EP1381583A1 - Polymergebundener katalysator zur enantioselektiven öffnung von prochiralen anhydriden - Google Patents
Polymergebundener katalysator zur enantioselektiven öffnung von prochiralen anhydridenInfo
- Publication number
- EP1381583A1 EP1381583A1 EP02706770A EP02706770A EP1381583A1 EP 1381583 A1 EP1381583 A1 EP 1381583A1 EP 02706770 A EP02706770 A EP 02706770A EP 02706770 A EP02706770 A EP 02706770A EP 1381583 A1 EP1381583 A1 EP 1381583A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- polymer
- catalyst
- alkyl
- use according
- reaction
- 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- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/11—Compounds covalently bound to a solid support
Definitions
- the present invention is directed to the use of optically active polymer enlarged catalysts.
- the invention is concerned with polymer-enlarged catalysts which have one or more structures of the general formula (I) or (II) as the active unit which determines the chiral induction.
- Homogeneously soluble polymer-enlarged chiral catalysts are important tools for the synthesis of enantiomerically enriched organic compounds, especially on an industrial scale, because on the one hand they help to produce the desired products in an extremely cost-effective manner due to their catalytic activity and the ability to recycle and reuse them. In addition, the reactions carried out with them do not show the phase change of the substrate and product which is inherent in the reaction for heterogeneously soluble polymer-enlarged catalysts. There is still a need for catalysts for use in the organic catalytic synthesis of chiral compounds. Janda and Bolm et al. reported on the recently synthesized representatives of the quinine / quinidine ligands (Chem. Co mun. 1999, 1917-1924; Eur. J. Org. Che. 1988, 21-27).
- the object of the present invention was therefore to specify further uses for homogeneously soluble polymer-enlarged catalysts of the quinine / quinidine type for the asymmetric synthesis of organic compounds.
- optically active homogeneously soluble polymer-enlarged catalysts comprising one or more structures of the general formula (I), (II) or (III) as the active unit which determines the chiral induction
- R 1 , R 2 independently of one another are H, (-CC 8 ) -alkyl,
- (C_-C 8 ) acyl (C 3 -C 8 ) cycloalkyl, (C 6 -C ⁇ 8 ) aryl, (C 7 -C_ 9 ) aralkyl, (C 3 -C ⁇ 8 ) heteroaryl, ( C 4 -C 19 ) heteroaralkyl, ((Ci-C 8 ) alkyl) ⁇ _ 3 - (C 3 -C 8 ) cycloalkyl, ((C_-C 8 ) alkyl) __ 3 - (C 6 -C 18 ) - Aryl, ((-C 8 -C 8 ) alkyl) _- 3 - (C 3 -C 8 ) heteroaryl, R 3 is H, or R 1 , R 2 or R 3 is the link to the polymer enlargement fication,
- R 4 DHQ (I) or DHQD (II) and R 5 is H or the linkage to a polymer, the desired optically enriched compounds are obtained in very excellent yields and with high enantiomeric excesses.
- the catalysts are very easy to separate from the low molecular weight compounds by means of the polymer bond, for example by filtration, and are therefore accessible to the extremely simple, but no less advantageous, recycling desired by the invention.
- the polymer enlargement can be chosen freely within the scope of the invention. It is limited on the one hand by practicality and cost considerations, and on the other hand by technical framework conditions (retention, solubility, etc.).
- Some polymer enlargements for catalysts are known from the prior art (Reetz et al., Angew. Chem. 1997, 109, 1559f .; Seebach et al., Helv. Chim Acta 1996, 79,
- the polymer enlargement is furthermore preferably formed by polyacrylates, polyacrylamides, polyvinylpyrrolidinones, polysiloxanes, polybutadienes, polyisoprenes, polyalkanes, polystyrenes, polyoxazolines or polyethers or mixtures thereof.
- polystyrenes are used to build up the polymer enlargement.
- a linker can be installed between the actual active unit and the polymer enlargement.
- the linker serves to build up a distance between the active unit and the polymer in order to reduce or eliminate mutual interactions which are disadvantageous for the reaction.
- the linkers can be freely chosen by the person skilled in the art. They are to be selected based on how well they are coupled to the polymer / monomer on the one hand and to the active center on the other. Suitable linkers can be found, inter alia, in the references mentioned above under the heading polymer enlargement. In .
- R means H, (-C 8 -C) alkyl, (C 6 -C 8 ) aryl, (C 7 -C 19 ) aralkyl, ((-C 8 ) alkyl) i- 3 - (Ce- Cis) aryl,
- linkers such as e.g. B. 1, 4 '-biphenyl, 1,2-ethylene, 1, 3-propylene, PEG- (2-10), ⁇ , ⁇ -siloxanylene or 1,4-phenylene and, ⁇ -l, 4-bisethylene benzene or Linkers which, starting from siloxanes of the general formula IV
- the size of the polymer enlargement should be such that the catalyst dissolves in the solvent to be used, so that one can work in a homogeneous phase.
- the catalyst used is therefore preferably a homogeneously soluble one. This avoids negative effects that occur due to the phase changes of the substrates and products that would otherwise be necessary when using heterogeneous catalysts.
- the polymer-enlarged catalysts can have an average molecular weight in the range from 1,000 to 1,000,000, preferably 5,000 to 500,000, particularly preferably 5,000 to 300,000, g / mol.
- linker / active unit can be attached to the polymer enlargement: a) the active unit causing the chiral induction is bound with a linked linker or directly to a monomer and this is copolymerized with further unmodified monomers, or b) the active unit causing the chiral induction is linked via a linker or directly to the finished polymer , Possibly.
- polymers can be prepared according to a) or b) and these can be block copolymerized with other polymers which also have the active units which determine the chiral induction or which do not have them.
- the units should be at such a distance from one another that a mutual negative influence on the reactivity (TOF, selectivity) is minimized or does not take place at all.
- the distance between the linker / active centers in the polymer should therefore preferably be in the range of 1-200 monomer units, preferably 5-25 monomer units.
- connection of the linker / active unit used which. can be easily functionalized or allow existing functionality to be used for connection.
- heteroatoms or unsaturated carbon atoms are preferred for establishing the bond.
- the aromatics present can be used as connection points to the linkers / active centers.
- Functionalities can be added to these aromatics, preferably in the 3-, 4-, 5-position, particularly preferably the 4- position, via normal aromatic chemistry to be well connected.
- para-hydroxy, para-chloromethyl or para-aminostyrene oil derivatives are advantageously suitable for this purpose.
- the linker or the active unit there is one acid group or ester group in the monomer constituent, to which the linker or the active unit can be attached before or after the polymerization, preferably via an ester or amide bond.
- Polysiloxanes as a polymer enlargement are preferably constructed in such a way that hydromethylsilane units are also present in addition to dimethylsilane units.
- the linker / active units can then still be coupled via hydrosilylation.
- These can preferably be linked to the functionalities envisaged in the polymer under hydrosilylation conditions (overview of the hydrosilylation reaction by Ojima in The Chemistry of Organic Silicon Compounds, 1989 John Wiley & Sons Ltd., 1480-1526).
- Suitable polysiloxanes modified in this way are known in the literature ("Siloxane polymers and copolymers", White et al., In Ed. S. Patai "The Chemistry of Organic Silicon Compounds” Wiley, Chichester, 1989, 46, 2954; C. Wandrey et al. TH: Asymmetry 1997, 8, 1975).
- connection of polymer to linker / active unit is synonymous with the connection of the active center (active unit) to the linker.
- connection options which have already been described in the prior art for the polymer enlargement of the monomeric active units (WO98 / 35927; Chem. Commun. 1999, 1917; Angew. Chem. 1997, 16, 1835; J. Am. Chem. Soc. 1996, 118, 7632; Tetrahedron Lett. 1997, 38, 1527; Eur. J. Org. Chem. 1998, 21; Angew. Chem. 1997, 109, 773; Chem. Commun. 1997, 2353; Tetrahedron: Asymmetry 1995, 6, 2687; ibid 1993, 4, 2351; Tetrahedron Lett.
- a polymer-enlarged catalyst for the purpose of the invention can also be produced according to the specification in DE10029600.
- the active units are preferably linked to the polymers / linkers via the following groups of compounds.
- the catalysts under consideration are particularly preferably used for the asymmetrical opening of prochiral anhydrides, the process being carried out in a membrane reactor.
- the continuous mode of operation which is possible in this apparatus in addition to the batch and semi-continuous mode of operation can, as desired, be carried out in cross-flow filtration mode (FIG. 2) or as dead-end filtration (FIG. 1).
- cross-flow filtration mode FIG. 2
- dead-end filtration FIG. 1
- reaction is operated in repetitive batch mode and the catalyst is washed in the membrane reactor between the reactions.
- Repetitive batch means carrying out the reaction several times in succession, with the reactants initially being fed to the reactor and, after the reaction has ended, the products being drawn off before the reactor is charged again.
- the catalyst remaining in the reactor is washed before the reactants are fed into the reactor. It has the task of removing reaction residues such as product, starting material and the like still adhering in the reactor from the reactor in order to be able to assume equally good starting conditions. It has been shown that the products are partially bound by the catalyst (eg acid-base pair).
- the washing can therefore preferably also serve this purpose and can be carried out in such a way that no product molecule in the reactor remains mixed or physically bound.
- this reaction of the anhydrides with the catalyst under conditions which help to prevent a reaction of the product with the catalyst.
- the fact that further bases are added to the reaction in order to suppress the acid-base reaction of the products with the catalyst should be regarded as such.
- a catalyst In order for a catalyst to appear suitable for use in a membrane reactor, it has to meet a wide variety of criteria. On the one hand, care must be taken to ensure that there is a correspondingly high retention capacity for the polymer-enlarged catalyst so that there is satisfactory activity in the reactor over a desired period of time without the catalyst having to be replenished continuously, which is disadvantageous in economic terms (DE19910691 ). Furthermore, the catalyst used should have an appropriate tof (turn over frequency) in order to be able to convert the substrate into the product in economically reasonable periods of time.
- the catalysts of the quinine / quinidine type known from the prior art with reaction rates in the period of 2 h and ee values of 85% could be optimized for use in the membrane reactor to reaction rates of 15 minutes and> 90% ee.
- the catalyst must be used in a 10-fold excess over the anhydride.
- the concept of in-situ recycling of the catalyst using a membrane reactor enables economical operation despite the high use of catalysts.
- Preparation of a polymer enlarged (DHQ) 2 AQN catalyst can look as follows.
- mixtures of polymer-enlarged polymers are understood to mean the fact that individual polymers of different provenance are polymerized together to form block polymers. Statistical mixtures of the monomers in the polymer are also possible.
- polymer enlargement is understood to mean the fact that one or more active units which are responsible for the chiral induction are copolymerized in a suitable form with further monomers, or that these units are coupled to an already existing polymer by methods known to the person skilled in the art.
- Forms of the units suitable for copolymerization are well known to the person skilled in the art and can be freely selected by him.
- the preferred procedure is to derivatize the molecule under consideration, depending on the type of copolymerization, with groups capable of copolymerization, e.g. in copolymerization with (meth) acrylates by coupling to acrylate molecules.
- (Ci-C ß ) alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl together with all binding isomers.
- a (C ⁇ -C I S) aryl radical is understood to mean an aromatic radical with 6 to 18 C atoms. In particular, these include compounds such as phenyl, naphthyl, anthryl, phenanthryl, biphenyl radicals.
- (Ci-C ⁇ ) alkoxy is a (C ⁇ -C 8 ) alkyl radical bonded to the molecule under consideration via an oxygen atom.
- a (C 7 -C 9 ) aralkyl radical is a via a (C_-C 8 ) -
- Alkyl residue bound to the molecule (C ⁇ -Cis) aryl residue.
- acrylate is also understood to mean the term methacrylate.
- (CI ⁇ CR) -haloalkyl is a (C_-C 8 ) -alkyl radical substituted with one or more halogen atoms.
- Halogen and fluorine are particularly suitable as halogen atoms.
- (C 3 -C 8 ) heteroaryl radical denotes a five-, six- or seven-membered aromatic ring system of 3 to 18 carbon atoms, which heteroatoms such as, for. B. has nitrogen, oxygen or sulfur in the ring.
- heteroaromatics are in particular radicals, such as 1-, 2-, 3-furyl, such as 1-, 2-, 3-pyrrolyl, 1-, 2-, 3-thienyl, 2-, 3-, 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7-indolyl, 3-, 4-, 5-pyrazolyl, 2-, 4-, 5-imidazolyl, acridinyl, quinolinyl, phenanthridinyl, 2-, 4-, 5-,
- 6-pyrimidinyl This can be substituted one or more times with (-CC 8 ) alkoxy, (-CC 8 ) haloalkyl, OH, halogen, NH 2 , NO 2 , SH, S- (-C 8 ) -alkyl.
- a (C 4 -C 1 9) -heteroaralkyl the (C 7 -C 1 9) -aralkyl corresponding heteroaromatic system is understood.
- the term (C_-C 8 ) alkylene chain is to be understood as a (C)-C 8 ) alkyl radical which is bonded to the molecule in question via two different C atoms. This can be substituted one or more times with (-CC 8 ) alkoxy, (-CC 8 ) haloalkyl, OH, halogen, NH 2 / NO 2 , SH, S- (C 8 -C 8 ) alkyl.
- Cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl or cycloocytyl radicals.
- Halogen is fluorine, chlorine, bromine, iodine.
- membrane reactor is understood to mean any reaction vessel in which the catalyst is enclosed in a reactor while low-molecular substances are fed to the reactor or can leave it.
- the membrane can be integrated directly into the reaction space or installed outside in a separate filtration module, in which the reaction solution flows continuously or intermittently through the filtration module and the retentate is returned to the reactor.
- Suitable embodiments include in W098 / 22415 and in Wandrey et al. in yearbook 1998, process engineering and chemical engineering, VDI p. 151ff .; Wandrey et al. in Applied Homogeneous Catalysis with Organometallic Compounds, Vol. 2, VCH 1996, pp. 832 ff .; Kragl et al. , Appl. Chem. 1996, 6, 684f. described.
- the substrate 1 shows a membrane reactor with dead-end filtration.
- the substrate 1 is transferred via a pump 2 into the reactor space 3, which has a membrane 5.
- the stirrer-operated reactor space contains the catalyst 4, the product 6 and unreacted substrate 1.
- the low molecular weight 6 is mainly filtered through the membrane 5.
- Fig. 2 shows a membrane reactor with cross-flow filtration.
- the substrate 7 is transferred here via the pump 8 into the stirred reactor space, in which the solvent, catalyst 9 and product 14 are also located.
- a solvent flow is set via the pump 16, which leads into the cross-flow filtration cell 15 via a heat exchanger 12 which may be present.
- the low molecular weight product 14 is separated off via the membrane 13.
- High molecular weight catalyst 9 is then passed back into the reactor 10 with the solvent flow, if necessary again via a heat exchanger 12 and possibly via the valve 11.
- the reaction was carried out in 10 ml of toluene. 0.25 mmol of anhydride and 2.5 mmol of methanol were used. Catalyst 3 was used as the catalyst. After the end of the reaction, the reaction solution was pressed out of the reactor via a membrane. The molecular weight-increased catalyst 3, however, remained behind the membrane. The next batch experiment was started by adding the starting materials, which were dissolved in toluene.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Claims
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10120455 | 2001-04-26 | ||
DE10120455 | 2001-04-26 | ||
DE10208592 | 2002-02-27 | ||
DE10208592A DE10208592A1 (de) | 2001-04-26 | 2002-02-27 | Polymergebundener Katalysator zur enantioselektiven Öffnung von prochiralen Anhydriden |
PCT/EP2002/003050 WO2002088047A1 (de) | 2001-04-26 | 2002-03-20 | Polymergebundener katalysator zur enantioselektiven öffnung von prochiralen anhydriden |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1381583A1 true EP1381583A1 (de) | 2004-01-21 |
Family
ID=26009171
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP02706770A Withdrawn EP1381583A1 (de) | 2001-04-26 | 2002-03-20 | Polymergebundener katalysator zur enantioselektiven öffnung von prochiralen anhydriden |
Country Status (4)
Country | Link |
---|---|
US (1) | US20040204606A1 (de) |
EP (1) | EP1381583A1 (de) |
JP (1) | JP2004527555A (de) |
WO (1) | WO2002088047A1 (de) |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19750007A1 (de) * | 1996-11-20 | 1998-05-28 | Degussa | Verfahren zur Herstellung von MeO-Peg-geschützten Dihydrochinin- oder Dihydrochinidinderivaten, neue Dihydrochinin- oder Dihydrochinidinderivate sowie Verwendung derselben |
DE19647892A1 (de) * | 1996-11-20 | 1998-06-04 | Forschungszentrum Juelich Gmbh | Verfahren zur katalytischen, enantioselektiven Reduktion von Ketonen |
CA2405535A1 (en) * | 2000-04-04 | 2001-10-11 | Brandeis University | Catalytic asymmetric desymmetrization of meso compounds |
-
2002
- 2002-03-20 WO PCT/EP2002/003050 patent/WO2002088047A1/de not_active Application Discontinuation
- 2002-03-20 EP EP02706770A patent/EP1381583A1/de not_active Withdrawn
- 2002-03-20 JP JP2002585353A patent/JP2004527555A/ja active Pending
- 2002-03-20 US US10/475,752 patent/US20040204606A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
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See references of WO02088047A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO2002088047A1 (de) | 2002-11-07 |
US20040204606A1 (en) | 2004-10-14 |
JP2004527555A (ja) | 2004-09-09 |
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