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WO2006006851A2 - Procede destine a preparer un ester enrichi eniantomeriquement ou son acide correspondant - Google Patents

Procede destine a preparer un ester enrichi eniantomeriquement ou son acide correspondant Download PDF

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Publication number
WO2006006851A2
WO2006006851A2 PCT/NL2005/000490 NL2005000490W WO2006006851A2 WO 2006006851 A2 WO2006006851 A2 WO 2006006851A2 NL 2005000490 W NL2005000490 W NL 2005000490W WO 2006006851 A2 WO2006006851 A2 WO 2006006851A2
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formula
stands
enantiomerically enriched
ester
alkyl
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PCT/NL2005/000490
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WO2006006851A3 (fr
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Daniel Mink
Joannes Gerardus Theodorus Kierkels
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Dsm Ip Assets B.V.
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Publication of WO2006006851A2 publication Critical patent/WO2006006851A2/fr
Publication of WO2006006851A3 publication Critical patent/WO2006006851A3/fr

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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
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
    • 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
    • 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
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters

Definitions

  • the invention relates to a process for the preparation of an enantiomerically enriched compound of formula 1
  • R A stands for OH or for SH or wherein R A stands for R 15 , wherein R 15 stands for SR 12 or OR 12 , wherein R 12 stands for an ester residue or wherein R A stands for OR 14 or SR 14 , wherein R 14 stands for an ester residue which is not the same as R 12 and wherein R 2 , R 3 and R 4 each independently stand for an optionally substituted (hetero)aryl, an optionally substituted alkyl, OR 5 , CO 2 R 6 , C(O)R 7 , SR 8 , NR 9 R 10 ,
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 each independently stand for H, an optionally substituted alkyl or for an optionally substituted (hetero)aryl, wherein R 2 , R 3 and R 4 are not the same and wherein R 2 and R 3 , R 2 and R 4 or R 3 and R 4 may form a (hetero)cycloalkyl together with the carbon atom to which they are attached, provided that said (hetero)cycloalkyl does not have a plane of symmetry and wherein R 23 stands for
  • R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 each independently stand for O, S or NR 22
  • Enzyme catalyzed stereoselective conversions for compounds with remote chiral centers are known.
  • remote chiral center is meant that the chiral center is at least three bonds away from the reactive center.
  • Fadnavis et. al. (1997) Tetrahedron Asymmetry, 8, 337-339 show a lipase catalyzed stereoselective esterification of racemic ⁇ -lipoic, having a chiral center four carbon atoms away from the reactive center, which resulted in the formation of a product with a maximum enantiomeric excess of 23.8%.
  • Enzyme catalyzed stereoselective conversion of compounds having quaternary chiral centers are also known.
  • Yee et. al. (1992) J. Org. Chem., 57, 3525-3527 describe the enzyme catalyzed stereoselective hydrolysis of tertiary ⁇ -substituted carboxylic acids esters.
  • Chem., 61 , 7398-7401 show stereoselective synthesis of the (S)- ⁇ . ⁇ -disubstituted phenethylamine from ⁇ , ⁇ -disubstituted amino acid esters using a lipase.
  • R 1 stands for OH, SH, SR 12 or OR 12 , wherein R 12 and R 23 , R 2 , R 3 and R 4 are as defined above in the presence of water, H 2 S, an alcohol of formula HOR 14 or a thiol of formula HSR 14 , wherein R 14 stands for an ester residue but is not the same as R 12 acting as a nucleophile and either collecting the remaining enantiomerically enriched compound of formula 1A
  • R 23 , R 1 , R 2 , R 3 and R 4 are as defined above, or collecting
  • R 23 , R 2 , R 3 , R 4 and R 14 are as defined above,
  • R 23 , R 2 , R 3 and R 4 are as defined above,
  • R 1 stands for OR 12 , SR 12 or SH - the resulting enantiomerically enriched acid of formula 2, wherein R 23 , R 2 , R 3 and R 4 are as defined above,
  • An additional advantage of the process of the present invention is that usually the resulting product and/or remaining compound has a relatively high enantiomeric excess (ee).
  • Chiral center has its conventional meaning in the art.
  • a C-atom having four different substituents is a chiral center.
  • Quaternary center has its conventional meaning in the art.
  • the chiral center is the C-atom substituted with R 2 , R 3 and R 4 .
  • This chiral center is also a quaternary center.
  • Reactive center has its conventional meaning in the art.
  • the reactive center is -C(O)R 1 .
  • R 2 , R 3 or R 4 stands for OR 13 , wherein R 13 stands for H, an optionally substituted alkyl or for an optionally substituted (hetero)aryl, preferably H; one of R 2 , R 3 or R 4 stands for a C 1 - C ⁇ -alkyl-, a Ce-Cnraryl-CrCn-alkyl- or a rest group; and one of R 2 , R 3 or R 4 stands for a Ci-C 8 -alkyl- rest group.
  • the ester residue represented by R 12 or by R 14 preferably stands for an alkyl group, for instance an alkyl group with 1-6 C-atoms or an aryl group, for instance an aryl group with 6-12 C-atoms, in particular a methyl, ethyl, propyl, isobutyl or tert. butyl group.
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 13 each independently stand for H, an optionally substituted alkyl of 1-12 C-atoms, more preferably of 1-8 C- atoms (C-atoms of the substituents included) or for a (hetero)aryl of 2-10 C-atoms (C- atoms of the substituents included).
  • the heteroatom(s) is/are chosen from the group of N 1 O and S.
  • R 2 and R 3 , R 2 and R 4 or R 3 and R 4 may form a (hetero)cycloalkyl of preferably 3-6 C-atoms, provided that said (hetero)cycloalkyl does not have a plane of symmetry.
  • R 23 may for example represent a C 3 -C 7 alkyl.
  • z stands for
  • R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 stand for O.
  • R 22 stands for an alkyl, aryl, aralkyl or alkaryl each of which is preferably not more than 10 C-atoms.
  • substituents include alkyl, (hetero)aryl, sulfonyl, alkoxycarbonyl, amidocarbonyl, nitrile, hydroxy, alkoxy, aryloxy, thioalkyl, mercapto, amino and fluorine.
  • enantiomerically enriched' having an enantiomeric excess (e.e.) of either the (R)- or (S) - enantiomer of a compound'.
  • the enantiomeric excess is > 80%, more preferably > 85%, even more preferably > 90%, in particular >95%, more in particular > 97%, even more in particular > 98%, most in particular > 99%.
  • hydrolytic enzyme is meant an enzyme with the ability to hydrolyze an ester group to form the corresponding acid group.
  • Hydrolytic enzymes are known to react with esters to form first a so-called enzyme-acyl complex, after which the enzyme-acyl complex is attacked by a nucleophile to form the resulting product and the free enzyme.
  • This resulting product may for example be a carboxylic acid in case H 2 O iS the nucleophile or a (different) ester in case the nucleophile is an alcohol or a thiol.
  • which ester is formed depends on the alcohol or thiol used. For instance if an alcohol of formula HOR 14 , wherein R 14 stands for an ester residue, but is not the same as R 12 is present in the process of the invention the resulting reaction product is the enantiomerically enriched ester of formula 3
  • R 23t R 2 , R 3 , R 4 and R 14 are as defined above.
  • R 14 stands for an ester residue, but is not the same as R 12 .
  • R 23 , R 2 , R 3 , R 4 and R 14 are as defined above.
  • 'stereoselectivity' of the hydrolytic enzyme is meant that the hydrolytic enzyme preferably catalyzes the conversion of one of the enantiomers of the compound of formula 1.
  • at least the C-atom substituted with R 2 , R 3 and R 4 is chiral (since R 2 , R 3 and R 4 are not the same) and the stereoselectivity of the hydrolytic enzyme should at least discriminate for this chiral center.
  • hydrolytic enzyme with a specific stereoselectivity If a hydrolytic enzyme with a specific stereoselectivity is used, one enantiomer is preferably converted. This means that if a hydrolytic enzyme with an opposite stereoselectivity is used, the other enantiomer is preferably converted.
  • Empirical methods that can predict the enantiomer that is preferably converted by the enzyme exist Hydrolases in organic synthesis. Eds. Kazlauskas and Bomscheuer. Wiley-VCH, 1999).
  • the person skilled in the art may also rely on experimental data.
  • an enzymatic reaction will either yield the (S)-product or the (R)-product, leaving behind the remaining substrate with the opposite stereochemical configuration.
  • the stereoselectivity of an enzyme may be expressed in terms of E- ratio, the ratio of the specificity constants V max /K m of the two enantiomers as described in C-S. Chen, Y Fujimoto, G. Girdaukas, C. J. Sih., J. Am. Chem. Soc. 1982, 704, 7294-7299.
  • the hydrolytic enzyme has an E-ratio > 5, more preferably an E- ratio > 10, even more preferably an E-ratio > 50, most preferably an E-ratio > 100.
  • the E-ratio of an enzyme may be enhanced using mutagenesis techniques known in the art, for example by using the gene site saturation mutagenesis (GSSM) method as described by DeSantis, G. et al., 2003, J. Am. Chem. Soc. VoI 125, no 38, p11477.
  • a stereoselective hydrolytic enzyme suitable for use in the present invention may for example be found in one of the general classes of hydrolytic enzymes, for instance in the group of esterases, lipases, proteases, peptidases or acylases, preferably in the group of esterases or lipases.
  • the hydrolytic enzyme may be derived from both eukaryotic and prokaryotic cells, including but not limited to those from the following mammalian sources: porcine liver, porcine pancreas, for example commercially available porcine pancreatic lipase type Il (L-3126, Sigma); porcine kidney and bovine pancreas; those from the plant source wheat germ; those from the following mold genera: Absidia; Aspergillus; Fusarium; Gibberella; Mucor, Neurospora; Trichoderma; Rhizopus; Rhizomucor, for example Rhizomucor miehei; Thermomyces, for example Thermomyces lanugenousus; those from the following bacterial genera: Achromobacter, Alcaligenes; Bacillus; for example Bacillus licheniformis; Brevibacterium; Corynebacterium; Providencia; Pseudomonas, for example Pseudomonas fluorescens, Pseudomonas cepas
  • Rhodococcus those from the following yeast genera: Candida, for example Candida rugose or Candida Antarctica; and those from the Actonomycete genus Nocardia.
  • the stereoselective hydrolytic enzyme is found in the group of enzymes classified as carboxylic ester hydrolases (EC 3.1.1 ) or in the group of enzymes classified as peptidases, for example EC 3.4.1 , EC 3.4.11 , EC 3.4.21 , more preferably EC 3.4.21.62, EC 3.4.22 or EC 3.4.23.
  • a stereoselective hydrolytic enzyme may also be found in the group of commercially available hydrolytic enzymes.
  • Examples of commercially available hydrolytic enzymes are: enzymes supplied by Fluka: Candida cylindracea lipase, lipase Hog pancreas, lipase Pseudomonas fluorescens, lipase Aspergillus oryzae, lipase Rhizopus niveus, lipase Rhizomucor miehei, lipase Candida antarctica, lipase Mucor javanicus, lipase Rhizopus arrhizus, lipase Penicillium roqueforti, lipase Candida lipolytica, lipoprotein lipase Pseudomonas sp., type B, lipoprotein lipase Pseudomonas cepacia, lipoprotein lipase Chromobacterium viscosum, esterase Bacillus stear
  • the stereoselective hydrolytic enzyme may be used in any form.
  • the hydrolytic enzyme may be used - for example in the form of a dispersion, a solution or in immobilized form - as crude enzyme, as a commercially available enzyme, as an enzyme further purified from a commercially available preparation, as an enzyme obtained from its source by a combination of known purification methods, in whole (optionally permeabilized and/or immobilized) cells that naturally or through genetic modification possess the required stereoselective hydrolytic enzyme activity, or in a lysate of cells with such activity.
  • Mutants of wild-type enzymes can for example be made by modifying the DNA encoding the wild type enzymes using mutagenesis techniques known to the person skilled in the art (random mutagenesis, site-directed mutagenesis, directed evolution, gene shuffling, etc.) so that the DNA encodes an enzyme that differs by at least one amino acid from the wild type enzyme and by effecting the expression of the thus modified DNA in a suitable (host) cell.
  • Mutants of the stereoselective hydrolytic enzyme may have improved properties with respect to (stereo)selectivity and/or activity and/or stability and/or solvent resistance and/or pH prophile and/or temperature prophile.
  • a stereoselective hydrolytic enzyme may for example be selected for the process of the invention by screening several enzymes or host cells expressing genes encoding enzymes for the presence of stereoselective hydrolytic activity. In general, the person skilled in the art is aware of how to screen for enzymes with a desired activity.
  • a suitable enzyme usually for selection of a suitable enzyme, conditions under which the substrate (in this case the compound of formula 1A) and the enzyme are brought into contact are chosen such that it is a good compromise between on the one hand the stability of the enzyme, the substrate and the reaction product and on the other hand the reaction velocity (which usually increases at higher temperatures). Screening for enzymes may be performed at any scale. For practical reasons, if large numbers of enzymes are screened, a reaction volume between 0.15ml and 10ml is used.
  • aqueous solutions are water and water with co-solvent, for example a water-miscible organic solvent or a water-immiscible solvent.
  • water-miscible organic solvents include methanol, ethanol, aceton, dioxane, acetonitrile, tetrahydrofuran, dimethylsulfoxide and dimethylformamide.
  • water-immiscible organic solvents include methyl-t-butyl ether, methyl-isobutyl ketone, toluene, hexane, xylene and iso-octane.
  • the amount of co-solvent is in principle not critical and is usually chosen between 5 and 25 % v/v.
  • the substrate is liquid it may be present in water as such. In case the substrate is solid, it may be advantageous that a co-solvent is also present.
  • a co-solvent is also present.
  • an analytical method for example TLC, HPLC or GC.
  • organic solvents examples include, methanol, ethanol, aceton, dioxane, acetonitril, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, t-butanol, methyl-t-butyl ether, methyl-isobuyl ketone, toluene, hexane, xylene and iso-octane.
  • organic solvents are, methanol, ethanol, aceton, dioxane, acetonitril, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, t-butanol, methyl-t-butyl ether, methyl-isobuyl ketone, toluene, hexane, xylene and iso-octane.
  • water-immiscible organic solvents are preferred.
  • the solvent may also be the alcohol of formula HOR 14 or the thiol
  • the enzyme/substrate ratio in the '(trans)esterification screening 1 or of the 'hydrolysis screening' is in principle not critical and may be chosen between 1/20 and 2/1.
  • the amount of substrate used is in principle also not critical and may for example be between 5mM and 1.5 M.
  • the pH of the 'hydrolysis screening' is in principle not critical and may for example be chosen between 5 and 10, preferably between 6 and 8 and may be kept constant by using a buffered aqueous solution using a buffer concentration of for example between 1OmM and 50OmM. Alternatively, the pH of the screening reaction may be kept constant by using an automated pH-stat system.
  • the temperature of the '(trans)esterification screening' or of the 'hydrolysis screening' is in principle not critical and may be chosen between 20 and 40 0 C. Alternatively, if an enzyme is sought, which should operate at high temperature, the temperature may be chosen a lot higher.
  • the choice of the reaction conditions of the process of the invention depends on the choice of hydrolytic enzyme. Usually, the temperature of the process is chosen between 0 and 90°C, in particular between 10 and 40 0 C; usually the pH of the process is chosen between 4 and 10.
  • the solvent may for example be water, an aqueous solvent, for example water with a water miscible organic solvent, for instance t-butanol, dioxane, methanol, ethanol, tetrahydrofuran, aceton or dimethylsulfoxide; or a two-phase system of water and a water immiscible solvent, for example toluene, hexane, heptane, methyl f-butyl ether, methyl iso-butyl ketone.
  • a water miscible organic solvent for instance t-butanol, dioxane, methanol, ethanol, tetrahydrofuran, aceton or dimethylsulfoxide
  • a water immiscible solvent for example toluene, hexane, heptane, methyl f-butyl ether, methyl iso-butyl ketone.
  • the solvent is preferably an organic solvent comprising at least 1 equivalent of HOR 14 or HSR 14 , wherein R 14 stands for an ester residue, but is not the same as R 12 .
  • organic solvents which may comprise the alcohol or thiol are THF, CH 3 CN, heptane, toluene, hexane, methyl-t-butyl-ether, methyl-iso-butyl ketone.
  • the organic solvent may also be the same as the alcohol or thiol used as the nucleophile.
  • Collecting includes for example isolation by means of conventional methods, for example ultrafiltration, concentration, column chromatography, extraction or crystallization and further reaction of the obtained product (resulting enantiomerically enriched acid of formula 2, ester of formula 3, compound of formula 4 or remaining enantiomerically enriched ester of formula 1).
  • the resulting and/or remaining enantiomerically enriched compounds produced in the process of the invention can suitably be used as building blocks in the preparation of pharmaceuticals.
  • the process of the invention is in particular very suitable for the preparation of enantiomerically enriched compounds of formula 5
  • R 3 respectively R 4 stands for a CrC ⁇ -alkyl-, a or a C 3 - C 8 -cycloalkyl-CrC 4 alkyl- rest group and wherein R 4 respectively R 3 stands for a Ci-C 8 - alkyl- rest group and wherein R 3 and R 4 are not the same and wherein R 12 stands for a C 1 -C 4 alkyl or benzylrest.
  • R 4 stands for a CrC ⁇ -alkyl-, a or a C 3 - C 8 -cycloalkyl-CrC 4 alkyl- rest group and wherein R 4 respectively R 3 stands for a Ci-C 8 - alkyl- rest group and wherein R 3 and R 4 are not the same and wherein R 12 stands for a C 1 -C 4 alkyl or benzylrest.
  • Cyclization of the compound of formula 5 can be performed in a manner known per se, for instance by using a base as described in WO 02/068403 or in US 6,500,963 B2.
  • bases suitable for the cyclization of the compound of formula 5 include: carbonate, OH, metalhydrides, for instance sodiumhydride; organometals, metalamides, for instance butyllithium; metaldialkyamides, for instance lithiumdiethylamide, lithiumdiisopropylamide and metalhexamethyldisilizanes, for instance lithiumhexamethyldisilizane.
  • metal cations may, for example be used lithium, sodium, potassium, rubidium, cesium, magnesium, calcium, titan, silicium, tin- and lanthanoide, preferably lithium or sodium, more preferably lithium.
  • a process for the preparation of enantiomerically enriched compounds of formula 6 is disclosed in US 6,500,963.
  • a disadvantage of said non- enzymatic process is that the process requires the use of an additional compound (a chiral amino alcohol), which either may need to be recycled in a non-qunatitative manner or which is lost.
  • the process of the invention is a commercially feasible enzymatic process. For instance, it only requires the use of catalytic amounts of stereoselective hydrolytic enzyme and the recovery of (expensive) chiral amino alcohol is not necessary.
  • Enantiomerically enriched 5,6-dihydro-4-hydroxy-2-pyrones such as the compounds of formula 6 are important building blocks for the synthesis of a number of pharmaceutically active compounds, for instance for non-peptidic HIV protease inhibitors, more specifically in the potent and orally bioavailable HIV-protease inhibitor tipranavir (US 6,500,963 B2). Also described in US 6,500, 963 B2 is a process for the preparation of tiphnavir from enantiomerically enriched 5,6-dihydro-4-hydroxy-2- pyrones, in particular from enantiomerically enriched 5,6-dihydro-4-hydroxy-6- phenethyl-6-propyl-2H-pyran-2-on. The preparation of the racemic mixture of the compound of formula 5 is for instance described in WO 02/068403, hereby included by reference.
  • Example 3 Determination of activity and enantioselectivity of different hvdrolvtic enzymes.
  • the HPLC was operated at 22°C at a flow rate of 1.2 mL/min using a mobile phase consisting of n-heptane/ethanol/trifluoroacetic acid (93/7/0.1 ). Detection of components was performed using a UV-detector at a wavelength of 254 nm.
  • the HPLC data were used to calculate the intrinsic enantioselectivity of the enzyme, referred to as the enantiomeric ratio (E-ratio).
  • the E-ratio can be considered as an enzyme constant and describes the ability of the enzyme to distinguish between the two enantiomers of a racemic mixture, in an enzyme catalyzed resolution reaction.
  • An enzyme may have a preference for either the (R)-enantiomer or the (S)-enantiomer.
  • the E-ratio commonly used in screening procedures, was first introduced by Chen et. a/. (J. Am. Chem. Soc. (1982), 104: 7294). In case of a non-selective reaction an E- ratio of 1 is obtained. The results are presented in the table below.

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Abstract

L'invention concerne un procédé de préparation d'un ester enrichi énantiomériquement ou son acide correspondant par conversion enzymatique du mélange correspondant d'énantiomères. L'ester ou l'acide enrichi énantiomériquement possède un centre chiral distant et quaternaire. Le procédé de l'invention est particulièrement utile dans la préparation de 5,6-dihydro-4-hydroxy-2-pyrones enrichis énantiomériquement, qui consiste en des blocs de construction importants pour la synthèse d'un certain nombre de composés actifs sur le plan pharmaceutique.
PCT/NL2005/000490 2004-07-08 2005-07-07 Procede destine a preparer un ester enrichi eniantomeriquement ou son acide correspondant WO2006006851A2 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004052831A2 (fr) * 2002-12-10 2004-06-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Procede de preparation de dihydropyrone optiquement active

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004052831A2 (fr) * 2002-12-10 2004-06-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Procede de preparation de dihydropyrone optiquement active

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ORRENIUS ET AL: "Simple conformation space search protocols for the evaluation of enantioselectivity of lipases" PROTEIN ENGINEERING, vol. 11, 1998, pages 1147-1153, XP002407814 *

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