EP1631563A1

EP1631563A1 - Protected 5,7-dihydroxy-4,4-dimethyl-3-oxoheptanoic acid esters and 5,7-dihydroxy-2-alkyl-4,4-dimethyl-3-oxoheptanoic acid esters for synthesizing epothilones and derivatives derivatives, and methods for producing these esters

Info

Publication number: EP1631563A1
Application number: EP04739609A
Authority: EP
Inventors: Juergen Westermann; Johannes Platzek; Orlin Petrov
Original assignee: Schering AG
Current assignee: Petrov Orlin; PLATZEK, JOHANNES; WESTERMANN, JUERGEN; Bayer Pharma AG
Priority date: 2003-06-07
Filing date: 2004-06-05
Publication date: 2006-03-08
Also published as: US7595418B2; JP2006527180A; WO2004108697A1; DE10326195A1; US20080015366A1

Abstract

The invention relates to protected 5,7-dihydroxy-4,4-dimethyl-3-oxoheptanoic acid esters and 5,7-dihydroxy-2-alkyl-4,4-dimethyl-3-oxoheptanoic acid esters for synthesizing epothilones and derivatives thereof, and to methods for producing these esters.

Description

Protected 5,7-dihydroxy-4,4-dimethyl-3-oxoheptanoic acid esters and 5,7-dihydroxy-2-alkyl-4,4-dimethyl-3-oxoheptanoic acid esters for the synthesis of epothilones and derivatives and processes for the preparation of these esters

introduction

The invention relates to protected 5,7-dihydroxy-4,4-dimethyl-3-oxoheptanoic acid esters and 5,7-dihydroxy-2-alkyl-4,4-dimethyl-3-oxoheptanoic acid esters for the synthesis of epothilones and derivatives and processes for Production of these esters, i.e. new intermediates and processes for their production and use.

The process for the production of new intermediates is based on inexpensive starting materials, supplies the intermediates in high enantiomeric purities, in high chemical purity, in good yields and allows large-scale production.

The invention is used in the synthesis of the C1-C6 segment required for the production of natural and synthetically modified epothilones or derivatives.

The natural epothilones are 16-membered macrolide rings isolated from cultures of the Myxobacte around Sorangium Cellosum and represent a class of promising antitumor agents that have been tested to be effective against a range of cancer lines.

An overview of the syntheses primarily from natural epothilones is provided by J. Mulzer et al. in J. Org. Chem. 2000, 65, 7456-7467.

In addition to the natural epothilones, a large number of synthetic epothilone derivatives are described in the literature, most of which vary within the radicals M and R ¹⁰ (for example in WO 99/01124, WO 99/02541, WO 00/037473, WO 0099/07692, WO 00/47584, WO 00/49021, WO 01/81342, WO 00/66589, WO 01/81341). M often stands for a heterocyclic radical and R for an alkyl radical. Most syntheses of natural epothilones and synthetic epothilone derivatives use the A building block fragment, which brings the carbon atoms Cs - C-io into the macrolide. Within this epothilone segment C1-C6, d is the Cs in the macrolide and C ₆ the C ₁₀ in the macrolide, etc.

la

ib

These compounds (fragments) can be in the form la with a cyclic ketal protective group or the open form Ib. Here R represents a C1-C4-alkyl radical, such as the methyl, ethyl, n- or i-propyl, n-butyl or tert-butyl radical or a C2-C4-alkenyl radical, such as the vinyl or allyl radical, PGi and PG ₂ are known to a person skilled in the art for a hydroxy function Protecting groups, such as, for example, methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert.butyldimethylsilyl, tert.butyldiphenylsilyl, tribenzylsilyl, triisopropyl, triisopropyl Butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, formyl, acetyl, propionyl, isopropionyl, butyryl, pivalyl, benzoyl radical. The TBDMS group or other silyl protecting groups are preferred. An overview of protective groups can be found, for example, in "Protective Groups in Organic Synthesis" (Theodora W. Green, John Wiley and Sons).

State of the art

A preparation of the epothilone C1-C6 segment of the formula III is described in patent applications WO 03/04063 and WO 03/015068. The starting compounds of type Ila or type IIb are converted in an organometallic reaction with an alkyl metal to a compound of the formula III.

M = Li, MgX, X = Cl, Br, I

R ₆ = alkyl, alkenyl, alkynyl, etc., see description

The conversion of the dialkylamide group in IIIa or the nitrile group in IIb can be achieved in a smooth reaction in a synthesis step to III. After hydrolysis of the reaction mixture, the product of formula III is obtained in a high yield. In comparison, the direct reaction of an organometal with an alkyl ester function -CO ₂ R ^{a is} not selective, since the intermediate ketone continues to react. In the case of the primary adducts from Ila or IIb, these are stabilized and do not react further to the carbinol in question as a side reaction.

The addition of a radical -CH ₂ -R ⁶ to a nitrile can be carried out more advantageously with alkyl lithium compounds as a reagent than with organomagnesium compounds. A process described in US 2002 / 0156289A1 (The University of Kansas USA) with EtMgBr provides a ketone from a nitrile in only 56% yield, while the reaction with methyl lithium takes place in 98% yield.

Disadvantages of the prior art

The availability of organolithium and organometallic compounds is limited. It would therefore be advantageous if standard lithium organyles could be used, which are commercially available or can be produced in a simple manner. With these, a further alkyl radical should be introduced in a subsequent alkylation step via α-alkylation of the methyl ketone of the formula purple. This would be particularly advantageous if the alkyl or alkenyl halide on which the organometallic compound is based is quite expensive or is not available, as is the case with the C4-C6 alkenyl halides, for example. For example, in the case of a homoallyl residue to be introduced, the underlying homoallyl bromide is very expensive. The production of, for example, but-3-en-1-lithium lithium also causes technical problems. In practice, the conversion of 1-bromobut-3-en to but-3-en-1-lithium is accompanied by the elimination to buta-1, 3-diene. In those cases in which the organometallic compounds are not accessible, it may be more advantageous if an intermediate of the formula IIa or IIb is reacted with a standard alkyl reagent such as, for example, methyl lithium, a compound of the form purple (R ⁶ = H) being obtained.

In a subsequent step, the alkylation is carried out with a suitable alkylating agent in the presence of a base to give a compound of the form IVa. The bisalkylation product of formula IVb is definitely undesirable.

In practice, the alkylation of alkyl ketones of the formula purple to the chain-extended alkyl ketones of the formula IVa requires special reaction conditions. Complexing agents are often required to stabilize the metal enolate. In 1965 House (J. Org. Chem. 1965, 30, 1341-1348) described that the alkylation reaction leads to a protonation and the bisalkylation competes with the monoalkylation. House postulated that the less substituted enolate is more aggregated and less reactive. The desired monoalkylation presupposes that in the reaction after the

Deprotonation of the α-carbon atom no re-metalation of the carbanion takes place.

In addition to the desired monoalkylation product, bisalkylation product IVb is also generally formed, and the conversion is often incomplete, so that starting material also remains. As a further side reaction, condensation reactions can also occur in the alkylation reaction. The reaction products such as monoalkylation product IVa, bisalkylation product IVb and starting material of the formula purple can generally only be separated with difficulty. The problem of bisalkylation has been discussed by A. Streitwieser et al. in Org. Lett., 2001, 3, 2599-2601. A problem with purification is that the reaction mixture consisting of starting material, monoalkylation product and bisalkylation product has to be separated.

Object of the invention

The present invention was intended to provide a process which allows only the monoalkylation product to IV a to be obtained in a simple manner in the alkylation of lilac. The epothilone segment C1-C6 (= monoalkylation product Iva) is a molecule with a high added value, in which high yield and high purity are desired.

Solution of the object of the present invention

The problem of selective alkylation is solved according to the invention in that a β-keto ester of the general form V is prepared from a compound of the general formula purple. Keto esters of the general formula V provide access to compounds of the general formula VI which, after saponification to VII and decarboxylation of the ester group, gives a product of the formula IVa.

V The compounds of the general formula V can be prepared by known methods from a compound of the general formula purple and an ester of carbonic acid, preferably dimethyl or diethyl carbonate. For example, sodium methylate, sodium ethanolate, potassium tert-butoxide or sodium hydride is used as the base. In addition to solvents such as THF, dioxane, etc., the carbonate itself can also serve as the solvent.

The alkylation of a ß-keto ester is a classic method for the alkylation of carbanions. Due to two adjacent activating carbonyl groups, the α-carbon is quite easily deprotonable and generally easy to alkylate (A.C. Cope, H.L Holmes, H.O. House, Org. React. 1957, 9, 107-331).

VI

It has been shown that the keto esters of the formula V can be alkylated well to give compounds of the general formula VI. As bases are metal hydroxides such as sodium, lithium, potassium or calcium hydroxide, metal hydrides such as sodium or lithium hydride, amine bases such as LDA (lithium diisopropylamide), sodium amide, LiHMDS (lithium hexamethyldisilazane), metal alkoxides such as, for. As sodium methylate, sodium ethylate, and alkali alcoholates of higher alcohols (alkali = lithium, sodium, potassium) are suitable.

R ⁶ in R ⁶ X, and thus in the general formulas IIIa, IVa, VI and VII has the meaning of C-ι-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl. C 1 -C ₆ alkyl can be straight-chain or branched, R ⁶ can also be an alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl and also. Aryl-alkyl mean in which alkyl in the alkoxy part is a C ₁ -C ₆ -alkyl radical and aryl is a phenyl or naphthyl radical and - Alkyl, alkenyl, alkynyl are a CC ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl radical. In particular, R ^{6 represents} the radical allyl, crotyl or benzyl.

The alkylation is carried out with the corresponding alkyl halides, allyl halides, benzyl halides, tosylates and the radical R ⁶

Alkyl sulfur ester derivatives of the formula R ⁶ X can be carried out. Alkyl chlorides, bromides, iodides and alkyl esters of sulfuric acid and alkyl esters of alkyl sulfonic acids or aryl sulfonic acids are preferably used as alkylating agents.

Surprisingly, no multiple alkylation is observed in the case of alkylation with allyl or benzyl halides. The reactions can be followed analytically well (GC, DC, HPLC). After the reaction has taken place, the reaction can be ended by adding sodium hydroxide to the reaction solution.

The inventive method has the advantage that no expensive complexing agents such. B. DMPU (dimethylpropyleneurea) are required. Also, no low temperature conditions are required for the alkylation. The alkylation can be carried out in a temperature range between 0 ° C and 50 ° C. The reactions are also robust and not very sensitive to moisture and air presence. If the conversion is incomplete, the base and alkylation agents can be added. Condensation products due to self-condensation do not occur.

As an alternative to the intermediate insulation of the compounds of the general formula VI, there is the possibility of saponifying them directly without intermediate insulation. This is preferably done by adding an aqueous solution of sodium or potassium hydroxide to the reaction solution with the compound of the general formula VI, a substance of the formula VII being obtained.

M = Na, Li, K, H

IVa

Acidification and controlled thermal treatment of the solution of a compound of the general formula VII give a compound of the general formula IVa with decarboxylation.

Acidification is preferably carried out with phosphoric acid or ammonium chloride solution, acidification takes place under pH control.

The process is characterized by the fact that the substances are stable in a certain pH range with regard to a possible protection group cleavage or ketal cleavage (with PG1 / PG2 = ketal group). The compounds of the general formula IVa are surprisingly stable in the alkaline range.

The compounds of general formula VII can be reacted at a temperature up to 100 ° C for decarboxylation. It has been found that the decarboxylation can be carried out at a pH of 4-9. The pH is crucial for the stability of the protective groups during decarboxalation. The compounds of the formula II, Iva, V and VI can be reacted further in solution without intermediate isolation. An advantage is the quality of the product produced by this process, which contains less than 1 percent of the educt purple and less than 1 percent of the bisalkylated compound IVb.

Due to the high quality of the raw product IVa, a simple purification of the raw product is, for. B. possible by distillation.

The compounds of the general formula VI can also be converted directly to the compounds of the general formula IVa by reacting the compounds of the general formula VI with lithium carbonate in DMF

(Dimethylformamide) at about 100 ° C with the addition of water. This reaction is referred to as dealkoxycarbonylation, in which CO ₂ is eliminated and an alkyl bromide is formed.

The compounds of the formula VI can also be prepared from a compound of the general formula IIb and a bromoester of the general formula VIII in a Reformatsky-type reaction with zinc under the action of ultrasound (K. Nakunan, B.-J. Uang, Synthesis 1989 , 571. R1 and R6 in the compounds of the general formulas VI and VIII have the meanings given previously in the general formula VI.

llb VIII VI

In the case of the synthesis of allyl-substituted compounds with R6 = allyl in the case of compounds of the formula VI, the allyl ester of the formula IX can be used for the synthesis.

One method for the synthesis of IX is the reaction of a compound of the general purple by reaction with diallyl carbonate in the presence of a base. The allyl ketoesters of the formula IX can also be obtained, for example, by transesterification of an alkyl ester of the general formula V.

The allyl keto ester of the general formula IX can also be used in a

Rearrangement reaction can be converted into the product of the general formula X.

This reaction is referred to in the literature as the Carroll reaction (M.F. Carroll, J. Chem. Soc. 1940, 1226). The Carroll reaction is referred to as a [3,3] sigmatropic rearrangement. An allyl keto ester is thermally treated for the reaction. The thermal rearrangement of allyl esters requires high temperatures (170-200 ° C). The method is often limited by the low thermal stability of the connections.

This rearrangement is favored in the presence of bases and can be carried out at milder temperatures (see J.Org. Chem., 1987, 52, 2988-2995). Preferably, an aluminum alkoxide such as z. B. AI (OiPr) ₃ (aluminum tri-isopropylate) can be used.

This reaction from IX to X can also be carried out by transesterifying an alkyl ester of the general formula V in the presence of a base, the subsequent reaction taking place with decarboxylation in the presence of aluminum alkoxides according to route A) and migration of the allyl group. Such palladium-catalyzed decarboxylations / allylations have been described by J. Tsuji et al. in J. Org. Chem., 1987, 52, 2988-2995. According to this method, allyl esters of the general formula IX can be converted into a homoallyl ketone of the general formula X with decarboxylation and simultaneous allylation.

Homoallylketon

IX X

R in the general formulas IX, X and XI can mean hydrogen or a straight-chain or branched-chain C ₆ -C ₆ alkyl radical, such as. B. have a methyl, ethyl or propyl radical.

The double bond in compounds of the general formula X can be converted to the saturated form of the compounds of the general formula XI using hydrogen using a palladium or platinum catalyst.

Homoallylketon

XI In addition to the compounds of the general formulas V, VI, VII, IX and X, the present invention also relates to the processes described here for their preparation.

The examples given below for a more detailed explanation of the present invention relate to the compounds in the natural 3S series. In addition to the 3S enantiomers, the 3R enantiomers and the racemates of the compounds of the general formulas V, VI, VII, IX and X are also claimed.

For all structures of the formulas II to X, PGi and PG ₂ can have the meanings mentioned at the outset under the compounds of the general formulas Ia and Ib; together they can mean the isopropylidene group or any ketal structure as a protective group.

By combining the reaction steps of the addition of methyl lithium to II to purple, synthesis of the β-keto ester of the formula V, selective subsequent alkylation to the keto ester of the formula VI and subsequent decarboxylation to VII, it was possible to obtain compounds of the formula IVa. The problem of selective alkylation was solved. The products are obtained in good yield and high purity. These individual reaction steps can be carried out separately or in a one-pot reaction without intermediate isolation of intermediates V, VI, VII, and IX.

The process according to the invention permits the selective monoalkylation of alkyl ketones. It is possible to introduce different alkyl radicals which are not available or are difficult to access as an organometallic compound. The problem for the synthesis of homoallyl ketones of the formula X was solved. The present invention is illustrated by the following examples:

Example 1 :

S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -3-methylbutan-2-one

To 183 g (1 mol) of the title compound from WO 03/014068 (Example 1e) 3 (S) - (3,5) acetone dimethyl ketal -2,2-dimethylpentanitrile, dissolved in 400 ml THF, are at -20 ° C 1000 ml of methyl lithium lithium bromide complex (1.5 M in diethyl ether) was added dropwise. Then 30 min. stirred at - 20 ° C and then warmed to room temperature. The mixture is stirred at room temperature for 2 h. 500 ml of saturated ammonium chloride solution are added and the mixture is stirred at room temperature for 6 hours while checking the pH. The product is extracted with hexane, the organic phase is separated off and washed twice with water. The organic phase is evaporated to dryness in vacuo. Yield: 195 g (98% of theory) of an oil.

Elemental analysis:

Example 2:

S-3- (2,2-Dimethyl- [1,3] dioxan-4-yl) -4-methyl-3-oxo-pentanoic acid methyl ester

47.5 g (1, 118 mol) of 60% paraffin-stabilized sodium hydride are washed paraffin-free with 200 ml of hexane and 285 ml of THF are added. 338 g (3.76 mol) of dimethyl carbonate are added. For this purpose, 95 g of S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -3-methyl-butan-2-one are extracted from 300 ml of THF Example 1 added. The solution is stirred at 67 ° C for 1 h. After 1 h, complete conversion is carried out by means of a thin-layer control (eluent ethyl acetate / hexane 1 +1 v / v). 1.18 mol (71.2 g) of acetic acid are added at room temperature to decompose the excess NaH. 300 ml of water are carefully added with stirring and stirring is continued until the evolution of gas is complete. The pH should be in the range 7-8. The product is extracted with methyl tert-butyl ether, washed with saturated sodium hydrogen carbonate solution and evaporated to dryness. 122.3 g (99% of theory) of product are obtained as a viscous oil.

Elemental analysis:

Example 3:

S-3- (2,2-Dimethyl- [1,3] dioxan-4-yl) -4-methyl-3-oxopentanoic acid ethyl ester

Analogously to Example 2, S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -4-methyl-3-oxopentanoic acid ethyl ester is prepared from the compound Example 1 and diethyl carbonate.

Elemental analysis:

Example 4: S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -4-methyl! -3-oxo-pentanoic acid allyl ester

Analogously to Example 2, S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -4-methyl-5-oxopentanoic acid allyl ester can be prepared from the compound Example 1 and diallyl carbonate.

Elemental analysis:

Example 5:

S-3- (2,2-Dimethyl- [, 1, 3] dioxan-4-yl) -4-methyl-3-oxo-pentanoic acid allyl ester

5.16 g (20 mmol) of S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -4-methyl-3-oxopentanoic acid methyl ester from Example 2 are dissolved in 100 ml of allyl alcohol and 1 ml of titanium tetraisopropoxide was stirred at 80 ° C. for 6 h. The allyl alcohol is distilled off, the residue is taken up in 100 ml of ethyl acetate and hydrolyzed with 20 ml of water. It is extracted with ethyl acetate and the organic phase is filtered through 20 g of silica gel. After concentration of the residue, 5.7 g (96% of theory) are obtained as an oil.

Example 6

(4S) -4- (2-Methyl-3-oxo-hept-6-ene-2-yl) -2,2-dimethyl- [1, 3] dioxanes

2.84 g (10 mmol) of S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -4-methyl-3-oxopentanoic acid allyl ester from Example 4 are mixed with 80 mg of tetrakis - Triphenylphosphine palladium in 20 ml of toluene was stirred at 100 ° C for 10 min. To Cooling is filtered through silica gel, washed with methyl tert-butyl ether and dried. 2.5 g of product (88% of theory) are obtained.

Elemental analysis:

Example 7

(4S) -4- (2-Methyl-3-oxo-hept-6-ene-2-yl) -2,2-dimethyl- [1,3] dioxanes

2.84 g (10 mmol) of S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -4-methyl-3-oxopentanoic acid allyl ester from Example 4 are dissolved in 20 ml of toluene stirred with 1 mmol aluminum triisopropoxide at 100 ° C for 1 h. After cooling, it is poured into 10 ml of water, the product is extracted with methyl tert-butyl ether and dried over sodium sulfate. 2.3 g of product are obtained after Kugelrohr distillation at 100 ° C / 1 mbar as an oil (81% of theory).

Example 8

S-3- (2,2-Dimethyl- [1,3] dioxan-4-yl) -3,5-dimethyl-3-oxopentanoic acid methyl ester

5.17 g (20 mmol) of S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -4-methyl-3-oxopentanoic acid methyl ester are dissolved in 18 ml of ethanol at 0 ° -10 ° C with 2.47 g (22 mmol) of potassium tert-butoxide and stirred for 10 min. At 20 ° C, 1.3 ml (3.08 g, 21 mmol) of methyl iodide are added, the temperature rising to 30 ° C. The mixture is stirred for a further 2 h, during which a white solid (NaI) precipitates. The reaction is followed by thin layer chromatography. Two thirds of the solution are further implemented in Example 9. The remaining third is sat. Neutralized ammonium chloride solution (pH7) and extracted the product with ethyl acetate. 1.75 g of product (96% of theory are obtained as an oil).

Elemental analysis

Example 9

2 - [(4S) -2,2-dimethyl-1,3-dioxan-4-yl] -2-methyl-3-pentanone

Two thirds of the solution from Example 8 (13.4 mmol) are mixed with 20 ml of 2N NaOH (40 mmol) and stirred at 40 ° C. for 2 h. The saponification is by means of

Thin layer chromatography followed. After the saponification,

Phosphoric acid (85%) neutralized (pH 7) and and the solution heated to 80 ° C for 30 min (CO2 evolution). After cooling with

Extracted methyl tertiary methyl ether and chromatographed the product. 2.5 g (90% of theory) of product are obtained. The spectroscopic data agree with the information described in Eur. Chem. J. 2996, 2, 1996, 1477-1482.

Example 10

S-3- (2,2-DimethyI- [1,3] dioxan-4-yl) -4-methyl-5-ethyl-3-oxopentanoic acid methyl ester 5.17 g (20 mmol) of S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -4-methyl-3-oxopentanoic acid methyl ester are dissolved in 18 ml of ethanol at 0 ° -10 ° C with 2.47 g (22 mmol) of potassium tert-butoxide and stirred for 10 min. At 20 ° C, 3.27 g (21 mmol) of ethyl iodide are added, the temperature rising to 30 ° C. The mixture is stirred for a further 2 h, during which a white solid (NaI) precipitates). The reaction is followed by thin layer chromatography. The reaction is mixed with ammonium chloride solution, extracted with methyl tert-methyl ester and filtered on silica gel. 4.2 g (92% of theory) are obtained as an oil.

Elemental analysis:

Example 11

2 - [(4S) -2,2-dimethyl-1,3-dioxan-4-yl] -2-methyl-3-hexanone

5.17 g (20 mmol) of S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -4-methyl-3-oxopentanoic acid methyl ester from Example 2 are dissolved in 18 ml of ethanol at 0 ° -10 ° C with 2.47 g (22 mmol) of potassium tert-butoxide and stirred for 10 min. At 20 ° C, 3.27 g (21 mmol) of ethyl iodide are added, the temperature rising to 30 ° C. The mixture is stirred for a further 2 h, during which a white solid (NaI) precipitates. The reaction is followed by thin layer chromatography. The reaction is mixed with 25 ml of 2N NaOH and stirred at 40 ° C for 2 h. After the saponification, neutralization is carried out with phosphoric acid (85%) (pH 7) and the solution is heated to 80 ° C. for 30 min with evolution of CO2

Extracted methyl tertiary methyl ether and distilled the product in a bulb tube (bp 100 ° C / 1 mbar). 4.1 g (89% of theory) of product are obtained.

Elemental analysis

Example 12

S-3- (2,2-Dimethyl- [1,3] dioxan-4-yl) -4-methyl-5-benzyl-pentanoic acid methyl ester

5.17 g (20 mmol) of S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -4-methyl-3-oxopentanoic acid methyl ester are dissolved in 18 ml of ethanol at 0 ° -10 ° C with 2.47 g (22 mmol) of potassium tert-butoxide and stirred for 10 min. At 20 ° C, 3.8 g (30 mmol) of benzyl chloride are added, the temperature rising to 30 ° C. The mixture is stirred for a further 2 h, a white solid (NaI) precipitates. The reaction is followed by thin layer chromatography. The reaction is mixed with ammonium chloride solution, extracted with methyl tert-methyl ester and filtered through silica gel. 6.9 g of product (99% of theory) are obtained as an oil.

Elemental analysis:

Example 13

2 - [(4S) -2,2-dimethyl-1,3-dioxan-4-yl] -2-methyl-3-pentanone

5.17 g (20 mmol) of S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -4-methyl-3-oxopentanoic acid methyl ester are dissolved in 18 ml of ethanol at 0 ° -10 ° C with 2.47 g (22 mmol) of potassium tert-butoxide and stirred for 10 min. At 20 ° C, 3.8 g (30 mmol) benzyl chloride was added, the temperature rising to 30 ° C. The reaction is followed by thin layer chromatography. After conversion is complete, 25 ml of 2N NaOH are added and the mixture is stirred at 40 ° C. for 2 h until the ester has reacted. After the saponification, the mixture is neutralized with phosphoric acid (85%) (pH 7) and the solution is heated to 80 ° C. for 30 minutes (CO 2 evolution). After cooling, the mixture is extracted with methyl tert-methyl ether and the product is chromatographed on silica gel. 5.64 g (97% of theory) of product are obtained.

Elemental analysis:

Example 14

S-3- (2,2-Dimethyl- [1,3] dioxan-4-yl) -2-allyl-4-methyl-3-oxopentanoic acid methyl ester

24.55 g (0.22 mol) of potassium tert-butoxide are suspended in 200 ml of ethanol. At 20 ° C., 51.6 g (0.2 mol) of S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -4-methyl-3-oxo-pentanoic acid methyl ester from Example 2 added and stirred for 30 min at this temperature. 36.29 g of allyl bromide (1-bromopropene) are added and the mixture is stirred at 40 ° C. for a further 1 h. It is hydrolyzed with ammonium chloride solution and hydrolyzed with ethyl acetate. The organic phase is washed with water and dried. 60 g of 96% of theory are obtained as an oil.

Example 15

(4S) -4- (2-Methyl-3-oxo-hept-6-ene-2-yl) -2,2-dimethyl- [1, 3] dioxane 31.2 g (0.1 mol) of S-3- (2,2-dimethyl- [1,3] dioxan-4-yl) -2-aliyl-4-methyl-3-oxopentanoic acid methyl ester from example 14 are dissolved in 200 ml of ethanol. 125 ml of 2N NaOH are added and the mixture is stirred at 40 ° C. for 2 h. The saponification is followed by thin layer chromatography. It is neutralized with 85% phosphoric acid (pH 7) and heated to 80 ° C. for 30 minutes to complete the decarboxylation. After cooling to 30 ° C, the product is extracted with methyl tert-butyl ether. After purification on silica gel with hexane and increasing ethyl acetate, 21.8 g of product are obtained (91% of theory).

The rotation value of a sample [α] _D is + 11.6 ° (1% in CHCI ₃ , 1 = 100 mm)

Example 16

(4S) -4- (2-Methyl-3-oxo-hept-6-ene-2-yl) -2,2-dimethyl- [1, 3] dioxanes

24.55 g ((0.22 mol) of potassium tert-butylate are suspended in 200 ml of ethanol. 51.6 g (0.2 mol) of S-3- (2,2-dimethyl- [1,3 ] dioxan-4-yl) -4-methyl-3-oxo-pentanoic acid methyl ester from Example 2 was added and the mixture was stirred at this temperature for 30 minutes, 36.29 g of allyl bromide (1-bromopropene) were added and the mixture was stirred at 40 ° C. for 1 hour The reaction is followed by thin layer chromatography. For the saponification, 250 ml of 2N NaOH are added, the mixture is stirred for 2 hours at 40 ° C. The saponification is followed by thin layer chromatography. It is neutralized with 85% phosphoric acid (pH 7) and for decarboxylation The product is extracted with methyl tert-butyl ether for 30 minutes at 80 ° C. After cooling to 30 ° C. After purification over silica gel with hexane and increasing ethyl acetate content, 43 g of product are obtained (89% of theory). Example 17

(4S) -4- (2-Methyl-3-oxo-heptan-2-yl) -2,2-dimethyl- [1, 3] dioxanes

24 g (0.1 mol) of (4S) -4- (2-methyl-3-oxo-hept-6-ene-2-yl) -2,2-dimethyl- [1,3] dioxanes from Example 17 are obtained in 480 ml of THF dissolved. 4.8 g of palladium on carbon (10%) are added at room temperature. It is hydrogenated at 10 bar of hydrogen for 2 hours until the hydrogen uptake has ended. The catalyst is filtered off, washed with THF and the product distilled at 95 ° C / 1 mbar. 21 g of product (87% of theory) are obtained.

Elemental analysis:

Claims

claims

1. Compounds of the general formula V

v

wherein

PG ¹ and PG ² for hydroxy protecting groups or together for one

Isopropylidene group and

R ¹ for a straight or branched chain, optionally unsaturated

Hydrocarbon residue with up to 6 carbon atoms.

2. Compounds of the general formula VI

VI

PG ¹ and PG ² for hydroxy protecting groups or together for one

Isopropylidene group and

R ¹ for a straight or branched chain, optionally unsaturated

Hydrocarbon residue with up to 6 carbon atoms, as well

R ⁶ for a -CC ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl radical, which may be straight-chain or branched, or for an alkoxyalkyl, alkoxy alkenyl, alkoxy alkynyl or aryl alkyl radical, wherein alkyl in the alkoxy part a -CC ₆ alkyl radical and

Aryl a phenyl or naphthyl radical and -alkyl-, alkenyl-, alkynyl a -CC ₆ - Are alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl.

3. Compounds of the general formula VII

VII

wherein

PG ¹ , PG ² and R ^{6 have} the meanings given in claim 2 and M is a lithium atom or the radical MgX with X in the meaning of a chlorine, bromine or iodine atom.

4. Compounds of the general formula IX

IX

wherein

PG ¹ and PG ^{2 have} the meaning given in claim 2 and

R ^b for a hydrogen atom or a straight or branched chain -C ₆ -

Alkyl radical.

5. Compounds of the general formula X

X

wherein

PG ¹ and PG ^{2 have} the meaning given in claim 2 and

R ^{b represents} a hydrogen atom or a straight or branched chain d-

Cβ-alkyl radical.