DE19735574A1 - New 3-hydroxy-5-oxo-hexanoic acid derivatives - Google Patents

New 3-hydroxy-5-oxo-hexanoic acid derivatives

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Publication number
DE19735574A1
DE19735574A1 DE19735574A DE19735574A DE19735574A1 DE 19735574 A1 DE19735574 A1 DE 19735574A1 DE 19735574 A DE19735574 A DE 19735574A DE 19735574 A DE19735574 A DE 19735574A DE 19735574 A1 DE19735574 A1 DE 19735574A1
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Germany
Prior art keywords
hydrogen
alkyl
aralkyl
aryl
aldehyde
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Withdrawn
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DE19735574A
Other languages
German (de)
Inventor
Ulrich Dr Klar
Wolfgang Dr Schwede
Werner Dr Skuballa
Bernd Dr Buchmann
Michael Dr Schirner
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
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Schering AG
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Publication date
Application filed by Schering AG filed Critical Schering AG
Priority to DE19735574A priority Critical patent/DE19735574A1/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 DK98946309T priority patent/DK1005465T3/en
Priority to DE59814067T priority patent/DE59814067D1/en
Priority to AU93409/98A priority patent/AU9340998A/en
Priority to US09/485,292 priority patent/US7407975B2/en
Priority to PT98946309T priority patent/PT1005465E/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 DE19735574A1 publication Critical patent/DE19735574A1/en
Priority to US12/178,039 priority patent/US20090018342A1/en
Withdrawn legal-status Critical Current

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Abstract

3-Hydroxy-5-oxo-hexanoic acid or -hexanal derivatives of formula (I) are new. R1 = H, OH or OR7; R7 = 1-20C alkyl, aryl or 7-10C aralkyl; R2 = H or protecting group; R3,R4 = H, 1-10C alkyl or 7-10C aralkyl; or R3 +R4 = (CH2)m; m = 2-6; R5,R6 = H, 1-10C alkyl, aryl or 7-20C aralkyl; provided that R1 in not OH if R2 = tert. butyl dimethylsilyl, R3-R5 = Me and R6 = H. A multi-stage process for preparing compounds (I; R3,R4 = Me), in which the above proviso does not apply, is claimed.

Description

Die Erfindung betrifft den in den Patentansprüchen gekennzeichneten Gegenstand, daß heißt neue [C-1(Carboxy)-C-6]-Fragmente, Verfahren zu 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 [C-1 (carboxy) -C-6] fragments, process for their preparation 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)
By Höfle et al. 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-Selektivi­ tät gegenüber Brust- und Darmzelllinien und ihrer im Vergleich zu Taxol deutlich hö­ heren 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 compared to breast and intestinal cell lines and their significantly higher compared to taxol activity against P-glycoprotein-forming, multi-resistant tumor lines and their This structure class appears for the development of a physical properties Drug particularly interesting.

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,

von Nicolaou et al. beschrieben. Die Stereochemie am C3 wird durch die Reation mit dem Browns Reagenz Allylisopinocamphenylboran (+)-Ipc2B(allyl) gesteuert.by Nicolaou et al. described. The stereochemistry at C3 is controlled by the reaction with the Browns reagent allyl isopinocamphenylborane (+) - Ipc 2 B (allyl).

Für eine industriell verwertbare Synthese ist es von Vorteil, wenn die Synthese ohne teure chirale Auxiliare durchgeführt werden kann.For an industrially usable synthesis, it is advantageous if the synthesis without expensive chiral auxiliaries can be performed.

Es bestand daher die Aufgabe, eine geeignete Synthese zu finden, die ohne teure chirale Auxiliare durchgeführt werden kann.The task was therefore to find a suitable synthesis without expensive chiral Auxiliary can be done.

Es wurde nun gefunden, daß die Verbindung (Ia) ohne Verwendung von chiralen Auxiliaren aus dem in großen Mengen verfügbaren Pantolacton hergestellt werden kann.It has now been found that compound (Ia) can be used without chiral Auxiliaries can be made from the pantolactone available in large quantities.

Somit betrifft die Erfindung ein Verfahren zur Herstellung von Verbindungen der all­ gemeinen Formel (Ia)
The invention thus relates to a process for the preparation of compounds of the general formula (Ia)

worin R1 Wasserstoff, OH, OR7
R7 C1-C20-Alkyl, Aryl oder C7-C10-Aralkyl, bedeutet,
R2 Wasserstoff oder eine geeignete Schutzgruppe,
R5 Wasserstoff, C1-C10-Alkyl, Aryl oder C7-C20-Aralkyl und
R6 Wasserstoff, C1-C10-Alkyl, Aryl oder C7-C20-Aralkyl
bedeuten und die Konfiguration am C3 (R), (S) oder ein Gemisch aus beiden sein kann, je nachdem welches Pantolacton oder Pantolacton-Gemisch für das Verfahren eingesetzt wird,
dadurch gekennzeichnet, daß
in einem Schritt 1
wherein R 1 is hydrogen, OH, OR 7
R 7 is C 1 -C 20 alkyl, aryl or C 7 -C 10 aralkyl,
R 2 is hydrogen or a suitable protective group,
R 5 is hydrogen, C 1 -C 10 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 and the configuration at C3 (R), (S) or a mixture of both can be, depending on which pantolactone or pantolactone mixture is used for the process,
characterized in that
in a step 1

die freie Hydroxygruppe des Pantolactons (II) unter wasserfreien Bedingungen mit 3,4-Dihydro-2H-pyran/p-Toluolsulfonsäure-Pyridiniumsalz (a) in den Tetrahydropyranylether (III) oder mit einem entsprechenden Reagenz in eine andere geeignete Schutzgruppe R2 überführt und das Lacton bei -70°C mit Diisobutylaluminiunihydrid (b) zum Lactol (IV) reduziert wird,
in einem Schritt 2
the free hydroxyl group of pantolactone (II) is converted under anhydrous conditions with 3,4-dihydro-2H-pyran / p-toluenesulfonic acid pyridinium salt (a) into the tetrahydropyranyl ether (III) or with a corresponding reagent into another suitable protective group R 2 and the lactone is reduced to -lactol (IV) at -70 ° C. with diisobutylaluminium unihydride (b),
in a step 2

das Lactol (IV) mit Methyltriphenylphosphoniumbromid/Butyllithium (c) geöffnet und gleichzeitig Wasser eliminiert wird zur offenkettigen Verbindung (V),
in einem Schritt 3
the lactol (IV) is opened with methyltriphenylphosphonium bromide / butyllithium (c) and at the same time water is eliminated to give the open-chain compound (V),
in a step 3

der primäre Alkohol mit Oxalylchlorid/Dimethylsulfoxid in Dichlormethan (d) zum Aldehyd (VI) oxidiert wird und der Aldehyd (VI) mit einer Organometallverbindung der Formel
the primary alcohol is oxidized with oxalyl chloride / dimethyl sulfoxide in dichloromethane (d) to the aldehyde (VI) and the aldehyde (VI) with an organometallic compound of the formula

R5CH2Y (e)
R 5 CH 2 Y (e)

worin Y Lithium oder MgX,
X Chlor, Brom oder Iod sein kann, und
R5 Wasserstoff, C1-C10-Alkyl, Aryl oder C7-C20-Aralkyl bedeutet,
umgesetzt wird, und
entweder
in einem Schritt 4
where Y is lithium or MgX,
X can be chlorine, bromine or iodine, and
R 5 denotes hydrogen, C 1 -C 10 alkyl, aryl or C 7 -C 20 aralkyl,
is implemented, and
either
in a step 4

der geschützte Allylalkohol einer Hydroborierung unter üblichen Bedingungen unterwor­ fen wird und beide Hydroxygruppen mit N-Methylmorphohno-N-Oxid/Tetrapropyl­ animoniumperruthenat oxidiert werden, und
in einem Schritt 5
the protected allyl alcohol is subjected to hydroboration under normal conditions and both hydroxyl groups are oxidized with N-methylmorphohno-N-oxide / tetrapropylammonium perruthenate, and
in a step 5

der gegebenenfalls aus Schritt 4 erhaltene Aldehyd noch zur Säure (X) oxidiert wird und gegebenenfalls die Säure verestert wird,
oder
in einem Schritt 4a
the aldehyde optionally obtained from step 4 is also oxidized to the acid (X) and the acid is optionally esterified,
or
in a step 4a

zuerst die Hydroxyfunktion oxidiert wird, dann mit Lithiumdiisopropylamid/R6Z
wobei R6 C1-C10-Alkyl, Aryl oder C7-C20-Aralkyl und
Z eine geeignete Abgangsgruppe bedeutet,
alkyliert wird, und dann wie in Schritt 4 die Hydroborierung (f) und die Oxidation (g) durchgeführt wird zum Aldehyd und gegebenenfalls der erhaltene Aldehyd (IXa) wie in Schritt 5 beschrieben oxidiert wird, und die Verbindungen der Formel (Ia)
the hydroxy function is first oxidized, then with lithium diisopropylamide / R 6 Z
wherein R 6 is C 1 -C 10 alkyl, aryl or C 7 -C 20 aralkyl and
Z represents a suitable leaving group,
is alkylated, and then, as in step 4, the hydroboration (f) and the oxidation (g) is carried out to the aldehyde and optionally the aldehyde (IXa) obtained is oxidized as described in step 5, and the compounds of the formula (Ia)

erhalten werden, die gegebenenfalls verestert werden können.are obtained, which can optionally be esterified.

Als Alkoholteile im Ester sind neben den oben erwähnten Estern auch zum Beispiel die Verbindungen der Formeln A, B oder C
In addition to the esters mentioned above, the alcohol parts in the ester include, for example, the compounds of the formulas A, B or C.

von Schinzer et al., Nicolaou et al. und Danishefsky et al. geeignet, die als Baustein für die Epothilonsynthese verwendet werden können und über die Hydroxygruppe mit der Carbonsäure der Formel Ia verestert werden können.by Schinzer et al., Nicolaou et al. and Danishefsky et al. suitable as a building block for the epothilone synthesis can be used and via the hydroxy group with the Carboxylic acid of the formula Ia can be esterified.

Eine geeignete Abgangsgruppe Z kann ein Halogenatom, p-Toluolsulfonat, oder die Gruppe -OSO2B sein, wobei B für C1-C4-Alkyl oder C1-C4-Perfluoralkyl steht.A suitable leaving group Z can be a halogen atom, p-toluenesulfonate, or the group -OSO 2 B, where B is C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl.

Ein Halogenatom kann Fluor, Chlor, Brom oder Iod sein, wobei Brom und Iod als gute Abgangsgruppen bevorzugt werden.A halogen atom can be fluorine, chlorine, bromine or iodine, with bromine and iodine being good Leaving groups are preferred.

Unter C1-C4-Perfluoralkyl sind geradkettige oder verzweigte vollständig fluorierte Al­ kylreste wie zum Beispiel CF3, C2F5, C3F7, C4F9 zu verstehen.C 1 -C 4 perfluoroalkyl is to be understood as straight-chain or branched, completely fluorinated alkyl radicals such as, for example, CF 3 , C 2 F 5 , C 3 F 7 , C 4 F 9 .

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

worin R1 Wasserstoff, OH, OR7 wobei
R7 C1-C20-Alkyl, Aryl oder C7-C10-Aralkyl, bedeutet,
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-C10-Alkyl, Aryl oder C7-C20-Aralkyl und
R6 Wasserstoff, C1-C10-Alkyl, Aryl oder C7-C20-Aralkyl bedeuten
wobei nicht R1 = OH sein darf, wenn R2 = tert.Butyldimethylsilyl, R3 = R4 = Methyl, R5 = Methyl und R6 = Wasserstoff sind,
und ihre Verwendung zur Synthese von Epothilon oder Epothilonderivaten. wherein R 1 is hydrogen, OH, OR 7 wherein
R 7 is C 1 -C 20 alkyl, aryl or C 7 -C 10 aralkyl,
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 10 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
where R 1 = OH must not be if R 2 = tert-butyldimethylsilyl, R 3 = R 4 = methyl, R 5 = methyl and R 6 = hydrogen,
and their use in the synthesis of epothilone or epothilone derivatives.

Der Disclaimer schließt die bereits von Nicolaou et al. beschriebene Struktur aus.The disclaimer excludes those already published by Nicolaou et al. described structure.

Als Alkylgruppen R3, R4, R5, und R6 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, De­ cyl.As alkyl groups R 3 , R 4 , R 5 and R 6 straight or branched chain alkyl groups with 1-10 carbon atoms are to be considered, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl , Neopentyl, heptyl, hexyl, decyl.

Als Alkylgruppen R7 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 7 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.

Die geeignete Schutzgruppe R2 kann zum Beispiel ein Ether oder Acylrest sein. Als Ether- und Acylreste kommen die dem Fachmann bekannten Reste in Betracht. Bevor­ zugt sind leicht abspaltbare Etherreste, wie beispielsweise der Methoxymethyl-, Tetrahydropyranyl-, Tetrahydrofuranyl-, Tri-isopropyl- oder Trimethylsilyl-, tert.- Butyldimethylsilyl-, tert.-Butyldiphenylsilyl-, Tribenzylsilylrest. Als Acylreste kommen z. B. Acetyl, Propionyl, Butyryl, Benzoyl, eine durch z. B. Amino- und/oder Hydroxygruppen substituierte Alkanoylgruppe oder auch die Benzyl- und p-Nitobenzylgruppen in Frage.The suitable protective group R 2 can be, for example, an ether or acyl radical. The radicals known to the person skilled in the art are suitable as ether and acyl radicals. Preference is given to easily removable ether residues, such as, for example, the methoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, tri-isopropyl or trimethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilyl, tribenzylsilyl residue. As acyl residues come e.g. B. acetyl, propionyl, butyryl, benzoyl, one by z. B. amino and / or hydroxy-substituted alkanoyl group or the benzyl and p-nitobenzyl groups in question.

Als Arylrest R5, R6 und R7 kommen substituierte und unsubstituierte carbocyclische oder heterocyclische Reste wie z. B. Phenyl, Naphtyl, Furyl, Thienyl, Thiazolyl-, Pyridyl, Pyrazolyl, Pyrimidinyl, Oxazolyl, Pyridazinyl, Pyrazinyl, Chinolyl, die mehrfach substituiert sein können durch Halogen, -NO2, -N3, -CN, -NH2, -COOH, -COOR, -OH, Alkyl, C1-C20-Acyl, C1-C20-Acyloxy-Gruppen, in Frage.Aryl radicals R 5 , R 6 and R 7 are substituted and unsubstituted carbocyclic or heterocyclic radicals such as, for. B. phenyl, naphthyl, furyl, thienyl, thiazolyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, which can be substituted several times by halogen, -NO 2 , -N 3 , -CN, -NH 2 , -COOH, -COOR, -OH, alkyl, C 1 -C 20 acyl, C 1 -C 20 acyloxy groups, in question.

Die Aralkylgruppen in R3, R4, R5, R6 und R7 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. Als Epothilonderivate sind alle offenkettigen cyclischen, makroliden oder auch nicht makroliden, zusätzlich substituierten oder nicht substituierten Strukturen zu verstehen, die sich von Epothilon ableiten lassen.The aralkyl groups in R 3 , R 4 , R 5 , R 6 and R 7 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. Epothilone derivatives are to be understood as all open-chain cyclic, macrolide or also non-macrolide, additionally substituted or unsubstituted structures which can be derived from epothilone.

In zu den Beispielen 8-8e analoger Weise sind die Verbindungen der allgemeinen Formel I mit R3, R4 in der Bedeutung von gemeinsam einer (CH2)m-Gruppe mit m = 2 bis 6, darstellbar. In a manner analogous to Examples 8-8e, the compounds of the general formula I with R 3 , R 4 can be represented together by a (CH 2 ) m group with m = 2 to 6.

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)-1-Oxa-2-oxo-3-(tetrahydropyran-2(RS)-yloxy)-4,4-dimethyl-cyclopentan(3S) -1-Oxa-2-oxo-3- (tetrahydropyran-2 (RS) -yloxy) -4,4-dimethyl-cyclopentane

Die Lösung von 74,1 g (569 mmol) D-(-)-Pantolacton in 1 l wasserfreiem Dichlormethan versetzt man unter einer Atmosphäre aus trockenem Argon mit 102 ml 3,4-Dihydro-2H- pyran, 2 g p-Toluolsulfonsäure-Pyridiniumsalz und rührt 16 Stunden bei 23°C. Man gießt in eine gesättigte Natriumhydrogencarbonatlösung, trennt die organische Phase ab und trocknet über Natriumsulfat. Nach Filtration und Lösungsmittelabzug chromatographiert man den Rückstand an ca. 5 kg feinem Kieselgel mit einem Gemisch aus n-Hexan und Ethylacetat. Isoliert werden 119,6 g (558 mmol, 98%) der Titelverbindung als farbloses Öl.
1H-NMR (CDCl3): δ = 1,13 (3H), 1,22 (3H), 1,46-1,91 (6H), 3,50-3,61 (1H), 3,86 (1H), 3,92 (1H), 4,01 (1H), 4,16 (1H), 5,16 (1H) ppm.The solution of 74.1 g (569 mmol) of D - (-) - pantolactone in 1 l of anhydrous dichloromethane is mixed with 102 ml of 3,4-dihydro-2H-pyran, 2 g of p-toluenesulfonic acid under an atmosphere of dry argon. Pyridinium salt and stirred at 23 ° C for 16 hours. It is poured into a saturated sodium bicarbonate solution, the organic phase is separated off and dried over sodium sulfate. After filtration and removal of the solvent, the residue is chromatographed on about 5 kg of fine silica gel with a mixture of n-hexane and ethyl acetate. 119.6 g (558 mmol, 98%) of the title compound are isolated as a colorless oil.
1 H NMR (CDCl 3 ): δ = 1.13 (3H), 1.22 (3H), 1.46-1.91 (6H), 3.50-3.61 (1H), 3.86 (1H), 3.92 (1H), 4.01 (1H), 4.16 (1H), 5.16 (1H) ppm.

Beispiel 2Example 2 (2RS,3S)-1-Oxa-2-hydroxy-3-(tetrahydropyran-2(RS)-yloxy)-4,4-dimethyl-cyclo­ pentan(2RS, 3S) -1-oxa-2-hydroxy-3- (tetrahydropyran-2 (RS) -yloxy) -4,4-dimethyl-cyclo pentane

Die Lösung von 117,5 g (548 mmol) der nach Beispiel 1 dargestellten Verbindung in 2,4 l wasserfreiem Toluol kühlt man unter einer Atmosphäre aus trockenem Argon auf -70°C, versetzt innerhalb 1 Stunde mit 540 ml einer 1,2 molaren Lösung von Diisobutyl­ aluminiumhydrid in Toluol und rührt noch 3 Stunden bei -70°C. Man läßt auf -20°C erwärmen, versetzt mit gesättigter Ammoniumchloridlösung, Wasser und trennt die aus­ gefallenen Aluminiumsalze durch Filtration über Celite ab. Das Filtrat wird mit Wasser und gesättigter Natriumchloridlösung gewaschen und über Magnesiumsulfat getrocknet. Isoliert werden nach Filtration und Lösungsmittelabzug 111,4 g (515 mmol, 94%) der Titelverbindung als farbloses Öl, das man ohne Reinigung weiter umsetzt.
IR (CHCl3): 3480, 3013, 2950, 2874, 1262, 1133, 1074, 1026 und 808 cm-1. The solution of 117.5 g (548 mmol) of the compound shown in Example 1 in 2.4 l of anhydrous toluene is cooled to -70 ° C. under an atmosphere of dry argon, and 540 ml of a 1.2 molar mixture are added within 1 hour Solution of diisobutyl aluminum hydride in toluene and stirred for a further 3 hours at -70 ° C. The mixture is allowed to warm to -20 ° C., mixed with saturated ammonium chloride solution, water and the aluminum salts which have precipitated are separated off by filtration through Celite. The filtrate is washed with water and saturated sodium chloride solution and dried over magnesium sulfate. After filtration and removal of solvent, 111.4 g (515 mmol, 94%) of the title compound are isolated as a colorless oil, which is reacted further without purification.
IR (CHCl 3 ): 3480, 3013, 2950, 2874, 1262, 1133, 1074, 1026 and 808 cm -1 .

Beispiel 3Example 3 (3S)-2,2-Dimethyl-3-(tetrahydropyran-2(R)-yloxy)-pent-4-en-1-ol und (3S)-2,2-Di­ methyl-3-(tetrahydropyran-2(S)-yloxy)-pent-4-en-1-ol(3S) -2,2-dimethyl-3- (tetrahydropyran-2 (R) -yloxy) pent-4-en-1-ol and (3S) -2,2-di methyl-3- (tetrahydropyran-2 (S) -yloxy) -pent-4-en-1-ol

Die Aufschlämmung von 295 g Methyl-triphenylphosphoniumbromid in 2,5 l wasser­ freiem Tetrahydrofuran versetzt man unter einer Atmosphäre aus trockenem Argon bei -60°C mit 313 ml einer 2,4 molaren Lösung von n-Butyllithium in n-Hexan, läßt auf 23°C erwärmen, eine Stunde nachrühren und kühlt auf 0°C. Man versetzt mit der Lösung von 66,2 g (306 mmol) der nach Beispiel 2 dargestellten Verbindung in 250 ml Tetrahydrofuran, läßt auf 23°C erwärmen und 18 Stunden rühren. Man gießt in eine gesättigte Natriumhydrogencarbonatlösung, extrahiert mehrfach mit Dichlormethan und trocknet die vereinigten organischen Extrakte über Natriumsulfat. Nach Filtration und Lösungsmittelabzug chromatographiert man den Rückstand an ca. 5 l feinem Kieselgel mit einem Gradientensystem aus n-Hexan und Ethylacetat. Isoliert werden 36,5 g (170 mmol, 56%) des unpolaren, 14,4 g (67,3 mmol, 22%) des polaren THP-Isomeren der Titelverbindung, sowie 7,2 g (33,3 mmol; 11%) des Ausgangsmaterials jeweils als farbloses Öl.
1H-NMR (CDCl3), unpolares Isomer: δ = 0,78 (3H), 0,92 (3H), 1,41-1,58 (4H), 1,63- 1,87 (2H), 3,18 (1H), 3,41 (1H), 3,48 (1H), 3,68 (1H), 3,94 (1H), 4,00 (1H), 4,43 (1H), 5,19 (1H), 5,27 (1H), 5,75 (1H) ppm.
1H-NMR (CDCl3), polares Isomer: δ = 0,83 (3H), 0,93 (3H), 1,42-1,87 (6H), 2,76 (1H), 3,30 (1H), 3,45 (1H), 3,58 (1H), 3,83 (1H), 3,89 (1H), 4,65 (1H), 5,12-5,27 (2H), 5,92 (1H) ppm.The slurry of 295 g of methyl triphenylphosphonium bromide in 2.5 l of water-free tetrahydrofuran is admixed with 313 ml of a 2.4 molar solution of n-butyllithium in n-hexane under an atmosphere of dry argon at -60 ° C. Warm ° C, stir for an hour and cool to 0 ° C. A solution of 66.2 g (306 mmol) of the compound shown in Example 2 in 250 ml of tetrahydrofuran is added, and the mixture is allowed to warm to 23 ° C. and stir for 18 hours. It is poured into a saturated sodium bicarbonate solution, extracted several times with dichloromethane and the combined organic extracts are dried over sodium sulfate. After filtration and removal of solvent, the residue is chromatographed on about 5 l of fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 36.5 g (170 mmol, 56%) of the non-polar, 14.4 g (67.3 mmol, 22%) of the polar THP isomer of the title compound and 7.2 g (33.3 mmol; 11% ) of the starting material as a colorless oil.
1 H-NMR (CDCl 3 ), non-polar isomer: δ = 0.78 (3H), 0.92 (3H), 1.41-1.58 (4H), 1.63-1.87 (2H), 3.18 (1H), 3.41 (1H), 3.48 (1H), 3.68 (1H), 3.94 (1H), 4.00 (1H), 4.43 (1H), 5 , 19 (1H), 5.27 (1H), 5.75 (1H) ppm.
1 H-NMR (CDCl 3 ), polar isomer: δ = 0.83 (3H), 0.93 (3H), 1.42-1.87 (6H), 2.76 (1H), 3.30 ( 1H), 3.45 (1H), 3.58 (1H), 3.83 (1H), 3.89 (1H), 4.65 (1H), 5.12-5.27 (2H), 5 , 92 (1H) ppm.

Beispiel 4Example 4 (3S)-4,4-Dimethyl-5-oxo-3-(tetrahydropyran-2-yloxy)-pent-1-en(3S) -4,4-Dimethyl-5-oxo-3- (tetrahydropyran-2-yloxy) pent-1-ene

Die Lösung von 2,8 ml Oxalylchlorid in 125 ml wasserfreiem Dichlormethan kühlt man unter einer Atmosphäre aus trockenem Argon auf -70°C, versetzt mit 4,6 ml Dimethyl­ sulfoxid, der Lösung von 5,0 g (23,3 mmol) der nach Beispiel 3 dargestellten Verbindung in 125 ml wasserfreiem Dichlormethan und rührt 0,5 Stunden. Anschließend versetzt man mit 14,3 ml Triethylamin, läßt 1 Stunde bei -30°C reagieren und versetzt mit n-Hexan und gesättigter Natriumhydrogencarbonatlösung. Die organische Phase wird abgetrennt, die wäßrige noch mehrfach mit n-Hexan extrahiert, die vereinigten organischen Extrakte mit Wasser gewaschen und über Magnesiumsulfat getrocknet. Man isoliert nach Aufarbeitung 6,1 g der Titelverbindung als farbloses Öl, die man ohne Reinigung weiter umsetzt. The solution of 2.8 ml of oxalyl chloride in 125 ml of anhydrous dichloromethane is cooled under an atmosphere of dry argon to -70 ° C, mixed with 4.6 ml of dimethyl sulfoxide, the solution of 5.0 g (23.3 mmol) of the compound shown in Example 3 in 125 ml of anhydrous dichloromethane and stir for 0.5 hours. Then you move with 14.3 ml of triethylamine, allowed to react for 1 hour at -30 ° C and mixed with n-hexane and saturated sodium bicarbonate solution. The organic phase is separated off aqueous extracted several times with n-hexane, the combined organic extracts with Washed water and dried over magnesium sulfate. It is isolated after working up 6.1 g of the title compound as a colorless oil, which is reacted further without purification.  

Beispiel 5Example 5 (3S,5RS)-4,4-Dimethyl-5-hydroxy-3-(tetrahydropyran-2-yloxy)-hept-1-en(3S, 5RS) -4,4-dimethyl-5-hydroxy-3- (tetrahydropyran-2-yloxy) hept-1-ene

Die Lösung von 6,1 g (max. 23,3 mmol) der nach Beispiel 5 dargestellten Verbindung in 68 ml wasserfreiem Diethylether versetzt man unter einer Atmosphäre aus trockenem Argon bei 0°C mit 11,67 ml einer 2,4 molaren Lösung von Ethylmagnesiumbromid in Diethylether, läßt auf 23°C erwärmen und 16 Stunden rühren. Man versetzt mit gesättig­ ter Ammoniumchloridlösung, trennt die organische Phase ab und trocknet über Natrium­ sulfat. Den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand reinigt man durch Chromatographie an feinem Kieselgel mit einem Gradientensystem aus n-Hexan und Ethylacetat. Isoliert werden 1,59 g (6,56 mmol, 28%) des unpolaren Diastereomers sowie 1,67 g (6,89 mmol, 30%) des polaren Diastereomers jeweils als farbloses Öl.
1H-NMR (CDCl3) unpolares Isomer: δ = 0,79 (3H), 0,84 (3H), 1,03 (3H), 1,23-1,62 (6H), 1,62-1,88 (2H), 3,41-3,58 (2H), 3,88-4,01 (2H), 4,08 (1H), 4,47 (1H), 5,20 (1H), 5,29 (1H), 5,78 (1H) ppm.
1H-NMR (CDCl3) polares Isomer: δ = 0,78 (3H), 0,93 (3H), 1,01 (3H), 1,38 (1H), 1,47- 1,85 (7H), 3,39-3,57 (3H), 3,90 (1H), 4,04 (1H), 4,62 (1H), 5,21 (1H), 5,32 (1H), 5,69 (1H) ppm.The solution of 6.1 g (max. 23.3 mmol) of the compound shown in Example 5 in 68 ml of anhydrous diethyl ether is mixed with 11.67 ml of a 2.4 molar solution of in an atmosphere of dry argon at 0 ° C. Ethylmagnesiumbromid in diethyl ether, allowed to warm to 23 ° C and stir for 16 hours. Saturated ammonium chloride solution is added, the organic phase is separated off 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. 1.59 g (6.56 mmol, 28%) of the non-polar diastereomer and 1.67 g (6.89 mmol, 30%) of the polar diastereomer are isolated in each case as a colorless oil.
1 H NMR (CDCl 3 ) non-polar isomer: δ = 0.79 (3H), 0.84 (3H), 1.03 (3H), 1.23-1.62 (6H), 1.62-1 , 88 (2H), 3.41-3.58 (2H), 3.88-4.01 (2H), 4.08 (1H), 4.47 (1H), 5.20 (1H), 5th , 29 (1H), 5.78 (1H) ppm.
1 H NMR (CDCl 3 ) polar isomer: δ = 0.78 (3H), 0.93 (3H), 1.01 (3H), 1.38 (1H), 1.47-1.85 (7H ), 3.39-3.57 (3H), 3.90 (1H), 4.04 (1H), 4.62 (1H), 5.21 (1H), 5.32 (1H), 5, 69 (1H) ppm.

Beispiel 6Example 6 Beispiel 7bExample 7b (3S,5S)-4,4-Dimethyl-3-(tetrahydropyran-2-yloxy)-heptan-1,5-diol und/oder (3S,5R)-4,4-Dimethyl-3-(tetrahydropyran-2-yloxy)-heptan-1,5-diol(3S, 5S) -4,4-dimethyl-3- (tetrahydropyran-2-yloxy) -heptan-1,5-diol and / or (3S, 5R) -4,4-dimethyl-3- (tetrahydropyran-2-yloxy) -heptan-1,5-diol

Die Lösung von 1,67 g (6,89 mmol) bzw. 1,59 g (6,56 mmol) des nach Beispiel 5 dar­ gestellten polaren bzw. unpolaren Alkohols in 83 ml bzw. 79 ml Tetrahydrofuran versetzt man unter einer Atmosphäre aus trockenem Argon bei 23°C mit 13,2 ml bzw. mit 12,6 ml einer 1 molaren Lösung von Boran in Tetrahydrofuran und läßt 1 Stunde reagieren. Anschließend versetzt man unter Eiskühlung mit 16,5 ml bzw. mit 15,7 ml einer 5%-igen Natronlauge sowie 8,3 ml bzw. 7,8 ml einer 30%-igen Wasserstoffper­ oxidlösung und rührt weitere 30 Minuten. Man gießt in Wasser, extrahiert mehrfach mit Ethylacetat, wäscht die vereinigten organischen Extrakte mit Wasser, gesättigter Natri­ umchloridlösung und trocknet über Magnesiumsulfat. Den nach Filtration und Lö­ sungsmittelabzug erhaltenen Rückstand reinigt man durch Chromatographie an feinem Kieselgel mit einem Gradientensystem aus n-Hexan und Ethylacetat. Isoliert werden 1,14 g (4,38 mmol, 67%) der Titelverbindungen jeweils als farbloses Öl.
1H-NMR (CDCl3) polares Isomer: δ = 0,78 (6H), 1,01 (3H), 1,28 (1H), 1,36-1,64 (6H), 1,64-1,94 (4H), 3,41-3,55 (2H), 3,60-3,82 (2H), 3,87 (1H), 3,99 (1H), 4,28 (1H), 4,56 (1H) ppm.The solution of 1.67 g (6.89 mmol) or 1.59 g (6.56 mmol) of the polar or non-polar alcohol prepared according to Example 5 in 83 ml or 79 ml of tetrahydrofuran is added under an atmosphere dry argon at 23 ° C with 13.2 ml or 12.6 ml of a 1 molar solution of borane in tetrahydrofuran and allowed to react for 1 hour. 16.5 ml or 15.7 ml of a 5% sodium hydroxide solution and 8.3 ml or 7.8 ml of a 30% hydrogen peroxide solution are then added while cooling with ice and the mixture is stirred for a further 30 minutes. It is poured into water, extracted several times with ethyl acetate, the combined organic extracts are washed with water, saturated sodium chloride solution and dried over magnesium 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. 1.14 g (4.38 mmol, 67%) of the title compounds are isolated in each case as a colorless oil.
1 H NMR (CDCl 3 ) polar isomer: δ = 0.78 (6H), 1.01 (3H), 1.28 (1H), 1.36-1.64 (6H), 1.64-1 , 94 (4H), 3.41-3.55 (2H), 3.60-3.82 (2H), 3.87 (1H), 3.99 (1H), 4.28 (1H), 4th , 56 (1H) ppm.

Beispiel 7Example 7 Beispiel 7a (3S)-4,4-Dimethyl-5-oxo-3-(tetrahydropyran-2-yloxy)-heptanalExample 7a (3S) -4,4-Dimethyl-5-oxo-3- (tetrahydropyran-2-yloxy) heptanal

Die Lösung von 100 mg (0,38 mmol) eines Gemisches der nach Beispiel 6 dargestellten Verbindungen in 6,2 ml wasserfreiem Dichlormethan versetzt man mit Molekularsieb (4A, ca. 80 Kugeln), 66,7 mg N-Methylmorpholino-N-oxid, 6,7 mg Tetrapropylammo­ niumperruthenat und rührt 16 Stunden bei 23°C unter einer Atmosphäre aus trockenem Argon. Man engt ein und reinigt das erhaltene Rohprodukt durch Chromatographie an ca. 200 ml feinem Kieselgel mit einem Gradientensystem aus n-Hexan und Ethylacetat.The solution of 100 mg (0.38 mmol) of a mixture of that shown in Example 6 Molecular sieve is added to compounds in 6.2 ml of anhydrous dichloromethane (4A, approx. 80 balls), 66.7 mg N-methylmorpholino-N-oxide, 6.7 mg tetrapropylammo nium perruthenate and stir for 16 hours at 23 ° C under an atmosphere of dry Argon. The mixture is concentrated and the crude product obtained is purified by chromatography on approx. 200 ml of fine silica gel with a gradient system consisting of n-hexane and ethyl acetate.

Beispiel 8Example 8 (S)-3-[1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutyl]-3-[(tetrahydro- 2H-pyran-2-yl)oxy]propansäure(S) -3- [1 - [[[dimethyl (1,1-dimethylethyl) silyl] oxy] methyl] cyclobutyl] -3 - [(tetrahydro- 2H-pyran-2-yl) oxy] propanoic acid

420 mg (3,75 mmol) Kaliumtert.butylat werden in 5 ml Diethylether suspendiert. Man addiert 16 µl Wasser und läßt 5 Minuten nachrühren. Anschließend wird eine Lösung von 398 mg (0,75 mmol) 8a in 5 ml Diethylether addiert. Man läßt 3 Stunden nachrühren. Danach wird die Reaktionslösung mit Wasser verdünnt und mit 10%iger Salzsäure neutralisiert. Man extrahiert mit Dichlormethan, wäscht die organische Phase mit gesät­ tigter wäßriger Natriumchloridlösung, trocknet über Natriumsulfat und engt im Vakuum ein. Säulenchromatographie des Rohprodukts an Kieselgel mit einem Gemisch aus Hexan/Ethylacetat ergibt 112 mg (0,3 mmol).
1H-NMR (CDCl3): δ = 0,01 (6H), 0,90 (9H), 1,30-2,25 (10H), 3,12 (1H), 3,50 (2H), 3,58 (1H), 3,98 (1H), 4,45 (1H) ppm.420 mg (3.75 mmol) of potassium tert-butoxide are suspended in 5 ml of diethyl ether. 16 μl of water are added and the mixture is stirred for 5 minutes. A solution of 398 mg (0.75 mmol) 8a in 5 ml diethyl ether is then added. The mixture is stirred for 3 hours. The reaction solution is then diluted with water and neutralized with 10% hydrochloric acid. It is extracted with dichloromethane, the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate gives 112 mg (0.3 mmol).
1 H-NMR (CDCl 3 ): δ = 0.01 (6H), 0.90 (9H), 1.30-2.25 (10H), 3.12 (1H), 3.50 (2H), 3.58 (1H), 3.98 (1H), 4.45 (1H) ppm.

Das Reaktionsprodukt kann nach Spaltung der Silylschutzgruppe durch Oxidation analog zu Beispiel 4 in den Aldehyd überführt, analog zu Beispiel 5 mit einer Grignardver­ bindung, beispielsweise mit Ethylmagnesiumbromid, zur Reaktion gebracht und durch anschließende Oxidation des erhaltenen Alkohols analog zu Beispiel 7 in eine Verbindung gemäß Anspruch 1 überführt werden, beispielsweise in (s)-3-[1-[1- Oxopropyl]cyclobutyl]-3-[(tetrahydro-2H-pyran-2-yl)oxy]propansäure.After cleavage of the silyl protective group by oxidation, the reaction product can be analogous converted to Example 4 in the aldehyde, analogously to Example 5 with a Grignardver bond, for example with ethyl magnesium bromide, brought to reaction and through subsequent oxidation of the alcohol obtained analogously to Example 7 into a compound transferred according to claim 1, for example in (s) -3- [1- [1- Oxopropyl] cyclobutyl] -3 - [(tetrahydro-2H-pyran-2-yl) oxy] propanoic acid.

Analog können folgende Verbindungen erhalten werden: The following compounds can be obtained analogously:  

Beispiel 8aExample 8a [1R-[1α(3S*),2β]]-2-Phenylcyclohexyl 3-[1-[[[dimethyl(1,1-dimethylethyl)silyl]­ oxy]methyl]cyclobutyl]-3-[(tetrahydro-2H-pyran-2-yl)oxy]propanoat[1R- [1α (3S *), 2β]] - 2-phenylcyclohexyl 3- [1 - [[[dimethyl (1,1-dimethylethyl) silyl] oxy] methyl] cyclobutyl] -3 - [(tetrahydro-2H-pyran-2-yl) oxy] propanoate

In Analogie zu Beispiel 1 setzt man 460 mg (1,03 mmol) der nach Beispiel 8b darge­ stellten Verbindung um und isoliert nach Aufarbeitung und Reinigung 398 mg (0,75 mmol, 73%) der Titelverbindung als farbloses Öl.
1H-NMR (CDCl3): δ = 0,01 (6H), 0,89 (9H), 1,24-1,97 (19H), 2,15-2,27 (3H), 2,66 (1H), 3,12 (1H), 3,50 (2H), 3,58 (1H), 3,98 (1H), 4,52 (1H), 4,87 (1H), 7,09-7,27 (5H) ppm.Analogously to Example 1, 460 mg (1.03 mmol) of the compound shown in Example 8b are reacted and, after workup and purification, 398 mg (0.75 mmol, 73%) of the title compound are isolated as a colorless oil.
1 H NMR (CDCl 3 ): δ = 0.01 (6H), 0.89 (9H), 1.24-1.97 (19H), 2.15-2.27 (3H), 2.66 (1H), 3.12 (1H), 3.50 (2H), 3.58 (1H), 3.98 (1H), 4.52 (1H), 4.87 (1H), 7.09- 7.27 (5H) ppm.

Beispiel 8bExample 8b [1R-[1a(R*),2b]]-2-Phenylcyclohexyl 3-[1-[[[dimethyl(1,1-dimethylethyl)silyl]­ oxy]methyl]cyclobutyl]-3-hydroxypropanoat (A) und [1R-[1a(S*),2b]]-2-Phenylcyclohexyl 3-[1-[[[dimethyl(1,1-dimethylethyl)silyl]­ oxy]methyl]cyclobutyl]-3-hydroxypropanoat (B)[1R- [1a (R *), 2b]] - 2-phenylcyclohexyl 3- [1 - [[[dimethyl (1,1-dimethylethyl) silyl] oxy] methyl] cyclobutyl] -3-hydroxypropanoate (A) and [1R- [1a (S *), 2b]] - 2-phenylcyclohexyl 3- [1 - [[[dimethyl (1,1-dimethylethyl) silyl] oxy] methyl] cyclobutyl] -3-hydroxypropanoate (B)

Aus 7,2 ml Diisopropylamin und Butyllithium (32 ml einer 1,6 molaren Lösung in Hexan) wird in absolutem Tetrahydrofuran Lithiumdiisopropylamid hergestellt. Dann addiert man bei -78°C eine Lösung von 11,2 g (1R-trans)-2-Phenylcyclohexyl acetat in 100 ml absolutem Tetrahydrofuran und läßt 30 Minuten bei dieser Temperatur nachrühren. Anschließend wird eine Lösung von 7,7 g (33,7 mmol) der nach Beispiel 8c dargestellten Verbindung in 50 ml Tetrahydrofuran addiert. Man läßt 1,5 Stunden bei -78°C nachrühren und gießt danach das Reaktionsgemisch auf gesättigte wäßrige Ammonium­ chloridlösung. Man extrahiert mit Ethylacetat, wäscht die organische Phase mit gesättig­ ter Natriumchloridlösung, trocknet über Natriumsulfat und engt im Vakuum ein. Nach Säulenchromatographie des Rohprodukts an Kieselgel mit einem Gemisch aus Hexan/Ethylacetat erhält man 6,34 g (14,2 mmol, 42%) der Titelverbindung A und 4,22 g (9,4 mmol, 28%) der Titelverbindung B.
1H-NMR (CDCl3) von A: δ = 0,04 (6H), 0,98 (9H), 2,69 (1H), 3,08 (1H), 3,60 (1H), 3,67 (1H), 3,78-3,84 (1H), 4,97 (1H), 7,15-7,30 (5H) ppm.
1H-NMR (CDCl3) von B: δ = 0,03 (6H) 0,90 (9H), 2,68 (1H), 2,80 (1H), 3,56 (2H), 3,68-3,72 (1H), 4,99 (1H), 7,18-7,30 m (5H) ppm. Lithium diisopropylamide is made from 7.2 ml diisopropylamine and butyllithium (32 ml of a 1.6 molar solution in hexane) in absolute tetrahydrofuran. A solution of 11.2 g of (1R-trans) -2-phenylcyclohexyl acetate in 100 ml of absolute tetrahydrofuran is then added at -78 ° C. and stirring is continued for 30 minutes at this temperature. A solution of 7.7 g (33.7 mmol) of the compound shown in Example 8c in 50 ml of tetrahydrofuran is then added. The mixture is stirred at -78 ° C for 1.5 hours and then poured the reaction mixture 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. Column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate gives 6.34 g (14.2 mmol, 42%) of the title compound A and 4.22 g (9.4 mmol, 28%) of the title compound B.
1 H NMR (CDCl 3 ) of A: δ = 0.04 (6H), 0.98 (9H), 2.69 (1H), 3.08 (1H), 3.60 (1H), 3, 67 (1H), 3.78-3.84 (1H), 4.97 (1H), 7.15-7.30 (5H) ppm.
1 H NMR (CDCl 3 ) of B: δ = 0.03 (6H) 0.90 (9H), 2.68 (1H), 2.80 (1H), 3.56 (2H), 3.68 -3.72 (1H), 4.99 (1H), 7.18-7.30 m (5H) ppm.

Beispiel 8cExample 8c 1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutancarbaldehyd1 - [[[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 (58,6 mmol) der nach Beispiel 8d dargestellten Verbindung in 80 ml Dichlormethan. Nach weiteren 15 Minuten Nachrührzeit werden 58 ml Triethylamin hinzugetropft. Anschließend läßt man auf 0°C erwärmen. Dann wird das Reaktionsge­ misch auf gesättigte Natriumhydrogencarbonatlösung gegossen. Man extrahiert mit Dichlormethan, wäscht die organische Phase mit gesättigter Natriumchloridlösung, trocknet über Natriumsulfat und engt im Vakuum ein. Nach Chromatographie des Roh­ produkts an Kieselgel mit einem Gemisch aus Hexan/Ethylacetat erhält man 7,7 g (33,7 mmol, 58%) der Titelverbindung.
1H-NMR (CDCl3): δ = 9,70 s (1H), 3,83 s (2H), 2,20-2,30 m (2H), 1,85-2,00 m (4H), 0,90 s (9H), 0,03 s (6H) 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 (58.6 mmol) of the compound shown in Example 8d 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 (33.7 mmol, 58%) of the title compound are obtained.
1 H-NMR (CDCl 3 ): δ = 9.70 s (1H), 3.83 s (2H), 2.20-2.30 m (2H), 1.85-2.00 m (4H) , 0.90 s (9H), 0.03 s (6H) ppm.

Beispiel 8dExample 8d 1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutanmethanol1 - [[[Dimethyl (1,1-dimethylethyl) silyl] oxy] methyl] cyclobutanemethanol

Zu einer Suspension von 3,4 g Natriumhydrid (60%ig in Öl) in 35 ml absolutem Tetrahydrofuran wird bei 0°C eine Lösung von 9,9 g (85 mmol) der nach Beispiel 8e dargestellten Verbindung in 100 ml absolutem Tetrahydrofuran gegeben. Man läßt 30 Minuten nachrühren und addiert dann eine Lösung von 12,8 g tert.Butyldimethylsilylchlorid in 50 ml Tetrahydrofuran. Man läßt eine Stunde bei 25°C nachrühren und gießt dann das Reaktionsgemisch auf gesattigte waßrige Natriumhydro­ gencarbonatlösung. 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 Säulen­ chromatographie an Kieselgel mit einem Gemisch aus Hexan/Ethylacetat gereinigt. Man erhält 13,5 g (58,6 mmol, 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 (85 mmol) of the compound shown in Example 8e in 100 ml of absolute tetrahydrofuran is added to a suspension of 3.4 g of sodium hydride (60% strength in oil) in 35 ml of absolute tetrahydrofuran at 0.degree. The mixture is stirred for 30 minutes and then a solution of 12.8 g of tert-butyldimethylsilyl chloride 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 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 in vacuo, the crude product obtained is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 13.5 g (58.6 mmol, 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.

Beispiel 8eExample 8e 1,1-Cyclobutandimethanol1,1-cyclobutane dimethanol

Zu einer Lösung von 20 g (99,9 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 ad­ diert 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, 85,2 mmol, 85%) wird ohne Aufreinigung in die Folgestufe in Beispiel 8d eingesetzt.To a solution of 20 g (99.9 mmol) of 1,1-cyclobutanedicarboxylic acid diethyl ester in 200 ml of absolute tetrahydrofuran are 170 ml of a 1.2 molar solution of at 0 ° C Dropped diisobutylaluminum hydride. The mixture is stirred at 0 ° C for an hour and ad then doses 30 ml of water. It is filtered through Celite. The filtrate is mixed with sodium sulfate dried and concentrated in vacuo. The crude product obtained (9.9 g, 85.2 mmol, 85%) is used without purification in the next stage in Example 8d.

Analoge Beispiele zu 8-8eAnalogous examples to 8-8e

Setzt man in die Reaktionssequenz anstelle von 1,1-Cyclobutandicarbonsäurediethylester die homologen Cyclopropyl-, Cycylopentyl-, Cyclohexyl- oder Cycloheptylderivate ein und setzt diese weiter mit den betreffenden Grignard-Reagenzien um, werden die Derivate der Tabelle nach Beispiel 8 erhalten.Put in the reaction sequence instead of 1,1-cyclobutanedicarboxylic acid diethyl ester the homologous cyclopropyl, cycylopentyl, cyclohexyl or cycloheptyl derivatives and continues to implement them with the relevant Grignard reagents, the Derivatives of the table obtained in Example 8.

Claims (3)

1. Verbindungen der allgemeinen Formel (I)
worin R1 Wasserstoff, OH, oder OR7, wobei
R7 C1-C20-Alkyl, Aryl oder C7-C10-Aralkyl, bedeutet,
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-C10-Alkyl, Aryl oder C7-C20-Aralkyl und
R6 Wasserstoff, C1-C10-Alkyl, Aryl oder C7-C20-Aralkyl bedeuten,
wobei nicht R1 = OH sein darf, wenn R2 = tert.Butyldimethylsilyl, R3 = R4 = Methyl, R5 = Methyl und R6 = Wasserstoff sind.1. Compounds of the general formula (I)
wherein R 1 is hydrogen, OH, or OR 7 , wherein
R 7 is C 1 -C 20 alkyl, aryl or C 7 -C 10 aralkyl,
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 10 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,
where R 1 = OH must not be if R 2 = tert-butyldimethylsilyl, R 3 = R 4 = methyl, R 5 = methyl and R 6 = hydrogen. 2. Verfahren zur Herstellung von Verbindungen der allgemeinen Formel (Ia)
worin R1 Wasserstoff, OH, OR7, wobei
R7 C1-C20-Alkyl, Aryl oder C7-C10-Aralkyl, bedeutet,
R2 Wasserstoff oder eine geeignete Schutzgruppe,
R5 Wasserstoff, C1-C10-Alkyl, Aryl oder C7-C20-Aralkyl und
R6 Wasserstoff- C1-C10-Alkyl, Aryl oder C7-C20-Aralkyl
bedeuten und die Konfiguration am C3 (R),(S) oder ein Gemisch aus beiden sein kann, je nachdem, welches Pantolacton oder Pantolacton-Gemisch für das Verfahren eingesetzt wird,
dadurch gekennzeichnet, daß
in einem Schritt 1
die freie Hydroxygruppe des Pantolactons (II) unter wasserfreien Bedingungen mit 3,4- Dihydro-2H-pyran/p-Toluolsulfonsäure-Pyridiniumsalz (a) in den Tetrahydropyranylether (III) oder mit einem entsprechenden Reagenz in eine andere geeignete Schutzgruppe R überführt und das Lacton bei -70°C mit Diisobutylaluminiumhydrid (b) zum Lactol (IV) reduziert wird,
in einem Schritt 2
das Lactol (IV) mit Methyltriphenylphosphoniumbromid/Butyllithium (c) geöffnet und gleichzeitig Wasser eliminiert wird zur offenkettigen Verbindung (V), und
in einem Schritt 3
der primäre Alkohol mit Oxalylchlorid/Dimethylsulfoxid in Dichlormethan (d) zum Aldehyd (VI) oxidiert wird und der Aldehyd (VI) mit einer Organometallverbindung der Formel
R5CH2Y (e)
worin Y Lithium oder MgX,
X Chlor, Brom oder Iod sein kann, und
R5 die oben genannte Bedeutung hat,
umgesetzt wird, und
entweder
in einem Schritt 4
der geschützte Allylalkohol einer Hydroborierung unter üblichen Bedingungen unterwor­ fen wird und beide Hydroxygruppen mit N-Methylmorpholino-N-Oxid/­ Tetrapropylammoniumperruthenat oxidiert werden, und
in einem Schritt 5
der gegebenenfalls aus Schritt 4 erhaltene Aldehyd noch zur Säure (X) oxidiert wird und gegebenenfalls die Säure verestert wird,
oder
in einem Schritt 4a
zuerst die Hydroxyfunktion oxidiert wird, dann mit Lithiumdiisopropylamid/R6Z
wobei R6 C1-C10-Alkyl, Aryl oder C7-C20-Aralkyl und
Z eine geeignete Abgangsgruppe bedeutet,
alkyliert wird, und dann wie in Schritt 4 die Hydroborierung (f) und die Oxidation (g) durchgeführt wird zum Aldehyd und gegebenenfalls der erhaltene Aldehyd (Ixa) wie in Schritt 5 beschrieben oxidiert wird, und die Verbindungen der Formel (Ia)
erhalten werden, die gegebenenfalls verestert werden können.2. Process for the preparation of compounds of the general formula (Ia)
wherein R 1 is hydrogen, OH, OR 7 , wherein
R 7 is C 1 -C 20 alkyl, aryl or C 7 -C 10 aralkyl,
R 2 is hydrogen or a suitable protective group,
R 5 is hydrogen, C 1 -C 10 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 and the configuration on C3 (R), (S) or a mixture of both can be, depending on which pantolactone or pantolactone mixture is used for the process,
characterized in that
in a step 1
the free hydroxyl group of pantolactone (II) under anhydrous conditions with 3,4-dihydro-2H-pyran / p-toluenesulfonic acid pyridinium salt (a) in the tetrahydropyranyl ether (III) or with a corresponding reagent in another suitable protective group R and the Lactone at -70 ° C with diisobutylaluminum hydride (b) is reduced to lactol (IV),
in a step 2
the lactol (IV) is opened with methyltriphenylphosphonium bromide / butyllithium (c) and at the same time water is eliminated to give the open-chain compound (V), and
in a step 3
the primary alcohol is oxidized with oxalyl chloride / dimethyl sulfoxide in dichloromethane (d) to the aldehyde (VI) and the aldehyde (VI) with an organometallic compound of the formula
R 5 CH 2 Y (e)
where Y is lithium or MgX,
X can be chlorine, bromine or iodine, and
R 5 has the meaning given above,
is implemented, and
either
in a step 4
the protected allyl alcohol is subjected to hydroboration under normal conditions and both hydroxyl groups are oxidized with N-methylmorpholino-N-oxide / tetrapropylammonium perruthenate, and
in a step 5
the aldehyde optionally obtained from step 4 is also oxidized to the acid (X) and the acid is optionally esterified,
or
in a step 4a
the hydroxy function is first oxidized, then with lithium diisopropylamide / R 6 Z
wherein R 6 is C 1 -C 10 alkyl, aryl or C 7 -C 20 aralkyl and
Z represents a suitable leaving group,
is alkylated, and then, as in step 4, the hydroboration (f) and the oxidation (g) is carried out to the aldehyde and, if appropriate, the aldehyde (Ixa) obtained is oxidized as described in step 5, and the compounds of the formula (Ia)
are obtained, which can optionally be esterified. 3. Verwendung von Verbindungen gemäß Anspruch 1 zur Synthese von Epothilon oder Epothilonderivaten.3. Use of compounds according to claim 1 for the synthesis of epothilone or Epothilone derivatives.
DE19735574A 1997-08-09 1997-08-09 New 3-hydroxy-5-oxo-hexanoic acid derivatives Withdrawn DE19735574A1 (en)

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US09/485,292 US7407975B2 (en) 1997-08-09 1998-08-10 Epothilone derivatives, method for producing same and their pharmaceutical use
EP98946309A EP1005465B1 (en) 1997-08-09 1998-08-10 New epothilone derivatives, method for producing same and their pharmaceutical use
CA002299608A CA2299608A1 (en) 1997-08-09 1998-08-10 New epothilone derivatives, method for producing same and their pharmaceutical use
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PT98946309T PT1005465E (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
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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

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* Cited by examiner, † Cited by third party
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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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