哪醇硼烷合成反应中的应用
CN108906124B (zh) * 2017-03-17 2020-11-17 苏州大学 三茂稀土金属配合物作为催化剂在催化酮和频哪醇硼烷合成反应中的应用
CN113816855A (zh) * 2021-08-19 2021-12-21 常州大学 合成手性烯丙基羧酸酯的方法

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