DE19813821A1 - New epothilone derivatives - Google Patents

New epothilone derivatives

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Publication number
DE19813821A1
DE19813821A1 DE19813821A DE19813821A DE19813821A1 DE 19813821 A1 DE19813821 A1 DE 19813821A1 DE 19813821 A DE19813821 A DE 19813821A DE 19813821 A DE19813821 A DE 19813821A DE 19813821 A1 DE19813821 A1 DE 19813821A1
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compound
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general formula
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Werner Skuballa
Wolfgang Schwede
Ulrich Klar
Bernd Buchmann
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Bayer Pharma AG
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Bayer Pharma AG
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Priority claimed from DK98946309T external-priority patent/DK1005465T3/en
Priority claimed from IN3413DE1998 external-priority patent/IN190805B/en
Publication of DE19813821A1 publication Critical patent/DE19813821A1/en
Application status is Withdrawn legal-status Critical

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Abstract

Epothilone derivatives (I) are new. They are prepared from a number of new and known starting compounds. Epothilone derivatives of formula (I) are new. R<1>a, R<1>b = H, 1-10C alkyl, aryl, 7-20C aralkyl or together form (CH2)m; m = 2-5; R<2>a, R<2>b = have the same meanings as R<1>a and R<1>b, provided that when D-E is CH2-CH2 or Y is O, then R<2>a and R<2>b are not H or CH3; R<3>, R<5> = H, 1-10C alkyl, aryl or 7-20C aralkyl; R<4>a, R<4>b have the same meanings as R<1>a, R<1>b or R<2>a, R<2>b; D-E = CH2-CH2, CH=CH, C?=C, epoxy, CH(OH)-CH(OH) or CH(OH)-CH2; R<6>, R<7> = H, or together form a bond or an O atom; R<8> = H, 1-10C alkyl, aryl or 7-20C aralkyl, which are all optionally substituted; X = O, two OR<23> groups, a 2-10C alkylene- alpha , w-dioxy group, H/OR<9> or CR<10>R<11>; R<23> = 1-20C alkyl; R<9> = H or a protecting group; R<10>, R<11> = H, 1-10C alkyl, aryl or 7-20C aralkyl, or together form a 5-7 membered carbocycle; Y = one O or two H atoms; Z = one O atom or H/OR<12>; and R<12> = H or a protecting group.

Description

Die Erfindung betrifft den in den Patentansprüchen gekennzeichneten Gegenstand, dh Verfahren zur Herstellung von C1-C6-Epothilon-Bausteinen zur Totalsynthese von Epothilon und Epothilon-Derivaten. The invention relates to the object characterized in the claims, ie, methods for the preparation of C1-C6-epothilone components, for the total synthesis of epothilone and epothilone derivatives.

Von Höfle et al. Höfle et al. wird die cytotoxische Wirkung der Naturstoffe Epothilon A (R = Wasserstoff) und Epothilon B (R = Methyl) is the cytotoxic effect of the natural substances epothilone A (R = hydrogen) and epothilone B (R = methyl)

z. z. B. in Angew. B. Angew. Chem. 1996, 108, 1671-1673 beschrieben. Chem. 1996, 108, 1671-1673 described. Wegen der in-vitro- Selektivität gegenüber Brust- und Darmzellinien und der im Vergleich zu Taxol deutlich höheren Aktivität gegen P-Glycoprotein-bildende, multiresistente Tumorzellinien sowie der gegenüber Taxol verbesserten physikalischen Eigenschaften (Faktor 30 höhere Wasserlöslichkeit) erscheint diese neuartige Strukturklasse für die Entwicklung eines Arzneimittels zur Therapie maligner Tumoren besonders interessant. Because of the in vitro selectivity for breast and Darmzellinien and compared to Taxol significantly higher activity against P-glycoprotein-forming multiresistant tumor cell lines as well as to taxol improved physical properties (a factor of 30 higher water) appears this novel structural class for the development a medicament for the treatment of malignant tumors particularly interesting.

Die Naturstoffe sind entweder chemisch als auch metabolisch für eine Arzneimittelentwicklung nicht ausreichend stabil oder bedürfen einer Verbesserung des Wirkprofils hinsichtlich biophysikalischer Parameter oder der Selektivitäten zwischen transformierten und nicht-transformierten Zellen. The natural products are either chemically and metabolically for a pharmaceutical development not sufficiently stable or require improvement of the profile of action with respect to biophysical parameters, or the selectivities between transformed and non-transformed cells. Zur Beseitigung dieser Nachteile sind Modifikationen an dem Naturstoff nötig. To eliminate these disadvantages are necessary modifications to the natural substance. Derartige Modifikationen sind nur auf totalsynthetischem Wege möglich und setzen Synthesestrategien voraus, die eine breite Modifikation des Naturstoffes ermöglichen. Such modifications are possible only to a total synthetic route and require synthesis strategies that enable a broad modification of the natural product. Ziel der Strukturveränderungen ist es somit, die therapeutische Breite zu erhöhen. The aim of the structural changes is therefore to increase the therapeutic range. Dies kann durch eine Verbesserung der Selektivität der Wirkung, eine Reduktion unerwünschter toxischer Nebenwirkungen und/oder Erhöhung der Wirkstärke erfolgen. This can be done by improving the selectivity of action, a reduction of unwanted toxic side effects and / or increasing the potency.

Es ist bekannt, daß die Verbindung der folgenden Formel It is known that the compound of the following formula

zur Synthese des C1-C6-Fragmentes (Epothilon-Zählweise) von Epothilon A verwendet werden kann (Schinzer et al, Chem. Eur. J. 1996, 2, No. 11, 1477-1482; Schinzer et al., Angew. Chem. 1997, 109, Nr. 5, S. 543-544). can be used for synthesis of the C1-C6 fragment (epothilone numbering) used by epothilone A (Schinzer et al, Chem Eur J. 1996, 2, No. 11, 1477-1482;.... Schinzer et al, Angew Chem . 1997, 109, No. 5, pp. 543-544).

Diese Synthese dieser Verbindung besitzt den Nachteil, daß die Gesamtausbeute mit 10,5% sehr niedrig, die notwendige Einführung der Chiralität an C-Atom 3 die Synthese eines teuren, chemisch instabilen, in äquimolaren Mengen einzusetzenden und nicht wiedergewinnbaren chiralen Hilfsstoffes erfordert und die damit erzielte optische Induktion mit ca. 80%ee unvollständig ist. This synthesis of this compound has the drawback that the total yield at 10.5% very low, the necessary introduction of chirality at C-atom 3 requires the synthesis of a costly, chemically unstable, to be used in equimolar amounts and not recoverable chiral auxiliary and the resulting scored optical induction is incomplete with 80% ee.

Für eine industriell verwertbare Synthese sind jedoch hohe Ausbeuten und hohe optische Reinheit notwendig. For an industrially utilizable synthesis, however, high yields and high optical purity are necessary.

In Angew. In Angew. Chem. 1997, 109, Nr. 1/2, S. 170-172 wird die Synthese eines (C1-C6)-Bausteins mit einer Carboxylgruppe an C-1, der für die Synthese von Epothilon oder Epothilonderivaten verwendet werden kann, Chem. 1997. 109, no. 1/2, pp 170-172, the synthesis of a (C1-C6) -Bausteins with a carboxyl group at C1, which can be used for the synthesis of epothilone or epothilone derivatives,

(TBS = tert.-Butyldimethylsilyl) von Nicolaou et al. (TBS = tert-butyldimethylsilyl) by Nicolaou et al. beschrieben. described. Die Stereochemie am C3 wird durch die Reaktion mit dem Brown Reagenz Allylisopinocamphenylboran (+)-Ipc 2 B(allyl) gesteuert, das äquimolar in die Reaktion eingesetzt werden muß und nicht wiedergewinnbar ist. The stereochemistry at C3 is determined by the reaction with the Brown reagent Allylisopinocamphenylboran (+) - B controlled Ipc 2 (allyl), which must be used in equimolar amounts in the reaction and is not recoverable.

Ebenso wird die Verwendung dieses Bausteins zur Synthese von Epothilon A und B und einiger Epothilon-Analoga in Nature, Vol. 387, 1997, S. 268-272, zur Synthese von Epothilon A und seinen Derivaten in J. Am. Likewise, the use of this block for the synthesis of epothilone A and B and several epothilone analogs in Nature, Vol. 387, 1997, pp 268-272, is the synthesis of epothilone A and its derivatives in J. Am. Chem. Soc., Vol. 119, No. Chem. Soc., Vol. 119, No. 34, 1997, S. 7960-7973 sowie zur Synthese von Epothilon A und B und einiger Epothilon- Analoga in J. Am. 34, 1997, pp 7960-7973 and for the synthesis of epothilone A and B and several epothilone analogues in J. Am. Chem. Soc., Vol. 119, No. Chem. Soc., Vol. 119, No. 34, 1997, S. 7974-7991 von Nicolaou et al. 34, 1997, pp 7974-7991 Nicolaou et al. beschrieben. described.

Ebenfalls von Nicolaou et al. Also by Nicolaou et al. wird in Angew. is in Angew. Chem. 1997, 109, Nr. 19, S. 2181-2187 die Herstellung von Epothilon A-Analoga mittels kombinatorischer Festphasensynthese beschrieben. Chem., 1997, 109, no. 19, pp 2181-2187 the production of epothilone A analogs described by means of combinatorial solid phase synthesis. Aus dieser Fundstelle gehen auch Epothilon B-Analoga hervor. and epothilone B analogs are listed in this reference. Als C1-C6-Bausteine werden z. As C1-C6 devices z. B. die nachstehenden Verbindungen eingesetzt: B. The following compounds are used:

Für eine industriell verwertbare Synthese ist es von Vorteil, wenn die Synthese ohne teure chirale Auxiliare durchgeführt oder wenn das chirale Auxiliar einfach zurückgewonnen werden kann. For industrially utilizable synthesis, it is advantageous if the synthesis is carried out without expensive chiral auxiliaries, or when the chiral auxiliary can be easily recovered.

Es bestand daher die Aufgabe, eine geeignete Synthese zu finden, die hohe Ausbeuten liefert, das gewünschte Produkt in hoher optischer Reinheit ergibt und ohne teure chirale Auxiliare auskommt bzw. eine Rückgewinnung des chiralen Auxiliars gestattet. It was therefore an object to find a suitable synthesis that provides high yields, yields the desired product in high optical purity and does not require costly chiral auxiliaries, or a recovery of the chiral auxiliary permitted.

Außerdem sollte die neue Synthese eine breite Variation von Substituenten in diesem Baustein und somit letztendlich in den daraus herzustellenden Epothilonderivaten zulassen. In addition, the new synthesis should allow a wide variation of substituents in this block and ultimately to the epothilone derivatives produced therefrom.

Es wurde gefunden, daß Synthesebausteine der allgemeinen Formel I It has been found that synthesis components of general formula I

worin wherein
R 3 OR 3a und R 3 and OR 3a
R 3a Wasserstoff oder eine Schutzgruppe PG R 3a is hydrogen or a protecting group PG
R 4a , R 4b gleich oder verschieden sind und Wasserstoff, C 1 -C 10 -Alkyl, C 7 -C 20 - Aralkyl, oder gemeinsam eine -(CH 2 ) m -Gruppe, R 4a, R 4b are the same or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 - aralkyl, or together a - (CH 2) m group,
m 2 bis 5, m is 2 to 5,
R 5a , R 5b gleich oder verschieden sind und Wasserstoff, C 1 -C 10 -Alkyl, C 7 -C 20 - Aralkyl, oder gemeinsam eine -(CH 2 ) p -Gruppe, R 5a, R 5b are the same or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 - aralkyl, or together are - (CH 2) p group,
p 2 bis 5, p is 2 to 5,
einschließlich aller Stereoisomeren sowie deren Gemische bedeuten sowie including all stereoisomers and mixtures thereof and mean
freie Carbonylgruppen in I ketalisiert sein können, free carbonyl groups can be ketalized in I,
leicht durch Umsetzung einer Verbindung der allgemeinen Formel II readily prepared by reacting a compound of general formula II

worin wherein
X ein Chlor- oder Bromatom ist, und der 2-Oxazolidinon-Ring entweder (4R,5S)- oder (4S,5R)-Konformation aufweist, X is a chlorine or bromine atom, and the 2-oxazolidinone ring is either (4R, 5S) - or (4S, 5R) having conformation,
mit einer Verbindung der allgemeinen Formel III with a compound of general formula III

worin wherein
R 4a , R 4b gleich oder verschieden sind und Wasserstoff, C 1 -C 10 -Alkyl, C 7 -C 20 - Aralkyl, oder gemeinsam eine -(CH 2 ) m -Gruppe, R 4a, R 4b are the same or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 - aralkyl, or together a - (CH 2) m group,
m 2 bis 5, m is 2 to 5,
R 5a , R 5b gleich oder verschieden sind und Wasserstoff, C 1 -C 10 -Alkyl, C 7 -C 20 - Aralkyl, oder gemeinsam eine -(CH 2 ) p -Gruppe, R 5a, R 5b are the same or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 - aralkyl, or together are - (CH 2) p group,
p 2 bis 5, p is 2 to 5,
bedeuten, mean,
zu einer Verbindung der allgemeinen Formel IV to a compound of general formula IV

worin wherein
der 2-Oxazolidinon-Ring (4R,5S)- und das 3'-Kohlenstoffatom R-Konformation oder der 2-Oxazolidinon-Ring (4S,5R)- und das 3'-Kohlenstoffatom S-Konformation aufweisen, exhibit and the 3'-carbon atom of S-conformation, - the 2-oxazolidinone ring (4R, 5S) - and the 3 'carbon atom of R-conformation, or the 2-oxazolidinone ring (4S, 5R)
sowie nach Schutz der 3'-Hydroxygruppe in IV mit einer Schutzgruppe PG, durch Abspaltung des Oxazolidinon-Restes und gegebenenfalls Abspaltung der Schutzgruppe PG hergestellt werden können. as well as for protection of the 3'-hydroxy group in IV PG can be prepared with a protecting group PG, by cleavage of the oxazolidinone radical and optionally cleavage of the protecting group.

Die Umsetzung einer Verbindung der allgemeinen Formel II mit einer Verbindung der allgemeinen Formel III gelingt nach Überführung der Verbindung der allgemeinen Formel II in ein Metallenolat durch Insertion eines Metalls oder Metallsalzes in die Kohlenstoff-Halogen-Bindung der Verbindung der allgemeinen Formel II. The reaction of a compound of general formula II with a compound of general formula III succeeds after conversion of the compound of general formula II into a metal enolate by insertion of a metal or metal salt into the carbon-halogen bond of the compound of general formula II.

Als Metall oder Metallsalz kommen generell alle dem Fachmann bekannten Metalle oder Metallsalze in Frage, die für eine Reformatzky-Reaktion geeignet sind (siehe z. BA Fürstner, Synthesis 1989, 571-590). As a metal or metal salt in general, all known to those skilled metals or metal salts are suitable that are suitable for a Reformatsky reaction (see, e.g., BA Fürstner, Synthesis 1989, 571-590).

Erfindungsgemäß wird vorzugsweise Chrom(II)chlorid verwendet. According to the invention chromium (II) chloride is preferably used.

Der Oxazolidon-Ring wird bei der Abspaltung aus den Verbindungen der allgemeinen Formel IV fast quantitativ und ohne Verlust der optischen Aktivität zurückgewonnen. The oxazolidone ring is recovered during the cleavage from the compounds of general formula IV almost quantitatively and without loss of optical activity.

Als Alkylgruppen R 4a , R 4b , R 5a und R 5b sind gerad- oder verzweigtkettige Alkylgruppen mit 1 bis maximal 10 Kohlenstoffatomen zu betrachten, wie beispielsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.-Butyl, Pentyl, Isopentyl, Neopentyl, Heptyl, Hexyl, Decyl. As alkyl groups R 4a, R 4b, R 5a and R 5b are straight or branched chain alkyl groups having 1 to a maximum of 10 carbon atoms to be considered, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl , neopentyl, heptyl, hexyl, decyl.

Die Alkylgruppen R 4a , R 4b , R 5a und R 5b können perfluoriert oder substituiert sein durch 1-5 Halogenatome, Hydroxygruppen, C 1 -C 4 -Alkoxygruppen und C 6 -C 12 - Arylgruppen (die durch 1-3 Halogenatome substituiert sein können). The alkyl groups of R 4a, R 4b, R 5a and R 5b may be perfluorinated or substituted by 1-5 halogen atoms, hydroxy groups, C 1 -C 4 alkoxy and C 6 -C 12 - aryl groups (which may be substituted by 1-3 halogen atoms can).

Die Aralkylgruppen in R 4a , R 4b , R 5a und R 5b können im Ring bis 14 C-Atome, bevorzugt 6 bis 10 enthalten und in der Alkylkette 1 bis 8, bevorzugt 1 bis 4 Atome. The aralkyl groups in R 4a, R 4b, R 5a and R 5b may in the ring up to 14 C-atoms, preferably, 6 to 10 and included in the alkyl chain 1 to 8, preferably 1 to 4 atoms. Als Aralkylreste kommen beispielweise in Betracht Benzyl, Phenylethyl, Naphthylmethyl, Naphthylethyl, Furylmethyl, Thienylethyl, Pyridylpropyl. As aralkyl radicals Examples of suitable benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl. Die Ringe können ein- bis dreifach substituiert sein durch Halogen, OH, O-Alkyl, NH 2 , CO 2 H, CO 2 -Alkyl, -NO 2 , -N 3 , -CN, C 1 -C 20 -Alkyl, C 1 -C 20 -Acyl, C 1 -C 20 -Acyloxy-Gruppen. The rings may be trisubstituted by halogen, OH, O-alkyl, NH 2, CO 2 H, CO 2 -alkyl, -NO 2, -N 3, -CN, C 1 -C 20 alkyl, mono- to C 1 -C 20 acyl, C 1 -C 20 acyloxy groups.

Als Schutzgruppe PG kommen alle, dem Fachmann als derartige Schutzgruppen bekannten Reste in Betracht. As the protecting group PG are all, in the art as such protective groups known radicals. Bevorzugt sind hierbei silylhaltige Schutzgruppen, wie beispielsweise der Trimethylsilyl-, Triethylsilyl-, tert.-Butyldimethylsilyl-, tert.- Butyldiphenylsilyl-, Tribenzylsilyl-, Triisopropylsilyl-Rest. Preference is given here silyl containing protecting groups such as the trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl radical.

Eine Übersicht über Schutzgruppen findet sich z. An overview of protecting groups can be found,. B. in "Protective Groups in Organic Synthesis" Theodora W. Green, John Wiley and Sons). Example, in "Protective Groups in Organic Synthesis", Theodora W. Green, John Wiley and Sons).

Halogen bedeutet Fluor, Chlor, Brom und Iod. Halogen is fluorine, chlorine, bromine and iodine.

Die für das erfindungsgemäße Verfahren benötigten Verbindungen der allgemeinen Formel II sind durch Acetylierung von (4R,5S)- bzw. (4S,5R)-4-Methyl-5-phenyl-2- oxazolidinon mit Brom- oder Chloracetylchlorid in Gegenwart einer starken Base, wie beispielsweise n-Butyllithium, zugänglich. The compounds of general formula II required for the inventive method are by acetylation of (4R, 5S) - and (4S, 5R) -4-methyl-5-phenyl-2-oxazolidinone with bromo- or chloroacetyl chloride in the presence of a strong base such as n-butyllithium, accessible.

Durch die Wahl des chiralen Auxiliars wird später die Stereochemie der Hydroxygruppe in Position 3 gesteuert. By the choice of the chiral auxiliary, the stereochemistry of the hydroxyl group is controlled in position 3 later.

Die für das erfindungsgemäße Verfahren benötigten Verbindungen der allgemeinen Formeln III sind käuflich oder lassen sich einfach herstellen. The compounds of general formula III required for the present process are commercially available or are readily prepared.

Sofern die Verbindungen der allgemeinen Formel III nicht käuflich sind, lassen sie sich beispielsweise nach den in Abb. 1 und 2 angegebenen Methoden herstellen. If the compounds of general formula III are not commercially available, they can be prepared for example according to the conditions shown in Fig. 1 and 2 methods.

Abb. 1 Ausgangsmaterial ist (substituierter) Malonester Fig. 1 starting material is (substituted) Malonester

Abb. 2 Fig. 2

Die gemäß vorliegender Erfindung hergestellten Bausteine der allgemeinen Formel I können analog zu beschriebenen, beispielsweise aus den auf der Seite 2 dieses Anmeldetextes (Schinzer et al.: Chem. Eur. J. 1996, 2, No. 11, 1477-1482; Angew. Chem. 1997, 109, Nr. 5, S. 543-544; Nicolaou et al.: Angew. Chem. 1997, 109, Nr. 1/2, S. 170-172; Nature, Vo. 387, 1997, S. 268-272; J. Am. Chem. Soc., Vol. 119, No. 34, 1997, S. 7960-7973; J. Am. Chem. Soc., Vol. 119, No. 34, 1997, S. 7974-7991; Angew. Chem. 1997, 109, Nr. 19, S. 2181-2187) hervorgehenden Methoden zur Synthese von Epothilon A und B sowie von im C 1 -C 6 -Abschnitt des Epothilongerüstes entsprechend modifizierten Epothilonderivaten verwendet werden. The present invention building blocks of the general formula I prepared can be described analogously, for example, from (on page 2 of this patent application, Schinzer et al .: Chem Eur J. 1996, 2, No. 11, 1477-1482;.. Angew. .. Chem. 1997, 109, No. 5, pp 543-544;.. Nicolaou et al .: Angew Chem 1997, 109, No. 1/2, pp 170-172;. Nature, Vo 387, 1997, S ... 268-272;.. J. Am Chem Soc, Vol 119, No. 34, 1997, pp 7960-7973;. J. Am Chem Soc, Vol 119, No. 34, 1997, S... S. 2181-2187 C6 section of the epothilone derivatives Epothilongerüstes suitably modified to be used) arising methods for the synthesis of epothilone A and B and of the C 1 Angew Chem 1997, 109, No. 19,;. 7974-7991....

Mit den Verbindungen der allgemeinen Formel I wird somit die eingangs geforderte Variabilität der Substituenten erreicht. With the compounds of general formula I the initially required variability of the substituents is thus achieved.

Ein großer Vorteil des erfindungsgemäßen Verfahrens liegt auch darin, daß sich das verwendete chirale Auxiliar (4R,5S)- bzw. (4S,5R)-4-Methyl-5-phenyl-2-oxazolidimon nach seiner Abspaltung aus der geschützten Verbindung der allgemeinen Formel IV einfach wiedergewinnen und erneut ohne Verlust an optischer Induktion in die Synthese wieder einsetzen läßt. and (4S, 5R) -4-methyl-5-phenyl-2-oxazolidimon after its cleavage from the protected compound of the general - a big advantage of the method according to the invention also in the fact that the chiral auxiliary used (4R, 5S) is IV easy to regain the formula and can replace it in the synthesis again without loss of optical induction.

Die auf diesen Wegen erhaltenen Bausteine, auch deren Enantiomere oder Gemische aus diesen Enantiomeren, eignen sich für die Aldokondensation mit einem Epothilonbaustein, der an C-7 (Epothilon-Zählweise) eine Carbonylfunktion trägt wie dies bei den oben genannten Totalsynthesen von Epothilon A und Epothilon B der Fall ist. The blocks obtained in these ways, also their enantiomers or mixtures of these enantiomers, are suitable for Aldokondensation with a Epothilonbaustein, the at C-7 (epothilone numbering) bears a carbonyl as in the above-mentioned total syntheses of epothilone A and epothilone B is the case.

Die Bausteine 1, deren Enantiomere oder Gemische aus diesen Enantiomeren eignen sich darüber hinaus für die Veresterung mit einem Epothilonbaustein, der an C-15 (Epothilion-Zählweise) eine Hydroxylfunktion trägt, wie dies bei den oben genannten Totalsynthesen von Epothilon A und B der Fall ist. The blocks 1, their enantiomers or mixtures of these enantiomers are suitable, moreover, for esterification with an Epothilonbaustein carrying a hydroxyl function at C-15 (Epothilion-counting method) as shown in the above-mentioned total syntheses of epothilone A and B of the case, is.

Die nachfolgenden Beispiele dienen der näheren Erläuterung des Erfindungsgegenstandes, ohne ihn auf diese beschränken zu wollen. The following examples serve to illustrate the subject invention, without wishing to be limited to these.

Beispiele Examples Ausgangsprodukte output products A) 2,2-Dimethyl-3-oxopentanal A) 2,2-Dimethyl-3-oxopentanal Aa) 4-(2-Methylprop-1-enyl)morpholin Aa) 4- (2-methylprop-1-enyl) morpholine

In einem 250 ml-Dreihalsrundkolben werden 43,6 g Morpholin vorgelegt. In a 250 ml three-necked round bottom flask 43.6 g of morpholine are introduced. Unter Eisbadkühlung werden bei einer Temperatur von 5°C innerhalb von 20 Minuten 46 ml Isobutylaldehyd zugetropft. With ice bath cooling 46 ml of isobutyraldehyde are added dropwise at a temperature of 5 ° C within 20 minutes. Dabei war eine starke Temperaturerhöhung zu beobachten (stark exotherme Reaktion). Here was a strong increase in temperature observed (highly exothermic reaction). Nach beendeter Zugabe wird der Ansatz über einen Wasserabscheider 4 Stunden refluxiert. After completion of the addition, the mixture through a water refluxed for 4 hours. Das Volumen des Wasserabscheiders wird mit Isobutylaldehyd gefüllt. The volume of the water is filled with isobutyl. Es werden 7,5 ml H 2 O abgeschieden. There are deposited 7.5 ml H 2 O. Nach Ablauf der Reaktion wird das Reaktionsgemisch im Vakuum destilliert. After the reaction, the reaction mixture is distilled in vacuo.
Ölbadtemperatur: 85°-90°C Oil bath temperature: 85 ° -90 ° C
Hauptlauf m = 58,37 g 82,03% Main fraction m = 58.37 g 82.03%
Siedepunkt: 59°C bei 11 mbar Boiling point: 59 ° C at 11 mbar
Ausbeute: 58,37 g 82,03% Aa). Yield: 58.37 g 82.03% Aa).

A) 2,2-Dimethyl-3-oxopentanal A) 2,2-Dimethyl-3-oxopentanal

In einem 1000 ml Dreihalsrundkolben wird die Lösung von 77,14 g Propionsäurechlorid in 200 ml Ether pa vorgelegt. In a 1000 ml three-necked round-bottomed flask, the solution of 77.14 g of propionic acid chloride in 200 ml of ether is submitted pa. Unter Eisbadkühlung wird innerhalb von 30 Minuten bei einer Reaktionstemperatur von 6°C eine Lösung von 117,73 g der unter Aa) erhaltenen Verbindung in 200 ml Ether p. With ice bath cooling, a solution of 117.73 g of the compound obtained under Aa) in 200 ml of ether p within 30 minutes at a reaction temperature of 6 ° C. A. zugetropft. A. dropwise. Ausfällung, weißer Niederschlag entsteht. Precipitation, white precipitate. Nach beendeter Zugabe wird der Ansatz 5 Stunden am Rückfluß gekocht und anschließend über Nacht bei Raumtemperatur gerührt. After completion of the addition, the mixture is boiled for 5 hours under reflux and then stirred overnight at room temperature. Der entstehende weiße Niederschlag, feuchtigkeitsempfindlich, wird abgesaugt, mit Ether gewaschen und an der Ölpumpe getrocknet. The resulting white precipitate, sensitive to moisture, is suctioned off, washed with ether and dried on the oil pump.
Rohprodukt: m = 65,26 g Hydrochlorid. Crude product: m = 65.26 g of hydrochloride.
Im Filtrat ist eine Nachfällung zu beobachten. In the filtrate a second precipitation is observed.
Rohprodukt m = 35,49 g Gesamt: m = 100,75 g. Crude product m = 35.49 g Total: m = 100.75 g.
Die 100,75 g Hydrochlorid werden in 150 ml H 2 O gelöst. The 100.75 g of the hydrochloride are dissolved in 150 ml H 2 O. Anschließend wird die Wasserphase mit NaHCO 3 insgesamt auf pH 0 5 eingestellt und dann 4 mal mit je 150 ml Ether extrahiert. Then the water phase is adjusted with NaHCO 3 to pH Total 0 5, and then extracted 4 times with 150 ml of ether. Die organische Phase wird einmal mit Sole gewaschen und dann über Na 2 SO 4 getrocknet. The organic phase is washed once with brine and then dried over Na 2 SO 4. Der Ether wird bei Normaldruck abdestilliert und der Rückstand wird im Vakuum über eine kleine Vigreux-Kolonne (6 Böden) destilliert. The ether is distilled off at normal pressure, and the residue is distilled in a vacuum via a small Vigreux column (6 trays).
Hauptlauf: m = 29,65 g 27,75% Main fraction: m = 29.65 g 27.75%
Siedepunkt: 62°C bei 15 mbar Boiling point: 62 ° C at 15 mbar
Ausbeute: 29,65 g 27,75% A). Yield: 29.65 g 27.75% A).

B) 2,2-Dimethyl-3-oxo-butanal B) 2,2-Dimethyl-3-oxo-butanal

Durchführung analog A). Procedure analogous to A).
Ansatz: 58,37g = 413,36 mMol Aa), M = 141,21 g/mol 100 ml Diethylether pA Approach: 58,37g = 413.36 mmol Aa), M = 141.21 g / mol 100 ml of diethyl ether pA
32,45 g = 413,38 mMol Acetylchlorid, M = 0 78,5 g/mol = 1,104 g/ml 32.45 g = 413.38 mmol of acetyl chloride, M = 0, 78.5 g / mol = 1.104 g / ml
100 ml Diäthylether pA übers Wochenende bei Raumtemperatur gerührt. 100 ml diethyl ether pA stirred over the weekend at room temperature.
Rohprodukt m = 72,07 g Hydrochlorid Crude product m = 72.07 g of hydrochloride
Aufarbeitung siehe Ab) For preparation, see Ab)
Ölbadtemperatur: 75°C bis 80°C Oil bath temperature: 75 ° C to 80 ° C
Hauptlauf: m = 18,75 g 39,74% Main fraction: m = 18.75 g 39.74%
Siedepunkt: 50°C bei 11 mbar Boiling point: 50 ° C at 11 mbar
Ausbeute m = 18,7 g 39,6% B). Yield m = 18.7 g 39.6% B).

C) 1-(1-Oxopropyl)cyclobutancarbaldehyd C) 1- (1-oxopropyl) cyclobutanecarbaldehyde Ca) 1,1-Cyclobutandimethanol Ca) 1.1-cyclobutanedimethanol

Zu einer Lösung von 20 g (100 mmol) 1,1-Cyclobutandicarbonsäurediethylester in 200 ml absolutem Tetrahydrofuran werden bei 0°C 170 ml einer 1,2 molaren Lösung von Diisobutylaluminiumhydrid getropft. To a solution of 20 g (100 mmol) of 1,1-Cyclobutandicarbonsäurediethylester in 200 ml of absolute tetrahydrofuran at 0 ° C 170 ml of a 1.2 molar solution of diisobutylaluminum hydride dropwise. Man läßt eine Stunde bei 0°C nachrühren und addiert dann 30 ml Wasser. The mixture is stirred one hour at 0 ° C and then added 30 ml of water. Es wird über Celite filtriert. It is filtered through Celite. Das Filtrat wird mit Natriumsulfat getrocknet und im Vakuum eingeengt. The filtrate is dried with sodium sulfate and concentrated in vacuo. Das erhaltene Rohprodukt (9,9 g) wird ohne Aufreinigung in die Folgestufe eingesetzt. The crude product obtained (9.9 g) is used in the next stage without purification.

Cb) 1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutanmethanol Cb) 1 - [[[dimethyl (1,1-dimethylethyl) silyl] oxy] methyl] cyclobutane methanol

Zu einer Suspension von 3,4 g Natriumhydrid (60%ig in Öl, 85 mmol)) in 35 ml absolutem Tetrahydrofuran wird bei 0°C eine Lösung von 9,9 g Ca) (85 mmol) in 100 ml absolutem Tetrahydrofuran gegeben. To a suspension of 3.4 g of sodium hydride (60% in oil, 85 mmol)) in 35 ml of absolute tetrahydrofuran at 0 ° C (a solution of 9.9 g Ca) 85 mmol) in 100 ml of absolute tetrahydrofuran. Man läßt 30 Minuten nachrühren und addiert dann eine Lösung von 12,8 g tert.Butyldimethylsilylchlorid (85 mmol) in 50 ml Tetrahydrofuran. Stirring is continued for 30 minutes and then added a solution of 12.8 g of t-butyldimethylsilyl chloride (85 mmol) in 50 ml of tetrahydrofuran. Man läßt eine Stunde bei 25°C nachrühren und gießt dann das Reaktionsgemisch auf gesättigte wäßrige Natriumhydrogencarbonatlösung. The mixture is stirred for one hour at 25 ° C and then pour the reaction mixture onto saturated aqueous sodium bicarbonate solution. Es wird mit Ethylacetat extrahiert. It is extracted with ethyl acetate. Die organische Phase wird mit gesättigter Natriumchloridlösung gewaschen und über Natriumsulfat getrocknet. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. Nach Abziehen des Lösungsmittels im Vakuum wird das erhaltene Rohprodukt durch Säulenchromatographie an Kieselgel mit einem Gemisch aus Hexan/Ethylacetat gereinigt. After removal of the solvent in vacuo, the crude product is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. Man erhält 13,5 g (69%) der Titelverbindung. Is obtained (69%) of the title compound 13.5 g.
1 H-NMR (CDCl 3 ): δ = 0,04 (6H), 0,90 (9H), 1,70-2,00 (6H), 3,70 (4H) ppm. 1 H-NMR (CDCl 3): δ = 0.04 (6H), 0.90 (9H), 1.70-2.00 (6H), 3.70 (4H) ppm.

Cc) 1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutancarbaldehyd Cc) 1 - [[[dimethyl (1,1-dimethylethyl) silyl] oxy] methyl] cyclobutanecarbaldehyde

8 ml Oxalylchlorid werden in 100 ml Dichlormethan gelöst. 8 ml of oxalyl chloride are dissolved in 100 ml of dichloromethane. Man kühlt auf -78°C und addiert 13 ml Dimethylsulfoxid. The mixture is cooled to -78 ° C and added 13 ml of dimethyl sulfoxide. Man läßt 3 Minuten nachrühren und addiert dann eine Lösung von 13,5 g Cb) (58,6 mmol) in 80 ml Dichlormethan. Stirring is continued for 3 minutes and then added a solution of 13.5 g of Cb) (58.6 mmol) in 80 ml of dichloromethane. Nach weiteren 15 Minuten Nachrührzeit werden 58 ml Triethylamin hinzugetropft. After another 15 minutes stirring time 58 ml triethylamine are added dropwise. Anschließend läßt man auf 0°C erwärmen. Then allowed to warm to 0 ° C. Dann wird das Reaktionsgemisch auf gesättigte Natriumhydrogen-carbonatlösung gegossen. Then the reaction mixture is poured onto saturated sodium hydrogen carbonate-. Man extrahiert mit Dichlormethan, wäscht die organische Phase mit gesättigter Natriumchloridlösung, trocknet über Natriumsulfat und engt im Vakuum ein. It is extracted with dichloromethane, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. Nach Chromatographie des Rohprodukts an Kieselgel mit einem Gemisch aus Hexan/Ethylacetat erhält man 7,7 g (58%) der Titelverbindung. After chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate 7.7 g (58%) of the title compound are obtained.
1 H-NMR (CDCl 3 ): δ = 0,03 (6H), 0,90 (9H), 1,85-2,00 (4H), 2,20-2,30 (2H), 3,83 (2H), 9,70 (1H) ppm. 1 H-NMR (CDCl 3): δ = 0.03 (6H), 0.90 (9H), 1.85-2.00 (4H), 2.20-2.30 (2H), 3.83 (2H), 9.70 (1H) ppm.

Cd) 1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]-α-ethylcyclobutanmethanol Cd) 1 - [[[dimethyl (1,1-dimethylethyl) silyl] oxy] methyl] -α-ethylcyclobutanmethanol

Eine Lösung von 7,7 g (33,7 mmol) der unter Cc) beschriebenen Verbindung in 80 ml Tetrahydrofuran wird bei 0°C zu 20 ml einer 2 molaren Lösung von Ethylmagnesium chlorid (40 mmol) in Tetrahydrofuran getropft. A solution of 7.7 g (33.7 mmol) of the compound, described under Cc) in 80 ml of tetrahydrofuran is added dropwise at 0 ° C to 20 ml of a 2 molar solution of ethylmagnesium chloride (40 mmol) in tetrahydrofuran. Man läßt 30 Minuten bei 0°C nachrühren und gießt dann das Reaktionsgemisch auf gesättigte Ammonium chloridlösung. The mixture is stirred for 30 minutes at 0 ° C and then pour the reaction mixture into saturated ammonium chloride solution. Es wird mit Ethylacetat extrahiert. It is extracted with ethyl acetate. Die organische Phase wird mit gesättigter Natriumchloridlösung gewaschen und über Natriumsulfat getrocknet. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. Nach dem Abziehen des Lösungsmittels wird das erhaltene Rohprodukt durch Säulenchromatographie an Kieselgel gereinigt. After removal of the solvent, the crude product is purified by column chromatography on silica gel. Man erhält 7,93 g (91,5%) der Titelverbindung. There is obtained (91.5%) of the title compound 7.93 g.
1 H-NMR (CDCl 3 ): δ = 0,09 s (6H), 0,90 s (9H), 1,05 (3H), 1,30-1,50 (3H), 1,70-1,90 (4H), 2,09 (1H), 3,19 (1H), 3,46 (1H), 3,72 (1H), 3,85 (1H) ppm. 1 H-NMR (CDCl 3): δ = 0.09 s (6H), 0.90 s (9H), 1.05 (3H), 1.30-1.50 (3H), 1.70 to 1 90 (4H), 2.09 (1H), 3.19 (1H), 3.46 (1H), 3.72 (1H), 3.85 (1H) ppm.

Ce) 1-[1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobut-1-yl]-1-propanon Ce) 1- [1 - [[[dimethyl (1,1-dimethylethyl) silyl] oxy] methyl] cyclobut-1-yl] -1-propanone

Zu 3,76 ml (43,8 mmol) Oxalylchlorid in 80 ml Dichlormethan werden bei -78°C 6 ml (85,7 mmol) Dimethylsulfoxid addiert. To 3.76 ml (43.8 mmol) of oxalyl chloride in 80 ml of dichloromethane at -78 ° C 6 ml (85.7 mmol) of dimethyl sulfoxide are added. Man läßt 3 Minuten nachrühren und addiert dann eine Lösung von 7,93 g (30,7 mmol) der unter Cd) beschriebenen Verbindung in 80 ml Dichlormethan. Stirring is continued for 3 minutes and then added a solution of 7.93 g (30.7 mmol) of the compound, described under Cd) in 80 ml of dichloromethane. Es wird weitere 15 Minuten bei -78°C nachgerührt. The mixture is stirred for another 15 minutes at -78 ° C. Anschließend wird eine Mischung aus 19 ml (136 mmol) Triethylamin und 40 ml Dichlormethan hinzugetropft. Then a mixture of 19 ml (136 mmol) of triethylamine and 40 ml dichloromethane is added dropwise. Man läßt auf -25°C erwärmen und rührt bei dieser Temperatur 30 Minuten nach. The mixture is allowed to warm to -25 ° C and stirred at this temperature for 30 minutes. Anschließend das Reaktionsgemisch auf gesättigte eiskalte Natriumhydrogencarbonatlösung gegossen. Then the reaction mixture poured onto saturated ice-cold sodium bicarbonate solution. Es wird mit Dichlormethan extrahiert. It is extracted with dichloromethane. Die organische Phase wird mit gesättigter Natriumchloridlösung gewaschen und über Natriumsulfat getrocknet. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. Nach dem Abziehen des Lösungsmittels wird das erhaltene Rohprodukt über Kieselgel filtriert. After removal of the solvent, the resulting crude product on silica gel is filtered. Man erhält 7,87 g (100%) der Titelverbindung. Is obtained (100%) of the title compound 7.87 g.
1 H-NMR (CDCl 3 ): δ = 0,05 (6H), 0,88 (9H), 1,04 (3H), 1,82-1,95 (4H), 2,33-2,47 (2H), 2,45-2,54 (2H), 3,81 (2H) ppm. 1 H-NMR (CDCl 3): δ = 0.05 (6H), 0.88 (9H), 1.04 (3H), 1.82 to 1.95 (4H), 2.33 to 2.47 (2H), 2.45 to 2.54 (2H), 3.81 (2H) ppm.

Cf) 1-[1-(Hydroxymethyl)cyclobut-1-yl]-1-propanon Cf) 1- [1- (Hydroxymethyl) cyclobut-1-yl] -1-propanone

7,87 g (30,7 mmol) der unter Ce) beschriebenen Verbindung werden in 100 ml Tetrahydrofuran gelöst. 7.87 g (30.7 mmol) of the compound described under Ce) is dissolved in 100 ml of tetrahydrofuran. Man addiert 15 ml einer 1 molaren Lösung von Tetrabutylammoniumfluorid und läßt 12 Stunden bei 25°C nachrühren. Adding 15 ml of a 1 molar solution of tetrabutylammonium fluoride and allowed 12 hours at 25 ° C stirred. Danach wird das Reaktionsgemisch auf gesättigte Natriumhydrogencarbonatlösung gegossen. Thereafter, the reaction mixture is poured onto saturated sodium bicarbonate solution. Man extrahiert mit Ethylacetat. The mixture is extracted with ethyl acetate. Die organische Phase wird mit gesättigter Natriumchloridlösung gewaschen und über Natriumsulfat getrocknet. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. Nach dem Abziehen des Lösungsmittels wird das erhaltene Rohprodukt durch Säulenchromatographie an Kieselgel gereinigt. After removal of the solvent, the crude product is purified by column chromatography on silica gel. Man erhält 3,19 g (73,4%) der Titelverbindung. There is obtained (73.4%) of the title compound 3.19 g.
1 H-NMR (CDCl 3 ): δ = 1,07 (3H), 1,86-2,08 (4H), 2,32-2,40 (2H), 2,55-2,65 (2H), 3,88 (2H) ppm. 1 H-NMR (CDCl 3): δ = 1.07 (3H), 1.86 to 2.08 (4H), 2.32 to 2.40 (2H), 2.55-2.65 (2H) , 3.88 (2H) ppm.

C) 1-(1-Oxopropyl)cyclobutancarbaldehyd C) 1- (1-oxopropyl) cyclobutanecarbaldehyde

Analog zu Beispiel Ce) werden aus 3,19 g (22,4 mmol) der unter Cf) beschriebenen Verbindung durch Oxidation 3,14 g (100%) der Titelverbindung erhalten. Analogously to Example Ce) are (from 3.19 g 22.4 mmol) of the compound described under Cf) by oxidation of 3.14 g (100%) of the title compound.
1 H-NMR (CDCl 3 ): δ = 1,07 (3H), 1,85-2,00 (2H), 2,40-2,53 (6H), 9,70(1H) ppm. 1 H-NMR (CDCl 3): δ = 1.07 (3H), 1.85-2.00 (2H), 2.40-2.53 (6H), 9.70 (1H) ppm.

Beispiel 1 example 1 (R)-4,4-Dimethyl-3-[3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-5-oxo-heptansäure (R) -4,4-dimethyl-3- [3 - [[dimethyl (1,1-dimethylethyl) silyl] oxy] -5-oxo-heptanoic acid

Zu einer Lösung von 190 mg des unter Beispiel 1c) hergestellten Silylethers in 2.5 ml einer Mischung aus Tetrahydrofuran und Wasser im Verhältnis 4 : 1 gibt man bei 0°C 0.17 ml einer 30%igen Wasserstoffperoxid-Lösung. To a solution of 190 mg of the silyl ether prepared in Example 1c) in 2.5 ml of a mixture of tetrahydrofuran and water in a ratio of 4: 1 are added 0.17ml of a 30% hydrogen peroxide solution at 0 ° C. Nach 5 Minuten Rühren wird dann eine Lösung von 15.8 mg Lithiumhydroxid in 0.83 ml Wasser hinzugegeben, und die Reaktionsmischung für 3 Stunden bei 25°C gerührt. After 5 minutes stirring a solution of 15.8 mg of lithium hydroxide in 0.83 ml of water is then added, and the reaction mixture stirred for 3 hours at 25 ° C. Anschließend wird mit einer Lösung von 208 mg Natriumsulfit in 1.24 ml Wasser versetzt und mit 10 ml Methylenchlorid extrahiert. The mixture is then treated with a solution of 208 mg of sodium sulfite in 1.24 ml of water and extracted with 10 ml methylene chloride. Die wäßrige Phase wird mit 5N Salzsäure auf pH=1 eingestellt und dreimal mit je 10 ml Essigester extrahiert. The aqueous phase is adjusted with 5N hydrochloric acid to pH = 1 and extracted three times with 10 ml Essigester. Nach dem Trocknen über Natriumsulfat und Filtration wird im Vakuum eingeengt. After drying over sodium sulfate and filtration, it is concentrated in vacuo. Zusätzlich wird die obige Methylenchlorid-Phase mit 5N Salzsäure gewaschen und dann diese wäßrige Phase dreimal mit je 10 ml Essigester extrahiert. Additionally, the above methylene chloride phase is washed with 5N hydrochloric acid and then extracted this aqueous phase three times with 10 ml Essigester. Nach dem Trocknen über Natriumsulfat und Filtration wird im Vakuum eingeengt und eine zusätzliche Menge an Rohprodukt erhalten. After drying over sodium sulfate and filtration, it is concentrated in vacuo to obtain an additional amount of crude product. Die vereinigten, so erhaltenen Rückstande reinigt man durch Chromatographie an Kieselgel. The combined residue thus obtained is purified by chromatography on silica gel. Mit Hexan/0-50% Essigester erhält man neben 70 mg (4R,5S)-4-Methyl-5-phenyloxazolidin-2-on 93 mg der Titelverbindung als farbloses Öl. With hexane / 0-50% Essigester obtained (4R, 5S) next to 70 mg -4-methyl-5-phenyloxazolidin-2-one 93 mg of the title compound as a colorless oil. [α] D = +15.5° (CHCl 3 ) [α] D = + 15.5 ° (CHCl 3)
1 H-NMR (CDCl 3 ): d = 0.03-0.08 (6H), 0.86 (9H), 1.01 (3H), 1.10 (3H), 1.15 (3H), 2.35 (1H), 2.4-2.7 (3H), 4.48 (1H) ppm. 1 H-NMR (CDCl3): d = 0:03 to 12:08 (6H), 0.86 (9H), 1:01 (3H), 1.10 (3H), 1.15 (3H), 2:35 (1H), 2.4-2.7 (3H), 4:48 (1H) ppm.

1a) (4R,5S)-3-(Bromacetyl)-4-methyl-5-phenyloxazolidin-2-on 1a) (4R, 5S) -3- (bromoacetyl) -4-methyl-5-phenyloxazolidin-2-one

Zu einer Lösung von 30.1 g (4R,5S)-4-Methyl-5-phenyloxazolidin-2-on in 500 ml Tetrahydrofuran gibt man innerhalb von 30 Minuten bei -70°C unter Stickstoff 117 ml einer 1.6 molaren Lösung von Butyllithium in Hexan zu. To a solution of 30.1 g of (4R, 5S) -4-methyl-5-phenyloxazolidin-2-one in 500 ml of tetrahydrofuran are added over 30 minutes at -70 ° C under nitrogen 117 ml of a 1.6 molar solution of butyllithium in hexane to. Anschließend wird eine Lösung von 26.8 g Bromacetylchlorid in 250 ml Tetrahydrofuran so zugetropft, daß die Temperatur nicht über -65°C steigt. Then a solution of 26.8 g of bromoacetyl chloride in 250 ml of tetrahydrofuran is added dropwise such that the temperature did not exceed -65 ° C increases. Nach 1.75 Stunden Rühren bei -70°C gibt man eine gesättigte Ammoniumchlorid-Lösung hinzu, gefolgt von 60 ml einer gesättigten Natriumhydrogencarbonat-Lösung und läßt auf 25°C kommen. After 1.75 hours of stirring at -70 ° C is added a saturated ammonium chloride solution was added, followed by 60 ml of a saturated sodium bicarbonate solution and allowed to come to 25 ° C. Nach Trennung der Phasen wird die wäßrige Phase zweimal mit je 100 ml Ether extrahiert. After separation of the phases, the aqueous phase is extracted twice with 100 ml of ether. Die vereinigten organischen Phasen werden mit halbkonzentrierter Natriumchlorid-Lösung gewaschen, über Natriumsulfat getrocknet und nach Filtration im Vakuum eingeengt. The combined organic phases are washed with semi-concentrated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo after filtration. Den so erhaltenen Rückstand reinigt man durch Chromatographie an Kieselgel. The residue thus obtained is purified by chromatography on silica gel. Mit Hexan/0-50% Ether erhält man 34.8 g der Titelverbindung als farbloses Öl. With hexane / 0-50% ether, 34.8 g of the title compound as a colorless oil.
1 H-NMR (CDCl 3 ): δ = 0.95 (3H), 4.57 (2H), 4.80 (2H), 5.76 (2H), 7.2-7.5 (5H) ppm. 1 H-NMR (CDCl 3): δ = 0.95 (3H), 4:57 (2H), 4.80 (2H), 5.76 (2H), 7.2-7.5 (5H) ppm.

1b) [4R-[3(R*),4α, 5α]]-3-[4,4-Dimethyl-1,5-dioxo-3-hydroxyheptyl]-4-methyl-5-phenyl oxazolidin-2-on 1b) [4R- [3 (R *), 4α, 5α]] - 3- [4,4-dimethyl-1,5-dioxo-3-hydroxyheptyl] -4-methyl-5-phenyl-oxazolidin-2-one

Zu einer Suspension von 5.0 g wasserfreiem Chrom(II)chlorid in 60 ml Tetrahydrofuran gibt man unter Argon 218 mg Lithiumiodid. To a suspension of 5.0 g of anhydrous chromium (II) chloride in 60 ml of tetrahydrofuran are added 218 mg of lithium iodide under argon. Anschließend wird eine Mischung von 2.09 g des literaturbekannten 2,2-Dimethyl-3-oxo-pentanal (siehe unter "Ausgangs produkte" Ab) und 5.34 g der vorstehend hergestellten Bromverbindung in 10 ml Tetrahydrofuran hinzugegeben. Then a mixture of 2.09 g of the literature known 2,2-dimethyl-3-oxo-pentanal (see under "starting products" Ab) and added 5.34 g of the bromo compound prepared above in 10 ml of tetrahydrofuran. Nach 2 Stunden Reaktionszeit wird mit 30 ml gesättigter Natriumchlorid-Lösung versetzt und 15 Minuten gerührt. After 2 hours reaction time, saturated sodium chloride solution is mixed with 30 ml and stirred for 15 minutes. Die wäßrige Phase wird dreimal mit je 200 ml Ether extrahiert. The aqueous phase is extracted three times with 200 ml of ether. Die vereinigten organischen Phasen werden mit halbkonzentrierter Natriumchlorid-Lösung gewaschen, über Natriumsulfat getrocknet und nach Filtration im Vakuum eingeengt. The combined organic phases are washed with semi-concentrated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo after filtration. Den so erhaltenen Rückstand reinigt man durch Chromatographie an Kieselgel. The residue thus obtained is purified by chromatography on silica gel. Mit Hexan/0-30% Essigester erhält man 1.55 g der Titelverbindung als farbloses Öl. With hexane / 0-30% Essigester obtained 1.55g of the title compound as a colorless oil.
1 H-NMR (CDCl 3 ): δ = 0.92 (3H), 1.06 (3H), 1.18 (3H), 1.23 (3H), 2.58 (2H), 3.07 (2H), 3.28 (1H), 4.35 (1H), 4.79 (1H), 5.70 (2H), 7.2-7.5 (5H) ppm. 1 H-NMR (CDCl 3): δ = 0.92 (3H), 1:06 (3H), 1.18 (3H), 1.23 (3H), 2:58 (2H), 3:07 (2H), 3.28 (1H), 4:35 (1H) , 4.79 (1H), 5.70 (2H), 7.2-7.5 (5H) ppm.

1c) [4R-[3(R*),4α,5α]-3-[4,4-Dimethyl-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-1,5- dioxoheptyl]-4-methyl-5-phenyloxazolidin-2-on 1c) [4R- [3 (R *), 4α, 5α] -3- [4,4-dimethyl-3 - [[dimethyl (1,1-dimethylethyl) silyl] oxy] -1,5-dioxoheptyl] - 4-methyl-5-phenyloxazolidin-2-one

Zu einer Lösung von 347 mg des vorstehend hergestellten Alkohols in 3 ml Methylenchlorid gibt man unter Argon bei -70°C 150 mg 2,6-Lutidin. To a solution of 347 mg of the above-produced alcohol in 3 ml of methylene chloride under argon at -70 ° C 150 mg of 2,6-lutidine. Nach 5 Minuten Rühren werden 344 mg tert.Butyldimethylsilyltrifluormethansulfonat hinzugegeben und für weitere 45 Minuten bei -70°C gerührt. After 5 minutes of stirring, 344 mg tert.Butyldimethylsilyltrifluormethansulfonat are added and stirred for a further 45 minutes at -70 ° C. Man versetzt mit 1 ml gesättigter Natriumchlorid-Lösung und läßt auf 25°C kommen. It is mixed with 1 ml of saturated sodium chloride solution and allowed to come to 25 ° C. Anschließend wird mit Ether verdünnt und die organische Phase mit gesättigter Natriumchlorid-Lösung gewaschen. It is then diluted with ether and the organic phase washed with saturated sodium chloride solution. Nach dem Trocknen über Natriumsulfat und Filtration wird im Vakuum eingeengt. After drying over sodium sulfate and filtration, it is concentrated in vacuo. Den so erhaltenen Rückstand reinigt man durch Chromatographie an Kieselgel. The residue thus obtained is purified by chromatography on silica gel. Mit Hexan/0-30% Essigester erhält man 192 mg der Titelverbindung als farblose kristalline Verbindung mit einem Schmelzpunkt von 111-112°C. With hexane / 0-30% Essigester obtained 192 mg of the title compound as a colorless crystalline compound with a melting point of 111-112 ° C.
1 H-NMR (CDCl 3 ): δ = 0.01-0.12 (6H), 0.86 (9H), 0.90 (3H), 1.00 (3H), 1.13 (3H), 1.17 (3H), 2.56 (2H), 3.05 (2H), 4.65-4.80 (2H), 5.68 (1H), 7.2-7.5 (5H) ppm. 1 H-NMR (CDCl 3): δ = 0:01 to 12:12 (6H), 0.86 (9H), 0.90 (3H), 1.00 (3H), 1.13 (3H), 1.17 (3H), 2:56 (2H), 3:05 ( 2H), 4.65-4.80 (2H), 5.68 (1H), 7.2-7.5 (5H) ppm.

Beispiel 2 example 2 (S)-4,4-Dimethyl-3-[3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-5-oxo-heptansäure (S) -4,4-dimethyl-3- [3 - [[dimethyl (1,1-dimethylethyl) silyl] oxy] -5-oxo-heptanoic acid

Die Verbindung wird in Analogie zu Beispiel 1 hergestellt. The compound is prepared in analogy to Example. 1 Als Ausgangsprodukt dient (4S,5R)-4-Methyl-5-phenyloxazolidin-2-on. (4S, 5R) serves as the starting product -4-methyl-5-phenyloxazolidin-2-one. NMR ist deckungsgleich mit Beispiel 1. NMR is identical with Example. 1
[α] D = -157° (CHCl 3 ). [α] D = -157 ° (CHCl 3).

2a) (4S,5R)-3-(Bromacetyl)-4-methyl-5-phenyloxazolidin-2-on 2a) (4S, 5R) -3- (bromoacetyl) -4-methyl-5-phenyloxazolidin-2-one

Die Darstellung erfolgt analog zu Beispiel 1a) ausgehend von (4S,5R)-4-Methyl-5- phenyloxazolidin-2-on. The compound is prepared analogously to Example 1a), starting from (4S, 5R) -4-methyl-5- phenyloxazolidin-2-one. NMR ist deckungsgleich mit 1a). NMR is congruent with 1a).

Beispiel 3 example 3 (S)-3-[3-[[Dimethyl(1,1-dimethyl)silyl]oxy]-3-[1-(1-oxopropyl)cyclobut-1-yl]propansäure (S) -3- [3 - [[dimethyl (1,1-dimethyl) silyl] oxy] -3- [1- (1-oxopropyl) cyclobut-1-yl] propanoic acid

Analog zu Beispiel 1 werden aus 2,79 g (5,9 mmol) der unter 3b) beschriebenen Verbindung 1,49 g (80%) der Titelverbindung und 941 mg zurückgewonnenes (4S,5R)-4-Methyl-5-phenyloxazolidin-2-on erhalten. Analogously to Example 1, from 2.79 g (5.9 mmol) of the compound described under 3b), 1.49 g (80%) of the title compound and 941 mg of recovered (4S, 5R) -4-methyl-5-phenyloxazolidin- 2-one. Die Titelverbindung und das zurückzugewinnende chirale Auxiliar lassen sich durch Chromatographie (analog Beispiel 1) oder auch fraktionierte Kristallisation trennen und danach durch Chromatographie gewünschtenfalls aufreinigen. The title compound and the chiral auxiliary to be recovered can be separated by chromatography (analogously to Example 1), or fractional crystallization to separate and then purified by chromatography, if desired.
1 H-NMR (CDCl 3 ): δ = 0.09 (3H), 0.19 (3H), 0.90 (9H), 1.08 (3H), 1.70-2.00 (3H), 2.20-2.40 (4H), 2.47 (1H), 2.50-2.70 (2H), 4.45 (1H) ppm. 1 H-NMR (CDCl 3): δ = 0:09 (3H), 0:19 (3H), 0.90 (9H), 1.08 (3H), 1.70-2.00 (3H), 2:20 to 2:40 (4H), 2:47 (1H); 2.50-2.70 (2H), 4.45 (1H) ppm.

3a) [4S-[3(R*),4α,5α]]-3-[3-Hydrnxy-1-oxo-3-[1-(1-oxopropyl)cyclobut-1-yl]propyl]4- methyl-5-phenyloxazolidin-2-on 3a) [4S- [3 (R *), 4α, 5α]] - 3- [3-Hydrnxy-1-oxo-3- [1- (1-oxopropyl) cyclobut-1-yl] propyl] 4-methyl -5-phenyl-oxazolidin-2-one

Analog zu Beispiel 1b) werden aus 3,14 g (22,4 mmol) der unter C) beschriebenen Verbindung, 9,7 g (78,8 mmol) wasserfreiem Chrom(II)chlorid, 9,69 g (32,5 mmol) 2a) und 300 mg (2,2 mmol) wasserfreiem Lithiumiodid in Tetrahydrofuran nach Säulenchromatographie an Kieselgel 3,0 g (37,4%) der Titelverbindung als farbloses Öl erhalten. Analogously to Example 1b) from 3.14 g (22.4 mmol) of the compound described under C), 9.7 g (78.8 mmol) of anhydrous chromium (II) chloride, 9.69 g (32.5 mmol ) 2a) and 300 mg (2.2 mmol) of anhydrous lithium iodide in tetrahydrofuran according to silica gel column chromatography, 3.0 g (37.4%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 ): δ = 0,93 (3H), 1,10 (3H), 1,80-2,03 (2H), 2,10-2,21 (1H), 2,26-2,35 (3H), 2,54-2,70 (2H), 3,03-3,08 (2H), 3,34 (1H), 4,39 (1H), 4,74-4,85 (1H), 5,69 (1H), 7,27-7,34 (2H), 7,36-7,49 (3H) ppm. 1 H-NMR (CDCl 3): δ = 0.93 (3H), 1.10 (3H), 1.80 to 2.03 (2H), 2.10-2.21 (1H), 2.26 -2.35 (3H), 2.54-2.70 (2H), 3.03 to 3.08 (2H), 3.34 (1H), 4.39 (1H), 4.74 to 4, 85 (1H), 5.69 (1H), 7.27-7.34 (2H), 7.36-7.49 (3H) ppm.

3b) [4S-[3(R*),4α,5α]]-3-[3-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-1-oxo-3-[1-(1- oxopropyl)cyclobut-1-yl]propyl]-4-methyl-5-phenyloxazolidin-2-on 3b) [4S- [3 (R *), 4α, 5α]] - 3- [3 - [[dimethyl (1,1-dimethylethyl) silyl] oxy] -1-oxo-3- [1- (1- oxopropyl) cyclobut-1-yl] propyl] -4-methyl-5-phenyloxazolidin-2-one

Analog zu Beispiel 1c) werden aus 3,0 g (8,35 mmol) der unter Beispiel 3a) beschriebenen Verbindung, tert.Butyldimethylsilyltrifluormethansulfonat und 2,6- Lutidin nach Umkristallisation aus Diisopropylether 2,79 g (70,6%) der Titelverbindung erhalten. Analogously to Example 1c) from 3.0 g (8.35 mmol) of the compound tert.Butyldimethylsilyltrifluormethansulfonat described under Example 3a) and 2,6-lutidine after recrystallization from diisopropyl ether 2.79 g (70.6%) of the title compound receive.
1 H-NMR (CDCl 3 ): δ = 0,10 (3H), 0,21 (3H), 0,92 (3H), 0,95 (9H), 1,10 (3H), 1,70-1,92 (2H), 2,02-2,16 (1H), 2,20-2,40 (3H), 2,50-2,72 (2H), 2,98-3,10 (2H), 4,63-4,75 (1H), 5,69 (1H), 7,28-7,35 (2H), 7,36-7,48 (3H) ppm. 1 H-NMR (CDCl 3): δ = 0.10 (3H), 0.21 (3H), 0.92 (3H), 0.95 (9H), 1.10 (3H), 1,70- 1.92 (2H), 2.02-2.16 (1H), 2.20-2.40 (3H), 2.50 to 2.72 (2H), 2.98 to 3.10 (2H) , 4.63 to 4.75 (1H), 5.69 (1H), 7.28-7.35 (2H), 7.36-7.48 (3H) ppm.

Beispiel 4 example 4 (R)-3-[3-[[Dimethyl(1,1-dimethyl)silyl]oxy)-3-[1-(1-oxopropyl)cyclobut-1-yl]propansäure (R) -3- [3 - [[dimethyl (1,1-dimethyl) silyl] oxy) -3- [1- (1-oxopropyl) cyclobut-1-yl] propanoic acid

Die Verbindung wird in Analogie zu Beispiel 3 hergestellt. The compound is prepared in analogy to Example 3. FIG. Als Ausgangsprodukt dient (4R,5S)-3-(Bromacetyl)4-methyl-5-phenyloxazolidin-2-on. (4R, 5S) serves -3- (bromoacetyl) 4-methyl-5-phenyloxazolidin-2-one as starting material. Das NMR-Spektrum ist deckungsgleich mit Beispiel 3. The NMR spectrum is identical with Example 3. FIG.

Durch die Wahl der Stereochemie an C4 und C5 des chiralen Auxiliars 4-Methyl-5- phenyl-2-oxazolidon läßt sich die Stereochemie in Position 3 steuern. By the choice of the stereochemistry at C4 and C5 of the chiral auxiliary 4-methyl-5- stereochemistry can be phenyl-2-oxazolidone be controlled in position. 3 Die Struktur des Intermediats 1 b) wurde durch eine Röntgenstrukturanalyse belegt. The structure of the intermediate 1b) was documented by X-ray structural analysis.

Claims (3)

1. Verfahren zur Herstellung von Verbindungen der allgemeinen Formel I 1. A process for the preparation of compounds of general formula I
worin wherein
R 3 OR 3a und R 3 and OR 3a
R 3a Wasserstoff oder eine Schutzgruppe PG R 3a is hydrogen or a protecting group PG
R 4a , R 4b gleich oder verschieden sind und Wasserstoff, C 1 -C 10 -Alkyl, C 7 -C 20 - Aralkyl, oder gemeinsam eine -(CH 2 ) m -Gruppe, R 4a, R 4b are the same or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 - aralkyl, or together a - (CH 2) m group,
m 2 bis 5, m is 2 to 5,
R 5a , R 5b gleich oder verschieden sind und Wasserstoff, C 1 -C 10 -Alkyl, C 7 -C 20 - Aralkyl, oder gemeinsam eine -(CH 2 ) p -Gruppe, R 5a, R 5b are the same or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 - aralkyl, or together are - (CH 2) p group,
p 2 bis 5, p is 2 to 5,
einschließlich aller Stereoisomeren sowie deren Gemische bedeuten sowie including all stereoisomers and mixtures thereof and mean
freie Carbonylgruppen in 1 ketalisiert sein können, free carbonyl groups can be ketalized 1,
dadurch gekennzeichnet , daß eine Verbindung der allgemeinen Formel II characterized in that a compound of general formula II
worin wherein
X ein Chlor- oder Bromatom ist, und der 2-Oxazolidinon-Ring entweder (4R,5S)- oder (4S,5R)-Konformation aufweist, X is a chlorine or bromine atom, and the 2-oxazolidinone ring is either (4R, 5S) - or (4S, 5R) having conformation,
mit einer Verbindung der allgemeinen Formel III with a compound of general formula III
worin R 4a , R 4b gleich oder verschieden sind und Wasserstoff, C 1 -C 10 -Alkyl, C 7 -C 20 - Aralkyl, oder gemeinsam eine -(CH 2 ) m -Gruppe, wherein R 4a, R 4b are the same or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 - aralkyl, or together a - (CH 2) m group,
m 2 bis 5, m is 2 to 5,
R 5a , R 5b gleich oder verschieden sind und Wasserstoff, C 1 -C 10 -Alkyl, C 7 -C 20 - Aralkyl, oder gemeinsam eine -(CH 2 ) p -Gruppe, R 5a, R 5b are the same or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 - aralkyl, or together are - (CH 2) p group,
p 2 bis 5, p is 2 to 5,
bedeuten, mean,
zu einer Verbindung der allgemeinen Formel IV umgesetzt to give a compound of the general formula IV
worin wherein
der 2-Oxazolidinon-Ring (4R,5S)- und das 3'-Kohlenstoffatom R-Konformation oder der 2-Oxazolidinon-Ring (4S,5R)- und das 3'-Kohlenstoffatom S-Konformation aufweisen, exhibit and the 3'-carbon atom of S-conformation, - the 2-oxazolidinone ring (4R, 5S) - and the 3 'carbon atom of R-conformation, or the 2-oxazolidinone ring (4S, 5R)
die 3'-Hydroxygruppe in IV mit einer Schutzgruppe PG geschützt, der Oxazolidinon- Ring abgespalten und gegebenenfalls die Schutzgruppe PG abgespalten wird. the 3'-hydroxyl group protected in IV with a protective group PG, the oxazolidinone ring, and optionally cleaved off the protecting group PG is cleaved off.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß die Verbindung der allgemeinen Formel II in Gegenwart von Chrom(II)chlorid mit einer Verbindung der allgemeinen Formel III umgesetzt wird. 2. The method according to claim 1, characterized in that the compound of general formula II in the presence of chromium (II) chloride is reacted with a compound of general formula III.
3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß der abgespaltene Oxazolidinon-Ring enantiomerenrein wiedergewonnen wird. 3. The method of claim 1 or 2, characterized in that the split off oxazolidinone ring is recovered in enantiomerically pure form.
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DE19813821A DE19813821A1 (en) 1998-03-20 1998-03-20 New epothilone derivatives
DK98946309T DK1005465T3 (en) 1997-08-09 1998-08-10 New epothilone derivatives, process for their preparation and their pharmaceutical use
US09/485,292 US7407975B2 (en) 1997-08-09 1998-08-10 Epothilone derivatives, method for producing same and their pharmaceutical use
AT98946309T AT368036T (en) 1997-08-09 1998-08-10 New epothilone derivatives, methods for their preparation and their pharmaceutical use
PT98946309T PT1005465E (en) 1997-08-09 1998-08-10 New epothilone derivatives, method for producing same and their pharmaceutical use
EP98946309A EP1005465B1 (en) 1997-08-09 1998-08-10 New epothilone derivatives, method for producing same and their pharmaceutical use
JP2000506196A JP2001512723A (en) 1997-08-09 1998-08-10 New epothilone derivatives, their preparation and their pharmaceutical use
PCT/EP1998/005064 WO1999007692A2 (en) 1997-08-09 1998-08-10 New epothilone derivatives, method for producing same and their pharmaceutical use
IL13441998A IL134419D0 (en) 1997-08-09 1998-08-10 Epothilone derivatives, process for the preparation thereof and pharmaceutical compositions containing the same
DE59814067A DE59814067D1 (en) 1997-08-09 1998-08-10 New epothilone derivatives, methods for their preparation and their pharmaceutical use
CA002299608A CA2299608A1 (en) 1997-08-09 1998-08-10 New epothilone derivatives, method for producing same and their pharmaceutical use
EP07013545A EP1847540A1 (en) 1997-08-09 1998-08-10 Nouveaux dérivés d'épothilone, leur procédé de production et leur utilisation pharmaceutique
ES98946309T ES2290993T3 (en) 1997-08-09 1998-08-10 New epothilone derivatives, process for their production and pharmaceutical use.
AU93409/98A AU9340998A (en) 1997-08-09 1998-08-10 New epothilone derivatives, method for producing same and their pharmaceutical use
IN3413DE1998 IN190805B (en) 1997-11-13 1998-11-16 A process for the production of epithilone derivatives
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7649006B2 (en) 2002-08-23 2010-01-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US7750164B2 (en) 1996-12-03 2010-07-06 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US7875638B2 (en) 2002-08-23 2011-01-25 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8481575B2 (en) 1996-12-03 2013-07-09 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US7750164B2 (en) 1996-12-03 2010-07-06 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
USRE41990E1 (en) 1996-12-03 2010-12-07 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US7759374B2 (en) 2002-08-23 2010-07-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US7875638B2 (en) 2002-08-23 2011-01-25 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US8110590B2 (en) 2002-08-23 2012-02-07 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US7649006B2 (en) 2002-08-23 2010-01-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US8513429B2 (en) 2002-08-23 2013-08-20 Sloan-Kettering Insitute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof

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