U.S. patent application number 11/954348 was filed with the patent office on 2008-05-08 for novel chiral heptyne derivatives for the preparation of epothilones and processes for their preparation.
Invention is credited to Klaus Graske, Orlin Petrov, Johannes Platzek, Werner Skuballa, Marc Willuhn.
Application Number | 20080108838 11/954348 |
Document ID | / |
Family ID | 34928801 |
Filed Date | 2008-05-08 |
United States Patent
Application |
20080108838 |
Kind Code |
A1 |
Platzek; Johannes ; et
al. |
May 8, 2008 |
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.
Inventors: |
Platzek; Johannes; (Berlin,
DE) ; Petrov; Orlin; (Berlin, DE) ; Willuhn;
Marc; (Berlin, DE) ; Graske; Klaus; (Berlin,
DE) ; Skuballa; Werner; (Berlin, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
34928801 |
Appl. No.: |
11/954348 |
Filed: |
December 12, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11110959 |
Apr 21, 2005 |
7326798 |
|
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11954348 |
Dec 12, 2007 |
|
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Current U.S.
Class: |
549/355 |
Current CPC
Class: |
C07D 309/12 20130101;
C07D 409/12 20130101; C07D 313/00 20130101; Y02P 20/55 20151101;
C07D 493/04 20130101 |
Class at
Publication: |
549/355 |
International
Class: |
C07D 313/00 20060101
C07D313/00 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 22, 2004 |
EP |
04090157.1 |
Claims
1. A process for preparing an epothilone or an epothilone
derivative comprising reacting a compound represented by formula
IA, ##STR9## wherein R is selected from the group consisting of
hydrogen, alkyl, and substituted alkyl; and X.sup.1 is an oxygen
protecting group; comprising reacting a compound of formula IV,
##STR10## wherein X.sup.1 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, ##STR11##
wherein R and X.sup.1 are as defined above, reacting compound of
formula III with a suitable oxidizing agent to form a compound of
formula II, ##STR12## wherein R and X.sup.1 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,
##STR13## wherein R is selected from the group consisting of
hydrogen, alkyl, and substituted alkyl; and X.sup.1 is an oxygen
protecting group; comprising reacting a compound of formula IV,
##STR14## wherein X.sup.1 is as defined above, with an activated
acid derivative of formula VI, ##STR15## 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, ##STR16## wherein R and
X.sup.1 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, ##STR17## wherein: R
is selected from the group consisting of hydrogen, alkyl, and
substituted alkyl; and, X.sub.1 is an oxygen protecting group.
15-26. (canceled)
Description
[0001] 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.
[0002] 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). ##STR1## 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.
[0003] Most syntheses of the natural epothilones and the synthetic
epothilone derivatives involve the joining of several structural
units. Structural unit B, which represents the C.sub.11-C.sub.16
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.
[0004] In most cases, the epothilone is synthesized by inserting
structural unit B as a protected hydroxy ketone (formula I,
X.sub.1=protecting group). The C.sub.1-C.sub.16 linkage is
carried-out by means of a Wittig reaction, while the
C.sub.10-C.sub.11 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). ##STR2##
[0005] 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.
[0006] 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.degree.
C.
[0007] A further synthesis is described in Helv. Chim. Acta 1990,
73, 733-738, whereby a compound of formula I (X.sub.1.dbd.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%.
[0008] 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.
[0009] 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.
[0010] 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.degree.
C.), expensive starting materials, or expensive purification
process. Therefore, the new synthesis offers many important
advantages.
[0011] 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:
##STR3## wherein
[0012] R is selected from the group consisting of hydrogen, alkyl,
and substituted alkyl, alkyl being preferred; and
[0013] X.sup.1 is an oxygen protecting group.
[0014] The compounds of formula IA can then be used for the
synthesis of epothilones and epothilone derivatives via various
steps known in the art.
[0015] 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: ##STR4## wherein R and X.sup.1 have the same
meaning as hereinbefore given under formula IA.
[0016] 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:
##STR5## wherein X.sup.1 has the same meaning as hereinbefore given
under formula IA.
[0017] Within the present description, the general definitions used
hereinbefore and hereinafter preferably have the following
meaning:
[0018] 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.
[0019] Examples of a substituted alkyl include --CH.sub.2-Halogen
or --C(Halogen).sub.3, especially preferred are --CH.sub.2F and
CF.sub.3.
[0020] 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.
[0021] The process steps making up the process of the invention and
the preferred aspects thereof can be described preferably as
follows:
[0022] 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.degree. 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.degree. 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.
[0023] 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:
[0024] For X.sup.1=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.
[0025] For X.sup.1=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.
[0026] For X.sup.1=tert-butyldiphenylsilyl: Culshaw, David et al.,
Tetrahedron Lett., 1985, 26, 47, 5837-5840.
[0027] For X.sup.1=MOM: Williams, David R. et al., J. Amer. Chem.
Soc., 1989, 111, 5, 1923-1925.
[0028] For X.sup.1=THP: Baker, Raymond et al., Tetrahedron Lett.,
1986, 27, 28, 3311-3314; Ireland, Robert E. et al., Tetrahedron,
1997, 53, 39, 13221-13256.
[0029] 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, ##STR6## wherein R is as hereinbefore
described, and X is an appropriate leaving group, preferably
halogen, --OCOR.sub.1, OR.sub.1, imidazole, 4-nitrophenol, Weinreb
residue, or mixed anhydrides, wherein R.sub.1 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.
[0030] It also proved to be advantageous in some cases to prepare
compounds of general formula IA directly from compounds of general
formula VII, ##STR7## 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).
[0031] 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.
[0032] Another alternative, is the hydrogenation of compounds of
general formula II to corresponding alkenes of general formula
VIII, ##STR8## 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.
[0033] 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
[0034] 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.degree. 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 NH.sub.4Cl is
added and further stirred for 10 min. The organic phase is washed
twice with 1300 ml H.sub.2O each and concentrated in vacuo to
dryness. 930 g of product is obtained. The obtained product is
directly used in the subsequent step.
[0035] Yield: approx. 100% (according to DC quantitatively)
[0036] Elementary Analysis TABLE-US-00001 Calc. C 68.99 H 9.80
Found C 68.75 H 10.03
[0037] .sup.1H-NMR (CD.sub.2Cl.sub.2), 400 MHz
[0038] 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
[0039] 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.
[0040] Yield: 94.1% of the theory
[0041] Elementary analysis: TABLE-US-00002 Calc. C 69.61 H 8.99
Found C 69.42 H 9.16
[0042] .sup.1H-NMR (CD.sub.2Cl.sub.2), 400 MHz
[0043] 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
[0044] 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-on-
e 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.
[0045] Yield: approx. 100% of the theory. (According to DC
quantitatively)
[0046] Elementary analysis: TABLE-US-00003 Calc. C 68.38 H 10.59
Found C 68.18 H 10.71
[0047] .sup.1H-NMR (CDCl.sub.3), 400 MHz
[0048] 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)
* * * * *