NOVEL CHIRAL HEPTYNE DERIVATIVES FOR THE PREPARATION OF EPOTHILONES AND PROCESSES FOR THEIR PREPARATION

Abstract

The invention relates to a new synthetic process for the production of key intermediates useful in the synthesis of epothilones or epothilone derivatives, to certain compounds used to produce these key intermediates and to a process to produce said compounds.

Description

The invention relates to a new synthetic process for the production of key intermediates useful in the synthesis of epothilones or epothilone derivatives, to certain compounds used to produce these key intermediates and to a process to produce said compounds. The process for the production of the key intermediates starts from readily available and cheap starting materials, yields products in high enantiomeric purity, in high chemical purity, in good yields and allows an industrial-scale production.

The invention is used in the synthesis of structural unit B of natural and synthetically-modified epothilones or derivatives. Epothilones are 16-membered macrolide compounds that find utility in the pharmaceutical field. Epothilones have been isolated from cultures of Myxobacterium Sorangium Cellosum and are representatives of a class of promising anti-tumor agents that were tested and found to be effective against a number of cancer lines. A survey of the syntheses for these compounds has been described by J. Mulzer et al., in Monatsh. Chem. 2000, 131, 205-238. These agents have the same biological mode of action as paclitaxel and other taxanes (see for paclitaxel, D. G. I. Kingston, Chem. Commun. 2001, 867-880), however, epothilones have also been shown to be active against a number of resistant cell lines (see S. J. Stachel et al., Curr. Pharmaceut. Design 2001, 7, 1277-1290; K.-H. Altmann, Curr. Opin. Chem. Biol. 2001, 5, 424-431).
In addition to natural epothilones, the literature describes a number of synthetic epothilone derivatives that vary for the most part in radicals M, T and R. In most cases, M stands for a heterocyclic radical. For natural epothilone A, R stands for hydrogen, whereas for epothilone B, R stands for methyl.

Most syntheses of the natural epothilones and the synthetic epothilone derivatives involve the joining of several structural units. Structural unit B, which represents the C₁₁-C₁₆ fragment, proved to be one of the strategically important structural units. It was, therefore, of great importance to develop an economical process for the production of structural unit B of epothilone syntheses.

In most cases, the epothilone is synthesized by inserting structural unit B as a protected hydroxy ketone (formula I, X₁=protecting group). The C₁-C₁₆ linkage is carried-out by means of a Wittig reaction, while the C₁₀-C₁₁ linkage is carried-out by means of an aldol reaction. Both reactions have already been described in the literature (see K. C. Nicolaou et al., Tetrahedron 1998, 54, 7127-7166; Angew. Chem. 1998, 110, 85-89; Chem. Eur. J. 1997, 3, 1971-1986; J. Am. Chem. Soc. 1997, 119, 7974-7991).

A possible preparation of structural unit B is described in, for example, WO 99/07692 and WO 00/47584. However, the syntheses presented there are expensive and based on the introduction of chirality using an expensive chiral auxiliary agent and thus not usable or feasible for an industrial-scale production of epothilone or epothilone derivatives.

WO 98/25929 and K. C. Nicolaou et al., J. Am. Chem. Soc. 1997, 119, 7974-7991 also describe tedious preparations of structural unit B by means of a chiral auxiliary agent. These preparations have additionally the technical disadvantage of introducing chirality at a reaction temperature of −100° C.

A further synthesis is described in Helv. Chim. Acta 1990, 73, 733-738, whereby a compound of formula I (X₁═H) is also used. This compound, however, is obtained from a costly synthesis involving diterpenes as starting materials (see also Chimia 1973, 27, 97-99) and results in an enantiomeric purity of only approx. 80 to 85%.

Moreover, it can be said that the processes described in the literature require a purification process involving several chromatographic steps, which is rather disadvantageous from a production stand point because this results in many general technical problems such as reconditioning of solvents, avoiding contamination of the environment, high cost, etc.

Due to low total yields, low space-time yields and high excesses of reagents, it has not been possible with any of the processes available to a person skilled in the art to economically prepare structural unit B on an industrial-scale. There was therefore a need for such an industrial-scale process and capable of being implemented on an operational scale, that allows for a universally usable intermediate compound for the production of structural unit B in the total synthesis of epothilones and epothilone derivatives.

The goal of the present invention is to provide a novel synthetic process for the production of intermediates used in the synthesis of epothilones and epothilone derivatives. In contrast to other published syntheses, the new route starts from economical starting materials, yields intermediate products in high enantiomeric purity, in high chemical purity, in good yields and allows an industrial-scale production. The prior art has the disadvantage of requiring either the use of expensive chiral auxiliary agents (in some cases at a temperature of −100° C.), expensive starting materials, or expensive purification process. Therefore, the new synthesis offers many important advantages.

The present invention relates to a synthetic route for the production of compounds of general formula IA, a key structural unit used in total epothilone or epothilone derivatives syntheses:
wherein

R is selected from the group consisting of hydrogen, alkyl, and substituted alkyl, alkyl being preferred; and

X¹ is an oxygen protecting group.

The compounds of formula IA can then be used for the synthesis of epothilones and epothilone derivatives via various steps known in the art.

The invention also relates to new compounds of general formulas II and III used for the production of compounds of general formula IA and to a process described herein for the production of these new compounds:
wherein R and X¹ have the same meaning as hereinbefore given under formula IA.

The invention especially relates to the synthesis of the compounds of formula IA (see reaction sequence) starting from compounds of general formula IV, a synthesis which is largely unrelated to any synthesis found in the literature related to epothilone syntheses and which has many important advantages:
wherein X¹ has the same meaning as hereinbefore given under formula IA.

Within the present description, the general definitions used hereinbefore and hereinafter preferably have the following meaning:

Alkyl can be a linear or branched alkyl, preferably having up to and including 12 carbon atoms. Examples of alkyl groups are linear alkyls such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl or n-dodecyl group or branched alkyl groups such as the iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, neo-pentyl, 2-pethylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylhexyl, 2,2-dimethylpentyl, 2,2,3-trimethylbutyl or 2,3,3-trimethylbutyl group. Especially preferred are methyl and ethyl.

Examples of a substituted alkyl include —CH₂-Halogen or —C(Halogen)₃, especially preferred are —CH₂F and CF₃.

A protecting group can be selected from the group comprising a silyl protecting group such as trimethylsilyl, tert-butyldimethylsilyl, triethylsilyl, tri(iso-propyl)silyl, dimethylphenylsilyl; lower alkanoyl, such as acetyl; benzoyl; tetrahydropyranyl; Mom protecting group, Mem protecting group; benzyl or substituted benzyl radicals such as 4-methoxybenzyl; or any other protecting group known from the literature (see for example T. W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons N.Y., 1981; P. J. Kocienski, Protecting Groups, Georg Thieme Verlag Stuttgart, 1994). Preferred are tetrahydropyranyl (THP) and tert-butyldimethylsilyl (TBDMS), with THP being especially preferred.

The process steps making up the process of the invention and the preferred aspects thereof can be described preferably as follows:

The reaction sequence starts with a compound of general formula IV as hereinbefore described which is reacted with an aldehyde of general formula V:
RCHO  V
wherein R is as hereinbefore described, under reaction conditions known to a person skilled in the art for such acetylene additions to aldehydes (see Shun, Annabelle L. K. Shi et al., J. Org. Chem., 2003, 68, 4, 1339-1347; Mukai, Chisato et al., J. Org. Chem., 2003, 68, 4, 1376-1385; Clark, J. Stephen et al., Org. Lett., 2003, 5, 1, 89-92; Chun, Jiong et al., J. Org. Chem., 2003, 68, 2, 348-354; Nomura, Izumi et al., Org.Lett., 2002, 4, 24, 4301-4304; Nielsen, Thomas E. et al., J. Org. Chem., 2002, 67, 18, 6366-6371; Kiyota, Hiromasa et al., Syn.Lett., 2003, 2, 219-220; Bailey et al., J. Chem. Soc., 1957, 3027, 3031; Nayler et al., J. Chem. Soc., 1955, 3037, 3045; Moureu, Bull. Soc.Chim.Fr., 33, 155; Theus et al., Helv.Chim.Acta, 1955, 38, 239, 249; Gredy, C.R.Hebd.Seances Acad. Sci., 1934, 199, 153; Ann.Chim.(Paris), <11> 4, 1935, 5, 36); preferably the alkyne is deprotonated at a temperature between −78 to 0° C. in an aprotic solvent, such as methyl-tert-butyl ether, 2-methyl-THF, dioxane, toluene, or THF, with a strong base such as BuLi, LDA or Li, Na, K-HMDS, or Grignard solution, such as MeMgCl, MeMgBr or isopropyl-MgBr, and subsequently added to the aldehyde, yielding a compound of general formula III as hereinbefore described; compound of general formula III is then oxidized with an oxidizing agent known to a person skilled in the art (see for example Shun, Annabelle L. K. Shi et al., J. Org. Chem., 2003, 68, 4, 1339-1347; Clark, J. Stephen et al., Org.Lett., 2003, 5,1,89-92; Chun, Jiong et al., J. Org. Chem., 2003, 68, 2, 348-354; Quesnelle, Claude A. et al., Bioorg. Med. Chem. Lett., 2003, 13, 3, 519-524; Barriga, Susana et al., J. Org. Chem., 2002, 67, 18, 6439-6448; Suzuki, Keisuke et al., Org.Lett., 2002, 4, 16, 2739-2742; Claeys, Sandra et al., Eur. J. Org. Chem., 2002, 6, 1051-1062; Tanaka, Katsunao et al., Bioorg. Med. Chem. Lett., 2002, 12, 4, 623-628; Rodriguez, David et al., Tetrahedron Lett., 2002, 43, 15, 2717-2720; Tanaka, Koichi et al., J. Chem. Soc.Perkin Trans., 2002, 1, 6, 713-714; Hao, Junliang et al., Tetrahedron Lett., 2002, 43, 1, 1-2; Hiegel et al., Synthetic Commun., 1992, 22(11), 1589; De Mico et al., J. Org. Chem., 1997, 62, 6974), especially manganese dioxide in THF, TEMPO oxidation, trichloroisocyanuric acid or under Swern oxidation conditions, to yield a compound of general formula II as hereinbefore described; the triple bond of compound of general formula II is then reduced using processes known to a person skilled in the art (see for example Crombie et al., J. Chem. Soc., 1958, 4435, 4443; Braude et al., J. Chem. Soc., 1949, 607, 613; Taber, Douglass F. et al., J. Org. Chem., 2002, 67, 23, 8273-8275; Bowden et al., J. Chem. Soc., 1946, 52; Fazio, Fabio et al., Tetrahedron Lett., 2002, 43, 5, 811-814; Gonzalez, Isabel C. et al. J. Amer. Chem. Soc., 2000, 122, 38, 9099-9108; Brimble, Margaret A. et al. Aust.J. Chem., 2000, 53, 10, 845-852); preferably the reduction is done under catalytic hydrogenation conditions, using Pd on carbon in THF, as well as in the presence of acetic acid esters, lower alcohols such as methanol, ethanol, isopropanol, 2-methyl-THF, at a temperature between 0 to 50° C., under 5 to 10 bar of pressure, and for a period of 1 to 10 hours, to yield a compound of general formula IA.

Compounds of general formula IV are known in the literature and can be prepared according to methods known to a person skilled in the art such as:

For X¹=TBS: Ireland, Robert E. et al., Tetrahedron, 1997, 53, 39, 13221-13256; Bhatt, Ulhas et al., J. Org. Chem., 2001, 66, 5, 1885-1893; Yan, Jingbo et al., J. Org. Chem., 1999, 64, 4, 1291-1301.

For X¹=benzyl: Takle, Andrew et al., Tetrahedron, 1990, 46, 13/14, 4503-4516; Ireland, Robert E. et al., J. Org. Chem., 1992, 57, 19, 5071-5073.

For X¹=tert-butyldiphenylsilyl: Culshaw, David et al., Tetrahedron Lett., 1985, 26, 47, 5837-5840.

For X¹=MOM: Williams, David R. et al., J. Amer. Chem. Soc., 1989, 111, 5, 1923-1925.

For X¹=THP: Baker, Raymond et al., Tetrahedron Lett., 1986, 27, 28, 3311-3314; Ireland, Robert E. et al., Tetrahedron, 1997, 53, 39, 13221-13256.

Alternatively, compounds of general formula II can be directly obtained by the reaction of a compound of general formula IV as hereinbefore described with an activated acid derivative of general formula VI,
wherein R is as hereinbefore described, and X is an appropriate leaving group, preferably halogen, —OCOR₁, OR₁, imidazole, 4-nitrophenol, Weinreb residue, or mixed anhydrides, wherein R₁ is alkyl. Compounds of general formula II are then subsequently converted to compounds of general formula IA as hereinbefore described in the reaction sequence. The reaction of compounds such as IV and VI has, for example, been described in the following literature:
Naka, Tadaatsu et al., Tetrahedron Lett., 2003, 44, 3, 443-446;
Nielsen, Thomas E. et al., J. Org. Chem., 2002, 67, 21, 7309-7313;
Hakogi, Toshikazu et al., Bioorg. Med. Chem. Lett., 2003, 13, 4, 661-664;
Nielsen, Thomas E. et al., J. Org. Chem., 2002, 67, 21, 7309-7313; and
Knoelker, Hans-Joachim et al., Tetrahedron, 2002, 58, 44, 8937-8946.

It also proved to be advantageous in some cases to prepare compounds of general formula IA directly from compounds of general formula VII,
by oxidating compounds of general formula VII using methods for the oxidation of secondary alcohols known to a person skilled in the art (see literature cited above).

Compounds of general formula VII are obtained from compounds of general formula III by reduction of the triple bond according to the methods hereinbefore described.

Another alternative, is the hydrogenation of compounds of general formula II to corresponding alkenes of general formula VIII,
followed by the oxidation of the corresponding alkenes, and their subsequent further hydrogenation to compounds of the general formula IA, or if the allyl alcohol VIII directly rearranges, compounds of general formula IA can be obtained as is described, for example in Paul, C.R.Hebd. Seances Acad.Sci., 1939, 208, 1320; Bull. Soc.Chim.Fr., 1941, <5>8, 509; and Cheeseman et al., J. Chem. Soc., 1949, 2034; Uma, Ramaling a et al., Eur.J. Org. Chem., 2001, 10, 3141-3146; Cherkaoui, Hassan et al., Tetrahedron, 2001, 57, 12, 2379-2384; Lee, Donghyun et al., Org.Lett., 2000, 2, 15, 2377-2380.

The reactions described above are preferably carried out under the conditions analogous to those given in the examples. The following examples are intended to illustrate the invention without being intended to restrict the scope of the invention:

EXAMPLES

Example 1

a) (2RS,6S)-6-Methyl-7-[(RS)-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy]hept-3-in-2-ol

2450 ml n-BuLi solution, 1.6 M, in hexane is added dropwise to a 650 g solution (3.566 mol) of (RS)-2-{[(S)-2-methylpent-4-in-1-yl]oxy}-3,4,5,6-tetrahydro-2H-pyrane (prepared in accordance with Ireland, Robert E. et al., Tetrahedron, 1997, 53, 39, 13221-13256.) in 325 ml of THF at −10° C. A solution of 310 g acetaldehyde in 1200 ml THF is then added dropwise. After 30 min., 3250 ml MTBE (methyl-tert.butylether) is added and 3250 ml 10% aq NH₄Cl is added and further stirred for 10 min. The organic phase is washed twice with 1300 ml H₂O each and concentrated in vacuo to dryness. 930 g of product is obtained. The obtained product is directly used in the subsequent step.

Yield: approx. 100% (according to DC quantitatively)

Elementary Analysis

	Calc.	C 68.99	H 9.80
	Found	C 68.75	H 10.03

¹H-NMR (CD₂Cl₂), 400 MHz

1H (ppm)/number of H

1.00 (3H)

1.4 (3H)

1.50−1.83 (6H)

1.92 (1H)

2.15+2.33 (2H)

3.25+3.6 (2H)

3.45+3.85 (2H)

4.48 (1H)

4.56 (1H)

b) (S)-6-Methyl-7-[(RS)-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy]hept-3-in-2-one

A 300 g (1.3255 mol) solution of (2RS,6S)-6-methyl-7-[(RS)-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy]hept-3-in-2-ol, dissolved in 600 ml of THF, is added by stirring to a suspension of 1500 g manganese dioxide in 2250 ml of THF, and stirring is continued at room temperature for 48 hours. The suspension is then filtered over silica gel and the solvent is removed in vacuo. 280 g of the product is obtained.

Yield: 94.1% of the theory

Elementary analysis:

	Calc.	C 69.61	H 8.99
	Found	C 69.42	H 9.16

¹H-NMR (CD₂Cl₂), 400 MHz

1H (ppm)/number of H

1.03 (3H)

1.5-1.85 (6H)

2.04 (1H)

2.3 (3H)

2.35+2.53 (2H)

3.2-3.3+3.6-3.65 (2H)

3.5+3.8 (2H)

4.55 (1H)

c) (S)-6-Methyl-7-[(RS)-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy]heptan-2-one

A 50 g solution (222.9 mmol) of (S)-6-methyl-7-[(RS)-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy]hept-3-in-2-one and 5 g palladium on carbon (10% Pd/C) in 400 ml of THF is hydrogenated for one hour at 8 bar hydrogen at room temperature. The catalyst is then filtered off, rewashed with little solvent and the solvent is removed in vacuo. 50.9 g of product is obtained.

Yield: approx. 100% of the theory. (According to DC quantitatively)

Elementary analysis:

	Calc.	C 68.38	H 10.59
	Found	C 68.18	H 10.71

¹H-NMR (CDCl₃), 400 MHz

1H (ppm)/number of H

0.91/0.93 (3H)

1.0-1.9 (11H)

2.13 (3H)

2.42 (2H)

3.19 (1H)

3.4-3.6 (2H)

3.85 (1H)

4.55 (1H)

Claims

1. A process for preparing an epothilone or an epothilone derivative comprising reacting a compound represented by formula IA,

wherein R is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; and X1 is an oxygen protecting group;

comprising reacting a compound of formula IV,

wherein X1 is as defined above, with an aldehyde of formula V,

RCHO  V

wherein R is as defined above, in the presence of a suitable base to form a compound of formula III,

wherein R and X1 are as defined above, reacting compound of formula III with a suitable oxidizing agent to form a compound of formula II,

wherein R and X1 are as defined above, and subsequently reacting compound II with a suitable reducing agent to form said compound of formula IA.

2. A process for preparing a compound represented by formula IA,

wherein R is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; and X1 is an oxygen protecting group;

comprising reacting a compound of formula IV,

wherein X1 is as defined above, with an activated acid derivative of formula VI,

wherein R is as described above; and X is a Weinreb residue, in the presence of a suitable base to form a compound of formula II,

wherein R and X1 are as defined above, and subsequently reacting the compound of formula II with a suitable reducing agent to form said compound of formula IA.

3-13. (canceled)

14. A method of preparing an epothilone or an epothilone derivative comprising reacting a compound of formula II,

wherein:

R is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; and, X1 is an oxygen protecting group.

15-26. (canceled)