DE19735575A1 - New di:hydroxy-butanal or -pentene derivatives - Google Patents

New di:hydroxy-butanal or -pentene derivatives

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Publication number
DE19735575A1
DE19735575A1 DE19735575A DE19735575A DE19735575A1 DE 19735575 A1 DE19735575 A1 DE 19735575A1 DE 19735575 A DE19735575 A DE 19735575A DE 19735575 A DE19735575 A DE 19735575A DE 19735575 A1 DE19735575 A1 DE 19735575A1
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Germany
Prior art keywords
alkyl
hydrogen
protective group
aryl
aralkyl
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Withdrawn
Application number
DE19735575A
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German (de)
Inventor
Ulrich Dr Klar
Wolfgang Dr Schwede
Werner Dr Skuballa
Bernd Dr Buchmann
Michael Dr Schirner
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Bayer Pharma AG
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Schering AG
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Publication date
Application filed by Schering AG filed Critical Schering AG
Priority to DE19735575A priority Critical patent/DE19735575A1/en
Priority to DE59814067T priority patent/DE59814067D1/en
Priority to IL13441998A priority patent/IL134419A0/en
Priority to ES98946309T priority patent/ES2290993T3/en
Priority to EP98946309A priority patent/EP1005465B1/en
Priority to CA002299608A priority patent/CA2299608A1/en
Priority to PT98946309T priority patent/PT1005465E/en
Priority to DK98946309T priority patent/DK1005465T3/en
Priority to US09/485,292 priority patent/US7407975B2/en
Priority to AU93409/98A priority patent/AU9340998A/en
Priority to PCT/EP1998/005064 priority patent/WO1999007692A2/en
Priority to EP07013545A priority patent/EP1847540A1/en
Priority to JP2000506196A priority patent/JP2001512723A/en
Priority to AT98946309T priority patent/ATE368036T1/en
Publication of DE19735575A1 publication Critical patent/DE19735575A1/en
Priority to US12/178,039 priority patent/US20090018342A1/en
Withdrawn legal-status Critical Current

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Abstract

1-Oxo-2,4-dihydroxy- (or 2-hydroxy-4-halo)-butane derivatives of formula (I) and pentene-3,5-diol derivatives of formula (X) are new. R1 = H, 1-20C alkyl, aryl or 7-20C aralkyl; R2 = H or protecting group; R3 = OH, halo or OR6; R6 = protecting group; R4 = H or 1-10C alkyl; R5 = H, 1-10C alkyl, aryl or 7-20C aralkyl; provided that in (I) (i) R2 is other than benzyl or tert. butyldimethylsilyl (TBDMS) if R3 = -O-TBDMS; and (ii) R2 and R6 do not together form -CH-(p-methoxyphenyl). A multi-stage process for preparing compounds (I; R1 other than H), in which the above provisos do not apply, optionally with further conversion of the product to a Wittig salt via (X), is claimed.

Description

Die Erfindung betrifft den in den Patentansprüchen gekennzeichneten Gegenstand, das heißt neue (C13-C15)-Fragmente, Verfahren zur ihrer Herstellung und ihre Verwendung zur Synthese von Epothilon und Epothilonderivaten.The invention relates to the object characterized in the claims that is called new (C13-C15) fragments, process for their production and their use for the synthesis of epothilone and epothilone derivatives.

Von Höfle et al wird die cytotoxische Wirkung von Epothilon A (R = Wasserstoff) und Epothilon B (R = Methyl)
Höfle et al described the cytotoxic effects of 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 ihrer im Vergleich zu Taxol deutlich höheren Aktivität gegen P-Glycoprotein-bildende, multiresistente Tumorlinien sowie ihre physikalischen Eigenschaften erscheint diese Strukturklasse für die Entwicklung eines Arzneimittels besonders interessant.e.g. B. in Angew. Chem. 1996, 108, 1671-1673. Because of the in vitro Selectivity to breast and intestinal cell lines and their compared to taxol significantly higher activity against P-glycoprotein-forming, multi-resistant tumor lines as well as their physical properties, this structure class appears for the Development of a drug particularly interesting.

Es ist bekannt, daß die Verbindung
It is known that the connection

zur Synthese von Epothilon A oder Epothilon B verwendet werden kann (Schinzer et. al. Chem. Eur. J. 1996, 2, No. 11, 1477-1482). Die von Schinzer et al. beschriebene Synthese führt die benötigte Chiralität über eine kinetische Racematspaltung nach SHARPLESS ein. Eine notwendige chromatographische Trennung, ungenügender Enantiomerenüberschuß und ein hoher Ausbeuteverlust (46% Ausbeute, 80% ee) sind die Folge. can be used for the synthesis of epothilone A or epothilone B (Schinzer et. al. Chem. Eur. J. 1996, 2, No. 11, 1477-1482). The by Schinzer et al. described Synthesis tracks the chirality required via kinetic resolution SHARPLESS on. A necessary chromatographic separation, insufficient Enantiomeric excess and a high loss in yield (46% yield, 80% ee) the consequence.  

Für die industrielle Verwertbarkeit ist es unerläßlich, daß in den Stufen einer Synthese möglichst hohe Ausbeuten erreicht werden. Daher entstand die Aufgabe, einen anderen Syntheseweg des für die Epothilonsynthese benötigten Bausteins zu finden.For industrial usability, it is essential that in the stages of a synthesis the highest possible yields can be achieved. Hence the task of another To find the synthetic route of the building block required for epothilone synthesis.

Es ist weiterhin bekannt, daß der oben genannte Synthesebaustein durch Wittig Reaktion mit dem Phosphonat der Formel (A) und dem Keton (B)
It is also known that the above-mentioned synthesis building block by Wittig reaction with the phosphonate of the formula (A) and the ketone (B)

erhalten werden kann.can be obtained.

Es wurde nun gefunden, daß der benötigte Synthesebaustein B als Verbindung der Formel I
It has now been found that the required synthesis building block B as a compound of formula I

leicht zugänglich ist aus der natürlich vorkommenden L-(-)-Äpfelsäure. Darüberhinaus ermöglicht das erfindungsgemäße Verfahren eine sehr breite Variation des C13-C15- Fragmentes.is easily accessible from the naturally occurring L - (-) - malic acid. Furthermore the method according to the invention enables a very wide variation of the C13-C15 Fragment.

Schema I beschreibt die Synthese beispielhaft für R1 = Methyl, R2 = tert.Butyl­ diphenylsilyl, R3 = Brom, Jod bzw. OR4 mit R4 = tert.Butyldimethylsilyl wie folgt:
Aus L-(-)-Äpfelsäure (II) wird mit Trifluoressigsäureanhydrid in Methanol bei Raum­ temperatur cyclisiert und mit Boran-Tetrahydrofuran-Komplex bei 0°C zum Dihydro­ hydroxy-(3H)-furanon (III) reduziert. Nach Schützen der Hydroxygruppe mit Tertiärbutyldiphenylsilylchlorid wird mit Diisobutylaluminiumhydrid bei -78°C zu V reduziert und mit dem entsprechenden Grignardreagenz RMgX der Lactolring geöffnet. Die erhaltene freie primäre Hydroxygruppe wird mit Tertiärbutyldimethylsilylchlorid geschützt und die sekundäre Hydroxygruppe mit Oxalylchlorid/Dimethylsulfoxid in Dichlormethan zum Keton oxidiert. Über eine Wittigreaktion kann nun z. B. der Thiazolbaustein eingeführt werden. Die Synthese des Thiazolbausteins selbst erfolgt nach literaturbekannten Methoden. Selektive Abspaltung der endständigen Hydroxy­ schutzgruppe in verdünntem Eisessig und anschließende Umsetzung mit Tetra­ brom(jod)methan/Triphenylphosphin/Pyridin führt zum Bromid oder ggf. zum Jodid. Scheme I describes the synthesis by way of example for R 1 = methyl, R 2 = tert-butyl diphenylsilyl, R 3 = bromine, iodine or OR 4 with R 4 = tert-butyldimethylsilyl as follows:
From L - (-) - malic acid (II) is cyclized with trifluoroacetic anhydride in methanol at room temperature and reduced with borane-tetrahydrofuran complex at 0 ° C to the dihydro hydroxy- (3H) -furanone (III). After protecting the hydroxy group with tertiary butyl diphenylsilyl chloride, the mixture is reduced to V with diisobutyl aluminum hydride at -78 ° C. and the lactol ring is opened with the appropriate Grignard reagent RMgX. The free primary hydroxyl group obtained is protected with tertiary butyldimethylsilyl chloride and the secondary hydroxyl group is oxidized to the ketone with oxalyl chloride / dimethyl sulfoxide in dichloromethane. About a Wittig reaction z. B. the thiazole building block. The synthesis of the thiazole block itself is carried out according to methods known from the literature. Selective cleavage of the terminal hydroxyl protective group in dilute glacial acetic acid and subsequent reaction with tetrabromo (iodine) methane / triphenylphosphine / pyridine leads to the bromide or possibly to the iodide.

Schema I Scheme I

Das Ausgangsmaterial ist preiswert enantiomerenrein erhältlich. Während der Synthese erfolgt auf keiner Stufe eine Racemisierung. Große Mengen können über diesen Weg hergestellt werden. Die chemische Ausbeute ist etwa dreimal so hoch, wie die von Schinzer et al. beschriebene.The starting material is inexpensively available enantiomerically pure. During the synthesis there is no racemization at any stage. Large amounts can be found this way getting produced. The chemical yield is about three times as high as that of Schinzer et al. described.

Die Erfindung betrifft somit ein Verfahren zur Herstellung der Verbindungen der allgemeinen Formel I
The invention thus relates to a process for the preparation of the compounds of the general formula I.

worin
R1 C1-C20-Alkyl, Aryl, C7-C20-Aralkyl
R2 Wasserstoff oder eine geeignete Schutzgruppe,
R3 OH, Halogen oder OR4
wobei R4 für eine geeignete Schutzgruppe steht,
bedeutet ,
dadurch gekennzeichnet, daß
in einem Schritt 1
wherein
R 1 is C 1 -C 20 alkyl, aryl, C 7 -C 20 aralkyl
R 2 is hydrogen or a suitable protective group,
R 3 OH, halogen or OR 4
where R 4 stands for a suitable protective group,
means
characterized in that
in a step 1

L-(-)-Äpfelsäure (II) mit Trifluoressigsäureanhydrid in Methanol cyclisiert und mit Boran-Tetrahydrofuran-Komplex zum Dihydrohydroxy-(3H)-furanon (III) reduziert wird,
in einem Schritt 2
L - (-) - malic acid (II) cyclized with trifluoroacetic anhydride in methanol and reduced to the dihydrohydroxy- (3H) -furanone (III) with borane-tetrahydrofuran complex,
in a step 2

die freie Hydroxygruppe des Dihydrohydroxy-(3H)-furanons (III) mit tert.Butyldiphenylsilylchlorid oder mit einem Reagenz für eine andere geeignete Schutzgruppe R2 unter bekannten Bedingungen geschützt, und das Furanon (IV) mit Diisobutylaluminiumhydrid zum Lactol (V) reduziert wird, und
in einem Schritt 3
the free hydroxyl group of dihydrohydroxy (3H) furanone (III) is protected with tert-butyldiphenylsilyl chloride or with a reagent for another suitable protective group R 2 under known conditions, and the furanone (IV) is reduced to lactol (V) with diisobutylaluminum hydride, and
in a step 3

mit einer Organometallverbindung der allgemeinen Formel (VI)
with an organometallic compound of the general formula (VI)

R1Y (VI)
R 1 Y (VI)

wobei R1 die oben angegebene Bedeutung hat
Y MgX oder Li und
X Chlor, Brom oder Iod bedeutet,
der Ring geöffnet, und die freigesetzte primäre Hydroxygruppe mit tert.Butyldimethylsilylchlorid oder einer geeigneten anderen Schutzgruppe geschützt wird, und
in einem Schritt 4
where R 1 has the meaning given above
Y MgX or Li and
X represents chlorine, bromine or iodine,
the ring is opened and the primary hydroxyl group released is protected with tert-butyldimethylsilyl chloride or a suitable other protective group, and
in a step 4

die sekundäre Hydroxygruppe mit Oxalylchlorid/Dimethylsulfoxid zum Keton (Ia) oxidiert wird und anschließend in an sich bekannter Weise gegebenenfalls mit einem geeigneten Wittigreagenz der allgemeinen Formel (IX)
the secondary hydroxyl group is oxidized with oxalyl chloride / dimethyl sulfoxide to the ketone (Ia) and then in a manner known per se, optionally with a suitable Wittig reagent of the general formula (IX)

worin
R4 Wasserstoff, C1-C,6-Alkyl und
R5 Wasserstoff, C1-C10-Alkyl, Aryl, C7-C20-Aralkyl
bedeutet, umgesetzt wird,
wherein
R 4 is hydrogen, C 1 -C 6 alkyl and
R 5 is hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl
means is implemented

und gegebenenfalls
in einem Schritt 5
and if necessary
in a step 5

die Schutzgruppe der primären Hydroxygruppe selektiv mit Eisessig/Wasser oder einem zur Abspaltung einer anderen Schutzgruppe R bekannten Reagenz entfernt wird, die freie Hydroxygruppe mit Tetrabrommethan/Triphenylphosphin/Pyridin in das Bromid (XII) oder mit einem entsprechenden Reagenz in ein anderes Halogenid (Jodid) überführt wird und das Halogenid gegebenenfalls mit Triphenylphosphin in ein Wittigsalz (XIII) überführt wird.selectively protect the primary hydroxy group with glacial acetic acid / water or a known to remove another protective group R is removed, the free hydroxy group with tetrabromomethane / triphenylphosphine / pyridine in the bromide (XII) or converted into another halide (iodide) with an appropriate reagent and the halide optionally with triphenylphosphine in a Wittigsalz (XIII) is transferred.

Die erfindungsgemäßen Verbindungen Xa und (XIII) können nach Freisetzen der geschützten Hydroxygruppe mit Verbindungen der Formel
The compounds Xa and (XIII) according to the invention can be released with compounds of the formula after the protected hydroxyl group has been released

worin R1 OH,
R2 Wasserstoff oder eine geeignete Schutzgruppe,
R3 und R4 gleich oder verschieden sind und Wasserstoff, C1-C10-Alkyl, C7-C10-Aralkyl oder gemeinsam eine -(CH2)m-Gruppe mit m = 2 bis 6,
R5 Wasserstoff, C1-C,0-Alkyl, Aryl oder C7-C20-Aralkyl und
R6 Wasserstoff, C1-C10-Alkyl, Aryl oder C7-C20-Aralkyl
bedeuten, oder ähnlichen Carbonsäuren
verestert werden.wherein R 1 OH,
R 2 is hydrogen or a suitable protective group,
R 3 and R 4 are identical or different and are hydrogen, C 1 -C 10 alkyl, C 7 -C 10 aralkyl or together a - (CH 2 ) m group with m = 2 to 6,
R 5 is hydrogen, C 1 -C 0 alkyl, aryl or C 7 -C 20 aralkyl and
R 6 is hydrogen, C 1 -C 10 alkyl, aryl or C 7 -C 20 aralkyl
mean, or similar carboxylic acids
to be esterified.

Für die Verknüpfung am anderen Kettenende z. B. durch Wittig Reaktion mit einem geeigneten Keton wie z. B. dem von Nicolaou et al. in Nature, Volk 387, 270, 1997 vorgeschlagenen Keton
For the link at the other end of the chain z. B. by Wittig reaction with a suitable ketone such. B. that of Nicolaou et al. ketone proposed in Nature, Volk 387, 270, 1997

ist Verbindung XIII geeignet.Compound XIII is suitable.

So können die Verbindungen Xa und XIII durch verschiedene Reaktionen in Vorstufen von Epothilonderivaten überführt werden.Thus, the compounds Xa and XIII can undergo various reactions in precursors be transferred from epothilone derivatives.

Je nach Einsetzen der entsprechenden Äpfelsäure läßt sich die Stereochemie der α-Keto­ hydroxyfunktion der Verbindungen Ia und XIII steuern.Depending on the use of the corresponding malic acid, the stereochemistry of the α-keto can be Control the hydroxy function of the compounds Ia and XIII.

Die Erfindung betrifft außerdem Verbindungen der allgemeinen Formel (Ia)
The invention also relates to compounds of the general formula (Ia)

worin
R1 Wasserstoff, C1-C20-Alkyl, Aryl, C7-C20-Aralkyl
R2 Wasserstoff oder eine geeignete Schutzgruppe, und
R3 OH, Halogen oder OR
wobei R6 für eine geeignete Schutzgruppe steht,
bedeutet,
und R2 nicht Benzyl oder tert.Butyldimethylsilyl sein darf, wenn R3 O-tert.Butyldimethylsilyl bedeutet und R2 nicht gemeinsam mit R6 eine -CH(P-Methoxyphenyl)-Gruppe sein darf, und
Verbindungen der allgemeinen Formel (X)
wherein
R 1 is hydrogen, C 1 -C 20 alkyl, aryl, C 7 -C 20 aralkyl
R 2 is hydrogen or a suitable protective group, and
R 3 OH, halogen or OR
where R 6 stands for a suitable protective group,
means
and R 2 must not be benzyl or tert-butyldimethylsilyl if R 3 is O-tert-butyldimethylsilyl and R 2 cannot together with R 6 be a -CH (P-methoxyphenyl) group, and
Compounds of the general formula (X)

worin
R1 Wasserstoff, C1-C20-Alkyl, Aryl, C7-C20-Aralkyl
R2 Wasserstoff oder eine geeignete Schutzgruppe,
R3 OH, Halogen oder OR6 wobei R6 für eine geeignete Schutzgruppe steht,
R4 Wasserstoff, C1-C10-Alkyl, Aryl, C7-C18-Aralkyl und unabhängig von R5;
R5 Wasserstoff, C1-C10-Alkyl, Aryl, C7-C18-Aralkyl
bedeutet.wherein
R 1 is hydrogen, C 1 -C 20 alkyl, aryl, C 7 -C 20 aralkyl
R 2 is hydrogen or a suitable protective group,
R 3 OH, halogen or OR 6 where R 6 represents a suitable protective group,
R 4 is hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 18 aralkyl and independently of R 5 ;
R 5 is hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 18 aralkyl
means.

Durch die Disclaimer sollen die bereits bekannten Verbindungen von Schinzer et al. (Chem. Eur. J. 1996, 2, No. 11, 1477-1482 ) ausgeschlossen werden.The disclaimer is intended to link the already known compounds by Schinzer et al. (Chem. Eur. J. 1996, 2, No. 11, 1477-1482) can be excluded.

Als Alkylgruppen R1 sind geradkettige oder verzweigte Alkylgruppen mit 1-20 Kohlen­ stoffatomen zu betrachten, wie beispielsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.-Butyl, Pentyl, Isopentyl, Neopentyl, Heptyl, Hexyl, Decyl.As alkyl groups R 1 are straight-chain or branched alkyl groups with 1-20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.

Als Alkylgruppen R4 und R5 sind gerad- oder verzweigtkettige Alkylgruppen mit 1-10 Kohlenstoffatomen zu betrachten, wie beispielsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.-Butyl, Pentyl, Isopentyl, Neopentyl, Heptyl, Hexyl, Decyl.The alkyl groups R 4 and R 5 are straight-chain or branched-chain alkyl groups with 1-10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, Decyl.

Die Alkylgruppen R können perfluoriert oder substituiert sein durch 1-5 Halogenatome, Hydroxygruppen, C1-C4-Alkoxygruppen, C6-C12-Arylgruppen, die durch 1-3 Halogenatome substituiert sein können, Di-(C1-C4)-Alkylamine und Tri-(C1-C4)- Alkylammonium.The alkyl groups R can be perfluorinated or substituted by 1-5 halogen atoms, hydroxyl groups, C 1 -C 4 alkoxy groups, C 6 -C 12 aryl groups which can be substituted by 1-3 halogen atoms, di- (C 1 -C 4 ) Alkylamines and tri- (C 1 -C 4 ) alkylammonium.

Die Alkoxy- sowie Acyloxygruppen sollen jeweils 1 bis 20 Kohlenstoffatome enthalten, wobei Methoxy-, Ethoxy- Propoxy- Isopropoxy-, t-Butyloxy-, Formyl, Acetyl, Propionyl- und Isopropionylgruppen bevorzugt sind. The alkoxy and acyloxy groups should each contain 1 to 20 carbon atoms, where methoxy, ethoxy, propoxy, isopropoxy, t-butyloxy, formyl, acetyl, Propionyl and isopropionyl groups are preferred.  

Als Arylrest R1 und R4 kommen substituierte und unsubstituierte carbocyclische oder heterocyclische Reste wie z. B. Phenyl, Naphtyl, Furyl, Thienyl, Pyridyl, 2-Pyridyl, 3-Pyridyl, 4-Pyridyl, Pyrazolyl, Pyrimidinyl, 2-Pyrimidinyl, 3-Pyrimidinyl, 4-Pyrimidinyl, Oxazolyl, Pyridazinyl, Pyrazinyl, Chinolyl, die mehrfach substituiert sein können durch Halogen, -NO2, -N3, -CN, -OH, -NH2, -CO2H, -CO2R C1-C20-Acyl, C1-C20-Acyloxy- Gruppen, in Frage.Aryl radicals R 1 and R 4 are substituted and unsubstituted carbocyclic or heterocyclic radicals such as, for. B. phenyl, naphthyl, furyl, thienyl, pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazolyl, pyrimidinyl, 2-pyrimidinyl, 3-pyrimidinyl, 4-pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, the multiple can be substituted by halogen, -NO 2 , -N 3 , -CN, -OH, -NH 2 , -CO 2 H, -CO 2 RC 1 -C 20 -acyl, C 1 -C 20 -acyloxy groups, in question.

Die Aralkylgruppen in R1 und R5 können im Ring bis 14 C-Atome enthalten, bevorzugt 6 bis 10 und in der Alkylkette 1 bis 6, bevorzugt 1 bis 4 Atome. Bevorzugte Aralkylreste sind z. B. Benzyl, Phenylethyl, Naphtylmethyl bzw. Naphtylethyl. Die Ringe können mehrfach substituiert sein durch Halogen, -NO2, -N3, -CN, Alkyl, C1-C20-Acyl, C1-C20- Acyloxy-Gruppen.The aralkyl groups in R 1 and R 5 can contain up to 14 carbon atoms in the ring, preferably 6 to 10 and in the alkyl chain 1 to 6, preferably 1 to 4 atoms. Preferred aralkyl radicals are e.g. B. benzyl, phenylethyl, naphthylmethyl or naphthylethyl. The rings can be substituted several times by halogen, -NO 2 , -N 3 , -CN, alkyl, C 1 -C 20 -acyl, C 1 -C 20 -acyloxy groups.

Als Schutzgruppen R2 und R6 kommen alle dem Fachmann bekannten Schutzgruppen für Alkohole in Frage. Eine Übersicht befindet sich z. B. in "Protective Groups in Organic Synthesis" Theodora W. Green, John Wiley and Sons). Es werden sowohl Methoden zur Synthese als auch Methoden zum Abspalten der Schutzgruppen beschrieben. Hervorzuheben sind Alkylether, besonders Methyl-, Ethyl- und t-Butylether oder substituierte Alkylether, wie z. B. Methoxymethyl-, Ethoxymethyl-, Benzyloxymethyl, Tetrahydropyranyl-, Tetrahydrofuranylether, Allylether, Benzylether und substituierte Benzylether sowie Silylether, wie z. B. Trimethylsilyl-, Tri-isopropylsilyl-, Triethylsilyl, t-Butyldimethylsilyl, t-Butyldiphenylsilylether; aber auch Ester, wie z. B. Formiate, Benzylformiate, Acetate, Propionate, Pivalate, Trichloracetate und Trifluoracetate. R2 und R6 können aber auch eine gemeinsame cyclische Ketaleinheit bedeuten, wie z. B. ein ggf. substituiertes Acetonid, wobei dann R2 und R6 gemeinsam für eine CR7R8- Gruppe stehen, worin R7 und R8 gleich oder verschieden sind und Wasserstoff, C1-C4- Alkyl, Aryl oder gemeinsam eine (CH2)n-Gruppe mit n = 2 bis 6 bedeuten, und die C1-C4-Alkylreste und die Arylreste gegebenenfalls substituiert sein können z. B. durch Methyl, Methoxy, oder Halogenatome.Suitable protective groups R 2 and R 6 are all protective groups for alcohols known to the person skilled in the art. An overview is z. B. in "Protective Groups in Organic Synthesis" Theodora W. Green, John Wiley and Sons). Methods for synthesis as well as methods for removing the protective groups are described. To be emphasized are alkyl ethers, especially methyl, ethyl and t-butyl ether or substituted alkyl ethers, such as. B. methoxymethyl, ethoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl ether, allyl ether, benzyl ether and substituted benzyl ether and silyl ether, such as. B. trimethylsilyl, tri-isopropylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl ether; but also esters, such as. B. formates, benzyl formates, acetates, propionates, pivalates, trichloroacetates and trifluoroacetates. R 2 and R 6 can also mean a common cyclic ketal unit, such as. B. an optionally substituted acetonide, in which case R 2 and R 6 together represent a CR 7 R 8 group, in which R 7 and R 8 are identical or different and are hydrogen, C 1 -C 4 -alkyl, aryl or together is a (CH 2 ) n group with n = 2 to 6, and the C 1 -C 4 alkyl radicals and the aryl radicals can be optionally substituted, for. B. by methyl, methoxy, or halogen atoms.

Die Schutzgruppen R2 und R6 müssen voneinander verschieden sein, da sie selektiv abspaltbar sein müssen.The protective groups R 2 and R 6 must be different from one another since they must be able to be split off selectively.

Als Halogen kommen Fluor, Chlor, Brom und Iod in Frage, bevorzugt Brom und Iod.Halogen is fluorine, chlorine, bromine and iodine, preferably bromine and iodine.

Die anderen Halogenide analog zu Formel XII können nach literaturbekannten Methoden aus dem Alkohol erhalten werden. The other halides analogous to formula XII can by methods known from the literature from which alcohol can be obtained.  

Als Epothilonderivate sind alle offenkettigen und cyclischen, makroliden oder auch nicht makroliden, zusätzlich substituierten oder nicht substituierten Strukturen zu verstehen, die sich von Epothilon ableiten lassen.As epothilone derivatives, all are open-chain and cyclic, macrolide or not to understand macrolide, additionally substituted or unsubstituted structures, which can be derived from epothilone.

Die nachfolgenden Beispiele dienen der näheren Erläuterung der Erfindungsgegenstandes, ohne ihn auf diese beschränken zu wollen.The following examples serve to explain the subject of the invention in more detail, without wanting to limit him to them.

Beispiel 1example 1 (3S)-5[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanon(3S) -5 [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -2-pentanone

Zu 7,37 ml Oxalylchlorid in 80 ml Dichlormethan werden bei -78°C 13 ml Dimethylsulfoxid addiert. Man läßt 3 Minuten nachrühren und addiert dann 10,46 g 1a in 100 ml Dichlormethan. Nach weiteren 15 Minuten Nachrührzeit werden 52 ml Triethylamin hinzugetropft. Anschließend läßt man auf 0°C erwärmen. Danach wird das Reaktionsgemisch auf gesättigte Natriumhydrogencarbonatlösung gegossen. Man extrahiert mit Dichlormethan, wäscht die organische Phase mit gesättigter Natriumchloridlösung, trocknet über Natriumsulfat und engt im Vakuum ein. Nach Säulenchromatographie des Rohprodukts an Kieselgel mit einem Gemisch aus Hexan/Ethylacetat werden 9,3 g 1 erhalten.
1H-NMR (CDCl3): δ = 7,60-7,70 (4H), 7,32-7,50 (6H), 4,25 (1H), 3,72 (1H), 3,58 (1H), 2,05 (3H), 1,90 (1H), 1,75 (1H), 1,13 (9H), 0,89 (9H), 0,01 (6H) ppm.To 7.37 ml of oxalyl chloride in 80 ml of dichloromethane, 13 ml of dimethyl sulfoxide are added at -78 ° C. The mixture is stirred for 3 minutes and then 10.46 g of 1a in 100 ml of dichloromethane are added. After a further 15 minutes of stirring, 52 ml of triethylamine are added dropwise. Then allowed to warm to 0 ° C. The reaction mixture is then 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 column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate, 9.3 g of 1 are obtained.
1 H NMR (CDCl 3 ): δ = 7.60-7.70 (4H), 7.32-7.50 (6H), 4.25 (1H), 3.72 (1H), 3.58 (1H), 2.05 (3H), 1.90 (1H), 1.75 (1H), 1.13 (9H), 0.89 (9H), 0.01 (6H) ppm.

Beispiel 1aExample 1a (3S)-5-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanol(3S) -5 - [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -2-pentanol

Zu einer Lösung von 11,42 g 1b und 3,25 g 1H-Imidazol in 120 ml NUN- Dimethylformamid werden 4,9 g tert-Butyldimethylsilylchlorid addiert. Man läßt 2 Stunden bei 25°C nachrühren und gießt dann das Reaktionsgemisch auf eiskalte gesättigte Natriumhydrogencarbonatlösung. Man extrahiert mit Ethylacetat, wäscht die organische Phase mit gesättigter Natriumchloridlösung, trocknet über Natriumsulfat und engt im Vakuum ein. Nach Säulenchromatographie des Rohprodukts an Kieselgel mit einem Gemisch aus Hexan/Ethylacetat werden 10,64 g 1a erhalten.
1H-NMR (CDCl3): δ = 7,60-7,70 (4H), 7,30-7,45 (6H), 3,70-3,80 (2H), 3,40 (1H), 3,00 (1H), 1,80 (1H), 1,60 (1H), 1,05-1,12 (12H), 0,82 (9H), 0,02 (6H) ppm. 4.9 g of tert-butyldimethylsilyl chloride are added to a solution of 11.42 g of 1b and 3.25 g of 1H-imidazole in 120 ml of NUN-dimethylformamide. The mixture is stirred for 2 hours at 25 ° C and then poured onto ice-cold saturated sodium bicarbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate, 10.64 g of 1a are obtained.
1 H-NMR (CDCl 3 ): δ = 7.60-7.70 (4H), 7.30-7.45 (6H), 3.70-3.80 (2H), 3.40 (1H) , 3.00 (1H), 1.80 (1H), 1.60 (1H), 1.05-1.12 (12H), 0.82 (9H), 0.02 (6H) ppm.

Beispiel 1bExample 1b (3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1,4-pentandiol(3S) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -1,4-pentanediol

Zu 20 ml einer 3 molaren Lösung von Methylmagnesiumchlorid in Tetrahydrofuran wird bei 0°C eine Lösung von 13,46 g 1c in 150 ml absolutem Tetrahydrofuran getropft. Man läßt eine Stunde bei 0°C nachrühren und gießt dann auf gesättigte wäßrige Ammoniumchloridlösung. Man extrahiert mit Ethylacetat, wäscht die organische Phase mit gesättigter Natriumchloridlösung, trocknet über Natriumsulfat und engt im Vakuum ein. Nach Säulenchromatographie des Rohprodukts an Kieselgel mit einem Gemisch aus Hexan/Ethylacetat werden 11,42 g 1b erhalten.
1H-NMR (CDCl3): δ = 7,65-7,75 (4H), 7,40-7,55 (6H), 5,20 (1H), 4,30 (2H), 3,70 (1H), 1,80 (2H), 1,05 (9H) ppm.A solution of 13.46 g of 1c in 150 ml of absolute tetrahydrofuran is added dropwise to 20 ml of a 3 molar solution of methylmagnesium chloride in tetrahydrofuran at 0.degree. The mixture is stirred for one hour at 0 ° C and then poured onto saturated aqueous ammonium chloride solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate, 11.42 g of 1b are obtained.
1 H NMR (CDCl 3 ): δ = 7.65-7.75 (4H), 7.40-7.55 (6H), 5.20 (1H), 4.30 (2H), 3.70 (1H), 1.80 (2H), 1.05 (9H) ppm.

Beispiel 1cExample 1c (3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]tetrahydro-2-furanol(3S) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] tetrahydro-2-furanol

Zu einer Lösung von 13,4 g 1d in 150 ml absolutem Tetrahydrofuran werden 80 ml einer 1 molaren Lösung von Diisobutylaluminiumhydrid in Hexan bei -78°C addiert. Man rührt 45 Minuten bei -78°C nach und quencht dann mit Wasser. Man extrahiert mit Ethylacetat, wäscht die organische Phase mit gesättigter Natriumchloridlösung, trocknet über Natriumsulfat und engt im Vakuum ein. Man erhält 13,46 g 1c, welches ohne Reinigung in die Folgestufe eingesetzt wird.80 ml of a solution of 13.4 g of 1d in 150 ml of absolute tetrahydrofuran 1 molar solution of diisobutylaluminum hydride in hexane added at -78 ° C. You stir 45 minutes at -78 ° C and then quenched with water. It is extracted with Ethyl acetate, the organic phase washes with saturated sodium chloride solution, dries over sodium sulfate and concentrated in vacuo. 13.46 g of 1c, which is without Cleaning is used in the next stage.

Beispiel 1dExample 1d (S)-Dihydro-3-[[(1,1-dimethylethyl)diphenylsllyl]oxy]-2(3H)-furanon(S) -Dihydro-3 - [[(1,1-dimethylethyl) diphenylsllyl] oxy] -2 (3H) furanone

Zu einer Lösung von 7,61 g 1e und 10 g Imidazol in 100 ml N,N-Dimethylformamid werden 24 ml tert.Butyldiphenylsilylchlorid addiert. Man läßt zwei Stunden bei 25°C nachrühren und gießt dann das Reaktionsgemisch auf eiskalte gesättigte Natriumhydrogencarbonatlösung. Man extrahiert mit Ethylacetat, wäscht die organische Phase mit gesättigter Natriumchloridlösung, trocknet über Natriumsulfat und engt im Vakuum ein. Nach Säulenchromatographie des Rohprodukts an Kieselgel mit einem Gemisch aus Hexan/Ethylacetat werden 13,4 g 1d erhalten.
1H-NMR (CDCl3): δ = 7,72 (2H), 7,70 (2H), 7,40-7,50 (6H), 4,30-4,42 (2H), 4,01 (1H), 2,10-2,30 (2H), 1,11 (9H) ppm. 24 ml of tert-butyldiphenylsilyl chloride are added to a solution of 7.61 g of 1e and 10 g of imidazole in 100 ml of N, N-dimethylformamide. The mixture is stirred for two hours at 25 ° C and then poured onto ice-cold saturated sodium bicarbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate, 13.4 g of 1d are obtained.
1 H NMR (CDCl 3 ): δ = 7.72 (2H), 7.70 (2H), 7.40-7.50 (6H), 4.30-4.42 (2H), 4.01 (1H), 2.10-2.30 (2H), 1.11 (9H) ppm.

Beispiel 1eExample 1e (S)-Dihydro-3-hydroxy-2(3H)-furanon(S) -dihydro-3-hydroxy-2 (3H) -furanone

10 g L-(-)-Äpfelsäure werden in 45 ml Trifluoressigsäureanhydrid 2 Stunden bei 25°C gerührt. Danach engt man im Vakuum ein, addiert zu dem Rückstand 7 ml Methanol und läßt 12 Stunden nachrühren. Anschließend wird im Vakuum eingeengt. Der erhaltene Rückstand wird in 150 ml absolutem Tetrahydrofuran gelöst. Man kühlt auf 0°C und addiert 150 ml Boran-Tetrahydrofuran-Komplex und läßt 2,5 Stunden bei 0°C nachrühren. Danach werden 150 ml Methanol addiert. Man läßt eine Stunde bei Raumtemperatur nachrühren und engt dann im Vakuum ein. Das erhaltene Rohprodukt wird in 80 ml Toluol gelöst. Man addiert 5 g Dowex® (aktiviert, sauer)und kocht eine Stunde unter Rückfluß. Anschließend wird das Dowex® abfiltriert und das Filtrat im Vakuum eingeengt. Das erhaltene Rohprodukt (7,61 g) wird ohne Aufreinigung in die Folgestufe eingesetzt.10 g of L - (-) - malic acid are dissolved in 45 ml of trifluoroacetic anhydride for 2 hours at 25 ° C touched. The mixture is then concentrated in vacuo, 7 ml of methanol and lets stir for 12 hours. It is then concentrated in vacuo. The received one The residue is dissolved in 150 ml of absolute tetrahydrofuran. Cool to 0 ° C and add 150 ml of borane-tetrahydrofuran complex and leave for 2.5 hours at 0 ° C stir. Then 150 ml of methanol are added. One leaves one hour Stir room temperature and then concentrated in vacuo. The crude product obtained is dissolved in 80 ml of toluene. Add 5 g of Dowex® (activated, acidic) and boil one Hour under reflux. Then the Dowex® is filtered off and the filtrate in the Vacuum concentrated. The crude product obtained (7.61 g) is in the without purification Subsequent stage used.

Beispiel 2Example 2 (R)-5-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanon(R) -5 - [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -2-pentanone

Analog zu Beispiel 1 werden aus 10,11 g 1a 8,85 g 2 erhalten. Das 1H-NMR-Spektrum ist deckungsgleich mit 1.Analogously to Example 1, 8.85 g 2 are obtained from 10.11 g 1a. The 1 H-NMR spectrum is congruent with 1.

Beispiel 2aExample 2a (3R)-5-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanol(3R) -5 - [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -2-pentanol

Analog zu Beispiel 1a werden aus 11 g 1b 10,11 g 1a erhalten. Das 1H-NMR-Spektrum ist deckungsgleich mit 1a.Analogously to Example 1a, 10.11 g 1a are obtained from 11 g 1b. The 1 H-NMR spectrum is congruent with 1a.

Beispiel 2bExample 2b (3R)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1,4-pentandiol(3R) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -1,4-pentanediol

Analog zu Beispiel 1b werden aus 12,95 g 2c 11 g 2b erhalten. Das 1H-NMR-Spektrum ist deckungsgleich mit 1b.Analogously to Example 1b, 11 g 2b are obtained from 12.95 g 2c. The 1 H-NMR spectrum is congruent with 1b.

Beispiel 2cExample 2c (3R)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]tetrahydro-2-ol(3R) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] tetrahydro-2-ol

Analog zu Beispiel 1c werden aus 12,9 g 2d 12,95 g 2c erhalten. Das 1H-NMR- Spektrum ist deckungsgleich mit 1c. Analogously to Example 1c, 12.95 g 2c are obtained from 12.9 g 2d. The 1 H-NMR spectrum is congruent with 1c.

Beispiel 2dExample 2d (R)-Dihydro-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2(3H)-on(R) -Dihydro-3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -2 (3H) -one

Analog zu Beispiel 1d werden aus 7,26 g 2e 12,9 g 2d erhalten. Das 1H-NMR-Spektrum ist deckungsgleich mit 1d.Analogously to example 1d, 12.9 g 2d are obtained from 7.26 g 2e. The 1 H-NMR spectrum is congruent with 1d.

Beispiel 2eExample 2e (R)-Dihydro-3-hydroxy-2(3H)-furanon(R) -dihydro-3-hydroxy-2 (3H) -furanone

10 g D-(+)-Äpfelsäure werden analog zu Beispiel 1e umgesetzt. Man erhält 7,26 g 2e. Das 1H-NMR-Spektrum ist deckungsgleich mit 1e.10 g of D - (+) - malic acid are reacted analogously to Example 1e. 7.26 g of 2e are obtained. The 1 H-NMR spectrum is congruent with 1e.

Beispiel 3Example 3 5-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanon5 - [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -2-pentanone

Analog zu Beispiel 1 werden aus 5,05 g 3a 4,3 g 3 erhalten. Das 1H-NMR-Spektrum ist deckungsgleich mit 1.Analogously to Example 1, 4.3 g 3 are obtained from 5.05 g 3a. The 1 H-NMR spectrum is congruent with 1.

Beispiel 3aExample 3a 5-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanol5 - [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -2-pentanol

Analog zu Beispiel 1a werden aus 5,5 g 3b 5,05 g 3a erhalten. Das 1H-NMR-Spektrum ist deckungsgleich mit 1a.Analogously to Example 1a, 5.05 g 3a are obtained from 5.5 g 3b. The 1 H-NMR spectrum is congruent with 1a.

Beispiel 3bExample 3b 3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1,4-pentandiol3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -1,4-pentanediol

Analog zu Beispiel 1b werden aus 6,51 g 3c 5,5 g 3b erhalten. Das 1H-NMR-Spektrum ist deckungsgleich mit 1b.Analogously to Example 1b, 5.5 g 3b are obtained from 6.51 g 3c. The 1 H-NMR spectrum is congruent with 1b.

Beispiel 3cExample 3c 3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]tetrahydro-2-ol3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] tetrahydro-2-ol

Analog zu Beispiel 1c werden aus 6,5 g 3d 6,51 g 3c erhalten. Das 1H-NMR-Spektrum ist deckungsgleich mit 1c.Analogously to Example 1c, 6.51 g of 3c are obtained from 6.5 g of 3d. The 1 H-NMR spectrum is congruent with 1c.

Beispiel 3dExample 3d Dihydro-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2(3H)-onDihydro-3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -2 (3H) -one

Analog zu Beispiel 1d werden aus 3,68 g 3e 6,5 g 3d erhalten. Das 1H-NMR-Spektrum ist deckungsgleich mit 1d. Analogously to example 1d, 6.5 g 3d are obtained from 3.68 g 3e. The 1 H-NMR spectrum is congruent with 1d.

Beispiel 3eExample 3e Dihydro-3-hydroxy-2(3R)-furanonDihydro-3-hydroxy-2 (3R) furanon

5 g racemische Äpfelsäure werden analog zu Beispiel 1e umgesetzt. Man erhält 3,68 g 3e. Das 1H-NMR-Spektrum ist deckungsgleich mit 1e.5 g of racemic malic acid are reacted analogously to Example 1e. 3.68 g of 3e are obtained. The 1H NMR spectrum is congruent with 1e.

Beispiel 4Example 4 (E,3S)-1-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-en(E, 3S) -1 - [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (2-methylthiazole- 4-yl) -pent-4-ene

Die Lösung von 6,82 g Diethyl(2-methylthlazol-4-yl)methanphosphonat in 300 ml wasserfreiem Tetrahydrofuran kühlt man unter einer Atmosphäre aus trockenem Argon auf -5°C, versetzt mit 16,2 ml einer 1,6 molaren Lösung von n-Buthyllithium in n-Hexan, läßt auf 23°C erwärmen und 2 Stunden rühren. Anschließend kühlt man auf -78°C, tropft die Lösung von 6,44 g (13,68 mmol) der nach Beispiel 1 dargestellten Verbindung in 150 ml Tetrahydrofuran zu, läßt auf 23°C erwärmen und 16 Stunden rühren. Man gießt in gesättigte Ammoniumchloridlösung, extrahiert mehrfach mit Ethylacetat, wäscht die vereinigten organischen Extrakte mit gesättigter Natriumchloridlösung und trocknet über Natriumsulfat. Den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand reinigt man durch Chromatographie an feinem Kieselgel mit einem Gradientensystem aus n-Hexan und Ethylacetat. Isoliert werden 6,46 g (11,4 mmol, 83%) der Titelverbindung als farbloses Öl.
1H-NMR (CDCl3): δ = -0,04 (6H), 0,83 (9H), 1,10 (9H), 1,79 (1H), 1,90 (1H), 1,97 (3H), 2,51 (3H), 3,51 (2H), 4,38 (1H), 6,22 (1H), 6,74 (1H), 7,23-7,47 (6H), 7,63 (2H), 7,70 (2H) ppm.The solution of 6.82 g of diethyl (2-methylthlazol-4-yl) methanephosphonate in 300 ml of anhydrous tetrahydrofuran is cooled to -5 ° C. under an atmosphere of dry argon, mixed with 16.2 ml of a 1.6 molar solution of n-Butyllithium in n-hexane, allowed to warm to 23 ° C. and stir for 2 hours. The mixture is then cooled to -78 ° C., the solution of 6.44 g (13.68 mmol) of the compound shown in Example 1 in 150 ml of tetrahydrofuran is added dropwise, and the mixture is heated to 23 ° C. and stirred for 16 hours. It is poured into saturated ammonium chloride solution, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 6.46 g (11.4 mmol, 83%) of the title compound are isolated as a colorless oil.
1 H NMR (CDCl 3 ): δ = -0.04 (6H), 0.83 (9H), 1.10 (9H), 1.79 (1H), 1.90 (1H), 1.97 (3H), 2.51 (3H), 3.51 (2H), 4.38 (1H), 6.22 (1H), 6.74 (1H), 7.23-7.47 (6H), 7.63 (2H), 7.70 (2H) ppm.

Beispiel 5Example 5 (Z,3S)-1-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1- dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(3-pyridyl)-pent-4-en (A) und (E,3S)-1- [[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4- methyl-5-(3-pyridyl)-pent-4-en (B)(Z, 3S) -1 - [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1- dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (3-pyridyl) pent-4-ene (A) and (E, 3S) -1- [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -4- methyl-5- (3-pyridyl) -pent-4-ene (B)

In Analogie zu Beispiel 4 setzt man 100 mg (0,21 mmol) der nach Beispiel 1 dargestellten Verbindung unter Verwendung von Diethyl(3-pyridyl)methanphosphonat um und isoliert nach Aufarbeitung und Reinigung 9 mg (16 µmol, 8%) der Titelverbindung A sowie 44 mg (81 µmol, 38%) der Titelverbindung B jeweils als farbloses Öl.
1H-NMR (CDCl3) von A: δ = -0,06 (6H), 0,81 (9H), 1,01 (9H), 1,75 (1H), 1,97 (4H), 3,48 (2H), 4,83 (1H), 6,11 (1H), 6,97 (1H), 7,11-7,30 (5H), 7,30-7,39 (2H), 7,39-7,50 (4H), 8,08 (1H), 8,33 (1H) ppm.
1H-NMR (CDCl3) von B: δ = -0,01 (6H), 0,85 (9H), 1,11 (9H), 1,78 (3H), 1,83 (1H), 1,97 (1H), 3,58 (2H), 4,42 (1H), 6,03 (1H), 7,21 (1H), 7,28-7,50 (7H), 7,62-7,75 (4H), 8,29 (1H), 8,41 (1H) ppm. In analogy to Example 4, 100 mg (0.21 mmol) of the compound shown in Example 1 are reacted using diethyl (3-pyridyl) methanephosphonate and, after workup and purification, 9 mg (16 μmol, 8%) of the title compound A is isolated and 44 mg (81 µmol, 38%) of the title compound B each as a colorless oil.
1 H NMR (CDCl 3 ) of A: δ = -0.06 (6H), 0.81 (9H), 1.01 (9H), 1.75 (1H), 1.97 (4H), 3 , 48 (2H), 4.83 (1H), 6.11 (1H), 6.97 (1H), 7.11-7.30 (5H), 7.30-7.39 (2H), 7 , 39-7.50 (4H), 8.08 (1H), 8.33 (1H) ppm.
1 H NMR (CDCl 3 ) of B: δ = -0.01 (6H), 0.85 (9H), 1.11 (9H), 1.78 (3H), 1.83 (1H), 1 , 97 (1H), 3.58 (2H), 4.42 (1H), 6.03 (1H), 7.21 (1H), 7.28-7.50 (7H), 7.62-7 , 75 (4H), 8.29 (1H), 8.41 (1H) ppm.

Beispiel 6Example 6 (E,3S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-en-1-ol(E, 3S) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (2-methylthiazol-4-yl) pent-4-en-1-ol

Die Lösung von 4,79 g (8,46 mmol) der nach Beispiel 4 dargestellten Verbindung in 48 ml Tetrahydrofuran versetzt man mit 48 ml eines 65 : 35 : 10-Gemisches aus Eisessig/Wasser/Tetrahydro und rührt 2,5 Tage bei 23°C. Man gießt in gesättigte Natriumcarbonatlösung, extrahiert mehrfach mit Ethylacetat, wäscht die vereinigten organischen Extrakte mit gesättigter Natriumchloridlösung und trocknet über Natriumsulfat. Den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand reinigt man durch Chromatographie an feinem Kieselgel mit einem Gradientensystem aus n-Hexan und Ethylacetat. Isoliert werden 3,42 g (7,57 mmol, 90%) der Titelverbindung als farbloses Öl.
1H-NMR (CDCl3): δ = 1,10 (9H), 1,53 (1H), 1,81 (2H), 1,96 (3H), 2,71 (3H), 3,59 (2H), 4,41 (1H), 6,38 (1H), 6,78 (1H), 7,26-7,49 (6H), 7,65 (2H), 7,72 (2H) ppm.The solution of 4.79 g (8.46 mmol) of the compound shown in Example 4 in 48 ml of tetrahydrofuran is mixed with 48 ml of a 65:35:10 mixture of glacial acetic acid / water / tetrahydro and stirred for 2.5 days at 23 ° C. It is poured into saturated sodium carbonate solution, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 3.42 g (7.57 mmol, 90%) of the title compound are isolated as a colorless oil.
1 H NMR (CDCl 3 ): δ = 1.10 (9H), 1.53 (1H), 1.81 (2H), 1.96 (3H), 2.71 (3H), 3.59 ( 2H), 4.41 (1H), 6.38 (1H), 6.78 (1H), 7.26-7.49 (6H), 7.65 (2H), 7.72 (2H) ppm.

Beispiel 7Example 7 (E,3S)-1-Brom-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methyllhiazol-4-yl)-pent-4-en(E, 3S) -1-bromo-3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (2-methyllhiazol-4-yl) pent-4-ene

Die Lösung von 378 mg (0,84 mmol) der nach Beispiel 6 dargestellten Verbindung in 9 ml Dichlormethan versetzt man bei 0°C unter einer Atmosphäre aus trockenem Argon mit 90 µl Pyridin, 439 mg Triphenylphosphin, 556 mg Tetrabrommethan und rührt 1 Stunde bei 0°C. Die Lösung chromatographiert man an feinem Kieselgel mit einem Gradientensystem aus n-Hexan und Ethylacetat. Isoliert werden 362 mg (0,70 mmol, 84%) der Titelverbindung als farbloses Öl.
1H-NMR (CDCl3): δ = 1,09 (9H), 1,95 (3H), 2,01-2,23 (2H), 2,71(3H), 3,15-3,35 (2H), 4,35 (1H), 6,30 (1H), 6,79 (1H), 7,25-7,49 (6H), 7,63 (2H), 7,69 (2H) ppm. The solution of 378 mg (0.84 mmol) of the compound shown in Example 6 in 9 ml of dichloromethane is mixed at 0 ° C. under an atmosphere of dry argon with 90 μl of pyridine, 439 mg of triphenylphosphine, 556 mg of tetrabromomethane and stirred for 1 hour 0 ° C. The solution is chromatographed on fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 362 mg (0.70 mmol, 84%) of the title compound are isolated as a colorless oil.
1 H NMR (CDCl 3 ): δ = 1.09 (9H), 1.95 (3H), 2.01-2.23 (2H), 2.71 (3H), 3.15-3.35 (2H), 4.35 (1H), 6.30 (1H), 6.79 (1H), 7.25-7.49 (6H), 7.63 (2H), 7.69 (2H) ppm .

Beispiel 8Example 8 (5E,3S)-[3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-en-1-yl]-triphenylphosphoriumbromid(5E, 3S) - [3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (2-methylthiazol-4-yl) -pent-4-en-1-yl] - triphenylphosphorium bromide

Die Lösung von 189 mg (0,37 mmol) der nach Beispiel 7 dargestellten Verbindung in 1 ml wasserfreiem Toluol versetzt man unter einer Atmosphäre aus trockenem Argon mit 96,1 mg Triphenylphosphin und erhitzt 24 Stunden unter Rückfluß. Nach dem Erkalten engt man ein und isoliert 286 mg (0,37 mmol, 100%) der Titelverbindung als kristallinen Feststoff, den man ohne Reinigung weiter umsetzt.The solution of 189 mg (0.37 mmol) of the compound shown in Example 7 in 1 ml of anhydrous toluene are added under an atmosphere of dry argon 96.1 mg triphenylphosphine and heated under reflux for 24 hours. After cooling is concentrated and 286 mg (0.37 mmol, 100%) of the title compound is isolated as crystalline Solid that can be reacted without cleaning.

Beispiel 9Example 9 (Z,3S)-1-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1- dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(3-pyridyl)-pent-4-en (A) und (E,3S)-1- [[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4- methyl-5-(3-pyridyl)-pent-4-en (B)(Z, 3S) -1 - [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1- dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (3-pyridyl) pent-4-ene (A) and (E, 3S) -1- [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -4- methyl-5- (3-pyridyl) -pent-4-ene (B)

In Analogie zu Beispiel 4 setzt man 4,8 g (10,2 mmol) der nach Beispiel 1 dargestellten Verbindung unter Verwendung von Diethyl(3-pyridyl)methanphosphonat um und isoliert nach Aufarbeitung und Reinigung 448 mg (0,82 mmol, 8%) der Titelverbindung A sowie 3,5 g (6,41 mmol, 63%) der Titelverbindung B jeweils als farbloses Öl.
1H-NMR (CDCl3) von A: δ = -0,06 (6H), 0,81 (9H), 1,01 (9H), 1,75 (1H), 1,97 (4H), 3,48 (2H), 4,83 (1H), 6,11 (1H), 6,97 (1H), 7,11-7,30 (5H), 7,30-7,39 (2H), 7,39-7,50 (4H), 8,08 (1H), 8,33 (1H) ppm.
1H-NMR (CDCl3) von B: δ = -0,01 (6H), 0,85 (9H), 1,11 (9H), 1,78 (3H), 1,83 (1H), 1,97 (1H), 3,58 (2H), 4,42 (1H), 6,03 (1H), 7,21 (1H), 7,28-7,50 (7H), 7,62-7,75 (4H), 8,29 (1H), 8,41 (1H) ppm. In analogy to Example 4, 4.8 g (10.2 mmol) of the compound shown in Example 1 are reacted using diethyl (3-pyridyl) methanephosphonate and, after workup and purification, 448 mg (0.82 mmol, 8% ) of the title compound A and 3.5 g (6.41 mmol, 63%) of the title compound B each as a colorless oil.
1 H NMR (CDCl 3 ) of A: δ = -0.06 (6H), 0.81 (9H), 1.01 (9H), 1.75 (1H), 1.97 (4H), 3 , 48 (2H), 4.83 (1H), 6.11 (1H), 6.97 (1H), 7.11-7.30 (5H), 7.30-7.39 (2H), 7 , 39-7.50 (4H), 8.08 (1H), 8.33 (1H) ppm.
1 H NMR (CDCl 3 ) of B: δ = -0.01 (6H), 0.85 (9H), 1.11 (9H), 1.78 (3H), 1.83 (1H), 1 , 97 (1H), 3.58 (2H), 4.42 (1H), 6.03 (1H), 7.21 (1H), 7.28-7.50 (7H), 7.62-7 , 75 (4H), 8.29 (1H), 8.41 (1H) ppm.

Beispiel 10Example 10 (E,3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(3-pyridyl)-pent-4-en-1-ol(E, 3S) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (3-pyridyl) pent-4-en-1-ol

Analog zu Beispiel 5 werden 3,5 g (6,41 mmol) der unter Beispiel 9B hergestellten Verbindung mit einem 65 : 35 : 10-Gemische aus Eisessig/Wasser/Tetrahydrofuran umgesetzt. Man erhält nach Aufreinigung 2,1 g (4,86 mmol, 76%).
1H-NMR (CDCl3): δ = 1,12 (9H), 1,75 (3H), 1,88 (2H), 3,65 (2H), 4,45 (1H), 6,25 (1H), 7,21 (1H), 7,28-7,50 (7H), 7,60-7,75 (4H), 8,30 (1H), 8,44 (1H) ppm.Analogously to Example 5, 3.5 g (6.41 mmol) of the compound prepared under Example 9B are reacted with a 65:35:10 mixture of glacial acetic acid / water / tetrahydrofuran. After purification, 2.1 g (4.86 mmol, 76%) are obtained.
1 H-NMR (CDCl 3 ): δ = 1.12 (9H), 1.75 (3H), 1.88 (2H), 3.65 (2H), 4.45 (1H), 6.25 ( 1H), 7.21 (1H), 7.28-7.50 (7H), 7.60-7.75 (4H), 8.30 (1H), 8.44 (1H) ppm.

Beispiel 11Example 11 (Z,3S)-1-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1- dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(4-pyridyl)-pent-4-en (A) und (E, [[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4- methyl-5-(4-pyridyl)-pent-4-en (B)(Z, 3S) -1 - [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1- dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (4-pyridyl) pent-4-ene (A) and (E, [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -4- methyl-5- (4-pyridyl) pent-4-ene (B)

In Analogie zu Beispiel 4 setzt man 4,59 g (9,75 mmol) der nach Beispiel 1 dargestellten Verbindung unter Verwendung von Diethyl(4-pyridyl)methanphosphonat um und isoliert nach Aufarbeitung und Reinigung 605 mg (1,11 mmol, 11%) der Titelverbindung A sowie 4,34 g (7,95 mmol, 82%) der Titelverbindung B jeweils als farbloses Öl.
1H-NMR (CDCl3) von A: δ = -0,05 (6H), 0,82 (9H), 1,02 (9H), 1,78 (1H), 1,96 (3H), 3,48 (2H), 4,92 (1H), 6,08 (1H), 6,73 (2H), 7,20-7,30 (4H), 7,32-7,40 (2H), 7,41-7,49 (4H), 8,30 (2H) ppm.
1H-NMR (CDCl3) von B: & = -0,04 (6H), 0,80 (9H), 1,08 (9H), 1,78 (3H), 1,91 (1H), 3,55 (2H), 4,39 (1H), 6,02 (1H), 6,93 (2H), 7,26-7,48 (6H), 7,60-7,72 (4H), 8,50 (2H) ppm.Analogously to Example 4, 4.59 g (9.75 mmol) of the compound shown in Example 1 is reacted using diethyl (4-pyridyl) methanephosphonate and, after workup and purification, 605 mg (1.11 mmol, 11%) ) of the title compound A and 4.34 g (7.95 mmol, 82%) of the title compound B each as a colorless oil.
1 H NMR (CDCl 3 ) of A: δ = -0.05 (6H), 0.82 (9H), 1.02 (9H), 1.78 (1H), 1.96 (3H), 3 , 48 (2H), 4.92 (1H), 6.08 (1H), 6.73 (2H), 7.20-7.30 (4H), 7.32-7.40 (2H), 7 , 41-7.49 (4H), 8.30 (2H) ppm.
1 H NMR (CDCl 3 ) of B: & = -0.04 (6H), 0.80 (9H), 1.08 (9H), 1.78 (3H), 1.91 (1H), 3 , 55 (2H), 4.39 (1H), 6.02 (1H), 6.93 (2H), 7.26-7.48 (6H), 7.60-7.72 (4H), 8 , 50 (2H) ppm.

Beispiel 12Example 12 (E,3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(4-pyridyl)-pent-4-en-1-ol(E, 3S) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (4-pyridyl) pent-4-en-1-ol

Analog zu Beispiel 5 werden 4,34 g (7,95 mmol) der unter Beispiel 11B hergestellten Verbindung mit einem 65 : 35 : 10-Gemische aus Eisessig/Wasser/Tetrahydrofuran umgesetzt. Man erhält nach Aufreinigung 2,92 g (6,76 mmol, 85%). 1H-NMR (CDCl3): δ = 1,12 (9H), 1,78 (3H), 1,87 (2H), 3,65 (2H), 4,42 (1H), 6,26 (1H), 6,97 (2H), 7,26-7,48 (6H), 7,60-7,72 (4H), 8,52 (2H) ppm. Analogously to Example 5, 4.34 g (7.95 mmol) of the compound prepared under Example 11B are reacted with a 65:35:10 mixture of glacial acetic acid / water / tetrahydrofuran. After purification, 2.92 g (6.76 mmol, 85%) are obtained. 1 H NMR (CDCl 3 ): δ = 1.12 (9H), 1.78 (3H), 1.87 (2H), 3.65 (2H), 4.42 (1H), 6.26 ( 1H), 6.97 (2H), 7.26-7.48 (6H), 7.60-7.72 (4H), 8.52 (2H) ppm.

Beispiel 13Example 13 (E,3S)-1-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1- dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-pyridyl)-pent-4-en(E, 3S) -1 - [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1- dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (2-pyridyl) pent-4-ene

In Analogie zu Beispiel 4 setzt man 2 g (4,23 mmol) der nach Beispiel 1 dargestellten Verbindung unter Verwendung von Diethyl(2-pyridyl)methanphosphonat um und isoliert nach Aufarbeitung und Reinigung 2 g (3,68 mmol, 87%) der Titelverbindung als farbloses Öl.
1H-NMR (CDCl3): δ = -0,06 (6H), 0,80 (9H), 1,09 (9H), 1,81 (1H), 1,90 (1H), 2,00 (3H), 3,53 (2H), 4,40 (1H), 6,22 (1H), 6,99 (1H), 7,06 (1H), 7,25-7,45 (6H), 7,58 (1H), 7,65-7,77 (4H), 8,58 (1H) ppm.Analogously to Example 4, 2 g (4.23 mmol) of the compound shown in Example 1 are reacted using diethyl (2-pyridyl) methanephosphonate and, after workup and purification, 2 g (3.68 mmol, 87%) of are isolated Title compound as a colorless oil.
1 H NMR (CDCl 3 ): δ = -0.06 (6H), 0.80 (9H), 1.09 (9H), 1.81 (1H), 1.90 (1H), 2.00 (3H), 3.53 (2H), 4.40 (1H), 6.22 (1H), 6.99 (1H), 7.06 (1H), 7.25-7.45 (6H), 7.58 (1H), 7.65-7.77 (4H), 8.58 (1H) ppm.

Beispiel 14Example 14 (E,3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-pyridyl)-pent-4-en-1-ol(E, 3S) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (2-pyridyl) pent-4-en-1-ol

Analog zu Beispiel 5 werden 2 g (3,68 mmol) der unter Beispiel 13 hergestellten Verbindung mit einem 65 : 35 : 10-Gemische aus Eisessig/Wasser/Tetrahydrofuran umgesetzt. Man erhält nach Aufreinigung 1,38 g (3,20 mmol, 87%).
1H-NMR (CDCl3): δ = 1,12 (9H), 1,85 (2H), 2,00 (3H), 3,62 (2H), 4,45 (1H), 6,44 (1H), 7,03 (1H), 7,08 (1H), 7,25-7,48 (6H), 7,59 (1H), 7,65-7,77 (4H), 8,58 (1H) ppm.Analogously to Example 5, 2 g (3.68 mmol) of the compound prepared in Example 13 are reacted with a 65:35:10 mixture of glacial acetic acid / water / tetrahydrofuran. After purification, 1.38 g (3.20 mmol, 87%) are obtained.
1 H NMR (CDCl 3 ): δ = 1.12 (9H), 1.85 (2H), 2.00 (3H), 3.62 (2H), 4.45 (1H), 6.44 ( 1H), 7.03 (1H), 7.08 (1H), 7.25-7.48 (6H), 7.59 (1H), 7.65-7.77 (4H), 8.58 ( 1H) ppm.

Claims (4)

1. Verbindungen der allgemeinen Formel (I)
worin
R1 Wasserstoff C1-C20-Alkyl, Aryl, C7-C20-Aralkyl
R2 Wasserstoff oder eine geeignete Schutzgruppe, und
R3 OH, Halogen oder OR6
wobei R6 für eine geeignete Schutzgruppe steht,
bedeutet,
und R2 nicht Benzyl oder tert.Butyldimethylsilyl sein darf, wenn R3 = O-tert.Butyldimethylsilyl bedeutet und R2 nicht gemeinsam mit R6 eine -CH(P-Methoxyphenyl)-Gruppe sein darf1. Compounds of the general formula (I)
wherein
R 1 is hydrogen C 1 -C 20 alkyl, aryl, C 7 -C 20 aralkyl
R 2 is hydrogen or a suitable protective group, and
R 3 OH, halogen or OR 6
where R 6 stands for a suitable protective group,
means
and R 2 must not be benzyl or tert-butyldimethylsilyl if R 3 = O-tert-butyldimethylsilyl and R 2 cannot together with R 6 be a -CH (P-methoxyphenyl) group 2. Verbindungen der allgemeinen Formel (X)
worin
R1 Wasserstoff C1-C20-Alkyl, Aryl, C7-C20-Aralkyl
R2 Wasserstoff oder eine geeignete Schutzgruppe,
R3 OH, Halogen oder OR6
wobei R6 für eine geeignete Schutzgruppe steht,
R4 Wasserstoff C1-C10-Alkyl und
R5 Wasserstoff C1-C10-Alkyl, Aryl, C7-C20-Aralkyl
bedeutet. 2. Compounds of the general formula (X)
wherein
R 1 is hydrogen C 1 -C 20 alkyl, aryl, C 7 -C 20 aralkyl
R 2 is hydrogen or a suitable protective group,
R 3 OH, halogen or OR 6
where R 6 stands for a suitable protective group,
R 4 is hydrogen C 1 -C 10 alkyl and
R 5 is hydrogen C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl
means. 3. Verfahren zur Herstellung der Verbindungen der allgemeinen Formel Ia
worin
R1 C1-C20-Alkyl, Aryl, C7-C20-Aralkyl
R2 Wasserstoff oder eine geeignete Schutzgruppe,
R3 OH, Halogen oder OR4 wobei R4 für eine geeignete Schutzgruppe steht,
bedeutet,
dadurch gekennzeichnet, daß
in einem Schritt 1
Äpfelsäure (II) mit Trifluoressigsäureanhydrid in Methanol cyclisiert, mit Boran- Tetrahydrofuran-Komplex zum Dihydrohydroxy-(3H)-furanon (III) reduziert wird,
in einem Schritt 2
die freie Hydroxygruppe des Dihydrohydroxy-(3H)-ons (III) mit tert.Butyldiphenylsilylchlorid oder mit einem Reagenz für eine andere geeignete Schutzgruppe R unter bekannten Bedingungen geschützt, und das Furanon (IV) mit Diisobutylaluminiumhydrid zum Lactol (V) reduziert wird, und
in einem Schritt 3
mit einer Organometallverbindung der allgemeinen Formel (VI)
R1Y (VI)
wobei R1 die oben angegebene Bedeutung hat
Y MgX oder Li und
X Chlor, Brom oder Iod bedeutet,
der Ring geöffnet, und die freigesetzte primäre Hydroxygruppe mit tert.Butyldimethylsilylchlorid oder einer geeigneten anderen von R2 verschiedenen Schutzgruppe geschützt wird, und
in einem Schritt 4
die sekundäre Hydroxygruppe mit Oxalylchlorid/Dimethylsulfoxid zum Keton (Ia) oxidiert wird
und anschließend in an sich bekannter Weise mit einem geeigneten Wittigreagenz der allgemeinen Formel (IX)
worin
R4 Wasserstoff, C1-C10-Alkyl und
R5 Wasserstoff, C1-C10-Alkyl, Aryl, C7-C20-Aralkyl bedeutet,
umgesetzt wird, und
gegebenenfalls
in einem Schritt 5
die Schutzgruppe der primären Hydroxygruppe selektiv mit Eisessig/Wasser oder einem zur Abspaltung einer anderen Schutzgruppe R6 bekannten Reagenz entfernt wird, die freie Hydroxygruppe mit Tetrabrommethan/Triphenylphosphin/Pyridin in das Bromid (XII) oder mit einem entsprechenden Reagenz in ein anderes Halogenid überführt wird und das Bromid gegebenenfalls mit Triphenylphosphin in ein Wittigsalz (XIII) überführt wird.3. Process for the preparation of the compounds of general formula Ia
wherein
R 1 is C 1 -C 20 alkyl, aryl, C 7 -C 20 aralkyl
R 2 is hydrogen or a suitable protective group,
R 3 OH, halogen or OR 4 where R 4 stands for a suitable protective group,
means
characterized in that
in a step 1
Malic acid (II) cyclized with trifluoroacetic anhydride in methanol, reduced to the dihydrohydroxy- (3H) -furanone (III) with borane-tetrahydrofuran complex,
in a step 2
the free hydroxy group of the dihydrohydroxy (3H) -one (III) is protected with tert-butyldiphenylsilyl chloride or with a reagent for another suitable protective group R under known conditions, and the furanone (IV) is reduced to lactol (V) with diisobutylaluminum hydride, and
in a step 3
with an organometallic compound of the general formula (VI)
R 1 Y (VI)
where R 1 has the meaning given above
Y MgX or Li and
X represents chlorine, bromine or iodine,
the ring is opened and the primary hydroxyl group released is protected with tert-butyldimethylsilyl chloride or a suitable other protective group other than R 2 , and
in a step 4
the secondary hydroxyl group is oxidized with oxalyl chloride / dimethyl sulfoxide to the ketone (Ia)
and then in a manner known per se with a suitable Wittig reagent of the general formula (IX)
wherein
R 4 is hydrogen, C 1 -C 10 alkyl and
R 5 denotes hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl,
is implemented, and
possibly
in a step 5
the protective group of the primary hydroxyl group is removed selectively with glacial acetic acid / water or a reagent known to split off another protective group R 6 , the free hydroxyl group is converted into the bromide (XII) or with a corresponding reagent into another halide using tetrabromomethane / triphenylphosphine / pyridine and the bromide is optionally converted into a Wittigsalz (XIII) with triphenylphosphine. 3. Verwendung der Verbindungen gemäß Anspruch 1 und 2 zur Synthese von Epothilon und Epothilonderivaten.3. Use of the compounds according to claim 1 and 2 for the synthesis of epothilone and epothilone derivatives.
DE19735575A 1997-08-09 1997-08-09 New di:hydroxy-butanal or -pentene derivatives Withdrawn DE19735575A1 (en)

Priority Applications (15)

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DE19735575A DE19735575A1 (en) 1997-08-09 1997-08-09 New di:hydroxy-butanal or -pentene derivatives
DK98946309T DK1005465T3 (en) 1997-08-09 1998-08-10 New epothilone derivatives, processes 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
ES98946309T ES2290993T3 (en) 1997-08-09 1998-08-10 NEW DERIVATIVES OF EPOTILONE, PROCESS FOR ITS PRODUCTION AND ITS PHARMACEUTICAL USE.
EP98946309A EP1005465B1 (en) 1997-08-09 1998-08-10 New 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
PT98946309T PT1005465E (en) 1997-08-09 1998-08-10 New epothilone derivatives, method for producing same and their pharmaceutical use
DE59814067T DE59814067D1 (en) 1997-08-09 1998-08-10 NEW EPOTHILON DERIVATIVES, PROCESS FOR THEIR PREPARATION 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
AU93409/98A AU9340998A (en) 1997-08-09 1998-08-10 New epothilone derivatives, method for producing same 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
EP07013545A EP1847540A1 (en) 1997-08-09 1998-08-10 Nouveaux dérivés d'épothilone, leur procédé de production et leur utilisation pharmaceutique
JP2000506196A JP2001512723A (en) 1997-08-09 1998-08-10 Novel epothilone derivatives, their preparation and their pharmaceutical use
AT98946309T ATE368036T1 (en) 1997-08-09 1998-08-10 NEW EPOTHILONE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR PHARMACEUTICAL USE
US12/178,039 US20090018342A1 (en) 1997-08-09 2008-07-23 New epothiolone derivatives, process for their production, and their pharmaceutical use

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Cited By (4)

* 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
WO2016162712A1 (en) 2015-04-07 2016-10-13 Metabolic Explorer Modified microorganism for the optimized production of 2,4-dihydroxyburyrate

Cited By (10)

* 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
WO2016162712A1 (en) 2015-04-07 2016-10-13 Metabolic Explorer Modified microorganism for the optimized production of 2,4-dihydroxyburyrate
US10415062B2 (en) 2015-04-07 2019-09-17 Metabolic Explorer Modified microorganism for the optimized production of 2,4-dihydroxybutyrate

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