WO2000069806A1 - Method for producing chiral amines - Google Patents

Method for producing chiral amines Download PDF

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WO2000069806A1
WO2000069806A1 PCT/EP2000/004149 EP0004149W WO0069806A1 WO 2000069806 A1 WO2000069806 A1 WO 2000069806A1 EP 0004149 W EP0004149 W EP 0004149W WO 0069806 A1 WO0069806 A1 WO 0069806A1
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alkyl
amines
phosphine
platinum metal
complex
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PCT/EP2000/004149
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German (de)
French (fr)
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Rudolf Fuchs
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Lonza Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • 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
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the invention relates to a process for the preparation of chiral amines of the general formula
  • R 1 is hydrogen, C 1-4 alkyl, aryl C 1-4 alkyl or acyl.
  • C 1 -C 4 alkyl here and below means all linear or branched primary, secondary or tertiary alkyl groups with up to 6 carbon atoms, that is to say, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, isopentyl, neopentyl, hexyl, etc.
  • Aryl here and in the following are to be understood in particular as groups such as phenyl or naphthyl, which may optionally carry one or more identical or different substituents such as halogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy.
  • Aryl-C 1-4 alkyl is accordingly to be understood as meaning the groups composed of aryl and C 1-4 alkyl, for example benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl or 4-phenylbutyl.
  • acyl means both acyclic or cyclic aliphatic and aromatic or heteroaromatic acid residues, for example acetyl, propionyl, butyryl, cyclohexane carbonyl, benzoyl, naphthoyl, furoyl or nicotinoyl.
  • Amines of the formula I are intermediates in the synthesis of antiviral active ingredients, such as lobueavir (EP-A-0 358 154, EP-A-0 452 729, WO-A-91/10665).
  • lobueavir EP-A-0 358 154, EP-A-0 452 729, WO-A-91/10665.
  • Several syntheses of such amines are known. Some of these run over the corresponding azides of the same configuration, which can be obtained by catalytic hydrogenation (BL Booth and PR Eastwood, J. Chem. Soc., Perkin Trans. 1 1995, 669-675) or reduction with borane (X. Chen et al. , Tetrahedron Lett. 1992, 33, 2249-2252) in the amines let lead.
  • the object of the present invention was therefore to provide a process which does not require expensive or dangerous reagents and which provides the desired diastereomers in good yield.
  • the object is achieved by the method according to claim 1.
  • R 1 is hydrogen, C 1-4 alkyl, aryl-C 1-4 alkyl or acyl, by homogeneous catalytic hydrogenation of oximes of the general formula
  • R 1 has the meaning given above, can be prepared in the presence of a platinum metal-phosphine complex.
  • Platinum metals are to be understood here as meaning both the “light” and the “heavy” platinum metals, that is to say ruthenium, rhodium and palladium as well as osmium, iridium and platinum.
  • the diastereoisomer formed in a smaller amount in each case with the reverse configuration on the carbon bearing the amino group can be separated off due to its different physical properties by conventional purification processes (e.g. chromatography).
  • Rhodium, ruthenium or iridium are preferably used as platinum metals.
  • Diphosphines are preferably used as phosphines.
  • diphosphines are substituted ferrocenes or substituted 1,1'-binaphthalenes, in particular optically active substituted ferrocenes. These have the general formula, for example
  • R a , R b and R c are hydrogen, tertiary phosphino groups or chiral C-alkyl groups substituted with a tertiary phosphino group, a tertiary amino group or an acyloxy group, with the proviso that a total of two tertiary phosphino groups are present and at most one substituted chiral group C ⁇ alkyl group is present, which is not in the position of R c .
  • the ferrocenes of the formula III are chiral, with the exception of those in which (i) R a and R b are identical and all substituents are achiral or (ii) R a and R b behave as an image and mirror image and R c is achiral or (iii ) either R a or R b denote hydrogen and the other two substituents are achiral or behave like an image and a mirror image.
  • Optically active ferrocenes of the formula III are known, for example, from EP-A-0 564 406; EP-A-0 612 758; A. Togni et al., Inorg. Chim. Acta 1994, 222, 213-224 and T. Hayashi et al., Bull. Chem. Soc. Jpn. 1980, 53, 1138-1151 are known or can be prepared analogously to the syntheses described there.
  • optically active substituted ferrocenes influences the diastereoselectivity of the process according to the invention, so that a higher diastereomeric excess (de) is achieved in the product when one of the two enantiomers is used.
  • the platinum metal-phosphine complex can be used as such or can be produced in situ. It is preferably produced in situ from the corresponding phosphine and a platinum metal olefin complex.
  • Particularly suitable platinum metal-olefin complexes are those with cyclic dienes such as 1,5-cyclooctadiene or norbornadiene as olefin ligands.
  • the hydrogenation is preferably carried out in a polar solvent; water-miscible solvents such as isopropyl alcohol or tetrahydrofuran are particularly preferred. These can be used both anhydrous and with a low water content of up to 10%, for example.
  • the process according to the invention is particularly preferably used to prepare those amines (I) in which R 1 is benzoyl.
  • Example 4 The procedure was as described in Example 4, but the temperature during the hydrogenation was 123 ° C. Yield and diastereomer ratio were identical to the values of Example 4 within the error limits.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The invention relates to amines of general formula (I) or to the mirror image thereof, wherein R1 means hydrogen, C¿1-6?-alkyl, aryl-C1-4-alkyl or acyl. The inventive amines are produced by means of steteroselective hydrogenation of the corresponding oximes in the presence of a platinum metal-phosphine-complex with homogeneous catalysis. The amines which can be produced by the invention are intermediate products in the synthesis of antiviral active agents such as lobucavir for instance.

Description

Verfahren zur Herstellung von chiralen AminenProcess for the preparation of chiral amines
Die Erfindung betrifft ein Verfahren zur Herstellung von chiralen Aminen der allgemeinen FormelThe invention relates to a process for the preparation of chiral amines of the general formula
Figure imgf000003_0001
Figure imgf000003_0001
oder deren Spiegelbild, worin R1 Wasserstoff, C^-Alkyl, Aryl-C^-alkyl oder Acyl bedeutet. Unter C^-Alkyl sind hier und im folgenden alle linearen oder verzweigten primären, sekundären oder tertiären Alkylgruppen mit bis zu 6 Kohlenstoffatomen zu verstehen, also beispielsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sec-Butyl, tert-Butyl, Pentyl, Isopentyl, Neopentyl, Hexyl usw.or their mirror image, in which R 1 is hydrogen, C 1-4 alkyl, aryl C 1-4 alkyl or acyl. C 1 -C 4 alkyl here and below means all linear or branched primary, secondary or tertiary alkyl groups with up to 6 carbon atoms, that is to say, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, isopentyl, neopentyl, hexyl, etc.
Unter Aryl sind hier und im folgenden insbesondere Gruppen wie Phenyl oder Naphthyl zu verstehen, die gegebenenfalls einen oder mehrere gleiche oder verschiedene Substituenten wie beispielsweise Halogen, C,^-Alkyl oder C^-Alkoxy tragen können. Unter Aryl-C^-alkyl sind dementsprechend die aus Aryl und C^-Alkyl zusammengesetzten Gruppen zu verstehen, also beispielsweise Benzyl, 1-Phenylethyl, 2-Phenylethyl, 3-Phenylpropyl oder 4-Phenylbutyl.Aryl here and in the following are to be understood in particular as groups such as phenyl or naphthyl, which may optionally carry one or more identical or different substituents such as halogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy. Aryl-C 1-4 alkyl is accordingly to be understood as meaning the groups composed of aryl and C 1-4 alkyl, for example benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl or 4-phenylbutyl.
Unter Acyl sind hier und im folgenden sowohl acyclische oder cyclische aliphatische als auch aromatische oder heteroaromatische Säurereste zu verstehen, also beispielsweise Acetyl, Propionyl, Butyryl, Cyclohexancarbonyl, Benzoyl, Naphthoyl, Furoyl oder Nicotinoyl.Here and below, acyl means both acyclic or cyclic aliphatic and aromatic or heteroaromatic acid residues, for example acetyl, propionyl, butyryl, cyclohexane carbonyl, benzoyl, naphthoyl, furoyl or nicotinoyl.
Amine der Formel I sind Zwischenprodukte in der Synthese von antiviralen Wirkstoffen wie beispielsweise Lobueavir (EP-A-0 358 154, EP-A-0 452 729, WO-A-91/10665). Es sind mehrere Synthesen solcher Amine bekannt. Einige davon verlaufen über die entsprechenden Azide gleicher Konfiguration, die sich durch katalytische Hydrierung (B. L. Booth und P. R. Eastwood, J. Chem. Soc., Perkin Trans. 1 1995, 669-675) oder Reduktion mit Boran (X. Chen et al., Tetrahedron Lett. 1992, 33, 2249-2252) in die Amine über- führen lassen. Wegen der bekannten Instabilität von Aziden eignen sich diese Verfahren schlecht für die Durchführung im technischen Massstab, ausserdem erfordern sie Ausgangsmaterialien, die bereits an allen chiralen Zentren die richtige Konfiguration besitzen. Andere bekannte Verfahren beruhen auf der Reduktion von entsprechenden Oximethern mit komplexen Borhydriden (B. L. Booth und P. R. Eastwood, loc. cit.; D. W. Norbeck et al., J. Med. Chem. 1990, 33, 1281-1285; EP-A-0 366 059; EP-A-0 452 729) oder der heterogenen katalytischen Hydrierung der entsprechenden Oxime (M. Honjo et al., Chem. Pharm. Bull. 1989, 37, 1413-1415). Nachteile dieser Verfahren sind der relativ hohe Preis von komplexen Borhydriden und die entstehenden borhaltigen Abfälle sowie die geringe Ausbeute im Fall der katalytischen Hydrierung, bei der das „falsche" Diastereomere (entgegengesetzte Konfiguration am die Aminogruppe tragenden Kohlenstoffatom) bevorzugt gebildet wird.Amines of the formula I are intermediates in the synthesis of antiviral active ingredients, such as lobueavir (EP-A-0 358 154, EP-A-0 452 729, WO-A-91/10665). Several syntheses of such amines are known. Some of these run over the corresponding azides of the same configuration, which can be obtained by catalytic hydrogenation (BL Booth and PR Eastwood, J. Chem. Soc., Perkin Trans. 1 1995, 669-675) or reduction with borane (X. Chen et al. , Tetrahedron Lett. 1992, 33, 2249-2252) in the amines let lead. Because of the known instability of azides, these processes are poorly suited to being carried out on an industrial scale, and they also require starting materials which already have the correct configuration at all chiral centers. Other known processes are based on the reduction of corresponding oxime ethers with complex borohydrides (BL Booth and PR Eastwood, loc. Cit .; DW Norbeck et al., J. Med. Chem. 1990, 33, 1281-1285; EP-A-0 366 059; EP-A-0 452 729) or the heterogeneous catalytic hydrogenation of the corresponding oximes (M. Honjo et al., Chem. Pharm. Bull. 1989, 37, 1413-1415). Disadvantages of these processes are the relatively high price of complex borohydrides and the resulting boron-containing wastes, and the low yield in the case of catalytic hydrogenation, in which the “wrong” diastereomer (opposite configuration on the carbon atom carrying the amino group) is preferably formed.
Aufgabe der vorliegenden Erfindung war daher, ein Verfahren bereitzustellen, das keine teuren oder gefährlichen Reagenzien erfordert und in guter Ausbeute das gewünschte Diastereomere liefert.The object of the present invention was therefore to provide a process which does not require expensive or dangerous reagents and which provides the desired diastereomers in good yield.
Erfmdungsgemäss wird die Aufgabe durch das Verfahren nach Patentanspruch 1 gelöst.According to the invention, the object is achieved by the method according to claim 1.
Es wurde gefunden, dass chirale Amine der allgemeinen FormelIt has been found that chiral amines have the general formula
Figure imgf000004_0001
Figure imgf000004_0001
oder deren Spiegelbild, worin R1 Wasserstoff, C^-Alkyl, Aryl-C^-alkyl oder Acyl bedeutet, durch homogene katalytische Hydrierung von Oximen der allgemeinen Formelor their mirror image, in which R 1 is hydrogen, C 1-4 alkyl, aryl-C 1-4 alkyl or acyl, by homogeneous catalytic hydrogenation of oximes of the general formula
Figure imgf000004_0002
oder deren Spiegelbild, worin R1 die oben genannte Bedeutung hat, in Gegenwart eines Platinmetall-Phosphin-Komplexes hergestellt werden können.
Figure imgf000004_0002
or their mirror image, in which R 1 has the meaning given above, can be prepared in the presence of a platinum metal-phosphine complex.
Unter Platinmetallen sind hier sowohl die „leichten" als auch die „schweren" Platinmetalle zu verstehen, also Ruthenium, Rhodium und Palladium sowie Osmium, Iridium und Platin. Das jeweils in geringerer Menge gebildete Diastereomere mit umgekehrter Konfiguration am die Aminogruppe tragenden Kohlenstoff kann wegen seiner abweichenden physikalischen Eigenschaften durch übliche Reinigungsverfahren (z. B. Chromatographie) abgetrennt werden.Platinum metals are to be understood here as meaning both the “light” and the “heavy” platinum metals, that is to say ruthenium, rhodium and palladium as well as osmium, iridium and platinum. The diastereoisomer formed in a smaller amount in each case with the reverse configuration on the carbon bearing the amino group can be separated off due to its different physical properties by conventional purification processes (e.g. chromatography).
Als Platinmetalle werden vorzugsweise Rhodium, Ruthenium oder Iridium eingesetzt.Rhodium, ruthenium or iridium are preferably used as platinum metals.
Als Phosphine werden vorzugsweise Diphosphine eingesetzt.Diphosphines are preferably used as phosphines.
Besonders bevorzugte Diphosphine sind substituierte Ferrocene oder substituierte 1,1 '-Bi- naphthaline, insbesondere optisch aktive substituierte Ferrocene. Diese besitzen beispielsweise die allgemeine FormelParticularly preferred diphosphines are substituted ferrocenes or substituted 1,1'-binaphthalenes, in particular optically active substituted ferrocenes. These have the general formula, for example
Figure imgf000005_0001
Figure imgf000005_0001
Hierin sind die Reste Ra, Rb und Rc Wasserstoff, tertiäre Phosphinogruppen oder mit einer tertiären Phosphinogruppe, einer tertiären Aminogruppe oder einer Acyloxygruppe substituierte chirale C -Alkylgruppen, mit der Massgabe, dass insgesamt zwei tertiäre Phosphinogruppen vorhanden sind und höchstens eine substituierte chirale C^-Alkylgruppe vorhanden ist, welche sich nicht in der Position von Rc befindet.The radicals R a , R b and R c here are hydrogen, tertiary phosphino groups or chiral C-alkyl groups substituted with a tertiary phosphino group, a tertiary amino group or an acyloxy group, with the proviso that a total of two tertiary phosphino groups are present and at most one substituted chiral group C ^ alkyl group is present, which is not in the position of R c .
Die Ferrocene der Formel III sind chiral, ausgenommen solche, bei denen (i) Ra und Rb gleich und alle Substituenten achiral sind oder (ii) Ra und Rb sich wie Bild und Spiegelbild verhalten und Rc achiral ist oder (iii) entweder Ra oder Rb Wasserstoff bedeuten und die beiden anderen Substituenten achiral sind oder sich wie Bild und Spiegelbild verhalten. Optisch aktive Ferrocene der Formel III sind beispielsweise aus EP-A-0 564 406; EP-A-0 612 758; A. Togni et al., Inorg. Chim. Acta 1994, 222, 213-224 und T. Hayashi et al., Bull. Chem. Soc. Jpn. 1980, 53, 1138-1151 bekannt oder analog zu den dort beschriebenen Synthesen herstellbar.The ferrocenes of the formula III are chiral, with the exception of those in which (i) R a and R b are identical and all substituents are achiral or (ii) R a and R b behave as an image and mirror image and R c is achiral or (iii ) either R a or R b denote hydrogen and the other two substituents are achiral or behave like an image and a mirror image. Optically active ferrocenes of the formula III are known, for example, from EP-A-0 564 406; EP-A-0 612 758; A. Togni et al., Inorg. Chim. Acta 1994, 222, 213-224 and T. Hayashi et al., Bull. Chem. Soc. Jpn. 1980, 53, 1138-1151 are known or can be prepared analogously to the syntheses described there.
Es hat sich gezeigt, dass die Verwendung von optisch aktiven substituierten Ferrocenen die Diastereoselektivität des erfindungsgemässen Verfahrens beeinflusst, so dass bei Einsatz eines der beiden Enantiomeren ein höherer diastereomerer Überschuss (de) im Produkt erzielt wird.It has been shown that the use of optically active substituted ferrocenes influences the diastereoselectivity of the process according to the invention, so that a higher diastereomeric excess (de) is achieved in the product when one of the two enantiomers is used.
Der Platinmetall-Phosphin-Komplex kann als solcher eingesetzt oder in situ hergestellt werden. Vorzugsweise wird er in situ aus dem entsprechenden Phosphin und einem Platin- metall-Olefin-Komplex hergestellt. Als Platinmetall-Olefin-Komplexe eignen sich insbesondere solche mit cyclischen Dienen wie 1,5-Cyclooctadien oder Norbornadien als Olefinliganden.The platinum metal-phosphine complex can be used as such or can be produced in situ. It is preferably produced in situ from the corresponding phosphine and a platinum metal olefin complex. Particularly suitable platinum metal-olefin complexes are those with cyclic dienes such as 1,5-cyclooctadiene or norbornadiene as olefin ligands.
Die Hydrierung wird vorzugsweise in einem polaren Lösungsmittel durchgeführt, besonders bevorzugt sind wassermischbare Lösungsmittel wie Isopropylalkohol oder Tetrahydrofuran. Diese können sowohl wasserfrei als auch mit einem geringen Wasseranteil von beispielsweise bis zu 10% eingesetzt werden.The hydrogenation is preferably carried out in a polar solvent; water-miscible solvents such as isopropyl alcohol or tetrahydrofuran are particularly preferred. These can be used both anhydrous and with a low water content of up to 10%, for example.
Besonders bevorzugt wird das erfindungsgemässe Verfahren zur Herstellung derjenigen Amine (I) eingesetzt, in denen R1 Benzoyl ist.The process according to the invention is particularly preferably used to prepare those amines (I) in which R 1 is benzoyl.
Die folgenden Beispiele verdeutlichen die Durchführung des erfindungsgemässen Verfahrens, ohne dass darin eine Einschränkung zu sehen ist.The following examples illustrate the implementation of the method according to the invention, without any limitation being seen therein.
Beispiel 1 (lS,2R,3R)-3-Aminocyclobutan-l,2-dimethanol-dibenzoatExample 1 (IS, 2R, 3R) -3-aminocyclobutane-1,2-dimethanol dibenzoate
(I, R1 = Benzoyl)(I, R 1 = benzoyl)
In einem Autoklaven wurden unter Argon 1 g (2,8 mmol) (lS,2R)-3-(Hydroxyimino)- 1,2-cyclobutandimethanol-dibenzoat, 18 mg (47,5 μmol) Bis(l,5-cyclooctadien)- rhodium(l)acetat und 28,7 mg (51,8 μmol) l,r-Bis(diphenylphosphino)ferrocen vorgelegt. Dann wurden 25 ml entgastes Tetrahydrofuran (3,5% Wassergehalt) zugegeben und das Gemisch bei 90 °C und 20-23 bar Wasserstoffdruck 12 h hydriert. Anschliessend wurde das Lösungsmittel abdestilliert und der Rückstand mittels HPLC analysiert. Ausbeute: 92%, Diastereomerenverhältnis (1S,2R,3R):(1S,2R,3S) = 81 :19; de = 62%.1 g (2.8 mmol) of (IS, 2R) -3- (hydroxyimino) -1,2-cyclobutanedimethanol dibenzoate, 18 mg (47.5 μmol) of bis (1,5-cyclooctadiene) were removed in an autoclave under argon. - rhodium (l) acetate and 28.7 mg (51.8 μmol) l, r-bis (diphenylphosphino) ferrocene. Then 25 ml of degassed tetrahydrofuran (3.5% water content) were added and the mixture was hydrogenated at 90 ° C. and 20-23 bar hydrogen pressure for 12 h. The solvent was then distilled off and the residue was analyzed by HPLC. Yield: 92%, diastereomer ratio (1S, 2R, 3R) :( 1S, 2R, 3S) = 81:19; de = 62%.
Beispiel 2 (lS,2R,3^)-3-AminocycIobutan-l,2-dimethanol-dibenzoatExample 2 (IS, 2R, 3 ^) - 3-aminocyclobutane-1,2-dimethanol dibenzoate
In einem Autoklaven wurden unter Argon 1 g (2,8 mmol) (lS,2R)-3-(Hydroxyimino)- 1,2-cyclobutandimethanol-dibenzoat, 16,4 mg (43 μmol) Bis(bicyclo[2.2.1]hepta-2,5- dien)rhodium(ι)tetrafluoroborat und 25 mg (40 μmol) (R)-NN-Dimethyl-l-[(S)-l',2-bis- (diphenylphosphino)ferrocenyl]ethylamin vorgelegt. Dann wurden 25 ml entgastes Tetrahydrofuran (3% Wassergehalt) zugegeben und das Gemisch bei 90 °C und 20-23 bar Wasserstoffdruck 12 h hydriert. Anschliessend wurde das Lösungsmittel abdestilliert und der Rückstand mittels HPLC analysiert. Ausbeute: 87%, Diastereomerenverhältnis (1S,2R,3R):(1S,2R,3S) = 84:16; de = 68%.1 g (2.8 mmol) of (IS, 2R) -3- (hydroxyimino) -1,2-cyclobutanedimethanol dibenzoate, 16.4 mg (43 μmol) of bis (bicyclo [2.2.1] hepta-2,5-diene) rhodium (ι) tetrafluoroborate and 25 mg (40 μmol) (R) -NN-dimethyl-l - [(S) -l ', 2-bis- (diphenylphosphino) ferrocenyl] ethylamine. 25 ml of degassed tetrahydrofuran (3% water content) were then added and the mixture was hydrogenated at 90 ° C. and 20-23 bar hydrogen pressure for 12 h. The solvent was then distilled off and the residue was analyzed by HPLC. Yield: 87%, diastereomer ratio (1S, 2R, 3R) :( 1S, 2R, 3S) = 84:16; de = 68%.
Beispiel 3 (lS,2R,3^)-3-Aminocyclobutan-l,2-dimethanol-dibenzoatExample 3 (IS, 2R, 3 ^) - 3-aminocyclobutane-1,2-dimethanol dibenzoate
In einem Autoklaven wurden unter Argon 1 g (2,8 mmol) (lS,2R)-3-(Hydroxyimino)- 1,2-cyclobutandimethanol-dibenzoat, 16,4 mg (43 μmol) Bis(l,5-cyclooctadien)- rhodium(l)acetat und 27,3 mg (50 μmol) (S)-Di-tert-butyl-[l-[(R)-2-(diphenylphosphino)- feιτocenyl]ethyl]phosphin vorgelegt. Dann wurden 25 ml entgastes Tetrahydrofuran (3% Wassergehalt) zugegeben und das Gemisch bei 90 °C und 20-23 bar Wasserstoffdruck 12 h hydriert. Anschliessend wurde das Lösungsmittel abdestilliert und der Rückstand mittels HPLC analysiert. Ausbeute: 88%, Diastereomerenverhältnis (1S,2R,3R):(1S,2R,3S) = 70:30; de = 40%. Beispiel 4 (lS,2R,3R)-3-Aminocyclobutan-l,2-dimethanol-dibenzoat1 g (2.8 mmol) of (IS, 2R) -3- (hydroxyimino) -1,2-cyclobutanedimethanol dibenzoate, 16.4 mg (43 μmol) of bis (1,5-cyclooctadiene) were removed in an autoclave under argon. - Rhodium (l) acetate and 27.3 mg (50 μmol) (S) -di-tert-butyl- [l - [(R) -2- (diphenylphosphino) - feιτocenyl] ethyl] phosphine submitted. 25 ml of degassed tetrahydrofuran (3% water content) were then added and the mixture was hydrogenated at 90 ° C. and 20-23 bar hydrogen pressure for 12 h. The solvent was then distilled off and the residue was analyzed by HPLC. Yield: 88%, diastereomer ratio (1S, 2R, 3R) :( 1S, 2R, 3S) = 70:30; de = 40%. Example 4 (IS, 2R, 3R) -3-aminocyclobutane-1,2-dimethanol dibenzoate
In einem Autoklaven wurden unter Argon 2 g (5,6 mmol) (lS,2R)-3-(Hydroxyimino)- 1,2-cyclobutandimethanol-dibenzoat, 15,2 mg (40 μmol) Bis(bicyclo[2.2.1]hepta-2,5- dien)rhodium(l)tetrafluoroborat und 29,3 mg (45 μmol) (S)-1-[(R)-1',2-Bis(diphenyl- phosphino)ferrocenyl]ethylacetat vorgelegt. Dann wurden 25 ml entgastes Tetrahydrofuran (4% Wassergehalt) zugegeben und das Gemisch bei 108 °C und 20-23 bar Wasserstoffdruck 12 h hydriert. Anschliessend wurde das Lösungsmittel abdestilliert und der Rückstand mittels HPLC analysiert. Ausbeute: 86%, Diastereomerenverhältnis (1S,2R,3R):(1S,2R,3S) = 81 :19; de = 62%.2 g (5.6 mmol) of (IS, 2R) -3- (hydroxyimino) -1,2-cyclobutanedimethanol dibenzoate, 15.2 mg (40 μmol) of bis (bicyclo [2.2.1] hepta-2,5-diene) rhodium (l) tetrafluoroborate and 29.3 mg (45 μmol) (S) -1 - [(R) -1 ', 2-bis (diphenylphosphino) ferrocenyl] ethyl acetate. Then 25 ml degassed tetrahydrofuran (4% water content) were added and the mixture was hydrogenated at 108 ° C. and 20-23 bar hydrogen pressure for 12 h. The solvent was then distilled off and the residue was analyzed by HPLC. Yield: 86%, diastereomer ratio (1S, 2R, 3R) :( 1S, 2R, 3S) = 81:19; de = 62%.
Beispiel 5 (lS,2R,3.R)-3-Aminocyclobutan-l,2-dimethanoI-dibenzoatExample 5 (lS, 2R,. 3 R) -3-aminocyclobutane-l, 2-dimethanoI dibenzoate
Es wurde verfahren wie in Beispiel 4 beschrieben, jedoch betrug die Temperatur bei der Hydrierung 123 °C. Ausbeute und Diastereomerenverhältnis waren innerhalb der Fehlergrenzen identisch mit den Werten von Beispiel 4.The procedure was as described in Example 4, but the temperature during the hydrogenation was 123 ° C. Yield and diastereomer ratio were identical to the values of Example 4 within the error limits.
Beispiel 6 (lS,2R,3R)-3-Aminocyclobutan-l,2-dimethanol-dibenzoatExample 6 (IS, 2R, 3R) -3-aminocyclobutane-1,2-dimethanol dibenzoate
In einem Autoklaven wurden unter Argon 1 g (2,8 mmol) (lS,2R)-3-(Hydroxyimino)- 1 ,2-cyclobutandimethanol-dibenzoat und 66 mg (36,6 μmol) (S)-Bis-[[l, -binaphthalin]- 2,2'-diylbis[bis(4-methylphenyl)phosphin-κE]]di-μ-chlorodichloro(N,N-diethylethanamin)- diruthenium vorgelegt. Dann wurden 25 ml entgastes Tetrahydrofuran (3% Wassergehalt) zugegeben und das Gemisch bei 103 °C und 20-23 bar Wasserstoffdruck 12 h hydriert. Anschliessend wurde das Lösungsmittel abdestilliert und der Rückstand mittels HPLC analysiert. Ausbeute: 87%, Diastereomerenverhältnis (1S,2R,3R):(1S,2R,3S) = 88:12; de = 76%).1 g (2.8 mmol) (lS, 2R) -3- (hydroxyimino) -1, 2-cyclobutanedimethanol dibenzoate and 66 mg (36.6 μmol) (S) -Bis - [[ l, -binaphthalene] - 2,2'-diylbis [bis (4-methylphenyl) phosphine-κE]] di-μ-chlorodichloro (N, N-diethylethanamine) - diruthenium. Then 25 ml of degassed tetrahydrofuran (3% water content) were added and the mixture was hydrogenated at 103 ° C. and 20-23 bar hydrogen pressure for 12 h. The solvent was then distilled off and the residue was analyzed by HPLC. Yield: 87%, diastereomer ratio (1S, 2R, 3R) :( 1S, 2R, 3S) = 88:12; de = 76%).
Beispiel 7 (lS,2R,3R)-3-Aminocyclobutan-l,2-dimethanoI-dibenzoatExample 7 (IS, 2R, 3R) -3-aminocyclobutane-1,2-dimethanoI-dibenzoate
In einem Autoklaven wurden unter Argon 1 g (2,8 mmol) (lS,2R)-3-(Hydroxyimino)- 1,2-cyclobutandimethanol-dibenzoat, 52,7 mg (56 μmol) (R)-Di-tert-butyl-[l-[(S)-2-(di- phenylphosphino)ferrocenyl]ethyl]phosphin-l,5-cyclooctadien-iridium(ι)-tetrafluoroborat- komplex vorgelegt. Dann wurden 25 ml entgastes Tetrahydrofuran (4% Wassergehalt) zugegeben und das Gemisch bei 108 °C und 20-23 bar Wasserstoffdruck 12 h hydriert. Anschliessend wurde das Lösungsmittel abdestilliert und der Rückstand mittels HPLC analysiert. Ausbeute: 41%, Diastereomerenverhältnis (1S,2R,3R):(1S,2R,3S) = 56:44; de = 8%.1 g (2.8 mmol) of (IS, 2R) -3- (hydroxyimino) -1,2-cyclobutanedimethanol dibenzoate, 52.7 mg (56 μmol) of (R) -Di-tert- Butyl- [l - [(S) -2- (diphenylphosphino) ferrocenyl] ethyl] phosphine-l, 5-cyclooctadiene-iridium (ι) -tetrafluoroborat- complex presented. Then 25 ml degassed tetrahydrofuran (4% water content) were added and the mixture was hydrogenated at 108 ° C. and 20-23 bar hydrogen pressure for 12 h. The solvent was then distilled off and the residue was analyzed by HPLC. Yield: 41%, diastereomer ratio (1S, 2R, 3R) :( 1S, 2R, 3S) = 56:44; de = 8%.
Beispiel 8 (lS,2R,3R)-3-Aminocyclobutan-l,2-dimethanoI-dibenzoatExample 8 (IS, 2R, 3R) -3-aminocyclobutane-1,2-dimethanoI-dibenzoate
In einem Autoklaven wurden unter Argon 2,2 g (6 mmol) (lS,2R)-3-(Hydroxyimino)- 1,2-cyclobutandimethanol-dibenzoat, 4,5 mg (11,8 μmol) Bis(l,5-cyclooctadien)- rhodium(l)acetat und 9,1 mg (14,2 μmol) (S)-l-[(R)-l',2-Bis(diphenylphosphino)- ferrocenyljethylacetat vorgelegt. Dann wurden 25 ml entgastes Tetrahydrofuran (3% Wassergehalt) zugegeben und das Gemisch bei 122 °C und 20-23 bar Wasserstoffdruck 7 h hydriert. Anschliessend wurde das Lösungsmittel abdestilliert und der Rückstand mittels HPLC analysiert. Ausbeute: 60%, Diastereomerenverhältnis (1S,2R,3R):(1S,2R,3S) = 56:44; de = 8%. 2.2 g (6 mmol) of (lS, 2R) -3- (hydroxyimino) -1,2-cyclobutanedimethanol dibenzoate, 4.5 mg (11.8 μmol) of bis (l, 5- cyclooctadiene) - rhodium (l) acetate and 9.1 mg (14.2 μmol) (S) -l - [(R) -l ', 2-bis (diphenylphosphino) - ferrocenylethyl acetate. Then 25 ml of degassed tetrahydrofuran (3% water content) were added and the mixture was hydrogenated at 122 ° C. and 20-23 bar hydrogen pressure for 7 h. The solvent was then distilled off and the residue was analyzed by HPLC. Yield: 60%, diastereomer ratio (1S, 2R, 3R) :( 1S, 2R, 3S) = 56:44; de = 8%.

Claims

Patentansprüche claims
1. Verfahren zur Herstellung von Aminen der allgemeinen Formel1. Process for the preparation of amines of the general formula
Figure imgf000010_0001
Figure imgf000010_0001
oder deren Spiegelbild, worin R1 Wasserstoff, C^-Alkyl, Aryl-C,^-alkyl oder Acyl bedeutet, dadurch gekennzeichnet, dass ein Oxim der allgemeinen Formelor their mirror image, in which R 1 is hydrogen, C 1-4 alkyl, aryl-C, C 1-4 alkyl or acyl, characterized in that an oxime of the general formula
Figure imgf000010_0002
Figure imgf000010_0002
beziehungsweise dessen Spiegelbild, worin R1 die oben genannte Bedeutung hat, in Gegenwart eines Platinmetall-Phosphin-Komplexes unter homogener Katalyse hydriert wird.or its mirror image, in which R 1 has the meaning given above, is hydrogenated in the presence of a platinum metal-phosphine complex with homogeneous catalysis.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass als Platinmetall Rhodium, Ruthenium oder Iridium eingesetzt wird.2. The method according to claim 1, characterized in that rhodium, ruthenium or iridium is used as the platinum metal.
3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass als Phosphin ein Diphosphin eingesetzt wird.3. The method according to claim 1 or 2, characterized in that a diphosphine is used as phosphine.
4. Verfahren nach Anspruch 3, dadurch gekennzeichnet, dass als Diphosphin ein substituiertes Ferrocen oder ein substituiertes l,l'-Binaphthalin eingesetzt wird.4. The method according to claim 3, characterized in that a substituted ferrocene or a substituted l, l'-binaphthalene is used as the diphosphine.
5. Verfahren nach Anspruch 4, dadurch gekennzeichnet, dass als Diphosphin ein optisch aktives substituiertes Ferrocen eingesetzt wird. 5. The method according to claim 4, characterized in that an optically active substituted ferrocene is used as the diphosphine.
6. Verfahren nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass der Platinmetall-Phosphin-Komplex in situ aus dem entsprechenden Phosphin und einem Platinmetall-Olefm-Komplex hergestellt wird.6. The method according to any one of claims 1 to 5, characterized in that the platinum metal-phosphine complex is prepared in situ from the corresponding phosphine and a platinum metal-olefin complex.
7. Verfahren nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, dass die Hydrierung in Isopropylalkohol oder Tetrahydrofuran, gegebenenfalls mit Zusatz von bis zu 10% Wasser, durchgeführt wird.7. The method according to any one of claims 1 to 6, characterized in that the hydrogenation is carried out in isopropyl alcohol or tetrahydrofuran, optionally with the addition of up to 10% water.
8. Verfahren nach einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, dass R1 Benzoyl ist. 8. The method according to any one of claims 1 to 7, characterized in that R 1 is benzoyl.
PCT/EP2000/004149 1999-05-17 2000-05-10 Method for producing chiral amines WO2000069806A1 (en)

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Publication number Priority date Publication date Assignee Title
CA2049047A1 (en) * 1990-01-12 1991-07-13 Mikio Honjo Process for producing carboxetanocin g or a intermediate therefor

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2049047A1 (en) * 1990-01-12 1991-07-13 Mikio Honjo Process for producing carboxetanocin g or a intermediate therefor

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