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DE102004032968A1 - Preparation of optically active alkyl succinic acid monoalkyl esters comprising enantioselective hydrogenation of ester compound in presence of catalyst, which carries phospholane ligand - Google Patents

Preparation of optically active alkyl succinic acid monoalkyl esters comprising enantioselective hydrogenation of ester compound in presence of catalyst, which carries phospholane ligand Download PDF

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DE102004032968A1
DE102004032968A1 DE200410032968 DE102004032968A DE102004032968A1 DE 102004032968 A1 DE102004032968 A1 DE 102004032968A1 DE 200410032968 DE200410032968 DE 200410032968 DE 102004032968 A DE102004032968 A DE 102004032968A DE 102004032968 A1 DE102004032968 A1 DE 102004032968A1
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catalyst
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Frank Dr. Hettche
Christoph Dr. Jäkel
Marko Dr. Friedrich
Rocco Dr. Paciello
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BASF SE
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Priority to JP2007519713A priority patent/JP2008505152A/en
Priority to EP05772382A priority patent/EP1765763A2/en
Priority to CN2005800228341A priority patent/CN1980883B/en
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
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Abstract

Preparation of optically active alkyl succinic acid monoalkyl esters (I) comprises enantioselective hydrogenation of ester compounds (II) in the presence of a catalyst, which carries a phospholane ligand (L). Preparation of optically active alkyl succinic acid monoalkyl esters of formula (I) comprises enantioselective hydrogenation of ester compound of formula (II) in the presence of a catalyst, which carries a phospholane ligand of formula (L). D, E : H or 1-10C alkyl; R : 1-10C alkyl, aryl or alkylaryl; R 2>1-6C alkyl, aryl or alkylaryl; R 1>H or R 2>; A : R 1>or heterocyclic compound of formula (b); and B1 : bridge member with 1-5C between two P-atom or Cp-Fe-Cp. [Image] [Image].

Description

Die Erfindung betrifft ein neues Verfahren zur Herstellung von optisch aktiven Alkylbernsteinsäuremonoalkylestern.The The invention relates to a novel process for the production of optical active alkyl succinic acid monoalkyl esters.

Stand der TechnikState of the art

Ein direkter selektiver Zugang zu Systemen des Typs III bzw. ihrer optischen Antipoden

Figure 00010001
über eine asymmetrische Hydrierung ausgehend von ihren direkten ungesättigten Vorläufern ist bislang nicht befriedigend gelöst.Direct selective access to Type III systems or their optical antipodes
Figure 00010001
asymmetric hydrogenation based on its direct unsaturated precursors has not yet been satisfactorily solved.

Dies zeigt sich z.B. bei der Darstellung von (2R)-Methylbernsteinsäure-4-methylester 4 aus billigem leicht zugänglichen Itaconsäuremonomethylester 3.This shows, e.g. in the preparation of (2R) -methylsuccinic acid 4-methyl ester 4 out of cheap easily accessible itaconate Third

Figure 00010002
Figure 00010002

  • K. Achiwa, Y. Ohga, Y. Itaka, Tetrahedron Lett. 1978, 19, 4683 erhalten Verbindung 4 mit 60% Enantiomerenüberschuss (= ee = [Gehalt Enantiomer 1 – Gehalt Enantiomer 2}/(Gehalt Enantiomer 1 + Enantiomer 2)) in Methanol.K. Achiwa, Y. Ohga, Y. Itaka, Tetrahedron Lett. 1978, 19, 4683 gives compound 4 with 60% enantiomeric excess (= ee = [content enantiomer 1 - content Enantiomer 2} / (content enantiomer 1 + enantiomer 2)) in methanol.
  • W. C. Christopfel, B. D. Vineyard, J. Am. Chem. Soc. 1979, 101, 4406 erhalten Verbindung 4 mit 55%ee in Methanol.W.C. Christopheel, B.D. Vineyard, J. Am. Chem. Soc. 1979, 101, 4406 obtain compound 4 with 55% ee in methanol.
  • S. Saito, Y. Nakamura, Y. Morita, Chem. Pharm, Bull. 1985, 33, 5284 erhalten Verbindung 4 mit 90%ee in Benzol/MeOH 1/4.S. Saito, Y. Nakamura, Y. Morita, Chem. Pharm, Bull. 1985, 33, 5284 gives compound 4 with 90% ee in benzene / MeOH 1/4.
  • H. Kawano, Y. Ishii, T. Ikariya, M. Saburi, S. Yoshikawa, Tetrahedron Lett. 1987, 28, 1905 erhalten Verbindung 4 mit 60%ee in Toluen/THF.H. Kawano, Y. Ishii, T. Ikariya, M. Saburi, S. Yoshikawa, Tetrahedron Lett. 1987, 28, 1905 obtained compound 4 with 60% ee in toluene / THF.
  • D. Carmichael, H. Doucet, J. M. Brown, Chem. Commun. 1999, 261 H. Kawano, T. Ikariya, Y. Ishii, M. Saburi, S. Yoshikawa et al., J. Chem. Soc. Perkin Trans. 11989, 1571 erhalten Verbindung 4 mit 94%ee in Methanol.D. Carmichael, H. Doucet, J.M. Brown, Chem. Commun. 1999, 261 H. Kawano, T. Ikariya, Y. Ishii, M. Saburi, S. Yoshikawa et al., J. Chem. Soc. Perkin Trans. 11989, 1571 is compound 4 94% ee in methanol.

U. Berens, M. Burk, A. Gerlach (WO 00/27855; EP 1 127 061 B1 ) erhalten Verbindung 4 mit 95%ee in Methanol.U. Berens, M. Burk, A. Gerlach (WO 00/27855; EP 1 127 061 B1 ) obtained Compound 4 with 95% ee in methanol.

Die bei den angeführten Verfahren erzielte optische Reinheit genügt damit ohne zusätzliche Anreicherungsschritte nicht den Anforderungen im Wirkstoffbereich, welche in den meisten Fällen einen Enantiomerenüberschuss von ≥ 98 % ee fordern.The at the listed Process achieved optical purity is sufficient without additional Enrichment steps do not meet the requirements in the field of active substances, which in most cases an enantiomeric excess of ≥ 98 Demand% ee.

Andere Verfahren, die zu einer höheren optischen Reinheit führen, verwenden entweder hohe Katalysatormengen, d.h. ein niedriges Substrat/Katalysatorverhältnis (s/c) , was für eine industrielle Erzeugung unwirtschaftlich ist, oder es werden Reaktionsbedingungen (vor allem Lösungsmittel) gewählt, die aus Umweltschutzgesichtspunkten oder aus Gründen der Arbeitssicherheit problematisch sind.Other Procedures leading to a higher lead to optical purity, use either high amounts of catalyst, i. a low substrate / catalyst ratio (s / c) , what kind of an industrial production is uneconomic, or it will become Reaction conditions (especially solvents) chosen, the for reasons of environmental protection or for reasons of occupational safety are problematic.

M. Ostermeier, B. Brunner, C. Korff, G. Helmchen, Eur. J. Org. Chem. 2003, 3453 erhalten Verbindung 4 bei einem s/c Verhältnis von 200/1 mit 97.3%ee in Dichlormethan, in C6H5CF3 wird, ebenfalls bei s/c 200/1, ein ee von 98.3% erzielt. In Dichlorethan wird eine Reinheit von 99.3%ee bei einem s/c Verhältnis von 1000/1 erreicht.M. Easter Meier, B. Brunner, C. Korff, G. Helmchen, Eur. J. Org. Chem. 2003, 3453 obtain Compound 4 at a S / C ratio of 200/1 with 97.3% ee in dichloromethane in the C6 H 5 CF 3 , also at s / c 200/1, achieved an ee of 98.3%. In dichloroethane, a purity of 99.3% ee is achieved at a s / c ratio of 1000/1.

Aus den o.g. Gründen sind alle diese Verfahren für eine einstufige direkte Synthese von optisch aktiven Bernsteinsäurealkylestern aus ihren billigen, leicht zugänglichen olefinischen Vorläufern im technischen Maßstab nicht geeignet.For the above reasons, all of these methods are for a one-step direct synthesis of optically active succinic acid alkyl esters from their cheap, readily available olefinic precursors on an industrial scale not suitable.

Es bestand daher die Aufgabe, ein neues Verfahren zur Herstellung von optisch aktiven Alkylbernsteinsäuremonoalkylestern bereitzustellen, welches bei niedrigen Katalysatormengen (s/c ≥ 20 000/1) und gleichzeitig umweltverträglichen Reaktionsbedingungen einen vollständigen Reaktionsumsatz sowie hohe optische Ausbeute (≥ 98 ee) erzielt, so dass es eine effiziente, umweltgerechte, kostengünstige technische Synthese erlaubt.It It was therefore the object of a new process for the preparation of optically active Alkylbernsteinsäuremonoalkylestern which can be prepared at low amounts of catalyst (s / c ≥ 20 000/1) and at the same time environmentally friendly Reaction conditions a complete reaction conversion as well high optical yield (≥ 98 ee), so that it is an efficient, environmentally sound, cost-effective technical Synthesis allowed.

Beschreibung der Erfindungdescription the invention

Gefunden wurde ein Verfahren zur Herstellung von optisch aktiven Alkylbernsteinsäuremonoalkylestern der Formel (I)

Figure 00030001
wobei D und E unabhängig voneinander H, C1-C10 Alkyl,
R C1-C10-Alkyl, Aryl oder Alkylaryl bedeuten,
indem man eine Verbindung der Formel (II)
Figure 00030002
wobei D, E und R die o.g. Bedeutungen besitzen,
in Gegenwart eines Katalysators, der einen Phospholanliganden der Formel (L) trägt,
Figure 00030003
wobei:
R1 und R2 unabhängig voneinander C1-C6-Alkyl, Aryl, Alkylaryl,
R1 außerdem Wasserstoff,
A entweder R1 oder
Figure 00030004
mit B = ein Brückenglied mit 1 – 5 C-Atomen zwischen den beiden P-Atomen oder Cp-Fe-Cp bedeuten.
enantioselektiv hydriert.A process has been found for the preparation of optically active alkyl succinic acid monoalkyl esters of the formula (I)
Figure 00030001
where D and E independently of one another are H, C 1 -C 10 -alkyl,
R is C 1 -C 10 -alkyl, aryl or alkylaryl,
by dissolving a compound of the formula (II)
Figure 00030002
where D, E and R have the abovementioned meanings,
in the presence of a catalyst bearing a phospholane ligand of formula (L),
Figure 00030003
in which:
R 1 and R 2 independently of one another are C 1 -C 6 -alkyl, aryl, alkylaryl,
R 1 also hydrogen,
A either R 1 or
Figure 00030004
where B = a bridge member with 1-5 C atoms between the two P atoms or Cp-Fe-Cp.
enantioselectively hydrogenated.

Die Verbindungen der Formel (I) sind optisch aktive Verbindungen, die jeweils ein Enantiomer (R oder S) darstellen sollen.The Compounds of the formula (I) are optically active compounds which are each intended to represent one enantiomer (R or S).

Unter enantioselektiver Hydrierung soll im folgenden verstanden werden, dass nicht beide Enantiomere in gleichem Ausmaß durch die Hydrierung entstehen, sondern dass ein Enantiomer (R bzw. S) in hoher optischer Reinheit, insbesondere mit einem ee-Wert von 98, 99, 99,5 % gebildet wird.Under enantioselective hydrogenation will be understood below that not both enantiomers are formed to the same extent by the hydrogenation, but that one enantiomer (R or S) in high optical purity, especially with an ee value of 98, 99, 99.5% is formed.

Die Ausgangsverbindungen der Formel (II) sind literaturbekannt und können leicht nach gängigen Methoden (für D=E=H; R=Me siehe z.B. A. R. Devi, S. Rajaram, Ind. J. Chem. 2000, 398, 294–296 oder R. C. Anand, V. A. Milhotra, J. Chem. Res. (S)1999, 378–379 oder R. N. Ram, I. Charles, Tetrahedron 1997, 53, 7335–7340) hergestellt werden. Bevorzugte Ausgangsverbindungen (II) sind solche, in denen D und E unabhängig voneinander die Bedeutung H, Methyl, Ethyl, Propyl, Butyl, Pentyl, Hexyl, Heptyl, Octyl, Nonyl, Decyl besitzen, wobei die Alkylbezeichnung sowohl die unverzweigten als auch die verzweigten Isomere umfasst. Besonders bevorzugt sind diejenigen Ausgangsverbindungen, bei denen D und E H und Methyl, insbesondere solche, bei denen D und E H bzw. D und E Methyl bedeuten. Weitere bevorzugte Ausgangsverbindungen (II) sind solche, bei denen D H und E Butyl bedeuten.The Starting compounds of the formula (II) are known from the literature and can be easily according to common Methods (for D = E = H; R = Me see, e.g. A.R. Devi, S. Rajaram, Ind. J. Chem. 2000, 398, 294-296 or R.C. Anand, V.A. Milhotra, J. Chem. Res. (S) 1999, 378-379 or R.N. Ram, I. Charles, Tetrahedron 1997, 53, 7335-7340) become. Preferred starting compounds (II) are those in which D and E independent each other is H, methyl, ethyl, propyl, butyl, pentyl, Hexyl, heptyl, octyl, nonyl, decyl, wherein the alkyl name includes both the unbranched and the branched isomers. Especially preferred are those starting compounds in which D and E H and methyl, especially those in which D and E are H and D, respectively and E is methyl. Further preferred starting compounds (II) are those in which D is H and E is butyl.

Der Rest R kann C1-C10-Alkyl bedeuten, wobei einzelne H-Atome des Alkylrests wiederum durch weitere Reste wie OH, NH2, NO2, CN, F, Cl, Br, J, ersetzt sein können. Weiterhin kann R auch Arylreste wie Phenyl, Naphtyl, sowie Alkylarylreste wie Benzyl bedeuten, wobei die Arylreste auch wiederum substituiert sein können. Bevorzugte Reste R sind Methyl, Ethyl, Propyl, i-Propyl und tert-Butyl. Besonders bevorzugt ist R = Methyl.The radical R may denote C 1 -C 10 -alkyl, wherein individual H atoms of the alkyl radical may in turn be replaced by further radicals such as OH, NH 2 , NO 2 , CN, F, Cl, Br, J. Furthermore, R can also be aryl radicals such as phenyl, naphthyl, and also alkylaryl radicals such as benzyl, where the aryl radicals can also be substituted again. Preferred radicals R are methyl, ethyl, propyl, i-propyl and tert-butyl. Particularly preferred is R = methyl.

Die Katalysatoren bestehen aus einem Metallatom der Gruppe Pd, Pt, Ru, Rh, Ni, Ir. Besonders bevorzugt sind Katalysatoren mit Rh, Ru oder Ir als Metallatom, insbesonder sind Rh Katalysatoren für das erfindungsgemässe Verfahren geeignet.The Catalysts consist of a metal atom of the group Pd, Pt, Ru, Rh, Ni, Ir. Particularly preferred are catalysts with Rh, Ru or Ir as a metal atom, in particular Rh are catalysts for the inventive method suitable.

Als Metallquellen für die Katalysatorherstellung können Precursor wie etwa Pd2(DBA)3, Pd(Oac)2, [Rh(COD)Cl]2, [Rh(COD)2)]X, Rh(acac)(CO)2, RuCl2(COD), Ru(COD)(methallyl)2, Ru(Ar)Cl2, Ar = Aryl, sowohl unsubstituiert als auch substituiert, [Ir(COD)Cl]2, [Ir(COD)2]X, Ni(allyl)X bevorzugt verwendet werden. Anstatt COD (= 1,5- Cyclooctadien) kann auch NBD (= Norbornadien) verwendet werden.As metal sources for catalyst preparation, precursors such as Pd 2 (DBA) 3 , Pd (Oac) 2 , [Rh (COD) Cl] 2 , [Rh (COD) 2 )] X, Rh (acac) (CO) 2 , RuCl 2 (COD), Ru (COD) (methallyl) 2 , Ru (Ar) Cl 2 , Ar = aryl, both unsubstituted and substituted, [Ir (COD) Cl] 2 , [Ir (COD) 2 ] X, Ni (allyl) X are preferably used. Instead of COD (= 1,5-cyclooctadiene), NBD (= norbornadiene) can also be used.

X kann dabei jedes dem Fachmann bekannte generell nutzbare Anion in der asymmetrischen Synthese sein. Beispiele für X sind Halogene wie Cl–, Br–, I–, BF4 – , ClO4 –, SbF6 –, PF6 –, CF3SO3 –, BAr4 –. Bevorzugt für X sind BF4 –, CF3SO3 –, SbF6 –, ClO4 –, insbesondere BF4 – und CF3SO3 –.X can be any generally known anion in asymmetric synthesis known to those skilled in the art. Examples of X are halogens, such as Cl -, Br -, I -, BF 4 -, ClO 4 -, SbF 6 -, PF 6 -, CF 3 SO 3 -, BAr 4 -. Preferred for X are BF 4 - , CF 3 SO 3 - , SbF 6 - , ClO 4 - , especially BF 4 - and CF 3 SO 3 - .

Des weiteren enthalten die Katalysatoren des erfindungsgemäßen Verfahrens einen oder mehrere Phospholanliganden der allgemeinen Formel (L). Bevorzugte Substituenten R1 und R2 sind H, Methyl, Ethyl, n-Propyl, isopropyl, n-Butyl, Isobutyl, tert.Butyl, Benzyl. Besonders bevorzugt ist die Substituentenkombination aus R1 = H und R2 = Methyl.Furthermore, the catalysts of the process according to the invention contain one or more phospholane ligands of the general formula (L). Preferred substituents R 1 and R 2 are H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, benzyl. The substituent combination of R 1 = H and R 2 = methyl is particularly preferred.

Weiterhin sind auch solche Reste R1 bevorzugt, bei denen die beiden R1 verbrückt sind wie z.B Isopropyliden oder Benzyliden.Furthermore, those radicals R 1 are preferred in which the two R 1 are bridged, such as isopropylidene or benzylidene.

Im Falle der Diphospholane sind solche bevorzugt bei denen

Figure 00050001
In the case of diphospholanes, those are preferred in which
Figure 00050001

Besonders bevorzugt sind solche Brückenglieder B bei denen n=1 oder 2 oder m=0 ist.Especially preferred are such bridge members B where n = 1 or 2 or m = 0.

Bevorzugte Liganden L sind solche, in denen A einen weiteren Phospholanrest zusammen mit einem Brückenglied B darstellt, wobei B eine Brücke aus 1 bis 5 C-Atomen zwischen den beiden Phosphoratomen darstellen kann. Der Ausdruck 1–5 C-Atome zwischen den beiden Phosphoratomen bedeutet nicht, dass B aus maximal 5 C-Atomen besteht, sondern dass die direkte Verbindung zwischen den beiden P-Atomen nicht mehr als 5 C-Atome umfasst. B kann beispielsweise ein Phenylring sein, falls die beiden P-Atome daran orthoständig verknüpft sind.Preferred ligands L are those in which A represents a further phospholane residue together with a bridging member B, where B can represent a bridge of 1 to 5 C atoms between the two phosphorus atoms. The expression 1-5 C atoms between the two phosphorus atoms does not mean that B consists of a maximum of 5 C atoms, but that the direct connection between the two P atoms no longer exists as 5 C atoms. For example, B may be a phenyl ring if the two P atoms are ortho attached to it.

Das Brückenglied B kann aber auch eine Ferrocen-artige Verbindung sein, bestehend aus substituierten oder unsubstituierten Cyclpentadienylresten (Cp), die sandwichartig ein Fe-Atom umfassen (Cp-Fe-Cp), wobei die P-Atome an die Cp-Reste gebunden sind.The bridge member B can also be a ferrocene-type compound consisting from substituted or unsubstituted cyclopentadienyl radicals (Cp), which sandwich a Fe atom (Cp-Fe-Cp), where the P atoms are bound to the Cp residues.

Besonders bevorzugte Liganden L sind:

Figure 00060001
Particularly preferred ligands L are:
Figure 00060001

Erfindungsgemäß mitumfasst sind nicht nur die hier formelmäßig abgebildeten Enantiomere sondern auch ihre optischen Antipoden.Included in the invention are not just the formulas shown here Enantiomers but also their optical antipodes.

Für die Herstellung der Rophos-Katalysatoren wird auf die EP 0 889 048 verwiesen, deren gesamter Inhalt hiermit in Bezug genommen wird.For the preparation of Rophos catalysts is on the EP 0 889 048 referenced, the entire contents of which are hereby incorporated by reference.

Ligand-Metall-Komplexe lassen sich herstellen, indem man in bekannter Weise (z.B. Uson, Inorg. Chim. Acta 73, 2751983, EP-A 0158875 , EP-A 437690) durch Umsetzung mit Rhodium-, Iridium-, Ruthenium-, Palladium-, Platin-; Nickelkomplexen, die labile Liganden enthalten (z.B. [RuCl2(COD)]n, [Rh(COD)2]BF4, [Rh(COD)2]CF3SO3 Rh(COD)2ClO4, [Ir(COD)Cl]2, p-Cymol-Rutheniumchlorid-dimer) katalytisch aktive Komplexe synthetisiert. Anstelle von COD kann auch NBD mit gutem Erfolg für die Herstellung der Komplexe eingesetzt werden.Ligand-metal complexes can be prepared by reacting in a known manner (eg Uson, Inorg. Chim. Acta 73, 2751983, EP-A 0158875, EP-A 437690) by reaction with rhodium, iridium, ruthenium, palladium -, platinum; Nickel complexes containing labile ligands (eg, [RuCl 2 (COD)] n , [Rh (COD) 2 ] BF 4 , [Rh (COD) 2 ] CF 3 SO 3 Rh (COD) 2 ClO 4 , [Ir (COD ) Cl] 2 , p-cymene-ruthenium chloride dimer) catalytically active complexes synthesized. Instead of COD, NBD can also be used successfully for the preparation of the complexes.

Wie dem Fachmann bekannt kann der Komplex (= Präkatalysator) vor Benutzung erzeugt, isoliert und anschließend „fertig" eingesetzt werden oder vor der eigentlichen Hydrierung im Reaktionsgefäß in situ erzeugt werden (s.u).As the expert knows the complex (= pre-catalyst) before use generated, isolated and then used "ready" or before the actual hydrogenation in the reaction vessel in situ be generated (s.u).

Als Lösungsmittel sind alle dem Fachmann für asymmetrische Hydrierung bekannten Lösungsmittel geeignet. Bevorzugte Lösungsmittel sind niedrige Alkylalkohole wie Methanol, Ethanol, Isopropanol, sowie Toluol, THF, Essigester. Besonders bevorzugt wird in dem erfindungsgemässen Verfahren Methanol als Lösungsmittel eingesetzt.When solvent are all the specialist for asymmetric hydrogenation known solvents suitable. preferred solvent are lower alkyl alcohols such as methanol, ethanol, isopropanol, as well as toluene, THF, ethyl acetate. Particular preference is given in the inventive method Methanol as solvent used.

Die erfindungsgemäße Hydrierung wird in der Regel bei einer Temperatur von –20 bis 150°C, bevorzugt bei 0 bis 100°C und besonders bevorzugt bei 10 – 80°C durchgeführt.The hydrogenation according to the invention is usually at a temperature of -20 to 150 ° C, preferably at 0 to 100 ° C and especially preferably carried out at 10 - 80 ° C.

Die erfindungsgemäße Hydrierung erlaubt es, Substrat/Katalysatorverhältnisse s/c ≥ 20 000/1 einzusetzen und liefert dabei ≥ 98 % ee. Selbst bei s/c 110 000/1 wird in der Regel ein ee von 98 % erreicht.The hydrogenation according to the invention allows substrate / catalyst ratios s / c ≥ 20 000/1 and provides ≥ 98 % ee. Even with s / c 110 000/1, as a rule, an ee of 98% reached.

Durch eine geeignete Immobilisierung des Katalysators lässt sich der Katalysatorverbrauch noch weiter absenken.By a suitable immobilization of the catalyst can be reduce the catalyst consumption even further.

Der Wasserstoffdruck kann in einem großen Bereich zwischen 0,1 bar und 300 bar für das erfindungsgemäße Hydrierverfahren variiert werden. Sehr gute Ergebnisse erhält man in einem Druckbereich von 1 – 50 bar, bevorzugt 1 – 20 bar.Of the Hydrogen pressure can be in a wide range between 0.1 bar and 300 bar for the hydrogenation process according to the invention be varied. Very good results are obtained in a pressure range from 1 to 50 bar, preferably 1 - 20 bar.

Die Aufarbeitung des Reaktionsgemisches erfolgt mit dem Fachmann bekannten Arbeitsweisen. Das Produkt kann z.B. in ein Carboxylat überführt , ausgefällt und so vom Katalysator abgetrennt werden, alternativ kann der Katalysator auch auf einem Bett adsorptiv gebunden werden, was eine leicht durchführbare chromatographische Reinigung erlaubt. Auch eine destillative Abtrennung des Produkts vom Katalysator ist möglich.The Workup of the reaction mixture is known to those skilled in the art Ways of working. The product may e.g. converted into a carboxylate, precipitated and be separated from the catalyst, alternatively, the catalyst also be adsorptively bound to a bed, which is an easily performed chromatographic Cleaning allowed. Also a distillative removal of the product from the catalyst is possible.

Weitere bevorzugte Ausführungsformen sind in den Unteransprüchen und dem experimentellen Teil beschrieben.Further preferred embodiments are in the subclaims and the experimental part.

Experimenteller TeilExperimental part

Beispiel 1example 1

Herstellung des optisch aktiven Methylbernsteinsäuremethylesters (s/c 20000/1)

Figure 00080001
Preparation of the optically active methylsuccinic acid methyl ester (s / c 20000/1)
Figure 00080001

In einem 4 l (Email)-Autoklav der Firma Pfaudler wurden unter Schutzgas 133 mg (0,182 mmol) (RophosARhCOD)CF3SO3 (=Präkatalysator) in 21 ml Methanol vorgelegt und 526 g (3,65 mol) 2-Methylenbernsteinsäure-4-monomethylester (= Substrat) gelöst in 704 ml Methanol zugegeben. Anschließend wurde bei 40°C und 5 bar Wasserstoff hydriert. Nach 4 h war das Substrat vollständig umgesetzt (1H-NMR, 500 MHz). Der Enantiomerenüberschuss des Produkts (2R)-Methylbernsteinsäure-4-monomethylester wurde gaschromatographisch zu >98% bestimmt (Firma: BGB-Analytik, Säulentyp: BGB-174, Länge: 30 m, Innendurchmesser: 0,25 ml, Filmdicke: 0,25 μm, Trägergas: Helium, Vordruck: 2,35 bar, Temperatur: 135°C, Aufheizrate: 1,2°C/min, Retentionszeit R-Enantiomer: 23,3 min, Retentionszeit S-Enantiomer: 22,6 min). Das s/c-Verhältnis betrug 20000:1.133 g (0.182 mmol) of (RophosARhCOD) CF 3 SO 3 (= precatalyst) in 21 ml of methanol were introduced under protective gas into a 4 l (enamel) autoclave from Pfaudler, and 526 g (3.65 mol) of 2-methylsuccinic acid were added. 4-monomethyl ester (= substrate) dissolved in 704 ml of methanol was added. The mixture was then hydrogenated at 40 ° C and 5 bar hydrogen. After 4 h, the substrate was fully reacted ( 1 H NMR, 500 MHz). The enantiomeric excess of the product (2R) -methylsuccinic acid 4-monomethyl ester was determined by gas chromatography to> 98% (company: BGB analysis, column type: BGB-174, length: 30 m, inner diameter: 0.25 ml, film thickness: 0.25 μm, carrier gas: helium, admission pressure: 2.35 bar, temperature: 135 ° C., heating rate: 1.2 ° C./min, retention time R enantiomer: 23.3 min, retention time S enantiomer: 22.6 min). The s / c ratio was 20,000: 1.

Beispiel 2Example 2

Herstellung des optisch aktiven Methylbernsteinsäuremethylesters (s/c 40000/1)Production of the optical active Methylbernsteinsäuremethylesters (s / c 40000/1)

Die in Beispiel 1 beschriebene Umsetzung wurde mit einem Katalysator/Substratverhältnis s/c von 40000/1 durchgeführt. Nach 4 h war das Substrat vollständig umgesetzt. Der Enantiomerenüberschuss des Produkts betrug > 98 %.The The reaction described in Example 1 was carried out with a catalyst / substrate ratio s / c carried out by 40000/1. After 4 hours, the substrate was complete implemented. The enantiomeric excess of the product was> 98 %.

Beispiel 3Example 3

Herstellung des optisch aktiven Methylbernsteinsäuremethylesters (s/c 110000/1)Production of the optical active Methylbernsteinsäuremethylesters (s / c 110000/1)

In einem 50 ml Glasautoklav wurden unter Schutzgas 5,73 g (39,8 mmol) 2-Methylenbernsteinsäure-4-monomethylester in 12 ml Methanol vorgelegt und mit 0,12 ml einer Lösung von 6,6 mg (RophosARhCOD)CF3SO3 (=Präkatalysator) in 3 ml Methanol versetzt (0,00036 mmol Präkatalysator). Anschließend wurde bei 60°C und 5 bar Wasserstoff hydriert. Nach 16 h war das Edukt vollständig umgesetzt. Der Enantiomerenüberschuss des Produkts betrug 98 %.5.73 g (39.8 mmol) of 2-methylsuccinic acid 4-monomethyl ester in 12 ml of methanol were initially introduced under protective gas in a 50 ml glass autoclave and 0.12 ml of a solution of 6.6 mg (RophosARhCOD) CF 3 SO 3 (= Precatalyst) in 3 ml of methanol (0.00036 mmol precatalyst). The mixture was then hydrogenated at 60 ° C and 5 bar hydrogen. After 16 h, the starting material was completely reacted. The enantiomeric excess of the product was 98%.

Beispiel 4Example 4

Herstellung des Präkatalysators in situ (allgemeine Arbeitsvorschrift)Preparation of the pre-catalyst in situ (general working instructions)

1,1 eq. RophosA-Bistriflat-Salz (Rophos * 2 CF3SO3H) werden mit 1,1 eq. Menge Base (vorzugsweise Amine wie Triethylamin, Hünigbase oder ähnlich) in Methanol gelöst und bei –10°C langsam zu einer Lösung von 1 eq. der Metallquelle, vorzugsweise (Rh[COD]2)X mit X = BF4, CF3SO3, SbF6, PF6, ClO4, BAr4) zugetropft. Anschließend lässt man das Gemisch auf Raumtemperatur kommen. Bei Benutzung des freien Liganden entfällt die Basenzugabe.1.1 eq. Rophos A bistriflate salt (Rophos * 2 CF 3 SO 3 H) is treated with 1.1 eq. Amount of base (preferably amines such as triethylamine, Hünig base or similar) dissolved in methanol and slowly added at -10 ° C to a solution of 1 eq. the metal source, preferably (Rh [COD] 2 ) X with X = BF 4 , CF 3 SO 3 , SbF 6 , PF 6 , ClO 4 , BAr 4 ) was added dropwise. Subsequently, the mixture is allowed to come to room temperature. When using the free ligand, the base addition is eliminated.

Claims (7)

Verfahren zur Herstellung von optisch aktiven Alkylbernsteinsäuremonoalkyl-, estern der Formel (I)
Figure 00100001
wobei D und E unabhängig voneinander H, C1-C10 Alkyl, R C1-C10-Alkyl, Aryl oder Alkylaryl bedeuten, indem man eine Verbindung der Formel (II)
Figure 00100002
wobei D, E und R die o.g. Bedeutungen besitzen, in Gegenwart eines Katalysators, der einen Phospholanliganden der Formel (L) trägt,
Figure 00100003
wobei: R1 und R2 unabhängig voneinander C1-C6-Alkyl, Aryl, Alkylaryl, R1 außerdem Wasserstoff, A entweder R1 oder
Figure 00110001
mit B = ein Brückenglied mit 1 – 5 C-Atomen zwischen den beiden P-Atomen oder Cp-Fe-Cp bedeuten. enantioselektiv hydriert.Process for the preparation of optically active alkylsuccinic acid monoalkyl, esters of the formula (I)
Figure 00100001
where D and E, independently of one another, denote H, C 1 -C 10 -alkyl, RC 1 -C 10 -alkyl, aryl or alkylaryl, by reacting a compound of the formula (II)
Figure 00100002
where D, E and R have the abovementioned meanings, in the presence of a catalyst which carries a phospholane ligand of the formula (L),
Figure 00100003
wherein: R 1 and R 2 are independently C 1 -C 6 alkyl, aryl, alkylaryl, R 1 also hydrogen, A is either R 1 or
Figure 00110001
where B = a bridge member with 1-5 C atoms between the two P atoms or Cp-Fe-Cp. enantioselectively hydrogenated. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass D und E Wasserstoff und R = Me bedeuten.Method according to claim 1, characterized in that that D and E are hydrogen and R = Me. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass als Ligand (L) ein Ligand aus der Gruppe Rophos A, Rophos B, Me-KetalPhos, Me-f-KetalPhos verwendet wird.Method according to claim 1, characterized in that as ligand (L) a ligand from the group Rophos A, Rophos B, Me-KetalPhos, Me-f-KetalPhos is used. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Hydrierung bei einem Wasserstoffdruck zwischen 1 und 20 bar ausgeführt wird.Method according to claim 1, characterized in that that the hydrogenation at a hydrogen pressure between 1 and 20 bar executed becomes. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Hydrierung in Methanol durchgeführt wird.Method according to claim 1, characterized in that the hydrogenation is carried out in methanol. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Hydrierung bei einer Temperatur zwischen 10°C und 80°C durchgeführt wird.Method according to claim 1, characterized in that the hydrogenation is carried out at a temperature between 10 ° C and 80 ° C. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass der verwendete Katalysator immobilisiert ist.Method according to claim 1, characterized in that that the catalyst used is immobilized.
DE200410032968 2004-07-07 2004-07-07 Preparation of optically active alkyl succinic acid monoalkyl esters comprising enantioselective hydrogenation of ester compound in presence of catalyst, which carries phospholane ligand Withdrawn DE102004032968A1 (en)

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