Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D317/34—Oxygen atoms
  • C07D317/36—Alkylene carbonates; Substituted alkylene carbonates

Definitions

• the present invention relates to a method of production of enantiomer-enriched alkylene carbonates of formula (I)
• (R) -propylene carbonate are of pharmaceutical interest.
• (R) -propylene carbonate is used as an intermediate in the production of pharmaceutical active substances, as described in, among others, EP1243590,
• (R) -propylene carbonate is generally synthesized "indirectly" in a two-stage process, in which, starting from chiral, preferably enantiomerically-pure (R)- propanediol already synthesized, isolated and purified in a first step, cyclization to (R) -propylene carbonate is carried out in a second step. Cyclization is carried out for example by reaction with a dialkyl carbonate in the presence of a base as catalyst in an alcohol as solvent (EP1243590, EP915894 and L. M. Schultze, H. H. Chapman, N. J. P. Dubree, R. J. Jones, K. M. Kent, T. T. Lee, M. S.
• (R) -propylene carbonate is obtained at 65% yield (EP943612) .
• a number of methods are known for the production and isolation of (R) -1,2- propanediol, for example the separation of racemic mixtures of rac-1, 2-propanediol via oxidation of the
• (R) -propylene carbonate can be produced starting from its racemate via enzymatic racemate separation (JP3747640).
• the remaining (R) -propylene carbonate is obtained with an enantioselectivity of 98% ee .
• a disadvantage with this procedure is once again the general limitation of racemate separations with a maximum achievable conversion of (R) -propylene carbonate of 50%.
• the - most cost-intensive - key step should always be combined with the cyclization without isolation and in particular purification of the respective enantiomerically-pure intermediate.
• the most efficient synthetic route is undoubtedly the direct, asymmetric conversion of a corresponding inexpensive and readily available prochiral substrate to the enantiomerically-pure intermediate and subsequent cyclization of the nonisolated or purified intermediate to (R) -propylene carbonate.
• the asymmetric conversion of a prochiral substrate to the desired product would offer the possibility of quantitative conversion (with theoretically 100% conversion), which is a clear advantage especially relative to the currently known methods of racemate separation with max. 50% conversion .
• the problem of the present invention was therefore to provide a method of production of enantiomer-enriched alkylene carbonates, in particular (R) -propylene carbonate, by which this compound can be produced in a simple manner starting from inexpensive prochiral compounds at a high degree of conversion and with high enantiomeric excess.
• Another problem of the present invention is to provide novel, particularly suitable intermediates for the production of enantiomer-enriched alkylene carbonates, especially (R) -propylene carbonate.
• a particular problem of the present invention was to design the production of enantiomer- enriched alkylene carbonates, especially (R) -propylene carbonate, in such a way that from the technical standpoint, the synthesis is advantageous against a background of economic and ecological considerations and in these respects is superior to the syntheses of the state of the art.
• R 1 represents a linear or arbitrarily branched (Ci-Cs) - alkyl or a (C3-C8) -cycloalkyl residue, the problem was solved in a simple, but no less advantageous manner for that, in that a derivative of formula (II)
• R 2 represents (Ci-C 8 ) -alkyl, (C 2 -C 8 ) -alkoxyalkyl, (C 6 - Ci 8 ) -aryl, (C 7 -Ci 9 ) -aralkyl, (C 3 -Ci 8 ) -heteroaryl, (C 4 -Ci 9 )- heteroaralkyl, (Ci-C 8 ) -alkyl- (C 6 -Ci 8 ) -aryl, (Ci-C 8 ) -alkyl- (C 3 -Ci 8 ) -heteroaryl, (C 3 -C 8 ) -cycloalkyl, (Ci-C 8 ) -alkyl- (C 3 -C 8 ) -cycloalkyl, (C 3 -C 8 ) -cycloalkyl, (C 3 -C 8 ) -cycloalkyl, (C 3 -C 8 )
• the cyclic carbonates can be obtained at yields greater than 90% and correspondingly good enantiomeric purities also greater than 90% ee .
• the drop in yield through formation of by-products as a result of cleavage of the unstable carbonates in the aqueous medium, which was certainly to be expected, is surprisingly only observed to a negligible extent or not at all.
• the present invention includes, as a central step, enantioselective reduction of the keto function present in molecule (II) .
• the reduction can in principle be carried out by the methods that would be considered for this by a person skilled in the art.
• Catalytic methods are advantageous in particular.
• conversion of the derivative of formula (II) to the alcohol of formula (III) using a chemical catalyst and/or biocatalyst is especially advantageous.
• Use of a biocatalyst is quite particularly advantageous. All the enzymes that a person skilled in the art would consider for the present purpose may be considered as the biocatalyst.
• alcohol dehydrogenases or glycerol dehydrogenases have in particular proved advantageous for the reduction in question.
• alcohol dehydrogenases for the stated purpose. All enzymes of this type that are known to a person skilled in the art can in principle be used as alcohol dehydrogenases that can be used as suitable biocatalysts in the method according to the invention, provided they are able to catalyse the conversion/reaction employed in the method according to the invention. This can be established in routine experiments.
• These dehydrogenases preferably originate from bacterial microorganisms or yeasts.
• LK-ADH Lactobacillus kefir
• LB-ADH Lactobacillus brevis
• TB-ADH Thermoanaerobium brockii
• the alcohol dehydrogenase (s) can in principle be used in the method according to the invention in the forms that are familiar to a person skilled in the art (see below) .
• alcohol dehydrogenases are, as oxidoreductases, cofactor-dependent enzymes, for successful execution of the reduction, the cofactor required for the enzyme used must be present in sufficient quantity in the reaction mixture, in order to ensure complete conversion of the ketone.
• cofactors are relatively expensive molecules, on economic grounds the use of the minimum possible amounts of cofactor is a decisive advantage.
• One possible way of being able to use less cofactor than the stoichiometrically required amount is to regenerate it with a second biocatalyst that is present in the charge.
• the enzyme that regenerates the cofactor that is used depends on the one hand on the cofactor used, but on the other hand also on the cosubstrate that is to be oxidized or reduced.
• Some enzymes for the regeneration of NAD(P)H are mentioned in Enzyme Catalysis in Organic Synthesis, Ed. : K. Drauz, H. Waldmann, 1995, VoI I, VCH, p.721.
• the so-called formate dehydrogenase (FDH) see also DE-A 10233046) and alternatively the so- called glucose dehydrogenase (a) M. Kataoka, K. Kita, M. Wada, Y. Yasohara, J. Hasegawa, S. Shimizu, Appl . Microbiol.
• Biotechnol. 2003, 62, 437-445; b) PCT Pat. Appl. WO2005121350, 2005) are of commercial interest and are obtainable on a large scale, and are used at present for the synthesis of amino acids and alcohols, and are accordingly advantageous . They can therefore also be used preferably in the method according to the invention for the regeneration of the cofactor.
• the FDH is derived from the organism Candida boidinii. Further-developed mutants thereof can also be used, e.g. such as are described in DE-A 19753350.
• a glucose dehydrogenase from Bacillus subtilis see inter alia: W. Hilt, G. Pfleiderer, P. Fortnagel, Biochim. Biophys.
• Thermoplasma acidophilum can preferably be used.
• Regeneration can, however, also be substrate-coupled, for example using isopropanol (examples of the technique of cofactor regeneration with isopropanol: a) W. Stampfer, B. Kosjek, C. Moitzi, W. Kroutil, K. Faber, Angew. Chem. 2002, 114, 1056-1059; b) M. Wolberg W. Hummel, C. Wandrey, M. Muller, Angew. Chem. 2000, 112, 4476-4478) .
• the stereospecific conversion/reaction can take place in any media that are suitable for this reaction.
• Catalysis can for example be carried out in purely aqueous solutions or in water-containing media enriched with organic solvents. They may be single-phase or multiphase systems.
• the reaction medium selected is not limiting for the method according to the invention, provided the enzyme chosen can catalyse the desired stereoselective reaction in it.
• the method is carried out with high initial concentrations of substrate.
• substrate typically >50 g/L, preferably >100 g/L and quite preferably >150 g/L.
• the substrate concentrations can optionally be maintained by continuous supply of fresh substrate solution during the catalytic conversion.
• the method can in principle be carried out at any suitable temperature.
• a person skilled in the art will preferably aim to obtain a yield of the desired product that is as high as possible, at highest possible purity and in the shortest possible time.
• the enzymes used should be sufficiently stable at the temperatures used, and the reaction should proceed with highest possible enantioselectivity .
• temperatures of 100 0 C may be reached.
• the temperature is based primarily on the catalytic optimum of the enzyme used. As the lower limit in aqueous systems,
• the pH value during the reaction is also based primarily on the stabilities of the enzymes and cofactors used and can be found by determining the conversion rates and adjusted accordingly for the method according to the invention.
• a preferred range for enzymes will be from pH 5 to 11, but in exceptional cases it may be above or below this, if one of the enzymes used has its catalytic maximum at a lower or higher value.
• a pH range from 5.5 to 10.0, especially from 6.0 to 9.0, can be used for carrying out the reaction.
• the enzymes in question, especially dehydrogenases, of the method according to the invention can be used either in free form as homogeneously purified compounds or as enzyme produced by recombinant technology.
• these polypeptides can also be used as a constituent of an intact "host organism” (genetically modified microorganism) or in conjunction with a cellular mass of the host organism that has been purified as required and if necessary digested.
• Lyophilization in the presence of surface-active substances e.g. Aerosol OT, polyvinylpyrrolidone, polyethylene glycol (PEG) or Brij 52 (diethylene glycol mono-cetyl ether) (Kamiya, N.; Okazaki, S. -Y.; Goto, M.
• Aerosol OT polyvinylpyrrolidone
• PEG polyethylene glycol
• Brij 52 diethylene glycol mono-cetyl ether
• Immobilization on Ni-NTA in combination with a polypeptide supplemented with a His-Tag is also preferred (Purification of proteins using polyhistidine affinity tags. Bornhorst, Joshua A.; Falke, Joseph J. Methods in Enzymology (2000), 326, 245-254) .
• CLEC Cofactor-bound cross- linked enzyme crystals
• the method described here can admittedly also be carried out with isolated enzymes (or immobilizates derived therefrom) in suitable reaction media, but in an especially preferred embodiment the method according to the invention is carried out using a whole-cell catalyst for the reaction, i.e. a system containing (at least one) whole cell (s) , with the cells preferably being capable of simultaneous expression of the desired alcohol dehydrogenase and of the enzyme that regenerates the cofactor.
• a whole-cell catalyst for the reaction i.e. a system containing (at least one) whole cell (s) , with the cells preferably being capable of simultaneous expression of the desired alcohol dehydrogenase and of the enzyme that regenerates the cofactor.
• Recombinant whole-cell catalysts are especially suitable (for the concept of method of using recombinant whole-cell catalysts for enantioselective reduction, see for example, among others: PCT/EP2005/06215) .
• the cell (s) thus preferably express (es) at least one enzyme (polypeptide) with alcohol dehydrogenase activity and at least one with activity for regeneration of the cofactor used.
• enzymes and/or the cells used are preferably derived from the organisms stated previously.
• cells that preferably express at least one enzyme (polypeptide) with alcohol dehydrogenase activity and only optionally one with activity for regeneration of the cofactor used.
• Suitable microorganisms that can be used are in principle all organisms known by a person skilled in the art for this purpose, e.g. yeasts such as Hansenula polymorpha, Pichia sp . , Saccharomyces cerevisiae, prokaryotes, such as E. coli, Bacillus subtilis or eukaryotes, such as mammalian cells, insect cells etc.
• yeasts such as Hansenula polymorpha, Pichia sp .
• Saccharomyces cerevisiae prokaryotes
• E. coli Bacillus subtilis or eukaryotes, such as mammalian cells, insect cells etc.
• strains of E. coli can be used for this purpose, in particular E.
• coli XLl Blue NM 522, JMlOl, JM109, JM105, RRl, DH50C, TOP 10 " or HBlOl. These strains are commonly known and are available for purchase. Quite preferably an organism is used as host organism as stated in DE-A 10155928.
• the advantage of such an organism is simultaneous expression of the two polypeptide systems suitable for the method according to the invention, so that just one recombinant (genetically modified) organism has to be employed for the method according to the invention.
• the corresponding coding nucleic acid sequences can lie on different plasmids with different numbers of copies and/or promoters of varying strength can be used for variable strength of expression of the nucleic acid sequences. With enzyme systems matched in this way, advantageously no accumulation of an intermediate occurs and the reaction in question can take place at an optimum overall velocity.
• a catalytic amount of cofactor can also be added to the whole-cell biocatalyst.
• the reaction system is used for example in a stirred reactor, a cascade of stirred reactors or in membrane reactors, which can be operated both batchwise and continuously.
• a stirred reactor a cascade of stirred reactors or in membrane reactors, which can be operated both batchwise and continuously.
• membrane reactor any reaction vessel in which the catalyst is enclosed in a reactor, whereas low- molecular materials are supplied to the reactor or can leave it.
• the membrane can then be incorporated directly in the reaction space or can be installed outside in a separate filtration module, with the reaction solution flowing continuously or intermittently through the filtration module and the retained material is returned to the reactor.
• Suitable embodiments are described inter alia in WO98/22415 and in Wandrey et al . in Gonzbuch 1998, Maschinenstechnik und Chemieingenieuroire, VDI p. 151ff.; Wandrey et al . in Applied Homogeneous Catalysis with Organometallic Compounds, Vol. 2, VCH 1996, p.832 ff.; Kragl et al . , Angew. Chem. 1996, 6, 684f.
• the continuous operating mode that is possible in this apparatus in addition to the batch and semicontinuous operation can for example be carried out in the cross- flow filtration mode or as dead-end filtration. Both process variants are described in principle in the state of the art (Engineering Processes for Bioseparations, Ed.: L. R. Weatherley, Heinemann, 1994, 135-165; Wandrey et al . , Tetrahedron Asymmetry 1999, 10, 923-928) . In a quite especially preferred embodiment, the method according to the invention is carried out as a one-pot reaction .
• R 2 represents (Ci-C 8 ) -alkyl, (C 2 -C 8 ) -alkoxyalkyl, (C 2 -C 8 )- alkenyl, (C 2 -C 8 ) -alkynyl, (C ⁇ -Cis) -aryl, (C7-C19) -aralkyl, (C 3 -Ci 8 ) -heteroaryl, (C 4 -Ci 9 ) -heteroaralkyl, (Ci-C 8 )- alkyl- (C 6 -Ci 8 ) -aryl, (Ci-C 8 ) -alkyl- (C 3 -Ci 8 ) -heteroaryl, (C 3 -C 8 ) -cycloalkyl, (Ci-C 8 ) -alkyl- (C 3 -C 8 ) -cycloalkyl, (C 3 -C 8 ) -cycloalkyl
• the corresponding derivative of type (II) is first dissolved in a preferably water-containing solvent.
• a preferably water-containing solvent optionally all additives that are necessary for the biocatalyst and for stabilizing it are added and the pH is adjusted if necessary, the biocatalyst is added to the solution and reduction of derivative (II) is thus carried out, with formation of the desired diol derivative of type (III) .
• the latter or the regioisomers of formula (IV) optionally partly resulting therefrom
• the cyclization step preferably in an acid environment, can take place directly in the reaction solution and/or during processing, in particular extraction and/or after completion of processing and isolation if necessary.
• a derivative (II) is dissolved directly in a cell medium suitable for the biocatalyst (expressing the desired enzymes) , the biocatalyst and optionally cofactors required for the enzymes are added and catalytic conversion to the desired enantiomer is carried out at a temperature at which the biocatalyst is stable and the enzymes have a high activity for the particular reaction that they catalyse .
• a further preferred embodiment comprises addition of the biocatalyst before adding the respective derivative of type (II) .
• (Ci-Cs) -alkyl residues methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl plus all of their bond isomers.
• the (Ci-Cs) -alkoxy residue corresponds to the (Ci-Cs) - alkyl residue with the proviso that it is bound to the molecule via an oxygen atom.
• (C2-C8) -alkoxyalkyl means residues in which the alkyl chain is interrupted by at least one oxygen function, and two oxygen atoms cannot be joined together.
• the number of carbon atoms shows the total number of carbon atoms contained in the residue.
• (C3-C8) -cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl residues etc. These can be substituted with one or more halogens and/or residues containing N-, O-, P-, S-, Si-atoms and/or can have N-, O-, P-, S-atoms in the ring, e.g. 1-, 2-, 3-, 4-piperidyl, 1-, 2-, 3-pyrrolidinyl, 2-, 3- tetrahydrofuryl, 2-, 3-, 4-morpholinyl .
• (C 3 -C 8 ) -cycloalkyl- (Ci-Cs) -alkyl residue designates a cycloalkyl residue as presented above, which is bound to the molecule via an alkyl residue as stated above.
• (Ci-Cs) -acyloxy means, within the scope of the invention, an alkyl residue as defined above with max. 8 carbon atoms, which is bound to the molecule via a COO function.
• (Ci-Cs) -acyl means, within the scope of the invention, an alkyl residue as defined above with max. 8 carbon atoms, which is bound to the molecule via a CO function.
• a (C6-Cis) -aryl residue means an aromatic residue with 6 to 18 carbon atoms.
• this includes compounds such as phenyl, naphthyl, anthryl, phenanthryl, biphenyl residues or systems of the type described previously, fused to the molecule in question, for example indenyl systems, which can optionally be substituted with halogen, (Ci-Cs) -alkyl, (Ci-C 8 ) -alkoxy, NH 2 , NH (Ci-C 8 ) -alkyl, N ( (Ci-C 8 ) -alkyl) 2 , OH, CF 3 , NH(Ci-C 8 ) -acyl, N ( (Ci-C 8 ) -acyl) 2, (Ci-C 8 ) -acyl, (Ci-C 8 ) -acyloxy.
• a (C7-C19) -aralkyl residue is a (C ⁇ -Cis) -aryl residue bound to the molecule via a (Ci-C 8 ) -alkyl residue.
• the halogens (Hal) comprise fluorine, chlorine, bromine and iodine.
• enantiomer-enriched or enantiomeric excess means, within the scope of the invention, the proportion of an enantiomer in the mixture with its optical antipode in a range of >50% and ⁇ 100%.
• (R) -propylene carbonate is any form of propylene carbonate in which the (R) -enantiomer is present relative to its optical antipode in the mixture at >90%ee, preferably >95%ee, >96%ee and especially preferably >97%ee.
• diastereomer-enriched denotes the proportion of a diastereomer in the mixture with the other possible diastereomers of the compound in question.
• the whole-cell catalyst of type E. coli DSM14459 containing an (R) -alcohol dehydrogenase from L. kefir and a glucose dehydrogenase from T. acidophilum (for production of the biocatalyst, see WO2005121350) , at a cell concentration of 55 g moist biomass / L, D-glucose (1.5 equivalents relative to the molar amount of ketone used) and 25 mmol 0-
• Processing is carried out by lowering the pH value to ⁇ 3 with concentrated hydrochloric acid and addition of 3.75 g of the filter aid Celite Hyflo Supercel to the reaction mixture, followed by filtration with application of vacuum.
• the filter cake is washed 4 times with 50 mL MTBE and the aqueous phase is extracted correspondingly with the three organic MTBE fractions obtained.
• the solvent is removed from the combined organic phases after drying over magnesium sulphate, yielding as raw product the optically active alcohol 3a at a yield of 50% (of which 12.7 mol.% is rearranged to give the regioisomeric alcohol 4a and 63.6 mol.% has already been cyclized to the desired (R) -propylene carbonate 1) .
• the enantioselectivity of the reaction is 99.67% ee .
• the whole-cell catalyst of type E. coli DSM14459 containing an (R) -alcohol dehydrogenase from L. kefir and a glucose dehydrogenase from T. acidophilum (for production of the biocatalyst, see WO2005121350) , at a cell concentration of 51 g moist biomass / L, D-glucose (1.5 equivalents relative to the molar amount of ketone used) and 25 mmol 0- (ethyloxycarbonyl) -hydroxyacetone, 2b, (corresponding to a substrate concentration of 0.5M) are added to 30 mL of an aqueous phosphate buffer (0.026 M; adjusted to pH 7.0) and the volume is topped up to 50 mL with water.
• an aqueous phosphate buffer 0.026 M; adjusted to pH 7.0
• the reaction mixture is stirred for a reaction time of 25.5 hours at room temperature, maintaining constant pH at -6.5 by adding sodium hydroxide solution (5M NaOH) . After a reaction time of 25.5 hours, conversion of >95% is determined (according to the consumption of sodium hydroxide solution and GC chromatography) . Processing is carried out by lowering the pH value to ⁇ 3 with concentrated hydrochloric acid and addition of 3.75 g of the filter aid Celite Hyflo Supercel to the reaction mixture, followed by filtration with application of vacuum. The filter cake is washed 4 times with 50 mL MTBE and the aqueous phase is extracted correspondingly with the three organic
• the whole-cell catalyst of type E. coli DSM14459 containing an (R) -alcohol dehydrogenase from L. kefir and a glucose dehydrogenase from T. acidophilum (for production of the biocatalyst, see WO2005121350) , at a cell concentration of 49 g moist biomass / L, D-glucose (1.5 equivalents relative to the molar amount of ketone used) and 25 mmol 0- (n- propoxycarbonyl) -hydroxyacetone, 2c, (corresponding to a substrate concentration of 0.5M) are added to 30 mL of an aqueous phosphate buffer (0.026 M; adjusted to pH 7.0) and the volume is topped up to 50 mL with water.
• an aqueous phosphate buffer 0.026 M; adjusted to pH 7.0
• the reaction mixture is stirred for a reaction time of 26 hours at room temperature, maintaining constant pH at -6.5 by adding sodium hydroxide solution (5M NaOH) . After a reaction time of 26 hours, conversion of >95% is determined (according to the consumption of sodium hydroxide solution and GC chromatography) . Processing is carried out by lowering the pH value to ⁇ 3 with concentrated hydrochloric acid and addition of 3.8 g of the filter aid Celite Hyflo Supercel to the reaction mixture, followed by filtration with application of vacuum. The filter cake is washed 4 times with 50 mL MTBE and the aqueous phase is extracted correspondingly with the three organic MTBE fractions obtained.
• the solvent is removed from the combined organic phases after drying over magnesium sulphate, yielding as raw product the optically active alcohol 3c at a yield of 72% (of which 37.3 mol.% is rearranged to give the regioisomeric alcohol 4c and 8.9 mol.% has already been cyclized to the desired (R) -propylene carbonate 1) .
• the enantioselectivity of the reaction is 98.85% ee .

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