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EP1641734A1 - Method for producing c1-c15 fragments of epothilones and the derivatives thereof - Google Patents

Method for producing c1-c15 fragments of epothilones and the derivatives thereof

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Publication number
EP1641734A1
EP1641734A1 EP04740122A EP04740122A EP1641734A1 EP 1641734 A1 EP1641734 A1 EP 1641734A1 EP 04740122 A EP04740122 A EP 04740122A EP 04740122 A EP04740122 A EP 04740122A EP 1641734 A1 EP1641734 A1 EP 1641734A1
Authority
EP
European Patent Office
Prior art keywords
group
hydrogen
alkyl
dihydroxy
dione
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04740122A
Other languages
German (de)
French (fr)
Inventor
Ulrich Klar
Bernd Buchmann
Wolfgang Schwede
Werner Skuballa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
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Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP1641734A1 publication Critical patent/EP1641734A1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/04—Saturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/17—Saturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • Epothilone A H
  • the object of the present invention is to provide a large amount of new C1-C12 epothilone building blocks which are suitable for the synthesis of a wide variety of epothilones and their derivatives, as described, for example, in WO 9907692, WO 0049020, WO 0001333 or DE 199210861 are used.
  • the present invention describes the novel production of the C1-C15 epothilone fragment of the general formula I,
  • o-alkyl, aryl, C7-C20-aralkyl, Rß, R 7 each have a hydrogen atom, together an additional bond or together an oxygen atom, G is a group X CR 8 -, a bi- or tricyclic aryl radical,
  • R 8 is hydrogen, halogen, CjC ⁇ n-alkyl, aryl, C7-C20-aralkyl, which can all be substituted
  • X is an oxygen atom, two alkoxy groups OR 3, a C2-C ⁇
  • Rl3a j Rl4a hydrogen, S ⁇ 2-alkyl, SO2-A1NI, S ⁇ 2-aralkyl or together a - (CH2) o group or together a CRl5aRl5b_Q rU pp ⁇ )
  • Rl3b Rl4b hydrogen, C 1 -C 20 -alkyl, aryl, C ⁇
  • Rl5b are identical or different and are hydrogen, C 1 -C 6 -alkyl, aryl, C 7 -C 20 aralkyl, or together a - (CH 2) q group, o 2 to 4, q 3 to 6,
  • Z is an oxygen atom or H / OR ⁇ where R12 is hydrogen or a protective group PG Z , including all stereoisomers and mixtures thereof, and etherified or esterified free hydroxyl groups in R ⁇ 3 and R14, ketalized free carbonyl groups in Z and R ⁇ 3 , in one Enol ether converted or reduced and free acid groups in R ⁇ 3 and R14 in whose salts can be converted with bases.
  • R12 is hydrogen or a protective group PG Z , including all stereoisomers and mixtures thereof, and etherified or esterified free hydroxyl groups in R ⁇ 3 and R14, ketalized free carbonyl groups in Z and R ⁇ 3 , in one Enol ether converted or reduced and free acid groups in R ⁇ 3 and R14 in whose salts can be converted with bases.
  • alkyl groups Ria, Rl b R 2a ; R 2b R 3) R 43, R 4b) R 5 (R ⁇ , R 10 7 R 11 f R f 13b Rl4b; RL5a j Rl5b U nd R2 are considered to straight or branched chain alkyl groups having 1-10 carbon atoms, such as methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl
  • the alkyl groups Ria, Rlb R2a, R 2b R 3 f R 4a, R 4b R 5 f R8 J R10 ) R 11, R 13b, R f 14b_ RL5a (Rl5b U nd R 3 may be perfluorinated or substituted by 1-5 halogen atoms, hydroxy, C-
  • R 2b j R 3 ; R 4a > R 4b R5_ R 8 f R 10 > R 11 f R 13b Rl4b j Rl5a and R ⁇ 5b are substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms such as, for example, phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, which are mono- or polysubstituted can be by halogen, OH, O-alkyl, CO2H, CO 2 -alkyl, -NH2, -NO2, -Nß, - CN, Cj-C20-alkyl, -C-C20-acyl, C-
  • Rl5b can in the ring up to 14 C- Contain atoms, preferably 6 to 10 and in the alkyl chain 1 to 8, preferably 1 to 4.
  • suitable aralkyl radicals are benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl.
  • the rings can be mono- or polysubstituted by Halogen, OH, O-alkyl, CO2H, CO 2 -alkyl, -NO 2, -N 3, -CN, C ⁇
  • Alkynyl groups R a and R2b are straight-chain or branched-chain alkyl groups with 1-10 carbon atoms in which at least one CC bond is replaced by a C ⁇ C bond, such as propynyl, butynyl, pentynyl, isopentynyl, heptynyl, heptadynyl , Decinyl, decatriinyl.
  • Preferred compounds I are those in which
  • R 5 is hydrogen, Ci-Cg-alkyl
  • R 8 is hydrogen, halogen, Ci-Cß-alkyl
  • Rl 5a ; Rl 5b are the same or different and are hydrogen, Cj-Cß-alkyl, aryl, C7-C-20-aralkyl, or together represent a - (CH2) q group, q 3 to 6.
  • R2b Ci-Cs-alkyl, C2-C6-alkenyl, C2-C6-alkynyl,
  • R 5 is hydrogen, Ci-Cß-alkyl, Rß, R7 together an additional bond,
  • R 8 is hydrogen, fluorine, chlorine, C 1 -C 3 -alkyl
  • Rl3a_ R 14a together form a CR 15a R 15b group, RlSb hydrogen, Ci-Cß-alkyl,
  • Rl5a ; Rl5b are the same and C ⁇
  • Rl5a > Rl5b are different and are hydrogen, aryl, q 4 or 5, Z is oxygen.
  • the representation of the new epothilone derivatives is based on the linkage of three partial fragments A, B and C.
  • the interfaces lie as indicated in the general formula I '.
  • A denotes a C1-C6 fragment (epothilone counting) of the general formula A-1
  • Ria ', Rl b' (R 2a ' ; R 2b' ⁇ R 13 ' and d R14' have the meanings already given for Ria, Rl b R 2a ; R 2b t R 13 and R14, including all stereoisomers and their mixtures, and free hydroxyl groups in R ⁇ 3 and R14 etherified or esterified, free
  • Carbonyl groups in A and R ⁇ 3 are ketalized, converted into an enol ether or reduced, and free acid groups in A can be converted into bases in their salts.
  • R3a ' ; R4a ') R4b' nd R 5 ' have the meanings given 5 already for R 3a, R4 and R, and V is an oxygen atom, two alkoxy groups OR ⁇ 7, a C2-C ⁇ o-alkylene- ⁇ , ⁇ - dioxy group, which can be straight-chain or branched or H / OR16, W one oxygen atom, two alkoxy groups OR ⁇ , a C2-C ⁇ o-alkylene- ⁇ , ⁇ -dioxy group, which can be straight-chain or branched or H / OR ⁇ 8 , R16_ R18 independently of one another Hydrogen or a protecting group PC,
  • R 17 , R 1 9 independently of one another are C 1 -C 20 -alkyl.
  • G ' has the meaning already given for G in the general formula I and R 7 ' is a hydrogen atom
  • R ⁇ , R ⁇ , R2a, R 2b, R 3, R 4a ; R 4b R 5 ; R8, R10, R 11, R 13b, R 14, f RL5a Rl5b j R17 J R19 JR 23 nd R 29 are straight or branched
  • Neopentyl, heptyl, hexyl, decyl Neopentyl, heptyl, hexyl, decyl.
  • R 23 and R 2 9 can be perfluorinated or substituted by 1-5 halogen atoms, hydroxyl groups, C-
  • Ci2 aryl groups (which can be substituted by 1-3 halogen atoms).
  • R 14b Rl5a and R ⁇ come substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms, such as, for example, phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, benzothazolyl, benzothazolol, benzothiazolyl can be mono- or polysubstituted by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, -NH 2 , -NO 2 , -N 3 , -CN, C «
  • the bi- and tricyclic aryl radicals G are substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms, such as, for example, naphthyl, anthryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzofuran, tololrahoxylolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinylinolinolinolinolinolinolinolinolinylinolinolinolinolinolinolinolinolinylolinolinolinolinolinolinylolinoxin Thienopyridinyl, pyridopyridinyl, benzopyrazolyl, benzotriazolyl, dihydroindolyl, which can be mono- or polysubstituted by halogen, OH, O-alkyl, CO
  • Rl5b can contain up to 14 carbon atoms, preferably 6 to 10 and in the alkyl chain 1 to 8, preferably 1 to 4 atoms in the ring.
  • aralkyl radicals examples include benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl.
  • the rings can be mono- or polysubstituted by halogen, OH, O-alkyl, CO2H, CO 2 -alkyl, -NO2, -N3, -CN, C ⁇
  • protective groups PG are alkyl- and / or aryl-substituted silyl, C 1 -C 20 -alkyl, C4-C7-cycloalkyl, which can additionally contain an oxygen atom in the ring, aryl, C7-C20-aralkyl, C ⁇
  • Suitable alkyl, silyl and acyl radicals for the protective groups PG are the radicals known to the person skilled in the art.
  • alkyl or silyl radicals from the corresponding alkyl and silyl ethers such as, for example, methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenyl -, Tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl radical and alkylsulfonyl and arylsulfonyl radicals.
  • acyl radicals are formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl, which can be substituted with amino and / or hydroxyl groups.
  • residues known to the person skilled in the art are suitable as amino protecting groups. Examples include the Alloc, Boc, Z, benzyl, f-Moc, Troc, stabase or benzostabase group.
  • the acyl groups PG can contain 1 to 20 carbon atoms, formyl, acetyl, propionyl, isopropionyl and pivalyl groups being preferred.
  • the index m in the alkylene group formed from R ⁇ a and R ⁇ b is preferably 1, 2, 3 or 4.
  • o-alkylene- ⁇ , ⁇ -dioxy group which is possible for V, W and X is preferably an ethylene ketal or neopentyl ketal group.
  • the partial fragments (synthesis building blocks) of the general formula A can be prepared, for example, as described in WO 99/07692 or DE 101 64 592.9.
  • the partial fragments (synthesis building blocks) of the general formula B can be prepared, for example, as described in WO 99/07692.
  • the partial fragments (synthesis building blocks) of the general formula C can be prepared, for example, as described in DE 197 51 200.3, DE 199 07 480.1, WO 99/07692 and WO 00/01333.
  • the compound B in which W has the meaning of an oxygen atom and a possibly present additional carbonyl group in V or a possibly present additional hydroxyl group in V (H / OR ⁇ 6 ) are protected, is optionally with the enolate of a carbonyl compound of the general formula A. alkylated in the presence of metal halides.
  • the enolate will produced by the action of strong bases such as lithium diisopropylamide, lithium hexamethyldisilazane at low temperatures.
  • R21 has the meaning of a phosphonium halide residue PPh3 + Hal ", preferably a PPh3 + 1" residue or a phosphonate residue or a phosphine oxide residue and any additional carbonyl groups which may be present, is protected by a Suitable base such as n-butyllithium, lithium diisopropylamide, potassium tert-butoxide, sodium or lithium hexamethyldisilazide deprotonated and reacted with a compound AB, in which V has the meaning of an oxygen atom.
  • a Suitable base such as n-butyllithium, lithium diisopropylamide, potassium tert-butoxide, sodium or lithium hexamethyldisilazide deprotonated and reacted with a compound AB, in which V has the meaning of an oxygen atom.
  • the fragment ABC thus obtained which contains the ring carbon atoms C1 to C15 of the later 16-membered macrocycle, is, for example, according to the methods described in WO 99/07692, WO 99/049154 or WO 00/01333 in the desired target compounds as described in the same patent applications are transferred.
  • the invention therefore also relates to a process for the preparation of the epothilone derivatives of the general formula II
  • G, OPG 2 and Z have the meanings given in the general formula I, in which compounds of the general formula I obtained by the process according to the invention are cyclized to give compounds of the general formula II.
  • the mixture is stirred for a further 2.5 hours at -70 ° C., poured into a saturated ammonium chloride solution and extracted several times with ethyl acetate.
  • the combined organic extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate and the residue obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel using a mobile phase mixture of n-hexane and ethyl acetate.
  • Example 1e (4S, 4 , R, 5 , S, 6 , S, 10 ⁇ / Z, 13 , S) -4- (2,6,10-trimethyl-3-oxo-4-allyl-5- (2H- tetrahydropyran-2-yloxy) -13- (2-methylbenzothiazol-5-yl) -13- (tert-butyldimethylsilyloxy) -tridec-10-ene-2-yl) -2,2-dimethyl-1, 3-dioxane Solution of 6.72 g of [(3S) -3- (2-methylbenzothiazol-5-yl) -3- (tert-butyldimethylsilyloxy) propyl] triphenylphosphonium iodide, which is analogous to that described in WO 99/07692, WO 99049154, WO 00/01333 has prepared, in 45 ml of anhydrous tetrahydrofuran, 9.5 ml of
  • Example 1g (3S, 6R, 7S, 8S, 12E / Z, 15S) -4.4, ⁇ , 12-tetramethyl-6-allyl-1, 3,7,15-tetrakis (tert-butyldimethylsilyloxy) -15 - (2-methylbenzothiazol-5-yl) -pentadec-12-en-5-one
  • the solution of the crude product shown in Example 1f (max. 13.4 mmol) in 340 ml of anhydrous dichloromethane is mixed at 0 ° C. with 20.
  • Example 1 i (3S, 6R, 7S, 8S, 12E / Z, 15S) -4, 4,8,12-tetramethyl-5-oxo-6-allyl-3,7,15-tris- (tert-butyldimethylsilyloxy) -15- (2-methyl-benzothiazol-5-yl) -pentadec-12-enal
  • Example 2e (3S, 6R, 7S, 8S) -4,4,8-trimethyl-5-oxotridecane-1, 3,7-triol
  • Compound A prepared in a mixture of 200 ml of ethanol and 50 ml of water is mixed with 6.7 g of p-toluenesulfonic acid monohydrate and stirred at 23 ° C. for 4 hours. Saturated sodium hydrogen carbonate solution is added, the mixture is extracted with dichloromethane and the combined organic extracts are dried over sodium sulfate. The residue obtained after filtration and removal of solvent is reacted further without purification. 5.8 g (max. 15.9 mmol) of the title compound are isolated as a colorless oil.
  • the mixture is left to react at 23 ° C. for 5 hours, poured into a saturated ammonium chloride solution and extracted several times with ethyl acetate.
  • the combined organic extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate and the residue obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel using a mobile phase mixture of n-hexane and ethyl acetate. 6.18 g (6.25 mmol, 90.6%) of the title compound are isolated as a colorless oil.

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Abstract

The invention relates to a method for producing C1-C15 fragments of epothilones and the derivatives thereof, whereby a C1-C6 fragment is bonded to a C7-C12 fragment to form a C1-C12 fragment which is then converted with a C13-C15 fragment to form the C1-C15 epothilone intermediate product to be produced. The thus produced C1-C15 epothilone intermediate products can be converted into the intrinsic active ingredients according to known methods. The invention also relates to the corresponding C1-C12 fragments.

Description

Verfahren für die Herstellung von C^-C-is-Fragmenten von Epothilonen und deren Derivaten Process for the preparation of C ^ -C-is fragments of epothilones and their derivatives
Von Höfle et al. wird die cytotoxische Wirkung der Naturstoffe Epothilon A (R Wasserstoff) und Epothilon B (R = Methyl)By Höfle et al. the cytotoxic effects of the natural substances epothilone A (R hydrogen) and epothilon B (R = methyl)
Epothilon A (R = H), Epothilon B (R=CH3) Epothilone A (R = H), epothilone B (R = CH 3 )
z.B. in Angew. Chem. 1996, 108, 1671-1673, beschrieben. Wegen der in-vitro- Selektivität gegenüber Brust- und Darmzelllinien und ihrer im Vergleich zu Taxol deutlich höheren Aktivität gegen P-Glycoprotein-bildende, multiresistente Tumorlinien sowie ihre gegenüber Taxol verbesserten physikalischen Eigenschaften, z.B eine um den Faktor 30 höhere Wasserlöslichkeit, ist diese neuartige Strukturklasse für die Entwicklung eines Arzneimittels zur Therapie maligner Tumoren besonders interessant.e.g. in Angew. Chem. 1996, 108, 1671-1673. This is novel because of the in vitro selectivity towards breast and intestinal cell lines and their significantly higher activity against P-glycoprotein-forming, multi-resistant tumor lines compared to Taxol, as well as their improved physical properties compared to Taxol, e.g. 30 times higher water solubility Structural class of particular interest for the development of a drug for the treatment of malignant tumors.
Die Aufgabe der vorliegenden Erfindung besteht darin, neue C1-C12-Epothilon- Bausteine in großer Menge zur Verfügung zu stellen, die sich für die Synthese unterschiedlichster Epothilone und deren Derivate wie sie beispielsweise in WO 9907692, WO 0049020, WO 0001333 oder DE 199210861 beschrieben sind, einsetzen lassen.The object of the present invention is to provide a large amount of new C1-C12 epothilone building blocks which are suitable for the synthesis of a wide variety of epothilones and their derivatives, as described, for example, in WO 9907692, WO 0049020, WO 0001333 or DE 199210861 are used.
Die vorliegende Erfindung beschreibt die neuartige Herstellung des C1-C15- Epothilon-Fragmentes der allgemeinen Formel I, The present invention describes the novel production of the C1-C15 epothilone fragment of the general formula I,
worinwherein
Rla> Rl b gleich oder verschieden sind und Wasserstoff, C-j-C-io-Alkyl, Aryl, C7-C20-Aralkyl, oder gemeinsam eine -(CH2)m-GruPPe mit m = 2, 3, 4 oder 5, R2a, R2b gleich oder verschieden sind und Wasserstoff, Ci-C-jQ-Al yl, C-2-C<ιo-Alkenyl, C2-Cιo-Alkinyl, Aryl, C7-C20-Aralkyl oder gemeinsam eine -(CH2)n-Gruppe mit n = 2, 3, 4 oder 5, R3 Wasserstoff, C-i-Cio-Alkyl, Aryl, C7-C20-Aralkyl,Rla > Rl b are the same or different and are hydrogen, CjC-io-alkyl, aryl, C7-C20-aralkyl, or together a - (CH2) mG ru PP em it m = 2, 3, 4 or 5, R2a, R2b are identical or different and are hydrogen, Ci-C-jQ-al yl, C-2-C <ιo-alkenyl, C2-Cιo-alkynyl, aryl, C7-C20-aralkyl or together a - (CH2) n group with n = 2, 3, 4 or 5, R 3 is hydrogen, Ci-Cio-alkyl, aryl, C7-C20-aralkyl,
R4a, R4b gleich oder verschieden sind und Wasserstoff, C-j-C-io-Alkyl, Aryl, C-7-C-20-Aralkyl oder gemeinsam eine -(CH2)p-Gruppe mit p = 2, 3, 4 oder 5, R5 Wasserstoff, C<| -C-| o-Alkyl, Aryl, C7-C20-Aralkyl, Rß, R7 je ein Wasserstoffatom, gemeinsam eine zusätzliche Bindung oder gemeinsam ein Sauerstoffatom, G eine Gruppe X=CR8-, ein bi- oder tricyclischer Arylrest,R4a, R4b are the same or different and are hydrogen, CjC-io-alkyl, aryl, C-7-C-20-aralkyl or together a - (CH2) p group with p = 2, 3, 4 or 5, R 5 Hydrogen, C <| C- | o-alkyl, aryl, C7-C20-aralkyl, Rß, R 7 each have a hydrogen atom, together an additional bond or together an oxygen atom, G is a group X = CR 8 -, a bi- or tricyclic aryl radical,
R8 Wasserstoff, Halogen, C-j-C^n-Alkyl, Aryl, C7-C20-Aralkyl, die alle substituiert sein können, X ein Sauerstoffatom, zwei Alkoxygruppen OR 3, eine C2-C<|o-Alkylen- α.ω-dioxygruppe, die geradkettig oder verzweigt sein kann, H/OR9 oder eine Gruppierung CR10R11 , wobei R 3 für einen Cι-C20-Alkylrest, Rß für Wasserstoff oder eine Schutzgruppe PGX, R10, R"ϊ 1 gleich oder verschieden sind und für Wasserstoff, einen C-|-C20-Alkyl-, Aryl-, C7-C-20-Aralkylrest oder R10 und R^ zusammen mit dem Methylenkohlen- stoffatom gemeinsam für einen 5- bis 7-gliedrigen carbocyclischen Ring stehen, R 3 CH20R1 Sa, CH2-Hal, CHO, CO2R13b, COHal, R14 Wasserstoff, OR1 a, Hai, OSθ2R14b,R 8 is hydrogen, halogen, CjC ^ n-alkyl, aryl, C7-C20-aralkyl, which can all be substituted, X is an oxygen atom, two alkoxy groups OR 3, a C2-C <| o-alkylene-α.ω-dioxy group , which can be straight-chain or branched, H / OR9 or a group CR10R11, where R 3 for a C 1 -C 20 -alkyl radical, Rß for hydrogen or a protective group PG X , R10, R " ϊ 1 are identical or different and for hydrogen, a C- | -C20-alkyl, aryl, C7-C-20-aralkyl radical or R10 and R ^ together with the methylene carbon together represent a 5- to 7-membered carbocyclic ring, R 3 CH 2 0R1 Sa, CH 2 -Hal, CHO, CO 2 R 13b , COHal, R14 hydrogen, OR 1 a , shark, OSθ2R 14b ,
Rl3aj Rl4a Wasserstoff, Sθ2-Alkyl, SO2-A1NI, Sθ2-Aralkyl oder gemeinsam eine -(CH2)o-Gruppe oder gemeinsam eine CRl5aRl5b_QrUppθ) Rl3b Rl4b Wasserstoff, Cι-C-20-Alkyl, Aryl, C<|-C-20-Aralkyl, l5a; Rl5b gleich oder verschieden sind und Wasserstoff, C-|-C-jo-Alkyl, Aryl, C7-C-20-Aralkyl, oder gemeinsam eine -(CH2)q-Gruppe, o 2 bis 4, q 3 bis 6,Rl3a j Rl4a hydrogen, Sθ2-alkyl, SO2-A1NI, Sθ2-aralkyl or together a - (CH2) o group or together a CRl5aRl5b_Q rU pp θ) Rl3b Rl4b hydrogen, C 1 -C 20 -alkyl, aryl, C < | -C-20 aralkyl, l5a ; Rl5b are identical or different and are hydrogen, C 1 -C 6 -alkyl, aryl, C 7 -C 20 aralkyl, or together a - (CH 2) q group, o 2 to 4, q 3 to 6,
R20 OPG3, NHR29, N3, R 20 OPG 3 , NHR 29 , N 3,
Z ein Sauerstoffatom oder H/OR^ wobei R12 Wasserstoff oder eine Schutzgruppe PGZ ist, einschließlich aller Stereoisomeren sowie deren Gemische bedeuten sowie freie Hydroxylgruppen in R^3 und R14 verethert oder verestert, freie Carbonylgruppen in Z und R^3 ketalisiert, in einen Enolether überführt oder reduziert sowie freie Säuregruppen in R^3 und R14 jn deren Salze mit Basen überführt sein können.Z is an oxygen atom or H / OR ^ where R12 is hydrogen or a protective group PG Z , including all stereoisomers and mixtures thereof, and etherified or esterified free hydroxyl groups in R ^ 3 and R14, ketalized free carbonyl groups in Z and R ^ 3 , in one Enol ether converted or reduced and free acid groups in R ^ 3 and R14 in whose salts can be converted with bases.
Als Alkylgruppen Ria, Rl b R2a; R2b R3) R43, R4b) R5( Rδ, R107 R11 f R13bf Rl4b; Rl5aj Rl5b Und R2 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. Die Alkylgruppen Ria, Rlb R2a, R2b R3f R4a, R4b R5f R8J R10) R11 , R13bf R14b_ Rl5a( Rl5b Und R 3 können perfluoriert oder substituiert sein durch 1-5 Halogenatome, Hydroxygruppen, C-|-C4-Alkoxygruppen, Cß-C^-Arylgruppen (die durch 1-3 Halogenatome substituiert sein können). Als Arylrest R^, R1 b R2a? R2bj R3; R4a> R4b R5_ R8f R10> R11 f R13b Rl4bj Rl5a und R^5b kommen substituierte und unsubstituierte carbocyclische oder heterocyclische Reste mit einem oder mehreren Heteroatomen wie z.B. Phenyl, Naphthyl, Furyl, Thienyl, Pyridyl, Pyrazolyl, Pyrimidinyl, Oxazolyl, Pyridazinyl, Pyrazinyl, Chinolyl, Thiazolyl, die einfach oder mehrfach substituiert sein können durch Halogen, OH, O-Alkyl, CO2H, Cθ2-Alkyl, -NH2, -NO2, -Nß, - CN, C-j-C20-Alkyl, Cι-C20-Acyl, C-|-C20-Acyloxy-Gruppen, in Frage. Die Aralkylgruppen in Ria, Rl b, R2a, R2b( R3; R4a; R4bj R5; R87 RI O, R11 f Rl3bj Rl4bj Rl5a unc| Rl5b können im Ring bis 14 C-Atome, bevorzugt 6 bis 10 und in der Alkylkette 1 bis 8, bevorzugt 1 bis 4 Atome enthalten. Als Aralkylreste kommen beispielweise in Betracht Benzyl, Phenylethyl, Naphthylmethyl, Naphthylethyl, Furylmethyl, Thienylethyl, Pyridylpropyl. Die Ringe können einfach oder mehrfach substituiert sein durch Halogen, OH, O- Alkyl, CO2H, Cθ2-Alkyl, -NO2, -N3, -CN, C<|-C20-Alkyl, C<|-C20-Acyl, C1-C20- Acyloxy-Gruppen.As alkyl groups Ria, Rl b R 2a ; R 2b R 3) R 43, R 4b) R 5 (Rδ, R 10 7 R 11 f R f 13b Rl4b; RL5a j Rl5b U nd R2 are considered to straight or branched chain alkyl groups having 1-10 carbon atoms, such as methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl The alkyl groups Ria, Rlb R2a, R 2b R 3 f R 4a, R 4b R 5 f R8 J R10 ) R 11, R 13b, R f 14b_ RL5a (Rl5b U nd R 3 may be perfluorinated or substituted by 1-5 halogen atoms, hydroxy, C- | -C4-alkoxy, C ^ CSS aryl groups (represented by 1-3 halogen atoms The aryl radical R ^, R 1 b R2a ? R 2b j R 3 ; R 4a > R 4b R5_ R 8 f R 10 > R 11 f R 13b Rl4b j Rl5a and R ^ 5b are substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms such as, for example, phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, which are mono- or polysubstituted can be by halogen, OH, O-alkyl, CO2H, CO 2 -alkyl, -NH2, -NO2, -Nß, - CN, Cj-C20-alkyl, -C-C20-acyl, C- | -C20-acyloxy groups , in question. The aralkyl groups in Ria, Rl b, R 2a, R 2b (R 3 ; R 4a ; R 4b j R 5 ; R 8 7 RI O, R 11 f Rl3b j Rl4b j Rl5a unc | Rl5b can in the ring up to 14 C- Contain atoms, preferably 6 to 10 and in the alkyl chain 1 to 8, preferably 1 to 4. Examples of suitable aralkyl radicals are benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl. The rings can be mono- or polysubstituted by Halogen, OH, O-alkyl, CO2H, CO 2 -alkyl, -NO 2, -N 3, -CN, C <| -C 20 -alkyl, C <| -C 20 -acyl, C1-C20-acyloxy groups.
Als Alkenylgruppen R a und R2b sind gerad- oder verzweigtkettige Alkylgruppen mit 1-10 Kohlenstoffatomen zu betrachten, in denen mindestens eine C-C-Bindung durch eine C=C-Bindung ersetzt ist, wie beispielsweise Propenyl, Butenyl, Isobutenyl, Pentenyl, Isopentenyl, Neopentenyl, Heptenyl, Heptadienyl, Decenyl, Decatrienyl.Alkenyl groups R a and R2b are straight-chain or branched-chain alkyl groups with 1-10 carbon atoms in which at least one CC bond is replaced by a C = C bond, such as propenyl, butenyl, isobutenyl, pentenyl, isopentenyl, neopentenyl , Heptenyl, heptadienyl, decenyl, decatrienyl.
Als Alkinylgruppen R a und R2b sind gerad- oder verzweigtkettige Alkylgruppen mit 1-10 Kohlenstoffatomen zu betrachten, in denen mindestens eine C-C- Bindung durch eine C≡C-Bindung ersetzt ist, wie beispielsweise Propinyl, Butinyl, Pentinyl, Isopentinyl, Heptinyl, Heptadiinyl, Decinyl, Decatriinyl.Alkynyl groups R a and R2b are straight-chain or branched-chain alkyl groups with 1-10 carbon atoms in which at least one CC bond is replaced by a C≡C bond, such as propynyl, butynyl, pentynyl, isopentynyl, heptynyl, heptadynyl , Decinyl, decatriinyl.
Bevorzugt sind solche Verbindungen I, in denenPreferred compounds I are those in which
Rla; Rl b gleich sind und C-j-Cß-Alkyl, oder gemeinsam eine -(CH2)nr Gruppe mit m = 2, 3 oder 4, R2a, R2b verschieden sind und Wasserstoff, C-j-Cß-Alkyl, C2-C1 Q-Alkenyl, C2-C1 o-Alkinyl oder C7-C20-Aralkyl,Rla ; Rl b are the same and Cj-Cß-alkyl, or together a - (CH2) nr group with m = 2, 3 or 4, R2a, R2b are different and hydrogen, Cj-Cß-alkyl, C2-C1 Q-alkenyl, C2-C1 o-alkynyl or C7-C20 aralkyl,
R5 Wasserstoff, Ci-Cg-Alkyl,R 5 is hydrogen, Ci-Cg-alkyl,
R8 Wasserstoff, Halogen, C-i-Cß-Alkyl,R 8 is hydrogen, halogen, Ci-Cß-alkyl,
Rl 5a; Rl 5b gleich oder verschieden sind und Wasserstoff, C-j-Cß-Alkyl, Aryl, C7-C-20-Aralkyl, oder gemeinsam eine -(CH2)q-Gruppe, q 3 bis 6, bedeuten.Rl 5a ; Rl 5b are the same or different and are hydrogen, Cj-Cß-alkyl, aryl, C7-C-20-aralkyl, or together represent a - (CH2) q group, q 3 to 6.
Besonders bevorzugt sind solche Verbindungen I, in denen Rl a> R1 b gleich sind und C-i-Cß-Alkyl, oder gemeinsam eine -(CH2)nr Gruppe mit m = 2, 3 oder 4,Particularly preferred compounds I are those in which Rl a > R 1 b are the same and Ci-Cß-alkyl, or together a - (CH2) nr group with m = 2, 3 or 4,
R2a Wasserstoff,R2a hydrogen,
R2b Ci-Cs-Alkyl, C2-C6-Alkenyl, C2-C6-Alkinyl,R2b Ci-Cs-alkyl, C2-C6-alkenyl, C2-C6-alkynyl,
R5 Wasserstoff, Ci-Cß-Alkyl, Rß, R7 gemeinsam eine zusätzliche Bindung,R 5 is hydrogen, Ci-Cß-alkyl, Rß, R7 together an additional bond,
G eine Gruppe X=CR8-, ein bicyclischer Arylrest,G is a group X = CR 8 -, a bicyclic aryl radical,
R8 Wasserstoff, Fluor, Chlor, C |-C3-Alkyl,R 8 is hydrogen, fluorine, chlorine, C 1 -C 3 -alkyl,
X Sauerstoff oder eine Gruppe CR1 °R1 1 , R10 Wasserstoff,X oxygen or a group CR 1 ° R 1 1 , R10 hydrogen,
R11 Aryl,R11 aryl,
R13 CH2ORl3a, CO2R13b,R1 3 CH 2 ORl 3 a, CO 2 R 13b ,
R14 OR143, R 14 OR143,
Rl3a_ R14a gemeinsam eine CR15a R15b -Gruppe, RlSb Wasserstoff, C-i-Cß-Alkyl,Rl3a_ R 14a together form a CR 15a R 15b group, RlSb hydrogen, Ci-Cß-alkyl,
Rl5a; Rl5b gleich sind und C<|-C3-Alkyl, oder gemeinsam eine -(CH2)q- Gruppe, oderRl5a ; Rl5b are the same and C <| -C3-alkyl, or together a - (CH2) q group, or
Rl5a> Rl5b verschieden sind und Wasserstoff, Aryl, q 4 oder 5, Z Sauerstoff bedeuten. Rl5a > Rl5b are different and are hydrogen, aryl, q 4 or 5, Z is oxygen.
Die Darstellung der neuen Epothilon-Derivate basiert auf der Verknüpfung dreier Teilfragmente A, B und C. Die Schnittstellen liegen wie in der allgemeinen Formel I' angedeutet.The representation of the new epothilone derivatives is based on the linkage of three partial fragments A, B and C. The interfaces lie as indicated in the general formula I '.
A bedeutet ein C1-C6-Fragment (Epothilon-Zählweise) der allgemeinen Formel A-1A denotes a C1-C6 fragment (epothilone counting) of the general formula A-1
worinwherein
Ria', Rl b'( R2a'; R2b'ι R13' und R14' die bereits für Ria, Rl b R2a; R2b t R13 und R14 genannten Bedeutungen haben einschließlich aller Stereoisomeren sowie deren Gemische bedeuten sowie freie Hydroxylgruppen in R^3 und R14 verethert oder verestert, freieRia ', Rl b' (R 2a '; R 2b' ι R 13 ' and d R14' have the meanings already given for Ria, Rl b R 2a ; R 2b t R 13 and R14, including all stereoisomers and their mixtures, and free hydroxyl groups in R ^ 3 and R14 etherified or esterified, free
Carbonylgruppen in A und R^3 ketalisiert, in einen Enolether überführt oder reduziert sowie freie Säuregruppen in A in deren Salze mit Basen überführt sein können.Carbonyl groups in A and R ^ 3 are ketalized, converted into an enol ether or reduced, and free acid groups in A can be converted into bases in their salts.
B steht für ein C7-C12-Fragment (Epothilon-Zählweise) der allgemeinen Formel B worinB stands for a C7-C12 fragment (epothilone counting) of the general formula B where
R3a'; R4a') R4b' Und R5' die bereits für R3a, R4 und R5 genannten Bedeutungen haben, und V ein Sauerstoffatom, zwei Alkoxygruppen OR^7, eine C2-C<ιo-Alkylen-α,ω- dioxygruppe, die geradkettig oder verzweigt sein kann oder H/OR16, W ein Sauerstoffatom, zwei Alkoxygruppen OR^, eine C2-Cιo-Alkylen-α,ω- dioxygruppe, die geradkettig oder verzweigt sein kann oder H/OR^8, R16_ R18 unabhängig voneinander Wasserstoff oder eine Schutzgruppe PC ,R3a '; R4a ') R4b' nd R 5 'have the meanings given 5 already for R 3a, R4 and R, and V is an oxygen atom, two alkoxy groups OR ^ 7, a C2-C <ιo-alkylene-α, ω- dioxy group, which can be straight-chain or branched or H / OR16, W one oxygen atom, two alkoxy groups OR ^, a C2-Cιo-alkylene-α, ω-dioxy group, which can be straight-chain or branched or H / OR ^ 8 , R16_ R18 independently of one another Hydrogen or a protecting group PC,
R17, R19 unabhängig voneinander C-j -C20-Alkyl, bedeuten.R 17 , R 1 9 independently of one another are C 1 -C 20 -alkyl.
C steht für ein C13-C15-Fragment (Epothilon-Zählweise) der allgemeinen Formel C stands for a C13-C15 fragment (epothilone counting) of the general formula
worinwherein
G' die bereits in der allgemeinen Formel I für G genannte Bedeutung hat und R7' ein Wasserstoffatom,G 'has the meaning already given for G in the general formula I and R 7 ' is a hydrogen atom,
R201 Halogen, N3, NHR29, eine Hydroxygruppe, eine geschützte Hydroxygruppe O-PG3, eine geschützte Aminogruppe NR29pG3, eine C-i-C-io-Alkylsulfonyloxygruppe, die gegebenenfalls perfluoriert sein kann, eine gegebenenfalls durch Cι-C4-Alkyl, Nitro, Chlor oder Brom substituierte Benzoyloxy-Gruppe, eine NR29sθ2CH3-Gruppe, eine NR29c(=O)CH3-Gruppe, eine CH2-C(=O)-CH3-Gruppe,R20 1 halogen, N3, NHR29, a hydroxyl group, a protected hydroxyl group O-PG 3 , a protected amino group NR29pG 3 , a CiC-io-alkylsulfonyloxy group, which can optionally be perfluorinated, one optionally by C 1 -C 4 -alkyl, nitro, chlorine or bromine-substituted benzoyloxy group, an NR29sθ2CH3 group, an NR29c (= O) CH3 group, a CH2-C (= O) -CH3 group,
R21 eine Hydroxygruppe, Halogen, eine geschützte Hydroxygruppe OPG3, ein Phosphoniumhalogenidrest PPh3+Hal" (Ph = Phenyl; Hai = F, CI, Br, I), ein Phosphonatrest P(O)(OQ)2 (Q = C-i-Cio-Al yl oder Phenyl) oder ein Phosphinoxidrest P(O)Ph2 (Ph = Phenyl), R 9 Wasserstoff, Cι-C6-Alkyl, bedeuten.R21 is a hydroxyl group, halogen, a protected hydroxyl group OPG 3 , a phosphonium halide residue PPh3 + Hal "(Ph = phenyl; Hai = F, CI, Br, I), a phosphonate residue P (O) (OQ) 2 (Q = Ci-Cio -Al yl or phenyl) or a phosphine oxide residue P (O) Ph2 (Ph = phenyl), R 9 is hydrogen, -CC 6 alkyl.
Als Alkylgruppen R^, R^, R2a, R2b, R3, R4a; R4b R5; R8, R10, R11, R13b R14 , Rl5af Rl5bj R17J R19J R23 Und R29 sind gerad- oder verzweigtkettigeAs alkyl groups R ^, R ^, R2a, R 2b, R 3, R 4a ; R 4b R 5 ; R8, R10, R 11, R 13b, R 14, f RL5a Rl5b j R17 J R19 JR 23 nd R 29 are straight or branched
Alkylgruppen mit 1-20 Kohlenstoffatomen zu betrachten, wie beispielsweiseConsider alkyl groups with 1-20 carbon atoms, such as
Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.-Butyl, Pentyl, Isopentyl,Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl,
Neopentyl, Heptyl, Hexyl, Decyl.Neopentyl, heptyl, hexyl, decyl.
Die Alkylgruppen Ri , R1 b R2a; R2b, R3S R4a; R4b_ R5; Rδj R10( R11 , Rl3b R14bj R15aj R15b> R17) R19? R23 und R29 können perfluoriert oder substituiert sein durch 1-5 Halogenatome, Hydroxygruppen, C-|-C4-Alkoxygruppen, CQ-The alkyl groups Ri, R 1 b R 2a ; R 2b, R3 SR 4a ; R 4b_ R 5 ; R δ j R 10 ( R11, Rl3b R 1 4b j R 15a j R 15b > R 17 ) R19 ? R 23 and R 2 9 can be perfluorinated or substituted by 1-5 halogen atoms, hydroxyl groups, C- | -C4-alkoxy groups, CQ-
Ci2-Arylgruppen (die durch 1-3 Halogenatome substituiert sein können).Ci2 aryl groups (which can be substituted by 1-3 halogen atoms).
Als Arylrest R^, R1b_ R2a; R2bj R3( R4a, R4b RÖ, R8; R10J R11 f R13b> As aryl radical R ^, R 1b_ R 2a ; R 2b j R3 (R 4a, R 4b RÖ, R8 ; R10 JR 11 f R 13b >
R14b Rl5a und R^ kommen substituierte und unsubstituierte carbocyclische oder heterocyclische Reste mit einem oder mehreren Heteroatomen wie z.B. Phenyl, Naphthyl, Furyl, Thienyl, Pyridyl, Pyrazolyl, Pyrimidinyl, Oxazolyl, Pyridazinyl, Pyrazinyl, Chinolyl, Thiazolyl, Benzothiazolyl, Benzoxazolyl, die einfach oder mehrfach substituiert sein können durch Halogen, OH, O-Alkyl, CO2H, CO2-Alkyl, -NH2, -NO2, -N3, -CN, C«|-C-20-Alkyl. C1-C20-Acyl, C<|-C2()- Acyloxy-Gruppen, in Frage. R 14b Rl5a and R ^ come substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms, such as, for example, phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, benzothazolyl, benzothazolol, benzothiazolyl can be mono- or polysubstituted by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, -NH 2 , -NO 2 , -N 3 , -CN, C « | -C-20-alkyl. C 1 -C20 acyl, C <| -C 2 () acyloxy groups, in question.
Als bi- und tricyclische Arylreste G kommen substituierte und unsubstituierte carbocyclische oder heterocyclische Reste mit einem oder mehreren Heteroatomen wie z.B. Naphthyl, Anthryl, Benzothiazolyl, Benzoxazolyl, Benzimidazolyl, Chinolyl, Isochinolyl, Benzoxazinyl, Benzofuran, Indolyl, Indazolyl, Chinoxalinyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, Thienopyridinyl, Pyridopyridinyl, Benzopyrazolyl, Benzotriazolyl, Dihydroindolyl, die einfach oder mehrfach substituiert sein können durch Halogen, OH, O-Alkyl, CO2H. CO2-Alkyl, -NH2, -NO2, -N3, -CN, C<|-C2o-Alkyl, C-i-C^o-Acyl, Cι-C2o- Acyloxy-Gruppen, in Frage. Die Aralkylgruppen in R1 a, Rl b, R2a> R2bj R3> R4a7 R4b R5, R8, R10J R1 1 , Rl3b; Rl4b Rl5a unc| Rl5b können im Ring bis 14 C-Atome, bevorzugt 6 bis 10 und in der Alkylkette 1 bis 8, bevorzugt 1 bis 4 Atome enthalten. Als Aralkylreste kommen beispielweise in Betracht Benzyl, Phenylethyl, Naphthylmethyl, Naphthylethyl, Furylmethyl, Thienylethyl, Pyridylpropyl. Die Ringe können einfach oder mehrfach substituiert sein durch Halogen, OH, O- Alkyl, CO2H, Cθ2-Alkyl, -NO2, -N3, -CN, C<|-C20-Alkyl, Cι-C20-Acyl, C1-C20- Acyloxy-Gruppen. Als Vertreter für die Schutzgruppen PG sind Alkyl- und/oder Aryl-substituiertes Silyl, Cι-C20-Alkyl, C4-C7-Cycloalkyl, das im Ring zusätzlich ein Sauerstoffatom enthalten kann, Aryl, C7-C20-Aralkyl, C<|-C20-Acyl sowie Aroyl zu nennen. Als Alkyl-, Silyl- und Acylreste für die Schutzgruppen PG kommen die dem Fachmann bekannten Reste in Betracht. Bevorzugt sind aus den entsprechenden Alkyl- und Silylethern leicht abspaltbare Alkyl- bzw. Silylreste, wie beispielsweise der Methoxymethyl-, Methoxyethyl, Ethoxyethyl-, Tetrahydropyranyl-, Tetrahydrofuranyl-, Trimethylsilyl-, Triethylsilyl-, tert.- Butyldimethylsilyl-, tert.-Butyldiphenylsilyl-, Tribenzylsilyl-, Triisopropylsilyl-, Benzyl, para-Nitrobenzyl-, para-Methoxybenzyl-Rest sowie Alkylsulfonyl- und Arylsulfonylreste. Als Acylreste kommen z.B. Formyl, Acetyl, Propionyl, Isopropionyl, Pivalyl-, Butyryl oder Benzoyl, die mit Amino- und/oder Hydroxygruppen substituiert sein können, in Frage. Als Aminoschutzgruppen kommen die dem Fachmann bekannten Reste in Betracht. Beispielsweise genannt seien die Alloc-, Boc-, Z-, Benzyl, f-Moc-, Troc-, Stabase- oder Benzostabase-Gruppe.The bi- and tricyclic aryl radicals G are substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms, such as, for example, naphthyl, anthryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzofuran, tololrahoxylolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinolinylinolinolinylinolinolinolinolinylinolinolinolinolinolinolinolinylolinolinolinolinolinolinolinolinolinylolinolinolinolinolinylinolinolinylolinoxin Thienopyridinyl, pyridopyridinyl, benzopyrazolyl, benzotriazolyl, dihydroindolyl, which can be mono- or polysubstituted by halogen, OH, O-alkyl, CO2H. CO 2 alkyl, -NH2, -NO 2 , -N 3 , -CN, C <| -C 2 o-alkyl, CiC ^ o-acyl, -C-C 2 o-acyloxy groups, in question. The aralkyl groups in R 1 a , Rl b, R2a > R 2b j R3 > R 4a 7 R4b R5, R 8, R10 J R1 1, Rl3b ; Rl4b Rl5a unc | Rl5b can contain up to 14 carbon atoms, preferably 6 to 10 and in the alkyl chain 1 to 8, preferably 1 to 4 atoms in the ring. Examples of suitable aralkyl radicals are benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl. The rings can be mono- or polysubstituted by halogen, OH, O-alkyl, CO2H, CO 2 -alkyl, -NO2, -N3, -CN, C <| -C20-alkyl, -C-C20-acyl, C1-C20- acyloxy groups. Representatives of the protective groups PG are alkyl- and / or aryl-substituted silyl, C 1 -C 20 -alkyl, C4-C7-cycloalkyl, which can additionally contain an oxygen atom in the ring, aryl, C7-C20-aralkyl, C <| - C20 acyl and aroyl to name. Suitable alkyl, silyl and acyl radicals for the protective groups PG are the radicals known to the person skilled in the art. Preferred are easily removable alkyl or silyl radicals from the corresponding alkyl and silyl ethers, such as, for example, methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenyl -, Tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl radical and alkylsulfonyl and arylsulfonyl radicals. Examples of suitable acyl radicals are formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl, which can be substituted with amino and / or hydroxyl groups. The residues known to the person skilled in the art are suitable as amino protecting groups. Examples include the Alloc, Boc, Z, benzyl, f-Moc, Troc, stabase or benzostabase group.
Die Acylgruppen PG können 1 bis 20 Kohlenstoffatome enthalten, wobei Formyl-, Acetyl-, Propionyl-, Isopropionyl und Pivalylgruppen bevorzugt sind. Der Index m in der aus R^a und R^ b gebildeten Alkylengruppe steht vorzugsweise für 1 , 2, 3 oder 4.The acyl groups PG can contain 1 to 20 carbon atoms, formyl, acetyl, propionyl, isopropionyl and pivalyl groups being preferred. The index m in the alkylene group formed from R ^ a and R ^ b is preferably 1, 2, 3 or 4.
Die für V, W und X mögliche C2-C-|o-Alkylen-α,ω-dioxygruppe ist vorzugsweise eine Ethylenketal- oder Neopentylketalgruppe.The C2-C- | o-alkylene-α, ω-dioxy group which is possible for V, W and X is preferably an ethylene ketal or neopentyl ketal group.
Darstellung der Teilfragmente A:Representation of partial fragments A:
Die Teilfragmente (Synthesebausteine) der allgemeinen Formel A lassen sich beispielsweise wie in WO 99/07692 oder DE 101 64 592.9 beschrieben herstellen.The partial fragments (synthesis building blocks) of the general formula A can be prepared, for example, as described in WO 99/07692 or DE 101 64 592.9.
Darstellung der Teilfragmente B:Representation of partial fragments B:
Die Teilfragmente (Synthesebausteine) der allgemeinen Formel B lassen sich beispielsweise wie in WO 99/07692 beschrieben herstellen.The partial fragments (synthesis building blocks) of the general formula B can be prepared, for example, as described in WO 99/07692.
Darstellung der Teilfragmente C: Die Teilfragmente (Synthesebausteine) der allgemeinen Formel C lassen sich beispielsweise wie in DE 197 51 200.3, DE 199 07 480.1 , WO 99/07692 und WO 00/01333 beschrieben, herstellen.Representation of the partial fragments C: The partial fragments (synthesis building blocks) of the general formula C can be prepared, for example, as described in DE 197 51 200.3, DE 199 07 480.1, WO 99/07692 and WO 00/01333.
Teilfragmente der allgemeinen Formel ABPartial fragments of the general formula AB
worin Ria", R2a'( R2b'; R4a'; R4b'> R5j R14't v und Z die bereits genannten Bedeutungen haben und PG"14 ein Wasserstoffatom oder eine Schutzgruppe PG darstellt, werden aus den zuvor genannten Fragmenten A und B nach dem in Schema 1 gezeigten Verfahren erhalten.in which Ria ", R2a ' (R 2b'; R4a '; R 4b '> R 5 j R 14 ' t v and Z have the meanings already mentioned and PG " 14 represents a hydrogen atom or a protective group PG are obtained from the aforementioned fragments A and B by the process shown in Scheme 1.
Schema 1Scheme 1
Schritt aa (A + B = AB):Step aa (A + B = AB):
Die Verbindung B, worin W die Bedeutung eines Sauerstoffatomes hat und eine eventuell vorhandene zusätzliche Carbonylgruppe in V bzw. eine eventuell vorhandene zusätzliche Hydroxygruppe in V (H/OR^6) geschützt sind, wird mit dem Enolat einer Carbonylverbindung der allgemeinen Formel A, gegebenenfalls in Gegenwart von Metallhalogeniden alkyliert. Das Enolat wird durch Einwirkung starker Basen wie z.B. Lithiumdiisopropylamid, Lithiumhexamethyldisilazan bei niedrigen Temperaturen hergestellt.The compound B, in which W has the meaning of an oxygen atom and a possibly present additional carbonyl group in V or a possibly present additional hydroxyl group in V (H / OR ^ 6 ) are protected, is optionally with the enolate of a carbonyl compound of the general formula A. alkylated in the presence of metal halides. The enolate will produced by the action of strong bases such as lithium diisopropylamide, lithium hexamethyldisilazane at low temperatures.
Teilfragmente der allgemeinen Formel ABC (AB + C)Partial fragments of the general formula ABC (AB + C)
ABC ABC
worin Ri a', Rlb', R2a'; R2b'> R3'; R43', R4b') R6, R7, R13, R14 G und Z die bereits genannten Bedeutungen haben und PG^ ein Wasserstoffatom oder eine Schutzgruppe PG darstellt, werden aus den zuvor beschriebenen Fragmenten AB und C nach dem in Schema 2 gezeigten Verfahren erhalten.wherein Ri a ', Rlb', R 2a '; R 2b '>R3'; R43 ', R 4b' ) R6, R 7, R 13, R 14 G and Z have the meanings already mentioned and PG ^ represents a hydrogen atom or a protective group PG, are obtained from the fragments AB and C described above by the process shown in Scheme 2.
Schema 2Scheme 2
AB ABC AB ABC
Schritt ac (AB + C => ABC):Step ac (AB + C => ABC):
Die Verbindung C, in der R21 die Bedeutung eines Phosphoniumhalogenid- restes PPh3+Hal", vorzugsweise eines PPh3+l" -Restes oder eines Phosphonatrestes oder eines Phosphinoxidrestes hat und eventuell vorhandene zusätzliche Carbonylgruppen gegebenenfalls geschützt sind, wird durch eine geeignete Base wie z.B. n-Butyllithium, Lithiumdiisopropylamid, Kalium- tert.butanolat, Natrium- oder Lithium-hexamethyldisilazid deprotoniert und mit einer Verbindung AB, worin V die Bedeutung eines Sauerstoffatomes hat, umgesetzt.The compound C, in which R21 has the meaning of a phosphonium halide residue PPh3 + Hal ", preferably a PPh3 + 1" residue or a phosphonate residue or a phosphine oxide residue and any additional carbonyl groups which may be present, is protected by a Suitable base such as n-butyllithium, lithium diisopropylamide, potassium tert-butoxide, sodium or lithium hexamethyldisilazide deprotonated and reacted with a compound AB, in which V has the meaning of an oxygen atom.
Das so erhaltene Fragment ABC, das die Ringkohlenstoffatome C1 bis C15 des späteren 16-gliedrigen Makrozyklus enthält, wird beispielsweise nach den in WO 99/07692, WO 99/049154 oder WO 00/01333 beschriebenen Verfahren in die gewünschten Zielverbindungen wie sie in gleichnamigen Patentanmeldungen genannt sind, überführt.The fragment ABC thus obtained, which contains the ring carbon atoms C1 to C15 of the later 16-membered macrocycle, is, for example, according to the methods described in WO 99/07692, WO 99/049154 or WO 00/01333 in the desired target compounds as described in the same patent applications are transferred.
Die Erfindung betrifft daher auch ein Verfahren zur Herstellung der Epothilon- Derivate der allgemeinen Formel IIThe invention therefore also relates to a process for the preparation of the epothilone derivatives of the general formula II
worin A-K eine Gruppe -O-C(=O), -OCH2-, -CH2C(=O)-, -NR29-C(=O)-, -NR29-where AK is a group -OC (= O), -OCH 2 -, -CH 2 C (= O) -, -NR 29 -C (= O) -, -NR 29 -
SO2- bedeutet, und die Substituenten R1a, R1b, R2a, R2b, R3, R4a, R4b, R5, R6, R7,SO 2 - and the substituents R 1a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 ,
G, OPG2 und Z die in der allgemeinen Formel I angegebenen Bedeutungen haben, bei dem Verbindungen der allgemeinen Formel I, erhalten nach dem erfindungsgemäßen Verfahren, zu Verbindungen der allgemeinen Formel II cyclisiert werden.G, OPG 2 and Z have the meanings given in the general formula I, in which compounds of the general formula I obtained by the process according to the invention are cyclized to give compounds of the general formula II.
Durch das hier beschriebene Verfahren (A+B => AB + C = ABC) gelingt es, das synthetisch aufwendiger herzustellende Fragment C zuletzt einzuführen. Dadurch reduzieren sich die Mengen an benötigtem Fragment C im Vergleich zur Verknüpfungsreihenfolge C+B = BC + A => ABC, was sowohl ökonomisch als ökologisch für die Herstellung des Fragmentes ABC von Vorteil ist. Beispiel 1The process described here (A + B => AB + C = ABC) succeeds in introducing the fragment C, which is more complex to produce synthetically, last. This reduces the amount of fragment C required in comparison to the linking sequence C + B = BC + A => ABC, which is economically and ecologically advantageous for the production of the fragment ABC. example 1
(SS.eRJS.δS.^Z.IδSJ^^.δ.^-Tetramethyl-δ-oxo-e-allyl-Sy.lδ-tris^tert.- butyldimethylsilyloxy)-15-(2-methylbenzothiazol-5-yl)-pentadec-12-ensäure(SS.eRJS.δS. ^ Z.IδSJ ^^. Δ. ^ - Tetramethyl-δ-oxo-e-allyl-Sy.lδ-tris ^ tert.-butyldimethylsilyloxy) -15- (2-methylbenzothiazol-5-yl ) -pentadec-12-enoic acid
Beispiel 1aExample 1a
(4S,4,R,5,S)6'S,10,RS)-4-(2)6-Dimethyl-3-oxo-4-allyl-5-hydroxy-10-(tert.- butyldiphenylsilyloxy)-undecan-2-yl)-2,2-dimethyl-1 ,3-dioxan (A) und (4S,4,R,5,S,6,S,10,RS)-4-(2,6-Dimethyl-3-oxo-4-allyl-5-hydroxy-10-(tert.- butyldiphenylsilyloxy)-undecan-2-yl)-2,2-dimethyl-1 ,3-dioxan (B) Die Lösung von 13,8 ml Diisopropylamin in 350 ml wasserfreiem Tetrahydrofuran versetzt man bei -30°C untereiner Atmosphäre aus trockenem Argon mit 39,5 ml einer 2,5molaren Lösung von n-Buthyllithium in n-Hexan, rührt 30 Minuten und kühlt auf -70°C. Innerhalb von 20 Minuten tropft man die Lösung von 22,6 g (94 mmol) (4S)-4-(2-Methyl-3-oxo-hept-6-en-2-yl)-2,2- dimethyl-1 ,3-dioxan, das man in Analogie zu dem in WO 99/07692, WO 99049154, WO 00/01333 beschriebenen Verfahren hergestellt hat, in 350 ml Tetrahydrofuran zu und läßt innerhalb von 2 Stunden auf -30°C erwärmen. Anschließend kühlt man erneut auf -70°C, versetzt mit der Lösung von 12,8 g wasserfreiem Zinkchlorid in 130 ml Tetrahydrofuran und tropft nach 15 Minuten die Lösung von 16,8 g (43,9 mmol) m(2S,6RS)-2-Methyl-6-(tert.-butyl- diphenylsilyloxy)-heptanal, das man in Analogie zu dem in WO 99/07692, WO 99049154, WO 00/01333 beschriebenen Verfahren hergestellt hat, in 400 ml Tetrahydrofuran zu. Man rührt noch 2,5 Stunden bei -70°C, gießt in eine gesättigte Ammoniumchloridlösung und extrahiert mehrfach mit Ethylacetat. Die vereinigten organischen Extrakte wäscht man mit Wasser und gesättigter Natriumchloridlösung, trocknet über Natriumsulfat und reinigt den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand durch Chromatographie an feinem Kieselgel mit einem Laufmittelgemisch aus n-Hexan und Ethylacetat. Isoliert werden 19,8 g (31 ,8 mmol, 72%) der Titelverbindung A, 2,28 g (3,7 mmol, 8%) der Titelverbindung B sowie 12,5g (4S)-4-(2-Methyl-3-oxo-hept-6-en- 2-yl)-2,2-dimethyl-1.3-dioxan jeweils als farbloses Öl.(4S, 4 , R, 5 , S ) 6'S, 10 , RS) -4- (2 ) 6-dimethyl-3-oxo-4-allyl-5-hydroxy-10- (tert-butyldiphenylsilyloxy) -undecane 2-yl) -2,2-dimethyl-1, 3-dioxane (A) and (4S, 4 , R, 5 , S, 6 , S, 10 , RS) -4- (2,6-dimethyl-3 -oxo-4-allyl-5-hydroxy-10- (tert-butyldiphenylsilyloxy) -undecan-2-yl) -2,2-dimethyl-1, 3-dioxane (B) The solution of 13.8 ml diisopropylamine in 350 ml of anhydrous tetrahydrofuran are added at -30 ° C under an atmosphere of dry argon with 39.5 ml of a 2.5 molar solution of n-butyllithium in n-hexane, stirred for 30 minutes and cooled to -70 ° C. The solution of 22.6 g (94 mmol) of (4S) -4- (2-methyl-3-oxo-hept-6-en-2-yl) -2,2-dimethyl-1 is added dropwise within 20 minutes , 3-dioxane, which was prepared in analogy to the process described in WO 99/07692, WO 99049154, WO 00/01333, in 350 ml of tetrahydrofuran and allowed to warm to -30 ° C. in the course of 2 hours. The mixture is then cooled again to -70 ° C., the solution of 12.8 g of anhydrous zinc chloride in 130 ml of tetrahydrofuran is added and, after 15 minutes, the solution of 16.8 g (43.9 mmol) m (2S, 6RS) - 2-Methyl-6- (tert-butyl-diphenylsilyloxy) -heptanal, which has been prepared in analogy to the process described in WO 99/07692, WO 99049154, WO 00/01333, in 400 ml of tetrahydrofuran. The mixture is stirred for a further 2.5 hours at -70 ° C., poured into a saturated ammonium chloride solution and extracted several times with ethyl acetate. The combined organic extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate and the residue obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel using a mobile phase mixture of n-hexane and ethyl acetate. 19.8 g (31.8 mmol, 72%) of the title compound A, 2.28 g (3.7 mmol, 8%) of the title compound B and 12.5 g (4S) -4- (2-methyl- 3-oxo-hept-6-en-2-yl) -2,2-dimethyl-1,3-dioxane each as a colorless oil.
1 H-NMR (CDCI3) von A: δ= 0,80 (3H), 0,96-1 ,06 (16H), 1 ,10-1 ,74 (4H), 1 ,23 (3H), 1 ,30 (3H), 1 ,37 (3H), 1 ,57 (3H), 2,21 (1 H), 2,43 (1 H), 2,88 (1 H), 3,32 (1 H), 3,44 (1 H), 3,86 (2H), 3,97 (1 H), 4,12 (2H), 4,97 (1 H), 5,03 (1 H), 5,70 (1H), 7,31- 7,44 (6H), 7,64-7,70 (4H) ppm.1 H-NMR (CDCI3) of A: δ = 0.80 (3H), 0.96-1, 06 (16H), 1, 10-1, 74 (4H), 1, 23 (3H), 1, 30 (3H), 1, 37 (3H), 1, 57 (3H), 2.21 (1 H), 2.43 (1 H), 2.88 (1 H), 3.32 (1 H) , 3.44 (1H), 3.86 (2H), 3.97 (1H), 4.12 (2H), 4.97 (1H), 5.03 (1H), 5.70 (1H), 7.31-7.44 (6H), 7.64-7.70 (4H) ppm.
1H-NMR (CDCI3) von B: δ= 0,89-1 ,55 (36H), 1 ,66 (1H), 2,30 (1H), 2,40 (1H), 2,66 (1 H), 3,28 (1 H), 3,51 (1 H), 3,78-417 (3H), 4,97 (1 H), 5,03 (1 H), 5,70 (1 H), 7,32-7,46 (6H), 7,64-7,71 (4H) ppm. Beispiel 1 b1H-NMR (CDCI3) of B: δ = 0.89-1, 55 (36H), 1.66 (1H), 2.30 (1H), 2.40 (1H), 2.66 (1H) , 3.28 (1H), 3.51 (1H), 3.78-417 (3H), 4.97 (1H), 5.03 (1H), 5.70 (1H), 7.32-7.46 (6H), 7.64-7.71 (4H) ppm. Example 1 b
(4S,4'R,5,S,6,S)10,RS)-4-(2,6-Dimethyl-3-oxo-4-allyl-5-(2H-tetrahydropyran-2- yloxy)-10-(tert.-butyldiphenylsilyloxy)-undecan-2-yl)-2,2-dimethyl-1 ,3-dioxan Die Lösung von 19,7 g (31 ,7 mmol) der nach Beispiel 1a dargestellten Verbindung A in 500 ml wasserfreiem Dichlormethan versetzt man mit 40 ml 3,4-Dihydro-(2H)-pyran, 1 ,6 g p-Toluolsulfonsäure-Pyridiniumsalz und rührt 2 Tage bei 23°C. Man gießt auf eine gesättigte Natriumhydrogencarbonatlösung, extrahiert mit Dichlormethan und trocknet die vereinigten organischen Extrakte über Natriumsulfat. Nach Filtration und Lösungsmittelabzug reinigt man den Rückstand durch Chromatographie an feinem Kieselgel mit einem Laufmittelgemisch aus n-Hexan und Ethylacetat. Isoliert werden 22,0 g (31 ,1 mmol, 98%) der Titelverbindung als farbloses Öl. H-NMR (CDCI3): δ= 0,87-1 ,91 (42H), 2,14-2,41 (1 H), 2,57 (1 H), 3,14-4,28 (8H), 4,40-4,53 (1H), 4,90-5,05 (2H), 5,58-5,89 (1H), 7,31-7,45 (6H), 7,64-7,70 (4H) ppm.(4S, 4'R, 5 , S, 6 , S ) 10 , RS) -4- (2,6-dimethyl-3-oxo-4-allyl-5- (2H-tetrahydropyran-2-yloxy) -10 - (tert-Butyldiphenylsilyloxy) -undecan-2-yl) -2,2-dimethyl-1, 3-dioxane The solution of 19.7 g (31.7 mmol) of compound A shown in Example 1a in 500 ml of anhydrous Dichloromethane is mixed with 40 ml of 3,4-dihydro- (2H) -pyran, 1.6 g of p-toluenesulfonic acid pyridinium salt and stirred at 23 ° C. for 2 days. It is poured onto a saturated sodium hydrogen carbonate solution, extracted with dichloromethane and the combined organic extracts are dried over sodium sulfate. After filtration and removal of the solvent, the residue is purified by chromatography on fine silica gel with a mobile phase mixture of n-hexane and ethyl acetate. 22.0 g (31.1 mmol, 98%) of the title compound are isolated as a colorless oil. H-NMR (CDCI3): δ = 0.87-1, 91 (42H), 2.14-2.41 (1 H), 2.57 (1 H), 3.14-4.28 (8H) , 4.40-4.53 (1H), 4.90-5.05 (2H), 5.58-5.89 (1H), 7.31-7.45 (6H), 7.64-7 , 70 (4H) ppm.
Beispiel 1c (4S,4'R,5,S,6,S,10,RS)-4-(2,6-Dimethyl-3-oxo-4-allyl-5-(2H-tetrahydropyran-2- yloxy)-10-hydroxy-undecan-2-yl)-2,2-dimethyl-1 ,3-dioxanExample 1c (4S, 4'R, 5 , S, 6 , S, 10 , RS) -4- (2,6-dimethyl-3-oxo-4-allyl-5- (2H-tetrahydropyran-2-yloxy) -10-hydroxy-undecan-2-yl) -2,2-dimethyl-1, 3-dioxane
Die Lösung von 22,0 g (31 ,1 mmol) der nach Beispiel 1b dargestellten Verbindung in 400 ml Tetrahydrofuran versetzt man mit 62,3 ml einer 1 molaren Lösung von Tetrabutylammoniumfluorid in Tetrahydrofuran und rührt 12 Stunden bei 80°C. Man gießt in eine gesättigte Natriumchloridlösung, verdünnt mit Wasser und extrahiert mehrfach mit Ethylacetat. Die vereinigten organischen Extrakte trocknet man über Natriumsulfat und reinigt den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand durch Chromatographie an feinem Kieselgel mit einem Laufmittelgemisch aus n- Hexan und Ethylacetat. Isoliert werden 13,6 g (29,0 mmol, 93%) der Titelverbindung als farbloses Öl. H-NMR (CDCI3): δ= 0,91-1 ,81 (34H), 2,14-2,42 (1 H), 2,58 (1 H), 3,15-3,46 (2H), 3,63-4,29 (6H), 4,38-4,57 (1 H), 4,89-5,06 (2H), 5,57-5,88 (1 H) ppm.The solution of 22.0 g (31.1 mmol) of the compound shown in Example 1b in 400 ml of tetrahydrofuran is mixed with 62.3 ml of a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran and stirred at 80 ° C. for 12 hours. It is poured into a saturated sodium chloride solution, diluted with water and extracted several times with ethyl acetate. The combined organic extracts are dried over sodium sulfate and the residue obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel with a mobile phase mixture of n-hexane and ethyl acetate. 13.6 g (29.0 mmol, 93%) of the title compound are isolated as a colorless oil. H-NMR (CDCI3): δ = 0.91-1, 81 (34H), 2.14-2.42 (1 H), 2.58 (1 H), 3.15-3.46 (2H) , 3.63-4.29 (6H), 4.38-4.57 (1H), 4.89-5.06 (2H), 5.57-5.88 (1H) ppm.
Beispiel 1d (4S,4,R,5'S,6,S)-4-(2,6-Dimethyl-3,10-dioxo-4-allyl-5-(2H-tetrahydropyran-2- yloxy)-undecan-2-yl)-2,2-dimethyl-1 ,3-dioxanExample 1d (4S, 4 , R, 5'S, 6 , S) -4- (2,6-dimethyl-3,10-dioxo-4-allyl-5- (2H-tetrahydropyran-2-yloxy) -undecane-2 -yl) -2,2-dimethyl-1,3-dioxane
Die Lösung von 13,6 g (29,0 mmol) der nach Beispiel 1c dargestellten Verbindung in 480 ml wasserfreiem Dichlormethan versetzt man ca. 1g Molekularsieb (4A), 6,06 g N-Methylmorpholin-N-Oxid, 400 mg Tetrapropylammoiniumperruthenat und rührt 18 Stunden bei 23°C. Man engt ein und reinigt den Rückstand durch Chromatographie an feinem Kieselgel mit einem Laufmittelgemisch aus n-Hexan und Ethylacetat. Isoliert werden 11 ,6 g (24,9 mmol, 86%) der Titelverbindung als farbloses Öl.About 1g is added to the solution of 13.6 g (29.0 mmol) of the compound shown in Example 1c in 480 ml of anhydrous dichloromethane Molecular sieve (4A), 6.06 g of N-methylmorpholine-N-oxide, 400 mg of tetrapropylammoinium perruthenate and stirred for 18 hours at 23 ° C. The mixture is concentrated and the residue is purified by chromatography on fine silica gel with a mobile phase mixture of n-hexane and ethyl acetate. 11.6 g (24.9 mmol, 86%) of the title compound are isolated as a colorless oil.
1 H-NMR (CDCI3): δ= 0,91-1 ,83 (29H), 2,13 (3H), 2,05-2,63 (4H), 3,15-4,02 (5H), 4,22 (1 H), 4,40+4,51 (1 H), 4,90-5,05 (2H), 5,57-5,δδ (1 H) ppm.1 H-NMR (CDCI3): δ = 0.91-1, 83 (29H), 2.13 (3H), 2.05-2.63 (4H), 3.15-4.02 (5H), 4.22 (1H), 4.40 + 4.51 (1H), 4.90-5.05 (2H), 5.57-5, δδ (1H) ppm.
Beispiel 1e (4S,4,R,5,S,6,S,10Ε/Z,13,S)-4-(2,6,10-Trimethyl-3-oxo-4-allyl-5-(2H- tetrahydropyran-2-yloxy)-13-(2-methylbenzothiazol-5-yl)-13-(tert- butyldimethylsilyloxy)-tridec-10-ene-2-yl)-2,2-dimethyl-1 ,3-dioxane Die Lösung von 6,72 g [(3S)-3-(2-methylbenzothiazol-5-yl)-3-(tert.- butyldimethylsilyloxy)-propyl]-triphenylphosphonium iodid, das man in Analogie zu dem in WO 99/07692, WO 99049154, WO 00/01333 beschriebenen Verfahren hergestellt hat, in 45 ml wasserfreiem Tetrahydrofuran versetzt man bei 0°C mit 9,5 ml einer 1 molaren Lösung von Natriumhexamethyldisilazan in Tetrahydrofuran und anschließend mit der Lösung von 3,0 g (6,43 mmol) der nach Beispiel 1d dargestellten Verbindung in 45 ml Tetrahydrofuran. Man läßt 5 Stunden bei 23°C reagieren, gießt in eine gesättigte Ammoniumchloridlösung und extrahiert mehrfach mit Ethylacetat. Die vereinigten organischen Extrakte wäscht man mit Wasser und gesättigter Natriumchloridlösung, trocknet über Natriumsulfat und reinigt den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand durch Chromatographie an feinem Kieselgel mit einem Laufmittelgemisch aus n-Hexan und Ethylacetat. Isoliert werden 4,25 g (5,52 mmol, 86%) der Titelverbindung als farbloses Öl.Example 1e (4S, 4 , R, 5 , S, 6 , S, 10Ε / Z, 13 , S) -4- (2,6,10-trimethyl-3-oxo-4-allyl-5- (2H- tetrahydropyran-2-yloxy) -13- (2-methylbenzothiazol-5-yl) -13- (tert-butyldimethylsilyloxy) -tridec-10-ene-2-yl) -2,2-dimethyl-1, 3-dioxane Solution of 6.72 g of [(3S) -3- (2-methylbenzothiazol-5-yl) -3- (tert-butyldimethylsilyloxy) propyl] triphenylphosphonium iodide, which is analogous to that described in WO 99/07692, WO 99049154, WO 00/01333 has prepared, in 45 ml of anhydrous tetrahydrofuran, 9.5 ml of a 1 molar solution of sodium hexamethyldisilazane in tetrahydrofuran are added at 0 ° C. and then the solution of 3.0 g (6.43 mmol) of the compound shown in Example 1d in 45 ml of tetrahydrofuran. The mixture is left to react at 23 ° C. for 5 hours, poured into a saturated ammonium chloride solution and extracted several times with ethyl acetate. The combined organic extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate and the residue obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel using a mobile phase mixture of n-hexane and ethyl acetate. 4.25 g (5.52 mmol, 86%) of the title compound are isolated as a colorless oil.
1 H-NMR (CDCI3): δ= -0,12 (3H), 0,03 (3H), 0,88 (9H), 0,82-2,65 (37H), 2,83 (3H), 3,14-4,29 (7H), 4,40-4,56 (1 H), 4,73 (1 H), 4,88-5,04 (2H), 5,15 (1 H), 5,58- 5,89 (1 H), 7,32 (1H), 7,72 (1 H), 7,36 (1 H) ppm.1 H-NMR (CDCI3): δ = -0.12 (3H), 0.03 (3H), 0.88 (9H), 0.82-2.65 (37H), 2.83 (3H), 3.14-4.29 (7H), 4.40-4.56 (1H), 4.73 (1H), 4.88-5.04 (2H), 5.15 (1H), 5.58-5.89 (1H), 7.32 (1H), 7.72 (1H), 7.36 (1H) ppm.
Beispiel 1fExample 1f
(3S,6R,7S,8S,12E/Z,15S)-4,4,8,12-Tetramethyl-5-oxo-6-allyl-15-(tert.- butyldimethylsilyloxy)-15-(2-methylbenzothiazol-5-yl)-pentadec-12-en-1 ,3,7-triol Die Lösung von 10,3 g (13,4 mmol) der nach Beispiel 1e dargestellten Verbindung in 270 ml Ethanol versetzt man mit 5,33 g p-Toluolsulfonsäure- Monohydrat und rührt 5 Stunden bei 23°C. Man engt ein, nimmt den Rückstand in Dichlormethan auf, wäscht mit gesättigter Natriumhydrogencarbonatlösung und trocknet über Natriumsulfat. Das nach Filtration und Lösungsmittelabzug erhaltene Rohprodukt wird ohne Reinigung weiter umgesetzt.(3S, 6R, 7S, 8S, 12E / Z, 15S) -4,4,8,12-tetramethyl-5-oxo-6-allyl-15- (tert-butyldimethylsilyloxy) -15- (2-methylbenzothiazole- 5-yl) -pentadec-12-en-1, 3,7-triol The solution of 10.3 g (13.4 mmol) of the compound shown in Example 1e in 270 ml of ethanol is mixed with 5.33 g of p- Toluenesulfonic acid monohydrate and stirred at 23 ° C for 5 hours. The mixture is concentrated, the residue is taken up in dichloromethane and washed with saturated sodium bicarbonate solution and dries over sodium sulfate. The crude product obtained after filtration and removal of solvent is reacted further without purification.
Beispiel 1g (3S,6R,7S,8S,12E/Z,15S)-4,4,δ,12-Tetramethyl-6-allyl-1 ,3,7,15-tetrakis-(tert.- butyldimethylsilyloxy)-15-(2-methylbenzothiazol-5-yl)-pentadec-12-en-5-on Die Lösung des nach Beispiel 1f dargestellten Rohproduktes (max. 13,4 mmol) in 340 ml wasserfreiem Dichlormethan versetzt man bei 0°C mit 20,8 ml 2,6- Lutidin, 20,2 ml Trifluormethansulfonsäure-(tert.-butyldimethylsilylester) und rührt 4 Stunden bei 0°C bis 23°C. Man wäscht mit einer 1 molaren Salzsäure, anschließend mit gesättigter Natriumhydrogencarbonatlösung und trocknet über Natriumsulfat. Nach Filtration und Lösungsmittelabzug reinigt man den Rückstand durch Chromatographie an feinem Kieselgel mit einem Laufmittelgemisch aus n-Hexan und Ethylacetat. Isoliert werden 12,0 g (12,1 mmol, 91 %) der Titelverbindung als farbloses Öl. H-NMR (CDCI3): δ= -0,13-0,08 (24H), 0,88 (36H), 0,89-1 ,67 (19H), 1 ,91 (2H), 2,19-2,52 (4H), 2,83 (3H), 3,13 (1 H), 3,49-3,71 (2H), 3,75 (1 H), 3,85 (1 H), 4,74 (1 H), 4,92 (1 H), 4,98 (1 H), 5,15 (1 H), 5,75 (1 H), 7,32 (1 H), 7,73 (1 H), 7,86 (1 H) ppm.Example 1g (3S, 6R, 7S, 8S, 12E / Z, 15S) -4.4, δ, 12-tetramethyl-6-allyl-1, 3,7,15-tetrakis (tert-butyldimethylsilyloxy) -15 - (2-methylbenzothiazol-5-yl) -pentadec-12-en-5-one The solution of the crude product shown in Example 1f (max. 13.4 mmol) in 340 ml of anhydrous dichloromethane is mixed at 0 ° C. with 20. 8 ml of 2,6-lutidine, 20.2 ml of trifluoromethanesulfonic acid (tert-butyldimethylsilyl ester) and stirred for 4 hours at 0 ° C. to 23 ° C. It is washed with 1 molar hydrochloric acid, then with saturated sodium bicarbonate solution and dried over sodium sulfate. After filtration and removal of the solvent, the residue is purified by chromatography on fine silica gel with a mobile phase mixture of n-hexane and ethyl acetate. 12.0 g (12.1 mmol, 91%) of the title compound are isolated as a colorless oil. H-NMR (CDCI3): δ = -0.13-0.08 (24H), 0.88 (36H), 0.89-1, 67 (19H), 1.91 (2H), 2.19- 2.52 (4H), 2.83 (3H), 3.13 (1H), 3.49-3.71 (2H), 3.75 (1H), 3.85 (1H), 4 , 74 (1H), 4.92 (1H), 4.98 (1H), 5.15 (1H), 5.75 (1H), 7.32 (1H), 7.73 (1H), 7.86 (1H) ppm.
Beispiel 1hExample 1h
(3S,6R,7S,8S,12E/Z,15S)-4,4,δ,12-Tetramethyl-6-allyl-1-hydroxy-3,7,15-tris- (tert.-butyldimethylsilyloxy)-15-(2-methylbenzothiazol-5-yl)-pentadec-12-en-5-on Die Lösung von 12,0 g (12,1 mmol) der nach Beispiel 1g dargestellten Verbindung in einem Gemisch aus 205 ml Dichlormethan und 100 ml Methanol versetzt man bei 0°C mit 2,68 g rac.-Campher-10-Sulfonsäure und rührt 3 Stunden bei 0°C. Man gießt auf eine gesättigte Natriumhydrogencarbonatlösung, extrahiert mit Dichlormethan und trocknet die vereinigten organischen Extrakte über Natriumsulfat. Nach Filtration und Lösungsmittelabzug reinigt man den Rückstand durch Chromatographie an feinem Kieselgel mit einem Laufmittelgemisch aus n-Hexan und Ethylacetat. Isoliert werden 9,07 g (10,4 mmol, 86%) der Titelverbindung als farbloses Öl. 1 H-NMR (CDCI3): δ= -0,13 (3H), 0,01-0,11 (15H), 0,80-0,95 (30H), 0,99-1 ,68 (13H), 1 ,48+1 ,65 (3H), 1 ,86-2,00 (3H), 2,20-2,52 (4H), 2,83 (3H), 3,12 (1 H), 3,65 (2H), 3,77 (1 H), 4,03 (1 H), 4,74 (1 H), 4,91-5,03 (2H), 5,16 (1 H), 5,75 (1 H), 7,32 (1 H), 7,73 (1 H), 7,86 (1 H) ppm.(3S, 6R, 7S, 8S, 12E / Z, 15S) -4.4, δ, 12-tetramethyl-6-allyl-1-hydroxy-3,7,15-tris (tert-butyldimethylsilyloxy) -15 - (2-methylbenzothiazol-5-yl) -pentadec-12-en-5-one The solution of 12.0 g (12.1 mmol) of the compound shown in Example 1g in a mixture of 205 ml of dichloromethane and 100 ml of methanol 2.68 g of rac.-camphor-10-sulfonic acid are added at 0 ° C. and the mixture is stirred at 0 ° C. for 3 hours. It is poured onto a saturated sodium hydrogen carbonate solution, extracted with dichloromethane and the combined organic extracts are dried over sodium sulfate. After filtration and removal of the solvent, the residue is purified by chromatography on fine silica gel with a mobile phase mixture of n-hexane and ethyl acetate. 9.07 g (10.4 mmol, 86%) of the title compound are isolated as a colorless oil. 1 H-NMR (CDCI3): δ = -0.13 (3H), 0.01-0.11 (15H), 0.80-0.95 (30H), 0.99-1, 68 (13H) , 1, 48 + 1, 65 (3H), 1, 86-2.00 (3H), 2.20-2.52 (4H), 2.83 (3H), 3.12 (1H), 3rd , 65 (2H), 3.77 (1H), 4.03 (1H), 4.74 (1H), 4.91-5.03 (2H), 5.16 (1H), 5th , 75 (1H), 7.32 (1H), 7.73 (1H), 7.86 (1H) ppm.
Beispiel 1 i (3S,6R,7S,8S,12E/Z,15S)-4 ,4,8,12-Tetramethyl-5-oxo-6-allyl-3,7,15-tris-(tert- butyldimethylsilyloxy)-15-(2-methylbenzothiazol-5-yl)-pentadec-12-enalExample 1 i (3S, 6R, 7S, 8S, 12E / Z, 15S) -4, 4,8,12-tetramethyl-5-oxo-6-allyl-3,7,15-tris- (tert-butyldimethylsilyloxy) -15- (2-methyl-benzothiazol-5-yl) -pentadec-12-enal
Die Lösung von 1 ,81 ml Oxalylchlorid in 95 ml wasserfreiem Dichlormethan versetzt man bei -70°C mit der Lösung von 2,94 ml Dimethylsulfoxid in 10 ml Dichlormethan und nach 10 Minuten mit der Lösung von 9,07 g (10,4 mmol) der nach Beispiel 1h dargestellten Verbindung in 95 ml Dichlormethan. Man rührt 30 Minuten bei -70°C, versetzt mit 9,2 ml Triethylamin und rührt weitere 30 Minuten bei -20°C. Man gießt auf eine gesättigte Natriumhydrogencarbonatlösung, extrahiert mit Dichlormethan und trocknet die vereinigten organischen Extrakte über Natriumsulfat. Nach Filtration und Lösungsmittelabzug reinigt man den Rückstand durch Chromatographie an feinem Kieselgel mit einem Laufmittelgemisch aus n-Hexan und Ethylacetat. Isoliert werden 8,83 g (10,1 mmol, 97%) der Titelverbindung als blass gelbes Öl.The solution of 1.81 ml of oxalyl chloride in 95 ml of anhydrous dichloromethane is mixed at -70 ° C. with the solution of 2.94 ml of dimethyl sulfoxide in 10 ml of dichloromethane and after 10 minutes with the solution of 9.07 g (10.4 mmol ) the compound shown in Example 1h in 95 ml dichloromethane. The mixture is stirred at -70 ° C. for 30 minutes, 9.2 ml of triethylamine are added and the mixture is stirred at -20 ° C. for a further 30 minutes. It is poured onto a saturated sodium hydrogen carbonate solution, extracted with dichloromethane and the combined organic extracts are dried over sodium sulfate. After filtration and removal of the solvent, the residue is purified by chromatography on fine silica gel with a mobile phase mixture of n-hexane and ethyl acetate. 8.83 g (10.1 mmol, 97%) of the title compound are isolated as a pale yellow oil.
Beispiel 1kExample 1k
(3S,6R,7S,8S,12Z,15S)-4 ,4,8,12-Tetramethyl-5-oxo-6-allyl-3,7,15-tris-(tert.- butyldimethylsilyloxy)-15-(2-methylbenzothiazol-5-yl)-pentadec-12-ensäure (A) und (3S,6R,7S,8S,12E,15S)-4,4,8,12-Tetramethyl-5-oxo-6-allyl-3,7,15-tris-(tert.- butyldimethylsilyloxy)-15-(2-methylbenzothiazol-5-yl)-pentadec-12-ensäure (B) Die Lösung von 8,83 g (10,1 mmol) der nach Beispiel 1i dargestellten Verbindung in einem Gemisch aus 310 ml tert.-Butanol, 235 ml Tetrahydrofuran und 78 ml Wasser versetzt man bei 0°C mit 4,41 g Natriumdihydrogenphosphat- Monohydrat, 70 ml 2-Methyl-2-buten, 7,5 g Natriumchlorit und rührt 1 Stunde bei 0°C. Man gießt auf eine gesättigte Natriumthiosulfatlösung, extrahiert mit Ethylacetat und trocknet die vereinigten organischen Extrakte über Natriumsulfat. Nach Filtration und Lösungsmittelabzug reinigt man den Rückstand durch Chromatographie an feinem Kieselgel mit einem Laufmittelgemisch aus n-Hexan und Ethylacetat. Isoliert werden 3,86 g (4,34 mmol, 43%) der Titelverbindung A sowie 3,96 g (4,46 mmol, 44%) der Titelverbindung B jeweils als farbloses Öl.(3S, 6R, 7S, 8S, 12Z, 15S) -4, 4,8,12-tetramethyl-5-oxo-6-allyl-3,7,15-tris- (tert-butyldimethylsilyloxy) -15- ( 2-methylbenzothiazol-5-yl) pentadec-12-enoic acid (A) and (3S, 6R, 7S, 8S, 12E, 15S) -4,4,8,12-tetramethyl-5-oxo-6-allyl- 3,7,15-tris- (tert-butyldimethylsilyloxy) -15- (2-methylbenzothiazol-5-yl) -pentadec-12-enoic acid (B) The solution of 8.83 g (10.1 mmol) of the after Example 1i compound shown in a mixture of 310 ml of tert-butanol, 235 ml of tetrahydrofuran and 78 ml of water is mixed at 0 ° C with 4.41 g of sodium dihydrogen phosphate monohydrate, 70 ml of 2-methyl-2-butene, 7.5 g of sodium chlorite and stir at 0 ° C for 1 hour. It is poured onto a saturated sodium thiosulfate solution, extracted with ethyl acetate and the combined organic extracts are dried over sodium sulfate. After filtration and removal of the solvent, the residue is purified by chromatography on fine silica gel with a mobile phase mixture of n-hexane and ethyl acetate. 3.86 g (4.34 mmol, 43%) of the title compound A and 3.96 g (4.46 mmol, 44%) of the title compound B are isolated in each case as a colorless oil.
1 H-NMR (CDCI3) von A: δ= -0.12 (3H), -0.03 (3H), 0.00 (3H), 0.07 (6H), 0.15 (3H), 0.85-0.90 (27H), 0.96 (3H), 1.03-1.95 (4H), 1.06 (3H), 1.18 (3H), 1.73 (3H), 1.74-1.95 (3H), 2.22-2.60 (7H), 2.33 (3H), 3.20 (1 H), 3.66 (1 H), 4.46 (1 H), 4.79 (1 H), 4.93 (1 H), 4.99 (1 H), 5.29 (1 H), 5.71 (1 H), 7.47 (1 H), 7.75 (1 H), 8.28 (1 H) ppm.1 H-NMR (CDCI3) of A: δ = -0.12 (3H), -0.03 (3H), 0.00 (3H), 0.07 (6H), 0.15 (3H), 0.85-0.90 (27H), 0.96 (3H) , 1.03-1.95 (4H), 1.06 (3H), 1.18 (3H), 1.73 (3H), 1.74-1.95 (3H), 2.22-2.60 (7H), 2.33 (3H), 3.20 (1H), 3.66 ( 1 H), 4.46 (1 H), 4.79 (1 H), 4.93 (1 H), 4.99 (1 H), 5.29 (1 H), 5.71 (1 H), 7.47 (1 H), 7.75 (1 H ), 8.28 (1H) ppm.
1 H-NMR (CDCI3) von B: δ= -0,10 (3H), 0,01 (6H), 0,06 (3H), 0,12 (3H), 0,16 (3H), 0,89 (30H), 1 ,00-1 ,48 (5H), 1 ,11 (3H), 1 ,21 (3H), 1 ,34 (3H), 1 ,76-2,03 (2H), 2,25-2,64 (6H), 2,84 (3H), 3,24 (1 H), 3,80 (1 H), 4,35 (1 H), 4,67 (1 H), 4,93- 5,04 (2H), 5,12 (1 H), 5,76 (1 H), 7,46 (1 H), 7,75 (1 H), 7,82 (1 H) ppm.1 H-NMR (CDCI3) of B: δ = -0.10 (3H), 0.01 (6H), 0.06 (3H), 0.12 (3H), 0.16 (3H), 0, 89 (30H), 1, 00-1, 48 (5H), 1, 11 (3H), 1, 21 (3H), 1, 34 (3H), 1, 76-2.03 (2H), 2.25-2.64 (6H), 2.84 (3H), 3.24 (1H), 3.80 (1H), 4.35 (1H), 4.67 ( 1H), 4.93-5.04 (2H), 5.12 (1H), 5.76 (1H), 7.46 (1H), 7.75 (1H), 7.82 (1H) ppm.
Beispiel 2Example 2
(3S,6R,7S,8S,12Z,15S)-4 ,4,8,12-Tetramethyl-5-oxo-6-allyl-3,7,15-tris-(tert.- butyldimethylsilyloxy)-15-(2-methylbenzothiazol-5-yl)-pentadec-12-ensäure(3S, 6R, 7S, 8S, 12Z, 15S) -4, 4,8,12-tetramethyl-5-oxo-6-allyl-3,7,15-tris- (tert-butyldimethylsilyloxy) -15- ( 2-methyl-benzothiazol-5-yl) -pentadec-12-enoic acid
Beispiel 2aExample 2a
(2S)-2-Methyl-6-oxo-heptanol(2S) -2-methyl-6-oxo-heptanol
Die Lösung von 20 g (87,6 mmol) (2S)-2-Methyl-6-oxo-heptan-1- (tetrahydropyran-2-yloxy), das man in Analogie zu den in DE 197 51 200.3 beschriebenen Verfahren hergestellt hat, in 400 ml wasserfreiem Ethanol versetzt man mit 8,33 g p-Toluolsulfonsäure-Monohydrat und rührt 2,5 Stunden bei 23°C. Man engt ein, nimmt den Rückstand in Dichlormethan auf, wäscht mit gesättigter Natriumhydrogencarbonatlösung und trocknet über Natriumsulfat. Den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand reinigt man durch Chromatographie an feinem Kieselgel mit einem Gemisch aus n-Hexan und Ethylacetat. Isoliert werden 10,6 g (73,5 mmol, 83,9%) der Titelverbindung als farbloses Öl.The solution of 20 g (87.6 mmol) (2S) -2-methyl-6-oxo-heptan-1- (tetrahydropyran-2-yloxy), which was prepared in analogy to the processes described in DE 197 51 200.3 , in 400 ml of anhydrous ethanol, 8.33 g of p-toluenesulfonic acid monohydrate are added and the mixture is stirred at 23 ° C. for 2.5 hours. It is concentrated, the residue is taken up in dichloromethane, washed with saturated sodium bicarbonate solution and dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on fine silica gel with a mixture of n-hexane and ethyl acetate. 10.6 g (73.5 mmol, 83.9%) of the title compound are isolated as a colorless oil.
1 H-NMR (CDCI3): δ= 0,93 (3H), 1 ,13 (1 H), 1 ,41 (1 H), 1 ,48-1 ,76 (4H), 2,14 (3H), 2,45 (2H), 3,48 (2H) ppm.1 H NMR (CDCI 3 ): δ = 0.93 (3H), 1.13 (1H), 1.41 (1H), 1.48-1.76 (4H), 2.14 (3H ), 2.45 (2H), 3.48 (2H) ppm.
Beispiel 2bExample 2b
2-Methyl-2-((2S)-2-methyl-1 -hydroxy-pent-5-yl)-1 ,3-dioxolan Die Lösung von 10,6 g (73,5 mmol) der nach Beispiel 2a dargestellten Verbindung in 550 ml wasserfreiem Toluol versetzt man mit 50 ml Ethylenglykol, katalytischen Mengen p-Toluolsulfonsäure-Monohydrat und kocht 3 Stunden unter Rückfluß am Wasserabscheider. Nach dem erkalten verdünnt man mit Ethylacetat, wäscht mit gesättigter Natriumhydrogencarbonatlösung, Wasser und trocknet über Natriumsulfat. Den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand reinigt man durch Chromatographie an feinem Kieselgel mit einem Gemisch aus n-Hexan und Ethylacetat. Isoliert werden 11 ,6 g (61 ,6 mmol, 83,8%) der Titelverbindung als farbloses Öl.2-Methyl-2 - ((2S) -2-methyl-1-hydroxy-pent-5-yl) -1, 3-dioxolane The solution of 10.6 g (73.5 mmol) of the compound shown in Example 2a in 550 ml of anhydrous toluene, 50 ml of ethylene glycol, catalytic amounts of p-toluenesulfonic acid monohydrate are added and the mixture is boiled under reflux for 3 hours on a water separator. After cooling, the mixture is diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on fine silica gel with a mixture of n-hexane and ethyl acetate. 11.6 g (61.6 mmol, 83.8%) of the title compound are isolated as a colorless oil.
1 H-NMR (CDCI3): δ= 0,92 (3H), 1 ,12 (1 H), 1 ,31 (3H), 1 ,32-1 ,69 (5H), 3,42 (2H), 3,50 (2H), 3,93 (4H) ppm. Beispiel 2c1 H-NMR (CDCI3): δ = 0.92 (3H), 1, 12 (1H), 1, 31 (3H), 1, 32-1, 69 (5H), 3.42 (2H), 3.50 (2H), 3.93 (4H) ppm. Example 2c
2-Methyl-2-((2S)-2-methyl-1 -oxo-pent-5-yl)-1 ,3-dioxolan2-methyl-2 - ((2S) -2-methyl-1-oxopent-5-yl) -1, 3-dioxolane
Die Lösung von 3,63 ml Oxalylchlorid in 200 ml Dichlormethan kühlt man unter einer Atmosphäre aus trockenem Argon auf -70°C, versetzt mit der Lösung von 5,92 ml Dimethylsulfoxid in 20 ml Dichlormethan und tropft nach 10 Minuten die Lösung von 5,0 g (26,6 mmol) der nach Beispiel 2b dargestellten Verbindung in 200 ml Dichlormethan zu. Nach 45 Minuten versetzt man mit 18,3 ml Triethylamin und läßt innerhalb einer Stunde auf 0°C erwärmen. Man wäscht mit Wasser und gesättigter Natriumchloridlösung und trocknet über Natriumsulfat. Den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand nimmt man in wenig Diethylether auf, filtriert über Celite und engt ein. Isoliert werden 5,1 g (max. 26,2 mmol) der Titelverbindung als blass gelbes Öl, das man ohne Reinigung weiter umsetzt. H-NMR (CDCI3) einer gereinigten analytischen Probe: δ= 1 ,09 (3H), 1 ,30 (3H), 1 ,32-1 ,77 (6H), 2,34 (1 H), 3,92 (4H), 9,61 (1 H) ppm.The solution of 3.63 ml of oxalyl chloride in 200 ml of dichloromethane is cooled to -70 ° C. under an atmosphere of dry argon, the solution of 5.92 ml of dimethyl sulfoxide in 20 ml of dichloromethane is added, and the solution of 5. 0 g (26.6 mmol) of the compound shown in Example 2b in 200 ml of dichloromethane. After 45 minutes, 18.3 ml of triethylamine are added and the mixture is allowed to warm to 0 ° C. within one hour. It is washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of the solvent is taken up in a little diethyl ether, filtered through Celite and concentrated. 5.1 g (max. 26.2 mmol) of the title compound are isolated as a pale yellow oil, which is reacted further without purification. H-NMR (CDCI3) of a purified analytical sample: δ = 1, 09 (3H), 1, 30 (3H), 1, 32-1, 77 (6H), 2.34 (1 H), 3.92 ( 4H), 9.61 (1H) ppm.
Beispiel 2dExample 2d
(4S,4,R,5,S>6'S,10'RS)-4-[2,6-Dimethyl-3-oxo-4-allyl-5-hydroxy-9-(2-methyl-1 ,3- dioxolan-2-yl)-nonan-2-yl]-2,2-dimethyl-1 ,3-dioxan (A) und (4S,4,S,5'R,6,S,10'RS)-4-[2,6-Dimethyl-3-oxo-4-allyl-5-hydroxy-9-(2-methyl-1 ,3- dioxolan-2-yl)-nonan-2-yl]-2,2-dimethyl-1 ,3-dioxan (B)(4S, 4 , R, 5 , S > 6'S, 10'RS) -4- [2,6-dimethyl-3-oxo-4-allyl-5-hydroxy-9- (2-methyl-1, 3- dioxolan-2-yl) nonan-2-yl] -2,2-dimethyl-1, 3-dioxane (A) and (4S, 4 , S, 5'R, 6 , S, 10'RS) -4 - [2,6-Dimethyl-3-oxo-4-allyl-5-hydroxy-9- (2-methyl-1,3-dioxolan-2-yl) nonan-2-yl] -2,2-dimethyl -1, 3-dioxane (B)
Die Lösung von 9,71 ml Diisopropylamin in 200 ml wasserfreiem Tetrahydrofuran versetzt man bei -30°C unter einer Atmosphäre aus trockenem Argon mit 27,7 ml einer 2,5molaren Lösung von n-Buthyllithium in n-Hexan, rührt 30 Minuten und kühlt auf -70°C. Innerhalb von 20 Minuten tropft man die Lösung von 15,96 g (66,4 mmol) (4S)-4-(2-Methyl-3-oxo-hept-6-en-2-yl)-2,2- dimethyl-1 ,3-dioxan, das man in Analogie zu dem in WO 99/07692, WO 99049154, WO 00/01333 beschriebenen Verfahren hergestellt hat, in 200 ml Tetrahydrofuran zu und läßt innerhalb von 2 Stunden auf -30°C erwärmen. Anschließend kühlt man erneut auf -70°C, versetzt mit der Lösung von 9,04 g wasserfreiem Zinkchlorid in 92 ml Tetrahydrofuran und tropft nach 15 Minuten die Lösung von 5,1 g (max 26,2 mmol) der nach Beispiel 2c dargestellten Verbindung in 240 ml Tetrahydrofuran zu. Man rührt noch 2 Stunden bei -70°C, gießt in eine gesättigte Ammoniumchloridlösung und extrahiert mehrfach mit Ethylacetat. Die vereinigten organischen Extrakte wäscht man mit Wasser und gesättigter Natriumchloridlösung, trocknet über Natriumsulfat und reinigt den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand durch Chromatographie an feinem Kieselgel mit einem Laufmittelgemisch aus n- Hexan und Ethylacetat. Isoliert werden 3,22 g (19,3 mmol, 73,5%) der Titelverbindung A, 0,706 g (1 ,65 mmol, 6,3%) der Titelverbindung B sowie 10,2 g (4S)-4-(2-Methyl-3-oxo-hept-6-en-2-yl)-2,2-dimethyl-1 ,3-dioxan jeweils als farbloses Öl. H-NMR (CDCI3) von A: δ= 0,37 (3H), 0,96 (3H), 1 ,10 (1 H), 1 ,23 (3H), 1 ,31 (6H), 1 ,37 (3H), 1 ,22-1 ,40 (2H), 1 ,43-1 ,84 (6H), 2,23 (1H), 2,43 (1H), 2,94 (1H), 3,34 (1 H), 3,48 (1 H), 3,81-4,01 (6H), 4,13 (1 H), 4,97 (1 H), 5,03 (1 H), 5,71 (1 H) ppm. 1 H-NMR (CDCI3) von B: δ= 0,88 (1 H), 0,97 (3H), 1 ,07 (3H), 1 ,16 (3H), 1 ,31 (6H), 1 ,40 (3H), 1 ,08-1 ,75 (8H), 2,32 (1 H), 2,42 (1 H), 2,69 (1 H), 3,31 (1 H), 3,56 (1 H), 3,81-4,00 (6H), 4,08 (1 H), 4,98 (1 H), 5,04 (1 H), 5,72 (1 H) ppm.The solution of 9.71 ml of diisopropylamine in 200 ml of anhydrous tetrahydrofuran is mixed at -30 ° C. under an atmosphere of dry argon with 27.7 ml of a 2.5 molar solution of n-butyllithium in n-hexane, stirred for 30 minutes and cooled to -70 ° C. The solution of 15.96 g (66.4 mmol) of (4S) -4- (2-methyl-3-oxo-hept-6-en-2-yl) -2,2-dimethyl is added dropwise within 20 minutes -1, 3-dioxane, which was prepared analogously to the process described in WO 99/07692, WO 99049154, WO 00/01333, in 200 ml of tetrahydrofuran and allowed to warm to -30 ° C. in the course of 2 hours. The mixture is then cooled again to -70 ° C., a solution of 9.04 g of anhydrous zinc chloride in 92 ml of tetrahydrofuran is added, and after 15 minutes the solution of 5.1 g (max. 26.2 mmol) of the compound shown in Example 2c is added dropwise in 240 ml of tetrahydrofuran. The mixture is stirred for a further 2 hours at -70 ° C., poured into a saturated ammonium chloride solution and extracted several times with ethyl acetate. The combined organic extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate and the residue obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel using a mobile phase mixture of n- Hexane and ethyl acetate. 3.22 g (19.3 mmol, 73.5%) of the title compound A, 0.706 g (1.65 mmol, 6.3%) of the title compound B and 10.2 g (4S) -4- (2nd -Methyl-3-oxo-hept-6-en-2-yl) -2,2-dimethyl-1, 3-dioxane, each as a colorless oil. H-NMR (CDCI3) of A: δ = 0.37 (3H), 0.96 (3H), 1, 10 (1 H), 1, 23 (3H), 1, 31 (6H), 1, 37 (3H), 1, 22-1, 40 (2H), 1, 43-1, 84 (6H), 2.23 (1H), 2.43 (1H), 2.94 (1H), 3.34 (1H), 3.48 (1H), 3.81-4.01 (6H), 4.13 (1H), 4.97 (1H), 5.03 (1H), 5, 71 (1H) ppm. 1 H-NMR (CDCI3) of B: δ = 0.88 (1 H), 0.97 (3H), 1, 07 (3H), 1, 16 (3H), 1, 31 (6H), 1, 40 (3H), 1, 08-1, 75 (8H), 2.32 (1 H), 2.42 (1 H), 2.69 (1 H), 3.31 (1 H), 3, 56 (1H), 3.81-4.00 (6H), 4.08 (1H), 4.98 (1H), 5.04 (1H), 5.72 (1H) ppm.
Beispiel 2e (3S,6R,7S,8S)-4,4,8-trimethyl-5-oxo-tridecan-1 ,3,7-triol Die Lösung von 6,78 g (15,9 mmol) der nach Beispiel 2d hergestellten Verbindung A in einem Gemisch aus 200 ml Ethanol und 50 ml Wassern versetzt man mit 6,7 g p-Toluolsulfonsäure-Monohydrat und rührt 4 Stunden bei 23°C. Man versetzt mit gesättigter Natriumhydrogencarbonatlösung, extrahiert mit Dichlormethan und trocknet die vereinigten organischen Extrakte über Natriumsulfat. Den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand setzt man ohne Reinigung weiter um. Isoliert werden 5,8 g (max. 15,9 mmol) der Titelverbindung als farbloses Öl.Example 2e (3S, 6R, 7S, 8S) -4,4,8-trimethyl-5-oxotridecane-1, 3,7-triol The solution of 6.78 g (15.9 mmol) of that according to Example 2d Compound A prepared in a mixture of 200 ml of ethanol and 50 ml of water is mixed with 6.7 g of p-toluenesulfonic acid monohydrate and stirred at 23 ° C. for 4 hours. Saturated sodium hydrogen carbonate solution is added, the mixture is extracted with dichloromethane and the combined organic extracts are dried over sodium sulfate. The residue obtained after filtration and removal of solvent is reacted further without purification. 5.8 g (max. 15.9 mmol) of the title compound are isolated as a colorless oil.
1 H-NMR (CDCI3): δ= 0,91 (3H), 1 ,06 (3H), 1 ,14 (1 H), 1 ,21 (3H), 1 ,48 (1 H), 1 ,57- 1 ,74 (4H), 2,13 (3H), 2,26 (1 H), 2,39-2,56 (4H), 2,92 (1H), 3,28 (1H), 3,32 (1H), 3,41 (1 H), 3,72 (1 H), 3,81-3,94 (2H), 4,04 (1 H), 4,99 (1 H), 5,05 (1 H), 5,70 (1 H) ppm. 1 H NMR (CDCI3): δ = 0.91 (3H), 1, 06 (3H), 1, 14 (1 H), 1, 21 (3H), 1, 48 (1 H), 1, 57 - 1.74 (4H), 2.13 (3H), 2.26 (1H), 2.39-2.56 (4H), 2.92 (1H), 3.28 (1H), 3, 32 (1H), 3.41 (1H), 3.72 (1H), 3.81-3.94 (2H), 4.04 (1H), 4.99 (1H), 5, 05 (1H), 5.70 (1H) ppm.
Beispiel 2f (3S,6R,7S,8S)-4,4,8-Trimethyl-1 ,3,7-tris-(tert.-butyldimethylsilyloxy)-tridecan-5- onExample 2f (3S, 6R, 7S, 8S) -4,4,8-trimethyl-1, 3,7-tris- (tert-butyldimethylsilyloxy) -tridecan-5-one
Die Lösung von 5,8 g (max. 15,9 mmol) der nach Beispiel 2e dargestellten Verbindung in 240 ml Dichlormethan versetzt man bei -70°C unter einer tmosphäre ais trockenem Argon mit 22 ml 2,6-Lutidin, 21 ,7 ml Trifluormethansulfonsäure-tert.butyldimethylsilylester und läßt innerhalb von 15 Stunden auf 23°C erwärmen. Man gießt auf gesättigte Natriumhydrogencarbonatlösung, extrahiert mit Dichlormethan, wäscht die vereinigten organischen Extrakte mit 1N Salzsäure und gesättigter Natriumhydrogencarbonatlösung und trocknet über Natriumsulfat. Den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand reinigt man durch Chromatographie an feinem Kieselgel mit einem Laufmittelgemisch aus n- Hexan und Ethylacetat. Isoliert werden 4,77 g (6,96 mmol, 43,8%) der Titelverbindung sowie 4,37 g eines Isomerengemisches der Silylenolether der Titelverbindung, die durch Behandlung mit Tetrabutylammoniumfluorid in Tetrahydrofuran in die Titelverbindung überführt werden können. 1 H-NMR (CDCI3): δ= 0,01-0,10 (18H), 0,89 (27H), 0,95 (3H), 1 ,05 (3H), 1 ,09 (1 H), 1 ,20 (3H), 1 ,33-1 ,76 (6H), 2,14 (3H), 2,26 (1 H), 2,35-2,50 (3H), 3,13 (1 H), 3,55 (1 H), 3,65 (1 H), 3,76 (1 H), 3,86 (1 H), 4,94 (1 H), 4,99 (1 H), 5,75 (1 H) ppm.The solution of 5.8 g (max. 15.9 mmol) of the compound shown in Example 2e in 240 ml of dichloromethane is mixed with 22 ml of 2,6-lutidine, 21, 7 at -70 ° C. under an atmosphere of dry argon ml of tert-butyldimethylsilyl trifluoromethanesulfonate and allowed to warm to 23 ° C. within 15 hours. It is poured onto saturated sodium bicarbonate solution, extracted with dichloromethane, the combined organic extracts are washed with 1N hydrochloric acid and saturated sodium bicarbonate solution and dried over sodium sulfate. The after Filtration and removal of the solvent obtained are purified by chromatography on fine silica gel with a mobile phase mixture of n-hexane and ethyl acetate. 4.77 g (6.96 mmol, 43.8%) of the title compound and 4.37 g of an isomer mixture of the silyl enol ethers of the title compound are isolated, which can be converted into the title compound by treatment with tetrabutylammonium fluoride in tetrahydrofuran. 1 H-NMR (CDCI3): δ = 0.01-0.10 (18H), 0.89 (27H), 0.95 (3H), 1.05 (3H), 1.09 (1H), 1, 20 (3H), 1, 33-1, 76 (6H), 2.14 (3H), 2.26 (1H), 2.35-2.50 (3H), 3.13 (1H ), 3.55 (1 H), 3.65 (1 H), 3.76 (1 H), 3.86 (1 H), 4.94 (1 H), 4.99 (1 H), 5.75 (1H) ppm.
Beispiel 2gExample 2g
(3S,6R,7S,8S,12E/Z,15S)-4,4,8,12-Tetramethyl-6-allyl-1 ,3,7,15-tetrakis-(tert.- butyldimethylsilyloxy)-15-(2-methylbenzothiazol-5-yl)-pentadec-12-en-5-on(3S, 6R, 7S, 8S, 12E / Z, 15S) -4,4,8,12-tetramethyl-6-allyl-1, 3,7,15-tetrakis (tert-butyldimethylsilyloxy) -15- ( 2-methyl-benzothiazol-5-yl) -pentadec-12-en-5-one
Die Lösung von 7,2 g [(3S)-3-(2-methylbenzothiazol-5-yl)-3-(tert.- butyldimethylsilyloxy)-propyl]-triphenylphosphonium iodid, das man in Analogie zu dem in WO 99/07692, WO 99049154, WO 00/01333 beschriebenen Verfahren hergestellt hat, in 50 ml wasserfreiem Tetrahydrofuran versetzt man bei 0°C mit 10,2 ml einer 1 molaren Lösung von Natriumhexamethyldisilazan in Tetrahydrofuran und anschließend mit der Lösung von 4,73 g (6,90 mmol) der nach Beispiel 2f dargestellten Verbindung in 50 ml Tetrahydrofuran. Man läßt 5 Stunden bei 23°C reagieren, gießt in eine gesättigte Ammoniumchloridlösung und extrahiert mehrfach mit Ethylacetat. Die vereinigten organischen Extrakte wäscht man mit Wasser und gesättigter Natriumchloridlösung, trocknet über Natriumsulfat und reinigt den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand durch Chromatographie an feinem Kieselgel mit einem Laufmittelgemisch aus n-Hexan und Ethylacetat. Isoliert werden 6,18 g (6,25 mmol, 90,6%) der Titelverbindung als farbloses Öl.The solution of 7.2 g of [(3S) -3- (2-methylbenzothiazol-5-yl) -3- (tert-butyldimethylsilyloxy) propyl] triphenylphosphonium iodide, which is analogous to that described in WO 99/07692 , WO 99049154, WO 00/01333 has prepared, in 50 ml of anhydrous tetrahydrofuran, 10.2 ml of a 1 molar solution of sodium hexamethyldisilazane in tetrahydrofuran are added at 0 ° C., followed by the solution of 4.73 g (6, 90 mmol) of the compound shown in Example 2f in 50 ml of tetrahydrofuran. The mixture is left to react at 23 ° C. for 5 hours, poured into a saturated ammonium chloride solution and extracted several times with ethyl acetate. The combined organic extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate and the residue obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel using a mobile phase mixture of n-hexane and ethyl acetate. 6.18 g (6.25 mmol, 90.6%) of the title compound are isolated as a colorless oil.
1 H-NMR (CDCI3): δ= -0,13-0,08 (24H), 0,88 (36H), 0,89-1 ,67 (19H), 1 ,91 (2H), 2,19-2,52 (4H), 2,83 (3H), 3,13 (1 H), 3,49-3,71 (2H), 3,75 (1 H), 3,85 (1 H), 4,74 (1 H), 4,92 (1 H), 4,98 (1 H), 5,15 (1 H), 5,75 (1 H), 7,32 (1 H), 7,73 (1 H), 7,86 (1 H) ppm. In Analogie zu Beispiel 1 wurden folgende AB-Fragmente hergestellt: Beispiel 3:1 H NMR (CDCI3): δ = -0.13-0.08 (24H), 0.88 (36H), 0.89-1, 67 (19H), 1.91 (2H), 2.19 -2.52 (4H), 2.83 (3H), 3.13 (1H), 3.49-3.71 (2H), 3.75 (1H), 3.85 (1H), 4.74 (1H), 4.92 (1H), 4.98 (1H), 5.15 (1H), 5.75 (1H), 7.32 (1H), 7, 73 (1H), 7.86 (1H) ppm. The following AB fragments were produced in analogy to Example 1: Example 3:
Summe C-13H24O3 C24H32θ2Si C37H58°5Si Mol: 228,32 380,62 610,94Sum C-13H24O3 C24H32θ2Si C37H58 ° 5Si mol: 228.32 380.62 610.94
Summe: c42H66°6Si C26H48°6 C26H46°6 Mol: 695,06 456,65 454,64Sum: c 42 H 66 ° 6 Si C 26 H 48 ° 6 C 26 H 46 ° 6 mol: 695.06 456.65 454.64
Summe: C18H34°5 Mol: 330,46 Sum: C 18 H 34 ° 5 mol: 330.46
Beispiel 4:Example 4:
°x° ° TBDPSO ° x ° ° TBDPSO
Summe: C24H34°2S C36H56θδSi C40H62O6Si i Mol: 382,62 596,92 667,02Sum: C 24 H 34 ° 2 S C36 H 56θδSi C 40 H 62 O 6 Si i Mol: 382.62 596.92 667.02
Summe: C25H46°6 C25 44°6 Mol: 442,64 440,62Sum: C 25 H 46 ° 6 C 25 44 ° 6 mol: 442.64 440.62
Beispiel 5:Example 5:
Summe: C24H34θ2Si C-i8H26°3 c42H60°5Si Sum: C24H34θ2Si C-i8H26 ° 3 c 42 H 60 ° 5 Si
Mol: 382,62 290,42 659,00Mol: 382.62 290.42 659.00
Summe: c47H68°6Si C31H50O6 C31H48O6 Mol: 757,14 518,74 516,72 Beispiel 6:Sum: c 47 H 68 ° 6 Si C 31 H 50 O 6 C 31 H 48 O 6 mol: 757.14 518.74 516.72 Example 6:
Summe: CιsH32θ3Si C24H34θ2Si C42H66O5S-2 Mol: 324,53 382,62 707,15Sum: CιsH32θ3Si C24H34θ2Si C42H66O5S-2 mol: 324.53 382.62 707.15
Summe C47H74θ6Si2 C28H48°6 C28 46°6 Mol: 791 ,26 489,68 478,66 Sum C 47 H74θ 6 Si2 C 28 H 48 ° 6 C 28 46 ° 6 mol: 791, 26 489.68 478.66
Beispiel 7:Example 7:
Summe: C12H22O3 C24H32θ2Si Mol: 214,30 380,60Sum: C12H22O3 C24H32θ2Si Mol: 214.30 380.60
Summe: C3ßH54θ5Si C4<| H62θ6Si C25H44C-6 C25H42O6 Mol: 594,91 679,03 440,62 438,61 Die Methylketone der so hergestellten AB-Bausteine lassen sich dann mit den Wittig- Salzen der unterschiedlichsten C-Bausteine kombinieren und in die besonders bevorzugten Wirkstoffe überführen:Sum: C3ßH54θ5Si C4 <| H62θ6Si C25H44C-6 C25H42O6 mol: 594.91 679.03 440.62 438.61 The methyl ketones of the AB building blocks thus produced can then be combined with the Wittig salts of a wide variety of C building blocks and converted into the particularly preferred active ingredients:
(4S,7R,8S,9S, 13Z, 16S(E))-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-16-[1 -methyl-2-(2- methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2-methyl-thiazole -4-yl) -vinyl] -oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S, 13Z, 16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1 - methyl-vinyl]-5,5,7.9, 13-pentamethyl-oxacydohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1 -methyl-vinyl]-4,8- dihydroxy-5,5,7,9, 13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1- methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S(E),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1 - methyl-vinyl]-8,8, 10,12,16-pentamethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-methyl-vinyl]- 7, 11 -dihydroxy-8,8, 10,12,16-pentamethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dion (4S,7R,8S,9S, 13Z, 16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-16-[1 -methyl-2- (2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- [2- (2-hydroxymethylthiazol-4-yl) -1 - methyl-vinyl] -5.5 , 7.9, 13-pentamethyl-oxacydohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-aminomethylthiazol-4-yl ) -1-methyl-vinyl] -4,8- dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2-methylthiazol-4-yl) vinyl] -4 , 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S (E), 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-methyl-vinyl] -8,8, 10,12,16-pentamethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethylthiazol-4-yl) -1-methyl-vinyl] - 7, 11 -dihydroxy-8 , 8, 10,12,16-pentamethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4.8 -Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1 -methyl-2- (2-methylthiazol-4-yl) vinyl] oxacyclohexadec-13-ene-2,6 -dione
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1- methyl-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1 -methyl-vinyl]-4,8- dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (1 S,3S(E),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-ethyl-8,8, 12,16-tetramethyl-3-[1 - methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S(E),7S,10R, 11 S,12S,16R)-7, 11 -Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1 - methyl-vinyl]-10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dion (1 S,3S(E),7S, 10R, 11 S, 12S, 16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1 -methyl-vinyl]- 7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dion(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- [2- (2-hydroxymethylthiazol-4-yl) -1-methyl-vinyl] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-aminomethylthiazole -4-yl) -1-methyl-vinyl] -4,8- dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione (1 S, 3S ( E), 7S, 10R, 11S, 12S, 16R) -7, 11 -dihydroxy-10-ethyl-8,8, 12,16-tetramethyl-3- [1 - methyl-2- (2-methylthiazole -4-yl) vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7 , 11-Dihydroxy-3- [2- (2-hydroxymethylthiazol-4-yl) -1 - methyl-vinyl] -10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S (E), 7S, 10R, 11 S, 12S, 16R) -3- [2- (2-aminomethylthiazol-4-yl) - 1-methyl-vinyl] - 7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-16-[1 -fluor-2-(2- methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1 -fluor- vinyl]-5,5,7,9, 13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-fluor-vinyl]-4,8- dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-fluor-2- (2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1- fluor-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S(Z),7S, 10R, 11 S, 12S, 16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1 -f luor-vinyl]-7, 11 - dihydroxy-8,8, 10,12,16-pentamethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-16-[1 -chlor-2-(2- methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-fluoro-2- (2-methyl-thiazole -4-yl) vinyl] oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2nd -hydroxymethyl-thiazol-4-yl) -1-fluoro-vinyl] -5,5,7,9, 13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-aminomethylthiazol-4-yl) -1-fluoro-vinyl] -4,8-dihydroxy-5,5 , 7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10 , 12,16-pentamethyl-3- [1-fluoro-2- (2-methylthiazol-4-yl) vinyl] -4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethylthiazol-4-yl) -1-fluoro-vinyl] -8 , 8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S (Z), 7S, 10R, 11 S, 12S, 16R) -3- [2- (2-aminomethylthiazol-4-yl) -1-fluorous vinyl] -7, 11 - dihydroxy-8,8, 10,12,16-pentamethyl-4, 17-dioxa- bicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9, 13-pentamethyl-16- [1-chloro-2- (2-methyl-thiazol-4-yl) vinyl] oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1 -chlor- vinyl]-5,5,7,9, 13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-chlor-vinyl]-4,8- dihydroxy-5,5,7,9, 13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-chlor- 2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1- chlor-vinyl]-8,8, 10,12,16-pentamethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S(Z),7S, 10R, 11 S, 12S, 16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1 -chlor-vinyl]-7, 11 - dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-16-[1 -fluor-2-(2- methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2-hydroxymethylthiazol-4-yl) -1-chloro-vinyl] -5.5 , 7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-aminomethyl-thiazole-4 -yl) -1-chloro-vinyl] -4,8- dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-chloro-2- (2-methylthiazol-4-yl) vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-chloro-vinyl] -8,8, 10,12,16-pentamethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S (Z), 7S, 10R, 11 S, 12S, 16R) -3- [2- (2-aminomethylthiazol-4-yl) -1-chloro-vinyl] -7, 11 - dihydroxy -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4th , 8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-fluoro-2- (2-methylthiazol-4-yl) vinyl] oxacyclohexadec-13-ene-2 , 6-dione
(4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1 -fluor- vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-fluor-vinyl]-4,8- dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (1 S,3S(Z),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-ethyl-8,8, 12, 16-tetramethyI-3-[1 - fluor-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S(Z),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1 - f luor-vinyl]-10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dion(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2-hydroxymethylthiazol-4-yl) -1-fluoro-vinyl] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-aminomethylthiazole -4-yl) -1-fluoro-vinyl] -4,8- dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione (1 S, 3S ( Z), 7S, 10R, 11S, 12S, 16R) -7, 11 -dihydroxy-10-ethyl-8,8, 12, 16-tetramethyI-3- [1 - fluoro-2- (2-methyl-thiazole -4-yl) vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S (Z), 7S, 10R, 11 S, 12S, 16R) -7 , 11 -Dihydroxy-3- [2- (2-hydroxymethylthiazol-4-yl) -1 - fluorine-vinyl] -10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo [14.1.0] heptadecane-5,9-dione
(1 S,3S(Z),7S, 10R, 11 S, 12S, 16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1 -fluor-vinyl]-7, 11 - dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dion (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-chlor-2-(2- methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1 -chlor- vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S(Z))-16-[2-(2-AminomethyI-thiazol-4-yl)-1 -chlor-vinyl]-4,8- dihydroxy-7-ethyI-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1- chlor-2-(2-methyl-thiazol-4-yl)-vinyl]-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S(Z),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1 - chlor-vinyl]-10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicycIo[14.1.0]heptadecane-5,9- dion (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-chlor-vinyl]-7,11- dihydroxy-10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dion(1 S, 3S (Z), 7S, 10R, 11 S, 12S, 16R) -3- [2- (2-aminomethylthiazol-4-yl) -1-fluoro-vinyl] -7, 11 - dihydroxy -10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) -4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-chloro-2- (2-methylthiazol-4-yl) vinyl] oxacyclohexadec-13-ene -2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2-hydroxymethylthiazol-4-yl) -1-chloro-vinyl] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-aminomethyl-thiazole -4-yl) -1-chloro-vinyl] -4,8- dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione (1S, 3S (Z ), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-chloro-2- (2-methyl-thiazole-4 -yl) -vinyl] -4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S (Z), 7S, 10R, 11 S, 12S, 16R) -7, 11 -Dihydroxy-3- [2- (2-hydroxymethylthiazol-4-yl) -1 - chloro-vinyl] -10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1 .0] heptadecane-5,9-dione (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethylthiazol-4-yl) -1-chloro vinyl] -7.11-dihydroxy-10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S,7R,8S,9S, 13Z, 16S(E))-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-16-[1 -methyl-2-(2- pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1- methyl-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S(E))-4,8-Dihydroxy-7-ethyI-5,5,9, 13-tetramethyl-16-[1 -methyl-2- (2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion (1 S,3S(E),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-ethyl-8,8, 12,16-tetramethyl-3-[1 - methyl-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5,7,9, 13-pentamethyl-16- [1-methyl-2- (2-pyridyl) - vinyl] -oxacyclohexadec-13-ene-2,6-dione (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl -3- [1- methyl-2- (2-pyridyl) vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-methyl-2- (2-pyridyl) vinyl] oxacyclohexadec-13-ene-2 , 6-dione (1 S, 3S (E), 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-10-ethyl-8,8, 12,16-tetramethyl-3- [1 - methyl-2- (2-pyridyl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione
(4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-16-[1 -f luor-2-(2- pyridyl)-vinyl]-oxacy ohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9, 13-pentamethyl-16- [1-fluorine-2- (2-pyridyl) -vinyl] -oxacy ohexadec-13-ene-2,6-dione
(1 S,3S(Z),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-8,8, 10,12,16-pentamethyl-3-[1 -fluor-2-(1 S, 3S (Z), 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-8,8, 10,12,16-pentamethyl-3- [1 -fluoro-2-
(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-16-[1 -chlor-2-(2- pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion(2-pyridyl) vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy -5,5,7,9, 13-pentamethyl-16- [1-chloro-2- (2-pyridyl) vinyl] oxacyclohexadec-13-ene-2,6-dione
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-chlor- 2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-16-[1 -fluor-2-(2- pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-chloro-2- (2-pyridyl ) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl -5,5,9, 13-tetramethyl-16- [1-fluoro-2- (2-pyridyl) vinyl] oxacyclohexadec-13-ene-2,6-dione
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1- fluor-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-chlor-2-(2- pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion (1 S,3S(Z),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-ethyl-8,8, 12,16-tetramethyl-3-[1 - chlor-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2- methyl-oxazol-4-yI)-vinyl]-oxacyclohexadec-13-ene-2,6-dion(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-fluoro-2- (2nd -pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7 -ethyl-5,5,9,13-tetramethyl-16- [1-chloro-2- (2-pyridyl) -vinyl] -oxacyclohexadec-13-ene-2,6-dione (1 S, 3S (Z) , 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-10-ethyl-8,8, 12,16-tetramethyl-3- [1 - chloro-2- (2-pyridyl) vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2-methyl-oxazole -4-yI) vinyl] -oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S, 13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1 - methyl-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S(E))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1 -methyl-vinyl]-4,8- dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion (1 S,3S(E),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-8,8, 10,12,16-pentamethyl-3-[1 - methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-oxazol-4-yl)-1- methyl-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethy!-oxazol-4-yl)-1-methyi-vinyl]-7,11- dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-16-[1 -methyl-2- (2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1- methyl-vinyl]-7-ethyI-5,5,9, 13-tetramethyl-oxacycIohexadec-13-ene-2,6-dion (4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-methyl-vinyl]-4,8- dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (1 S,3S(E),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-ethyl-8,8, 12, 16-tetramethyl-3-[1 - methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-oxazol-4-yl)-1- methyl-vinyl]-10-ethyI-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dion (1 S,3S(E),7S, 10R, 11 S, 12S, 16R)-3-[2-(2-Aminomethyl-oxazol-4-y!)-1 -methyl-vinyl]-7, 11 - dihydroxy-10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dion(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1 - methyl-vinyl] -5.5 , 7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-aminomethyl-oxazol-4 -yl) -1-methyl-vinyl] -4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione (1 S, 3S (E), 7S , 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-8,8, 10,12,16-pentamethyl-3- [1 - methyl-2- (2-methyl-oxazol-4-yl) - vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [ 2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl-vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9 -dione (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethy! -oxazol-4-yl) -1-methyl-vinyl] -7.11- dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-methyl-2- (2-methyl-oxazol-4-yl) vinyl] oxacyclohexadec-13-ene 2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl-vinyl] -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S , 9S, 13Z, 16S (E)) - 16- [2- (2-aminomethyl-oxazol-4-yl) -1-methyl-vinyl] -4,8-dihydroxy-7-ethyl-5,5,9 , 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7, 11 -dihydroxy-10-ethyl-8.8 , 12, 16-tetramethyl-3- [1-methyl-2- (2-methyl-oxazol-4-yl) vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl-vinyl] -10 -ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S (E), 7S, 10R, 11 S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-y!) - 1 -methyl-vinyl] -7, 11 - dihydroxy-10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione
(4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-16-[1 -fluor-2-(2- methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1 -fluor- vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-fluoro-2- (2-methyl-oxazole -4-yl) vinyl] oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2nd -hydroxymethyl-oxazol-4-yl) -1-fluoro-vinyl] -5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S, 13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1 -fluor-vinyl]-4,8- dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-aminomethyloxazol-4-yl) -1-fluoro-vinyl] -4,8-dihydroxy-5,5 7,9,13--pentamethyl-oxacyclohexadec-13-ene-2,6-dione,
(1 S,3S(Z),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-8,8, 10,12,16-pentamethyl-3-[1 -fluor-2-(1 S, 3S (Z), 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-8,8, 10,12,16-pentamethyl-3- [1 -fluoro-2-
(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-oxazol-4-yl)-1- f luor-vinyl]-8,8, 10,12,16-pentamethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S(Z),7S, 10R, 11 S, 12S, 16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1 -fluor-vinyl]-7, 11 - dihydroxy-8,8, 10,12,16-pentamethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-chlor-2-(2- methyI-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1 -chlor- vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1 -chlor-vinyl]-4,8- dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion (1 S,3S(Z),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-8,8, 10,12,16-pentamethyl-3-[1 -chlor- 2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion(2-methyl-oxazol-4-yl) vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1- fluorous vinyl] -8.8, 10,12,16-pentamethyl-4, 17- dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione (1 S, 3S (Z), 7S, 10R, 11 S, 12S, 16R) -3- [2- (2-aminomethyloxazol-4-yl) -1-fluoro-vinyl] -7, 11 - dihydroxy -8,8, 10,12,16-pentamethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4 , 8-Dihydroxy-5,5,7,9,13-pentamethyl-16- [1-chloro-2- (2-methyl-oxazol-4-yl) vinyl] oxacyclohexadec-13-ene-2,6 -dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro-vinyl] -5 , 5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-aminomethyl-oxazole -4-yl) -1-chloro-vinyl] -4,8- dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione (1 S, 3S (Z) , 7S, 10R, 11S, 12S, 16R) -7, 11 -dihydroxy-8,8, 10,12,16-pentamethyl-3- [1-chloro-2- (2-methyl-oxazol-4-yl ) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione
(1 S,3S(Z),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-[2-(2-hydroxymethyl-oxazol-4-yl)-1 - chlor-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S(Z),7S, 10R, 11 S, 12S, 16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1 -chlor-vinyl]-7, 11 - dihydroxy-8,8, 10,12,16-pentamethyI-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-16-[1 -fluor-2-(2- methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion(1 S, 3S (Z), 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1 - chloro-vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S (Z), 7S, 10R, 11 S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-chloro-vinyl] -7, 11 - dihydroxy-8,8, 10,12,16-pentamethyI-4, 17-dioxa -bicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9, 13-tetramethyl -16- [1-Fluoro-2- (2-methyl-oxazol-4-yl) vinyl] oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z, 16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yI)-1 -fluor- vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1 -fluor-vinyl]-4,8- dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yI) -1-fluoro-vinyl] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-aminomethyl-oxazole -4-yl) -1-fluoro-vinyl] -4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12>16-tetramethyl-3-[1- fluor-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-oxazol-4-yl)-1- fluor-vinyl]-10-ethyl-8,8, 12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dion(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12 > 16-tetramethyl-3- [1-fluoro-2- (2nd -methyl-oxazol-4-yl) vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R ) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluoro-vinyl] -10-ethyl-8,8, 12,16-tetramethyl-4,17- dioxa-bicyclo [14.1.0] heptadecane-5,9-dione
(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-fluor-vinyl]-7,11- dihydroxy-10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dion(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyloxazol-4-yl) -1-fluoro-vinyl] -7,11-dihydroxy-10 -ethyl-8,8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-16-[1 -chior-2-(2- methyl-oxazol-4-yl)-vinyl]-oxacyc!ohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-16- [1-chloro-2- (2-methyl -oxazole-4-yl) vinyl] -oxacyc! ohexadec-13-ene-2,6-dione
(4S,7R,8S,9S, 13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1 -chlor- vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1 -chlor-vinyl]-4,8- dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1- chlor-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyI-oxazol-4-yl)-1- chlor-vinyl]-10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dion(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro-vinyl] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-aminomethyl-oxazole -4-yl) -1-chloro-vinyl] -4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione (1S, 3S (Z ), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-chloro-2- (2-methyl-oxazole-4 -yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro-vinyl] -10 -ethyl-8,8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(1 S,3S(Z),7S, 10R, 11 S, 12S, 16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1 -chlor-vinyl]-7, 11 - dihydroxy-10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dion(1 S, 3S (Z), 7S, 10R, 11 S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-chloro-vinyl] -7, 11 - dihydroxy -10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S,7R,8S,9S, 13Z, 16S(E))-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-16-[2-(2-methyl- thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5,7,9, 13-pentamethyl-16- [2- (2-methylthiazol-4-yl ) vinyl] -oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-vinyl]- 5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- [2- (2-hydroxymethylthiazol-4-yl) vinyl] - 5,5,7,9 , 13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-vinyl]-4,8-dihydroxy-(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-Aminomethyl-thiazol-4-yl) -vinyl] -4,8-dihydroxy-
5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione
(1 S,3S(E),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-8,8, 10,12,16-pentamethyl-3-[2-(2- methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)- vinyl]-8,8, 10,12,16-pentamethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion(1 S, 3S (E), 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-8,8, 10,12,16-pentamethyl-3- [2- (2-methyl-thiazole -4-yl) vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7.11 -Dihydroxy-3- [2- (2-hydroxymethylthiazol-4-yl) - vinyl] -8.8, 10,12,16-pentamethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5 , 9-dione
(1 S,3S(E),7S, 10R, 1 S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-vinyl]-7,11 - dihydroxy-8,8, 10,12,16-pentamethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion(1 S, 3S (E), 7S, 10R, 1 S, 12S, 16R) -3- [2- (2-aminomethylthiazol-4-yl) vinyl] -7.11 - dihydroxy-8.8 , 10,12,16-pentamethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S,7R,8S,9S, 13Z, 16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-16-[2-(2-methyl- thiazol-4-yl)-vinyI]-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-16- [2- (2-methylthiazole-4 yl) -vinyl] -oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S, 13Z, 16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-vinyl]-7- ethyl-5,5,9, 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- [2- (2-hydroxymethylthiazol-4-yl) vinyl] -7-ethyl-5,5 , 9, 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S, 13Z, 16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-vinyl]-4,8-dihydroxy-7- ethyl-5,5,9, 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (1 S,3S(E),7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-ethyl-8,8, 12,16-tetramethyl-3-[2-(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-aminomethylthiazol-4-yl) vinyl] -4,8-dihydroxy-7-ethyl-5,5 , 9, 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione (1 S, 3S (E), 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-10-ethyl-8 , 8, 12,16-tetramethyl-3- [2-
(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion(2-methyl-thiazol-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione
(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yI)- vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethylthiazol-4-yI) - vinyl] -10-ethyl-8 , 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione
(1 S,3S(E),7S, 10R, 11 S, 12S, 16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-vinyl]-7, 11 - dihydroxy-10-ethyl-8,8, 12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dion(1 S, 3S (E), 7S, 10R, 11 S, 12S, 16R) -3- [2- (2-aminomethylthiazol-4-yl) vinyl] -7, 11 - dihydroxy-10-ethyl -8.8, 12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[2-(2-pyridyl)- vinyl]-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [2- (2-pyridyl) vinyl] oxacyclohexadec -13-ene-2,6-dione
(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[2-(2- pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[2-(2-pyridyl)- vinyl]-oxacyclohexadec-13-ene-2,6-dion(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [2- (2-pyridyl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [2- (2-pyridyl) - vinyl] -oxacyclohexadec-13-ene-2,6-dione
(1 S,3S(E),7S, 10R, 1 S, 12S, 16R)-7, 11 -Dihydroxy-10-ethyl-8,8, 12,16-tetramethy!-3-[2-(1 S, 3S (E), 7S, 10R, 1 S, 12S, 16R) -7, 11 -dihydroxy-10-ethyl-8,8, 12,16-tetramethy! -3- [2-
(2-pyridy I )-vi nyl]-4 , 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-(2-methyl- benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion(2-pyridy I) vi nyl] -4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy- 5,5,7,9,13-pentamethyl-16- (2-methylbenzothiazol-5-yl) oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)- 5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy- 5,5,7,9, 13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) - 5,5,7,9,13-pentamethyl-oxacyclohexadec-13- ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-5,5,7,9, 13 pentamethyl-oxacyclohexadec-13-ene-2,6-dione
(1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 1 -Dihydroxy-8,8, 10,12,16-pentamethyl-3-(2-methyl- benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion(1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 1 -dihydroxy-8,8, 10,12,16-pentamethyl-3- (2-methyl-benzothiazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione
(1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)-(1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -
8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy- 8,8,10,12,16-pentamethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-16-(2-methyl- benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-ethyl- 5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- ( 2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (4S , 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -oxacyclohexadec-13- ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-ethyl- 5,5,9 , 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S, 13Z, 16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-ethyl-(4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-ethyl-
5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-ethyl-8,8, 12,16-tetramethyl-3-(2- methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)- 10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7, 11 -dihydroxy-10- ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-propyl-5,5,9,13-tetramethyl-16-(2-methyl- benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion(1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-10-ethyl-8,8, 12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl ) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-3- (2- hydroxymethyl-benzothiazol-5-yl) - 10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7, 11 -dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa- bicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-propyl-5,5,9,13-tetramethyl-16- ( 2-methylbenzothiazol-5-yl) oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7- propyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-propyl- 5,5,9, 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-propyl-8,8, 12, 16-tetramethyl-3-(2- methyl-benzothiazol-5-yl)-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S,7S,10R,11 S,12S,16R)-7,11 -Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)- 10-propyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7, 11 -dihydroxy-10- propyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-7-butyl-5,5,9, 13-tetramethyl-16-(2-methyl- benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-propyl-5.5 , 9, 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-10-propyl-8,8, 12, 16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7.11 -Dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) - 10-propyl-8,8, 12, 16- tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -3- (2-aminomethyl-benzothiazole-5- yl) -7, 11 -dihydroxy-10-propyl-8,8, 12, 16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S , 13Z, 16S) -4,8-dihydroxy-7-butyl-5,5,9,13-tetramethyl-16- (2-methylbenzothiazol-5-yl) -oxacyclohexadec-13-ene-2,6- dion
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-butyl- 5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-butyl- 5,5,9, 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-butyl-5.5 , 9, 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-butyl-8,8, 12,16-tetramethyl-3-(2- methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)- 10-butyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-10- butyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-allyl-5,5,9,13-tetramethyl-16-(2-methyl- benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-allyl- 5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion(1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-10-butyl-8,8, 12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl ) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl- benzothiazol-5-yl) - 10-butyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S, 7S, 10R, 11S , 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7.11-dihydroxy-10-butyl-8.8, 12.16-tetramethyl-4, 17-dioxa-bicyclo [14.1. 0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-allyl-5,5,9,13-tetramethyl-16- (2-methyl- benzothiazol-5-yl) oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl ) -7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-allyl-(4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-allyl-
5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-allyl-8,8, 12, 16-tetramethyl-3-(2- methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)- 10-allyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7, 11 -dihydroxy-10- allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-7-prop-2-inyl-5,5,9, 13-tetramethyl-16-(2-methyl- benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion(1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-10-allyl-8,8, 12, 16-tetramethyl-3- (2-methyl-benzothiazol-5-yl ) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl- benzothiazol-5-yl) - 10-allyl-8,8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7, 11 -dihydroxy-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [ 14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-prop-2-ynyl-5,5,9, 13-tetramethyl-16 - (2-methylbenzothiazol-5-yl) oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-prop- 2-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-prop-2-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-prop-2- inyl-5,5,9, 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-prop-2-inyl-8,8, 12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl)-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)- 10-prop-2-inyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-10- prop-2-inyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-7-but-3-enyl-5,5,9, 13-tetramethyl-16-(2-methyl- benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-prop-2-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-ene-2,6-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-10-prop-2-ynyl-8,8, 12 , 16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) - 10-prop-2-ynyl-8,8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazole- 5-yl) -7,11-dihydroxy-10-prop-2-ynyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (4S , 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-but-3-enyl-5,5,9, 13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) - oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-but-3- enyl-5,5,9, 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-but-3- enyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-but-3-enyl-5,5,9, 13- tetramethyl-oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-but -3-enyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-3-(2- methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5 -yl) -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione
(1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)-(1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -
10-but-3-eny 1-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-10- but-3-enyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-but-3-inyl-5,5,9,13-tetramethyl-16-(2-methyl- benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-but-3- inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion10-but-3-eny 1-8,8, 12, 16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S, 7S, 10R, 11S, 12S , 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo [ 14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-but-3-ynyl-5,5,9,13-tetramethyl-16 - (2-methylbenzothiazol-5-yl) oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl -benzothiazol-5-yl) -7-but-3-ynyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S, 13Z, 16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-but-3- inyl-5,5,9, 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-but-3-ynyl-5,5,9, 13- tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-but-3-inyl-8,8, 12,16-tetramethyl-3-(2- methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)- 10-but-3-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7, 11 -dihydroxy-10- but-3-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-16-(2-methyl- benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion(1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-10-but-3-ynyl-8,8, 12,16-tetramethyl-3- (2-methyl-benzothiazole -5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- ( 2-hydroxymethyl-benzothiazol-5-yl) - 10-but-3-ynyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1st S, 3S, 7S, 10R, 11 S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7, 11 -dihydroxy-10-but-3-ynyl-8,8,12, 16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-5,5,7,9 , 13-pentamethyl-16- (2-methylbenzoxazol-5-yl) oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -
5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S, 13Z, 16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-5,5,7,9, 13- pentamethyl-oxacyclohexadec-13-ene-2,6-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-8,8, 10,12,16-pentamethyl-3-(2-methyl- benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)- 8,8,10,12,16-pentamethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7, 11 -dihydroxy- 8,8,10,12,16-pentamethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-(2-methyl- benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-5,5,7,9, 13-pentamethyl-oxacyclohexadec-13- ene-2,6-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-8,8, 10,12,16-pentamethyl-3- (2-methyl- benzoxazol-5-yl) -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) - 8,8,10,12,16-pentamethyl- 4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7, 11 -dihydroxy- 8,8,10,12,16-pentamethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S ) -4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl) -oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-ethyl- 5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethy!-benzoxazol-5-yI)-4,8-dihydroxy-7-ethyl- 5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-ethyl- 5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethy! -Benzoxazol-5-yI) -4,8-dihydroxy-7-ethyl-5, 5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-ethyl-8,8, 12, 16-tetramethyl-3-(2- methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-10- ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10- ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-propyl-5,5,9,13-tetramethyl-16-(2-methyl- benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-propyl- 5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion(1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-10-ethyl-8,8, 12, 16-tetramethyl-3- (2-methyl-benzoxazol-5-yl ) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl- benzoxazol-5-yl) -10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S, 7S, 10R, 11S , 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1. 0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-propyl-5,5,9,13-tetramethyl-16- (2-methyl- benzoxazol-5-yl) oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl ) -7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-propyl- 5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione
(1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-propyl-8,8, 12,16-tetramethyl-3-(2- methyl-benzoxazol-5-yl)-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-10- propyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7, 11 -dihydroxy-10- propyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-7-butyl-5,5,9, 13-tetramethyl-16-(2-methyl- benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion(1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-10-propyl-8,8, 12,16-tetramethyl-3- (2-methyl-benzoxazol-5-yl ) -4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl- benzoxazol-5-yl) -10-propyl-8,8, 12, 16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7, 11 -dihydroxy-10-propyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [ 14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-butyl-5,5,9, 13-tetramethyl-16- (2- methyl-benzoxazol-5-yl) -oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-butyl- 5,5,9, 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-butyl-5,5,9, 13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-butyl- 5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (1 S.3S.7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-butyl-8,8, 12,16-tetraιmethyl-3-(2- methyI-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S,7S,10R,11 S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-10- butyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion(4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione (1 S.3S.7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-10-butyl-8,8, 12,16-tetraιmethyl-3- ( 2-methyl-benzoxazol-5-yl) -4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-butyl-8,8,12,16- tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione
(1 S,3S,7S, 10R, 11 S, 12S, 16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7, 11 -dihydroxy-10- butyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-7-allyl-5,5,9, 13-tetramethyl-16-(2-methyl- benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion(1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7, 11 -dihydroxy-10-butyl-8,8,12,16- tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-allyl-5,5,9 , 13-tetramethyl-16- (2-methylbenzoxazol-5-yl) oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-allyl- 5,5,9, 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S,13Z,16S)-16-(2-AminomethyI-benzoxazol-5-yl)-4,8-dihydroxy-7-allyl- 5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-allyl-5,5,9, 13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-allyl- 5.5 9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-allyl-8,8,12,16-tetramethyl-3-(2- methyI-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione
(1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-10- allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10- allyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-7-prop-2-inyl-5,5,9, 13-tetramethyl-16-(2-methyl- benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-prop-2- inyI-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion(1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10- allyl-8,8,12,16- tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-allyl-8,8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z , 16S) -4,8-dihydroxy-7-prop-2-ynyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl) -oxacyclohexadec-13-ene-2, 6-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-prop-2-ynyl-5,5,9 , 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-prop-2- inyl-5,5,9,13-tetramethyl-oxacycIohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-prop-2-ynyl-5,5,9,13- tetramethyl-oxacycIohexadec-13-ene-2,6-dione
(1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-prop-2-inyl-8,8, 12, 16-tetramethyl-3-(1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-10-prop-2-ynyl-8,8, 12, 16-tetramethyl-3-
(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-10- prop-2-inyl-8,8, 12,16-tetramethyI-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10- prop-2-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-7-but-3-enyl-5,5,9, 13-tetramethyl-16-(2-methyl- benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion(2-methyl-benzoxazol-5-yl) -4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7.11 -Dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10- prop-2-ynyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5 , 9-dione (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-prop-2-ynyl-8, 8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-but -3-enyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl) oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-but-3- enyl-5,5,9, 13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S, 13Z, 16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-but-3- enyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-but-3-enyl-8,8, 12,16-tetramethyI-3-(2- methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-10- but-3-enyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7, 11 -dihydroxy-10- but-3-enyl-8,8,12,16-tetramethyI-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-7-but-3-inyl-5,5,9, 13-tetramethyl-16-(2-methyl- benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-but-3-enyl-5,5,9, 13- tetramethyl-oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-but -3- enyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy- 10-but-3-enyl-8,8, 12,16-tetramethyl-3- (2-methyl-benzoxazol-5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9- dion (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-but-3-enyl-8,8,12, 16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -3- (2-aminomethyl-benzoxazole- 5-yl) -7, 11 -dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione (4S , 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-but-3-ynyl-5,5,9, 13-tetramethyl-16- (2-methyl-benzoxazol-5-yl) - oxacyclohexadec-13-ene-2,6-dione
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-but-3- inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-but-3- inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-but-3-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-ene-2,6-dione (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-but -3-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione
(1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-but-3-inyl-8,8, 12,16-tetramethyl-3-(2- methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion(1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-10-but-3-ynyl-8,8, 12,16-tetramethyl-3- (2-methyl-benzoxazole -5-yl) -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione
(1 S,3S,7S, 10R, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-10- but-3-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S,3S,7S, 10R, 11 S, 12S, 16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7, 11 -dihydroxy-10- but-3-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-but-3-ynyl-8,8, 12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -3- (2-aminomethyl- benzoxazol-5-yl) -7, 11 -dihydroxy-10-but-3-ynyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione

Claims

Patentansprüche claims
1. Verfahren zur Herstellung von C-j-C-is-Epothilon-Fragmenten der allgemeinen Formel I,1. Process for the preparation of C-j-C-is-epothilone fragments of the general formula I,
worinwherein
R1 a, R1 D gleich oder verschieden sind und Wasserstoff, C<|-C-κ)-Alkyl, Aryl, C7-C20-Aralkyl, oder gemeinsam eine -(CH2)m-Gruppe mit m = 2, 3, 4 oder 5,R 1 a , R 1 D are the same or different and are hydrogen, C <| -C-κ) -alkyl, aryl, C7-C20-aralkyl, or together a - (CH2) m group with m = 2, 3, 4 or 5,
R2a, R^b gleich oder verschieden sind und Wasserstoff, C-j-Ci o-Alkyl, C2-Cι o-Alkenyl, C2-C<|o-Alkinyl, Aryl, C7-C20-Aralkyl oder gemeinsam eine -(CH2)n-Gruppe mit n = 2, 3, 4 oder 5, R3 Wasserstoff, C<| -Ci Q-Alkyl, Aryl, C7-C20-Aralkyl, R4a, R^b gleich oder verschieden sind und Wasserstoff, C- -C-jo-Alkyl, Aryl, C7-C20-Aralkyl oder gemeinsam eine -(CH2)p-Gruppe mit p = 2, 3, 4 oder 5, R5 Wasserstoff, Ci -Ci o-Alkyl, Aryl, C7-C20-Aralkyl,R 2a , R ^ b are the same or different and are hydrogen, Cj-Ci o-alkyl, C2-Cι o-alkenyl, C2-C <| o-alkynyl, aryl, C7-C20-aralkyl or together a - (CH2) n group with n = 2, 3, 4 or 5, R 3 is hydrogen, C <| -Ci Q-alkyl, aryl, C7-C20-aralkyl, R 4a , R ^ b are the same or different and are hydrogen, C- -C-jo-alkyl, aryl, C7-C20-aralkyl or together a - (CH2) p group with p = 2, 3, 4 or 5, R 5 is hydrogen, Ci-Cio-alkyl, aryl, C7-C20-aralkyl,
Rß, R7 je ein Wasserstoffatom, gemeinsam eine zusätzliche Bindung oder gemeinsam ein Sauerstoffatom,Rß, R7 each represent a hydrogen atom, together an additional bond or together an oxygen atom,
G eine Gruppe X=CRδ-, ein bi- oder tricyclischer Arylrest,G is a group X = CRδ, a bi- or tricyclic aryl radical,
R8 Wasserstoff, Halogen, C-|-C20-Alkyl, Aryl, C7-C20-Aralkyl, die alle substituiert sein können, X ein Sauerstoffatom, zwei Alkoxygruppen OR23, eine C2-C-κ)-Alkylen- α,ω-dioxygruppe, die geradkettig oder verzweigt sein kann, H/OR9 oder eine Gruppierung CR^ 0R11 , wobei R23 für einen Cι-C20-Alkylrest, Rß für Wasserstoff oder eine Schutzgruppe PGX, R10. Rl 1 gleich oder verschieden sind und für Wasserstoff, einen Cι-C20-Alkyl-, Aryl-, C7-C20-Aralkylrest oder R10 und R^ zusammen mit dem Methylenkohlen- stoffatom gemeinsam für einen 5- bis 7-gliedrigen carbocyclischen Ring stehen, R13 CH20R13a, CH2-Hal, CHO, CO2R13b, COHal,R 8 is hydrogen, halogen, C 1 -C 20 -alkyl, aryl, C7-C20-aralkyl, all of which can be substituted, X is an oxygen atom, two alkoxy groups OR 23 , a C2-C-κ) alkylene-α, ω-dioxy group, which can be straight-chain or branched, H / OR9 or a group CR ^ 0R11, where R 23 is for a Cι-C20 -Alkylrest, Rß for hydrogen or a protective group PG X , R10. Rl 1 are the same or different and represent hydrogen, a -CC20-alkyl, aryl, C7-C20-aralkyl radical or R10 and R ^ together with the methylene carbon atom together represent a 5- to 7-membered carbocyclic ring, R1 3 CH 2 0R1 3a , CH 2 -Hal, CHO, CO2R 13b , COHal,
R14 Wasserstoff, ORl4a, Hai, OSθ2R14b, R 3a, R14a Wasserstoff, Sθ2-Alkyl, Sθ2-Aryl, Sθ2~Aralkyl oder gemeinsam eine -(CH2)o-Gruppe oder gemeinsam eine CR^aRl5b_GrUppe; Rl3b Rl4b Wasserstoff, Cι-C20-Alkyl, Aryl, C<|-C20-Aralkyl, Rl5a> Rl5b gleich oder verschieden sind und Wasserstoff, C^-C-i o-Alkyl, Aryl, C7-C2fj-Aralkyl, oder gemeinsam eine -(CH2)q-Gruppe, o 2 bis 4, q 3 bis 6,R14 hydrogen, ORl 4a , Hai, OSθ2R 14b , R 3a , R 14a hydrogen, Sθ2-alkyl, Sθ2-aryl, Sθ2 ~ aralkyl or together a - (CH2) o group or together a CR ^ aRl5b_G rU ppe ; Rl3b Rl4b are hydrogen, C 1 -C 20 -alkyl, aryl, C <| -C20-aralkyl, Rl5a > Rl5b are identical or different and are hydrogen, C 1 -C 8 -alkyl, aryl, C7-C2fj-aralkyl, or together a - (CH2) q group, o 2 to 4, q 3 to 6,
R20 OPG3, NHR29, N3, R 20 OPG 3 , NHR 29 , N 3 ,
Z ein Sauerstoffatom oder H/OR12, wobei R^2 Wasserstoff oder eine Schutzgruppe PGZ ist, einschließlich aller Stereoisomeren sowie deren Gemische bedeuten sowie freie Hydroxylgruppen in R^3 und R^4 verethert oder verestert, freie Carbonylgruppen in Z und R^3 ketalisiert, in einen Enolether überführt oder reduziert sowie freie Säuregruppen in R^3 und R^4 in deren Salze mit Basen überführt sein können,Z is an oxygen atom or H / OR 12 , where R ^ 2 is hydrogen or a protective group PG Z , including all stereoisomers and mixtures thereof, and etherifies or esterifies free hydroxyl groups in R ^ 3 and R ^ 4 , free carbonyl groups in Z and R ^ 3 ketalized, converted into an enol ether or reduced and free acid groups in R ^ 3 and R ^ 4 in their salts can be converted with bases,
dadurch gekennzeichnet, daßcharacterized in that
ein C1-C6-Fragment (Epothilon-Zählweise) der allgemeinen Formel A a C1-C6 fragment (epothilone counting) of the general formula A
worinwherein
Rla', Rlb', R2a'; R2b') R13' un R14' dje bereits für Rl , Rlb R2a, R2b , R13 und R^4 genannten Bedeutungen haben einschließlich aller Stereoisomeren sowie deren Gemische sowie freie Hydroxylgruppen in R^3 und R^4 verethert oder verestert, freie Carbonylgruppen in A und R^3 ketalisiert, in einen Enolether überführt oder reduziert sowie freie Säuregruppen in A in deren Salze mit Basen überführt sein können,Rl a ', Rlb', R2a '; R 2b ' ) R 13' and R14 ' d j e meanings already mentioned for Rl, Rlb R2a, R 2b, R 13 and R ^ 4 have etherified including all stereoisomers and their mixtures and free hydroxyl groups in R ^ 3 and R ^ 4 or esterified, free carbonyl groups in A and R ^ 3 ketalized, converted into an enol ether or reduced, and free acid groups in A in whose salts can be converted with bases,
mit einem C7-C12-Fragment (Epothilon-Zählweise) der allgemeinen Formelwith a C7-C12 fragment (epothilone counting) of the general formula
B B
worinwherein
R3a', R a', R b' und R5' die bereits für R3a, R4 und R5 genanntenR 3a ', R a ', R b 'and R 5 ' those already mentioned for R 3a , R 4 and R 5
Bedeutungen haben, undHave meanings, and
V ein Sauerstoffatom, zwei Alkoxygruppen OR^, eine C2-C<|o-Alkylen-α,ω- dioxygruppe, die geradkettig oder verzweigt sein kann oder H/OR16,V is an oxygen atom, two alkoxy groups OR ^, a C2-C <| o-alkylene-α, ω-dioxy group, which can be straight-chain or branched or H / OR16,
W ein Sauerstoffatom, zwei Alkoxygruppen OR^9, eine C2-Cιo-Alkylen-α,ω- dioxygruppe, die geradkettig oder verzweigt sein kann oder H/0R18; W is an oxygen atom, two alkoxy groups OR ^ 9 , a C2-Cιo-alkylene-α, ω-dioxy group, which can be straight-chain or branched, or H / 0R18 ;
R16J R18 unabhängig voneinander Wasserstoff oder eine Schutzgruppe PC, R^ I Θ unabhängig voneinander C-|-C20-Alkyl, bedeuten,R16 J R18 independently of one another are hydrogen or a protective group PC, R ^ I Θ independently of one another are C- | -C20-alkyl,
zu einem Teilfragment der allgemeinen Formel AB ABto a partial fragment of the general formula AB FROM
worinwherein
Rla', Rl ', R23', R3', R43', R4b'j R5; R13'; R14', und Z die bereits genannten Bedeutungen haben undRl a ', Rl', R23 ', R3 ', R43', R 4b ' j R 5 ; R13 '; R14 'and Z have the meanings already mentioned and
PG^4 ein Wasserstoffatom oder eine Schutzgruppe PG darstellt, umgesetzt, undPG ^ 4 represents a hydrogen atom or a protective group PG, implemented, and
dieses Teilfragment der allgemeinen Formel AB mit einem C13-C15-Fragment (Epothilon-Zählweise) der allgemeinen Formel Cthis partial fragment of the general formula AB with a C13-C15 fragment (epothilone counting) of the general formula C
worinwherein
G1 die bereits in der allgemeinen Formel I für G genannte Bedeutung hat und R?1 ein Wasserstoffatom,G 1 has the meaning already given for G in the general formula I and R? 1 is a hydrogen atom,
R20' Halogen, N3, NHR29 eine Hydroxygruppe, eine geschützte Hydroxygruppe O-PG3, eine geschützte Aminogruppe NR29PG3, eine C-j-Cio-Alkylsulfonyloxygruppe, die gegebenenfalls perfluoriert sein kann, eine gegebenenfalls durch C-j-C^Alkyl, Nitro, Chlor oder Brom substituierte Benzoyloxy-Gruppe, eine NR29S02CH3-Gruppe, eine NR 9C(=O)CH3-Gruppe, eine CH2-C(=O)-CH3-Gruppe, R2^ eine Hydroxygruppe, Halogen, eine geschützte Hydroxygruppe OPG3, ein Phosphoniumhalogenidrest PPh3+Hal" (Ph = Phenyl; Hai = F, CI, Br, I), ein Phosphonatrest P(O)(OQ)2 (Q = C-j-Ci o-Alkyl oder Phenyl) oder ein Phosphinoxidrest P(O)Ph2 (Ph = Phenyl), R29 Wasserstoff, C-j-Cβ-Alkyl, bedeuten,R 2 0 'halogen, N3, NHR 29 a hydroxyl group, a protected hydroxyl group O-PG 3 , a protected amino group NR 29 PG 3 , a Cj-Cio-alkylsulfonyloxy group, which may optionally be perfluorinated, one optionally by CjC ^ alkyl, nitro , Chlorine or bromine substituted benzoyloxy group, an NR 29 S02CH3 group, an NR 9 C (= O) CH3 group, a CH2-C (= O) -CH3 group, R 2 ^ a hydroxy group, halogen, a protected hydroxy group OPG 3 , a phosphonium halide residue PPh3 + Hal "(Ph = phenyl; Hai = F, CI, Br, I), a phosphonate residue P (O) (OQ) 2 (Q = Cj-Ci o-alkyl or phenyl) or a phosphine oxide residue P (O) Ph2 (Ph = phenyl), R29 is hydrogen, Cj-Cβ-alkyl,
zu einer Verbindung der allgemeinen Formel ABC ( = Verbindung der allgemeinen Formel I)to a compound of the general formula ABC (= compound of the general formula I)
ABC ABC
worinwherein
Ria', Rlb'; R23', R2b'( R3'; R43', R4b'j R6, R7, R13, R14, Q und Z die bereits genannten Bedeutungen haben undRia ', Rlb'; R23 ', R 2b' (R 3 ';R43', R 4b ' j R 6, R 7, R13, R14, Q and Z have the meanings already mentioned and
PG14 ein Wasserstoffatom oder eine Schutzgruppe PG darstellt,PG 14 represents a hydrogen atom or a protective group PG,
umgesetzt wird.is implemented.
2. Verfahren nach Anspruch 1 , dadurch gekennzeichnet, daß eine Verbindung der allgemeinen Formel I,2. The method according to claim 1, characterized in that a compound of general formula I,
worinwherein
Rla Rl b gleich sind und C-j-Cg-Alkyl, oder gemeinsam eine -(CH2)nrRla Rl b are the same and C-j-Cg-alkyl, or together a - (CH2) nr
Gruppe mit m = 2, 3 oder 4,Group with m = 2, 3 or 4,
R2a, R D verschieden sind und Wasserstoff, C-i-Cg-Alkyl, C2-C<|o-Alkenyl, C2-C-|o-Al inyl oder C7-C20-Aralkyl, R5 Wasserstoff, Ci-Cρ-Alkyl,R 2a , R D are different and are hydrogen, Ci-Cg-alkyl, C2-C <| o-alkenyl, C2-C- | o-alinyl or C7-C20-aralkyl, R 5 is hydrogen, Ci-Cρ-alkyl .
R8 Wasserstoff, Halogen, Ci-Cß-Alkyl, l5aj Rl5b gleich oder verschieden sind und Wasserstoff, C-|-C6-Alkyl, Aryl, C7-C20-Aralkyl, oder gemeinsam eine -(CH2)q-Gruppe, q 3 bis 6, bedeuten, hergestellt wird.R 8 is hydrogen, halogen, Ci-Cß-alkyl, l5a j Rl5b are the same or different and are hydrogen, C- | -C6-alkyl, aryl, C7-C20-aralkyl, or together a - (CH2) q group, q 3 to 6 mean will be produced.
3. Verfahren nach Anspruch 1 , dadurch gekennzeichnet, daß eine Verbindung der allgemeinen Formel I,3. The method according to claim 1, characterized in that a compound of general formula I,
worinwherein
Ria, Rlb gleich sind und C<|-C3-Alkyl, oder gemeinsam eine -(CH2)m- Gruppe mit m = 2, 3 oder 4,Ria, Rlb are the same and C <| -C3-alkyl, or together a - (CH2) m group with m = 2, 3 or 4,
R2a Wasserstoff,R2a hydrogen,
R2b C<|-C5-Alkyl, C2-C6-Alkenyl, C2-C6-Alkinyl,R2b C <| -C5-alkyl, C2-C6-alkenyl, C2-C6-alkynyl,
R5 Wasserstoff, C<|-C3-Alkyl,R 5 is hydrogen, C <| -C3-alkyl,
Rß, R? gemeinsam eine zusätzliche Bindung, G eine Gruppe X=CR8-, ein bicyclischer Arylrest,Rß, R? together an additional bond, G is a group X = CR 8 -, a bicyclic aryl radical,
R8 Wasserstoff, Fluor, Chlor, C-|-C3-Alkyl,R 8 is hydrogen, fluorine, chlorine, C- | -C3-alkyl,
X Sauerstoff oder eine Gruppe CR1 °R11 ,X oxygen or a group CR1 ° R 1 1,
R1° Wasserstoff,R1 ° hydrogen,
R11 Aryl, R13 CH2ORl3a, CO2Rl3b,R11 aryl, R13 CH 2 ORl 3a , CO 2 Rl 3b ,
R14 ORl a, R 14 ORl a ,
Rl3a7 Rl4a gemeinsam eine CR 5aRl5b -Gruppe,Rl3a 7 Rl4a together form a CR 5a Rl 5b group,
R13b Wasserstoff, C-i-Cβ-Alkyl, R 13b is hydrogen, Ci-Cβ-alkyl,
R 5a, Rl5b gleich sind und Cι-C3-Alkyl, oder gemeinsam eine -(CH2)q- Gruppe, oderR 5a, Rl5b are the same and -CC alkyl, or together a - (CH2) q group, or
Rl5a, Rl5b verschieden sind und Wasserstoff, Aryl, q 4 oder 5,Rl5a, Rl5b are different and are hydrogen, aryl, q 4 or 5,
Z Sauerstoff bedeuten,Z is oxygen,
hergestellt wird. will be produced.
4. Verfahren zur Herstellung der Epothilon-Derivate der allgemeinen Formel II4. Process for the preparation of the epothilone derivatives of the general formula II
worin die Substituenten R1a, R1b, R2a, R2b, R3, R4a, R4b, R5, R6, R7, G, OPG2 und Z die in der allgemeinen Formel I angegebenen Bedeutungen haben, und A-K eine Gruppe -O-C(=O), -OCH2-, -CH2C(=O)-, -NR29-C(=O)-, -NR29-SO2- bedeutet, dadurch gekennzeichnet, daß ein nach einem der vorstehenden Ansprüche 1 bis 3 erhaltenes Epothilon-Vorprodukt der allgemeinen Formel I cyclisiert wird.wherein the substituents R 1a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 , G, OPG 2 and Z have the meanings given in the general formula I, and AK is a group -OC (= O), -OCH 2 -, -CH 2 C (= O) -, -NR 29 -C (= O) -, -NR 29 -SO 2 -, characterized in that a epothilone precursor of general formula I obtained according to one of the preceding claims 1 to 3 is cyclized.
5. Verbindungen der allgemeinen Formel AB5. Compounds of the general formula AB
AB FROM
worin Rla', V und Z die bereits genannten Bedeutungen haben und PG14 ein Wasserstoffatom oder eine Schutzgruppe PG darstellt. where Rl a ', V and Z have the meanings already mentioned and PG1 4 represents a hydrogen atom or a protective group PG.
EP04740122A 2003-07-03 2004-06-19 Method for producing c1-c15 fragments of epothilones and the derivatives thereof Withdrawn EP1641734A1 (en)

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US5969145A (en) * 1996-08-30 1999-10-19 Novartis Ag Process for the production of epothilones and intermediate products within the process
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US6518421B1 (en) * 2000-03-20 2003-02-11 Bristol-Myers Squibb Company Process for the preparation of epothilone analogs
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US6933385B2 (en) * 2001-08-03 2005-08-23 Schering Ag Protected 3,5-dihydroxy-2,2-dimethyl-valeroamides for the synthesis of epothilones and derivatives and process for the production and the use
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