DE19830060A1 - New epothilone derivatives, used as mitosis regulators e.g. for treating malignant tumors, psoriasis or arthritis - Google Patents

Abstract

Epothilone derivatives (I) are new. Epothilone derivatives of formula (I) (including stereoisomers and their mixtures) are new. R1a, R1b, R2a, R2b, R3, R4a, R4b = H, 1-10C alkyl, aryl or 7-20C aralkyl; or R1a + R1b or R2a + R2b or R4a + R4b = (CH2)n; n = 2-5; D'-E = CH2CH2, CH=CH, C?=C, oxirane-2,3-diyl, CH(OH)CH(OH) or CH(OH)CH2; R5 = 1-10C alkyl, aryl or 7-20C aralkyl; R6, R7 = H or together form an additional bond or O; R25 = H or 1-10C alkyl (optionally substituted by one or more of halo and/or OH); R8 = H; or 1-20C alkyl, aryl or 7-20C aralkyl (all optionally substituted); X = O, (OR9)2, 2-20C alkylene- alpha ,w-dioxy, (H, OR10) or CR11R12; R9 = 1-20C alkyl; R10 = H or protecting group; R11, R12 = H, 1-20C alkyl, aryl or 7-20C aralkyl; or CR11R12 = 5-7 membered carbocyclic ring; Y = O or H2; Z' = H or (H, OR13); R13 = H or protecting group. Independent claims are included for: (i) the preparation of (I); and (ii) novel intermediates of formulae (B), (C), (BC) and (ABC). R17 = OH, halo, protected hydroxy, PPh3<+>.halo<->, P(O)(OQ)2 or P(O)Ph2; Ph = phenyl; Q = 1-10C alkyl or Ph; R20 = H or protecting group; U = as for X; V, W = as X but not CR11R12; P' = protecting group.

Description

By Höfle et al. the cytotoxic effects of the natural substances epothilone A (R = hydrogen) and epothilone B (R = methyl)

e.g. B. in Angew. Chem. 1996, 108, 1671-1673. Because of the in vitro Selectivity towards breast and intestinal cell lines and their compared to taxol clearly higher activity against P-glycoprotein-forming, multi-resistant tumor lines and their physical properties improved over Taxol, e.g. B. one by a factor of 30 higher water solubility, is this novel structural class for the development of a Drug for the treatment of malignant tumors particularly interesting.

The natural products are both chemical and metabolic for one Drug development not sufficiently stable. To eliminate these drawbacks Modifications to the natural product necessary. Such modifications are only on total synthetic path possible and presuppose synthesis strategies that a wide Allow modification of the natural product. The aim of the structural changes is also to increase the therapeutic range. This can be done by improving Selectivity of action and / or a reduction in undesirable toxic Side effects and / or an increase in potency occur.

The total synthesis of epothilone A is by Schinzer et al. in Chem. Eur. J. 1996, 2, No. 11, 1477-1482 and in Angew. Chem. 1997, 109, No. 5, pp. 543-544).

Epothilone derivatives have already been described by Höfle et al. described in WO 97/19086. These derivatives were made from natural epothilone A or B.

Another synthesis of epothilone and epothilone derivatives was by Nicolaou et al. in Appl. Chem. 1997, 109, No. 1/2, pp. 170-172. The synthesis of epothilone A and B and some epothilone analogues were described in Nature, Vol. 387, 1997, pp. 268-272, the Synthesis of epothilone A and its derivatives in J. Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7960-7973 and the synthesis of epothilones A and B and some epothilone  Analogues in J. Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7974-7991 also from Nicolaou et al. described.

Nicolaou et al. describe in Angew. Chem. 1997, 109, No. 19, pp. 2181-2187 the production of epothilone A analogues by means of combinatorial solid phase synthesis. Some epothilone B analogues are also described there.

The object of the present invention is to provide new epothilone derivatives To make available both chemically and metabolically for one Drug development are sufficiently stable and that in terms of their therapeutic Broad, their selectivity of action and / or undesirable toxic side effects and / or their potency are superior to natural derivatives.

The present invention describes the new epothilone derivatives of the general formula I

wherein
R ^1a , R ^{1b are the} same or different and are hydrogen, C ₁ -C ₁₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl, or together a - (CH ₂ ) _m group with m = 2, 3, 4 or 5,
R ^2a , R ^{2b are} identical or different and are hydrogen, C ₁ -C ₁₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl or together a - (CH ₂ ) _n group with n = 2, 3, 4 or 5 ,
R ^{3 is} hydrogen, C ₁ -C ₁₀ alkyl, aryl, C ₇ -C ₁₀ aralkyl,
R ^4a , R ^{4b are the} same or different and are hydrogen, C ₁ -C ₁₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl or together a - (CH ₂ ) _p group with p = 2, 3, 4 or 5 ,

DE a group
R ^{5 is} C ₁ -C ₁₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl,
R ⁶ , R ⁷ each represent a hydrogen atom, together an additional bond or an oxygen atom,
R ^{8 is} hydrogen, C ₁ -C ₂₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl, all of which can be substituted,
X is an oxygen atom, two alkoxy groups OR ⁹ , a C ₂ -C ₁₀ alkylene-α, ω- dioxy group, which can be straight-chain or branched, H / OR ¹⁰ or a grouping CR ¹¹ R ¹² ,
in which
R ^{9 represents} a C ₁ -C ₂₀ alkyl radical,
R ¹⁰ for hydrogen or a protective group PG ¹ ,
R ¹¹ , R ^{12 are the} same or different and represent a hydrogen atom, a C ₁ -C ₂₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl radical or R ¹¹ and R ¹² together with the methylene carbon atom for a 5 to 7-membered carbocyclic ring
stand,
Y is an oxygen atom or two hydrogen atoms,
Z is an oxygen atom or H / OR ¹³ ,
in which
R ^{13 is} hydrogen or a protective group PG ²
is
mean,
including all stereoisomers of these compounds and also their mixtures.

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 represents a C ₁ -C ₆ fragment (epothilone counting) of the general formula

wherein
R ^{1a '} , R ^1b' , R ^2a and R ^{2b 'have} the meanings already given for R ^1a , R ^1b , R ^2a and R ^2b and
R ¹⁴ CH ₂ OR ^14a , CH ₂ -Hal, CHO, CO ₂ R ^14b , COHal,
R ¹⁵ hydrogen, OR ^15a , Hal, OSO ₂ R ^15b ,
R ^14a , R ^{15a are} hydrogen, SO ₂ alkyl, SO ₂ aryl, SO ₂ aralkyl or together a - (CH ₂ ) _o group or together a CR ^16a R ^16b group,
R ^14b , R ^{15b are} hydrogen, C ₁ -C ₂₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl,
R ^16a , R ^{16b are} identical or different and are hydrogen, C ₁ -C ₁₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl, or together a - (CH ₂ ) _q group,
Hal halogen,
o 2 to 4,
q 3 to 6,
including all stereoisomers and mixtures thereof, and etherifying or esterifying free hydroxyl groups in R ¹⁴ and R ¹⁵ , ketalizing free carbonyl groups in A and R ^14, converting them to an enol ether or reducing them, and free acid groups in A in whose salts may be converted with bases.

B stands for a C7-C12 fragment (epothilone counting) of the general formula

wherein
R ^{3 '} , R ^4a' and R ^{4b 'have} the meanings already given for R ³ , R ^4a and R ^4b , and
R ^{17 is} a hydroxyl group, halogen, a protected hydroxyl group OPG ³ , a phosphonium halide residue PPh ₃ ⁺Hal⁻ (Ph = phenyl; Hal = F, Cl, Br, I), a phosphonate residue P (O) (OQ) ₂ (Q = C ₁ -C ₁₀ alkyl or phenyl) or a phosphine oxide residue P (O) Ph ₂ (Ph = phenyl),
V is an oxygen atom, two alkoxy groups OR ¹⁸ , a C ₂ -C ₁₀ alkylene-α, ω- dioxy group, which can be straight-chain or branched, or H / OR ¹⁹ ,
R ¹⁸ C ₁ -C ₂₀ alkyl,
R ^{19 is} a hydrogen or a protective group PG ⁴
mean.

C stands for a C13-C16 fragment (epothilone counting) of the general formula

wherein
R ^{5 '} , R ^{8' have} the meaning already given in general formula I for R ⁵ and R ⁸ and
R ^{20 is} a hydrogen atom or a protective group PG ⁵
U is an oxygen atom, two alkoxy groups OR ⁹ , a C ₁ -C ₁₀ alkylene-α, ω- dioxy group, which can be straight-chain or branched, H / OR ¹⁰ or a grouping CR ¹¹ R ¹² ,
in which
R ^{9 represents} a C ₁ -C ₂₀ alkyl radical,
R ¹⁰ for hydrogen or a protective group PG ⁶ ,
R ¹¹ , R ^{12 are the} same or different and represent a hydrogen atom, a C ₁ -C ₂₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl radical or R ¹¹ and R ¹² together with the methylene carbon atom for a 5 to 7-membered carbocyclic ring
W is an oxygen atom, two alkoxy groups OR ²¹ , a C ₂ -C ₁₀ alkylene-α, ω- dioxy group, which can be straight-chain or branched, or H / OR ²² ,
stand,
in which
R ^{21 represents} a C ₁ -C ₂₀ alkyl radical,
R ²² for hydrogen or a protective group PG ⁷ ,
mean.

As alkyl groups R ^1a , R ^1b , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ^14b , R ^15b , R ^16a , R ^16b and R ¹⁸ are straight or branched chain alkyl groups with 1-20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.

The alkyl groups R ^1a , R ^1b , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ^14b , R ^15b , R ^16a , R ^16b and R ¹⁸ can be perfluorinated or substituted by 1-5 halogen atoms, hydroxy groups, C ₁ -C ₄ alkoxy groups, C ₆ -C ₁₂ aryl groups (which can be substituted by 1-3 halogen atoms).

As aryl radical R ^1a a, R ^1b , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁸ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ^14b , R ^15b , R ^16a and R ^16b come substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms such as. B. phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, which can be mono- or polysubstituted by halogen, OH, O-alkyl, CO ₂ H, CO ₂ -alkyl , -NH ₂ , -NO ₂ , -N ₃ , -CN, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ acyl, C ₁ - C ₂₀ acyloxy groups, in question.

The aralkyl groups in R ^1a , R ^1b , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁸ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ^14b , R ^15b , R ^16a and R ^16b may contain up to 14 carbon atoms, preferably 6 to 10, and 1 to 8, preferably 1 to 4, atoms in the alkyl chain. Examples of suitable aralkyl radicals are benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl. The rings can be mono- or polysubstituted by halogen, OH, O-alkyl, CO ₂ H, CO ₂ alkyl, -NO ₂ , -N ₃ , -CN, C ₁ - C ₂₀ alkyl, C ₁ -C ₂₀ Acyl, C ₁ -C ₂₀ acyloxy groups.

The alkoxy groups contained in X in general formula I are each intended to be 1 to 20 Contain carbon atoms, where methoxy, ethoxy, propoxy, isopropoxy and t-Butyloxy groups are preferred.

Representatives for the protective groups PG are alkyl- and / or aryl-substituted silyl, C ₁ -C ₂₀ -alkyl, C ₄ -C ₇ -cycloalkyl, which may additionally contain an oxygen atom in the ring, aryl, C ₇ -C ₂₀ - Aralkyl, C ₁ -C ₂₀ acyl and aroyl to name.

Those skilled in the art come as alkyl, silyl and acyl radicals for the protective groups PG known residues. Preferred from the corresponding alkyl and Silyl ethers easily removable alkyl or silyl radicals, such as the Methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, Trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilyl, tribenzylsilyl, Triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl radical and Alkylsulfonyl and arylsulfonyl radicals. As acyl residues come e.g. B. formyl, acetyl, propionyl, Isopropionyl, pivalyl, butyryl or benzoyl with amino and / or hydroxy groups can be substituted in question.  

The acyl groups PG ¹ and PG ² in R ¹⁰ and R ¹³ 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 ^1a and R ^1b is preferably 2, 3 or 4.

The C ₂ -C ₁₀ -alkylene-α, ω-dioxy group which is possible for X is preferably an ethylene ketal or neopentyl ketal group.

The substituents in the compounds of general formula I can be chosen so that
Y, Z, R ^1a , R ^1b , R ^2a , R ^2b and R ^{5 can} all have the meanings given in the general formula I, and the rest of the molecule is identical to the naturally occurring epothilone A or B, or
R ³ , R ^4a , R ^4b , DE, R ⁵ , R ⁶ and R ^{7 can} all have the meanings given in the general formula I, and the rest of the molecule is identical to the naturally occurring epothilone A or B. or
R ⁵ , R ⁶ , R ⁷ , R ⁸ and X can all have the meanings given in the general formula I, and the rest of the molecule is identical to the naturally occurring epothilone A or B or
Y, Z, R ^1a , R ^1b , R ^2a , R ^2b , R ³ , R ^4a , R ^4b , DE, R ⁵ , R ⁶ and R ^{7 can} all have the meanings given in the general formula I, and the rest of the molecule is identical to the naturally occurring epothilone A or B or
Y, Z, R ^1a , R ^1b , R ^2a , R ^2b , R ⁵ , R ⁶ , R ⁷ , R ⁸ and X can all have the meanings given in general formula I, and the rest of the molecule is identical to that naturally occurring epothilone A or B or
R ³ , R ^4a , R ^4b , DE, R ⁵ , R ⁶ , R ⁷ , R ⁸ and X can all have the meanings given in general formula I, and the rest of the molecule is identical to the naturally occurring epothilone A or B.

A further variant according to the invention provides those compounds in which R ^{5 represents} a methyl, ethyl or propyl group, in which case preferably R ⁶ and R ⁷ together mean an additional bond or an epoxy group.

The compounds mentioned below are preferred according to the invention:
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1.8, 8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1.8, 8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl4-oxazolyl) ethenyl) -1-oxa-5,5, 7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1.8, 8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1.8, 8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) 1-oxa- 5,5,7,9 , 14-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) - 1,8,8,10, 12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and (1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-3- ( 1-methyl-2- (pyridyl) ethenyl) - 1,8,8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-7-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,9,14-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1,8,8,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane 5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1,8,8,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) 4,8-dihydroxy-5,5-dimethylene-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1 -oxa-7,9,14-trimethyl-cyclohexadec-13-en-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8-dimethylene-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -1,10,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-8,8-dimethylene-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -1,10,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5-trimethylene-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1-oxa-7,9,14-trimethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8-trimethylene-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -1,10,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-8,8-trimethylene-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -1,10,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) 4,8-dihydroxy-14-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa -5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.10] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) 4,8-dihydroxy-14-ethyl-16- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1-oxa -5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) - 8,8,10,12-tetramethyl4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-14-ethyl-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5, 5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8, 10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy1-ethyl-3- (1-methyl-2- (2-pyridyl) ethenyl) -8,8,10, 12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) 4,8-dihydroxy-7,14-diethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1 -oxa-5,5,9-trimethyl-cyclohexadec-13-en-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1,10-diethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -8,8,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1,10-diethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -8,8,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) 4,8-dihydroxy-14-proyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa -5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1-propyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1-propyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1.8, 8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1.8, 8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane 5.9 dione
(45.7R, 85.9S, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) 1-oxa-5.5 , 7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1.8, 8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-oxazol-1-yl) ethenyl) - 1,8,8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13E, 16S (E)) 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa- 5,5,7,9 , 14-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) - 1,8,8,10, 12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) - 1,8,8,10, 12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 95.13E, 16S (E)) - 4,8-dihydroxy-7-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,9,14-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1,8,8,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1,8,8,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-14-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-Dihydroxy-14-proyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1-propyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1-propyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione

Representation of the partial fragments A

The partial fragments (synthesis building blocks) of the general formula A can be easily removed

• a) a pantolactone of the general formula IIa
  wherein
  R ^{1a '} , R ^1b' each represent a methyl group
  or
• b) a malonic acid dialkyl ester of the general formula XXVIII
  wherein
  R ^{1a '} , R ^{1b' have} the meaning given in the general formula A, and alkyl independently of one another is a C ₁ -C ₂₀ alkyl, C ₃ -C ₁₀ cycloalkyl or C ₄ -C ₂₀ alkylcycloalkyl radical,

manufacture as a starting product.

The partial fragments A in which R ^{1a '} = R ^1b' = methyl can be produced from inexpensive pantolactone in an efficient manner with an optical purity of <98% ee.

The synthesis is shown in the following scheme 1 using the example of D - (-) - pantolactone described. L - (+) - pantolactone gives the corresponding A-II to A-XIV  enantiomeric compounds ent-A-II to ent-A-XIV and from racemic DL-pantolactone the corresponding racemic compounds rac-A-II to rac-A-XIV:

Scheme 1

Step a (A-II ⇒ A-III)

The free hydroxyl group of pantolactone (A-II) is protected by the methods known to those skilled in the art. As a protective group PG ⁸ come the protective groups known to those skilled in the art, such as B. the methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl-, para-, benzyl Methoxybenzyl, formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl in question.

An overview is z. B. in "Protective Groups in Organic Synthesis" Theodora W. Green, John Wiley and Sons).

Protecting groups which are preferred under acidic reaction conditions can be split, such as. B. the methoxymethyl, tetrahydropyranyl, Tetrahydrofuranyl, trimethylsilyl radical.

The tetrahydropyranyl radical is particularly preferred.

Step b (A-III ⇒ A-IV)

The protected lactone A-III is reduced to lactol A-IV. Suitable as reducing agents modified in their reactivity aluminum hydrides such. B. Diisobutyl aluminum hydride. The reaction takes place in an inert solvent such as. B. toluene, preferably at low temperatures.

Step c (A-IV ⇒ A-V)

Lactol A-IV is opened with the addition of one carbon atom to the hydroxyolefin A-V. For this purpose, the methods known to the person skilled in the art such as B. the olefination according to Tebbe, the Wittig or Wittig / Horner reaction, the addition of a organometallic compound with elimination of water. The is preferred Wittig reaction using methyltriarylphosphonium halides such as. B. Methyltriphenylphosphonium bromide with strong bases such as. B. n-butyllithium, potassium tert-butanolate, sodium ethanolate, sodium hexamethyldisilazane; is preferred as the base n-butyllithium.

Step d (A-V ⇒ A-VI)

The free hydroxyl group in AV is protected by methods known to those skilled in the art. The protective groups PG ⁹ are the protective groups known to the person skilled in the art, as already mentioned above for PG ⁸ in step a (A-II ⇒ A-III).

Protecting groups which cleave under the action of fluoride are preferred can be such. B. the trimethylsilyl, tert-butyldimethylsilyl, tert. Butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl radical.

The tert-butyldimethylsilyl, the triisopropylsilyl and the tert-butyldiphenylsilyl residue.

Step e (A-VI ⇒ A-VII)

Anti-Markovnikov water is added to the double bond in A-VI. Suitable for this known to those skilled in the art such. B. implementation with boranes, their subsequent oxidation to the corresponding boric acid esters and their Saponification. Preferred boranes are, for. B. the borane-tetrahydrofuran complex, the  Borane-dimethyl sulfide complex, 9-borabicyclo [3.3.1] nonane in an inert solvent such as tetrahydrofuran or diethyl ether. As an oxidizing agent preferably hydrogen peroxide used, preferably for the saponification of the boresters Alkali hydroxides such as e.g. B. sodium hydroxide.

Step f (A-VI ⇒ A-VII)

The protective group PG ⁸ introduced under step a) is then cleaved by the processes known to the person skilled in the art. If it is an acidic cleavable protective group, dilute mineral acids in aqueous alcoholic solutions are suitable for the cleavage, the use of catalytic amounts of acids such as. B. para-toluenesulfonic acid, para-toluenesulfonic acid pyridinium salt, camphorsulfonic acid in alcoholic solutions, preferably in ethanol or isopropanol.

Step g (A-VII ⇒ A-IX)

A common protection of both alcohol functions of the mono-protected 1,3-diol in A-VII is by direct ketalization with a carbonyl compound of the general formula R ^16a -CO-R ^16b , or by transketalization with a ketal of the general formulas, R ^16a -C (OC ₂ H ₅ ) ₂ -R ^16b , R ^16a -C (OC ₂ H ₄ ) ₂ -R ^16b , R ^16a -C (OCH ₂ C (CH ₃ ) ₂ CH ₂ O) -R ^16b wherein R ^16a and R ^{16b are} each have the meanings given, possible under acid catalysis. Suitable acids are the acids already mentioned under step f); preference is given to the use of para-toluenesulfonic acid, optionally with the addition of copper (II) or cobalt (II) salts such as, for. B. copper (II) sulfate.

Step h (A-VIII ⇒ A-IX)

Protection of both alcohol functions of the 1,3-diol in A-VIII is possible by direct ketalization with a carbonyl compound of the general formula R ^16a -CO-R ^16b , or by transketalization with a ketal of the general formulas, R ^16a -C (OC ₂ H ₅ ) ₂ -R ^16b , R ^16a -C (OC ₂ H ₄ ) ₂ -R ^16b , R ^16a -C (OCH ₂ C (CH ₃ ) ₂ CH ₂ O) -R ^16b wherein each of R ^16a and R ^{16b is} the above Have meanings possible under acid catalysis. Transketalization with 2,2-dimethoxypropane is preferred. Suitable acids are the acids already mentioned under step f); preference is given to using camphorsulfonic acid.

Step i (A-IX ⇒ A-X)

The protective group PG ⁹ introduced under step d) is then cleaved by the processes known to the person skilled in the art. If it is a silyl ether, the reaction with fluorides such as tetrabutylammonium fluoride, the hydrogen fluoride-pyridine complex, potassium fluoride or the use of dilute mineral acids, the use of catalytic amounts of acids such as e.g. B. para-toluenesulfonic acid, para-toluenesulfonic acid pyridinium salt camphorsulfonic acid in alcoholic solutions, preferably in ethanol or isopropanol.

Step k (A-X ⇒ A-XI)

The oxidation of the primary alcohol in A-X to the aldehyde takes place according to the Methods known to those skilled in the art. The oxidation may also be mentioned, for example Pyridinium chlorochromate, pyridinium dichromate, chromium trioxide-pyridine complex, the Oxidation according to Swern or related methods e.g. B. using Oxalyl chloride in dimethyl sulfoxide, the use of Dess-Martin periodinans, the Use of nitrogen oxides such. B. N-methyl-morpholino-N-oxide in the presence suitable catalysts such. B. tetrapropylammonium perruthenate in inert Solvents. Oxidation according to Swern and with N-methyl-morpholino- N-oxide using tetrapropylammonium perruthenate.

Step l (A-XI ⇒ A-XII)

The conversion of the aldehydes A-XI to alcohols of the formula A-XII takes place with organometallic compounds of the general formula M-CHR ^{2a '} R ^2b' , in which M is an alkali metal, preferably lithium or a divalent metal MX, in which X represents a halogen and the radicals R ^{2a '} and R ^2b' each have the meanings given above. Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.

Step m (A-XII ⇒ A-XIII)

The oxidation of the secondary alcohol in A-XII A-XIII takes place according to the, under step k) conditions mentioned. Oxidation with N-methyl-morpholino-N-oxide is preferred using tetrapropylammonium permthenate.

Step n (A-XIII ⇒ A-XIV)

In the event that R ^{2a '} in A-XIII is hydrogen, there is the option of introducing a second radical R ^2a' which has the meanings mentioned above, except hydrogen. For this, using strong bases such as. B. lithium diisopropylamide converted the ketone in A-XIII into the enolate and reacted with a compound of the general formula XR ^2a a, in which X represents a halogen. The halogen X is preferably chlorine, bromine and iodine.

The route described above can also be used to synthesize C1-C6-epothilone building blocks which contain a carboxylic acid or its ester at C-1 (R ¹⁴ = CO ₂ R ^14b in A).

The synthesis of the building block A-XXII is shown in the following scheme 2 using the example of D - (-) - Pantolactone-derived intermediate A-V described. From L - (+) - pantolactone the corresponding ent-A-V compounds which are enantiomeric to A-V to A-XXVII are obtained to ent-A-XXVII and the corresponding racemic DL-pantolactone Compounds rac-A-V to rac-A-XXVII:

Scheme 2

Step o (A-V ⇒ A-XV)

The oxidation of the primary alcohol in A-V to the aldehyde A-XV takes place according to, below Step k) conditions mentioned. The oxidation method according to Swern is preferred.

Step p (A-XV ⇒ A-XVI)

The reaction of the aldehydes A-XV to alcohols of the formula A-XVI takes place with organometallic compounds of the general formula M-CHR ^{2a '} R ^2b' , in which M is an alkali metal, preferably lithium or a divalent metal MX, in which X represents a halogen and the radicals R ^{2a '} and R ^2b' each have the meanings given above. Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.

Step q (A-XVI ⇒ A-XVII)

Anti-Markovnikov water is added to the double bond in A-XVI. For this the methods described under e) are suitable.

Step r (A-XVII ⇒ A-XVIII)

The free hydroxy group in A-XVII is protected by the methods known to those skilled in the art. The protective groups PG ^{10 which} are known to the person skilled in the art, as already mentioned above for PG ⁸ in step a (A-II ⇒ A-III), are suitable.

Protective groups which are preferred are those which are basic or hydrogenolytic Reaction conditions can be split, such as. B. benzyl, para-nitrobenzyl, Acetyl, propionyl, butyryl, benzoyl radical.

The benzoyl radical is particularly preferred.

Step s (A-XVIlI ⇒ A-XIX)

The oxidation of the secondary alcohol in A-XVII to the ketone A-XIX takes place according to the conditions mentioned under step k). Oxidation with N-methyl is preferred morpholino-N-oxide using tetrapropylammonium perruthenate.

Step t (A-XIX ⇒ A-XX)

The protection group PG ¹⁰ in XIX is now split selectively. If it is a hydrogenolytically cleavable protective group, hydrogenation is preferably carried out in the presence of palladium or platinum catalysts in inert solvents such as, for example, ethyl acetate or ethanol. If it is a basic cleavable protective group, the saponification with carbonates in alcoholic solution such as. As potassium carbonate in methanol, the saponification with aqueous solutions of alkali metal hydroxides such. B. lithium hydroxide or sodium hydroxide using organic, water-miscible solvents such as. As methanol, ethanol, tetrahydrofuran or dioxane.

Step u (A-XVII ⇒ A-XXI)

The oxidation of the alcohols in A-XVII to ketoaldehyde A-XXI is carried out according to, below Step k) conditions mentioned. Oxidation with N-methylmorpholino is preferred. N-oxide using tetrapropylammonium perruthenate as well as the method to Swern.

Step v (A-XX ⇒ A-XXI)

The oxidation of the primary alcohol in A-XX to ketoaldehyde A-XXI takes place according to the conditions mentioned under step k). Oxidation with N-methyl morpholino-N-oxide using tetrapropylammonium perruthenate.

Step w (A-XXI ⇒ A-XXII)

The oxidation of the aldehyde in A-XXI to the carboxylic acid A-XXII (R ^14b = hydrogen) takes place according to the methods known to the person skilled in the art. For example, the oxidation according to Jones, the oxidation with potassium permanganate, for example in an aqueous system of tert-butanol and sodium dihydrogen phosphate, the oxidation with sodium chlorite in aqueous tert-butanol, optionally in the presence of a chlorine scavenger such as, for. B. 2-methyl-2-butene.

The oxidation of the aldehyde in A-XXI to the ester A-XXII, in which R ^{14b has} the meanings given above and is not hydrogen, can for example with pyridinium dichromate and the desired alcohol HO-R ^14b in an inert solvent such as. B. dimethylformamide.

Step x (A-VII ⇒ A-XXIII)

The oxidation of the primary alcohol in A-VII to the aldehyde A-XXIII takes place according to, below Step k) conditions mentioned. Oxidation with N-methylmorpholino is preferred. N-oxide using tetrapropylammonium perruthenate as well as the method to Swern.

Step y (A-XXIII ⇒ A-XXIV)

The oxidation of the aldehyde A-XXIII to the carboxylic acid or its ester A-XXIV takes place according to the conditions already described under w).

Step z (A-XXIV ⇒ A-XXV)

The protective group PG ⁹ introduced under step d) is split as described under step i.

Step aa (A-XXV ⇒ A-XXVI)

The oxidation of the primary alcohol in A-XXV to the aldehyde A-XXVI takes place according to conditions mentioned under step k). Oxidation with N-methyl morpholino-N-oxide using tetrapropylammonium perruthenate and the Swern method.

Step off (A-XXVI ⇒ A-XXVII)

The conversion of the aldehydes A-XXVI to alcohols of the formula A-XXVII takes place according to the conditions mentioned under step l).

Step ac (A-XXVII → A-XXII)

The oxidation of the secondary alcohol in A-XXVII to ketone A-XXII takes place according to the conditions mentioned under step k). Oxidation with N-methyl morpholino-N-oxide using tetrapropylammonium perruthenate.

The compounds of the formula A, in which R ^{1a '} and R ^{1b' can} all have the meanings given in the general formula A, can also be prepared efficiently and with high optical purity from cheap or easily accessible malonic acid dialkyl esters.

The synthesis is described in Scheme 3 below:

Step ad (A-XXVIII ⇒ A-XXIX)

Correspondingly substituted malonic acid ester derivatives A-XXVIII, which are either commercially available or by the processes known to the person skilled in the art from malonic acids or their Alkyl esters can be produced are reduced to diols A-XXIX. For this suitable are the reducing agents known to the person skilled in the art, such as, for. B. Diisobutylaluminium hydride, complex metal hydrides such as. B. Lithium aluminum hydride.

Step ae (A-XXIX ⇒ A-XXX)

A free hydroxyl group in A-XXIX is selectively protected by methods known to those skilled in the art. The protective groups PG ¹¹ are the protective groups known to the person skilled in the art, as already mentioned above for PG ⁸ in step a (A-II ⇒ A-III).

Protective groups containing silicon are preferred.

Step af (A-XXX ⇒ A-XXXI)

The oxidation of the remaining primary hydroxyl group in A-XXX to the aldehyde A-XXXI takes place according to the conditions mentioned under step k). Oxidation with is preferred N-methyl-morpholino-N-oxide using tetrapropylammonium per-ruthenate,  the use of pyridinium chlorochromate, pyridinium dichromate and the method to Swern.

Step ag (A-XXXI ⇒ A-XXXII)

The aldehydes A-XXXI are reacted with an ester of acetic acid chG ¹ OC (O) CH ₃ , in which chG ^{1 is} a chiral auxiliary group, in the sense of an aldol reaction. The compounds chG ¹ OC (O) CH ₃ are used in optically pure form in the aldol reaction. The type of chiral auxiliary group determines whether the aldol reaction proceeds with high diastereoselectivity or results in a diastereomer mixture that can be separated by physical methods. An overview of comparable diastereoselective aldol reactions can be found in Angew. Chem. 99 (1987), 24-37. Suitable chiral auxiliary groups chG ¹ -OH are, for example, optically pure 2-phenylcyclohexanol, pulegol, 2-hydroxy-1,2,2-triphenylethanol, 8-phenylmenthol.

Step ah (A-XXXII ⇒ A-XXXIII)

The diastereomerically pure compounds A-XXXII can then be converted into enantiomerically pure compounds of the type A-XXXIII or ent-A-XXXIII by saponification of the ester unit with simultaneous release of the reusable chiral auxiliary component chG ¹ -OH by processes known to the person skilled in the art. Suitable for saponification are carbonates in alcoholic solution such as. B. potassium carbonate in methanol, aqueous solutions of alkali metal hydroxides such. B. lithium hydroxide or sodium hydroxide using organic, water-miscible solvents such as. As methanol, ethanol, tetrahydrofuran or dioxane.

Step ai (A-XXXII ⇒ A-VIII)

As an alternative to step ah, the chiral auxiliary group can also be removed reductively. On in this way the enantiomerically pure compounds of type A-VIII or ent-A-VIII receive. The reduction can be carried out by the methods known to the person skilled in the art be performed. As a reducing agent such. B. diisobutyl aluminum hydride and complex metal hydrides such as B. lithium aluminum hydride in question.

The compounds A-VIII or ent-A-VIII can, as described above, in compounds of type A-XIII or ent-A-XIII are transferred. According to Compounds of type A-XXXIII or ent-A-XXXIII described above Convey processes in compounds of type A-XXII or ent-A-XXII.

As an alternative to the route described above, the sequence can also be carried out without using a chiral auxiliary group chG ¹ . In this way, racemic mixtures of compounds of the rac-A-VIII or rac-A-XXXIII type are then obtained via the corresponding racemic precursors. These mixtures can in turn by the methods known to those skilled in the racemate resolution, for. B. Chromatography on chiral columns. The synthesis can also be continued with the racemic mixtures.

Representation of the partial fragments B

Scheme 4

Step a (B-II ⇒ B-III)

A hydroxyl group in B-II is protected by the methods known to the person skilled in the art. The protective groups PG ¹² are the protective groups known to the person skilled in the art, as already mentioned above for PG ⁸ in step a (A-II ⇒ A-III).

Protective groups containing silicon are preferred which operate under acidic reaction conditions or application of fluoride can be cleaved, such as. B. the trimethylsilyl,  Triethylsilyl-, tert-butyldimethylsilyl-, tert-butyldiphenylsilyl-, tribenzylsilyl-, Triisopropylsilyl residue.

The tert-butyldimethylsilyl radical is particularly preferred.

Step b (B-III ⇒ B-IV)

The free hydroxyl group in B-III is according to the methods known to those skilled in a leaving group LG transferred. As a leaving group LG are, for example Halogens such as B. bromine or iodine or alkyl or aryl sulfonates, which from the corresponding sulfonic acid halides or sulfonic anhydrides according to the Methods known to those skilled in the art can be produced.

Trifluoromethanesulfonate is preferred as the leaving group LG.

Step c (B-IV ⇒ B-VII)

The compound B-IV is alkylated with the enolate of a carbonyl compound of the general formula BV, in which chG ^{2 can be} a simple alkoxy group or else a chiral auxiliary group, by the methods known to the person skilled in the art. The enolate is by the action of strong bases such as. B. lithium diisopropylamide, lithium hexamethyldisilazane at low temperatures. As a chiral auxiliary group chG ² -H (B-VI) are chiral, optically pure and inexpensive alcohols such as. B. Pulegol, 2-phenylcyclohexanol, 2-hydroxy-1,2,2-triphenylethanol, 8-phenylmenthol or optically pure and inexpensive, reactive NH-containing compounds such as. B. amines, amino acids, lactams or oxazolidinones. Oxazolidinones are preferred, particularly preferably the compounds of the formulas B-VIa to B-VId. The choice of the particular antipode determines the absolute stereochemistry of the α-carbonyl carbon of the compound of the general formula B-VII. In this way, the compounds of the general formulas B-VII to B-XVII or their respective enantiomers ent-B-VII to ent-B-XVII can be obtained enantiomerically pure. As chG ² -H (B-VI) an achiral alcohol such as. B. ethanol, the racemic compounds rac-B-VII to rac-B-XVII are obtained.

Step d (B-VII ⇒ B-VIII)

If the group chG ^{2 represents} one of the chiral auxiliary groups mentioned under step c, this is recovered by transesterification of B-VII into an alkyl ester of the general formula B-VIII. The transesterification takes place according to the methods known to the person skilled in the art. The transesterification with simple alcohols such as. B. methanol or ethanol in the presence of appropriate titanium (IV) alcoholates.

Step e (B-VIII ⇒ B-IX)

The ester in B-VIII is reduced to alcohol B-IX. Suitable reducing agents are reducing agents known to the person skilled in the art, such as, for. B. aluminum hydrides such. B. Lithium aluminum hydride or diisobutyl aluminum hydride. The reaction takes place in one inert solvents such as B. diethyl ether, tetrahydrofuran, toluene.

Step e (B-VII ⇒ B-IX)

As an alternative to steps d) and e), the carbonyl group in B-VII can be reduced directly to the alcohols of the general formula B-IX under the conditions mentioned under step e). The chiral auxiliary component chG ² -H can also be recovered here.

Step f (B-IX ⇒ B-X)

In the event that R ^{3 is} not a hydrogen atom, the primary hydroxyl group in B-IX is first oxidized to the corresponding aldehyde by methods known to those skilled in the art. Examples include oxidation with pyridinium chlorochromate, pyridinium dichromate, chromium trioxide-pyridine complex, oxidation according to Swern or related methods, e.g. B. using oxalyl chloride in dimethyl sulfoxide, the use of Dess-Martin periodinane, the use of nitrogen oxides such as. B. N-methyl-morpholino-N-oxide in the presence of suitable catalysts such. B. tetrapropylammonium perruthenate in inert solvents. Oxidation according to Swern and with N-methyl-morpholino-N-oxide using tetrapropylammonium perruthenate is preferred.

The aldehydes thus obtained can then be converted into corresponding alcohols with organometallic compounds of the general formula MR ³ , in which M is an alkali metal, preferably lithium or a divalent metal MX, in which X represents a halogen and the radical R ^{3 has} the meanings given above. Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.

The free hydroxyl group of the secondary alcohol thus obtained (R ³ ≠ H) or, in the case of R ³ = H, the free hydroxyl group in B-IX is protected by the methods known to the person skilled in the art. The protective groups PG ¹³ are the protective groups known to the person skilled in the art, as already mentioned above for PG ⁸ in step a (A-II ⇒ A-III).

Protecting groups which are preferred under acidic reaction conditions can be split, such as. B. the methoxymethyl, tetrahydropyranyl, Tetrahydrofuranyl, trimethylsilyl radical.

The tetrahydropyranyl radical is particularly preferred.

Step g (B-X ⇒ B-XI)

The protective group PG ¹² introduced under step a) is then split according to the methods known to the person skilled in the art. If it is a silyl ether, the reaction with fluorides such as tetrabutylammonium fluoride, the hydrogen fluoride-pyridine complex, potassium fluoride or the use of dilute mineral acids, the use of catalytic amounts of acids such as e.g. B. para-toluenesulfonic acid, para-toluenesulfonic acid pyridinium salt, camphorsulfonic acid in alcoholic solutions, preferably in ethanol or isopropanol.

Step h (B-XI ⇒ B-XII)

If necessary, the free primary hydroxyl group according to the expert known method converted into a halide. Preferred halides are chlorine especially bromine and iodine. The substitution of the hydroxyl group for a bromine can e.g. B. using triphenylphosphine / tetrabromomethane but also after each other processes known to the person skilled in the art. The establishment of an iodine atom can the bromide by substitution e.g. B. Finkelstein with sodium iodide in acetone. The direct conversion of the hydroxyl group into the iodide is also possible, for. More colorful Use of elemental iodine, imidazole and triphenylphosphine in dichloromethane.

Step i (B-XII ⇒ B-XIII)

Should the linkage of the C13-C16 unit with position 12 of the epothilone residue or epothilone fragments, eg. B. a C7-C12 unit by Wittig reaction such. B. in Nature Vol. 387, 268-272 (1997), the triphenyl phosphonium halides (R ¹⁷ = P (Ph) ₃ ⁺Hal⁻) alkyl are starting from the halides B-XII according to the methods known to those skilled in the art - Or aryl phosphonates (R ¹⁷ = P (O) (OQ) ₂ ) or phosphine oxides (R ¹⁷ = P (O) Ph ₂ ) of type B-XII. Ph is phenyl; Hal represents F, Cl, Br or I and Q is a C ₁ -C ₁₀ alkyl or phenyl radical.

For the representation of the phosphonium salts, z. B. the implementation of corresponding halides with triphenylphosphine in solvents such as toluene or Benzene optionally in the presence of a base such as triethylamine or Diisopropylethylamine.

The representation of the phosphonates can, for. B. by reaction of the halides B-XI with a metalated dialkyl phosphite. The metalation is usually done with strong bases such as B. Butyllithium.

The representation of the phosphine oxides z. B. by reacting the halides B-XI with metallized diphenylphosphine and subsequent oxidation. For the Metal bases are also suitable for strong bases such as butyllithium. The subsequent one  Oxidation to phosphine oxide can then e.g. B. with dilute aqueous Hydrogen peroxide solution.

Alternatively, the compounds of the general formula B-XIII can be obtained via the method in Scheme 5 described way are made.

Scheme 5

Step k (B-XIV ⇒ B-XV)

Starting from cheaply available ethyl acetate derivatives of the general formula B-XIV, in which R ^{4a '} and R ^{4b' have} the abovementioned meanings, the ester enolate is reacted by the action of strong bases such as, for. B. lithium diisopropylamide, lithium hexamethyldisilazane at low temperatures and reacted with 3-halo-1-propyne, preferably 3-bromo-1-propyne to give compounds of general formula B-XV.

Step l (B-XV ⇒ B-XVI)

The reduction of the ester B-XV to the alcohol B-XVI is carried out according to the steps e) described methods, preferably using diisobutyl aluminum hydride.

Step m (B-XVI ⇒ B-XVII)

In the event that R ^{3 is} not a hydrogen atom, the primary hydroxyl group in B-XVI is first oxidized to the corresponding aldehyde by methods known to those skilled in the art. Examples include oxidation with pyridinium chlorochromate, pyridinium dichromate, chromium trioxide-pyridine complex, oxidation according to Swern or related methods, e.g. B. using oxalyl chloride in dimethyl sulfoxide, the use of Dess-Martin periodinane, the use of nitrogen oxides such as. B. N-methyl-morpholino-N-oxide in the presence of suitable catalysts such. B. tetrapropylammonium perruthenate in inert solvents. Oxidation according to Swern and with N-methyl-morpholino-N-oxide using tetrapropylammonium perruthenate is preferred.

The aldehydes thus obtained can then be converted into corresponding alcohols with organometallic compounds of the general formula MR ³ , in which M is an alkali metal, preferably lithium or a divalent metal MX, in which X represents a halogen and the radical R ^{3 has} the meanings given above. Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.

The free hydroxyl group of the secondary alcohol thus obtained (R ³ ≠ H) or, in the case R ³ = H, the free hydroxyl group in B-XVII is protected by the methods known to the person skilled in the art. The protective groups PG ¹⁴ are the protective groups known to the person skilled in the art, as already mentioned above for PG ⁸ in step a (A-II ⇒ A-III).

Protective groups containing silicon are preferred which operate under acidic reaction conditions or application of fluoride can be cleaved, such as. B. the trimethylsilyl, Triethylsilyl-, tert-butyldimethylsilyl-, tert-butyldiphenylsilyl-, tribenzylsilyl-, Triisopropylsilyl residue.

The tert-butyldimethylsilyl radical is particularly preferred.

Step n (B-XVII ⇒ B-XI)

The acetylene B-XVII can be deprotonated by the processes known to the person skilled in the art and the acetylide obtained with formaldehyde to an alcohol of the general formula B-XI be implemented. For deprotonation, alkyl alkali compounds such as. B. Butyllithium or other strong bases such as e.g. B. Alkalihexamethyldisilazane or Lithium diisopropylamide. N-Butyllithium is preferred.

In the way described in Scheme 5, the racemic compounds rac-B-XI are obtained first. The rac-B-XV or rac-B-XVI stages according to Scheme 6 optionally offer the possibility of chemical resolution and thus also access to the enantiomerically pure compounds B-XVI or ent-B-XVI, provided that R ^{4a 'is} not is identical to R ^{4b '} .

Scheme 6

Step o (rac-B-XV ⇒ B-XVa)

The racemic compound rac-B-XV can be transesterified with a chiral, optically obtainable alcohol chG ³ -OH by the methods known to the person skilled in the art, for example the process mentioned under step d), to give a mixture of the diastereomeric esters B-XVa and with separate simple chromatographic methods. Examples of suitable chiral alcohols are pulegol, 2-phenylcyclohexanol, 2-hydroxy-1,2,2-triphenylethanol and 8-phenylmenthol.

Step p (B-XVa ⇒ B-XVI and ent-B-XVI)

The diastereomerically pure esters B-XVa can each be reduced to the alcohols B-XVI or ent-B-XVI by the process described in step e, the auxiliary component chG ³ -OH described in step o being able to be recovered.

Step q (rac-B-XVI ⇒ B-XVIa)

The racemic compound rac-B-XVI can be reacted with a chiral, optically obtainable acid chG ⁴ -CO ₂ H, its ester, anhydride or acid halide according to the methods known to the person skilled in the art to a mixture of the diastereomeric esters B-XVIa and with separate simple chromatographic methods. Examples of suitable chiral acids are malic acid, tartaric acid or their derivatives.

Step r (B-XVIa ⇒ B-XVI and ent-B-XVI)

The diastereomerically pure esters B-XVIa can each be reduced to the alcohols B-XVI or ent-B-XVI by the process described in step e, or saponified by the methods known to the person skilled in the art, the auxiliary component described in step u being used in the latter case chG ⁴ -CO ₂ H can be recovered.

Representation of the partial fragments C

Partial fragments of the formula C can be made from inexpensive, inexpensive malic acid be produced efficiently with high optical purity (<99.5% ee).

The synthesis is shown in the following scheme 7 using the example of L - (-) - malic acid (C-I) described. Starting from D (+) - malic acid (ent-C-I), the corresponding ones are obtained enantiomeric compounds (ent-C-II to ent-C-XI) and starting from racemic Malic acid (rac-C-I) the corresponding racemic compounds (rac-C-II bis rac-C-XI).

Scheme 7

Step a (malic acid C-I ⇒ C-II)

L - (-) - Malic acid is produced using a method known from the literature (Liebigs Ann. Chem. 1993, 1273-1278) converted into the hydroxylactone C-II.

Step b (C-II ⇒ C-III)

The free hydroxy group in compound C-II is protected by methods known to those skilled in the art. The protective groups PG ¹⁵ are the protective groups known to the person skilled in the art, as already mentioned above for PG ⁸ in step a (A-II ⇒ A-III).

Protecting groups which cleave under the action of fluoride are preferred can be, but are stable under weakly acidic reaction conditions, such as. B. the tert-butyldiphenylsilyl, tert-butyldimethylsilyl or triisopropylsilyl radical.

The tert-butyldiphenylsilyl- and the tert-butyldimethylsilyl- Rest.

Step c (C-III ⇒ C-IV)

Lactone C-III becomes lactol C-IV according to the methods known to the person skilled in the art reduced. Modified reactants are suitable as reducing agents Aluminum hydrides such as B. Diisobutylaluminum hydride. The reaction takes place in one inert solvents such as B. toluene, preferably at low temperatures (-20 to -100 ° C).

Step d (C-IV ⇒ C-V)

The conversion of the lactol C-IV to compounds of the formula CV takes place with organometallic compounds of the general formula MR ⁸ in which M is an alkali metal, preferably lithium or a divalent metal MX, in which X represents a halogen and R ⁸ 'has the meanings given above . Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.

Step e (C-V ⇒ C-VI)

The primary hydroxyl group in compound C-V is according to those skilled in the art known methods selectively protected against the secondary hydroxyl group.

The protective groups PG ¹⁶ are the protective groups known to the person skilled in the art, as already mentioned above for PG ⁸ in step a (A-II ⇒ A-III).

Protecting groups which are preferred under weakly acidic reaction conditions are preferred can be split, such as. B. the trimethylsilyl, triethylsilyl, tert.- Butyldimethylsilyl residue.

The tert-butyldimethylsilyl radical is particularly preferred.  

Step f (C-VI ⇒ C-VII)

The oxidation of the secondary alcohol in C-VI to the ketone C-VII takes place according to the Methods known to those skilled in the art. The oxidation may also be mentioned, for example Pyridinium chlorochromate, pyridinium dichromate, chromium trioxide-pyridine complex, the Oxidation according to Swern or related methods e.g. B. using Oxalyl chloride in dimethyl sulfoxide, the use of Dess-Martin periodinans, the Use of nitrogen oxides such. B. N-methyl-morpholino-N-oxide in the presence suitable catalysts such. B. tetrapropylammonium perruthenate in inert Solvents. Swern oxidation is preferred.

Step g (C-VII ⇒ C-VIII)

For compounds in which U is CR ^{11 '} R ^12' , this grouping is established according to the methods known to the person skilled in the art. Methods such as B. the Wittig or Wittig / Horner reaction, the addition of an organometallic compound MCHR ^{11 '} R ^12' with elimination of water. The Wittig and Wittig / Horner reaction using phosphonium halides of the type CR ^{11 '} R ^12' P (Ph) ₃ 3Hal Phosph or phosphonates of the type CR ^{11 '} R ^12' P (O) (Oalkyl) _{2 is} preferred Ph is phenyl, R ^{11 '} , R ^12' and halogen in the meanings already mentioned with strong bases such as. B. n-butyllithium, potassium tert-butoxide, sodium ethanolate, sodium hexamethyldisilazane; n-butyllithium is preferred as the base.

For compounds in which U represents two alkoxy groups OR ⁹ or a C ₂ -C ₁₀ alkylene-α, ω-dioxy group, the ketone is prepared according to methods known to the person skilled in the art, for example using an alcohol HOR ⁹ or a C ₂ -C ₁₀ -Alkylene-α, ω- diols ketalisiert under acid catalysis.

Step h (C-VIII ⇒ C-IX)

The protective group PG ¹⁶ introduced under e is now selectively cleaved in the presence of PG ¹⁵ using the methods known to those skilled in the art. If the protective group can be split off with acid, the cleavage is preferably carried out under weakly acidic conditions, such as, for. B. by reaction with dilute organic acids in inert solvents. Acetic acid is preferred.

Step i (C-IX ⇒ C-X)

The oxidation of the primary alcohol in C-IX to the aldehyde of the general formula C-X takes place according to the methods known to the skilled worker. For example, the Oxidation with pyridinium chlorochromate, pyridinium dichromate, chromium trioxide pyride in Complex, the oxidation by Swern or related methods z. B. using of oxalyl chloride in dimethyl sulfoxide, the use of the Dess-Martin periodinane, the  Use of nitrogen oxides such. B. N-methyl-morpholino-N-oxide in the presence suitable catalysts such. B. tetrapropylammonium perruthenate in inert Solvents. Oxidation according to Swern and with N-methyl-morpholino- N-oxide using tetrapropylammonium perruthenate.

Step k (C-X ⇒ C-XI)

The conversion of the aldehydes CX to alcohols of the general formula C-XI takes place according to the methods known to the person skilled in the art with organometallic compounds of the general formula MR ^{5 '} , in which M represents an alkali metal, preferably lithium or a divalent metal MX, in which X represents a halogen and the radical R ^{5 'has} the meaning given above. Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.

Step l (C-XI ⇒ C-XII)

The oxidation of the alcohol C-XI to the ketone of the general formula C-XII takes place after the method mentioned under k) or by Jones oxidation. The is preferred Oxidation according to Jones.  

Representation of the partial fragments ABC and their cyclization to I.

Partial fragments of the general formula AB

wherein R ³ , R ^4a , R ^4b , R ⁵ , R ⁶ , R ⁷ , R ²⁰ , D, E, U and V have the meanings already mentioned, are from the previously described fragments B and C according to that shown in Scheme 8 Procedure received.

Scheme 8

Step a (B + C ⇒ BC)

The compound B, in which R ^{17 has} the meaning of a Wittigsalzes and any additional carbonyl groups that may be present are protected by a suitable base such as, for. B. de-protonated n-butyllithium, lithium diisopropylamide, potassium tert-butoxide, sodium or lithium hexamethyldisilazide and reacted with a compound C, in which W has the meaning of an oxygen atom.

Partial fragments of the general formula ABC

wherein R ^1a , R ^1b , R ^2a , R ^2b , R ³ , R ^4a , R ^4b , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁴ , R ¹⁵ , D, E, U and Z are those already mentioned Have meanings are obtained from the fragments AB and C described above by the method shown in Scheme 9.

Scheme 9

Step b (BC + A ⇒ ABC)

The compound BC, in which V has the meaning of an oxygen atom and possibly existing additional carbonyl groups are protected with the enolate Carbonyl compound of the general formula A, wherein Z has the meaning of a Has oxygen atom, alkylated. The enolate is by the action of strong bases such as. B. Lithium diisopropylamide, lithium hexamethyldisilazane at low temperatures manufactured.

Step c (ABC ⇒ I)

The compounds ABC, in which R ^{14 is} a carboxylic acid CO ₂ H and R ^{20 is} a hydrogen atom, are converted according to the methods known to the person skilled in the art for the formation of large macrolides to give compounds of the formula I in which Y is an oxygen atom . The method described in "Reagents for Organic Synthesis, Vol. 16, p 353" is preferred using 2,4,6-trichlorobenzoic acid chloride and suitable bases such as, for. B. triethylamine, 4-dimethylaminopyridine, sodium hydride.

Step d (ABC ⇒ I)

The compounds ABC, in which R ^{14 represents} a group CH ₂ OH and R ^{20 represents} a hydrogen atom, can preferably be converted into compounds of the formula I, in which Y has the meaning of two hydrogen atoms, using triphenylphosphine and azodiesters such as, for example, diethyl azodicarboxylate.

The compounds ABC, in which R ^{14 represents} a group CH ₂ OSO ₂ alkyl or CH ₂ OSO ₂ aryl or CH ₂ OSO ₂ aralkyl and R ^{20 represents} a hydrogen atom, can be deprotonated with suitable bases such as sodium hydride, n-butyllithium, 4 -Dimethylaminopyridine, Hünig base, alkylihexamethyldisilazanes cyclize to compounds of the formula I in which Y has the meaning of two hydrogen atoms.

The invention also relates to this process for the preparation of the compounds of general formula I and the new intermediates of the general formulas B, C, BC and ABC including all stereoisomers of these compounds and also theirs Mixtures.  

The flexible functionalization of the described modules A, B and C also ensures a linking sequence which deviates from the method described above and which leads to the modules ABC. These procedures are summarized in the following table:

Using these methods, building blocks A, B and C can be created as in Scheme 10 specified, link:

Scheme 10

Free hydroxyl groups in I, A, B, C, AB, ABC can be etherified or Esterification, free carbonyl groups by ketalization, enol ether formation or Reduction further functional changes.

The invention also relates to these processes for the preparation of the epothilone derivatives general formula.  

Biological effects and areas of application of the new derivatives

The new compounds of formula I are valuable pharmaceuticals. You interact with Tubulin by stabilizing microtubules formed and are therefore able to To influence cell division in a phase-specific manner. This especially affects fast growing, neoplastic cells, their growth through intercellular regulatory mechanisms is largely unaffected. In principle, active substances of this type are suitable for Treatment of malignant tumors. As an example, the Therapy of ovarian, stomach, colon, adeno, breast, lung, head and neck Carcinomas, malignant melanoma, acute lymphocytic and myelocytic Leukemia. The compounds of the invention are suitable because of their Properties principally for anti-angiogenesis therapy and for treatment chronic inflammatory diseases such as psoriasis or Arthritis. To avoid uncontrolled cell growth on and the better In principle, compatibility of medical implants can be included in this Apply or introduce polymeric materials used. The invention Compounds can be used alone or to achieve additive or synergistic Effects in combination with other principles applicable in tumor therapy and substance classes can be used.

Examples include the combination with

• ⇒ platinum complexes such as B. cisplatin, carboplatin,
• ⇒ intercalating substances e.g. B. from the class of anthracyclines such. B. Doxorubicin or from the class of antrapyrazoles such. B. C1-941,
• ⇒ substances interacting with tubulin e.g. B. from the class of Vinka alkaloids such as B. vincristine, vinblastine or from the class of taxanes such. B. Taxol, Taxotere or from the class of macrolides such. B. rhizoxin or others Connections such as B. colchicine, combretastatin A-4,
• ⇒ DNA topoisomerase inhibitors such as B. camptothecin, etoposide, topotecan, Teniposide,
• ⇒ Folate or pyrimidine antimetabolites such as B. lometrexol, gemcitubin,
• ⇒ DNA alkylating compounds such. B. adozelesin, dystamycin A,
• ⇒ Inhibitors of growth factors (e.g. PDGF, EGF, TGFb, EGF) such as e.g. B. Somatostatin, suramin, bombesin antagonists,
• ⇒ Inhibitors of protein tyrosine kinase or protein kinases A or C such as B. Erbstatin, Genistein, Staurosporin, Ilmofosin, 8-CI-cAMP,
• ⇒ Anti-hormones from the class of anti-gestagens such as B. Mifepristone, Onapristone or from the class of anti-estrogens such. B. Tamoxifen or from the class of Antiandrogens such as B. cyproterone acetate,  
• ⇒ Metastasis inhibiting compounds e.g. B. from the class of eicosanoids such. B. PGI ₂ , PGE ₁ , 6-oxo-PGE ₁ and their stable derivatives (e.g. Iloprost, Cicaprost, Misoprostol).
• ⇒ Inhibitors of oncogenic RAS proteins that promote mitotic signal transduction such as inhibitors of farnesyl protein transferase,
• ⇒ natural or artificially produced antibodies against factors or their Receptors that promote tumor growth are directed such as that erbB2 antibodies,

The invention also relates to pharmaceuticals based on the pharmaceutically acceptable, ie. H. in the doses used, non-toxic compounds of the general formula I, optionally together with the usual auxiliaries and carriers.

The compounds of the invention can according to known methods of Galenics for pharmaceutical preparations for enteral, percutaneous, parenteral or local application are processed. They can be in the form of tablets, coated tablets, gel capsules, granules, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels be administered.

The active ingredient (s) can be used with the auxiliaries customary in galenics, such as. B. Gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens or myrj, magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, Wetting, dispersing, emulsifying, preserving and flavoring agents for Flavor correction (e.g. essential oils) can be mixed.

The invention thus also relates to pharmaceutical compositions which act as contain substance at least one compound of the invention. Contains one dose unit about 0.1-100 mg of active ingredient (s). The dosage of the compounds according to the invention lies in humans at about 0.1-1000 mg per day.

The following examples serve to explain the invention in greater detail, without it want to restrict to:  

example 1 (4S, 7R, 8S, 9S, 13 (E), 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4- thiazolyl) ethenyl) -1-oxa-5,5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione Example 1a (3S) -1-Oxa-2-Oxo-3- (tetrahydropyran-2 (RS) -yloxy) -4,4-dimethyl-cyclopentane

The solution of 74.1 g (569 mmol) of D - (-) - pantolactone in 1 l of anhydrous dichloromethane is mixed with 102 ml of 3,4-dihydro-2H-pyran, 2 g of p-toluenesulfonic acid under an atmosphere of dry argon. Pyridinium salt and stirred at 23 ° C for 16 hours. It is poured into a saturated sodium bicarbonate solution, the organic phase is separated off and dried over sodium sulfate. After filtration and removal of the solvent, the residue is chromatographed on about 5 kg of fine silica gel with a mixture of n-hexane and ethyl acetate. 119.6 g (558 mmol, 98%) of the title compound are isolated as a colorless oil.
¹ H NMR (CDCl ₃ ): δ = 1.13 (3H), 1.22 (3H), 1.46-1.91 (6H), 3.50-3.61 (1H), 3.86 (1H), 3.92 (1H), 4.01 (1H), 4.16 (1H), 5.16 (1H) ppm.

Example 1b (2RS, 3S) -1-oxa-2-hydroxy-3- (tetrahydropyran-2 (RS) -yloxy) -4,4-dimethyl cyclopentane

The solution of 117.5 g (548 mmol) of the compound shown in Example 1a in 2.4 l of anhydrous toluene is cooled to -70 ° C. under an atmosphere of dry argon, and 540 ml of a 1.2 molar mixture are added within 1 hour Solution of diisobutylaluminium hydride in toluene and stirred for a further 3 hours at -70 ° C. The mixture is allowed to warm to -20 ° C., mixed with saturated ammonium chloride solution, water and the precipitated aluminum salts are separated off by filtration through Celite. The filtrate is washed with water and saturated sodium chloride solution and dried over magnesium sulfate. After filtration and removal of the solvent, 111.4 g (515 mmol, 94%) of the title compound are isolated as a colorless oil, which is reacted further without Re 53879 00070 552 001000280000000200012000285915376800040 0002019830060 00004 53760.
IR (CHCl ₃ ): 3480, 3013, 2950, 2874, 1262, 1133, 1074, 1026 and 808 cm ^-1 .

Example 1c (3S) -2,2-dimethyl-3- (tetrhydropyran-2 (R) -yloxy) -pent-4-en-1-ol and (3S) -2,2- Dimethyl-3- (tetrahydropyran-2 (S) -yloxy) pentan-1-ol

The slurry of 295 g of methyl triphenylphosphonium bromide in 2.5 l of anhydrous tetrahydrofuran is admixed with 313 ml of a 2.4 molar solution of n-butyllithium in n-hexane under an atmosphere of dry argon at -60 ° C. Warm up C, stir for an hour and cool to 0 ° C. A solution of 66.2 g (306 mmol) of the compound shown in Example 1b in 250 ml of tetrahydrofuran is added, and the mixture is allowed to warm to 23 ° C. and stir for 18 hours. It is poured into a saturated sodium bicarbonate solution, extracted several times with dichloromethane and the combined organic extracts are dried over sodium sulfate. After filtration and removal of solvent, the residue is chromatographed on about 5 l of fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 36.5 g (170 mmol, 56%) of the non-polar, 14.4 g (67.3 mmol, 22%) of the polar THP isomer of the title compound and 7.2 g (33.3 mmol; 11% ) of the starting material as a colorless oil.
¹ H-NMR (CDCl ₃ ), non-polar isomer: δ = 0.78 (3H), 0.92 (3H), 1.41-1.58 (4H), 1.63-1.87 (2H), 3.18 (1H), 3.41 (1H), 3.48 (1H), 3.68 (1H), 3.94 (1H), 4.00 (1H), 4.43 (1H), 5 , 19 (1H), 5.27 (1H), 5.75 (1H) ppm.
¹ H-NMR (CDCl ₃ ), polar isomer: δ = 0.83 (3H), 0.93 (3H), 1.42-1.87 (6H), 2.76 (1H), 3.30 ( 1H), 3.45 (1H), 3.58 (1H), 3.83 (1H), 3.89 (1H), 4.65 (1H), 5.12-5.27 (2H), 5 , 92 (1H) ppm.

Example 1d (3S) -1- (tert-butyldiphenylsilyloxy) -2,2-dimethylpentane-3- (tetrahydropyran-2- yloxy) pent-4-ene

The solution of 59.3 g (277 mmol) of the THP isomer mixture shown in Example 1c in 1000 ml of anhydrous dimethylformamide is mixed with 28 g of imidazole, 85 ml of tert-butyldiphenylchlorosilane under an atmosphere of dry argon and stirred for 16 hours 23 ° C. It is poured into water, extracted several times with dichloromethane, the combined organic extracts are washed with water and dried over sodium sulfate. After filtration and removal of the solvent, the residue is chromatographed on fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 106.7 g (236 mmol, 85%) of the title compound are isolated as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.89 (3H), 0.99 (3H), 1.08 (9H), 1.34-1.82 (6H), 3.40 (1H), 3.51 (2H), 3.76 (1H), 4.02 (1H), 4.67 (1H), 5.18 (1H), 5.23 (1H), 5.68 (1H), 7 , 30-7.48 (6H), 7.60-7.73 (4H) ppm.

Example 1e (3S) -1- (tert-butyldiphenylsilyloxy) -2,2-dimethyl-3- (tetrahydropyran-2-yloxy) - pentan-5-ol

The solution of 3.09 g (6.83 mmol) of the compound shown in Example 1d in 82 ml of tetrahydrofuran is mixed with 13.1 ml of a 1 molar solution of borane in tetrahydrofuran and under an atmosphere of dry argon at 23 ° C. allows to react for 1 hour. 16.4 ml of a 5% sodium hydroxide solution and 8.2 ml of a 30% hydrogen peroxide solution are then added while cooling with ice and the mixture is stirred for a further 30 minutes. It is poured into water, extracted several times with ethyl acetate, the combined organic extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 1.78 g (3.78 mmol, 55%) of the title compound are isolated as a chromatographically separable mixture of the two THP epimers and 0.44 g (1.14 mmol, 17%) of the title compound from Example 6 in each case as a colorless oil.
¹ H-NMR (CDCl ₃ ), non-polar THP isomer: δ = 0.80 (3H), 0.88 (3H), 1.10 (9H), 1.18-1.80 (9H), 3, 27 (1H), 3.39 (1H), 3.48 (1H), 3.64 (1H), 3.83 (1H), 3.90-4.08 (2H), 4.49 (1H) , 7.31-7.50 (6H), 7.58-7.73 (4H) ppm.
¹ H-NMR (CDCl ₃ ), polar THP isomer: δ = 0.89 (3H), 0.98 (3H), 1.08 (9H), 1.36-1.60 (4H), 1, 62-1.79 (3H), 1.88 (1H), 2.03 (1H), 3.37 (1H), 3.50 (1H), 3.57 (1H), 3.62-3, 83 (4H), 4.70 (1H), 7.30-7.48 (6H), 7.61-7.73 (4H) ppm.

Example 1f (3S) -1- (tert-Butyldiphenylsilyloxy) -2,2-dimethyl-3-hydroxy-pent-4-ene

The solution of 106.7 g (236 mmol) of the compound shown in Example 1d in 1.5 l of anhydrous ethanol is mixed under an atmosphere of dry argon with 5.9 g of pyridinium p-toluenesulfonate and heated at 50 ° C. for 6 hours . After removal of the solvent, the residue is chromatographed on fine silica gel with a mixture of n-hexane and ethyl acetate. 82.6 g (224 mmol, 95%) of the title compound are isolated as a colorless oil which also contains about 5 g of ethoxy tetrahydropyran.
¹ H-NMR (CDCl ₃ ) of an analytical sample: δ = 0.89 (6H), 1.08 (9H), 3.45 (1H), 3.49 (1H), 3.58 (1H), 4 , 09 (1H), 5.21 (1H), 5.33 (1H), 5.93 (1H), 7.34-7.51 (6H), 7.63-7.73 (4H) ppm.

Example 1g (3S) -1- (tert -butyldiphenylsilyloxy) -2,2-dimethylpentan-3,5-diol

The solution of 570 mg (1.55 mmol) of the compound shown in Example 1f is reacted analogously to Example 1e and, after workup and purification, 410 mg (1.06 mmol, 68%) of the title compound is isolated as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.82 (3H), 0.93 (3H), 1.08 (9H), 1.56-1.79 (2H), 3.11 (1H), 3.50 (2H), 3.78-3.92 (3H), 4.02 (1H), 7.34-7.51 (6H), 7.61-7.71 (4H) ppm.

Example 1h 4 (S) - [2-methyl-1- (tert-butyldiphenylsilyloxy) prop-2-yl] -2,2-dimethyl- [1,3] dioxane

The solution of 100 mg (0.212 mmol) of the compounds shown in Example 1e in 2.6 ml of anhydrous acetone is mixed with 78.9 mg of copper (II) sulfate, a spatula tip of p-toluenesulfonic acid monohydrate and stirred under an atmosphere of dry argon 16 hours at 23 ° C. Saturated sodium hydrogen carbonate solution is added, the mixture is extracted several times with diethyl ether, washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 24 mg (56 µmol, 27%) of the title compound are isolated as a colorless oil.
¹ H NMR (CDCl ₃ ): δ = 0.83 (3H), 0.89 (3H), 1.07 (9H), 1.30 (1H), 1.36 (3H), 1.44 ( 3H), 1.71 (1H), 3.24 (1H), 3.62 (1H), 3.86 (1H), 3.91-4.03 (2H), 7.31-7.48 ( 6H), 7.61-7.74 (4H) ppm.

Variant II

320 mg (0.88 mmol) of the compound shown in Example 1g are set in analogy to example 1h; Variant I um and isolated after workup and purification 234 mg (0.548 mmol, 62%) of the title compound.

Variant III

The solution of 5.60 g (14.5 mmol) of the compound shown in Example 1g in 250 ml of anhydrous dichloromethane are added under an atmosphere of dry Argon with 10 ml 2,2-dimethoxypropane, 145 mg camphor-10-sulfonic acid and stir 6 Hours at 23 ° C. Triethylamine, diluted with ethyl acetate, is washed with saturated sodium bicarbonate solution and dries over sodium sulfate. To Filtration and removal of solvent chromatograph the residue on fine Silica gel with a mixture of n-hexane and ethyl acetate. 5.52 g (12.9 mmol, 89%) of the title compound as a colorless oil.

Example 1i (4S) 4- (2-methyl-1-hydroxyprop-2-yl) -2,2-dimethyl- [1,3] dioxane

The solution of 5.6 g (13.1 mmol) of the compound shown in Example 1h in 75 ml of anhydrous tetrahydrofuran is mixed with 39 ml of a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran under an atmosphere of dry argon and heated to 50 ° for 16 hours C. Saturated sodium hydrogen carbonate solution is added, the mixture is extracted several times with ethyl acetate, washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 2.43 g (12.9 mmol, 99%) of the title compound are isolated as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.87 (3H), 0.90 (3H), 1.35 (1H), 1.37 (3H), 1.43 (3H), 1.77 ( 1H), 2.93 (1H), 3.36 (1H), 3.53 (1H), 3.79 (1H), 3.87 (1H), 3.96 (1H) ppm.

Example 1k (4S) -4- (2-Methyl-1-oxo-prop-2-yl) -2,2-dimethyl- [1,3] dioxane

The solution of 0.13 ml of oxalyl chloride in 5.7 ml of anhydrous dichloromethane is cooled under an atmosphere of dry argon to -70 ° C, mixed with 0.21 ml Dimethyl sulfoxide, the solution of 200 mg (1.06 mmol) of that shown in Example 1i Compound in 5.7 ml of anhydrous dichloromethane and stirred for 0.5 hours. Subsequently 0.65 ml of triethylamine are added, the mixture is left to react at -30 ° C. for 1 hour and mixed with n-hexane and saturated sodium bicarbonate solution. The organic phase will separated, the aqueous extracted several times with n-hexane, the combined organic extracts washed with water and dried over magnesium sulfate. The after filtration and removal of the solvent, the residue is used without purification further around.

Example 1l (4S) -4 - ((3RS) -2-methyl-3-hydroxy-pent-2-yl) -2,2-dimethyl- [1,3] dioxane

The solution of 900 mg (4.83 mmol) of the compound shown in Example 1k in 14 ml of anhydrous diethyl ether is mixed with 2.42 ml of a 2.4 molar solution of ethyl magnesium bromide in diethyl ether under an atmosphere of dry argon at 0 ° C. Warm up to 23 ° C and stir for 16 hours. Saturated ammonium chloride solution is added, the organic phase is separated off and dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 863 mg (3.99 mmol, 83%) of the chromatographically separable 3R and 3S epimers of the title compound and 77 mg of the title compound described in Example 1i are each isolated as a colorless oil.
¹ H-NMR (CDCl ₃ ) non-polar isomer: δ = 0.86 (3H), 0.89 (3H), 1.03 (3H), 1.25-1.37 (2H), 1.37 (3H ), 1.46 (3H), 1.49 (1H), 1.84 (1H), 3.35 (1H), 3.55 (1H), 3.81-4.02 (3H) ppm.
¹ H NMR (CDCl ₃ ) polar isomer: δ = 0.72 (3H), 0.91 (3H), 0.99 (3H), 1.25-1.44 (2H), 1.38 (3H ), 1.43-1.60 (1H), 1.49 (3H), 1.76 (1H), 3.39 (1H), 3.63 (1H), 3.79-4.03 (3H ) ppm.

Example 1m (4S) -4- (2-Methyl-1-3-oxopent-2-yl) -2,2-dimethyl- [1,3] dioxane

The solution of 850 mg (3.93 mmol) of a mixture of the compounds shown in Example 1l in 63 ml of anhydrous dichloromethane is mixed with molecular sieve (4A, approx. 80 spheres), 690 mg of N-methylmorpholino-N-oxide, 70 mg of tetrapropylammonium perruthenate and stirred for 16 hours at 23 ° C under an atmosphere of dry argon. The mixture is concentrated and the crude product obtained is purified by chromatography on about 200 ml of fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 728 mg (3.39 mmol, 86%) of the title compound are isolated as a colorless oil.
¹ H NMR (CDCl ₃ ): δ = 1.00 (3H), 1.07 (3H), 1.11 (3H), 1.31 (3H), 1.32 (3H), 1.41 ( 3H), 1.62 (1H), 2.52 (2H), 3.86 (1H), 3.97 (1H), 4.05 (1H) ppm.

Example 1n 4-tert-butyldimethylsilyloxy-but-2-in-1-ol

A solution of 175 g of tert-butyldimethylsilyl chloride in 100 ml of a 1: 1 mixture of hexane and. Is slowly added dropwise at 0 ° C. under nitrogen to a solution of 100 g of 2-butyn-1-ol and 158 g of imidazole in 300 ml of dimethylformamide Dimethylformamide and stirred for 2 hours at 0 ° C and 16 hours at 22 ° C. The reaction mixture is diluted with 2.5 l of ether, washed once with water, once with 5% sulfuric acid, once with water, once with saturated sodium hydrogen carbonate solution and with semi-saturated sodium chloride solution. After drying over sodium sulfate and filtration, the mixture is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-40% ether, 74.3 g of the title compound are obtained as a colorless oil.
IR (film): 3367, 2929, 2858, 1472, 1362, 1255, 1132, 1083, 1015, 837, 778 cm ^-1 .

Example 1o (4R, 5S, 2'S) -4-methyl-5-phenyl-3- [1-oxo-2-methyl-6- (tert-butyldimethylsilyloxy) -hex- 4-in-1-yl] -2-oxazolidinone

11.3 ml of lutidine are added under nitrogen to 21 g of a solution of the silyl ether prepared according to Example 1n in 125 ml of toluene. The mixture is then cooled to -40 ° C. and 17.7 ml of trifluoromethanesulfonic anhydride are added dropwise at this temperature. Then diluted with 100 ml of hexane and stirred for 10 minutes. This solution is added under nitrogen via a reverse frit to a solution consisting of 17.8 g of hexamethyldisilazane in 140 ml of tetrahydrofuran with 73.5 ml of a 1.6 M solution of butyllithium in hexane at -60 ° C (10 minutes stirring time) and 23.3 g (4R, 5S ) -4-methyl-5-phenyl-3-propionyl-2-oxazolidinone in 62 ml of tetrahydrofuran (30 minutes stirring time). The mixture is left to stir at -60 ° C. for 1 hour, 6 ml of acetic acid in 5 ml of tetrahydrofuran are then added, and the reaction mixture is allowed to warm to 22 ° C. The mixture is poured into 80 ml of water and extracted three times with ether. The combined organic phases are washed twice with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the mixture is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-20% ether, 16.0 g of the title compound is obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.10 (6H), 0.90 (9H), 0.92 (3H), 1.28 (3H), 2.47 (1H), 2.61 (1H), 3.96 (1H), 4.26 (2H) , 4.78 (1H), 5.68 (1H), 7.31 (1H), 7.3-7.5 (3H) ppm.

Example 1p (2S) -2-Methyl-6- (tert-butyldimethylsilyloxy) -4-hexynoic acid ethyl ester

9.0 ml of titanium (IV) ethylate are added to a solution of 39.3 g of the alkylation product prepared according to Example 10 in 120 ml of ethanol and the mixture is heated under reflux for 4 hours. The reaction mixture is concentrated in vacuo and the residue is dissolved in 100 ml of ethyl acetate. 3 ml of water are added, the mixture is stirred for 20 minutes, the precipitate is filtered off with suction and washed well with ethyl acetate. The filtrate is concentrated, 200 ml of hexane are added and the precipitate is filtered off. The precipitate is washed well with hexane. The filtrate is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-20% ether, 25.4 g of the title compound is obtained as a colorless oil.
¹ H-NMR (CD ₂ Cl ₂ ): δ = 0.10 (3H), 0.90 (9H), 1.2-1.3 (6H), 2.37 (1H), 2.54 (1H), 2.60 (1H), 4.12 (2H), 4.27 (2H) ppm.

Example 1g (2S) -2-Methyl-6- (tert-butyldimethylsilyloxy) hexanoic acid ethyl ester

A solution of 10.5 g of the ester prepared according to Example 1p in 200 ml of ethyl acetate is mixed with 1 g of 10% palladium on carbon and stirred for 3 hours at 22 ° C. in a hydrogen atmosphere. The catalyst is then filtered off, washed well with ethyl acetate and the filtrate is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-10% ether, 9.95 g of the title compound is obtained as a colorless oil.
¹ H-NMR (CD ₂ Cl ₂ ): δ = 0.01 (6H), 0.84 (9H), 1.07 (3H), 1.18 (3H), 1.2-1.7 (6H), 2.38 (1H), 3.57 (2H), 4.05 (2H) ppm.

Example 1r (2S) -2-methyl-6- (tert-butyldimethylsilyloxy) hexan-1-ol

63 ml of a 1.2 M solution of diisobutylaluminum hydride in toluene are added to a solution of 9.94 g of the ester prepared according to Example 1q in 130 ml of toluene at -40 ° C. under nitrogen and the mixture is stirred for 1 hour at this temperature. Subsequently, 15 ml of isopropanol are carefully added and after 10 minutes 30 ml of water are added, the mixture is allowed to come to 22 ° C. and the mixture is stirred at this temperature for 2 hours. The precipitate is filtered off, washed well with ethyl acetate and the filtrate is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-30% ether, 7.9 g of the title compound is obtained as a colorless oil. [α] _D -8.1 ° (c = 0.97, CHCl ₃ ).
¹ H NMR (CDCl ₃ ): δ = 0.07 (3H), 0.89 (9H), 0.91 (3H), 1.0-1.7 (7H), 3.48 (2H), 3.52 (2H) ppm.

Example 1s (2S) -2-methyl-6- (tert-butyldimethylsilyloxy) -1- (tetrahydro-2H-pyran-2-yloxy) hexane

To 6.4 g of the alcohol prepared according to Example 1r in 26 ml of methylene chloride is added at 0 ° C under argon 3.52 ml of dihydropyran followed by 49 mg of p-toluenesulfonic acid monohydrate. After stirring for 1.5 hours at 0 ° C., 10 ml of saturated sodium bicarbonate solution are added and the mixture is diluted with ether. The organic phase is washed twice with semi-saturated sodium chloride solution and dried over sodium sulfate. After filtration, the mixture is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-5% ether, 4.75 g of the title compound is obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.05 (6H), 0.89 (9H), 0.92 (3H), 1.0-1.9 (13H), 3.19 (1H), 3.50 (1H), 3.55-3.65 (3H), 4.87 (1H), 4.57 (1H) ppm.

Example 1t (5S) -5-methyl-6- (tetrahydro-2H-pyran-2-yloxy) hexan-1-ol

13.5 g of tetrabutylammonium fluoride trihydrate are added to a solution of 4.7 g of the THP ether prepared in Example 1s in 170 ml of tetrahydrofuran under nitrogen and the mixture is stirred for 3 hours. The reaction mixture is then diluted with 800 ml of ether and washed three times with 20 ml of semi-saturated sodium chloride solution and dried over sodium sulfate. After filtration, the mixture is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-50% ethyl acetate, 2.88 g of the title compound is obtained as a colorless oil.
¹ H-NMR (CD ₂ Cl ₂ ): δ = 0.90 / 0.92 (3H), 1.1-1.9 (13H), 3.18 (1H), 3.40-3.65 (4H), 3.82 (1H), 4.53 (1H) ppm.

Example 1u (2S) -6-iodo-2-methyl-1- (tetrahydro-2H-pyran-2-yloxy) hexane

12.9 g of iodine are added to a solution of 13.4 g of triphenylphosphine and 3.47 g of imidazole in 200 ml of methylene chloride. The alcohol prepared according to Example 1t is then added dropwise in 50 ml of methylene chloride at 22 ° C. and the mixture is stirred for 30 minutes. The mixture is then concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 5% ether, 10.2 g of the title compound is obtained as a pale yellow oil.
¹ H NMR (CDCl ₃ ): δ = 0.94 / 0.95 (3H), 1.0-1.9 (13H), 3.1-3.3 (3H), 3.4-3.7 (2H), 3.85 (1H), 4.57 (1H) ppm.

Example 1v (5S) -5-Methyl-6- (tetrahydro-2H-pyran-2-yloxy) hex-1-yl-triphenylphosphonium iodide

A mixture of 10.2 g of the iodide prepared above, 40.9 g of triphenylphosphine and 12.1 g of N-ethyldiisopropylamine are stirred at 80 ° C. for 6 hours. After cooling, it is dissolved in 30 ml of methylene chloride, mixed with 500 ml of ether, stirred for 10 minutes and then decanted off. This is repeated four more times. The residue thus obtained is dissolved in anhydrous tetrahydrofuran, mixed with toluene and concentrated in vacuo. 17.1 g of the title compound are obtained as a solid foam.
¹ H-NMR (CDCl ₃ ): δ = 0.85 / 0.86 (3H), 1.10 (1H), 1.7-1.9 (13H), 3.13 (1H), 3.40-3.55 (2H), 3.64 (1H), 3.79 (1H ), 4.49 (1H), 7.6-7.9 (15H) ppm.

Example 1w (S) -dihydro-3-hydroxy-2 (3H) -furanone

10 g of L - (-) - malic acid add 45 ml of trifluoroacetic anhydride for 2 hours at 25 ° C touched. The mixture is then concentrated in vacuo, 7 ml of methanol and lets stir for 12 hours. It is then concentrated in vacuo. The received one The residue is dissolved in 150 ml of absolute tetrahydrofuran. Cool to 0 ° C and add 150 ml of borane-tetrahydrofuran complex and leave for 2.5 hours at 0 ° C stir. Then 150 ml of methanol are added. One leaves one hour Stir room temperature and then concentrated in vacuo. The crude product obtained is dissolved in 80 ml of toluene. Add 5 g of Dowex® (activated, acidic) and boil one Hour under reflux. Then the Dowex® is filtered off and the filtrate in the Vacuum concentrated. The crude product obtained (7.61 g) is in the without purification Subsequent stage used.

Example 1x (S) -Dihydro-3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -2 (3H) -furanone

24 ml of tert-butyldiphenylsilyl chloride are added to a solution of 7.61 g of the substance described in Example 1w and 10 g of imidazole in 100 ml of N, N-dimethylformamide. The mixture is left to stir at 25 ° C. for two hours and then the reaction mixture is poured onto ice-cold saturated sodium hydrogen carbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate, 13.4 g of the title compound are obtained.
¹ H NMR (CDCl ₃ ): δ = 7.72 (2H), 7.70 (2H), 7.40-7.50 (6H), 4.30-4.42 (2H), 4.01 (1H), 2.10-2.30 (2H), 1.11 (9H) ppm.

Example 1y (2RS, 3S) -34 [(1,1-dimethylethyl) diphenylsilyl] oxy] tetrahydro-2-furanol

To a solution of 13.4 g of the substance described in Example 1x in 150 ml absolute tetrahydrofuran, 80 ml of a 1 molar solution of Diisobutylaluminum hydride in hexane added at -78 ° C. The mixture is stirred at -78 ° C for 45 minutes then quenched with water. It is extracted with ethyl acetate, the is washed organic phase with saturated sodium chloride solution, dries over sodium sulfate and constricts in a vacuum. 13.46 g of the title compound are obtained, which in without purification the next stage is used.

Example 1z (2RS, 3S) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -1,4-pentanediol

A solution of 13.46 g of the substance described in Example 1y in 150 ml of absolute tetrahydrofuran is added dropwise to 20 ml of a 3 molar solution of methylmagnesium chloride in tetrahydrofuran at 0.degree. The mixture is stirred for one hour at 0 ° C and then poured onto saturated aqueous ammonium chloride solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate, 11.42 g of the title compound are obtained.
¹ H NMR (CDCl ₃ ): δ = 7.65-7.75 (4H), 7.40-7.55 (6H), 5.20 (1H), 4.30 (2H), 3.70 (1H), 1.80 (2H), 1.05 (9H) ppm.

Example 1aa (2RS, 3S) -5 - [[Dimethyl (1,1-dimethylethyl) silyl] oxy] -3 - [[(1,1- dimethylethyl) diphenylsilyl] oxy] -2-pentanol

4.9 g of tert-butyldimethylsilyl chloride are added to a solution of 11.42 g of the substance described in Example 1z and 3.25 g of 1H-imidazole in 120 ml of N, N-dimethylformamide. The mixture is stirred for 2 hours at 25 ° C and then poured onto ice-cold saturated sodium bicarbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate, 10.64 g of the title compound are obtained.
¹ H-NMR (CDCl ₃ ): δ = 7.60-7.70 (4H), 7.30-7.45 (6H), 3.70-3.80 (2H), 3.40 (1H) , 3.00 (1H), 1.80 (1H), 1.60 (1H), 1.05-1.12 (12H), 0.82 (9H), 0.02 (6H) ppm.

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

To 7.37 ml of oxalyl chloride in 80 ml of dichloromethane, 13 ml of dimethyl sulfoxide are added at -78 ° C. The mixture is stirred for 3 minutes and then 10.46 g of the substance described in Example 1aa are added in 100 ml of dichloromethane. After a further 15 minutes of stirring, 52 ml of triethylamine are added dropwise. Then allowed to warm to 0 ° C. The reaction mixture is then poured onto saturated sodium bicarbonate solution. It is extracted with dichloromethane, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate, 9.3 g of the title compound are obtained.
¹ H NMR (CDCl ₃ ): δ = 7.60-7.70 (4H), 7.32-7.50 (6H), 4.25 (1H), 3.72 (1H), 3.58 (1H), 2.05 (3H), 1.90 (1H), 1.75 (1H), 1.13 (9H), 0.89 (9H), 0.01 (6H) ppm.

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

The solution of 6.82 g of diethyl (2-methylthiazol-4-yl) methanephosphonate in 300 ml of anhydrous tetrahydrofuran is cooled to -5 ° C. under an atmosphere of dry argon, mixed with 16.2 ml of a 1.6 molar solution of n-Butyllithium in n-hexane, allowed to warm to 23 ° C. and stir for 2 hours. The mixture is then cooled to -78 ° C., the solution of 6.44 g (13.68 mmol) of the compound shown in Example 1ab in 150 ml of tetrahydrofuran is added dropwise, the mixture is heated to 23 ° C. and stirred for 16 hours. It is poured into saturated ammonium chloride solution, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 6.46 g (11.4 mmol, 83%) of the title compound are isolated as a colorless oil.
¹ H NMR (CDCl ₃ ): δ = -0.04 (6H), 0.83 (9H), 1.10 (9H), 1.79 (1H), 1.90 (1H), 1.97 (3H), 2.51 (3H), 3.51 (2H), 4.38 (1H), 6.22 (1H), 6.74 (1H), 7.23-7.47 (6H), 7.63 (2H) 7; 70 (2H) ppm.

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

The solution of 4.79 g (8.46 mmol) of the compound shown in Example 1ac in 48 ml of tetrahydrofuran is mixed with 48 ml of a 65:35:10 mixture of glacial acetic acid / water / tetrahydrofuran and stirred at 23 for 2.5 days ° C. It is poured into saturated sodium carbonate solution, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 3.42 g (7.57 mmol, 90%) of the title compound are isolated as a colorless oil.
¹ H NMR (CDCl ₃ ): δ = 1.10 (9H), 1.53 (1H), 1.81 (2H), 1.96 (3H), 2.71 (3H), 3.59 ( 2H), 4.41 (1H), 6.38 (1H), 6.78 (1H), 7.26-7.49 (6H), 7.65 (2H), 7.72 (2H) ppm.

Example 1ae (E, 3S) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (2-methylthiazol-4-yl) - pent-4-enal

2.73 ml of dimethyl sulfoxide in 11.5 ml of methylene chloride are added dropwise to 1.55 ml of oxalyl chloride in 14.4 ml of methylene chloride at -70.degree. The mixture is stirred for 10 minutes and then 6.0 g of the alcohol described in Example 1ad are added to 11.5 ml of methylene chloride. After a further 2 hours of stirring, 5.55 ml of triethylamine are added dropwise. Then allowed to warm to -40 ° C within one hour and then add the reaction mixture to 30 ml of water. It is extracted twice with methylene chloride, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product thus obtained is used in the next step without further purification.
¹ H-NMR (CDCl ₃ ): δ = 1.09 (9H), 2.01 (3H), 2.51 (1H), 2.66 (1H), 2.72 (3H), 4.69 (1H), 6.43 (1H), 6.81 (1H) , 7.3-7.8 (10H), 9.63 (1H) ppm.

Example 1af (E, 4S, 2RS) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -5-methyl-6- (2-methylthiazole-4- yl) -hex-5-en-2-ol

6.94 ml of a 3 molar methylmagnesium chloride solution in tetrahydrofuran are added dropwise at -10 ° C. under nitrogen to a solution of 5.9 g of the aldehyde prepared above in 83 ml of tetrahydrofuran. After stirring for 30 minutes at -10 ° C., the reaction mixture is poured onto saturated ammonium chloride solution and extracted three times with ether. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product thus obtained is purified by chromatography on silica gel. With hexane / 0-80% ethyl acetate, 5.3 g of the title compound are obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 1.00-1.15 (12H), 1.55-1.90 (2H), 1.90 / 2.04 (3H), 2.69 / 2.72 (3H), 3.90 (1H), 4.40 / 4.48 (1H) , 6.23 / 6.51 (1H), 6.69 / 6.80 (1H), 7.20-7.50 (6H), 7.60-7.80 (4H) ppm.

Example 1ag (E, 4S) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -5-methyl-6- (2-methylthiazol-4-yl) - hex-5-en-2-one

22.5 ml of Jones reagent are added dropwise to a solution of 5.25 g of the alcohol described above in 113 ml of acetone at -40 ° C. and the mixture is stirred vigorously. The reaction mixture is allowed to warm to -10 ° C. within one hour, 0.5 ml of isopropanol is added and the mixture is stirred for another 15 minutes. It is then diluted with ether, washed four times with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-60% ethyl acetate, 4.01 g of the title compound is obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 1.07 (9H), 1.94 (3H), 2.00 (3H), 2.59 (1H), 2.70 (3H), 2.74 (1H), 4.73 (1H), 6.29 (1H) , 6.75 (1H), 7.25-7.50 (6H), 7.60-7.75 (4H) ppm.

Example 1ah (1E, 5E / Z, 3S, 10S) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -2,5,10-trimethyl-1- (2- methylthiazol-4-yl) -11- (tetrahydro-2H-pyran-2-yloxy) -undec-1,5-diene

11.5 ml of a 1 molar solution of sodium bis (trimethylsilylamide) in tetrahydrofuran are added to a solution of 7.24 g of the phosphonium salt described in Example 1v in 80 ml of tetrahydrofuran at 0 ° C. under argon and then stirred for 30 minutes at 22 ° C. 2.61 g of the ketone prepared in Example 1ag in 8 ml of tetrahydrofuran are then added at -40 ° C. and the mixture is stirred at this temperature for 45 minutes. The reaction mixture is poured onto saturated ammonium chloride solution and extracted four times with ether. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained was purified by chromatography on silica gel using those from two further batches in which a total of 3.57 g of the ketone from Example 1ag were reacted. With hexane / 0-70% ether, 3.7 g of the title compound is obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.80-0.92 (3H), 0.92-1.95 (13H), 1.07 (9H), 1.30 / 1.44 (3H), 1.98 / 1.99 (3H), 2.15-2.40 (2H) , 2.70 (3H), 3.08 / 3.18 (1H), 3.47-3.62 (2H), 3.85 1H), 4.27 (1H), 4.55 (1H), 5.05 (1H), 6.19 (1H), 6.78 (1H), 7.24 -7.48 (6H), 7.57-7.78 (4H) ppm.

Example 1ai (6E / Z, 10E, 2S, 9S) -9 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -2,7,10-trimethyl-11- (2- methylthiazol-4-yl) -undec-6,10-dien-1-ol

156 mg of pyridinium p-toluenesulfonate are added to a solution of 4.0 g of the compound prepared in Example 1ah in 21 ml of ethanol and the mixture is stirred under argon at 50 ° C. for 24 hours. It is then concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-60% ethyl acetate, 2.59 g of the title compound is obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.82 / 0.85 (3H), 0.91 (2H), 1.08 (9H), 1.05-1.90 (5H), 1.38 / 1.45 (3H), 2.00 (3H), 2.20 -2.40 (2H), 2.70 (3H), 3.30-3.48 (2H), 4.26 (1H), 4.98 / 5.05 (1H), 6.15 / 6.18 (1H), 6.79 (1H), 7.20-7.50 (6H), 7.60 -7.76 (4H) ppm.

Example 1ak (6E / Z, 10E, 2S, 9S) -9 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -2,7,10-trimethyl-11- (2- methylthiazol-4-yl) -undec-6,10-dienal

0.729 ml of dimethyl sulfoxide in 3.0 ml of methylene chloride are added dropwise to 0.416 ml of oxalyl chloride in 3.5 ml of methylene chloride at -70 ° C. The mixture is stirred for 10 minutes and then 2.0 g of the alcohol prepared above in 3.0 ml of methylene chloride are added. After a further 2 hours of stirring, 1.49 ml of triethylamine are added dropwise. Then allowed to warm to 40 ° C within one hour and then add the reaction mixture to 15 ml of water. It is extracted twice with methylene chloride, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product thus obtained (1.96 g) is used in the next step without further purification.
¹ H-NMR (CDCl ₃ ): δ = 0.97 / 1.01 (3H), 1.07 (9H), 1.0-2.1 (6H), 1.45 / 1.55 (3H), 2.00 / 2.01 (3H), 2.10-2.48 (3H) , 2.69 (3H), 4.25 / 4.27 (1H), 5.01 / 5.03 (1H), 6.16 / 6.17 (1H), 6.79 (1H), 7.25-7.50 (6H), 7.58-7.77 (4H), 9.49 / 9.54 ( 1H) ppm.

Example 1al (4S (4R, 5S, 6S, 11E / Z, 13S, 14E)) - 4- (13 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -15- (2- methyl-4-thiazolyl) -3-oxo-5-hydroxy-2,4,6,11,14-pentamethyl-pentadeca-10,14-diene 2-yl) -2,2-dimethyl- [1,3] dioxane (A) and (4S (4R, 5R, 63.11E / Z, 13S, 14E)) - 4- (13 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -15- (2- methyl-4-thiazolyl) -3-oxo-5-hydroxy-2,4,6,11,14-pentamethyl-pentadeca-10,14-diene 2-yl) -2,2-dimethyl- [1,3] dioxane (B)

1.92 ml of a 2.4 molar solution of butyllithium in hexane are added to a solution of 0.62 ml of diisopropylamine in 3 ml of tetrahydrofuran at -30 ° C. under argon. After stirring for 15 minutes, the mixture is cooled to -70 ° C. and a solution of 857 mg of the compound prepared according to Example 1l in 3 ml of tetrahydrofuran is added dropwise. After stirring for one hour, 500 mg of the aldehyde prepared in Example 1ak in 3 ml of tetrahydrofuran are added dropwise. After stirring at this temperature for 1.5 hours, the reaction mixture is poured onto saturated ammonium chloride solution and extracted several times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-50% ether, 1.62 g of the title compound (A) is obtained as a colorless oil, and 0.12 g of the diastereomeric compound B as a slightly yellow-colored oil.
¹ H-NMR (CDCl ₃ ) of A: δ = 0.75 / 0.79 (3H), 1.00 / 1.01 (3H), 1.05 (9H), 1.09 / 1.10 (3H), 1.20 (3H), 1.30 / 1.43 (3H) , 1.35 (3H), 1.43 (3H), 0.80-1.95 (10H), 1.96 / 1.99 (3H), 2.03-2.40 (2H), 2.70 (3H), 3.18-3.40 (2H), 3.80-4.09 (3H) , 4.27 (1H), 5.06 (1H), 6.18 (1H), 6.79 (1H), 7.22-7.48 (6H), 7.58-7.77 (4H) ppm.
¹ H-NMR (CDCl ₃ ) of B: δ = 0.80-2.80 (18H), 1.02 (3H), 1.08 (12H), 1.28 (3H), 1.33 (3H), 1.41 / 1.42 (3H), 1.97 / 1.98 (3H), 2.71 (3H), 3.13-3.57 (2H), 3.75-4.15 (3H), 4.26 (1H), 5.03 (1H), 6.18 (1H), 6.78 (1H), 7.22-7.50 (6H), 7.53-7.70 (4H) ppm.

Example 1am (4S (4R, 5S, 6S, 11E / Z, 13S, 14E)) - 4- (13 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -15- (2- methyl-4-thiazolyl) -3-oxo-5- (tetrahydropyran-2-yloxy) -2,4,6,11,14-pentamethyl- pentadeca-10,14-dien-2-yl) -2,2-dimethyl- [1,3] dioxane

200 mg of p-toluenesulfonic acid monohydrate and 3.03 ml of dihydropyran are added to a solution of the title compound A prepared above in 30 ml of methylene chloride and the mixture is stirred at 22 ° C. for 3 days. Then the reaction mixture is poured onto saturated sodium bicarbonate solution and extracted with methylene chloride. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-40% ethyl acetate, 1.53 g of the title compound is obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.8-2.55 (37H), 1.06 (9H), 1.96 / 1.98 (3H), 2.69 (3H), 3.10-4.15 (8H), 4.26 (1H), 4.40 -4.63 (1H), 5.05 (1H), 6.17 (1H), 6.78 (1H), 7.21-7.48 (6H), 7.55-7.74 (4H) ppm.

Example 1 (4S (4R, 5S, 6S, 11E / Z, 13S, 14E)) - 4- (13-hydroxy-15- (2-methyl-4-thiazolyl) -3-oxo-5- (tetrahydropyran-2-yloxy) -2,4,6,11,14-pentamethyl-pentadeca-10,14-dien-2-yl) -2,2- dimethyl- [1,3] dioxane

5.34 ml of a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran are added to a solution of the compound prepared above in 50 ml of tetrahydrofuran and the mixture is first stirred at 22 ° C. for 12 hours and then at 50 ° C. for 4 hours. Then the reaction mixture is poured onto saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-80% ethyl acetate, 851 mg of the title compound is obtained as a colorless oil.
¹ H NMR (CDCl ₃ ): δ = 0.80-2.60 (39H), 2.07 (3H), 2.73 (3H), 3.28 (1H), 3.45 (1H), 3.60-4.33 (6H), 4.43-4.61 (1H), 5.25-5.43 (1H), 6.60 (1H), 6.95 (1H) ppm.

Example 1ao (3S, 6R, 7S, 8S, 12E / Z, 15S, 16E) -17- (2-methyl-4-thiazolyl) -5-oxo-4,4,6,8,13,16- hexamethyl-heptadeca-12,16-diene-1,3,7,15-tetraol

445 mg of p-toluenesulfonic acid monohydrate are added to a solution of 725 mg of the alcohol prepared above in 33 ml of ethanol and the mixture is stirred under nitrogen at 22 ° C. for 3.5 hours. Then the reaction mixture is poured onto saturated sodium hydrogen carbonate solution and extracted with methylene chloride. The organic phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-100% ethyl acetate / 0-10% methanol, 505 mg of the title compound is obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.84 / 0.87 (3H), 1.07 (3H), 1.13 (3H), 1.23 (3H), 1.68 / 1.77 (3H), 1.00-1.85 (10H), 2.06 (3H ), 2.08-2.6 (3H), 2.72 (3H), 3.20-3.51 (4H), 3.89 (2H), 4.05 (1H), 4.23 / 4.29 (1H), 5.30 / 5.40 (1H), 6.61 (1H), 6.96 / 6.97 (1H) ppm.

Example 1ap (3S, 6R, 7S, 8S, 12E / Z, 15S, 16E) -17- (2-methyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyl- 1,3,7,15-tetrakis - [[dimethyl- (1,1-dimethylethyl) silyl] oxy] -heptadeca-12,16-dien-5-one

4 ml of 2,6-lutidine are added to a solution of 490 mg of the tetrol prepared above in 30 ml of methylene chloride at -70 ° C. under argon and then 3.9 ml of tert-butyldimethylsilyl trifluoromethanesulfonate are added dropwise and the mixture is stirred at -70 ° C. for 24 hours . Then the reaction mixture is poured onto saturated sodium bicarbonate solution and extracted with methylene chloride. The organic phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-50% ethyl acetate, 742 mg of the title compound is obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.00-0.15 (24H), 0.90 (39H), 0.95-1.75 (9H), 1.05 (3H), 1.06 (3H), 1.22 (3H), 1.53 / 1.62 (3H), 2.00 / 2.02 (3H), 2.21 (2H), 2.71 (3H), 3.15 (1H), 3.58 (1H), 3.67 (1H), 3.77 (1H), 3.90 (1H), 4.23 (1H) , 5.18 (1H), 6.49 (1H), 6.92 / 6.93 (1H) ppm.

Example 1aq (3S, 6R, 7S, 8S, 12E / Z, 15S, 16E) -17- (2-methyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyl-1- hydroxy-3,7,15-tris - [[dimethyl- (1,1-dimethylethyl) silyl] oxy] -heptadeca-12,16-dien-5-one

179 mg of camphor-10-sulfonic acid are added at 0 ° C. under argon to a solution of 735 mg of the silyl ether prepared above in a mixture of 8 ml of dichloromethane and 8 ml of methanol, the mixture is allowed to warm to 22 ° C. and is stirred for a further 1.5 hours . Then 0.6 ml of triethylamine is added, poured into a saturated sodium bicarbonate solution and extracted several times with dichloromethane. The organic phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-20% ethyl acetate, 527 mg of the title compound is obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.00-0.17 (18H), 0.93 (30H), 1.09 (9H), 0.90-1.54 (8H), 1.66 / 1.73 (3H), 1.93 (2H), 2.00 / 2.03 (3H), 2.20 (2H), 2.73 (3H), 3.15 (1H), 3.67 (2H), 3.81 (1H), 4.10 (1H), 4.23 (1H), 5.20 (1H), 6.47 (1H), 6.92 /6.94 (1H) ppm.

Example 1ar (3S, 6R, 7S, 8S, 12E / Z, 15S, 16E) -17- (2-methyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyl- 3,7,15-tris - [[dimethyl- (1,1-diimethylethyl) silyl] oxy] -5-oxo-heptadeca-12,16-dienal

1.28 g of Collins reagent is added to a solution of 520 mg of the alcohol prepared above in 30 ml of methylene chloride at 0 ° C. under argon and the mixture is stirred at 0 ° C. for 15 minutes. Then Celite is added and the mixture is diluted with ether. It is filtered off through Celite, washed well with ether and the filtrate is concentrated in vacuo. The title compound (463 mg) thus obtained is used in the next step as a pale yellow oil without further purification.
¹ H NMR (CDCl ₃ ): δ = 0.0-0.17 (18H), 0.91 (30H), 1.05 (3H), 1.10 (3H), 1.27 (3H), 1.65 / 1.72 (3H), 1.00-1.62 (8H ), 2.00 / 2.03 (3H), 2.21 (2H), 2.30-2.58 (3H), 2.72 (3H), 3.14 (1H), 3.79 (1H), 4.23 (1H), 5.20 (1H), 6.47 (1H) , 6.92 / 6.94 (1H) ppm.

Example 1as (3S, 6R, 7S, 8S, 12Z, 15S, 16E) -17- (2-methyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyl- 3,7,15-tris - [[dimethyl- (1,1-dimethylethyl) silyl] oxy] -5-oxo-heptadeca-12,16-dienoic acid (A) and (3S, 6R, 7S, 8S, 12E, 15S, 16E) -17- (2-methyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyl- 3,7,15-tris - [[dimethyl- (1,1-dimethylethyl) silyl] oxy] -5-oxo-heptadeca-12,16-dienoic acid (B)

To a solution of 530 mg of the aldehyde prepared above in 19.5 ml of acetone, 1.5 ml of a standardized 8N chromosulfuric acid solution are added at -30 ° C. and the mixture is stirred for 45 minutes. It is poured into a mixture of water and diethyl ether and the organic phase is washed twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel twice. With hexane / 0-90% ethyl acetate, 162 mg of the title compound A are obtained as a non-polar component and 171 mg of the title compound B as a polar component as colorless oils.
¹ H NMR (CDCl ₃ ) of A: δ = 0.00-0.18 (18H), 0.88 (30H), 0.90-1.68 (7H), 1.09 (3H), 1.17 (3H), 1.20 (3H), 1.75 (3H ), 1.98 (3H), 2.00-2.50 (4H), 2.72 (3H), 3.16 (1H), 3.73 (1H), 4.33 (1H), 4.43 (1H), 5.23 (1H), 6.72 (1H), 6.97 (1H) ppm.
¹ H NMR (CDCl ₃ ) of B: δ = 0.00-0.17 (18H), 0.90 (30H), 0.90-1.45 (7H), 1.07 (3H), 1.13 (3H), 1.23 (3H), 1.63 (3H ), 1.97 (3H), 1.85-2.58 (4H), 2.51 (3H), 3.17 (1H), 3.80 (1H), 4.21 (1H), 4.39 (1H), 5.18 (1H), 6.46 (1H), 6.92 (1H) ppm.

Example 1at (3S, 6R, 7S, 8S, 12E, 15S, 16E) -17- (2-methyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyl-3,7- bis - [[dimethyl- (1,1-dimethylethyl) silyl] oxy] -15-hydroxy-5-oxo-heptadeca-12.16- dienic acid

0.59 ml of a 1 molar solution of tetrabutylammonium fluoride is added to a solution of 50 mg of the title compound B prepared in Example 1as in 1.5 ml of tetrahydrofuran at 22 ° C. under argon and the mixture is stirred for 16 hours. Then the reaction mixture is poured onto ice-cold saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phases are washed once with 1N hydrochloric acid and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-80% ethyl acetate, 42 mg of the title compound is obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.00-0.15 (12H), 0.91 (21H), 1.07 (3H), 1.13 (3H), 1.23 (3H), 0.80-1.50 (9H), 1.69 (3H), 2.03 (3H), 2.11-2.58 (4H), 2.73 (3H), 3.15 (1H), 3.80 (1H), 4.24 (1H), 4.41 (1H), 5.31 (1H), 6.53 (1H), 6.95 (1H ) ppm.

Example 1au (4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-bis - [[dimethyl- (1,1-dimethylethyl) silyl] oxy] -16- (1- methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5,5,7,9,14-pentamethyl-cyclohexadec- 13-en-2,6-dione

75 μl of triethylamine, 50 μl of 2,4,6-trichlorobenzoyl chloride are added to a solution of 118 mg of the acid prepared above in 6 ml of tetrahydrofuran under argon and the mixture is stirred for 15 minutes. This solution is added dropwise to a solution of 1-5 mg of 4-dimethylaminopyridine in 90 ml of toluene within 3 hours and the mixture is stirred at 23 ° C. for a further 15 minutes. It is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-40% ethyl acetate, 87 mg of the title compound is obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.00-0.17 (12H), 0.87 (9H), 0.93 (9H), 0.96 (3H), 1.12 (3H), 1.14 (3H), 1.21 (3H), 1.63 ( 3H), 2.14 (3H), 1.00-2.37 (10H), 2.49 (1H), 2.62 (1H), 2.73 (1H), 2.82 (1H), 3.05 (1H), 3.92 (1H), 4.20 (1H), 5.31 (1H), 5.37 (1H), 6.59 (1H), 6.95 (1H) ppm.

example 1 (4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4- thiazolyl) ethenyl) -1-oxa-5,5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione

348 ul of a 20% solution of trifluoroacetic acid in methylene chloride are added to a solution of 45 mg of the lactone prepared above in 1.5 ml of methylene chloride at -10 ° C. under argon. The mixture is allowed to warm to 0 ° C. and is stirred at this temperature for 5 hours. The reaction mixture is then concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-80% ethyl acetate, 22.4 mg of the title compound is obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.99 (3H), 1.08 (3H), 1.20 (3H), 1.31 (3H), 1.64 (3H), 1.05-1.75 (5H), 1.90 (1H), 2.01 ( 3H), 2.21 (2H), 2.34 (1H), 2.49-2.52 (3H), 2.72 (3H), 3.10 (1H), 3.22 (1H), 3.77 (1H), 4.02 (1H), 5.31 (1H), 5.52 (1H), 6.58 (1H), 6.98 (1H) ppm.

Example 2 (1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4- thiazolyl) ethenyl) -1,8,8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9- dion (A) and (1R, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4- thiazolyl) ethenyl) -1,8,8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9- dion (B)

To a solution of 20 mg of the title compound prepared according to Example 1 in 0.4 ml of acetonitrile, 233 μl of a 0.1037 molar EDTA-diSodium salt solution and 389 μl of 1,1,1-trifluoroacetone are added at 0 ° C. under argon. A mixture of 47.6 mg oxone and 27.3 mg sodium hydrogen carbonate is then added and the mixture is stirred at 0 ° C. for 2.5 hours. Then sodium thiosulfate solution is added and the mixture is extracted several times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. A second batch of the same size provides another batch of raw product. The combined crude products thus obtained are pre-cleaned by preparative thick layer chromatography with hexane / 50% ethyl acetate. The actual separation of the title compounds A and B is carried out by HPLC separation (Chiralpak AD 10 µm; hexane: ethanol 85:15). In this way, 6.7 mg of the title compound A and 16.2 mg of the title compound B are obtained as colorless oils.
¹ H-NMR (CDCl ₃ ) of A: δ = 0.99 (3H), 1.05 (3H), 1.16 (3H), 1.43 (3H), 1.45 (3H), 1.05-1.72 (8H), 2.00 (2H), 2.09 (3H), 2.44 (2H), 2.72 (3H), 2.89 (1H), 3.50 (1H), 3.83 (1H), 4.14 (1H), 4.50 (1H), 5.62 (1H), 6.57 (1H), 6.98 (1H) ppm.
¹ H-NMR (CDCl ₃ ) of B: δ = 1.03 (3H), 1.13 (3H), 1.23 (3H), 1.34 (3H), 1.36 (3H), 1.07-1.72 (7H), 1.70 (1H), 2.08 (3H), 2.22 (2H), 2.50 (1H), 2.60 (1H), 2.72 (3H), 2.93 (1H), 3.25 (1H), 3.57 (1H), 3.82 (1H), 4.05 (1H), 5.44 (1H), 6.66 (1H), 6.98 (1H) ppm.

Example 3 (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4- thiazolyl) ethenyl) -1-oxa-5,5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione Example 3a (3S, 6R, 7S, 8S, 12Z, 15S, 16E) -17- (2-methyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyl-3,7- bis - [[dimethyl- (1,1-dimethylethyl) silyl] oxy] -15-hydroxy-5-oxo-heptadeca-12.16- dienic acid

Analogously to Example 1s, 150 mg of the title compound A prepared in Example 1r are reacted. 81 mg of the title compound are obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.00-0.16 (12H), 0.90 (21H), 1.08 (3H), 1.17 (3H), 1.18 (3H), 0.80-2.28 (8H), 1.78 (3H), 2.03 (3H), 2.30-2.55 (4H), 2.73 (3H), 3.14 (1H), 3.78 (1H), 4.28 (1H), 4.42 (1H), 5.38 (1H), 6.78 (1H), 6.97 (1H ) ppm.

Example 3b (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-bis - [[dimethyl- (1,1-dimethylethyl) silyl] oxy] -16- (1- methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5,5,7,9,14-pentamethyl-cyclohexadec- 13-en-2,6-dione

Analogously to Example 1au, 81 mg of the compound prepared above are reacted. 75 mg are obtained after column chromatography, which are again purified by preparative thick-layer chromatography with hexane / 10% ethyl acetate. 58 mg of the title compound are obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.00-0.17 (12H), 0.79-0.99 (24H), 1.09 (3H), 1.16 (3H), 1.72 (3H), 1.00-1.92 (8H), 2.12 (3H ), 2.31 (2H), 2.68 (1H), 2.71 (1H), 2.88 (1H), 2.99 (2H), 3.89 (1H), 3.98 (1H), 5.06 (1H), 5.27 (1H), 6.59 (1H ), 6.98 (1H) ppm.

Example 3 (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4- thiazolyl) ethenyl) -1-oxa-5,5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 27 mg of the compound prepared above are reacted. The purification is carried out by preparative thick-layer chromatography with hexane / 20% ethyl acetate. 17.4 mg of the title compound are obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 1.02 (3H), 1.11 (3H), 1.20 (3H), 1.35 (3H), 1.75 (3H), 1.10-2.05 (7H), 2.10 (3H), 2.20 ( 1H), 2.39 (1H), 2.51 (1H), 2.70 (3H), 2.83-3.01 (2H), 3.14 (1H), 3.80 (1H), 3.42 (1H), 4.20 (1H), 5.23 (1H), 5.40 (1H), 6.62 (1H), 6.98 (1H) ppm.

Example 4 (1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4- thiazolyl) ethenyl) -1,8,8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9- dion (A) and (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4- thiazolyl) ethenyl) -1,8,8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.O] heptadecane-5,9- dion (B)

Analogously to Example 2, 15 mg of the compound prepared in Example 3 are reacted. The purification is carried out only by preparative thick layer chromatography. 0.3 mg of the title compound A and 11 mg of the title compound B are obtained as colorless oils.
¹ H-NMR (CDCl ₃ ) of A: δ = 0.94 (3H), 1.04 (3H), 1.10 (3H), 1.41 (3H), 1.43 (3H), 1.05-2.20 (7H), 2.12 (3H), 2.24-2.65 (4H), 2.73 (3H), 3.32 (1H), 3.40-3.82 (2H), 4.07 (1H), 5.80 (1H), 6.62 (1H), 6.98 (1H) ppm.
¹ H-NMR (CDCl ₃ ) of B: δ = 1.03 (3H), 1.15 (3H), 1.21 (3H), 1.36 (3H), 1.38 (3H), 1.10-1.97 (9H), 2.05 (3H), 2.09 (1H), 2.42 (1H), 2.53 (1H), 2.70 (3H), 2.72 (1H), 3.14 (1H), 3.67 (1H), 3.81 (1H), 4.12 (1H), 5.49 (1H), 6.56 (1H), 6.97 (1H) ppm.

Claims (18)

1. epothilone derivatives of the general formula I,
wherein
R ^1a , R ^{1b are the} same or different and are hydrogen, C ₁ -C ₁₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl, or together a - (CH ₂ ) _m group with m = 2, 3, 4 or 5,
R ^2a , R ^{2b are} identical or different and are hydrogen, C ₁ -C ₁₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl or together a - (CH ₂ ) _n group with n = 2, 3, 4 or 5 ,
R ^{3 is} hydrogen, C ₁ -C ₁₀ alkyl, aryl, C ₇ -C ₁₀ aralkyl,
R ^4a , R ^{4b are the} same or different and are hydrogen, C ₁ -C ₁₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl or together a - (CH ₂ ) _p group with p = 2, 3, 4 or 5 ,
DE a group
R ^{5 is} C ₁ -C ₁₀ alkyl, aryl, C ₇ -C ₁₀ aralkyl,
R ⁶ , R ⁷ each represent a hydrogen atom, together an additional bond or an oxygen atom,
R ^{8 is} hydrogen, C ₁ -C ₂₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl, all of which can be substituted,
X is an oxygen atom, two alkoxy groups OR ⁹ , a C ₂ -C ₁₀ alkylene-α, ω-dioxy group, which can be straight-chain or branched, H / OR ¹⁰ or a grouping CR ¹¹ R ¹² , where
R ^{9 represents} a C ₁ -C ₂₀ alkyl radical,
R ¹⁰ for hydrogen or a protecting group PG ¹ , R ¹¹ , R ^{12 are the} same or different and for hydrogen, a C ₁ -C ₂₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl radical or R ¹¹ and R ¹² together together with the methylene carbon atom for a 5- to 7-membered carbocyclic ring
stand,
Y is an oxygen atom or two hydrogen atoms,
Z is an oxygen atom or H / OR ¹³ ,
in which
R ^{13 is} hydrogen or a protective group PG ² ,
mean,
including all stereoisomers of these compounds and their mixtures. 2. epothilone derivatives of the general formula I according to claim 1, wherein Y, Z, R ^1a , R ^1b , R ^2a , R ^2b and R ^{5 can} all have the meanings given in general formula I, and the rest of the molecule are identical is with the naturally occurring epothilone A or B. 3. epothilone derivatives of the general formula I according to claim 1, wherein R ³ , R ^4a , R ^4b , DE, R ⁵ , R ⁶ and R ^{7 can} all have the meanings given in the general formula I, and the rest of the molecule is identical to the naturally occurring epothilone A or B. 4. epothilone derivatives of general formula I according to claim 1, wherein R ⁵ , R ⁶ , R ⁷ , R ⁸ and X can all have the meanings given in general formula I, and the rest of the molecule is identical to that which occurs naturally Epothilon A or B. 5. epothilone derivatives of the general formula I according to claim 1, wherein Y, Z, R ^1a , R ^1b , R ^2a , R ^2b , R ³ , R ^4a , R ^4b , DE, R ⁵ , R ⁶ and R ⁷ all can have the meanings given in the general formula I, and the rest of the molecule is identical to the naturally occurring epothilone A or B. 6. epothilone derivatives of the general formula I according to claim 1, wherein Y, Z, R ^1a , R ^1b , R ^2a , R ^2b , R ⁵ , R ⁶ , R ⁷ , R ⁸ and X are all those in the general formula I. may have the meanings given, and the rest of the molecule is identical to the naturally occurring epothilone A or B. 7. epothilone derivatives of the general formula I according to claim 1, wherein R ³ , R ^4a , R ^4b , DE, R ⁵ , R ⁶ , R ⁷ , R ⁸ and X can all have the meanings given in the general formula I, and the rest of the molecule is identical to the naturally occurring epothilone A or B. 8. epothilone derivatives of the general formula I according to claim 1, wherein R ^{5 represents} a methyl, ethyl or propyl group. 9. epothilone derivatives of the general formula I according to claim 8, wherein R ⁶ and R ⁷ together mean an additional bond. 10. epothilone derivatives of the general formula I according to claim 8, wherein R ⁶ and R ⁷ together represent an epoxy group. 11. Compounds of general formula I according to claim 1, namely
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 1 6R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1.8 , 8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1.8, 8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1.8, 8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1.8, 8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa- 5,5,7, 9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) - 1,8,8,10, 12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-3- (1-methyl-2- (pyridyl) ethenyl) - 1,8,8,10,12- pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-7-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,9,14-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1,8,8,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1,8,8,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5-dimethylene-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1-oxa-7,9,14-trimethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8-dimethylene-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -1,10,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-8,8-dimethylene-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -1,10,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5-trimethylene-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1-oxa-7,9,14-trimethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8-trimethylene-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -1,10,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-8,8-trimethylene-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -1,10,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-14-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-14-ethyl-16- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1- oxa-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-14-ethyl-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5, 5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8, 10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8, 10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-7,14-diethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1-oxa-5,5,9-trimethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1,10-diethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -8,8,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1,10-diethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -8,8,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-14-proyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1-propyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo (14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1-propyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1.8, 8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 35 (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1.8, 8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13E, 165 (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) - 1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1.8, 8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-oxazol-1-yl-) ethenyl) -1,8,8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa- 5,5,7, 9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) - 1,8,8,10, 12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) - 1,8,8,10, 12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-7-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,9,14-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1,8,8,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1,8,8,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-14-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-Dihydroxy-14-proyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1-propyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and
(1R, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1-propyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenylyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione. 12. A process for the preparation of the epothilone derivatives of the general formula I according to claim 1
wherein
the substituents have the meanings given in the general formula I, characterized in that a fragment of the general formula B
wherein
R ^{3 '} , R ^4a' and R ^{4b 'have} the meanings already given for R ³ , R ^4a and R ^4b , and
R ^{17 is} a hydroxyl group, halogen, a protected hydroxyl group OPG ³ , a phosphonium halide residue PPh ₃ + Hal⁻ (Ph = phenyl; Hal = F, Cl, Br, I), a phosphonate residue P (O) (OQ) ₂ (Q = C ₁ -C ₁₀ alkyl or phenyl) or a phosphine oxide residue P (O) Ph ₂ (Ph = phenyl),
mean,
with a fragment of the general formula C
wherein
R ^{5 '} , R ^{8' have} the meaning already given in general formula I for R ⁵ and R ⁸ and
R ^{20 is} a hydrogen atom or a protective group PG ⁵
U is an oxygen atom, two alkoxy groups OR ⁹ , a C ₂ -C ₁₀ alkylene-α, ω- dioxy group, which can be straight-chain or branched, H / OR ¹⁰ or a grouping CR ¹¹ R ¹² ,
in which
R ^{9 represents} a C ₁ -C ₂₀ alkyl radical,
R ¹⁰ for hydrogen or a protective group PG ⁶ ,
R ¹¹ , R ^{12 are the} same or different and represent a hydrogen atom, a C ₁ -C ₂₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl radical or R ¹¹ and R ¹² together with the methylene carbon atom for a 5 to 7-membered carbocyclic ring
W is an oxygen atom, two alkoxy groups OR ²¹ , a C ₂ -C ₁₀ -alkylene-α, ω- dioxy group, which can be straight-chain or branched or H / OR ²² ,
in which
R ^{21 represents} a C ₁ -C ₂₀ alkyl radical,
R ²² for hydrogen or a protective group PG ⁷ ,
mean,
to a partial fragment of the general formula BC
wherein
R ³ , R ^4a , R ^4b , R ⁵ , R ⁶ , R ⁷ , R ²⁰ , D, E, U and V have the meanings already mentioned,
implemented and this partial fragment BC with a fragment of the general formula A
wherein
R ^{1a '} , R ^1b' , R ^{2a '} and R ^{2b' have} the meanings already mentioned for R ^1a , R ^1b , R ^2a and R ^2b and
R ¹⁴ CH ₂ OR ^14a , CH ₂ -Hal, CHO, CO ₂ R ^14b , COHal,
R ¹⁵ hydrogen, OR ^15a , Hal, OSO ₂ R ^15b ,
R ^14a , R ^{15a are} hydrogen, SO ₂ alkyl, SO ₂ aryl, SO ₂ aralkyl or together a - (CH ₂ ) _o group or together a CR ^16a R ^16b group,
R ^14b , R ^{15b are} hydrogen, C ₁ -C ₂₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl,
R ^16a , R ^{16b are} identical or different and are hydrogen, C ₁ -C ₁₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl, or together a - (CH ₂ ) _q group,
Hal halogen,
o 2 to 4,
q 3 to 6,
including all stereoisomers and mixtures thereof, and etherifying or esterifying free hydroxyl groups in R ¹⁴ and R ¹⁵ , ketalizing free carbonyl groups in A and R ^14, converting them to an enol ether or reducing them, and free acid groups in A in whose salts may be converted with bases,
to a partial fragment of the general formula ABC
wherein R ^1a , R ^1b , R ^2a , R ^2b , R ³ , R ^4a , R ^4b , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁴ , R ¹⁵ , D, E, U and Z are those already mentioned Have meanings
implemented and this partial fragment of the general formula ABC is cyclized to an epothilone derivative of the general formula. 13. Intermediates of the general formula B
wherein
R ^{3 '} , R ^4a' and R ^{4b 'have} the meanings already given for R ³ , R ^4a and R ^4b , and
R ^{17 is} a hydroxyl group, halogen, a protected hydroxyl group OPG ³ , a phosphonium halide residue PPh ₃ ⁺Hal⁻ (Ph = phenyl; Hal = F, Cl, Br, I), a phosphonate residue P (O) (OQ) ₂ (Q = C ₁ -C ₁₀ alkyl or phenyl) or a phosphine oxide residue P (O) Ph ₂ (Ph = phenyl)
mean. 14. Intermediates of the general formula C
wherein
R ^{5 '} , R ^{8' have} the meaning already given in general formula I for R ⁵ and R ⁸ and
R ^{20 is} a hydrogen atom or a protective group PG ⁵
U is an oxygen atom, two alkoxy groups OR ⁹ , a C ₂ -C ₁₀ alkylene-α, ω- dioxy group, which can be straight-chain or branched, H / OR ¹⁰ or a grouping CR ¹¹ R ¹² ,
in which
R ⁹ for a C ₁ -C ₂₀ alkyl radical, R ¹⁰ for hydrogen or a protective group PG ⁶ ,
R ¹¹ , R ^{12 are the} same or different and are hydrogen, a C ₁ -C ₂₀ alkyl, aryl, C ₇ -C ₂₀ aralkyl radical or
R ¹¹ and R ¹² together with the methylene carbon atom together for a 5- to 7-membered carbocyclic ring
W is an oxygen atom, two alkoxy groups OR ²¹ , a C ₂ -C ₁₀ -alkylene-α, ω- dioxy group, which can be straight-chain or branched or H / OR ²² ,
in which
R ^{21 represents} a C ₁ -C ₂₀ alkyl radical,
R ²² for hydrogen or a protective group PG ⁷ ,
mean. 15. Intermediates of the general formula BC
wherein
R ³ , R ^4a , R ^4b , R ⁵ , R ⁶ , R ⁷ , R ²⁰ , D, E, U and V have the meanings already mentioned. 16. Intermediates of the general formula ABC
wherein
R ^1a , R ^1b , R ^2a , R ^2b , R ³ , R ^4a , R ^4b , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁴ , R ¹⁵ , D, E, U and Z have the meanings already mentioned to have. 17. Pharmaceutical preparations containing at least one compound of general formula I according to claim 1 and a pharmaceutically acceptable Carrier. 18. Use of the compounds of general formula I according to claim 1 for Manufacture of drugs.