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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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Germany
Prior art keywords
alkyl
general formula
compound
aralkyl
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
DE19813821A
Other languages
German (de)
Inventor
Werner Skuballa
Wolfgang Schwede
Ulrich Klar
Bernd Buchmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Priority to DE19813821A priority Critical patent/DE19813821A1/en
Priority to US09/485,292 priority patent/US7407975B2/en
Priority to AT98946309T priority patent/ATE368036T1/en
Priority to ES98946309T priority patent/ES2290993T3/en
Priority to DE59814067T priority patent/DE59814067D1/en
Priority to PT98946309T priority patent/PT1005465E/en
Priority to AU93409/98A priority patent/AU9340998A/en
Priority to EP98946309A priority patent/EP1005465B1/en
Priority to CA002299608A priority patent/CA2299608A1/en
Priority to IL13441998A priority patent/IL134419A0/en
Priority to EP07013545A priority patent/EP1847540A1/en
Priority to JP2000506196A priority patent/JP2001512723A/en
Priority to DK98946309T priority patent/DK1005465T3/en
Priority to PCT/EP1998/005064 priority patent/WO1999007692A2/en
Priority to IN3413DE1998 priority patent/IN190805B/en
Publication of DE19813821A1 publication Critical patent/DE19813821A1/en
Priority to US12/178,039 priority patent/US20090018342A1/en
Withdrawn legal-status Critical Current

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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, d. h. Verfahren zur Herstellung von C1-C6-Epothilon-Bausteinen zur Totalsynthese von Epothilon und Epothilon-Derivaten.The invention relates to the subject matter characterized in the claims, d. H. Process for the production of C1-C6-epothilone building blocks for total synthesis of epothilone and epothilone derivatives.

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

z. B. in Angew. Chem. 1996, 108, 1671-1673 beschrieben. 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.e.g. B. in Angew. Chem. 1996, 108, 1671-1673. Because of the in vitro Selectivity towards breast and intestinal cell lines and compared to taxol significantly higher activity against P-glycoprotein-forming, multi-resistant Tumor cell lines as well as the physical improved compared to Taxol Properties (factor 30 higher water solubility) appear this new Structural class for the development of a drug 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. Zur Beseitigung dieser Nachteile sind Modifikationen an dem Naturstoff nötig. Derartige Modifikationen sind nur auf totalsynthetischem Wege möglich und setzen Synthesestrategien voraus, die eine breite Modifikation des Naturstoffes ermöglichen. Ziel der Strukturveränderungen ist es somit, die therapeutische Breite zu erhöhen. Dies kann durch eine Verbesserung der Selektivität der Wirkung, eine Reduktion unerwünschter toxischer Nebenwirkungen und/oder Erhöhung der Wirkstärke erfolgen.The natural products are either chemical as well as metabolic for one Drug development not sufficiently stable or in need of improvement the activity profile with regard to biophysical parameters or the selectivities between transformed and non-transformed cells. To eliminate this Disadvantages are modifications to the natural product. Such modifications are only possible with a total synthesis and presuppose synthesis strategies that enable a broad modification of the natural product. goal of Structural changes are therefore to increase the therapeutic range. This can by improving the selectivity of the effect, reducing unwanted toxic side effects and / or increase in 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).for the synthesis of the C1-C6 fragment (epothilone counting) of epothilon A can be used (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 disadvantage that the overall yield with 10.5% very low, the necessary introduction of chirality at C atom 3 Synthesis of an expensive, chemically unstable, equimolar amount and requires a non-recoverable chiral excipient and the resultant optical induction is incomplete with approx. 80% ee.

Für eine industriell verwertbare Synthese sind jedoch hohe Ausbeuten und hohe optische Reinheit notwendig.However, high yields are high for an industrially usable synthesis optical purity necessary.

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,
In Angew. Chem. 1997, 109, No. 1/2, pp. 170-172 the synthesis of a (C1-C6) building block with a carboxyl group at C-1, which can be used for the synthesis of epothilone or epothilone derivatives,

(TBS = tert.-Butyldimethylsilyl) von Nicolaou et al. beschrieben. Die Stereochemie am C3 wird durch die Reaktion mit dem Brown Reagenz Allylisopinocamphenylboran (+)-Ipc2B(allyl) gesteuert, das äquimolar in die Reaktion eingesetzt werden muß und nicht wiedergewinnbar ist.(TBS = tert-butyldimethylsilyl) by Nicolaou et al. described. The stereochemistry at C3 is controlled by the reaction with the Brown reagent allylisopinocamphenylborane (+) - Ipc 2 B (allyl), which must be used in the reaction equimolar 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. 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. Chem. Soc., Vol. 119, No. 34, 1997, S. 7974-7991 von Nicolaou et al. beschrieben.Likewise, the use of this building block for the synthesis of epothilones A and B and some epothilone analogues in Nature, Vol. 387, 1997, pp. 268-272, for synthesis of epothilone A and its derivatives in J. Am. Chem. Soc., Vol. 119, No. 34, 1997, Pp. 7960-7973 and for the synthesis of epothilones A and B and some epothilone Analogues in J. Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7974-7991 by Nicolaou et al. described.

Ebenfalls von Nicolaou et al. wird in Angew. Chem. 1997, 109, Nr. 19, S. 2181-2187 die Herstellung von Epothilon A-Analoga mittels kombinatorischer Festphasensynthese beschrieben. Aus dieser Fundstelle gehen auch Epothilon B-Analoga hervor. Als C1-C6-Bausteine werden z. B. die nachstehenden Verbindungen eingesetzt:
Also by Nicolaou et al. is in Angew. Chem. 1997, 109, No. 19, pp. 2181-2187 describes the preparation of epothilone A analogues by means of combinatorial solid phase synthesis. Epothilone B analogues also emerge from this site. As C1-C6 blocks z. 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 an industrially usable synthesis, it is advantageous if the synthesis without expensive chiral auxiliaries performed or if the chiral auxiliaries simply can be 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.The task was therefore to find a suitable synthesis, the high one Yields, the desired product results in high optical purity and without expensive chiral auxiliaries or a recovery of the chiral Auxiliaries allowed.

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 have a wide variety of substituents in it Building block and thus ultimately in the epothilone derivatives to be produced from it allow.

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

worin
R3 OR3a und
R3a Wasserstoff oder eine Schutzgruppe PG
R4a, R4b gleich oder verschieden sind und Wasserstoff, C1-C10-Alkyl, C7-C20- Aralkyl, oder gemeinsam eine -(CH2)m-Gruppe,
m 2 bis 5,
R5a, R5b gleich oder verschieden sind und Wasserstoff, C1-C10-Alkyl, C7-C20- Aralkyl, oder gemeinsam eine -(CH2)p-Gruppe,
p 2 bis 5,
einschließlich aller Stereoisomeren sowie deren Gemische bedeuten sowie
freie Carbonylgruppen in I ketalisiert sein können,
leicht durch Umsetzung einer Verbindung der allgemeinen Formel II
wherein
R 3 OR 3a and
R 3a is hydrogen or a protective group PG
R 4a , R 4b are identical or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 aralkyl, or together a - (CH 2 ) m group,
m 2 to 5,
R 5a , R 5b are identical or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 aralkyl, or together a - (CH 2 ) p group,
p 2 to 5,
including all stereoisomers and their mixtures mean as well
free carbonyl groups in I can be ketalized,
easily by reacting a compound of general formula II

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

worin
R4a, R4b gleich oder verschieden sind und Wasserstoff, C1-C10-Alkyl, C7-C20- Aralkyl, oder gemeinsam eine -(CH2)m-Gruppe,
m 2 bis 5,
R5a, R5b gleich oder verschieden sind und Wasserstoff, C1-C10-Alkyl, C7-C20- Aralkyl, oder gemeinsam eine -(CH2)p-Gruppe,
p 2 bis 5,
bedeuten,
zu einer Verbindung der allgemeinen Formel IV
wherein
R 4a , R 4b are identical or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 aralkyl, or together a - (CH 2 ) m group,
m 2 to 5,
R 5a , R 5b are identical or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 aralkyl, or together a - (CH 2 ) p group,
p 2 to 5,
mean,
to a compound of general formula IV

worin
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,
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.wherein
the 2-oxazolidinone ring (4R, 5S) - and the 3'-carbon atom R-conformation or the 2-oxazolidinone ring (4S, 5R) - and the 3'-carbon atom S-conformation,
and after protecting the 3'-hydroxy group in IV with a protective group PG, by splitting off the oxazolidinone residue and optionally splitting off the protective group PG.

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 transfer of the compound of the general Formula II in a metal enolate by inserting 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. B. A. Fürstner, Synthesis 1989, 571-590).All metals known to the person skilled in the art generally come as metal or metal salt or metal salts that are suitable for a Reformatzky reaction (see e.g. B. A. 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 split off from the compounds of the general Formula IV recovered almost quantitatively and without loss of optical activity.

Als Alkylgruppen R4a, R4b, R5a und R5b 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.Alkyl groups R 4a , R 4b , R 5a and R 5b are straight-chain or branched-chain alkyl groups with 1 to a maximum of 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl , Neopentyl, heptyl, hexyl, decyl.

Die Alkylgruppen R4a, R4b, R5a und R5b können perfluoriert oder substituiert sein durch 1-5 Halogenatome, Hydroxygruppen, C1-C4-Alkoxygruppen und C6-C12- Arylgruppen (die durch 1-3 Halogenatome substituiert sein können). The alkyl groups R 4a , R 4b , R 5a and R 5b can be perfluorinated or substituted by 1-5 halogen atoms, hydroxy groups, C 1 -C 4 alkoxy groups and C 6 -C 12 aryl groups (which are substituted by 1-3 halogen atoms can).

Die Aralkylgruppen in R4a, R4b, R5a und R5b können im Ring bis 14 C-Atome, bevorzugt 6 bis 10 enthalten und in der Alkylkette 1 bis 8, bevorzugt 1 bis 4 Atome. Als Aralkylreste kommen beispielweise in Betracht Benzyl, Phenylethyl, Naphthylmethyl, Naphthylethyl, Furylmethyl, Thienylethyl, Pyridylpropyl. Die Ringe können ein- bis dreifach substituiert sein durch Halogen, OH, O-Alkyl, NH2, CO2H, CO2-Alkyl, -NO2, -N3, -CN, C1-C20-Alkyl, C1-C20-Acyl, C1-C20-Acyloxy-Gruppen.The aralkyl groups in R 4a , R 4b , R 5a and R 5b can contain up to 14 C atoms, preferably 6 to 10, in the ring and 1 to 8, preferably 1 to 4 atoms in the alkyl chain. Examples of suitable aralkyl radicals are benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl. The rings can be mono- to trisubstituted by 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 groups.

Als Schutzgruppe PG kommen alle, dem Fachmann als derartige Schutzgruppen bekannten Reste in Betracht. Bevorzugt sind hierbei silylhaltige Schutzgruppen, wie beispielsweise der Trimethylsilyl-, Triethylsilyl-, tert.-Butyldimethylsilyl-, tert.- Butyldiphenylsilyl-, Tribenzylsilyl-, Triisopropylsilyl-Rest.The PG protective group includes all those skilled in the art as such protective groups known residues. Protective groups containing silyl, such as for example trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert. Butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl radical.

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

Halogen bedeutet Fluor, Chlor, Brom und Iod.Halogen means 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 general compounds required for the process according to the invention Formula II are by acetylation of (4R, 5S) - or (4S, 5R) -4-methyl-5-phenyl-2- oxazolidinone with bromine or chloroacetyl chloride in the presence of a strong base, such as for example, n-butyllithium.

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

Die für das erfindungsgemäße Verfahren benötigten Verbindungen der allgemeinen Formeln III sind käuflich oder lassen sich einfach herstellen.The general compounds required for the process according to the invention Formulas III are commercially available or can be easily manufactured.

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 the general formula III are not commercially available, they can be prepared, for example, by the methods given in FIGS. 1 and 2.

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

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 C1-C6-Abschnitt des Epothilongerüstes entsprechend modifizierten Epothilonderivaten verwendet werden.The building blocks of general formula I prepared according to the present invention can be described analogously, for example from the on page 2 of this application text (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, p . 268-272; J. Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7960-7973; J. Am. Chem. Soc., Vol. 119, No. 34, 1997, S . 7974-7991; Angew. Chem. 1997, 109, No. 19, pp. 2181-2187), resulting methods for the synthesis of epothilones A and B and of epothilone derivatives modified accordingly in the C 1 -C 6 section of the epothilone structure.

Mit den Verbindungen der allgemeinen Formel I wird somit die eingangs geforderte Variabilität der Substituenten erreicht.The compounds of the general formula I are thus the ones required at the outset Variability of the substituents 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.A great advantage of the method according to the invention is that the chiral auxiliary used (4R, 5S) - or (4S, 5R) -4-methyl-5-phenyl-2-oxazolidimone after it has been split off from the protected compound of the general formula IV simply recover and again without loss of optical induction in the Synthesis can be used again.

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 building blocks obtained in this way, including their enantiomers or Mixtures of these enantiomers are suitable for aldocondensation with a Epothilone building block that carries a carbonyl function at C-7 (epothilone counting) this in the above-mentioned total syntheses of epothilone A and epothilone B Case is.

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 building blocks 1, whose enantiomers or mixtures of these enantiomers are suitable is also interested in esterification with an epothilone building block attached to C-15 (Epothilion counting) carries a hydroxyl function as in the above Total synthesis of epothilones A and B is the case.

Die nachfolgenden Beispiele dienen der näheren Erläuterung des Erfindungsgegenstandes, ohne ihn auf diese beschränken zu wollen.The following examples serve to explain the Subject of the invention, without wishing to restrict it to these.

BeispieleExamples AusgangsprodukteStarting products A) 2,2-Dimethyl-3-oxopentanalA) 2,2-dimethyl-3-oxopentanal Aa) 4-(2-Methylprop-1-enyl)morpholinAa) 4- (2-methylprop-1-enyl) morpholine

In einem 250 ml-Dreihalsrundkolben werden 43,6 g Morpholin vorgelegt. Unter Eisbadkühlung werden bei einer Temperatur von 5°C innerhalb von 20 Minuten 46 ml Isobutylaldehyd zugetropft. Dabei war eine starke Temperaturerhöhung zu beobachten (stark exotherme Reaktion). Nach beendeter Zugabe wird der Ansatz über einen Wasserabscheider 4 Stunden refluxiert. Das Volumen des Wasserabscheiders wird mit Isobutylaldehyd gefüllt. Es werden 7,5 ml H2O abgeschieden. Nach Ablauf der Reaktion wird das Reaktionsgemisch im Vakuum destilliert.
Ölbadtemperatur: 85°-90°C
Hauptlauf m = 58,37 g 82,03%
Siedepunkt: 59°C bei 11 mbar
Ausbeute: 58,37 g 82,03% Aa).43.6 g of morpholine are placed in a 250 ml round-bottomed flask. With ice bath cooling, 46 ml of isobutylaldehyde are added dropwise at a temperature of 5 ° C. in the course of 20 minutes. A strong temperature increase was observed (strongly exothermic reaction). When the addition is complete, the mixture is refluxed for 4 hours on a water separator. The volume of the water separator is filled with isobutyl aldehyde. 7.5 ml of H 2 O are deposited. After the reaction has ended, the reaction mixture is distilled in vacuo.
Oil bath temperature: 85 ° -90 ° C
Main run m = 58.37 g 82.03%
Boiling point: 59 ° C at 11 mbar
Yield: 58.37 g 82.03% Aa).

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

In einem 1000 ml Dreihalsrundkolben wird die Lösung von 77,14 g Propionsäurechlorid in 200 ml Ether p.a. vorgelegt. 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. A. zugetropft. Ausfällung, weißer Niederschlag entsteht. Nach beendeter Zugabe wird der Ansatz 5 Stunden am Rückfluß gekocht und anschließend über Nacht bei Raumtemperatur gerührt. Der entstehende weiße Niederschlag, feuchtigkeitsempfindlich, wird abgesaugt, mit Ether gewaschen und an der Ölpumpe getrocknet.
Rohprodukt: m = 65,26 g Hydrochlorid.
Im Filtrat ist eine Nachfällung zu beobachten.
Rohprodukt m = 35,49 g Gesamt: m = 100,75 g.
Die 100,75 g Hydrochlorid werden in 150 ml H2O gelöst. Anschließend wird die Wasserphase mit NaHCO3 insgesamt auf pH 0 5 eingestellt und dann 4 mal mit je 150 ml Ether extrahiert. Die organische Phase wird einmal mit Sole gewaschen und dann über Na2SO4 getrocknet. Der Ether wird bei Normaldruck abdestilliert und der Rückstand wird im Vakuum über eine kleine Vigreux-Kolonne (6 Böden) destilliert.
Hauptlauf: m = 29,65 g 27,75%
Siedepunkt: 62°C bei 15 mbar
Ausbeute: 29,65 g 27,75% A).The solution of 77.14 g of propionic acid chloride in 200 ml of ether is placed in a 1000 ml round-bottomed flask. With ice bath cooling, a solution of 117.73 g of the compound obtained under Aa) in 200 ml of ether p. A. added dropwise. Precipitation, white precipitation occurs. When the addition is complete, the mixture is refluxed for 5 hours and then stirred overnight at room temperature. The resulting white precipitate, sensitive to moisture, is filtered off, washed with ether and dried on an oil pump.
Crude product: m = 65.26 g hydrochloride.
A re-precipitation can be observed in the filtrate.
Crude product m = 35.49 g total: m = 100.75 g.
The 100.75 g hydrochloride are dissolved in 150 ml H 2 O. The total water phase is then adjusted to pH 0 5 using NaHCO 3 and then extracted 4 times with 150 ml of ether each time. The organic phase is washed once with brine and then dried over Na 2 SO 4 . The ether is distilled off at normal pressure and the residue is distilled in vacuo through a small Vigreux column (6 trays).
Main run: m = 29.65 g 27.75%
Boiling point: 62 ° C at 15 mbar
Yield: 29.65 g 27.75% A).

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

Durchführung analog A).
Ansatz: 58,37g = 413,36 mMol Aa), M = 141,21 g/mol 100 ml Diethylether p.A.
32,45 g = 413,38 mMol Acetylchlorid, M = 0 78,5 g/mol = 1,104 g/ml
100 ml Diäthylether p.A. übers Wochenende bei Raumtemperatur gerührt.
Rohprodukt m = 72,07 g Hydrochlorid
Aufarbeitung siehe Ab)
Ölbadtemperatur: 75°C bis 80°C
Hauptlauf: m = 18,75 g 39,74%
Siedepunkt: 50°C bei 11 mbar
Ausbeute m = 18,7 g 39,6% B).Implementation analogous to A).
Batch: 58.37 g = 413.36 mmol Aa), M = 141.21 g / mol 100 ml diethyl ether pA
32.45 g = 413.38 mmol acetyl chloride, M = 0 78.5 g / mol = 1.104 g / ml
100 ml of diethyl ether pA stirred over the weekend at room temperature.
Crude product m = 72.07 g hydrochloride
Refurbishment see Ab)
Oil bath temperature: 75 ° C to 80 ° C
Main run: m = 18.75 g 39.74%
Boiling point: 50 ° C at 11 mbar
Yield m = 18.7 g 39.6% B).

C) 1-(1-Oxopropyl)cyclobutancarbaldehydC) 1- (1-oxopropyl) cyclobutane carbaldehyde Ca) 1,1-CyclobutandimethanolCa) 1,1-cyclobutane dimethanol

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. Man läßt eine Stunde bei 0°C nachrühren und addiert dann 30 ml Wasser. Es wird über Celite filtriert. Das Filtrat wird mit Natriumsulfat getrocknet und im Vakuum eingeengt. Das erhaltene Rohprodukt (9,9 g) wird ohne Aufreinigung in die Folgestufe eingesetzt.To a solution of 20 g (100 mmol) of 1,1-cyclobutanedicarboxylic acid diethyl ester in 200 ml of absolute tetrahydrofuran become 170 ml of a 1.2 molar solution at 0 ° C dropped from diisobutylaluminum hydride. The mixture is left to stir at 0 ° C. for one hour and then add 30 ml of water. It is filtered through Celite. The filtrate is with Dried sodium sulfate and concentrated in vacuo. The crude product obtained (9.9 g) is used in the next stage without purification.

Cb) 1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutanmethanolCb) 1 - [[[Dimethyl (1,1-dimethylethyl) silyl] oxy] methyl] cyclobutanemethanol

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. Man läßt 30 Minuten nachrühren und addiert dann eine Lösung von 12,8 g tert.Butyldimethylsilylchlorid (85 mmol) in 50 ml Tetrahydrofuran. Man läßt eine Stunde bei 25°C nachrühren und gießt dann das Reaktionsgemisch auf gesättigte wäßrige Natriumhydrogencarbonatlösung. Es wird mit Ethylacetat extrahiert. Die organische Phase wird mit gesättigter Natriumchloridlösung gewaschen und über Natriumsulfat getrocknet. Nach Abziehen des Lösungsmittels im Vakuum wird das erhaltene Rohprodukt durch Säulenchromatographie an Kieselgel mit einem Gemisch aus Hexan/Ethylacetat gereinigt. Man erhält 13,5 g (69%) der Titelverbindung.
1H-NMR (CDCl3): δ = 0,04 (6H), 0,90 (9H), 1,70-2,00 (6H), 3,70 (4H) ppm.A solution of 9.9 g Ca) (85 mmol) in 100 ml absolute tetrahydrofuran is added at 0 ° C. to a suspension of 3.4 g sodium hydride (60% in oil, 85 mmol) in 35 ml absolute tetrahydrofuran. The mixture is stirred for 30 minutes and then a solution of 12.8 g of tert-butyldimethylsilyl chloride (85 mmol) in 50 ml of tetrahydrofuran is added. The mixture is left to stir at 25 ° C. for one hour and then the reaction mixture is poured onto saturated aqueous sodium hydrogen carbonate solution. It is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. After the solvent has been stripped off in vacuo, the crude product obtained is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 13.5 g (69%) of the title compound are obtained.
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]cyclobutancarbaldehydCc) 1 - [[[Dimethyl (1,1-dimethylethyl) silyl] oxy] methyl] cyclobutane carbaldehyde

8 ml Oxalylchlorid werden in 100 ml Dichlormethan gelöst. Man kühlt auf -78°C und addiert 13 ml Dimethylsulfoxid. Man läßt 3 Minuten nachrühren und addiert dann eine Lösung von 13,5 g Cb) (58,6 mmol) in 80 ml Dichlormethan. Nach weiteren 15 Minuten Nachrührzeit werden 58 ml Triethylamin hinzugetropft. Anschließend läßt man auf 0°C erwärmen. Dann wird das Reaktionsgemisch auf gesättigte Natriumhydrogen-carbonatlösung gegossen. Man extrahiert mit Dichlormethan, wäscht die organische Phase mit gesättigter Natriumchloridlösung, trocknet über Natriumsulfat und engt im Vakuum ein. Nach Chromatographie des Rohprodukts an Kieselgel mit einem Gemisch aus Hexan/Ethylacetat erhält man 7,7 g (58%) der Titelverbindung.
1H-NMR (CDCl3): δ = 0,03 (6H), 0,90 (9H), 1,85-2,00 (4H), 2,20-2,30 (2H), 3,83 (2H), 9,70 (1H) ppm.8 ml of oxalyl chloride are dissolved in 100 ml of dichloromethane. The mixture is cooled to -78 ° C. and 13 ml of dimethyl sulfoxide are added. The mixture is stirred for 3 minutes and then a solution of 13.5 g of Cb) (58.6 mmol) in 80 ml of dichloromethane is added. After a further 15 minutes of stirring, 58 ml of triethylamine are added dropwise. Then allowed to warm to 0 ° C. Then the reaction mixture is poured onto saturated sodium bicarbonate solution. It is extracted with dichloromethane, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. 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.

Cd) 1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]-α-ethylcyclobutanmethanolCd) 1 - [[[Dimethyl (1,1-dimethylethyl) silyl] oxy] methyl] -α-ethylcyclobutanemethanol

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. Man läßt 30 Minuten bei 0°C nachrühren und gießt dann das Reaktionsgemisch auf gesättigte Ammonium­ chloridlösung. Es wird mit Ethylacetat extrahiert. Die organische Phase wird mit gesättigter Natriumchloridlösung gewaschen und über Natriumsulfat getrocknet. Nach dem Abziehen des Lösungsmittels wird das erhaltene Rohprodukt durch Säulenchromatographie an Kieselgel gereinigt. Man erhält 7,93 g (91,5%) der Titelverbindung.
1H-NMR (CDCl3): 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.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. The mixture is left to stir at 0 ° C. for 30 minutes and then the reaction mixture is poured onto saturated ammonium chloride solution. It is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. After the solvent has been stripped off, the crude product obtained is purified by column chromatography on silica gel. 7.93 g (91.5%) of the title compound are obtained.
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.

Ce) 1-[1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobut-1-yl]-1-propanonCe) 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. 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. Es wird weitere 15 Minuten bei -78°C nachgerührt. Anschließend wird eine Mischung aus 19 ml (136 mmol) Triethylamin und 40 ml Dichlormethan hinzugetropft. Man läßt auf -25°C erwärmen und rührt bei dieser Temperatur 30 Minuten nach. Anschließend das Reaktionsgemisch auf gesättigte eiskalte Natriumhydrogencarbonatlösung gegossen. Es wird mit Dichlormethan extrahiert. Die organische Phase wird mit gesättigter Natriumchloridlösung gewaschen und über Natriumsulfat getrocknet. Nach dem Abziehen des Lösungsmittels wird das erhaltene Rohprodukt über Kieselgel filtriert. Man erhält 7,87 g (100%) der Titelverbindung.
1H-NMR (CDCl3): 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.6 ml (85.7 mmol) of dimethyl sulfoxide are added to 3.76 ml (43.8 mmol) of oxalyl chloride in 80 ml of dichloromethane at -78 ° C. The mixture is stirred for 3 minutes and then a solution of 7.93 g (30.7 mmol) of the compound described under Cd) in 80 ml of dichloromethane is added. The mixture is stirred at -78 ° C for a further 15 minutes. A mixture of 19 ml (136 mmol) of triethylamine and 40 ml of dichloromethane is then added dropwise. The mixture is allowed to warm to -25 ° C. and is stirred at this temperature for 30 minutes. Then the reaction mixture was poured onto saturated ice-cold sodium hydrogen carbonate solution. It is extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. After the solvent has been stripped off, the crude product obtained is filtered through silica gel. 7.87 g (100%) of the title compound are obtained.
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.

Cf) 1-[1-(Hydroxymethyl)cyclobut-1-yl]-1-propanonCf) 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. Man addiert 15 ml einer 1 molaren Lösung von Tetrabutylammoniumfluorid und läßt 12 Stunden bei 25°C nachrühren. Danach wird das Reaktionsgemisch auf gesättigte Natriumhydrogencarbonatlösung gegossen. Man extrahiert mit Ethylacetat. Die organische Phase wird mit gesättigter Natriumchloridlösung gewaschen und über Natriumsulfat getrocknet. Nach dem Abziehen des Lösungsmittels wird das erhaltene Rohprodukt durch Säulenchromatographie an Kieselgel gereinigt. Man erhält 3,19 g (73,4%) der Titelverbindung.
1H-NMR (CDCl3): δ = 1,07 (3H), 1,86-2,08 (4H), 2,32-2,40 (2H), 2,55-2,65 (2H), 3,88 (2H) ppm.7.87 g (30.7 mmol) of the compound described under Ce) are dissolved in 100 ml of tetrahydrofuran. 15 ml of a 1 molar solution of tetrabutylammonium fluoride are added and the mixture is stirred at 25 ° C. for 12 hours. The reaction mixture is then poured onto saturated sodium bicarbonate solution. It is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. After the solvent has been stripped off, the crude product obtained is purified by column chromatography on silica gel. 3.19 g (73.4%) of the title compound are obtained.
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.

C) 1-(1-Oxopropyl)cyclobutancarbaldehydC) 1- (1-oxopropyl) cyclobutane carbaldehyde

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.
1H-NMR (CDCl3): δ = 1,07 (3H), 1,85-2,00 (2H), 2,40-2,53 (6H), 9,70(1H) ppm.Analogously to Example Ce), 3.14 g (100%) of the title compound are obtained from 3.19 g (22.4 mmol) of the compound described under Cf) by oxidation.
1 H NMR (CDCl 3 ): δ = 1.07 (3H), 1.85-2.00 (2H), 2.40-2.53 (6H), 9.70 (1H) ppm.

Beispiel 1example 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. 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. Anschließend wird mit einer Lösung von 208 mg Natriumsulfit in 1.24 ml Wasser versetzt und mit 10 ml Methylenchlorid extrahiert. Die wäßrige Phase wird mit 5N Salzsäure auf pH=1 eingestellt und dreimal mit je 10 ml Essigester extrahiert. Nach dem Trocknen über Natriumsulfat und Filtration wird im Vakuum eingeengt. Zusätzlich wird die obige Methylenchlorid-Phase mit 5N Salzsäure gewaschen und dann diese wäßrige Phase dreimal mit je 10 ml Essigester extrahiert. Nach dem Trocknen über Natriumsulfat und Filtration wird im Vakuum eingeengt und eine zusätzliche Menge an Rohprodukt erhalten. Die vereinigten, so erhaltenen Rückstande reinigt man durch Chromatographie an Kieselgel. 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. [α]D = +15.5° (CHCl3)
1H-NMR (CDCl3): 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.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, 0.17 ml of a 30% hydrogen peroxide solution is added at 0 ° C. After stirring for 5 minutes, a solution of 15.8 mg of lithium hydroxide in 0.83 ml of water is then added, and the reaction mixture is stirred at 25 ° C. for 3 hours. A solution of 208 mg of sodium sulfite in 1.24 ml of water is then added and the mixture is extracted with 10 ml of methylene chloride. The aqueous phase is adjusted to pH = 1 with 5N hydrochloric acid and extracted three times with 10 ml of ethyl acetate each time. After drying over sodium sulfate and filtration, the mixture is concentrated in vacuo. In addition, the above methylene chloride phase is washed with 5N hydrochloric acid and then this aqueous phase is extracted three times with 10 ml of ethyl acetate. After drying over sodium sulfate and filtration, the mixture is concentrated in vacuo and an additional amount of crude product is obtained. The combined residues thus obtained are purified by chromatography on silica gel. With hexane / 0-50% ethyl acetate, 70 mg of (4R, 5S) -4-methyl-5-phenyloxazolidin-2-one and 93 mg of the title compound are obtained as a colorless oil. [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.

1a) (4R,5S)-3-(Bromacetyl)-4-methyl-5-phenyloxazolidin-2-on1a) (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. Anschließend wird eine Lösung von 26.8 g Bromacetylchlorid in 250 ml Tetrahydrofuran so zugetropft, daß die Temperatur nicht über -65°C steigt. 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. Nach Trennung der Phasen wird die wäßrige Phase zweimal mit je 100 ml Ether extrahiert. Die vereinigten organischen Phasen werden mit halbkonzentrierter Natriumchlorid-Lösung gewaschen, über Natriumsulfat getrocknet und nach Filtration im Vakuum eingeengt. Den so erhaltenen Rückstand reinigt man durch Chromatographie an Kieselgel. Mit Hexan/0-50% Ether erhält man 34.8 g der Titelverbindung als farbloses Öl.
1H-NMR (CDCl3): δ = 0.95 (3H), 4.57 (2H), 4.80 (2H), 5.76 (2H), 7.2-7.5 (5H) ppm.117 ml of a 1.6 molar solution of butyllithium in hexane are added to a solution of 30.1 g of (4R, 5S) -4-methyl-5-phenyloxazolidin-2-one in 500 ml of tetrahydrofuran within 30 minutes at -70 ° C. under nitrogen to. A solution of 26.8 g of bromoacetyl chloride in 250 ml of tetrahydrofuran is then added dropwise so that the temperature does not rise above -65 ° C. After stirring for 1.75 hours at -70 ° C., a saturated ammonium chloride solution is added, followed by 60 ml of a saturated sodium hydrogen carbonate solution and allowed to come to 25 ° C. After the phases have been separated, the aqueous phase is extracted twice with 100 ml of ether each time. The combined organic phases are washed with half-concentrated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-50% ether, 34.8 g of the title compound is obtained 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.

1b) [4R-[3(R*),4α, 5α]]-3-[4,4-Dimethyl-1,5-dioxo-3-hydroxyheptyl]-4-methyl-5-phenyl­ oxazolidin-2-on1b) [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. 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. Nach 2 Stunden Reaktionszeit wird mit 30 ml gesättigter Natriumchlorid-Lösung versetzt und 15 Minuten gerührt. Die wäßrige Phase wird dreimal mit je 200 ml Ether extrahiert. Die vereinigten organischen Phasen werden mit halbkonzentrierter Natriumchlorid-Lösung gewaschen, über Natriumsulfat getrocknet und nach Filtration im Vakuum eingeengt. Den so erhaltenen Rückstand reinigt man durch Chromatographie an Kieselgel. Mit Hexan/0-30% Essigester erhält man 1.55 g der Titelverbindung als farbloses Öl.
1H-NMR (CDCl3): 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.218 mg of lithium iodide are added to a suspension of 5.0 g of anhydrous chromium (II) chloride in 60 ml of tetrahydrofuran under argon. Then a mixture of 2.09 g of the literature-known 2,2-dimethyl-3-oxo-pentanal (see under "Starting Products" Ab) and 5.34 g of the bromine compound prepared above in 10 ml of tetrahydrofuran is added. After a reaction time of 2 hours, 30 ml of saturated sodium chloride solution are added and the mixture is stirred for 15 minutes. The aqueous phase is extracted three times with 200 ml ether. The combined organic phases are washed with half-concentrated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-30% ethyl acetate, 1.55 g of the title compound is obtained 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.

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-on1c) [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. Nach 5 Minuten Rühren werden 344 mg tert.Butyldimethylsilyltrifluormethansulfonat hinzugegeben und für weitere 45 Minuten bei -70°C gerührt. Man versetzt mit 1 ml gesättigter Natriumchlorid-Lösung und läßt auf 25°C kommen. Anschließend wird mit Ether verdünnt und die organische Phase mit gesättigter Natriumchlorid-Lösung gewaschen. Nach dem Trocknen über Natriumsulfat und Filtration wird im Vakuum eingeengt. Den so erhaltenen Rückstand reinigt man durch Chromatographie an Kieselgel. Mit Hexan/0-30% Essigester erhält man 192 mg der Titelverbindung als farblose kristalline Verbindung mit einem Schmelzpunkt von 111-112°C.
1H-NMR (CDCl3): 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.150 mg of 2,6-lutidine are added under argon at -70 ° C. to a solution of 347 mg of the alcohol prepared above in 3 ml of methylene chloride. After 5 minutes of stirring, 344 mg of tert-butyldimethylsilyltrifluoromethanesulfonate are added and the mixture is stirred at -70 ° C. for a further 45 minutes. It is mixed with 1 ml of saturated sodium chloride solution and allowed to come to 25 ° C. The mixture is then diluted with ether and the organic phase is washed with saturated sodium chloride solution. After drying over sodium sulfate and filtration, the mixture is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-30% ethyl acetate, 192 mg of the title compound is obtained 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.

Beispiel 2Example 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. Als Ausgangsprodukt dient (4S,5R)-4-Methyl-5-phenyloxazolidin-2-on. NMR ist deckungsgleich mit Beispiel 1.
[α]D = -157° (CHCl3).The compound is produced in analogy to Example 1. (4S, 5R) -4-methyl-5-phenyloxazolidin-2-one serves as the starting product. NMR is congruent with Example 1.
[α] D = -157 ° (CHCl 3 ).

2a) (4S,5R)-3-(Bromacetyl)-4-methyl-5-phenyloxazolidin-2-on2a) (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. NMR ist deckungsgleich mit 1a).The illustration is carried out analogously to Example 1a) starting from (4S, 5R) -4-methyl-5- phenyloxazolidin-2-one. NMR is congruent with 1a).

Beispiel 3Example 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. 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.
1H-NMR (CDCl3): 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.Analogously to Example 1, 2.79 g (5.9 mmol) of the compound described under 3b) give 1.49 g (80%) of the title compound and 941 mg of recovered (4S, 5R) -4-methyl-5-phenyloxazolidine 2-one received. The title compound and the chiral auxiliary to be recovered can be separated by chromatography (analogously to Example 1) or fractional crystallization and then, if desired, purified by chromatography.
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.

3a) [4S-[3(R*),4α,5α]]-3-[3-Hydrnxy-1-oxo-3-[1-(1-oxopropyl)cyclobut-1-yl]propyl]4- methyl-5-phenyloxazolidin-2-on3a) [4S- [3 (R *), 4α, 5α]] - 3- [3-hydroxy-1-oxo-3- [1- (1-oxopropyl) cyclobut-1-yl] propyl] 4- methyl-5-phenyloxazolidin-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.
1H-NMR (CDCl3): 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.Analogously to Example 1b), 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 after column chromatography on silica gel 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.

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-on3b) [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.
1H-NMR (CDCl3): 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.Analogously to Example 1c), from 3.0 g (8.35 mmol) of the compound described in Example 3a), tert-butyldimethylsilyl trifluoromethanesulfonate 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.

Beispiel 4Example 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. Als Ausgangsprodukt dient (4R,5S)-3-(Bromacetyl)4-methyl-5-phenyloxazolidin-2-on. Das NMR-Spektrum ist deckungsgleich mit Beispiel 3.The connection is made in analogy to Example 3. Serves as the starting product (4R, 5S) -3- (bromoacetyl) 4-methyl-5-phenyloxazolidin-2-one. The NMR spectrum is congruent with Example 3.

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. Die Struktur des Intermediats 1 b) wurde durch eine Röntgenstrukturanalyse belegt.By choosing the stereochemistry at C4 and C5 of the chiral auxiliary 4-methyl-5- phenyl-2-oxazolidone, the stereochemistry can be controlled in position 3. The structure of intermediate 1 b) was confirmed by an X-ray structure analysis.

Claims (3)

1. Verfahren zur Herstellung von Verbindungen der allgemeinen Formel I
worin
R3 OR3a und
R3a Wasserstoff oder eine Schutzgruppe PG
R4a, R4b gleich oder verschieden sind und Wasserstoff, C1-C10-Alkyl, C7-C20- Aralkyl, oder gemeinsam eine -(CH2)m-Gruppe,
m 2 bis 5,
R5a, R5b gleich oder verschieden sind und Wasserstoff, C1-C10-Alkyl, C7-C20- Aralkyl, oder gemeinsam eine -(CH2)p-Gruppe,
p 2 bis 5,
einschließlich aller Stereoisomeren sowie deren Gemische bedeuten sowie
freie Carbonylgruppen in 1 ketalisiert sein können,
dadurch gekennzeichnet, daß eine Verbindung der allgemeinen Formel II
worin
X ein Chlor- oder Bromatom ist, und der 2-Oxazolidinon-Ring entweder (4R,5S)- oder (4S,5R)-Konformation aufweist,
mit einer Verbindung der allgemeinen Formel III
worin R4a, R4b gleich oder verschieden sind und Wasserstoff, C1-C10-Alkyl, C7-C20- Aralkyl, oder gemeinsam eine -(CH2)m-Gruppe,
m 2 bis 5,
R5a, R5b gleich oder verschieden sind und Wasserstoff, C1-C10-Alkyl, C7-C20- Aralkyl, oder gemeinsam eine -(CH2)p-Gruppe,
p 2 bis 5,
bedeuten,
zu einer Verbindung der allgemeinen Formel IV umgesetzt
worin
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,
die 3'-Hydroxygruppe in IV mit einer Schutzgruppe PG geschützt, der Oxazolidinon- Ring abgespalten und gegebenenfalls die Schutzgruppe PG abgespalten wird.1. Process for the preparation of compounds of general formula I.
wherein
R 3 OR 3a and
R 3a is hydrogen or a protective group PG
R 4a , R 4b are identical or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 aralkyl, or together a - (CH 2 ) m group,
m 2 to 5,
R 5a , R 5b are identical or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 aralkyl, or together a - (CH 2 ) p group,
p 2 to 5,
including all stereoisomers and their mixtures mean as well
free carbonyl groups in 1 can be ketalized,
characterized in that a compound of general formula II
wherein
X is a chlorine or bromine atom and the 2-oxazolidinone ring has either (4R, 5S) or (4S, 5R) conformation,
with a compound of general formula III
in which R 4a , R 4b are identical or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 aralkyl, or together a - (CH 2 ) m group,
m 2 to 5,
R 5a , R 5b are identical or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 20 aralkyl, or together a - (CH 2 ) p group,
p 2 to 5,
mean,
converted into a compound of general formula IV
wherein
the 2-oxazolidinone ring (4R, 5S) - and the 3'-carbon atom R-conformation or the 2-oxazolidinone ring (4S, 5R) - and the 3'-carbon atom S-conformation,
the 3'-hydroxy group in IV is protected with a protective group PG, the oxazolidinone ring is split off and the protective group PG is split off if necessary. 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 connection of the general formula II in the presence of chromium (II) chloride with a compound of general formula III is implemented.   3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß der abgespaltene Oxazolidinon-Ring enantiomerenrein wiedergewonnen wird.3. The method according to claim 1 or 2, characterized in that the cleaved oxazolidinone ring is recovered enantiomerically pure.
DE19813821A 1997-08-09 1998-03-20 New epothilone derivatives Withdrawn DE19813821A1 (en)

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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 DERIVATIVES OF EPOTILONE, PROCESS FOR ITS PRODUCTION AND ITS PHARMACEUTICAL USE.
DE59814067T DE59814067D1 (en) 1997-08-09 1998-08-10 NEW EPOTHILON DERIVATIVES, PROCESS 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
AU93409/98A AU9340998A (en) 1997-08-09 1998-08-10 New epothilone derivatives, method for producing same 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
CA002299608A CA2299608A1 (en) 1997-08-09 1998-08-10 New epothilone derivatives, method for producing same and their pharmaceutical use
IL13441998A IL134419A0 (en) 1997-08-09 1998-08-10 Epothilone derivatives, process for the preparation thereof and pharmaceutical compositions containing the same
AT98946309T ATE368036T1 (en) 1997-08-09 1998-08-10 NEW EPOTHILONE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR PHARMACEUTICAL USE
JP2000506196A JP2001512723A (en) 1997-08-09 1998-08-10 Novel epothilone derivatives, their preparation and their pharmaceutical use
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PCT/EP1998/005064 WO1999007692A2 (en) 1997-08-09 1998-08-10 New epothilone derivatives, method for producing same and their pharmaceutical use
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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
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
US8481575B2 (en) 1996-12-03 2013-07-09 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US7649006B2 (en) 2002-08-23 2010-01-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues 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
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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